A Randomized, Double-Blind, Placebo-Controlled Trial Of TOL-463 Insert for Suppression Of Bacterial Vaginosis (BV) [SUBVert]
Phase: PHASE2
Conditions: Bacterial Vaginosis
Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

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A Randomized, Double-Blind, Placebo-Controlled Trial of TOL-463 Insert for Suppression 
of Bacterial Vaginosis (BV) [SUBVert] 
DMID Protocol Number:  18-0017 
DMID Funding Mechanism: 
Contract – HHSN2722013000121  
Task Order – HHSN272000016 
 
Pharmaceutical Support:  Toltec Pharmaceuticals LLC 
IND Sponsor:  NIAID 
Lead Principal Investigator:  Jeanne Marrazzo, MD, MPH 
DMID Clinical Project Manager:  Jonathan Glock, MPH 
Version Number:  5.0 
09 December 2020 
 
 
 

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STATEMENT OF ASSURANCE 
Each Institution will hold a current Federal Wide Assurance (FWA) issued by the Office for 
Human Research Protections (OHRP) for federally-funded human subjects research.  Each FWA 
will designate at least one Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC) registered with OHRP, for which the research will be reviewed and approved by the 
IRB/IEC and will be subject to continuing review [45 CFR 46.103(b)]. The IRB/IEC designated 
under an FWA may include an institution’s IRB/IEC, an independent IRB/IEC, or an IRB/IEC of 
another institution after establishing a written agreement with that other institution. 
 

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STATEMENT OF COMPLIANCE 
The study trial will be carried out in accordance with Good Clinical Practice (GCP) and as 
required by the following: 
• 
United States Code of Federal Regulations (CFR) 45 CFR Part 46: Protection of Human 
Subjects 
• 
Food and Drug Administration (FDA) Regulations, as applicable: 21 CFR Part 50 (Protection 
of Human Subjects), 21 CFR Part 54 (Financial Disclosure by Clinical Investigators), 21 
CFR Part 56 (Institutional Review Boards), 21 CFR Part 11, and 21 CFR Part 312 
(Investigational New Drug Application) 
• 
International Conference on Harmonisation, (ICH): Good Clinical Practice (ICH E6); 62 
Federal Register 25691 (1997); and future revisions 
• 
Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects of 
Research, Report of the National Commission for the Protection of Human Subjects of 
Biomedical and Behavioral Research 
• 
National Institutes of Health (NIH) Office of Extramural Research (OER), Research 
Involving Human Subjects, as applicable 
• 
National Institute of Allergy and Infectious Diseases (NIAID) Clinical Terms of Award, as 
applicable 
• 
Applicable Federal, State, and Local Regulations and Guidance 

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SIGNATURE PAGE 
The signature below provides the necessary assurance 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 E6 Good Clinical Practice (GCP) guidelines. 
I agree to conduct the study in compliance with GCP and applicable regulatory requirements. 
I agree to conduct the study in accordance with the current protocol and will not make changes to 
the protocol without obtaining the sponsor’s approval and IRB/IEC approval, except when 
necessary to protect the safety, rights, or welfare of participants. 
Principal Investigator and Site Investigator: 
 
Signed: 
 
Date: 
 
 
Jeanne Marrazzo, MD, MPH 
University of Alabama at Birmingham 
 
 
 
Site Investigator: 
 
Signed: 
 
Date: 
 
 
Harold C. Wiesenfeld, MD, CM 
University of Pittsburgh 
 
 
 
 
 

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Site Investigator: 
 
Signed: 
 
Date: 
 
 
Audrey French, MD 
Cook County Health 
 
 
 
Site Investigator: 
 
Signed: 
 
Date: 
 
 
Sheldon Morris, MD, MPH 
UC San Diego AntiViral Research Center (AVRC) 
 
 
 
 

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TABLE OF CONTENTS 
STATEMENT OF ASSURANCE ...................................................................................................2 
STATEMENT OF COMPLIANCE .................................................................................................3 
SIGNATURE PAGE .......................................................................................................................4 
TABLE OF CONTENTS .................................................................................................................6 
LIST OF TABLES .........................................................................................................................11 
LIST OF FIGURES .......................................................................................................................12 
LIST OF ABBREVIATIONS ........................................................................................................13 
PROTOCOL SUMMARY .............................................................................................................17 
 
KEY ROLES.........................................................................................................................21 
 
BACKGROUND AND SCIENTIFIC RATIONALE ..........................................................22 
 
Background .................................................................................................................22 
 
Scientific Rationale .....................................................................................................22 
2.2.1 Purpose of Study ............................................................................................22 
2.2.2 Purpose of Study ............................................................................................23 
2.2.3 Study Population ............................................................................................23 
 
Potential Risks and Benefits .......................................................................................23 
2.3.1 Potential Risks ...............................................................................................23 
 
Potential Risks Associated with TOL-463 .......................................24 
2.3.2 Potential Benefits ...........................................................................................24 
 
STUDY DESIGN, OBJECTIVES AND ENDPOINTS OR OUTCOME MEASURES .....25 
 
Study Design Description ...........................................................................................25 
 
Study Objectives .........................................................................................................26 
3.2.1 Primary ...........................................................................................................26 
3.2.2 Secondary .......................................................................................................26 
3.2.3 Exploratory ....................................................................................................26 
 
Study Endpoints ..........................................................................................................27 

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3.3.1 Primary Endpoint ...........................................................................................27 
3.3.2 Secondary Endpoints .....................................................................................27 
3.3.3 Exploratory Endpoint .....................................................................................27 
 
STUDY INTERVENTION/INVESTIGATIONAL PRODUCT .........................................28 
 
Study Product Description ..........................................................................................28 
4.1.1 Formulation, Packaging, and Labeling ..........................................................28 
4.1.2 Product Storage and Stability .........................................................................28 
 
Acquisition/Distribution .............................................................................................29 
 
Dosage, Preparation, Dispensing and Administration of Study 
Intervention/Investigational Product.........................................................................30 
 
Accountability Procedures for the Study Intervention/Investigational Product(s) .....30 
 
SELECTION OF PARTICIPANTS AND STUDY ENROLLMENT AND 
WITHDRAWAL ..................................................................................................................32 
 
Eligibility Criteria .......................................................................................................32 
5.1.1 Participant Inclusion Criteria .........................................................................32 
 
Screening Visit(s) Inclusion Criteria: ...............................................33 
 
Enrollment Visit Inclusion Criteria: .................................................34 
5.1.2 Participant Exclusion Criteria ........................................................................34 
 
Screening Visit(s) Exclusion Criteria: ..............................................35 
 
Enrollment Visit Exclusion Criteria: ................................................35 
 
Withdrawal from the Study, Discontinuation of Study Product, or Study Termination
 ..................................................................................................................................36 
5.2.1 Withdrawal from the Study or Discontinuation of the Study Product ...........36 
 
Reasons for Study Withdrawal .........................................................36 
 
Handling of Withdrawals ..................................................................37 
 
Discontinuation of Study Product .....................................................37 
5.2.2 Participant Replacement ................................................................................38 
5.2.3 Study Termination .........................................................................................38 

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STUDY PROCEDURES ......................................................................................................39 
 
Visit 0 (Day -15 to -8) Screening ...............................................................................39 
 
Visit 1 (Day 1) Enrollment .........................................................................................40 
 
Planned Study Visits ...................................................................................................42 
6.3.1 Visit 2 (Day 29 [Window:  Days 29-35]) Follow-up .....................................42 
6.3.2 Visit 3 (Day 57 [Window:  Days 57-63]) Follow-up .....................................43 
6.3.3 Visit 4 (Day 85 [Window:  Days 85-91]) Follow-up (TOC) .........................44 
6.3.4 Early Termination Visit .................................................................................45 
 
Unscheduled Study Visits ...........................................................................................46 
 
Protocol Deviations ....................................................................................................47 
 
DESCRIPTION OF CLINICAL AND LABORATORY EVALUATIONS .......................48 
 
Clinical Evaluations ....................................................................................................48 
7.1.1 Assessment of Concomitant Medications/Treatments other than Study 
Product ...........................................................................................................49 
7.1.2 Assessment of Participant Compliance with Study 
Intervention/Investigational Product ..............................................................50 
 
Laboratory Evaluations ...............................................................................................50 
7.2.1 Clinical Laboratory Evaluations ....................................................................50 
 
Laboratory Specimen Preparation, Handling, and Storage ...............51 
 
Laboratory Specimen Shipping ........................................................52 
 
ASSESSMENT OF SAFETY ...............................................................................................53 
 
Assessing and Recording Safety Parameters ..............................................................53 
8.1.1 Adverse Events (AEs) ....................................................................................53 
 
Adverse Events Grading ...................................................................53 
8.1.2 Serious Adverse Events (SAEs) .....................................................................55 
 
Specification of Safety Parameters .............................................................................55 
 
Reporting Procedures ..................................................................................................56 
8.3.1 Reporting Serious Adverse Events ................................................................56 

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8.3.2 Regulatory Reporting for Studies Conducted Under DMID-Sponsored IND
 ........................................................................................................................57 
8.3.3 Reporting of Pregnancy .................................................................................57 
 
Type and Duration of Follow-up of Participants after Adverse Events .....................58 
 
Procedures to be Followed in the Event of Abnormal Laboratory Test Values or 
Abnormal Clinical Findings......................................................................................58 
 
Halting Rules ..............................................................................................................58 
 
Safety Oversight (ISM plus DSMB)...........................................................................59 
8.7.1 Independent Safety Monitor (ISM) ................................................................59 
8.7.2 Data and Safety Monitoring Board (DSMB) .................................................59 
 
HUMAN SUBJECTS PROTECTION .................................................................................61 
 
Institutional Review Board .........................................................................................61 
 
Informed Consent Process ..........................................................................................62 
 
Consent for Future Use of Stored Specimens and Data .............................................64 
 
Exclusion of Women, Minorities, and Children (Special Populations) ......................65 
 
Participant Confidentiality ..........................................................................................65 
 
Certificate of Confidentiality ......................................................................................66 
 
Costs, Participant Compensation, and Research Related Injuries ..............................67 
 
STATISTICAL CONSIDERATIONS .................................................................................68 
 Study Hypotheses .......................................................................................................68 
 Sample Size Considerations .......................................................................................68 
 Treatment Assignment Procedures .............................................................................68 
10.3.1 Randomization Procedures ............................................................................68 
10.3.2 Masking Procedures .......................................................................................69 
 Planned Interim Analyses ...........................................................................................69 
10.4.1 Interim Safety Review ...................................................................................69 
10.4.2 Interim Efficacy Review ................................................................................69 
 Final Analysis Plan .....................................................................................................70 

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10.5.1 Analysis Populations ......................................................................................70 
10.5.2 Baseline Characteristics .................................................................................70 
10.5.3 Safety Analysis Plan ......................................................................................71 
10.5.4 Efficacy Analysis Plan ...................................................................................71 
 Primary Efficacy Analysis ................................................................71 
 Secondary Efficacy Analyses ...........................................................72 
 Exploratory and Other Efficacy Analyses ........................................72 
 
SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/DOCUMENTS ..............74 
 
QUALITY CONTROL AND QUALITY ASSURANCE ...................................................75 
 
DATA HANDLING AND RECORD KEEPING ................................................................76 
 Data Management Responsibilities ............................................................................76 
 Data Coordinating Center/Biostatistician Responsibilities ........................................76 
 Data Capture Methods ................................................................................................76 
 Types of Data ..............................................................................................................77 
 Study Records Retention ............................................................................................77 
 
CLINICAL MONITORING .................................................................................................78 
 
PUBLICATION POLICY ....................................................................................................79 
 
LITERATURE REFERENCES ............................................................................................80 
 
APPENDICES ......................................................................................................................81 
 
Schedule of Events............................................................................82 
 
Toxicity Grading Table .....................................................................86 
 
 

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LIST OF TABLES 
Table 17-1: Schedule of Events .....................................................................................................82 
Table 17-2: Toxicity Grading Table ..............................................................................................86 
 
 

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LIST OF FIGURES 
Figure 1: 
 Schematic of Study Design ........................................................................................19 
 
 

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LIST OF ABBREVIATIONS 
AE 
Adverse Event/Adverse Experience 
ASCUS 
Atypical Squamous Cells of Undetermined Significance 
BV 
Bacterial Vaginosis 
CDC 
Centers for Disease Control and Prevention 
CFR 
Code of Federal Regulations 
CI 
Confidence Interval 
CIN 
Cervical Intraepithelial Neoplasia 
CMS 
Clinical Materials Services 
CoC 
Certificate of Confidentiality 
CRF 
Case Report Form 
CROMS 
Clinical Research Operations and Management Support 
CTM 
Clinical Trial Material 
C. trachomatis 
Chlamydia trachomatis 
DCF 
Data Collection Form 
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 
Federal Wide Assurance 

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GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
HIV 
Human Immunodeficiency Virus 
HPF 
High-power field 
HPV 
Human Papillomavirus 
IATA 
International Air Transport Association 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IEC 
Independent or Institutional Ethics Committee 
IND 
Investigational New Drug Application 
IP 
Investigational Product 
IRB 
Institutional Review Board 
ISM 
Independent Safety Monitor 
ITT 
Intent-to-Treat 
KOH 
Potassium Hydroxide 
LDPE 
Low-Density Polyethylene 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
Modified Intent-to-Treat 
MOP 
Manual of Procedures 
N 
Number (typically refers to participants) 
NAAT 
Nucleic Acid Amplification Test 
N. gonorrhoeae 
Neisseria gonorrhoeae 

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NIAID 
National Institute of Allergy and Infectious Diseases, NIH, 
DHHS 
NIH 
National Institutes of Health 
OER 
Office of Extramural Research 
OHRP 
Office for Human Research Protections 
PCR 
Polymerase Chain Reaction 
PD 
Protocol Deviation 
PI 
Principal Investigator 
PID 
Pelvic Inflammatory Disease 
PP 
Per-Protocol 
PPROM 
Preterm Premature Rupture of Membranes 
PVC 
Polyvinyl Chloride 
QA 
Quality Assurance 
QC 
Quality Control 
SAE 
Serious Adverse Event/Serious Adverse Experience 
SAP 
Statistical Analysis Plan 
SDCC 
Statistical and Data Coordinating Center 
SIC 
Screening Informed Consent  
SOP 
Standard Operating Procedure 
STI 
Sexually Transmitted Infection 
SubI 
Sub Investigator 
TEAE 
Treatment-Emergent Adverse Event 
TOC 
Test of Cure 
T. vaginalis 
Trichomonas vaginalis 

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US 
United States 
USP-NF 
United States Pharmacopeia and The National Formulary 
WBC 
White blood cell 
VVC 
Vulvovaginal Candidiasis 
V0 
Visit 0, Screening  
V1 
Visit 1, Enrollment 
V2 
Visit 2, First Follow-up, weeks 1-4  
V3 
Visit 3, Second Follow-up, weeks 5-8 
V4 
Visit 4, Third/Final Follow-up, weeks 9-12 
 
 
 
 

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PROTOCOL SUMMARY 
 
Title: 
A Randomized, Double-Blind, Placebo-Controlled Trial of TOL-
463 Insert for Suppression of Bacterial Vaginosis (BV) 
Design of the Study: 
 
TOL-463 Insert or placebo as determined by randomization, 
administered twice-weekly for 12 weeks, with 3 in-clinic follow-
up visits post enrollment (V1) at Visit 2 (Day 29), Visit 3 (Day 
57) and Visit 4 /TOC (Day 85) for safety, clinical, and laboratory 
assessment.  
Study Phase: 
II 
Study Population: 
Approximately 600 adult females, 18-55 years of age, with at 
least three diagnoses of BV in the prior 12 months, including the 
diagnosis at the initial screening visit to enroll approximately 
250 participants (to achieve 200 evaluable participants).   
Number of Sites: 
Four (Birmingham, Alabama; Pittsburgh, Pennsylvania; 
Chicago, Illinois; San Diego, California) 
Description of Study 
Product: 
TOL-463 Insert or placebo administered vaginally twice-weekly 
for 12 weeks  
Study Objectives: 
 
Primary: 
• 
To evaluate the clinical efficacy of a twice-weekly 
application of TOL-463 vaginal insert in suppression of BV 
in women with a history of recurrent BV (RBV) following 
successful induction with oral metronidazole or a CDC-
recommended BV treatment 

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Secondary: 
• 
To evaluate the time to BV recurrence as defined by clinical 
criteria 
• 
To evaluate the incidence of vaginal symptoms over study 
participation  
• 
To evaluate acceptability of a twice-weekly application of 
TOL-463 vaginal insert in suppression of BV  
• 
To evaluate the safety of TOL-463 vaginal insert compared 
to placebo, including the incidence of secondary VVC 
Exploratory: 
• 
To evaluate the performance of the BD Max Vaginal Panel in 
characterizing clinical and microbiologic outcomes of the 
intervention 
Duration of Individual 
Participant Participation: 
Participation will include a Screening Visit, an Enrollment Visit, 
and 3 clinical follow-up visits.  Total participation for each 
participant will be approximately 100 days 
Estimated Time to Last 
Participant/Last Study Day: 
Approximately 24 months.   
 
 

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Figure 1: 
 Schematic of Study Design 
 
 
 
 
 
Randomize (1:1) 
125 subjects 
TOL-463 
Insert 
125 subjects 
Placebo 
Total 600: Screening:  Obtain Screening informed consent; perform screening; collect history, 
conduct clinical assessments and pregnancy test. 
Study Visit 0:  
Screening 
(Day -15 to -8) 
 
Study Visit 1:   
 Enrollment (Day 1) 
BV infection-Treat with 
Metronidazole or a CDC-
recommended BV treatment 
BV cleared? 
Dispense IP and issue participant memory aid 
Amsel positive for 
BV (>2) and/or BV 
symptoms 
Amsel negative for 
BV (≤2) and 
Asymptomatic 
End of study 
participation 
Enrollment: Obtain Enrollment informed 
consent 

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Assessment of Final Study 
Outcomes Measures 
Conduct clinical evaluations; assess AEs; collect IP containers; review 
memory aid; complete satisfaction questionnaire 
Conduct clinical evaluations; assess AEs; collect IP containers/dispense 
IP; review memory aid– participants with >2 Amsel criteria will be 
terminated (complete satisfaction questionnaire) 
Conduct clinical evaluations; assess AEs; collect IP containers/dispense 
IP; review memory aid – participants with >2 Amsel criteria will be 
terminated (complete satisfaction questionnaire) 
Study Visit 2:  
Follow-up 
(Day 29-35) 
Study Visit 3:  
Follow-up 
(Day 57-63) 
Study Visit 4:  
Follow-up/TOC 
(Day 85-91) 

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KEY ROLES 
Lead Principal 
Investigator: 
 
DMID Clinical Project 
Manager: 
 
Jeanne Marrazzo, MD, MPH 
University of Alabama at Birmingham School of Medicine 
Tinsley Harrison Tower 215 
1900 University Blvd. 
Birmingham, AL 35294-0006 
 
 
Jonathan Glock, MPH 
DMID/NIAID/NIH 
5601 Fishers Lane, 8E48 
Rockville, MD 20852 
 
 
 
Statistical and Data 
Coordinating Center 
(SDCC): 
 
The Emmes Company, LLC 
401 N. Washington St. Suite 700  
Rockville, MD 20850  
(301) 251-1161 
 

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BACKGROUND AND SCIENTIFIC RATIONALE 
 
Background  
Bacterial vaginosis (BV) and vulvovaginal candidiasis (VVC), collectively referred to as 
vaginitis, are the two most prevalent lower reproductive tract infections, affecting tens of 
millions of women annually in the United States (US) and far more globally.  BV is 
characterized by a general depletion of specific Lactobacillus species that are necessary for 
maintaining vaginal health and a dramatic increase in commensal organisms, notably 
Gardnerella vaginalis and other anaerobes; a local inflammatory response to Candida species 
(primarily C. albicans) characterizes VVC. Although currently recommended regimens afford 
reliable symptom relief, failure rates for BV and VVC are as high as 83% and 60%, respectively, 
[1-3] and in which the survival of resistant biofilm communities have been increasingly 
implicated.  These failure rates represent an important public health concern because these 
infections are associated with a host of serious complications including increased risk of 
acquiring and transmitting human immunodeficiency virus (HIV) and other sexually transmitted 
infections (STIs) and adverse pregnancy outcomes, including preterm premature rupture of 
membranes (PPROM), preterm birth and low birth weight infants.[4-6] 
This study will assess the efficacy of TOL-463 insert in suppressing BV.   
 
Scientific Rationale 
2.2.1 
Purpose of Study 
BV is the most common reason that women in the US seek clinical care for vulvovaginal 
complaints and is the most commonly diagnosed cause of this syndrome across all care settings, 
including prenatal clinics, primary care clinics, and women’s health settings.[4, 7] Well-executed 
studies indicate that up to one-third of adult women in the US may have BV at any given 
time,[8] and the population attributable risk in the US of BV for pre-term (early) deliveries, 
which are associated with substantial infant and maternal morbidity, has been estimated to be as 
high as 30%.[7] This is likely mediated by ascendant infection with the anaerobic bacteria 
associated with BV and their precipitation of intra-amniotic infection and subsequently PPROM 
and preterm delivery. Moreover, it is well established that BV increases women’s risk of upper 
reproductive tract infection (pelvic inflammatory disease (PID)) and of acquiring and 
transmitting other genital infections, notably HIV, human papillomavirus (HPV), and genital 
herpes.[4] Unfortunately, current treatment options are limited to nitroimidazole and 

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clindamycin-based regimens, and despite the broad scientific consensus recognizing the serious 
adverse outcomes associated with BV, these treatment options are suboptimal. While some 
women derive immediate relief from the available antibiotic-based therapies, therapeutic cure 
rates remain low; moreover, recurrence after initially successful treatment is the rule. Over 70% 
of women in prospective studies experience recurrence in the year following treatment, often 
multiple times.[4, 9] New and innovative approaches for the immediate treatment and ongoing 
suppression for BV are urgently needed, especially ones that can address the exceedingly 
common problem of BV persistence and recurrence. 
2.2.2 
Purpose of Study 
This study will evaluate the safety and efficacy of twice-weekly doses of TOL-463 Insert as an 
agent for the suppression of BV following successful induction therapy with a standard course 
oral metronidazole or a CDC-recommended BV treatment.  Participants will be randomized to 
receive either TOL-463 Insert or placebo.   
2.2.3 
Study Population 
Women between the ages of 18 and 55 presenting to US health clinics and responding to 
advertisements will be invited to participate in this study.  Women who are pregnant will not be 
permitted to enroll as TOL-463 Insert has not been studied in pregnancy.   
 
Potential Risks and Benefits 
2.3.1 
Potential Risks 
There may be some physical discomfort associated with pelvic examination and with obtaining 
vaginal secretions for microscopy and diagnostic tests. If a Pap smear is needed it may cause 
minor cramping or minimal bleeding afterwards.  Information concerning participants’ sexual 
history is necessarily detailed given the study’s objectives and may provoke some minor 
psychological or emotional stress when requested; women who receive a new diagnosis of a STI 
during the study may also experience minor psychological or emotional stress. The oral 
metronidazole that eligible screened participants will take is recommended by the CDC for the 
treatment of BV but does have side effects as described in the packaging insert.  If a different 
regimen recommended for the treatment of BV by the CDC is used, refer to the packaging insert 
for the potential side effects.  Participants who develop VVC during study participation and use 
oral fluconazole may experience possible side effects as described in the packaging insert.   It is 
possible that a participant’s cleared BV may not be suppressed by TOL-463 Insert or placebo. If 
this happens, study staff will provide alternative treatment at no cost to the participant. 

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Potential Risks Associated with TOL-463 
The safety and tolerability of TOL-463 are supported by the results of completed Phase I and 
Phase II clinical studies sponsored by the NIH through the NIAID, Division of Microbiology and 
Infectious Diseases (DMID Protocol No. 11-0077 and 15-0039, respectively). The findings are 
consistent with the two-week Good Laboratory Practice (GLP) vaginal irritation and toxicity 
study of TOL-463 with toxicokinetic endpoints in rabbits, also sponsored by the NIH, 
demonstrating absence of safety signals and minimal systemic exposure to TOL-463. The most 
common treatment-related adverse events, (AEs), reported in TOL-463 clinical trials were 
localized in nature, e.g., vulvovaginal burning and pruritus, and none led to discontinuation of 
study product. All treatment-related AEs were mild to moderate in intensity and self-limiting. No 
serious or severe AEs related to TOL-463 were reported. Please refer to Investigator’s Brochure 
(IB) for additional information. 
2.3.2 
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.    
The main therapeutic component of the study product is recognized as an effective component of 
multi-drug regimens to prevent recurrent BV.[10-12] Thus, women may benefit from the use of a 
novel agent that incorporates this chemical compound into therapeutic form for these infections.    

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STUDY DESIGN, OBJECTIVES AND ENDPOINTS OR 
OUTCOME MEASURES 
 
Study Design Description 
Schematic of Study Design - See Figure 1. 
This is a Phase II randomized, double-blind, placebo-controlled study screening approximately 
600 adult females 18-55 years of age to enroll approximately 250 participants to achieve 200 
evaluable participants at the test of cure (TOC) visit. The study is designed to determine the 
clinical efficacy of an investigational product (IP), TOL-463 Insert, manufactured by Toltec 
Pharmaceuticals, in suppressing RBV when administered to women who have a history of RBV 
and have been successfully cleared of their current BV infection using oral metronidazole, 500 
mg twice a day for 7 days or another CDC-recommended BV treatment.   
Participants who consent to screening will have baseline clinical information collected at Visit 0, 
screening (Day -15 to -8), (V0). This information will consist of demographics, current vaginal 
symptoms, medical and sexual history, concomitant medications, and clinical and laboratory 
findings. Participants will undergo a pelvic examination and have vaginal specimens collected 
for confirmation of BV and for diagnostic testing for common STIs (C. trachomatis, N. 
gonorrhoeae, and T. vaginalis). Women with a clinical diagnosis of BV who meet all other 
screening Inclusion/Exclusion criteria will be treated with oral metronidazole, 500 mg twice a 
day for 7 days, or another CDC-recommended BV treatment, and scheduled for a Visit 1, 
enrollment, (V1) in 8 to 15 days.  At the enrollment visit, women who test negative for BV, 
defined as ≤ 2 of 4 Amsel criteria and absence of symptoms of BV (absence of homogenous 
discharge and odor), will be offered to review and sign the Enrollment consent.  Women who 
consent and qualify will be enrolled and randomized (1:1) to one of two groups (TOL-463 Insert 
or placebo).  IP will be administered vaginally, twice-weekly for 12 weeks. Follow-up clinic 
visits will occur at Visit 2 (V2), Visit 3 (V3), and Visit 4 (V4).  For women with cleared BV at 
enrollment, the primary endpoint will be clinical failure, RBV occurring by V4.   
Safety will be measured by participant report, targeted physical examination, and pelvic 
examination. All AEs will be collected through V4. Safety oversight will be provided by a Data 
and Safety Monitoring Board (DSMB). 
Laboratory testing will include urine pregnancy, nucleic acid amplification tests (NAATs) for 
chlamydia, gonorrhea, and trichomoniasis, and Gram stain for Nugent scoring, as well as 
assessment of vaginal pH, saline microscopy (clue cells, motile trichomonads, yeast forms), and 

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KOH preparation at each site’s local lab.  Candida culture will be performed as clinically 
indicated. Polymerase Chain Reaction, PCR-based molecular diagnosis of BV through a multi-
organism PCR algorithm on the BD Max Vaginal Panel will be performed at a certified 
laboratory for all scheduled study visits.   
The duration of the study for participants who are enrolled and randomized will be 
approximately 100 days. For those not enrolled, participation will end at their V1, Day 1.   
Enrollment is expected to be completed in approximately twenty four months. 
All participants will be asked to abstain from anal, receptive oral, and vaginal sexual intercourse 
within one hour of IP administration and for 24 hours after. Participants who are sexually active 
will be required to use an effective form of birth control during study participation through the 
final visit/V4. A simplified participant memory aid will be provided to study participants to 
document symptoms, AEs, and protocol compliance.   
For additional details on study procedures and evaluations and study schedule by study visits, see 
Sections 6 and 7 and Appendix A 
 
Study Objectives 
3.2.1 
Primary  
• To evaluate the clinical efficacy of a twice-weekly application of TOL-463 vaginal insert in 
suppression of BV in women with a history of recurrent BV (RBV) following successful 
induction with oral metronidazole or another CDC-recommended BV treatment. 
3.2.2 
Secondary 
• To evaluate the time to BV recurrence as defined by clinical criteria. 
• To evaluate the incidence of vaginal symptoms over study participation. 
• To evaluate acceptability of a twice-weekly application of TOL-463 vaginal insert in 
suppression of BV.  
• To evaluate the safety of TOL-463 vaginal insert compared to placebo, including the 
incidence of secondary VVC. 
3.2.3 
Exploratory  
• To evaluate the performance of the BD Max Vaginal Panel in characterizing clinical and 
microbiologic outcomes of the intervention. 

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Study Endpoints  
3.3.1 
Primary Endpoint 
• 
Among participants with RBV at baseline, the proportion of participants with recurrent BV 
by V4 as defined by clinical cure [Study day 85-91]. 
Recurrence of BV at each follow-up visit is defined as > 2 of the following Amsel criteria: 
a. Positive KOH whiff test  
b. Homogeneous discharge characteristic of BV 
c. Clue cells ≥ 20% of vaginal squamous epithelial cells 
d. Vaginal pH > 4.5 
3.3.2 
Secondary Endpoints 
1. Time to BV recurrence. 
2. Proportion of participants reporting BV symptoms through the follow-up period. 
3. Number of participants satisfied with the study treatment through the follow-up period. 
4. The occurrence of AEs considered product-related following initiation of study treatment 
and through the final study visit. 
5. The occurrence of culture confirmed secondary VVC following initiation of study 
treatment and through the final study visit.  
3.3.3 
Exploratory Endpoint  
• To evaluate the performance of the BD Max Vaginal Panel in characterizing clinical and 
microbiologic outcomes of the intervention. 

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STUDY INTERVENTION/INVESTIGATIONAL 
PRODUCT 
Oral metronidazole, 500mg, is acquired locally at each site and provided to participants as 
standard of care for women with BV who are eligible during the Screening Visit, V0.  Store per 
manufacturer’s instructions. If another CDC-recommended BV treatment is provided to 
participants, it would be acquired locally at each site and stored per manufacturer’s instructions.   
Oral fluconazole is acquired locally at each site and provided to participants as standard of care 
for women with VVC infections.  Store per manufacturer’s instructions.  
 
Study Product Description  
TOL-463 is a non-azole vaginal anti-infective drug candidate designed as a dual-indication 
therapy for BV and VVC. The product is formulated as a hydrophilic melt insert. All excipients 
are United States Pharmacopeia and The National Formulary (USP-NF) materials and are 
formulated at levels consistent with the acceptable use ranges specified within the FDA Inactive 
Ingredient Guide. 
4.1.1 
Formulation, Packaging, and Labeling 
TOL-463 Vaginal Inserts and Placebo  
TOL-463 vaginal inserts and matching Placebo vaginal inserts will be supplied in 2.0 cc/g low-
density polyethylene (LDPE) + polyvinyl chloride (PVC) plastic unit-dose insert molds with ten 
vaginal applicators.  
All study product will be labeled according to manufacturer or regulatory specifications and 
include the statement “Caution:  New Drug – Limited by Federal law to Investigational Use.”  
Clinical trial material (CTM) will be double blinded and ongoing stability studies conducted on 
those CTM lots to support the conduct of the clinical trial.  
Please see IB for additional information. 
4.1.2 
Product Storage and Stability 
TOL-463 Vaginal Inserts 
The TOL-463 inserts should be stored at room temperature (20-25°C/68-77°F) and are expected 
to be stable for at least 24 months under these conditions based on stability data for TOL-463 

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research lots and Phase I and Phase II CTM. Stability testing of the TOL-463 insert lot 
manufactured for this study will remain ongoing throughout the course of the trial to ensure 
product integrity under the specified storage conditions.  
 
Placebo for Vaginal Inserts 
Placebo inserts should also be stored at room temperature (20-25°C/68-77°F).  Stability testing 
of the placebo insert lot manufactured for this study will remain ongoing throughout the course 
of the trial to ensure product integrity under the specified storage conditions.  
 
Acquisition/Distribution 
TOL-463 Vaginal Inserts 
TOL-463 Vaginal Inserts are manufactured and provided by Toltec Pharmaceuticals.  
Placebo for Vaginal Inserts 
Placebo Vaginal Inserts are manufactured and provided by Toltec Pharmaceuticals.  
Upon request by DMID, the investigational products will be transferred to the following address:  
DMID Clinical Materials Services (CMS) 
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. 

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Dosage, Preparation, Dispensing and Administration of Study 
Intervention/Investigational Product 
The Research Pharmacist or delegated study staff is responsible for ensuring that the policies and 
regulations within their jurisdiction are followed when preparing and dispensing study products. 
This includes following requirements as they pertain to prescriptions, medication prescribing 
orders and labeling. In addition, instructions specific to a trial or about a study product must also 
be followed. A Site Research Pharmacist may be delegated the responsibility of IP 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 IP. These personnel must be licensed, trained, and qualified to prepare 
investigational study product and must be authorized to dispense the IP under state and local 
rules and regulations.   
Participants will be randomized to one of two IPs, as follows: 
• TOL-463 Vaginal Insert: Administered vaginally as a single 2 g unit dose twice a week with 
a minimum of a two-day duration in between doses for twelve weeks with the aid of a 
disposable applicator. 
• Placebo:  Administered vaginally as a single 2 g unit dose twice a week with a minimum of a 
two-day duration in between doses for twelve weeks with the aid of a disposable applicator. 
 
Accountability Procedures for the Study Intervention/Investigational 
Product(s) 
Fisher will ship packaged IP to the investigational sites.  At each site, the IP will be stored 
appropriately, including segregation in a secure location and under controlled storage condition 
and in accordance with applicable regulatory requirements and administered by the delegated 
study personnel.  A drug accountability log will be filled out for all IP at the sites.   
After receipt of the IP, the site PI is responsible for its distribution and disposition and has 
ultimate responsibility for IP accountability. The site PI may delegate to a site research 
pharmacist or an appropriately qualified staff member the responsibility for IP 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 
IP. All IP, whether administered or not, must be documented on the appropriate IP accountability 

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record or dispensing log. The sponsor's monitoring staff will verify the participating clinical 
sites’ IP accountability records and dispensing logs per the study monitoring plan. 
Used and unused IP will be retained until monitored and released for disposition, as applicable. 
This can occur on an ongoing basis for used IP. 
Used IP and its packaging may be destroyed in accordance with site-specific SOPs following 
each monitoring visit where IP accountability is monitored, and discrepancies resolved.  
However, retaining used IP and/or its packaging until a monitoring visit occurs is only required 
when the local institution’s SOP mandates.  If local SOPs allow destruction of IP and its 
packaging, both can be destroyed per the site’s SOPs prior to monitoring visits and after written 
permission is given by DMID.  The site will ensure a double count of the IP and the packaging is 
performed and documented before destruction for use in monitor reconciliation.  Further 
instructions are described in the protocol-specific MOP. 
Unused dispensed IP and its packaging returned (from study participants) to the site will be 
accounted for at the site and participant compliance will be recorded.  Any unused returned IP 
and its packaging will be disposed in accordance with site-specific SOPs.  
Upon completion or termination of the study and after the final monitoring visit where IP 
accountability is monitored, and resolution of any discrepancies, final disposition of the unused 
(never dispensed IP) will be disposed in accordance with the Manual of Procedures (MOP) and 
site-specific SOPs. 

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SELECTION OF PARTICIPANTS AND STUDY 
ENROLLMENT AND WITHDRAWAL 
This study will screen approximately 600 women 18-55 years of age who have recurrent RBV, 
defined as a current BV infection and at least two previous episodes of BV by documentation or 
self-report in the past year.  Women who meet Screening eligibility will be treated with a 
standard course of oral metronidazole or another CDC-recommended BV treatment.  Participants 
will return within approximately one week of completing the metronidazole treatment or other 
CDC-recommended BV treatment, for assessment of clinical cure.  Clinical cure of BV is 
defined as ≤ 2 of 4 Amsel criteria and absence of reported symptoms of BV (i.e. no malodorous 
discharge consistent with BV).   
Participants who return for the Enrollment Visit, V1 and are determined to be clinically cured 
will be offered to review and sign the Enrollment consent.  Participants who consent and meet 
Enrollment eligibility will be randomized in a 1:1 ratio to twice weekly blinded suppressive 
therapy with TOL-463 or placebo.  It is estimated that approximately 250 participants will be 
eligible for Enrollment with approximately 125 participants in each suppressive therapy group.   
No exemptions will be granted on Screening or Enrollment eligibility criteria for this DMID-
sponsored trial.   
Participants will be recruited from health clinics in the U.S. 
Those participants who enroll in the study will undergo up to 3 scheduled Follow-up visits to 
evaluate clinical diagnosis of BV at each visit.  Participants who develop vaginal symptoms 
between scheduled visits will be asked to return for an unscheduled visit.  If at any time during a 
follow-up visit a participant is diagnosed with clinical BV (> 2 Amsel criteria), the study 
endpoint of BV reoccurrence is met, and participation in the study will end.   
The study will target a total of 200 evaluable participants.  
 
Eligibility Criteria 
5.1.1 
Participant Inclusion Criteria  
Women must meet all of the following inclusion criteria to be eligible for inclusion in the study.  

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Screening Visit(s) Inclusion Criteria: 
1. Women with a current BV infection and a history of at least two previous episodes of BV 
by documentation or self-report in the past year. V0 diagnosis is based on the presence of 
≥ 3Amsel criteria*; 
*Homogeneous vaginal discharge; positive KOH whiff test; vaginal pH of > 4.5; and ≥ 
20% clue cells.   
2. Willing and able to provide written informed consent; 
3. Age 18-55 years of age at the time of V0; 
4. General good health based on medical history, targeted physical examination, and pelvic 
examination; 
5. For participants 21 years of age or older, Pap test performed within the past 3 years, with 
the most recent result being normal or ASCUS HPV negative OR Pap smear collected at 
V0*; 
*Consistent with current Pap screening guidelines, a Pap smear must be performed at V0, 
for women who meet the following criteria and cannot provide documentation or self-
report of a normal or ASCUS HPV negative Pap smear, conducted within the prior 3 
years: (a) has not had a hysterectomy or (b) has had a hysterectomy and has a history of 
cervical intraepithelial neoplasia grade 2+ (CIN2+) in the past 20 years.  
Note:  If a Pap smear is conducted at V0, the results are not required prior to enrollment. 
6. Have a negative urine pregnancy test at V0, if of childbearing potential; 
7. Must be of non-childbearing potential* OR must be using an effective method of birth 
control** and must be willing to continue the method through the end of IP 
administration.   
*Defined as post-menopausal, or status post bilateral tubal ligation, or status post bilateral 
oophorectomy or status post hysterectomy. 
**Acceptable methods are defined as: 
a. IUDs or hormonal contraceptives for at least 22 days prior to screening.  Note:  
Intravaginal contraceptive rings (e.g., NuvaRing) are not acceptable forms of birth 
control for this study. 
b. Consistent use of a barrier method, including diaphragms or condoms, for at least 
13 days prior to screening.  
c. Abstinence from vaginal sexual intercourse for at least 13 days prior to screening.  
d. Exclusively same-sex relationship. 
e. Monogamous relationship with vasectomized partner.  
8. Willing and able to cooperate to the extent and degree required by this protocol at the 
discretion of the investigator. 

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Enrollment Visit Inclusion Criteria: 
In addition to confirming all relevant Screening Visit Inclusion Criteria, women must meet 
all of the following criteria to be eligible for enrollment in the study. 
1. Willing and able to provide Enrollment written informed consent; 
2. After completion of metronidazole induction therapy or another CDC-recommended BV 
treatment, no clinical evidence of BV* and absence of symptoms of BV** at V1; 
*As defined by ≤ 2 of 4 Amsel criteria. 
**Defined as absence of vaginal discharge and odor consistent with BV.   
3. Must have a negative urine pregnancy test at V1, if of childbearing potential; 
4. Willing to refrain from any intravaginal products/medications* other than the IP 
throughout the course of the trial; 
* For example: douches, antifungal or antibacterial preparations, lubricants, contraceptive 
creams, gels, foams, sponges, spermicides. 
5. Must agree to abstain from receptive oral, anal, and vaginal sexual intercourse one hour 
prior to IP administration and for 24 hours after; 
6. Willing to refrain from using tampons or menstrual cups for 24 hours after IP 
administration. 
7. Must be of non-childbearing potential* OR must be using an effective method of birth 
control** and must be willing to continue the method through the end of IP 
administration.   
*Defined as post-menopausal, or status post bilateral tubal ligation, or status post bilateral 
oophorectomy or status post hysterectomy. 
**Acceptable methods are defined as: 
a. IUDs or hormonal contraceptives for at least 30 days prior to using IP.  Note:  
Intravaginal contraceptive rings (e.g., NuvaRing) are not acceptable forms of birth 
control for this study. 
b. Consistent use of a barrier method, including diaphragms or condoms, for at least 
21 days prior to using IP.  
c. Abstinence from vaginal sexual intercourse for at least 21 days prior to using IP.  
d. Exclusively same-sex relationship. 
e. Monogamous relationship with vasectomized partner.  
 
5.1.2 
Participant Exclusion Criteria 
Women who meet any of the following exclusion criteria will be excluded from the study. 

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Screening Visit(s) Exclusion Criteria: 
1. Diagnosis of another vaginal or vulvar condition that may confuse interpretation of 
response to IP*;  
*For example: erosive lichen planus, desquamative inflammatory vaginitis, or contact 
dermatitis involving the vulvar epithelium.   
2. Concurrent VVC infection with inability to be treated with oral fluconazole;  
3. Infectious cause of cervicitis (e.g., N. gonorrhoeae, C. trachomatis, or T. vaginalis) 
confirmed on physical examination and/or with laboratory testing**+;    
** Women may be rescreened for eligibility following successful treatment of 
confounding STI.  
+Results of NAAT testing will be reviewed prior to enrollment. 
4. Active genital lesions, including ulcers or vesicles consistent with herpes or warts; 
5. Planned ongoing immunosuppressive therapy or systemic antibiotic treatment during the 
course of the study; 
6. History of hypersensitivity, allergy or other contraindication(s) to metronidazole or other 
CDC-recommended BV treatment used to treat subject; 
7. History of hypersensitivity to any TOL-463 formulation components (see IB for product 
information); 
8. Current or untreated cervical intraepithelial neoplasia (CIN) or cervical carcinoma; 
9. Currently pregnant or nursing; 
10. Any other condition that, in the opinion of the investigator, would interfere with 
participation in the study; 
11. Previous enrollment in the study or at the investigator’s discretion. 
 
Enrollment Visit Exclusion Criteria: 
In addition to confirming all Screening Visit Exclusion Criteria, women who meet any of the 
following criteria will not be eligible for enrollment in the study.   
1. Active menses or significant vaginal bleeding as determined by the study clinician at 
V1*; 
* Note: women who are menstruating may be reevaluated for study enrollment within the 
enrollment window. 
2. Use of vaginal or systemic antibiotic or antifungal since V0, other than oral 
metronidazole, CDC-recommended BV treatment, or oral fluconazole, as per protocol; 
3. Evidence or suspicion of infectious cause of cervicitis or active genital lesion on pelvic 
examination at V1;  
4. Concurrent VVC infection at V1 with inability to treat with oral fluconazole;  

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5. Use of any investigational drug within 30 days prior to V1 or planned/anticipated use 
during study participation. 
 
Withdrawal from the Study, Discontinuation of Study Product, or 
Study Termination  
5.2.1 
Withdrawal from the Study or Discontinuation of the Study Product  
 
Reasons for Study Withdrawal 
Participants may voluntarily withdraw their consent for further study participation at any time 
and for any reason without penalty or prejudice to future medical care.   
Participants may be required to withdraw from further study participation after discussion with 
the investigator for the following reasons:  
• 
AE(s) judged to be severe (Grade 3) and related to IP 
• 
SAE(s) judged to be related to IP 
• 
Diagnosis of VVC at any follow-up visits, V2 or V3, or unscheduled visit(s) and cannot 
be treated with oral fluconazole 
• 
A Pap test result from V0 that was anything other than normal or ASCUS HPV negative; 
participant is no longer eligible for the study.  
• 
Medical disease or condition, or new clinical finding(s) for which continued 
participation, in the opinion of the investigator might compromise the safety of the 
participant, interfere with the participant’s successfully completion of the study, or 
interfere with the evaluation of responses 
• 
Violation of eligibility criteria 
• 
Significant deviation from the treatment plan specified in the protocol (i.e., incorrect 
administration of IP, failure to attend study visits) 
• 
Participant lost to follow-up 
• 
At the discretion of the investigator 
  

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Handling of Withdrawals 
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).  The investigator will inform the 
participant that data that has already been collected will be retained and analyzed even if the 
participant withdraws from this study.  
If withdrawal occurs after enrollment, any participant with an ongoing AE will be followed until 
the AE is resolved or until the participant’s condition becomes stable.  
Participants who request to withdraw their consent from further study participation after study 
treatment with IP, 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 visit(s).  The Early Termination Visit procedures are listed in 
Section 6.3.4.  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, emails, etc., 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.  Withdrawal of participants from the analysis populations is discussed in 
Section 10.5.1. 
 
Discontinuation of Study Product 
A participant may discontinue use of the IP as a result of their own decision, due to the 
investigator’s discretion, or due to an AE.  All participants who discontinue use of the IP will be 
encouraged to complete the Early Termination Visit.  The Early Termination Visit procedures 
are listed in Section 6.3.4.      
If the participant discontinued use of the IP due to an AE, she will be given appropriate care and 
treatment under medical supervision until the condition has resolved or becomes stable.  If the 
participant consents, every attempt will be made to follow all AEs through resolution.   

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5.2.2 
Participant Replacement 
Participants who sign the Enrollment Informed Consent (EIC), are randomized and receive IP 
and then subsequently withdraw, or are withdrawn from this study, or are lost to follow-up will 
not be replaced.  Participants who withdraw consent after signing the EIC form and are 
randomized but have not received IP may be replaced.   
5.2.3 
Study Termination  
Although the study sponsor has every intention of completing the study, the sponsor reserves the 
right to terminate the study at any time for clinical or administrative reasons. Reasons for 
termination include, but are not limited to, study closure due to DSMB review and 
recommendation or at the discretion of DMID. 
If the study is prematurely terminated for any reason, the investigator will promptly inform the 
study participants and assure appropriate therapy or follow-up for the participants, as necessary. 
The investigator will provide a detailed written explanation of the termination to the IRB/IEC. 

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STUDY PROCEDURES 
Study visit information is listed in this section, Section 7, and the Schedule of Events (Appendix 
A). Further instructions are described in the protocol-specific MOP. 
 
Visit 0 (Day -15 to -8) 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 will be signed prior to performing any study procedures, including any screening 
procedures. 
• 
Demographic information will be collected from the participant. 
• 
Eligibility criteria will be reviewed with the participant. 
At this juncture, if a potential participant is not eligible, information regarding reason for screen 
failure will be noted and the participant will not have any additional screening procedures 
completed. 
• 
Complete medical history will be obtained by both interview of participants and review of 
medical records, if available, to assure eligibility.  
• 
Vaginal symptoms such as odor, itching, irritation, and discharge will be reviewed with the 
participant. 
• 
Sexual history for the past 30 days will be collected. 
• 
A urine pregnancy test will be performed on all participants of childbearing potential and 
must be negative prior to administration of oral metronidazole or other CDC-recommend BV 
treatment induction therapy. 
• 
All concomitant medications taken in the last 30 days will be recorded on the appropriate 
data collection form (DCF). 
• 
A pelvic examination to include examination of external genitalia will be conducted using a 
non-lubricated speculum and swabs and samples obtained for analysis of Amsel criteria; 
KOH and saline microscopy for identification of yeast forms, trichomonas, and clue cells; 
NAAT for C. trachomatis, N. gonorrhoeae, and T. vaginalis; BD Max baseline test; future 
analysis, for participants who consented to future use of their specimens; and Gram staining 

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for Nugent scoring.  Instructions for obtaining vaginal swab specimens for these assessments 
are outlined in the protocol-specific MOP. Gram stain Nugent scoring will be conducted in 
the Central Laboratory; all other testing will be conducted locally. A Pap smear should also 
be done for any participant who meets the following criteria and cannot provide 
documentation (which can include self-report) of a normal or ASCUS HPV negative Pap test 
within the prior 3 years: is 21 years of age or older and (a) has not had a hysterectomy or (b) 
has had a hysterectomy and has a history of CIN2+ in the past 20 years. If a Pap smear is 
conducted at V0, the results are not required prior to enrollment. 
• 
Vulvovaginal signs such as erythema, edema, excoriation, and discharge will be documented 
and graded by severity, as applicable. 
• 
A clinical determination for BV will be made based on evaluation of Amsel criteria; the 
presence of 3/4 criteria is required for a diagnosis of BV at this initial screening.  
• 
BV positive participants meeting all other study criteria will be provided with oral 
metronidazole, 500 mg twice daily for 7 days or another CDC-recommended BV treatment. 
• 
Participants will be scheduled to return for Visit 1 (Day 1) Enrollment to assess response to 
metronidazole or other CDC-recommended BV treatment induction therapy and if 
determined to be a clinical BV cure (by Amsel criteria) and asymptomatic will be invited to 
review and sign the EIC.  If participants are not able to keep the scheduled Visit 1 and exceed 
the 15-day window, the participant must be re-screened before they can be enrolled. 
 
Visit 1 (Day 1) Enrollment 
• 
Study personnel will review screening study eligibility criteria to ensure unchanged since the 
initial screening visit. 
• 
Vaginal symptoms such as odor, itching, irritation, and discharge will be reviewed with the 
participant. 
• 
Vulvovaginal signs such as erythema, edema, excoriation, and discharge, will be documented 
and graded by severity, as applicable. 
• 
A pelvic examination to include examination of external genitalia will be conducted using a 
non-lubricated speculum and swabs and samples obtained for analysis of Amsel criteria; 
KOH and saline microscopy for identification of yeast forms, trichomonas, and clue cells.   
Instructions for obtaining vaginal swab specimens for these assessments are outlined in the 
protocol specific MOP.  

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• A clinical determination to confirm BV cure, determined by ≤ 2 of 4 Amsel criteria and 
absence of BV symptoms, are considered eligible for study enrollment.  Participants who do 
not clear BV will be informed that they are no longer eligible.  Participants who are BV 
cured with a secondary VVC infection but appropriate candidates for oral fluconazole 
treatment can be enrolled. Treatment with oral fluconazole will be per clinic standard of care 
and provided at no cost to the participant.  
• Participants who no longer have BV, will be asked to read and sign the EIC at this time.  The 
EIC form will be signed prior to performing any study procedures. 
• Enrollment eligibility criteria will be reviewed with the participant. 
• Medical history will be reviewed and updated as appropriate. 
• 
Interim sexual history since the last clinic visit will be collected. 
• 
A urine pregnancy test will be performed on all participants of childbearing potential and 
must be negative.  
• 
All concomitant medications taken since V0 will be recorded on the appropriate DCF. 
Previously recorded medications will be updated as appropriate. 
• 
Participants will be registered in Advantage eClinical after being classified as negative for 
BV and eligible for the study, and randomly assigned to active treatment (TOL-463 Insert) or 
placebo. 
• 
A targeted physical examination including height and weight will be performed by a 
qualified study clinician. 
• 
Collect vaginal swabs for Gram staining for Nugent scoring; the BD Max test; and for future 
analysis, for participants who consented to future use of their specimens. See the protocol-
specific MOP for guidance on swab collection. 
• 
Participants with clinical evidence of VVC based on vulvovaginal signs (edema, erythema, 
and/or excoriation) and symptoms (vulvovaginal itching, burning, and/or irritation) will have 
a confirmatory vaginal Candida culture and treated as appropriate with oral fluconazole.  
Participants who cannot take oral fluconazole will be terminated from the study. 
• 
Blinded IP based on randomization assignment will be provided to the participant in a 
prepared kit with other study supplies. 

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• 
Study protocol requirements and dosing instructions will be reviewed with the participant 
and a participant memory aid and written study instructions provided.  Participants will be 
counseled to refrain from receptive oral, anal, and vaginal sexual intercourse 24 hours prior 
to the next study visit, as this can affect the accuracy of vaginal pH measurement.  
• 
Participants will be scheduled to return for follow-up at Visit 2 (Day 29). 
• 
Study staff will contact participants as a reminder for Visit 2 and to discuss adherence to IP 
and any barriers to IP use. 
 
Planned Study Visits 
6.3.1 
Visit 2 (Day 29 [Window:  Days 29-35]) Follow-up  
• 
Medical history will be reviewed and updated as appropriate. 
• 
Interim sexual history since the last clinic visit will be collected. 
• 
Vaginal symptoms will be assessed.  
• 
A urine pregnancy test will be performed on all participants of childbearing potential. 
• 
Compliance with the study protocol criteria will be assessed; all used and unused study IP 
packaging will be collected as relevant and recorded. 
• 
Participant memory aid will be collected and reviewed.   
• 
All concomitant medications taken since V1 will be recorded on the appropriate DCF. 
Previously recorded medications will be updated as appropriate. 
• 
Study personnel will discuss with participants and assess and record all AE/SAEs. Previously 
recorded AE/SAEs will be updated as appropriate. 
• 
If clinically indicated, a targeted physical examination will be performed by a qualified study 
clinician. 
• 
A pelvic examination to include examination of external genitalia will be conducted, and 
swabs and samples taken for analysis of Amsel criteria; KOH and saline microscopy for 
identification of yeast forms, trichomonas, and clue cells; Gram staining; the BD Max test; 
and for future analysis, for participants who consented to future use of their specimens. 
Instructions for obtaining vaginal swab specimens for these assessments are outlined in the 

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protocol specific MOP. Gram stain Nugent scoring will be conducted in the Central 
Laboratory; all other testing will be conducted locally. 
• 
Participants with clinical evidence of VVC based on vulvovaginal signs (edema, erythema, 
and/or excoriation) and symptoms (vulvovaginal itching, burning, and/or irritation) will have 
a confirmatory vaginal Candida culture and treated as appropriate with oral fluconazole.  
Participants who cannot take oral fluconazole will be terminated from the study. 
• 
Vulvovaginal signs will be assessed and graded by severity, as applicable.  
• 
A clinical determination for BV recurrence will be made based on evaluation of Amsel 
criteria. The presence of >2 of 4 Amsel criteria is required for a diagnosis of BV recurrence.  
Participants with a clinical diagnosis of BV recurrence will complete a satisfaction 
questionnaire and will be terminated from the study. 
• 
Participants who are negative for BV recurrence as determined by ≤ 2 of 4 Amsel criteria 
will be scheduled for the next return visit, blinded IP and memory aid will be provided, and 
protocol requirements and dosing instructions reviewed.  Participants will be counseled to 
refrain from receptive oral, anal, and vaginal sexual intercourse 24 hours prior to the next 
study visit, as this can affect the accuracy of vaginal pH measurement.   
• Study staff will contact participants as a reminder for Visit 3 and to discuss adherence to IP 
and any barriers to IP use. 
6.3.2 
Visit 3 (Day 57 [Window:  Days 57-63]) Follow-up 
• 
Medical history will be reviewed and updated as appropriate. 
• 
Interim sexual history since the last clinic visit will be collected. 
• 
Vaginal symptoms will be assessed.    
• 
A urine pregnancy test will be performed on all participants of childbearing potential. 
• 
Compliance with the study protocol criteria will be assessed; all used and unused study IP 
packaging will be collected as relevant and recorded. 
• Participant memory aid will be collected and reviewed. 
• 
All concomitant medications taken since V2 will be recorded on the appropriate DCF. 
Previously recorded medications will be updated as appropriate. 

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• 
Study personnel will discuss with participants and assess and record all AE/SAEs. Previously 
recorded AE/SAEs will be updated as appropriate. 
• 
If clinically indicated, a targeted physical examination will be performed by a qualified study 
clinician. 
• 
A pelvic examination to include examination of external genitalia will be conducted, and 
swabs and samples taken for analysis of Amsel criteria; KOH and saline microscopy for 
identification of yeast forms, trichomonas, and clue cells; Gram staining; the BD Max test; 
and for future analysis, for participants who consented to future use of their specimens. 
Instructions for obtaining vaginal swab specimens for these assessments are outlined in the 
protocol specific MOP. Gram stain Nugent scoring will be conducted in the Central 
Laboratory; all other testing will be conducted locally. 
• 
Participants with clinical evidence of VVC based on vulvovaginal signs (edema, erythema, 
and/or excoriation) and symptoms (vulvovaginal itching, burning, and/or irritation) will have 
a confirmatory vaginal Candida culture and treated as appropriate with oral fluconazole.  
Participants who cannot take oral fluconazole will be terminated from the study. 
• 
Vulvovaginal signs will be assessed and graded by severity, as applicable. A clinical 
determination for BV recurrence will be made based on evaluation of Amsel criteria.  The 
presence of >2 of 4 Amsel criteria is required for a diagnosis of BV recurrence.  Participants 
with a clinical diagnosis of BV recurrence will complete a satisfaction questionnaire and will 
be terminated from the study 
• 
Participants who are negative for BV recurrence determined as ≤ 2 of 4 Amsel criteria will be 
scheduled for the next return visit, blinded IP and memory aid will be provided, and protocol 
requirements and dosing instructions reviewed.  Participants will be counseled to refrain 
from receptive oral, anal, and vaginal sexual intercourse 24 hours prior to the next study visit, 
as this can affect the accuracy of vaginal pH measurement.   
• 
Study staff will contact participants as a reminder for Visit 4 and to discuss adherence to IP 
and any barriers to IP use. 
6.3.3 
Visit 4 (Day 85 [Window:  Days 85-91]) Follow-up (TOC) 
• 
Medical history will be reviewed and updated as appropriate. 
• 
Interim sexual history since the last clinic visit will be collected. 
• 
Vaginal symptoms will be assessed.    

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• 
A urine pregnancy test will be performed on all participants of childbearing potential. 
• 
Compliance with the study protocol criteria will be assessed; all used and unused study IP 
packaging will be collected as relevant and recorded. 
• 
Participant memory aid will be collected and reviewed. 
• 
All concomitant medications taken since V3 will be recorded on the appropriate DCF. 
Previously recorded medications will be updated as appropriate. 
• 
Study personnel will discuss with participants and assess and record all AE/SAEs. Previously 
recorded AE/SAEs will be updated as appropriate. 
• 
If clinically indicated, a targeted physical examination will be performed by a qualified study 
clinician. 
• 
A pelvic examination to include examination of external genitalia will be conducted, and 
swabs and samples taken for analysis of Amsel criteria; KOH and saline microscopy for 
identification of yeast forms, trichomonas, and clue cells; Gram staining; BD Max test; and 
for future analysis, for participants who consented to future use of their specimens. 
Instructions for obtaining vaginal swab specimens for these assessments are outlined in the 
protocol specific MOP. Gram stain Nugent scoring will be conducted in the Central 
Laboratory; all other testing will be conducted locally. 
• 
Participants with clinical evidence of VVC based on vulvovaginal signs (edema, erythema, 
and/or excoriation) and symptoms (vulvovaginal itching, burning, and/or irritation) will have 
a confirmatory vaginal Candida culture and treated.  
• 
Vulvovaginal signs will be assessed and graded by severity, as applicable. A clinical 
determination for BV recurrence will be made based on evaluation of Amsel criteria.  The 
presence of >2 of 4 Amsel criteria is required for a diagnosis of BV recurrence. 
• 
Participant will complete a satisfaction questionnaire. 
6.3.4 
Early Termination Visit  
The V4 assessments and DCFs (see Section 6.3.3) must be completed at the early termination 
visit for participants who withdraw, or are withdrawn, or terminated from the study. If a 
participant withdraws between scheduled visits, the participant will be asked to return to the 
clinic to perform the V4 assessments. 

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Unscheduled Study Visits  
Unscheduled visits may occur at any time during the study. For example, for problems with the 
study medication or development of intercurrent vaginal symptoms.  Any of the following 
activities will be performed at the discretion of the site PI: 
• 
Medical history will be reviewed and updated as appropriate. 
• 
Interim sexual history since the last clinic visit will be collected. 
• 
Vaginal symptoms will be assessed.    
• 
A urine pregnancy test will be performed on all participants of childbearing potential. 
• 
Compliance with the study protocol criteria will be assessed; any used and unused study IP 
packaging will be collected as relevant and recorded. 
• 
Participant memory aid will be collected and reviewed. 
• 
All concomitant medications taken since the last study visit will be recorded on the 
appropriate DCF. Previously recorded medications will be updated as appropriate. 
• 
Study personnel will discuss with participants and assess and record all AEs/SAEs. 
Previously recorded AEs/SAEs will be updated as appropriate. 
• 
If clinically indicated, a targeted physical examination will be performed by a qualified study 
clinician. 
• 
A pelvic examination to include examination of external genitalia will be conducted, and 
swabs and samples taken for analysis of Amsel criteria; KOH and saline microscopy for 
identification of yeast forms, trichomonas, and clue cells; and Gram staining. Instructions for 
obtaining vaginal swab specimens for these assessments are outlined in the protocol specific 
MOP. Gram stain Nugent scoring will be conducted in the Central Laboratory; all other 
testing will be conducted locally. 
• 
Participants with clinical evidence of VVC based on vulvovaginal signs (edema, erythema, 
and/or excoriation) and symptoms (vulvovaginal itching, burning, and/or irritation) will have 
a confirmatory vaginal Candida culture and treated as appropriate with oral fluconazole.  
Participants who cannot take oral fluconazole will be terminated from the study. 
• 
Vulvovaginal signs will be assessed and graded by severity, as applicable. A clinical 
determination for BV recurrence will be made based on evaluation of Amsel criteria. The 

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presence of >2 of 4 Amsel criteria is required for a diagnosis of BV recurrence.  Participants 
with a clinical diagnosis of BV recurrence will complete a satisfaction questionnaire and will 
be terminated from the study. 
• 
Participants who are negative for BV determined as ≤ 2 of 4 Amsel criteria will be scheduled 
for the next return visit, blinded IP and a memory aid will be provided as needed, and 
protocol requirements and dosing instructions reviewed. 
 
Protocol Deviations 
A protocol deviation (PD) is any noncompliance with the clinical trial protocol, GCP, or MOP 
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 should be developed by the 
site and implemented promptly 
These practices are consistent with ICH E6: 
4.5 
Compliance with Protocol, Sections 4.5.1, 4.5.2, and 4.5.3 
5.1 
Quality Assurance and Quality Control, Section 5.1.1 
5.20 
Noncompliance, Sections 5.20.1, and 5.20.2. 
It is the responsibility of the site PI and other study staff to use continuous vigilance to identify 
and report deviations within 5 working days of identification of the PD, or within 5 working days 
of the scheduled protocol-required activity.  All deviations must be promptly reported to DMID, 
via the SDCC’s electronic study database. 
NOTE:  Those sites participating in trials with a designated “central unit” will follow the 
reporting requirements specified in their protocols and MOPs.  The “central unit” will be 
responsible for submission of the PD to TRI/ICON DMID CROMS.   
All PDs, as defined above, must be addressed in study participant DCFs.  A completed copy of 
the DMID PD Form must be maintained in the Regulatory File, as well as in the participant's 
study folder.  PDs must be submitted to the central IRB/IEC and to the local IRB/IEC per their 
guidelines.  The site PI and other study staff are responsible for knowing and adhering to their 
IRB requirements. 

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DESCRIPTION OF CLINICAL AND LABORATORY 
EVALUATIONS 
 
Clinical Evaluations 
Complete medical history will be obtained by interview of the participants at V0 and will be 
updated at each clinic visit. At 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 V0. Participants will be 
queried at V1 thru V4 regarding sexual activity since the previous clinic visit. 
Medications history (concomitant medications) will include a review of all current medications 
taken 30 days prior to the screening visit and through study completion. Prescription and over-
the-counter drugs will be included as well as vitamins, herbs and supplements. Assessment of 
eligibility will also include a review of all permitted and prohibited medications per the 
Participant Inclusion and Exclusion Criteria (see Section 5). 
A pelvic examination including examination of external genitalia, will be performed at the 
screening visit, V0. A targeted physical examination including height and weight will be 
performed at enrollment visit, V1, and if clinically indicated for follow-up visits, and pelvic 
examination will be performed at the enrollment visit, V1, and at each of the follow-up visits, V2 
thru V4. All physical examinations will be performed by a qualified study clinician.   
Study IP, memory aids and instructions will be provided to participants at the enrollment visit, 
V1 and return visits, V2 and V3.  Compliance with the study IP will be assessed at all follow-up 
visits and contacts (V2-V4 and as needed at unscheduled and early termination visits) and 
recorded.   
A pelvic examination and vulvovaginal examination for the evaluation of the vulva, vagina, and 
cervix will be performed by the site PI or qualified designee.  At the screening visit, V0, these 
examinations will be done for the purpose of determining eligibility.  At the enrollment visit, V1, 
Follow-up visits (V2-V4), or an unscheduled visit these examinations will be done for the 
purpose of evaluating treatment efficacy and the presence of treatment-emergent AEs (TEAEs).   
Pelvic Examination: 
During the initial screening visit, V0 pelvic examination, the clinical diagnosis of BV will be 
based on the presence of 3/4 of the following Amsel criteria: 

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1. Homogenous vaginal discharge characteristic of BV;  
2. A fishy odor of the vaginal discharge with the addition of a drop of 10% KOH (positive 
whiff test);  
3. Clue cells ≥ 20% of the total vaginal squamous epithelial cells on saline microscopy; 
4. Vaginal fluid pH >4.5. 
Instructions for obtaining and determining the presence of Amsel clinical criteria can be found in 
the protocol-specific MOP. 
During the enrollment visit’s, V1 pelvic examination, a clinical determination to confirm BV 
cure following metronidazole or CDC-recommended BV treatment induction will be determined 
by ≤ 2 of 4 Amsel criteria and absence of BV symptoms (defined as absence of homogenous 
discharge and odor).  
At all other follow-up visits on suppressive study IP (V2-V4), a clinical determination of BV 
recurrence will be determined as > 2 of 4 Amsel criteria by pelvic examination.  
For the enrollment V1 or follow-up (V2 – V4) visits, participants will be scheduled outside of 
menses as soon as possible after cessation of menstruation.  
At all follow-up visits (V2-V4), a clinical diagnosis of VVC will be based on vulvovaginal signs 
(edema, erythema, and excoriation) and symptoms (itching, burning, and irritation) and a 
positive KOH microscopy with identification of yeast forms (hyphae/pseudohyphae) or budding 
yeasts. A confirmatory Candida culture with speciation will also be performed; Candida culture 
in the setting of incomplete criteria for the clinical diagnosis may be obtained at the discretion of 
the study clinician.  
7.1.1 
Assessment of Concomitant Medications/Treatments other than Study Product 
Administration of any medications, therapies, or vaccines will be recorded on the appropriate 
DCF. Concomitant medications will include all medications taken 30 days prior to the initial 
screening visit V0, through V4 or early termination, whichever occurs first. Prescription and 
over-the-counter drugs will be included, as well as herbs, vitamins, and supplements. 
Participants who have received study IP and are subsequently diagnosed with a concomitant 
infection that requires systemic antibiotics will receive treatment according to the local clinic’s 
standard protocols but will be considered non-evaluable for efficacy and terminated from the 
study. However, participants who have received study IP and are subsequently diagnosed with 
VVC can remain in the study and be considered evaluable for efficacy if they are appropriate 
candidates for oral fluconazole therapy.   

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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 IP should not be used unless 
absolutely necessary.  
Refer to Section 5 (Selection of Participants and Study Enrollment and Withdrawal) for 
medications that are prohibited for study eligibility and throughout study participation. 
7.1.2 
Assessment of Participant Compliance with Study Intervention/Investigational 
Product  
The TOL-463 Insert and placebo are inserted by the study participant. 
At each follow up visit, V2 through V4, participants will be asked to bring the study IP 
packaging, unused inserts (if any) and memory aid corresponding to the return visit (V2, V3 or 
V4) to the study personnel.  Study personnel will review adherence to the study IP schedule with 
the participants, including the participant memory aid, and record this on the appropriate DCF at 
each follow-up visit and any unscheduled visits.  Study personnel will record the number of 
unused inserts and empty packaging returned at each of the follow-up visits, V2 thru V4. 
Compliance with the study protocol will be assessed and documented by study personnel at each 
of the follow-up visits, V2 thru V4, and at any unscheduled visits. Study personnel may discard 
the participant’s memory aid after documenting compliance.  Refer to 4.4 for instructions on 
handling of returned study IP packaging.  
 
Laboratory Evaluations 
7.2.1 
Clinical Laboratory Evaluations 
At the screening visit, V0, diagnostic laboratory tests for determination of C. trachomatis, N. 
gonorrhoeae, and T. vaginalis (NAATs) will be performed locally. Vaginal Gram stain Nugent 
scoring for microbiologic confirmation of clinical findings will be conducted in the Central 
Laboratory. BD Max baseline testing will be conducted at a certified laboratory.  Instructions for 
obtaining vaginal swab specimens for these assessments are outlined in the protocol-specific 
MOP.   
A urine pregnancy test will be performed at all visits on all participants of childbearing potential.  
Screening and enrollment visit results must be negative and known prior to randomization on 
V1. 

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At all scheduled study visits a BD Max test will be conducted at a certified laboratory.  At the 
enrollment and follow-up visits, vaginal Gram stain Nugent scoring for microbiologic 
confirmation of clinical findings will be conducted in the Central Laboratory.  At the follow-up 
visits participants with clinically diagnosed VVC will have a confirmatory culture for vaginal 
Candida with speciation performed locally.   
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 Nugent score of ≥7 will be used to define a microbiologic recurrence of 
BV for ancillary analysis. 
 
Candida Culture for Determination of VVC: 
For participants with a clinical diagnosis of VVC at V1-V4, a vaginal swab should also be taken 
for confirmation of Candida by culture with speciation.  See the protocol-specific MOP for 
further details. 
 
Laboratory Specimen Preparation, Handling, and Storage 
Specimen preparation, handling, and storage will be done according to local clinic SOPs. The 
enrolled participants study specimens collected for the BD Max testing and gram stain slides will 
be stored until the end of the study and then destroyed. Likewise, for enrolled participants, the 
additional vaginal swab collection and non-albicans Candida strain cultures only will be stored 
for future use.  Additional details can be found in the protocol-specific MOP. 

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Laboratory Specimen Shipping 
Gram stain and BD Max specimen shipment to the Central Laboratory will occur according to all 
applicable International Air Transport Association (IATA) requirements. The Central Laboratory 
address is as follows: 
 
UAB Infectious Diseases Laboratory 
703 19th Street South 
ZRB 242 
Birmingham, AL 35294 
Additional details can be found in the protocol-specific MOP. 

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ASSESSMENT OF SAFETY 
 
Assessing and Recording Safety Parameters 
Safety will be monitored throughout the study by targeted physical and pelvic examination; and 
participant reporting. Safety will be assessed by the frequency and severity of:  
1. Serious AEs occurring after randomization and from the time of the IP dose through V4. 
2. Non-serious AEs occurring after randomization and from the time of the IP dose through 
V4. 
8.1.1 
Adverse Events (AEs) 
ICH E6 defines an AE as any untoward medical occurrence in a participant 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 (investigational) product.  The occurrence of an AE may come to the attention 
of study personnel during study visits and interviews of a study participant presenting for 
medical care, or upon review by a study monitor.  
All AEs not meeting the criteria for “serious adverse events” should be captured on the 
appropriated CRF.  Information to be collected for AEs includes event description, date of onset, 
clinician’s assessment of severity, relationship to IP (assessed only by those with the training and 
authority to make a diagnosis, or his/her designee), date 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 participant is screened will 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 IP. 
 
Adverse Events Grading 
FDA defines an AE as any untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered drug-related. All AEs (laboratory and clinical symptoms) will 
be graded for severity and assessed for relationship to IP (see definitions). AEs characterized as 
intermittent require documentation of onset and duration of each episode.  The start and stop date 
of each reported AE will be recorded on the appropriate DCF and electronic case report form, 

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(eCRF). Changes in the severity of an AE will be documented to allow an assessment of the 
duration of the event at each level of intensity. 
Severity of Event:   
All AEs will be assessed by the clinician using a protocol-defined grading system (refer to 
Appendix B).  For events not included in the protocol-defined grading system, the following 
guidelines will be used to quantify severity: 
• 
Mild (Grade 1):  Events that are usually transient and may require only minimal or no 
treatment and generally do not interfere with the participant’s daily activities. 
• 
Moderate (Grade 2):  Events that are usually alleviated with additional specific therapeutic 
intervention.  The event interferes with usual activities of daily living, causing discomfort but 
poses no significant or permanent risk of harm to the research participant. 
• 
Severe (Grade 3):  Events interrupt usual activities of daily living, or significantly affects 
clinical status, or may require intensive therapeutic intervention.  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 to be performed. AEs characterized as intermittent require 
documentation of onset and duration of each episode. 
Relationship to Study Products: The clinician’s assessment of the AE’s relationship to IP will 
be done by those with the training and authority to make an assessment, or his/her designee, and 
the assessment will be part of the documentation process.  Whether the AE is related or not, is 
not a factor in determining what is or is not reported in this trial.  If there is any doubt as to 
whether a clinical observation is an AE, the event should be reported.   
In a clinical trial, the study medication must always be suspect.  The relationship to study 
medication will be assessed for AEs using the terms related or not related: 
• 
Related – There is a reasonable possibility that the study product caused the AE. Reasonable 
possibility means that there is evidence to suggest a causal relationship between the study 
medication and the AE. 
• 
Not Related – There is not a reasonable possibility that the administration of the study 
medication caused the event. 

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8.1.2 
Serious Adverse Events (SAEs) 
An AE or suspected adverse reaction is considered a SAE if, in the view of either the site PI 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 AE is considered “life-threatening” if, in the view of either 
the site PI or sponsor, its occurrence places the participant at immediate risk of death.  It does not 
include an AE that, had it occurred in a more severe form, might have caused death. 
All SAEs will be: 
• 
Assessed for severity and relationship to study product and alternate etiology (if not related 
to study product) by a licensed study physician or by the Institution as the site PI or Sub 
Investigator, (SubI). 
• 
Recorded on the appropriate SAE DCF and eCRF. 
• 
Followed through resolution by a licensed study physician.  
• 
Reviewed and evaluated by DMID, an Independent Safety Monitor (ISM) (as deemed 
necessary), the DSMB (periodic review unless related), and the IRB/IEC. 
 
Specification of Safety Parameters 
Safety specifications are noted in Section 8.1 

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Reporting Procedures 
8.3.1 
Reporting 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 Number: 1-800-275-7619 (US) or 1-301-897-1710 (outside US) 
SAE Email Address: PVG@dmidcroms.com 
In addition to the SAE form, select SAE data fields must also be entered into the Advantage 
eClinical® system. Please see the protocol-specific MOP for details regarding this procedure.  
Other supporting documentation of the event may be requested by the DMID Pharmacovigilance 
Group and should be provided as soon as possible.  
The site will send a copy of the SAE report(s) to the ISM (as deemed necessary) when they are 
provided to the DMID Pharmacovigilance Group.  The DMID Medical Monitor and DMID 
Clinical Project 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 site PI or appropriate SubI becomes aware of an 
SAE that is suspected to be related to study medication, the site PI or appropriate SubI will report 
the event to the DMID Pharmacovigilance Group. 
 

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8.3.2 
Regulatory Reporting for Studies Conducted Under DMID-Sponsored IND 
Following notification from the site PI or appropriate SubI, DMID, as the IND sponsor, will 
report any suspected unexpected SAE.  DMID will report an AE as a suspected unexpected AE 
only if there is evidence to suggest a causal relationship between the study intervention and the 
AE.  DMID will submit an IND safety report to the FDA and will notify all participating site PIs 
(i.e., all PIs to whom the sponsor is providing drug under its IND or under any PI’s IND) of 
potential serious risks from clinical studies or any other source, as soon as possible.  DMID will 
report to the FDA any unexpected fatal or life-threatening suspected adverse reaction as soon as 
possible, but in no case later than 7 calendar days after the sponsor’s initial receipt of the 
information.  If the event is not fatal or life-threatening the IND safety report will be submitted 
within 15 calendar days after the sponsor determines that the information qualifies for reporting 
as specified in 21 CFR Part 312.32.  Relevant follow up information to an IND safety report will 
be submitted as soon as the information is available.  Upon request from FDA, DMID will 
submit to the FDA any additional data or information that the agency deems necessary, as soon 
as possible, but in no case later than 15 calendar days after receiving the request.   
All SAEs designated as “not related” to study product(s), will be reported to the FDA at least 
annually in a summary format. 
8.3.3 
Reporting of Pregnancy 
Participants of child-bearing potential will be counseled to continue using acceptable forms of 
birth control during the study period. If a participant becomes pregnant during the study, dosing 
will be discontinued immediately, and early termination assessments will be performed. A 
pregnancy reporting form will be completed for any study participant who becomes pregnant 
through seven days after the last IP dose. 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 include collecting data on the following information: 
• prior maternal history including congenital abnormalities or pregnancy complications; 
• estimated and actual date of delivery or end of pregnancy; 
• pregnancy outcome (live birth, stillbirth, miscarriage or elective termination); 

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• mode of delivery; 
• maternal complications; and 
• neonatal complications (i.e., lethal or nonlethal congenital abnormality). 
Pregnancies occurring in study participants will be reported via Advantage eClinical 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, V4. 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 DCF. 
 
Procedures to be Followed in the Event of Abnormal Laboratory 
Test Values or Abnormal Clinical Findings 
The site PI or appropriate SubI is responsible for reporting all AEs/SAEs that are observed or 
reported during the study, regardless of their relationship to study product. AEs/SAEs, abnormal 
clinical laboratory values, or abnormal clinical findings will be documented, reported, and 
followed appropriately.  
 
Halting Rules 
Further enrollment will be halted for DSMB review/recommendation if any of the following are 
reported.  
If one or more participants experience an SAE judged by an investigator to be related to study IP  
If two or more participants experience an AE that is judged to be Grade 3 and related to study IP 
An overall pattern of symptomatic, clinical, or laboratory events that the DMID Medical Monitor 
or DSMB consider associated with study drug and that may appear minor in terms of individual 
events, but that may collectively represent a serious potential concern for safety 

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If any of the halting rules are met, the study will not continue with the remaining enrollments or 
study treatments without a review by and recommendation from the DSMB to proceed. 
DMID retains the authority to suspend additional enrollment and administration of study product 
during the entire study, as applicable. 
 
Safety Oversight (ISM plus DSMB) 
8.7.1 
Independent Safety Monitor (ISM) 
An 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. 
8.7.2 
Data and Safety Monitoring Board (DSMB) 
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 study and should not have scientific, 
financial or other conflict of interest related to this 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: 
• An initial organizational meeting will be held prior to the study starting and enrollment of 
participants. 
• At specified times during the course of study as defined in the DSMB Charter.   
• Ad hoc meeting convened to address a specific safety concern such as when a halting rule 
is met or for immediate concerns regarding observations during the study. 
• A final closeout review will be held within six months after the database is locked to 
review all cumulative safety data. 

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The DSMB will operate under the rules of a DMID-approved charter that will be written at the 
organizational meeting of the DSMB. Procedures for DSMB reviews/meetings will be defined in 
the charter. Reports may include enrollment and demographic information, medical history, 
concomitant medications, physical assessments, clinical laboratory values, dosing compliance, 
and solicited and unsolicited AE/SAEs.  As an outcome of each review/meeting, the DSMB will 
make a recommendation as to the advisability of proceeding with the study administrations (as 
applicable), and to continue, modify, or terminate the study.  
DMID or the DSMB chair may convene the DSMB on an ad hoc basis according to protocol 
criteria or if there are immediate concerns regarding observations during the course of the study. 
The DMID Medical Monitor is empowered to stop enrollment and study treatment if AEs that 
meet the halting criteria are reported. The DMID Medical Monitor and the ISM (as deemed 
necessary) will be responsible for reviewing SAEs in real time. The DSMB will review SAEs on 
a regular basis and ad hoc during the study. 

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HUMAN SUBJECTS PROTECTION 
 
Institutional Review Board 
Each site PI will obtain IRB approval for this protocol to be conducted at the research site(s) and 
send supporting documentation to the DMID before initiating recruitment of participants.  The 
investigator will submit applicable information to the IRB on which it relies for the review, to 
conduct the review in accordance with 45 CFR 46, ICH E6 GCP, and as applicable, 21 CFR 56 
(Institutional Review Boards) and 21 CFR 50 (Protection of Human Subjects), other federal, 
state, and local regulations. The IRB must be registered with OHRP as applicable to the research.  
DMID must receive the documentation that verifies IRB approval for this protocol, informed 
consent documents (optional pre-screen ICF, SIC and EIC), and upon request any recruitment 
material and handouts or surveys intended for the participants, prior to the recruitment, 
screening, and enrollment of participants. 
Should amendments to the protocol or consent forms be required, the amendments will be 
approved by the sponsor and provided to the site PI for IRB submission.  IRB review and 
approval will occur at least annually throughout the enrollment and follow-up of participants and 
may cease if annual review is no longer required by applicable regulations and the IRB.  The PI 
will notify the IRB of deviations from the protocol and reportable SAEs, as applicable to the IRB 
policy. 
Each institution engaged in this research will hold a current FWA issued by OHRP for federally 
funded research.  The FWA number will be provided to DMID. 
A single IRB of record will be accountable for compliance with regulatory requirements for this 
multi-centered study, at participating sites.  A Reliance Agreement, also called an IRB 
Authorization Agreement will be required to be signed by institutions involved in the study and 
permits the local IRB to cede review to the single IRB.  The IRB Authorization Agreement will 
set forth the specific responsibilities of the IRB and each participating site.  Participating sites 
will then rely on the IRB of record to satisfy the regulatory requirements relevant to the IRB 
review. The participating sites will maintain essential required documentation of IRB reviews, 
approvals, and correspondence, and must provide copies of any agreements and essential 
documentation to the DMID or regulatory authorities upon request. 

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Informed Consent Process 
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 and an optional pre-screen consent form:  SIC for the screening procedures (determination 
of eligibility confirmed by initial clinical BV diagnosis and then subsequent confirmation of BV 
cleared post induction treatment); an EIC for the full study; and an optional pre-screen consent 
form to aid in initial BV diagnosis.  At the enrollment visit, V1, upon confirmation of BV cure 
and confirmation of eligibility, the participant will then need to be consented using the EIC prior 
to continuation.  Participants will receive a concise and focused presentation of key information 
about the clinical trial, verbally and with the written consent forms. The explanation will be 
organized and presented in lay terminology and language that facilitates understanding why the 
individual might or might not want to participate. 
The site PI, or designated study staff will describe the protocol to potential participants face-to-
face. The key information about the purpose of the study, the procedures and experimental 
aspects of the study, risks and discomforts, any expected benefits to the participant, and 
alternative treatment will be presented to the participant.   
Participants will also receive an explanation that the trial involves research, and a detailed 
summary of the proposed study procedures and study interventions/medications.  This will 
include aspects of the trial that are experimental, the probability for random assignment to Tol-
463 Insert vs. placebo, any expected benefits, all possible risks (including a statement that the 
study medication may involve risks to the participant or to the embryo or fetus, if the participant 
may become pregnant, that are currently unforeseeable), the expected duration of the 
participant’s participation in the trial, alternative procedures that may be available and the 
important potential benefits and risks of these available alternative procedures.  
Participants will be informed that they will be notified in a timely manner if information 
becomes available that may be relevant to their willingness to continue participation in the trial. 
Participants will receive an explanation as to whether any compensation and any medical 
treatments are available if injury occurs, and, if so, what they consist of, or where further 
information may be obtained. Participants will be informed of the anticipated financial expenses, 
if any, to the participant for participating in the screening and enrollment visits, as well as any 
anticipated prorated payments, if any, to the participant for participating in the trial. They will be 
informed of whom to contact (e.g., the investigator) for answers to any questions relating to the 
research project.  

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Information will also include the foreseeable circumstances and/or reasons under which the 
participant’s participation in the trial may be terminated. The participants will be informed that 
participation is voluntary and that they are free to withdraw from the study for any reason at any 
time without penalty or loss of benefits to which the participant is otherwise entitled.   
The extent of the confidentiality of the participants’ records will be defined, and participants will 
be informed that applicable data protection legislation will be followed. Participants will be 
informed that the monitor(s), auditors(s), IRB, NIAID, and regulatory authority(ies) will be 
granted direct access to the participant’s original medical records for verification of clinical trial 
procedures and/or data without violating the confidentiality of the participant, to the extent 
permitted by the applicable laws and regulations, and that, by signing a written informed consent 
form (ICF), the participant is authorizing such access.  
Participants will be informed that records identifying the participant will be kept confidential, 
and, to the extent permitted by the applicable laws and/or regulations, will not be made publicly 
available and, if the results of the trial are published, the participant’s identity will remain 
confidential. Participants will be informed whether private information collected from this 
research and/or specimens will be used for additional research, even if identifiers are removed.   
Participants will be allowed sufficient time to consider participation in this research trial and 
have the opportunity to discuss this trial with their family, friends or legally authorized 
representative, or think about it prior to agreeing to participate. 
The SIC, EIC, and optional pre-screen consent forms will be IRB-approved, and participants will 
be asked to read and review the SIC form and if applicable, the EIC or pre-screen consent form. 
Participants must sign the SIC form prior to starting any screening study procedures being done 
specifically for this trial.  Likewise, if applicable participants must sign the EIC form prior to 
starting any study procedures. 
Once signed, a copy of all consent forms will be given to the participant for their records.  The 
participant(s) may withdraw consent at any time throughout the course of the trial.  The rights 
and welfare of the participant(s) will be protected by emphasizing to them that the quality of 
their medical care will not be adversely affected if they decline to participate in this study. 
Study staff may employ IRB approved recruitment efforts prior to obtaining the participant’s 
consent; however, before conducting protocol-specific screening activities the SIC must be 
signed. Site clinical staff may pre-screen via chart review and refer potential participants to the 
study staff.   

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New information will be communicated by the site PI to participants who sign the EIC form to 
participate in this trial in accordance with IRB requirements.  The EIC form will be updated and 
participants will be re-consented per IRB requirements, if necessary.  Participants will be given a 
copy of all EIC forms that they sign. 
 
Consent for Future Use of Stored Specimens and Data 
Both the screening and enrolled participant populations will be consented to potentially have 
extra vaginal swab specimens collected and stored for future research use only.  Additionally, for 
participants who consent, any non-albicans Candida strain cultures will be stored for future 
research use only.  Participants who do not consent to have vaginal swab specimens stored for 
future use can still participate in the study.  If the participant consents, an extra swab will be 
collected at V0 and if the participant is enrolled and consents, one extra swab will be collected at 
all scheduled study visits.  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 stored 
appropriately at a secure UAB facility.   
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 (approved 
by the single IRB) or as otherwise authorized under applicable law and after review and approval 
by DMID, the single IRB, and the IRB of the researcher requesting the specimens. 
There will be no direct benefit to the participant from allowing the specimens to be stored and 
used for future purposes.  However, the results may provide information that will help in the 
diagnosis or treatment of future patients.  Refer to section 2.3.1 for potential participant risks 
when obtaining the vaginal swab specimen(s) for future use.  During this study, specimens saved 
for future use will be identified only by the participant number which will allow linkage of the 
specimens to study data but not to any personal identifiers.  Since participant study records are 
securely maintained by study staff, there is minimal risk of breach of confidentiality.  At the end 
of the study, the future use specimens will be stored in a secure location and unlinked from any 
information that could connect them with identifiable data from this study. 
The participant’s future use specimen will be kept indefinitely until it is used up or destroyed.  It 
may be used to develop new tests or products.  For example, the specimens could be used to test 
a new method for detecting vaginal infections, or to study why BV can cause pregnancy 
problems, or why BV can increase women’s risk of HIV infection.  In some instances, these may 
have potential commercial value.  No genetic testing or whole genetic sequencing will be 
performed on the samples.   

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 If a participant decides at any time that she does not want the specimen stored for future 
research, she must contact the study staff 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. 
 
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.  
Persons who are unable to fully participate in the study due to an inability to provide informed 
consent will not be enrolled, for example non-English speakers, children, illiterate or non-writing 
individuals. This exclusion is to ensure participants who cannot fully understand the implications 
of study participation due to language or cognitive barriers are not recruited.   
 
Participant Confidentiality 
Participants will have code numbers and will not be identified by name.  Participant 
confidentiality is strictly held in trust by the participating site PIs, their study staff, and the 
sponsor(s) and their agents. This confidentiality includes the study protocol, documentation, 
investigation data, participant’s clinical information, testing of biological specimens, and all 
other information generated during participation in the study. No information concerning the 
study, or the data generated from the study will be released to any unauthorized third party 
without prior written approval of the DMID. Authorized third parties include OHRP or other 
government agencies as part of their duties, the FDA, single IRB, NIH, study staff, study 
monitors, Toltec, and designees.  Participant confidentiality will be maintained when study 
results are published or discussed in conferences.   
All information provided by the sponsor and all data and information generated by the 
participating site 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 
participant; or (4) study results that may be published as described in Section 15.  If the 

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confidentiality provisions in the executed site contracts for the conduct of this trial are 
inconsistent with this statement, the site contract’s confidentiality provisions shall apply rather 
than this statement. 
The study monitor, or other authorized representatives of the sponsor, or governmental 
regulatory agencies such as the FDA 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 participants in this study. The participating sites will 
permit access to such records. 
 
Certificate of Confidentiality 
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 research 
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 study, or 
for information that must be released in order to meet the requirements of the FDA. 
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 research information, then the researchers may not use the Certificate to withhold that 
information.   
The CoC does not prevent the participating sites from reporting without the participant’s consent, 
information that would identify the participant as a participant in the study regarding matters that 
must be legally reported including: child and elder abuse, sexual abuse, or wanting to harm 
themselves or others.   
The release of individual private information or specimens for other research will only occur if 
consent was obtained from the individual to whom the information, document, or biospecimen 
pertains, or for the purposes of other research that is in compliance with applicable Federal 
regulations governing the protection of human participants in research.  

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Costs, Participant Compensation, and Research Related Injuries 
There is no cost to participants for taking part in this trial.   
Procedures and treatment for clinical care may be billed to the participant, participant’s insurance 
or third party.  Participants may be compensated for their participation in this trial.  
Compensation will be in accordance with the local IRB’s policies and procedures, and subject to 
IRB approval. 
If it is determined by the site PI that an injury occurred to a participant as a direct result of the 
tests or treatments that are done for this trial, then referrals to appropriate health care facilities 
will be provided to the participant.  Study staff will try to reduce, control, and treat any 
complications from this trial.  Immediate medical treatment may be provided by the participating 
site.  No financial compensation will be provided to the participant by the NIAID, NIH, or by the 
participating site for any injury suffered due to participation in this trial. 
 

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STATISTICAL CONSIDERATIONS 
 
Study Hypotheses 
The primary objective of the study is to evaluate the clinical efficacy of a twice-weekly 
application of the TOL-463 vaginal insert for the suppression of BV following successful 
induction with oral metronidazole or other CDC-recommended BV treatment in women with a 
history of recurrent BV.  Clinical efficacy (suppression) is defined by clinical cure (see Section 
3.3.1).   There is one planned hypothesis test with respect to the primary outcome measure.  The 
hypothesis test compares the proportion of participants with recurrent BV by V4 between 
treatment arms.  The null hypothesis for the comparison is that there is no difference in cure rates 
between treatments, with a two-sided alternative.  The test will be conducted using the Pearson 
Chi-Square test at the 5% two-sided significance level. 
 
Sample Size Considerations 
As detailed in Section 10.5, efficacy analyses will be performed in an evaluable subset of the 
enrolled population; this subset was used to derive the study’s sample size.  Assuming a 40% BV 
recurrence rate among women receiving placebo and a 50% reduction in recurrence among 
women treated with TOL-463 (i.e. 20% recurrence rate among TOL-463 recipients) and a 1:1 
allocation ratio between treatment arms, a sample size of 200 evaluable participants will provide 
at least 85% power using the Chi-Square Test.  Assuming 80% of enrolled participants will be 
evaluable for the primary analysis, the enrollment target is set to 250 to achieve 200 evaluable 
participants. 
 
Treatment Assignment Procedures 
10.3.1 
Randomization Procedures 
Participants will be randomized 1:1 to receive one of two treatments: TOL-463 vaginal inserts or 
Placebo vaginal inserts.  
The list of randomized treatment assignments will be prepared by statisticians at the SDCC and 
included in the enrollment module of the Emmes’ Internet Data Entry System (IDES). 
Advantage eClinical® will assign each participant to a blinded treatment number from the list 
after demographic and eligibility data have been entered. Each site will have a supply of blinded 
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participant for twelve weeks. The packaged study drug kits contain three, separate four-week kits 
to be dispensed to the participant at Enrollment V1 and Follow-ups V2 and V3 as applicable.  
Once a participant is assigned a treatment number, the corresponding kit will be distributed to the 
participant.  
Instructions for using the enrollment module are included in the IDES User’s Guide. Manual 
back-up randomization procedures are provided in the MOP for use in case the site temporarily 
loses Internet access, or the online enrollment system is unavailable. 
The trial will use a site-stratified, permuted, blocked randomization scheme. Permuted blocked 
randomization is used to avoid the potential for serious imbalance in the number of participants 
assigned to each group, which can occur in simple randomization procedures. 
10.3.2 
Masking Procedures 
Participants, the study staff who dispense study drug and perform study assessments after study 
drug administration, data entry personnel at the sites, and laboratory personnel will be blinded to 
treatment assignment. The DSMB may receive efficacy data in aggregate and presented by 
treatment group, as specified in the DSMB charter. The DSMB may request to be completely 
unblinded to individual study drug assignments, as needed, to adequately assess SAEs. Refer to 
the MOP for unblinding procedures. 
Study drug will be prepared at Fisher BioServices in blinded numbered kits. All kits will look 
identical and contain an identical number of inserts. Emmes will provide an unblinded list 
identifying the treatment identity (TOL-463 or placebo) in each kit to the Fisher staff responsible 
for preparing study drug kits. Clinicians, investigators, and all blinded staff will not have access 
to this list until after the trial has ended. 
 
Planned Interim Analyses 
10.4.1 
Interim Safety Review  
The study will be monitored to determine if any of the safety halting rules described in Section 
8.6 are met. The DSMB will meet and review safety data and enrollment data at specified times 
during the course of study and at a study closeout meeting, as defined in the Section 8.7.2 and 
the DSMB Charter. 
10.4.2 
Interim Efficacy Review 
There are no planned interim efficacy analyses for this study. 

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Final Analysis Plan 
A separate statistical analysis plan, (SAP) document will be generated which will contain the 
details of the analyses. This section outlines the major components of the analyses. 
10.5.1 
Analysis Populations 
Safety Population: This analysis population includes all randomized participants who received at 
least one dose of study treatment.   
Modified Intent-to-Treat (mITT) Population: This analysis population includes all randomized 
participants who are evaluable.  
The mITT population will be used as the primary efficacy analysis population. 
Per-Protocol (PP) Population: This analysis population includes all randomized participants who 
met all inclusion/exclusion criteria throughout the study, are evaluable (defined below), 
complied with the assigned IP, and returned to the study site for the TOC visit within the 
specified window (Visit 4 [Window: Day 85-91]) or were followed up to their diagnosis of 
recurrent BV.  
Evaluable is defined as follows:  
• Negative STI tests taken at baseline (C. trachomatis, N. gonorrhoeae, or T. vaginalis);  
• For participants 21 years of age or older, documentation of or self-report of a normal or 
ASCUS HPV negative Pap test prior to screening, or a Pap smear performed at 
screening/enrollment with normal result 
A participant is compliant with the study treatment if she misses < 2 non-consecutive doses of IP 
per month, as assessed by participant memory aid and returned IP and packaging at each follow 
up visit (V2, V3, V4). 
In the unlikely event of an error in randomization or IP administration (i.e., incorrect treatment), 
participants will be grouped by the treatment they actually received in safety analyses but will be 
grouped by their intended randomized assignment in efficacy analyses. 
10.5.2 
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, 

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standard deviation, median, minimum, and maximum. For categorical variables, descriptive 
statistics will include counts and percentages per category. 
10.5.3 
Safety Analysis Plan 
Safety evaluations will be based on the incidence, severity, and type of AEs, SAEs, clinically 
significant physical and pelvic examination findings as detailed in Section 9. In addition, the 
incidence of culture confirmed secondary VVC will be evaluated. Safety variables will be 
tabulated and presented for all participants in the safety population, grouped by type of infection 
and treatment. 
AEs and SAEs will be coded by MedDRA® for preferred term and system organ class. The rate 
and exact 95% confidence intervals (CIs) of AEs in aggregate, as well as by MedDRA® 
categories, will be computed. The number of SAEs is likely to be small in this study and will be 
reported by a detailed listing showing the type, MedDRA® coding, relevant dates (IP 
administration dates and AE onset and resolution dates), severity, relatedness, and outcome for 
each event. 
The occurrence of culture confirmed secondary VVC following initiation of study treatment and 
through the final study visit will be summarized in aggregate and by treatment group.  
10.5.4 
Efficacy Analysis Plan 
 
Primary Efficacy Analysis 
The primary efficacy analysis estimates the clinical efficacy rate of TOL-463. At each follow-up 
visit, the following Amsel criteria will be assessed: 
a. Positive KOH whiff test  
b. Homogeneous discharge characteristic of BV 
c. Clue cells ≥ 20% of vaginal squamous epithelial cells 
d. Vaginal pH > 4.5 
For the primary analysis, a participant is deemed to experience a recurrence of BV at a follow-up 
visit if >2 of the above criteria are met.   A participant has clinical suppression of BV if she 
meets two or fewer of the criteria at each observed follow-up visit through V4. 
The proportion of participants with recurrent BV up to and including V4 will be summarized 
overall and by treatment group along with two-sided 95% Wilson CIs.  The primary analysis will 
be performed in the mITT analysis population. Secondary analyses of the primary outcome 
measure will be performed in the PP analysis population. Recurrence status of participants who 

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are withdrawn or drop out early before an observed recurrence will be imputed; multiple 
imputation methods may be explored, and details will be provided in the SAP document. 
In addition, the rate of recurrence, which considers the amount of observed follow-up time for 
each participant, will be estimated within each treatment group along with corresponding 95% 
CIs.  Any additional sensitivity and/or corroborative analyses to be performed will be described 
in the separate SAP document. 
 
Secondary Efficacy Analyses 
The secondary efficacy analyses are briefly described below. Secondary efficacy analyses will be 
performed in the mITT and PP analysis populations, where appropriate. Details of these analyses 
and any sensitivity analyses will be specified in the separate SAP document. 
For the analysis of Secondary Objective 1, the median time to BV recurrence will be estimated 
by treatment group using Kaplan-Meier estimates.  For participants who experience BV 
recurrence by V4, the time of BV recurrence will be defined as the midpoint between the earliest 
time point of a positive BV diagnosis (post-baseline) and the previous observed time-point. For 
participants without BV recurrence at or before V4, the BV recurrence endpoint will be coded as 
censored, with time to recurrence defined as the elapsed time from the first dose of IP, to the 
earliest of: V4 time-point, the last observed time-point prior to loss to follow-up, or the time-
point at which the participant became ineligible for the particular analysis population. 
For the analysis of Secondary Objective 2, the proportion of participants experiencing vaginal 
symptoms as assessed by the participant via the daily memory aid will be estimated overall, by 
symptom category, and by treatment group. 
For the analysis of Secondary Objective 3, responses to the satisfaction questionnaire will be 
summarized overall and by treatment group. Categorical responses will be summarized using 
contingency tables and/or odds ratios, while continuous responses will be summarized using 
measures of central tendency such as the mean or median, and measures of dispersion such as the 
standard deviation or interquartile range. 
 
Exploratory and Other Efficacy Analyses 
Descriptions of the analyses to assess the exploratory objective as well as other analyses that will 
support the primary and secondary efficacy analyses will be provided in the separate SAP 
document. 

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Examples of additional analyses that will support the primary and secondary efficacy analyses 
will include, but not limited to, summaries of Nugent scores by visit and treatment group, and 
explorations of recurrences by demographic and other baseline characteristics. 
 

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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 participating 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 study records for the purposes of quality 
assurance (QA) reviews, audits, monitoring, and evaluation of the study safety and progress. 
These representatives will be permitted access to all source data and source documents, which 
include, but are not limited to, hospital records, clinical and office charts, laboratory notes, 
memoranda,  participants’ 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. Source data are all information, original records of 
clinical findings, observations, or other activities in a clinical trial necessary for the 
reconstruction and evaluation of the trial.  DCF’s will be provided by the SDCC. 

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

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DATA HANDLING AND RECORD KEEPING 
 
Data Management Responsibilities 
The site PI is responsible for ensuring the accuracy, completeness, legibility, and timeliness of 
the data reported.   
DCFs will be derived from the eCRFs and provided by the SDCC to record and maintain data for 
each participant screened and enrolled in the study.  All DCFs should be completed in a neat, 
legible manner to ensure accurate interpretation of data.  Black or blue ink is required to ensure 
clarity of reproduced copies.  When making a change or correction, cross out the original entry 
with a single line and initial and date the change.  Do not erase, overwrite, or use correction fluid 
or tap on the original.   
Data reported in the eCRF derived from the source DCFs should be consistent or the 
discrepancies should be explained. 
The sponsor and/or its designee will provide guidance to the site PIs and other study personnel 
on making corrections to the DCFs and eCRF. 
 
Data Coordinating Center/Biostatistician Responsibilities 
All DCFs and laboratory reports must be reviewed by the clinical team and data entry personnel, 
who will ensure that they are accurate and complete.  AEs must be recorded on the appropriate 
DCF, assessed for severity and relationship, and reviewed by the site PI or his/her designee. 
Data collection is the responsibility of the study personnel at the participating clinical study site 
under the supervision of the site PI.  During the study, the site PI must maintain complete and 
accurate documentation for the study. 
The SDCC for this study will be responsible for data management, quality review, analysis, and 
reporting of the study data. 
 
Data Capture Methods 
Clinical data (including, but not limited to, AE/SAEs, concomitant medications, medical history, 
physical assessments, and clinical laboratory values) will be collected on DCFs by study 
personnel then entered into eCRFs via a 21 CFR Part 11-compliant internet data entry system, 
Advantage eClinical, provided by the SDCC.  The data system includes password protection and 

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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 DCFs completed by the 
study personnel. 
 
Types of Data 
Data for this trial will include clinical, safety, and outcome measures. 
 
Study Records Retention 
Study records and reports including, but not limited to, eCRFs, source documents, ICFs, 
laboratory test results, and IP inventory records will be retained for 2 years after a marketing 
application is approved for the IP for the indication for which it is being investigated; or, if no 
application is to be filed or if the application is not approved for the IP, until 2 years after the 
investigation is discontinued and the FDA has been notified. These documents will be retained 
for a longer period, however, if required by local regulations. SICs and EICs for future use will 
be maintained as long as the sample/specimen exists. 
No records will be destroyed without the written consent of the sponsor. It is the responsibility of 
the sponsor to inform the site PI when these documents no longer need to be retained. The 
participating sites must contact DMID for authorization prior to the destruction of any study 
records. 
 

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CLINICAL MONITORING 
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 this trial is 
conducted in accordance with the protocol, protocol-specific MOP and applicable sponsor SOPs.  
A separate monitoring plan document should be developed to describe who will conduct the 
monitoring, at what frequency monitoring will be done, and what level of detail monitoring will 
be conducted.  Most DMID sponsored studies are monitored by TRI/ICON DMID CROMS, and 
the clinical monitoring plan is written jointly by DMID and TRI/ICON.  Preference is given to a 
separate monitoring plan to be agreed upon with the Office of Clinical Research Affairs 
(OCRA), which will describe protocol-specific items to be monitored.  The monitoring plan must 
include the number of participant charts to be reviewed, which/what proportion of data fields and 
what will be monitored, who will be responsible for conducting the monitoring visits, and who 
will be responsible for ensuring that monitoring findings are addressed. 
Site visits will be made at standard intervals as defined by the monitoring plan and may be made 
more frequently as directed by DMID.  Monitoring visits will include, but are not limited to, 
review of regulatory files, accountability records, eCRFs, informed consent forms (SIC and 
EIC), medical and laboratory reports, and protocol and GCP compliance.  Site monitors will 
have access to each participating site, study personnel, and all study documentation according to 
the DMID-approved monitoring plan.  Study monitors will meet with site PIs to discuss any 
problems and actions to be taken and will document site visit findings and discussions. 
 

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PUBLICATION POLICY 
Following completion of the study, the lead PI is expected to publish the results of this research 
in a scientific journal.  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 participant. 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 SAP 
will be posted on ClincialTrials.gov. 
For this trial the responsible party is NIAID which will register the trial and post results.   
The responsible party does not plan to request certification of delayed posting. 
Refer to: 
• 
Public Law 110-85, Section 801, Clinical Trial Databases 
• 
42CFR11 
• 
NIH NOT-OD-16-149 

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LITERATURE REFERENCES 
1. 
Muzny, C. and J. Schwebke, Biofilms: an underappreciated mechanism of treatment 
failure and recurrence in vaginal infections. Clin Infect Dis, 2015. 61(4): p. 601-606. 
2. 
Diflucan [package insert]. New York, NY:  Pfizer. 2018. 
3. 
Nuvessa [package insert]. Irvine, CA:  Allergan. 2016. 
4. 
Marrazzo, J., et al., Bacterial Vaginosis: Identifying Research Gaps Proceedings of a 
Workshop Sponsored by DHHS/NIH/NIAID November 19-20, 2008. Sex Transm Dis, 
2010. 37(12): p. 732-744. 
5. 
Aguin, T. and J. Sobel, Vulvovaginal Candidiasis in Pregnancy. Curr Infect Dis Rep, 2015. 
17(6): p. 462. 
6. 
van de Wijgert, J., et al., Bacterial vaginosis and vaginal yeast, but not vaginal cleansing, 
increase HIV-1 acquisition in African women. J Acquir Immune Defic Syndr, 2008. 48(2): 
p. 203-210. 
7. 
Bradshaw, C. and R. Brotman, Making inroads into improving treatment of bacterial 
vaginosis – striving for long-term cure. BMC Infect Dis, 2015. 15(1): p. 292. 
8. 
Allsworth, J. and J. Peipert, Prevalence of bacterial vaginosis: 2001-2004 National Health 
and Nutrition Examination Survey data. Obstet Gynecol, 2007. 109(1): p. 114-120. 
9. 
Sobel, J., et al., Suppressive antibacterial therapy with 0.75% metronidazole vaginal gel 
to prevent recurrent bacterial vaginosis. Am J Obstet Gynecol, 2006. 194(5): p. 1283-
1289. 
10. 
CDC Sexually Transmitted Diseases Treatment Guidelines. MMWR, 2015. 64(3): p. 1-
138. 
11. 
Nyirjesy, P., Management of persistent vaginitis. Obstet Gynecol, 2014. 124(5): p. 1135-
1146. 
12. 
Reichman, O., R. Akins, and J. Sobel, Boric acid addition to suppressive antimicrobial 
therapy for recurrent bacterial vaginosis. Sex Transm Dis, 2009. 36(11): p. 732-734. 
 
 
 
 
 

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APPENDICES 
Schedule of Events 
Female Genital Grading Table for Physical Examination Findings 

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 Schedule of Events  
Table 17-1: Schedule of Events 
Procedures 
Visit 0/V0 
Screening 
(Day -15 
to -8) 
Visit 1/V1 
Enrollment 
(Day 1) 
Visit 
2/V2 
Follow-
up 
(Days 
29-35) 
Visit 3/V3 
Follow-up 
(Days 57-
63) 
Visit 
4/V4/TOC 
(Days 85-
91) 
Unscheduled 
Visit 
Early 
Termination 
Visit 
Signed consent form1 
X 
X 
 
 
 
 
 
Review of Inclusion/Exclusion criteria 
X 
X 
 
 
 
 
 
Collection of Demographics 
X 
 
 
 
 
 
 
Review of Medical History2, 3 
X 
X 
X 
X 
X 
(X) 
X 
Review of Sexual History4 
X 
X 
X 
X 
X 
(X) 
X 
Urine Pregnancy Test12 
X 
X 
X 
X 
X 
(X) 
X 
Review of Concomitant Medications5 
X 
X 
X 
X 
X 
(X) 
X 
Pelvic Examination3,6, 13 
X 
X 
X 
X 
X 
(X) 
X 
Clinical assessment of Vulvovaginal 
signs 
X 
X 
X 
X 
X 
(X) 
X 

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Procedures 
Visit 0/V0 
Screening 
(Day -15 
to -8) 
Visit 1/V1 
Enrollment 
(Day 1) 
Visit 
2/V2 
Follow-
up 
(Days 
29-35) 
Visit 3/V3 
Follow-up 
(Days 57-
63) 
Visit 
4/V4/TOC 
(Days 85-
91) 
Unscheduled 
Visit 
Early 
Termination 
Visit 
STI Screen (C. trachomatis, N. 
gonorrhoeae, and T. vaginalis)7 
X 
 
 
 
 
 
 
Clinical Determination of presence or 
absence of BV (Amsel Criteria) 
X 
X 
X 
X 
X 
(X) 
X 
Gram stain evaluation/Nugent score for 
BV 
X 
X 
X 
X 
X 
(X) 
X 
BD Max Test 
X 
X 
X 
X 
X 
 
X 
Future Analysis Specimen Collection11 
(X) 
(X) 
(X) 
(X) 
(X) 
 
(X) 
Dispense Oral Metronidazole (or other 
CDC-recommended BV treatment) 
X 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
Targeted Physical Examination8 
 
X 
(X) 
(X) 
(X) 
(X) 
(X) 
IP Dispensation, Participant Instructions 
 
X 
X 
X 
 
(X) 
 
Participant Memory Aid9 
 
X 
X 
X 
X 
(X) 
X 
Reminder contact (for Visits 1, 2, and 3) 
 
X 
X 
X 
 
 
 
Assessment of IP compliance (via 
review of Memory Aid and IP return) 
 
 
X 
X 
X 
(X) 
X 

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Procedures 
Visit 0/V0 
Screening 
(Day -15 
to -8) 
Visit 1/V1 
Enrollment 
(Day 1) 
Visit 
2/V2 
Follow-
up 
(Days 
29-35) 
Visit 3/V3 
Follow-up 
(Days 57-
63) 
Visit 
4/V4/TOC 
(Days 85-
91) 
Unscheduled 
Visit 
Early 
Termination 
Visit 
Participant Assessment of Vaginal 
Symptoms  
X 
X 
X 
X 
X 
(X) 
X 
Candida Culture10 
 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
Assessment of AEs/SAEs   
 
 
X 
X 
X 
(X) 
X 
Participant satisfaction questionnaire 
 
 
(X) 
(X) 
X 
 
X 
(X) – As indicated/appropriate.  
1. At V0 the participant is signing the SIC Form. At V1 the participant will then sign the EIC Form.   
2. At V0 collect complete medical symptom history; at subsequent visits, review and update medical symptom history as appropriate.  
3. A Pap smear should be done at V0 for any participant who meets the following criteria and cannot provide documentation (which 
can include self-report) of a normal or ASCUS HPV negative Pap test within the prior 3 years: is 21 years of age or older and (a) has 
not had a hysterectomy or (b) has had a hysterectomy and has a history of CIN grade 2+ (CIN2+) in the past 20 years. If a Pap smear 
is conducted at V0, the results are not required prior to enrollment. 
4.  At V0, collect sexual history for the past 30 days; at subsequent visits, collect interim sexual history since the last visit. 
5.  At V0, collect concomitant medications taken in the last 30 days; at subsequent visits, collect concomitant medications taken since 
the last visit. 
6. At V1, one pelvic exam is performed and if the participant is enrolled and randomized additional vaginal swabs are collected. 
7. Participants who test positive for STIs may be reconsidered for eligibility once the treatment course is complete. 

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8. At the enrollment visit, V1, this will include weight and height measurements.  At all follow-up visits, a targeted physical exam is 
only performed when clinically indicated. 
9. After randomization, the participant will be provided with the Participant Memory Aid for the first 4 weeks of the study.  At each of 
the follow-up visits, V2-V4, the Memory Aid will be reviewed/collected, and a new Memory Aid for the next 4 weeks will be 
provided.  
10. At the enrollment visit, V1, and all follow-up visits V2-V4, participants with clinical evidence of VVC and symptoms will have a 
confirmatory Candida culture performed and treated as appropriate with oral fluconazole. 
11. A Future Analysis Specimen Collection is only performed for participants who consented to future use of their specimens. 
12.  A urine pregnancy test is only required for participants of childbearing potential. 
13.  The pelvic exam includes KOH and saline microscopy for identification of yeast forms, trichomonas and clue cells. 
 

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Toxicity Grading Table 
Note:  the following table is adapted from the Division of AIDS Table for Grading the Severity 
of Adult and Pediatric Adverse Events, Addendum 1: Female Genital Grading Table for Use in 
Microbicide Studies (V1.0, November 2007) 
Table 17-2: Toxicity Grading Table 
INDIVIDUAL SIGNS/SYMPTOMS 
PARAMETER 
GRADE 0  
NORMAL 
GRADE 1 
MILD 
GRADE 2    
MODERATE 
GRADE 3          
SEVERE 
GENERAL 
Odor 
No 
complaint 
Mild-moderate 
unpleasant 
Severe unpleasant 
odor 
NA 
PAIN AND TENDERNESS 
(Specify Area: Vulvar/Perineum, Vagina, Cervix (including cervical motion tenderness), 
Uterus, Adnexae, Pelvic/Lower Abdominal, or Ovulatory) 
*Note – if both pain and tenderness are present, only report the one with the most severe 
grade 
Pain* 1 
None 
Pain causing 
no or minimal 
interference 
with usual 
social & 
functional 
activities 
Pain causing greater 
than minimal 
interference with 
usual social & 
functional activities 
or the need for non-
narcotic medication 
Pain causing inability 
to perform usual 
social & functional 
activities or the need 
for narcotic 
medication OR 
hospitalization (other 
than emergency room 
visit) indicated 
Tenderness* 1 
None 
Mild 
tenderness 
Moderate 
tenderness 
Severe tenderness 

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Dyspareunia (pain with 
sexual activity) 
None 
Pain causing 
no or minimal 
interference 
with sexual 
function 
Pain causing greater 
than minimal 
interference with 
sexual function 
NA 
Dysmenorrhea/cramping 
with menses 
None 
Pain causing 
no or minimal 
interference 
with usual 
social & 
functional 
activities 
Pain causing greater 
than minimal 
interference with 
usual social & 
functional activities 
or the need for non-
narcotic medication 
Pain causing inability 
to perform usual 
social or functional 
activities or the need 
for narcotic 
medication 
1 If pain or tenderness is included in the grading of another category (e.g., PID), it should not be 
graded again in the pain or tenderness category 
 
 
 

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INDIVIDUAL SIGNS/SYMPTOMS 
PARAMETER 
GRADE 0       
NORMAL 
GRADE 1       
MILD 
GRADE 2       
MODERATE 
GRADE 3       
SEVERE 
GENITOURINARY SIGNS/SYMPTOMS – VULVA 
Vulvar/vaginal 
itching 
None 
Itching causing no, 
mild, or moderate 
interference with 
usual social & 
functional 
activities 
Itching causing 
inability to 
perform usual 
social & functional 
activities; may 
require 
intervention such 
as antihistamine or 
bathing to provide 
relief 
NA 
Vulvar edema 
None 
Mild, non-pitting 
edema 
Moderate, 1-2+ 
pitting edema 
3+ pitting edema, 
severe enough to 
require urinary 
drainage, or 
weeping edema ± 
skin breakdown 
Vulvar erythema 
None 
Erythema covering 
< 50% of vulvar 
surface 
Erythema covering 
≥ 50% of vulvar 
surface 
NA 
Vulvar lesions 
(findings seen only 
by colposcopy 
should not be 
included here) 
Normal variants 
including skin 
tags, moles, scars, 
etc. 
Blisters, 
ulcerations, or 
pustules - no 
treatment indicated 
Blisters, 
ulcerations or 
pustules, with 
treatment indicated 
Severe epithelial 
disruption with 
hospitalization 
indicated (other 
than emergency 
room visit) 

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Vulvar rash 
None 
Rash covering < 
50% of vulvar 
surface 
Rash covering ≥ 
50% of vulvar 
surface 
Severe epithelial 
disruption with 
hospitalization 
indicated (other 
than emergency 
room visit) 
Bartholin’s or 
Skene's gland 
No findings 
Cyst with no 
inflammation 
Cyst or abscess 
with outpatient 
intervention 
indicated 
Cyst or abscess 
with 
hospitalization 
indicated, (other 
than emergency 
room visit) 
including 
necrotizing 
fasciitis from 
Bartholin’s abscess 
GENITOURINARY SIGNS/SYMPTOMS – VAGINA  
** Note – if vaginal discharge is present both by history and on examination, only report 
the one with the most severe grade 
Vaginal edema 
None 
Mild-moderate 
engorgement 
Loss of ruggae and 
friability 
NA 
Vaginal erythema None 
Erythema covering 
< 50% of vaginal 
surface 
Erythema covering 
≥ 50% of vaginal 
surface 
NA 
Vaginal dryness 
No complaint 
Dryness causing 
no or minimal 
interference with 
usual sexual, 
social, & 
functional 
activities 
Dryness causing 
greater than 
minimal 
interference with 
usual sexual, 
social, & 
functional 
activities 
NA 
 

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INDIVIDUAL SIGNS/SYMPTOMS 
PARAMETER 
GRADE 0       
NORMAL 
GRADE 1       
MILD 
GRADE 2       
MODERATE 
GRADE 3       
SEVERE 
Vaginal discharge 
by participant 
report ** 
Participant's usual 
amount of 
discharge, 
regardless of color 
or quantity 
Mild-moderate 
increase in amount 
above participant 
baseline - no 
sanitary protection 
i d
Profuse increase in 
discharge requiring 
pad use or other 
hygienic 
intervention 
NA 
Vaginal discharge 
as observed by 
clinician ** (red or 
brown discharge 
should be reported 
under bleeding, not 
discharge) 
Slight amount of 
discharge, any 
color 
Mild-moderate 
increase in amount 
Significant 
increase in amount 
with pooling in 
vagina on 
examination 
NA 
Vaginal abrasions 
or lacerations 
(including 
probable applicator 
injuries) 
None 
Superficial 
disruptions and 
disruptions 
extending through 
the mucosa with 
minimal impact on 
life 
Large disruptions 
extending through 
the mucosa or 
large superficial 
disruptions, 
hospitalization not 
indicated 
Large disruptions 
extending through 
the mucosa or 
large superficial 
disruptions 
including 
lacerations, 
hospitalization 
indicated (other 
than emergency 
room visit) 
Vaginal lesions 
(findings seen only 
by colposcopy 
should not be 
included here) 
Normal variants 
including skin 
tags, moles, scars, 
etc. 
Blisters, 
ulcerations, or 
pustules, no 
treatment indicated 
Blisters, 
ulcerations, or 
pustules with 
treatment indicated 
Severe epithelial 
disruption 
requiring 
hospitalization 
(other than 
emergency room 
visit) 

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Vaginal and 
Cervical masses  
(polyps, myomas, 
or possible 
malignancy) 
None or normal 
variants such as 
Nabothian cyst or 
Gartner duct cyst 
Polyp or myoma or 
undiagnosed mass 
without symptoms 
Polyp, myoma, or 
undiagnosed mass 
causing mild 
symptoms, e.g., 
bleeding/pain not 
requiring more 
than mild 
analgesia 
Polyp, myoma, or 
undiagnosed mass 
causing severe 
symptoms, e.g., 
bleeding/pain 
affecting bladder 
and bowel 
function, or visible 
cervical cancer 
GENITOURINARY SIGNS/SYMPTOMS – CERVIX 
Cervical edema 
and friability 
None 
Edema without 
friability 
Friable cervix 
NA 
Cervical erythema None 
Erythema covering 
< 50% of cervix 
Erythema covering 
≥ 50% of cervix 
NA 
Cervical discharge White or clear 
discharge 
Small amount of 
purulent discharge 
at os 
Purulent discharge 
extending onto 
cervix or vagina 
NA 
Visible cervical 
lesions (findings 
seen only by 
colposcopy should 
not be included 
here) 
Normal variants 
including skin 
tags, moles, scars, 
etc. 
Blisters, 
ulcerations, or 
pustules, no 
treatment indicated 
Blisters, 
ulcerations, or 
pustules with 
treatment indicated 
NA 
 
 
 

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INDIVIDUAL SIGNS/SYMPTOMS 
PARAMETER 
GRADE 0       
NORMAL 
GRADE 1       
MILD 
GRADE 2       
MODERATE 
GRADE 3       
SEVERE 
GENITOURINARY SIGNS/SYMPTOMS – UTERUS 
Uterine 
masses/enlargeme
nt based on 
bimanual 
examination 
Normal to 8 week 
size, no palpable 
myomas 
Enlarged uterus 
and mild 
symptoms, e.g., 
bleeding/pain 
requiring mild 
analgesics 
Enlarged 
uterus/myoma with 
moderate pain or 
symptoms, e.g., 
bleeding 
Mass causing 
severe 
bleeding/pain or 
with impact on 
bowel/bladder 
function or 
requires 
transfusion or 
surgery 
Polyp, submucosal 
fibroid, or 
thickened 
endometrium 
detected by 
transvaginal 
ultrasound (new or 
increasing in size 
from prior exam) 
None or 
unchanged/reduce
d in size from prior 
exam 
New myomas < 6 
cm diameter 
(single or multiple) 
or diameter 
increased < 6 cm 
since prior exam 
New myomas ≥ 6 
cm diameter 
(single or multiple) 
or diameter 
increased ≥ 6 cm 
since prior exam 
Hospitalization 
(other than 
emergency room 
visit) and/or 
surgery indicated 
GENITOURINARY SIGNS/SYMPTOMS – ADNEXA 
Not pregnancy- or 
infection-related 
adnexal masses 
based on bimanual 
exam (use if no 
ultrasound done; if 
ultrasound done, 
use ultrasound 
categories below) 
None, ≤ 4 cm, 
normal size ovary 
> 4 cm with 
minimal or no 
symptoms 
> 4 cm with severe 
symptoms, e.g., 
pain, but 
hospitalization not 
indicated (see 
footnote #1) 
> 4 cm with severe 
symptoms, e.g., 
pain and 
hospitalization 
indicated (other 
than emergency 
room visit) (see 
footnote #1) 

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Hydrosalpinx 
based on 
ultrasound 
None 
Asymptomatic, 
suspected 
hydrosalpinx 
Hydrosalpinx with 
pain, but without 
evidence of 
infection or 
ectopic pregnancy 
Signs/symptoms of 
infection with 
hospitalization 
(other than 
emergency room 
visit) and/or 
surgery indicated 
Adnexal mass 
based on 
ultrasound 
None 
Simple cyst, 
asymptomatic 
Simple cyst, 
symptomatic 
Malignant mass 
suspicious for 
malignancy 
 
 
 

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INDIVIDUAL SIGNS/SYMPTOMS 
PARAMETER 
GRADE 0 
NORMAL 
GRADE 1   
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GENITOURINARY SIGNS/SYMPTOMS – ABDOMEN 
Abdominal mass 
not palpable on 
pelvic exam of 
unknown diagnosis 
None or known 
(pre-existing) mass 
unchanged in size 
New mass or 
increased size of 
known mass 
requiring mild 
analgesia with 
minimal impact 
New mass or 
increased size of 
known mass with 
moderate 
symptoms 
Mass causing 
severe bleeding/ 
pain with impact 
on bladder/bowel 
function or with 
hospitalization 
(other than 
emergency room 
visit) indicated or 
malignancy 
GENITOURINARY SIGNS/SYMPTOMS – URINARY TRACT 
Urinary 
frequency 
None 
Up to 2 times 
participant’s 
normal 
frequency 
> 2 times 
participant’s 
normal 
frequency 
NA 
Dysuria 
None 
Superficial 
only 
Deep ± 
superficial 
Inability to void due to pain 
Hematuria 
None 
Microscopic, 
no 
intervention 
indicated 
(beyond 
evaluation for 
infection) 
Gross blood 
in urine or 
medical 
intervention/ 
evaluation 
indicated 
(beyond 
evaluation for 
infection) 
Persistent bleeding with transfusion, 
hospitalization (other than emergency 
room visit) or intervention indicated to 
obtain hemostasis (endoscopy, 
interventional radiology, or operative) 

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COMPOSITE SIGNS/SYMPTOMS 
(Use instead of individual categories if 2 or more signs/symptoms are present) 
PARAMETER 
GRADE 0 
NORMAL 
GRADE 1   
MILD        
(Use if all 
signs/ 
symptoms 
would 
individually be 
Grade 0 or 1) 
GRADE 2 
MODERATE 
(Use if one or 
more 
signs/symptom
s would 
individually be 
Grade 2 and 
all others 
Grade 0 or 1) 
GRADE 3 SEVERE (Use if 
one or more signs/symptoms 
would individually 
be Grade 3) 
 
 
NO ORGANISM IDENTIFIED BUT INADEQUATE TESTING PERFORMED 
Vulvovaginitis 
(combinations 
of pain, itching, 
erythema, 
edema, rash, 
tenderness, or 
discharge) 
None 
Mild 
signs/symptoms 
Moderate 
signs/symptoms 
Severe signs/ 
symptoms 
Cervicitis 
(combinations 
of dyspareunia, 
erythema, 
edema, 
tenderness, and 
discharge) 
None 
Mild signs/ 
symptoms 
Moderate signs/ 
symptoms 
Severe signs/ 
symptoms 

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PID (if 
Gonorrhea or 
Chlamydia 
identified use 
that category) 
None 
NA 
Cervicitis with 
mild uterine 
tenderness, ± 
mild cervical 
motion 
tenderness, no 
signs of 
peritoneal 
More diffuse tenderness, any 
signs of peritoneal irritation, 
or indications for 
hospitalization (other than 
emergency room visit) 
including tubo-ovarian abscess 
NO ORGANISM IDENTIFIED AFTER APPROPRIATE TESTING PERFORMED 
Vulvovaginitis 
(combinations 
of pain, itching, 
erythema, 
edema, rash, 
tenderness, or 
discharge) 
None 
Mild signs/ 
symptoms 
Moderate signs/ 
symptoms 
Severe signs/ 
symptoms 
Cervicitis 
(combinations 
of dyspareunia, 
erythema, 
edema, 
tenderness, and 
discharge) 
None 
Mild signs/ 
symptoms 
Moderate signs/ 
symptoms 
Severe signs/ 
symptoms 
PID (if 
Gonorrhea or 
Chlamydia 
identified use 
that category) 
None 
NA 
Cervicitis with 
mild uterine 
tenderness, ± 
mild cervical 
motion 
tenderness, no 
signs of 
peritoneal 
irritation 
More diffuse tenderness, any 
signs of peritoneal irritation, 
or indications for 
hospitalization (other than 
emergency room visit) 
including tubo-ovarian abscess 

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INFECTIONS AND DYSPLASIA 
PARAMETER 
GRADE 0       
NORMAL 
GRADE 1       
MILD 
GRADE 2      
MODERATE 
GRADE 3       
SEVERE 
GENITOURINARY INFECTIONS 
Genital herpes 
No lesions 
Characteristic 
ulcerative or 
vesicular lesions 
confirmed by 
culture, PCR, 
Tzanck prep or 
other diagnostic 
test of lesion or 
previous type- 
specific serology, 
covering < 25% of 
vulva, vagina, or 
cervix 
Same criteria as 
mild but covering 
25-50% of vulvar, 
vaginal, or cervical 
surface 
Same criteria as 
mild but covering 
> 50% of vulvar, 
vaginal, or cervical 
surface and/or 
symptoms of 
significant 
systemic 
involvement, e.g., 
encephalitis, 
hepatitis 
Candida 
Absence of 
symptoms 
regardless of 
candida test results 
Positive culture, 
wet mount, or 
other laboratory 
test for yeast, with 
mild symptoms 
Positive culture, 
wet mount, or 
other laboratory 
test for yeast, with 
moderate to severe 
symptoms 
NA 
Trichomonas 
Negative 
NA 
Positive wet 
mount, culture, 
PCR or other 
licensed test, 
excluding pap 
smear, showing T. 
vaginalis, 
regardless of 
symptoms 
NA 

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Chlamydia 
Negative 
NA 
Positive culture or 
other diagnostic 
test for Chlamydia, 
asymptomatic or 
with mild uterine 
or cervical motion 
tenderness (no 
signs of peritoneal 
irritation) 
Positive test for 
Chlamydia with 
abdominal or 
uterine or adnexal 
tenderness on 
examination, with 
or without adnexal 
mass, diffuse 
tenderness, any 
signs of peritoneal 
irritation, or 
indications for 
hospitalization 
(other than 
emergency room 
visit) including 
tubo-ovarian 
abscess 
 
 
 

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INFECTIONS AND DYSPLASIA 
PARAMETER 
GRADE 0 
NORMAL 
GRADE 1   
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
Gonorrhea 
Negative 
NA 
Positive culture or 
other diagnostic 
test for Gonorrhea, 
asymptomatic or 
with mild uterine 
or cervical motion 
tenderness (no 
signs of peritoneal 
irritation) 
Positive test for 
Gonorrhea with 
abdominal or 
uterine or adnexal 
tenderness on 
examination, with 
or without adnexal 
mass, diffuse 
tenderness, any 
signs of peritoneal 
irritation, or 
indications for 
hospitalization 
(other than 
emergency room 
visit) including 
tubo-ovarian 
abscess or 
disseminated 
gonococcal 
infection 
Urinary tract 
infection (by 
urinalysis and 
urine culture) 
Negative 
5-10 WBC/hpf on 
urinalysis with a 
negative culture 
per protocol 
definition (with or 
without symptoms) 
> 10 WBC/hpf on 
urinalysis OR a 
positive culture per 
protocol definition 
(with or without 
symptoms) 
Pyelonephritis or 
sepsis (septicemia) 
due to urinary tract 
infection 

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Syphilis 
Negative 
treponemal or non- 
treponemal test or 
both positive with 
known treatment 
and stable titers (< 
4 fold increase) 
NA 
Syphilis diagnosed 
by a positive 
treponemal test 
along with a 
positive non- 
treponemal test 
and no previous 
treatment or a 
four- fold rise in 
titer on the non-
treponemal test 
after previous 
treatment 
regardless of 
symptoms or non- 
oral lesions 
positive by 
darkfield exam for 
treponemes 
Syphilis in the 
presence of 
neurologic 
symptoms or a 
positive CSF 
VDRL or FTA-
ABS 
GENITAL DYSPLASIA 
Condyloma 
(specify site: 
cervical, vaginal, 
vulvar, perianal) 
None 
Condylomata 
causing no or mild 
interference with 
daily function 
Condylomata 
causing moderate 
interference with 
daily function 
Condylomata 
causing severe 
interference with 
daily function, 
secondary 
infection, or 
hospitalization 
(other than 
emergency room 
visit) indicated 
 
 

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INFECTIONS AND DYSPLASIA 
PARAMETER 
GRADE 0       
NORMAL 
GRADE 1       
MILD 
GRADE 2       
MODERATE 
GRADE 3       
SEVERE 
 
Intraepithelial 
Neoplasia by 
biopsy (VIN, CIN, 
VAIN) 
None 
Intraepithelial  
Neoplasia 1 (IN1) 
Intraepithelial 
Neoplasia 2 (IN2) 
Carcinoma in situ 
(CIS) or Invasive 
carcinoma 
Pap (use this 
category only if 
treatment 
performed without 
diagnostic testing, 
otherwise use 
biopsy category 
above) 
nl PAP 
ASCUS or LSIL 
HSIL 
Carcinoma in situ 
or carcinoma