Conditions: Syphilis
Keywords: Benzathine penicillin G Early Syphillis HIV Phase 4
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 249
Healthy volunteers: no

Brief summary:
This is a phase 4, randomized, open-label, multicenter trial to evaluate the efficacy of a single injected dose of Benzathine Penicillin G (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 human immunodeficiency virus (HIV)-infected and HIV-uninfected subjects. The study will enroll 560 adults (to achieve 420 evaluable subjects) aged 18 years or older with untreated early syphilis (primary, secondary, or early latent). It will be conducted at 9 sites in the US and last for 48 months with patient participation duration of 12 months. The primary objective is to compare the serological response to therapy in subjects with early (primary, secondary, or early latent) syphilis treated with Benzathine Penicillin G (BPG) 2.4 million units (MU) once or weekly for three successive weeks.

Detailed description:
This is a phase 4, randomized, open-label, multicenter trial to evaluate the efficacy of a single injected dose of Benzathine Penicillin G (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 human immunodeficiency virus (HIV)-infected and HIV-uninfected subjects. The study will enroll 560 adults (to achieve 420 evaluable subjects) aged 18 years or older with untreated early syphilis (primary, secondary, or early latent). It will be conducted at 9 sites in the US and last for 48 months with patient participation duration of 12 months. The primary objective is to compare the serological response to therapy in subjects with early (primary, secondary, or early latent) syphilis treated with Benzathine Penicillin G (BPG) 2.4 million units (MU) once or weekly for three successive weeks. The secondary objectives are: 1) to determine if the difference in response to therapy between treatment arms by Month 6 differs among subjects with or without HIV infection; 2) to determine the impact of multiple BPG injected doses on subject compliance with study product and adherence to the corresponding scheduled visits; 3) to determine the incidence and manifestations of the Jarisch-Herxheimer reaction among subjects treated for early syphilis with BPG; 4) to collect prospective data up to Month 12 on the serological response to therapy in subjects treated for early syphilis with either BPG regimen; 5) to compare epidemiological characteristics of early syphilis among subjects with or without HIV infection.

Arms:
arm 1: 2.4 million units (MU) of Benzathine penicillin G (BPG) intramuscularly on Day 1, n=280 arm 2: 2.4 million units (MU) of Benzathine penicillin G (BPG) intramuscularly weekly for three successive weeks, n=280

Interventions: intervention 1: Benzathine Penicillin
Intervention descriptions: intervention 1: BPG will be administered as a deep intramuscular injection in the upper, outer quadrant of the buttock.

Protocol document:
ICF_000.pdf: 
Page 1 of 11 
LSUHSC-NO; SN Taylor 
DMID 17-0101 (IRB #: 19-121) 
Consent Rev. date: May 2, 2019  
Protocol Revision #: 2.0; 28 January 2019 
                                                
Consent to Participate in a Research Study 
 
KEY INFORMATION FOR: 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 #: 17-0101) 
 
Taking place at: LSU-CrescentCare Sexual Health Center 
 
 
We are asking you to choose whether or not to participate in a research study that will compare the effect of 1 dose of 
benzathine penicillin G (BPG) to 3 weekly doses of BPG and to determine whether the effects of 1 dose of BPG or 3 
weekly doses of BPG are different in HIV-infected and HIV-uninfected subjects. Syphilis is a bacterial infection that can be 
transmitted through sexual contact. People infected with syphilis may have sores, rashes, fever, headache, or sore throat. 
There are 4 stages of syphilis: primary, secondary, latent, and tertiary. This research study will include people who have 
untreated primary, secondary, or early latent syphilis. This page is to give you key information to help you decide whether 
to participate. We have included detailed information after this page. Please ask the research team any questions you 
have as you read this document. If you have questions later, the contact information for the research investigator in 
charge of the study is listed below.   
WHAT IS THE STUDY ABOUT AND HOW LONG WILL IT LAST?   
By doing this study, we hope to understand how well BPG received once or weekly for 3 weeks works against syphilis 
infections. This study will enroll subjects who have untreated primary, secondary, or early latent syphilis. Your 
participation in this research will include a total of 8 visits, including today’s visit, over the next 12 months. The second 
visit will be 6 to 12 days from today, and the third visit will be 12 to 24 days from today. The remaining 5 visits will be 
about 1 month, 3 months, 6 months, 9 months, and 12 months from today. The study procedures for today’s visit will 
take about 90 minutes in addition to any non-study procedures you may be completing at the clinic. The study 
procedures for each of the future visits will take about 60 to 75 minutes in addition to any non-study procedures you 
may be completing at the clinic. During each visit, you will have about 1-2 tablespoons of blood drawn. For a complete 
description of what will be done with the blood samples, refer to the Detailed Consent.   
WHAT ARE KEY REASONS YOU MIGHT CHOOSE TO PARTICIPATE IN THIS STUDY? 
The main reason you might choose to participate in this study is that you would be volunteering to contribute information 
about how our understanding of how well future patients with syphilis may better be treated. For a complete description 
of benefits, refer to the Detailed Consent. 
WHAT ARE KEY REASONS YOU MIGHT CHOOSE NOT TO PARTICIPATE IN THIS STUDY? 
The main reason you may not want to volunteer for this study is that you may get no direct benefit from being in the 
study. For a complete description of benefits, refer to the Detailed Consent. 
DO YOU HAVE TO TAKE PART IN THE STUDY? 
If you decide to take part in the study, it should be because you really want to participate. You will not lose any services, 
benefits or rights you would normally have if you choose not to participate.  
WHAT IF YOU HAVE QUESTIONS, SUGGESTIONS OR CONCERNS? 
The person in charge of the study is Dr Stephanie Taylor of the Louisiana State University Health Sciences Center of 
New Orleans, Department of Medicine. If you have questions, suggestions, or concerns regarding this study or you want 
to withdraw from the study his/her contact information is Phone # (504) 
 (Office). 
 
If you have questions about your rights as a subject, or want to discuss problems, concerns or questions, or obtain 
information or offer input, you can contact the Chancellor of the LSU Health Sciences Center of New Orleans at (504) 
568-4801. 
 
I.D. #:___________________ 


Page 2 of 11 
LSUHSC-NO; SN Taylor 
DMID 17-0101 (IRB #: 19-121) 
Consent Rev. date: May 2, 2019  
Protocol Revision #: 2.0; 28 January 2019 
 
 
LOUISIANA STATE UNIVERSITY HEALTH SCIENCES CENTER – NEW ORLEANS 
 
Informed Consent Form 
 
1. Study 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 (DMID Protocol #: 17-0101) 
 
2. Performance Sites:  
LSU-CrescentCare Sexual Health Center 
3308 Tulane Ave., 5th Floor 
New Orleans, LA 70119 
 
3. Investigators:  
 
Principal Investigator: Stephanie N. Taylor, MD 
1542 Tulane Ave., 
 
New Orleans, LA 70112 
Phone:  504-
 (Office) 
 
Co-Investigator: Rebecca A. Lillis, MD 
1542 Tulane Ave., 
 
New Orleans, LA 70112 
Phone: 504-
 (Office) 
 
In case of research injury during business hours contact Dr. Stephanie N. Taylor 
at 504- 
. After hours, or on weekends and holidays contact Dr. Taylor at 
the 24-hour number: 504-
 
 
Sponsor:    
Division of Microbiology and Infectious Diseases (DMID), National Institutes of 
Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH). 
Bethesda, MD 
United States 
 
4. Purpose of the Study:  Syphilis is a bacterial infection that can be transmitted through sexual contact. 
People infected with syphilis may have sores, rashes, fever, headache, or sore throat. There are 4 stages of 
syphilis: primary, secondary, latent, and tertiary. This research study will include people who have untreated 
primary, secondary, or early latent syphilis. 
 
Treating syphilis with an effective antibiotic is important because untreated infection can affect the central 
nervous or cardiovascular systems and can be passed to sexual partners or to babies born to mothers who 
have syphilis. Syphilis infection might also increase the risk of HIV-uninfected people getting HIV, or HIV-
infected people transmitting HIV to others. 
 
For people who are not allergic to penicillin, syphilis is usually treated with benzathine penicillin G (BPG), 2.4 
million units (MU). BPG is approved by the US Food & Drug Administration (FDA), and the Centers for 
Disease Control and Prevention (CDC) recommends giving BPG once to treat primary, secondary, or early 
latent syphilis. Some doctors treat early syphilis with 2.4 MU of BPG weekly for 3 weeks. However, there has 
not been much research comparing 1 dose of BPG to 3 doses of BPG.  
 
The purposes of this study are to compare the effect of 1 dose of BPG to 3 weekly doses of BPG in all 
subjects; and to determine whether the effects of 1 dose of BPG or 3 weekly doses of BPG are different in 
HIV-infected and HIV-uninfected subjects. 
 


Page 3 of 11 
LSUHSC-NO; SN Taylor 
DMID 17-0101 (IRB #: 19-121) 
Consent Rev. date: May 2, 2019  
Protocol Revision #: 2.0; 28 January 2019 
 
5. Description of the Study: Approximately 560 adults who are at least 18 years old will be enrolled in this 
study, which is taking place at 10 sites in the US. The LSU-CrescentCare Sexual Health Center is one of the 
centers where this research will be conducted. At this site, 60 individuals will be participating in this research 
study. 
 
You are being asked to take part in this research study because you have untreated primary, secondary, or 
early latent syphilis and are at least 18 years old. Your participation is your choice. You do not have to be 
part of this study. Please ask questions if there is anything you do not understand. 
 
If you choose to enroll in the study and sign this consent form, the following will happen: 
 
Visit 1 – Screening/Enrollment (Today; this will take about 90 minutes): 
 You will be asked a few questions about yourself (such as your age, education level, race, and ethnicity) 
and your health. Some questions are about your sexual activities, medicine use, and current symptoms. 
Your answers will be kept confidential.   
 We may review your medical records from the past 14 days, if available, to confirm you are eligible for 
the study. If you have an HIV viral load test result available in your medical record from the past six 
months, we may note this result. 
 You will be asked to provide contact information, including your telephone number(s), address, and email. 
The study staff will use the contact information to follow up with you to remind you about your 
appointments. The study staff may contact you by telephone, text message, or email. You may tell the 
study staff if you prefer one type of contact over the others. 
 You will have a physical exam that includes taking your vital signs (temperature, heart rate, respiration 
rate, and blood pressure) and looking at your genitals, rectum, mouth, skin, and lymph nodes. 
 If you have one or more lesions (sores), we may swab one or more of them with a cotton swab. 
 If you are of childbearing potential, you will have a pregnancy test (urine or blood). The pregnancy test 
must be negative, and you must agree to use an acceptable method of birth control for the entire time 
you are part of the trial to participate in the study. If you are breastfeeding, you cannot participate in the 
study.  
 You will have about 1-2 tablespoons of blood drawn for the following: 
o syphilis testing;   
o HIV testing if you have not tested positive for HIV infection in the past (if, at any time during this 
study, you test positive for HIV infection, you will be immediately provided with counseling and 
you will be referred for confirmatory testing and clinical care); 
o storage and future testing; 
o CD4 cell count (if you are HIV-infected and have not had your CD4 cell count measured within 
the last 30 days).  
 You will be tested for chlamydia and gonorrhea if you have not been tested for these diseases and you 
have been sexually active in the past 14 days. You may also have other sexually transmitted infection 
testing if study staff think this is needed. 
 
To be in the study, you must be willing to receive 3 doses of BPG if you are assigned to Arm 2 (described 
below) and to return for all follow-up procedures. You will not be allowed to participate if you are allergic (or 
think you may be allergic) to penicillin or similar antibiotics known as beta-lactams. 
 
After you have completed the tests and procedures above, and if you are eligible to be in the study, you will 
be randomized (like the flip of a coin) to receive one or the other treatment for syphilis. If you are in Arm 1, 
you will receive BPG once. If you are in Arm 2, you will receive BPG weekly for 3 weeks. The arm that you 
will be in will be chosen by chance: half of the people in the study will receive BPG once, and half of the 
people in the study will receive BPG weekly for 3 weeks. We will tell you which treatment you will receive. 
  


Page 4 of 11 
LSUHSC-NO; SN Taylor 
DMID 17-0101 (IRB #: 19-121) 
Consent Rev. date: May 2, 2019  
Protocol Revision #: 2.0; 28 January 2019 
 
Arm 1: BPG 2.4 MU administered once as a divided dose in each buttock (total of 2 injections).  
OR 
Arm 2: BPG 2.4 MU administered as a divided dose in each buttock for 3 consecutive weeks (2 injections 
each week for a total of 6 injections).  
 
At the clinic today, you will receive BPG as two 2-mL injections, one in each buttock. If you are in Arm 1, this 
will be the only time you will receive BPG in the study. If you are in Arm 2, you will also receive BPG again 
at Visits 2 and 3. After you receive BPG, while other visit activities are being completed, you will be observed 
for adverse events that may occur due to receiving BPG.  
 
Study staff will review the study requirements with you and will schedule Visit 2. Study staff will give you a 
checklist to use to keep track of any side effects you have after receiving the BPG. You will be asked to have 
this checklist handy for the Non-Visit Contact described below and to bring it with you to Visit 2. If you feel 
feverish any time between Visit 1 and the Non-Visit Contact described below, you will be asked to take your 
temperature using a thermometer at home, if possible, and note the highest temperature to report to study 
staff during the Non-Visit Contact. 
 
Non-Visit Contact (about 24-48 hours after Visit 1): 
 Study staff will contact you to ask if you have had any side effects after receiving the BPG. Based on the 
preferred contact method you indicated at Visit 1, this contact may be a phone call, text message, or 
email. If you are contacted by text message or email, the message will provide a phone number to call if 
you have had any side effects. 
 
Visit 2 – Week 1 (Day 7 to 13; this will take about 60 to 75 minutes): 
 Study staff will determine if you still have signs of syphilis. 
 You will be asked about your health, including questions about your sexual activities, medicine use, and 
symptoms since your last visit. You may have sexually transmitted infection testing if study staff think this 
is needed.   
 We may review your medical records since your last study visit, if available. If you have an HIV viral load 
test result available in your medical record since your last study visit, we may note this result. 
 If study staff could not contact you by phone call, text message, or email after Visit 1, they will review any 
side effects that you may have had. 
 If you are of childbearing potential, you will have a urine pregnancy test. 
 Study staff will ask you if you had any problems. 
 You will have a physical exam like at Visit 1. 
 If you have one or more lesions (sores), we may swab one or more of them with a cotton swab. 
 You will have about 1-2 tablespoons of blood drawn for the following: 
o syphilis testing; 
o storage and future testing.  
 If you are in Arm 2, you will receive BPG for the second time as two 2-mL injections, one in each buttock. 
After you receive BPG, while other visit activities are being completed, you will be observed for adverse 
events that may occur due to receiving BPG. 
 Study staff will review your contact information and schedule you for Visit 3.  
 


Page 5 of 11 
LSUHSC-NO; SN Taylor 
DMID 17-0101 (IRB #: 19-121) 
Consent Rev. date: May 2, 2019  
Protocol Revision #: 2.0; 28 January 2019 
 
Visit 3 – Week 2 (6 to 12 days after Visit 2; this will take about 60 to 75 minutes): 
 Study staff will determine if you still have signs of syphilis. 
 You will be asked about your health, including questions about your sexual activities, medicine use, and 
symptoms since your last visit. You may have sexually transmitted infection testing if study staff think this 
is needed.  
 We may review your medical records since your last study visit, if available. If you have an HIV viral load 
test result available in your medical record since your last study visit, we may note this result. 
 If you are of childbearing potential, you will have a urine pregnancy test. 
 Study staff will ask you if you had any problems. 
 You will have a physical exam like at Visit 1. 
 If you have one or more lesions (sores), we may swab one or more of them with a cotton swab. 
 You will have about 1-2 tablespoons of blood drawn for the following: 
o syphilis testing; 
o storage and future testing.  
 If you are in Arm 2, you will receive BPG for the third and final time as two 2-mL injections, one in each 
buttock. After you receive BPG, while other visit activities are being completed, you will be observed for 
adverse events that may occur due to receiving BPG. 
 Study staff will review your contact information and schedule you for Visit 4.  
  
 Visit 4 – Month 1 (Day 30 ± 7 days; this will take about 60 to 75 minutes): 
 You will be asked about your health, including questions about your sexual activities, medicine use, and 
symptoms since your last visit. You may have sexually transmitted infection testing if study staff think this 
is needed.  
 We may review your medical records since your last study visit, if available. If you have an HIV viral load 
test result available in your medical record since your last study visit, we may note this result. 
 If you are of childbearing potential, you will have a urine pregnancy test. 
 Study staff will ask you if you had any problems. 
 You will have a physical exam like at Visit 1. 
 If you have one or more lesions (sores), we may swab one or more of them with a cotton swab. 
 You will have about 1-2 tablespoons of blood drawn for the following: 
o syphilis testing; 
o storage and future testing;  
o CD4 cell count (if you are HIV-infected and have not had your CD4 cell count measured within 
the last 30 days). 
 Study staff will review your contact information and schedule you for Visit 5.  
 
Visit 5 – Month 3 (Day 90 ± 21 days; this will take about 60 to 75 minutes): 
 You will be asked about your health, including questions about your sexual activities, medicine use, and 
symptoms since your last visit. You may have sexually transmitted infection testing if study staff think this 
is needed.  
 We may review your medical records since your last study visit, if available. 
 If you are of childbearing potential, you will have a urine pregnancy test. 
 If you have one or more lesions (sores), we may swab one or more of them with a cotton swab. 
 You will have a physical exam like at Visit 1. 
 You will have about 1-2 tablespoons of blood drawn for the following: 
o syphilis testing; 
o storage and future testing;  
o HIV testing (if you have not tested positive for HIV infection in the past). 
 Study staff will review your contact information and schedule you for Visit 6. 
  


Page 6 of 11 
LSUHSC-NO; SN Taylor 
DMID 17-0101 (IRB #: 19-121) 
Consent Rev. date: May 2, 2019  
Protocol Revision #: 2.0; 28 January 2019 
 
Visit 6 – Month 6 (Day 180 ± 21 days; this will take about 60 to 75 minutes): 
 You will be asked about your health, including questions about your sexual activities, medicine use, and 
symptoms since your last visit. You may have sexually transmitted infection testing if study staff think this 
is needed.  
 We may review your medical records since your last study visit, if available. 
 If you are of childbearing potential, you will have a urine pregnancy test. 
 You will have a physical exam like at Visit 1. 
 If you have one or more lesions (sores), we may swab one or more of them with a cotton swab. 
 You will have about 1-2 tablespoons of blood drawn for the following: 
o syphilis testing; 
o storage and future testing; 
o CD4 cell count (if you are HIV-infected and have not had your CD4 cell count measured within 
the last 30 days); 
o HIV testing (if you have not tested positive for HIV infection in the past). 
 Study staff will review your contact information and schedule you for Visit 7.  
 
Visit 7 – Month 9 (Day 270 ± 28 days; this will take about 60 to 75 minutes): 
 You will be asked about your health, including questions about your sexual activities, medicine use, and 
symptoms since your last visit. You may have sexually transmitted infection testing if study staff think this 
is needed.  
 We may review your medical records since your last study visit, if available. 
 If you are of childbearing potential, you will have a urine pregnancy test. 
 You will have a physical exam like at Visit 1. 
 If you have one or more lesions (sores), we may swab one or more of them with a cotton swab. 
 You will have about 1-2 tablespoons of blood drawn for the following: 
o syphilis testing; 
o storage and future testing;  
o HIV testing (if you have not tested positive for HIV infection in the past). 
 Study staff will review your contact information and schedule you for Visit 8.  
 
Visit 8 – Month 12 (Day 360 ± 28 days; this will take about 60 to 75 minutes): 
 You will be asked about your health, including questions about your sexual activities, medicine use, and 
symptoms since your last visit. You may have sexually transmitted infection testing if study staff think this 
is needed.  
 We may review your medical records since your last study visit, if available. 
 If you are of childbearing potential, you will have a urine pregnancy test. 
 You will have a physical exam like at Visit 1. 
 If you have one or more lesions (sores), we may swab one or more of them with a cotton swab. 
 You will have about 1-2 tablespoons of blood drawn for the following: 
o syphilis testing; 
o storage and future testing;  
o CD4 cell count (if you are HIV-infected and have not had your CD4 cell count measured within 
the last 30 days); 
o HIV testing (if you have not tested positive for HIV infection in the past). 
 Study staff will review your contact information.  
 
 
 
 
 


Page 7 of 11 
LSUHSC-NO; SN Taylor 
DMID 17-0101 (IRB #: 19-121) 
Consent Rev. date: May 2, 2019  
Protocol Revision #: 2.0; 28 January 2019 
 
Unscheduled Visit 
You may be asked to come to the clinic if you have new or worsening symptoms, or if a study doctor feels 
you should be seen for any reason. At that visit, the following may occur: 
 You may be asked about your health, including questions about your sexual activities, medicine use, and 
symptoms since your last visit. You may have sexually transmitted infection testing if study staff think this 
is needed.  
 We may review your medical records since your last study visit, if available. 
 You may be asked to confirm your contact information. 
 If you are of childbearing potential, you may have a urine pregnancy test. 
 Study staff may ask you if you had any problems. 
 You may have a physical exam like at Visit 1. 
 If you have one or more lesions (sores), we may swab one or more of them with a cotton swab. 
 
You will only have 8 visits unless: 
1. You have a new problem found during a physical examination. If you have a new problem, we may 
contact you to refer you to another care provider for appropriate treatment outside of the study. 
2. You become pregnant during the study. If this happens, you will not receive any more BPG as part of 
the study, and the Early Termination Visit described below will be completed. Study staff will also contact 
you to ask about the outcome of your pregnancy, and your baby will be monitored for up to 2 months 
after birth.   
 
After all tests required for this study are finished, instead of discarding leftover blood samples, we will save 
them for possible future research related to syphilis. You do not have to agree to allow us to store your 
samples for future research in order for you to participate in this study. If you choose not allow us to store 
your samples for future research, they will be destroyed after completion of the study. 
 
You will be asked to confirm your willingness to allow your leftover samples to be stored for future research 
at the end of this consent form. 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by US Law. 
This website will not include information that can identify you. At most, the website will include a summary of 
the results. You can search this website at any time. 
 
The National Clinical Trials number for this study is NCT03637660. 
 
6. Benefits to Subjects: You may get no direct benefit from being in the study. However, the study may help 
us understand how well BPG received once or weekly for 3 weeks works against syphilis infections. The 
study will provide information that might benefit future patients. 
 
7. Risks to Subjects: You may become embarrassed, worried, or nervous when answering questions about 
your sexual activity. All information will be confidential. You may feel worried or anxious while waiting for your 
test results. Trained study staff are available to help with any feelings or questions you may have.  
 
You may feel temporary pain or discomfort during blood draws. There is a small risk of infection or bruising 
at the site of the blood draw. 
 
You may experience an emotional episode in relation to STI/HIV test results. If that happens, comfort and 
counseling will be provided.  
 
 
 


Page 8 of 11 
LSUHSC-NO; SN Taylor 
DMID 17-0101 (IRB #: 19-121) 
Consent Rev. date: May 2, 2019  
Protocol Revision #: 2.0; 28 January 2019 
 
BPG is the standard therapy for treating syphilis, which means it is not an experimental treatment. BPG is 
generally well tolerated. However, you may feel temporary pain or discomfort during the BPG injection. 
Potential side effects after the BPG injection could include bruising, a skin rash, an allergic reaction, or other 
unforeseen risks.  
 
When patients with syphilis are treated, they may sometimes have a fever and/or flu-like symptoms (chills, 
muscle pain, weakness, flushing, worsening of skin rash, fast or fluttering heartbeat, joint pain, nausea, 
headache, or dizziness) while the bacteria causing syphilis are being killed. This is called a Jarisch-
Herxheimer reaction, and it usually happens within 24 hours (most often within 6-8 hours) of the first dose. 
This is not an allergic reaction and usually goes away without treatment in a day. One recent study showed 
that less than 1 in 3 people will develop this reaction, and that it is mild in most people with early syphilis.  
 
Previous studies have not shown harmful effects for fetuses when BPG is used during pregnancy. However, 
it is possible there may be some side effects for fetuses that we do not know about yet, and so you will not 
be allowed to participate in this study if you are pregnant. You will also not be allowed to participate if you 
are breastfeeding, because BPG is excreted in breast milk and could be harmful to breastfed babies. 
 
8. Alternatives to Participating in the Study:  You do not have to participate in this study if you do not want 
to. If you choose not to participate, you will be offered testing and standard treatment for early syphilis with 
1 dose of BPG 2.4 MU administered once as a divided dose in each buttock (total of 2 injections) from LSU-
CrescentCare Sexual Health Center. 
 
9. Subject Removal: If you decide to stop being part of the study any time after you receive the first dose of 
BPG but before Visit 8, you will be asked to continue scheduled study procedures, if possible, to see how 
well the BPG worked. If you decide not to complete the remaining visits, you will be asked to return to the 
clinic for an Early Termination Visit. At that visit, the items listed above for Visit 8 will occur if you agree to 
them. 
 
The study doctor has the right to take you out of the study for any of the following reasons: 
 you have a side effect related to BPG; 
 the study (in the opinion of the doctor) would pose a health risk to you; 
 you are not eligible for the study; 
 you fail to follow the study requirements; 
 you receive other antibiotic therapy active against syphilis infection outside the study; 
 the study is stopped. 
 
10. Subject’s Right to Refuse to Participate or Withdraw:  Your participation in this study is completely 
voluntary. Your doctor may be involved as study staff in this study. You may talk about your care with another 
doctor who is not part of this study. You do not have to be part of this study. You may decide to no longer 
participate in the study. If you decide to not allow the use of your confidential information, you will also be 
withdrawn from further participation in this study. Any information from your participation in this study may 
continue to be used. To no longer be in this study, you will need to tell the study staff. Your decision to no 
longer participate in this study will have no effect on your relationship or care with the LSU-CrescentCare 
Sexual Health Center. Should significant new findings take place during the course of the research that may 
relate to your willingness to continue participation, that information will be provided to you. 
 
11. Subject’s Right to Privacy: Participation in a research study may involve a loss of privacy. We will do our 
best to make sure that your personal information is kept private. Your records will be kept as confidential as 
possible under the law. Your individual identity will not be used in any reports or publications resulting from 
this study. 
 


Page 9 of 11 
LSUHSC-NO; SN Taylor 
DMID 17-0101 (IRB #: 19-121) 
Consent Rev. date: May 2, 2019  
Protocol Revision #: 2.0; 28 January 2019 
 
To help us protect your privacy, we have a Certificate of Confidentiality (CoC) from the NIH. The researchers 
can use this CoC to legally refuse to give information that may identify you in any federal, state, or local civil, 
criminal, administrative, legislative, or other proceedings, for example, if there is a court subpoena. 
 
Because it is very important that we can contact you during the study, you will be asked to provide contact 
information like your address, phone number(s), and email address. We ask for at least two additional 
contacts (e.g., family member or friend) who know how to reach you or would have new contact information 
for you. The research staff may call your contact(s) if your numbers are changed or disconnected. We will 
not give out confidential information if we need to get in touch with your contacts. 
 
12. Release of Information:  The researchers will use the CoC to resist any demands for information that would 
identify you, except for reporting of communicable diseases to state and local health departments. The CoC 
will not be used to prevent disclosure to state or local authorities for child and elder abuse, sexual abuse, or 
wanting to harm yourself or others. The CoC cannot be used for information in your medical records. 
 
The NIH, as the sponsor of this research study, the FDA, and the LSUHSC-NO Institutional Review Board 
(IRB) of the institution where the study is being conducted may review and obtain information (which may 
include your identifiable medical information) related to this study. (An IRB is a committee that watches over 
the safety and rights of research participants.) The sponsor has an agreement with a company that will be 
the monitoring group to review the research study. Staff from the clinical monitoring group may review study 
information (which may include your identifiable medical information) for accuracy and completeness.   
 
13. Financial Information:  The medicine that you get as part of this study will be provided free of charge. There 
will be no cost to you to take part in the study. Your insurance will not be billed for any of the study procedures. 
Treatments or procedures done according to local clinic practice may be charged to your insurance. 
 
If you complete the procedures, you will receive the following for your time, transportation, and other 
expenses: Visit 1:  $40.00  debit card; Visit 2:  $50.00 added to same debit card; Visit 3:  $50.00 added to 
same debit card; Visit 4:  $50.00 added to same debit card; Visit 5:  $50.00 added to same debit card; Visit 
6:  $50.00 added to same debit card; Visit 7:  $50.00 added to same debit card; Visit 8:  $50.00 added to 
same debit card. 
 
The reloadable debit card will be activated by your study doctor or nurse within 48 hours of your Visit 1, and 
money will be added to the same debit card by your study doctor or nurse within 48 hours of each visit. This 
will be done by computer using the card company’s website. If the card is lost or stolen, you will have to 
contact the Greenphire Company at 215-
. You will have to pay $7.00 for a new card if it is lost or 
stolen. Clinic staff will not be able to help you get another card. You must call the company yourself. No 
follow-up visit will be required. 
 
The staff at LSU-CrescentCare Sexual Health Center makes efforts to prevent and treat any injuries that 
might happen. If you think you are hurt because of this study, contact the study staff at LSU-CrescentCare 
Sexual Health Center right away.  
 
Emergency care for injuries related to this study will be done by the staff of LSU-CrescentCare Sexual Health 
Center. It is possible that LSU-CrescentCare Sexual Health Center may bill your insurance for the cost. If 
your injury needs more medical care, you may  be responsible for the costs. The NIH will not pay for treatment 
or provide any compensation in the case of injury. In general, no long-term medical care or financial 
compensation for research-related injuries will be provided by the NIH or the federal government. You do not 
      give up any legal rights by signing this form.  
 
 


Page 10 of 11 
LSUHSC-NO; SN Taylor 
DMID 17-0101 (IRB #: 19-121) 
Consent Rev. date: May 2, 2019  
Protocol Revision #: 2.0; 28 January 2019 
 
14. Signatures:  
 
The study has been discussed with me and all my questions have been answered. Additional questions 
regarding the study should be directed to the investigators listed on page 1 of this consent form. If I have 
questions about subject’s rights, or want to discuss problems, concerns or questions, or obtain information 
or offer input, I can contact the Chancellor of the LSU Health Sciences Center New Orleans at (504) 
. I agree with the terms above, acknowledge I have been given a copy of the consent form, and agree 
to participate in this study. I have not waived any of my legal rights by signing this consent form. 
 
 
______________________________________  
                            _______________ 
 
Signature of Subject 
 
 
 
 
                            Date 
 
 
_______________________________________ 
 
 
Printed Name of Subject 
 
 
 
After all tests required for this study are finished, instead of discarding leftover blood samples, we will save 
them for possible future research related to syphilis. We may also collect additional blood for future research 
related to syphilis. The swab samples we take from syphilis lesions will be used to sequence syphilis bacteria 
DNA but not your human DNA. No genetic testing will be done on left over specimens. 
 
We may share some of these samples and the information we collect about you with researchers outside of 
the study. The samples could be tested in the future to research topics related to syphilis. The samples and 
the information we collect about you will not have your name or other identifying information on them at any 
time; they will only have a coded number on them. These specimens will not be linked to your identity. We 
will share only information that was collected as part of the study. 
 
You do not have to agree to allow us to store your samples for future research. If you choose not to allow us 
to store your samples for future research, they will be destroyed after completion of the study. There is no 
time limit on how long your samples will be stored. Your medical care at this clinic will not be affected if you 
do not allow us to store your samples for future research. 
 
If you decide at any time that you do not want the samples stored for future research, you must contact the 
study staff who will then notify the laboratory/specimen archive staff. Laboratory staff will mark the samples 
with a “destroy” label and destroy them at the end of this study, or they will remove the samples from storage 
and destroy them as soon as possible.  
 
Please write your initials in one of the spaces below. You will be treated the same no matter which you 
choose.   
 
 
I give permission for my specimens to be stored for future use as described above.  
 
 
 
Yes _____ (Initial – Do not check) 
No _____ (Initial – Do not check) 
 
I may withdraw my consent for storage of my samples by submitting a request in writing to the investigator. 
 
 
 
__________________________________ 
 
                            _______________ 
 
Signature of Subject 
 
 
 
 
                            Date 
 


Page 11 of 11 
LSUHSC-NO; SN Taylor 
DMID 17-0101 (IRB #: 19-121) 
Consent Rev. date: May 2, 2019  
Protocol Revision #: 2.0; 28 January 2019 
 
 
The study subject has indicated to me that the subject is unable to read. I certify that have read this consent 
form to the subject and explained that by completing the signature line above the subject has agreed to take 
part.  
 
 
 
_______________________________________ 
 
                _______________ 
 
Signature of Reader 
 
 
 
 
 
                Date 
 
    
 
_______________________________________ 
 
 
Printed Name 
 
 
 
 
 
 
 
_______________________________________ 
 
                _______________ 
 
Signature of Witness 
 
 
 
 
 
                Date 
 
 
      _______________________________________ 
 
 
Printed Name 
 
 
 
CERTIFICATION OF INFORMED CONSENT: 
 
I certify that I have explained the nature and purpose of this research study to the above-named individual, 
and I have discussed the potential benefits and possible risks of study participation. Any questions the 
individual(s) have about this study have been answered, and we will always be available to address future 
questions as they arise. I further certify that no research component of this protocol was begun until after this 
consent form was signed. 
 
 
 
___________________________________ 
 
                                
 
 
              
Printed Name of Person Obtaining Consent 
 
 
                    
 
 
 
___________________________________ 
 
 
             _________________ 
 
Signature of Person Obtaining Consent  
 
 
             Date 
 
 

SAP_002.pdf: 
CLINICAL RESEARCH IN INFECTIOUS DISEASES 
 
 
 
STATISTICAL ANALYSIS PLAN 
for 
DMID Protocol: 17-0101 
 
Study 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 
 
NCT03637660 
 
Version 1.0 
 
DATE: 22-Dec-2022 
 
THIS COMMUNICATION IS PRIVILEGED AND CONFIDENTIAL  
 
 


Statistical Analysis Plan - DMID Protocol: 17-0101 
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STUDY TITLE 
Protocol Number Code: 
DMID Protocol: 17-0101 
Protocol Version: 
Version 4.0 
Development Phase: 
Phase IV 
Products: 
Benzathine Penicillin G 
Form/Route: 
Intramuscular 
Indication Studied: 
Syphilis 
Sponsor: 
Division of Microbiology and Infectious Diseases 
National Institute of Allergy and Infectious Diseases 
National Institutes of Health 
Clinical Trial Initiation Date: 
12 September 2018 
Date of the Analysis Plan: 
22 December 2022 
Version Number: 
1.0 
This study was performed in compliance with Good Clinical Practice. 
Information contained in this publication is the property of Division of Microbiology and Infectious Diseases and is confidential. This information 
may not be disclosed to third parties without written authorization from Division of Microbiology and Infectious Diseases. This report may not be 
reproduced, stored in a retrieval system or transmitted in any form or by any means - electronic, mechanical, recording or otherwise - without 
the prior authorization from Division of Microbiology and Infectious Diseases. This document must be returned to Division of Microbiology and 
Infectious Diseases upon request. 
 


Statistical Analysis Plan - DMID Protocol: 17-0101 
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TABLE OF CONTENTS 
STUDY TITLE ............................................................................................................................... II 
TABLE OF CONTENTS ...............................................................................................................III 
LIST OF ABBREVIATIONS ....................................................................................................... VI 
1. 
PREFACE .....................................................................................................................1 
2. 
INTRODUCTION ........................................................................................................2 
2.1. 
Study background .........................................................................................................2 
2.2. 
Purpose of the Analyses ................................................................................................2 
3. 
STUDY OBJECTIVES AND ENDPOINTS ................................................................3 
3.1. 
Study Objectives ...........................................................................................................3 
3.1.1. 
Primary Objective .........................................................................................................3 
3.1.2. 
Secondary Objectives ...................................................................................................3 
3.2. 
Study Outcome Measures .............................................................................................3 
3.2.1. 
Primary Outcome Measure ...........................................................................................3 
3.2.2. 
Secondary Outcome Measures .....................................................................................3 
3.3. 
Study Definitions and Derived Variables .....................................................................4 
3.3.1. 
Serological Response to Therapy .................................................................................4 
3.3.1.1. 
Primary Outcome Analysis ...........................................................................................4 
3.3.1.2. 
Secondary Outcome Analysis .......................................................................................4 
3.3.1.3. 
Sensitivity Analysis for the Primary Outcome .............................................................4 
3.3.1.4. 
Exploratory Analysis for the Primary Outcome ...........................................................5 
3.3.2. 
Treatment Adherence ....................................................................................................5 
3.3.3. 
Jarisch-Herxheimer Reaction ........................................................................................6 
3.3.4. 
Baseline Value ..............................................................................................................6 
4. 
INVESTIGATIONAL PLAN .......................................................................................7 
4.1. 
Overall Study Design and Plan .....................................................................................7 
4.2. 
Discussion of Study Design, Including the Choice of Control Groups ........................8 
4.3. 
Selection of Study Population ......................................................................................8 
4.4. 
Treatments ....................................................................................................................9 
4.4.1. 
Treatments Administered ..............................................................................................9 
4.4.2. 
Identity of Investigational Product(s) .........................................................................10 
4.4.3. 
Method of Assigning Subjects to Treatment Groups (Randomization) .....................10 


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4.4.4. 
Selection of Doses in the Study ..................................................................................10 
4.4.5. 
Selection and Timing of Dose for Each Subject .........................................................11 
4.4.6. 
Blinding ......................................................................................................................11 
4.4.7. 
Prior and Concomitant Therapy ..................................................................................11 
4.5. 
Efficacy (Immunogenicity) and Safety Variables ......................................................11 
5. 
SAMPLE SIZE CONSIDERATIONS .......................................................................14 
5.1. 
Study with Planned Sample Size ................................................................................14 
5.2. 
Study with Smaller Sample Size .................................................................................14 
6. 
GENERAL STATISTICAL CONSIDERATIONS ....................................................17 
6.1. 
General Principles .......................................................................................................17 
6.1.1. 
Pseudo Code ...............................................................................................................17 
6.2. 
Timing of Analyses .....................................................................................................18 
6.3. 
Analysis Populations ..................................................................................................18 
6.3.1. 
Safety Analyses ..........................................................................................................18 
6.3.2. 
Efficacy Analyses .......................................................................................................19 
6.3.2.1. 
Intent-to-Treat Population ..........................................................................................19 
6.3.2.2. 
Modified Intent-to-Treat (mITT) Population ..............................................................19 
6.3.2.3. 
Evaluable Population ..................................................................................................19 
6.3.2.4. 
Analysis Population Summaries .................................................................................20 
6.4. 
Covariates and Subgroups ..........................................................................................20 
6.5. 
Missing Data ...............................................................................................................20 
6.6. 
Interim Analyses and Data Monitoring ......................................................................21 
6.7. 
Multicenter Studies .....................................................................................................22 
6.8. 
Multiple Comparisons/Multiplicity ............................................................................22 
7. 
STUDY SUBJECTS ...................................................................................................23 
7.1. 
Disposition of Subjects ...............................................................................................23 
7.2. 
Protocol Deviations ....................................................................................................23 
8. 
EFFICACY EVALUATION ......................................................................................24 
8.1. 
Primary Efficacy Analysis ..........................................................................................24 
8.1.1. 
Sensitivity Analyses for Primary Efficacy Outcome ..................................................24 
8.2. 
Secondary Efficacy Analyses .....................................................................................24 


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8.2.1. 
Efficacy by 12 Months ................................................................................................24 
8.2.2. 
Efficacy by 6 Months Among Subjects with and without HIV Infection ..................25 
8.2.3. 
Efficacy by 12 Months Among Subjects with and without HIV Infection ................25 
8.2.4. 
Treatment Compliance by Treatment Group ..............................................................25 
8.2.5. 
Demographics and Baseline Characteristics by HIV status .......................................26 
8.3. 
Exploratory Efficacy Analyses ...................................................................................26 
8.4. 
Clinical Laboratory Evaluations .................................................................................26 
9. 
SAFETY EVALUATION ..........................................................................................27 
9.1. 
Prior Conditions ..........................................................................................................27 
9.1.1. 
Prior and Concurrent Medical Conditions ..................................................................27 
9.1.2. 
Prior and Concomitant Medications ...........................................................................27 
9.2. 
Measurements of Treatment Compliance ...................................................................27 
9.3. 
Adverse Events ...........................................................................................................27 
9.3.1. 
Solicited Events and Symptoms .................................................................................28 
9.3.2. 
Unsolicited Adverse Events ........................................................................................28 
9.4. 
Deaths, Serious Adverse Events and other Significant Adverse Events ....................29 
9.5. 
Pregnancies .................................................................................................................29 
9.6. 
Vital Signs and Physical Evaluations .........................................................................29 
9.7. 
Other Safety Measures ................................................................................................29 
10. 
PHARMACOKINETICS ...........................................................................................30 
11. 
IMMUNOGENICITY ................................................................................................31 
12. 
OTHER ANALYSES .................................................................................................32 
13. 
REPORTING CONVENTIONS ................................................................................33 
14. 
TECHNICAL DETAILS ............................................................................................34 
15. 
SUMMARY OF CHANGES IN THE CONDUCT OF THE STUDY OR 
PLANNED ANALYSES ............................................................................................35 
16. 
REFERENCES ...........................................................................................................36 
17. 
LISTING OF TABLES, FIGURES, AND LISTINGS ..............................................37 
APPENDICES ...............................................................................................................................38 
APPENDIX 1. TABLE MOCK-UPS..........................................................................................39 
APPENDIX 2. FIGURE MOCK-UPS ........................................................................................96 
APPENDIX 3. LISTINGS MOCK-UPS ...................................................................................106 


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LIST OF ABBREVIATIONS 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase 
BP 
Blood Pressure  
BPG 
Benzathine Penicillin G 
BUN 
Blood Urea Nitrogen 
C 
Celsius 
CI 
Confidence Interval 
CRF 
Case Report Form 
DMID 
Division of Microbiology and Infectious Diseases 
DSMB 
Data and Safety Monitoring Board 
EDC 
Electronic Data Capture 
ELISA 
Enzyme-linked Immunosorbent Assay 
ER 
Emergency Room 
F 
Fahrenheit 
GGT 
Gamma Glutamyl Transferase 
GMT 
Geometric Mean Titer 
GMFR 
Geometric Mean Fold Rise 
ICH 
International Conference on Harmonisation 
IRB 
Institutional Review Board 
ITT 
Intention to Treat 
L 
Liter 
LLN 
Lower Limit of Normal 
mcg 
Microgram 
MedDRA 
Medical Dictionary for Regulatory Activities  
mEq 
Milliequivalent 
mg 
Milligram 
mITT 
Modified Intention to Treat 
mL 
Milliliter 
MAR 
Missing at Random 
MCAR 
Missing Completely at Random 


Statistical Analysis Plan - DMID Protocol: 17-0101 
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List of Abbreviations (continued) 
 
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MNAR 
Missing Not at Random 
N 
Number (typically refers to subjects) 
NIH 
National Institutes of Health 
PI 
Principal Investigator 
PP 
Per Protocol 
PT 
Preferred Term 
RBC 
Red Blood Cell 
RCD 
Reverse Cumulative Distribution  
RPR 
Rapid Plasma Reagin 
SAE 
Serious Adverse Event 
SD 
Standard Deviation 
SDCC 
Statistical and Data Coordinating Center 
SMC 
Safety Monitoring Committee 
SOC  
System Organ Class 
SOP 
Standard Operating Procedures 
TFL 
Tables, figures, and listings 
TPPA 
Treponema pallidum Particle Agglutination 
U 
Units 
ULN 
Upper Limit of Normal 
WBC 
White Blood Cell 
WHO 
World Health Organization 
 


Statistical Analysis Plan - DMID Protocol: 17-0101 
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1. 
PREFACE 
The Statistical Analysis Plan (SAP) for “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 17-0101) describes and expands upon the 
statistical information presented in the protocol. 
This document describes all planned analyses and provides reasons and justifications for these analyses. It 
also includes sample tables, figures, and listings (TFL) planned for the final analyses. Regarding the final 
analyses and Clinical Study Report (CSR), this SAP follows the International Conference on Harmonisation 
of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) Guidelines, as indicated 
in Topic E3 (Structure and Content of Clinical Study Reports), and more generally is consistent with Topic E8 
(General Considerations for Clinical Trials) and Topic E9 (Statistical Principles for Clinical Trials). This SAP 
also follows the FDA guidance regarding the COVID-19 public health emergency. 1. Contingency measures 
implemented to manage study conduct during disruption of the study as a result of COVID-19 control 
measures. 2. All participants affected by the COVID-19 will be highlighted. 3. Analyses and corresponding 
discussions that address the impact of implemented contingency measures. 4. Any protocol deviation due to 
COVID-19 will be documented. 
The structure and content of the SAP provides sufficient detail to meet the requirements identified by the 
FDA and ICH, while all work planned and reported for this SAP will follow internationally accepted 
guidelines published by the American Statistical Association and the Royal Statistical Society for statistical 
practice.  
This document contains four sections: (1) a review of the study design, (2) general statistical considerations, 
(3) comprehensive statistical analysis methods for efficacy and safety outcomes, and (4) a list of proposed 
tables and figures. Within the table, figure, and listing mock-ups (Appendices Appendix 1, Appendix 2, and 
Appendix 3), references to CSR sections are included. Any deviation from this SAP will be described and 
justified in protocol amendments and/or in the CSR, as appropriate. The reader of this SAP is encouraged to 
also review the study protocol for details on conduct of the study and the operational aspects of clinical 
assessments. 


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2. 
INTRODUCTION 
2.1. 
Study background 
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[2]. 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[3].  Further rising P&S rates in women led to a 28% increase in congenital syphilis cases 
in the US between 2015 and 2016[4]. 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[4] 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 [5]. 
Penicillin is currently the only recommended treatment for syphilis (alternative therapies may be used in 
persons with penicillin allergy[6]. 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)[6, 7], 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 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. 
Purpose of the Analyses 
These analyses will assess the efficacy and safety of a single dose or three successive weekly doses regimen 
of Benzathine Penicillin G 2.4 Million units for the treatment of early Syphilis in subjects with or without 
HIV infection and will be included in the clinical study report. 


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3. 
STUDY OBJECTIVES AND ENDPOINTS 
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 
1. To determine if the difference in response to therapy between treatment arms by Month 6 differs 
among subjects with or without HIV infection 
2. To determine the impact of multiple BPG injected doses on subject compliance with study product and 
adherence to scheduled visits  
3. To determine the incidence and manifestations of the Jarisch-Herxheimer reaction among subjects 
treated for early syphilis with BPG 
4. To collect prospective data up to Month 12 on the serological response to therapy in subjects treated 
for early syphilis with either BPG regimen  
5. 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 
1. 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 
2. The proportion of subjects in each treatment group with a 4-fold decline in RPR titers or seroreversion 
by Month 12 
3. 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 
4. The proportion of subjects (overall and in each treatment group) who receive all assigned doses within 
the assigned visit windows 
5. 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 
6. 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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3.3. 
Study Definitions and Derived Variables  
3.3.1. 
Serological Response to Therapy 
3.3.1.1. 
Primary Outcome Analysis 
For the primary analysis, serological response to therapy by Month 6 will be defined as follows, where 
available RPR results from all visits prior to the end of month 6 visit window (i.e. scheduled visits up to and 
including the Month 6 visit, early termination visit, or any unscheduled visit that occurred prior to the end of 
month 6 visit window), will be evaluated:  
• 4-fold or greater decline in RPR titer at any visit prior to the end of month 6 visit window compared to 
baseline, OR  
• RPR-negative at any visit prior to the end of month 6 visit window (i.e., seroreversion). 
It is possible that a subject reaches 4-fold decline in RPR titer at an earlier visit but increases again later to 
less than 4-fold decline. In this case, it will be classified as a serological response. 
For the primary analysis, subjects who do not meet either of the above criteria will be classified as not 
experiencing serological response by Month 6. 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 after retreatment will not be used for analyses. See Section 6.5 for appropriate handling of visits 
with missing RPR test and titer results.  
3.3.1.2. 
Secondary Outcome Analysis 
For the secondary analysis, serological response to therapy by Month 12 will be defined as follows, where 
available RPR results from all visits prior to the end of Month 12 visit window (i.e. scheduled visits and early 
termination visit that occurred between scheduled visits up to and including the Month 12 visit), will be 
evaluated:  
• 4-fold or greater decline in RPR titer at any visit prior to or including the Month 12 compared to 
baseline, OR  
• RPR-negative at any visit prior to or including the Month 12 (i.e., seroreversion). 
It is possible that a subject reaches 4-fold decline in RPR titer at an earlier visit but increases again later to 
less than 4-fold decline. In this case, it will be classified as a serological response. 
For the secondary analysis, subjects who do not meet either of the above criteria will be classified as not 
experiencing serological response by Month 12. 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. See Section 6.5 for appropriate handling of 
visits with missing RPR test and titer results.  
3.3.1.3. 
Sensitivity Analysis for the Primary Outcome 
We are going to do two sensitivity analyses for the primary outcome.  
1. Due to the COVID-19 pandemic, a certain number of subjects discontinued the study treatment or 
early terminated from the study. If these subjects do not have enough data to demonstrate serological 
response, they will be classified as failure. By removing these subjects from the analysis, we will 


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reduce cases of false failure. This analysis will be performed with ITT, mITT and evaluable 
populations 
2. For the second sensitivity analysis of the primary outcome, serological response to therapy by Month 6 
will be defined as follows, where available RPR results from the last available visit prior to the end of 
month 6 visit window (i.e. scheduled visits up to and including the Month 6 visit and early termination 
visit that occurred prior to the end of month 6 visit window), will be evaluated:  
• 4-fold or greater decline in RPR titer at the last available visits prior to the end of month 6 visit 
window compared to baseline, OR  
• RPR-negative at the last available visit prior to the end of month 6 visit window (i.e., seroreversion). 
In this definition, if a subject reaches 4-fold decline in RPR titer at an earlier visit but increases again later to 
less than 4-fold decline, they will be classified as a serological non-response. 
3.3.1.4. 
Exploratory Analysis for the Primary Outcome 
Exploratory analyses of the primary outcome will consider the following alternative serological response 
classifications:  
• Response:  
o 4-fold or more decline in RPR titer at any visit prior to the end of month 6 visit window compared 
to baseline, 
or 
o RPR-negative (i.e., seroreversion) at any visit prior to the end of month 6 visit window. 
• Non-Response:  
o RPR-positive at all visits,  
and  
o Less than 4-fold decline in RPR titer at all visits prior to the end of month 6 visit window 
compared to baseline,  
and  
o Less than 4-fold increase in RPR titer at all visits prior to the end of month 6 visit window  
• Failure:  
o 4-fold or greater increase in RPR titer without a clear history of re-exposure at any visit prior to the 
end of month 6 visit window,  
and  
o Less than 4-fold decline in RPR titer at all visits compared to baseline. 
3.3.2. 
Treatment Adherence  
All BPG injections will be directly observed by the administering clinician. Compliance with study product 
will be defined as the subject received all assigned doses within the assigned visit windows. A subject is not 
adherent to study product if they miss at least one dose or receive at least one dose out of the visit window. 
An exception to this rule is that a subject is considered as compliant to the study product if they received all 


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doses according to the schedule they were given, even if the schedule itself might be out of the normal visit 
window.  
3.3.3. 
Jarisch-Herxheimer Reaction 
Approximately 24 - 48 hours after Visit 1, subjects are contacted and evaluated for symptoms of a Jarisch-
Herxheimer reaction. The symptoms of a Jarisch-Herxheimer reaction include feverishness, chills, myalgia, 
weakness, flushing, worsening of skin rash, tachycardia (i.e., fast heartbeat), heart palpitations, arthralgia, 
nausea, headache, and dizziness. The incidence and severity of each symptom will be reported. 
3.3.4. 
Baseline Value 
The baseline value will be defined as the last value obtained prior to the first dose of study product. If a 
subject did not receive any dose, the enrollment date will be used as the first dose date for any determinations. 
For efficacy outcomes, the baseline value which is simultaneously measured in sera collected throughout 
study participation at a single reference laboratory will be used as baseline when calculating the serological 
response. The HIV status at baseline was determined by a two-step process. Firstly, the participant will be 
asked if she/he has a known HIV positive status, if the answer is yes, then baseline HIV status will be classed 
as  positive. If the participant indicates that their status is not known to them, usually an HIV test is performed 
to determine the HIV status at baseline. But if a HIV test wasn't performed at baseline, the HIV status at 
baseline will be unknown.  


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4. 
INVESTIGATIONAL PLAN 
4.1. 
Overall Study Design and Plan 
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 are 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 is conducted at 10 sites in the US and 
will enroll approximately 560 subjects to achieve 420 evaluable. 
The study involves 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 undergo a brief sexual and medical history and a directed physical examination; all women of 
childbearing potential have a urine or serum pregnancy test performed as part of qualification for study 
participation; all subjects 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 have specimens collected for 
chlamydia and gonorrhea testing. Subjects have specimens collected for other STI testing as indicated by local 
standard of care and subject history. All eligible subjects are 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 24-48 hours after Visit 1 to assess for 
symptoms of a Jarisch-Herxheimer reaction as described in protocol 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 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 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 are 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 protocol Section 5.1); see 
protocol Section 8.2.2. 
Safety is 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) are recorded through Month 1. Safety 
oversight is provided by a Data and Safety Monitoring Board (DSMB) and site Independent Safety Monitors 
(ISMs) as described in protocol Section 9.6. 
While sites perform their own serological testing as needed for subject management, serological testing to 
determine study outcomes and serum banking is performed at the Central Laboratory (University of Alabama 
at Birmingham). 
The duration of the study for each subject is 12 months. Enrollment is expected to be completed in 36 months. 
Table 1 presents the schematic of the study design and Table 2 presents the schedule of events. 


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4.2. 
Discussion of Study Design, Including the Choice of Control Groups 
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. Hence, the 
longer duration of therapy (BPG 2.4 MU weekly for three successive weeks) was to be compared with a 
single dose regimen by the serological response to therapy among persons with or without HIV infection. 
Subjects are randomized at a 1:1 ratio to receive one of the two BPG treatments. 
4.3. 
Selection of Study Population 
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. 
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. 


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**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 
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 any investigational drugs 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. 
4.4. 
Treatments 
4.4.1. 
Treatments Administered  
BPG is administered as a deep IM injection in the upper, outer quadrant of the buttock. Participants are 
randomized using a 1:1 ratio to receive one or the two BPG treatments: 


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• 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 
The dates of first treatment are presented for all subjects who received at least one dose of study product (i.e. 
the Safety Population, defined in Section 6.3.1) by site in Table 3 and treatment group in Table 4. 
4.4.2. 
Identity of Investigational Product(s) 
BPG contains penicillin G benzathine in aqueous suspension with sodium citrate buffer and, as 
weight/volume, approximately 0.5% lecithin, 0.6% carboxymethylcellulose, 0.6% povidone, 0.1% 
methylparaben, and 0.01% propylparaben. Bicillin® L-A suspension in the disposable-syringe formulation is 
viscous and opaque and is available in a 2-mL size containing 1.2 MU BPG per syringe. It is labeled for deep 
IM injection only, not for intravenous (IV) use. 
4.4.3. 
Method of Assigning Subjects to Treatment Groups (Randomization) 
Enrollment of subjects is done online using the enrollment module of Emmes Advantage eClinical®. Subjects 
are 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 uses 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 is by study site. While HIV status may not be 
known at the time of randomization, subjects are classified as HIV-infected or HIV-uninfected to assess the 
secondary HIV status subgroup objective, and randomization is limited as follows: 
• If 280 subjects who were HIV-infected at baseline are confirmed evaluable, additional subjects who 
are known to be HIV-infected are not 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 are allowed to enroll thereafter. 
The list of randomized treatment assignments is prepared by statisticians at Emmes and included in the 
enrollment module of its Internet Data Entry System (IDES). IDES assigns 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. 
4.4.4. 
Selection of Doses in the Study 
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 


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4.4.5. 
Selection and Timing of Dose for Each Subject 
At the time of enrollment, subjects are randomized to receive either one dose of BPG (Arm 1) or three doses 
of BPG over 3 weeks (Arm 2). All eligible subjects will receive a dose of BPG on day 1. Subjects enrolled in 
Arm 2 will also receive a dose of BPG at Visit 2 (Week 1) and a dose of BPG at Visit 3 (Week 2). Subjects in 
Arm 2 should receive the three doses at a minimum of 7-day intervals per the BPG package insert. 
The following describes the dose assigned for each treatment group: 
Study 
Groups 
Visit 1, Day 1 
Visit 2, Week 1  
(Day 7 to 13) 
Visit 3, Week 2  
(6 to 12 days after Visit 2) 
Arm 1 
BPG 2.4 MU injected as two IM 2-
mL injections 
None 
None 
Arm 2 
BPG 2.4 MU injected as two IM 2-
mL injections 
BPG 2.4 MU injected as two IM 2-
mL injections 
BPG 2.4 MU injected as two IM 2-
mL injections 
4.4.6. 
Blinding 
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. 
4.4.7. 
Prior and Concomitant Therapy  
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 protocol Section 5 (Subject Inclusion and Exclusion Criteria) for medications that are prohibited for 
study eligibility and throughout study participation. 
4.5. 
Efficacy (Immunogenicity) and Safety Variables 
For safety and efficacy analyses, multiple observations within specific visit period are accepted. In the case of 
multiple observations within a specific window, the assessment value that is closest to the scheduled visit 
window will be used in the analyses for the post-baseline records, except the RPR data collected from early 
termination at an unscheduled visit could be used for serological response determination in addition to the 
data from the scheduled visits. For screening and baseline visits, the last assessment value will be used. All 


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the recorded data will be listed. If observations have the same distance to the scheduled assessment, the latest 
one will be used.  
Efficacy Variables 
See Section 3.3 for efficacy variable definitions. Serological response is the primary efficacy variable, which 
is defined in Section 3.3.1; The treatment schedule adherence is defined in Section 3.3.2.  
Safety Variables 
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.  
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.  
Severity of Event: All AEs will be assessed by the clinician using a protocol-defined grading system (see 
protocol 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. 


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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. See 
Section 3.3 for efficacy variable definitions.  
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 defined in Section 3.3.3 and 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 protocol Appendix B). 
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, 
•  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. 


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5. 
SAMPLE SIZE CONSIDERATIONS 
5.1. 
Study with Planned Sample Size 
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 subjects. 
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. 
5.2. 
Study with Smaller Sample Size 
When sample size is small, the statistical power will decrease. A simulation study was performed to explore 
the proposed method for the analysis across a small sample sizes.  In particular, data was simulated under the 
following three conditions: 
• Outcome data in both the 1-dose and 3-dose arms sampled from a binomial distribution with rate = 
0.788. 
• Outcome data in the 1-dose arm sampled from a binomial distribution with rate = 0.738, while the 3-
dose arm data was sampled from a distribution with rate = 0.788. 


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• Outcome data in the 1-dose arm sampled from a binomial distribution with rate = 0.688, while the 3-
dose arm data was sampled from a distribution with rate = 0.788. 
• Outcome data in the 1-dose arm sampled from a binomial distribution with rate = 0.588, while the 3-
dose arm data was sampled from a distribution with rate = 0.788. 
For each of the above scenarios, we simulated performing the analysis at the 40% and 50% time point (i.e. 
once we achieve 40% or 50% of the evaluable target). There are multiple ways to construct the futility 
bounds; two alpha-spending methods were explored here: O’Brien-Fleming Analog (OBF), and alpha-time 
(α-Time).   
The table below provides three summaries from the simulation study: 
• The probability of meeting the futility criterion at the analysis with smaller sample size (i.e. the 
probability of demonstrating 3-dose is superior to 1-dose). 
• The probability of making a non-inferiority (NI) claim at the analysis with target sample size. 
• The mean and standard deviation of the conditional power (CP) estimates across all simulated 
scenarios. 
Scenario 
Percent of Target 
Sample size 
Futility Bound 
Method 
Prob. of Meeting 
Futility Criterion 
(%) 
Prob. of NI Claim  
(%) 
Mean (SD) CP at 
Interim  
(%) 
P1 = 0.788 
P3 = 0.788 
40% 
OBF 
<1 
80 
80 (19) 
α-Time 
1 
78 
78 (20) 
50% 
OBF 
<1 
79 
79 (22) 
α-Time 
1 
77 
77 (23) 
P1 = 0.738 
P3 = 0.788 
40% 
OBF 
2 
32 
63 (25) 
α-Time 
5 
30 
60 (25) 
50% 
OBF 
4 
33 
57 (29) 
α-Time 
8 
28 
54 (29) 
P1 = 0.688 
P3 = 0.788 
40% 
OBF 
8 
5.0 
44 (27) 
α-Time 
18 
4.5 
42 (26) 
50% 
OBF 
18 
4.4 
33 (28) 
α-Time 
27 
4.2 
31 (27) 
P1 = 0.588 
P3 = 0.788 
40% 
OBF 
48 
<1 
13 (16) 
α-Time 
66 
<1 
12 (16) 
50% 
OBF 
73 
<1 
5 (11) 
α-Time 
82 
<1 
5 (10) 
The potential outcomes from the above scenarios are: When null hypothesis response rate in one-dose arm is 
0.688 and null hypothesis response rate in three-dose arm: 0.788, as indicated in Section 5.1, the probability 
of claim non-inferiority is less than 5%, and the statistical power is less than 45%. The issue is less that the 


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non-inferiority design is causing issues but more so that the analysis with small sample size is an under-
powered.  


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6. 
GENERAL STATISTICAL CONSIDERATIONS 
6.1. 
General Principles 
Most of the continuous variables will be summarized using the following descriptive statistics: N (non-
missing sample size), mean, standard deviation, median, maximum and minimum. RPR titer will be 
summarized using N (non-missing sample size), Geometric Mean Titer (GMT), and 95% confidence interval. 
The frequency and percentages (based on the non-missing sample size) of observed levels will be reported for 
all categorical measures. Wilson confidence intervals for binomial proportions and differences in binomial 
proportions will be computed for efficacy variables and safety variables. For the hypothesis tests comparing 
treatment groups with respect to the compliance endpoint, the two-sided Pearson Chi-Square test with the 
Yates continuity correction will be used. For the above tests, a 5% two-sided significance level will be used. 
For the hypothesis tests comparing treatment groups with respect to efficacy outcomes, the Farrington-
Manning test at the 5% one-sided level of significance will be used.  A noninferiority hypothesis test will be 
conducted using the Farrington-Manning test at the 5% one-sided level of significance to formally compare 
the treatment arms, that is, whether the one-dose group is non-inferior to the three-dose group.  
For all efficacy outcome measures, the Intent-to-Treat (ITT) population (see Section 6.3) will be used as the 
primary analysis population and the primary analysis will be repeated as a secondary analysis in the mITT and 
the Evaluable analysis populations. The secondary efficacy analyses will be performed in the ITT and 
Evaluable analysis populations. For all safety analyses, the Safety population will be used as the analysis 
population. 
In general, all data will be listed, sorted by site, treatment and subject, and when appropriate by visit number 
within subject. All summary tables will be structured with a column/sub-table for each treatment group in the 
order (One dose BPG 2.4 MU, Three doses BPG 2.4 MU, and All Subjects) and will be annotated with the 
total population size relevant to that table/treatment, including any missing observations.  
Note that in the data listings, Subject ID is the unique subject identifier, not the Study ID used on study and 
dates will not be included, only Study Day. Study Day 1 will be the day of the first dose of treatment. 
6.1.1. 
Pseudo Code 
The following SAS® pseudo code will be used to calculate the following: 
Farrington-Manning test at 5% one-sided significance level and risk difference (and 95% asymptotic CI) from 
2x2 table: 
proc freq; 
table treatment*analysis_variable /riskdiff (noninf margin=.1 method=fm); 
ods output PdiffNoninf=outdn; 
run; 
 
Cochran-Mantel-Haenszel Chi-square test and Breslow-Day test for h x 2 x 2 table: 
proc freq; 
   
Table strata*treatment*analysis_variable / relrisk plots(only)=relriskplot(stats) CMH; 
    
ods output CMH=outputdsn1; 
ods output BreslowDayTest=outputdsn2; 
run; 
 


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Chi-Square test at 5% two-sided significance level and odds ratio (and 95% asymptotic CI) from 2x2 table: 
proc freq; 
   
Table treatment*analysis_variable / chisq; 
    
ods output ChiSq=outputdsn1; 
 
ods output RelativeRisks=outputdsn2; 
run; 
 
95% Wilson CI for proportions/percentages: 
proc freq; 
Table treatment*analysisvariable / binomial(wilson); 
    
ods output binomialcls=outputdsn; 
run; 
 
95% Wilson CI for difference in proportions (produces Newcombe CI): 
proc freq; 
   
Table treatment*analysisvariable / riskdiff(cl=Wilson); 
   
Exact Riskdiff; 
    
ods output pdiffcls=outputdsn; 
run; 
 
t-test for independent samples 
proc ttest sides=2 alpha=0.05; 
 
class HIV_status; 
 
var analysis_variable; 
run; 
 
Logistic Regression 
proc logistic; 
class var_1 var_2 var_3/ param=glm; 
model y = var_1 var_2 var_3; 
run; 
6.2. 
Timing of Analyses 
There is no planned interim analysis of efficacy data. The final analysis for primary, secondary efficacy 
outcomes by Month 6 and safety data will be performed after an interim database lock when all subjects have 
been followed through Visit 6, at month 6 (Window: 180±21 days). The final analysis for all other outcomes 
will be performed after the final database lock when all subjects have been followed through Visit 8, the final 
study visit, at Month 12 (Window: 360±28 days). 
6.3. 
Analysis Populations 
6.3.1. 
Safety Analyses 
All safety analyses will be performed in the safety analysis population. The safety population includes all 
randomized subjects who received at least one dose of study product.  


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6.3.2. 
Efficacy Analyses 
All efficacy analyses will be performed in the Intent-to-Treat population and Evaluable population. The 
primary analysis will be performed in the ITT population and repeated as a secondary analysis in the mITT 
and the Evaluable analysis populations. The secondary efficacy analyses will be performed in the ITT and 
Evaluable populations.  
6.3.2.1. 
Intent-to-Treat Population 
The ITT population includes all randomized subjects, regardless of whether they received study treatment or 
were compliant with the administration procedures or schedule. In the unlikely event of an error in 
randomization or study product administration (such as, incorrect dosing schedule), subjects will be grouped 
by their intended randomized assignment. 
6.3.2.2. 
Modified Intent-to-Treat (mITT) Population  
The mITT population includes all randomized subjects who are eligible at the baseline visit and whose TPPA 
(Treponema pallidum Particle Agglutination) result is positive at the baseline visit and/or at Visit 5 (Month 3), 
if repeat testing was performed.  
6.3.2.3. 
Evaluable Population 
Two Evaluable populations (by Month  6 and by Month 12) are of interest per the primary and secondary 
study endpoints. 
Both Evaluable populations include 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 RPR titer 
data available at baseline and applicable follow-up visit(s) (have RPR test data available at baseline and at 
least one follow-up visit at or before Month 6 visit for the Evaluable population by Month 6; have RPR titer 
data available at baseline and at least one follow-up visits between month 6 and Month 12 visit and (for HIV-
uninfected subjects only) HIV-uninfected status persists through applicable follow-up visit(s). According to 
CDC guideline, an interval of 10-14 days between injections is acceptable, so subjects who receive all doses 
within this interval will be considered as 'received all assigned doses of BPG'.  
If a subject receives antibiotic(s) active against T. pallidum for reasons other than syphilis between enrollment 
and the applicable follow-up visit(s), following situations will be considered:  
a. if a subject has valid baseline and at least one follow-up RPR value before receiving antibiotic(s) 
active against T. pallidum for reasons other than syphilis, those RPR values (or seronegative) prior to 
receiving antibiotic(s) will be kept and used to evaluate the efficacy outcome, and the subject will be 
included in the evaluable population. 
b. if a subject has valid baseline but no follow-up RPR value before (s)he receives antibiotic(s) active 
against T. pallidum for reasons other than syphilis, the subject will be excluded from evaluable 
population. 
c. Receipt of antibiotic(s) active against T. pallidum for reasons other than syphilis will not exclude 
subjects or their data post-antibiotic from the ITT or mITT populations. 
If a subject receives antibiotic(s) active against T. pallidum between enrollment and the applicable follow-up 
visit(s) for retreatment of syphilis, the subject may be included in all analyses if they are otherwise eligible for 


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the analysis.  Those RPR values (or seronegative) prior to and/or on the data of receiving retreatment will be 
kept and used to evaluate the efficacy outcome, those RPR values after receiving retreatment will not be used 
for analysis, and the subject will be included in both ITT and evaluable population. 
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. A separated listing of subjects, their concurrent medications, and their sexual history data 
will be provided to the committee for review. 
In the unlikely event of an error in randomization or study product administration (i.e., incorrect dosing 
schedule), subjects will be grouped by the product they actual received.  
6.3.2.4. 
Analysis Population Summaries 
Table 5 summarizes the ITT and mITT population eligibilities by randomized treatment group and reasons for 
exclusion. Table 6 summarizes the Safety and Evaluable population eligibilities by actual treatment group and 
reasons for exclusion. Subjects will be included in the count for a particular reason for exclusion if they met 
that criterion. As subjects may meet more than one criterion for exclusion, the “Excluded from…” counts may 
be less than the sum of the individual reason counts. A listing of the subjects excluded from each of the 
analysis populations and the reasons for exclusion will be provided (Listing 1).   
6.4. 
 Covariates and Subgroups 
The protocol defines formal subgroup analyses. Subgroups are defined by the baseline HIV status (HIV-
infected and HIV-uninfected). Demographics, baseline characteristics and sexual history will be reported by 
baseline HIV status. The point estimates of the treatment-specific proportions within each HIV status 
subgroup, difference in proportions and corresponding 95% confidence intervals will be reported. For each 
HIV status subgroup, a hypothesis test will be conducted to compare the treatment arms with respect to 
response rate across HIV status subgroups. The homogeneity of odds ratios will be tested to determine if the 
difference between the treatment groups with respect to response rates varies by HIV status. Logistic 
regression analyses will be used to assess the association of treatment with Jarisch-Herxheimer reaction after 
adjusting for HIV co-infection status and time point post-dose. 
6.5. 
Missing Data 
For the primary analysis, serological response is defined by 4-fold or more decline compared to baseline or 
seronegative any visit prior to the end of Month 6 visit window. Though the ITT and mITT populations 
include subjects who may not have adequate serological data to determine their response status for any 
reason, the above definition is equivalent to the Best Case Imputation, which means the lowest RPR value or 
seronegative from the available visits will be used impute the missing values and to evaluate the serological 
response. If there were no follow-up RPR values by the end of month 6 visit window, the missing value will 
be imputed by the baseline value, which is also the best case in the situation. 
As one of the two sensitivity analyses, the primary outcome will be defined based on the last available visit by 
month 6. The Last Observation Carried Forward (LOCF) will be used to impute the missing visit. When a 
subject did not have any follow-up RPR values from the collected data by month 6, we will use the last 
available visit before the end of month 6 visit window to impute the serological response.  


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If a subject missed visits, discontinued treatment or early terminated due to Covid-19, the subject will be 
recorded and reported. Also, another sensitivity analysis will be performed to evaluate the impact by Covid-
19 by removing those subjects who discontinued treatment or early terminated. 
6.6. 
Interim Analyses and Data Monitoring 
There are no planned interim analyses of efficacy data. However, when all enrolled subjects have completed 
the Month 6 visit (or are past the visit window), the efficacy data through Month 6 and all available safety 
data will be locked and all planned analyses for this data will be performed. If a table or figure includes 
summary for both month 6 and post month 6 data, then the table or figure will be generated for locked data at 
month 6 and will then be updated once the final data is available.  
The remainder of the data through Month 12 will be analyzed once all the study data is entered, cleaned, 
monitored and locked. Individual subject listings, which reveal the individual treatment assignments, will only 
be generated at the final analysis after all Month 12 data have been locked. 
The study is monitored to determine if any of the safety halting rules are met. The halting rules are: 
• 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. A summary of halting rules 
is provided in Table 7. DMID retains the authority to suspend additional enrollment and administration of the 
study drug during the entire study, as applicable. 
An ISM at each clinical research site oversees the safety of research subjects at that site and provides 
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 is conducted by a DSMB that is an independent group of experts that monitors subject safety 
and advises DMID. The DSMB members are 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 
consists of members with appropriate expertise to contribute to the interpretation of the data from this trial. 
The DSMB reviews safety and enrollment data when half of the study subjects have been enrolled and 
observed for SAEs through the Month 1 Visit.  
The DSMB reviews 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 operates under the rules of a DMID-approved charter that are written at the organizational 
meeting of the DSMB. As an outcome of each review/meeting, the DSMB makes a recommendation as to the 


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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 is responsible for reviewing SAEs in real time. The DSMB reviews SAEs on a 
regular basis and ad hoc during the study. 
6.7. 
Multicenter Studies 
Safety and efficacy data will be pooled across all clinical sites. Center effects are not anticipated because the 
sites are using standardized procedures for administration of study product and assessment of solicited and 
unsolicited adverse events, and the study relies on the central laboratory for the assessment of serological data 
and clinical efficacy endpoints. 
6.8. 
Multiple Comparisons/Multiplicity 
No adjustments for multiplicity are planned. 


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7. 
STUDY SUBJECTS 
7.1. 
Disposition of Subjects 
The disposition of subjects in the study will be tabulated by randomized treatment group and all subjects. 
Table 8 will present a summary of the reasons that subjects were screened but not enrolled. Table 9 will show 
the number of subjects enrolled, randomized, treated, complied with treatment, completed Month 6 RPR 
blood draw, completed Month 12 RPR blood draw, and completed the study. A listing of subjects who 
terminated early from study or discontinued treatment and the reason for early termination or treatment 
discontinuation will be included in Listing 2. The subjects who terminated early or discontinued treatment due 
to Covid-19 pandemic will be flagged in the listing. 
A flowchart showing the disposition of study subjects, adapted from the CONSORT statement will be 
included (Figure 1). This figure will present the number of subjects screened, enrolled, lost to follow-up, and 
analyzed, by treatment arm. 
7.2. 
Protocol Deviations 
A summary of subject-specific protocol deviations will be presented by the deviation category, the type of 
deviation, and randomized treatment group for all enrolled subjects (Table 10). All subject-specific protocol 
deviations and non-subject-specific protocol deviations will be included in Appendix 3 as data listings 
(Listing 3 and Listing 4, respectively). 
 


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8. 
EFFICACY EVALUATION 
8.1. 
Primary Efficacy Analysis 
For the primary analysis of the comparison of efficacy of one dose versus three doses of BPG 2.4 MU, the 
number and proportion of subjects with serological response and 95% confidence interval will be summarized 
overall and by treatment. The point estimates for the treatment-specific proportion with a one-sided 95% 
confidence interval (CI) will be reported. The difference in proportions and corresponding one-sided 95% CI 
will also be reported. Serological response for the primary analysis is defined in Section 3.3.1. The primary 
analysis will be performed in the ITT population. The primary analysis will be repeated as a secondary 
analysis in the mITT and Evaluable populations.  
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%.  
H0: P3 – P1 ≥ 0.10 
H1: P3 – P1 < 0.10 
The null and alternative hypotheses for the secondary HIV status subgroup objective are defined similarly. 
For the hypothesis tests comparing treatment groups with respect to efficacy outcomes, the Farrington-
Manning test at the 5% one-sided level of significance will be used. 
Table 11 will summarize the primary outcome for ITT, mITT and Evaluable populations. Figure 2, Figure 3, 
and Figure 4 will present the individual efficacy response data at each visit for ITT, mITT and Evaluable 
populations by treatment group by Month 6. Figure 11 will present the Non inferiority test result for the 
primary outcome between two treatment groups by Month 6. Listing 5 will present the individual efficacy 
response data for all randomized subjects. Individual subject listings of TPPA test results (Listing 24) will be 
provided. 
8.1.1. 
Sensitivity Analyses for Primary Efficacy Outcome 
One sensitivity analysis is do the same analysis with primary outcome except removing subjects who early 
terminated from study due to Covid-19 pandemic. The second sensitivity analysis of the Primary outcome will 
be performed with a different definition of the outcome, the last available value prior to Month 6 for each 
subject. The outcome is defined in Section 6.5. Table 31 and Table 32 will present sensitivity analyses, the 
Serological response to Therapy at Month 6 by treatment Group. The analyses will be performed in the ITT, 
mITT, and Evaluable populations. 
8.2. 
Secondary Efficacy Analyses  
The secondary efficacy analyses will be performed in the ITT and Evaluable populations.  
8.2.1. 
Efficacy by 12 Months 
Summaries of the number and proportion of subjects with serological response and difference in proportion 
with 95% Wilson confidence intervals by Month 12 by treatment group in the ITT population and the 
Evaluable population by Month 12 will be presented in Table 12.  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 setup of the noninferiority test will be analogous to that of the primary analysis. Figure 5, and Figure 6 
will present the individual efficacy response data at each visit for ITT, and Evaluable populations by 


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treatment group by Month 12. Figure 12 will present the Non inferiority test result for the primary outcome 
between two treatment groups by Month 12.  
8.2.2. 
Efficacy by 6 Months Among Subjects with and without HIV Infection 
The response rate of the two treatment arms across HIV status subgroups (HIV-infected, HIV-uninfected) will 
be summarized in Table 13 for the ITT and Evaluable populations. The Breslow-Day test for the homogeneity 
of odds ratios and Cochran-Mantel-Haenszel Chi-square test will be used to determine if the difference 
between the two treatment groups with respect to response rates varies by HIV status. 
Table 14 will present the summaries of the number and proportion of subjects with serological response and 
by each timepoint by treatment group in the ITT population. 
Table 15 will present the summaries of the number and proportion of subjects with serological response and 
difference in proportions with 95% Wilson confidence intervals by Month 6 by treatment group and baseline 
HIV status in the ITT population and the Evaluable population by Month 6, respectively.  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 setup of the noninferiority test will be analogous to 
that of the primary analysis, performed within each subgroup. 
Figure 7 and Figure 8 will present the individual efficacy response data at each visit for all randomized 
subjects by treatment group and baseline HIV Status by Month 6 in the ITT, and Evaluable populations. 
Individual subject listings of HIV testing outcomes (Listing 23) will be provided. 
8.2.3. 
Efficacy by 12 Months Among Subjects with and without HIV Infection 
Table 16 will present the summaries of the number and proportion of subjects with serological response and 
difference in proportions with 95% Wilson confidence intervals by Month 12 by treatment group and baseline 
HIV status in the ITT population and the Evaluable population by Month 12, respectively. 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 geometric mean titers and geometric mean fold declines from baseline will be summarized by each visit 
for each treatment group, overall and within HIV status subgroups in the ITT and Evaluable populations 
(Table 17, Table 18, and Table 19). Figure 9 and Figure 10 will present the individual efficacy response data 
at each visit for all randomized subjects by treatment group and baseline HIV Status by Month 12 in the ITT, 
and Evaluable populations. 
8.2.4. 
Treatment Compliance by Treatment Group 
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 group in ITT and Evaluable populations. The point estimates for the treatment-specific proportions 
and difference in proportions as well as corresponding 95% confidence intervals will be presented. 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 (Table 20). Listing 6 will present the individual compliance data for all enrolled 
subjects.  


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8.2.5. 
Demographics and Baseline Characteristics by HIV status 
Categorical and continuous demographics, and baseline socio-epidemiologic characteristics will be 
summarized overall and by baseline HIV status subgroup in the ITT population (Table 21 and Table 22). 
Baseline sexual history will be summarized overall and by baseline HIV status subgroup in the ITT 
populations (Table 23, Table 24). Categorical and continuous sexual history questions through Month 6 and 
Month 12 will be summarized overall and by baseline HIV status subgroup in the ITT and corresponding 
Evaluable populations (Table 25, Table 26, Table 27, Table 28, Table 29, and Table 30). 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.  
Individual subject listing will be presented for all demographics and other baseline socio-epidemiologic 
characteristics (Listing 7). Individual subject listing of baseline and follow-up sexual behavior history for all 
enrolled subjects will be presented in Listing 8 and Listing 9. Sexually Transmitted Disease history at baseline 
for all enrolled subjects will be presented in Listing 10. Sexually Transmitted Infections testing result will be 
present in Listing 11. 
8.3. 
Exploratory Efficacy Analyses 
The exploratory efficacy analysis will be performed to support the primary efficacy analysis by applying the 
alternative serological response classification stated in Section 3.3.1. The serological response will be 
classified into three levels which are Response, Non-Response and Failure. Similar summary as primary 
efficacy analysis will be presented in Table 33 for ITT, mITT and Evaluable populations. 
8.4. 
Clinical Laboratory Evaluations 
RPR test evaluations will be presented in Listing 5. Individual subject listings of HIV testing outcomes 
(Listing 23) and TPPA test results (Listing 24) will be provided. Descriptive statistics for CD4 (Table 49) and 
Viral Load (Table 50), including mean, standard deviation, median, minimum and maximum values by time 
point and actual treatment group will be summarized. 
 


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9. 
SAFETY EVALUATION 
9.1. 
Prior Conditions 
All current illnesses and past pre-existing medical conditions will be MedDRA® coded using MedDRA 
dictionary version 23.1 or higher. Concomitant medications will be coded to the Anatomical Therapeutic 
Classification using the WHO Drug Dictionary. 
9.1.1. 
Prior and Concurrent Medical Conditions 
Summaries of subjects’ pre-existing and concurrent medical conditions will be presented by randomized 
treatment group for the Safety Population (Table 34). An individual subject listing for all enrolled subjects 
will be presented for all medical conditions (Listing 12). 
9.1.2. 
Prior and Concomitant Medications  
The use of prior and concomitant medications taken during the study will be recorded on the CRFs. 
Summaries of medications that were started prior to dosing and continuing at the time of dosing as well as 
medications that were started during dosing or during follow up will be presented by WHO Drug Anatomical 
Codes (ATC) Level 1 and Level 2 and actual treatment group for subjects in the Safety population (Table 35). 
An individual subject listing for all enrolled subjects will be presented for all concomitant medications 
(Listing 13). 
9.2. 
Measurements of Treatment Compliance 
Subjects are randomized to receive either one dose of BPG (Arm 1) or three doses of BPG over 3 weeks (Arm 
2). Subjects are compliant to the treatment if all doses per randomization are received, and the corresponding 
visit days are within the assigned visit window. See Section 3.3.2 for the definition of adherence to scheduled 
visits. See compliance tables for secondary efficacy analyses in Section 8.2. 
The number of subjects not compliant with study treatment will be presented by treatment group as part of the 
subject disposition table (Table 9). An individual subject listing of treatment compliance for all enrolled 
subjects will be provided in Listing 6. 
9.3. 
Adverse Events 
When calculating the incidence of adverse events (i.e., on a per subject basis), each subject will only be 
counted once and any repetitions of adverse events within a subject will be ignored; the denominator will be 
the total safety population size and population within the actual treatment group. AEs/SAEs (including 
solicited reactogenicity AEs and other unsolicited AEs) occurring from the time of study product 
administration through the Month 1 visit are collected. All adverse events reported will be included in the 
summaries and analyses. All analyses in Section 9.3 will be performed in the safety analysis population using 
the actual treatment received. An overall summary of adverse events will be presented in Table 36. 


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9.3.1. 
Solicited Events and Symptoms 
Reactogenicity events are AEs that are common and known to occur for the study drug being studied. For this 
study, 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) will be assessed at the visits specified in protocol Section 7 and will 
be graded on a scale of 1 (mild), 2 (moderate) and 3 (severe) by using a protocol-defined grading system (see 
protocol Appendix B). 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. 
The number and percent of subjects reporting at least one solicited adverse event will be summarized for each 
solicited adverse event along with the 95% Wilson CI and presented in Table 37.  
The number and percentage of subjects reporting each solicited systemic adverse event will be summarized by 
the maximum severity, and actual treatment group along with the 95% Wilson CIs (Table 38). The number 
and percentage of subjects reporting each solicited local adverse event will be summarized by the maximum 
severity, dose, and actual treatment group along with the 95% Wilson CIs (Table 39).  
The percentage of subjects reporting each solicited systemic adverse event (i.e. Jarisch-Herxheimer reaction) 
by maximum severity per subject and Time Post First Dose will be presented in Figure 13. The percentage of 
subjects reporting each solicited systemic adverse event by maximum severity of solicited local symptoms per 
Subject and Dose will be presented in Figure 14.  
Logistic regression analyses will be used to assess the association of treatment with Jarisch-Herxheimer 
reaction after adjusting for HIV co-infection status and onset time post-dose (Table 40). The binary outcome 
is whether the subject experienced any symptoms of the Jarisch-Herxheimer Reaction in the 24-hours 
following Visit 1. The onset time of Jarisch-Herxheimer Reaction is categorized into 0-12 hours, >12-24 
hours, >24-48 hours. Crude and adjusted odds ratios and 95% Wald CIs will be presented.   
Solicited systemic and local reactions by subject will be presented in Listing 14 and Listing 15 . 
9.3.2. 
Unsolicited Adverse Events 
The number of subjects, the proportion of subjects who experienced unsolicited AEs and SAEs following the 
first dose of the study product through Visit 4 (Month 1, Day 30 ± 7 days), and the 95% Wilson CIs for the 
proportion of subjects who experienced unsolicited AEs and SAEs related to study product through Visit 4 
will be presented for the safety population and actual treatment group. Denominators for percentages are the 
number of subjects who received the study product being summarized. 
Unsolicited adverse events by subject will be presented in Listing 16. 
The following summaries for unsolicited adverse events will be presented by MedDRA® system organ class, 
preferred term, and treatment group: 
• Subject incidence and total frequency of adverse events over time by dose with 95% CI (Table 41); 
• Subject incidence and total frequency of related adverse events over time by dose with 95% CI 
(Table 42); 
• Summary of severity and relationship to study product for the unsolicited adverse events (Table 43);  


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• Subject incidence and percentage by maximum severity and maximum relationship to study product 
for all subjects (Table 44); 
• The number of adverse events occurring in ≥ 5% of subjects in any treatment group (Table 45, 
Table 46); 
• Subject listing of serious adverse events (Table 47); 
• Subject listing of non-serious adverse events of moderate or greater severity (Table 48); 
• Bar chart of total frequency of adverse events by severity and MedDRA® system organ class 
(Figure 15); 
• Bar chart of subject incidence of adverse events by severity and MedDRA® system organ class 
(Figure 16); 
• Bar chart of total frequency of adverse events by relationship to study product and MedDRA® system 
organ class (Figure 17); 
• Bar chart of subject incidence of adverse events by relationship to study product and MedDRA® 
system organ class (Figure 18); 
9.4. 
Deaths, Serious Adverse Events and other Significant Adverse Events 
A listing of deaths and serious adverse events will be presented including Subject ID, treatment group, 
Adverse Event Description, Dose Number Associated with, SAE onset day and duration post associated dose, 
Reason Reported as an SAE, Relationship to Treatment, Alternate Etiology if Not Related, Outcome, and 
Duration of Event in days (Table 47). 
9.5. 
Pregnancies 
For any subjects in the Safety population who became pregnant during the study, every attempt will be made 
to follow these subjects to completion of pregnancy to document the outcome, including information 
regarding any complications with pregnancy and/or delivery. Listings of pregnancies and outcomes, including 
the total pregnancies, number of live births, and number of spontaneous abortions, elective abortions or still 
births will be presented (Listing 17, Listing 18, Listing 19, Listing 20, and Listing 21). 
9.6. 
Vital Signs and Physical Evaluations 
At Visit 2 and Visit 3, subjects will be evaluated for resolution of signs of syphilis documented at Visit 1. An 
individual subject listing of syphilis signs by visits 1, 2 and 3 will be presented (Listing 22). 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. Each vital sign for subjects in the 
Safety Population will be summarized by visit, treatment group and grading of severity (Table 51, Table 52, 
Table 53, Table 54, and Table 55). Subject listings will be provided for HIV test result (Listing 23), TPPA test 
result (Listing 24), vital signs (Listing 25) and physical exam findings (Listing 26).  
9.7. 
Other Safety Measures 
N/A 


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10. 
PHARMACOKINETICS 
N/A 
 


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11. 
IMMUNOGENICITY 
N/A 
 


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12. 
OTHER ANALYSES 
N/A 
 


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13. 
REPORTING CONVENTIONS 
P-values ≥0.001 and ≤0.999 will be reported to three decimal places; p-values less than 0.001 will be reported 
as “<0.001”; p-values greater than 0.999 will be reported as “> 0.999“. The mean, median, standard deviation, 
and any other statistics other than quantiles, will be reported to one decimal place greater than the original 
data. Quantiles other than the median will use the same number of decimal places as the original data. 
Proportions will be presented to two decimal places; values <0.01 will be presented as “<0.01”. Percentages 
will be reported to the nearest whole number; values < 1% will be presented as “<1”. Estimated parameters, 
not on the same scale as raw observations (e.g. regression coefficients) will be reported to three significant 
figures. 


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14. 
TECHNICAL DETAILS 
SAS version 9.4 or above will be used to generate all tables, figures and listings. 


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15. 
SUMMARY OF CHANGES IN THE CONDUCT OF THE STUDY OR 
PLANNED ANALYSES 
There are no changes in the conduct of the study or planned analyses. 


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16. 
REFERENCES 
1. Drummond R. CONSORT Revised: Improving the Reporting of Randomized Clinical Trials. JAMA. 
2001; 285(15):2006-2007. 
2. Hook, E.W., Syphilis. Lancet, 2017. 389(10078): p. 1550-1557. 
3. CDC Sexually transmitted disease surveillance 2016. 2017, U.S. Department of Health 
and Human Services: Atlanta. 
4. CDC Sexually transmitted disease surveillance 2015. 2016, U.S. Department of Health 
and Human Services: Atlanta. 
5. CDC Sexually transmitted disease surveillance 2012. 2013, U.S. Department of Health 
and Human Services: Atlanta. 
6.  Workowski, K.A. and G.A. Bolan, Sexually transmitted diseases treatment guidelines, 
2015. MMWR Recomm Rep, 2015. 64(Rr-03): p. 1-137. 
7. 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. 
8. 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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17. 
LISTING OF TABLES, FIGURES, AND LISTINGS  
Table, figure, and listing shells are presented in Appendices 1, 2, and 3. 
 


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APPENDICES 


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APPENDIX 1. TABLE MOCK-UPS 
LIST OF TABLES 
Table 1: 
Study Design ...............................................................................................................43 
Table 2: 
Schedule of Study Procedures ....................................................................................44 
Table 3: 
Dates of First Treatment by Site – Safety Population ................................................46 
Table 4: 
Dates of First Treatment by Treatment Group - Safety Population ............................47 
Table 5: 
ITT and mITT Analysis Population Eligibilities by Treatment Group - All 
Enrolled subjects .........................................................................................................48 
Table 6: 
Safety and Evaluable Population Eligibilities by Treatment Group ...........................49 
Table 7: 
Summary of Halting Rules - Safety Population .........................................................51 
Table 8: 
Summary of Screen Failures .......................................................................................52 
Table 9: 
Subject Disposition by Treatment Group- All Enrolled Subjects ..............................53 
Table 10: Distribution of Protocol Deviations by Category, Type, and Treatment 
Group – All Enrolled subjects ....................................................................................54 
Table 11: Serological Response to Therapy by Month 6 by Treatment Group ..........................55 
Table 12: Serological Response to Therapy by Month 12 by Treatment Group ........................56 
Table 13: Summary Statistics for Comparison of Treatment Groups with Respect to 
Response Rate across Baseline HIV Status by Month 6 ............................................57 
Table 14: Serological Response to Therapy by Each Timepoint by Treatment Group - 
ITT Population ............................................................................................................58 
Table 15: Serological Response to Therapy by Month 6 by Treatment Group and 
Baseline HIV Status ....................................................................................................59 
Table 16: Serological Response to Therapy at Month 12 by Treatment Group and 
Baseline HIV Status ....................................................................................................59 
Table 17: RPR Geometric Mean Titer (GMT) and RPR Geometric Mean Fold Decline 
(GMFD) by Visit, Treatment Group and Baseline HIV Status — ITT 
Population ...................................................................................................................60 
Table 18: RPR Geometric Mean Titer (GMT) and RPR Geometric Mean Fold Decline 
(GMFD) by Visit, Treatment Group and Baseline HIV Status— Evaluable 
Population by Month 6 ...............................................................................................61 
Table 19: RPR Geometric Mean Titer (GMT) and RPR Geometric Mean Fold Decline 
(GMFD) by Visit, Treatment Group and Baseline HIV Status— Evaluable 
Population by Month 12 .............................................................................................61 
Table 20: Subjects Compliant with Study Product by Treatment Group ...................................62 


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Table 21: Summary of Categorical Demographics and Socio-epidemiologic 
Characteristics at Baseline by HIV Status and Treatment Group — ITT 
Population ...................................................................................................................63 
Table 22: Summary of Continuous Demographics and Socio-epidemiologic 
Characteristics at Baseline by HIV Status and Treatment Group — ITT 
Population ...................................................................................................................64 
Table 23: Summary of Categorical Sexual History at Baseline by HIV Status and 
Treatment Group — ITT Population ..........................................................................65 
Table 24: Summary of Continuous Sexual History at Baseline by HIV Status and 
Treatment Group — ITT Population ..........................................................................68 
Table 25: Summary of Categorical Sexual History through Month 6 by Baseline HIV 
Status and Treatment Group— ITT Population ..........................................................70 
Table 26: Summary of Categorical Sexual History through Month 12 by Baseline HIV 
Status and Treatment Group — ITT Population .........................................................71 
Table 27: Summary of Categorical Sexual History through Month 6 by Baseline HIV 
Status and Treatment Group — Evaluable Population by Month 6 ...........................71 
Table 28: Summary of Categorical Sexual History through Month 12 by Baseline HIV 
Status and Treatment Group — Evaluable Population by Month 12 .........................71 
Table 29: Summary of Continuous Sexual History through Month 6 by Baseline HIV 
Status and Treatment Group .......................................................................................72 
Table 30: Summary of Continuous Sexual History through Month 12 by Baseline HIV 
Status and Treatment Group .......................................................................................72 
Table 31: Sensitivity analysis 1 - Serological Response to Therapy at Month 6 by 
Treatment Group – Removing Early Termination Due to COVID ............................73 
Table 32: Sensitivity analysis 2 - Serological Response to Therapy at Month 6 by 
Treatment Group – Re-defined Serological Response ...............................................74 
Table 33: Exploratory Analysis---Serological Response to Therapy by Month 6 by 
Treatment Group .........................................................................................................75 
Table 34: Summary of Subjects with Pre-Existing Medical Conditions by MedDRA 
System Organ Class and Treatment Group - Safety Population .................................76 
Table 35: Number and Percentage of Subjects with Prior and Concomitant 
Medications by WHO Drug Classification and Treatment Group - Safety 
Population ...................................................................................................................77 
Table 36: Overall Summary of Adverse Events - Safety Population .........................................78 
Table 37: Number and Percentage of Subjects Experiencing Solicited Events with 95% 
Confidence Intervals by Symptom and Treatment Group — Safety 
Population ...................................................................................................................79 


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Table 38: Number and Percentage of Subjects Experiencing Solicited Systemic Events 
by Symptom, Maximum Severity and Treatment Group — Safety Population .........80 
Table 39: Number and Percentage of Subjects Experiencing Solicited Local Events 
with 95% Confidence Intervals by Symptom, Maximum Severity, Dose, and 
Treatment Group — Safety Population ......................................................................83 
Table 40: The Association of Treatment with Jarisch-Herxheimer Reaction after 
Adjusting for HIV Co-infection status and Jarisch-Herxheimer Reaction 
(JHR) Onset Time Post-dose by Logistic Regression - Safety Population ................85 
Table 41: Number and Percentage of Subjects Experiencing Unsolicited Adverse 
Events with 95% Confidence Intervals by MedDRA System Organ Class 
and Preferred Term, Dose Number, and Treatment Group — Safety 
Population ...................................................................................................................86 
Table 42: Number and Percentage of Subjects Experiencing Related Unsolicited 
Adverse Events with 95% Confidence Intervals by MedDRA System Organ 
Class and Preferred Term, Dose Number, and Treatment Group — Safety 
Population ...................................................................................................................86 
Table 43: Number of Unsolicited Adverse Events by MedDRA System Organ Class 
and Preferred Term, Maximum Severity and Relationship, and Treatment 
Group — Safety Population ........................................................................................87 
Table 44: Number and Percentage of Subjects Experiencing Unsolicited Adverse 
Events by MedDRA System Organ Class and Preferred Term, Maximum 
Severity and Relationship, and Treatment Group — Safety Population ....................88 
Table 45: Unsolicited Adverse Events Occurring in ≥5% of Subjects in Any Treatment 
Group by MedDRA System Organ Class, Preferred Term, and Treatment 
Group - Safety Population ..........................................................................................89 
Table 46: Solicited Adverse Events Occurring in ≥5% of Subjects in Any Treatment 
Group by MedDRA System Organ Class, Preferred Term, and Treatment 
Group - Safety Population ..........................................................................................89 
Table 47: Listing of Serious Adverse Events – All Enrolled Subjects .......................................90 
Table 48: Listing of Non-Serious, Unsolicited Adverse Events – All Enrolled Subjects ..........91 
Table 49: Laboratory Summary Statistics by Time Point and Treatment Group – CD4 
Count in HIV-infected Subjects ..................................................................................93 
Table 50: Laboratory Summary Statistics by Time Point and Treatment Group – Viral 
Load in HIV-infected Subjects ...................................................................................94 
Table 51: Vital Signs by Maximum Severity, Time Point, and Treatment Group – Any 
Assessment – Safety Population .................................................................................95 
Table 52: Vital Signs by Maximum Severity, Time Point, and Treatment Group – 
Temperature – Safety Population ...............................................................................95 


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Table 53: Vital Signs by Maximum Severity, Time Point, and Treatment Group – 
Blood Pressure – Safety Population ...........................................................................95 
Table 54: Vital Signs by Maximum Severity, Time Point, and Treatment Group – 
Pulse – Safety Population ...........................................................................................95 
Table 55: Vital Signs by Maximum Severity, Time Point, and Treatment Group – 
Respiration – Safety Population .................................................................................95 


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Table 1: 
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  
 
Study Visit 6 
Month 6 
 
 
Study Visit 7 
Month  
 
 
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 
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 count on HIV-infected subjects 
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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Table 2: 
Schedule of Study Procedures 
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 


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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 
(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 and 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 exposure for STI testing per local standard of care and subject history. 
9 It is optional to swab subject’s oral cavity and lesions, if lesions are present. See protocol 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 protocol 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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Table 3: 
Dates of First Treatment by Site – Safety Population 
[Implementation Note:  Dates will be categorized based on length of enrollment period; try breaking the calendar year into halves first, if too many rows, 
will discuss and adjust the length.] 
Dates of Dosing 
Site 1 
(N = X) 
Site 2 
(N = X) 
… 
All Subjects 
(N = X) 
n 
% 
n 
% 
… 
n 
% 
DDMMMYYYY-DDMMMYYYY 
x 
x 
x 
x 
… 
x 
x 
DDMMMYYYY-DDMMMYYYY 
x 
x 
x 
x 
… 
x 
x 
DDMMMYYYY-DDMMMYYYY 
x 
x 
x 
x 
… 
x 
x 
DDMMMYYYY-DDMMMYYYY 
x 
x 
x 
x 
… 
x 
x 
Note: N=Number of subjects in the safety population 
 


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Table 4: 
Dates of First Treatment by Treatment Group - Safety Population 
[Implementation Note:  Dates will be categorized based on length of enrollment period; try breaking the calendar year into halves first, if too many rows, 
will discuss and adjust the length.] 
Dates of Dosing 
One Dose BPG 2.4 MU 
(N = X) 
Three Doses BPG 2.4 MU 
(N = X) 
All Subjects 
(N = X) 
n 
% 
n 
% 
n 
% 
DDMMMYYYY-DDMMMYYYY 
x 
x 
x 
x 
x 
x 
DDMMMYYYY-DDMMMYYYY 
x 
x 
x 
x 
x 
x 
DDMMMYYYY-DDMMMYYYY 
x 
x 
x 
x 
x 
x 
DDMMMYYYY-DDMMMYYYY 
x 
x 
x 
x 
x 
x 
Note: N=Number of subjects in the safety population 
 


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Table 5: 
ITT and mITT Analysis Population Eligibilities by Treatment Group - All Enrolled subjects 
 
 
One Dose BPG 2.4 MU 
(N = X) 
Three Doses BPG 2.4 MU 
(N = X) 
All Subjects 
(N=X) 
Analysis Population 
Eligibility Category 
Reason Subjects Excluded 
n 
% 
n 
% 
n 
% 
Intent-to-Treat Analysis Population 
Eligible for ITT Population 
N/A 
x 
100 
x 
100 
x 
100 
Excluded from ITT Population 
Any Reason 
x 
- 
x 
- 
x 
- 
Failed screening 
x 
- 
x 
- 
x 
- 
Modified Intent-to-Treat Analysis 
Population 
Eligible for mITT Population 
N/A 
x 
xx 
x 
xx 
x 
xx 
Excluded from mITT Population 
Any Reason 
x 
xx 
x 
xx 
x 
xx 
not eligible at the baseline visit 
x 
xx 
x 
xx 
x 
xx 
Did not have a positive TPPA result 
at the baseline visit and/or at Visit 5 
(Month 3), if repeat testing was 
performed 
x 
xx 
x 
xx 
x 
xx 
Notes: N, the denominator of percentages is the number of enrolled subjects in the specified treatment.  
Treatment group is the intended randomized group. 
Refer to Listing 1 for subjects who are excluded from the Analysis populations. 


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Table 6: 
Safety and Evaluable Population Eligibilities by Treatment Group 
 
 
One Dose BPG 2.4 
MU 
(N = X) 
Three Doses BPG 
2.4 MU 
(N = X) 
All Subjects 
(N=X) 
Analysis Population 
Eligibility Category 
Reason Subjects Excluded 
n 
% 
n 
% 
n 
% 
Safety Analysis Population 
Eligible for Safety 
Population 
N/A 
x 
x 
x 
x 
x 
x 
Excluded from Safety 
Population 
Any Reason 
x 
x 
x 
x 
x 
x 
Did not receive at least one dose of study product 
x 
x 
x 
x 
x 
x 
Evaluable Analysis Population 
by Month 6 
Eligible for Evaluable 
Population by Month 6 
N/A 
x 
x 
x 
x 
x 
x 
Excluded from Evaluable 
Population by Month 6 
Any Reason 
x 
x 
x 
x 
x 
x 
HIV status unknown at the baseline visit 
x 
x 
x 
x 
x 
x 
Did not have a positive TPPA result at the baseline visit and/or at 
Visit 5 (Month 3), if repeat testing was performed 
x 
x 
x 
x 
x 
x 
Did not receive all assigned doses of BPG 
x 
x 
x 
x 
x 
x 
Did not have adequate RPR titer data available at baseline and 
applicable follow-up visit(s) by Month 6 
x 
x 
x 
x 
x 
x 
Received antibiotic(s) active against T. pallidum between 
enrollment and the applicable follow-up visit(s) by Month 6 for 
reasons other than syphilis infectiona 
x 
x 
x 
x 
x 
x 
HIV-uninfected status did not persist through applicable follow-up 
visit(s) by Month 6 (for HIV-uninfected subjects only) 
x 
x 
x 
x 
x 
x 
Evaluable Analysis Population 
by Month 12 
Eligible for Evaluable 
Population by Month 12 
N/A 
x 
x 
x 
x 
x 
x 
Excluded from Evaluable 
Population by Month 12 
Any Reason 
x 
x 
x 
x 
x 
x 
HIV status unknown at or before the baseline visit 
x 
x 
x 
x 
x 
x 
Did not have a positive TPPA result at the baseline visit and/or at 
Visit 5 (Month 3), if repeat testing was performed 
x 
x 
x 
x 
x 
x 
Did not receive all assigned doses of BPG 
x 
x 
x 
x 
x 
x 
Did not have adequate RPR titer data available at baseline and 
applicable follow-up visit(s) by Month 12 
x 
x 
x 
x 
x 
x 


Statistical Analysis Plan - DMID Protocol: 17-0101 
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One Dose BPG 2.4 
MU 
(N = X) 
Three Doses BPG 
2.4 MU 
(N = X) 
All Subjects 
(N=X) 
Analysis Population 
Eligibility Category 
Reason Subjects Excluded 
n 
% 
n 
% 
n 
% 
Received antibiotic(s) active against T. pallidum between 
enrollment and the applicable follow-up visit(s) by Month 12 a 
x 
x 
x 
x 
x 
x 
HIV-uninfected status did not persist through applicable follow-up 
visit(s) by Month 12 (for HIV-uninfected subjects only) 
x 
x 
x 
x 
x 
x 
Notes: Denominator of percentages is the number of enrolled subjects in the specified treatment group. N=number of enrolled subjects in the specified treatment group 
Treatment group is the actual treatment a subject received. 
Refer to Listing 1 for subjects who are excluded from the Analysis populations. 
a A blinded case review committee reviewed subjects’ data and determined if the antibiotics use effect the subjects’ inclusion eligibility in evaluable populations. 
 


Statistical Analysis Plan - DMID Protocol: 17-0101 
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Table 7: 
Summary of Halting Rules - Safety Population 
Halting Rules 
Halting Rule Triggered (Yes/No) 
# Contributing to Halting Rule/ Total 
Needed to Halt 
If one or more subjects experience an SAE judged by an investigator to be related to the study drug 
Yes/No 
x/1 
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 
Yes/No 
x/1 


Statistical Analysis Plan - DMID Protocol: 17-0101 
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Table 8: 
Summary of Screen Failures 
Inclusion/Exclusion Category 
Inclusion/Exclusion Criterion 
na 
%b 
Inclusion and Exclusion 
Number of subjects failing any eligibility criterion 
x 
100 
Inclusion 
Any inclusion criterion 
x 
xx 
 
[inclusion criterion 1] 
x 
xx 
 
[inclusion criterion 2] 
x 
xx 
 
[inclusion criterion 3] 
x 
xx 
Exclusion 
Any exclusion criterion 
x 
xx 
 
[exclusion criterion 1] 
x 
xx 
 
[exclusion criterion 2] 
x 
xx 
 
[exclusion criterion 3] 
x 
xx 
a More than one criterion may be marked per subject. 
b Denominator for percentages is the total number of screen failures. 


Statistical Analysis Plan - DMID Protocol: 17-0101 
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Table 9: 
Subject Disposition by Treatment Group- All Enrolled Subjects 
Subject 
Disposition  
One Dose BPG 2.4 MU 
(N = X) 
Three Doses BPG 2.4 MU 
(N = X) 
All Subjects 
(N=X) 
n 
% 
n 
% 
n 
% 
Screened 
N/A 
N/A 
N/A 
N/A 
x 
N/A 
Enrolled/Randomized 
x 
100 
x 
100 
x 
100 
Received the First Dose of Treatment 
x 
xx 
x 
xx 
x 
xx 
Received All Scheduled Treatmenta 
x 
xx 
x 
xx 
x 
xx 
Complied with Treatmentb 
x 
xx 
x 
xx 
x 
xx 
Completed Month 6 RPR Blood Draw   
x 
xx 
x 
xx 
x 
xx 
Completed Month 12 RPR Blood Draw   
x 
xx 
x 
xx 
x 
xx 
Completed Follow-up Visit 8 – Month 12 (Day 360±28 days)a 
x 
xx 
x 
xx 
x 
xx 
Notes: N=Number of enrolled subjects in the specified treatment group. 
a Refer to Listing 2 for reasons subjects discontinued or terminated early. 
b Subjects are considered compliant to the treatment if subjects receive all assigned doses within the assigned visit windows. 
 


Statistical Analysis Plan - DMID Protocol: 17-0101 
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Table 10: 
Distribution of Protocol Deviations by Category, Type, and Treatment Group – All 
Enrolled subjects 
Category 
Deviation Type 
One Dose BPG 2.4 
MU 
(N = X) 
Three Doses BPG 2.4 
MU 
(N = X) 
All Subjects 
(N=X) 
No. of 
Subj. 
No. of 
Dev. 
No. of 
Subj. 
No. of 
Dev. 
No. of 
Subj. 
No. of 
Dev. 
Treatment 
administration schedule 
Any type 
x 
x 
x 
x 
x 
x 
 
Out of window visit 
x 
x 
x 
x 
x 
x 
 
Missed visit/visit not conducted 
x 
x 
x 
x 
x 
x 
 
Missed treatment administration 
x 
x 
x 
x 
x 
x 
 
Delayed treatment administration 
x 
x 
x 
x 
x 
x 
 
Other 
x 
x 
x 
x 
x 
x 
Follow-up visit 
schedule 
Any type 
x 
x 
x 
x 
x 
x 
 
Out of window visit 
x 
x 
x 
x 
x 
x 
 
Missed visit/visit not conducted 
x 
x 
x 
x 
x 
x 
 
Other 
x 
x 
x 
x 
x 
x 
Protocol 
procedure/assessment 
Any type 
x 
x 
x 
x 
x 
x 
 
Incorrect version of ICF signed 
x 
x 
x 
x 
x 
x 
 
Blood not collected 
x 
x 
x 
x 
x 
x 
 
Other specimen not collected 
x 
x 
x 
x 
x 
x 
 
Too few aliquots obtained 
x 
x 
x 
x 
x 
x 
 
Specimen result not obtained 
x 
x 
x 
x 
x 
x 
 
Required procedure not conducted 
x 
x 
x 
x 
x 
x 
 
Required procedure done incorrectly 
x 
x 
x 
x 
x 
x 
 
Study product temperature excursion 
x 
x 
x 
x 
x 
x 
 
Specimen temperature excursion 
x 
x 
x 
x 
x 
x 
 
Other 
x 
x 
x 
x 
x 
x 
Treatment 
administration 
Any type 
x 
x 
x 
x 
x 
x 
 
Required procedure done incorrectly 
x 
x 
x 
x 
x 
x 
 
Study product temperature excursion 
x 
x 
x 
x 
x 
x 
 
Other 
x 
x 
x 
x 
x 
x 
Note: N=Number of enrolled subjects randomized to the specified treatment group.  
 
 


Statistical Analysis Plan - DMID Protocol: 17-0101 
Version 1.0 
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Table 11: 
Serological Response to Therapy by Month 6 by Treatment Group  
Population  
Treatment Group* 
Number of Subjects 
with Serological 
Response, n 
Number of Subjects, 
N 
Proportion of Subjects with 
Serological Response (95% 
CI)a 
Difference in Proportion of Subjects 
with Serological Response Between 
Two Treatment Groups (95% CI)a 
P-Valueb 
ITT Population 
One Dose BPG 2.4 MU 
xxx 
xxx 
0.xx(0.xx, 0.xx) 
0.xx(0.xx, 0.xx) 
0.xxx 
Three Doses BPG 2.4 MU 
xxx 
xxx 
0.xx(0.xx, 0.xx) 
mITT Population 
One Dose BPG 2.4 MU 
xxx 
xxx 
0.xx(0.xx, 0.xx) 
0.xx(0.xx, 0.xx) 
0.xxx 
Three Doses BPG 2.4 MU 
xxx 
xxx 
0.xx(0.xx, 0.xx) 
Evaluable 
Population 
One Dose BPG 2.4 MU 
xxx 
xxx 
0.xx(0.xx, 0.xx) 
0.xx(0.xx, 0.xx) 
0.xxx 
Three Doses BPG 2.4 MU 
xxx 
xxx 
0.xx(0.xx, 0.xx) 
aThe denominator for proportion is based on the number of subjects enrolled in the specified treatment group and analysis population. 95% CI = 95% Wilson Confidence Interval 
b P-value is calculated based on the noninferiority analysis for the proportion difference (one-dose group is non-inferior to three-dose group) by Farrington-Manning method with a 10% margin. 
*Treatment group is the intended randomized group for ITT and mITT populations. Treatment group is the actual treatment a subject received for the Evaluable population. 


Statistical Analysis Plan - DMID Protocol: 17-0101 
Version 1.0 
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Table 12: 
Serological Response to Therapy by Month 12 by Treatment Group  
Population  
Treatment Group 
Number of 
Subjects with 
Serological 
Response, n 
Number of 
Subjects, N 
Proportion of Subjects 
with Serological Response 
(95% CI)a 
Difference in Proportion of Subjects 
with Serological Response Between 
Two Treatment Groups (95% CI) 
P-Valueb 
ITT Population 
One Dose BPG 2.4 MU 
xxx 
xxx 
0.xx(0.xx, 0.xx) 
0.xx(0.xx, 0.xx) 
0.xxx 
Three Doses BPG 2.4 MU 
xxx 
xxx 
0.xx(0.xx, 0.xx) 
Evaluable 
Population 
One Dose BPG 2.4 MU 
xxx 
xxx 
0.xx(0.xx, 0.xx) 
0.xx(0.xx, 0.xx) 
0.xxx 
Three Doses BPG 2.4 MU 
xxx 
xxx 
0.xx(0.xx, 0.xx) 
aThe denominator for proportion is based on the number of subjects enrolled in the specified treatment group and analysis population. 95% CI = 95% Wilson Confidence Interval 
b P-value is calculated based on the noninferiority analysis for the proportion difference (one-dose group is non-inferior to three-dose group) by Farrington-Manning method with a 10% margin. 
*Treatment group is the intended randomized group for ITT population. Treatment group is the actual treatment a subject received for the Evaluable population. 


Statistical Analysis Plan - DMID Protocol: 17-0101 
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22DEC2022 
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Table 13: 
Summary Statistics for Comparison of Treatment Groups with Respect to Response Rate across Baseline HIV Status by Month 6 
Population  
Test Method 
Statistic 
Result 
ITT Population 
Cochran-Mantel-Haenszel Test 
Relative Risk - HIV positive (95% CI) 
x.xxx(x.xxx, x.xxx) 
Relative Risk - HIV negative (95% CI) 
x.xxx(x.xxx, x.xxx) 
Common Relative Riska (95% CI) 
x.xxx(x.xxx, x.xxx) 
P-value 
0.xxx 
Breslow-Day Test for 
Homogeneity of the Odds Ratios 
Common Odds Ratio 
x.xxx(x.xxx, x.xxx) 
P-value 
0.xxx 
Evaluable Population 
Cochran-Mantel-Haenszel Test 
Relative Risk - HIV positive (95% CI) 
x.xxx(x.xxx, x.xxx) 
Relative Risk - HIV negative (95% CI) 
x.xxx(x.xxx, x.xxx) 
Common Relative Riska (95% CI) 
x.xxx(x.xxx, x.xxx) 
P-value 
0.xxx 
Breslow-Day Test for 
Homogeneity of the Odds Ratios 
Common Odds Ratio 
x.xxx(x.xxx, x.xxx) 
P-value 
0.xxx 
a The denominator for proportion is based on the number of subjects enrolled in the specified treatment group, HIV status and analysis population. The numerator is the number of subjects who were 
responders in in the specified treatment group, HIV status and analysis population. 


Statistical Analysis Plan - DMID Protocol: 17-0101 
Version 1.0 
22DEC2022 
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Table 14: 
Serological Response to Therapy by Each Timepoint by Treatment Group - ITT Population 
Time 
Treatment Group 
Number of Subjects with Serological 
Response, n 
Number of Subjects, N 
Proportion of Subjects with Serological 
Response (95% CI)a 
Week 1 
One Dose BPG 2.4 MU 
xxx 
xxx 
0.xx(0.xx, 0.xx) 
 
Three Doses BPG 2.4 MU 
xxx 
xxx 
0.xx(0.xx, 0.xx) 
Week 2 
One Dose BPG 2.4 MU 
xxx 
xxx 
0.xx(0.xx, 0.xx) 
 
Three Doses BPG 2.4 MU 
xxx 
xxx 
0.xx(0.xx, 0.xx) 
Week 3 
One Dose BPG 2.4 MU 
xxx 
xxx 
0.xx(0.xx, 0.xx) 
 
Three Doses BPG 2.4 MU 
xxx 
xxx 
0.xx(0.xx, 0.xx) 
Month 1 
One Dose BPG 2.4 MU 
xxx 
xxx 
0.xx(0.xx, 0.xx) 
 
Three Doses BPG 2.4 MU 
xxx 
xxx 
0.xx(0.xx, 0.xx) 
Month 3 
One Dose BPG 2.4 MU 
xxx 
xxx 
0.xx(0.xx, 0.xx) 
 
Three Doses BPG 2.4 MU 
xxx 
xxx 
0.xx(0.xx, 0.xx) 
Month 6 
One Dose BPG 2.4 MU 
xxx 
xxx 
0.xx(0.xx, 0.xx) 
 
Three Doses BPG 2.4 MU 
xxx 
xxx 
0.xx(0.xx, 0.xx) 
Month 9 
One Dose BPG 2.4 MU 
xxx 
xxx 
0.xx(0.xx, 0.xx) 
 
Three Doses BPG 2.4 MU 
xxx 
xxx 
0.xx(0.xx, 0.xx) 
Month 12 
One Dose BPG 2.4 MU 
xxx 
xxx 
0.xx(0.xx, 0.xx) 
 
Three Doses BPG 2.4 MU 
xxx 
xxx 
0.xx(0.xx, 0.xx) 
aThe denominator for proportion is based on the number of subjects enrolled in the specified treatment group and analysis population. 95% CI = 95% Wilson Confidence Interval 


Statistical Analysis Plan - DMID Protocol: 17-0101 
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Table 15: 
Serological Response to Therapy by Month 6 by Treatment Group and Baseline HIV Status  
Population 
Baseline HIV Status 
Treatment Group 
Number of Subjects 
with Serological 
Response, n 
Number of 
Subjects, N 
Proportion of Subject with 
Serological Response (95% 
CI) 
Difference in Proportion of 
Subjects with Serological 
Response Between Two 
Treatment Groups 
ITT Population 
HIV-infected 
One Dose BPG 2.4 MU 
xxx 
xxx 
0.xx (0.xx, 0.xx) 
0.xx (0.xx, 0.xx) 
Three Doses BPG 2.4 MU 
xxx 
xxx 
0.xx (0.xx, 0.xx) 
All Subjects 
xxx 
xxx 
0.xx (0.xx, 0.xx) 
N/A 
HIV-uninfected 
One Dose BPG 2.4 MU 
xxx 
xxx 
0.xx (0.xx, 0.xx) 
0.xx (0.xx, 0.xx) 
Three Doses BPG 2.4 MU 
xxx 
xxx 
0.xx (0.xx, 0.xx) 
All Subjects 
xxx 
xxx 
0.xx (0.xx, 0.xx) 
N/A 
Evaluable Population 
HIV-infected 
One Dose BPG 2.4 MU 
xxx 
xxx 
0.xx (0.xx, 0.xx) 
0.xx (0.xx, 0.xx) 
Three Doses BPG 2.4 MU 
xxx 
xxx 
0.xx (0.xx, 0.xx) 
All Subjects 
xxx 
xxx 
0.xx (0.xx, 0.xx) 
N/A 
HIV-uninfected 
One Dose BPG 2.4 MU 
xxx 
xxx 
0.xx (0.xx, 0.xx) 
0.xx (0.xx, 0.xx) 
Three Doses BPG 2.4 MU 
xxx 
xxx 
0.xx (0.xx, 0.xx) 
All Subjects 
xxx 
xxx 
0.xx (0.xx, 0.xx) 
N/A 
Notes: The denominator for proportion is based on the number of subjects enrolled in the respective treatment group and analysis population. 
95% CI= 95% Wilson Confidence Interval 
 
Tables with similar format: 
Table 16: 
Serological Response to Therapy at Month 12 by Treatment Group and Baseline HIV Status  


Statistical Analysis Plan - DMID Protocol: 17-0101 
Version 1.0 
22DEC2022 
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Table 17: 
RPR Geometric Mean Titer (GMT) and RPR Geometric Mean Fold Decline (GMFD) by Visit, Treatment Group and Baseline 
HIV Status — ITT Population 
[Implementation Note: Visit 1 will not have GMFD or GMFD 95% CI rows.] 
Time Point 
Statistic 
One Dose BPG 2.4 MU 
(N = X) 
Three Doses BPG 2.4 MU 
(N = X) 
All Subjects 
(N=X) 
HIV-infected 
HIV-
uninfected 
All 
HIV-infected 
HIV-
uninfected 
All 
HIV-infected 
HIV-
uninfected 
All 
Baseline 
n 
x 
x 
x 
x 
x 
x 
x 
x 
x 
GMT 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
95% CI 
x.xx, x.xx 
x.xx, x.xx 
x.xx, x.xx 
x.xx, x.xx 
x.xx, x.xx 
x.xx, x.xx 
x.xx, x.xx 
x.xx, x.xx 
x.xx, x.xx 
Week 1 
n 
x 
x 
x 
x 
x 
x 
x 
x 
x 
GMT 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
GMT 95% CI 
x.xx, x.xx 
x.xx, x.xx 
x.xx, x.xx 
x.xx, x.xx 
x.xx, x.xx 
x.xx, x.xx 
x.xx, x.xx 
x.xx, x.xx 
x.xx, x.xx 
GMFD 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
GMFD 95% CI 
x.xx, x.xx 
x.xx, x.xx 
x.xx, x.xx 
x.xx, x.xx 
x.xx, x.xx 
x.xx, x.xx 
x.xx, x.xx 
x.xx, x.xx 
x.xx, x.xx 
Week 2 
n 
x 
x 
x 
x 
x 
x 
x 
x 
x 
GMT 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
GMT 95% CI 
x.xx, x.xx 
x.xx, x.xx 
x.xx, x.xx 
x.xx, x.xx 
x.xx, x.xx 
x.xx, x.xx 
x.xx, x.xx 
x.xx, x.xx 
x.xx, x.xx 
GMFD 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
GMFD 95% CI 
x.xx, x.xx 
x.xx, x.xx 
x.xx, x.xx 
x.xx, x.xx 
x.xx, x.xx 
x.xx, x.xx 
x.xx, x.xx 
x.xx, x.xx 
x.xx, x.xx 
Month 1 
n 
x 
x 
x 
x 
x 
x 
x 
x 
x 
GMT 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
GMT 95% CI 
x.xx, x.xx 
x.xx, x.xx 
x.xx, x.xx 
x.xx, x.xx 
x.xx, x.xx 
x.xx, x.xx 
x.xx, x.xx 
x.xx, x.xx 
x.xx, x.xx 
GMFD 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
GMFD 95% CI 
x.xx, x.xx 
x.xx, x.xx 
x.xx, x.xx 
x.xx, x.xx 
x.xx, x.xx 
x.xx, x.xx 
x.xx, x.xx 
x.xx, x.xx 
x.xx, x.xx 
Month 2 
n 
x 
x 
x 
x 
x 
x 
x 
x 
x 
GMT 
x.xx, x.xx 
x.xx, x.xx 
x.xx, x.xx 
x.xx, x.xx 
x.xx, x.xx 
x.xx, x.xx 
x.xx, x.xx 
x.xx, x.xx 
x.xx, x.xx 
GMT 95% CI 
x.xx, x.xx 
x.xx, x.xx 
x.xx, x.xx 
x.xx, x.xx 
x.xx, x.xx 
x.xx, x.xx 
x.xx, x.xx 
x.xx, x.xx 
x.xx, x.xx 
GMFD 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
GMFD 95% CI 
x.xx, x.xx 
x.xx, x.xx 
x.xx, x.xx 
x.xx, x.xx 
x.xx, x.xx 
x.xx, x.xx 
x.xx, x.xx 
x.xx, x.xx 
x.xx, x.xx 


Statistical Analysis Plan - DMID Protocol: 17-0101 
Version 1.0 
22DEC2022 
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Time Point 
Statistic 
One Dose BPG 2.4 MU 
(N = X) 
Three Doses BPG 2.4 MU 
(N = X) 
All Subjects 
(N=X) 
HIV-infected 
HIV-
uninfected 
All 
HIV-infected 
HIV-
uninfected 
All 
HIV-infected 
HIV-
uninfected 
All 
Month 6 
n 
x 
x 
x 
x 
x 
x 
x 
x 
x 
GMT 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
GMT 95% CI 
x.xx, x.xx 
x.xx, x.xx 
x.xx, x.xx 
x.xx, x.xx 
x.xx, x.xx 
x.xx, x.xx 
x.xx, x.xx 
x.xx, x.xx 
x.xx, x.xx 
GMFD 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
GMFD 95% CI 
x.xx, x.xx 
x.xx, x.xx 
x.xx, x.xx 
x.xx, x.xx 
x.xx, x.xx 
x.xx, x.xx 
x.xx, x.xx 
x.xx, x.xx 
x.xx, x.xx 
Month 9 
n 
x 
x 
x 
x 
x 
x 
x 
x 
x 
GMT 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
GMT 95% CI 
x.xx, x.xx 
x.xx, x.xx 
x.xx, x.xx 
x.xx, x.xx 
x.xx, x.xx 
x.xx, x.xx 
x.xx, x.xx 
x.xx, x.xx 
x.xx, x.xx 
GMFD 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
GMFD 95% CI 
x.xx, x.xx 
x.xx, x.xx 
x.xx, x.xx 
x.xx, x.xx 
x.xx, x.xx 
x.xx, x.xx 
x.xx, x.xx 
x.xx, x.xx 
x.xx, x.xx 
Month 12 
n 
x 
x 
x 
x 
x 
x 
x 
x 
x 
GMT 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
GMT 95% CI 
x.xx, x.xx 
x.xx, x.xx 
x.xx, x.xx 
x.xx, x.xx 
x.xx, x.xx 
x.xx, x.xx 
x.xx, x.xx 
x.xx, x.xx 
x.xx, x.xx 
GMFD 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
GMFD 95% CI 
x.xx, x.xx 
x.xx, x.xx 
x.xx, x.xx 
x.xx, x.xx 
x.xx, x.xx 
x.xx, x.xx 
x.xx, x.xx 
x.xx, x.xx 
x.xx, x.xx 
Notes: N=Number of subjects who had RPR titer results available in the specified analysis population in the specified treatment group at the specified visit. RPR titer results from the early termination 
visit that occurred between scheduled visits are excluded. 
GMFD represents the geometric mean fold decline in antibody counts compared to baseline 
Tables with similar format: 
Table 18: 
RPR Geometric Mean Titer (GMT) and RPR Geometric Mean Fold Decline (GMFD) by Visit, Treatment Group and Baseline 
HIV Status— Evaluable Population by Month 6 
Table 19: 
RPR Geometric Mean Titer (GMT) and RPR Geometric Mean Fold Decline (GMFD) by Visit, Treatment Group and Baseline 
HIV Status— Evaluable Population by Month 12 


Statistical Analysis Plan - DMID Protocol: 17-0101 
Version 1.0 
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Table 20: 
Subjects Compliant with Study Product by Treatment Group  
Population 
Treatment Group 
Number of 
Complianta 
Subjects, n 
Number of 
Subjects, N 
Proportion (95% CI) 
Difference in 
Proportion Between 
Two Treatment Groups 
(95% CI) 
P-Valueb 
ITT Population 
One Dose BPG 2.4 MU 
xxx 
xxx 
0.xx (0.xx, 0.xx) 
0.xx (0.xx, 0.xx) 
0.xxx 
Three Doses BPG 2.4 MU 
xxx 
xxx 
0.xx (0.xx, 0.xx) 
All Subjects 
xxx 
xxx 
0.xx (0.xx, 0.xx) 
N/A 
N/A 
Evaluable Population by Month 6 
One Dose BPG 2.4 MU 
xxx 
xxx 
0.xx (0.xx, 0.xx) 
0.xx (0.xx, 0.xx) 
0.xxx 
Three Doses BPG 2.4 MU 
xxx 
xxx 
0.xx (0.xx, 0.xx) 
All Subjects 
xxx 
xxx 
0.xx (0.xx, 0.xx) 
N/A 
N/A 
Evaluable Population by Month 12 
One Dose BPG 2.4 MU 
xxx 
xxx 
0.xx (0.xx, 0.xx) 
0.xx (0.xx, 0.xx) 
0.xxx 
Three Doses BPG 2.4 MU 
xxx 
xxx 
0.xx (0.xx, 0.xx) 
All Subjects 
xxx 
xxx 
0.xx (0.xx, 0.xx) 
N/A 
N/A 
Notes: The denominator for proportion is based on the number of subjects enrolled in the specified treatment group and analysis population. 
95% CI= 95% Wilson Confidence Interval 
a Subjects are compliant if they receive all assigned doses within the assigned visit windows. 
b P-value is calculated based on the two-sided Pearson Chi-Square test at the .05 level of significance. 
 


Statistical Analysis Plan - DMID Protocol: 17-0101 
Version 1.0 
22DEC2022 
- 63 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Table 21: 
Summary of Categorical Demographics and Socio-epidemiologic Characteristics at Baseline by HIV Status and Treatment Group 
— ITT Population 
Variable 
Characteristic 
One Dose BPG 2.4 MU 
Three Doses BPG 2.4 MU 
All Subjects 
HIV-
infected 
(N=X) 
HIV-
uninfected 
(N=X) 
All Subjects 
(N=X) 
HIV-
infected 
(N=X) 
HIV-
uninfected 
(N=X) 
All Subjects 
(N=X) 
HIV-
infected 
(N=X) 
HIV-
uninfected 
(N=X) 
All Subjects 
(N=X) 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Sex 
Male  
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Female 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Ethnicity  
Not Hispanic or Latino 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Hispanic or Latino 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Not Reported 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Unknown 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Race  
American Indian or Alaskan Native 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Asian 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Native Hawaiian or Other Pacific 
Islander 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Black or African American 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
White 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Multi-Racial 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Unknown 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
Highest level 
of education 
completed? 
Did not complete high school 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Completed high school 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Completed junior college 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
undergraduate degree 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Completed graduate degree 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 


Statistical Analysis Plan - DMID Protocol: 17-0101 
Version 1.0 
22DEC2022 
- 64 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Table 22: 
Summary of Continuous Demographics and Socio-epidemiologic Characteristics at Baseline by HIV Status and Treatment Group 
— ITT Population 
Variable 
Statistic 
One Dose BPG 2.4 MU 
Three Doses BPG 2.4 MU 
All Subjects 
HIV-infected 
(N=X) 
HIV-
uninfected 
(N=X) 
All Subjects 
(N=X) 
HIV-infected 
(N=X) 
HIV-
uninfected 
(N=X) 
All Subjects 
(N=X) 
HIV-infected 
(N=X) 
HIV-
uninfected 
(N=X) 
All Subjects 
(N=X) 
Age 
Mean (SD) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
Median  
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
Min, Max 
x, x 
x, x 
x, x 
x, x 
x, x 
x, x 
x, x 
x, x 
x, x 
Years of formal 
education  
Mean (SD) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
Median  
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
Min, Max 
x, x 
x, x 
x, x 
x, x 
x, x 
x, x 
x, x 
x, x 
x, x 


Statistical Analysis Plan - DMID Protocol: 17-0101 
Version 1.0 
22DEC2022 
- 65 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Table 23: 
Summary of Categorical Sexual History at Baseline by HIV Status and Treatment Group — ITT Population 
Variable 
Characteristic 
One Dose BPG 2.4 MU 
Three Doses BPG 2.4 MU 
All Subjects 
HIV-infected 
(N=X) 
HIV-
uninfected 
(N=X) 
All Subjects 
(N=X) 
HIV-infected 
(N=X) 
HIV-
uninfected 
(N=X) 
All Subjects 
(N=X) 
HIV-
infected 
(N=X) 
HIV-
uninfected 
(N=X) 
All 
Subjects 
(N=X) 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Gender identity 
Man 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Woman 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Trans male  
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Trans female  
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Non-conforming 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Multiple 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Non-binary 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Other 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Declined to respond 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Sexual orientation 
Heterosexual 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Homosexual 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Bisexual 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Other 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Declined to respond 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Sexual partner 
Men 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Women 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Trans males 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Transferals 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Multiple 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Other 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Declined to respond 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 


Statistical Analysis Plan - DMID Protocol: 17-0101 
Version 1.0 
22DEC2022 
- 66 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Variable 
Characteristic 
One Dose BPG 2.4 MU 
Three Doses BPG 2.4 MU 
All Subjects 
HIV-infected 
(N=X) 
HIV-
uninfected 
(N=X) 
All Subjects 
(N=X) 
HIV-infected 
(N=X) 
HIV-
uninfected 
(N=X) 
All Subjects 
(N=X) 
HIV-
infected 
(N=X) 
HIV-
uninfected 
(N=X) 
All 
Subjects 
(N=X) 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Sexual intercourse in 
the past 60 days? 
Yes 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
No 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Unknown 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
If yes to 
above 
question, 
Sites of 
exposure 
Oral receptive 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Oral active  
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Rectal receptive 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Rectal insertive 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Genital/vaginal 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Condom or 
barrier for 
protection? 
Always 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Sometimes 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Never 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Any known exposures 
to an STD in the past 60 
days? 
Yes 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
No 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Unknown 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Diagnosed with 
gonorrhea in the past 60 
days? 
Yes 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
No 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Tested for gonorrhea in 
the past 14 days? 
Yes 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
No 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
If yes to 
above 
question, 
Test 
results? 
Positive 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Negative 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 


Statistical Analysis Plan - DMID Protocol: 17-0101 
Version 1.0 
22DEC2022 
- 67 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Variable 
Characteristic 
One Dose BPG 2.4 MU 
Three Doses BPG 2.4 MU 
All Subjects 
HIV-infected 
(N=X) 
HIV-
uninfected 
(N=X) 
All Subjects 
(N=X) 
HIV-infected 
(N=X) 
HIV-
uninfected 
(N=X) 
All Subjects 
(N=X) 
HIV-
infected 
(N=X) 
HIV-
uninfected 
(N=X) 
All 
Subjects 
(N=X) 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Diagnosed with 
chlamydia in the past 
60 days? 
Yes 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
No 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Tested for chlamydia in 
the past 14 days? 
Yes 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
No 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
If yes to 
above 
question, 
Test 
results? 
Positive 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Negative 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Diagnosed with any 
other STI in the past 60 
days? 
Yes 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
No 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 


Statistical Analysis Plan - DMID Protocol: 17-0101 
Version 1.0 
22DEC2022 
- 68 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Table 24: 
Summary of Continuous Sexual History at Baseline by HIV Status and Treatment Group — ITT Population 
Variable 
Statistic 
One Dose BPG 2.4 MU 
Three Doses BPG 2.4 MU 
All Subjects 
HIV-
infected 
(N=X) 
HIV-
uninfected 
(N=X) 
All Subjects 
(N=X) 
HIV-infected 
(N=X) 
HIV-
uninfected 
(N=X) 
All Subjects 
(N=X) 
HIV-infected 
(N=X) 
HIV-
uninfected 
(N=X) 
All Subjects 
(N=X) 
Days since last had 
sexual intercourse in the 
past 60 days 
Mean (SD) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
Median  
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
Min, Max 
x, x 
x, x 
x, x 
x, x 
x, x 
x, x 
x, x 
x, x 
x, x 
Total number of partners 
in the past 60 days 
Mean (SD) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
Median  
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
Min, Max 
x, x 
x, x 
x, x 
x, x 
x, x 
x, x 
x, x 
x, x 
x, x 
Number of new partners 
Mean (SD) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
Median  
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
Min, Max 
x, x 
x, x 
x, x 
x, x 
x, x 
x, x 
x, x 
x, x 
x, x 
Number of regular 
partners 
Mean (SD) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
Median  
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
Min, Max 
x, x 
x, x 
x, x 
x, x 
x, x 
x, x 
x, x 
x, x 
x, x 
Number of occasional 
partners 
Mean (SD) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
Median  
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
Min, Max 
x, x 
x, x 
x, x 
x, x 
x, x 
x, x 
x, x 
x, x 
x, x 
Number of male partners 
Mean (SD) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
Median  
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
Min, Max 
x, x 
x, x 
x, x 
x, x 
x, x 
x, x 
x, x 
x, x 
x, x 
Number of female 
partners 
Mean (SD) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
Median  
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
Min, Max 
x, x 
x, x 
x, x 
x, x 
x, x 
x, x 
x, x 
x, x 
x, x 


Statistical Analysis Plan - DMID Protocol: 17-0101 
Version 1.0 
22DEC2022 
- 69 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Variable 
Statistic 
One Dose BPG 2.4 MU 
Three Doses BPG 2.4 MU 
All Subjects 
HIV-
infected 
(N=X) 
HIV-
uninfected 
(N=X) 
All Subjects 
(N=X) 
HIV-infected 
(N=X) 
HIV-
uninfected 
(N=X) 
All Subjects 
(N=X) 
HIV-infected 
(N=X) 
HIV-
uninfected 
(N=X) 
All Subjects 
(N=X) 
Days since last diagnosed 
with gonorrhea in the 
past 60 days 
Mean (SD) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
Median  
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
Min, Max 
x, x 
x, x 
x, x 
x, x 
x, x 
x, x 
x, x 
x, x 
x, x 
Days since last diagnosed 
with chlamydia in the 
past 60 days 
Mean (SD) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
Median  
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
Min, Max 
x, x 
x, x 
x, x 
x, x 
x, x 
x, x 
x, x 
x, x 
x, x 
Days since last diagnosed 
with any other STI in the 
past 60 days 
Mean (SD) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
Median  
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
Min, Max 
x, x 
x, x 
x, x 
x, x 
x, x 
x, x 
x, x 
x, x 
x, x 


Statistical Analysis Plan - DMID Protocol: 17-0101 
Version 1.0 
22DEC2022 
- 70 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Table 25: 
Summary of Categorical Sexual History through Month 6 by Baseline HIV Status and Treatment Group— ITT Population 
[Implementation notes for table 25, 27, and 29, the Time will be Week1 Week2 month1. Month 3 and Month 6; and for table 26, 28 and 30, the Time 
will be Month 9 and Month 12.] 
Time 
Variable 
Characteristic 
One Dose BPG 2.4 MU 
Three Doses BPG 2.4 MU 
All Subjects 
Baseline 
HIV-
infected 
(N=X) 
Baseline 
HIV-
uninfected 
(N=X) 
All 
Subjects 
(N=X) 
Baseline 
HIV-
infected 
(N=X) 
Baseline 
HIV-
uninfected 
(N=X) 
All 
Subjects 
(N=X) 
Baseline 
HIV-
infected 
(N=X) 
Baseline 
HIV-
uninfected 
(N=X) 
All 
Subjects 
(N=X) 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Week 1 
Sexual intercourse since last visit? 
Yes 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
No 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Unknown 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Since last visit, if the subject had sexual 
intercourse, indicate sites of exposure 
Oral receptive 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Oral active  
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Rectal receptive 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Rectal insertive 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Genital/vaginal 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Since last visit, if the subject had sexual 
intercourse, how often did the subject 
use a condom or barrier for protection? 
Always 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Sometimes 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Never 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Any known exposures to syphilis since 
last visit? 
Yes 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
No 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Unknown 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Any known exposures to another STD 
since last visit? 
Yes 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
No 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Unknown 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 


Statistical Analysis Plan - DMID Protocol: 17-0101 
Version 1.0 
22DEC2022 
- 71 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Time 
Variable 
Characteristic 
One Dose BPG 2.4 MU 
Three Doses BPG 2.4 MU 
All Subjects 
Baseline 
HIV-
infected 
(N=X) 
Baseline 
HIV-
uninfected 
(N=X) 
All 
Subjects 
(N=X) 
Baseline 
HIV-
infected 
(N=X) 
Baseline 
HIV-
uninfected 
(N=X) 
All 
Subjects 
(N=X) 
Baseline 
HIV-
infected 
(N=X) 
Baseline 
HIV-
uninfected 
(N=X) 
All 
Subjects 
(N=X) 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Since last visit, was the subject treated 
or does the subject require retreatment 
for syphilis infection apart from study 
treatment received according to their 
randomization assignment? 
Yes 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
No 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Unknown 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Since last visit, if the subject was treated 
or require retreatment for syphilis 
infection apart from study treatment 
received according to their 
randomization, how was retreatment 
need determined? 
Local RPR 
results 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Known re-
exposure 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Return of or 
worsening 
symptoms 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Other 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Week 2 … 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tables with similar format: 
Table 26: 
Summary of Categorical Sexual History through Month 12 by Baseline HIV Status and Treatment Group — ITT Population 
Table 27: 
Summary of Categorical Sexual History through Month 6 by Baseline HIV Status and Treatment Group — Evaluable Population 
by Month 6 
Table 28: 
Summary of Categorical Sexual History through Month 12 by Baseline HIV Status and Treatment Group — Evaluable 
Population by Month 12 
 


Statistical Analysis Plan - DMID Protocol: 17-0101 
Version 1.0 
22DEC2022 
- 72 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Table 29: 
Summary of Continuous Sexual History through Month 6 by Baseline HIV Status and Treatment Group 
Population 
Time 
Variable 
Statistic 
One Dose BPG 2.4 MU 
Three Doses BPG 2.4 MU 
All Subjects 
HIV-
infected 
(N=X) 
HIV-
uninfected 
(N=X) 
All 
Subjects 
(N=X) 
HIV-
infected 
(N=X) 
HIV-
uninfected 
(N=X) 
All 
Subjects 
(N=X) 
HIV-
infected 
(N=X) 
HIV-
uninfected 
(N=X) 
All 
Subjects 
(N=X) 
ITT Population 
Week 1 
Total number of 
partners since last 
visit 
Mean (SD) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
Median  
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
Min, Max 
x, x 
x, x 
x, x 
x, x 
x, x 
x, x 
x, x 
x, x 
x, x 
Number of new 
partners since last 
visit 
Mean (SD) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
Median  
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
Min, Max 
x, x 
x, x 
x, x 
x, x 
x, x 
x, x 
x, x 
x, x 
x, x 
Number of 
continuing partners 
since last visit 
Mean (SD) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
Median  
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
Min, Max 
x, x 
x, x 
x, x 
x, x 
x, x 
x, x 
x, x 
x, x 
x, x 
Week 2… 
 
 
 
 
 
 
 
 
 
 
 
Evaluable 
Population by 
Month 6 
Week 1 
Total number of 
partners 
Mean (SD) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
Median  
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
Min, Max 
x, x 
x, x 
x, x 
x, x 
x, x 
x, x 
x, x 
x, x 
x, x 
Number of new 
partners 
Mean (SD) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
Median  
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
Min, Max 
x, x 
x, x 
x, x 
x, x 
x, x 
x, x 
x, x 
x, x 
x, x 
Number of 
continuing partners 
Mean (SD) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
Median  
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
Min, Max 
x, x 
x, x 
x, x 
x, x 
x, x 
x, x 
x, x 
x, x 
x, x 
Week 2…. 
 
 
 
 
 
 
 
 
 
 
 
Notes: N= Number of enrolled subjects in the specified baseline HIV status subgroup and analysis population. 
Baseline is the Screening/Enrollment - Visit 1. 
The numbers at each visit within the table specified period were totaled before deriving the summary statistics. 
Tables with similar format: 
Table 30: 
Summary of Continuous Sexual History through Month 12 by Baseline HIV Status and Treatment Group 


Statistical Analysis Plan - DMID Protocol: 17-0101 
Version 1.0 
22DEC2022 
- 73 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Table 31: 
Sensitivity analysis 1 - Serological Response to Therapy at Month 6 by Treatment Group – Removing Early Termination Due to 
COVID 
Population 
Treatment Group* 
Number of Subjects with 
Serological Response, n 
Number of Subjects, N 
Proportion of Subjects 
with Serological Response 
(95% CI)a 
Difference in Proportion 
of Subjects with 
Serological Response 
Between Two Treatment 
Groups (95% CI)a 
P-Value 
ITT Population 
One Dose BPG 2.4 MU 
xxx 
xxx 
0.xx(0.xx, 0.xx) 
0.xx(0.xx, 0.xx) 
0.xxx 
Three Doses BPG 2.4 MU 
xxx 
xxx 
0.xx(0.xx, 0.xx) 
All Subjects 
xxx 
xxx 
0.xx(0.xx, 0.xx) 
N/A 
N/A 
mITT Population 
One Dose BPG 2.4 MU 
xxx 
xxx 
0.xx(0.xx, 0.xx) 
0.xx(0.xx, 0.xx) 
0.xxx 
Three Doses BPG 2.4 MU 
xxx 
xxx 
0.xx(0.xx, 0.xx) 
All Subjects 
xxx 
xxx 
0.xx(0.xx, 0.xx) 
N/A 
N/A 
Evaluable 
Population 
One Dose BPG 2.4 MU 
xxx 
xxx 
0.xx(0.xx, 0.xx) 
0.xx(0.xx, 0.xx) 
0.xxx 
Three Doses BPG 2.4 MU 
xxx 
xxx 
0.xx(0.xx, 0.xx) 
All Subjects 
xxx 
xxx 
0.xx(0.xx, 0.xx) 
N/A 
N/A 
Notes: The denominator for proportion is based on the number of subjects enrolled in the specified treatment group and analysis population. 
a 95% CI= 95% Wilson Confidence Interval 
 


Statistical Analysis Plan - DMID Protocol: 17-0101 
Version 1.0 
22DEC2022 
- 74 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Table 32: 
Sensitivity analysis 2 - Serological Response to Therapy at Month 6 by Treatment Group – Re-defined Serological Response 
Population 
Treatment Group* 
Number of Subjects 
with Serological 
Response, n 
Number of Subjects, 
N 
Proportion of Subjects 
with Serological Response 
(95% CI)a 
Difference in Proportion of Subjects with 
Serological Response Between Two 
Treatment Groups (95% CI)a 
P-Value 
ITT Population 
One Dose BPG 2.4 MU 
xxx 
xxx 
0.xx(0.xx, 0.xx) 
0.xx(0.xx, 0.xx) 
0.xxx 
Three Doses BPG 2.4 MU 
xxx 
xxx 
0.xx(0.xx, 0.xx) 
All Subjects 
xxx 
xxx 
0.xx(0.xx, 0.xx) 
N/A 
N/A 
mITT Population 
One Dose BPG 2.4 MU 
xxx 
xxx 
0.xx(0.xx, 0.xx) 
0.xx(0.xx, 0.xx) 
0.xxx 
Three Doses BPG 2.4 MU 
xxx 
xxx 
0.xx(0.xx, 0.xx) 
All Subjects 
xxx 
xxx 
0.xx(0.xx, 0.xx) 
N/A 
N/A 
Evaluable 
Population 
One Dose BPG 2.4 MU 
xxx 
xxx 
0.xx(0.xx, 0.xx) 
0.xx(0.xx, 0.xx) 
0.xxx 
Three Doses BPG 2.4 MU 
xxx 
xxx 
0.xx(0.xx, 0.xx) 
All Subjects 
xxx 
xxx 
0.xx(0.xx, 0.xx) 
N/A 
N/A 
Notes: The denominator for proportion is based on the number of subjects enrolled in the specified treatment group and analysis population. 
a 95% CI= 95% Wilson Confidence Interval 


Statistical Analysis Plan - DMID Protocol: 17-0101 
Version 1.0 
22DEC2022 
- 75 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Table 33: 
Exploratory Analysis---Serological Response to Therapy by Month 6 by Treatment Group  
[Implementation Notes: Treatment group is the intended randomized group for ITT and mITT populations. Treatment group is the actual treatment a 
subject received for the Evaluable populations.] 
Population 
Treatment Group 
Number (Proportion) of 
Subjects with Serological 
Responsea 
Number (Proportion) of 
Subjects with Serological 
Non-Responsea 
Number (Proportion) of 
Subjects with Failurea 
Serological Response 
Number of Subjects,  
N 
ITT Population 
One Dose BPG 2.4 MU 
xxx (0.xx) 
xxx (0.xx) 
xxx (0.xx) 
xxx 
Three Doses BPG 2.4 MU 
xxx (0.xx) 
xxx (0.xx) 
xxx (0.xx) 
xxx 
All Subjects 
xxx (0.xx) 
xxx (0.xx) 
xxx (0.xx) 
xxx 
mITT Population 
One Dose BPG 2.4 MU 
xxx (0.xx) 
xxx (0.xx) 
xxx (0.xx) 
xxx 
Three Doses BPG 2.4 MU 
xxx (0.xx) 
xxx (0.xx) 
xxx (0.xx) 
xxx 
All Subjects 
xxx (0.xx) 
xxx (0.xx) 
xxx (0.xx) 
xxx 
Evaluable Population 
One Dose BPG 2.4 MU 
xxx (0.xx) 
xxx (0.xx) 
xxx (0.xx) 
xxx 
Three Doses BPG 2.4 MU 
xxx (0.xx) 
xxx (0.xx) 
xxx (0.xx) 
xxx 
All Subjects 
xxx (0.xx) 
xxx (0.xx) 
xxx (0.xx) 
xxx 
Notes: The denominator for proportion is based on the number of subjects enrolled in the specified treatment group and analysis population. 
95% CI= 95% Wilson Confidence Interval 
a Alternative serological response classifications – 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, and less than 4-fold decline in RPR titer at all visit compared to baseline. 
 


Statistical Analysis Plan - DMID Protocol: 17-0101 
Version 1.0 
22DEC2022 
- 76 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Table 34: 
Summary of Subjects with Pre-Existing Medical Conditions by MedDRA System Organ 
Class and Treatment Group - Safety Population  
MedDRA System Organ Class 
One Dose BPG 2.4 MU 
(N = X) 
Three Doses BPG 2.4 MU 
(N = X) 
All Subjects 
(N=X) 
n 
% 
n 
% 
n 
% 
Any SOC 
x 
x 
x 
x 
x 
x 
[SOC 1] 
x 
x 
x 
x 
x 
x 
[SOC 2] 
x 
x 
x 
x 
x 
x 
Notes: N=number of subjects in the specified treatment group in the Safety Population. 
n = Number of subjects reporting medical history within the specified SOC. 
A subject is only counted once per SOC. 
 


Statistical Analysis Plan - DMID Protocol: 17-0101 
Version 1.0 
22DEC2022 
- 77 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Table 35: 
Number and Percentage of Subjects with Prior and Concomitant Medications by WHO 
Drug Classification and Treatment Group - Safety Population 
WHO Drug Code 
Level 1, Anatomic Group 
WHO Drug Code 
Level 2, Therapeutic 
Subgroup 
One Dose BPG 2.4 MU 
(N = X) 
Three Doses BPG 2.4 
MU 
(N = X) 
All Subjects 
(N=X) 
n 
% 
n 
% 
n 
% 
Any Level 1 Codes 
Any Level 2 Codes 
x 
x 
x 
x 
x 
x 
[ATC Level 1 - 1] 
Any  
x 
x 
x 
x 
x 
x 
 
[ATC 2 - 1] 
x 
x 
x 
x 
x 
x 
 
[ATC 2 - 2] 
x 
x 
x 
x 
x 
x 
 
[ATC 2 - 3] 
x 
x 
x 
x 
x 
x 
[ATC Level 1 – 2] 
Any 
x 
x 
x 
x 
x 
x 
 
[ATC 2 - 1] 
x 
x 
x 
x 
x 
x 
 
[ATC 2 - 2] 
x 
x 
x 
x 
x 
x 
 
[ATC 2 - 3] 
x 
x 
x 
x 
x 
x 
Notes: N= Number of subjects in the specified treatment group and the Safety population 
n=Number of subjects reporting taking at least one medication in the specific WHO Drug Class. 
 


Statistical Analysis Plan - DMID Protocol: 17-0101 
Version 1.0 
22DEC2022 
- 78 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Table 36: 
Overall Summary of Adverse Events - Safety Population 
 
One Dose BPG 2.4 MU 
(N = X) 
Three Doses BPG 2.4 MU 
(N = X) 
All Subjects 
(N=X) 
Subjectsa with 
n 
% 
n 
% 
N 
% 
At least one local solicited adverse event 
x 
x 
x 
x 
x 
x 
At least one systemic solicited adverse event 
x 
x 
x 
x 
x 
x 
At least one unsolicited adverse event 
x 
x 
x 
x 
x 
x 
At least one related unsolicited adverse event 
x 
x 
x 
x 
x 
x 
     Mild (Grade 1) 
x 
x 
x 
x 
x 
x 
     Moderate (Grade 2)  
x 
x 
x 
x 
x 
x 
     Severe (Grade 3)  
x 
x 
x 
x 
x 
x 
     Not yet assessed 
 
 
 
 
 
 
At least one severe (Grade 3) unsolicited adverse event 
x 
x 
x 
x 
x 
x 
     Related  
x 
x 
x 
x 
x 
x 
     Unrelated 
x 
x 
x 
x 
x 
x 
At least one serious adverse eventb 
x 
x 
x 
x 
x 
x 
At least one related, serious adverse event 
x 
x 
x 
x 
x 
x 
At least one adverse event leading to early terminationc  
x 
x 
x 
x 
x 
x 
Notes: N = Number of subjects in the Safety Population 
a Subjects are counted once for each category regardless of the number of events. 
b A listing of Serious Adverse Events is included in Table 47 
c As reported on the Adverse Event eCRF. 


Statistical Analysis Plan - DMID Protocol: 17-0101 
Version 1.0 
22DEC2022 
- 79 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Table 37: 
Number and Percentage of Subjects Experiencing Solicited Events with 95% Confidence Intervals by Symptom and Treatment 
Group — Safety Population 
Category 
Solicited Adverse Event 
One Dose BPG 2.4 MU 
(N = X) 
Three Doses BPG 2.4 MU 
(N = X) 
All Subjects 
(N=X) 
n 
% 
95% CI 
n 
% 
95% CI 
n 
% 
95% CI 
Solicited Adverse Events 
Any Solicited Adverse Event 
x 
x 
x.x, x.x 
x 
x 
x.x, x.x 
x 
x 
x.x, x.x 
Solicited Local Adverse Events 
Any Local Adverse Event 
x 
x 
x.x, x.x 
x 
x 
x.x, x.x 
x 
x 
x.x, x.x 
 
      Pain or tenderness 
x 
x 
x.x, x.x 
x 
x 
x.x, x.x 
x 
x 
x.x, x.x 
 
      Erythema or redness 
x 
x 
x.x, x.x 
x 
x 
x.x, x.x 
x 
x 
x.x, x.x 
 
      Induration or swelling 
x 
x 
x.x, x.x 
x 
x 
x.x, x.x 
x 
x 
x.x, x.x 
Solicited Systemic Adverse Events 
Any Systemic Adverse Event  
(Jarisch-Herxheimer reaction) 
x 
x 
x.x, x.x 
x 
x 
x.x, x.x 
x 
x 
x.x, x.x 
 
Feverishness 
x 
x 
x.x, x.x 
x 
x 
x.x, x.x 
x 
x 
x.x, x.x 
 
Chills 
x 
x 
x.x, x.x 
x 
x 
x.x, x.x 
x 
x 
x.x, x.x 
 
Myalgia 
x 
x 
x.x, x.x 
x 
x 
x.x, x.x 
x 
x 
x.x, x.x 
 
Weakness 
x 
x 
x.x, x.x 
x 
x 
x.x, x.x 
x 
x 
x.x, x.x 
 
Flushing 
x 
x 
x.x, x.x 
x 
x 
x.x, x.x 
x 
x 
x.x, x.x 
 
Worsening of skin rash 
x 
x 
x.x, x.x 
x 
x 
x.x, x.x 
x 
x 
x.x, x.x 
 
Tachycardia 
x 
x 
x.x, x.x 
x 
x 
x.x, x.x 
x 
x 
x.x, x.x 
 
Heart palpitations 
x 
x 
x.x, x.x 
x 
x 
x.x, x.x 
x 
x 
x.x, x.x 
 
Generalized arthralgia 
x 
x 
x.x, x.x 
x 
x 
x.x, x.x 
x 
x 
x.x, x.x 
 
Nausea 
x 
x 
x.x, x.x 
x 
x 
x.x, x.x 
x 
x 
x.x, x.x 
 
Headache 
x 
x 
x.x, x.x 
x 
x 
x.x, x.x 
x 
x 
x.x, x.x 
 
Dizziness 
x 
x 
x.x, x.x 
x 
x 
x.x, x.x 
x 
x 
x.x, x.x 
Notes: N = number of subjects in the specified treatment group in the Safety Population. 95% CI= 95% Wilson Confidence Interval 
A subject is only counted once per solicited adverse event. 


Statistical Analysis Plan - DMID Protocol: 17-0101 
Version 1.0 
22DEC2022 
- 80 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Table 38: 
Number and Percentage of Subjects Experiencing Solicited Systemic Events by Symptom, Maximum Severity and Treatment 
Group — Safety Population  
 
Severity 
One Dose BPG 2.4 MU 
(N = X) 
Three Doses BPG 2.4 MU 
(N = X) 
All Subjects 
(N=X) 
n 
% 
95% CI 
n 
% 
95% CI 
n 
% 
95% CI 
Any Solicited Systemic Event 
Any severity 
x 
x 
x,x 
x 
x 
x,x 
x 
x 
x,x 
None 
x 
x 
x,x 
x 
x 
x,x 
x 
x 
x,x 
Mild 
x 
x 
x,x 
x 
x 
x,x 
x 
x 
x,x 
Moderate 
x 
x 
x,x 
x 
x 
x,x 
x 
x 
x,x 
Severe 
x 
x 
x,x 
x 
x 
x,x 
x 
x 
x,x 
Jarisch-Herxheimer 
Reaction 
Feverishness 
Any severity 
x 
x 
x,x 
x 
x 
x,x 
x 
x 
x,x 
None 
x 
x 
x,x 
x 
x 
x,x 
x 
x 
x,x 
Mild 
x 
x 
x,x 
x 
x 
x,x 
x 
x 
x,x 
Moderate 
x 
x 
x,x 
x 
x 
x,x 
x 
x 
x,x 
Severe 
x 
x 
x,x 
x 
x 
x,x 
x 
x 
x,x 
Chills 
Any severity 
x 
x 
x,x 
x 
x 
x,x 
x 
x 
x,x 
None 
x 
x 
x,x 
x 
x 
x,x 
x 
x 
x,x 
Mild 
x 
x 
x,x 
x 
x 
x,x 
x 
x 
x,x 
Moderate 
x 
x 
x,x 
x 
x 
x,x 
x 
x 
x,x 
Severe 
x 
x 
x,x 
x 
x 
x,x 
x 
x 
x,x 
Myalgia 
Any severity 
x 
x 
x,x 
x 
x 
x,x 
x 
x 
x,x 
None 
x 
x 
x,x 
x 
x 
x,x 
x 
x 
x,x 
Mild 
x 
x 
x,x 
x 
x 
x,x 
x 
x 
x,x 
Moderate 
x 
x 
x,x 
x 
x 
x,x 
x 
x 
x,x 
Severe 
x 
x 
x,x 
x 
x 
x,x 
x 
x 
x,x 


Statistical Analysis Plan - DMID Protocol: 17-0101 
Version 1.0 
22DEC2022 
- 81 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
 
Severity 
One Dose BPG 2.4 MU 
(N = X) 
Three Doses BPG 2.4 MU 
(N = X) 
All Subjects 
(N=X) 
n 
% 
95% CI 
n 
% 
95% CI 
n 
% 
95% CI 
Weakness 
Any severity 
x 
x 
x,x 
x 
x 
x,x 
x 
x 
x,x 
None 
x 
x 
x,x 
x 
x 
x,x 
x 
x 
x,x 
Mild 
x 
x 
x,x 
x 
x 
x,x 
x 
x 
x,x 
Moderate 
x 
x 
x,x 
x 
x 
x,x 
x 
x 
x,x 
Severe 
x 
x 
x,x 
x 
x 
x,x 
x 
x 
x,x 
Flushing 
Any severity 
x 
x 
x,x 
x 
x 
x,x 
x 
x 
x,x 
None 
x 
x 
x,x 
x 
x 
x,x 
x 
x 
x,x 
Mild 
x 
x 
x,x 
x 
x 
x,x 
x 
x 
x,x 
Moderate 
x 
x 
x,x 
x 
x 
x,x 
x 
x 
x,x 
Severe 
x 
x 
x,x 
x 
x 
x,x 
x 
x 
x,x 
Worsening of skin 
rash 
Any severity 
x 
x 
x,x 
x 
x 
x,x 
x 
x 
x,x 
None 
x 
x 
x,x 
x 
x 
x,x 
x 
x 
x,x 
Mild 
x 
x 
x,x 
x 
x 
x,x 
x 
x 
x,x 
Moderate 
x 
x 
x,x 
x 
x 
x,x 
x 
x 
x,x 
Severe 
x 
x 
x,x 
x 
x 
x,x 
x 
x 
x,x 
Tachycardia 
Any severity 
x 
x 
x,x 
x 
x 
x,x 
x 
x 
x,x 
None 
x 
x 
x,x 
x 
x 
x,x 
x 
x 
x,x 
Mild 
x 
x 
x,x 
x 
x 
x,x 
x 
x 
x,x 
Moderate 
x 
x 
x,x 
x 
x 
x,x 
x 
x 
x,x 
Severe 
x 
x 
x,x 
x 
x 
x,x 
x 
x 
x,x 
Heart palpitations 
Any severity 
x 
x 
x,x 
x 
x 
x,x 
x 
x 
x,x 
None 
x 
x 
x,x 
x 
x 
x,x 
x 
x 
x,x 
Mild 
x 
x 
x,x 
x 
x 
x,x 
x 
x 
x,x 
Moderate 
x 
x 
x,x 
x 
x 
x,x 
x 
x 
x,x 
Severe 
x 
x 
x,x 
x 
x 
x,x 
x 
x 
x,x 


Statistical Analysis Plan - DMID Protocol: 17-0101 
Version 1.0 
22DEC2022 
- 82 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
 
Severity 
One Dose BPG 2.4 MU 
(N = X) 
Three Doses BPG 2.4 MU 
(N = X) 
All Subjects 
(N=X) 
n 
% 
95% CI 
n 
% 
95% CI 
n 
% 
95% CI 
Generalized 
arthralgia 
Any severity 
x 
x 
x,x 
x 
x 
x,x 
x 
x 
x,x 
None 
x 
x 
x,x 
x 
x 
x,x 
x 
x 
x,x 
Mild 
x 
x 
x,x 
x 
x 
x,x 
x 
x 
x,x 
Moderate 
x 
x 
x,x 
x 
x 
x,x 
x 
x 
x,x 
Severe 
x 
x 
x,x 
x 
x 
x,x 
x 
x 
x,x 
Nausea 
Any severity 
x 
x 
x,x 
x 
x 
x,x 
x 
x 
x,x 
None 
x 
x 
x,x 
x 
x 
x,x 
x 
x 
x,x 
Mild 
x 
x 
x,x 
x 
x 
x,x 
x 
x 
x,x 
Moderate 
x 
x 
x,x 
x 
x 
x,x 
x 
x 
x,x 
Severe 
x 
x 
x,x 
x 
x 
x,x 
x 
x 
x,x 
Headache 
Any severity 
x 
x 
x,x 
x 
x 
x,x 
x 
x 
x,x 
None 
x 
x 
x,x 
x 
x 
x,x 
x 
x 
x,x 
Mild 
x 
x 
x,x 
x 
x 
x,x 
x 
x 
x,x 
Moderate 
x 
x 
x,x 
x 
x 
x,x 
x 
x 
x,x 
Severe 
x 
x 
x,x 
x 
x 
x,x 
x 
x 
x,x 
Dizziness 
Any severity 
x 
x 
x,x 
x 
x 
x,x 
x 
x 
x,x 
None 
x 
x 
x,x 
x 
x 
x,x 
x 
x 
x,x 
Mild 
x 
x 
x,x 
x 
x 
x,x 
x 
x 
x,x 
Moderate 
x 
x 
x,x 
x 
x 
x,x 
x 
x 
x,x 
Severe 
x 
x 
x,x 
x 
x 
x,x 
x 
x 
x,x 
Note: Denominator for percentages is the number of subjects in the specified treatment group in the Safety Population with solicited adverse event data available after the first dose of study product. 95% 
CI= 95% Wilson Confidence Interval 


Statistical Analysis Plan - DMID Protocol: 17-0101 
Version 1.0 
22DEC2022 
- 83 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Table 39: 
Number and Percentage of Subjects Experiencing Solicited Local Events with 95% Confidence Intervals by Symptom, Maximum 
Severity, Dose, and Treatment Group — Safety Population  
[Implementation note applies to all tables: If the table will be multi-page, move the footnote/explanation to the footer so that it repeats for each page of 
the table.] 
[Implementation note: Post each dose, use whichever is more severe between most severe response among days 1-6 and the maximum 
severity/measurement after day 6 from ZRL.]  
Solicited 
Adverse Event 
Severitya 
Post Dose 1 
[One Dose BPG 2.4 MU 
Group] 
(N=X) 
Post Dose 1 
[Three Doses BPG 2.4 
MU Group] 
(N=X) 
Post Dose 2 
[Three Doses BPG 2.4 
MU Group] 
(N=X) 
Post Dose 3 
[Three Doses BPG 2.4 
MU Group] 
(N=X) 
Post Any Dose 
[Three Doses BPG 2.4 
MU Group] 
(N=X) 
Overall 
(N=X) 
n 
% 
95% CI 
n 
% 
95% CI 
n 
% 
95% 
CI 
n 
% 
95% CI 
n 
% 
95% CI 
n 
% 
95% CI 
Any Solicited 
Local Event 
Any Severity 
x 
x 
x,x 
x 
x 
x,x 
x 
x 
x,x 
x 
x 
x,x 
x 
x 
x,x 
x 
x 
x,x 
None 
x 
x 
x,x 
x 
x 
x,x 
x 
x 
x,x 
x 
x 
x,x 
x 
x 
x,x 
x 
x 
x,x 
Mild 
x 
x 
x,x 
x 
x 
x,x 
x 
x 
x,x 
x 
x 
x,x 
x 
x 
x,x 
x 
x 
x,x 
Moderate 
x 
x 
x,x 
x 
x 
x,x 
x 
x 
x,x 
x 
x 
x,x 
x 
x 
x,x 
x 
x 
x,x 
Severe 
x 
x 
x,x 
x 
x 
x,x 
x 
x 
x,x 
x 
x 
x,x 
x 
x 
x,x 
x 
x 
x,x 
Pain or 
tenderness 
Any Severity 
x 
x 
x,x 
x 
x 
x,x 
x 
x 
x,x 
x 
x 
x,x 
x 
x 
x,x 
x 
x 
x,x 
None 
x 
x 
x,x 
x 
x 
x,x 
x 
x 
x,x 
x 
x 
x,x 
x 
x 
x,x 
x 
x 
x,x 
Mild 
x 
x 
x,x 
x 
x 
x,x 
x 
x 
x,x 
x 
x 
x,x 
x 
x 
x,x 
x 
x 
x,x 
Moderate 
x 
x 
x,x 
x 
x 
x,x 
x 
x 
x,x 
x 
x 
x,x 
x 
x 
x,x 
x 
x 
x,x 
Severe 
x 
x 
x,x 
x 
x 
x,x 
x 
x 
x,x 
x 
x 
x,x 
x 
x 
x,x 
x 
x 
x,x 
Erythema or 
redness 
Any Severity 
x 
x 
x,x 
x 
x 
x,x 
x 
x 
x,x 
x 
x 
x,x 
x 
x 
x,x 
x 
x 
x,x 
None 
x 
x 
x,x 
x 
x 
x,x 
x 
x 
x,x 
x 
x 
x,x 
x 
x 
x,x 
x 
x 
x,x 
Mild 
x 
x 
x,x 
x 
x 
x,x 
x 
x 
x,x 
x 
x 
x,x 
x 
x 
x,x 
x 
x 
x,x 
Moderate 
x 
x 
x,x 
x 
x 
x,x 
x 
x 
x,x 
x 
x 
x,x 
x 
x 
x,x 
x 
x 
x,x 
Severe 
x 
x 
x,x 
x 
x 
x,x 
x 
x 
x,x 
x 
x 
x,x 
x 
x 
x,x 
x 
x 
x,x 


Statistical Analysis Plan - DMID Protocol: 17-0101 
Version 1.0 
22DEC2022 
- 84 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Solicited 
Adverse Event 
Severitya 
Post Dose 1 
[One Dose BPG 2.4 MU 
Group] 
(N=X) 
Post Dose 1 
[Three Doses BPG 2.4 
MU Group] 
(N=X) 
Post Dose 2 
[Three Doses BPG 2.4 
MU Group] 
(N=X) 
Post Dose 3 
[Three Doses BPG 2.4 
MU Group] 
(N=X) 
Post Any Dose 
[Three Doses BPG 2.4 
MU Group] 
(N=X) 
Overall 
(N=X) 
n 
% 
95% CI 
n 
% 
95% CI 
n 
% 
95% 
CI 
n 
% 
95% CI 
n 
% 
95% CI 
n 
% 
95% CI 
Induration or 
swelling 
Any Severity 
x 
x 
x,x 
x 
x 
x,x 
x 
x 
x,x 
x 
x 
x,x 
x 
x 
x,x 
x 
x 
x,x 
None 
x 
x 
x,x 
x 
x 
x,x 
x 
x 
x,x 
x 
x 
x,x 
x 
x 
x,x 
x 
x 
x,x 
Mild 
x 
x 
x,x 
x 
x 
x,x 
x 
x 
x,x 
x 
x 
x,x 
x 
x 
x,x 
x 
x 
x,x 
Moderate 
x 
x 
x,x 
x 
x 
x,x 
x 
x 
x,x 
x 
x 
x,x 
x 
x 
x,x 
x 
x 
x,x 
Severe 
x 
x 
x,x 
x 
x 
x,x 
x 
x 
x,x 
x 
x 
x,x 
x 
x 
x,x 
x 
x 
x,x 
Notes: Denominator for percentages is the number of subjects in the specified treatment group and the Safety Population with solicited adverse event data available after the first dose of study product 
95% CI= 95% Wilson Confidence Interval 
a Each subject’s maximum severity is reported for each solicited adverse event across all doses. 
 


Statistical Analysis Plan - DMID Protocol: 17-0101 
Version 1.0 
22DEC2022 
- 85 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Table 40: 
The Association of Treatment with Jarisch-Herxheimer Reaction after Adjusting for HIV Co-infection status and Jarisch-
Herxheimer Reaction (JHR) Onset Time Post-dose by Logistic Regression - Safety Population 
Risk Factors 
Odds Ratio a 
P-Value 
Adjusted Odds Ratiob 
95% Wald CIs 
P-Value 
Three Doses BPG 2.4 MU Group vs  
One Dose BPG 2.4 MU Group (ref) 
x.x 
x.xxx 
x.x 
x,x 
x.xxx 
Baseline HIV-infected vs Baseline HIV-
uninfected (ref) 
x.x 
x.xxx 
x.x 
x,x 
x.xxx 
JHR Onset Time Post-dose: 
0-12 hours vs >24-48 hours (ref) 
x.x 
x.xxx 
x.x 
x,x 
x.xxx 
JHR Onset Time Post-dose: 
>12-24 hours vs >24-48 hours (ref) 
x.x 
x.xxx 
x.x 
x,x 
x.xxx 
Note: P-value is from corresponding the logistic regression model for the variable. 
a Odds ratio is from univariate models; 
b Odds ratio is from the adjusted logistic model 


Statistical Analysis Plan - DMID Protocol: 17-0101 
Version 1.0 
22DEC2022 
- 86 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Table 41: 
Number and Percentage of Subjects Experiencing Unsolicited Adverse Events with 95% Confidence Intervals by MedDRA 
System Organ Class and Preferred Term, Dose Number, and Treatment Group — Safety Population 
MedDRA System 
Organ Class 
MedDRA 
Preferred Term 
Post Dose 1 
[One Dose BPG 2.4 
MU Group] 
(N = X) 
Post Dose 1 
[Three Doses BPG 2.4 
MU Group] 
(N = X) 
Post Dose 2 
[Three Doses BPG 2.4 
MU Group] 
(N = X) 
Post Dose 3 
[Three Doses BPG 2.4 
MU Group] 
(N = X) 
Post Any Dose 
[Three Doses BPG 2.4 
MU Group] 
(N = X) 
Overall 
(N = X) 
n 
% 
95% 
CI 
n 
% 
95% 
CI 
n 
% 
95% 
CI 
n 
% 
95% 
CI 
n 
% 
95% 
CI 
n 
% 
95% 
CI 
Any SOC 
Any PT 
x 
x 
x, x 
x 
x 
x, x 
x 
x 
x, x 
x 
x 
x, x 
x 
x 
x, x 
x 
X 
x, x 
[SOC 1] 
Any PT 
x 
x 
x, x 
x 
x 
x, x 
x 
x 
x, x 
x 
x 
x, x 
x 
x 
x, x 
x 
X 
x, x 
 
[PT 1] 
x 
x 
x, x 
x 
x 
x, x 
x 
x 
x, x 
x 
x 
x, x 
x 
x 
x, x 
x 
X 
x, x 
 
[PT 2] 
x 
x 
x, x 
x 
x 
x, x 
x 
x 
x, x 
x 
x 
x, x 
x 
x 
x, x 
x 
X 
x, x 
Notes: N = number of subjects in the specified treatment group and the Safety Population 
This table presents number and percentage of subjects. 95% CI= 95% Wilson Confidence Interval 
For each timepoint, a subject is only counted once per PT. For a subject who had an AE ongoing through multiple doses, do we count the subject once at the earliest dose when the AE started? That is, 
AE ongoing from post dose 1 to post dose 2, we’ll count the subject once in the post dose 1 column, and not in the post dose 2 column. 
 
Table with similar format: 
Table 42: 
Number and Percentage of Subjects Experiencing Related Unsolicited Adverse Events with 95% Confidence Intervals by 
MedDRA System Organ Class and Preferred Term, Dose Number, and Treatment Group — Safety Population 


Statistical Analysis Plan - DMID Protocol: 17-0101 
Version 1.0 
22DEC2022 
- 87 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Table 43: 
Number of Unsolicited Adverse Events by MedDRA System Organ Class and Preferred Term, Maximum Severity and 
Relationship, and Treatment Group — Safety Population 
[Implementation note: check if there were any Not Yet Determined events, report if yes.] 
MedDRA 
SOC 
Preferred 
Term 
Severity 
One Dose BPG 2.4 MU 
(n = X) 
Three Doses BPG 2.4 MU 
(n = X) 
All Subjects 
(n = X) 
Related 
Not Related 
Total 
Related 
Not Related 
Total 
Related 
Not Related 
Total 
Any SOC 
Any PT 
Any Severity 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
 
 
Mild 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
 
 
Moderate 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
 
 
Severe 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
SOC 1 
PT 1 
Any Severity 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
 
 
Mild 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
 
 
Moderate 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
 
 
Severe 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
 
PT 2 
Any Severity 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
 
 
Mild 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
 
 
Moderate 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
 
 
Severe 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
Note: n = Number of events for subjects in the Safety Population. 
 


Statistical Analysis Plan - DMID Protocol: 17-0101 
Version 1.0 
22DEC2022 
- 88 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Table 44: 
Number and Percentage of Subjects Experiencing Unsolicited Adverse Events by MedDRA System Organ Class and Preferred 
Term, Maximum Severity and Relationship, and Treatment Group — Safety Population 
MedDRA 
System Organ 
Class 
Preferred 
Term 
Severity 
One Dose BPG 2.4 MU 
(N = X) 
Three Doses BPG 2.4 MU 
(N = X) 
All Subjects 
(N = X) 
Related 
Not Related 
Total 
Related 
Not Related 
Total 
Related 
Not Related 
Total 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Any SOC 
Any PT 
Any Severity 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
 
 
Mild 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
 
 
Moderate 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
 
 
Severe 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
SOC 1 
PT 1 
Any Severity 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
 
 
Mild 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
 
 
Moderate 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
 
 
Severe 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
 
PT 2 
Any Severity 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
 
 
Mild 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
 
 
Moderate 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
 
 
Severe 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
x  
xx 
Notes: N = Number of subjects in the Safety Population. 
For severity, a subject is counted once per preferred term and is summarized according to their highest severity. 
 


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Table 45: 
Unsolicited Adverse Events Occurring in ≥5% of Subjects in Any Treatment Group by MedDRA System Organ Class, Preferred 
Term, and Treatment Group - Safety Population 
Preferred Term 
MedDRA System Organ Class 
One Dose BPG 2.4 MU 
(N = X) 
Three Doses BPG 2.4 MU 
(N = X) 
All Subjects 
(N=X) 
n 
% 
Events 
n 
% 
Events 
n 
% 
Events 
Serious Adverse Events 
All  
All 
x 
x 
x 
x 
x 
x 
x 
X 
x 
PT1 
SOC1 
x 
x 
x 
x 
x 
x 
x 
X 
x 
Etc. 
Etc. 
x 
x 
x 
x 
x 
x 
x 
X 
x 
Non-serious Adverse Events 
All  
All 
x 
x 
x 
x 
x 
x 
x 
X 
x 
PT1 
SOC1 
x 
x 
x 
x 
x 
x 
x 
X 
x 
Etc 
Etc 
x 
x 
x 
x 
x 
x 
x 
X 
x 
N = number of subjects in the specified treatment group and the Safety Population  
n= number of subjects reporting event.  
Events= total frequency of events reported. 
 
Table with similar format: 
Table 46: 
Solicited Adverse Events Occurring in ≥5% of Subjects in Any Treatment Group by MedDRA System Organ Class, Preferred 
Term, and Treatment Group - Safety Population 
 


Statistical Analysis Plan - DMID Protocol: 17-0101 
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Table 47: 
Listing of Serious Adverse Events – All Enrolled Subjects  
[Implementation Notes: If the event is ongoing (no stop date), indicate “ongoing” in the “Duration” column. In the “If Not Related, Alternate Etiology” 
column, merge the 2 data fields for collecting alternate etiology, separate by a colon. If there are no comments for an event, populate ‘Comments’ row 
with ‘None’. In the CSR, Subject ID should be USUBJID (not PATID) for purposes of de-identification. Listing should be sorted by treatment group, 
Subject ID, AE Number. 
Show footnote if the following scenario exist: Notes: Subjects are excluded from Safety Population if it is unknown whether they received at least one 
dose, but the adverse events of such subjects are included in the AE listings] 
Adverse 
Event 
Associated 
with Dose 
No. 
No. of Days 
Post 
Associated 
Dose 
Duration 
(Days) 
Severity 
SAE? 
Relationship 
to Study 
Treatment 
In Not 
Related, 
Alternative 
Etiology 
Action Taken 
with Study 
Treatment 
Subject 
Discontinued 
Due to AE 
Outcome 
MedDRA 
System 
Organ 
Class 
MedDRA 
Preferred 
Term 
Treatment Group: ,  Subject ID:   , AE Number:  
xxxxxxx 
xx 
x 
x 
xxxxxx 
xxxxxx 
xxxxxx 
xxxxx 
xxxxxx 
Y/N 
xxxxx 
xxxxx 
xxxxx 
Comments: xxxxxxxxxxxxx 
 
Treatment Group: ,  Subject ID:   , AE Number:  
xxxxxxx 
xx 
x 
x 
xxxxxx 
xxxxxx 
xxxxxx 
xxxxx 
xxxxxx 
Y/N 
xxxxx 
Xxxxx 
xxxxx 
Comments: xxxxxxxxxxxxx 


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Table 48: 
Listing of Non-Serious, Unsolicited Adverse Events – All Enrolled Subjects  
[Implementation Notes: If the event is ongoing (no stop date), indicate “ongoing” in the “Duration” column. In the “If Not Related, Alternate Etiology” 
column, merge the 2 data fields for collecting alternate etiology, separate by a colon. If there are no comments for an event, populate ‘Comments’ row 
with ‘None’. In the CSR, Subject ID should be USUBJID (not PATID) for purposes of de-identification. Listing should be sorted by Treatment Group, 
Subject ID, AE Number. 
Show footnote if the following scenario exist: Notes: Subjects are excluded from Safety Population if it is unknown whether they received at least one 
dose, but the adverse events of such subjects are included in the AE listings.] 
Adverse 
Event 
Associated 
with Dose 
No. 
No. of Days 
Post 
Associated 
Dose 
Duration 
(Days) 
Severity 
SAE? 
Relationship 
to Study 
Treatment 
In Not Related, 
Alternative 
Etiology 
Action Taken 
with Study 
Treatment 
Subject 
Discontinued 
Due to AE 
Outcome 
MedDRA 
System 
Organ 
Class 
MedDRA 
Preferred 
Term 
Treatment Group: ,  Subject ID:   , AE Number:  
xxxxxxx 
xx 
x 
x 
xxxxxx 
xxxxxx 
xxxxxx 
xxxxx 
xxxxxx 
Y/N 
xxxxx 
xxxxx 
xxxxx 
Comments: xxxxxxxxxxxxx 
 
Treatment Group: ,  Subject ID:   , AE Number:  
xxxxxxx 
xx 
x 
x 
xxxxxx 
xxxxxx 
xxxxxx 
xxxxx 
xxxxxx 
Y/N 
xxxxx 
Xxxxx 
xxxxx 
Comments: xxxxxxxxxxxxx 


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Narratives of Deaths, Other Serious and Significant Adverse Events 
(not included in SAP, but this is a placeholder for the CSR)


Statistical Analysis Plan - DMID Protocol: 17-0101 
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Table 49: 
Laboratory Summary Statistics by Time Point and Treatment Group – CD4 Count in HIV-infected Subjects 
[Implementation notes:  
1. For calculated fields (Mean, SD, Median), decimal place should be the format in which the data were collected + 1 extra place. For Min, Max, decimal 
place should be in the same format in which the data were collected. 
2. If there are test results at interim visits, e.g., 06S, 06T, include them in the corresponding scheduled visit under “Time Point” column, e.g., Visit 6.] 
Time Point 
Variable 
Treatment Group 
N 
Mean 
Standard Deviation 
Median 
Min, Max 
Visit 1 
(Day 1) 
CD4 count 
One Dose BPG 2.4 MU 
x 
xx.x 
xx.x 
xx.x 
xx.x, xx.x 
Three Doses BPG 2.4 MU 
 
 
 
 
 
Visit 4 
(Day 30±7 days) 
CD4 count 
One Dose BPG 2.4 MU 
 
 
 
 
 
Three Doses BPG 2.4 MU 
 
 
 
 
 
Change from 
Baseline 
One Dose BPG 2.4 MU 
 
 
 
 
 
Three Doses BPG 2.4 MU 
 
 
 
 
 
Visit 6 
(Day 180±21 days) 
CD4 count 
One Dose BPG 2.4 MU 
 
 
 
 
 
Three Doses BPG 2.4 MU 
 
 
 
 
 
Change from 
Baseline 
One Dose BPG 2.4 MU 
 
 
 
 
 
Three Doses BPG 2.4 MU 
 
 
 
 
 
Visit 8 
(Day 360±28 days) 
CD4 count 
One Dose BPG 2.4 MU 
 
 
 
 
 
Three Doses BPG 2.4 MU 
 
 
 
 
 
Change from 
Baseline 
One Dose BPG 2.4 MU 
 
 
 
 
 
Three Doses BPG 2.4 MU 
 
 
 
 
 
Note: N = Number of subjects in the Safety Population who had CD4 Counts at the specified time point. Test results between scheduled visits are included in the most recent visits.  
 


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Table 50: 
Laboratory Summary Statistics by Time Point and Treatment Group – Viral Load in HIV-infected Subjects 
[Implementation notes:  
1. For calculated fields (Mean, SD, Median), decimal place should be the format in which the data were collected + 1 extra place. For Min, Max, decimal 
place should be in the same format in which the data were collected. 
2. If there are test results at interim visits, e.g., 06S, 06T, include them in the corresponding scheduled visit under “Time Point” column, e.g., Visit 6.] 
Time Point 
Treatment Group 
N 
Mean 
Standard Deviation 
Median 
Min, Max 
Detectable Viral Load 
Visit 1 
(Day 1) 
One Dose BPG 2.4 MU 
x 
xx.x 
xx.x 
xx.x 
xx.x, xx.x 
Three Doses BPG 2.4 MU 
 
 
 
 
 
Visit 2  
(Day 7-13days) 
One Dose BPG 2.4 MU 
 
 
 
 
 
Three Doses BPG 2.4 MU 
 
 
 
 
 
Visit 3  
(Day 13±23 days) 
One Dose BPG 2.4 MU 
 
 
 
 
 
Three Doses BPG 2.4 MU 
 
 
 
 
 
Visit 4  
(Day 30±7 days) 
One Dose BPG 2.4 MU 
 
 
 
 
 
Three Doses BPG 2.4 MU 
 
 
 
 
 
Notes: N = Number of subjects in the Safety Population who had CD4 Counts at the specified time point. 
 


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Table 51: 
Vital Signs by Maximum Severity, Time Point, and Treatment Group – Any Assessment – Safety Population 
[Implementation Note: Generate one table for “Any Assessment” and one table for each assessment as listed below.] 
Time Point 
Treatment Group 
N 
None 
Mild 
Moderate 
Severe 
Missing 
n 
% 
n 
% 
n 
% 
n 
% 
N 
% 
Visit 1 
One Dose BPG 2.4 MU 
x 
x 
xx 
x 
xx 
x 
xx 
x 
xx 
X 
xx 
 
Three Doses BPG 2.4 MU 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
Visit 8 
One Dose BPG 2.4 MU 
 
 
 
 
 
 
 
 
 
 
 
 
Three Doses BPG 2.4 MU 
 
 
 
 
 
 
 
 
 
 
 
Max Severity Post Baseline 
One Dose BPG 2.4 MU 
 
 
 
 
 
 
 
 
 
 
 
 
Three Doses BPG 2.4 MU 
 
 
 
 
 
 
 
 
 
 
 
Notes: The “Max Severity Post Baseline” row indicate the maximum severity experienced by each subject at any time point post baseline, including unscheduled assessments. N = Number of subjects in 
the Safety Population. 
Grading scales: 
Temperature: Grade 1: 38.0 - <38.6°C; Grade 2: 38.6 - <39.3°C; Grade 3: ≥39.3°C 
Blood Pressure: Grade 1: 140 – 159 mmHg systolic OR 90 – 99 mmHg diastolic; Grade 2: 160 – 179 mmHg systolic OR 100 – 109 mmHg diastolic; Grade 3: ≥180 mmHg systolic OR ≥110 mmHg 
diastolic OR hospitalization indicated 
Pulse: Grade 1: 101-115 or 50-54 or 45-50 if baseline <60bpm; Grade 2: 116-130 or 45-49 or 40-44 if baseline <60bpm; Grade 3: >130 or ventricular dysrhythmias or <45 or <40 if baseline <60bpm 
Respiration: Grade 1: 23-25; Grade 2: 26-30; Grade 3: >30 
 
Tables with similar format: 
Table 52: 
Vital Signs by Maximum Severity, Time Point, and Treatment Group – Temperature – Safety Population 
Table 53: 
Vital Signs by Maximum Severity, Time Point, and Treatment Group – Blood Pressure – Safety Population 
Table 54: 
Vital Signs by Maximum Severity, Time Point, and Treatment Group – Pulse – Safety Population 
Table 55: 
Vital Signs by Maximum Severity, Time Point, and Treatment Group – Respiration – Safety Population 
 


Statistical Analysis Plan - DMID Protocol: 17-0101 
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APPENDIX 2. FIGURE MOCK-UPS 
LIST OF FIGURES 
Figure 1: 
CONSORT Flow Diagram .........................................................................................97 
Figure 2: 
Rapid Plasma Reagin Titer per Subject by Month 6 -ITT population ........................98 
Figure 3: 
Rapid Plasma Reagin Titer per Subject by Month 6 -mITT population .....................98 
Figure 4: 
Rapid Plasma Reagin Titer per Subject by Month 6 -Evaluable population ..............98 
Figure 5: 
Rapid Plasma Reagin Titer per Subject by Month 12 -ITT population ......................98 
Figure 6: 
Rapid Plasma Reagin Titer per Subject by Month 12 -Evaluable population ............98 
Figure 7: 
Rapid Plasma Reagin Titer per Subject by Treatment and Baseline HIV 
Status by Month 6 -ITT population ............................................................................98 
Figure 8: 
Rapid Plasma Reagin Titer per Subject by Treatment and Baseline HIV 
Status by Month 6 -Evaluable population ..................................................................98 
Figure 9: 
Rapid Plasma Reagin Titer per Subject by Treatment and Baseline HIV 
Status by Month 12 -ITT population ..........................................................................98 
Figure 10: Rapid Plasma Reagin Titer per Subject by Treatment and Baseline HIV 
Status by Month 12 -Evaluable population ................................................................98 
Figure 11: Difference in Proportion of Subjects with Serological Response Between 
Two Treatment Groups by Month 6 ...........................................................................99 
Figure 12: Difference in Proportion of Subjects with Serological Response Between 
Two Treatment Groups by Month 12 .........................................................................99 
Figure 13: Maximum Severity of Jarisch-Herxheimer reaction per Subject by Time Post 
First Dose - Safety Population ..................................................................................100 
Figure 14: Maximum Severity of Solicited Local Symptoms per Subject by Dose - 
Safety Population ......................................................................................................101 
Figure 15: Number of Related Unsolicited Adverse Events by MedDRA System Organ 
Class and Severity - Safety Population .....................................................................102 
Figure 16: Number and Percentage of Subjects Experiencing Related Unsolicited 
Adverse Events by MedDRA® System Organ Class and Maximum Severity 
- Safety Population ...................................................................................................103 
Figure 17: Number of Unsolicited Adverse Events by MedDRA System Organ Class 
and Relationship to Treatment - Safety Population ..................................................104 
Figure 18: Number and Percentage of Subjects Experiencing Unsolicited Adverse 
Events by MedDRA System Organ Class and Relationship to Treatment - 
Safety Population ......................................................................................................105 
 


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Figure 1: 
CONSORT Flow Diagram 
 
Allocated to One Dose BPG 2.4 MU (n=x) 
 Received allocated intervention (n=x) 
 Did not receive allocated intervention (n=x) 
[Reason 1] (x), [Reason 2] (x) 
Discontinued Intervention (n=x) 
 [Covid-19] (x), [Reason 2] (x) 
Early Termination (n=x) 
 [Covid-19] (x), [Reason 2] (x) 
Analysed for ITT analyses (n=x) 
 Excluded from ITT analyses (n=x) 
[Reason 1] (x), [Reason 2] (x) 
Analysed for mITT analyses (n=x) 
 Excluded from mITT analyses (n=x) 
[Reason 1] (x), [Reason 2] (x) 
Analysed for Evaluable by Month 6 
analyses (n=x) 
 Excluded from Evaluable by Month 6 
analyses (n=x) 
[Reason 1] (x), [Reason 2] (x) 
Analysed for Evaluable by Month 12 
analyses (n=x) 
 Excluded from Evaluable by Month 12 
analyses (n=x) 
[Reason 1] (x), [Reason 2] (x 
Analyzed for safety (n=x) 
 Excluded from safety analyses (n=x) 
[Reason 1] (x), [Reason 2] (x) 
Assessed for Eligibility (n=x) 
Excluded* (n=x) 
   [Reason 1] (n=x) 
   Concern of potential risk (n=x) 
Randomized (n=x) 
Allocation 
Analysis 
Follow-Up 
Enrollment 
Allocated to Three Doses BPG 2.4 MU (n=x) 
 Received allocated intervention (n=x) 
 Did not receive allocated intervention (n=x) 
[Reason 1] (x), [Reason 2] (x) 
Analysed for ITT analyses (n=x) 
 Excluded from ITT analyses (n=x) 
[Reason 1] (x), [Reason 2] (x) 
Analysed for mITT analyses (n=x) 
 Excluded from mITT analyses (n=x) 
[Reason 1] (x), [Reason 2] (x) 
Analysed for Evaluable by Month 6 
analyses (n=x) 
 Excluded from Evaluable by Month 6 
analyses (n=x) 
[Reason 1] (x), [Reason 2] (x) 
Analysed for Evaluable by Month 12 
analyses (n=x) 
 Excluded from Evaluable by Month 12 
analyses (n=x) 
[Reason 1] (x), [Reason 2] (x 
Analyzed for safety (n=x) 
 Excluded from safety analyses (n=x) 
[Reason 1] (x), [Reason 2] (x) 
Excluded* (n=x) 
   Failed to Ranomization 


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Figure 2: 
Rapid Plasma Reagin Titer per Subject by Month 6 -ITT population  
[Implementation Notes: this is a generic plot 
• Change the “Visits” (X axis) into “Time”, then label the X-axis by “Baseline”, “Week 1” “Week 2”, 
“Month 1”,  “Month 3”, and “Month 6”. 
• The dash line is the RPR titer for each subject at each timepoint; 
• The black line is the Geometric Mean Titer at each time point 
• Change the Group names to the treatment arms. 
• Color can be changed] 
 
Figures with a similar format: 
Figure 3: 
Rapid Plasma Reagin Titer per Subject by Month 6 -mITT population  
Figure 4: 
Rapid Plasma Reagin Titer per Subject by Month 6 -Evaluable population  
Figure 5: 
Rapid Plasma Reagin Titer per Subject by Month 12 -ITT population  
Figure 6: 
Rapid Plasma Reagin Titer per Subject by Month 12 -Evaluable population  
Figure 7: 
Rapid Plasma Reagin Titer per Subject by Treatment and Baseline HIV Status by Month 
6 -ITT population  
Figure 8: 
Rapid Plasma Reagin Titer per Subject by Treatment and Baseline HIV Status by Month 
6 -Evaluable population  
Figure 9: 
Rapid Plasma Reagin Titer per Subject by Treatment and Baseline HIV Status by Month 
12 -ITT population  
Figure 10: 
Rapid Plasma Reagin Titer per Subject by Treatment and Baseline HIV Status by Month 
12 -Evaluable population 


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Figure 11: 
Difference in Proportion of Subjects with Serological Response Between Two Treatment 
Groups by Month 6 
[Implementation Notes: this is a generic plot,  
The dark block is the estimates of difference of proportion of serological response between three dose vs one 
dose; the horizontal line and two bars are the one-sided 95% confidence interval;   
The dash vertical line is the non-inferiority margin 0.10.   ]  
 
 
Figures with a similar format: 
Figure 12: 
Difference in Proportion of Subjects with Serological Response Between Two Treatment 
Groups by Month 12


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Figure 13: 
Maximum Severity of Jarisch-Herxheimer reaction per Subject by Time Post First Dose - 
Safety Population 
[Implementation Notes: 
• Include a panel on the right for “All Subjects” 
• Change the time points (vertical axis) into “Time Post First Dose (Hours)” 0-12 hours, >12-24 hours, 
>24-48 hours] 
 
 


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Figure 14: 
Maximum Severity of Solicited Local Symptoms per Subject by Dose - Safety Population 
[Implementation Notes: 
• Include a panel on the right for “All Subjects” 
• Change the time points into “Dose” Post Dose 1, Post Dose 2, Post Dose 3] 
 
 


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Figure 15: 
Number of Related Unsolicited Adverse Events by MedDRA System Organ Class and 
Severity - Safety Population 
[Implementation Notes: 
• Include a panel on the right for “All Subjects”] 
 
 


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Figure 16: 
Number and Percentage of Subjects Experiencing Related Unsolicited Adverse Events by 
MedDRA® System Organ Class and Maximum Severity - Safety Population 
[Implementation Notes: 
• Include a panel on the right for “All Subjects”] 
 
 


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Figure 17: 
Number of Unsolicited Adverse Events by MedDRA System Organ Class and Relationship to Treatment - Safety Population 
[Implementation Note: 
• Include “Any SOC” bars 
• Two treatment groups are One Dose BPG 2.4 MU and Three Doses BPG 2.4 MU 
• Put “All Subjects” panel on the right] 
 


Statistical Analysis Plan - DMID Protocol: 17-0101 
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Figure 18: 
Number and Percentage of Subjects Experiencing Unsolicited Adverse Events by MedDRA System Organ Class and Relationship 
to Treatment - Safety Population 
[Implementation Note: 
• Include “Any SOC” bars 
• Two treatment groups are One Dose BPG 2.4 MU and Three Doses BPG 2.4 MU 
• Put “All Subjects” panel on the right 
• Legend see Figure 5, number of subject/total] 
 


Statistical Analysis Plan - DMID Protocol: 17-0101 
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APPENDIX 3. LISTINGS MOCK-UPS 
LISTINGS 
Listing 1: Subjects Excluded from Analysis Populations .........................................................108 
Listing 2: Early Terminations or Discontinued Subjects-All Enrolled Subjects ......................109 
Listing 3: Subject-Specific Protocol Deviations-All Enrolled Subjects ...................................110 
Listing 4: Non-Subject-Specific Protocol Deviations ...............................................................111 
Listing 5: Individual Efficacy Response Data - All Enrolled Subjects .....................................112 
Listing 6: Compliance Data - All Enrolled Subjects .................................................................113 
Listing 7: Demographic and Other Baseline Characteristics - All Enrolled Subjects ..............114 
Listing 8: Sexual Behavior History Part I -All Enrolled Subjects ............................................115 
Listing 9: Sexual Behavior History Part II - All Enrolled Subjects ..........................................116 
Listing 10: Sexual Behavior History Part III  - Sexually Transmitted Disease Testing 
History at Baseline - All Enrolled Subjects ..............................................................117 
Listing 11: Sexually Transmitted Infections (STI) Testing result ..............................................118 
Listing 12: Pre-Existing and Concurrent Medical Conditions ....................................................119 
Listing 13: Concomitant Medications .........................................................................................120 
Listing 14: Solicited Systemic Reaction Events – Safety Population .........................................121 
Listing 15: Solicited Local Reaction Events – Safety Population ..............................................122 
Listing 16: Unsolicited Adverse Events - Safety Population ......................................................124 
Listing 17: Pregnancy Reports – Maternal Information .............................................................125 
Listing 18: Pregnancy Reports – Gravida and Para ....................................................................126 
Listing 19: Pregnancy Reports – Live Birth Outcomes ..............................................................127 
Listing 20: Pregnancy Reports – Still Birth Outcomes ...............................................................128 
Listing 21: Pregnancy Reports – Spontaneous, Elective, or Therapeutic Abortion 
Outcomes ..................................................................................................................129 
Listing 22: Syphilis Clinical Assessment ....................................................................................130 
Listing 23: HIV Testing – All Enrolled Subjects ........................................................................131 
Listing 24: TPPA Testing - All Enrolled Subjects ......................................................................132 
Listing 25: Vital Signs – Safety Population ................................................................................133 
Listing 26: Abnormal Physical Exam Findings ..........................................................................134 
 


Statistical Analysis Plan - DMID Protocol: 17-0101 
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Listing of Subjects Receiving Investigational Product 
(not included in SAP, but this is a placeholder for the CSR) 
 


Statistical Analysis Plan - DMID Protocol: 17-0101 
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Listing 1: 
Subjects Excluded from Analysis Populations 
Implementation Notes:   
1. Sort order will be Treatment group, Subject ID 
2. Reasons Subject Excluded 1) should be N/A if the subject was not excluded from any analysis population; 2) should match the same verbiage that is 
used on the Analysis population tables unless it’s a special case recorded in the study plan with the reason confirmed by the PI before study lock.] 
Randomized Treatment Group 
Subject ID 
Analyses in which 
Subject is Included 
Analyses from which  
Subject is Excluded 
Results Available? 
Reason(s) Subject Excluded 
One Dose BPG 2.4 MU /  
Three Doses BPG 2.4 MU 
xxxxxx 
[e.g., Safety, ITT, mITT, 
Evaluable by Month 6, Evaluable 
by Month 12] 
[e.g., Safety, ITT, mITT, 
Evaluable by Month 6, Evaluable 
by Month 12] 
Yes/No 
xxxxx/N/A 
One Dose BPG 2.4 MU /  
Three Doses BPG 2.4 MU 
xxxxxx 
[e.g., Safety, ITT, mITT, 
Evaluable by Month 6, Evaluable 
by Month 12] 
[e.g., Safety, ITT, mITT Evaluable 
by Month 6, Evaluable by Month 
12] 
Yes/No 
xxxxx/N/A 
One Dose BPG 2.4 MU /  
Three Doses BPG 2.4 MU 
xxxxxx 
[e.g., Safety, ITT, mITT, 
Evaluable by Month 6, Evaluable 
by Month 12] 
[e.g., Safety, ITT, mITT Evaluable 
by Month 6, Evaluable by Month 
12] 
Yes/No 
xxxxx/N/A 
Note: If the subject was excluded from any analysis population, “Yes” in the “Results Available” column indicates that available data were removed from the analysis. If the subject was not excluded 
from any analysis population, “Yes” in the “Results Available” column indicates that data was available for all analysis populations. “No” indicates that no data were available for inclusion in the 
analysis. 


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Listing 2: 
Early Terminations or Discontinued Subjects-All Enrolled Subjects 
[Implementation Notes:   
1.  Sort order will be by Treatment Group, Subject ID, Category 
2. Category will be "Early Termination" or "Treatment Discontinuation". If a subject discontinued treatment and terminated early, they will have two 
records. 
3. In the “Reason” column, concatenate any “specify” fields, including AE number and DV number.] 
Randomized Treatment Group 
Subject ID 
Category 
Study Day Corresponding to Early 
Termination/Treatment 
Discontinuation/Completion 
Reason for Early Termination or 
Treatment Discontinuation 
One Dose BPG 2.4 MU / 
Three Doses BPG 2.4 MU 
xxxxxxx 
Early Termination/Treatment 
Discontinuation 
xx 
xxxxxxxxxxxxxxxxx/N/A 
One Dose BPG 2.4 MU / 
Three Doses BPG 2.4 MU 
xxxxxxx 
Early Termination/Treatment 
Discontinuation 
xx 
xxxxxxxxxxxxxxxxx/N/A 
Note.  Subjects who had early terminated or discontinued due to Covid-19 are flagged. 


Statistical Analysis Plan - DMID Protocol: 17-0101 
Version 1.0 
22DEC2022 
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PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Listing 3: 
Subject-Specific Protocol Deviations-All Enrolled Subjects 
[Implementation Notes:   
1. Treatment group is the randomized treatment group. 
2. Sort order will be by Treatment Group, Subject ID, Deviation Number. 
3. Deviation description column will contain all subfields concatenated together.   
4. In the Reason for Deviation column concatenate any specified fields.] 
Treatment 
Group 
Subject ID 
Deviation 
Number 
Study 
Day 
Deviation 
Description 
Deviation 
Category 
Reason for 
Deviation 
Deviation 
Affected 
Product 
Stability? 
Deviation 
Resulted in 
AE? 
Deviation 
Resulted in 
Subject 
Termination? 
Deviation 
Resolution 
Comments 
xxxx 
xxxxx 
xx 
xx 
xxxxxxx 
xxxxxxxxxxx 
xxxxxxx 
Yes/No/ 
N/A 
Yes/No 
Yes/No 
Yes/No 
xxxxxxxxxxx 
xxxx 
xxxxx 
xx 
xx 
xxxxxxx 
xxxxxxxxxxx 
xxxxxxx 
Yes/No/ 
N/A 
Yes/No 
Yes/No 
Yes/No 
-- 
Note.  Subjects who had deviation due to Covid-19 are flagged. 
 


Statistical Analysis Plan - DMID Protocol: 17-0101 
Version 1.0 
22DEC2022 
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PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Listing 4: 
Non-Subject-Specific Protocol Deviations 
[Implementation Notes:   
1. Sort order will be by Site Name, Start Date 
2. In the Deviation column concatenate any specified fields  
3. In the Reason for Deviation column concatenate any specified fields.] 
Site 
Start Day 
Deviation 
End Day 
Reason for 
Deviation 
Deviation Resulted 
in Subject 
Termination? 
Deviation Affected 
Product Stability? 
Deviation 
Category 
Deviation 
Resolution 
Comments 
xxxx 
xx 
xxxx 
xx 
xxxx 
Yes/No 
Yes/No/N/A 
xxxx 
xxxx 
Xxxx 
xxxx 
xx 
xxxx 
xx 
xxxx 
Yes/No 
Yes/No/N/A 
xxxx 
xxxx 
Xxxx 
Note.  Deviation due to Covid-19 are flagged. 


Statistical Analysis Plan - DMID Protocol: 17-0101 
Version 1.0 
22DEC2022 
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PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Listing 5: 
Individual Efficacy Response Data - All Enrolled Subjects 
[Implementation Notes:   
1. Sort order will be by Treatment Group and Subject ID, Planned Time Point. ] 
Randomized Treatment 
Group 
Subject 
ID 
Planned Time 
Point 
Actual 
Testing 
Study Day 
RPR  
Result 
RPR 
Titer 
 Ratio to 
baseline 
Serological 
Response to 
Therapy by 
Month 6  
Serological 
Response to 
Therapy by 
Month 12 
Serological Response to Therapy 
for Exploratory Efficacy Analysis 
One Dose BPG 2.4 MU / Three 
Doses BPG 2.4 MU 
xxxxx 
Visit 1 
xxx 
REACTIVE/NON-
REACTIVE/INVALID 
xxx 
- 
- 
 
- 
One Dose BPG 2.4 MU / Three 
Doses BPG 2.4 MU 
xxxxx 
Visit 2 
xxx 
REACTIVE/NON-
REACTIVE/INVALID 
xxx 
xx 
Response/  
Non-Response 
Response/  
Non-Response 
Response/ 
Non-Response/ 
Failure 
One Dose BPG 2.4 MU / Three 
Doses BPG 2.4 MU 
xxxxx 
Visit 3 
xxx 
REACTIVE/NON-
REACTIVE/INVALID 
xxx 
xx 
One Dose BPG 2.4 MU / Three 
Doses BPG 2.4 MU 
xxxxx 
Visit 4 
xxx 
REACTIVE/NON-
REACTIVE/INVALID 
xxx 
xx 
One Dose BPG 2.4 MU / Three 
Doses BPG 2.4 MU 
xxxxx 
Visit 5 
xxx 
REACTIVE/NON-
REACTIVE/INVALID 
xxx 
xx 
One Dose BPG 2.4 MU / Three 
Doses BPG 2.4 MU 
xxxxx 
Visit 6 
xxx 
REACTIVE/NON-
REACTIVE/INVALID 
xxx 
xx 
One Dose BPG 2.4 MU / Three 
Doses BPG 2.4 MU 
xxxxx 
Early 
Termination 
prior to month 
6 
xxx 
REACTIVE/NON-
REACTIVE/INVALID 
xxx 
xx 
 
One Dose BPG 2.4 MU / Three 
Doses BPG 2.4 MU 
xxxxx 
Visit 7 
xxx 
REACTIVE/NON-
REACTIVE/INVALID 
xxx 
xx 
NA 
NA 
One Dose BPG 2.4 MU / Three 
Doses BPG 2.4 MU 
xxxxx 
Visit 8 
xxx 
REACTIVE/NON-
REACTIVE/INVALID 
xxx 
xx 
One Dose BPG 2.4 MU / Three 
Doses BPG 2.4 MU 
xxxxx 
Early 
Termination 
after month 8 
xxx 
REACTIVE/NON-
REACTIVE/INVALID 
xxx 
xx 


Statistical Analysis Plan - DMID Protocol: 17-0101 
Version 1.0 
22DEC2022 
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PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Listing 6: 
Compliance Data - All Enrolled Subjects 
[Implementation Notes: 
1. Sort order is Randomized treatment Group, Subject ID, Visit.] 
Treatment Group 
Subject ID 
Planned Time Point 
Actual Study Day 
Dose Administered within the 
Assigned Visit Window? 
Compliance Status 
One Dose BPG 2.4 MU 
xxxxxx 
Visit 1 
xx 
Yes/No 
Compliant/Non-compliant 
Three Doses BPG 2.4 MU 
xxxxxx 
 Visit 1 
xx 
Yes/No 
Compliant/Non-compliant 
Visit 2 
xx 
Yes/No 
Visit 3 
xx 
Yes/No 
 


Statistical Analysis Plan - DMID Protocol: 17-0101 
Version 1.0 
22DEC2022 
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PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Listing 7: 
Demographic and Other Baseline Characteristics - All Enrolled Subjects 
[Implementation Notes:   
1. Sort order will be by Treatment Group, Subject ID 
2. For the Race column, if a subject is Multi-Racial, all races will be listed, separated by a comma] 
Randomized Treatment 
Group 
Subject ID 
Sex 
Age at Enrollment 
(years) 
Ethnicity 
Race 
Baseline HIV 
Status 
Highest Level of 
Education the Subject 
Has Completed 
Number of Years of 
Formal Education 
the Subject 
Completed 
One Dose BPG 2.4 MU / 
Three Doses BPG 2.4 MU 
xxxxxx 
Male/Female 
xx 
xxxxxx 
xxxxxx 
HIV-
infected/HIV-
uninfected 
xxx/xxx/xxx/xxx/xxx 
xx 
One Dose BPG 2.4 MU / 
Three Doses BPG 2.4 MU 
xxxxxx 
Male/Female 
xx 
xxxxxx 
xxxxxx 
HIV-
infected/HIV-
uninfected 
xxx/xxx/xxx/xxx/xxx 
xx 
One Dose BPG 2.4 MU / 
Three Doses BPG 2.4 MU 
xxxxxx 
Male/Female 
xx 
xxxxxx 
xxxxxx 
HIV-
infected/HIV-
uninfected 
xxx/xxx/xxx/xxx/xxx 
xx 
 


Statistical Analysis Plan - DMID Protocol: 17-0101 
Version 1.0 
22DEC2022 
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PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Listing 8: 
Sexual Behavior History Part I -All Enrolled Subjects 
[Implementation Notes:   
1. Sort order will be by Treatment Group, Subject ID 
2. If the subject has used “other” gender identity or sexual orientation, list the specified field in the cell. 
4. Missing response will be populated as “Not Reported”. 
5. For “Any known exposures to STD” variable, if response was Yes or Unknown, concatenate the SX2 Comments field.] 
Time Point 
Subject's gender 
identity 
Subject's sexual 
orientation 
Subject’s sexual 
partner 
Treated or Require 
Retreatment for Syphilisa  
How was 
retreatment 
need 
determinedb? 
Any known exposures 
to syphilis since the last 
study visit?  
Any known 
exposures to STDc? 
Treatment Group:    , Subject ID: 
Visit 1 
Man / Woman / Trans 
Male / Trans Female / 
Genderqueer / Multiple / 
Non-binary / Other 
Heterosexual / Homosexual / 
Bisexual / Other 
xxx / xxx/… 
N/A 
N/A 
N/A 
Yes / No / Unknown 
Visit 2 
N/A 
N/A 
N/A 
Yes/No/Unknown 
xxxx 
Yes/No/Unknown 
Yes / No / Unknown 
Visit 3 
N/A 
N/A 
N/A 
Yes/No/Unknown 
xxxx 
Yes/No/Unknown 
Yes / No / Unknown 
Visit 4 
N/A 
N/A 
N/A 
Yes/No/Unknown 
xxxx 
Yes/No/Unknown 
Yes / No / Unknown 
Visit 5 
N/A 
N/A 
N/A 
Yes/No/Unknown 
xxxx 
Yes/No/Unknown 
Yes / No / Unknown 
Visit 6 
N/A 
N/A 
N/A 
Yes/No/Unknown 
xxxx 
Yes/No/Unknown 
Yes / No / Unknown 
Visit 7 
N/A 
N/A 
N/A 
Yes/No/Unknown 
xxxx 
Yes/No/Unknown 
Yes / No / Unknown 
Visit 8 
N/A 
N/A 
N/A 
Yes/No/Unknown 
xxxx 
Yes/No/Unknown 
Yes / No / Unknown 
Notes: Subject’s gender identity, subject’s sexual orientation, and subject’s sexual partner are baseline questions only. Treated or require retreatment for syphilis, how was retreatment determined, and 
any known exposures to syphilis since the last study visit are follow-up questions only. 
a Was the subject treated or does the subject require retreatment for syphilis infection apart from study treatment received according to their randomization assignment?  
b If the subject was treated or require retreatment for syphilis infection apart from study treatment received according to their randomization assignment, how was retreatment need determined?  
c The question is “Did the subject have any known exposures to an STD in the past 60 days?” for Visit 1, and “Any known exposures to another STD since the last study visit?” for the follow-up visits. 


Statistical Analysis Plan - DMID Protocol: 17-0101 
Version 1.0 
22DEC2022 
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PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Listing 9: 
Sexual Behavior History Part II - All Enrolled Subjects 
[Implementation Notes:   
1. Sort order will be by Treatment Group, Subject ID  
3. Missing response will be populated as “Not Reported”. 
4. If the subject had sexual intercourse in the past 60 days or since the last visit, then the cells will be “N/A”.] 
Time 
Point 
Has the Subject Had 
Sexual Intercourse in 
the Specified 
Timeframe? 
Days Since the 
Subject Last 
Had Sexual 
Intercourse in 
the Specified 
Timeframe 
Sites of Exposure in 
the Specified 
Timeframe 
How Often Was 
a Condom or 
Barrier for 
Protection Used 
in the Specified 
Timeframe? 
Total 
Number of 
Sexual 
Partners in 
the Specified 
Timeframe 
Number of 
New 
Partners in 
the Specified 
Timeframe 
Number of 
Regular 
Partners in 
the Specified 
Timeframe 
Number of 
Occasional 
Partners in 
the Specified 
Timeframe 
Number of 
Male 
Partners in 
the Specified 
Timeframe 
Number of 
Female 
Partners in 
the Specified 
Timeframe 
Number of 
Continuing 
Partners in 
the Specified 
Timeframe 
Treatment Group:    , Subject ID: 
Visit 1 
Yes / No / Unknown 
xx / N/A 
Oral receptive / Oral 
active / Rectal receptive 
/ Rectal insertive / 
Genital/vaginal / N/A 
Always / 
Sometimes / 
Never / N/A 
xx 
xx 
xx 
xx 
xx 
xx 
N/A 
Visit 2 
Yes / No / Unknown 
xx 
Oral receptive / Oral 
active / Rectal receptive 
/ Rectal insertive / 
Genital/vaginal /  N/A 
Always / 
Sometimes / 
Never / N/A 
xx 
xx 
N/A 
N/A 
N/A 
N/A 
xx 
Visit 3 
Yes / No / Unknown 
xx 
xxxx 
xxxx 
xx 
xx 
N/A 
N/A 
N/A 
N/A 
xx 
Visit 4 
Yes / No / Unknown 
xx 
xxxx 
xxxx 
xx 
xx 
N/A 
N/A 
N/A 
N/A 
xx 
Visit 5 
Yes / No / Unknown 
xx 
xxxx 
xxxx 
xx 
xx 
N/A 
N/A 
N/A 
N/A 
xx 
Visit 6 
Yes / No / Unknown 
xx 
xxxx 
xxxx 
xx 
xx 
N/A 
N/A 
N/A 
N/A 
xx 
Visit 7 
Yes / No / Unknown 
xx 
xxxx 
xxxx 
xx 
xx 
N/A 
N/A 
N/A 
N/A 
xx 
Visit 8 
Yes / No / Unknown 
xx 
xxxx 
xxxx 
xx 
xx 
N/A 
N/A 
N/A 
N/A 
xx 
Notes: The specified timeframe for visit 1 is “in the past 60 days”, and “since the last visit” for the follow-up visits. 
For Visit 1, if subject had not had sexual intercourse in the past 60 days, response to the rest of the variables in this table will be N/A. For the follow-up visits, if subject had not had sexual intercourse 
since the previous visit, response to rest of the variables in this table will be N/A. Unscheduled visit assessments are included. 
Number of continuing partners is a variable for follow-up visits only. Number of regular partners, number of occasional partners, number of male partners and number of female partners are for Visit 1 
only. 
 


Statistical Analysis Plan - DMID Protocol: 17-0101 
Version 1.0 
22DEC2022 
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PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Listing 10: 
Sexual Behavior History Part III  - Sexually Transmitted Disease Testing History at Baseline - All Enrolled Subjects 
[Implementation Notes:   
1. Sort order will be by Actual Treatment Group, Subject ID 
2. If all subjects received the correct treatment, only display a single “Treatment Group” column.] 
Treatment Group 
Subject 
ID 
Has been 
diagnosed 
with 
gonorrhea in 
the past 60 
days? 
Days since the 
subject last 
diagnosed 
with 
gonorrheal in 
the past 60 
days 
Has the 
subject been 
tested for 
gonorrhea in 
the past 14 
days? 
In the past 14 
days, if the 
subject had 
been tested 
for 
gonorrhea, 
what were the 
test results? 
Has been 
diagnosed 
with 
chlamydia in 
the past 60 
days? 
Days since 
the subject 
last 
diagnosed 
with 
chlamydia in 
the past 60 
days 
Has the 
subject been 
tested for 
chlamydia in 
the past 14 
days? 
In the past 14 
days, if the 
subject had 
been tested 
for 
chlamydia, 
what were the 
test results? 
Has been 
diagnosed 
with any 
other STI in 
the past 60 
days? 
Days since 
the subject 
last 
diagnosed 
with any 
other STI in 
the past 60 
days 
One Dose BPG 2.4 MU / 
Three Doses BPG 2.4 MU 
xxxxxx 
Yes / No  
xx 
Yes / No 
Positive / 
Negative 
Yes / No 
xx 
Yes / No 
Positive / 
Negative 
Yes / No 
xx 
One Dose BPG 2.4 MU / 
Three Doses BPG 2.4 MU 
xxxxxx 
Yes / No  
xx 
Yes / No 
Positive / 
Negative 
Yes / No 
xx 
Yes / No 
Positive / 
Negative 
Yes / No 
xx 
 


Statistical Analysis Plan - DMID Protocol: 17-0101 
Version 1.0 
22DEC2022 
- 118 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Listing 11: 
Sexually Transmitted Infections (STI) Testing result 
[Implementation Notes:   
1. Sort order will be by Treatment Group, Subject ID, and time point] 
Treatment 
Group 
Subject 
ID 
Time 
Point 
Was STI 
testing 
performed? 
Test type 
Was testing 
performed? 
Specimen 
collection date 
Site of specimen collection 
Test Result 
 
xxxx 
Visit 1 
Yes / No / NA 
chlamydia 
Yes / No 
ddMMMyyyy 
Genitourinary / Pharyngeal/ 
Rectal 
Positive 
/negative 
gonorrhea 
Yes / No 
ddMMMyyyy 
Genitourinary / Pharyngeal/ 
Rectal 
Positive 
/negative 
Other STIs 
Yes / No 
ddMMMyyyy 
Genitourinary / Pharyngeal/ 
Rectal 
Positive 
/negative 
specify STI  
Yes / No 
ddMMMyyyy 
Genitourinary / Pharyngeal/ 
Rectal 
Positive 
/negative 
Visit 2 
Yes / No / NA 
chlamydia 
Yes / No 
ddMMMyyyy 
Genitourinary / Pharyngeal/ 
Rectal 
Positive 
/negative 
gonorrhea 
Yes / No 
ddMMMyyyy 
Genitourinary / Pharyngeal/ 
Rectal 
Positive 
/negative 
Other STIs 
Yes / No 
ddMMMyyyy 
Genitourinary / Pharyngeal/ 
Rectal 
Positive 
/negative 
specify STI  
Yes / No 
ddMMMyyyy 
Genitourinary / Pharyngeal/ 
Rectal 
Positive 
/negative 
Visit 3 
Yes / No / NA 
chlamydia 
Yes / No 
ddMMMyyyy 
Genitourinary / Pharyngeal/ 
Rectal 
Positive 
/negative 
gonorrhea 
Yes / No 
ddMMMyyyy 
Genitourinary / Pharyngeal/ 
Rectal 
Positive 
/negative 
Other STIs 
Yes / No 
ddMMMyyyy 
Genitourinary / Pharyngeal/ 
Rectal 
Positive 
/negative 
specify STI  
Yes / No 
ddMMMyyyy 
Genitourinary / Pharyngeal/ 
Rectal 
Positive 
/negative 
… 
 
 
 
 
 
 
Visit 8 
Yes / No / NA 
chlamydia 
Yes / No 
ddMMMyyyy 
Genitourinary / Pharyngeal/ 
Rectal 
Positive 
/negative 
gonorrhea 
Yes / No 
ddMMMyyyy 
Genitourinary / Pharyngeal/ 
Rectal 
Positive 
/negative 
Other STIs 
Yes / No 
ddMMMyyyy 
Genitourinary / Pharyngeal/ 
Rectal 
Positive 
/negative 
specify STI  
Yes / No 
ddMMMyyyy 
Genitourinary / Pharyngeal/ 
Rectal 
Positive 
/negative 
xxxx 
xxxx 
… 
… 
… 
… 
… 
… 
… 
 


Statistical Analysis Plan - DMID Protocol: 17-0101 
Version 1.0 
22DEC2022 
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PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Listing 12: 
Pre-Existing and Concurrent Medical Conditions  
[Implementation Notes: 
1. Sort order is Treatment Group, Subject ID, MH Number. 
2. "Condition Start Day" and "Condition End Day" are relative to enrollment (which is Day 1, day before enrollment is Day -1).  Display the study days 
for start day and end day that are during the study, as well as within the past 14 days prior to the study. For medical history start/end dates that are > 14 
days prior to enrollment, rather than use exact study days, categorize as follows: 
- > 5 years prior to enrollment 
- 1-5 years prior to enrollment 
-1-12 months prior to enrollment 
-If Ongoing at the end of the study, display "Ongoing' in the "Condition End Day" column. 
-If ending is unknown at the end of the study, display "Unknown" in the "Condition End Day" column.] 
Randomized Treatment Group 
Subject ID 
MH Number 
Medical History 
Term 
Condition 
Start Day 
Condition End Day 
MedDRA System 
Organ Class 
MedDRA Preferred 
Term 
One Dose BPG 2.4 MU / 
Three Doses BPG 2.4 MU 
xxxxxx 
xxx 
xxxxxx 
xx 
xx 
xxxxxx 
xxxxxx 
One Dose BPG 2.4 MU / 
Three Doses BPG 2.4 MU 
xxxxxx 
xxx 
xxxxxx 
xx 
xx 
xxxxxx 
xxxxxx 
Note: This listing includes subjects who had pre-existing and/or concurrent medical conditions among all enrolled subjects. 
 


Statistical Analysis Plan - DMID Protocol: 17-0101 
Version 1.0 
22DEC2022 
- 120 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Listing 13: 
Concomitant Medications  
[Implementation Notes: 
1. Sort order is treatment group, Subject ID, concomitant medication number. 
2. 'Medication Start Day' and 'Medication End Day' are relative to enrollment (which is Day 1, day before enrollment is Day -1).  Display the study days 
for start day and end day that are during the study, as well as within 30 days prior to the study. For medication start/end dates that are > 30 days prior to 
enrollment, rather than use exact days, categorize as follows: 
- > 5 years prior to enrollment 
- 1- 5 years prior to enrollment 
- 1-12 months prior to enrollment. 
- For 'Medication End Day', if medication is Ongoing, display 'Ongoing' in the Medication End Day' column.   
- For 'Medication End Day', if end of medication is unknown, display 'Unknown' in the 'Medication End Day' column.  
3. If a Medication is taken for an AE, then concatenate the conmed with the Advere Events by AENUM and report the AETERM, plus the AE Number.  
4. If a Medication is taken for an MH, then concatenate the conmed with the Medical History event by MHNUM and report the MHTERM, plus the MH 
Number. 
5. Include the birth control information in this dataset.  The birth control information is coming from the RP/SUPPRP or BC1 dataset.] 
Treatment Group 
Subject ID 
Concomitant 
Medication 
Number 
Medication 
Medication 
Start Day 
Medication 
End Day 
Indication 
Taken for an AE? 
(AE Description; 
AE Number) 
Taken for a condition on 
Medical History? 
(MH Description; MH 
Number) 
ATC Level 1  
(ATC Level 2) 
One Dose BPG 2.4 MU / 
Three Doses BPG 2.4 MU 
xxxxxx 
xx 
xxxxxx 
xx 
xx 
xxxxxx 
Yes/No 
xxxxx; xx 
Yes/No 
xxxxx; xx 
 
One Dose BPG 2.4 MU / 
Three Doses BPG 2.4 MU 
xxxxxx 
xx 
xxxxxx 
xx 
xx 
xxxxxx 
Yes/No 
xxxxx; xx 
Yes/No 
xxxxx; xx 
 
Note: This listing consists of subjects who had pre-existing and/or concurrent medical conditions among all enrolled subjects. 


Statistical Analysis Plan - DMID Protocol: 17-0101 
Version 1.0 
22DEC2022 
- 121 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Listing 14: 
Solicited Systemic Reaction Events – Safety Population 
[Implementation Notes: 
1. Sort order is Treatment group, Subject ID, Study Day.] 
Randomized 
Treatment Group Subject ID 
Study Day of 
symptoms 
reviewed: 
Reporting time 
(24-hr clock) 
Jarisch-
Herxheimer 
Reaction 
Symtom 
Study Day of 
Symptom Start Date 
Start Time 
(24-hr clock, 
hh:mm) 
Study Day of 
Symptom Stop Date 
Stop Time 
(24-hr clock, 
hh:mm) 
Ongoing 
Maximum 
Severity 
 
 
 
 
Feverishness 
 
 
 
 
 
 
 
 
 
 
Chills 
 
 
 
 
 
 
 
 
 
 
Myalgia 
 
 
 
 
 
 
 
 
 
 
Weakness 
 
 
 
 
 
 
 
 
 
 
Flushing 
 
 
 
 
 
 
 
 
 
 
Worsening of 
skin rash 
 
 
 
 
 
 
 
 
 
 
Tachycardia 
 
 
 
 
 
 
 
 
 
 
Heart 
palpitations 
 
 
 
 
 
 
 
 
 
 
Generalized 
arthralgia 
 
 
 
 
 
 
 
 
 
 
Nausea 
 
 
 
 
 
 
 
 
 
 
Headache 
 
 
 
 
 
 
 
 
 
 
Dizziness 
 
 
 
 
 
 
Notes: Subject who did not experience any symptoms of the Jarisch-Herxheimer Reaction in the 24-hours following Visit 1 will not be listed.  
Symptoms that did not occur will not be listed. 
 


Statistical Analysis Plan - DMID Protocol: 17-0101 
Version 1.0 
22DEC2022 
- 122 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Listing 15: 
Solicited Local Reaction Events – Safety Population 
[Implementation Notes: 
1. Sort order is treatment group, Subject ID, Study Day. 
2. Subjects in one-dose group will only have rows for dose 1. Subjects in 3-dose group each will have rows for all 3 doses.] 
Dose 
Number 
Post 
Dose 
Day 
Pain or Tenderness Severity /  
Study Day of Stop Date Post-dosea 
Erythema or Redness Severity Diameter (mm) /  
Study Day of Stop Date Post-dosea 
Induration or Swelling Severity Diameter (mm) /  
Study Day of Stop Date Post-dosea 
Treatment Group: Subject ID: 
1 
1 
None or Mild (x) or Moderate (x) or Severe (x) / Not Done 
None or Mild (x) or Moderate (x) or Severe (x) / Not Done 
None or Mild (x) or Moderate (x) or Severe (x) / Not Done 
1 
2 
None or Mild (x) or Moderate (x) or Severe (x) / Not Done 
None or Mild (x) or Moderate (x) or Severe (x) / Not Done 
None or Mild (x) or Moderate (x) or Severe (x) / Not Done 
1 
3 
None or Mild (x) or Moderate (x) or Severe (x) / Not Done 
None or Mild (x) or Moderate (x) or Severe (x) / Not Done 
None or Mild (x) or Moderate (x) or Severe (x) / Not Done 
1 
4 
None or Mild (x) or Moderate (x) or Severe (x) / Not Done 
None or Mild (x) or Moderate (x) or Severe (x) / Not Done 
None or Mild (x) or Moderate (x) or Severe (x) / Not Done 
1 
5 
None or Mild (x) or Moderate (x) or Severe (x) / Not Done 
None or Mild (x) or Moderate (x) or Severe (x) / Not Done 
None or Mild (x) or Moderate (x) or Severe (x) / Not Done 
1 
6 
None or Mild (x) or Moderate (x) or Severe (x) / Not Done 
None or Mild (x) or Moderate (x) or Severe (x) / Not Done 
None or Mild (x) or Moderate (x) or Severe (x) / Not Done 
1 
>6 
Mild (x) or Moderate (x) or Severe (x) / x or N/A 
Mild (x) or Moderate (x) or Severe (x) / x or N/A 
Mild (x) or Moderate (x) or Severe (x) / x or N/A 
2 
1 
None or Mild (x) or Moderate (x) or Severe (x) / Not Done 
None or Mild (x) or Moderate (x) or Severe (x) / Not Done 
None or Mild (x) or Moderate (x) or Severe (x) / Not Done 
2 
2 
None or Mild (x) or Moderate (x) or Severe (x) / Not Done 
None or Mild (x) or Moderate (x) or Severe (x) / Not Done 
None or Mild (x) or Moderate (x) or Severe (x) / Not Done 
2 
3 
None or Mild (x) or Moderate (x) or Severe (x) / Not Done 
None or Mild (x) or Moderate (x) or Severe (x) / Not Done 
None or Mild (x) or Moderate (x) or Severe (x) / Not Done 
2 
4 
None or Mild (x) or Moderate (x) or Severe (x) / Not Done 
None or Mild (x) or Moderate (x) or Severe (x) / Not Done 
None or Mild (x) or Moderate (x) or Severe (x) / Not Done 
2 
5 
None or Mild (x) or Moderate (x) or Severe (x) / Not Done 
None or Mild (x) or Moderate (x) or Severe (x) / Not Done 
None or Mild (x) or Moderate (x) or Severe (x) / Not Done 
2 
6 
None or Mild (x) or Moderate (x) or Severe (x) / Not Done 
None or Mild (x) or Moderate (x) or Severe (x) / Not Done 
None or Mild (x) or Moderate (x) or Severe (x) / Not Done 
2 
>6 
Mild (x) or Moderate (x) or Severe (x) / x or N/A 
Mild (x) or Moderate (x) or Severe (x) / x or N/A 
Mild (x) or Moderate (x) or Severe (x) / x or N/A 
3 
1 
None or Mild (x) or Moderate (x) or Severe (x) / Not Done 
None or Mild (x) or Moderate (x) or Severe (x) / Not Done 
None or Mild (x) or Moderate (x) or Severe (x) / Not Done 
3 
2 
None or Mild (x) or Moderate (x) or Severe (x) / Not Done 
None or Mild (x) or Moderate (x) or Severe (x) / Not Done 
None or Mild (x) or Moderate (x) or Severe (x) / Not Done 
3 
3 
None or Mild (x) or Moderate (x) or Severe (x) / Not Done 
None or Mild (x) or Moderate (x) or Severe (x) / Not Done 
None or Mild (x) or Moderate (x) or Severe (x) / Not Done 
3 
4 
None or Mild (x) or Moderate (x) or Severe (x) / Not Done 
None or Mild (x) or Moderate (x) or Severe (x) / Not Done 
None or Mild (x) or Moderate (x) or Severe (x) / Not Done 
3 
5 
None or Mild (x) or Moderate (x) or Severe (x) / Not Done 
None or Mild (x) or Moderate (x) or Severe (x) / Not Done 
None or Mild (x) or Moderate (x) or Severe (x) / Not Done 


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Dose 
Number 
Post 
Dose 
Day 
Pain or Tenderness Severity /  
Study Day of Stop Date Post-dosea 
Erythema or Redness Severity Diameter (mm) /  
Study Day of Stop Date Post-dosea 
Induration or Swelling Severity Diameter (mm) /  
Study Day of Stop Date Post-dosea 
3 
6 
None or Mild (x) or Moderate (x) or Severe (x) / Not Done 
None or Mild (x) or Moderate (x) or Severe (x) / Not Done 
None or Mild (x) or Moderate (x) or Severe (x) / Not Done 
3 
>6 
Mild (x) or Moderate (x) or Severe (x) / x or N/A 
Mild (x) or Moderate (x) or Severe (x) / x or N/A 
Mild (x) or Moderate (x) or Severe (x) / x or N/A 
Notes: For Post Dose Day 1 to 6 rows, display the symptom diameters in parentheses next to the severity for Erythema/Redness and Iduration/Swelling; if the Severity of the symptom is None or Not Done, no 
diameter will be displayed. 
a For Post Dose Day >6 rows, if the symptom was ongoing after day 6, Study Day of Stop Day Post-dose will be displayed under each symptom column after Severity separated by a ‘/’; if the symptom was not 
ongoing after day 6, N/A will be displayed under each symptom column. 


Statistical Analysis Plan - DMID Protocol: 17-0101 
Version 1.0 
22DEC2022 
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PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Listing 16: 
Unsolicited Adverse Events - Safety Population 
[Implementation Notes: 
1. Sort order is treatment group, Subject ID, AE Number.] 
Adverse 
Event 
Associated 
with Dose 
No. 
No. of Days 
Post 
Associated 
Dose  
Duration 
(Days) 
Severity 
SAE? 
Relationship 
to Study 
Treatment 
In Not Related, 
Alternative 
Etiology 
Action Taken 
with Study 
Treatment 
Subject 
Discontinued 
Due to AE 
Outcome 
MedDRA 
System 
Organ 
Class 
MedDRA 
Preferred 
Term 
Treatment Group: ,  Subject ID:   , AE Number:  
xxxxxxx 
xx 
x 
x 
xxxxxx 
xxxxxx 
xxxxxx 
xxxxx 
xxxxxx 
Y/N 
xxxxx 
xxxxx 
xxxxx 
Comments: xxxxxxxxxxxxx 
 
Treatment Group: ,  Subject ID:   , AE Number:  
xxxxxxx 
xx 
x 
x 
xxxxxx 
xxxxxx 
xxxxxx 
xxxxx 
xxxxxx 
Y/N 
xxxxx 
Xxxxx 
xxxxx 
Comments: xxxxxxxxxxxxx 
 
Note: For listing of SAEs only, see Table 47. 


Statistical Analysis Plan - DMID Protocol: 17-0101 
Version 1.0 
22DEC2022 
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Listing 17: 
Pregnancy Reports – Maternal Information 
[Implementation Notes: 
1. Sort order is treatment group, Subject ID] 
Randomized 
Treatment 
Group  
Subject 
ID  
Pregnancy 
Number 
Study Day 
Corresponding 
to Estimated 
Date of 
Conception 
Source of 
Maternal 
Information 
Pregnancy 
Status 
Mother’s 
Pre-
Pregnancy 
BMI 
Mother’s 
Weight 
Gain 
During 
Pregnancy 
Tobacco, 
Alcohol, or 
Drug Use 
During 
Pregnancy? 
Medications 
During 
Pregnancy? 
Maternal 
Complications 
During 
Pregnancy? 
Maternal 
Complications 
During Labor, 
Delivery, or 
Post-Partum? 
One Dose BPG 
2.4 MU / 
Three Doses 
BPG 2.4 MU 
xxxxxx 
xx 
xx 
xxx 
xxx 
xxx 
xxx 
Y/N 
Y/N 
Y/N 
Y/N 
One Dose BPG 
2.4 MU / 
Three Doses 
BPG 2.4 MU 
xxxxxx 
xx 
xx 
xxx 
xxx 
xxx 
xxx 
Y/N 
Y/N 
Y/N 
Y/N 
Note: Maternal Complications are included in the Adverse Event Listing. Medications taken during pregnancy are included in the Concomitant Medications Listing. 
 


Statistical Analysis Plan - DMID Protocol: 17-0101 
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22DEC2022 
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Listing 18: 
Pregnancy Reports – Gravida and Para 
 
 
 
Live Births 
 
 
 
 
 
Subject 
ID 
Pregnancy 
Number 
Gravida 
Extremely 
Preterm 
Births 
Very 
Preterm 
Births 
Early 
Preterm 
Births 
Late 
Preterm 
Births 
Early 
Term 
Births 
Full 
Term 
Births 
Late 
Term 
Births 
Post 
Term 
Births 
Still 
Births 
Spontaneous 
Abortion/ 
Miscarriage 
Elective 
Abortions 
Therapeutic 
Abortions 
Major 
Congenital 
Anomaly with 
Previous 
Pregnancy? 
xxxxxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
Xxx 
Y/N 
xxxxxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
Xxx 
Y/N 
Note: Gravida includes the current pregnancy, para events do not. 
 


Statistical Analysis Plan - DMID Protocol: 17-0101 
Version 1.0 
22DEC2022 
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PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Listing 19: 
Pregnancy Reports – Live Birth Outcomes 
Subject 
ID 
Pregnancy 
Number 
Fetus 
Number 
Pregnancy 
Outcome 
(for this 
Fetus) 
Fetal 
Distress 
During 
Labor and 
Delivery? 
Delivery 
Method 
Gestational 
Age at Live 
Birth  
Size for 
Gestational 
Age 
Apgar 
Score, 1 
minute 
Apgar 
Score, 5 
minutes 
Cord 
pH 
Congenital 
Anomalies? 
Illnesses/ 
Hospitalizations 
within 1 Month of 
Birth? 
xxxxxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
Y/N 
xxx 
xxxxxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
Y/N 
xxx 
Note: Congenital Anomalies are included in the Adverse Event listing. 


Statistical Analysis Plan - DMID Protocol: 17-0101 
Version 1.0 
22DEC2022 
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Listing 20: 
Pregnancy Reports – Still Birth Outcomes 
Subject 
ID 
Date of 
Initial 
Report 
Fetus 
Number 
Pregnancy 
Outcome (for 
this Fetus) 
Fetal 
Distress 
During 
Labor and 
Delivery? 
Delivery 
Method 
Gestational 
Age at Still 
Birth 
Size for 
Gestational 
Age 
Cord 
pH 
Congenital 
Anomalies? 
Autopsy 
Performed? 
If Autopsy, 
Etiology for 
Still Birth 
Identified? 
xxxxxx 
xx 
xxx 
xxxxxxx 
Y/N 
xxxxxxx 
xxx 
xxx 
xx 
Y/N 
Y/N 
xxxxxxx 


Statistical Analysis Plan - DMID Protocol: 17-0101 
Version 1.0 
22DEC2022 
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PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Listing 21: 
Pregnancy Reports – Spontaneous, Elective, or Therapeutic Abortion Outcomes 
Subject 
ID 
Date of Initial 
Report 
Fetus Number 
Pregnancy Outcome  
(for this Fetus) 
Gestational Age at 
Termination 
Abnormality in Product of Conception? 
Reason for Therapeutic 
Abortion 
xxxxxx 
xx 
xxx 
xxxxx 
xxxx 
Y/N 
Xxxxxxx 
 


Statistical Analysis Plan - DMID Protocol: 17-0101 
Version 1.0 
22DEC2022 
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Listing 22: 
Syphilis Clinical Assessment 
[Implementation Note:  
Sort order: Treatment Group, Subject ID,  Clinical diagnosis of untreated syphilis at baseline, and Planned Time Point. 
In the “If Yes, specify type of rash” column and “If present at follow-up visit, specify” column, concatenate “If Other, specify field” by “:”. 
“If Yes, specify type of rash”= “N/A”  and “If Yes, specify rash location”= “N/A”  when “Rash (other than plantar/palmar) or lesion”= “No”.] 
Planned 
Time 
Point  
Actual 
Study 
Day  
Rash or lesion? If 
Yes, specify type of 
rash 
If Rash or lesion 
was present, 
specify rash 
location 
If Rash or lesion 
was present at 
follow-up visit, 
specify 
Palmar/plantar rash? If 
Yes, specify type of rash Condylomata lata 
If Condylomata 
lata was present at 
follow-up visit, 
specify 
Mucous 
patch 
If Mucous 
patch was 
present at 
follow-up 
visit, specify 
New or 
worsening 
signs? If Yes, 
specify 
Treatment Group: subject ID , Clinical diagnosis of untreated syphilis at baseline: Primary/ Secondary/ Early latent: 
Visit 1 
x 
Yes/No, Macular/ 
Papular/ Maculo-
papular/ Papulo-
squamous/ Other:xx 
Face and head/ 
Trunk/ Genital 
region/ Extremities 
N/A 
Yes/No, Macular/ 
Papular/ Maculo-papular/ 
Papulo-squamous/ 
Other:xx 
Yes/No 
N/A 
Yes/No 
N/A 
N/A 
Visit 2 
x 
Yes/No, Macular/ 
Papular/ Maculo-
papular/ Papulo-
squamous/ Other:xx 
Face and head/ 
Trunk/ Genital 
region/ Extremities 
New sign/ 
Worsening/No 
change/Improving/
Other:xx 
Yes/No, Macular/ 
Papular/ Maculo-papular/ 
Papulo-squamous/ 
Other:xx 
Yes/No 
New sign/ 
Worsening/No 
change/Improving/
Other:xx 
Yes/No 
New sign/ 
Worsening/ 
No change/ 
Improving/ 
Other:xx 
Yes: xxx /No 
Visit 3 
x 
Yes/No, Macular/ 
Papular/ Maculo-
papular/ Papulo-
squamous/ Other:xx 
Face and head/ 
Trunk/ Genital 
region/ Extremities 
New sign/ 
Worsening/ No 
change/Improving/
Other:xx 
Yes/No, Macular/ 
Papular/ Maculo-papular/ 
Papulo-squamous/ 
Other:xx 
Yes/No 
New sign/ 
Worsening/No 
change/Improving/
Other:xx 
Yes/No 
New sign/ 
Worsening/ 
No change/ 
Improving/ 
Other:xx 
Yes: xxx /No 
 


Statistical Analysis Plan - DMID Protocol: 17-0101 
Version 1.0 
22DEC2022 
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PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Listing 23: 
HIV Testing – All Enrolled Subjects 
[Implementation Notes: 
1.Sort order is Baseline HIV Status, treatment group, Subject ID, Study Visit. 
2.If all subjects received the correct treatment, only display “Treatment Group”. 
3.If there are test results at interim visits, e.g., 06S, 06T, display the corresponding scheduled visit under “Study Visit” column, e.g., Visit 6.] 
Study 
Visit 
Blood Collection 
Date for HIV CD4 
Count 
Blood Collection 
Date for Viral 
Load 
Blood Collection 
Date for HIV Test 
Had CD4 count 
record in the 
past 30 days? 
If No CD4 record, 
was an HIV CD4 
count performed 
HIV CD4 Count 
(cells/mm3) 
Had viral load 
record in the 
past 6 monthsa? 
Was result 
detectable? 
Viral Load 
Result 
(copies/mL) 
Was an HIV 
test performed? 
HIV Test 
Result 
Baseline HIV Status: Known Positive/ Unknown or Known Negative, Randomized Treatment Group: ,  Subject ID:    
Visit 1  
dd/MMM/yyyy 
dd/MMM/yyyy 
dd/MMM/yyyy 
Yes / No 
Yes / No 
xxxx 
Yes / No 
Yes / No xxxxx or <xx 
Yes / No 
Negative/ 
Positive 
Visit 2  
N/A 
dd/MMM/yyyy 
N/A 
N/A 
N/A 
N/A 
Yes / No / N/A 
Yes / No xxxxx or <xx 
N/A 
N/A 
Visit 3  
N/A 
dd/MMM/yyyy 
N/A 
N/A 
N/A 
N/A 
Yes / No / N/A 
Yes / No xxxxx or <xx 
N/A 
N/A 
Visit 4  
dd/MMM/yyyy 
dd/MMM/yyyy 
N/A 
Yes / No / N/A 
Yes / No 
xxxx 
Yes / No / N/A 
Yes / No xxxxx or <xx 
N/A 
N/A 
Visit 5  
N/A 
N/A 
dd/MMM/yyyy 
N/A 
N/A 
N/A 
N/A 
N/A 
N/A 
Yes / No 
Negative/ 
Positive 
Visit 6  
dd/MMM/yyyy 
N/A 
dd/MMM/yyyy 
Yes / No / N/A 
Yes / No 
xxxx 
N/A 
N/A 
N/A 
Yes / No 
Negative/ 
Positive 
Visit 7  
N/A 
N/A 
dd/MMM/yyyy 
N/A 
N/A 
N/A 
N/A 
N/A 
N/A 
Yes / No 
Negative/ 
Positive 
Visit 8  
dd/MMM/yyyy 
N/A 
dd/MMM/yyyy 
Yes / No / N/A 
Yes / No 
xxxx 
N/A 
N/A 
N/A 
Yes / No 
Negative/ 
Positive 
Notes: For the follow-up visits, HIV Testing could be done at Visits 5 – 8 Only; HIV CD4 Count could be done at Visits 4, 6, 8 Only; HIV Viral Load could be done at Visits 2, 3, 4 Only. 
a For Visit 1, the question is “Do the subject’s medical records include a viral load in the past 6 months?”; For follow-up visits, the question is “Do the subject’s medical records include a viral load since 
the last visit?”. 
 


Statistical Analysis Plan - DMID Protocol: 17-0101 
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Listing 24: 
TPPA Testing - All Enrolled Subjects 
[Implementation Notes:   
1. Sort order will be by Actual Treatment Group and Subject ID, Planned Time Point.  
2. Only show Visit 5 if V1 was non-reactive and a repeat testing was done for the subject. Remove data entry error where there are results at visits 
other than V1 after QC.] 
Randomized Treatment Group 
Subject ID 
Planned Time Point 
Actual Study Day 
TPPA Result 
One Dose BPG 2.4 MU / Three Doses BPG 2.4 MU 
xxxxx 
Visit 1 
xxx 
REACTIVE/NON-REACTIVE/INVALID 
One Dose BPG 2.4 MU / Three Doses BPG 2.4 MU 
xxxxx 
Visit 5 
xxx 
REACTIVE/NON-REACTIVE/INVALID 
 


Statistical Analysis Plan - DMID Protocol: 17-0101 
Version 1.0 
22DEC2022 
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Listing 25: 
Vital Signs – Safety Population 
[Implementation Notes: 
1. Sort order is treatment group, Subject ID, Study Day.] 
Randomized Treatment Group 
Subject ID 
Planned Time Point 
Actual Study 
Day 
Temperature 
(°F) 
Systolic Blood 
Pressure 
(mmHg) 
Diastolic Blood 
Pressure 
(mmHg) 
Pulse 
(beats/min) 
Respiratory 
Rate 
(breaths/min) 
One Dose BPG 2.4 MU / 
Three Doses BPG 2.4 MU 
xxxxxxx 
Visit 1 (Day 1) 
xx 
xx 
xx 
xx 
Xx 
xx 
One Dose BPG 2.4 MU / 
Three Doses BPG 2.4 MU 
xxxxxxx 
Visit 2, Week1  
(Day 7 to 13) 
xx 
xx 
xx 
xx 
Xx 
xx 
One Dose BPG 2.4 MU / 
Three Doses BPG 2.4 MU 
xxxxxxx 
Visit 3, Week 2  
(6 to 12 days after Visit 2) 
xx 
xx 
xx 
xx 
Xx 
xx 
One Dose BPG 2.4 MU / 
Three Doses BPG 2.4 MU 
xxxxxxx 
Visit 4, Month 1  
(Day 30 ± 7 days) 
xx 
xx 
xx 
xx 
Xx 
xx 
One Dose BPG 2.4 MU / 
Three Doses BPG 2.4 MU 
xxxxxxx 
Visit 5, Month 3  
(Day 90 ± 21 days) 
xx 
xx 
xx 
xx 
Xx 
xx 
One Dose BPG 2.4 MU / 
Three Doses BPG 2.4 MU 
xxxxxxx 
Visit 6, Month 6  
(Day 180 ± 21 days) 
xx 
xx 
xx 
xx 
Xx 
xx 
One Dose BPG 2.4 MU / 
Three Doses BPG 2.4 MU 
xxxxxxx 
Visit 7, Month 9  
(Day 270 ± 28 days) 
xx 
xx 
xx 
xx 
Xx 
xx 
One Dose BPG 2.4 MU / 
Three Doses BPG 2.4 MU 
xxxxxxx 
Visit 8, Week 12  
(Day 360 ± 28 days) 
xx 
xx 
xx 
xx 
Xx 
xx 
 


Statistical Analysis Plan - DMID Protocol: 17-0101 
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PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Listing 26: 
Abnormal Physical Exam Findings 
[Implementation Notes: 
1.Sort order is actual treatment group, Subject ID, Study Day. 
3.Only abnormal findings will be presented. 
4.If the physical exam was reported as an AE, then concatenate the Physical exam with the Adverse Events by AENUM and report the AETERM, plus 
the AE Number 
5. If a subject had more than one abnormal finding at a visit, list each abnormality on a separate row.] 
Actual Treatment Group 
Subject ID 
Planned Time Point 
Actual Study 
Day 
Body System 
Abnormal Finding 
Reported as an AE? 
(AE Description; AE Number) 
One Dose BPG 2.4 MU / 
Three Doses BPG 2.4 MU 
xxxxxxx 
Visit 1 (Day 1) 
xxx 
xxxxxxxx 
Genitourinary / Lymph nodes / Rectal / 
Skin / Oral 
N/A 
One Dose BPG 2.4 MU / 
Three Doses BPG 2.4 MU 
xxxxxxx 
Visit 2, Week1 (Day 7 to 
13) 
xxx 
xxxxxxxx 
Genitourinary / Lymph nodes / Rectal / 
Skin / Oral 
No / Yes, Solicited AE / Yes, 
Unsolicited AE, 
xxxxxx; xx 
One Dose BPG 2.4 MU / 
Three Doses BPG 2.4 MU 
xxxxxxx 
Visit 3, Week 2 (6 to 12 
days after Visit 2) 
xxx 
xxxxxxxx 
Genitourinary / Lymph nodes / Rectal / 
Skin / Oral 
No / Yes, Solicited AE / Yes, 
Unsolicited AE, 
xxxxxx; xx 
One Dose BPG 2.4 MU / 
Three Doses BPG 2.4 MU 
xxxxxxx 
Visit 4, Month 1 (Day 30 
± 7 days) 
xxx 
xxxxxxxx 
Genitourinary / Lymph nodes / Rectal / 
Skin / Oral 
No / Yes, Solicited AE / Yes, 
Unsolicited AE, 
xxxxxx; xx 
One Dose BPG 2.4 MU / 
Three Doses BPG 2.4 MU 
xxxxxxx 
Visit 5, Month 3 (Day 90 
± 21 days) 
xxx 
xxxxxxxx 
Genitourinary / Lymph nodes / Rectal / 
Skin / Oral 
No / Yes, Solicited AE / Yes, 
Unsolicited AE, 
xxxxxx; xx 
One Dose BPG 2.4 MU / 
Three Doses BPG 2.4 MU 
xxxxxxx 
Visit 6, Month 6 (Day 
180 ± 21 days) 
xxx 
xxxxxxxx 
Genitourinary / Lymph nodes / Rectal / 
Skin / Oral 
No / Yes, Solicited AE / Yes, 
Unsolicited AE, 
xxxxxx; xx 
One Dose BPG 2.4 MU / 
Three Doses BPG 2.4 MU 
xxxxxxx 
Visit 7, Month 9 (Day 
270 ± 28 days) 
xxx 
xxxxxxxx 
Genitourinary / Lymph nodes / Rectal / 
Skin / Oral 
No / Yes, Solicited AE / Yes, 
Unsolicited AE, 
xxxxxx; xx 
One Dose BPG 2.4 MU / 
Three Doses BPG 2.4 MU 
xxxxxxx 
Visit 8, Week 12 (Day 
360 ± 28 days) 
xxx 
xxxxxxxx 
Genitourinary / Lymph nodes / Rectal / 
Skin / Oral 
No / Yes, Solicited AE / Yes, 
Unsolicited AE, 
xxxxxx; xx 
Note: This list consists of subjects who had abnormal findings.  
 

Prot_001.pdf: 
DMID Protocol 17-0101 
Version 4.0 
22 June 2020 
 ____________________________________________________________________________________________ 
 
 ____________________________________________________________________________________________ 
1 
 
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 


DMID Protocol 17-0101 
Version 4.0 
22 June 2020 
 ____________________________________________________________________________________________ 
 
 ____________________________________________________________________________________________ 
2 
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. 
 
 
 
 
 
 
 


DMID Protocol 17-0101 
Version 4.0 
22 June 2020 
 ____________________________________________________________________________________________ 
 
 ____________________________________________________________________________________________ 
3 
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 
 
 
 
 
 
 


DMID Protocol 17-0101 
Version 4.0 
22 June 2020 
 ____________________________________________________________________________________________ 
 
 ____________________________________________________________________________________________ 
4 
 
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 
 
 
 
 


DMID Protocol 17-0101 
Version 4.0 
22 June 2020 
 ____________________________________________________________________________________________ 
 
 ____________________________________________________________________________________________ 
5 
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 


DMID Protocol 17-0101 
Version 4.0 
22 June 2020 
 ____________________________________________________________________________________________ 
 
 ____________________________________________________________________________________________ 
6 
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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8 
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 
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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 
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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 
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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. 
• 
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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-
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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