Clinical trial NCT03930745
Conditions: Bacterial Vaginosis
Keywords: Bacterial vaginosis Candida albicans Double-Blind Gardnerella vaginalis Phase II Placebo Randomized Suppression TOL-463 insert
Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Start date: 2019-09-09; Completion date: 2021-12-06
Enrollment: 81 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
A Phase II randomized, double-blind, placebo-controlled study screening approximately 600 adult females, aged 18-55, with a goal 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, in suppressing Recurrent Bacterial Vaginosis (RBV) when administered to women who have a history of RBV and have been successfully cleared of their current Bacterial Vaginosis (BV) infection administering 500 mg of oral metronidazole, twice a day for 7 days or another CDC-recommended BV treatment. Patient participation will be approximately 100 days while the study is conducted at 4 sites within the United States. The primary objective of the study is 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 RBV following successful induction with oral metronidazole or a CDC-recommended BV treatment.

Detailed description:
This is a Phase II randomized, double-blind, placebo-controlled study screening approximately 600 adult females, aged 18-55, with a goal 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, in suppressing Recurrent Bacterial Vaginosis (RBV) when administered to women who have a history of RBV and have been successfully cleared of their current Bacterial Vaginosis (BV) infection administering 500 mg of oral metronidazole, twice a day for 7 days or another CDC-recommended BV treatment. Patient participation will be approximately 100 days while the study is conducted at 4 sites within the United States. The primary objective of the study is 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 RBV following successful induction with oral metronidazole or a CDC-recommended BV treatment. Secondary objectives of the study are: 1) to evaluate the time to BV recurrence as defined by clinical criteria, 2) to evaluate the incidence of vaginal symptoms over study participation, 3) to evaluate acceptability of a twice-weekly application of TOL-463 vaginal insert in suppression of BV, and 4) to evaluate the safety of TOL-463 vaginal insert compared to placebo, including the incidence of secondary vulvovaginal candidiasis (VVC). The null hypothesis for the comparison is that there is no difference in cure rates between treatments, with a two-sided alternative.

Arms: arm 1: TOL-463 insert administered vaginally twice a week for twelve weeks. N=125 arm 2: Matching placebo insert administered vaginally twice a week for twelve weeks. N=125
Interventions: intervention 1: Placebo intervention 2: TOL-463
Intervention descriptions: intervention 1: Placebo vaginal inserts. intervention 2: TOL-463 is a non-azole vaginal anti-infective drug candidate designed as a dual-indication therapy for BV and VVC.

Protocol documents:
Prot_000.pdf: 
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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 
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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 
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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 
study drug kits pre-labeled with treatment numbers, each containing sufficient doses to treat a 


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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 
 

SAP_001.pdf: 
 
 
CLINICAL RESEARCH IN INFECTIOUS DISEASES 
 
 
 
STATISTICAL ANALYSIS PLAN 
for 
DMID Protocol: 18-0017 
Study Title: 
A Randomized, Double-Blind, Placebo-Controlled 
Trial of TOL-463 Insert for Suppression of Bacterial 
Vaginosis (BV) [SUBVert] 
 
NCT03930745 
 
Version 1.0 
 
DATE: 07MAR2022 
 
THIS COMMUNICATION IS PRIVILEGED AND CONFIDENTIAL  
 
 


Statistical Analysis Plan - DMID Protocol: 18-0017  
Version 1.0 
07MAR2022 
- ii - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
STUDY TITLE 
Protocol Number Code: 
DMID Protocol: 18-0017 
Development Phase: 
Phase II 
Products: 
TOL-463 Insert or placebo 
Form/Route: 
Self-insert vaginally twice-weekly for 12 weeks 
Indication Studied: 
Bacterial vaginosis (BV) 
Sponsor: 
Division of Microbiology and Infectious Diseases 
National Institute of Allergy and Infectious Diseases 
National Institutes of Health 
Clinical Trial Initiation Date: 
19AUG2019 
Clinical Trial Completion Date: 
TBD 
Date of the Analysis Plan: 
07MAR2022 
Version Number: 
1.0 
This study was performed in compliance with Good Clinical Practice. 
Information contained in this publication is the property of Division of Microbiology and Infectious Diseases and is confidential. This information 
may not be disclosed to third parties without written authorization from Division of Microbiology and Infectious Diseases. This report may not be 
reproduced, stored in a retrieval system or transmitted in any form or by any means - electronic, mechanical, recording or otherwise - without 
the prior authorization from Division of Microbiology and Infectious Diseases. This document must be returned to Division of Microbiology and 
Infectious Diseases upon request. 
 


Statistical Analysis Plan - DMID Protocol: 18-0017  
Version 1.0 
07MAR2022 
- iii - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
TABLE OF CONTENTS 
STUDY TITLE ............................................................................................................................... II 
TABLE OF CONTENTS ...............................................................................................................III 
LIST OF ABBREVIATIONS ....................................................................................................... VI 
1. 
PREFACE .....................................................................................................................1 
2. 
INTRODUCTION ........................................................................................................2 
2.1. 
Study Background ........................................................................................................2 
2.2. 
Purpose of the Analyses ................................................................................................2 
3. 
STUDY OBJECTIVES AND ENDPOINTS ................................................................3 
3.1. 
Study Objectives ...........................................................................................................3 
3.1.1. 
Primary Objective .........................................................................................................3 
3.1.2. 
Secondary Objectives ...................................................................................................3 
3.1.3. 
Exploratory Objective ...................................................................................................3 
3.2. 
Endpoints ......................................................................................................................3 
3.2.1. 
Primary Endpoint ..........................................................................................................3 
3.2.2. 
Secondary Endpoints ....................................................................................................3 
3.2.3. 
Exploratory Endpoint ....................................................................................................4 
3.3. 
Study Definitions and Derived Variables .....................................................................4 
4. 
INVESTIGATIONAL PLAN .......................................................................................6 
4.1. 
Overall Study Design and Plan .....................................................................................6 
4.2. 
Discussion of Study Design, Including the Choice of Control Groups ........................8 
4.3. 
Selection of Study Population ......................................................................................8 
4.3.1. 
Participant Inclusion Criteria ........................................................................................8 
4.3.1.1. 
Screening Visit(s) Inclusion Criteria ............................................................................8 
4.3.1.2. 
Enrollment Visit Inclusion Criteria ..............................................................................9 
4.3.2. 
Participant Exclusion Criteria .....................................................................................10 
4.3.2.1. 
Screening Visit(s) Exclusion Criteria .........................................................................10 
4.3.2.2. 
Enrollment Visit Exclusion Criteria ...........................................................................11 
4.4. 
Treatments ..................................................................................................................11 
4.4.1. 
Treatments Administered ............................................................................................11 
4.4.2. 
Identity of Investigational Product(s) .........................................................................11 


Statistical Analysis Plan - DMID Protocol: 18-0017  
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Table of Contents (continued) 
- iv - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
4.4.3. 
Method of Assigning Subjects to Treatment Groups (Randomization) .....................11 
4.4.4. 
Selection of Doses in the Study ..................................................................................12 
4.4.5. 
Selection and Timing of Dose for Each Subject .........................................................12 
4.4.6. 
Blinding ......................................................................................................................12 
4.4.7. 
Prior and Concomitant Therapy ..................................................................................12 
4.4.8. 
Treatment Compliance ................................................................................................13 
4.5. 
Efficacy (Immunogenicity) and Safety Variables ......................................................13 
4.5.1. 
Efficacy variables .......................................................................................................13 
4.5.2. 
Safety variables ...........................................................................................................14 
4.5.2.1. 
Adverse Events (AEs) .................................................................................................14 
4.5.2.2. 
Adverse Events Grading .............................................................................................15 
4.5.2.3. 
Relationship to Study Products:..................................................................................15 
4.5.2.4. 
Serious Adverse Events (SAEs) .................................................................................16 
5. 
SAMPLE SIZE CONSIDERATIONS .......................................................................17 
6. 
GENERAL STATISTICAL CONSIDERATIONS ....................................................18 
6.1. 
General Principles .......................................................................................................18 
6.2. 
Timing of Analyses .....................................................................................................18 
6.3. 
Analysis Populations ..................................................................................................18 
6.4. 
Covariates and Subgroups ..........................................................................................19 
6.5. 
Missing Data ...............................................................................................................19 
6.6. 
Interim Analyses and Data Monitoring ......................................................................19 
6.7. 
Multicenter Studies .....................................................................................................20 
6.8. 
Multiple Comparisons/Multiplicity ............................................................................20 
7. 
STUDY SUBJECTS ...................................................................................................21 
7.1. 
Disposition of Subjects ...............................................................................................21 
7.2. 
Protocol Deviations ....................................................................................................21 
8. 
EFFICACY EVALUATION ......................................................................................22 
8.1. 
Primary Efficacy Analysis ..........................................................................................22 
8.2. 
Secondary Efficacy Analyses .....................................................................................23 
8.3. 
Exploratory Efficacy Analyses ...................................................................................24 
8.4. 
Other Analyses ............................................................................................................24 


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9. 
SAFETY EVALUATION ..........................................................................................25 
9.1. 
Demographic and Other Baseline Characteristics ......................................................25 
9.1.1. 
Prior and Concurrent Medical Conditions ..................................................................25 
9.1.2. 
Prior and Concomitant Medications ...........................................................................25 
9.1.3. 
Gynecologic and Sexual History ................................................................................25 
9.2. 
Measurements of Treatment Compliance ...................................................................25 
9.3. 
Adverse Events ...........................................................................................................25 
9.4. 
Deaths, Serious Adverse Events and other Significant Adverse Events ....................26 
9.5. 
Pregnancies .................................................................................................................26 
9.6. 
Vital Signs and Physical Evaluations .........................................................................27 
9.7. 
Concomitant Medications ...........................................................................................27 
9.8. 
Pelvic Examination Measures.....................................................................................27 
9.9. 
Other Laboratory Measures ........................................................................................27 
10. 
PHARMACOKINETICS ...........................................................................................28 
11. 
IMMUNOGENICITY ................................................................................................29 
12. 
OTHER ANALYSES .................................................................................................30 
13. 
REPORTING CONVENTIONS ................................................................................31 
14. 
TECHNICAL DETAILS ............................................................................................32 
15. 
SUMMARY OF CHANGES IN THE CONDUCT OF THE STUDY OR 
PLANNED ANALYSES ............................................................................................33 
16. 
REFERENCES ...........................................................................................................34 
17. 
LISTING OF TABLES, FIGURES, AND LISTINGS ..............................................35 
APPENDICES ...............................................................................................................................36 
APPENDIX 1. TABLE MOCK-UPS..........................................................................................37 
APPENDIX 2. FIGURE MOCK-UPS ........................................................................................84 
APPENDIX 3. LISTINGS MOCK-UPS .....................................................................................90 
 


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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 
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 Harmonization 
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 


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MedDRAÒ 
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 
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 
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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1. 
PREFACE 
The Statistical Analysis Plan (SAP) for “A Randomized, Double-Blind, Placebo-Controlled Trial of TOL-463 
Insert for Suppression of Bacterial Vaginosis (BV)” (DMID Protocol 18-0017) describes and expands upon 
the statistical information presented in the protocol. 
This document describes all planned analyses and provides reasons and justifications for these analyses. It 
also includes sample Tables, Figures and Listings (TFL) planned for the final analyses. Regarding the final 
analyses and Clinical Study Report (CSR), this SAP follows the International Conference on Harmonization 
of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) Guidelines, as indicated 
in Topic E3 (Structure and Content of Clinical Study Reports), and more generally is consistent with Topic E8 
(General Considerations for Clinical Trials) and Topic E9 (Statistical Principles for Clinical Trials). The 
structure and content of the SAP provides sufficient detail to meet the requirements identified by the FDA and 
ICH, while all work planned and reported for this SAP will follow internationally accepted guidelines 
published by the American Statistical Association and the Royal Statistical Society for statistical practice.  
This document contains a review of the study design, general statistical considerations, comprehensive 
statistical analysis methods for efficacy and safety outcomes, and a list of proposed tables and figures. Any 
deviation from this SAP will be described and justified in protocol amendments and/or in the CSR, as 
appropriate. The reader of this SAP is encouraged to also review the study protocol for details on conduct of 
the study and the operational aspects of clinical assessments. 


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2. 
INTRODUCTION 
2.1. 
Study Background 
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, 
recurrence probability within 6 months 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] 
2.2. 
Purpose of the Analyses 
These analyses will assess the efficacy and safety of TOL-463 Insert as compared to placebo insert self-
administered vaginally twice-weekly for 12 weeks in suppressing BV following successful induction with oral 
metronidazole or another CDC-recommended BV treatment, and will be included in the clinical study report. 


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3. 
STUDY OBJECTIVES AND ENDPOINTS 
3.1. 
Study Objectives 
3.1.1. 
Primary Objective 
To 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. 
3.1.2. 
Secondary Objectives 
1. To evaluate the time to BV recurrence as defined by clinical criteria. 
2. To evaluate the incidence of vaginal symptoms over study participation. 
3. To evaluate acceptability of a twice-weekly application of TOL-463 vaginal insert in suppression of 
BV. 
4. To evaluate the safety of TOL-463 vaginal insert compared to placebo, including the incidence of 
secondary VVC. 
3.1.3. 
Exploratory Objective 
To evaluate the performance of the BD Max Vaginal Panel in characterizing clinical and microbiologic 
outcomes of the intervention. 
3.2. 
Endpoints 
3.2.1. 
Primary Endpoint 
Among participants with a history of BV and negative (<=2 Amsel criteria and asymptomatic) at enrollment, 
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 
3.2.2. 
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. 


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5. The occurrence of culture confirmed secondary VVC following initiation of study treatment and 
through the final study visit. 
3.2.3. 
Exploratory Endpoint 
To evaluate the performance of the BD Max Vaginal Panel in characterizing clinical and microbiologic 
outcomes of the intervention. 
3.3. 
Study Definitions and Derived Variables  
Clinical Diagnosis of BV: 
The clinical diagnosis of BV will be based on the presence of  following 4 Amsel criteria by pelvic 
examination, where >2 is BV recurrence; and <= 2 is BV suppression: 
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. 
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): 
1. Lactobacillus: Large Gram-negative rods 
2. Gardnerella/Bacteroides spp: thin, curved, Gram-variable rods 
3. 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. 
Clinical Diagnosis of VVC: 
A clinical diagnosis of VVC at V1-V4 will be based on a clinician’s review of 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.  
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. Candida culture in the setting of incomplete criteria for 
the clinical diagnosis may be obtained at the discretion of the study clinician.   
Study Completion and Early Termination  
Completion, i.e., completed follow‐up includes participants who remained BV suppressed and were followed‐
up through Visit 4 as well as participant whose participation ended prior to Visit 4 due to a clinical BV 


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diagnosis. Terminated Early includes participants who terminated from the study prior to Visit 4 for reasons 
other than a clinical BV diagnosis or for diagnosis with recurrent BV off study. 
BD Max Vaginal Panel Performance Evaluation 
Sensitivity = TP/(TP + FN) = (Number of true positives)/(Number of sick individuals in the population)  
Specificity = TN/(TN + FP) = (Number of true negatives)/(Number of all well individuals in the population) 
PPV=TP/(TP+FP) = (Number of true positives)/(Number of positive calls) 
NPV=TN/(TN+FN) = (Number of true negatives)/(Number of negative calls) 
 


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4. 
INVESTIGATIONAL PLAN 
4.1. 
Overall Study Design and Plan 
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 in total (125 per arm) 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 self-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,  recurrence of BV 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 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 eighteen 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. 
Figure 1 below presents the schematic of the study design and Table 1 presents the schedule of events. 


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Figure 1: 
 Schematic of Study Design 
 


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4.2. 
Discussion of Study Design, Including the Choice of Control Groups 
It is hypothesized that a twice-weekly application of TOL-463 vaginal insert will be clinically effective in 
suppressing BV in women with a history of RBV following successful induction with oral metronidazole or 
other CDC-recommended BV treatment. A placebo-blinded, randomized controlled trial is necessary to 
definitively evaluate the clinical efficacy of TOL-463 Insert. This trial aims to meet this need. 
4.3. 
Selection of Study Population 
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.  
4.3.1. 
Participant Inclusion Criteria 
Women must meet all of the following inclusion criteria to be eligible for inclusion in the study. 
4.3.1.1. 
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; 


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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. 
4.3.1.2. 
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. 


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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.  
4.3.2. 
Participant Exclusion Criteria 
Women who meet any of the following exclusion criteria will be excluded from the study. 
4.3.2.1. 
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. 


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4.3.2.2. 
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;  
5. Use of any investigational drug within 30 days prior to V1 or planned/anticipated use during study 
participation. 
4.4. 
Treatments 
4.4.1. 
Treatments Administered  
Participants will be randomized to one of two arms, as follows: 
• TOL-463 Vaginal Insert: Self-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:  Self-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. 
4.4.2. 
Identity of Investigational Product(s) 
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. 
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.  
Placebo Vaginal Inserts are manufactured and provided by Toltec Pharmaceuticals.  
4.4.3. 
 Method of Assigning Subjects to Treatment Groups (Randomization) 
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 study drug kits pre-labeled with treatment numbers, each 


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containing sufficient doses to treat a 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 block 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. 
4.4.4. 
Selection of Doses in the Study 
Participants will be randomized to one of two arms, 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. 
4.4.5. 
Selection and Timing of Dose for Each Subject 
All subjects will receive TOL-463 Vaginal Insert or 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.  
4.4.6. 
Blinding 
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.  
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. 
4.4.7. 
Prior and Concomitant Therapy  
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 


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be excluded from per-protocol analyses 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.   
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.  
4.4.8. 
Treatment Compliance 
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.   
The protocol defines that 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).  
A blinded case review committee will review subjects’ data to determine if they were compliant with the 
study treatment throughout the study, for cases that could not be determined programmatically. Subjects will 
be further excluded from per-protocol population analyses if they were not compliant with the study treatment 
throughout the study, see section 6.3 . 
4.5. 
Efficacy (Immunogenicity) and Safety Variables 
Multiple observations within specific visit period are acceptable. In the case of multiple observations within a 
specific window, the assessment value that is closest to the scheduled visit window will be used in the 
analyses for the post-baseline records. Whether to use and how to use the observations from early termination 
at an unscheduled visit along with the observations obtained at the corresponding scheduled visit will be 
specified in the applicable tables. For screening and baseline visits, the last assessment value will be used. All 
the recorded data will be listed. If observations have the same distance to the scheduled assessment, the latest 
one will be used. 
4.5.1. 
Efficacy variables 
The primary efficacy analysis estimates the clinical efficacy rate of TOL-463. At each follow-up visit, the 
Amsel criteria will be assessed, see definition in section 3.3 . 
For the primary analysis, a participant is deemed to experience a recurrence of BV at a follow-up visit if >2 of 
the Amsel criteria are met or diagnosed of BV recurrence off site. A participant has clinical suppression of 
BV if she meets ≤ 2 of the criteria at each observed follow-up visit through V4. See below and section 6.5 for 
handling missing BV status by TOC (visit 4). 


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The proportion of participants with recurrence of BV (treatment failure) 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.  
For the mITT analysis population, the BV status of subjects whose status cannot be determined by the TOC 
visit for any reason or those who withdrew or those who dropped out early will be considered ‘treatment 
failure’ for primary recurrence endpoint. For the PP analysis population, subjects whose BV status cannot be 
determined by the TOC visit for any reason will be excluded from the analysis. For secondary endpoints, 
missing values will be further excluded from the mITT and PP populations. 
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. We will use a 
person-time approach as discussed in section 8.1.   
Secondary efficacy analyses will be performed in the mITT and PP analysis populations.  
For the analysis of Secondary Objective 1, the time to BV recurrence will be estimated by treatment group 
using Kaplan-Meier estimates. For participants who experience clinically diagnosed BV recurrence in study 
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. Subjects with BV recurrence diagnosed 
off study will be treated as missing time to BV recurrence and excluded from the analyses for secondary 
endpoints, as defined above and in Section 6.5. 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 BV symptoms 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.  
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 Section 8.4. 
4.5.2. 
Safety variables 
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. 
4.5.2.1. 
 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 


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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. 
4.5.2.2. 
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, (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 protocol 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. 
4.5.2.3. 
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.   


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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. 
4.5.2.4. 
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. 


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5. 
SAMPLE SIZE CONSIDERATIONS 
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 a total of 250 participants to achieve 200 
evaluable participants. 
The study was closed early due to the uncertain future of the study product’s manufacture and availability. It 
was unrelated to the safety and efficacy of the study product. The power of the actual sample size will be 
provided in the CSR.  


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6. 
GENERAL STATISTICAL CONSIDERATIONS 
6.1. 
General Principles 
Tabulations will be used extensively to summarize the data. All continuous variables will be summarized 
using the following descriptive statistics: n (sample size), mean, standard deviation, median, maximum and 
minimum. The frequency and percentages (based on the sample size) of observed levels will be reported for 
all categorical measures. Missing data will be denoted by n and %. Wilson confidence intervals for binomial 
proportions and difference in binomial proportions will be computed for efficacy variables. 
All summary tables will be structured with a column/sub-table for each treatment group (TOL-463 Vaginal 
Insert, Placebo) and overall (All Subjects), or each site and overall. The total population size relevant to that 
table/column if applicable, including any missing observations will be displayed in the tables. 
Participants will be excluded from Safety Population if it is unknown whether they received at least one dose, 
so if they had adverse events, those events would not be included in the safety summary tables, but they will 
be included in the AE listings. Repeat participants are counted once in all TFLs except for the safety analyses, 
when a participant met safety population criteria in both enrollments, the participant will be counted twice, 
i.e., each enrollment will be treated distinctly in the safety summary tables. 
Data listings will be provided for all data. Note that in the data listings, Subject ID is the unique subject 
identifier, not the Study ID used on study and dates will not be included, only Study Day.   
6.2. 
Timing of Analyses 
The final analysis will be performed after database lock when all subjects have been followed through Visit 4, 
the final study visit, at Day 85-91. 
6.3. 
Analysis Populations 
Safety Population: This analysis population includes all randomized participants who received at least one 
dose of study treatment. Participants with any evidence of dosing according to the memory aid or study IP 
packaging return will be included in the Safety population. 
Modified Intent-to-Treat (mITT) Population: This analysis population includes all randomized participants 
who are evaluable (see below). If a participant was enrolled more than once, (participants are allowed to be 
re-enrolled under PI’s discretion for scenarios such as, the first enrollment terminated due to the COVID-19 
shelter in place order or became ineligible after enrollment.) only the set of data from the most recent 
enrollment will be included in the mITT population. 
The mITT population will be used as the primary efficacy analysis population. 
Per-Protocol (PP) Population: This analysis population includes all randomized participants who are 
evaluable, complied with the assigned IP (see section 4.4.8 ), 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. Participants who violated any inclusion/exclusion criterion at any point during the study or 
engaged in receptive oral, anal, or vaginal sexual intercourse within 24 hours prior to a study visit will be 
excluded from the PP population. If a participant was enrolled more than once, (participants are allowed to be 
re-enrolled under PI’s discretion for scenarios such as, the first enrollment terminated due to the COVID-19 


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shelter in place order or became ineligible after enrollment.) only the set of data from the most recent 
enrollment will be included in the PP population. 
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. 
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 
6.4. 
Covariates and Subgroups 
The protocol does not define any formal subgroup analyses, and the study is not adequately powered to 
perform subgroup analyses.  
6.5. 
Missing Data 
For primary BV recurrence endpoint: 
For the mITT analysis population, the BV status of subjects whose status cannot be determined by the TOC 
visit (visit 4) for any reason will be considered ‘treatment failure’, including subjects who discontinued early 
from the study and lack of treatment effect.  
For the PP analysis population, subjects whose BV status cannot be determined by the TOC visit for any 
reason will be excluded from the analysis.  
For secondary endpoints, missing values will be further excluded from the mITT and PP populations. 
6.6. 
Interim Analyses and Data Monitoring 
The study will be monitored to determine if any of the safety halting rules described in section 8.6 in the 
protocol 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 in the protocol and the 
DSMB Charter.  
There are no planned interim efficacy analyses for this study. 
Further enrollment will be halted for DSMB review/recommendation if any of the following are reported.  
1. If one or more participants experience an SAE judged by an investigator to be related to study IP  
2. If two or more participants experience an AE that is judged to be Grade 3 and related to study IP 
3. 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. A summary of halting rules 
is provided in Table 39. 
DMID retains the authority to suspend additional enrollment and administration of study product during the 
entire study, as applicable. 
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. 
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. 
6.7. 
Multicenter Studies 
Safety and efficacy data will be pooled across all clinical sites. Center effects are not anticipated because 
treatment is self-administered, the sites are using standardized procedures for assessment of unsolicited 
adverse events, and the study relies on a central laboratory for Gram stain Nugent scoring and BD Max. 
However, as an exploratory analysis, the primary efficacy outcome measure will be tabulated by clinical site 
(Table 13).  
6.8. 
Multiple Comparisons/Multiplicity 
There is only one primary endpoint. No adjustments for multiple testing are planned. 


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7. 
STUDY SUBJECTS 
7.1. 
Disposition of Subjects 
Table 2 will present the number of subjects who failed screening and number of subjects that failed to meet 
each eligibility criterion. Table 3 will present the disposition of subjects overall and by randomized treatment 
group. Table 4 summarizes the Safety, mITT and PP analysis population eligibilities by treatment group, and 
reasons excluded. Subjects will be included in the count for a particular reason for exclusion if they met that 
criterion. As subjects may meet more than one criterion for exclusion, the “Any Reason” counts may be less 
than the sum of the individual reason counts. Listing 1 provides the subjects excluded from each of the 
analysis populations and the reasons for exclusion. A listing of subjects who terminated early from the study 
or discontinued treatment and the reason for early termination or treatment discontinuation will be included in 
Listing 2 . A listing of subjects who terminated early from the study due to study disruptions from the 
COVID-19 pandemic will be included in Listing 3.  
Figure 2 is a flowchart showing the disposition of study subjects in the safety and efficacy analyses, adapted 
from the CONSORT statement [7]. It shows the number of subjects eligible, enrolled and randomized, and 
analyzed for the safety and efficacy analyses, overall and by treatment group. 
7.2. 
Protocol Deviations 
Table 5 summarizes subject-specific protocol deviations by deviation category, deviation type, and treatment 
group for all subjects. All subject-specific protocol deviations and non-subject specific protocol deviations 
will be included in Listing 4 and Listing 5, respectively. 


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8. 
EFFICACY EVALUATION 
8.1. 
Primary Efficacy Analysis 
The primary efficacy endpoint for the final analysis is the proportion of subjects with recurrent BV by Test of 
Cure (TOC, Visit 4 window: Day 85-91) as defined in section 3.3, and in section 6.5 for missing BV status by 
TOC. 
The number of subjects, the proportion of subjects with RBV up to and including V4 will be presented overall 
and by treatment group with two-sided 95% Wilson confidence interval (no continuity correction). In 
addition, the difference in proportions between the TOL-463 Vaginal Insert arm and the Placebo group and 
95% Newcombe confidence intervals (based on the Wilson CI for the individual proportions) will be 
presented. See Table 6.  
The pseudocode to fit the above analyses is below: 
proc freq data=dataset; 
Table treatment*cure /chisq riskdiff(Newcombe) binomial(wilson) out=output  
alpha=.05; 
run; 
The primary efficacy analysis will be performed in the mITT population (Table 6). As a sensitivity analysis, 
the primary endpoint will additionally be assessed among all subjects in the mITT population except those 
terminated early due to study disruptions from the COVID-19 pandemic (Table 7). Analysis of the primary 
outcome measure will be repeated in the PP analysis population (secondary analysis of primary outcome). See 
Table 8. 
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 Exact Poisson 95% confidence intervals 
[8]. We will use a person-time approach as follows. For participants who experience BV recurrence by any 
visit, the time (in days) 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 with BV 
recurrence diagnosed off study, the time (in days) of BV recurrence will be defined as the midpoint between 
the early termination time point of a positive BV diagnosis off study (post-baseline) and the previous 
observed time-point. For the participants who did not experience BV recurrence by V4 will contribute the 
total duration they participated in the study (in days). The participants who withdrew or dropped out early will 
contribute the number of days they participated in the study. The rate of recurrence = number of recurrence / 
time each person was observed, totaled for all persons. We will present the estimated recurrence rate in each 
group and overall, in the mITT population, then repeated in the PP population. See Table 9 and Table 10. The 
individual time to BV recurrence defined for rate of recurrence is provided in Listing 7. 
For efficacy response data, a subject listing of individual Amsel criteria will be provided in Listing 6 for all 
enrolled subjects, where individual Nugent score will also be included. A summary of Amsel criteria is 
provided for subjects by visit and treatment group for mITT analysis population in Table 11 and will be 
repeated in the PP analysis population as a corroborative analysis (Table 12). 
As an exploratory analysis, the primary efficacy outcome measure summaries in the mITT population will be 
tabulated by clinical site (Table 13). 


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As an ancillary analysis, a summary of Nugent score by visit, category (0-3 normal; 4-6 intermediate; and 7-
10 BV) and treatment group for subjects in the mITT population will be presented (Table 14).  
8.2. 
Secondary Efficacy Analyses 
Secondary efficacy analyses will be performed in the mITT as the primary population. All the analyses will be 
repeated in the PP analysis populations as corroborative and sensitivity analyses. 
The analysis of Secondary Objective 1, time to BV recurrence will take into account the observed follow-up 
time for each participant (time-to-event analysis). For this analysis, the outcome will be the time to RBV 
diagnosis in days from the enrollment visit (day 1). For the participants whose RBV was diagnosed at a 
scheduled or unscheduled visit, their 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. Participants with missing time to BV recurrence will be 
further excluded from analyses in mITT and PP populations, including subjects who had BV recurrence 
diagnosed off study or subjects who were unknown whether they used any study products. The individual 
time to BV recurrence defined for secondary objective 1 for mITT and PP populations are also provided in 
Listing 7. 
The null hypothesis for the comparison is that there is no difference in the time to BV recurrence throughout 
the study between treatment arms, with a two-sided alternative that considers the possibility of a difference in 
either direction. Kaplan-Meier (KM) curves and associated 95% confidence bands (by treatment groups) will 
be presented to visually assess the treatment group-specific time-to-recurrence pattern over time. The median 
time to BV recurrence cannot be calculated because the assumed BV recurrence in the two treatment groups 
are 20% and 40%. Appropriate quartiles of the time to recurrence will be presented by each treatment group 
and overall. The KM curves will be presented in Figure 3 for mITT population and in Figure 4 for PP 
population. The estimate of survival time at which 25% of the subjects have recurrent BV, i.e., 25th percentile 
of the time to recurrence, by each treatment group and overall will be described in the footnote of the figures. 
The pseudocode to fit the above analyses is below: 
proc lifetest method=KM plots=survival(cb=hw test atrisk) data=dataset outs=surv;  
 
strata treatment / test=logrank; 
Time time*censor(censored_value);  
run;  
For the Secondary Objective 2, the proportion of participants experiencing vaginal symptoms will be 
estimated overall, by symptom category, and by treatment group at each visit. See Table 15 for mITT 
population and Table 16 for PP population. A subject listing of BV symptoms will be presented (Listing 8) 


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For the Secondary Objective 3, responses to the satisfaction questionnaire will be summarized overall and by 
treatment group. See Table 17 for mITT population and Table 18 for PP population. Individual subject listings 
will be presented for all responses to satisfaction questionnaire (Listing 9). 
8.3. 
Exploratory Efficacy Analyses 
The exploratory endpoint is to evaluate the performance of the BD Max Vaginal Panel in characterizing 
clinical and microbiologic outcomes of the intervention. Amsel criteria of 3 or more will be considered as the 
gold standard for the RBV clinical outcome. Nugent score of ≥7 will be considered as the gold standard for 
the microbiologic BV outcome. For BD Max Vaginal Panel testing result of BV compared to clinical and 
microbiologic outcomes, we will present sensitivity, specificity, positive predictive value (PPV), and negative 
predictive value (NPV) and corresponding 95% Wilson CI by study visit (Table 19). The individual BD Max 
BV result will also be listed in Listing 6.  
8.4. 
Other Analyses 
For all enrolled subjects at the screening visit, the original clinical BV diagnosis using Amsel criteria will be 
compared to the Nugent score assessment in Table 20. Listing 6 will include the individual Amsel criteria 
assessments and Nugent score at the screening visit. 


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9. 
SAFETY EVALUATION 
9.1. 
Demographic and Other Baseline Characteristics 
Demographics and baseline characteristic of the participants will be summarized by clinical sites (Table 21 
and Table 23) and treatment groups (Table 22 and Table 24) for all enrolled subjects. Summaries of age, 
ethnicity, race, and concurrent VVC status at baseline that can be treated by Fluconazole will be presented. 
Ethnicity is categorized as Hispanic or Latino, or not Hispanic and not Latino. In accordance with NIH 
reporting policy, subjects may self-designate as belonging to more than one race (Multi-Racial) or may refuse 
to identify a race (Unknown), the latter reflected in the Case Report Form (CRF) as “No” to each racial 
option. Individual subject listings will be presented for all demographics (Listing 10).  
9.1.1. 
Prior and Concurrent Medical Conditions 
All current illnesses and past pre-existing medical conditions will be MedDRA® coded using MedDRA 
dictionary version 22.1 or higher. Summaries of subjects’ pre-existing medical conditions will be presented by 
randomized treatment group for all enrolled subjects (Table 25). 
An individual subject listing for all enrolled subjects will be presented for all medical conditions (Listing 11). 
9.1.2. 
 Prior and Concomitant Medications  
Concomitant medications will be coded to the Anatomical Therapeutic Classification using the WHO Drug 
Dictionary. The use of prior and concomitant medications taken during the study will be recorded on the 
CRFs. Summaries of medications that were started prior to dosing and during follow-up will be presented by 
WHO Drug Terms 2 and 3 and treatment group (Table 26). 
An individual subject listing will be presented for all concomitant medications (Listing 12). 
9.1.3. 
Gynecologic and Sexual History  
The number of times the subject had BV in the past 12 months obtained at screening visit will be presented by 
treatment group and clinical site in the demographics tables (Table 23 and Table 24). Individual subject 
listings of screening and baseline (Listing 13) and follow-up (Listing 14) sexual history for all enrolled 
subjects will be presented. 
9.2. 
Measurements of Treatment Compliance 
See section 4.4.8. for the definition of treatment compliance that will be used for efficacy analyses. The 
subject disposition table (Table 3) will present the number and percentage of subject complied with the study 
treatment by treatment group. Compliance listing will be provided (Listing 15). 
9.3. 
Adverse Events 
Safety evaluations will be based on the incidence, severity, and type of AEs, SAEs, clinically significant 
physical and pelvic examination findings. 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 number of SAEs 
is likely to be small in this study and will be reported by a detailed listing showing the type, MedDRA® 


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coding, relevant dates (IP administration dates and AE onset and resolution dates), severity, relatedness, and 
outcome for each event. 
Participants will be excluded from Safety Population if it is unknown whether they received at least one dose, 
so if they had adverse events, those events would not be included in the safety summary tables or figures, but 
they will be included in the AE listings. A repeat subject will be re-enrolled under a unique Subject ID and be 
treated as a distinct subject. If a repeat participant met safety population criteria in both enrollments, the 
participant will be counted twice, i.e., each enrollment will be treated distinctly in the safety summary tables. 
All adverse events reported will be documented as unsolicited AEs for this study.  
The analyses of Secondary Objective 4 will be conducted in the Safety Population.  
When calculating the incidence of adverse events (i.e., on a per subject basis), each subject will only be 
counted once and any repetitions of adverse events within a subject will be ignored; the denominator will be 
the total safety population size and population within the actual treatment group.  
The number of subjects, the proportion of subjects with related AE/SAE, and the 95% Wilson confidence 
interval for the proportion of subjects who experienced unsolicited AEs/ SAEs related to study product will be 
presented overall and by treatment group. In addition, the difference in proportions between the TOL-463 
Vaginal Insert arm and the Placebo group and 95% Newcomb confidence intervals (based on the Wilson CI 
for the individual proportions) will be presented. The occurrence of AEs considered product-related following 
initiation of study treatment and through the final study visit will be presented in Table 27.  
Table 28 provides an overall summary of AEs and SAEs. Table 29 summarizes all AEs in terms of 
MedDRA System Organ Class (SOC), severity, and relationship to study treatment. Table 30 and Table 31 
summarizes AEs on the subject level, where a subject is counted once per Preferred Term and is summarized 
according to their highest severity and closest relationship for the treatment arm and placebo arm respectively. 
The number and percentage of subjects experiencing unsolicited adverse events with 95% Wilson Confidence 
Intervals by MedDRA® System Organ Class, and Preferred Term, and Treatment Group will be presented in 
Table 32. The number of adverse events occurring in 5% of subjects in any treatment group will be presented 
in Table 33. Figure 5 provides a bar chart of total frequency of adverse events by severity and MedDRA® 
system organ class. Figure 6 provides a bar chart of total frequency of adverse events by relationship and 
MedDRA® system organ class. Details of reported AEs are included in Table 34. 
9.4. 
Deaths, Serious Adverse Events and other Significant Adverse Events 
A listing of deaths and serious adverse events will be presented including Subject ID, infection type, treatment 
group, Adverse Event Description, SAE Onset Date, Reason Reported as an SAE, Relationship to Treatment, 
Alternate Etiology if not Related, Outcome, and Duration of Event in days (Table 35). 
9.5. 
Pregnancies 
For any subjects in the Safety population who became pregnant during the study, every attempt will be made 
to follow these subjects to completion of pregnancy to document the outcome, including information 
regarding any complications with pregnancy and/or delivery. A listing of the total pregnancies, number of live 
births, and number of spontaneous abortions, elective abortions or still births will be presented (Listing 16).  


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9.6. 
Vital Signs and Physical Evaluations 
Vital sign measurements include systolic blood pressure, diastolic blood pressure, and oral temperature, which 
were no longer collected at any study visits beginning with protocol version 2. Weight and Height were 
collected at Visit 0/Screening under protocol version 1 or Visit 1/Enrollment beginning with protocol version 
2. See Listing 17.  
The targeted physical examination data will be summarized by study day, infection type and treatment group 
for subjects in the Safety population. The following body systems will be assessed: Abdomen; 
Cardiovascular/heart; Extremities; General Appearance; Head, ears, eyes, nose, and throat; Lymph nodes; 
Musculoskeletal; Neck; Neurological; Pulmonary/Chest; and Skin (Listing 18).  
9.7. 
Concomitant Medications 
Refer to section 9.1.2. 
9.8. 
Pelvic Examination Measures 
The analyses of Secondary Objective 5 will be conducted in the Safety Population.  
The number of subjects, the proportion of subjects with culture confirmed secondary VVC, and the 95% 
Wilson confidence interval for the proportion of subjects with culture confirmed secondary VVC following 
the initiation of the study treatment through the follow-up period will be presented overall and by treatment 
group. In addition, the difference in proportions between the TOL-463 Vaginal Insert arm and the Placebo 
group and 95% Newcomb confidence intervals (based on the Wilson CI for the individual proportions) will be 
presented.  
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 will be presented in Table 36 . Table 
37 will present the 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, which clinician’s review of clinical diagnosis of VVC will be based on, as well as the culture 
confirmed VVC. Listing 19 will present the individual culture confirmed VVC and clinically diagnosed VVC 
data, including data summarized in Table 37 and the yeast forms identified from the yeast culture. 
Additional measurements from the pelvic examinations will be summarized and listed. Table 38 presents 
genital lesion consistent with active HSV or HPV, Motile Trichomonads present on normal saline wet mount 
microscopy that indicates Trichomonas vaginalis by treatment group and visit. Individual listing of genital 
lesion consistent with active HSV or HPV, motile trichomonads and additional abnormal pelvic exam 
findings will be listed in Listing 20.  
9.9. 
Other Laboratory Measures 
Listing 21 will present the results of NAAT STI tests (C. trachomatis, N. gonorrhoeae, or T. vaginalis) Pap 
smear records and test and screening/enrollment for evaluable definition (see section 6.3).  


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10. 
PHARMACOKINETICS 
Not applicable for this study. 


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11. 
IMMUNOGENICITY 
Not applicable for this study. 


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12. 
OTHER ANALYSES 
There are no additional analyses planned for this study. 


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13. 
REPORTING CONVENTIONS 
P-values ≥0.001 and ≤0.999 will be reported to 3 decimal places; p-values less than 0.001 will be reported as 
“<0.001”; p-values greater than 0.999 will be reported as “>0.999”.  The mean, standard deviation, and other 
statistics will be reported to 1 decimal place greater than the original data. The minimum and maximum will 
use the same number of decimal places as the original data. If there are an even number of observations, the 
median will be reported to one decimal place greater than the original data. If there are an odd number of 
observations, the median will use the same number of decimal places as the original data. Quantiles other than 
the median will use the same number of decimal places as the original data. Proportions will be presented as 2 
decimal places; values greater than zero but <0.01 will be presented as “<0.01”. Percentages will be reported 
to the nearest whole number; values greater than zero but < 1% will be presented as “<1”; values greater than 
99% but less than 100% will be reported as >99%. Estimated parameters, not on the same scale as raw 
observations (e.g. regression coefficients) will be reported to 3 significant figures. 


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14. 
TECHNICAL DETAILS 
SAS version 9.4 or above will be used to generate all TFL. 


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15. 
SUMMARY OF CHANGES IN THE CONDUCT OF THE STUDY OR 
PLANNED ANALYSES 
The analyses described in this SAP coincide with the analysis descriptions provided in the study protocol.  


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16. 
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 aWorkshop 
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. Drummond R. CONSORT Revised: Improving the Reporting of Randomized Clinical Trials. JAMA. 
2001; 285(15):2006-2007. 
8. Xinxin G. and Zhaohui S, Confidence Intervals Are a Programmer’s Friend. PharmaSUG, 
2015. Retrieved from https://www.pharmasug.org/proceedings/2015/SP/PharmaSUG-2015-SP06.pdf  
 


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17. 
LISTING OF TABLES, FIGURES, AND LISTINGS  
Table, figure, and listing shells are presented in Appendices 1, 2, and 3. 
 


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APPENDICES 


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APPENDIX 1. TABLE MOCK-UPS 
 


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LIST OF TABLES 
Table 1: 
Schedule of Events .....................................................................................................40 
Table 2: 
Ineligibility Summary of Screen Failures ...................................................................42 
Table 3: 
Subject Disposition by Treatment Group – All Enrolled Subjects .............................43 
Table 4: 
Analysis Populations by Treatment Group .................................................................44 
Table 5: 
Distribution of Protocol Deviations by Category, Type, and Treatment 
Group – All Enrolled Subjects ....................................................................................45 
Table 6: 
Proportion of Subjects with Recurrent Bacterial Vaginosis by the Test of 
Cure Visit by Treatment Group – mITT Population ..................................................46 
Table 7: 
Proportion of Subjects with Recurrent Bacterial Vaginosis by the Test of 
Cure Visit by Treatment Group – mITT Population, Excluding Subjects 
Terminated Early due to COVID-19 ..........................................................................47 
Table 8: 
Proportion of Subjects with Recurrent Bacterial Vaginosis by the Test of 
Cure Visit by Treatment Group – PP Population .......................................................48 
Table 9: 
Rate of Recurrent Bacterial Vaginosis by the Test of Cure Visit by 
Treatment Group – mITT Population .........................................................................49 
Table 10: Rate of Recurrent Bacterial Vaginosis by the Test of Cure Visit by 
Treatment Group – PP Population ..............................................................................50 
Table 11: Summary of Amsel Criteria by Study Visit and Treatment group – mITT 
Population ...................................................................................................................51 
Table 12: Summary of Amsel Criteria by Study Visit and Treatment group – PP 
Population ...................................................................................................................52 
Table 13: Proportion of Subjects with Recurrent Bacterial Vaginosis by the Test of 
Cure Visit by Treatment Group and by Site – mITT Population ...............................53 
Table 14: Nugent Scores by Category, Study Visit, and Treatment Group - mITT 
Population ...................................................................................................................54 
Table 15: Summary of Proportion of Participants Reporting BV Symptoms – mITT 
Population ...................................................................................................................55 
Table 16: Summary of Proportion of Participants Reporting BV Symptoms – PP 
Population ...................................................................................................................56 
Table 17: Summary of Responses to the Satisfaction Questionnaire – mITT Population ..........57 
Table 18: Summary of Responses to the Satisfaction Questionnaire – PP Population ..............59 
Table 19: Performance of BD Max Vaginal Panel .....................................................................61 
Table 20: Original Clinical BV Diagnosis and the Nugent Score Assessment at the 
Screening Visit - All Enrolled Subjects ......................................................................62 
Table 21: Summary of Categorical Demographic and Baseline Characteristics by Site - 
All Enrolled Subjects ..................................................................................................63 


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Table 22: Summary of Categorical Demographic and Baseline Characteristics by 
Treatment Group - All Enrolled Subjects ...................................................................64 
Table 23: Summary of Continuous Demographic and Baseline Characteristics by Site - 
All Enrolled Subjects ..................................................................................................65 
Table 24: Summary of Continuous Demographic and Baseline Characteristics by 
Treatment Group - All Enrolled Subjects ...................................................................66 
Table 25: Summary of Subjects with Pre-Existing Medical Conditions by MedDRA 
System Organ Class and Treatment Group – All Enrolled Subjects ..........................67 
Table 26: Number and Percentage of Subjects with Prior and Concomitant 
Medications by WHO Drug Classification and Treatment Group – Safety 
Population ...................................................................................................................68 
Table 27: Occurrence of Related Adverse Events (AE) Overall and by Treatment 
Groups – Safety Population ........................................................................................69 
Table 28: Overall Summary of Adverse Events – Safety Population .........................................70 
Table 29: Unsolicited Adverse Events Cross-Classified by MedDRA System Organ 
Class and Preferred Term, Severity, and Relationship to Study Treatment - 
Safety Population ........................................................................................................71 
Table 30: Number and Percentage of Subjects Experiencing Unsolicited Adverse 
Events by MedDRA System Organ Class and Preferred Term, Severity, and 
Relationship – TOL-463 Vaginal Insert Group - Safety Population ..........................72 
Table 31: Number and Percentage of Subjects Experiencing Unsolicited Adverse 
Events by MedDRA System Organ Class and Preferred Term, Severity, and 
Relationship – Placebo Group - Safety Population ....................................................73 
Table 32: Number and Percentage of Subjects Experiencing Unsolicited Adverse 
Events with 95% Confidence Intervals by MedDRA® System Organ Class, 
and Preferred Term, and Treatment Group .................................................................74 
Table 33: Unsolicited Adverse Events Occurring in 5% of Subjects in Any Treatment 
Group by MedDRA System Organ Class and Preferred Term, and Treatment 
Group - Safety Population ..........................................................................................75 
Table 34: Listing of Non-Serious, Unsolicited Adverse Events – All Enrolled Subjects ..........76 
Table 35: Listing of Serious Adverse Events – All Enrolled Subjects .......................................77 
Table 36: Occurrence of Culture Confirmed Secondary Vulvovaginal Candidiasis 
(VVC) Overall and by Treatment Groups – Safety Population ..................................78 
Table 37: Summary of Proportion of Participants Reporting Vulvovaginal Symptoms 
and Signs, Yeast Form, and Clinical Diagnosed and Culture Confirmed 
Vulvovaginal Candidiasis – Safety Population ..........................................................79 
Table 38: Additional Pelvic Examination Measures ..................................................................82 
Table 39: Summary of Halting Rules – Safety Population .........................................................83 
 


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Table 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 
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 
 
 
 


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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 
Assessment of IP compliance  
(via review of Memory Aid and IP return) 
 
 
X 
X 
X 
(X) 
X 
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. 
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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Table 2: 
Ineligibility Summary of Screen Failures 
Inclusion/Exclusion Category 
Inclusion/Exclusion Criterion 
na 
%b 
Inclusion and Exclusion 
Number of subjects failing any eligibility criterion 
x 
100 
Inclusion 
Any inclusion criterion 
x 
xx 
 
[inclusion criterion 1] 
x 
xx 
 
[inclusion criterion 2] 
x 
xx 
 
[inclusion criterion 3] 
x 
xx 
Exclusion 
Any exclusion criterion 
x 
xx 
 
[exclusion criterion 1] 
x 
xx 
 
[exclusion criterion 2] 
x 
xx 
 
[exclusion criterion 3] 
x 
xx 
Eligible but Not Enrolled 
Any Reason 
x 
xx 
 
Time commitment 
x 
xx 
 
Concern of risks 
x 
xx 
 
Number of procedures 
x 
xx 
 
Unable to contact subject 
x 
xx 
a More than one criterion may be marked per subject. 
b Denominator for percentages is the total number of screen failures. 
 


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Table 3: 
Subject Disposition by Treatment Group – All Enrolled Subjects 
Subject 
Disposition  
TOL-463 Vaginal Insert  
(N=X) 
Placebo 
(N=X) 
All Subjects 
(N=X) 
n 
% 
n 
% 
n 
% 
Screened 
N/A 
N/A 
N/A 
N/A 
x 
N/A 
Enrolled/Randomized 
x 
100 
x 
100 
x 
100 
Treatment Dispensed 
x 
xx 
x 
xx 
x 
xx 
Received Treatmenta 
x 
xx 
x 
xx 
x 
xx 
    Received Treatment - Unknowna 
x 
xx 
x 
xx 
x 
xx 
Completed Follow-upb 
x 
xx 
x 
xx 
x 
xx 
Complied with Study Treatment throughout 
Participationc 
x 
xx 
x 
xx 
x 
xx 
Early Discontinuation from Treatmentd 
x 
xx 
x 
xx 
x 
xx 
Early Termination from Studyb 
x 
xx 
x 
xx 
x 
xx 
a Received Treatment includes subjects who successfully received at least one dose of study treatment. It is unknown whether subjects received 
at least one dose if they were terminated early before Visit 2 and a Study Product Dispensing assessment at the early termination visit could not 
be conducted. 
b Completed Follow‐up includes subjects who remained BV suppressed and were followed‐up through Visit 4 as well as subjects whose 
participation ended prior to Visit 4 due to a clinical BV diagnosis. Terminated Early includes subjects who terminated from the study early for 
reasons other than a clinical BV diagnosis. 
c  A blinded case review committee reviewed subjects’ data to determine treatment compliance throughout the study for each 
subject. 
dSubjects who discontinued treatment due to RBV are included. 


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Table 4: 
Analysis Populations by Treatment Group 
Analysis Populations 
Reason Subjects Excluded 
TOL-463 Vaginal 
Insert 
(N=X) 
Placebo 
(N=X) 
All Subjects 
(N=X) 
n 
% 
n 
% 
% 
n 
Eligible for Safety Analysis 
Population 
N/A 
x 
xx 
x 
xx 
x 
xx 
Excluded from Safety Analysis 
Population 
Any Reason 
x 
xx 
x 
xx 
x 
xx 
 
Did not receive at least one dose of 
study product 
x 
xx 
x 
xx 
x 
xx 
Eligible for Modified Intent-to-
Treat Analysis (mITT) 
Population 
N/A 
x 
xx 
x 
xx 
x 
xx 
Excluded from for Modified 
Intent-to-Treat Analysis (mITT) 
Population 
Any Reason 
x 
xx 
x 
xx 
x 
xx 
 
Positive NAAT test results at baseline 
for C. trachomatis, N. gonorrhoeae, or 
T. vaginalis 
x 
xx 
x 
xx 
x 
xx 
 
HPV Criteriona 
x 
xx 
x 
xx 
x 
xx 
Eligible for Per-Protocol (PP) 
Analysis Population 
N/A 
x 
xx 
x 
xx 
x 
xx 
Excluded from Per-Protocol (PP) 
Analysis Population 
Any Reason 
x 
xx 
x 
xx 
x 
xx 
 
Did not meet inclusion/exclusion criteria 
x 
xx 
x 
xx 
x 
xx 
 
Positive NAAT test results at baseline 
for C. trachomatis, N. gonorrhoeae, or 
T. vaginalis 
x 
xx 
x 
xx 
x 
xx 
 
HPV Criteriona 
x 
xx 
x 
xx 
x 
xx 
 
Was not compliant with study product 
x 
xx 
x 
xx 
x 
xx 
 
Did not return to study site for the TOC 
visit within the specified window (Visit 
4, Day 85-91) 
x 
xx 
x 
xx 
x 
xx 
 
Was not followed up to the diagnosis of 
recurrent BV 
x 
xx 
x 
xx 
x 
xx 
Notes: N=Number of all enrolled subjects 
a For participants 21 years of age or older, documentation of or self-report of abnormal, or ASCUS HPV Positive Pap test prior to screening, or 
Pap smear performed at screening/enrollment with abnormal result. 


Statistical Analysis Plan - DMID Protocol: 18-0017  
Version 1.0 
07MAR2022 
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PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Table 5: 
Distribution of Protocol Deviations by Category, Type, and Treatment Group – All 
Enrolled Subjects 
Category 
Deviation Type 
TOL-463 Vaginal Insert  
(N=X) 
Placebo 
(N=X) 
All Subjects 
(N=X) 
No. of 
Subj. 
No. of 
Dev. 
No. of 
Subj. 
No. of 
Dev. 
No. of 
Subj. 
No. of 
Dev. 
Eligibility/enrollment 
Any type 
x 
x 
x 
x 
x 
x 
 
Did not meet inclusion criterion 
x 
x 
x 
x 
x 
x 
 
Met exclusion criterion 
x 
x 
x 
x 
x 
x 
 
ICF not signed prior to study procedures 
x 
x 
x 
x 
x 
x 
 
Other 
x 
x 
x 
x 
x 
x 
Treatment administration 
schedule 
Any type 
x 
x 
x 
x 
x 
x 
 
Out of window visit 
x 
x 
x 
x 
x 
x 
 
Missed visit/visit not conducted 
x 
x 
x 
x 
x 
x 
 
Missed treatment administration 
x 
x 
x 
x 
x 
x 
 
Delayed treatment administration 
x 
x 
x 
x 
x 
x 
 
Other 
x 
x 
x 
x 
x 
x 
Follow-up visit schedule 
Any type 
x 
x 
x 
x 
x 
x 
 
Out of window visit 
x 
x 
x 
x 
x 
x 
 
Missed visit/visit not conducted 
x 
x 
x 
x 
x 
x 
 
Other 
x 
x 
x 
x 
x 
x 
Protocol 
procedure/assessment 
Any type 
x 
x 
x 
x 
x 
x 
 
Incorrect version of ICF signed 
x 
x 
x 
x 
x 
x 
 
Swab not collected 
x 
x 
x 
x 
x 
x 
 
Urine not collected 
x 
x 
x 
x 
x 
x 
 
Other specimen not collected 
x 
x 
x 
x 
x 
x 
 
Specimen result not obtained 
x 
x 
x 
x 
x 
x 
 
Required procedure not conducted 
x 
x 
x 
x 
x 
x 
 
Required procedure done incorrectly 
x 
x 
x 
x 
x 
x 
 
Study product temperature excursion 
x 
x 
x 
x 
x 
x 
 
Specimen temperature excursion 
x 
x 
x 
x 
x 
x 
 
Other 
x 
x 
x 
x 
x 
x 
Treatment administration 
Any type 
x 
x 
x 
x 
x 
x 
 
Required procedure done incorrectly 
x 
x 
x 
x 
x 
x 
 
Study product temperature excursion 
x 
x 
x 
x 
x 
x 
 
Other 
x 
x 
x 
x 
x 
x 
Blinding policy/procedure 
Any type 
x 
x 
x 
x 
x 
x 
 
Treatment unblinded 
x 
x 
x 
x 
x 
x 
 
Other 
x 
x 
x 
x 
x 
x 
Note: N=Number of enrolled subjects randomized to the specified treatment group 


Statistical Analysis Plan - DMID Protocol: 18-0017  
Version 1.0 
07MAR2022 
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PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Table 6: 
Proportion of Subjects with Recurrent Bacterial Vaginosis by the Test of Cure Visit by 
Treatment Group – mITT Population 
Treatment 
Group 
Number of 
Subjects 
N 
Number of 
Subjects with 
RBV 
n 
Proportion of 
Subjects with 
RBV 
Proportion of 
Subjects with 
RBV 
95% CIa 
Difference in 
Proportions of 
Subjects with RBV 
between Treatment 
Arms 
Difference in 
Proportions of 
Subjects with RBV 
between Treatment 
Arms 95% CIb 
TOL-463 
Vaginal Insert 
x 
x 
0.xx 
0.xx, 0.xx 
0.xx 
0.xx, 0.xx 
Placebo 
x 
x 
0.xx 
0.xx, 0.xx 
Notes: The denominator for proportions is based on the number of subjects enrolled in the respective treatment group. 
a 95% Wilson confidence interval for the proportion of subjects with RBV. 
b 95% Newcombe confidence interval for difference in proportions between arms. 


Statistical Analysis Plan - DMID Protocol: 18-0017  
Version 1.0 
07MAR2022 
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PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Table 7: 
Proportion of Subjects with Recurrent Bacterial Vaginosis by the Test of Cure Visit by 
Treatment Group – mITT Population, Excluding Subjects Terminated Early due to 
COVID-19 
Treatment 
Group 
Number of 
Subjects 
Na 
Number of 
Subjects with 
RBV 
n 
Proportion of 
Subjects with 
RBV 
Proportion of 
Subjects with 
RBV 
95% CIb 
Difference in 
Proportions of 
Subjects with RBV 
between Treatment 
Arms 
Difference in 
Proportions of 
Subjects with RBV 
between Treatment 
Arms 95% CIc 
TOL-463 
Vaginal Insert 
x 
x 
0.xx 
0.xx, 0.xx 
0.xx 
0.xx, 0.xx 
Placebo 
x 
x 
0.xx 
0.xx, 0.xx 
Notes: The denominator for proportions is based on the number of subjects enrolled in the respective treatment group. 
a This analysis includes all subjects in the mITT population except those terminated early due to study disruptions resulting from shelter in place 
orders in response to the COVID-19 pandemic. 
b 95% Wilson confidence interval for the proportion of subjects with RBV. 
c 95% Newcombe confidence interval for difference in proportions between arms. 


Statistical Analysis Plan - DMID Protocol: 18-0017  
Version 1.0 
07MAR2022 
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PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Table 8: 
Proportion of Subjects with Recurrent Bacterial Vaginosis by the Test of Cure Visit by 
Treatment Group – PP Population 
Treatment 
Group 
Number of 
Subjects 
N 
Number of 
Subjects with 
RBV 
n 
Proportion of 
Subjects with 
RBV 
Proportion of 
Subjects with RBV 
95% CIa 
Difference in 
Proportions of 
Subjects with RBV 
between Treatment 
Arms 
Difference in 
Proportions of 
Subjects with RBV 
between Treatment 
Arms 95% CIb 
TOL-463 
Vaginal Insert 
x 
x 
0.xx 
0.xx, 0.xx 
0.xx 
0.xx, 0.xx 
Placebo 
x 
x 
0.xx 
0.xx, 0.xx 
Notes: The denominator for proportions is based on the number of subjects enrolled in the respective treatment group. 
a 95% Wilson confidence interval for the proportion of subjects with RBV. 
b 95% Newcombe confidence interval for difference in proportions between arms. 


Statistical Analysis Plan - DMID Protocol: 18-0017  
Version 1.0 
07MAR2022 
- 49 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Table 9: 
Rate of Recurrent Bacterial Vaginosis by the Test of Cure Visit by Treatment Group – 
mITT Population 
Treatment Group 
Number of Subjects with 
RBV 
Person-days 
Rate of RBV 
Rate of RBV 
95% CIa 
TOL-463 Vaginal Insert 
x 
x 
0.xx 
0.xx, 0.xx 
Placebo 
x 
x 
0.xx 
0.xx, 0.xx 
a Exact Poisson 95% confidence intervals. 


Statistical Analysis Plan - DMID Protocol: 18-0017  
Version 1.0 
07MAR2022 
- 50 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Table 10: 
Rate of Recurrent Bacterial Vaginosis by the Test of Cure Visit by Treatment Group – 
PP Population 
Treatment Group 
Number of Subjects with 
RBV 
Person-days 
Rate of RBV 
Rate of RBV 
95% CIa 
TOL-463 Vaginal Insert 
x 
x 
0.xx 
0.xx, 0.xx 
Placebo 
x 
x 
0.xx 
0.xx, 0.xx 
a Exact Poisson 95% confidence intervals. 


Statistical Analysis Plan - DMID Protocol: 18-0017  
Version 1.0 
07MAR2022 
- 51 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Table 11: 
Summary of Amsel Criteria by Study Visit and Treatment group – mITT Population 
Amsel Criteria 
Subcategories 
and 
Summary 
Statistics 
TOL-463 Vaginal Insert 
(N = xxx) 
Placebo 
(N = xxx) 
All Subjects 
(N = xxx) 
Visit 1 
(N = xxx) 
Visit 2 
(N = xxx) 
Visit 3 
(N = xxx) 
Visit 4 
(N = xxx) 
Visit 1 
(N = xxx) 
Visit 2 
(N = xxx) 
Visit 3 
(N = xxx) 
Visit 4 
(N = xxx) 
Visit 1 
(N = xxx) 
Visit 2 
(N = xxx) 
Visit 3 
(N = xxx) 
Visit 4 
(N = xxx) 
Presence of Amsel 
Criteria 
0/4 (%) 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
1/4 (%) 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
2/4 (%) 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
3/4 (%) 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
4/4 (%) 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
pH 
>4.5 (%) 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Mean 
x.xx 
x.xx 
x.xx 
x.xx 
x.xx 
x.xx 
x.xx 
x.xx 
x.xx 
x.xx 
x.xx 
x.xx 
Standard 
Deviation of 
Mean 
x.xx 
x.xx 
x.xx 
x.xx 
x.xx 
x.xx 
x.xx 
x.xx 
x.xx 
x.xx 
x.xx 
x.xx 
Mean Change 
from Visit 1 
N/A 
x.xx 
x.xx 
x.xx 
N/A 
x.xx 
x.xx 
x.xx 
N/A 
x.xx 
x.xx 
x.xx 
Standard 
Deviation of 
Mean Change 
from Visit 1 
N/A 
x.xx 
x.xx 
x.xx 
N/A 
x.xx 
x.xx 
x.xx 
N/A 
x.xx 
x.xx 
x.xx 
Clue Cells >=20% 
Present (%) 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Amine ("whiff") 
test on KOH wet 
mount 
Positive (%) 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Homogenous 
vaginal discharge 
characteristic of BV 
Yes (%) 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Notes: N=Number of subjects in the mITT population in the specified group and timepoint.  
Data from the previous enrollment(s) of a repeat subject are excluded.  
Observations from early termination at an unscheduled visit will be summarized into the preceding scheduled visit. From the scheduled visit and the corresponding unscheduled early termination visit, 
use the visit with the maximum number of present Amsel criteria for Presence of Amsel Criteria and report each corresponding Amsel criterion from that visit. 


Statistical Analysis Plan - DMID Protocol: 18-0017  
Version 1.0 
07MAR2022 
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PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Table 12: 
Summary of Amsel Criteria by Study Visit and Treatment group – PP Population 
Amsel Criteria 
Subcategories 
and 
Summary 
Statistics 
TOL-463 Vaginal Insert 
(N = xxx) 
Placebo 
(N = xxx) 
All Subjects 
(N = xxx) 
Visit 1 
(N = xxx) 
Visit 2 
(N = xxx) 
Visit 3 
(N = xxx) 
Visit 4 
(N = xxx) 
Visit 1 
(N = xxx) 
Visit 2 
(N = xxx) 
Visit 3 
(N = xxx) 
Visit 4 
(N = xxx) 
Visit 1 
(N = xxx) 
Visit 2 
(N = xxx) 
Visit 3 
(N = xxx) 
Visit 4 
(N = xxx) 
Presence of Amsel 
Criteria 
0/4 (%) 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
1/4 (%) 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
2/4 (%) 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
3/4 (%) 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
4/4 (%) 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
pH 
>4.5 (%) 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Mean 
x.xx 
x.xx 
x.xx 
x.xx 
x.xx 
x.xx 
x.xx 
x.xx 
x.xx 
x.xx 
x.xx 
x.xx 
Standard 
Deviation of 
Mean 
x.xx 
x.xx 
x.xx 
x.xx 
x.xx 
x.xx 
x.xx 
x.xx 
x.xx 
x.xx 
x.xx 
x.xx 
Mean Change 
from Visit 1 
N/A 
x.xx 
x.xx 
x.xx 
N/A 
x.xx 
x.xx 
x.xx 
N/A 
x.xx 
x.xx 
x.xx 
Standard 
Deviation of 
Mean Change 
from Visit 1 
N/A 
x.xx 
x.xx 
x.xx 
N/A 
x.xx 
x.xx 
x.xx 
N/A 
x.xx 
x.xx 
x.xx 
Clue Cells >=20% 
Present (%) 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Amine ("whiff") 
test on KOH wet 
mount 
Positive (%) 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Homogenous 
vaginal discharge 
characteristic of BV 
Yes (%) 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Notes: N=Number of subjects in the PP population in the specified group and timepoint.  
Data from the previous enrollment(s) of a repeat subject are excluded.  


Statistical Analysis Plan - DMID Protocol: 18-0017  
Version 1.0 
07MAR2022 
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PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Table 13: 
Proportion of Subjects with Recurrent Bacterial Vaginosis by the Test of Cure Visit by 
Treatment Group and by Site – mITT Population 
Treatment Group 
Number of 
Subjects 
N 
Number of 
Subjects with 
RBV 
n 
Proportion of 
Subjects with RBV 
Proportion of 
Subjects with RBV 
95% CIa 
Difference in Proportions of 
Subjects with RBV between 
Treatment Arms (95% CIb) 
University of Alabama 
TOL-463 Vaginal 
Insert 
x 
x 
0.xx 
0.xx, 0.xx 
0.xx (0.xx, 0.xx) 
Placebo 
x 
x 
0.xx 
0.xx, 0.xx 
University of Pittsburgh 
TOL-463 Vaginal 
Insert 
x 
x 
0.xx 
0.xx, 0.xx 
0.xx (0.xx, 0.xx) 
Placebo 
x 
x 
0.xx 
0.xx, 0.xx 
University of California 
TOL-463 Vaginal 
Insert 
x 
x 
0.xx 
0.xx, 0.xx 
0.xx (0.xx, 0.xx) 
Placebo 
x 
x 
0.xx 
0.xx, 0.xx 
Notes: The denominator for proportions is based on the number of subjects enrolled in the respective treatment group. 
a 95% Wilson confidence interval for the proportion of subjects with RBV. 
b 95% Newcombe confidence interval for difference in proportions between arms. 


Statistical Analysis Plan - DMID Protocol: 18-0017  
Version 1.0 
07MAR2022 
- 54 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Table 14: 
Nugent Scores by Category, Study Visit, and Treatment Group - mITT Population 
Nugent Score 
Category 
TOL-463 Vaginal Insert 
(N = xxx) 
Placebo 
(N = xxx) 
All Subjects 
(N = xxx) 
Visit 1 
(N = xxx) 
Visit 2 
(N = xxx) 
Visit 3 
(N = xxx) 
Visit 4 
(N = xxx) 
Visit 1 
(N = xxx) 
Visit 2 
(N = xxx) 
Visit 3 
(N = xxx) 
Visit 4 
(N = xxx) 
Visit 1 
(N = xxx) 
Visit 2 
(N = xxx) 
Visit 3 
(N = xxx) 
Visit 4 
(N = xxx) 
0-3 (Normal) (%) 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
4-6 (Intermediate) (%) 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
7-10 (BV) (%) 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Notes: N=Number of subjects in the mITT population in the specified group. Data shown in this table are percentages, where N is the denominator. 


Statistical Analysis Plan - DMID Protocol: 18-0017  
Version 1.0 
07MAR2022 
- 55 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Table 15: 
Summary of Proportion of Participants Reporting BV Symptoms – mITT Population 
Symptoms and 
Signs 
Symptoms 
Subcategories  
TOL-463 Vaginal Insert 
(N=X) 
Placebo 
(N=X) 
All Subjects 
(N=X) 
Visit 0 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 0 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 0 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Abnormal Vaginal 
Discharge 
n 
n 
n 
n 
n 
n 
n 
n 
n 
n 
n 
n 
n 
n 
n 
n 
No  
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Yes, consistent with 
BV  
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Yes, other  
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Vaginal Odor 
n 
n 
n 
n 
n 
n 
n 
n 
n 
n 
n 
n 
n 
n 
n 
n 
No  
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Yes, consistent with 
BV 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Yes, other  
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Notes: N=Number of subjects in the mITT population in the specified group.  
Subjects will be further excluded if no data is available at the specified timepoint, n=Number of subjects with available data for the specified category at the specified timepoint, and 
these counts are shown in the row of n, whereas the data shown in the rows of each response level in this table are percentages, where n is the denominator.  
For post-enrollment visits, observations from early termination at an unscheduled visit will be summarized into the preceding scheduled visit. For Vaginal Discharge and Odor 
responses from the scheduled visit and the corresponding unscheduled early termination visit, count the subject in “Yes, consistent with BV” when at least one response was “Yes, 
consistent with BV”; count the subject in “Yes, other” when no response was in “Yes, consistent with BV” and at least one response was from “Yes, other”; count the subject in 
“No” when all responses were “No”.  


Statistical Analysis Plan - DMID Protocol: 18-0017  
Version 1.0 
07MAR2022 
- 56 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Table 16: 
Summary of Proportion of Participants Reporting BV Symptoms – PP Population 
Symptoms and 
Signs 
Subcategories  
TOL-463 Vaginal Insert 
(N=X) 
Placebo 
(N=X) 
All Subjects 
(N=X) 
Visit 0 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 0 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 0 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Abnormal 
Vaginal 
Discharge 
n 
n 
n 
n 
n 
n 
n 
n 
n 
n 
n 
n 
n 
n 
n 
n 
No  
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Yes, consistent with 
BV  
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Yes, other  
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Vaginal Odor 
n 
n 
n 
n 
n 
n 
n 
n 
n 
n 
n 
n 
n 
n 
n 
n 
No  
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Yes, consistent with 
BV 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Yes, other  
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Notes: N=Number of subjects in the PP population in the specified group.  
Subjects will be further excluded if no data is available at the specified timepoint, n=Number of subjects with available data for the specified category at the specified timepoint.  
Data shown in this table are percentages, where n is the denominator. 


Statistical Analysis Plan - DMID Protocol: 18-0017  
Version 1.0 
07MAR2022 
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PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Table 17: 
Summary of Responses to the Satisfaction Questionnaire – mITT Population 
Satisfaction Questions  
Responses 
TOL-463 Vaginal Insert 
(N=X) 
Placebo 
(N=X) 
All Subjects 
(N=X) 
How Easy to Use 
n 
n 
n 
n 
Extremely dissatisfied 
x 
x 
x 
Very dissatisfied 
x 
x 
x 
Dissatisfied 
x 
x 
x 
Somewhat satisfied 
x 
x 
x 
Satisfied 
x 
x 
x 
Very satisfied 
x 
x 
x 
Extremely satisfied 
x 
x 
x 
How Often to Use 
n 
n 
n 
n 
Extremely dissatisfied 
x 
x 
x 
Very dissatisfied 
x 
x 
x 
Dissatisfied 
x 
x 
x 
Somewhat satisfied 
x 
x 
x 
Satisfied 
x 
x 
x 
Very satisfied 
x 
x 
x 
Extremely satisfied 
x 
x 
x 
How Convenient to Use 
n 
n 
n 
n 
Extremely inconvenient 
x 
x 
x 
Very inconvenient 
x 
x 
x 
Inconvenient 
x 
x 
x 
Somewhat convenient 
x 
x 
x 
Convenient 
x 
x 
x 
Very convenient 
x 
x 
x 


Statistical Analysis Plan - DMID Protocol: 18-0017  
Version 1.0 
07MAR2022 
- 58 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Satisfaction Questions  
Responses 
TOL-463 Vaginal Insert 
(N=X) 
Placebo 
(N=X) 
All Subjects 
(N=X) 
Extremely convenient 
x 
x 
x 
Overall Satisfaction 
n 
n 
n 
n 
Extremely dissatisfied 
x 
x 
x 
Very dissatisfied 
x 
x 
x 
Dissatisfied 
x 
x 
x 
Somewhat satisfied 
x 
x 
x 
Satisfied 
x 
x 
x 
Very satisfied 
x 
x 
x 
Extremely satisfied 
x 
x 
x 
Would Use Again 
n 
n 
n 
n 
Yes 
x 
x 
x 
Notes: N=Number of subjects in the mITT population in the specified group.  
Subjects will be further excluded if no data is available, n=Number of subjects with available data for the specified question, and these counts are shown in the row of n, whereas the data shown in the 
rows of each response level in this table are percentages, where n is the denominator. 
The questions are structured as “How satisfied or dissatisfied are you with …”, where the following part of the question is shown in the table. 


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Table 18: 
Summary of Responses to the Satisfaction Questionnaire – PP Population 
Satisfaction Questions  
Responses 
TOL-463 Vaginal Insert 
(N=X) 
Placebo 
(N=X) 
All Subjects 
(N=X) 
How Easy to Use 
n 
n 
n 
n 
Extremely dissatisfied 
x 
x 
x 
Very dissatisfied 
x 
x 
x 
Dissatisfied 
x 
x 
x 
Somewhat satisfied 
x 
x 
x 
Satisfied 
x 
x 
x 
Very satisfied 
x 
x 
x 
Extremely satisfied 
x 
x 
x 
How Often to Use 
n 
n 
n 
n 
Extremely dissatisfied 
x 
x 
x 
Very dissatisfied 
x 
x 
x 
Dissatisfied 
x 
x 
x 
Somewhat satisfied 
x 
x 
x 
Satisfied 
x 
x 
x 
Very satisfied 
x 
x 
x 
Extremely satisfied 
x 
x 
x 
How Convenient to Use 
n 
n 
n 
n 
Extremely inconvenient 
x 
x 
x 
Very inconvenient 
x 
x 
x 
Inconvenient 
x 
x 
x 
Somewhat convenient 
x 
x 
x 
Convenient 
x 
x 
x 
Very convenient 
x 
x 
x 


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Satisfaction Questions  
Responses 
TOL-463 Vaginal Insert 
(N=X) 
Placebo 
(N=X) 
All Subjects 
(N=X) 
Extremely convenient 
x 
x 
x 
Overall Satisfaction 
n 
n 
n 
n 
Extremely dissatisfied 
x 
x 
x 
Very dissatisfied 
x 
x 
x 
Dissatisfied 
x 
x 
x 
Somewhat satisfied 
x 
x 
x 
Satisfied 
x 
x 
x 
Very satisfied 
x 
x 
x 
Extremely satisfied 
x 
x 
x 
Would Use Again 
n 
n 
n 
n 
Yes 
x 
x 
x 
Notes: N=Number of subjects in the PP population in the specified group.  
Subjects will be further excluded if no data is available, n=Number of subjects with available data for the specified question, and these counts are shown in the row of n, whereas the data shown in the 
rows of each response level in this table are percentages, where n is the denominator. 
The questions are structured as “How satisfied or dissatisfied are you with …”, where the following part of the question is shown in the table. 


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Table 19: 
Performance of BD Max Vaginal Panel  
Study Visit 
Condition 
N 
Prevalence 
BD Max Proportion 
of Positives  
Sensitivity (%) 
(95% CI) 
Specificity (%) 
(95% CI) 
PPVa (%) 
(95% CI) 
NPVb (%) 
(95% CI) 
Visit 1 - 
Enrollment 
Clinical BV 
x 
0.xx 
0.xx 
x (0.xx, 0.xx) 
x (0.xx, 0.xx) 
x (0.xx, 0.xx) 
x (0.xx, 0.xx) 
Microbiological 
BV 
x 
0.xx 
0.xx 
x (0.xx, 0.xx) 
x (0.xx, 0.xx) 
x (0.xx, 0.xx) 
x (0.xx, 0.xx) 
Visit 2 – Month 2 
Clinical BV 
x 
0.xx 
0.xx 
x (0.xx, 0.xx) 
x (0.xx, 0.xx) 
x (0.xx, 0.xx) 
x (0.xx, 0.xx) 
Microbiological 
BV 
x 
0.xx 
0.xx 
x (0.xx, 0.xx) 
x (0.xx, 0.xx) 
x (0.xx, 0.xx) 
x (0.xx, 0.xx) 
Visit 3 – Month 3 
Clinical BV 
x 
0.xx 
0.xx 
x (0.xx, 0.xx) 
x (0.xx, 0.xx) 
x (0.xx, 0.xx) 
x (0.xx, 0.xx) 
Microbiological 
BV 
x 
0.xx 
0.xx 
x (0.xx, 0.xx) 
x (0.xx, 0.xx) 
x (0.xx, 0.xx) 
x (0.xx, 0.xx) 
Visit 4 – Month 4 
Clinical BV 
x 
0.xx 
0.xx 
x (0.xx, 0.xx) 
x (0.xx, 0.xx) 
x (0.xx, 0.xx) 
x (0.xx, 0.xx) 
Microbiological 
BV 
x 
0.xx 
0.xx 
x (0.xx, 0.xx) 
x (0.xx, 0.xx) 
x (0.xx, 0.xx) 
x (0.xx, 0.xx) 
Notes: N is number of subjects with available BV results from both the standard diagnosis method (clinical diagnosis or microbiological diagnosis as specified by the row) and the BD Max Vaginal 
Panel testing method. 
95% CI Wilson confidence interval is provided in this table. 
a Positive Predictive Value 
b Negative Predictive Value 


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Table 20: 
Original Clinical BV Diagnosis and the Nugent Score Assessment at the Screening Visit - All Enrolled Subjects 
BV Diagnosis Methods 
Subcategories and Summary 
Statistics 
TOL-463 Vaginal Insert 
(N = xxx) 
Placebo 
(N = xxx) 
All Subjects 
(N = xxx) 
Nugent Score Category 
0-3 (Normal) (%) 
x 
x 
x 
4-6 (Intermediate) (%) 
x 
x 
x 
7-10 (BV) (%) 
x 
x 
x 
Presence of Amsel Criteria 
0/4 (%) 
x 
x 
x 
1/4 (%) 
x 
x 
x 
2/4 (%) 
x 
x 
x 
3/4 (%) 
x 
x 
x 
4/4 (%) 
x 
x 
x 
pH 
>4.5 (%) 
x 
x 
x 
Mean 
x 
x 
x 
Standard Deviation of Mean 
x 
x 
x 
Clue Cells >=20% 
Present (%) 
x 
x 
x 
Amine ("whiff") test on KOH wet mount 
Positive (%) 
x 
x 
x 
Homogenous vaginal discharge characteristic of BV 
Yes (%) 
x 
x 
x 
Notes: N=Number of enrolled subjects in the specified group.  
For percentages shown in this table, N is the denominator. 


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Table 21: 
Summary of Categorical Demographic and Baseline Characteristics by Site - All Enrolled Subjects 
Variable 
Characteristic 
University of Alabama 
(N=X) 
University of Pittsburgh 
(N=X) 
University of California 
(N=X) 
All Subjects 
(N=X) 
n 
% 
n 
% 
n 
% 
n 
% 
Sex 
Female 
x 
x 
x 
x 
x 
x 
x 
xx 
Ethnicity  
Hispanic or Latino  
x 
x 
x 
x 
x 
x 
x 
xx 
Not Hispanic or Latino 
x 
x 
x 
x 
x 
x 
x 
xx 
Not Reported 
x 
x 
x 
x 
x 
x 
x 
xx 
Unknown 
x 
x 
x 
x 
x 
x 
x 
xx 
Race  
American Indian or Alaskan Native 
x 
x 
x 
x 
x 
x 
x 
xx 
Asian 
x 
x 
x 
x 
x 
x 
x 
xx 
Native Hawaiian or Other Pacific 
Islander 
x 
x 
x 
x 
x 
x 
x 
xx 
Black or African American 
x 
x 
x 
x 
x 
x 
x 
xx 
White 
x 
x 
x 
x 
x 
x 
x 
xx 
Multi-Racial 
x 
x 
x 
x 
x 
x 
x 
xx 
Unknown 
x 
x 
x 
x 
x 
x 
x 
xx 
Concurrent VVC 
Statusa 
Positive 
x 
x 
x 
x 
x 
x 
x 
xx 
Negative 
x 
x 
x 
x 
x 
x 
x 
xx 
Notes: N=Number of enrolled subjects in the specified group. Data from the previous enrollment(s) of a repeat subject are excluded. 
a Culture confirmed Vulvovaginal Candidiasis at baseline. 
 
 


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Table 22: 
Summary of Categorical Demographic and Baseline Characteristics by Treatment Group - All Enrolled Subjects 
Variable 
Characteristic 
TOL-463 
(N=X) 
Placebo 
(N=X) 
All Subjects 
(N=X) 
n 
n 
n 
n 
n 
% 
Sex 
Female 
x 
x 
x 
x 
x 
xx 
Ethnicity  
Not Hispanic or Latino 
x 
x 
x 
x 
x 
xx 
Hispanic or Latino 
x 
x 
x 
x 
x 
xx 
Not Reported 
x 
x 
x 
x 
x 
xx 
Unknown 
x 
x 
x 
x 
x 
xx 
Race  
American Indian or Alaskan Native 
x 
x 
x 
x 
x 
xx 
Asian 
x 
x 
x 
x 
x 
xx 
Native Hawaiian or Other Pacific Islander 
x 
x 
x 
x 
x 
xx 
Black or African American 
x 
x 
x 
x 
x 
xx 
White 
x 
x 
x 
x 
x 
xx 
Multi-Racial 
x 
x 
x 
x 
x 
xx 
Unknown 
x 
x 
x 
x 
x 
xx 
Concurrent VVC Statusa 
Positive 
x 
x 
x 
x 
x 
xx 
Negative 
x 
x 
x 
x 
x 
xx 
Notes: N=Number of enrolled subjects in the specified group. Data from the previous enrollment(s) of a repeat subject are excluded. 
a Culture confirmed Vulvovaginal Candidiasis at baseline. 


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Table 23: 
Summary of Continuous Demographic and Baseline Characteristics by Site - All Enrolled Subjects 
Variable 
Statistic 
University of Alabama 
(N=X) 
University of Pittsburgh 
(N=X) 
University of California 
(N=X) 
All Subjects 
(N=X) 
Age (years) 
Mean 
xx 
xx 
xx 
xx 
Standard Deviation 
xx 
xx 
xx 
xx 
Median 
x 
x 
x 
x 
Minimum 
x 
x 
x 
x 
Maximum 
x 
x 
x 
x 
No. of Times Subject Had 
BV in the Past 12 Months 
Obtained at Screening Visit 
Mean 
xx 
xx 
xx 
xx 
Standard Deviation 
xx 
xx 
xx 
xx 
Median 
x 
x 
x 
x 
Minimum 
x 
x 
x 
x 
Maximum 
x 
x 
x 
x 
Notes: N=Number of enrolled subjects in the specified group. Data from the previous enrollment(s) of a repeat subject are excluded. 


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Table 24: 
Summary of Continuous Demographic and Baseline Characteristics by Treatment Group - All Enrolled Subjects 
Variable 
Statistic 
TOL-463 
(N=X) 
Placebo 
(N=X) 
All Subjects 
(N=X) 
Age (years) 
Mean 
xx 
xx 
xx 
Standard Deviation 
xx 
xx 
xx 
Median 
x 
x 
x 
Minimum 
x 
x 
x 
Maximum 
x 
x 
x 
No. of Times Subject Had BV in the Past 
12 Months Obtained at Screening Visit 
Mean 
xx 
xx 
xx 
Standard Deviation 
xx 
xx 
xx 
Median 
x 
x 
x 
Minimum 
x 
x 
x 
Maximum 
x 
x 
x 
Notes: N=Number of enrolled subjects in the specified group. Data from the previous enrollment(s) of a repeat subject are excluded. 


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Table 25: 
Summary of Subjects with Pre-Existing Medical Conditions by MedDRA System Organ Class and Treatment Group – All 
Enrolled Subjects 
MedDRA System Organ Class 
TOL-463 Vaginal Insert 
(N=X) 
Placebo 
(N=X) 
All Subjects 
(N=X) 
n 
% 
n 
% 
n 
% 
Any SOC 
x 
xx 
x 
xx 
x 
xx 
[SOC 1] 
x 
xx 
x 
xx 
x 
xx 
[SOC 2] 
x 
xx 
x 
xx 
x 
xx 
Notes: N= Number of enrolled subjects in the specified group; n = Number of subjects reporting medical history within the specified SOC. A subject is only counted once per SOC. 


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Table 26: 
Number and Percentage of Subjects with Prior and Concomitant Medications by WHO Drug Classification and Treatment 
Group – Safety Population 
WHO Drug Code 
Level 1, Anatomic Group 
WHO Drug Code 
Level 2, Therapeutic Subgroup 
TOL-463 Vaginal Insert 
(N=X) 
Placebo 
(N=X) 
All Subjects 
(N=X) 
n 
% 
n 
% 
n 
% 
Any Level 1 Codes 
Any Level 2 Codes 
x 
xx 
x 
xx 
x 
xx 
[ATC Level 1 - 1] 
Any [ATC 1 – 1] 
x 
xx 
x 
xx 
x 
xx 
 
[ATC 2 - 1] 
x 
xx 
x 
xx 
x 
xx 
 
[ATC 2 - 2] 
x 
xx 
x 
xx 
x 
xx 
 
[ATC 2 - 3] 
x 
xx 
x 
xx 
x 
xx 
[ATC Level 1 – 2] 
[ATC 2 - 1] 
x 
xx 
x 
xx 
x 
xx 
 
[ATC 2 - 2] 
x 
xx 
x 
xx 
x 
xx 
 
[ATC 2 - 3] 
x 
xx 
x 
xx 
x 
xx 
N = Number of subjects in the Safety Population. n=Number of subjects reporting taking at least one medication in the specific WHO Drug Class. 


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Table 27: 
Occurrence of Related Adverse Events (AE) Overall and by Treatment Groups – Safety Population 
Treatment Group 
Number of 
Subjects 
N 
Number of 
Subjects with 
Related AE 
n 
Proportion of 
Subjects with 
Related AE 
Proportion of Subjects with 
Related AE 
95% CIa 
Difference in Proportions of 
Subjects with Related AE 
between Treatment Arms 
Difference in Proportions of 
Subjects with Related AE 
between Treatment Arms 95% 
CIb 
TOL-463 Vaginal 
Insert 
x 
x 
0.xx 
0.xx, 0.xx 
0.xx 
0.xx, 0.xx 
Placebo 
x 
x 
0.xx 
0.xx, 0.xx 
Notes: The denominator for proportions is based on the number of subjects who used at least one insert in the respective treatment group.  
a 95% Wilson confidence interval for the proportion of subjects with Related AE. 
b 95% Newcombe confidence interval for difference in proportions between arms. 


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Table 28: 
Overall Summary of Adverse Events – Safety Population 
Subjectsa with 
TOL-463 Vaginal 
Insert 
(N = xx) 
Placebo 
(N = xx) 
All Subjects 
(N = xx) 
n 
% 
n 
% 
n 
% 
At least one unsolicited adverse event 
x 
x 
x 
x 
x 
x 
At least one related unsolicited adverse event 
x 
x 
x 
x 
x 
x 
     Mild (Grade 1) 
x 
x 
x 
x 
x 
x 
     Moderate (Grade 2)  
x 
x 
x 
x 
x 
x 
     Severe (Grade 3)  
x 
x 
x 
x 
x 
x 
At least one severe (Grade 3) unsolicited adverse event 
x 
x 
x 
x 
x 
x 
     Related  
x 
x 
x 
x 
x 
x 
     Unrelated 
x 
x 
x 
x 
x 
x 
At least one serious adverse event 
x 
x 
x 
x 
x 
x 
At least one related, serious adverse event 
x 
x 
x 
x 
x 
x 
At least one adverse event leading to early terminationc  
x 
x 
x 
x 
x 
x 
Notes: Subjects are excluded from Safety Population if it is unknown whether they received at least one dose, but the adverse events of such subjects are included in the AE listings. A repeat subject 
will be re-enrolled under a unique Subject ID and be treated as a distinct subject in this table. 
N = Number of subjects in the Safety Population 
a Subjects are counted once for each category regardless of the number of events. 
b A listing of Serious Adverse Events is included in Table 34 . 
c As reported on the Adverse Event eCRF. 
 


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Table 29: 
Unsolicited Adverse Events Cross-Classified by MedDRA System Organ Class and Preferred Term, Severity, and Relationship to 
Study Treatment - Safety Population 
MedDRA System 
Organ Class 
Preferred Term 
Severity 
TOL-463 Vaginal Insert 
(N = xx) 
Placebo 
(N = xx) 
All Subjects 
(N = xx) 
Related 
Not 
Related 
Total 
Related 
Not 
Related 
Total 
Related 
Not 
Related 
Total 
n 
n 
n 
n 
n 
n 
n 
n 
n 
Any SOC 
Any PT 
Any Severity 
x  
x  
x  
x  
x  
x  
x  
x  
x  
 
 
Mild 
x  
x  
x  
x  
x  
x  
x  
x  
x  
 
 
Moderate 
x  
x  
x  
x  
x  
x  
x  
x  
x  
 
 
Severe 
x  
x  
x  
x  
x  
x  
x  
x  
x  
SOC 1 
PT 1 
Any Severity 
x  
x  
x  
x  
x  
x  
x  
x  
x  
 
 
Mild 
x  
x  
x  
x  
x  
x  
x  
x  
x  
 
 
Moderate 
x  
x  
x  
x  
x  
x  
x  
x  
x  
 
 
Severe 
x  
x  
x  
x  
x  
x  
x  
x  
x  
 
PT 2 
Any Severity 
x  
x  
x  
x  
x  
x  
x  
x  
x  
 
 
Mild 
x  
x  
x  
x  
x  
x  
x  
x  
x  
 
 
Moderate 
x  
x  
x  
x  
x  
x  
x  
x  
x  
 
 
Severe 
x  
x  
x  
x  
x  
x  
x  
x  
x  
Notes: N= Number of subjects in the Safety population. Subjects are excluded from Safety Population if it is unknown whether they received at least one dose, but the adverse events of such subjects 
are included in the AE listings. A repeat subject will be re-enrolled under a unique Subject ID and be treated as a distinct subject in this table.  


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Table 30: 
Number and Percentage of Subjects Experiencing Unsolicited Adverse Events by MedDRA System Organ Class and Preferred 
Term, Severity, and Relationship – TOL-463 Vaginal Insert Group - Safety Population  
[Implementation note: Do not show “however, a subject will be counted once again under the “Not Yet Determined” column if they have events that fall 
under this category.” in the footnote if such scenario doesn’t exist.] 
MedDRA System Organ Class 
MedDRA Preferred Term 
Any Incidence 
Severity 
Relationship to Treatment 
Mild 
Moderate 
Severe 
Not Related 
Related 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Any SOC 
Any PT 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
[SOC 1] 
Any PT 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
[PT 1] 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
[PT 2] 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
[SOC 2] 
Any PT 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
[PT 1] 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
[PT 2] 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Notes: A subject is only counted once per PT and is summarized according to their highest severity and closest relationship, however, a subject will be counted once again under the “Not Yet 
Determined” column if they have events that fall under this category. 
Subjects are excluded from Safety Population if it is unknown whether they received at least one dose, but the adverse events of such subjects are included in the AE listings. 
A repeat subject will be re-enrolled under a unique Subject ID and be treated as a distinct subject in this table.  


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Table 31: 
Number and Percentage of Subjects Experiencing Unsolicited Adverse Events by MedDRA System Organ Class and Preferred 
Term, Severity, and Relationship – Placebo Group - Safety Population  
[Implementation note: Do not show “however, a subject will be counted once again under the “Not Yet Determined” column if they have events that fall 
under this category.” in the footnote if such scenario doesn’t exist.] 
MedDRA System Organ Class 
MedDRA Preferred Term 
Any Incidence 
Severity 
Relationship to Treatment 
Mild 
Moderate 
Severe 
Not Related 
Related 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Any SOC 
Any PT 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
[SOC 1] 
Any PT 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
[PT 1] 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
[PT 2] 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
[SOC 2] 
Any PT 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
[PT 1] 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
[PT 2] 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Notes: A subject is only counted once per PT and is summarized according to their highest severity and closest relationship, however, a subject will be counted once again under the “Not Yet 
Determined” column if they have events that fall under this category. 
Subjects are excluded from Safety Population if it is unknown whether they received at least one dose, but the adverse events of such subjects are included in the AE listings. 
A repeat subject will be re-enrolled under a unique Subject ID and be treated as a distinct subject in this table.  


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Table 32: 
Number and Percentage of Subjects Experiencing Unsolicited Adverse Events with 95% Confidence Intervals by MedDRA® 
System Organ Class, and Preferred Term, and Treatment Group 
MedDRA® System Organ Class 
MedDRA® Preferred Term 
TOL-463 Vaginal Insert 
(N=X) 
Placebo 
(N=X) 
All Subjects 
(N=X) 
n 
% 
95% CI 
n 
% 
95% CI 
n 
% 
95% CI 
Any SOC 
Any PT 
x 
x 
x, x 
x 
x 
x, x 
x 
x 
x, x 
[SOC 1] 
Any PT 
x 
x 
x, x 
x 
x 
x, x 
x 
x 
x, x 
 
[PT 1] 
x 
x 
x, x 
x 
x 
x, x 
x 
x 
x, x 
 
[PT 2] 
x 
x 
x, x 
x 
x 
x, x 
x 
x 
x, x 
[SOC 2] 
Any PT 
x 
x 
x, x 
x 
x 
x, x 
x 
x 
x, x 
 
[PT 1] 
x 
x 
x, x 
x 
x 
x, x 
x 
x 
x, x 
 
[PT 2] 
x 
x 
x, x 
x 
x 
x, x 
x 
x 
x, x 
Notes: N = number of subjects in the Safety Analysis Population who received the specified dose. 
This table presents number and percentage of subjects. 
A subject is only counted once per PT/timepoint. 
95% Wilson CI is provided. 


Statistical Analysis Plan - DMID Protocol: 18-0017  
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Table 33: 
Unsolicited Adverse Events Occurring in 5% of Subjects in Any Treatment Group by MedDRA System Organ Class and 
Preferred Term, and Treatment Group - Safety Population 
Preferred Term 
MedDRA System Organ Class 
TOL-463 Vaginal Insert 
(N=X) 
Placebo 
(N=X) 
All Subjects 
(N=X) 
n 
% 
Events 
n 
% 
Events 
n 
% 
Events 
Serious Adverse Events 
All  
All 
x 
x 
x 
x 
x 
x 
x 
x 
x 
PT1 
SOC1 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Etc. 
Etc. 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Other (Non-serious) Adverse Events 
All  
All 
x 
x 
x 
x 
x 
x 
x 
x 
x 
PT1 
SOC1 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Etc 
Etc 
x 
x 
x 
x 
x 
x 
x 
x 
x 
N = number of subjects in the Safety Population (number of subjects at risk).  
n= number of subjects reporting event.  
Events= total frequency of events reported. 
 


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Table 34: 
Listing of Non-Serious, Unsolicited Adverse Events – All Enrolled Subjects 
[Implementation notes: If the event is ongoing (no stop date), indicate “ongoing” in the “Duration” column. In the “If Not Related, Alternate Etiology” 
column, merge the 2 data fields for collecting alternate etiology, separate by a colon. If there are no comments for an event, populate ‘Comments’ row 
with ‘None’. In the CSR, Subject ID should be USUBJID (not PATID) for purposes of de-identification. Listing should be sorted by Treatment Group, 
Subject ID, AE Number. 
Show footnote if the following scenario exist: Notes: Subjects are excluded from Safety Population if it is unknown whether they received at least one 
dose, but the adverse events of such subjects are included in the AE listings.] 
Adverse 
Event 
No. of Days 
Post First 
Dose 
Duration 
(Days) 
Severity 
Relationship 
to Study 
Treatment 
If Not 
Related, 
Alternative 
Etiology 
Action Taken 
with Study 
Treatment 
Subject 
Discontinued 
Due to AE 
Outcome 
MedDRA 
System Organ 
Class 
MedDRA 
Preferred 
Term 
Treatment Group: , Subject ID: , AE Number:  
 
 
 
 
 
 
 
 
 
 
 
Comments: 
 
Treatment Group: , Subject ID: ,  AE Number:  
 
 
 
 
 
 
 
 
 
 
 
Comments: 
 
 


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Table 35: 
Listing of Serious Adverse Events – All Enrolled Subjects 
[Implementation notes: If the event is ongoing (no stop date), indicate “ongoing” in the “Duration” column. In the “If Not Related, Alternate Etiology” 
column, merge the 2 data fields for collecting alternate etiology, separate by a colon. If there are no comments for an event, populate ‘Comments’ row 
with ‘None’. In the CSR, Subject ID should be USUBJID (not PATID) for purposes of de-identification. Listing should be sorted by Treatment Group, 
Subject ID, AE Number. 
Show footnote if the following scenario exist: Notes: Subjects are excluded from Safety Population if it is unknown whether they received at least one 
dose, but the adverse events of such subjects are included in the AE listings] 
Adverse 
Event 
No. of 
Days Post 
First Dose  
Duration 
(Days) 
Reason 
Reported as 
an SAE 
Severity 
Relationship to 
Study 
Treatment 
If Not Related, 
Alternative 
Etiology 
Action Taken 
with Study 
Treatment 
Subject 
Discontinued 
Due to AE 
Outcome 
MedDRA 
System 
Organ Class 
MedDRA 
Preferred 
Term 
Treatment Group: , Subject ID: , AE Number:  
 
 
 
 
 
 
 
 
 
 
 
 
Comments: 
 
Treatment Group: , Subject ID: , AE Number:  
 
 
 
 
 
 
 
 
 
 
 
 
Comments: 
 
 


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Table 36: 
Occurrence of Culture Confirmed Secondary Vulvovaginal Candidiasis (VVC) Overall and by Treatment Groups – Safety 
Population 
Treatment Group 
Number of Subjects 
N  
Number of Subjects 
with VVCa 
n 
Proportion of Subjects 
with VVC 
Proportion of Subjects 
with VVC 
95% CIb 
Difference in Proportion of 
Subjects with VVC between 
Treatment Arms 
Difference in Proportion of 
Subjects with VVC between 
Treatment Arms 95% CIc 
TOL-463 Vaginal Insert 
x 
x 
0.xx 
0.xx, 0.xx 
0.xx 
0.xx, 0.xx 
Placebo 
x 
x 
0.xx 
0.xx, 0.xx 
Notes: The denominator for proportions is based on the number of subjects who used at least one insert in the respective treatment group.  
a The occurrence of culture confirmed secondary VVC following initiation of study treatment and through the final study visit is calculated. Subjects enrolled with concurrent VVC at baseline (visit 1) 
that can be treated with oral fluconazole is not counted towards n.  
b 95% Wilson confidence interval for the proportion of subjects with VVC. 
c 95% Newcombe confidence interval for difference in proportions between arms. 


Statistical Analysis Plan - DMID Protocol: 18-0017  
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Table 37: 
Summary of Proportion of Participants Reporting Vulvovaginal Symptoms and Signs, Yeast Form, and Clinical Diagnosed and 
Culture Confirmed Vulvovaginal Candidiasis – Safety Population 
Symptoms/Signs Severity  
TOL-463 Vaginal Insert 
(N=X) 
Placebo 
(N=X) 
All Subjects 
(N=X) 
Visit 0 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 0 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 0 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Burning 
n 
n 
n 
n 
n 
n 
n 
n 
n 
n 
n 
n 
n 
n 
n 
n 
None 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Mild 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Moderate 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Severe 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Irritation 
n 
n 
n 
n 
n 
n 
n 
n 
n 
n 
n 
n 
n 
n 
n 
n 
None 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Mild 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Moderate 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Severe 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Itching 
n 
n 
n 
n 
n 
n 
n 
n 
n 
n 
n 
n 
n 
n 
n 
n 
None 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Mild 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Moderate 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Severe 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Edema 
n 
n 
n 
n 
n 
n 
n 
n 
n 
n 
n 
n 
n 
n 
n 
n 
Absent 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Mild 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Moderate 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Severe 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 


Statistical Analysis Plan - DMID Protocol: 18-0017  
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Symptoms/Signs Severity  
TOL-463 Vaginal Insert 
(N=X) 
Placebo 
(N=X) 
All Subjects 
(N=X) 
Visit 0 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 0 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 0 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Erythema 
n 
n 
n 
n 
n 
n 
n 
n 
n 
n 
n 
n 
n 
n 
n 
n 
Absent 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Mild 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Moderate 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Severe 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Excoriation 
n 
n 
n 
n 
n 
n 
n 
n 
n 
n 
n 
n 
n 
n 
n 
n 
Absent 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Mild 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Moderate 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Severe 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
KOH Wet Mount Microscopy: Yeast (budding, branching, hyphae) 
n 
n 
n 
n 
n 
n 
n 
n 
n 
n 
n 
n 
n 
n 
n 
n 
Absent 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Present 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Clinical Diagnosis of Vulvovaginal Candidiasis 
n 
N/A 
n 
n 
n 
n 
N/A 
n 
n 
n 
n 
N/A 
n 
n 
n 
n 
Yes 
N/A 
x 
x 
x 
x 
N/A 
x 
x 
x 
x 
N/A 
x 
x 
x 
x 
No 
N/A 
x 
x 
x 
x 
N/A 
x 
x 
x 
x 
N/A 
x 
x 
x 
x 
Culture Confirmed Vulvovaginal Candidiasis 
n 
N/A 
n 
n 
n 
n 
N/A 
n 
n 
n 
n 
N/A 
n 
n 
n 
n 
Yes 
N/A 
x 
x 
x 
x 
N/A 
x 
x 
x 
x 
N/A 
x 
x 
x 
x 
No 
N/A 
x 
x 
x 
x 
N/A 
x 
x 
x 
x 
N/A 
x 
x 
x 
x 


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Symptoms/Signs Severity  
TOL-463 Vaginal Insert 
(N=X) 
Placebo 
(N=X) 
All Subjects 
(N=X) 
Visit 0 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 0 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 0 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Notes: N=Number of subjects in the Safety population in the specified group.  
Subjects will be further excluded if no data is available at the specified timepoint, n=Number of subjects with available data for the specified category at the specified timepoint, and 
these counts are shown in the row of n, whereas the data shown in the rows of each response level in this table are percentages, where n is the denominator.  
Observations from early termination at an unscheduled visit will be summarized into the preceding scheduled visit. For Burning, Irritation, Itching, Edema, Erythema, and 
Excoriation, the maximum severity level from the scheduled visit and the corresponding unscheduled early termination visit will be counted. For KOH wet mount Microcopy 
responses from the scheduled visit and the corresponding unscheduled early termination visit, count the subject in “Present” when at least one response was “Present”, and count 
“Absent” when all responses were “Absent”. 


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Table 38: 
Additional Pelvic Examination Measures 
Measures  
TOL-463 Vaginal Insert 
(N=X) 
Placebo 
(N=X) 
All Subjects 
(N=X) 
Visit 0 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 0 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 0 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Genital lesion consistent with active HSV or HPV: 
n 
n 
n 
n 
n 
n 
n 
n 
n 
n 
n 
n 
n 
n 
n 
n 
Absent 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Present 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Motile Trichomonads 
n 
n 
n 
n 
n 
n 
n 
n 
n 
n 
n 
n 
n 
n 
n 
n 
Absent 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Present 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Notes: N=Number of subjects in the Safety population in the specified group.  
Subjects will be further excluded if no data is available at the specified timepoint, n=Number of subjects with available data for the specified category at the specified timepoint, and 
these counts are shown in the row of n, whereas the data shown in the rows of each response level in this table are percentages, where n is the denominator.  
Observations from early termination at an unscheduled visit will be summarized into the preceding scheduled visit. For responses from the scheduled visit and the corresponding 
unscheduled early termination visit, count the subject in “Present” when at least one response was “Present”, and count “Absent” when all responses were “Absent”. 


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Table 39: 
Summary of Halting Rules – Safety Population 
Halting 
Rule # 
 
Rule 
Halting Rule 
Triggered 
(Yes/No) 
# Contributing to 
Halting Rule/ 
Total Needed to Halt 
1 
If one or more participants experience an SAE judged by an investigator to be related to study IP 
Yes/No 
x/1 
2 
If two or more participants experience an AE that is judged to be Grade 3 and related to study IP 
Yes/No 
x/2 
3 
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. 
Yes/No 
0 


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APPENDIX 2.  FIGURE MOCK-UPS 
 
 


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LIST OF FIGURES 
Figure 1: 
 Schematic of Study Design ..........................................................................................7 
Figure 2: 
CONSORT Flow Diagram .........................................................................................86 
Figure 3: 
Time to Bacterial Vaginosis Recurrence - mITT population .....................................87 
Figure 4: 
Time to Bacterial Vaginosis Recurrence - PP population ..........................................87 
Figure 5: 
Number and Severity of Unsolicited Adverse Events by MedDRA System 
Organ Class - Safety Population .................................................................................88 
Figure 6: 
Number of Unsolicited Adverse Events by MedDRA System Organ Class 
and Relationship - Safety Population .........................................................................89 


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Figure 2: 
CONSORT Flow Diagram 
 
 


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Figure 3: 
Time to Bacterial Vaginosis Recurrence - mITT population 
[Implementation notes: 3 curves are for overall and each treatment group. X-axis label: Time (Days) to 
Bacterial Vaginosis Recurrence, x-axis label: Proportion of Survival. 
Display, number of subjects at risk table with ticks at day 0, 15, 30, 45, 60, 75, 90 on x-axis, and 95% HW 
confidence bands of the curves in the plot. Legend names: Treatment arm, All, TOL-463 Vaginal Insert, 
Placebo. Obtain the estimates in the footnote from the SAS proc lifetest Quartile Estimates output table.] 
 
Notes: The estimate of survival time at which 25% of the overall subjects are expected to have recurrent BV (Proportion of survival 
equals to 0.75 at y-axis) is X days (95% CI: X - X), and correspondingly, X days (95% CI: X - X) for the TOL-463 group and X 
days (95% CI: X - X) for the Placebo group. 
 
Figure with similar format: 
Figure 4: 
Time to Bacterial Vaginosis Recurrence - PP population 
 


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Figure 5: 
Number and Severity of Unsolicited Adverse Events by MedDRA System Organ Class - 
Safety Population 
 
Figures will have 3 panels: TOL-463 Vaginal Insert, Placebo, All Subjects 
Show footnote if the following scenario exist: Notes: Subjects are excluded from Safety Population if it is 
unknown whether they received at least one dose, but the adverse events of such subjects are included in the 
AE listings 


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Figure 6: 
Number of Unsolicited Adverse Events by MedDRA System Organ Class and 
Relationship - Safety Population 
 
Figures will have 3 panels:  TOL-463 Vaginal Insert, Placebo, All Subjects 
Show footnote if the following scenario exist: Notes: Subjects are excluded from Safety Population if it is 
unknown whether they received at least one dose, but the adverse events of such subjects are included in the 
AE listings 
 


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APPENDIX 3. LISTINGS MOCK-UPS 
 
 


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LISTINGS 
Listing 1: Subjects Excluded from Analysis Populations ...........................................................92 
Listing 2: Early Terminations or Discontinued Subjects ............................................................93 
Listing 3: Subjects Terminated Early due to the COVID-19 Pandemic .....................................94 
Listing 4: Subject-Specific Protocol Deviations .........................................................................95 
Listing 5: Non-Subject-Specific Protocol Deviations .................................................................96 
Listing 6: Amsel Criteria and Nugent Score for BV ...................................................................97 
Listing 7: Individual Time to Recurrent Bacterial Vaginosis (RBV) .........................................98 
Listing 8: Individual Bacterial Vaginosis (BV) Symptoms ........................................................99 
Listing 9: Individual Response to Satisfaction Questionnaire ..................................................100 
Listing 10: Demographics Data ..................................................................................................101 
Listing 11: Pre-Existing and Concurrent Medical Conditions ....................................................102 
Listing 12: Concomitant Medications .........................................................................................103 
Listing 13: Screening and Baseline Gynecologic and Sexual History - All Enrolled 
Subjects .....................................................................................................................104 
Listing 14: Follow-up Gynecologic and Sexual History - All Enrolled Subjects .......................105 
Listing 15: Compliance Data ......................................................................................................106 
Listing 16: Pregnancy Reports ....................................................................................................107 
Listing 17: Vital Signs ................................................................................................................109 
Listing 18: Abnormal Physical Exam Findings ..........................................................................110 
Listing 19: Listing of Clinical Diagnosis of Vulvovaginal Candidiasis (VVC) and 
Culture Confirmed VVC ...........................................................................................111 
Listing 20: Pelvic Examination Findings ....................................................................................112 
Listing 21: Results of STI Tests and Pap Smear at Screening/Enrollment – All Enrolled 
Subjects .....................................................................................................................113 
 


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Listing 1: 
Subjects Excluded from Analysis Populations 
Treatment Group 
Subject ID 
Analyses in which 
Subject is Included 
Analyses from which  
Subject is Excluded 
Results Available? 
Reason Subject Excluded 
TOL-463 Vaginal Insert/Placebo 
xxxxxx 
[e.g., Safety, mITT, PP] 
[e.g., Safety, mITT, PP, Day x] 
Yes/No 
xxxxxx 
TOL-463 Vaginal Insert/Placebo 
xxxxxx 
[e.g., Safety, mITT, PP] 
[e.g., Safety, mITT, PP, Day x] 
Yes/No 
xxxxxx 
TOL-463 Vaginal Insert/Placebo 
xxxxxx 
[e.g., Safety, mITT, PP] 
[e.g., Safety, mITT, PP, Day x] 
Yes/No 
xxxxxx 
Note: “Yes” in the “Results available” column indicates that available data were removed from the analysis. “No” indicates that no data were available for inclusion in the analysis. 
 


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Listing 2: 
Early Terminations or Discontinued Subjects 
Implementation Notes:   
1. Sort order will be by Actual Treatment Group, Subject ID, Category. 
2. Category will be "Early Termination" or "Treatment Discontinuation". If a subject discontinued treatment, they will have two records. 
3. In the “Reason” column, concatenate any “specify” fields, including AE number and DV number. 
Treatment Group 
 Subject 
ID 
Site 
Category 
Reason for Early Termination 
or Treatment Discontinuation 
Study Day Corresponding to 
Early Termination/Treatment 
Discontinuation 
Last Completed Study Visit 
Prior to Termination 
TOL-463 Vaginal 
Insert/Placebo 
xxxxxx 
xx 
Early Termination/ Treatment 
Discontinuation 
xxxxxxxx 
xx 
Visit x 
TOL-463 Vaginal 
Insert/Placebo 
xxxxxx 
xx 
Early Termination/Treatment 
Discontinuation 
xxxxxxxx 
xx 
Visit x 
TOL-463 Vaginal 
Insert/Placebo 
xxxxxx 
xx 
Early Termination/Treatment 
Discontinuation 
xxxxxxxx 
xx 
Visit x 
Notes: Subjects listed do not include those terminated early due to study disruptions resulting from the COVID-19 pandemic. See Listing 3 for a complete listing of early terminations 
due to COVID-19 shelter in place orders.  
 


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Listing 3: 
Subjects Terminated Early due to the COVID-19 Pandemic 
Implementation Notes:   
1. Sort order will be by Actual Treatment Group, Subject ID, Category. 
2. Category will be "Early Termination" or "Treatment Discontinuation". If a subject discontinued treatment, they will have two records. 
3. In the “Reason” column, concatenate any “specify” fields, including AE number and DV number. 
Treatment Group 
 Subject 
ID 
Site 
Category 
Reason for Early Termination 
or Treatment Discontinuation 
Study Day Corresponding to 
Early Termination/Treatment 
Discontinuation 
Last Completed Study Visit 
Prior to Termination 
TOL-463 Vaginal 
Insert/Placebo 
xxxxxx 
xx 
Early Termination/ Treatment 
Discontinuation 
xxxxxxxx 
xx 
Visit x 
TOL-463 Vaginal 
Insert/Placebo 
xxxxxx 
xx 
Early Termination/Treatment 
Discontinuation 
xxxxxxxx 
xx 
Visit x 
TOL-463 Vaginal 
Insert/Placebo 
xxxxxx 
xx 
Early Termination/Treatment 
Discontinuation 
xxxxxxxx 
xx 
Visit x 
Notes: Subjects listed were terminated early due to study disruptions resulting from shelter in place orders in response to the COVID-19 pandemic. 


Statistical Analysis Plan - DMID Protocol: 18-0017  
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Listing 4: 
Subject-Specific Protocol Deviations 
Implementation Notes:   
1. Sort order will be by Actual Treatment Group, Subject ID, Deviation Number. 
2. In the Deviation Description column concatenate any specify fields.  
3. In the Reason for Deviation column concatenate any specify fields. 
Treatment 
Group 
Subject 
ID 
DV Number 
Deviation 
Description 
Deviation 
Category 
Study Day 
Reason for 
Deviation 
Deviation 
Resulted 
in AE? 
Deviation Resulted 
in Subject 
Termination? 
Deviation 
Affected 
Product Stability? 
Deviation 
Resolution 
Comments 
TOL-463 Vaginal 
Insert /Placebo 
xxxxxx 
xx 
xxxxxxxx 
xxxxxxxx 
xx 
xxxxxxxx 
Yes/No 
Yes/No 
Yes/No 
Yes/No 
xxxxxxxx 
TOL-463 Vaginal 
Insert /Placebo 
xxxxxx 
xx 
xxxxxxxx 
xxxxxxxx 
xx 
xxxxxxxx 
Yes/No 
Yes/No 
Yes/No 
Yes/No 
xxxxxxxx 


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Listing 5: 
Non-Subject-Specific Protocol Deviations 
Implementation Notes:   
1. Sort order will be by Site, Start Day. 
2. In the Deviation Description column concatenate any specify fields. 
3. In the Reason for Deviation column concatenate any specify fields. 
Site 
Start Date  
Deviation 
Description 
End Date 
Reason for 
Deviation 
Deviation 
Resulted in 
Subject 
Termination? 
Deviation 
Affected 
Product 
Stability? 
Deviation 
Category 
Deviation 
Resolution 
Comments 
xxxx 
ddMMMyyyy 
xxxx 
ddMMMyyyy 
xxxx 
Yes/No 
Yes/No 
xx 
xxxx 
xxxxxxxx 
xxxx 
ddMMMyyyy 
xxxx 
ddMMMyyyy 
xxxx 
Yes/No 
Yes/No 
xx 
Xxxx 
xxxxxxxx 


Statistical Analysis Plan - DMID Protocol: 18-0017  
Version 1.0 
07MAR2022 
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PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Listing 6: 
Amsel Criteria and Nugent Score for BV 
[Implementation notes: Continue for all subjects. List any unscheduled visit (should be for a termination visit), if exist.]  
Subject 
ID 
Treatment 
Group 
Visit 
Stud
y Day 
Amine ("whiff") test 
on KOH wet 
mount 
Homogeneous 
Vaginal 
discharge 
characteristic 
of BV 
Clue cells > or = 
20% of the total 
vaginal squamous 
epithelial cells on 
saline microscopy 
(%) 
Vaginal 
pH 
Presence 
of Amsel 
Criteria  
Clinical 
Diagnosis of BV  
Nugent 
Score 
BD Max BV Result 
xxxxxx 
TOL-463 
Vaginal 
Insert/Placebo 
00 
-xx 
Positive/Negative/Not 
Assessed 
Yes/No/Not 
Assesses 
Present/Absent/Not 
Assessed 
xx.x/Not 
Assessed 
0/1/2/3/4 
Positive/Negative 
x 
Positive/Negative 
01 
xx 
Positive/Negative/Not 
Assessed 
Yes/No/Not 
Assesses 
Present/Absent/Not 
Assessed 
xx.x/Not 
Assessed 
0/1/2/3/4 
Positive/Negative 
x 
Positive/Negative 
02 
xx 
Positive/Negative/Not 
Assessed 
Yes/No/Not 
Assesses 
Present/Absent/Not 
Assessed 
xx.x/Not 
Assessed 
0/1/2/3/4 
Positive/Negative 
x 
Positive/Negative 
03 
xx 
Positive/Negative/Not 
Assessed 
Yes/No/Not 
Assesses 
Present/Absent/Not 
Assessed 
xx.x/Not 
Assessed 
0/1/2/3/4 
Positive/Negative 
x 
Positive/Negative 
04 
xx 
Positive/Negative/Not 
Assessed 
Yes/No/Not 
Assesses 
Present/Absent/Not 
Assessed 
xx.x/Not 
Assessed 
0/1/2/3/4 
Positive/Negative 
x 
Positive/Negative 
Notes: Clinical diagnosis of BV is based on the presence of Amsel criteria (Positive when Amsel criteria >2). Vaginal pH > 4.5 will meet the pH criterion. 


Statistical Analysis Plan - DMID Protocol: 18-0017  
Version 1.0 
07MAR2022 
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PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Listing 7: 
Individual Time to Recurrent Bacterial Vaginosis (RBV) 
Subject ID 
Treatment Group 
Clinical Diagnosis of BV by 
Visit 4 [Window: Day 85-91] 
Time to RBV Definition 1a 
Time to RBV Definition 2b 
Time to RBV Definition 3c 
xxxxxx 
TOL-463 Vaginal Insert/Placebo 
Positive/Negative 
x 
x/N/A 
x/N/A 
a For rate of recurrence in both mITT and PP populations. For participants who experience BV recurrence by any visit, the time (in days) 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 with BV recurrence diagnosed off study, the time (in days) of BV recurrence will 
be defined as the midpoint between the early termination time point of a positive BV diagnosis off study (post-baseline) and the previous observed time-point. For the participants who did not 
experience BV recurrence by V4 will contribute the total duration they participated in the study (in days). The participants who withdrew or dropped out early will contribute the number of days they 
participated in the study. 
b For secondary objective 1 in mITT population. For the participants whose RBV was diagnosed at a scheduled or unscheduled visit, their 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. Participants with missing time to BV recurrence will be further excluded from analyses in mITT and PP 
populations (time to RBV denoted as N/A in this listing), including subjects who had BV recurrence diagnosed off study or subjects who were unknown whether they used any study products. 
c For secondary objective 1 in PP population. See b for definition of the time to RBV. 


Statistical Analysis Plan - DMID Protocol: 18-0017  
Version 1.0 
07MAR2022 
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PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Listing 8: 
Individual Bacterial Vaginosis (BV) Symptoms 
Subject ID 
Treatment Group 
Planned Time Point 
Actual Study Day 
Abnormal Vaginal Discharge 
Vaginal Odor 
xxxxx 
TOL-463 Vaginal Insert /Placebo 
Visit 0 - Screening  
(Day -15 to -8) 
xxx 
No/Yes, vaginal discharge consistent 
with BV/Yes, other: specify 
No/Yes, fishy odor consistent with 
BV/Yes, other: specify 
xxxxx 
TOL-463 Vaginal Insert /Placebo 
Visit 1 – Enrollment 
(Day 1) 
xxx 
No/Yes, vaginal discharge consistent 
with BV/Yes, other: specify 
No/Yes, fishy odor consistent with 
BV/Yes, other: specify 
xxxxx 
TOL-463 Vaginal Insert /Placebo 
Visit 2 – Month 2 
(Days 29-35) 
xxx 
No/Yes, vaginal discharge consistent 
with BV/Yes, other: specify 
No/Yes, fishy odor consistent with 
BV/Yes, other: specify 
xxxxx 
TOL-463 Vaginal Insert /Placebo 
Visit 3 – Month 3 
(Days 57-63) 
xxx 
No/Yes, vaginal discharge consistent 
with BV/Yes, other: specify 
No/Yes, fishy odor consistent with 
BV/Yes, other: specify 
xxxxx 
TOL-463 Vaginal Insert /Placebo 
Visit 4 – Month 4 
(Days 85-91) 
xxx 
No/Yes, vaginal discharge consistent 
with BV/Yes, other: specify 
No/Yes, fishy odor consistent with 
BV/Yes, other: specify 
xxxxx 
TOL-463 Vaginal Insert /Placebo 
Early Termination 
xxx 
No/Yes, vaginal discharge consistent 
with BV/Yes, other: specify 
No/Yes, fishy odor consistent with 
BV/Yes, other: specify 


Statistical Analysis Plan - DMID Protocol: 18-0017  
Version 1.0 
07MAR2022 
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PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Listing 9: 
Individual Response to Satisfaction Questionnaire 
Subject ID 
Treatment Group 
Study Day 
Completed 
Questionnaire 
Reason Not Done 
How Easy to Use 
How Often to 
Use 
How Convenient 
to Use 
Overall 
Satisfaction 
Would 
Use Again 
xxxxxx 
TOL-463 Vaginal 
Insert/Placebo 
xx 
Yes/No 
Subject refusal/Clinic 
error/Subject unable to 
comply/Investigator 
decision/Other/N/A (if 
completed) 
Extremely 
dissatisfied/ 
Very dissatisfied/ 
Dissatisfied/ 
Somewhat 
satisfied/ 
Satisfied/ 
Very satisfied/ 
Extremely 
satisfied 
Extremely 
dissatisfied/ 
Very dissatisfied/ 
Dissatisfied/ 
Somewhat 
satisfied/ 
Satisfied/ 
Very satisfied/ 
Extremely 
satisfied 
Extremely 
inconvenient/ 
Very inconvenient / 
Inconvenient / 
Somewhat 
convenient / 
Convenient / 
Very convenient / 
Extremely 
convenient 
Extremely 
dissatisfied/ 
Very dissatisfied/ 
Dissatisfied/ 
Somewhat 
satisfied/ 
Satisfied/ 
Very satisfied/ 
Extremely 
satisfied 
Yes/No 


Statistical Analysis Plan - DMID Protocol: 18-0017  
Version 1.0 
07MAR2022 
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PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Listing 10: 
Demographics Data 
[Implementation Note: If a subject is multi-racial, in “Race” column, note “Multiple: (list races, separated by a comma).” 
For studies in infants and young children, may be more appropriate to use weeks or months for age at enrollment.] 
Subject ID 
Treatment Group 
Age at Enrollment (years) 
Ethnicity 
Race 
xxxxxx 
TOL-463 Vaginal Insert/Placebo 
XX 
xxxxx 
xxxxxx 
xxxxxx 
TOL-463 Vaginal Insert/Placebo 
XX 
xxxxx 
xxxxxx 
xxxxxx 
TOL-463 Vaginal Insert/Placebo 
XX 
xxxxx 
xxxxxx 


Statistical Analysis Plan - DMID Protocol: 18-0017  
Version 1.0 
07MAR2022 
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PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Listing 11: 
Pre-Existing and Concurrent Medical Conditions 
Implementation Notes: 
1. Sort order will be by Actual Treatment Group, Subject ID, Concomitant Medication Number. 
Treatment 
Group 
 Subject ID 
MH Number 
Medical History Term 
Condition Start Day  
Condition End Day 
MedDRA System Organ Class 
MedDRA Preferred Term 
TOL-463 
Vaginal 
Insert/Placebo 
xxxxxx 
xx 
xxxxxx 
ddMMMyyyy 
ddMMMyyyy 
xxxxxx 
xxxxxx 
TOL-463 
Vaginal 
Insert/Placebo 
xxxxxx 
xx 
xxxxxx 
ddMMMyyyy 
ddMMMyyyy 
xxxxxx 
xxxxxx 
Note: This listing includes subjects who had pre-existing and/or concurrent medical conditions among all enrolled subjects. 


Statistical Analysis Plan - DMID Protocol: 18-0017  
Version 1.0 
07MAR2022 
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PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Listing 12: 
Concomitant Medications 
Treatment 
Group 
Subject ID 
CM 
Number 
Medication 
Medication Start 
Day 
Medication End 
Day 
Indication 
Taken for an AE? 
(AE Description; 
Number) 
Taken for a condition 
on Medical History? 
(MH Description; 
Number) 
ATC Level 1  
(ATC Level 2) 
TOL-463 
Vaginal 
Insert/Placebo 
xxxxxx 
xx 
xxxxxx 
ddMMMyyyy 
ddMMMyyyy 
xxxxxx 
Yes/No 
xxxxx; xx 
Yes/No 
xxxxx; xx 
xxxxxx 
(xxxxxx) 
TOL-463 
Vaginal 
Insert/Placebo 
xxxxxx 
xx 
xxxxxx 
ddMMMyyyy 
ddMMMyyyy 
xxxxxx 
Yes/No 
xxxxx; xx 
Yes/No 
xxxxx; xx 
xxxxxx 
TOL-463 
Vaginal 
Insert/Placebo 
xxxxxx 
xx 
xxxxxx 
ddMMMyyyy 
ddMMMyyyy 
xxxxxx 
Yes/No 
xxxxx; xx 
Yes/No 
xxxxx; xx 
(xxxxxx) 


Statistical Analysis Plan - DMID Protocol: 18-0017  
Version 1.0 
07MAR2022 
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PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Listing 13: 
Screening and Baseline Gynecologic and Sexual History - All Enrolled Subjects 
Treatment 
Group 
Subject ID 
Screening 
Baseline 
Treated for BV in 
the Past 30 Days 
Currently Use 
Sanitary Product 
No. of times has 
the subject had 
BV in the past 
12 months 
First Day of Last 
Menstrual Perioda 
Douched or 
Applied Any 
Intravaginal 
Products or 
Medications 
Had Sex Since 
Screening Visit 
Type of Sex 
How often did the 
subject use a 
condom for 
Vaginal Sex? 
TOL-463 
Vaginal 
Insert 
/Placebo 
xxxxxx 
Yes/No 
[Oral Metronidazole, 
Vaginal 
Metroge,Vaginal 
Clindamycin, 
Other:Specify] 
Yes/N/A 
[Pads/pantyliners, 
Menstrual Cups, 
Tampons, Other: 
Specify] 
x 
DDMMMYYY/N/A 
Yes/No 
Yes/No 
Vaginal sex, 
Receptive oral 
sex, 
Anal/rectal sex/ 
N/A 
Never/Less than 
50% of the 
time/About 50% of 
the time/ More 
than 50% of the 
time/Always/ N/A 
TOL-463 
Vaginal 
Insert 
/Placebo 
xxxxxx 
Yes/No 
[Oral Metronidazole, 
Vaginal 
Metroge,Vaginal 
Clindamycin, 
Other:Specify] 
Yes/N/A 
[Pads/pantyliners, 
Menstrual Cups, 
Tampons, Other: 
Specify] 
x 
DDMMMYYY/N/A 
Yes/No 
Yes/No 
Vaginal sex, 
Receptive oral 
sex, 
Anal/rectal sex/ 
N/A 
Never/Less than 
50% of the 
time/About 50% of 
the time/ More 
than 50% of the 
time/Always/ N/A 
a If the subject did not have period since screening, use the response collected at the screening visit; N/A if subject is post-menopausal or amenorrheic on current hormonal birth control method. 


Statistical Analysis Plan - DMID Protocol: 18-0017  
Version 1.0 
07MAR2022 
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PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Listing 14: 
Follow-up Gynecologic and Sexual History - All Enrolled Subjects 
Treatment Group Subject ID 
Visit 
Study Day 
Douched or Applied Any Intravaginal 
Products or Medications Since Last Visit 
Had Sex Since Last Visit 
Type of Sex (Sex in the Past 
24 Hours before Visit) 
How often did the subject use 
a condom for Vaginal Sex? 
TOL-463 Vaginal 
Insert /Placebo 
xxxxxx 
xx 
xx 
Yes/No  
Yes/No 
Vaginal sex (Yes/No), 
Receptive oral sex (Yes/No), 
Anal/rectal sex (Yes/No)/ 
N/A 
Never/Less than 50% of the 
time/About 50% of the time/ 
More than 50% of the 
time/Always/ N/A 
TOL-463 Vaginal 
Insert /Placebo 
xxxxxx 
xx 
xx 
Yes/No  
Yes/No 
Vaginal sex (Yes/No), 
Receptive oral sex (Yes/No), 
Anal/rectal sex (Yes/No),/ 
N/A 
Never/Less than 50% of the 
time/About 50% of the time/ 
More than 50% of the 
time/Always/ N/A 


Statistical Analysis Plan - DMID Protocol: 18-0017  
Version 1.0 
07MAR2022 
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PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Listing 15: 
Compliance Data 
Implementation Notes: 
Continue for all subjects. 
If all subjects received the correct treatment, only display a single “Treatment Group” column. 
Include data at unscheduled visits. 
Study Days of Inserts Administration column: concatenate study days by a comma. 
Sort by planned treatment group, USUBJID where all subjects who completed the study listed before all subject who terminated the study, Visit number. 
Planned Treatment 
Group  
Actual Treatment 
Group 
Subject ID  
Study Day of 
Completion /Early 
Termination  
Visit 
Number of Inserts 
Used/Unused 
Study Days of 
Insert 
Administration 
Compliant Since 
Last Visita 
(Assessment Day) 
Compliance 
Determination 
Throughout the 
Studyb 
TOL-463 Vaginal 
Insert/Placebo 
TOL-463 Vaginal 
Insert/Placebo 
xxxxxx 
x / N/A or N/A / x 
02 
x/x 
x, x, x, x, x, x, x, x 
Yes/No (x) 
Yes/No 
03 
x/x 
x, U, x, x, x, x, x, x 
Yes/No (x) 
04 
x/x 
x, x, x, x, x, x 
Yes/No (x) 
Notes: For early terminated participants, compliance with study treatment will be determined through study participation. 
When a study day of insert administration is unknown, it is denoted by “U”. 
a The participant did not miss >=2 consecutive or >= 3 nonconsecutive doses of IP since the last assessment, as recorded in data collection form. 
b For cases that could not be programmatically determined, the determination of treatment compliance throughout the study was provided by a blinded case review committee. 


Statistical Analysis Plan - DMID Protocol: 18-0017  
Version 1.0 
07MAR2022 
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PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Listing 16: 
Pregnancy Reports  
Pregnancy Reports – Maternal Information 
Treatment 
Group 
Subject ID  
Pregnancy 
Number 
Study Day 
Corresponding 
to Estimated 
Date of 
Conception 
Source of 
Maternal 
Information 
Pregnancy 
Status 
Mother’s 
Pre-
Pregnancy 
BMI 
Mother’s 
Weight 
Gain 
During 
Pregnancy 
Tobacco, 
Alcohol, or 
Drug Use 
During 
Pregnancy? 
Medications 
During 
Pregnancy? 
Maternal 
Complications 
During 
Pregnancy? 
Maternal 
Complications 
During 
Labor, 
Delivery, or 
Post-Partum? 
TOL-463 
Vaginal 
Insert/Placebo 
xxxxxx 
xx 
xx 
xxx 
xxx 
xxx 
xxx 
Y/N 
Y/N 
Y/N 
Y/N 
TOL-463 
Vaginal 
Insert/Placebo 
xxxxxx 
xx 
xx 
xxx 
xxx 
xxx 
xxx 
Y/N 
Y/N 
Y/N 
Y/N 
Note: Maternal Complications are included in the Adverse Event Listing. Medications taken during pregnancy are included in the Concomitant Medications Listing. 
Pregnancy Reports – Gravida and Para 
 
 
 
Live Births 
 
 
 
 
 
Subject 
ID 
Pregnancy 
Number 
Gravida 
Extremely 
Preterm 
Births 
Very 
Preterm 
Births 
Early 
Preterm 
Births 
Late 
Preterm 
Births 
Early 
Term 
Births 
Full 
Term 
Births 
Late 
Term 
Births 
Post 
Term 
Births 
Still 
Births 
Spontaneous 
Abortion/ 
Miscarriage 
Elective 
Abortions 
Therapeutic 
Abortions 
Major 
Congenital 
Anomaly with 
Previous 
Pregnancy? 
xxxxxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
Y/N 
xxxxxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
Y/N 
Note: Gravida includes the current pregnancy, para events do not. 


Statistical Analysis Plan - DMID Protocol: 18-0017  
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07MAR2022 
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PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Pregnancy Reports – Live Birth Outcomes 
Subject 
ID 
Pregnancy 
Number 
Fetus 
Number 
Pregnancy 
Outcome 
(for this 
Fetus) 
Fetal 
Distress 
During 
Labor and 
Delivery? 
Delivery 
Method 
Gestational 
Age at Live 
Birth  
Size for 
Gestational 
Age 
Apgar 
Score, 1 
minute 
Apgar 
Score, 5 
minutes 
Cord 
pH 
Congenital 
Anomalies? 
Illnesses/ 
Hospitalizations 
within 1 Month of 
Birth? 
xxxxxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
Y/N 
xxx 
xxxxxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
Y/N 
xxx 
Note: Congenital Anomalies are included in the Adverse Event listing. 
 
Pregnancy Reports – Still Birth Outcomes 
Subject 
ID 
Date of 
Initial 
Report 
Fetus 
Number 
Pregnancy 
Outcome (for 
this Fetus) 
Fetal 
Distress 
During 
Labor and 
Delivery? 
Delivery 
Method 
Gestational 
Age at Still 
Birth 
Size for 
Gestational 
Age 
Cord 
pH 
Congenital 
Anomalies? 
Autopsy 
Performed? 
If Autopsy, 
Etiology for 
Still Birth 
Identified? 
xxxxxx 
xx 
xxx 
xxxxxxx 
Y/N 
xxxxxxx 
xxx 
xxx 
xx 
Y/N 
Y/N 
xxxxxxx 
 
Pregnancy Reports – Spontaneous, Elective, or Therapeutic Abortion Outcomes 
Subject 
ID 
Date of Initial 
Report 
Fetus Number 
Pregnancy Outcome 
(for this Fetus) 
Gestational Age at 
Termination 
Abnormality in Product of Conception? 
Reason for Therapeutic 
Abortion 
xxxxxx 
xx 
xxx 
xxxxx 
xxxx 
Y/N 
xxxxxxx 


Statistical Analysis Plan - DMID Protocol: 18-0017  
Version 1.0 
07MAR2022 
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PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Listing 17: 
Vital Signs 
Planned Time Point 
Actual Study Day 
Temperature 
(oC) 
Systolic Blood 
Pressure 
(mmHg) 
Diastolic Blood 
Pressure 
(mmHg) 
Weight  
(kg) 
Height 
(cm) 
Treatment Group:    , Subject ID: 
Visit 0 - Screening  
(Day -15 to -8) 
x 
xx.x 
(Grade 1/Grade2/Grade3) 
xx 
(Grade 1/Grade2/Grade3) 
xx 
(Grade 1/Grade2/Grade3) 
xx.x 
xx.x 
Visit 1 – Enrollment 
(Day 1) 
x 
xx.x 
(Grade 1/Grade2/Grade3) 
xx 
(Grade 1/Grade2/Grade3) 
xx 
(Grade 1/Grade2/Grade3) 
xx.x 
xx.x 
Visit 2 – Month 2 
(Days 29-35) 
x 
xx.x 
(Grade 1/Grade2/Grade3) 
xx 
(Grade 1/Grade2/Grade3) 
xx 
(Grade 1/Grade2/Grade3) 
N/A 
N/A 
Visit 3 – Month 3 
(Days 57-63) 
x 
xx.x 
(Grade 1/Grade2/Grade3) 
xx 
(Grade 1/Grade2/Grade3) 
xx 
(Grade 1/Grade2/Grade3) 
N/A 
N/A 
Visit 4 – Month 4 
(Days 85-91) 
x 
xx.x 
(Grade 1/Grade2/Grade3) 
xx 
(Grade 1/Grade2/Grade3) 
xx 
(Grade 1/Grade2/Grade3) 
N/A 
N/A 
Early Termination 
x 
xx.x 
(Grade 1/Grade2/Grade3) 
xx 
(Grade 1/Grade2/Grade3) 
xx 
(Grade 1/Grade2/Grade3) 
N/A 
N/A 
Notes: Oral temperature and blood pressure were no longer collected at any study visits beginning with protocol version 2. Weight and Height were collected at Visit 0/Screening or Visit 1/Enrollment. 
The grading scale is shown in the parentheses beneath the measurement when the measurement is in an abnormal scale. 
Temperature (oral, °C) Grade 0 Normal: <38.0; Grade 1 Mild: 38.0 - 38.4; Grade 2 Moderate: 38.5 - 38.9; Grade 3 Severe: >38.9. 
Hypertension (systolic) – mmHg Grade 0 Normal: 90-140; Grade 1 Mild: 141-150; Grade 2 Moderate: 151-160; Grade 3 Severe: >160. 
Hypotension (systolic) – mmHg Grade 0 Normal: 90-140; Grade 1 Mild: 85-89; Grade 2 Moderate: 80-84; Grade 3 Severe: <80. 
Hypertension (diastolic) – mmHg Grade 0 Normal: <91; Grade 1 Mild: 91-95; Grade 2 Moderate: 96-100; Grade 3 Severe: >100. 


Statistical Analysis Plan - DMID Protocol: 18-0017  
Version 1.0 
07MAR2022 
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PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Listing 18: 
Abnormal Physical Exam Findings 
Treatment Group 
Subject ID 
Planned Time 
Point 
Actual 
Study Day 
Body System 
Abnormal Finding 
Reported as an AE? 
(AE Number: 
Description) 
TOL-463 Vaginal 
Insert/Placebo 
xxxxxxx 
Visit 1 – Enrollment 
(Day 1) 
xxx 
xxxxxxxx 
Abdomen/Cardiovascular/heart/Extremities/ General appearance/HEENT/ 
Lymph node/Musculoskeletal/Neck/Neurological/Pulmonary/chest/Skin 
N/A 
TOL-463 Vaginal 
Insert/Placebo 
xxxxxxx 
Visit 2 – Month 2 
(Days 29-35) 
xxx 
xxxxxxxx 
Abdomen/Cardiovascular/heart/Extremities/ General appearance/HEENT/ 
Lymph node/Musculoskeletal/Neck/Neurological/Pulmonary/chest/Skin 
No / Yes, AE,#: xxxxx 
TOL-463 Vaginal 
Insert/Placebo 
xxxxxxx 
Visit 3 – Month 3 
(Days 57-63) 
xxx 
xxxxxxxx 
Abdomen/Cardiovascular/heart/Extremities/ General appearance/HEENT/ 
Lymph node/Musculoskeletal/Neck/Neurological/Pulmonary/chest/Skin 
No / Yes, AE,#: xxxxx 
TOL-463 Vaginal 
Insert/Placebo 
xxxxxxx 
Visit 4 – Month 4 
(Days 85-91) 
xxx 
xxxxxxxx 
Abdomen/Cardiovascular/heart/Extremities/ General appearance/HEENT/ 
Lymph node/Musculoskeletal/Neck/Neurological/Pulmonary/chest/Skin 
No / Yes, AE,#: xxxxx 
TOL-463 Vaginal 
Insert/Placebo 
xxxxxxx 
Early Termination 
xxx 
xxxxxxxx 
Abdomen/Cardiovascular/heart/Extremities/ General appearance/HEENT/ 
Lymph node/Musculoskeletal/Neck/Neurological/Pulmonary/chest/Skin 
No / Yes, AE,#: xxxxx 
Note: At the enrollment visit, V1, physical exam will include weight and height measurements.  At all follow-up visits, a targeted physical exam is only performed when clinically indicated 


Statistical Analysis Plan - DMID Protocol: 18-0017  
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07MAR2022 
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PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Listing 19: 
Listing of Clinical Diagnosis of Vulvovaginal Candidiasis (VVC) and Culture Confirmed VVC 
Subject ID 
Treatment 
Group 
Planned 
Time Point 
Actual 
Study Day 
Edema 
 (Severity) 
Erythema 
 (Severity) 
 Excoriation 
(Severity) 
 Itching 
(Severity) 
Burning 
(Severity) 
Irritation 
(Severity) 
KOH Wet 
Mount: 
Yeast 
(Budding, 
Branching, 
Hyphae) 
Clinical 
Diagnosis of 
 VVC 
Yeast 
Culture 
Confirmed 
VVCa 
Species of 
Yeast 
Forms, If 
Positive 
Yeast 
Culture 
xxxxx 
TOL-463 
Vaginal 
Insert 
/Placebo 
Visit 0 – 
Screening 
(Day -15 to 
-8) 
xxx 
Absent/Mild/
Moderate/ 
Severe 
Absent/Mild/
Moderate/ 
Severe 
Absent/Mild/
Moderate/ 
Severe 
None/Mild/
Moderate/ 
Severe 
None/Mild/
Moderate/ 
Severe 
None/Mild/
Moderate/ 
Severe 
Absent/Prese
nt 
Yes/No 
Positive/Neg
ative /N/A 
C. albicans/ 
C. glabrata/ 
Other: 
Specify/N/A 
xxxxx 
TOL-463 
Vaginal 
Insert 
/Placebo 
Visit 1 – 
Enrollment 
(Day 1) 
xxx 
Absent/Mild/
Moderate/ 
Severe 
Absent/Mild/
Moderate/ 
Severe 
Absent/Mild/
Moderate/ 
Severe 
None/Mild/
Moderate/ 
Severe 
None/Mild/
Moderate/ 
Severe 
None/Mild/
Moderate/ 
Severe 
Absent/Prese
nt 
Yes/No 
Positive/Neg
ative /N/A 
C. albicans/ 
C. glabrata/ 
Other: 
Specify/N/A 
xxxxx 
TOL-463 
Vaginal 
Insert 
/Placebo 
Visit 2 – 
Month 2 
(Days 29-
35) 
xxx 
Absent/Mild/
Moderate/ 
Severe 
Absent/Mild/
Moderate/ 
Severe 
Absent/Mild/
Moderate/ 
Severe 
None/Mild/
Moderate/ 
Severe 
None/Mild/
Moderate/ 
Severe 
None/Mild/
Moderate/ 
Severe 
Absent/Prese
nt 
Yes/No 
Positive/Neg
ative /N/A 
C. albicans/ 
C. glabrata/ 
Other: 
Specify/N/A 
xxxxx 
TOL-463 
Vaginal 
Insert 
/Placebo 
Visit 3 – 
Month 3 
(Days 57-
63) 
xxx 
Absent/Mild/
Moderate/ 
Severe 
Absent/Mild/
Moderate/ 
Severe 
Absent/Mild/
Moderate/ 
Severe 
None/Mild/
Moderate/ 
Severe 
None/Mild/
Moderate/ 
Severe 
None/Mild/
Moderate/ 
Severe 
Absent/Prese
nt 
Yes/No 
Positive/Neg
ative /N/A 
C. albicans/ 
C. glabrata/ 
Other: 
Specify/N/A 
xxxxx 
TOL-463 
Vaginal 
Insert 
/Placebo 
Visit 4 – 
Month 4 
(Days 85-
91) 
xxx 
Absent/Mild/
Moderate/ 
Severe 
Absent/Mild/
Moderate/ 
Severe 
Absent/Mild/
Moderate/ 
Severe 
None/Mild/
Moderate/ 
Severe 
None/Mild/
Moderate/ 
Severe 
None/Mild/
Moderate/ 
Severe 
Absent/Prese
nt 
Yes/No 
Positive/Neg
ative /N/A 
C. albicans/ 
C. glabrata/ 
Other: 
Specify/N/A 
xxxxx 
TOL-463 
Vaginal 
Insert 
/Placebo 
Early 
Termination 
xxx 
Absent/Mild/
Moderate/ 
Severe 
Absent/Mild/
Moderate/ 
Severe 
Absent/Mild/
Moderate/ 
Severe 
None/Mild/
Moderate/ 
Severe 
None/Mild/
Moderate/ 
Severe 
None/Mild/
Moderate/ 
Severe 
Absent/Prese
nt 
Yes/No 
Positive/Neg
ative /N/A 
C. albicans/ 
C. glabrata/ 
Other: 
Specify/N/A 
a Yeast culture was not performed if subject did not have clinical diagnosis of VVC, along with other reasons that the culture was not done, all denoted as N/A. 


Statistical Analysis Plan - DMID Protocol: 18-0017  
Version 1.0 
07MAR2022 
112 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Listing 20: 
Pelvic Examination Findings 
Treatment Group 
Subject ID 
Planned Time Point 
Actual Study 
Day 
 Genital lesion consistent with 
active HSV or HPV 
 Motile 
Trichomonads 
Abnormal Findings 
Reported as 
an AE? 
(AE 
Number: 
Description) 
TOL-463 Vaginal 
Insert/Placebo 
xxxxxxx 
Visit 0 - Screening  
(Day -15 to -8) 
xxx 
Present/Absent 
Present/Absent 
xxxxxx/None 
No / Yes, 
AE,#: xxxxx 
TOL-463 Vaginal 
Insert/Placebo 
xxxxxxx 
Visit 1 – Enrollment 
(Day 1) 
xxx 
Present/Absent 
Present/Absent 
xxxxxx/None 
No / Yes, 
AE,#: xxxxx 
TOL-463 Vaginal 
Insert/Placebo 
xxxxxxx 
Visit 2 – Month 2 
(Days 29-35) 
xxx 
Present/Absent 
Present/Absent 
xxxxxx/None 
No / Yes, 
AE,#: xxxxx 
TOL-463 Vaginal 
Insert/Placebo 
xxxxxxx 
Visit 3 – Month 3 
(Days 57-63) 
xxx 
Present/Absent 
Present/Absent 
xxxxxx/None 
No / Yes, 
AE,#: xxxxx 
TOL-463 Vaginal 
Insert/Placebo 
xxxxxxx 
Visit 4 – Month 4 
(Days 85-91) 
xxx 
Present/Absent 
Present/Absent 
xxxxxx/None 
No / Yes, 
AE,#: xxxxx 
TOL-463 Vaginal 
Insert/Placebo 
xxxxxxx 
Early Termination 
xxx 
Present/Absent 
Present/Absent 
xxxxxx/None 
No / Yes, 
AE,#: xxxxx 


Statistical Analysis Plan - DMID Protocol: 18-0017  
Version 1.0 
07MAR2022 
113 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Listing 21: 
Results of STI Tests and Pap Smear at Screening/Enrollment – All Enrolled Subjects 
Treatment Group 
Subject ID 
Normal or ASCUS 
HPV Negative Pap 
Test Within the 
Past 3 Yearsa 
Pap Smear Performed 
(Study Day) 
NAAT testing for chlamydia 
(Study Day) 
NAAT testing for gonorrhea 
(Study Day) 
NAAT testing for 
trichomoniasis 
(Study Day) 
TOL-463 Vaginal 
Insert/Placebo 
xxxxxxx 
Yes/No/N/A 
Normal / ASCUS HPV 
Negative/ Abnormal: specify 
(-x) 
Negative/Positive/Indeterminate 
(-x) 
Negative/Positive/Indeterminate 
(-x) 
Negative/Positive/Indeterminate 
(-x) 
a N/A if the subject is <21 years of age or has had a hysterectomy without history of cervical intraepithelial neoplasia grade 2+ (CIN2+) in the past 20 years.