A Randomized, Double-Blind, Placebo Controlled, Phase 2 Study to Assess Treatment of Gardnerella Vaginalis Vaginal Colonization With Amoxicillin
Phase: PHASE2
Conditions: Vaginitis Gardnerella
Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

DMID Protocol 16-0073 GV 
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i 
 
A Randomized, Double-Blind, Placebo Controlled, Phase 2 
Study to Assess Treatment of Gardnerella Vaginalis Vaginal 
Colonization with Amoxicillin 
DMID Protocol Number: 16-0073 
 
DMID Funding Mechanism: HHSN2722013000121; HHSN272000011 
Principal Investigator: Jane Schwebke, MD 
DMID Protocol Champion: Delmyra Turpin, RN, MPH, CCRP 
DMID Medical Monitor: Mohamed Elsafy, M.D 
DMID Scientific Lead:  Carolyn Deal, Ph.D. 
Version Number:  6.0 
23 May 2019 
 
 
 
 
 

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ii 
STATEMENT OF COMPLIANCE 
The study will be carried out in accordance with Good Clinical Practice (GCP) as required by the 
following: 
• 
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) 
• 
ICH E6; 62 Federal Register 25691 (1997)  
• 
NIH Clinical Terms of Award 
 
All key personnel (all individuals responsible for the design and conduct of this study) have 
completed Human Subjects Protection Training. 
 

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SIGNATURE PAGE 
The signature below constitutes the approval of this protocol and the attachments, and provides 
the necessary assurances that this trial will be conducted according to all stipulations of the 
protocol, including all statements regarding confidentiality, and according to local legal and 
regulatory requirements and applicable US federal regulations and ICH guidelines. 
 
Principal Investigator and Site Investigator: 
 
 
Date: 
 
Jane Schwebke, MD 
University of Alabama at Birmingham 
 
 
Site Investigator: 
 
 
 
 
Date: 
 
Candice McNeil, MD, MPH 
Wake Forest University Health Sciences 
 
 
 

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TABLE OF CONTENTS 
Page 
Statement of Compliance 
ii 
Signature Page 
iii 
Table of Contents 
iv 
List of Abbreviations 
vii 
Protocol Summary 
ix 
1 
Key Roles 
1 
2 
Background Information and Scientific Rationale 
3 
 
Background Information .......................................................................................... 3 
 
Rationale ................................................................................................................ 3 
 
Potential Risks and Benefits ................................................................................... 4 
2.3.1 
Potential Risks ............................................................................................ 4 
2.3.2 
Known Potential Benefits............................................................................. 4 
3 
Objectives 
5 
 
Study Objectives ..................................................................................................... 5 
3.1.1 
Primary objective: ........................................................................................ 5 
3.1.2 
Secondary objective: ................................................................................... 5 
3.1.3 
Exploratory objective: .................................................................................. 5 
 
Study Outcome Measures ...................................................................................... 5 
3.2.1 
Primary Outcome Measures ........................................................................ 5 
3.2.2 
Secondary Outcome Measures ................................................................... 5 
3.2.3 
Exploratory Outcome Measures .................................................................. 5 
4 
Study Design 
6 
5 
Study Enrollment and Withdrawal 
8 
 
Participant Inclusion Criteria ................................................................................... 8 
 
Participant Exclusion Criteria .................................................................................. 9 
 
Treatment Assignment Procedures ....................................................................... 10 
5.3.1 
Randomization Procedures ....................................................................... 10 
5.3.2 
Masking Procedures .................................................................................. 10 
5.3.3 
Reasons for Withdrawal ............................................................................ 11 
5.3.4 
Handling of Withdrawals ............................................................................ 11 
5.3.5 
Termination of Study ................................................................................. 12 
6 
Study Intervention/Investigational Product 
13 
 
Study Product Description .................................................................................... 13 
6.1.1 
Acquisition ................................................................................................. 13 
6.1.2 
Formulation, Packaging, and Labeling....................................................... 13 
6.1.3 
Product Storage and Stability .................................................................... 14 
 
Dosage, Preparation and Administration of Study Intervention/Investigational 
Product ................................................................................................................. 14 
6.2.1 
Dosage ...................................................................................................... 14 

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6.2.2 
Preparation ............................................................................................... 14 
6.2.3 
Administration ........................................................................................... 15 
 
Accountability Procedures for the Study Intervention/Investigational Product(s) ... 15 
 
Assessment of Participant Compliance with Study Intervention/Investigational 
Product ................................................................................................................. 15 
 
Concomitant Medications/Treatments ................................................................... 16 
7 
Study Schedule 
17 
 
Visit 0 (Day -14 to -7) Screening ........................................................................... 17 
 
Visit 1 (Day 1) Enrollment ..................................................................................... 18 
 
Visit 2 (Day 15 [Window: Days 15-21]) Follow-up (ToC) ....................................... 19 
 
Early Termination Visit .......................................................................................... 19 
 
Unscheduled Visit ................................................................................................. 20 
8 
Study Procedures/Evaluations 
21 
 
Clinical Evaluations ............................................................................................... 21 
 
Laboratory Evaluations ......................................................................................... 22 
8.2.1 
Clinical Laboratory Evaluations ................................................................. 22 
8.2.2 
Special Assays or Procedures ................................................................... 23 
8.2.3 
Specimen Preparation, Handling, and Shipping ........................................ 23 
9 
Assessment of Safety 
24 
 
Specification of Safety Parameters ....................................................................... 24 
 
Methods and Timing for Assessing, Recording, and Analyzing Safety 
Parameters ........................................................................................................... 24 
9.2.1 
Adverse Events ......................................................................................... 24 
9.2.2 
Serious Adverse Events ............................................................................ 26 
9.2.3 
Procedures to be Followed in the Event of Abnormal Clinical Findings ..... 26 
 
Reporting Procedures ........................................................................................... 27 
9.3.1 
Serious Adverse Events ............................................................................ 27 
9.3.2 
Regulatory Reporting for Studies Not Conducted Under 
DMID-Sponsored IND ............................................................................... 27 
9.3.3 
Reporting of Pregnancy ............................................................................. 28 
 
Type and Duration of Follow-up of Participants after Adverse Events ................... 28 
 
Halting Rules ........................................................................................................ 29 
 
Safety Oversight (ISM plus DSMB) ....................................................................... 29 
10 
Clinical Monitoring 
31 
 
Site Monitoring Plan .............................................................................................. 31 
11 
Statistical Considerations 
32 
 
Study Hypotheses ................................................................................................. 32 
 
Sample Size Considerations ................................................................................. 32 
 
Planned Interim Analyses ..................................................................................... 32 
11.3.1 Safety Review ........................................................................................... 32 
11.3.2 Efficacy Review ......................................................................................... 33 
 
Final Analysis Plan ............................................................................................... 33 

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11.4.1 Analysis Populations ................................................................................. 33 
11.4.2 Baseline Characteristics ............................................................................ 34 
11.4.3 Safety Analysis Plan .................................................................................. 34 
11.4.4 Efficacy Analysis Plan ............................................................................... 34 
12 
Source Documents and Access to Source Data/Documents 
36 
13 
Quality Control and Quality Assurance 
37 
14 
Ethics/Protection of Human Subjects 
38 
 
Ethical Standard ................................................................................................... 38 
 
Institutional Review Board .................................................................................... 38 
 
Informed Consent Process ................................................................................... 38 
 
Exclusion of Women, Minorities, and Children (Special Populations) .................... 39 
 
Subject Confidentiality .......................................................................................... 39 
 
Study Discontinuation ........................................................................................... 41 
 
Future Use of Stored Specimens .......................................................................... 41 
15 
Data Handling and Record Keeping 
42 
 
Data Management Responsibilities ....................................................................... 42 
 
Data Capture Methods .......................................................................................... 42 
 
Types of Data ....................................................................................................... 43 
 
Timing/Reports ..................................................................................................... 43 
 
Study Records Retention ...................................................................................... 43 
 
Protocol Deviations ............................................................................................... 43 
16 
Publication Policy 
44 
17 
Literature References 
46 
Appendix A: Schedule of Events 
47 
Appendix B:  Toxicology Table 
49 
 
 

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LIST OF ABBREVIATIONS 
AE 
Adverse Event/Adverse Experience 
BV 
Bacterial Vaginosis 
CFR 
Code of Federal Regulations 
CoC 
Certificate of Confidentiality 
CRF 
Case Report Form 
CROMS 
Clinical Research Operations and Management Support 
CSR 
Clinical Study Report 
DHHS 
Department of Health and Human Services 
DMID 
Division of Microbiology and Infectious Diseases, NIAID, NIH, 
DHHS 
DSMB 
Data and Safety Monitoring Board 
eCRF 
Electronic Case Report Form 
EIC 
Enrollment Informed Consent 
FDA 
Food and Drug Administration 
FWA 
Federalwide Assurance 
GCP 
Good Clinical Practice  
GV 
Gardnerella Vaginalis 
HIPAA 
Health Insurance Portability and Accountability Act 
IATA 
International Air Transport Association 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
ICMJE 
International Committee of Medical Journal Editors 
IDES 
Emmes Corporation’s Internet Data Entry System 
IEC 
Independent or Institutional Ethics Committee 
IND 
Investigational New Drug Application 
IRB 
Institutional Review Board 
ISM 
Independent Safety Monitor 
ITT 
Intent-to-Treat 
JAMA 
Journal of the American Medical Association 
MedDRA 
Medical Dictionary for Regulatory Activities 
MOP 
Manual of Procedures 
N 
Number (typically refers to subjects) 
NAAT 
Nucleic Acid Amplification Test 
NIAID 
National Institute of Allergy and Infectious Diseases, NIH, 
DHHS 
NIH 
National Institutes of Health 
OCRA 
Office of Clinical Research Affairs, DMID, NIAID, NIH, DHHS 
OHRP 
Office for Human Research Protections 
OHSR 
Office for Human Subjects Research 

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ORA 
Office of Regulatory Affairs, DMID, NIAID, NIH, DHHS 
PHI 
Protected Health Information 
PI 
Principal Investigator 
PK 
Pharmacokinetics 
PP 
Per-Protocol 
QA 
Quality Assurance 
QC 
Quality Control 
SAE 
Serious Adverse Event/Serious Adverse Experience 
SDCC 
Statistical and Data Coordinating Center 
SI 
Site Investigator 
SIC 
Screening Informed Consent 
SOP 
Standard Operating Procedure 
STD 
Sexually Transmitted Disease 
STI 
Sexually Transmitted Infection 
T. vaginalis 
Trichomonas vaginalis 
ToC 
Test of Cure 
US 
United States 
 
 
 
 

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PROTOCOL SUMMARY 
 
Title: 
A Randomized, Double-Blind, Placebo Controlled, Phase 2 
Study to Assess Treatment of Gardnerella vaginalis Vaginal 
Colonization with Amoxicillin 
Phase: 
II  
Population: 
Approximately 245 healthy women will be screened to enroll 
98 participants (to achieve 82 evaluable participants) ages 18-
45 with no evidence of vaginitis (yeast, trichomonas, bacterial 
vaginosis (BV)); presence of Gardnerella vaginalis (GV) 
detected by NAAT; willing to use condoms during the study; 
not currently menstruating.  
Number of Sites: 
Two US clinics:  University of Alabama at Birmingham and 
Wake Forest University Health Sciences 
Study Duration: 
Approximately 24 months is anticipated for enrollment and 
completion of participation.  
Participation Duration: 
It is anticipated that each participant will be part of the protocol 
for approximately 22 days (screening visit, enrollment visit, 
and 1 follow-up visit). 
Description of Agent or 
Intervention: 
Amoxicillin 2 x 250 mg capsules PO bid 7 days or placebo 
 
Objectives: 
 
Primary:  To determine if treatment with amoxicillin eradicates 
GV in women who are colonized/infected with GV but have no 
clinical evidence of BV. 
Secondary: 
• 
To evaluate the safety and tolerability of amoxicillin 
compared to placebo. 
Exploratory:  
• 
To determine the demographic and behavioral factors 
associated with vaginal colonization of GV; 

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Description of Study 
Design: 
This is a randomized, double-blind, placebo-controlled Phase 
2 study.  It is anticipated that 245 women will be screened in 
order to enroll 98 participants to achieve 82 evaluable 
participants.  Participants will be randomized to amoxicillin 2 x 
250 mg PO bid or placebo, for 7 days.  Participation will 
include three visits in total – a Screening Visit, an Enrollment 
Visit, and 1 Follow- up visit.  Total participation for each 
woman will be approximately 22 days.   
Estimated Time to 
Complete Enrollment: 
Approximately 24 months 

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Schematic of Study Design:  
Total N:  ~245 screened to enroll 98 (to achieve 82 evaluable) 
 
 
Study Visit 0:   
Screening 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Visit 1: 
Enrollment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Enrollment:  review tests results from Screening Visit, review eligibility, obtain 
informed consent; collect interim sexual history, medical history, and concomitant 
medications 
Randomize  
Dispense study product and issue participant memory aid  
Remind all participants to abstain from vaginal intercourse or use a condom to prevent 
GV reinfection 
N subjects - 
49 
Arm 1
N subjects - 
49 
Arm 2 
Screening:  obtain informed consent; perform screening; collect demographics, sexual 
history, medical history and concomitant medications;  
conduct clinical assessments and pregnancy test 
Samples Collected:   Urine for pregnancy testing; Vaginal swab specimen for testing of 
yeast, trichomonas and BV/abnormal vaginal flora and NAAT testing for T. vaginalis; 
Vaginal swab specimen for testing of GV, BV, and future use  
 
NAAT for GV 
Negative 
 
End of study 
participation 
 
NAAT for GV  
Positive 
 
Vaginitis (yeast, 
trichomonas, or 
BV/abnormal vaginal 
flora) Confirmed  
 
Ineligible:  End of 
study participation 
No  
Vaginitis 
(yeast, trichomonas, or 
BV/abnormal vaginal flora) 

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Study Visit 2: 
Follow-up (ToC) 
 
 
 
 
 
 
 
 
 
 
 
 
Collect interim sexual history, medical history, and concomitant medications; 
assess AEs; 
conduct clinical assessment 
Samples Collected: Vaginal swab specimen for testing of yeast, trichomonas and 
BV/abnormal vaginal flora; Vaginal swab specimen for testing of GV, BV, and future use  
 
 
Assessment of Final Study 
Outcome Measures 
 

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KEY ROLES 
Individuals: 
 
 
Principal Investigator and Site Investigator:   
Jane Schwebke, MD 
University of Alabama at Birmingham 
703 19th Street South 
Birmingham, AL 35294  
Phone: 205-975-5665 
Fax: 205-975-7764  
Email:  schwebke@uab.edu 
 
Site Investigator: 
Candice McNeil, MD, MPH 
Wake Forest University Health Sciences 
Medical Center Boulevard 
Winston-Salem, NC 27157 
Phone: 336-716-4556 
Fax:  336-716-3825 
Email:  cmcneil@wakehealth.edu 
Institutions: 
 
NIH – Division of 
Microbiology and 
Infectious Diseases,  
DMID  
 
 
 
 
Scientific Lead 
Carolyn Deal, PhD 
Medical Monitor  
Mohamed Elsafy, MD  
Clinical Project Manager   
Delmyra Turpin, RN, MPH, CCRP 
 
Pharmacist 
Binh Hoang, RPh, PharmaD, MBA 
 
 
 

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Statistical and Data 
Coordinating Center 
The Emmes Corporation 
 
Statistician 
Michael Wierzbicki, PhD  
 
Statistician  
Adrienne Kuxhausen, MS 
 
Project Manager  
Hannah Kwak, MHS  
 
Operations Coordinating 
Center 
FHI360 
Protocol Specialist 
Noelle Myler, CCRA 
Research Assistant 
Mary Briggs 
 
 
 
UAMS STI CTG Statistical 
Consultant                        
University of Arkansas for Medical Sciences 
Page C. Moore, Ph.D. 
 
 
 
 
 
 
 
 

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2 
BACKGROUND INFORMATION AND SCIENTIFIC 
RATIONALE 
 
Background Information 
Bacterial Vaginosis (BV) is the most common cause of vaginitis worldwide and is strongly 
associated with important public health issues including preterm birth and 
acquisition/transmission of HIV and other STDs(1, 2).  Although the exact cause of BV is 
unclear, the current epidemiologic data strongly support the hypothesis that BV is sexually 
transmitted(3).  Further, there is mounting data to suggest that Gardnerella vaginalis (GV) is the 
founder organism that is sexually transmitted(3).  Once GV is established, there is a resultant 
change in the vaginal microbiome characterized by loss of lactobacilli and an increase in 
anaerobic organisms leading to the syndrome of BV(3, 4).  GV is nearly universally found in 
women with BV.  However, it may also be found in women who do not meet the current 
definition of BV, leading some to question its pathogenicity.  Others have hypothesized that 
there are strain differences among GV in terms of virulence factors(5). 
 
Rationale 
If GV is necessary for the development of BV, then eradication of GV in women who do not 
meet the clinical criteria for BV should abort the future development of BV.  Amoxicillin was 
chosen as the therapeutic intervention because it is highly active against GV but has limited 
efficacy against anaerobes associated with BV.  This Phase 2 study will determine if GV in the 
vaginal flora will be eradicated by amoxicillin.  If amoxicillin successfully eradicates GV, we will 
develop the next step to examine prevention of BV through screening and treatment of GV. 
The amoxicillin dose will be 2 x 250 mg capsules PO twice a day for 7 days.  Placebo will be 
similarly packaged. 
Generally healthy women between ages 18 and 45 presenting to Health/STD clinics and 
responding to advertisements will be invited to participate in this study.  Women who are 
pregnant will not be permitted to enroll. 
 
 

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Potential Risks and Benefits 
2.3.1 Potential Risks 
The primary associated risk with this study is a possible Adverse Event, AE, secondary to 
amoxicillin.  These could include allergic reaction, rash, nausea, vomiting, diarrhea or other 
unforeseen events.  Amoxicillin may lead to penicillin allergy in the infant of nursing mothers.  
Amoxicillin can reduce the effectiveness of hormonal contraceptives. 
Potential risks may include irritation from vaginal swabs or minor bleeding if the swabs are not 
used according to instructions.  Information concerning participants’ sexual history is necessarily 
detailed given the study’s objectives and may provoke some minor psychological or emotional 
stress when requested.  Participation in research may involve a loss of privacy.  Participant 
records will be kept as confidential as is possible under the law.  Individual identity will not be 
used in any reports or publications resulting from this study. 
There is no current standard of care for a positive GV test result and women who test positive 
but do not have symptoms are usually not given any treatment.  Thus, if a participant’s GV test 
result remains positive after completion of the study, no further participant contact by study staff 
is required.   
2.3.2 Known Potential Benefits 
Participants may benefit from this study by finding out more about the specific cause of any 
vaginal symptoms they may be experiencing. Participants may benefit from pre- and post-test 
counseling, treatment, and referrals, as necessary. It has previously been observed that 
participants are empowered by knowing, for example, more about what BV is and how it can be 
prevented.    
 

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3 
OBJECTIVES 
 
Study Objectives 
3.1.1 Primary objective:   
• 
To determine if treatment with amoxicillin eradicates GV in women who are 
colonized/infected with GV but have no clinical evidence of BV. 
3.1.2 Secondary objective: 
• 
To evaluate the safety and tolerability of amoxicillin compared to placebo.    
3.1.3 Exploratory objective: 
• 
To determine the demographic and behavioral factors associated with vaginal 
colonization of GV. 
 
Study Outcome Measures 
3.2.1 Primary Outcome Measures 
• 
The proportion of participants with eradication of GV in each study arm at Visit 2 
(Day 15-21) as assessed by NAAT. 
3.2.2 Secondary Outcome Measures 
• 
The proportion of participants reporting related adverse events (AEs and SAEs) in 
each study arm following the first dose of study product through Visit 2 (Day 15-21). 
3.2.3 Exploratory Outcome Measures 
• 
The demographic and behavioral factors among women in the NAAT screening 
population without vaginitis who are baseline GV positive and women who are 
baseline GV negative   

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STUDY DESIGN 
This is a randomized, double-blind, placebo-controlled Phase 2 study screening approximately 
245 adult females 18-45 years of age to enroll approximately 98 participants to achieve 82 
evaluable participants at the test of cure (ToC) visit.  The study is designed to determine if 
amoxicillin will eradicate vaginal colonization/infection with GV when administered to women 
who are colonized/infected with GV but have no clinical evidence of BV.  Women who consent 
to screening participation will undergo pelvic examination on entry and vaginal specimens 
collected for pH, whiff test and wet prep microscopy (Amsel criteria with the exception of 
evaluation of vaginal discharge), Nugent score, NAAT for trichomonas,  and quantitative NAAT 
for GV.  At Visit 1 (Enrollment - Day 1) women who tested positive for GV by NAAT, negative for 
BV by Nugent and negative for trichomonas by NAAT will be enrolled and randomized to one of 
two groups (amoxicillin or placebo).  A ToC will be completed at Visit 2 (Day 15-21).  
Baseline information will be collected from all women at the screening visit (Visit 0 (Day -14 to -
7).  This information will consist of demographics, medical and sexual history, concomitant 
medications, and clinical and laboratory findings.  Vaginal swabs will be collected as noted 
above. Women who test positive for vaginitis at the screening visit will be screen failures. At the 
Enrollment Visit (Visit 1, Day 1) women who tested positive for GV, negative for abnormal 
flora/BV, and negative for trichomonas will be enrolled and randomized.  Those who were 
negative for GV will be screen failures and will not continue in the study, but, their, 
demographic, medical, and sexual history as well as baseline swabs will be used for 
comparisons to the GV positive women for an exploratory objective. 
Women who are enrolled will be asked to return for one further visit, Visit 2 (Day 15-21), where 
a ToC will be completed (a pelvic exam completed with the same specimens taken as those at 
baseline with the exception of the trichomonas NAAT). 
Participants will be queried regarding any adverse outcomes and all AEs will be collected 
through Visit 2.  Safety oversight will be provided by an Independent Safety Monitor (ISM) at 
each clinical site and by a Data Monitoring Safety Board (DSMB). The DSMB members will 
meet at specified times during the course of the study as defined in the DSMB Charter.     
Laboratory testing will include nucleic acid amplification test (NAAT) for trichomonas at each 
site’s local lab; Nugent score for BV at Dr. Schwebke’s Lab; quantitative NAAT for GV at 
LabCorp Research and Development Laboratory; and assessment of vaginal pH, saline 
microscopy (yeast, trichomonas, clue cells) at each site’s local lab. 
The duration of the study for participants who are enrolled and randomized will be 
approximately 22 days.  For those not enrolled, participation will end at their post screening 
follow up phone call.  It is expected that enrollment will be completed in approximately 12 
months. 

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Women will be asked to abstain from vaginal intercourse or use condoms at all times for vaginal 
intercourse during their participation independent of birth control use or if participant is of non-
childbearing potential.  This restriction is to prevent participants from GV reinfection.   
For details on study procedures and evaluations and study schedule by study visits, see 
Sections 7, 8, and Appendix A: Schedule of Events. 

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5 
STUDY ENROLLMENT AND WITHDRAWAL 
Approximately 245 adult females ages 18-45, who are in good health, will be screened to enroll 
approximately 98 participants to achieve 82 evaluable participants.  No exemptions are granted 
on inclusion/exclusion criteria in DMID sponsored trials. 
Women will be recruited from Health/STD clinics.   
Participants screened who test positive for GV by NAAT, negative for BV by Nugent (Nugent 
score 0-3) and negative for trichomonas by NAAT, will be enrolled and randomized.   
Participants screened who test positive for vaginitis (i.e., yeast, trichomonas, or BV/abnormal 
vaginal flora) will be notified during the screening visit that they are not eligible to participate in 
the study.   
Participants screened who test negative for GV by NAAT will be notified by a post screening 
visit telephone call that they are not eligible to participate in the study.  They will be counseled 
that asymptomatic GV does not require medical treatment and given instructions on relevant 
reasons to pursue medical care. 
 
Participant Inclusion Criteria 
 
Section 8 has details of all testing. 
 
Women eligible to enroll in this this study must meet all of the inclusion criteria: 
 
1. Women ages 18-45, inclusive; 
2. No evidence of vaginitis (yeast, trichomonas, and BV/abnormal vaginal flora) or other 
vaginal conditions which in the opinion of the investigator could be confounders*; 
 *These causes will initially be detected by wet mount microscopy with trichomonas 
during the screening procedures and later confirmed by NAAT and BV/abnormal vaginal 
flora confirmed by Nugent scoring (Nugent score of 4-10) (see Section 8); 
3. Presence of GV detected by NAAT*; 
*results of NAAT testing will be available prior to return for Enrollment visit; 
4. Willing to use condoms during vaginal intercourse while participating in the study; 
5. Not currently menstruating at screening visit; 
6. Willing and able to provide written informed consent; 
7. Negative urine pregnancy test on all participants of childbearing potential at study 
screening;  

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8. Participant must be of non-childbearing potential* or must be using highly effective 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. 
**In addition to the required use of condoms by the male partner during study 
participation, participants must agree to avoid becoming pregnant by using one 
of the following acceptable method of birth control for 30 days prior to screening 
and for the duration of the study; 
• 
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 
• 
Abstinence; 
 
9. Participant is not planning on taking antibiotics or using any intravaginal microbicides 
from the Screening visit through the Visit 2 Follow-up (ToC); 
10. Participant is willing and able to cooperate to the extent and degree required by this 
protocol at the discretion of the investigator. 
 
 
Participant Exclusion Criteria 
 
Participants eligible to participate in this study must not meet any of the following exclusion 
criteria: 
1. Pregnant or nursing; 
2. Allergic to penicillin, amoxicillin, cephalosporins, or other β-lactam antibiotic; 
3. Use of antibiotics in the past 14 days prior to screening visit;  
4. HIV infected;  

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5. Women taking immunosuppressive agents; 
6. History of renal impairment; 
7. Use of any investigational drug within the past 30 days prior to screening; 
8. Any other condition that, in the opinion of the investigator, would interfere with 
participation in the study. 
 
Treatment Assignment Procedures 
Enrollment of participants will be done online using the enrollment module of AdvantageEDCSM.  
Participants will be randomized using a 1:1 ratio to receive product or placebo after providing 
consent and confirmation of eligibility based on the study inclusion and exclusion criteria. 
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 participants 
assigned to each group, an imbalance that can occur in the simple randomization procedures.  
Stratification will be by study site. 
5.3.1 Randomization Procedures 
The list of randomized treatment assignments will be prepared by statisticians at the Emmes 
Corporation and provided to the research pharmacist at UAB who will prepare the study 
treatment. The research pharmacist will label each vial of study treatment with a blinded 
treatment number according to the randomization scheme. The list of randomized treatment 
assignments will be included in the enrollment module of The Emmes Corporation’s Internet 
Data Entry System (IDES).  IDES will assign each enrolled participant a blinded treatment code 
from the list after demographic and eligibility data have been entered into the system.   
Instructions for use of the enrollment module are included in the IDES User’s Guide.   
Each site will have a supply of blinded vials pre-labeled with treatment numbers, each 
containing sufficient doses to treat a participant for seven days. Once a participant is assigned a 
treatment number, the corresponding vial will be distributed to the participant. 
5.3.2 Masking Procedures 
The active and placebo arms of this 2-arm study will be masked by providing identical study 
vials to participants in the two arms.  All participants and clinical investigators participating in 
this trial will be blinded with respect to treatment assignment.  The research pharmacy at UAB 
will over-encapsulate the amoxicillin capsules for the active treatment arm and will create 
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The participants, the study personnel who perform study assessments after administration and 
those dispensing study medication, data entry personnel at the sites, and laboratory personnel 
will be blinded to treatment assignment.  The DSMB may receive data in aggregate and 
presented by treatment group, but without the treatment group identified. The DSMB may be 
unblinded to individual study treatment assignments, as needed, to adequately assess safety 
issues.  Refer to the MOP for unblinding procedures. 
5.3.3 Reasons for Withdrawal 
Participants may withdraw voluntarily from participation in the study at any time.  Participants 
may also withdraw voluntarily from receiving the study intervention for any reason.  An 
investigator may also withdraw a participant from receiving further study intervention.  Any 
participant who has received at least one dose of study drug will be continued in efficacy and 
safety follow-up, if the participant agrees. 
Any enrolled participant may withdraw or be withdrawn from the study for the following reasons: 
• 
The participant withdraws consent 
• 
The study is terminated 
• 
For any reason that, in the opinion of the investigator, precludes the participant's 
participation in the study 
• 
Participant is lost to follow-up 
If a participant withdraws or is withdrawn prior to completion of the study, the reason for this 
decision must be recorded in the case report forms (CRFs). A participant who voluntarily 
withdraws from the study or has been discontinued from receiving further treatment will be 
encouraged to permit continued follow-up of AEs and to follow scheduled visits.  Participants 
should be asked to continue scheduled evaluations, complete an end-of-study evaluation, and 
be given appropriate care under medical supervision until the symptoms of any AE resolve or 
the participant’s condition becomes stable. 
Refer to Section 7.4 for procedures to be followed if a participant withdraws from the study. 
Withdrawal of participants from analysis populations is discussed in Section 11.4.1.  
5.3.4 Handling of Withdrawals 
Participants who withdraw, or are withdrawn from the efficacy endpoint analysis, or are lost to 
follow-up after signing the Enrollment Informed Consent (EIC) form, randomization, and receipt 
of study product will not be replaced. Participants who withdraw consent after signing the EIC 
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If withdrawal occurs after study treatment, the participant 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 participant will be followed until the AE is resolved or until the participant’s 
condition becomes stable. 
Participants who request to withdraw their consent after study treatment from further 
participation in the study will be reminded of the importance of continuing in the study for safety 
evaluations and will be encouraged to complete the Early Termination Visit if they choose not to 
complete the remaining study visits. The Early Termination Visit procedures are listed in Section 
7.4. Participants who choose to decline continuation in study participation will no longer be 
contacted for follow-up. 
In the case of participants who fail to appear for a follow-up safety assessment, extensive effort 
(i.e., three documented contact attempts via phone calls and/or e-mails, made on separate 
occasions) will be made to locate or recall them or at least to determine their health status. 
Participants who cannot be located after extensive effort will no longer be contacted for follow-
up. These efforts will be documented in the participant’s records.  
If a participant is withdrawn from the study due to an AE that prohibits continued participation in 
the study, she will be given appropriate care and treatment under medical supervision until the 
condition has resolved or becomes stable.  
Safety and efficacy data will be collected on any participant who is withdrawn from the efficacy 
endpoint analysis. Refer to Section 11 for details on how participants who are withdrawn will be 
handled during analysis. 
5.3.5 Termination of Study  
DMID reserves the right to terminate the study at any time for clinical or administrative reasons.  

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6 
STUDY INTERVENTION/INVESTIGATIONAL PRODUCT 
 
Study Product Description 
Amoxicillin, USP is a semisynthetic antibiotic, an analog of ampicillin, with a broad spectrum of 
bactericidal activity against many gram-positive and gram-negative microorganisms.  Amoxicillin 
is similar to penicillin in its bactericidal action against susceptible bacteria during the stage of 
active multiplication. It acts through the inhibition of cell wall biosynthesis that leads to the death 
of the bacteria. 
6.1.1 Acquisition 
The antibiotic to be used in this study is FDA-approved for use in the US for gynecological and 
other infections. Amoxicillin 250 mg generic capsules and placebo will be purchased in bulk 
from the UAB Research Pharmacy.  
The research pharmacy will over-encapsulate the amoxicillin capsules for the active treatment 
arm and will create identical appearing placebo capsules containing lactose.  The UAB 
pharmacy will package the capsules (amoxicillin or placebo) into individual doses. This includes 
encapsulation, packaging, blinding and labeling according to the randomization schedule for 
each site and applicable regulatory requirements. The UAB pharmacy will ship the medication to 
Fisher BioServices at the following address: 
  
DMID Clinical Materials Services (CMS) Contract  
Fisher BioServices 
20439 Seneca Meadows Parkway 
Germantown, MD 20876 
Phone : (240) 477-1350 
Fax : (240) 477-1360 
Email : DMID.CMS@thermofisher.com  
Study products will be shipped from the DMID Clinical Materials Services (CMS) to the 
investigational site upon request and approval by NIAID DMID. 
6.1.2 Formulation, Packaging, and Labeling 
Amoxicillin 
Amoxicillin will be supplied as 250 mg amoxicillin trihydrate.  Each active capsule of amoxicillin 
will be placed in a gelatin capsule. The gelatin capsules are Swedish orange capsules from 
Capsugel. Each vial contains 28 capsules. 
Placebo for Amoxicillin  

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Each placebo capsule will be filled with lactose only and will be identical in appearance to the 
capsule with the active ingredient. The lactose filler is Lactose U.S.P. and the small amount 
should not be a problem even for persons who are lactose-intolerant. Participants may 
experience some mild bloating.  Each vial contains 28 capsules. 
The active and placebo capsules will be placed into amber prescription vials and labeled with a 
treatment number and allocated according to the randomization scheme generated by Emmes. 
Vials will be placed into plastic bags with a sheet of instructions for each arm. 
6.1.3 Product Storage and Stability 
All study medications are stable at room temperature and will be stored at 20-25°C/68-77°F. 
 
Dosage, Preparation and Administration of Study 
Intervention/Investigational Product  
6.2.1 Dosage 
 
Participants will be randomized to one of two study products as follows: 
 
• 
Amoxicillin 2 x 250mg capsules PO twice a day for 7 days 
• 
Placebo 2 capsules PO twice a day for 7 days 
 
6.2.2  Preparation 
 
A Site Research Pharmacist may be delegated the responsibility of study product 
dispensation. The Research Pharmacist must be a licensed, registered pharmacist and is the 
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 the study product. These personnel must be licensed, trained, 
and qualified to prepare investigational study product and must be authorized to dispense the 
study product under state and local rules and regulations.   
 
 

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6.2.3 Administration 
 
All active and placebo study products will be orally administered. 
 
Each participant will receive a single vial of medication.  Section 6.1.2 explains the packaging.  
Section 4 explains the design and study arms.  After randomization of the participant, the study 
clinician will obtain the next available drug number and vial of medication for that drug number.    
The participant will be given instructions on how and when to take the medication and to bring 
the vial back to the clinic at the next follow-up visit. 
 
 
Accountability Procedures for the Study 
Intervention/Investigational Product(s) 
Fisher will ship packaged study medication to the investigational sites.  At each site, study 
product will be kept in a locked storage cabinet at the clinic and administered by the study 
personnel.  A drug accountability log should be filled out for all study medications at the sites.   
After receipt of the study product, the site PI is responsible for its distribution and disposition 
and has ultimate responsibility for study product accountability. The site PI may delegate to a 
Site Research Pharmacist or an appropriately qualified staff member the responsibility for study 
product accountability.  The designee will be responsible for maintaining complete records and 
documentation of product receipt, accountability, dispensation, temperature and storage 
conditions, and final disposition of study product. All study product, whether administered or not, 
must be documented on the appropriate study product accountability record or dispensing log. 
The sponsor's monitoring staff will verify the participating clinical sites’ study product 
accountability records and dispensing logs per the study monitoring plan. 
Unused dispensed study product returned to the site will be accounted for at the site and 
participant compliance will be recorded.  Any unused returned study product will be disposed of 
according to the site’s SOPs.  Upon completion or termination of the study and after the final 
monitoring visit, final disposition of the unused never dispensed study product will be 
determined by DMID and communicated to the participating sites by the DMID Clinical Project 
Manager. 
 
 
Assessment of Participant Compliance with Study 
Intervention/Investigational Product  
 

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Participants will be asked to bring the vial of medication and memory aid to the study personnel 
at their follow-up visit.  Study personnel will review adherence to the study medication schedule 
with the participants, including the participant’s memory aid, and record this on the appropriate 
data collection form at Visit 2 (ToC) and any Unscheduled Visits.  Study personnel will record 
the number of pills returned.  The participant’s memory aid may be discarded by the study 
personnel post review with the participant. 
 
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 14 days prior to 
the screening visit through Visit 2 or early termination, whichever occurs first. Prescription and 
over-the-counter drugs will be included, as well as intravaginal products, herbs, vitamins, and 
supplements.  Previously recorded medications will be updated as appropriate. 
Participants who have received study drug and are subsequently diagnosed with a concomitant 
infection that requires systemic antibiotics will receive treatment according to the local clinic’s 
standard protocols.  
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 the study product should not be used 
unless absolutely necessary.  
Refer to Section 5 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 (Study Procedures/Evaluations), and 
the Appendix A: Schedule of Events. Further instructions are described in the protocol-specific 
Manual of Procedures (MOP). 
 
Visit 0 (Day -14 to -7) Screening 
• 
Potential participants will be provided with a description of the study (purpose and study 
procedures) and asked to read and sign the Screening Informed Consent form, (SIC). 
The SIC form will be signed prior to performing any study eligibility procedures. 
• 
Eligibility criteria will be reviewed with participants.  
• 
Demographic information will be collected from the participant. 
• 
Sexual history for the past 90 days will be collected.  
• 
Medical history will be collected only on active conditions within one year prior to 
screening.  All concomitant medications taken in the last 14 days prior to the screening 
visit will be recorded on the appropriate data collection form. 
• 
A urine pregnancy test will be performed on all participants of childbearing potential and 
must be negative prior to administration of study product. 
• 
A pelvic examination will be conducted for the collection of vaginal swab specimens for: 
pH, whiff test, and wet prep microscopy (Amsel criteria with the exception of 
evaluation of vaginal discharge), Nugent score, NAAT for trichomonas, quantitative 
NAAT for GV, and future use. If the on-site microscopy reveals a vaginal infection (i.e., 
yeast, trichomonas, and BV/abnormal vaginal flora), the remaining specimens that 
were collected will be discarded as the participant is not eligible for the study. For this 
study, vulvovaginal candidiasis will be defined by the presence of budding yeast 
and/or pseudohyphae; trichomoniasis will be defined by the presence of motile 
trichomonads on wet prep or a positive NAAT for T. vaginalis; abnormal flora/BV by 
the presence of at least 2/3 of the following criteria – pH >4.5, positive whiff test, ≥ 
20% clue cells.  These stricter criteria will eliminate those women with intermediated 
flora as well as BV. We will not evaluate the presence of vaginal discharge per se due 
to the subjective nature of this observation. If these vaginal infections are found on the 
screening wet prep the participant will not be eligible for the study.  
AFTER VISIT 0 ENDS AND PRIOR TO VISIT 1 
• 
Women whose tests from the screening visit return positive for GV by NAAT, negative 
for abnormal flora/BV by Nugent score of 0-3 and negative for trichomonas by NAAT 

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will return for the Enrollment visit, which is scheduled at the end of the screening visit. 
• 
Women whose tests from the screening visit return negative for GV by NAAT will be 
called and informed that they are no longer eligible.  
• 
Women whose tests from the Screening visit return positive for GV by NAAT and also 
test positive for either BV or trichomonas will be called and informed that they are no 
longer eligible. 
 
Visit 1 (Day 1) Enrollment 
• 
Test results from the screening visit will be reviewed and the following actions 
completed: 
• 
Participants whose tests from the screening visit return positive for GV by NAAT, 
negative for abnormal flora/BV by Nugent (Nugent score 0-3) and negative for 
trichomonas by NAAT, are considered eligible for study participation. 
• 
Study personnel will review study eligibility to ensure unchanged since the screening 
visit.  Pregnancy test result from screening visit will be reviewed and confirmed to be 
negative.  
• 
Screened participants who are deemed eligible will be asked to read and sign the 
Enrollment Informed Consent form, (EIC). The EIC form will be signed prior to 
performing any study procedures. 
• 
Interim sexual history since the screening visit will be collected. 
• 
Medical history will be reviewed and updated as appropriate. 
• 
All concomitant medications taken since the screening visit will be recorded on the 
appropriate data collection form. Previously recorded medications will be updated as 
appropriate. 
• 
Participants will then be enrolled and randomized to treatment vs. placebo (via 
Advantage EDC) and instructed to take the medication twice per day for 7 days.    
• 
Study personnel will schedule randomized participants to return for follow-up at Visit 2 
(Day 15-21). 
• 
Study drug, memory aid and instructions will be provided to participants prior to 
departure from clinic.  Remind participant to abstain from vaginal intercourse or use 
condoms at all times for vaginal intercourse until next visit independent of birth control 
use or if participant is of non-childbearing potential.  This restriction is to prevent 
participants from GV reinfection.    

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Visit 2 (Day 15 [Window: Days 15-21]) Follow-up (ToC) 
• 
Interim sexual history since the last clinic visit will be collected. 
• 
Medical history will be reviewed and updated as appropriate. 
• 
All concomitant medications taken since Visit 1 will be recorded on the appropriate data 
collection form. Previously recorded medications will be updated as appropriate. 
• 
Compliance with the study protocol criteria will be assessed via review of participant 
memory aid, drug return, and review with participant. 
• 
Study personnel will discuss with participants and assess and record all AE/SAEs. 
• 
A pelvic examination will be conducted for the collection of vaginal swab specimens as 
done at screening, with the exception of trichomonas NAAT. 
• 
If the Visit 2 GV specimen is still positive by NAAT no further participant contact is 
needed.    
 
Early Termination Visit 
The following assessments will be performed at the early termination visit for participants who 
withdraw, or are withdrawn or terminated from this study: 
• 
Interim sexual history since the last clinic visit will be collected. 
• 
Medical history will be reviewed and updated as appropriate. 
• 
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. 
• 
Compliance with the study protocol criteria will be assessed via review of participant 
memory aid, drug return, and review with participant. 
• 
Study personnel will discuss with participants and assess and record all AEs/SAEs. 
Previously recorded AEs/SAEs will be updated as appropriate. 
• 
If indicated for symptoms, a pelvic examination will be conducted for the collection of 
vaginal swab specimens for: 
• 
pH, whiff test, and wet prep to determine the etiology of current symptoms. 

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Unscheduled Visit  
Participants may be seen for unscheduled visits as necessary.  For example, for problems with 
the medication, development of intercurrent vaginal symptoms, or need for treatment of 
trichomonas. 
Any of the following activities may be conducted at the discretion of the site PI: 
• 
Interim sexual history since the last clinic visit will be collected. 
• 
Medical history will be reviewed and updated as appropriate. 
• 
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. 
• 
Compliance with the study protocol criteria will be assessed via review of participant 
memory aid, drug return, and review with participant. 
• 
Study personnel will discuss with participants and assess and record all AEs/SAEs. 
Previously recorded AEs/SAEs will be updated as appropriate. 
• 
If indicated for symptoms, a pelvic examination will be conducted for the collection of 
vaginal swab specimens for: 
• 
pH, whiff test, and wet prep to determine the etiology of current symptoms. 
 

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8 
STUDY PROCEDURES/EVALUATIONS 
 
Clinical Evaluations 
Medical history only on active conditions within one year prior to screening will be obtained by 
interview of the participants at Visit 0 and will be updated at each clinic visit. At the follow-up 
visits, an interim medical history will be obtained by interview of the participants noting any 
changes since the previous visit. 
Sexual history will be obtained by interview of the participants at Visit 0. Participants will be 
queried at Visit 1 and Visit 2 (and as needed at unscheduled and early termination visits) 
regarding sexual activity and condom use since the previous clinic visit. 
Medications history (concomitant medications) will include a review of all current medications 
and medications taken 14 days prior to the screening visit and through study completion. This 
will occur at Visits 0, 1, and 2, and as needed at unscheduled and early termination visits. 
Prescription and over-the-counter drugs will be included (lubricants, intravaginal products, 
vitamins, herbs and supplements). Assessment of eligibility will also include a review of all 
permitted and prohibited medications per the Participant Inclusion and Exclusion Criteria (see 
Section 5.1). 
Study drug, memory aid and instructions will be provided to participants at Visit 1.  Compliance 
with the study drug will be assessed at Visit 2 (and as needed at unscheduled and early 
termination visits) via review of participant memory aid, drug return, and review with participant. 
AE/SAE assessment will be reviewed with participants at Visit 2 (and as needed at unscheduled 
and early termination visits) and recorded.   
A pelvic examination will be performed on Visit 0 and 2, and as indicated at unscheduled or 
early termination visits. All pelvic examinations will be performed by a qualified study clinician.   
Pelvic Examination: 
During pelvic examination, the following will be used for the clinical diagnosis of BV by Amsel 
criteria. Instructions for obtaining and determining the presence of Amsel clinical criteria can be 
found in the protocol-specific MOP and consist of the following: 
1) A fishy odor of the vaginal discharge with the addition of a drop of 10% KOH (positive 
whiff test);  
2) Clue cells ≥ 20% of the total vaginal squamous epithelial cells on saline microscopy; 
3) Vaginal fluid pH > 4.5. 
 

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Laboratory Evaluations 
8.2.1 Clinical Laboratory Evaluations 
A urine pregnancy test will be performed at the site during the screening visit and must be 
negative prior to participant being eligible for enrollment.  NAAT for trichomonas will be 
performed by the local lab. Nugent score for BV will be performed in Dr. Schwebke’s lab.  
Quantitative NAAT for GV will be performed at LabCorp Research and Development 
Laboratory.   
Bedside Evaluation of Vaginitis 
A vaginal swab specimen should be used to determine the vaginal pH using ColorpHast pH 
paper.  Vaginal secretions should be placed into 0.3 cc of saline and examined within 10 
minutes of collection by microscopy to detect the presence of yeast, trichomonas, and clue 
cells.  A drop of the suspension would be mixed with 10% KOH for the “whiff” test and KOH 
fungal prep. 
Nugent Criteria for Determination of BV: 
A vaginal swab for microbiologic assessment of BV by Nugent criteria should be performed. The 
Nugent score utilizes a 0-10 point scale for evaluation of vaginal flora and is based on the 
weighted sum score of the following three bacterial morphotypes calculated from the slide exam 
under oil immersion (1000x): 
• 
Lactobacillus: Large Gram-negative rods 
• 
Gardnerella/Bacteroides spp: thin, curved, Gram-variable rods 
• 
Mobiluncus spp: thin, curved, Gram-variable rods 
The Nugent score is interpreted as follows: 0-3 normal; 4-6 intermediate; and 7-10 BV. For the 
purposes of this study, a score > 3 is considered abnormal, and a score of 0-3 is considered 
normal. 
NAAT testing for T. vaginalis 
This is to be performed by the site lab using FDA cleared methods. 
 
 

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8.2.2 Special Assays or Procedures 
The specific details regarding the preparation of the samples collected for GV NAAT testing can 
be found in the protocol-specific MOP. 
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 
Gram stain specimen shipment for Nugent scoring to the UAB Central laboratory will be 
performed according to all applicable International Air Transport Association (ATA) 
requirements. The UAB Central laboratory address is as follows: 
UAB Infectious Diseases Laboratory 
                                  1900 University Blvd 
                                  THT 220 
                                  Birmingham, AL 35294 
Shipment of GV NAAT isolates to LabCorp will be performed according to all applicable 
International Air Transport (IATA) requirements.  LabCorp address is as follows: 
                                  ATTN: Molecular R&D 6500 
                                  LabCorp 
                                  1447 York Court 
                                  Burlington, NC 27215 
 
 

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9 
ASSESSMENT OF SAFETY 
 
Specification of Safety Parameters 
Safety will be monitored throughout the study by a pelvic examination.  Safety will be assessed 
by the frequency and severity of: 
1. Serious adverse events occurring from the time of the study dose through Visit 2. 
2. Non-serious adverse events occurring from the time of the study dose through Visit 2. 
 
Methods and Timing for Assessing, Recording, and Analyzing 
Safety Parameters 
9.2.1 Adverse Events 
Adverse Event:   
ICH E6 defines an AE as any untoward medical occurrence in a patient or clinical investigation 
participant administered a pharmaceutical product regardless of its causal relationship to the 
study treatment.  An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally associated with the use of 
medicinal product.  The occurrence of an AE may come to the attention of study personnel 
during study visits and interviews of a study recipient presenting for medical care, or upon 
review by a study monitor.  
All AEs including local and systemic reactions not meeting the criteria for “serious adverse 
events” should be captured on the appropriate CRF.  Information to be collected includes event 
description, time of onset, clinician’s assessment of severity, relationship to study product 
(assessed only by those with the training and authority to make a diagnosis, which would 
include MD, PA, Nurse Practitioner, DO, or DDS), 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 patient is screened should be 
considered as baseline 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 study product.  

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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:  The following guidelines will be used to quantify intensity: 
Gastrointestinal side effects which include nausea, vomiting, diarrhea, and abdominal pain will 
be assessed on a scale of 1 to 3 according to the toxicology table in Appendix B:  Toxicology 
Table of this protocol.   
Systemic reactions which include allergic reaction, headache, fatigue, and myalgia will be 
assessed on a scale of 1 to 3 according to the toxicology table in Appendix B:  Toxicology Table 
of this protocol.   
All other AEs will be graded using the following general criteria: 
Mild:  events require minimal or no treatment and do not interfere with the patient’s daily 
activities. 
Moderate:  events result in a low level of inconvenience or concern with the therapeutic 
measures. Moderate events may cause some interference with functioning. 
Severe:  events interrupt a patient’s usual daily activity and may require systemic drug therapy 
or other treatment. Severe events are usually incapacitating. 
Changes in the severity of an AE should be documented to allow an assessment of the duration 
of the event at each level of intensity.  Adverse events characterized as intermittent require 
documentation of onset and duration of each episode. 
Relationship to Study Products:  The clinician’s assessment of an AE's relationship to study 
medication 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, the 
event should be reported.  All AEs must have their relationship to study product assessed using 
the terms “related” or “not related”.  In a clinical trial, the study product must always be suspect.  
To help assess, the following guidelines are used. 
• 
Related – There is a reasonable possibility that the study product caused the adverse event. 
Reasonable possibility means that there is evidence to suggest a causal relationship 
between the study product and the adverse event. 
• 
Not Related – There is not a reasonable possibility that the administration of the study 
product caused the event. 

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9.2.2 Serious Adverse Events 
Serious Adverse Event (SAE):  
An adverse event 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 adverse event*,  
• 
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 participant 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. 
* Life-threatening adverse event. An adverse event is considered “life-threatening” if, in the view 
of either the investigator or sponsor, its occurrence places the participant at immediate risk of 
death.  It does not include an adverse event, had it occurred in a more severe form, might have 
caused death. 
All SAEs will be: 
• 
recorded on the appropriate SAE form and eCRF 
• 
followed through resolution by a study clinician as defined in section 9.4 
• 
reviewed and evaluated by a study clinician 
9.2.3 Procedures to be Followed in the Event of Abnormal Clinical Findings 
The site PI is responsible for reporting all AEs/SAEs that are observed or reported during the 
study, regardless of their relationship to study product.  AEs/SAEs or abnormal clinical findings 
will be documented, reported and followed appropriately. 

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Reporting Procedures 
 
The Protocol Chair will monitor all adverse events and report serious adverse events to DMID 
and each site’s local IRB within 24 hours. 
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:  
 
DMID Pharmacovigilance Group 
Clinical Research Operations and Management Support (CROMS) 
6500 Rock Spring Dr. Suite 650 
Bethesda, MD 20817, USA 
SAE Hot Line: 1-800-537-9979 (US) or 1-301-897-1709 (outside US) 
SAE FAX Phone Number: 1-800-275-7619 (US) or 1-301-897-1710 (outside US) 
SAE Email Address: PVG@dmidcroms.com 
 
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 participant 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 study product, 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 IND, MEDWATCH will be used to report related 
AEs.  DMID should be copied simultaneously when an alternate method of reporting is utilized. 

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9.3.3 Reporting of Pregnancy 
Participants of child-bearing potential will be counseled to continue using acceptable forms of 
birth control as well as condoms during the study period. If a participant becomes pregnant 
during the study, dosing will be discontinued immediately. A pregnancy reporting form will be 
completed for any study participant who becomes pregnant during the study period. The site will 
maintain contact with pregnant study participants to obtain pregnancy outcome information. The 
pregnant participant will be followed until delivery or until the end of pregnancy (in the case of 
miscarriage or pregnancy termination). Infants born to these study participants will also be 
monitored for SAEs (congenital anomalies or other birth defects) and other complications for up 
to two 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; 
• 
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 study participants will be reported via AdvantageEDCSM on the 
Pregnancy Report form.   
 
 
Type and Duration of Follow-up of Participants after Adverse 
Events 
AEs and SAEs will be followed from the time of study treatment through resolution even if this 
extends beyond the study reporting period, Visit 2. 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. 

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Halting Rules 
Further enrollment will be halted for DSMB review/recommendation if any two participants 
experience an adverse event that is judged to be Severe (Grade 3) and related to study product. 
DMID retains the authority to suspend additional enrollment and administration of study product 
during the entire study, as applicable. 
 
Safety Oversight (ISM plus DSMB) 
An Independent Safety Monitor (ISM) at each clinical research site will oversee the safety of 
research participants at that site and will provide independent written evaluation of SAEs and 
related Grade 3 AEs to the DMID Clinical Project Manager and DMID Medical Monitor. The ISM 
will serve as an independent consultant for the site PI on participant-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 participant 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 study progress and participant, clinical, and safety data at the following 
time points: 
• 
At specified times during the course of study as defined in the DSMB Charter, 
• 
Ad hoc when a halting rule is met, for immediate concerns regarding observations during 
the study, or as needed. 
• 
A final closeout meeting will be held at the end of the study after the database is locked 
and when the final study report is available. 
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. The DSMB members will meet at 
specified times during the course of the study as defined in the DSMB Charter. 
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 course of the 
study. The DMID Medical Monitor is empowered to stop enrollment and study treatment if 
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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 
 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, 
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 standard 
operating procedures.  Monitoring visits will include, but are not limited to, inspection of study 
facilities, review of regulatory files, accountability records, CRFs, IC forms, printouts of medical 
and laboratory reports from the electronic medical records (EMR) system, and 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 
 Study Hypotheses 
There is one planned formal test of hypothesis which compares amoxicillin to placebo with 
respect to the primary efficacy outcome measure. The hypothesis test compares the proportion 
of participants with eradication of GV in each study arm through Visit 2 (Day 15-21) as assessed 
by NAAT.  
The null hypothesis for the comparison is that there is no difference in proportions between 
study arms, with a two-sided alternative. The test will be conducted using a Pearson Chi-Square 
test with Yates continuity correction at the 5% two-sided significance level. The hypothesis will 
be tested in the Intent-to-Treat (ITT) efficacy analysis population for the primary analysis and 
repeated as a secondary analysis in the Per-Protocol (PP) analysis population. 
 Sample Size Considerations 
Sample size calculations are based on detecting a decrease in GV colonization rate from 80% 
among participants receiving placebo to as large as 44% among participants receiving 
amoxicillin.  Using the two-sided Pearson Chi-Square test with Yates continuity correction, 
significance level of 0.05, and assuming an amoxicillin to placebo allocation ratio of 1:1, 82 
women (41 in each arm) would provide 90% power to detect a difference in colonization rates of 
36% (i.e. 44% colonization rate in the amoxicillin arm).  
Assuming a 15% drop-out rate between enrollment and the ToC visit approximately 98 women 
will need to be randomized to obtain 82 women evaluable for the primary analysis.  Assuming 
40% of women without BV will have a positive NAAT test for GV at screening, approximately 
245 women without BV will need to be screened to randomize 98 women in the study. 
 Planned Interim Analyses  
11.3.1 Safety Review  
The DSMB may review study progress and participant safety data at specified times 
during the course of study, as defined in the DSMB Charter. The study will be monitored to 
determine if any of the safety halting rules described above in Section 9.5 are met. The halting 
rules do not utilize any statistical criteria and no formal hypothesis testing is planned to occur for 
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11.3.2 Efficacy Review 
There are no planned interim efficacy analyses for this study. 
 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 participants.  
The ITT population will be used as the primary efficacy analysis population. 
Safety Population: This analysis population includes all randomized participants who received 
at least one dose of study treatment. 
Per-Protocol (PP) Population: This analysis population includes all randomized participants 
who met all inclusion/exclusion criteria, are evaluable, adhered to the assigned study treatment 
regimen (as defined below), and returned to the study site for the ToC visit within the specified 
window (Visit 2 [Window: Day 15 -21]) and did not experience any of the following after 
enrollment: 
• 
Unprotected vaginal sexual intercourse between Visit 1 and Visit 2 
• 
New pregnancy reported by the subject 
• 
Receipt of any antibiotic or intravaginal microbicide other than study drug  
Participants are deemed evaluable if their BV and GV status can be determined at screening 
and their GV status can be determined at Visit 2.  Participants who are missing Gram stain, GV 
NAAT, or Amsel results at screening are not evaluable.  Participants who are missing GV NAAT 
results at the Visit 2 are not evaluable. 
A Participant is considered adherent to the study treatment regimen if she uses at least 80% of 
the scheduled doses (i.e. at least 12 of the 14 doses) of study treatment, as assessed by the 
number of pills returned. If pill count cannot be assessed, participant report will be used to 
assess adherence.  
In the unlikely event of an error in randomization or study product administration, participants 
will be grouped by the formulation they actually received in the PP and Safety analyses but will 
be grouped by their intended randomized assignment in the ITT analysis.  

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NAAT Screening Population: This analysis population includes all screened women who are 
evaluated for GV by NAAT. 
The NAAT screening population will be used as the exploratory efficacy analysis population. 
11.4.2 Baseline Characteristics 
Baseline and demographic characteristics will be summarized overall and by treatment. 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. 
11.4.3 Safety Analysis Plan 
Safety evaluations will be based on the incidence, severity, and type of adverse events and 
serious adverse events as detailed in Section 9. Safety variables will be tabulated and 
presented for all participants in the Safety population, grouped by treatment. 
Unsolicited AEs will be coded by MedDRA® for preferred term and system organ class. The 
proportion of participants and exact 95% confidence intervals of AEs will be computed in 
aggregate, as well as by MedDRA® categories. The number of SAEs will be reported by a 
detailed listing showing the type, MedDRA® coding, relevant dates (treatment dosing dates and 
AE onset and resolution dates), severity, relatedness, and outcome for each event. 
In addition to the descriptive analyses described above, the proportion of participants who 
experience related adverse events in each study arm following the first dose of study product 
through Visit 2 (Day 15-21) will be summarized overall and by treatment group.   In addition, the 
proportion of participants who discontinue study product early due to adverse events will be 
summarized overall and by treatment group. 
11.4.4 Efficacy Analysis Plan 
11.4.4.1 
Primary Efficacy Analysis 
For the primary analysis of the efficacy of amoxicillin in women who are infected with GV but 
have no clinical evidence of BV, the number and proportion of women with eradication of GV at 
Visit 2 (Day 15-21) will be summarized overall and by treatment group.  The point estimates for 
the arm-specific proportions and difference in proportions as well as corresponding 95% 
confidence intervals will be reported.  A test of hypothesis will be conducted using Pearson Chi-
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formally compare the treatment groups.  The primary analysis will be performed in the ITT 
analysis population and repeated as a secondary analysis in the PP analysis population. 
Eradication of GV is defined by a negative NAAT result for GV at Visit 2 (Day 15-21).  
Participants who have a missing GV NAAT result at the ToC visit are excluded from the PP 
analyses, and will be classified as treatment failures in the ITT analyses. 
11.4.4.2 
Exploratory Efficacy Analysis 
Details of the exploratory efficacy analysis, as well as any additional exploratory analyses that 
may be performed to supplement the primary analysis, will be described in the separate 
Statistical Analysis Plan. As an example of the latter, demographic and baseline characteristics 
of participants who received amoxicillin and were positive for BV by Nugent Score and Amsel 
Criteria at Visit 2 (Day 15-21) will be summarized. 
 
 
 

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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 participants.  Each site will permit authorized representatives of the 
DMID, its designees, and appropriate regulatory agencies to examine (and when required by 
applicable law, to copy) clinical records for the purposes of quality assurance reviews, audits, 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 
participant files and records kept at the pharmacy, at the laboratories, and medico-technical 
departments involved in the clinical trial.  Data collection forms will be derived from the eCRFs 
and be provided by the Statistical and Data Coordinating Center (SDCC). 

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13 
QUALITY CONTROL AND QUALITY ASSURANCE  
Following a written DMID-accepted site quality management plan, the participating sites are 
responsible for conducting routine quality assurance (QA) and quality control (QC) activities to 
internally monitor study progress and protocol compliance. Each 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. Each 
site PI will ensure all study personnel are appropriately trained and applicable documentations 
are maintained on site. 
The SDCC will implement quality control procedures beginning with the data entry system and 
generate data quality control 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 
 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); and future revisions, 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. 
 Institutional Review Board 
Prior to enrollment of participants into this trial, the approved protocol and informed consent 
forms will be reviewed and approved by the appropriate IRB listed on its FWA.  A copy of the 
IRB letter of approval will be provided to DMID.   
The IRB Federal Wide Assurance 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. 
 Informed Consent Process 
The site PI, or designated study staff, will choose participants in accordance with the eligibility 
criteria detailed in Section 5. Before any study procedures are performed, participants must sign 
the Screening Informed Consent Form and, if applicable the Enrollment Informed Consent form 
that both comply with the requirements of 21 CFR Part 50 and 45 CFR 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. There will be two consent 
forms: Screening Informed Consent (SIC) for the screening procedures (determination of 
eligibility confirmed upon receipt of the GV results within 7-14 days post specimen collection) 
and an Enrollment Informed Consent (EIC) for the full study. Upon receipt of the GV test results 
and review of the original screening criteria, the participant is confirmed to be eligible, they will 
then need to be consented using the EIC prior to continuation. 
Before any screening or study procedures are performed, participants will receive a 
comprehensive explanation of the proposed screening procedures, study procedures and study 
interventions/products, 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 

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obtaining proper informed consent. Participants will also receive a detailed explanation of the 
proposed use and disclosure of their protected health information (PHI), including specifically 
their specimens. Participants will be allowed sufficient time to consider participation in the 
screening portion and enrollment in the trial, after having the nature and risks of both the 
screening and trial explained to them. Participants 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. 
Both the SIC and EIC will describe in detail the study interventions/products, study procedures, 
risks, and possible benefits given to participants. Neither informed consent form can include any 
exculpatory statements. Both informed consent forms will be IRB-approved, and participants will 
be asked to read and review the appropriate document. Upon reviewing the appropriate 
document, the site PI (or designee) will discuss the research study to participants and answer 
any questions that may arise. Participants must sign the informed consent form(s), 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 study 
product. 
Study personnel may employ IRB-approved recruitment efforts prior to obtaining the 
participant’s consent; however, before any study procedures are performed to determine 
protocol eligibility, the SIC must be signed. Participants will be given a copy of all informed 
consent forms that they sign. 
By signing the SIC and EIC, participants agree to complete all evaluations required by the trial, 
unless the participant withdraws voluntarily or is terminated from the trial for any reason. 
The rights and welfare of participants will be protected by emphasizing to participants that the 
quality of their medical care will not be adversely affected if they decline to participate in or 
withdraw from this trial. 
 Exclusion of Women, Minorities, and Children (Special 
Populations) 
This trial will be inclusive of female adults who meet the Participant 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.  
 Subject Confidentiality 
Subjects will be identified by a participant number and not by name. Subject confidentiality is 
strictly held in trust by the participating site PIs, their study personnel, the sponsor, and their 

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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. 
All information provided by the sponsor and all data and information generated by the 
participating sites as part of the trial (other than a participant’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, 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, we have received a Certificate of Confidentiality, CoC.  With this CoC, the 
participating sites cannot be forced to release information that may identify the participant, even 
by a court subpoena, in any federal, state, or local civil, criminal, administrative, legislative, or 
other proceedings.  The participating sites will use the CoC to resist any demands for 
information that would identify the participant, except as explained below. 
The CoC cannot be used to resist a demand for information from personnel of the United States 
Government that is used for auditing or evaluation of federally funded projects, like this or local 
laws, such as for reporting of communicable diseases. 
A CoC does not prevent the participant from voluntarily releasing information about themselves 
or their involvement in this research.  If any person or agency obtains a written consent to 
receive study information, then the participating sites may not use the CoC to withhold that 
information.   
The CoC does not prevent the participating sites from reporting without the participant’s 
consent, information that would identify the subject as a participant in the study regarding 

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matters that must be legally reported including: child and elder abuse, sexual abuse, or wanting 
to harm themselves or others. 
 Study Discontinuation 
If the trial is discontinued, participants who sign the EIC and are randomized and treated will 
continue to be followed for safety assessments. No further study product will be administered. 
 Future Use of Stored Specimens 
Both the screening and enrolled subject populations will be consented to have vaginal swab 
samples stored for future vaginitis research.  Storage of samples is optional and not a 
requirement for the study. If the participant consents to storage and future use of specimens, 
specimens will be kept at the UAB Central laboratory and LabCorp.  Participants 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 SIC and EIC or as otherwise authorized 
under applicable law and after review and approval by the DMID and the IRB of the researcher 
requesting the specimens. 
Archived specimens will be identified only by the participant number which will allow linkage of 
the specimens to study data but not to any personal identifiers.   
There will be no direct benefit to the participant from allowing the specimen 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. 
The participant’s specimen will be kept until it is used up or destroyed.  It may be used to 
develop new tests or products.  In some instances, these may have potential commercial value.   
If a participant decides at any time that she does not want the specimen stored for future 
research she must contact the study nurse/doctor who will then notify the laboratory/specimen 
archive.  The laboratory staff will then mark the specimens by adding a “Destroy” label and they 
will be destroyed at the end of this study or removed from storage and destroyed. 
 

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15 
DATA HANDLING AND RECORD KEEPING 
The investigator 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 the sites to 
record and maintain data for each participant enrolled in the study.  All source documents 
should be completed in a neat, legible manner to ensure accurate interpretation of data.  
Permanent ink is required to ensure clarity of reproduced copies.  When making a change or 
correction, the original entry should be crossed out with a single line, and the change should be 
initialed and dated.  Do not erase, overwrite, or use correction fluid or tape on the original.  
Data reported in the eCRF should be consistent with the data collection form/source documents 
or the discrepancies should be documented.   
The sponsor and/or its designee will provide guidance to investigators on making corrections to 
the data collection forms and eCRFs. 
 Data Management Responsibilities 
All data collection forms and laboratory reports must be reviewed by the clinical team and data 
entry staff, who will ensure that they are accurate and complete.  Adverse events must be 
graded, assessed for severity and causality, and reviewed by the site PI or designee.  Data 
collection is the responsibility of the clinical trial staff at the site under the supervision of the Site 
PI.  During the study, the investigator must maintain complete and accurate documentation for 
the study. 
The Emmes Corporation will serve as SDCC for this study and will be responsible for data 
management, quality review, analysis, and reporting of the study data. 
 Data Capture Methods 
Clinical data (including AEs and concomitant medications) will be entered into a 21 CFR Part 11-
compliant internet data entry system provided by The Emmes Corporation.  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/source documents. 

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 Types of Data 
Data for this study will include safety, laboratory, and outcome measures. 
 Timing/Reports 
 
Safety data will be provided to the DSMB and investigators as per the DSMB Charter.  
 Study Records Retention 
 
Records and documents pertaining to the conduct of this study, including data collection forms, 
source documents, consent forms, 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. 
 Protocol Deviations 
A protocol deviation is any noncompliance with the clinical trial protocol, Good Clinical Practice 
(GCP), or Manual of Procedures requirements.  The noncompliance may be either on the part of 
the participant, the investigator, 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 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 Emmes 
Corporation’s IDES. 
All deviations from the protocol must be addressed in study data collection forms.  A completed 
copy of the DMID approved Protocol Deviation (PD) Form must be maintained in the Regulatory 
File.  Protocol deviations must be submitted to the local IRB/IEC per their guidelines.  The site 
PI/study staff is 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. 
 
Following completion of the study, the lead principal investigator (PI) is expected to publish the 
results of this research in a scientific journal. The International Committee of Medical Journal 
Editors (ICMJE) member journals have adopted a trials-registration policy as a condition for 
publication. This policy requires that all clinical trials be registered in a public trials registry such 
as ClinicalTrials.gov* (http://clinicaltrials.gov/), which is sponsored by the National Library of 
Medicine. Other biomedical journals are considering adopting similar policies. 
 
The ICMJE defines a clinical trial as any research project that prospectively assigns human 
subjects to intervention or comparison groups to study the cause-and-effect relationship 
between a medical intervention and a health outcome. Studies designed for other purposes, 
such as to study pharmacokinetics (PK) or major toxicity (e.g., Phase I trials), would be exempt 
from this policy. 
 

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Results of any exploratory immunogenicity analysis will not be published prior to publication of 
the primary immunogenicity results for this study. 
 
Refer to Public Law 110-85, Section 801, Clinical Trial Databases. 
 
*Journal Citation: 
De Angelis C, Drazen JM, Frizelle FA, Haug C, Hoey J, Horton R, et al. Clinical trial registration: a statement from the 
International Committee of Medical Journal Editors. N Engl J Med. 2004;351:1250-1. 
 

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46 
17 
LITERATURE REFERENCES 
1. 
Hillier SL. The vaginal microbial ecosystem and resistance to HIV. AIDS research 
and human retroviruses. 1998;14 Suppl 1:S17-21. 
2. 
Eschenbach DA. Bacterial vaginosis and anaerobes in obstetric-gynecologic 
infection. Clinical infectious diseases : an official publication of the Infectious Diseases 
Society of America. 1993;16 Suppl 4:S282-7. 
3. 
Schwebke JR, Muzny CA, Josey WE. Role of Gardnerella vaginalis in the 
pathogenesis of bacterial vaginosis: a conceptual model. The Journal of infectious 
diseases. 2014;210(3):338-43. 
4. 
Eschenbach DA, Hillier S, Critchlow C, Stevens C, DeRouen T, Holmes KK. 
Diagnosis and clinical manifestations of bacterial vaginosis. American journal of 
obstetrics and gynecology. 1988;158(4):819-28. 
5. 
Ahmed A, Earl J, Retchless A, Hillier SL, Rabe LK, Cherpes TL, et al. 
Comparative genomic analyses of 17 clinical isolates of Gardnerella vaginalis provide 
evidence of multiple genetically isolated clades consistent with subspeciation into 
genovars. Journal of bacteriology. 2012;194(15):3922-37. 

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APPENDIX A: SCHEDULE OF EVENTS 
 
Screening 
Enrollment 
Follow-Up 
Unscheduled  
Early Termination  
Visit 0 
(Day -14 to -7) 
Visit 1 
(Day 1) 
Visit 2 
(Day 15  
[Window: 15-
21]) 
Signed Consent Form1 
X 
X 
 
 
 
Assessment of Eligibility Criteria 
X 
X 
 
 
 
Collection of Demographics 
X 
 
 
 
 
Review of Sexual History 
X 
X 
X 
(X) 
X 
Review of Medical History2 
X 
X 
X 
(X) 
X 
Review of Concomitant Medications  
X 
X 
X 
(X) 
X 
Randomization 
 
X 
 
 
 
Dispense memory aid and instructions 
 
X 
 
 
 
Reminder on abstinence or condom 
use during vaginal intercourse to 
prevent GV reinfection 
 
X 
 
 
 
Study Intervention 
 
X 
 
 
 
Pelvic Examination 
X 
 
X 
(X) 
(X) 
Assessment of Adverse Events 
 
 
X 
X 
X 
Assessment of study drug compliance 
(via review of memory aid and drug 
return) 
 
 
X 
(X) 
(X) 
Clinical 
Laboratory 
Urine Pregnancy Test 
X 
 
 
 
 
Trichomonas, NAAT 
Test 
X 
 
 
 
 
pH, whiff test, and wet 
microscopy (Amsel 
criteria) 
X 
 
X 
(X) 
(X) 
Research 
Laboratory 
 
 
BV, Nugent score 
X 
 
X 
(X) 
(X) 

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Screening 
Enrollment 
Follow-Up 
Unscheduled  
Early Termination  
Visit 0 
(Day -14 to -7) 
Visit 1 
(Day 1) 
Visit 2 
(Day 15  
[Window: 15-
21]) 
Research 
Laboratory 
Future Use3 
X 
 
X 
(X) 
(X) 
LabCorp 
GV, quantitative 
NAAT 
X 
 
X 
(X) 
(X) 
 
 
(X) – As indicated/appropriate. 
1At Visit 0 the participant is signing the Screening Informed Consent Form.  At Visit 1 the participant 
will then sign the Enrollment Informed Consent Form. 
2 Medical history is to be originally collected only on active conditions within one year prior to 
screening. Then at follow up visits, the active conditions will be reviewed and any new conditions 
captured. 
3 At Visit 0 Screening and at Visit 2, participants that agree will have an extra swab specimen 
collected for future use.   
 
 
 

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APPENDIX B:  TOXICOLOGY TABLE 
Gastrointestinal 
Grade 1 
Grade 2 
Grade 3 
Nausea 
No interference with 
activity 
Some interference 
with activity 
Prevents daily 
activities 
Vomiting 
No interference with 
activity or 1 - 2 
episodes/24 hours 
Some interference 
with activity or > 2 
episodes/24 hours 
 
Prevents daily activity 
or requires IV 
hydration 
Diarrhea 
2 - 3 loose or watery 
stools or < 400 
gms/24 hours 
4 - 5 loose or watery 
stools or 400 - 800 
gms/24 hours 
6 or more loose or 
watery stools or > 
800gms/24 hours or 
requires IV hydration 
Abdominal Pain 
Does not interfere 
with activity 
Repeated use of non-
narcotic pain reliever 
> 24 hours or 
interferes with activity 
Any use of narcotic 
pain reliever or 
prevents daily activity 
Systemic Reactions 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Allergic Reaction 
Pruritus without rash 
Localized urticaria 
OR requires oral 
therapy 
Generalized urticaria; 
angioedema OR 
anaphylaxis OR 
requires epinephrine 
Headache 
No interference with 
activity 
Repeated use of non-
narcotic pain reliever 
>24 hours OR some 
interference with 
activity 
Significant; any use 
of narcotic pain 
reliever OR prevents 
daily activity OR 
requires triptans 
Fatigue 
No interference with 
activity 
Some interference 
with activity 
Significant; prevents 
daily activity 
Myalgia 
No interference with 
activity 
Some interference 
with activity 
Significant; prevents 
daily activity