Clinical trial NCT02766023
Conditions: Bacterial Vaginosis
Keywords: CTV-05 LACTIN-V Lactobacillus MetroGel® Vaginitis
Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Start date: 2016-06-03; Completion date: 2019-02-11
Enrollment: 228 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This Phase 2b trial is designed to provide a screening evaluation for the hypothesis that, following a 5-day treatment with MetroGel® to treat BV, L. crispatus CTV-05 (LACTIN-V, Osel, Inc.) administered at 2 x 10\^9 cfu/dose using a vaginal applicator reduces the 12-week incidence of BV recurrence when compared to placebo. The primary objectives of this study are: 1) To estimate the efficacy of repeated doses of LACTIN-V (2 x 10\^9 cfu/dose) as compared to placebo in preventing BV recurrence by 12 weeks following treatment of BV with MetroGel vaginal gel (MetroGel). 2) To assess the safety of LACTIN-V over 24 weeks by comparing the incidence of AEs between individuals randomized to LACTIN-V or placebo.

Detailed description:
This is a Phase II-b multicenter randomized double-blind placebo-controlled trial to assess the efficacy of repeated doses of LACTIN-V compared to placebo in preventing BV recurrence in women diagnosed with BV. The study will also assess the safety of LACTIN-V by comparing the incidence of AEs between women randomized to LACTIN-V or placebo. The study plans to enroll 228 non-pregnant, pre-menopausal women age 18 to 45 years. Women will be randomized 2:1 to receive LACTIN-V or placebo. Potentially eligible women will start a standard 5-day course of MetroGel. Women will return to the study clinic within 2 days after completing the 5-day course of MetroGel to re-evaluate eligibility criteria and review the BV test results from the screening visit. Women with Amsel criteria \> /=3 and Nugent score 4-10 will be instructed to administer the LACTIN-V or placebo at home for 5 consecutive days and then twice weekly for 10 weeks. The primary objectives of this study are: 1) To estimate the efficacy of repeated doses of LACTIN-V (2 x109 cfu/dose) as compared to placebo in preventing BV recurrence by 12 weeks following treatment of BV with MetroGel vaginal gel (MetroGel). 2) To assess the safety of LACTIN-V over 24 weeks by comparing the incidence of AEs between individuals randomized to LACTIN-V or placebo. Secondary objectives are: 1) To investigate the colonization of LACTIN-V (presence of L. crispatus CTV-05 in the vaginal specimen) and fluctuations over 12 weeks, in relation to menses and sexual intercourse 2) To evaluate user acceptability and tolerability of LACTIN-V over 12 weeks, including perceptions around method of delivery and dosing. 3) To measure long-term colonization of LACTIN-V at 24 weeks (12 weeks after last dosing) 4) To estimate the long-term efficacy of repeated doses of LACTIN-V (2 x 109 cfu/dose) as compared to placebo in preventing BV recurrence at 24 weeks (12 weeks after last dosing)

Arms: arm 1: Subjects receive 5-day course of metronidazole gel 7.5 mg/gm daily applied vaginally. Subjects then receive LACTIN-V 2x10\^9 cfu/dose applied vaginally for 5 days then twice weekly for 10 weeks. N=152 arm 2: Subjects receive 5-day course of metronidazole gel 7.5 mg/gm daily applied vaginally. Subjects then receive placebo applied vaginally for 5 days then twice weekly for 10 weeks. N=76
Interventions: intervention 1: Lactobacillus crispatus CTV-05 intervention 2: Metronidazole intervention 3: Placebo
Intervention descriptions: intervention 1: LACTIN-V is an intravaginal live biotherapeutic product composed of Lactobacillus crispatus CTV-05 (LACTIN-V, Osel Inc) in a vaginal applicator. Subjects receive 2x10\^9 cfu/dose applied vaginally daily x 5 days then twice weekly x 10 weeks. intervention 2: Metronidazole is a nitroimidazole. Metronidazole gel (MetroGel) is applied vaginally 7.5 mg/gm daily for 5 days intervention 3: Placebo formulation applied vaginally, daily x 5 days then twice weekly x 10 weeks.

Protocol documents:
Prot_000.pdf: 
Phase II-b Randomized Double-Blind Placebo-Controlled 
Trial of Lactobacillus crispatus CTV-05 (LACTIN-V) to Prevent 
the Recurrence of Bacterial Vaginosis  
A Study of the Sexually Transmitted Infection Clinical Trials Group  
(STI CTG) 
DMID Protocol Number: 14-0029 
DMID Funding Mechanism: 
Contract Number: HHSN272201 3000141 
Task Order Number: HHSN27200003 
Pharmaceutical Support Provided by: Osel, Inc. 
IND Sponsor: 
Division of Microbiology and Infectious Diseases 
National Institute of Allergy and Infectious Diseases 
National Institutes of Health 
5601 Fishers Lane 
Bethesda, MD 20892 
Principal Investigator: Craig R. Cohen, MD, MPH 
DMID Clinical Project Manager: Jonathan Glock, MPH 
DMID Medical Monitor: Soju Chang, MD 
 DMID Medical Officer: Jill Long, MD, MPH   
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STATEMENT OF COMPLIANCE 
The study will be carried out in accordance with Good Clinical Practice (GCP) as required by the 
following  
• 
United States (US) Code of Federal Regulations (CFR) applicable to clinical studies 
(45 CFR Part 46; 21 CFR Part 50, 21 CFR Part 56, and 21 CFR Part 312) 
• 
ICH E6; 62 Federal Register 25691 (1997)  
• 
NIH Clinical Terms of Award 
All key personnel (all individuals responsible for the design and conduct of this study) have 
completed Human Subjects Protection Training. 


 
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SIGNATURE PAGE 
The signature below constitutes the approval of this protocol and the attachments, and provides 
the necessary assurances that this trial will be conducted according to all stipulations of the 
protocol, including all statements regarding confidentiality, and according to local legal and 
regulatory requirements and applicable US federal regulations and ICH guidelines. 
 
Site Investigator: 
 
Signed: 
 
Date: 
 
 
Name 
Title 
 
 
 
 


 
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TABLE OF CONTENTS 
Page 
STATEMENT OF COMPLIANCE ................................................................................................. i 
SIGNATURE PAGE .................................................................................................................... ii 
LIST OF ABBREVIATIONS ........................................................................................................ vi 
PROTOCOL SUMMARY .......................................................................................................... viii 
SCHEMATIC OF STUDY DESIGN: ........................................................................................... ix 
1.0 
KEY ROLES ....................................................................................................................... 1 
2.0 
BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE ...................................... 4 
2.1 
Background Information .......................................................................................... 4 
2.2 
Rationale ................................................................................................................ 6 
2.3 
Potential Risks and Benefits ................................................................................... 8 
2.3.1 
Potential Risks ............................................................................................ 8 
2.3.2 
Known Potential Benefits........................................................................... 11 
3.0 
OBJECTIVES ................................................................................................................... 12 
3.1 
Study Objectives ................................................................................................... 12 
3.2 
Study Outcome Measures .................................................................................... 12 
3.2.1 
Primary Efficacy Outcome Measure .......................................................... 12 
3.2.2 
Primary Safety Outcome Measure ............................................................. 12 
3.2.3 
Secondary Efficacy Outcome Measures .................................................... 13 
4.0 
STUDY DESIGN .............................................................................................................. 14 
5.0 
STUDY ENROLLMENT AND WITHDRAWAL .................................................................. 15 
5.1 
Subject Inclusion Criteria ...................................................................................... 15 
5.2 
Subject Exclusion Criteria ..................................................................................... 16 
5.3 
Treatment Assignment Procedures ....................................................................... 17 
5.3.1 
Randomization Procedures ....................................................................... 17 
5.3.2 
Masking Procedures .................................................................................. 17 
5.3.3 
Reasons for Withdrawal ............................................................................ 17 
5.3.4 
Handling of Withdrawals ............................................................................ 18 
5.3.5 
Termination of Study ................................................................................. 19 
6.0 
STUDY PRODUCT .......................................................................................................... 20 
6.1 
Study Product Description .................................................................................... 20 
6.1.1 
Acquisition ................................................................................................. 20 
6.1.2 
Formulation, Packaging, and Labeling....................................................... 20 
6.2 
Dosage, Preparation, and Administration of Study Product ................................... 22 
6.3 
Accountability Procedures for the Study Investigational Product ........................... 22 
6.4 
Assessment of Subject Compliance with Study Product ....................................... 22 
6.5 
Concomitant Medications/Treatments ................................................................... 22 


 
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7.0 
STUDY SCHEDULE ......................................................................................................... 24 
7.1 
Screening Visit 0 (Day -30 to Day -5) .................................................................... 24 
7.1.1 
Rescreening Visit ...................................................................................... 26 
7.2 
Enrollment Visit 1 (Day 1) ..................................................................................... 27 
7.3 
Follow-up Study Visit 2, Week 4, Day 28 (Allowable Days 21-35) ......................... 30 
7.4 
Follow-up Study Visit 3, Week 8, Day 56 (Allowable Days 49-63) ......................... 31 
7.5 
Follow-Up Study Visit 4, Week 12, Day 84 (Allowable Days 77-91) ...................... 31 
7.6 
Telephone Interview, Visit 5, Week 16, Day 112 (Allowable Days 105-119) .......... 33 
7.7 
Telephone Interview, Visit 6, Week 20, Day 140 (Allowable Days 133-146) .......... 33 
7.8 
Final Study Visit 7, Week 24, Day 168 (Allowable Days 161-175) ......................... 34 
7.9 
Study Product Discontinuation/Early Termination Visit .......................................... 35 
7.10 
Unscheduled Visit ................................................................................................. 36 
8.0 
STUDY PROCEDURES/EVALUATIONS ......................................................................... 39 
8.1 
Clinical Evaluations ............................................................................................... 39 
8.2 
Laboratory Evaluations ......................................................................................... 39 
8.2.1 
Clinical Laboratory Evaluations ................................................................. 39 
8.2.2 
Special Assays or Procedures ................................................................... 39 
8.2.3 
Specimen Preparation, Handling, and Shipping ........................................ 39 
9.0 
ASSESSMENT OF SAFETY ............................................................................................ 40 
9.1 
Specification of Safety Parameters ....................................................................... 40 
9.2 
Methods and Timing for Assessing, Recording, and Analyzing Safety 
Parameters ........................................................................................................... 40 
9.2.1 
Adverse Events ......................................................................................... 40 
9.2.2 
Serious Adverse Events ............................................................................ 41 
9.2.3 
Procedures to be followed in the Event of Abnormal Laboratory Test 
Values or Abnormal Clinical Findings ........................................................ 42 
9.3 
Reporting Procedures ........................................................................................... 42 
9.3.1 
Serious Adverse Events ............................................................................ 42 
9.3.2 
Regulatory Reporting for Studies Conducted Under DMID-Sponsored 
IND ............................................................................................................ 43 
9.3.3 
Reporting of Pregnancy ............................................................................. 43 
9.4 
Type and Duration of Follow-up of Subjects after Adverse Events ........................ 44 
9.5 
Halting Rules ........................................................................................................ 44 
9.6 
Safety Oversight (ISM plus DSMB) ....................................................................... 44 
10.0 CLINICAL MONITORING ................................................................................................. 45 
10.1 
Site Monitoring Plan .............................................................................................. 45 
11.0 STATISTICAL CONSIDERATIONS .................................................................................. 46 
11.1 
Introduction ........................................................................................................... 46 
11.2 
Study Objectives and Outcome Measures ............................................................ 46 
11.3 
Study Hypotheses ................................................................................................. 46 
11.4 
Sample Size Considerations ................................................................................. 47 
11.5 
Planned Interim Analyses ..................................................................................... 47 


 
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11.5.1 Safety Review ........................................................................................... 47 
11.5.2 Efficacy Review ......................................................................................... 47 
11.6 
Final Analysis Plan ............................................................................................... 47 
11.6.1 General Principles ..................................................................................... 47 
11.6.2 Data Analysis Populations ......................................................................... 48 
11.6.3 Safety Analyses ........................................................................................ 49 
11.6.4 Efficacy Analyses ...................................................................................... 50 
12.0 SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/ DOCUMENTS ................. 53 
13.0 QUALITY CONTROL AND QUALITY ASSURANCE ........................................................ 54 
14.0 ETHICS/PROTECTION OF HUMAN SUBJECTS ............................................................ 55 
14.1 
Ethical Standard ................................................................................................... 55 
14.2 
Institutional Review Board .................................................................................... 55 
14.3 
Informed Consent Process ................................................................................... 55 
14.4 
Exclusion of Women, Minorities, and Children (Special Populations) .................... 55 
14.5 
Subject Confidentiality .......................................................................................... 56 
14.6 
Study Discontinuation ........................................................................................... 56 
14.7 
Future Use of Stored Specimens .......................................................................... 56 
15.0 DATA HANDLING AND RECORD KEEPING ................................................................... 57 
15.1 
Data Management Responsibilities ....................................................................... 57 
15.2 
Data Capture Methods .......................................................................................... 57 
15.3 
Types of Data ....................................................................................................... 57 
15.4 
Timing/Reports ..................................................................................................... 58 
15.5 
Study Records Retention ...................................................................................... 58 
15.6 
Protocol Deviations ............................................................................................... 58 
16.0 PUBLICATION POLICY ................................................................................................... 59 
17.0 LITERATURE REFERENCES .......................................................................................... 60 
APPENDICES ........................................................................................................................... 63 
 
Appendix A 
Schedule of Events 
 
Appendix B 
Division of AIDS Table for Grading the Severity of Adult and Pediatric  
 
 
 
Adverse Events, December 2004; Addendum 1: Female Genital Grading   
 
 
Table for Use in Microbicide Studies, November 2007 
 
Appendix C 
 DAIDS Toxicity Table for Grading the Severity of Adult and Pediatric  
 
 
 
Adverse Events, Version 1.0 - December 2004 (Clarification dated August  
 
 
2009)  


 
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LIST OF ABBREVIATIONS 
AE 
Adverse Event 
ATP 
According to Protocol 
βHCG 
BV 
Beta Human Chorionic Gonadotropin  
Bacterial Vaginosis 
CAPRISA 
CAR 
CC 
cfu 
CMH 
CI 
CRF 
CROMS 
DAIDS 
DHHS 
DMID 
Centre for the AIDS Programme of Research in South Africa 
Clinical Agents Repository 
Complete Case 
Colony Forming Units 
Cochran-Mantel-Haenszel 
Confidence Interval 
Case Report Form 
Clinical Research Operations and Management Support 
Division of AIDS, NIAID, NIH, DHHS 
Department of Health and Human Services 
Division of Microbiology and Infectious Diseases, NIAID, NIH, DHHS 
DSMB 
Data and Safety Monitoring Board 
ELISA 
FDA 
GCP 
Enzyme-linked Immunosorbent Assay 
Food and Drug Administration 
Good Clinical Practice 
GMP 
ICF 
Good Manufacturing Practice 
Informed Consent Form 
ICH 
ICMJE 
IDES 
IEC 
International Conference on Harmonisation 
International Committee of Medical Journal Editors 
Internet Data Entry System 
Independent or Institutional Ethics Committee 
IRB 
Institutional Review Board 
ISM 
Independent Safety Monitor 
ITT 
LACTIN-V 
LOCF 
MedDRA 
MetroGel 
mITT 
MOP 
Intent-to-treat 
Lactobacillus crispatus CTV-05 
Last Observation Carried Forward 
Medical Dictionary for Regulatory Activities 
MetroGel vaginal gel 
Modified Intent-to-Treat 
Manual of Procedures 
N 
Number (typically refers to participants) 
NIAID 
National Institute of Allergy and Infectious Diseases, NIH, DHHS 
NIH 
National Institutes of Health 
OCRA 
Office of Clinical Research Affairs, DMID, NIAID, NIH, DHHS 


 
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OHRP 
Office for Human Research Protections 
ORA 
Office of Regulatory Affairs, DMID, NIAID, NIH, DHHS 
OSEL 
pH 
PI 
Office of Science and Engineering Laboratories 
Potential Hydrogen 
Principal Investigator 
PP 
qPCR 
RR 
rUTI 
SAE 
SDCC 
Per Protocol 
Quantitative Polymerase Chain Reaction  
Rate Ratio 
Recurrent Urinary Tract Infection 
Serious Adverse Event 
Statistical and Data Coordinating Center 
SMC 
Safety Monitoring Committee 
SOP 
STAR 
STI 
STI-CTG 
US 
UTI 
Standard Operating Procedure 
Sexually Transmitted Infections Treatment and Research  
Sexually Transmitted Infection 
Sexually Transmitted Infections Clinical Trials Group 
United States 
Urinary Tract Infection 
 


 
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PROTOCOL SUMMARY 
Title:  
Phase II-b Randomized Double-Blind Placebo-Controlled Trial 
of Lactobacillus crispatus CTV-05 (LACTIN-V)  to Prevent the 
Recurrence of Bacterial Vaginosis 
Phase: 
II-b 
Population: 
228 non-pregnant, pre-menopausal women age 18 to 45 years 
diagnosed with bacterial vaginosis (BV) 
Number of Sites: 
Study Duration: 
Four U.S. sites  
72 weeks after enrollment of the first participant  
Participant Participation 
Duration: 
24 weeks per participant 
Description of Agent: 
 
 
 
 
 
 
Primary Objectives 
 
 
 
 
 
 
Secondary Objectives 
 
 
 
 
 
 
 
 
 
 
 
Exploratory Objective  
 
 
 
Description of Study Design:  
Time to Complete Enrollment: 
Lactobacillus (L.) crispatus CTV-05 (LACTIN-V) contains a 
naturally occurring vaginal strain of L. crispatus CTV-05, 
preserved as a powder applied by a vaginal applicator.  
LACTIN-V at 2 x 109 cfu/dose or matching placebo will be 
administered by vaginal applicator once daily for 5 consecutive 
days, followed by twice weekly for 10 consecutive additional 
weeks. 
1) To estimate the efficacy of repeated doses of LACTIN-V (2 x 
109 cfu/dose) as compared to placebo in preventing BV 
recurrence by 12 weeks following treatment of BV with 
MetroGel vaginal gel (MetroGel) 
2) To assess the safety of LACTIN-V over 24 weeks by 
comparing the incidence of AEs between individuals 
randomized to LACTIN-V or placebo 
1) To investigate the colonization of LACTIN-V (presence of L. 
crispatus CTV-05 in the vaginal specimen) and fluctuations 
over 12 weeks, in relation to menses and sexual intercourse 
2) To evaluate user acceptability and tolerability of LACTIN-V 
over 12 weeks, including perceptions around method of 
delivery and dosing  
3) To measure long-term colonization of LACTIN-V at 24 
weeks (12 weeks after last dosing) 
4) To estimate the long-term efficacy of repeated doses of 
LACTIN-V (2 x 109 cfu/dose) as compared to placebo in 
preventing BV recurrence at 24 weeks (12 weeks after last 
dosing) 
To estimate the efficacy of repeated doses of LACTIN-V (2 x 109 
cfu/dose) as compared to placebo in preventing repeated (more 
than one) episodes of BV recurrence up to 12 weeks following 
treatment of BV with MetroGel  
See schematic 
48 weeks 


 
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SCHEMATIC OF STUDY DESIGN: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Screening Visit 
Eligible women with Amsel criteria ≥3 and  
Nugent score 4-10  
Eligible women will start 5-day treatment with MetroGel 
Enroll and randomize 2:1 
LACTIN-V 
Self-administered once x5 days 
then twice weekly x10 weeks 
PLACEBO 
Self-administered once x5 days 
then twice weekly x10 weeks 
Follow-up visits at weeks 4, 8, 12, and 24 
Telephone interview at weeks 16 and 20 
Confirm eligibility and enroll within 2 days after 
completing MetroGel 


 
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1.0 
KEY ROLES 
DMID Clinical Project Manager 
Jonathan Glock, MPH 
HHS, NIH, NIAID, DMID, STD Branch 
5601 Fishers Lane 
Rockville, MD  20892 
(240) 627-3258 
jglock@niaid.nih.gov 
 
Principal Investigator 
Craig Cohen, MD, MPH 
550 16th Street (Mission Bay Campus, 
GHS Building) 
San Francisco, CA 94158 
(415) 476-5874 
Craig.Cohen@ucsf.edu 
 
Co- Principal Investigator 
Anke Hemmerling, MD, PhD, MPH 
550 16th Street (Mission Bay Campus, 
GHS Building) 
San Francisco, CA 94158 
(415) 476-5878 
Anke.Hemmerling@ucsf.edu 
 
DMID Medical Monitor 
Soju Chang, MD 
HHS, NIH, NIAID, DMID, OCRA 
5601 Fishers Lane 
Rockville, MD  20892 
(240) 292-4178 
changsoju@niaid.nih.gov 
 
DMID Medical Officer 
Jill Long, MD, MPH 
HHS, NIH, NIAID, DMID, STD Branch 
5601 Fishers Lane 
Rockville, MD  20892 
(240) 627-3305 
jill.long@nih.gov 
 


 
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Clinical Operations Manager 
Sean McCarthy 
STAR STI-CTG Coordinating Center 
Social & Scientific Systems, Inc. 
8757 Georgia Avenue, 12th Floor  
Silver Spring MD 20910 
(301) 628-3394 
smccarthy@s-3.com 
 
SDCC Project Manager 
Jason Thompson, MS 
The Emmes Corporation 
401 N. Washington Street, Suite 700 
Rockville, MD 20850 
(301) 251-1161 x2708 
jthompson@emmes.com 
 
SDCC Data Manager 
Hannah Kwak 
The Emmes Corporation 
401 N. Washington Street, Suite 700 
Rockville, MD 20850 
(301) 251-1161 x239 
hkwak@emmes.com 
 
SDCC Statistician 
Michael R. Wierzbicki, PhD 
The Emmes Corporation 
401 N. Washington Street, Suite 700 
Rockville, MD 20850 
(301) 251-1161 x181 
mwierzbicki@emmes.com 
 
Site Principal Investigators: 
San Francisco General Hospital 
Misa Peron-Burdick, MD 
Department of OB/GYN, Ward 6D 
San Francisco General Hospital 
1001 Potrero Street 
San Francisco, CA 94110 
(415) 206-2937 
misa.perron-burdick@ucsf.edu 
 


 
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Stroger Hospital of Cook County 
Audrey French, MD 
1900 West Polk Street, Room 1243 
Chicago, IL 60612 
(312) 864-4578 
afrench@cookcountyhhs.org 
 
University of California, San Diego 
Antiviral Research Center (UCSD 
AVRC) 
Sheldon Morris, MD, MPH 
220 Dickinson Street, Suite A 
San Diego, CA 92103 
(619) 543-4761 
shmorris@ucsd.edu 
 
Washington University Infectious 
Disease Clinical Research Unit 
Hilary Reno, MD, PhD 
620 South Taylor, Suite 200 
St. Louis, MO 63110 
(314) 747-5496 
hreno@dom.wustl.edu 
 
Industry Representatives: 
Executive Chairman 
Peter Lee, MD 
Osel, Inc. 
320 Logue Avenue 
Mountain View, CA 94043 
(650) 964-4679 
plee@oselinc.com 
 
Director of Product Development 
Thomas Parks, PhD 
Osel, Inc. 
320 Logue Avenue 
Mountain View, CA 94043 
(650) 964-4679 
tparks@oselinc.com 
 


 
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2.0 
BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE 
 
2.1 
Background Information 
 
Bacterial vaginosis (BV), characterized by an imbalanced vaginal flora deficient in 
naturally occurring acid-producing lactobacilli, is one of the most frequent vaginal 
infections and affects about 15–50% of reproductive aged women globally [1]. Many 
women are unaware of their condition. BV has been associated with significant 
gynecologic and obstetric complications, such as pelvic inflammatory disease [2], 
endometritis [3] and post-operative infections, including post-cesarean endometritis [4] 
and post-hysterectomy vaginal cuff cellulitis [5]. Strong associations have also been 
reported between BV and pre-term delivery, miscarriage [6], and amniotic fluid infections 
[7]. Studies have linked BV to both female HIV-1 acquisition, and female-to-male HIV 
transmission [8-10]. A recent study showed that the presence of lactobacilli decrease the 
odds for fetal inflammatory responses to placental colonization with pathogens [11]. 
Following standard antibiotic treatment of BV, 20–75% of women relapse within 1–3 
months [12, 13]. The high risk of recurrence and sequelae suggests that investigational 
studies of new agents like live biotherapeutic products [14] may be effective for the 
improved treatment and prevention of BV.  
 
Reconstituting a normal, Lactobacillus-predominant vaginal flora has been promoted for 
many years as a microbial defense against pathogens. The vaginal live biotherapeutic  
product Lactobacillus (L.) crispatus CTV-05 (LACTIN-V) was developed by Osel, Inc. in 
Mountain View, California, and is designed to replenish the vaginal lactobacilli population 
following conventional antibiotic treatment with MetroGel® (topical metronidazole gel 
0.75%). The product contains a naturally occurring vaginal strain of L. crispatus CTV-05, 
preserved as a powder applied by a vaginal applicator. Since the Lactobacillus strain 
used in LACTIN-V is a commensal organism normally present in the vagina associated 
with vaginal health, the product has an excellent pre-clinical and clinical safety profile.   
 
Early studies of LACTIN-V administered the product in gelatin-coated capsules. After the 
completion of a Phase I safety trial testing low doses of 106 and 108 cfu/dose or placebo, 
a Phase II multisite placebo-controlled trial tested a dose of 5 x 108 cfu of LACTIN-V 
administered in a gelatin capsule in 149 women with BV following standard antibiotic 
treatment. The product was dosed for 5 consecutive days followed by a weekly dose 
over 10 additional weeks. After 4 months, colonization efficiency in the LACTIN-V group 
reached 42% in the intent-to-treat (ITT) cohort and 59% in the according-to-protocol 
(ATP) cohort. Although not statistically significant, the time to first BV recurrence was 
longer in the LACTIN-V arm (118.7 days) compared to the placebo arm (98.7 days, p = 
0.37). The proportion of women in the LACTIN-V treatment group successfully colonized 
with L. crispatus CTV-05 experienced fewer episodes of recurrent symptomatic BV 
(12.5%) than those who were not colonized (36%), or those in the placebo group (30%). 
The product had a good safety profile with mostly mild (Grade 1 severity) adverse events 
(AEs) including vaginal discharge, odor and pruritus, each affecting less than 40% of 
participants. AEs were evenly distributed between LACTIN-V and placebo arms (Osel, 
personal communication).   


 
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LACTIN-V has also been evaluated as a therapeutic agent to prevent recurrent urinary 
tract infections (rUTI). In a Phase II study in 100 women who received antibiotic 
treatment for cystitis, those who additionally received 108 cfu of LACTIN-V administered 
in a gelatin capsule over 5 consecutive days followed by a weekly dose over 10 
additional weeks had a reduction in rUTI from 27% in the placebo arm to 15% in the 
LACTIN-V arm (response rate [RR] = 0.5, 95% confidence interval [CI] 0.2-1.2) in 
comparison to the placebo arm. Among women receiving LACTIN-V who had detected 
high levels of vaginal colonization with L. crispatus, the reduction of rUTI reached 
statistical significance (RR=0.07, 95% CI 0.02-0.3). Interestingly, high levels of pre-
existing endogenous L. crispatus strains in women receiving placebo did not provide 
protection against rUTI [15]. 
 
Our research team at the University of California, San Francisco (UCSF) and Osel 
hypothesized that the efficacy of LACTIN-V to prevent BV recurrence could be improved 
by increasing the vaginal colonization rate of L. crispatus CTV-05. In order to achieve 
this, a vaginal applicator was developed capable of delivering a higher dose of LACTIN-
V powder (up to 2 x 109 cfu/dose) directly to the vagina without the impediment of a 
gelatin capsule, which was found to dissolve slowly in the vaginal environment. The new 
dosage form was first studied in a small Phase I escalating dose trial at UCSF to assess 
safety, tolerability and acceptability of three doses [5 X 108 cfu/dose (150mg), 1 X 109 
cfu/dose (300mg), 2 x 109 cfu/dose (600mg)] of LACTIN-V (IND No. 11363).  Four 
healthy women were randomized 3:1 to receive LACTIN-V or placebo at each dose 
level.  The product was found to be safe and well tolerated at all three doses. All AEs 
were Grade 1 and 2 severity and evenly distributed between LACTIN-V and placebo 
groups [16]. This study was followed by a Phase II-a trial of 24 women diagnosed with 
BV randomized 3:1 to LACTIN-V (2 x 109 cfu/dose) vs. an inert placebo administered 
daily for 5 days, and once weekly for 2 weeks. Participants completed a 5-day treatment 
course with MetroGel and within 24-72 hours initiated a regimen of high-dose LACTIN-V 
or inert placebo, administered once daily for 5 consecutive days and then once weekly 
over 2 additional weeks. After 4 weeks, colonization efficiency in the LACTIN-V group 
reached 61% (95%CI: 36%-83%) in the ITT cohort and 78% (95%CI: 40%-97%) in the 
ATP cohort [17]. We also explored the effect of endogenous lactobacilli and BV-
associated bacteria on vaginal colonization with the exogenous L. crispatus CTV-05 
using DNA extraction from vaginal swabs and bacterium-specific quantitative 
polymerase chain reaction (qPCR) assays. The median vaginal concentrations of BV-
associated bacteria (Megasphaera, Atopobium spp., Leptotrichia, Sneathia, Gardnerella 
(G.) vaginalis, Lactobacillus iners, Clostridium-like bacteria, BVAB1-3) declined after 
metronidazole treatment. In participants who subsequently colonized with L. crispatus 
CTV-05, this trend was maintained throughout the study. Participants who did not 
colonize with CTV-05 saw a resurgence of G. vaginalis, Leptotrichia/Sneathia species, 
A. vaginae, and BVAB2 concentration during the course of the study. This provides 
supporting evidence that these bacteria are important in the pathogenesis of BV and 
may impede the success of treatment with both antibiotics and live biotherapeutic 
products [18]. 
 
Collecting a larger body of data on colonization and efficacy of unmodified Lactobacillus 
strains to prevent BV recurrence will greatly contribute to the efforts of developing 
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technology for the prevention of HIV-1 and other genital tract infections. In the completed 
Centre for the AIDS Programme of Research in South Africa (CAPRISA)-004 trial that 
tested vaginally delivered 1% tenofovir gel for HIV-1 prevention [19], participants with 
recurrent symptoms of vaginal irritation and inflammation had a higher risk of HIV-1 
acquisition even in the 1% tenofovir gel arm (Karim SA, personal communication). In 
addition, a strong link has been shown between high-diversity cervicovaginal microbiota 
with low Lactobacillus levels and genital inflammation in a study of South African 
women. This genital inflammation was accompanied by increased numbers of activated 
HIV-infectable CD4+ cells in the cervix, providing a potential cellular link to increased 
HIV acquisition risk [20]. Thus, normalization of vaginal flora through use of exogenous 
vaginal Lactobacillus crispatus, and subsequent reduction of inflammation in the genital 
tract, could potentially enhance HIV-1 prevention associated with tenofovir gel use and 
other topical pre-exposure prophylaxis therapies under development [21].  
 
In the Phase II-a clinical trial, 19 (79%) of 24 participants agreed or strongly agreed that 
they would use the product again indicating that satisfaction of the product was high. 
Four women with persistent symptomatic BV at study exit were significantly less satisfied 
with the product (p=0.03); only two of these four women would use the product again.  
Efficacy, improved vaginal health, and being a ‘natural’ alternative to antibiotics were 
mentioned as positive attributes, and messiness and leakage arose as a negative 
attribute of the product [17]. In order to address participant concerns for messiness and 
leakage, Osel has increased the potency of LACTIN-V. Thus, while 600mg of powder 
was used in the Phase II-a trial, a lesser amount of powder is required to deliver the 
same dose of CTV-05 (2 x 109 cfu). Overall, these results suggest that women are highly 
interested in live biotherapeutics and future studies testing these products should include 
an acceptability component with both quantitative and qualitative components to fully 
characterize women’s satisfaction with the product.  
 
CTV-05 is a strain of L. crispatus, a gram-positive rod isolated from the vagina of a 
healthy woman. L.crispatus is found naturally in the vaginas of healthy women and is 
commonly found as a component of the natural human intestinal flora.  It is a facultative 
anaerobe, homofermentor of lactic acid, fastidious in its growth, and capable of H2O2 
production.  Unlike most commercially available strains of Lactobacillus, CTV-05 
adheres well to vaginal epithelial cells and is capable of colonizing the vaginal 
epithelium.   
 
LACTIN-V administered as a capsule has been tested in four trials (LV 001-004) with a 
dose level up to 5 x 108 cfu/capsule. Since the dose of 5 x 108 cfu/capsule resulted in 
colonization rates lower than desired, several changes to the study product were made. 
The higher dose of 2 x 109 cfu/dose delivered via vaginal applicator as dried powder 
directly into the upper vaginal vault has been tested in a Phase 1 trial (LV-005) in 12 
healthy women and subsequently in a Phase II-a trial (LV-006) in 24 women with BV. 
 
2.2 
Rationale 
 
This Phase II-b trial is designed to provide a screening evaluation for the hypothesis 
that, following a 5-day course of MetroGel to treat BV, LACTIN-V administered at 2 x 109 
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≥50% when compared to placebo. Based on the achieved colonization rate of L. 
crispatus CTV-05 at 2 x 109 cfu/dose of LACTIN-V, coupled with prior data from the 
Phase II-a clinical trial suggesting that vaginal colonization with L. crispatus CTV-05 was 
associated with a reduced risk of BV recurrence, the next logical step is to perform a 
larger Phase II-b trial.  
 
We plan to enroll 228 women in a 2:1 ratio of LACTIN-V to placebo to estimate the 
effectiveness of 2 x 109 cfu/dose of LACTIN-V to prevent the recurrence of BV following 
standard antibiotic treatment with MetroGel and establish longer term safety and 
acceptability data up to 24 weeks.  
 
The study will be conducted at domestic sites with a known track record of recruiting 
participants in other BV studies to enable enrollment of all 228 women over 48 weeks. 
This will allow the study to complete study follow up 18 months after the first woman 
enrolls in the trial. This timeline assumes that all sites initiate enrollment at about the 
same time.  
 
2.2.1 Rationale for BV Enrollment Criteria  
 
We are planning to enroll women with untreated BV (asymptomatic or 
symptomatic) as diagnosed during the screening visit defined by at least three of 
the following four Amsel criteria AND a Nugent score ≥4 on a Gram stain in the 
laboratory using the Nugent scoring system. 
 
The current 2015 CDC Sexually Transmitted Diseases Treatment Guidelines 
specify on page 69 that the clinical Amsel criteria can be used for the diagnosis 
of BV, and require three of the following symptoms or signs [22]: 
 
• 
Homogeneous, thin, grayish-white discharge that smoothly coats the vaginal 
walls;  
• 
Vaginal pH >4.5;  
• 
Positive whiff-amine test, defined as the presence of a fishy odor when a drop 
of 10% potassium hydroxide (KOH) is added to a sample of vaginal 
discharge;  
• 
Presence of clue cells (>20%) on microscopy.  
 
Detection of three of these criteria has been correlated with results by Gram stain 
[23, 24]. 
 
The recent 2013 Food and Drug Administration (FDA) draft guidance for the use 
of metronidazole gel suggests all four Amsel criteria for inclusion, and states that 
a Nugent score of four or higher is recommended for inclusion [25]. 
 
Recent studies enrolling participants with BV since 2012 routinely combined 
Amsel criteria and Nugent scores for BV diagnosis at enrollment and follow up 
(see Table 2.2.1). 


 
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Table 2.2.1: 
 
Author 
Year 
Enrollment Criteria 
  
  
Amsel 
Only 
Nugent  
Only 
Combination of 
Amsel (A) and Nugent (N) 
Bradshaw [26] 
2013 
  
  
≥3 A and N=4-10 
Cruciani [27] 
2013 
  
  
≥3 A and N=4-10 
Donders [28] 
2013 
  
  
≥3 A and N=4-10 
Bradshaw [29] 
2012 
  
  
N = 7-10 or ≥3 A and N=4-10 
Balkus [30] 
2012 
  
  
≥3 A and N=7-10 
Weissenbacher 
[31] 
2012 
A=4 
Schwebke [32] 
2011 
A=4 
 
Marrazzo [33] 
2012 
  
  
≥3 A and N=4-10 
Madhivanan 
[34] 
2014 
  
  
≥3 A and N=7-10 
 
In practice intermediate (N=4-6) and high Nugent scores (N=7-10) are almost 
exclusively linked to Amsel criteria no lower than three. A study conducted by 
Schwebke et al [35] showed this and the data of our previous LV-006 Phase II-a 
study confirms this finding (Hemmerling 2010, subanalysis unpublished). For all 
96 BV measurements (24 enrolled participants at four time points), Nugent 
scores of 4-10 correlated with Amsel criteria of 3 or 4. The same data set showed 
that whenever Amsel criteria reached 4 (19 of 96 measurements), the 
corresponding Nugent score was 8 or higher, never corresponding with lower 
intermediate Nugent score of 4-6.   
 
After weighing recent FDA guidance, CDC guidelines, our data from previous 
studies, and reviewing recent BV enrollment practices of other studies, we 
propose to adopt the same enrollment criteria as the vast majority of recent 
studies: a combined requirement of at least 3 of 4 Amsel criteria and a Nugent 
score of 4-10.  
 
2.3 
Potential Risks and Benefits 
 
2.3.1 Potential Risks 
 
2.3.1.1 LACTIN-V and Placebo  
 
The study product contains a naturally occurring strain of L. crispatus 
CTV-05. To date, there has been considerable amount of experience 
using LACTIN-V at concentrations up to 2 x 109 cfu/dose without any 
apparent related adverse effects, with the exception of a short duration 
of asymptomatic vaginal discharge.  No serious adverse events have 
been reported in Protocol No. LV-001, LV-002 and LV-004 using 
LACTIN-V at 5 x 106 and 5 x 108 cfu/dose, and no subject left the 
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adverse event has been experienced by more than one subject.  In 
Protocol No. LV-003, using LACTIN-V at 5 x 108 cfu/dose, one subject 
in the placebo control substance group experienced three 
simultaneous SAEs unrelated to LACTIN-V. Two subjects in the 
LACTIN-V group discontinued study treatment due to AEs; one subject 
became pregnant and the other reported nausea and diarrhea, which 
required treatment.   
 
Safety results of the recently completed Phase II-a trial (LV-006) 
assessing colonization efficiency, safety, tolerability and acceptability 
of LACTIN-V at 2 x 109 cfu/ dose in 24 women with BV show that no 
AE Grade 3 or higher and no SAE was observed during the clinical 
phase of the study.  Based on the DAIDS Toxicity Table Addendum for 
Vaginal Microbicide Studies (November 2007) [36] designed to 
standardize AE assessment, a total of 120 total AEs were reported, 
108 (90%) of which were Grade 1 and 12 (10.0%) were Grade 2 
severity. The most common genitourinary AEs included vaginal 
discharge of study product (46%), abdominal pain (46%) and dysuria 
(21%). AEs were evenly distributed between LACTIN-V and placebo 
groups. All enrolled women (n=24) reported at least one AE.  A single 
participant receiving placebo discontinued herself from study product 
due to a moderate AE (vaginal irritation).   
 
Risks from the administration of LACTIN-V are low since colonization 
with this type of organism is strongly associated with improved vaginal 
health.  No systemic risks are anticipated since this is an organism that 
is applied topically and not expected to be absorbed. These risks will 
be explained in the written informed consent form.  No pregnant 
women, fetuses, prisoners, children, persons with an active STI or 
humans undergoing in vitro fertilization are included in this study. 
 
Adverse effects that may be associated with LACTIN-V include those 
seen with other vaginally administered products, and include: 
Most likely:  
• 
Vaginal, genital or menstrual symptoms: vaginal discharge 
 
Less likely:  
• 
Gastrointestinal symptoms: abdominal (stomach area) pain, 
constipation, diarrhea, nausea, vomiting 
• 
Urinary symptoms: needing to urinate urgently, needing to urinate 
at night and pain with urination 
• 
Vaginal, genital or menstrual symptoms: genital itching, bleeding 
between menstrual periods, delayed menstrual periods, vaginal 
odor, vaginal burning sensation, vaginal irritation, vaginal bleeding, 
vaginal dryness, genital swelling, rash, vaginal candidiasis (yeast 
infection) 
• 
Other symptoms: lower back pain 
 


 
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Rare but potentially life-threatening:  
• 
Allergic reaction (including anaphylaxis) to the study product 
 
2.3.1.2 MetroGel vaginal gel 
 
MetroGel vaginal gel is indicated in the treatment of bacterial 
vaginosis. It is contraindicated in patients with a prior history of 
hypersensitivity to metronidazole, parabens, other ingredients of the 
formulation, or other nitroimidazole derivatives. 
 
Rare but serious* 
• 
Convulsive Seizures and Peripheral Neuropathy: Convulsive 
seizures and peripheral neuropathy, the latter characterized mainly 
by numbness or paresthesia of an extremity, have been reported in 
patients treated with oral or intravenous metronidazole. The 
appearance of abnormal neurologic signs demands the prompt 
discontinuation of metronidazole vaginal gel therapy. 
Metronidazole vaginal gel should be administered with caution to 
patients with central nervous system diseases. 
• 
Psychotic Reactions: Psychotic reactions have been reported in 
alcoholic patients who were using oral metronidazole and 
disulfiram concurrently. Metronidazole vaginal gel should not be 
administered to patients who have taken disulfiram within the last 
two weeks. 
 
*MetroGel vaginal gel affords minimal peak serum levels and systemic 
exposure (AUCs) of metronidazole compared to 500 mg oral 
metronidazole dosing. Although these lower levels of exposure are 
less likely to produce the common reactions seen with oral  
metronidazole, the possibility of these and other reactions cannot be 
excluded presently.  Data from well-controlled trials directly comparing 
metronidazole administered orally to metronidazole administered 
vaginally are not available. 
 
2.3.1.3 Study Procedures  
 
Participants may experience discomfort when having pelvic exams 
and/or undergoing phlebotomy for this study. During phlebotomy, they 
also may feel dizzy or faint, or develop a bruise, swelling or infection 
where the needle is inserted. 
 
2.3.1.4 Disclosure of Sexually Transmitted Infections  
 
Participants may become embarrassed, worried, or anxious when 
receiving HIV and STI counseling. They may become worried or 
anxious while waiting for their HIV and STI test results.  
 


 
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2.3.1.5 Procedures for Minimizing Potential Risks 
 
Allergic reactions (including anaphylaxis): Participants with a known 
allergy to components of the study product will be excluded from 
enrollment.  If an allergy or sensitivity occurs during the course of the 
study, the participant will be advised to immediately discontinue study 
product use and seek medical attention. This event will be recorded on 
an AE form. 
 
STI testing: Participants will receive counseling prior to testing. 
Counselors will prepare them for possible feelings of anxiety and the 
ramifications of a positive test result. All results will be kept confidential 
by the study physician/nurse and will be maintained in a limited access 
database. 
 
2.3.2 
Known Potential Benefits 
 
There may be no direct benefits to participants in this study. However, 
participants and others may benefit in the future from information learned from 
this study. Information learned in this study may lead to the development of a 
safe and effective live biotherapeutic product that can prevent the recurrence of 
BV. Participants will have HIV testing and pelvic exam performed during 
screening. Participants will be screened for a number of STIs and a prescription 
will be provided, if applicable, following CDC STD Treatment Guidelines. 
Participants testing positive for BV during screening will receive study-supplied 
MetroGel.  
 


 
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3.0 
OBJECTIVES 
3.1 
Study Objectives 
 
3.1.1 Primary Objectives 
1) To estimate the efficacy of repeated doses of LACTIN-V (2 x 109 cfu/dose) as 
compared to placebo in preventing BV recurrence by 12 weeks following 
treatment of BV with MetroGel 
2) To assess the safety of LACTIN-V over 24 weeks by comparing the incidence 
of AEs between individuals randomized to LACTIN-V or placebo 
 
3.1.2 Secondary Objectives 
1) To investigate the colonization of LACTIN-V (presence of L. crispatus CTV-05 
in the vaginal specimen) and fluctuations over 12 weeks, in relation to 
menses and sexual intercourse 
2) To evaluate user acceptability and tolerability of LACTIN-V over 12 weeks, 
including perceptions around method of delivery and dosing  
3) To measure long-term colonization of LACTIN-V at 24 weeks (12 weeks after 
last dosing) 
4) To estimate the long-term efficacy of repeated doses of LACTIN-V (2 x 109 
cfu/dose) as compared to placebo in preventing BV recurrence at 24 weeks 
(12 weeks after last dosing) 
 
3.1.3 Exploratory Objective 
To estimate the efficacy of repeated doses of LACTIN-V (2 x 109 cfu/dose) as  
compared to placebo in preventing repeated (more than one) episodes of BV  
recurrence up to 12 weeks following treatment of BV with MetroGel 
 
3.2 
Study Outcome Measures 
 
3.2.1 Primary Efficacy Outcome Measure 
The proportion of participants with a positive BV diagnosis in each study arm by 
Visit 4 (Week 12, Day 84) 
 
BV recurrence is defined by Amsel criteria 3-4 and Nugent score 4-10. Following 
FDA draft guidance all BV diagnoses during follow-up visits are considered 
incident, as they occur at least 22-30 days after the commencement of MetroGel 
treatment and consequently are treatment failures or new infections [25].  For the 
purpose of this trial, treatment failure and new infection will both be considered 
recurrent BV. 
 
3.2.2 Primary Safety Outcome Measure 
The proportion of participants reporting product-related AEs and SAEs in each 
study arm through Visit 7 (Week 24, Day 168) 
 


 
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3.2.3 Secondary Efficacy Outcome Measures 
 
Secondary Outcome Measure 1  
The proportion of participants experiencing successful colonization with L. 
crispatus CTV-05 following dose of study product through Visit 4 (Week 12, Day 
84) in the LACTIN-V arm, overall and by occurrence of menses and intercourse 
 
Secondary Outcome Measure 2 
The proportion of participants experiencing successful colonization with L. 
crispatus CTV-05 following dose of study product at Visit 7 (Week 24, Day 168) 
in the LACTIN-V arm, overall and by occurrence of menses and intercourse 
 
Secondary Outcome Measure 3 
Tolerability of LACTIN-V and the applicator will be measured by: 
1. The proportion of participants who discontinue study product early in each 
study arm due to adverse events 
 
Acceptability of LACTIN-V and the applicator will be measured by: 
1. The proportion of participants who are compliant with the complete dose 
regimen in each study arm as assessed by participant reporting and 
applicator staining  
2. Self-administered questionnaires about acceptability of the study product in 
each study arm 
 
Secondary Outcome Measure 4 
The proportion of participants with a positive BV diagnosis in each study arm by 
Visit 7 (Week 24, Day 168) 
 
Exploratory Outcome Measure 
The statistical parameterizations of the exploratory objective will include, but are 
not limited to, the following: 
1. The number of BV recurrences per 12 weeks of follow-up 
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4.0 STUDY DESIGN 
This is a Phase II-b multicenter randomized double-blind placebo-controlled trial to assess the 
efficacy of repeated doses of LACTIN-V compared to placebo in preventing BV recurrence in 
women diagnosed with BV. The study will also assess the safety of LACTIN-V by comparing the 
incidence of AEs between women randomized to LACTIN-V or placebo. The study plans to 
enroll 228 sexually-experienced, pre-menopausal women age 18 to 45 years. Women will be 
randomized 2:1 to receive LACTIN-V or placebo. 
  
Women will be consented and will have a history and physical examination to include a pelvic 
exam with STI diagnostics and testing for BV.  Potentially eligible women with Amsel criteria ≥3 
will have a vaginal smear sent to a central laboratory for Gram stain evaluation by Nugent 
score.  Blood will be obtained for HIV and syphilis serologies, a vaginal swab for gonorrhea, 
chlamydia and trichomonas molecular testing, and urine for βhCG. Potentially eligible women 
will start a standard 5-day course of MetroGel.  
 
Women will return to the study clinic within 2 days after completing the 5-day course of 
MetroGel to re-evaluate eligibility criteria and review the BV test results from the screening visit. 
Women with Amsel criteria ≥3 and Nugent score 4-10 will be instructed to administer the 
LACTIN-V  or placebo at home for 5 consecutive days and then twice weekly for 10 weeks.   
LACTIN-V (or placebo) will be administered at 2 x 109 cfu/dose by vaginal applicator. 
 
Women will complete a memory aid to record times of product application, menses, sexual 
intercourse, concomitant medications, condom use and any AEs. Reminders will be sent to 
women in order to increase adherence with all doses and prior to scheduled follow-up visits. 
Women will complete either a paper or electronic memory aid. If the electronic version of the 
memory aid is utilized by the participant, the study clinic will be alerted of any potential AEs 
reported by the participant for follow-up and reporting as deemed necessary. 
 
Follow-up visits are scheduled 4, 8, 12 and 24 weeks after enrollment. A memory aid to gauge 
symptoms and AEs will be reviewed, a questionnaire to collect clinical, including AEs, data will 
be administered and a pelvic exam will be performed to detect genital tract AEs. Vaginal swabs 
for wet mount evaluation (Amsel criteria) and Gram stain evaluation (Nugent score) will be 
collected. A vaginal swab for L. crispatus (including CTV-05) identification will be collected. 
Vaginal applicators will be collected at Visits 2, 3, and 4 and stained with Trypan Blue upon 
return to the site as a proxy for product use. Telephone interviews will be scheduled between 
the 12 and 24 week visits, at 16 and 20 weeks after enrollment. 


 
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5.0 STUDY ENROLLMENT AND WITHDRAWAL 
The study plans to enroll 228 non-pregnant, pre-menopausal women age 18 to 45 years 
diagnosed with symptomatic or asymptomatic BV. Eligibility criteria for participation in the study 
are described in detail in sections 5.1 and 5.2.  A screening consent form will be used for 
procedures to determine eligibility and an enrollment consent form will be used for study 
participation if eligibility is confirmed. Pregnant women, men and children are excluded from 
study participation (see section 14.4). 
 
5.1 
Subject Inclusion Criteria 
Participants must meet all of the inclusion criteria in order to be eligible to participate in 
the study: 
1. Capable of reading and writing English and voluntarily provide written informed 
consent to participate in the study and comply with all study procedures 
2. Untreated BV (asymptomatic or symptomatic) as diagnosed during the screening 
visit defined by >3 Amsel criteria  
Note: Amsel criteria include the following:  
• 
Homogeneous, thin, grayish-white discharge that smoothly coats the vaginal 
walls;  
• 
Vaginal pH >4.5;  
• 
Positive whiff-amine test, defined as the presence of a fishy odor when a drop of 
10% potassium hydroxide (KOH) is added to a sample of vaginal discharge;  
• 
Presence of clue cells (>20% on microscopy). 
3. Untreated BV (asymptomatic or symptomatic) as confirmed in the laboratory using 
the Nugent scoring system (Nugent Score ≥4) 
4. Otherwise healthy pre-menopausal women 18–45 years of age on the day of 
screening 
5. Regular predictable menstrual cycles or amenorrheic for at least 3 months due to 
use of a long-acting progestin or continuous use of oral contraceptives 
6. Willing to be asked questions about personal medical health and sexual history 
7. Willing to apply study agent vaginally and comply with study examinations 
8. Agree to abstain from sexual intercourse during the first 5 consecutive days of study 
product administration, 12 hours prior to study visits and for 12 hours after each 
study product application  
9. Agree to abstain from the use of any other intravaginal product throughout the trial 
period from the time of screening through Visit 7 (Week 24, Day 168)  
Note: Intravaginal products include contraceptive creams such as Gynol II, gels, 
foams, sponges, lubricants not approved by the study investigators, and douches.   
Limit use of tampons during menstruation to unscented products. 
10. Must be of non-childbearing potential or if of childbearing potential, must agree to 
use a reliable method of birth control for the duration of the study  
Note: Reliable methods of birth control include tubal ligation, male partner with a  
vasectomy, a steroidal contraceptive (oral, patch, injectable or implantable), IUD,  
condoms or abstinence. 


 
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5.2 
Subject Exclusion Criteria 
 
Participants meeting any of the following criteria at screening, or when assessed at the 
enrollment visit, will be excluded from the study: 
1. Urogenital infection at screening 
Note: Urogenital infection includes urinary tract infection, Trichomonas (T.) vaginalis, 
Neisseria (N.) gonorrhoeae, Chlamydia (C.) trachomatis, Treponema (T.) pallidum, 
or vulvo-vaginal candidiasis.  
2. Diagnosis of two or more outbreaks of N. gonorrhoeae, C. trachomatis, T. pallidum, 
T. vaginalis, or herpes simplex virus (herpes genitalis) within 6 months prior to 
screening 
3. Positive for syphilis or HIV at screening 
4. Current pregnancy or within 2 months of last pregnancy and/or currently 
breastfeeding** 
5. Vaginal or systemic antibiotic or antifungal therapy (other than MetroGel given as 
part of study procedures) within 21 days of screening or within 30 days of 
enrollment**  
6. Use of disulfiram within past 2 weeks or other contraindication to use of MetroGel** 
7. Any condition requiring regular periodic use of systemic antibiotics during 
participation in the trial 
8. Active genital herpes lesion (if not resolved by enrollment)** 
9. Investigational drug use other than LACTIN-V within 30 days or 10 half-lives of the 
drug, whichever is longer, of enrollment visit**  
10. Other planned participation in an investigational drug study while participating in this 
study** 
11. Menopause defined as more than 12 consecutive months of amenorrhea without 
another known cause including pregnancy  
12. IUD insertion or removal, pelvic surgery, cervical cryotherapy or cervical laser 
treatment within the last 2 months prior to screening 
13. Use of vaginal ring (eg, NuvaRing) within 3 days of screening or during the course of 
the study** 
14. Failure to complete 5 days of MetroGel with the last dose taken no later than 48 
hours prior to randomization*** 
15. Use of new long-acting hormonal treatments. Participant may be enrolled if stable 
(>3 months) on existing therapy as determined by the principal investigator** 
16. Known allergy to any component of LACTIN-V/placebo or MetroGel or to 
nitroimidazole derivatives or latex (condoms) 
17. Any social, medical, or psychiatric condition including history of drug or alcohol 
abuse that in the opinion of the investigator would make it unlikely for the participant 
to comply with the study 
 
** Note: Criteria will be assessed at screening and enrollment. 
*** Note: Criteria will be assessed at enrollment. 


 
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5.3 
Treatment Assignment Procedures 
 
5.3.1 Randomization Procedures 
Women will be randomized at the enrollment visit 1 upon completion of the initial 
standardized antibiotic treatment with 0.75% topical MetroGel.   
Women will be randomly assigned to receive LACTIN-V at 2 x 109 cfu/dose or 
placebo in a 2:1 ratio. The 2:1 randomization was selected to increase precision 
of the estimated effectiveness of LACTIN-V to prevent recurrence of BV 12 
weeks after treatment with MetroGel.  
The list of randomized treatment assignments will be prepared by statisticians at 
The Emmes Corporation and provided to Fisher Bioservices. Fisher Bioservices 
will label each box of study treatment applicators sequentially with a treatment 
number according to the randomization scheme in a 2:1 (LACTIN-V to placebo) 
ratio.  
 
Instructions for use of the enrollment module are included in the 
AdvantageEDCSM User’s Guide.   
 
5.3.2 Masking Procedures 
At the time of enrollment, the site pharmacist will select the next available box of 
study product applicators in sequential order and will distribute to masked study 
personnel with no labels that identify the product or applicators as LACTIN-V or 
placebo.  No masking procedures are required for the MetroGel.   
 
The site pharmacist, participants, study personnel who perform study 
assessments, data entry personnel at the sites, and laboratory personnel 
performing study assays will be masked to treatment assignment. The Data and 
Safety Monitoring Board (DSMB) may receive data in aggregate and presented 
by treatment group, but without the treatment group identified. The DSMB may 
be unmasked to individual study treatment assignments, as needed, to 
adequately assess safety issues. Refer to the MOP for unmasking procedures, 
including emergency unblinding procedures. 
 
5.3.3 Reasons for Withdrawal 
 
5.3.3.1 Screening Failures 
Participants with the following diagnoses at the screening visit (Visit 0) 
will be considered screening failures and will be treated or referred for 
appropriate follow-up.  All screening failures will be replaced unless the 
diagnosis allows for Rescreening. 
 
• 
A diagnosis of a UTI, yeast vaginitis or an STI (T. vaginalis, N. 
gonorrhoeae, C. Trachomatis, T.pallidum), or vulvo-vaginal 
candidiasis) 
• 
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A history of herpes genitalis does not exclude participants from 
participation as long as no active lesions are present at the enrollment 
visit and the participant experienced no more than one active outbreak 
of herpes genitalis within 6 months prior to screening. 
 
Participants diagnosed with a UTI at the screening visit (Visit 0) may 
choose to return to clinic for rescreening at least 21 days after 
completing antibiotic treatment. Participants diagnosed with an STI or 
participants with yeast vaginitis at the screening visit may be re-
screened at least 21 days after completing antibiotic treatment. 
Participants with active genital herpes lesions at enrollment are 
ineligible but can be re-screened after the outbreak has subsided. All 
screening procedures must be repeated unless otherwise clinically 
indicated.  
 
Participants who are eligible after screening but are subsequently 
deemed ineligible at the enrollment visit or do not return for the 
enrollment visit are considered screen-failures. 
 
5.3.3.2 Withdrawal after Enrollment 
 
Participants may withdraw or be withdrawn for any of the reasons given 
below.  The reason for withdrawal will be recorded in the data collection 
form.  
• 
Participant withdraws consent 
• 
Pregnancy or breastfeeding 
• 
Adverse event which requires discontinuation of the treatment 
regimen or results in inability to comply with study procedures 
• 
Discretionary decision by the site investigator  
• 
At the discretion of the IRB, FDA, NIH, or other government 
agencies as part of their duties to ensure that research participants 
are protected, or the industry supporter or its designee 
• 
Study is terminated 
 
5.3.4 Handling of Withdrawals 
 
All randomized participants who are discontinued from receiving further study 
product will continue to be followed through Visit 7 (Week 24, Day 168). Once a 
participant is randomized, she will not be replaced.  Withdrawals and drop-outs 
will not be replaced. 
 
If withdrawal of consent or study product discontinuation occurs after study 
treatment is initiated, the participant will be asked to continue scheduled study 
procedures including safety evaluations, if possible, and be given appropriate 
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the study are continuing.  The participant will be followed until the AE is resolved 
or until the participant’s condition becomes stable. 
 
Participants who withdraw their consent for further participation in the study after 
their study treatment ends or discontinue study product early will be reminded of 
the importance of continuing in the study for safety evaluations. Participants will 
be encouraged to complete the Early Termination evaluations described in 
section 7.9 if they choose not to complete the remaining study visits.   
 
Participants who enroll in the study but do not return for study visits after a 
minimum of three attempts to contact them over a 2-week period will be 
considered lost to follow-up. 
 
5.3.5 Termination of Study  
 
Study closure may occur due to DSMB review, or at the discretion of the 
Institutional Review Board (IRB), FDA, DMID, and other government agencies as 
part of their duties to ensure that research participants are protected or the 
industry supporter or its designee. 
 


 
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6.0 
STUDY PRODUCT 
6.1 
Study Product Description 
 
LACTIN-V (Lactobacillus crispatus CTV-05)  
LACTIN-V contains a naturally occurring vaginal strain of Lactobacillus (L.) crispatus 
CTV-05, preserved as a powder and applied by a vaginal applicator. 
 
MetroGel vaginal gel (metro nidazo le gel) 
MetroGel vaginal gel is the intravaginal dosage form of the synthetic antibacterial agent, 
metronidazole, USP at a concentration of 0.75%. Metronidazole is a member of the 
imidazole class of antibacterial agents and is classified therapeutically as an 
antiprotozoal and antibacterial agent. Chemically, metronidazole is a 2-methyl-5-nitro 
imidazole-1-ethanol.  
 
At the Screening visit, eligible participants will receive MetroGel for the treatment of BV 
as described in section 7.0.  Participants who receive MetroGel, but do not complete the 
full MetroGel treatment, do not return for the Enrollment visit, or are otherwise found 
ineligible to be randomized to study treatment will not be enrolled into the study and will 
not be followed for safety or for AEs. 
 
6.1.1 Acquisition 
 
LACTIN-V and placebo 
Osel, Inc. will provide LACTIN-V and placebo. Upon request by DMID, LACTIN-V 
and placebo will be transferred to the following address:  
 
DMID Clinical Agents Repository (CAR) 
Fisher BioServices 
20439 Seneca Meadows Parkway 
Germantown, MD 20876 
Tel: (240) 477-1350 
Fax: (240) 477-1360 
Email: DMID.CAR@ThermoFisher.com 
 
MetroGel vaginal gel 
MetroGel vaginal gel will be purchased and supplied by the DMID CAR. 
 
LACTIN-V, placebo and MetroGel vaginal gel will be shipped from the DMID 
CAR to the study site upon request and approval by DMID. 
 
6.1.2 Formulation, Packaging, and Labeling 
 
LACTIN-V and placebo 
Each applicator will contain a LACTIN-V powder formulation containing L. 
crispatus CTV-05 at a potency of 2 x 109 cfu/dose.  LACTIN-V powder contains 
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matching placebo formulation without L. crispatus CTV-05 is supplied in an 
identical applicator containing placebo powder.  
 
LACTIN-V or placebo pre-filled applicators will be individually packaged in heat-
sealed foil pouches, each containing one desiccant packet.  Each participant will 
receive one box containing 25 applicators. Each foil pouch and box will be 
labeled with the study number and unique participant number.  
 
The foil pouches and boxes will be labeled by the Osel Study Product Supplier.  
Each label will contain the study number and the FDA-required cautionary 
statement “Caution- New drug -Limited by Federal Law to Investigational Use.”  
The label of each box of study product applicators will also include the unique 
participant number and the statements: “Store at home in a cool, dry place out of 
reach of children (at room temperature).” 
 
MetroGel vaginal gel 
MetroGel vaginal gel is a gelled purified water solution, containing metronidazole 
at a concentration of 7.5 mg/g (0.75%). The gel is formulated at pH 4.0. The gel 
also contains carbomer 934P, edetate disodium, methylparaben, propylparaben, 
propylene gycol and sodium hydroxide.  
 
MetroGel vaginal gel is supplied in a 70 gram tube. Each participant will receive 
one box of MetroGel vaginal gel sufficient for the 5-day course of treatment. 
 
6.1.3 Product Storage and Stability 
 
LACTIN-V and placebo 
 
LACTIN-V and placebo applicators will be shipped overnight in an appropriate 
container on frozen gel packs and immediately placed into temperature-
controlled conditions (2–8°C) upon arrival. 
 
The study sites will store LACTIN-V and placebo applicators at 2-8°C.  
 
Participants will be instructed to store study product boxes in a cool, dry place, 
out of reach of children. 
 
MetroGel vaginal gel 
Store at controlled room temperature 15° to 30 °C (59 ° to 8 6 °F). Protect from 
freezing. 
 


 
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6.2 
Dosage, Preparation, and Administration of Study Product 
 
LACTIN-V and placebo 
Eligible participants will be instructed on how to insert the pre-filled applicator (LACTIN-V 
at 2 x 109 cfu/dose, or the placebo control substance) and will administer the first dose 
under direct supervision by the study clinician before leaving the clinic (Day 1). Study 
personnel will verify that each carton contains all 24 remaining applicators and this will 
be recorded on the appropriate Case Report Form (CRF).  Participants will be instructed 
to administer one dose once a day at bedtime for the next 4 days (beginning on Day 2), 
and then two times a week for 10 weeks. The remaining 20 applicators will be used for 
the two doses each week during weeks 2 through 11. 
 
MetroGel vaginal gel 
Participants will be instructed to administer one dose once a day at bedtime for 5 days 
initiated as soon as possible (ideally within 5 days of diagnosis at the screening or 
follow-up visit for symptomatic participants, or within 24 days of the screening visit for 
asymptomatic participants (see section 7.0 for additional details).  
 
6.3 
Accountability Procedures for the Study Investigational Product 
 
 
After receipt of the study product, the site Principal Investigator (PI) is responsible for 
 
distribution and disposition of these study products, and has ultimate responsibility for 
 
drug accountability. The PI may delegate this responsibility to the site pharmacist 
 
(or designee).  The site pharmacist (or designee) must maintain study product 
 
records and document logs of receipt, accountability, and storage temperature 
 
conditions. These study product accountability and dispensing logs must be maintained 
 
in the study file.  Upon completion of the study and after the final monitoring visit, 
 
unused applicators will be retained until monitored and released for disposition as 
 
per the Sponsor. Used LACTIN-V or placebo applicators will be collected and stained to 
 
determine if the participant used the study product and then disposed of after 
 
evaluation. For detailed information regarding final disposition of study product see 
 
the protocol-specific MOP.   
 
6.4 
Assessment of Subject Compliance with Study Product  
 
Compliance with study product will be assessed by participant self-report and applicator 
staining as described in the MOP. 
 
6.5 
Concomitant Medications/Treatments 
 
The study requires documentation of all medications (name, dose, route, frequency of 
dosing, and reason for use) taken by participants 30 days prior to screening through Visit 
7 (Week 24, Day 168) or early termination, whichever occurs first.  
 
The following medications are permitted throughout the study: 
• 
Vitamins and other nutritional supplements   
• 
Hormonal  contraceptives 


 
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• 
Cough medicine 
• 
Non-steroidal anti-inflammatory drugs 
• 
Prescription and over-the counter medications for allergies and asthma 
• 
Herbal, naturopathic, and traditional preparations (eg, Chinese traditional 
medications)  
• 
Externally applied topical medications (except genital area)  
• 
Antibiotics prescribed during the trial, including for MetroGel for BV  
 
The following medications are prohibited throughout the study, and participants will be 
instructed to not use them throughout the study up to Visit 7 (Week 24, Day 168): 
 
• 
Immune suppressants 
• 
Investigational drug preparations other than the study product 
• 
Intravaginal medications/preparations and topical medications/preparations other 
than the study product applied to the external genitalia  
 
Any other medication/treatment not listed as permitted or prohibited is subject to the judgment of 
the investigator. 


 
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7.0 
STUDY SCHEDULE 
7.1 
Screening Visit 0 (Day -30 to Day -5) 
The purpose of the screening visit is to identify participants who satisfy all eligibility 
criteria, including the diagnosis of symptomatic or asymptomatic bacterial vaginosis. 
Participants who agree to be screened will be asked to sign the screening informed 
consent form that will describe the purpose of the screening, the procedures to be 
followed, and the risks and benefits of screening and will include a separate section for 
consent to store samples for future use.  A copy of the consent form will be given to the 
participant and this fact will be documented in the medical record. A separate consent 
form will be completed during the enrollment visit after study eligibility is established. 
 
Participants will be asked to provide contact information (ie, address, email address, 
home/cell phone number, emergency contact), which will be recorded on appropriate 
form.  
 
At the screening visit (Visit 0) the woman's menstrual cycle history will be evaluated to 
ensure regular menstrual cycles (or amenorrhea due to long-acting contraceptives). 
Depending on the timing of her menstrual cycle, the screening procedure will be as 
follows: 
1. If she has just finished her menstrual cycle or is within the first half of her cycle with 
12 days or more expected until the onset of the next menstrual cycle, (latest 
screening visit on the 16th day of a regular 28-day cycle), she will proceed with 
screening, and will be able to complete screening, the treatment course of BV with 5 
days of topical MetroGel, the Enrollment Visit (Visit 1) (in case of eligibility confirmed 
by the laboratory results of the screening visit) within 48 hours of her last MetroGel 
administration, and the 5 days of continuous product use starting during the 
enrollment visit  (Visit 1).  
2. If she is menstruating at the time of the screening visit she will be asked to return for 
the screening visit as soon as possible after her menstrual cycle ends.  
3. If she is in the second half of her cycle with less than 12 days expected before the 
onset of the next menstrual bleeding, she will proceed with screening, but will be 
instructed to wait until after her next period before starting the 5-day treatment 
course of MetroGel.   
 
The screening visit must also be timed depending on her availability to return for the 
enrollment visit (visit 1) within 12-48 hours after the termination of the 5-day course of 
MetroGel. MetroGel treatment for women with symptomatic BV should be initiated as 
soon as possible (ideally within 5 days of diagnosis at the screening visit). For women 
diagnosed with asymptomatic BV at the screening visit, MetroGel should be initiated 
according to her menstrual cycle and within 24 days of the screening visit to ensure the 
time window between screening and enrollment is not more than 30 days.  
 
Women must start MetroGel treatment on a Tuesday, Wednesday, Thursday, Friday or 
Saturday (NOT Sunday or Monday) in order to return for enrollment and within 12-48 
hours after the 5th dose of her MetroGel treatment on the subsequent weekday Monday 
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Table 7.1  
 
TUE 
WED 
THU 
FRI 
SAT 
SUN 
MON 
TUE 
WED 
THU 
FRI 
SAT 
SUN 
MON 
TUE 
5 day MetroGel 
Break 
 12-48 
 hours 
Enrollment  
5 days study product 
 
 
 
 
 
5 day MetroGel 
Break 
 12-48 
 hours 
Enrollment  
5 days study product 
 
 
 
 
 
5 day MetroGel 
Break 
 12-48 
 hours 
Enrollment  
5 days study product 
 
 
 
 
 
5 day MetroGel 
Break 
 12-48 
 hours 
Enrollment  
5 days study product 
 
 
 
 
 
5 day MetroGel 
Break 
 12-48 
 hours 
Enrollment  
5 days study product 
 
Participants who give informed consent will undergo the following procedures and 
assessments at the Screening Visit: 
1. Assessment of eligibility 
2. Detailed structured interview to obtain demographic information, medical, 
gynecological and sexual history to include assessment of STI and HIV risk  
3. Review of concomitant medications 
4. Acceptability questionnaire to determine participant’s experiences with BV and use of 
vaginal products in the past 
5. Complete physical and pelvic examination by a study physician or nurse that will 
include vital signs, including temperature, height and weight, and examination of 
respiratory and cardiovascular systems 
6. The pelvic examination will be conducted in the following order: 
a. Examination of the external genitalia 
b. Speculum insertion and examination of vagina, fornices and cervix with naked 
eye.  Water will be used to ease speculum insertion.  No lubricant should be 
used as it could contain chlorhexidine which may kill Lactobacillus. 
c. Vaginal swab for vaginal pH 
d. Vaginal swab for wet mount taken from the posterior fornix for trichomoniasis, 
yeast vaginitis, and clue cells and for amine test (whiff test)  
e. Vaginal swab for Gram stain (Nugent scoring system) 
f. Vaginal swabs (no more than two) for storage and future identification of vaginal 
bacteria, and possible multiomic (e.g. proteomics, metabolomics, etc.) testing 
g. Cervical (or vaginal) swabs for nucleic acid amplification of N. gonorrhoeae, C. 
trachomatis, and T. vaginalis 
7. Clean catch urine dipstick; urinalysis if abnormal results indicate 
8. Rapid urine βhCG pregnancy test. If the test is positive, the screening visit will be 
terminated as the woman is not eligible.  
9. Blood draw for Syphilis serology testing and HIV testing by standardized algorithms 
10. If the examiner suspects or confirms a UTI, vulvo-vaginal candidiasis, or an STI 
(T.vaginalis, N. gonorrhoeae, C.trachomatis, T. pallidum), the woman will be referred 
to standard of care treatment and may be invited for rescreening (see section 7.1.1). 
11. All clinical and laboratory findings at the time of the evaluation will be recorded on 
the CRF. These findings will include observations present on the pelvic exam, such 


 
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as genital findings including location; presence or absence and character of vaginal 
or cervical discharge or lesions; and results of any on-site tests. 
12. Participants diagnosed with BV by Amsel criteria ≥3 who agree to be treated with 
MetroGel and meet all eligibility criteria will be invited to return for the enrollment visit 
immediately after the completion of MetroGel, pending confirmation of BV diagnosis 
by Nugent score 4-10 and laboratory test results for STIs and HIV. 
13. Participants with confirmed BV by Amsel criteria ≥3 will be given 0.75% topical 
MetroGel to apply vaginally once daily in the evening for 5 consecutive days. Should 
the woman be in the first half of her menstrual cycle and her period is not expected 
for the next 12 days, she should start MetroGel on the evening of the screening visit. 
It also needs to be timed in accordance with her availability to return for the 
enrollment visit (Visit 1) within 12-48 hours after the completion of the 5-day course 
of MetroGel. See scheduling sequences in Table 7.1. MetroGel treatment for women 
with symptomatic BV should be initiated as soon as possible (ideally within 5 days of 
diagnosis at the Screening Visit). For women diagnosed with asymptomatic BV at the 
screening visit, MetroGel treatment needs to be initiated according to her menstrual 
cycle and within 24 days of the screening visit to ensure the time window between 
screening and enrollment is not more than 30 days.  
14. Participants will be advised to return for the enrollment visit within 12-48 hours after 
completion of MetroGel treatment. 
15. Non-spermicidal condoms will be dispensed. 
At screening, women with evidence of any STI diagnosed according to the study site’s 
protocol will be referred to standard of care treatment in compliance with current CDC 
STD Treatment Guidelines. If laboratory test results received after the screening visit 
determine ineligibility, the woman will be managed as clinically indicated for her 
respective condition and contacted to cancel her scheduled enrollment visit.  She will not 
be eligible for rescreening until 21 days after resolution of the abnormality (see section 
7.1.1). 
 
7.1.1 Rescreening Visit 
 
At least 21 days after completion of successful treatment for UTI or STI, 
participants will be invited for rescreening. At rescreening, the following 
procedures will be repeated to determine the diagnosis of bacterial vaginosis and 
eligibility for enrollment into the study. 
 
1. Detailed structure interview to obtain demographic information and medical, 
gynecological and sexual history to include assessment of STI and HIV risk 
2. Review of concomitant medications 
3. Complete physical and pelvic examination by a study physician or nurse that 
will include vital signs, including temperature, height and weight, and 
examination of respiratory and cardiovascular systems 
4. The pelvic examination will be conducted in the following order: 
a. Examination of the external genitalia 
b. Speculum insertion and examination of vagina, fornices and cervix with 
naked eye. Water will be used to ease speculum insertion. No lubricant 


 
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should be used as it could contain chlorhexidine which may kill 
Lactobacillus. 
c. Vaginal swab for vaginal pH 
d. Vaginal swab for wet mount taken from the posterior fornix for 
trichomoniasis, yeast vaginitis, and clue cells and for amine test (whiff 
test) 
e. Vaginal swab for Gram stain (Nugent scoring system) 
f. Vaginal swabs (no more than two) for storage and future identification of 
vaginal bacteria, and possible multiomic (e.g. proteomics, metabolomics, 
etc.) testing 
g. Cervical (or vaginal) swabs for nucleic acid amplification of N. 
gonorrhoeae, C. trachomatis, and T. vaginalis 
5. Clean catch urine dipstick; urinalysis if abnormal results indicate 
6. Rapid urine βhCG pregnancy test  
7. Blood draw for Syphilis serology testing and HIV testing by standardized 
algorithms if re-screening occurs more than 90 days after initial screening 
visit 
 
7.2 
Enrollment Visit 1 (Day 1) 
 
Only women who are diagnosed at the screening visit with BV (by Amsel criteria ≥3 and 
have a Nugent score 4-10 on the vaginal specimen collected at the screening visit) and 
complete a 5-day course of MetroGel are eligible to enroll in the study.  These women 
will be scheduled to return for the enrollment visit within 12-48 hours after completing the 
5th dose of MetroGel treatment. 
 
Once eligibility is determined from screening tests, the woman will be asked to sign the 
enrollment consent form which will describe the purpose of the study, the procedures to 
be followed, the risks and benefits of the study, and will include a separate section for 
consent to store samples for future use. A copy of the consent form will be given to her 
and this fact will be documented in her medical record.  
 
After signing the enrollment consent form, she will be asked to verify previously reported 
contact information which will be recorded on the appropriate form.  
 
At the enrollment visit, her menstrual cycle history will be re-evaluated to ensure regular 
menstrual cycles (or amenorrhea with long-acting contraceptives) and that menstruation 
will not be expected during the next 5 days when the use of the study product for 5 
consecutive days (days 1-5) has to occur. If she is not currently having menstrual 
bleeding and her period is not to be expected within the next 5 days, she will proceed 
with the enrollment visit. Before commencing with the enrollment exam, eligibility should 
be confirmed by reviewing the medical history and ALL results of the screening visit 
(including all laboratory results which must be complete). In addition, it must be 
confirmed that she completed MetroGel treatment on 5 consecutive days, and that the 
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If still eligible, participants will undergo the following procedures at the enrollment visit 
(Day 1): 
1. Detailed confirmation of demographic information, medical, gynecological and sexual 
history obtained to include assessment of STI and HIV risk  
2. Review of concomitant medications 
3. Symptom-directed physical and pelvic examination by a study physician or nurse that 
will include vital signs, including temperature, height and weight, and examination of 
respiratory and cardiovascular systems 
4. The pelvic examination will be conducted in the following order: 
a. Examination of the external genitalia 
b. Speculum insertion and examination of vagina, fornices and cervix with naked 
eye.  Water will be used to ease speculum insertion.  No lubricant should be 
used as it could contain chlorhexidine which may kill Lactobacillus. 
c. Vaginal pH 
d. Vaginal swab for wet mount taken from the posterior fornix for yeast vaginitis and 
clue cells and for amine test (whiff test)  
e. Vaginal swab for Gram stain (Nugent scoring system) 
f. Vaginal swabs (no more than two) for storage and future identification of vaginal 
bacteria, and possible multiomic (e.g. proteomics, metabolomics, etc.) testing 
g. Vaginal swabs for L. crispatus identification with qPCR 
If indicated, cervical (or vaginal) swabs for nucleic acid amplification of N. 
gonorrhoeae, C. trachomatis, and T. vaginalis 
Women with findings on pelvic exam at the enrollment visit, including active 
genital herpes lesions or for other reasons will be considered screening failures, 
will not be enrolled and will be referred for further evaluation. 
5. If indicated, clean catch urine dipstick; urinalysis if abnormal results indicate 
6. Rapid urine βhCG pregnancy test. If the test is positive, the enrollment visit will be 
terminated as the woman is not eligible.  
7. All clinical and laboratory findings at the time of the evaluation will be recorded on 
the CRF. These findings will include observations present on the pelvic exam such 
as genital findings including location; presence or absence, and character of vaginal 
or cervical discharge or lesions; and results of any on-site tests. 
8. If the clinician suspects the participant developed an STI since the screening visit, 
appropriate tests will be conducted and if needed the woman will be referred to 
standard of care treatment in compliance with current CDC STD Treatment 
Guidelines. The participant cannot be enrolled at this time but could be invited for 
rescreening after completion of treatment, if indicated.  
9. Randomization and enrollment into AdvantageEDCSM  
10. LACTIN-V/placebo and applicator will be dispensed to participants. Participants will 
self-administer the first dose of LACTIN-V/placebo in the clinic during this visit. 
Participants will then be instructed to administer one dose of LACTIN-V/or placebo 
once a day at bedtime for the next 4 days (beginning on Day 2) and then twice 
weekly for 10 weeks. Participants will be instructed to transport the pre-filled 
applicators while avoiding exposure to high temperatures. 


 
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11. Participants will be given a memory aid or a web link (with a username and 
temporary password) and instructed to make an entry following each insertion of a 
pre-filled applicator beginning with the first application at Visit 1 (Day 1). Any 
symptoms that occur during the study up until Visit 7 (Week 24, Day168) will be 
recorded on the memory aid. Participants not using the web link will be reminded to 
return with the paper memory aid at each study visit where it will be reviewed. 
12. Participants will be instructed to abstain from sexual intercourse during the first 5 
days of study product administration, for 12 hours after the weekly study product 
applications and 12 hours before study Visit 2 (Week 4, Day 28), Visit 3 (Week 8, 
Day 56), Visit 4 (Week 12, Day 84) and Visit 7 (Week 24, Day 168).  
13. Participants will receive non-spermicidal lubricated condoms for their male sexual 
partners who will be encouraged to use condoms from Visit 1 (Day 1) through Visit 7 
(Week 24, Day 168) if they engage in vaginal intercourse. 
14. Participants will be instructed not to use scented tampons or any other vaginal 
products through Visit 7 (Week 24, Day 168). 
15. Participants will be advised to return for Visit 2 (Week 4, Day 28), Visit 3 (Week 8, 
Day 56) and Visit 4 (Week 12, Day 84) with allowable scheduling within 7 days of the 
target date. Depending on the time of the enrollment and the average length of the 
woman’s menstrual cycle, careful attention should be paid to the approximate time of 
her next menstrual period when scheduling those visits. Later adjustments of those 
dates may be necessary.  
16. Participants will be asked to collect all used applicators and store them as described 
in the MOP.  
17. Participants will be asked to return all used applicators at their next visit.  
 
Participants immediately diagnosed with yeast on the wet mount (with or without 
discharge or vaginitis symptoms) during the enrollment visit will be referred for standard 
treatment. They will not be randomized and will not be invited for rescreening.  
 
If available test results at the enrollment visit suggest a UTI, cervicitis, vulvovaginitis, or 
active genital herpes lesion, the woman will be managed as clinically indicated and not 
randomized at this time, but invited for rescreening after completion of treatment. 
 
The antibiotics administered to treat BV need time to eliminate pathogens and the 
vaginal flora needs time to naturally replenish its lactobacilli population. By standard 
definition, a treatment of BV is only considered to have failed if Amsel criteria or Nugent 
score on Gram stain diagnose BV to persist at 22-30 days after the initiation of the 
antibiotic treatment. As a result, women who continue to have BV during the enrollment 
visit will not be re-treated with MetroGel at the time of enrollment, as additional time is 
needed for BV to resolve after antibiotic treatment. Thus, they are not considered 
treatment failures at this time (approximately 2 days after termination of antibiotic 
treatment). 
 
Participants diagnosed with an STI after randomization (when showing symptoms at 
subsequent visits that are confirmed with laboratory testing) will be referred for standard 
treatment and continue to receive study product.  
 


 
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7.3 
Follow-up Study Visit 2, Week 4, Day 28 (Allowable Days 21-35) 
 
The following procedures and assessments will be performed at Visit 2, Week 4, Day 28: 
1. Participants will return on Day 28. Staff will review the memory aid with the 
participant. The participant will be asked about symptoms, concomitant medications 
and any medical problems since the last visit, which will be recorded on the 
appropriate CRF. The participant will be asked to provide exact dates and times of 
the study product administration. 
2. Medical, gynecological and sexual history to include assessment of STI and HIV risk 
3. Symptom-directed physical and pelvic examination by a study physician or nurse that 
will include vital signs, including temperature, and examination of respiratory and 
cardiovascular systems, as well as assessment of symptoms and adverse events 
4. The pelvic examination will be conducted in the following order: 
a. Examination of the external genitalia 
b. Speculum insertion and examination of vagina, fornices and cervix with naked 
eye.  Water will be used to ease speculum insertion. No lubricant should be used 
as it could contain chlorhexidine which may kill Lactobacillus. 
c. Vaginal pH 
d. Vaginal swab for wet mount taken from the posterior fornix for yeast vaginitis and 
clue cells and for amine test (whiff test)  
e. Vaginal swab for Gram stain (Nugent scoring system) 
f. Vaginal swabs (no more than two) for storage and future identification of vaginal 
bacteria, and possible multiomic (e.g. proteomics, metabolomics, etc.) testing 
g. Vaginal swabs for L. crispatus identification with qPCR 
h. If indicated, cervical (or vaginal) swab for nucleic acid amplification of N. 
gonorrhoeae, C. trachomatis, and T.  vaginalis 
5. If indicated, clean catch urine dipstick; urinalysis if abnormal results indicate  
6. If indicated, urine βhCG pregnancy test 
7. All clinical and laboratory findings at the time of the evaluation will be recorded on 
the CRF. These findings will include observations present on the pelvic exam such 
as genital findings including location; presence or absence, and character of vaginal 
or cervical discharge or lesions; and results of any on-site tests. 
8. Participants will be reminded not to use scented tampons or any other vaginal 
products through Visit 7 (Week 24, Day 168).   
9. Participants will be reminded to abstain from sexual intercourse for 12 hours after 
each study product application and for 12 hours before the remaining study visits at 
Visit 3 (Week 8, Day 56), Visit 4 (Week 12, Day 84) and Visit 7 (Week 24, Day 168).  
10. Participants will receive non-spermicidal lubricated condoms for their male sexual 
partners.  Participants will be encouraged to use condoms if they engage in vaginal 
intercourse through Visit 7 (Week 24, Day 168). 
11. Participants will be asked if they still have the remaining applicators for the twice 
weekly doses stored at home. If not, they will receive additional pre-filled applicators 
to administer twice weekly through week 11. Participants will be instructed to 
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12. Participants will be instructed to collect all used applicators and store them as 
described in the MOP and to return all used applicators at their next visit, Visit 3 
(Week 8, Day 56). 
13. Applicators used since the last study visit will be collected. Applicators will be stained 
and tested as described in the MOP. 
14. An appointment for the follow-up visit will be scheduled. Depending on the time of 
the enrollment and the average length of the participant’s menstrual cycle, careful 
attention should be paid to the approximate time of the participant’s next menstrual 
period when scheduling those visits. Later adjustments of those dates may be 
necessary. 
Women with vaginal discharge or vaginitis symptoms who were diagnosed with yeast on 
the wet mount during the follow-up visit will be referred for standard treatment and 
continue to receive study product. 
  
If the test results at the follow-up visit suggest a urinary tract infection, cervicitis or 
vulvovaginitis, the participant will be referred for standard treatment and continue to 
receive study product. 
 
If the clinician suspects the woman to have developed an STI since the last visit, 
appropriate tests will be conducted and if needed the woman will be referred to standard 
of care treatment in compliance with current CDC STD Treatment Guidelines. The 
participant should be treated in case of positive findings and continue to use study 
product. 
 
Women who develop symptomatic BV confirmed by wet mount Amsel criteria ≥3 (with or 
without confirmatory Gram stain) at least 4 weeks after the last MetroGel treatment will 
be retreated with MetroGel. This practice follows CDC treatment guidelines and FDA 
recommendations. The 5-day course of MetroGel will begin as soon as possible.  
Women will skip their regularly scheduled dose of study product until 24 hours after their 
last dose of MetroGel when study product dosing will continue twice weekly. Women 
diagnosed with asymptomatic BV during the follow-up visit will not be retreated with 
MetroGel.  
 
7.4 
Follow-up Study Visit 3, Week 8, Day 56 (Allowable Days 49-63) 
The same procedures and assessments performed at Study Visit 2, Week 4, Day 28 will 
also be done at this visit. 
 
7.5 
Follow-Up Study Visit 4, Week 12, Day 84 (Allowable Days 77-91) 
The following procedures and assessments will be performed at Visit 4, Week 12, Day 
84: 
1. Participants will return on Day 84. Staff will review the memory aid with the 
participant. The participant will be asked about symptoms, concomitant medications 
and any medical problems since the last visit, which will be recorded on the 
appropriate CRF. The participant will be asked to provide exact dates and times of 
the study product administration.   
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3. Symptom-directed physical and pelvic examination by a study physician or nurse that 
will include vital signs, including temperature, and examination of respiratory and 
cardiovascular systems, as well as assessment of symptoms and adverse events 
4. The pelvic examination will be conducted in the following order: 
a. Examination of the external genitalia 
b. Speculum insertion and examination of vagina, fornices and cervix with naked 
eye.  Water will be used to ease speculum insertion.  No lubricant should be 
used as it could contain chlorhexidine which may kill Lactobacillus. 
c. Vaginal pH 
d. Vaginal swab for wet mount taken from the posterior fornix for yeast vaginitis and 
clue cells and for amine test (whiff test)  
e. Vaginal swab for Gram stain (Nugent scoring system) 
f. Vaginal swabs (no more than two) for storage and future identification of vaginal 
bacteria, and possible multiomic (e.g. proteomics, metabolomics, etc.) testing   
g. Vaginal swabs for L. crispatus identification with qPCR 
h. If indicated, cervical (or vaginal) swab for nucleic acid amplification of N. 
gonorrhoeae, C. trachomatis, and T. vaginalis 
5. If indicated, clean catch urine dipstick; urinalysis if abnormal results indicate 
6. If indicated, urine βhCG pregnancy test 
7. All clinical and laboratory findings at the time of the evaluation will be recorded on 
the CRF. These findings will include observations present on the pelvic exam such 
as genital findings including location; presence or absence, and character of vaginal 
or cervical discharge or lesions; and results of any on-site tests. 
8. Participants will be asked to answer a detailed self-administered questionnaire 
assessing the acceptability of the study product and the applicator to evaluate the 
possible change of attitudes over time.   
9. Participants will be reminded not to use scented tampons or any other vaginal 
products through Visit 7 (Week 24, Day 168).   
10. Participants will be reminded to abstain from sexual intercourse for 12 hours before 
study Visit 7 (Week 24, Day 168).  
11. Participants will receive non-spermicidal lubricated condoms for their male sexual 
partners.  Participants will be encouraged to use condoms if they engage in vaginal 
intercourse through Visit 7 (Week 24, Day 168). 
12. Applicators used since the last study visit will be collected. Applicators will be stained 
and tested as described in the MOP. 
13. An appointment for a telephone interview at Visit 5 (Week 16, Day 112) and at Visit 6 
(Week 20, Day 140) will be scheduled. 
14. An appointment for the next follow-up visit, Visit 7 (Week 24, Day 168) will be 
scheduled. Depending on the time of the enrollment and the average length of the 
participant’s menstrual cycle, careful attention should be paid to the approximate 
time of the participant’s next menstrual period when scheduling those visits. Later 
adjustments of those dates may be necessary. 
Women with vaginal discharge or vaginitis symptoms who were diagnosed with yeast on 
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If the test results at the follow-up visit suggest a urinary tract infection, cervicitis or 
vulvovaginitis, the participant will be referred for standard treatment.  
 
If the clinician suspects the woman to have developed an STI since the last visit, 
appropriate tests will be conducted and if needed the woman will be referred to standard 
of care treatment in compliance with current CDC STD Treatment Guidelines. The 
participant should be treated in case of positive findings. 
 
Women who develop symptomatic BV confirmed by wet mount Amsel criteria ≥3 (with or 
without confirmatory Gram stain) at least 4 weeks after the last MetroGel treatment will 
be retreated with MetroGel. This practice follows CDC treatment guidelines and FDA 
recommendations. The 5-day course of MetroGel will begin as soon as possible.  
Women will skip their regularly scheduled dose of study product until 24 hours after their 
last dose of MetroGel when study product dosing will continue twice weekly. Women 
diagnosed with asymptomatic BV during the follow-up visit will not be retreated with 
MetroGel.  
 
7.6 
Telephone Interview, Visit 5, Week 16, Day 112 (Allowable Days 105-119) 
 
Between Visit 4 (Week 12, Day 84) and Visit 7 (Week 24, Day 168), communication with 
participants will be continued by monthly telephone interviews.  
1. Participants will be called for a prearranged telephone interview at Day 112. Staff will 
review the memory aid with the participant. The participant will be asked about 
symptoms, concomitant medications, last menses, sexual activity and any medical 
problems since the last visit, which will be recorded on the appropriate CRF.  
2. Participants are invited to present at the clinic for an unscheduled visit if the site 
investigator deems it necessary after reviewing any medical problems or symptoms. 
3. Participants will be reminded not to use scented tampons or any other vaginal 
products through Visit 7 (Week 24, Day 168).   
4. Participants will be reminded to abstain from sexual intercourse for 12 hours before 
the last study visit, Visit 7 (Week 24, Day 168). 
5. An appointment for the next telephone interview at Visit 6 (Week 20, Day 140) will be 
confirmed or rescheduled if necessary. 
6. An appointment for the final visit, Visit 7 (Week 24, Day 168) will be confirmed. 
Depending on the time of the enrollment and the average length of the participant’s 
menstrual cycle, careful attention should be paid to the approximate time of the 
participant’s next menstrual period when scheduling those visits. Later adjustments 
of those dates may be necessary. 
 
If the participant fails to cancel the appointment and reschedule, and is unreachable 
during the agreed upon time for the telephone interview, the study team will make three 
attempts to reach the participant to reschedule the telephone interview.  
 
7.7 
Telephone Interview, Visit 6, Week 20, Day 140 (Allowable Days 133-146) 
 
The same assessments and instructions at Telephone Interview, Visit 5, Week 16, Day 
112 will also be done during this telephone interview.  


 
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7.8 
Final Study Visit 7, Week 24, Day 168 (Allowable Days 161-175) 
 
The following procedures and assessments will be performed at Visit 7, Week 24, Day 
168.  
1. Participants will return on Day 168. Staff will review the memory aid with the 
participant. The participant will be asked about symptoms, concomitant medications 
and any medical problems since the last visit, which will be recorded on the 
appropriate CRF.   
2. Medical, gynecological and sexual history to include assessment of STI and HIV risk 
3. Symptom-directed physical and pelvic examination by a study physician or nurse that 
will include vital signs, including temperature, and examination of respiratory and 
cardiovascular systems, as well as assessment of symptoms and adverse events 
4. The pelvic examination will be conducted in the following order: 
a. Examination of the external genitalia 
b. Speculum insertion and examination of vagina, fornices and cervix with naked 
eye.  Water will be used to ease speculum insertion.  No lubricant should be 
used as it could contain chlorhexidine which may kill Lactobacillus. 
c. Vaginal pH 
d. Vaginal swab for wet mount taken from the posterior fornix for yeast vaginitis and 
clue cells and for amine test (whiff test)  
e. Vaginal swab for Gram stain (Nugent scoring system) 
f. Vaginal swabs (no more than two) for storage and future identification of vaginal 
bacteria, and possible multiomic (e.g. proteomics, metabolomics, etc.) testing 
g. Vaginal swabs for L. crispatus identification with qPCR 
h. If indicated, cervical (or vaginal) swab for nucleic acid amplification of N. 
gonorrhoeae, C. trachomatis, and T. vaginalis 
5. If indicated, clean catch urine dipstick; urinalysis if abnormal results indicate 
urinalysis 
6. If indicated, urine βhCG pregnancy test. 
7. All clinical and laboratory findings at the time of the evaluation will be recorded on 
the CRF. These findings will include observations present on the pelvic exam such 
as genital findings including location; presence or absence, and character of vaginal 
or cervical discharge or lesions; and results of any on-site tests. 
 
Women with vaginal discharge or vaginitis symptoms who were diagnosed with yeast on 
the wet mount during the follow-up visit will be referred for standard treatment.  
 
If the test results at the follow-up visit suggest a urinary tract infection, cervicitis or 
vulvovaginitis, the participant will be referred for standard treatment.  
 
If the clinician suspects the woman to have developed an STI since the last visit, 
appropriate tests will be conducted and if needed the woman will be referred to standard 
of care treatment in compliance with current CDC STD Treatment Guidelines. The 
participant should be treated in case of positive findings. 
 


 
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Women who develop symptomatic BV confirmed by wet mount Amsel criteria ≥3 (with or 
without confirmatory Gram stain) at least 4 weeks after the last MetroGel treatment will 
be retreated with MetroGel. This practice follows CDC treatment guidelines and FDA 
recommendations. The 5-day course of MetroGel will begin as soon as possible.  
Women will skip their regularly scheduled dose of study product until 24 hours after their 
last dose of MetroGel when study product dosing will continue twice weekly. Women 
diagnosed with asymptomatic BV during the follow-up visit will not be retreated with 
MetroGel.  
 
7.9 
Study Product Discontinuation/Early Termination Visit 
 
Study product discontinuation and early termination evaluations will be performed as 
described below. Women who must discontinue taking the study product, for reasons 
described in section 5.3.3.2, before the end of the study-defined treatment period, will be 
asked to stay in the study to be followed on study/off treatment until study completion. 
Women who terminate their participation in the study early will be asked to have one 
final study visit but could return to be followed on study/off treatment until study 
completion if circumstances of the termination change. 
1. Staff will review the memory aid with the participant if the participant declines to 
return for follow-up visits.  The participant will be asked about symptoms, 
concomitant medications and any medical problems since the last visit, which will be 
recorded on the appropriate CRF. The participant will be asked to provide exact 
dates and times of the study product administration.   
2. Medical, gynecological and sexual history to include assessment of STI and HIV risk 
3. Symptom-directed physical and pelvic examination by a study physician or nurse that 
will include vital signs, including temperature, and examination of respiratory and 
cardiovascular systems, as well as assessment of symptoms and adverse events 
4. The pelvic examination will be conducted in the following order: 
a. Examination of the external genitalia 
b. Speculum insertion and examination of vagina, fornices and cervix with naked 
eye.  Water will be used to ease speculum insertion.  No lubricant should be 
used as it could contain chlorhexidine which may kill Lactobacillus. 
c. Vaginal pH 
d. Vaginal swab for wet mount taken from the posterior fornix for yeast vaginitis and 
clue cells and for amine test (whiff test)  
e. Vaginal swab for Gram stain (Nugent scoring system) 
f. Vaginal swabs (no more than two) for storage and future identification of vaginal 
bacteria, and possible multiomic (e.g. proteomics, metabolomics, etc.) testing 
g. If indicated, cervical (or vaginal) swab for nucleic acid amplification of N. 
gonorrhoeae, C. trachomatis, and T. vaginalis 
h. Other tests as deemed necessary by the site investigator in response to 
symptoms presented at this visit 
5. If indicated, clean catch urine dipstick; urinalysis if abnormal results indicate  
6. If indicated, urine βhCG pregnancy test 
7. All clinical and laboratory findings at the time of the evaluation will be recorded on 
the CRF. These findings will include observations present on the pelvic exam such 


 
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as genital findings including location; presence or absence, and character of vaginal 
or cervical discharge or lesions; and results of any on-site tests. 
8. Applicators used since the last study visit will be collected.  Any remaining unused 
applicators will also be collected.  
9. Administer acceptability questionnaire 
10. Dispense condoms to subjects who discontinue study product but remain in follow 
up. 
11. If the clinician suspects the participant developed an STI since the last visit, 
appropriate tests will be conducted and if needed the woman will be referred to 
standard of care treatment in compliance with current CDC STD Treatment 
Guidelines. 
 
7.10 Unscheduled Visit  
 
An unscheduled visit following a participant’s request or the site investigator’s 
recommendation should be recorded on the appropriate CRF. The following procedures 
and assessments may be performed at the unscheduled visit: 
1. Staff will review the memory aid with the participant. The participant will be asked 
about symptoms, concomitant medications and any medical problems since the last 
visit, which will be recorded on the appropriate CRF. Additionally, the participant will 
be asked to provide exact dates and times of the study product administration.   
2. Medical, gynecological and sexual history to include assessment of STI and HIV risk 
3. Symptom-directed physical and pelvic examination by a study physician or nurse that 
will include vital signs, including temperature, and examination of respiratory and 
cardiovascular systems, as well as assessment of symptoms and adverse events 
4. The pelvic examination will be conducted in the following order: 
a. Examination of the external genitalia 
b. Speculum insertion and examination of vagina, fornices and cervix with naked 
eye.  Water will be used to ease speculum insertion.  No lubricant should be 
used as it could contain chlorhexidine which may kill Lactobacillus. 
c. Vaginal pH 
d. Vaginal swab for wet mount taken from the posterior fornix for yeast vaginitis and 
clue cells and for amine test (whiff test)  
e. Vaginal swab for Gram stain (Nugent scoring system) 
f. Vaginal swabs (no more than two) for storage and future identification of vaginal 
bacteria, and possible multiomic (e.g. proteomics, metabolomics, etc.) testing 
g. Vaginal swabs for L. crispatus identification with qPCR 
h. If indicated, cervical (or vaginal) swab for nucleic acid amplification of N. 
gonorrhoeae, C. trachomatis, and T. vaginalis 
i. 
Other tests as deemed necessary by the site investigator in response to 
symptoms presented at this visit 
5. If indicated, clean catch urine dipstick; urinalysis if abnormal results indicate 
6. If indicated, βhCG pregnancy test 
7. All clinical and laboratory findings at the time of the evaluation will be recorded on 
the CRF. These findings will include observations present on the pelvic exam such 


 
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as genital findings including location; presence or absence, and character of vaginal 
or cervical discharge or lesions; and results of any on-site tests. 
8. The applicators used since the last study visit will be collected. Applicators will be 
stained and tested as described in the MOP. 
9. An additional unscheduled visit as deemed necessary by the site investigator to 
ensure short-term surveillance will be planned.  
10. If the site investigator decides together with the participant that study product use 
can continue, participants will be asked if they still have the remaining applicators for 
the twice weekly doses stored at home. If not, they will receive additional pre-filled 
applicators to administer twice weekly through week 11. Participants will be 
instructed to transport the pre-filled applicators while avoiding exposure to high 
temperatures. 
11. Participants will be reminded not to use scented tampons or any other vaginal 
products through Visit 7 (Week 24, Day 168).   
12. Participants will be reminded to abstain from sexual intercourse for 12 hours after 
each study product application and 12 hours before the remaining study visits.  
13. Participants will receive non-spermicidal lubricated condoms for their male sexual 
partners.  Participants will be encouraged to use condoms if they engage in vaginal 
intercourse through Visit 7 (Week 24, Day 168). 
14. Participants will be instructed to collect all used applicators and store them as 
described in the MOP and to return all used applicators at their next visit. 
15. An appointment for the next regular follow-up visit will be scheduled. Depending on 
the time of the enrollment and the average length of the participant’s menstrual 
cycle, careful attention should be paid to the approximate time of the participant’s 
next menstrual period when scheduling those visits. Later adjustments of those dates 
may be necessary. 
 
Women with vaginal discharge or vaginitis symptoms who were diagnosed with yeast on 
the wet mount during the follow-up visit will be referred for standard treatment and 
continue to receive study product.  
 
If the test results at the follow-up visit suggest a urinary tract infection, cervicitis or 
vulvovaginitis, the participant will be referred for standard treatment and continue to 
receive study product. 
 
If the clinician suspects the woman to have developed an STI since the last visit, 
appropriate tests will be conducted and if needed the woman will be referred to standard 
of care treatment in compliance with current CDC STD Treatment Guidelines. The 
participant should be treated in case of positive findings and continue to use study 
product. 
 


 
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Women who develop symptomatic BV confirmed by wet mount Amsel criteria ≥3 (with or 
without confirmatory Gram stain) at least 4 weeks after the last MetroGel treatment will 
be retreated with MetroGel. This practice follows CDC treatment guidelines and FDA 
recommendations. The 5-day course of MetroGel will begin as soon as possible.  
Women will skip their regularly scheduled dose of study product until 24 hours after their 
last dose of MetroGel when study product dosing will continue twice weekly. Women 
diagnosed with asymptomatic BV during the follow-up visit will not be retreated with 
MetroGel.  
 


 
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8.0 
STUDY PROCEDURES/EVALUATIONS 
 
8.1 
Clinical Evaluations 
 
The following assessments and procedures will be performed: 
• 
Sociodemographic and participant contact information 
• 
Medical, gynecological and sexual history 
• 
Review of concomitant medications 
• 
Physical exam to include vital signs 
• 
Pelvic exam 
• 
Acceptability questionnaire 
 
8.2 
Laboratory Evaluations 
 
8.2.1 Clinical Laboratory Evaluations 
At each clinical site, the following tests will be performed using approved 
standard in-house tests: 
• 
Pregnancy will be tested by standard rapid urine βhCG assays.   
• 
Urine will be tested by urine dipstick for evidence of urinary tract infection, 
with follow-up urine culture for positives.   
• 
HIV testing will be conducted using standardized algorithms.*   
• 
Syphilis will be tested by rapid plasma reagin with a confirmatory 
agglutination.*   
*NOTE: The total blood required is approximately 15mL (3 teaspoons). 
• 
Cervical (or vaginal) swabs will be tested for N. gonorrhoeae, C. trachomatis 
and T. vaginalis by nucleic acid amplification.  
The following test will be performed by a central laboratory for all clinical sites: 
• 
Gram-stained vaginal smear by Nugent's scoring system for diagnosis of BV  
 
8.2.2 Special Assays or Procedures 
Vaginal specimens will be analyzed for vaginal colonization with L. crispatus 
using qPCR assays and will be performed by a central laboratory at UCSF.  
At UCSF, and at UCSF expense, a vaginal specimen will be stored for future 
testing of other bacteria associated with BV (cultivable and uncultivable) by 16S 
rRNA qPCR pending the availability of non-STI CTG research funds. 
 
8.2.3 Specimen Preparation, Handling, and Shipping 
8.2.3.1 Instructions for Specimen Preparation, Handling, and Storage 
Instructions for specimen preparation, handling, and storage will be 
described in the MOP. 
8.2.3.2 Specimen Shipment 
Instructions for specimen shipment will be described in the MOP. 


 
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9.0 
ASSESSMENT OF SAFETY 
9.1 
Specification of Safety Parameters 
 
All AEs and SAEs will be collected through Study Visit 7, Week 24, Day 168. 
 
9.2 
Methods and Timing for Assessing, Recording, and Analyzing Safety Parameters 
 
9.2.1 Adverse Events 
 
ICH (International Conference on Harmonisation) E6 defines an AE as any 
untoward medical occurrence in a patient or clinical investigation subject 
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 including local and systemic reactions not meeting the criteria for “serious 
adverse events” should be captured on the appropriate CRF and will include: 
• 
Vaginal bleeding other than menstruation 
• 
Abnormal vaginal discharge 
• 
Abnormal vaginal odor 
• 
Genital itching 
• 
Genital burning 
• 
External genital irritation  
• 
External genital swelling 
• 
Nausea  
• 
Vomiting 
• 
Abdominal pain/cramps 
• 
Diarrhea 
• 
Constipation 
• 
Genital rash 
• 
Pain/burning with urination 
• 
Frequent urination 
• 
Blood in urine 
• 
Headache 
 
Information to be collected includes event description, time of onset, clinician’s 
assessment of severity, relationship to study product (assessed only by those 
with the training and authority to make a diagnosis), and time of 
resolution/stabilization of the event.  All AEs occurring while on study must be 
documented appropriately regardless of relationship.  All AEs will be followed to 
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Any medical condition that is present at the time that the participant is screened 
should be considered as baseline and not reported as an AE.  However, if it 
deteriorates at any time during the study, it should be recorded as an AE. 
All AEs must be graded for severity and relationship to study product. The  
FDA defines an AE as any untoward medical occurrence associated with the use 
of a drug in humans, whether or not considered drug related. 
Severity of Event:  All AEs will be assessed by the clinician using a protocol 
defined grading system.  For events not included in the protocol defined grading 
system, than the following guidelines will be used to quantify intensity.  
 
• 
Mild:  Events require minimal or no treatment and do not interfere with the 
participant’s daily activities. 
• 
Moderate:  Events result in a low level of inconvenience or concern with the 
therapeutic measures. Moderate events may cause some interference with 
functioning. 
• 
Severe:  Events interrupt a participant’s usual daily activity and may require 
systemic drug therapy or other treatment. Severe events are usually 
incapacitating. 
 
Changes in the severity of an AE should be documented to allow an assessment 
of the duration of the event at each level of intensity 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 an AE’s 
relationship to test article is part of the documentation process, but it is not a 
factor in determining what is or is not reported in the study.  If there is any doubt 
as to whether a clinical observation is an AE, the event should be reported.  All 
AEs must have their relationship to study product assessed using the terms:  
related or not related.  In a clinical trial, the study product must always be 
suspect.  To help assess, the following guidelines are used. 
 
• 
Related: There is a reasonable possibility that the study product caused the 
AE. Reasonable possibility means that there is evidence to suggest a causal 
relationship between the study product and the AE. 
• 
Not Related: There is not a reasonable possibility that the administration of 
the study product caused the event. 
 
9.2.2 Serious Adverse Events 
 
An AE or SAE reaction is considered “serious” if, in the view of either the 
investigator or sponsor, it results in any of the following outcomes:  
• 
Death 
• 
A life-threatening adverse event*  
• 
Inpatient hospitalization or prolongation of existing hospitalization  
• 
A persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions  


 
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• 
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 investigator 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: 
• 
Recorded on the appropriate SAE form and eCRF 
• 
Followed through resolution by a study physician 
• 
Reviewed and evaluated by the study chairs, relevant IRBs, DMID and the 
DSMB 
 
9.2.3 Procedures to be followed in the Event of Abnormal Laboratory Test Values or 
Abnormal Clinical Findings 
The site principal investigator or appropriate sub-investigator is responsible for 
reporting all AE/SAEs that are observed or reported during the study, regardless 
of their relationship to study product.  AE/SAEs, abnormal laboratory values, or 
abnormal clinical findings will be documented, reported, and followed 
appropriately.  
For grading abnormal gynecological events, refer to Appendix B, Division of 
AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, 
December 2004; Addendum 1: Female Genital Grading Table for Use in 
Microbicide Studies, November 2007. 
For grading abnormal laboratory and clinical events, refer to Appendix C, DAIDS 
Toxicity Table for Grading the Severity of Adult and Pediatric Adverse Events, 
Version 1.0 - December 2004 (Clarification dated August 2009). 
To meet FDA approved Clinical Data Interchange Standards Consortium 
(CDISC) data standards, Appendix B and Appendix C were revised to remove 
Grade 4 toxicities and combine them with Grade 3 toxicities. 
 
9.3 
Reporting Procedures 
 
9.3.1 Serious Adverse Events 
AEs will be followed until resolution even if this extends beyond the study-
reporting period.  Resolution of an AE is defined as the return to pretreatment 
status or stabilization of the condition with the expectation that it will remain 
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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 20814, USA 
SAE Hot Line: 1-800-537-9979 (US) or 1-301-897-1709 (outside US) 
SAE FAX Phone Number: 1-800-275-7619 (US) or 1-301-897-1710 (outside US) 
SAE Email Address: PVG@dmidcroms.com 
 
Other supporting documentation of the event may be requested by the DMID 
Pharmacovigilance Group and should be provided as soon as possible.  
 
The DMID medical monitor and clinical protocol manager will be notified of the 
SAE by the DMID Pharmacovigilance Group.  The DMID medical monitor will 
review and assess the SAE for regulatory reporting and potential impact on study 
subject safety and protocol conduct.  
 
At any time after completion of the study, if the investigator becomes aware of an 
SAE that is suspected to be related to study product, the investigator will report 
the event to the DMID Pharmacovigilance Group.  
 
9.3.2 Regulatory Reporting for Studies Conducted Under DMID-Sponsored IND 
 
Following notification from the site principal investigator or appropriate sub-
investigator, DMID, the Investigational New Drug (IND) sponsor, will report any 
suspected adverse reaction that is both serious and unexpected.  DMID will 
report an AE as a suspected adverse reaction only if there is evidence to suggest 
a causal relationship between the drug and the AE.  DMID will notify FDA and all 
participating site principal investigators (i.e., all principal investigators to whom 
the sponsor is providing drug under its IND(s) or under any principal 
investigator’s IND(s) in an IND safety report of potential serious risks from clinical 
trials or any other source, as soon as possible, but in no case later than 15 
calendar days after the sponsor determines that the information qualifies for 
reporting as specified in 21 CFR Part 312.32.  DMID will also notify FDA of 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.  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 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. 
 
9.3.3 Reporting of Pregnancy 
 


 
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Pregnancies occurring in study participants will be reported on the Pregnancy 
Report form.  Efforts will be made to follow all pregnancies reported during the 
course of the study to pregnancy outcome pending the participant’s permission. 
 
9.4 
Type and Duration of Follow-up of Subjects 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. Resolution of an AE/SAE is defined 
as the return to pretreatment status or stabilization of the condition with the expectation 
that it will remain chronic. 
 
Follow-up procedures, evaluations, and outcomes will be recorded on the appropriate 
data collection form. 
 
9.5 
Halting Rules 
 
Study enrollment and dosing will be halted and an ad hoc DSMB review will be 
performed if any of the following occur at any time during the study: 
1) One or more participants experience a treatment-related SAE. 
2) Two or more participants experience treatment-related vulvar and/or vaginal 
ulceration, abscess, or necrosis.  
3) Four or more participants experience a treatment-related severe (Grade 3) systemic 
adverse event.  
4) An overall pattern of symptomatic, clinical, or laboratory events that the DMID, 
medical monitor or DSMB consider associated with study product and that may 
collectively represent a serious potential concern for safety. 
A decision to reinitiate the study and proceed with study treatments will be made based 
on the recommendation of the DSMB and DMID. 
 
9.6 
Safety Oversight (ISM plus DSMB) 
 
An Independent Safety Monitor (ISM) at each clinical research site will oversee the 
safety of research subjects at that site, and will provide independent written evaluation of 
SAEs and related Grade 3 AEs to the DMID Clinical Project Manager and DMID Medical 
Monitor. The ISM will serve as an independent consultant for the site PI on subject-
related issues. The ISM will communicate with the site PI and study PIs to resolve any 
issues. 
 
Safety oversight will be under the direction of a DSMB, consisting of at least 3 voting 
members. The DSMB will meet after a third of the 228 participants complete Study Visit 
2 (Week 4), and then annually to assess safety and efficacy data on each arm of the 
study. The DSMB will review aggregate safety data for increased rate of occurrence of 
serious suspected adverse reactions. If halting rules are initiated, more frequent 
meetings may be held. The DMSB will operate under the rules of a DMID-approved 
charter that will be written at the organizational meeting of the DSMB. At this time, each 
data element that the DSMB needs to assess will be clearly defined. The DSMB will 
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10.0 CLINICAL MONITORING 
10.1 Site Monitoring Plan 
Site monitoring is conducted to ensure that the human subject protections, study and 
laboratory procedures, study intervention administration, and data collection processes 
are of high quality and meet sponsor, ICH/GCP guidelines and applicable regulations, 
and that the study is conducted in accordance with the protocol, protocol-specific MOP 
and applicable sponsor standard operating procedures.  DMID, the sponsoring agency, 
or its designee will conduct site-monitoring visits as detailed in the clinical monitoring 
plan. 
 
Site visits will be made at standard intervals as defined by DMID 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, CRFs or eCRFs, informed consent 
forms, medical and laboratory reports, and protocol and GCP compliance.  Site monitors 
will have access to the study site, study personnel, and all study documentation 
according to the DMID-approved site monitoring plan.  Study monitors will meet with site 
principal investigators to discuss any problems and actions to be taken and document 
visit findings and discussions. 
 


 
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11.0 STATISTICAL CONSIDERATIONS 
11.1 Introduction 
 
This is a Phase II-b multicenter randomized double-blind placebo-controlled trial to 
assess the safety and efficacy of repeated doses of LACTIN-V in comparison with 
placebo in preventing BV recurrence in women diagnosed with BV.  The study plans to 
enroll 228 sexually-experienced, pre-menopausal women age 18 to 45 years who are 
using a reliable method of birth control.  Potentially eligible women will start a standard 
5-day course of MetroGel.  After completing the 5-day course of MetroGel, eligible 
participants will be randomized 2:1 to receive LACTIN-V or matching placebo.  There will 
be five clinic visits and two telephone interviews over 24 weeks. 
 
11.2 Study Objectives and Outcome Measures 
 
As described in section 3.1 and 3.2, the primary study objectives are to compare 
LACTIN-V with placebo following a 5-day treatment course with MetroGel to treat BV 
with respect to safety and efficacy.  The primary safety outcome measure is the 
proportion of participants reporting AEs and SAEs considered product-related following 
dose of study product in each study arm through Visit 7 (Week 24, Day 168).  The 
primary efficacy outcome measure is the proportion of participants who experience BV 
recurrence (i.e. positive BV diagnosis) in each study arm by Visit 4 (Week 12, Day 84). 
 
Following FDA guidelines [25], all BV diagnoses during follow-up visits are considered 
incident, as they occur at least 22-30 days after the commencement of MetroGel 
treatment and consequently are treatment failures or new infections.  For the purpose of 
this trial, treatment failure and new infection will both be considered recurrent BV. 
 
11.3 Study Hypotheses 
 
There are two planned formal tests of hypotheses which compare LACTIN-V to placebo, 
with respect to the primary safety and efficacy outcome measures.  The first hypothesis 
test compares the proportion of participants in each study arm who experience AEs or 
SAEs considered product related following the first dose of study product through Visit 7 
(Week 24, Day 168).  The second hypothesis test compares the proportion of 
participants in each study arm who experience BV recurrence by Visit 4 (Week 12, Day 
84).   
 
The null hypothesis for each comparison is that there is no difference in proportions 
between study arms, with a two-sided alternative.  The test for the primary safety 
hypothesis will be conducted using the Fisher’s exact test at the 5% two-sided level of 
significance without adjustment for multiplicity.  The test for the primary efficacy 
hypothesis will be conducted using the Pearson’s chi-square test at the 5% two-sided 
level of significance without adjustment for multiplicity.  No adjustments for multiplicity 
will be used as this is a Phase II-b trial which will provide screening evidence about 
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The primary safety hypothesis will be tested in the safety data analysis population. The 
primary efficacy analysis will be conducted in the Complete Case analysis population, 
and repeated as a secondary analysis in the modified intent-to-treat and Per Protocol 
analysis populations.  See Section 11.6.2 for definitions of and rationales for use of the 
analysis populations. 
 
11.4 Sample Size Considerations 
 
Sample size calculations are based on the assumption of detecting a 50% reduction in 
the cumulative proportion of participants who experience BV recurrence by 12 weeks 
post-administration of study product among participants receiving LACTIN-V compared 
to those receiving placebo in a complete case analysis at the 0.05 significance level.  
The proportion of participants among controls who will experience BV recurrence at 12 
weeks is assumed to be 30%.  We assume a LACTIN-V to placebo allocation ratio of 2:1 
and 10% of subjects drop-out from the Complete Case population.  Given logistical and 
feasibility constraints on the sample size and that this is a Phase II-b trial which will 
provide screening evidence about safety and efficacy for a subsequent Phase III trial, 
this trial is powered at the 70% level.  Given the assumptions above, a sample size of 
228 participants is required to detect a 50% reduction in the cumulative proportion of 
participants experiencing recurrence in the Complete Case population with 70% power 
using the Pearson Chi-Square test.   
 
11.5 Planned Interim Analyses 
 
11.5.1 Safety Review  
 
As described in Section 9.6, the DSMB will meet and review safety data and 
enrollment data after one-third (N = 76) enrolled participants have completed 
Visit 2 (Day 28) and then annually thereafter.  The study will be monitored to 
determine if any of the safety halting rules described above in Section 9.5 are 
met.  The halting rules do not utilize any statistical criteria and no formal 
hypothesis testing is planned to occur for the safety and enrollment data reviews. 
 
11.5.2 Efficacy Review 
 
There is no planned interim analysis of efficacy data for this study. 
 
11.6 Final Analysis Plan 
 
11.6.1 General Principles 
 
Tabulations will be used extensively to summarize the data.  Summary statistics 
displayed for continuous data will include measures of central tendency such as 
the mean or median, and measures of dispersion such as the standard deviation 
or inter-quartile range.  Summary statistics for discrete data will include 
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In presenting statistical inferences, the statistical claim (i.e. null and alternative 
hypotheses) will be clearly stated, the method used for hypothesis testing or 
confidence interval estimation will be described and appropriately referenced, 
and the assumptions underlying the methods will be validated. 
 
Analytical and/or graphical methods for assessing goodness of model fit may be 
performed.   
 
More details of the analyses to be performed will be included in a separate 
Statistical Analysis Plan. 
 
11.6.2 Data Analysis Populations 
 
The safety population will include all randomized participants who received study 
treatment. 
 
The Modified Intent-To-Treat (mITT) population will include all randomized 
participants who met all inclusion/exclusion criteria, received study product, and 
returned for at least one post-baseline visit.   
 
The Complete Case (CC) population will include all participants in the mITT 
population who were followed up until the first diagnosis of BV or through Visit 4 
(Week 12, Day 84), or discontinued from the study as a treatment failure.  The 
CC population will be used as the primary efficacy analysis population for the test 
of LACTIN-V to placebo. 
 
The Per-Protocol (PP) population will include all randomized participants who 
met all inclusion/exclusion criteria, complied with the assigned study product, 
were followed up until the first diagnosis of BV or through Visit 4, or discontinued 
from the study as a treatment failure. 
 
A participant is compliant with the assigned study product if she takes at least 
75% of the scheduled doses prior to the first diagnosis of BV or through Visit 4 
(Week 12, Day 84). 
 
Prior to unblinding, a blinded case review committee will review participants with 
a reported concomitant infection/disease/procedure that may interfere with study 
product, use of concomitant medications or products that may interfere with study 
product, significant protocol deviations, and other events that may impact study 
product effectiveness or study analyses.  On a case-by-case basis, the case 
review committee will determine if each participant will be included in PP 
population, if and when a participant should be censored or removed from PP 
analyses, and/or any other analytical requirements for the participant. 
 
For the primary efficacy analysis participants who discontinue for reasons other 
than lack of treatment effect, as well as participants with a missing or non-
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excluded from the CC and PP populations, but included in the mITT population 
using imputation methods noted in Section 11.6.4.1. 
 
11.6.3 Safety Analyses 
 
Solicited AEs will be analyzed by taking the most severe response over the 
follow-up period, dichotomizing into a binary variable (none versus mild, 
moderate, or severe) and using standard techniques, such as exact confidence 
intervals, to summarize the event rates.   
 
Standard summary statistics, including 95% confidence intervals will be 
computed.  Additionally, graded results may either be analyzed as a binary 
variable (normal, abnormal) or multinomial variable (Grade 0, Grade 1, Grade 2, 
Grade 3) using either logistic regression or ordinal logistic regression respectively 
to make treatment group comparisons. 
 
Unsolicited AEs will be coded by MedDRA® for preferred term and system organ 
class. The proportion of participants and exact 95% confidence intervals of AEs 
in aggregate, as well as by MedDRA® categories, will be computed.  The 
number of SAEs will be reported by a detailed listing showing the type, 
MedDRA® coding, relevant dates (treatment dosing dates and AE onset and 
resolution dates), severity, relatedness, and outcome for each event. 
 
11.6.3.1 
Analysis of Primary Safety Outcome Measure 
 
The primary safety outcome measure is the proportion of participants 
reporting product-related AEs and SAEs in each study arm through 
Visit 7 (Week 24, Day 168). 
 
The outcome will be assessed in the safety analysis population.  The 
outcome will be reported by study arm.  The point estimates for the 
arm-specific proportions and difference in proportions along with the 
corresponding standard errors will be reported.  Fisher’s exact test at 
the 5% two-sided level of significance level without adjustment for 
multiplicity will be used for the comparison of proportions between 
study arms.   
 
As described in Section 11.6.3, additional descriptive analyses of 
adverse event data and clinical safety laboratory values will be 
performed. 
 
11.6.3.2 
Analysis of Secondary Safety Outcome Measure 
The secondary safety outcome measure is the tolerability of LACTIN-
V measured by the proportion of participants who discontinue study 
product due to adverse events in each study arm.   
 
The outcome will be assessed in the safety analysis population.  The 
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arm-specific proportions and difference in proportions along with the 
corresponding standard errors will be reported.  Fisher’s exact test at 
the 5% two-sided level of significance level without adjustment for 
multiplicity will be used for the comparison of proportions between 
study arms. 
 
11.6.4 Efficacy Analyses 
 
11.6.4.1 
Analysis of Primary Efficacy Outcome Measure 
 
The primary efficacy outcome measure is the proportion of 
participants with a positive BV diagnosis in each study arm by Visit 4 
(Week 12, Day 84) after study product administration. 
 
As described in Section 3.1.2, the Amsel Criteria and Nugent criteria 
will be used to determine diagnosis of BV recurrence.  Cumulative 
proportion of BV recurrence by Visit 4 is defined as follows: the 
numerator is the number of participants who experience recurrence at 
least once through Visit 4 in the particular analysis population and the 
denominator is the number of participants included in the particular 
analysis population. 
 
The primary efficacy outcome measure will be assessed in the CC 
population.  Use of the mITT population has previously been 
recommended by the FDA where missing values from participants 
who drop out early are imputed using Last Observation Carried 
Forward (LOCF) [25].  However, this includes participants who 
dropped out after completing at least one-follow-up visit, but before 
their first positive diagnosis.  LOCF would classify such participants as 
‘not recurrent.’  Thus, it is possible that the estimated proportions of 
treatment successes in a study arm could be larger than they are in 
reality.  Thus LOCF could result in an over-optimistic estimate of 
treatment effect, conflicting with the following rational for using an ITT 
analysis population stated in ICH E9 [37]:  “[ITT analysis] tends to 
avoid over-optimistic estimates of efficacy resulting from a per 
protocol analysis, since the non-compliers included in the [ITT] 
analysis set will generally diminish the estimated treatment effect.”   
To assess the effect of the choice of analysis population on the 
primary analysis, the analysis will be repeated as a secondary 
analysis in the mITT and PP populations.  The mITT population 
includes participants who discontinue for reasons other than lack of 
treatment effect, as well as participants with a missing or non-
evaluable Amsel or Nugent result with no positive result at another 
visit.  The missing results will be imputed using LOCF.  To assess the 
effect of missing data and the method of imputation on the primary 
analysis, a sensitivity analysis will be performed.  The details of the 
sensitivity analysis will be detailed in the Statistical Analysis Plan. 
 


 
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As described in Section 11.3, a test of hypothesis will be performed. 
The analysis will be based on comparisons of cumulative proportion of 
BV recurrence between study groups by the Visit 4 using the Pearson 
Chi-Square test (or, if more appropriate, Fisher’s Exact Test) for 
differences in proportions between two independent groups.  The 
point estimates for the within-arm proportions, odds ratio, and 
corresponding two-sided level 95% confidence interval will be 
reported.  A secondary time-to-event analysis of the primary efficacy 
outcome measure will be performed.  Details of the analysis will be 
included in the Statistical Analysis Plan. 
 
11.6.4.2 
Analysis of Secondary Efficacy Outcome Measures 
 
All secondary efficacy outcomes measures will be assessed in the 
mITT, CC, and PP populations separately.   
 
The secondary efficacy outcome measures are as follows: 
1. The proportion of participants experiencing successful 
colonization with L. crispatus CTV-05 following dose of study 
product through Visit 4 (Week 12, Day 84) in the LACTIN-V arm, 
overall and stratified by occurrence of menses and intercourse. 
2. The proportion of participants experiencing successful 
colonization with L. crispatus CTV-05 following dose of study 
product at Visit 7 (Week 24,Day 168) in the LACTIN-V arm, overall 
and stratified by occurrence of menses and intercourse 
3. A) The proportion of participants compliant with the dose regimen 
in each study arm as assessed by participant reporting and 
applicator staining 
B) Summaries from a self-administered questionnaire about 
acceptability of the study product in each study arm 
4. The proportion of participants with a positive BV diagnosis in each 
study arm by Visit 7 (Week 24, Day 168) 
 
Secondary outcome measures 1 and 2 will be reported within the 
LACTIN-V arm and across time.  The point estimates for the overall 
proportions and stratified proportions, along with the corresponding 
standard errors, will be reported.  A secondary time-to-event analysis 
of secondary outcome measure 1 will also be performed, which will be 
described in the Statistical Analysis Plan. 
 
Secondary Outcome 3A will be reported by study arm.  The point 
estimates for the arm-specific proportions and difference in 
proportions along with the corresponding standard errors will be 
reported.  Pearson’s chi-square test or, if more appropriate, Fisher’s 
exact test, at the 5% two-sided level of significance level without 
adjustment for multiplicity will be used for the comparisons of 
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For Secondary Outcome 3B, responses to the self-administered 
questionnaire will be summarized by study arm.  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 inter-
quartile range. 
 
The analysis of Secondary Outcome 4 will be based on comparisons 
of cumulative proportion of BV recurrence between study groups by 
the Visit 7 using the Pearson Chi-Square test or Fisher’s Exact Test 
for differences in proportions between two independent groups.  The 
point estimates for the within-arm proportions, odds ratio, and 
corresponding two-sided level 95% confidence interval will be 
reported.  A secondary time-to-event analysis of secondary outcome 
measure 4 will also be performed, which will be described in the 
Statistical Analysis Plan. 
 
11.6.4.3 
Analysis of Exploratory Efficacy Outcome 
 
The statistical parameterizations of the exploratory objective will 
include, but are not limited to, the following: 
• 
The number of positive BV diagnoses per 12 weeks of follow-
up 
• 
The probability of positive BV diagnoses during the 12 weeks 
of follow-up 
 
For the first parameterization, a Poisson regression model will be fit to 
estimate the 12-week incidence of positive BV diagnoses in each of 
the treatment arms and to compare the incidence in the LACTIN-V 
arm to that in the placebo arm.  
 
For the second parameterization, a repeated measures logistic 
regression model will be fit to estimate the probability of positive BV 
diagnoses in each of the treatment arms and to compare the 
probability of recurrence in the LACTIN-V arm to that in the placebo 
arm.  
 
As the exploratory analyses include participants who received 
additional MetroGel treatment after experiencing symptomatic BV at a 
particular follow-up visit, a sensitivity analysis will be performed to 
assess the effect of the additional treatment on the outcome.  Details 
of the sensitivity analysis will be provided in the Statistical Analysis 
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12.0 SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/ 
DOCUMENTS 
Each participating site will maintain appropriate medical and research records for this trial, in 
compliance with ICH E6, Section 4.9 and regulatory and institutional requirements for the 
protection of confidentiality of participants.  Each site will permit authorized representatives of 
the DMID, its designees, and appropriate regulatory agencies to examine (and when required 
by applicable law, to copy) clinical records for the purposes of quality assurance reviews, audits, 
and evaluation of the study safety and progress.  These representatives will be permitted 
access to all source data, which include, but are not limited to, hospital records, clinical and 
office charts, laboratory notes, memoranda, evaluation checklists, pharmacy dispensing 
records, recorded data from automated instruments, copies or transcriptions certified after 
verification as being accurate and complete, microfiches, photographic negatives, microfilm or 
magnetic media, x-rays, and participant files and records kept at the pharmacy, at the 
laboratories, and medico-technical departments involved in the clinical trial.  Data collection 
forms will be derived from the eCRFs and be provided by the Statistical and Data Coordinating 
Center (SDCC). 
 
 


 
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13.0 QUALITY CONTROL AND QUALITY ASSURANCE 
The SDCC will implement quality control procedures beginning with the data entry system and 
generate data quality control checks that will be run on the database. Any missing data or data 
anomalies will be communicated to the site(s) for prompt clarification and resolution. 
 
The investigational sites are responsible for conducting routine quality control (QC) and quality 
assurance (QA) activities to internally monitor study progress and protocol compliance.  All sites 
will follow Sexually Transmitted Infections Treatment and Research (STAR) STI-CTG Standard 
Operating Procedures. A Clinical Quality Management Plan (CQMP) is in place for ensuring 
compliance with the protocol, applicable federal regulations, and Good Clinical Practice 
guidelines.  
 
The Principal Investigator will provide direct access to all trial-related sites, source 
data/documents, and reports for the purpose of monitoring and auditing by the sponsor, and 
inspection by local and regulatory authorities.  
 
The Principal Investigator will ensure all study personnel are appropriately trained and 
applicable documentations are maintained on site.  
 


 
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14.0 ETHICS/PROTECTION OF HUMAN SUBJECTS 
14.1 Ethical Standard 
The investigator will ensure that this study is conducted in full conformity with the 
principles set forth in the Belmont Report: Ethical Principles and Guidelines for the 
Protection of Human Subjects of Research of the US National Commission for the 
Protection of Human Subjects of Biomedical and Behavioral Research (April 18, 1979) 
and codified in 45 CFR Part 46 and/or the ICH E6; 62 Federal Regulations 25691 
(1997). 
 
14.2 Institutional Review Board 
Each participating institution will provide for the review and approval of this protocol and 
the associated informed consent documents and recruitment material by an appropriate 
independent ethics committee (IEC) or IRB registered with the OHRP.  Any amendments 
to the protocol or consent materials will also be approved before they are placed into 
use. 
 
14.3 Informed Consent Process 
Informed consent is a process that is initiated prior to the participant’s agreeing to 
participate in the study and continuing throughout the participant’s study participation.  
Extensive discussion of risks and possible benefits of this therapy will be provided to the 
participant and their families.  For this study, separate screening and enrollment consent 
forms will be used. Consent forms describing in detail the study interventions, products, 
study procedures, and risks are given to the participant and written documentation of 
informed consent is required prior to starting intervention or administering study product.  
Consent forms will be IRB-approved and the participant will be asked to read and review 
the document. Upon reviewing the document, the investigator will explain the research 
study to the participant and answer any questions that may arise.  The participants will 
sign the informed consent document prior to any procedures being done specifically for 
the study. The participants should have the opportunity to discuss the study with their 
surrogates or think about it prior to agreeing to participate.  The participants may 
withdraw consent at any time throughout the course of the trial.  A copy of the informed 
consent document will be given to the participants for their records.  The rights and 
welfare of the participants 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. 
 
14.4 Exclusion of Women, Minorities, and Children (Special Populations) 
This trial will enroll adult women who meet the participant inclusion criteria regardless of 
religion or ethnic background.   
The following populations will be excluded from study participation:  
• 
Pregnant women 
Pregnant women are not eligible for this study because there are no current 
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• 
Men 
Men are not eligible for this study as the study evaluates the uterine cervix and 
vagina for changes associated with the use of LACTIN-V. 
• 
Children 
The NIH has mandated that children (defined as anyone under the age of 21) be 
included in research trials when appropriate. This study will enroll children aged 18 to 
20 who are able to give informed consent. This study meets "Justifications for 
Exclusion" criteria for younger children as set forth by the NIH. Specifically, 
"insufficient data are available in adults to judge potential risk in children" and 
"children should not be the initial group to be involved in research studies."  
 
14.5 Subject Confidentiality 
Participant confidentiality is strictly held in trust by the participating investigators, their 
staff, and the sponsor(s) and their agents.  This confidentiality is extended to cover 
testing of biological samples and genetic tests in addition to the clinical information 
relating to participating participants. 
 
The study protocol, documentation, data, and all other information generated will be held 
in strict confidence.  No information concerning the study or the data will be released to 
any unauthorized third party without prior written approval of the sponsor. 
 
The study monitor or other authorized representatives of the sponsor may inspect all 
documents and records required to be maintained by the investigator, including but not 
limited to, medical records (office, clinic, or hospital) and pharmacy records for the 
participants in this study.  The clinical study site will permit access to such records. 
 
14.6 Study Discontinuation 
If the trial is discontinued, participants who sign the informed consent form, and are 
randomized and treated will continue to be followed for safety assessments.  No further 
study product will be administered. 
 
14.7 Future Use of Stored Specimens  
Vaginal swabs (no more than two) will be collected at each visit and stored for future 
use. These swabs will be in addition to the swabs being collected to test for sexually 
transmitted infections and bacterial vaginosis. The additional swabs may be used for 
future testing and identification of vaginal bacteria. Samples will be kept confidential and 
coded with a unique ID. Upon request and ethical approval, these samples may also be 
made available to other researchers to test for the bacteria, and possible multiomic (e.g. 
proteomics, metabolomics, etc.) testing. Storage of samples is optional and not a 
requirement for the study. Participants will be asked to consent separately to have their 
specimens stored. Consent can be withdrawn at any time and refusal or withdrawal of 
consent will not affect study participation. 


 
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15.0 DATA HANDLING AND RECORD KEEPING 
The investigator is responsible for ensuring the accuracy, completeness, legibility, and 
timeliness of the data reported.   
 
Data collection forms will be derived from the eCRFs and provided by the SDCC to the sites to 
record and maintain data for each participant enrolled in the study.  All source documents 
should be completed in a neat, legible manner to ensure accurate interpretation of data.  
Permanent ink is required to ensure clarity of reproduced copies.  When making a change or 
correction, the original entry should be crossed out with a single line, and the change should be 
initialed and dated.  Do not erase, overwrite, or use correction fluid or tape on the original.  
Data reported in the eCRF should be consistent with the data collection form/source documents 
or the discrepancies should be documented.   
 
The sponsor and/or its designee will provide guidance to investigators on making corrections to 
the data collection forms and eCRFs. 
 
15.1 Data Management Responsibilities 
 
All source documents and laboratory reports must be reviewed by the clinical team and 
data entry staff, who will ensure that they are accurate and complete.  Adverse events 
must be graded, assessed for severity and causality, and reviewed by the site principal 
investigator (PI) or designee. 
 
Data collection is the responsibility of the clinical trial staff at the site under the 
supervision of the site PI.  During the study, the investigator must maintain complete and 
accurate documentation for the study. 
 
The Emmes Corporation will serve as the Statistical and Data Coordinating Center for 
this study and will be responsible for data management, quality review, analysis, and 
reporting of the study data. 
 
15.2 Data Capture Methods 
 
Clinical data (including, but not limited to, AE/SAEs, concomitant medications, and 
reactogenicity data) and clinical laboratory data will be entered into a 21 CFR Part 11-
compliant Internet Data Entry System, AdvantageEDCSM, provided by The Emmes 
Corporation.  The data system includes password protection and internal quality checks, 
such as automatic range checks, to identify data that appear inconsistent, incomplete, or 
inaccurate.  Clinical data will be entered directly from the source documents.  
 
15.3 Types of Data 
 
Data for this study will include clinical, efficacy, safety, laboratory and outcome 
measures (eg, AEs, SAEs, and reduction of BV reoccurrence). 
 


 
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15.4 Timing/Reports 
A final report will be prepared following the availability of all the safety and laboratory 
data.  Interim statistical reports may be generated as deemed necessary and 
appropriate by DMID.  Safety and laboratory data summary reports may be generated 
for the DSMB. 
 
15.5 Study Records Retention 
 
Study documents should be retained for a minimum of 2 years after the last approval of 
a marketing application in an ICH region and until there are no pending or contemplated 
marketing applications in an ICH region or at least 2 years have elapsed since the formal 
discontinuation of clinical development of the investigational product. These documents 
should be retained for a longer period, however, if required by local regulations.  No 
records will be destroyed without the written consent of the sponsor, if applicable.  It is 
the responsibility of the sponsor to inform the investigator when these documents no 
longer need to be retained. 
 
15.6 Protocol Deviations 
 
A protocol deviation is any noncompliance with the clinical trial protocol, Good Clinical 
Practice (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 are to be developed by the site and implemented promptly.  
 
These practices are consistent with ICH E6: 
 
4.5 
Compliance with Protocol, sections 4.5.1, 4.5.2, and 4.5.3 
 
5.1 
Quality Assurance and Quality Control, section 5.1.1 
 
5.20 
Noncompliance, sections 5.20.1, and 5.20.2. I 
 
It is the responsibility of the site to use continuous vigilance to identify and report 
deviations within 5 working days of identification of the protocol deviation, or within 5 
working days of the scheduled protocol-required activity.  All deviations must be 
promptly reported to DMID, via the SDCC’s AdvantageEDCSM.  
 
All deviations from the protocol must be addressed in study subject data collection 
forms.  A completed copy of the DMID-approved Protocol Deviation Form must be 
maintained in the regulatory file, as well as in the participant’s source document.  
Protocol deviations must be sent to the local IRB/IEC per their guidelines. The site 
PI/study staff is responsible for knowing and adhering to their IRB/IEC requirements 
 


 
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16.0 PUBLICATION POLICY 
Following completion of the study, the Investigator is expected to publish the results of this 
research in a scientific journal.  Publication of the results of this study will be governed by 
STICTG policies and the International Committee of Medical Journal Editors (ICMJE) member 
journals, which have adopted a trials-registration policy as a condition for publication.   
 
This policy requires that all clinical trials be registered in a public trials registry such as 
ClinicalTrials.gov  which is sponsored by the National Library of Medicine.  Other biomedical 
journals are considering adopting similar policies.  It is the responsibility of DMID to register this 
trial in an acceptable registry.  Any clinical trial starting enrollment after 01 July 2005 must be 
registered on or before patient enrollment.  For trials that began enrollment prior to this date, the 
ICMJE member journals will require registration by 13 September 2005, before considering the 
results of the trial for publication 
 
The ICMJE defines a clinical trial as any research project that prospectively assigns human 
participants to intervention or comparison groups to study the cause-and-effect relationship 
between a medical intervention and a health outcome.  Studies designed for other purposes, 
such as to study pharmacokinetics or major toxicity (eg, Phase 1 trials), would be exempt from 
this policy. 
 
Any presentation, abstract, or manuscript will be made available by the Investigator to the STI-
CTG Manuscript Review Committee, DMID, and Osel Inc. for review prior to submission. 
 


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60 
 
17.0 LITERATURE REFERENCES 
1. 
Allsworth JE and Peipert JF. Prevalence of bacterial vaginosis: 2001-2004 National Health 
and Nutrition Examination Survey data. Obstet Gynecol 2007;109(1):114-20. 
 
2. 
Eschenbach DA, Hillier S, Critchlow C, et al. Diagnosis and clinical manifestations of 
bacterial vaginosis. Am J Obstet Gynecol 1988;158(4):819-28. 
 
3. 
Hillier SL, Kiviat NB, Hawes SE, et al. Role of bacterial vaginosis-associated 
microorganisms in endometritis. Am J Obstet Gynecol 1996;175(2):435-41. 
 
4. 
Watts DH, Krohn MA, Hillier SL, et al. Bacterial vaginosis as a risk factor for post-cesarean 
endometritis. Obstet Gynecol 1990;75(1):52-8. 
 
5. 
Soper DE. Bacterial vaginosis and postoperative infections. Am J Obstet Gynecol. 1993 
Aug;169(2 Pt 2):467-9. 
 
6. 
Kurki T, Sivonen A, Renkonen OV, et al. Bacterial vaginosis in early pregnancy and 
pregnancy outcome. Obstet Gynecol 1992;80(2):173-7. 
 
7. 
Hillier SL, Martius J, Krohn M, et al. A case-control study of chorioamnionic infection and 
histologic chorioamnionitis in prematurity. N Engl J Med 1988;319(15):972-8. 
 
8. 
Taha TE, Hoover DR, Dallabetta GA, et al. Bacterial vaginosis and disturbances of vaginal 
flora: association with increased acquisition of HIV. AIDS 1998;12(13):1699-706. 
 
9. 
Myer L, Denny L, Telerant R, et al. Bacterial vaginosis and susceptibility to HIV infection in 
South African women: a nested case-control study. J Infect Dis 2005;192(8):1372-80. 
 
10. Cohen CR, Lingappa JR, Baeten JM, et al. Bacterial vaginosis associated with increased 
risk of female-to-male HIV-1 transmission: a prospective cohort analysis among African 
couples. PLoS Med. 2012;9(6):e1001251. doi: 10.1371/journal.pmed.1001251. Epub 2012 
Jun 26. 
 
11. Fichorova RN, Onderdonk AB, Yamamoto H, et al. Maternal microbe-specific modulation of 
inflammatory response in extremely low-gestational-age newborns. MBio 2011;2(1). 
 
12. Bradshaw CS, Morton AN, Hocking J, et al. High recurrence rates of bacterial vaginosis 
over the course of 12 months after oral metronidazole therapy and factors associated with 
recurrence. J Infect Dis 2006;193(11):1478-86. 
 
13. Bukusi EA, Thomas KK, Nguti R, Cohen CR, et al. Topical Penile Microbicide Use by Men 
to Prevent Recurrent Bacterial Vaginosis in Sex Partners: A Randomized Clinical Trial. Sex 
Transm Dis. 2011 Jun;38(6):483-9. 
 
14. Bolton M van der Straten A and Cohen CR. Probiotics: potential to prevent HIV and 
sexually transmitted infections in women. Sex Transm Dis 2008;35(3):214-25. 
 


 
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15. Stapleton AE, Au-Yeung M, Hooton TM, et al. Randomized, Placebo-Controlled Phase 2 
Trial of a Lactobacillus crispatus Probiotic Given Intravaginally for Prevention of Recurrent 
Urinary Tract Infection. Clin Infect Dis 2011;52(10):1212-7. 
 
16. Hemmerling A, Harrison W, Schroeder A, et al. Phase 1 dose-ranging safety trial of 
Lactobacillus crispatus CTV-05 for the prevention of bacterial vaginosis. Sex Transm Dis 
2009;36(9):564-9. 
 
17. Hemmerling A, Harrison W, Schroeder A, et al. Phase 2a Study Assessing Colonization 
Efficiency, Safety and Acceptability of Lactobacillus crispatus CTV-05 (LACTIN-V) in 
Women with Bacterial Vaginosis. Sex Transm Dis 2010;37(12):745-50. 
 
18. Ngugi BM, Hemmerling A, Bukusi EA, et al. Effects of BV-Associated Bacteria and Sexual 
Intercourse on Vaginal Colonization with the Probiotic Lactobacillus crispatus CTV-05. Sex 
Transm Dis. 2011 Nov;38(11):1020-7. doi: 10.1097/OLQ.0b013e3182267ac4. 
 
19. Abdool Karim Q, Abdool Karim SS, Frohlich JA, et al. Effectiveness and safety of tenofovir 
gel, an antiretroviral microbicide, for the prevention of HIV infection in women. Science. 
2010;329(5996):1168-1174.  
 
20. Anahtar MN, Byrne EH, Koherty KE, et al. Cervicovaginal bacteria are a major modulator of 
host inflammatory responses in the female genital tract. Immunity 2015;42(5):965-76. 
 
21. Cohen CR, Moscicki  AB, Scott ME, et al. Increased levels of immune activation in the 
genital tract of healthy young women from sub-Saharan Africa. AIDS 2010;24(13):2069-74. 
 
22. CDC Sexually Transmitted Treatment Guidelines.  
http://www.cdc.gov/std/tg2015/tg-2015-print.pdf 
 
23. Schwebke JR, Hillier SL, Sobel JD, et al. Validity of the vaginal gram stain for the diagnosis 
of bacterial vaginosis. Obstet Gynecol 1996;88(4 Pt 1):573–6. 
 
24. Amsel R, Totten PA, Spiegel CA, et al. Nonspecific vaginitis. Diagnostic criteria and 
microbial and epidemiologic associations. Am J Med 1983;74:14–22. 
 
25. FDA Draft Guidance for the Use of Metronidazole Gel. 
http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/u
cm345807.pdf 
 
26. Bradshaw CS, Vodstrcil LA, Hocking JS, et al. (2013). Recurrence of bacterial vaginosis is 
significantly associated with post-treatment sexual activities and hormonal contraceptive 
use. Clinical Infectious Diseases, 56(6), 777. 
 
27. Cruciani F, Wasinger V, Turroni S, et al. (2013). Proteome profiles of vaginal fluids from 
women affected by bacterial vaginosis and healthy controls: Outcomes of rifaximin 
treatment.  J of Antimicrobial Chemo 68(11), 2648.  
 


 
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28. Donders GG, Guaschino S, Peters K, et al. (2013). A multicenter, double-blind, 
randomized, placebo-controlled study of rifaximin for the treatment of bacterial vaginosis 
Int. J. Gynaecol Obstet, 120(2):131-136. doi: 10.1016/j.ijgo.2012.08.022 
 
29. Bradshaw CS, Pirotta M, Guingand DD, et al. (2012). Efficacy of oral metronidazole with 
vaginal clindamycin or vaginal probiotic for bacterial vaginosis: Randomized placebo-
controlled double-blind trial. PLoS One, 7(4) doihttp://0-
dx.doi.org.library.touro.edu/10.1371/journal.pone.0034540 
 
30. Balkus JE, Jaoko W, Mandaliya K, et al. (2012). The posttrial effect of oral periodic 
presumptive treatment for vaginal infections on the incidence of bacterial vaginosis and 
Lactobacillus colonization. Sex Transm Dis., 39(5):361-5. doi: 
10.1097/OLQ.0b013e31824790d7  
 
31. Weissenbacher ER, Donders G, Unzeitig V, et al. Fluomizin Study Group. (2012). 
A comparison of dequalinium chloride vaginal tablets and clindamycin vaginal cream in the 
treatment of bacterial vaginosis. a single-blind, randomized clinical trial of efficacy and 
safety. 2012;73(1):8-15.doi:10.1159/000332398.Epub 2011 Dec 24. 
 
32. Schwebke JR, Desmond RA. (2011). Tinidazole vs metronidazole for the treatment 
of bacterial vaginosis. Am J Obstet Gynecol, 204(3):211.e1-6. doi: 
10.1016/j.ajog.2010.10.898 
 
33. Marrazzo JM, Fiedler TL, Srinivasan S, et al. (2012). Extravaginal reservoirs of 
vaginal bacteria as risk factors for incident bacterial vaginosis. J Infect Dis., 205(10):1580-8. 
doi: 10.1093/infdis/jis242 
 
34. Madhivanan P, Raphael E, Rumphs A, et al. (2014). Characterization of 
culturable vaginal Lactobacillus species among women with and 
without bacterial vaginosis from the United States and India: a cross-sectional study. J Med 
Microbiol. 63(Pt 7):931-5. doi: 10.1099/jmm.0.073080-0 
 
35. Schwebke JR, Hillier SL, Sobel JD, et al. Validity of the vaginal gram stain for the diagnosis 
of bacterial vaginosis. Obstet Gynecol 1996;88(4 Pt 1):573–6. 
 
36. Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, 
December 2004; Addendum 1: Female Genital Grading Table for Use in Microbicide 
Studies, November 2007 
 
37. International Conference on Harmonisation (ICH) E9. 
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E9/Step4/
E9_Guideline.pdf 
 
 


 
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APPENDICES 
Appendix A  
 
Schedule of Events 
 
Appendix B  
 
Division of AIDS Table for Grading the Severity of Adult and  
 
 
 
 
Pediatric Adverse Events, December 2004; Addendum 1: Female   
 
 
 
Genital Grading Table for Use in Microbicide Studies, November   
 
 
 
2007 
 
Appendix C 
 
DAIDS Toxicity Table for Grading the Severity of Adult and Pediatric  
 
 
 
Adverse Events, Version 1.0 - December 2004 (Clarification dated  
 
 
 
August 2009


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Appendix A 
Schedule of Events 
 
Study Treatment 
 
Study Follow Up  
 
Evaluation 
Screening 
Visit 0 
Day -30 to -5
Enrollment Visit 1 
Day 1 
Study Visit 2  
Day 28 (Week 4) 
Study Visit 3  
Day 56 (Week 8) 
Study Visit 4  
Day 84 (Week 12) 
Phone Visit 5   
Day 112 
(Week 16)
Phone Visit 6   
Day 140  
(Week 20) 
Study Visit 7   
Day 168  
(Week 24) 
Unscheduled Visit 
Study Product  
Discontinuation 
Early  Termination 
Visit 
Visit window 
 
 
 
± 1 week 
 
Signed consent form 
X 
X 
 
 
 
 
 
 
 
 
 
Assessment of eligibility criteria 
X 
X 
 
 
 
 
 
 
 
 
 
Demographics 
X 
X 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
Detailed medical, gynecological and sexual history 
X 
 
 
 
 
 
 
 
 
 
 
Dispense MetroGel  
X 
 
(X) 
(X) 
(X) 
 
 
 
 
 
 
Dispense LACTIN-V/placebo and applicators 
 
X 
(X) 
(X) 
 
 
 
 
 
 
 
Dispense condoms 
X 
X 
X 
X 
X 
 
 
 
X 
X 
 
Dispense memory aid or instructions on using web 
based memory aid 
 
X 
 
 
 
 
 
 
 
 
 
Brief  medical, gynecological and sexual history 
 
X 
X 
X 
X 
 
 
X 
X 
X 
X 
Review of concomitant medications  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study intervention 
 
X 
X 
X 
X 
 
 
 
 
 
 
Physical 
Examination 
Complete 
X 
 
 
 
 
 
 
 
 
 
 
Symptom-directed 
 
X 
X 
X 
X 
 
 
X 
X 
X 
X 
Vital signs 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
X 
Pelvic examination 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
X 
Review memory aid and symptoms 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Reminder to abstain from sexual intercourse 
 
X 
X 
X 
X 
X 
X 
 
X 
 
 


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65 
 
Study Treatment 
 
Study Follow Up  
 
Evaluation 
Screening 
Visit 0 
Day -30 to -5
Enrollment Visit 1 
Day 1 
Study Visit 2  
Day 28 (Week 4) 
Study Visit 3  
Day 56 (Week 8) 
Study Visit 4  
Day 84 (Week 12) 
Phone Visit 5   
Day 112 
(Week 16)
Phone Visit 6   
Day 140  
(Week 20) 
Study Visit 7   
Day 168  
(Week 24) 
Unscheduled Visit 
Study Product  
Discontinuation 
Early  Termination 
Visit 
Reminder not to use vaginal products 
 
X 
X 
X 
X 
X 
X 
 
X 
 
 
Reminder to collect and return used applicators 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
Assessment of adverse events 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Clinical 
Laboratory 
Clean catch urine dipstick 
X 
(X) 
(X) 
(X) 
(X) 
 
 
(X) 
(X) 
(X) 
(X) 
Urinalysis 
(X) 
(X) 
(X) 
(X) 
(X) 
 
 
(X) 
(X) 
(X) 
(X) 
Rapid urine βhCG pregnancy test 
X 
X 
(X) 
(X) 
(X) 
 
 
(X) 
(X) 
(X) 
(X) 
HIV and syphilis serology (total blood 
required is approximately 15mL (3 
teaspoons)  
X 
 
 
 
 
 
 
 
 
 
 
Vaginal swab for N. gonorrhoeae, C. 
trachomatis, T. vaginalis 
X 
(X) 
(X) 
(X) 
(X) 
 
 
(X) 
 (X) 
(X) 
(X) 
Research 
Laboratory 
Vaginal swab for pH 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
X 
Vaginal swab for wet mount, amine test 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
X 
Vaginal swab for Gram stain  
X 
X 
X 
X 
X 
 
 
X 
X 
X 
X 
Vaginal swab for storage and future 
identification of vaginal bacteria  
X 
X 
X 
X 
X 
 
 
X 
 X 
X 
   X 
Vaginal swab for qPCR (L. crispatus 
identification) 
 
X 
X 
X 
X 
 
 
X 
 X 
X 
   X 
Other 
Procedures 
Acceptability questionnaire 
X 
 
 
 
X 
 
 
 
 
X 
X 
Staining of used applicators 
 
 
X* 
 
 
 
 
 
 
Telephone interview 
 
 
 
 
 
X 
X 
 
 
 
 
 
(X) if indicated 
X* per site discretion


 
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APPENDIX B 
DIVISION OF AIDS TABLE FOR GRADING THE SEVERITY OF 
ADULT AND PEDIATRIC ADVERSE EVENTS PUBLISH DATE: DECEMBER 2004 
 
Addendum 1 
 
Female Genital Grading Table for Use in Microbicide Studies 
NOTE: For protocols utilizing this Addendum, when the same parameter appears in both this Female Genital Grading Table and 
the main DAIDS AE Grading Table, use the grading scheme in this table. 
 
 
 
November 2007  
Page 1 of 12  
Version 1.0 
 
 
 
INDIVIDUAL SIGNS/SYMPTOMS 
PARAMETER 
GRADE 0 
NORMAL 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GENERAL 
Odor 
No complaint 
Mild-moderate unpleasant 
odor 
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 
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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APPENDIX B (Cont'd) 
DIVISION OF AIDS TABLE FOR GRADING THE SEVERITY OF 
ADULT AND PEDIATRIC ADVERSE EVENTS PUBLISH DATE: DECEMBER 2004 
Addendum 1 
Female Genital Grading Table for Use in Microbicide Studies 
NOTE: For protocols utilizing this Addendum, when the same parameter appears in both this Female Genital Grading Table and the main DAIDS AE Grading 
Table, use the grading scheme in this table. 
 
 
November 2007  
Page 2 of 12  
Version 1.0 
 
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) 
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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APPENDIX B (Cont'd) 
DIVISION OF AIDS TABLE FOR GRADING THE SEVERITY OF 
ADULT AND PEDIATRIC ADVERSE EVENTS PUBLISH DATE: DECEMBER 2004 
Addendum 1 
Female Genital Grading Table for Use in Microbicide Studies 
NOTE: For protocols utilizing this Addendum, when the same parameter appears in both this Female Genital Grading Table and the main DAIDS AE Grading 
Table, use the grading scheme in this table. 
 
 
November 2007  
Page 3 of 12  
Version 1.0 
 
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 required 
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) 
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 
Purulent discharge 
extending onto cervix or 
i
NA 


 
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APPENDIX B (Cont'd) 
DIVISION OF AIDS TABLE FOR GRADING THE SEVERITY OF 
ADULT AND PEDIATRIC ADVERSE EVENTS PUBLISH DATE: DECEMBER 2004 
Addendum 1 
Female Genital Grading Table for Use in Microbicide Studies 
NOTE: For protocols utilizing this Addendum, when the same parameter appears in both this Female Genital Grading Table and the main DAIDS AE Grading 
Table, use the grading scheme in this table. 
 
 
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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 
 
 
INDIVIDUAL SIGNS/SYMPTOMS 
 
PARAMETER 
 
GRADE 0 
NORMAL 
 
GRADE 1 
MILD 
 
GRADE 2 
MODERATE 
 
GRADE 3 
SEVERE 
GENITOURINARY SIGNS/SYMPTOMS – UTERUS 
Uterine 
masses/enlargement 
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/reduced 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) 
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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APPENDIX B (Cont'd) 
DIVISION OF AIDS TABLE FOR GRADING THE SEVERITY OF 
ADULT AND PEDIATRIC ADVERSE EVENTS PUBLISH DATE: DECEMBER 2004 
Addendum 1 
Female Genital Grading Table for Use in Microbicide Studies 
NOTE: For protocols utilizing this Addendum, when the same parameter appears in both this Female Genital Grading Table and the main DAIDS AE Grading 
Table, use the grading scheme in this table. 
 
 
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Version 1.0 
 
 
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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APPENDIX B (Cont'd) 
DIVISION OF AIDS TABLE FOR GRADING THE SEVERITY OF 
ADULT AND PEDIATRIC ADVERSE EVENTS PUBLISH DATE: DECEMBER 2004 
Addendum 1 
Female Genital Grading Table for Use in Microbicide Studies 
NOTE: For protocols utilizing this Addendum, when the same parameter appears in both this Female Genital Grading Table and the main DAIDS AE Grading 
Table, use the grading scheme in this table. 
 
 
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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/symptoms 
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 
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 
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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APPENDIX B (Cont'd) 
DIVISION OF AIDS TABLE FOR GRADING THE SEVERITY OF 
ADULT AND PEDIATRIC ADVERSE EVENTS PUBLISH DATE: DECEMBER 2004 
Addendum 1 
Female Genital Grading Table for Use in Microbicide Studies 
NOTE: For protocols utilizing this Addendum, when the same parameter appears in both this Female Genital Grading Table and the main DAIDS AE Grading 
Table, use the grading scheme in this table. 
 
 
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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 
Bacterial Vaginosis (BV) 
Negative 
Asymptomatic BV 
diagnosed by Amsel 
criteria, wet mount, Gram 
stain, or licensed 
diagnostic test 
Symptomatic confirmed by 
wet mount, Gram stain, or 
any licensed diagnostic 
test 
NA 
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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APPENDIX B (Cont'd) 
DIVISION OF AIDS TABLE FOR GRADING THE SEVERITY OF 
ADULT AND PEDIATRIC ADVERSE EVENTS PUBLISH DATE: DECEMBER 2004 
Addendum 1 
Female Genital Grading Table for Use in Microbicide Studies 
NOTE: For protocols utilizing this Addendum, when the same parameter appears in both this Female Genital Grading Table and the main DAIDS AE Grading 
Table, use the grading scheme in this table. 
 
 
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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 
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 
th
t
l t
t
Criteria for Grade 
2 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 
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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APPENDIX B (Cont'd) 
DIVISION OF AIDS TABLE FOR GRADING THE SEVERITY OF 
ADULT AND PEDIATRIC ADVERSE EVENTS PUBLISH DATE: DECEMBER 2004 
Addendum 1 
Female Genital Grading Table for Use in Microbicide Studies 
NOTE: For protocols utilizing this Addendum, when the same parameter appears in both this Female Genital Grading Table and the main DAIDS AE Grading 
Table, use the grading scheme in this table. 
 
 
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Version 1.0 
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 


 
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APPENDIX B (Cont'd) 
DIVISION OF AIDS TABLE FOR GRADING THE SEVERITY OF 
ADULT AND PEDIATRIC ADVERSE EVENTS PUBLISH DATE: DECEMBER 2004 
Addendum 1 
Female Genital Grading Table for Use in Microbicide Studies 
NOTE: For protocols utilizing this Addendum, when the same parameter appears in both this Female Genital Grading Table and the main DAIDS AE Grading 
Table, use the grading scheme in this table. 
 
 
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UTERINE BLEEDING AND PREGNANCY COMPLICATIONS 
 
PARAMETER 
 
GRADE 0 
NORMAL 
 
GRADE 1 
MILD 
 
GRADE 2 
MODERATE 
 
GRADE 3 
SEVERE 
ABNORMAL UTERINE BLEEDING UNRELATED TO PREGNANCY 
Menorrhagia 2 (prolonged 
and/or heavy menstrual 
bleeding) 
Participant report of 
normal bleeding relative to 
her baseline 
Increase from usual with 
no or minimal 
interference with usual 
social & functional 
activities (including 
sexual functioning) 
Increase from usual with 
moderate interference 
with usual social & 
functional activities 
(including sexual) 
Incapacitating or severe 
interference  with usual 
social & functional 
activities (including 
sexual functioning), 
transfusion indicated 
Metrorrhagia 2 
(intermenstrual or 
frequent bleeding) 
None or any 
expected 
nonmenstrual 
bleeding 
Increase from usual with 
no or minimal 
interference  with usual 
social & functional 
activities (including 
sexual functioning) 
Increase from usual with 
moderate interference 
with usual social & 
functional activities 
(including sexual) 
Incapacitating or severe 
interference with usual 
social & functional 
activities (including 
sexual functioning), 
transfusion indicated 
Unexplained infrequent 
bleeding (excludes 
expected absence of 
menses due to hormonal 
contraception or 
pregnancy/ postpartum) 
Participant report of 
normal or expected 
bleeding frequency 
No menses for 1-3 
months (missed menses) 
No menses for > 3 
months (oligomenorrhea/ 
amenorrhea) 
NA 
Postcoital bleeding 
None 
Occasional (< 25% of 
coital acts) OR Increase 
from usual with no or 
minimal interference with 
usual social functioning 
(including sexual 
functioning) 
Frequent (25-75% of 
coital acts) OR Increase 
from usual with moderate 
interference with usual 
social functioning 
(including sexual) 
Consistent (> 75% of 
coital acts) OR 
Incapacitating or severe 
interference with usual 
social functioning 
(including sexual 
functioning), transfusion 
indicated 
 
 
 
 
2  If both Menorrhagia and Metrorrhagia are present, a single adverse event should be reported as “Menometrorrhagia” and graded per the Menorrhagia 
grading scale. 


 
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APPENDIX B (Cont'd) 
DIVISION OF AIDS TABLE FOR GRADING THE SEVERITY OF 
ADULT AND PEDIATRIC ADVERSE EVENTS PUBLISH DATE: DECEMBER 2004 
Addendum 1 
Female Genital Grading Table for Use in Microbicide Studies 
NOTE: For protocols utilizing this Addendum, when the same parameter appears in both this Female Genital Grading Table and the main DAIDS AE Grading 
Table, use the grading scheme in this table. 
 
 
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UTERINE BLEEDING AND PREGNANCY COMPLICATIONS 
 
PARAMETER 
 
GRADE 0 
NORMAL 
 
GRADE 1 
MILD 
 
GRADE 2 
MODERATE 
 
GRADE 3 
SEVERE 
 
COMPLICATIONS OF PREGNANCY 
First trimester bleeding 
None 
Spotting or bleeding less 
than menses with 
continuation of 
pregnancy 
Bleeding like menses or 
heavier with continuation 
of pregnancy 
Spontaneous abortion, 
or profuse bleeding 
with dizziness or 
orthostatic hypotension, 
transfusion indicated 
Postabortal 
endometritis/salpingitis 
None 
Low grade fever and 
uterine tenderness, 
resolved with oral 
antibiotics 
Moderate symptoms, 
requiring ≤ 3 days of 
parenteral antibiotics 
Severe symptoms 
requiring > 3 days of IV 
antibiotics or development 
of tubo-ovarian abscess or 
diffuse peritonitis or 
severe uterine infection for 
which operative 
intervention indicated 
Postpartum hemorrhage 
EBL < 500 cc for vaginal 
delivery or < 1000 cc 
after CS or reported as 
normal 
EBL 500-1000 for vaginal 
delivery or 1000-1500 for 
CS or reported as slightly 
increased 
EBL > 1000 for vaginal 
delivery or > 1500 for CS, 
with or without mild 
dizziness, no transfusion 
required 
Hemorrhage at a level 
for which transfusion of 
packed cells or any 
amount of other blood 
components is indicated  
Postpartum endometritis 
None 
Low grade fever and 
uterine tenderness, 
resolved with oral 
antibiotics 
Moderate symptoms, 
treated by ≤ 3 days of 
parenteral antibiotics 
Severe symptoms treated 
with > 3 days of IV 
antibiotics or addition of 
heparin or infection for 
which operative 
intervention is indicated 
Chorioamnionitis 
None 
Fever (38°C –38.4°C or 
100.4°F– 100.9°F) with 
two or more: FHR> 160 
BPM, maternal HR> 120, 
uterine tenderness 
between contractions or 
purulent AF or preterm 
labor 
Same as Grade 1 plus 
fever 38.5°C –40°C or 
101°F –104°F 
Criteria for Grade 2 plus 
fetal distress or fever > 
40°C or 104°F or either 
fetal demise or maternal 
symptoms of shock 


 
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APPENDIX B (Cont'd) 
DIVISION OF AIDS TABLE FOR GRADING THE SEVERITY OF 
ADULT AND PEDIATRIC ADVERSE EVENTS PUBLISH DATE: DECEMBER 2004 
Addendum 1 
Female Genital Grading Table for Use in Microbicide Studies 
NOTE: For protocols utilizing this Addendum, when the same parameter appears in both this Female Genital Grading Table and the main DAIDS AE 
Grading Table, use the grading scheme in this table. 
 
 
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Version 1.0 
 
 
UTERINE BLEEDING AND PREGNANCY COMPLICATIONS 
 
PARAMETER 
 
GRADE 0 
NORMAL 
 
GRADE 1 
MILD 
 
GRADE 2 
MODERATE 
 
GRADE 3 
SEVERE 
Episiotomy infection 
None 
Mild erythema, 
edema, and 
tenderness of wound 
Fever > 38°C or 
100.4°F with erythema, 
edema, and tenderness 
of wound 
Fever with wound 
dehiscence or 
debridement required or 
signs shock or necrotizing 
fasciitis 
Second/third trimester 
bleeding 
None 
Bleeding less than 
menses 
Bleeding like menses or 
greater, but not requiring 
intervention 
Bleeding or coagulopathy  
requiring delivery or 
other intervention, e.g., 
transfusion, or fetal 
demise 
Preterm rupture of 
membranes 
None 
NA 
Preterm rupture with 
hospitalization but not 
resulting in delivery at 
less than 37 weeks’ 
gestation 
Delivery at < 37 weeks 
gestation or ≤ 2500 
grams birth weight 
Preterm contractions 
None 
Preterm contractions 
which resolve without 
medical intervention 
Preterm contractions 
with cervical change 
which result in medical 
intervention but not 
resulting in preterm 
delivery 
Delivery at < 37 weeks 
gestation or ≤ 2500 
grams birth weight 
Poor fetal growth 
At or above 10th 
percentile 
Fetal growth < 10th 
percentile but ≥ 3rd 
percentile for gestational 
age by ultrasound or 
newborn exam 
NA 
Fetal growth < 3rd 
percentile for gestational 
age by ultrasound or 
newborn exam 
 


 
 
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APPENDIX C 
DIVISION OF AIDS TABLE FOR GRADING THE SEVERITY OF 
ADULT AND PEDIATRIC ADVERSE EVENTS  
VERSION 1.0, DECEMBER, 2004; CLARIFICATION AUGUST 2009  
 
28-Dec-04/Clarification Aug 09 
Page 1 of 16 
Version 1.0/Clarification 1 
The Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (“DAIDS AE Grading 
Table”) is a descriptive terminology which can be utilized for Adverse Event (AE) reporting. A grading (severity) 
scale is provided for each AE term. 
 
This clarification of the DAIDS Table for Grading the Severity of Adult and Pediatric AE’s provides 
additional explanation of the DAIDS AE Grading Table and clarifies some of the parameters. 
 
I. 
Instructions and Clarifications 
 
Grading Adult and Pediatric AEs 
The DAIDS AE Grading Table includes parameters for grading both Adult and Pediatric AEs. When a single set of 
parameters is not appropriate for grading specific types of AEs for both Adult and Pediatric populations, separate 
sets of parameters for Adult and/or Pediatric populations (with specified respective age ranges) are given in the 
Table. If there is no distinction in the Table between Adult and Pediatric values for a type of AE, then the single 
set of parameters listed is to be used for grading the severity of both Adult and Pediatric events of that type. 
Note: In the classification of adverse events, the term “severe” is not the same as “serious.” Severity is 
an indication of the intensity of a specific event (as in mild, moderate, or severe chest pain). The term 
“serious” relates to a participant/event outcome or action criteria, usually 
associated with events that pose a threat to a participant’s life or functioning. 
 
Addenda 1-3 Grading Tables for Microbicide Studies 
For protocols involving topical application of products to the female genital tract, male genital area or rectum, 
strong consideration should be given to using Appendices I-III as the primary grading scales for these areas. The 
protocol would need to specifically state that one or more of the Appendices would be 
primary (and thus take precedence over the main Grading Table) for items that are listed in both the 
Appendix and the main Grading Table. 
• 
Addendum 1 - Female Genital Grading Table for Use in Microbicide Studies - PDF 
• 
Addendum 2 - Male Genital Grading Table for Use in Microbicide Studies - PDF 
• 
Addendum 3 - Rectal Grading Table for Use in Microbicide Studies - PDF 
 
Grade 5  
For any AE where the outcome is death, the severity of the AE is classified as Grade 5.    
 
Estimating Severity Grade for Parameters Not Identified in the Table 
In order to grade a clinical AE that is not identified in the DAIDS AE grading table, use the category 
“Estimating Severity Grade” located on Page 3. 
 
Determining Severity Grade for Parameters “Between Grades” 
If the severity of a clinical AE could fall under either one of two grades (e.g., the severity of an AE could be either 
Grade 2 or Grade 3), select the higher of the two grades for the AE. If a laboratory value that is graded as a 
multiple of the ULN or LLN falls between two grades, select the higher of the two grades for the AE. For example, 
Grade 1 is 2.5 x ULN and Grade 2 is 2.6 x ULN for a parameter. If the lab value is 
2.53 x ULN (which is between the two grades), the severity of this AE would be Grade 2, the higher of the two 
grades. 
 
Values Below Grade 1  
Any laboratory value that is between either the LLN or ULN and Grade 1 should not be graded.  


 
 
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APPENDIX C 
DIVISION OF AIDS TABLE FOR GRADING THE SEVERITY OF 
ADULT AND PEDIATRIC ADVERSE EVENTS  
VERSION 1.0, DECEMBER, 2004; CLARIFICATION AUGUST 2009  
 
28-Dec-04/Clarification Aug 09 
Page 2 of 16 
Version 1.0/Clarification 1 
Determining Severity Grade when Local Laboratory Normal Values Overlap with Grade 1 Ranges 
In these situations, the severity grading is based on the ranges in the DAIDS AE Grading Table, even when 
there is a reference to the local lab LLN. 
 
For example: Phosphate, Serum, Low, Adult and Pediatric > 14 years (Page 20) Grade 1 range is 2.50 mg/dL - < 
LLN. A particular laboratory’s normal range for Phosphate is 2.1 – 3.8 mg/dL. A participant’s actual lab value is 
2.5.  In this case, the value of 2.5 exceeds the LLN for the local lab, but will be graded as Grade 1 per DAIDS AE 
Grading Table. 
. 
 
II.   Definitions of terms used in the Table: 
 
Basic Self-care Functions 
Adult 
Activities such as bathing, dressing, toileting, transfer/movement, 
continence, and feeding. 
Young Children 
Activities that are age and culturally appropriate (e.g., feeding self with 
culturally appropriate eating implement). 
LLN 
Lower limit of normal 
Medical Intervention 
Use of pharmacologic or biologic agent(s) for treatment of an AE. 
NA 
Not Applicable 
Operative Intervention 
Surgical OR other invasive mechanical procedures. 
ULN 
Upper limit of normal 
Usual Social & Functional 
Activities 
Adult 
Adaptive tasks and desirable activities, such as going to work, 
shopping, cooking, use of transportation, pursuing a hobby, etc. 
Young Children 
Activities that are age and culturally appropriate (e.g., social 
interactions, play activities, learning tasks, etc.). 
 


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APPENDIX C 
DIVISION OF AIDS TABLE FOR GRADING THE SEVERITY OF 
ADULT AND PEDIATRIC ADVERSE EVENTS  
VERSION 1.0, DECEMBER, 2004; CLARIFICATION AUGUST 2009  
Basic Self-care Functions – Adult: Activities such as bathing, dressing, toileting, transfer/movement, continence, and feeding. 
Basic Self-care Functions – Young Children: Activities that are age and culturally appropriate (e.g., feeding self with culturally appropriate eating 
implement). 
Usual Social & Functional Activities – Adult: Adaptive tasks and desirable activities, such as going to work, shopping, cooking, use of 
transportation, pursuing a hobby, etc. 
Usual Social & Functional Activities – Young Children: Activities that are age and culturally appropriate (e.g., social interactions, play activities, 
learning tasks, etc.). 
 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
ESTIMATING SEVERITY GRADE 
Clinical adverse event NOT 
identified elsewhere in this 
DAIDS AE Grading Table 
Symptoms causing no or 
minimal interference with 
usual social & functional 
activities 
Symptoms causing greater 
than minimal interference with 
usual social & functional 
activities 
Symptoms causing inability to 
perform usual social & 
functional activities OR 
Medical or operative 
intervention indicated to 
prevent permanent 
impairment, persistent 
disability, or death 
SYSTEMIC 
Acute systemic allergic 
reaction 
Localized urticaria (wheals) 
with no medical intervention 
indicated 
Localized urticaria with medical 
intervention indicated OR Mild 
angioedema with no medical 
intervention indicated 
Generalized urticaria OR 
Angioedema with medical 
intervention indicated OR 
Symptomatic mild 
Bronchospasm OR Acute 
anaphylaxis OR Life- 
threatening bronchospasm OR 
Laryngeal edema 
Chills 
Symptoms causing no or 
minimal interference with usual 
social & functional activities 
Symptoms causing greater 
than minimal interference with 
usual social & functional 
activities 
Symptoms causing inability to 
perform usual social & 
functional activities 
Fatigue 
Malaise 
Symptoms causing no or 
minimal interference with 
usual social & functional 
activities 
Symptoms causing greater 
than minimal interference with 
usual social & functional 
activities 
Symptoms causing inability to 
perform usual social & 
functional activities 
Fever (nonaxillary) 
37.7 – 38.6°C 
38.7 – 39.3°C 
> 39.4  
Pain (indicate body site) DO 
NOT use for pain due to 
injection (See Injection Site 
Reactions: Injection site 
pain) See also Headache, 
Arthralgia, and Myalgia 
Pain causing no or minimal 
interference with usual 
social & functional activities 
Pain causing greater than 
minimal interference with 
usual social & functional 
activities 
Pain causing inability to 
perform usual social & 
functional activities OR 
Hospitalization (other than 
emergency room visit) 
indicated 


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APPENDIX C 
DIVISION OF AIDS TABLE FOR GRADING THE SEVERITY OF 
ADULT AND PEDIATRIC ADVERSE EVENTS  
VERSION 1.0, DECEMBER, 2004; CLARIFICATION AUGUST 2009  
Basic Self-care Functions – Adult: Activities such as bathing, dressing, toileting, transfer/movement, continence, and feeding. 
Basic Self-care Functions – Young Children: Activities that are age and culturally appropriate (e.g., feeding self with culturally appropriate eating 
implement). 
Usual Social & Functional Activities – Adult: Adaptive tasks and desirable activities, such as going to work, shopping, cooking, use of 
transportation, pursuing a hobby, etc. 
Usual Social & Functional Activities – Young Children: Activities that are age and culturally appropriate (e.g., social interactions, play activities, 
learning tasks, etc.). 
 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
Unintentional weight loss 
NA 
5 – 9% loss in body weight 
from baseline 
> 10% loss in body weight from 
baseline OR Aggressive 
intervention indicated [e.g., tube 
feeding or total parenteral 
nutrition (TPN)] 
 INFECTION 
Infection (any other than HIV 
infection) 
Localized, no systemic 
antimicrobial treatment 
indicated AND Symptoms 
causing no or minimal 
interference with usual social 
& functional activities 
Systemic antimicrobial 
treatment indicated OR 
Symptoms causing greater 
than minimal interference with 
usual social & functional 
activities 
Systemic antimicrobial 
treatment indicated AND 
Symptoms causing inability to 
perform usual social & 
functional activities OR 
Operative intervention (other 
than simple incision and 
drainage) indicated 
 INJECTION SITE REACTIONS 
Injection site pain (pain without 
touching) Or Tenderness (pain 
when area is touched) 
Pain/tenderness causing no 
or minimal limitation of use of 
limb 
Pain/tenderness limiting use of 
limb OR Pain/tenderness 
causing greater than minimal 
interference with usual social 
& functional activities 
Pain/tenderness causing 
inability to perform usual social 
& functional activities OR 
Hospitalization (other than 
emergency room visit) indicated 
for management of 
pain/tenderness 
Injection site reaction (localized) 
Adult > 15 years 
Erythema OR Induration of 
5x5 cm – 9x9 cm (or 25 cm
2 – 
81cm2) 
Erythema OR Induration OR 
Edema > 9 cm any diameter 
(or > 81 cm2) 
Ulceration OR Secondary 
infection OR Phlebitis OR 
Sterile abscess OR Drainage 
OR Necrosis (involving dermis 
and deeper tissue) 
Pediatric ≤ 15 years 
Erythema OR Induration OR 
Edema present but ≤ 2.5 cm 
diameter 
Erythema OR Induration OR 
Edema > 2.5 cm diameter but 
< 50% surface area of the 
extremity segment (e.g., upper 
arm/thigh) 
Erythema OR Induration OR 
Edema involving ≥ 50% surface 
area of the extremity segment 
(e.g., upper arm/thigh) OR 
Ulceration OR Secondary 
infection OR Phlebitis OR 
Sterile abscess OR Drainage 
OR Necrosis (involving dermis 
and deeper tissue) 
 


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APPENDIX C 
DIVISION OF AIDS TABLE FOR GRADING THE SEVERITY OF 
ADULT AND PEDIATRIC ADVERSE EVENTS  
VERSION 1.0, DECEMBER, 2004; CLARIFICATION AUGUST 2009  
Basic Self-care Functions – Adult: Activities such as bathing, dressing, toileting, transfer/movement, continence, and feeding. 
Basic Self-care Functions – Young Children: Activities that are age and culturally appropriate (e.g., feeding self with culturally appropriate eating 
implement). 
Usual Social & Functional Activities – Adult: Adaptive tasks and desirable activities, such as going to work, shopping, cooking, use of 
transportation, pursuing a hobby, etc. 
Usual Social & Functional Activities – Young Children: Activities that are age and culturally appropriate (e.g., social interactions, play activities, 
learning tasks, etc.). 
 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
Pruritis associated with 
injection 
See also Skin: Pruritis (itching 
- no skin lesions) 
Itching localized to injection 
site AND Relieved 
spontaneously or with 
< 48 hours treatment 
Itching beyond the injection 
site but not generalized OR 
Itching localized to injection 
site requiring48 
hours treatment 
Generalized  itching causing 
inability to perform usual social 
& functional activities 
 
SKIN - DERMATOLOGICAL 
Alopecia 
Thinning detectable by study 
participant (or by caregiver  for 
young children and disabled  
adults) 
Thinning or patchy hair loss 
detectable by health care 
provider 
Complete hair loss 
Cutaneous  reaction - rash 
Localized  macular rash 
Diffuse macular, 
maculopapular, or morbilliform  
rash OR Target lesions 
Diffuse macular, 
maculopapular, or morbilliform  
rash with vesicles or limited 
number of bullae OR 
Superficial ulcerations of 
mucous  membrane limited to 
one site 
Hyperpigmentation 
Slight or localized 
Marked or generalized 
NA 
Hypopigmentation 
Slight or localized 
Marked or generalized 
NA 
Pruritis (itching - no skin 
lesions) 
(See also Injection Site 
Reactions: Pruritis associated 
with injection) 
Itching causing  no or minimal 
interference with usual social 
& functional activities 
Itching causing greater than 
minimal interference  with 
usual social & functional 
activities 
Itching causing inability to 
perform usual social & 
functional activities 
CARDIOVASCULAR 
Cardiac  arrhythmia (general) 
(By ECG or physical exam) 
Asymptomatic AND No 
intervention indicated 
Asymptomatic AND Non-
urgent medical intervention  
indicated 
Symptomatic AND medical 
intervention indicated 
Cardiac- ischemia/infarction 
NA 
NA 
Symptomatic ischemia (stable 
angina) OR Testing consistent 
with ischemia OR Unstable 
angina OR Acute myocardial 
infarction 
 
 


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APPENDIX C 
DIVISION OF AIDS TABLE FOR GRADING THE SEVERITY OF 
ADULT AND PEDIATRIC ADVERSE EVENTS  
VERSION 1.0, DECEMBER, 2004; CLARIFICATION AUGUST 2009  
Basic Self-care Functions – Adult: Activities such as bathing, dressing, toileting, transfer/movement, continence, and feeding. 
Basic Self-care Functions – Young Children: Activities that are age and culturally appropriate (e.g., feeding self with culturally appropriate eating 
implement). 
Usual Social & Functional Activities – Adult: Adaptive tasks and desirable activities, such as going to work, shopping, cooking, use of 
transportation, pursuing a hobby, etc. 
Usual Social & Functional Activities – Young Children: Activities that are age and culturally appropriate (e.g., social interactions, play activities, 
learning tasks, etc.). 
 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
Hemorrhage (significant acute 
blood loss) 
NA 
Symptomatic AND No 
transfusion indicated 
 Symptomatic AND 
Transfusion of  packed RBCs  
indicated 
Hypertension 
Adult > 17 years (with repeat 
testing at same visit) 
140 – 159 mmHg systolic OR 
90 – 99 mmHg diastolic 
160 – 179 mmHg systolic OR 
100 – 109 mmHg diastolic 
≥ 180 mmHg systolic OR ≥ 
110 mmHg diastolic OR 
Hospitalization indicated 
(other than emergency room 
visit) 
Correction: in Grade 2 to 160 - 179 from > 160-179 (systolic) and to ≥ 100 -109 from > 100-109 (diastolic) and in Grade 3 to 
≥ 180 from > 180 (systolic) and to ≥ 110  from > 110 (diastolic). 
Pediatric ≤ 17 years (with 
repeat testing at same visit) 
NA 
91st – 94th percentile adjusted 
for age, height, and gender 
(systolic and/or diastolic) 
≥ 95th percentile adjusted for 
age, height, and gender 
(systolic and/or diastolic) OR 
Hospitalization indicated 
(other than emergency room 
visit) 
Hypotension 
NA 
Symptomatic, corrected with 
oral fluid replacement 
Symptomatic, IV fluids 
indicated OR Use of 
vasopressors or mechanical 
assistance to maintain blood 
pressure 
Pericardial effusion 
Asymptomatic, small effusion 
requiring no intervention 
Asymptomatic, moderate or 
larger effusion requiring no 
intervention 
Effusion with non-life 
threatening physiologic 
consequences OR Effusion 
with non-urgent intervention 
indicated OR Life-threatening 
consequences (e.g., 
tamponade) OR Urgent 
intervention indicated) 
Prolonged PR interval 
Adult > 16 years 
PR interval 0.21 – 0.25 sec 
PR interval > 0.25 sec 
Type II 2nd degree AV block 
OR Ventricular pause > 3.0 
sec OR Complete AV block 
Pediatric ≤ 16 years 
1st degree AV block (PR > 
normal for age and rate) 
Type I 2nd degree AV 
block 
Type II 2nd degree AV 
block OR Complete AV block 


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APPENDIX C 
DIVISION OF AIDS TABLE FOR GRADING THE SEVERITY OF 
ADULT AND PEDIATRIC ADVERSE EVENTS  
VERSION 1.0, DECEMBER, 2004; CLARIFICATION AUGUST 2009  
Basic Self-care Functions – Adult: Activities such as bathing, dressing, toileting, transfer/movement, continence, and feeding. 
Basic Self-care Functions – Young Children: Activities that are age and culturally appropriate (e.g., feeding self with culturally appropriate eating 
implement). 
Usual Social & Functional Activities – Adult: Adaptive tasks and desirable activities, such as going to work, shopping, cooking, use of 
transportation, pursuing a hobby, etc. 
Usual Social & Functional Activities – Young Children: Activities that are age and culturally appropriate (e.g., social interactions, play activities, 
learning tasks, etc.). 
 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
Prolonged QTc 
Adult > 16 years 
Asymptomatic, QTc interval 
0.45 – 0.47 sec OR Increase 
interval < 0.03 sec above 
baseline 
Asymptomatic, QTc interval 
0.48 – 0.49 sec OR Increase 
in interval 0.03 – 0.05 sec 
above baseline 
Asymptomatic, QTc interval ≥ 0.50 
sec OR Increase in interval ≥ 0.06 
sec above baseline OR Life-
threatening consequences (e.g., 
Torsade de pointes or other 
associated serious ventricular 
dysrhythmia) 
Pediatric ≤ 16 years 
Asymptomatic, QTc interval 
0.450 – 0.464 sec 
Asymptomatic, QTc interval 
0.465 – 0.479 sec 
 Asymptomatic, QTc interval ≥ 
0.480 sec OR Life-threatening 
consequences, (e.g., Torsade de 
pointes or other associated serious 
ventricular dysrhythmia) 
Thrombosis/embolism 
NA 
Deep vein thrombosis AND No 
intervention indicated (e.g., 
anticoagulation, lysis filter, 
invasive procedure) 
Deep vein thrombosis AND 
Intervention indicated (e.g., 
anticoagulation, lysis filter, invasive 
procedure) OR Embolic event (e.g., 
pulmonary embolism, life-
threatening thrombus) 
Vasovagal episode 
(associated with a procedure 
of any kind) 
Present without loss of 
consciousness 
Present with transient loss of 
consciousness 
NA 
Ventricular dysfunction 
(congestive heart failure) 
NA 
Asymptomatic diagnostic 
finding AND intervention 
indicated 
New onset with symptoms OR 
Worsening symptomatic congestive 
heart failure OR Life-threatening 
congestive heart failure 
 GASTROINTESTINAL 
Anorexia 
Loss of appetite without 
decreased oral intake 
Loss of appetite associated 
with decreased oral intake 
without significant weight loss 
Loss of appetite associated with 
significant weight loss OR Life-
threatening consequences OR 
Aggressive intervention indicated 
[e.g., tube feeding or total 
parenteral nutrition (TPN)] 
Comment: Please note that, while the grading scale provided for Unintentional Weight Loss may be used as a guideline when grading 
anorexia, this is not a requirement and should not be used as a substitute for clinical judgment. 
Ascites 
Asymptomatic 
Symptomatic AND 
Intervention indicated (e.g., 
diuretics or therapeutic 
paracentesis) 
Symptomatic despite intervention 
OR Life-threatening consequences 


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APPENDIX C 
DIVISION OF AIDS TABLE FOR GRADING THE SEVERITY OF 
ADULT AND PEDIATRIC ADVERSE EVENTS  
VERSION 1.0, DECEMBER, 2004; CLARIFICATION AUGUST 2009  
Basic Self-care Functions – Adult: Activities such as bathing, dressing, toileting, transfer/movement, continence, and feeding. 
Basic Self-care Functions – Young Children: Activities that are age and culturally appropriate (e.g., feeding self with culturally appropriate eating 
implement). 
Usual Social & Functional Activities – Adult: Adaptive tasks and desirable activities, such as going to work, shopping, cooking, use of 
transportation, pursuing a hobby, etc. 
Usual Social & Functional Activities – Young Children: Activities that are age and culturally appropriate (e.g., social interactions, play activities, 
learning tasks, etc.). 
 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
Cholecystitis 
NA 
Symptomatic AND Medical 
intervention indicated 
Radiologic, endoscopic, or 
operative intervention 
indicated OR Life-
threatening consequences 
(e.g., sepsis or perforation) 
Constipation 
NA 
Persistent constipation 
requiring regular use 
of dietary 
modifications, 
laxatives, or enemas 
Obstipation with manual 
evacuation indicated OR 
Life-threatening 
consequences (e.g., 
obstruction) 
Diarrhea 
Adult and Pediatric ≥ 1 
year 
Transient or intermittent 
episodes of unformed stools 
OR Increase of ≤ 3 stools over 
baseline per 24-hour period 
Persistent episodes of 
unformed to watery stools OR 
Increase of 
4 – 6 stools over baseline per 
24-hour period 
Bloody diarrhea OR 
Increase of ≥ 7 stools per 
24-hour period OR IV fluid 
replacement indicated OR 
Life-threatening 
consequences (e.g., 
hypotensive shock) 
Pediatric < 1 year 
Liquid stools (more unformed 
than usual) but usual number of 
stools 
Liquid stools with increased 
number of stools OR Mild 
dehydration 
Liquid stools with moderate 
dehydration OR Liquid stools 
resulting in severe 
dehydration with aggressive 
rehydration indicated OR 
Hypotensive shock 
Dysphagia- 
Odynophagia 
Symptomatic but able to eat 
usual diet 
Symptoms causing altered 
dietary intake without 
medical intervention 
indicated 
Symptoms causing severely 
altered dietary intake with 
medical intervention 
indicated OR Life-
threatening reduction in oral 
intake 
Mucositis/stomatitis (clinical 
exam) Indicate site (e.g., larynx, 
oral) See Genitourinary for 
Vulvovaginitis.   
See also Dysphagia- 
Odynophagia and Proctitis 
Erythema of the mucosa 
Patchy pseudomembranes or 
ulcerations 
Confluent 
pseudomembranes or 
ulcerations OR Mucosal 
bleeding with minor trauma 
OR Tissue necrosis OR 
Diffuse spontaneous 
mucosal bleeding OR Life-
threatening consequences 


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APPENDIX C 
DIVISION OF AIDS TABLE FOR GRADING THE SEVERITY OF 
ADULT AND PEDIATRIC ADVERSE EVENTS  
VERSION 1.0, DECEMBER, 2004; CLARIFICATION AUGUST 2009  
Basic Self-care Functions – Adult: Activities such as bathing, dressing, toileting, transfer/movement, continence, and feeding. 
Basic Self-care Functions – Young Children: Activities that are age and culturally appropriate (e.g., feeding self with culturally appropriate eating 
implement). 
Usual Social & Functional Activities – Adult: Adaptive tasks and desirable activities, such as going to work, shopping, cooking, use of 
transportation, pursuing a hobby, etc. 
Usual Social & Functional Activities – Young Children: Activities that are age and culturally appropriate (e.g., social interactions, play activities, 
learning tasks, etc.). 
 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
Nausea 
Transient (< 24 hours) or 
intermittent nausea with no or 
minimal interference with oral 
intake 
Persistent nausea resulting in 
decreased oral intake for 24 – 
48 hours 
Persistent nausea resulting in 
minimal oral intake for > 48 
hours OR Aggressive 
rehydration indicated (e.g., IV 
fluids) OR Life-threatening 
consequences (e.g., 
hypotensive shock) 
Pancreatitis 
NA 
Symptomatic AND 
Hospitalization not indicated 
(other than emergency room 
visit) 
Symptomatic AND 
Hospitalization indicated 
(other than emergency room 
visit) OR Life-threatening 
consequences (e.g., 
circulatory failure, 
hemorrhage, sepsis) 
Proctitis (functional- 
symptomatic) Also see 
Mucositis/stomatitis for clinical 
exam 
Rectal discomfort AND No 
intervention indicated 
Symptoms causing greater 
than minimal interference with 
usual social & functional 
activities OR Medical 
intervention indicated 
Symptoms causing inability to 
perform usual social & 
functional activities OR 
Operative intervention 
indicated OR Life-threatening 
consequences (e.g., 
perforation)  
Vomiting 
Transient or intermittent vomiting 
with no or minimal interference 
with oral intake 
Frequent episodes of vomiting 
with no or mild dehydration 
Persistent vomiting resulting in 
orthostatic hypotension OR 
Aggressive rehydration 
indicated (e.g., IV fluids) or 
Life-threatening 
consequences (e.g., 
hypotensive shock) 
 
 


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APPENDIX C 
DIVISION OF AIDS TABLE FOR GRADING THE SEVERITY OF 
ADULT AND PEDIATRIC ADVERSE EVENTS  
VERSION 1.0, DECEMBER, 2004; CLARIFICATION AUGUST 2009  
Basic Self-care Functions – Adult: Activities such as bathing, dressing, toileting, transfer/movement, continence, and feeding. 
Basic Self-care Functions – Young Children: Activities that are age and culturally appropriate (e.g., feeding self with culturally appropriate eating 
implement). 
Usual Social & Functional Activities – Adult: Adaptive tasks and desirable activities, such as going to work, shopping, cooking, use of 
transportation, pursuing a hobby, etc. 
Usual Social & Functional Activities – Young Children: Activities that are age and culturally appropriate (e.g., social interactions, play activities, 
learning tasks, etc.). 
 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
NEUROLOGIC 
Alteration in personality-
behavior or in mood (e.g., 
agitation, anxiety, depression, 
mania, psychosis) 
Alteration causing no or minimal 
interference with usual social & 
functional activities 
Alteration causing greater than 
minimal interference with 
usual social & functional 
activities 
Alteration causing inability to 
perform usual social & 
functional Activities OR 
Behavior potentially harmful to 
self or others. 
Altered Mental Status For 
Dementia, see Cognitive and 
behavioral/attentional 
disturbance (including dementia 
and attention deficit disorder) 
Changes causing no or minimal 
interference with usual social & 
functional activities 
Mild lethargy or somnolence 
causing greater than minimal 
interference with usual social 
& functional activities 
Confusion, memory 
impairment, lethargy, or 
somnolence causing inability 
to perform usual social & 
functional activities OR 
Delirium OR obtundation, OR 
coma 
Ataxia 
Asymptomatic ataxia detectable 
on exam OR Minimal ataxia 
causing no or minimal 
interference with usual social & 
functional activities 
Symptomatic ataxia causing 
greater than minimal 
interference with usual social 
& functional activities 
Symptomatic ataxia causing 
inability to perform usual 
social & functional activities 
OR Disabling ataxia causing 
inability to perform basic self-
care functions 
 
 


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APPENDIX C 
DIVISION OF AIDS TABLE FOR GRADING THE SEVERITY OF 
ADULT AND PEDIATRIC ADVERSE EVENTS  
VERSION 1.0, DECEMBER, 2004; CLARIFICATION AUGUST 2009  
Basic Self-care Functions – Adult: Activities such as bathing, dressing, toileting, transfer/movement, continence, and feeding. 
Basic Self-care Functions – Young Children: Activities that are age and culturally appropriate (e.g., feeding self with culturally appropriate eating 
implement). 
Usual Social & Functional Activities – Adult: Adaptive tasks and desirable activities, such as going to work, shopping, cooking, use of 
transportation, pursuing a hobby, etc. 
Usual Social & Functional Activities – Young Children: Activities that are age and culturally appropriate (e.g., social interactions, play activities, 
learning tasks, etc.). 
 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
Cognitive and 
behavioral/attentional 
disturbance (including 
dementia and attention 
deficit disorder) 
Disability causing no 
or minimal interference 
with usual social & 
functional activities OR 
Specialized resources 
not indicated 
Disability causing 
greater than minimal 
interference with usual 
social & functional 
activities OR 
Specialized resources 
on part-time basis 
i di
t d
Disability causing inability to perform usual social & 
functional activities OR Specialized resources on a 
full-time basis indicated OR Disability causing 
inability to perform basic self-care functions OR 
Institutionalization indicated 
CNS ischemia (acute) 
NA 
NA 
Transient ischemic attack OR Cerebral vascular 
accident (CVA, stroke) with neurological deficit 
Developmental delay – 
Pediatric ≤ 16 years 
Mild developmental 
delay, either motor or 
cognitive, as 
determined by 
comparison with a 
developmental 
screening tool 
appropriate for the 
setting 
Moderate 
developmental delay, 
either motor or 
cognitive, as 
determined by 
comparison with a 
developmental 
screening tool 
appropriate for the 
setting 
Severe developmental delay, either motor or 
cognitive, as determined by comparison with a 
developmental screening tool appropriate for the 
setting OR Developmental regression, either motor 
or cognitive, as determined by comparison with a 
developmental screening tool appropriate for the 
setting 
Headache 
Symptoms causing no 
or minimal interference 
with usual social & 
functional activities 
Symptoms causing 
greater than minimal 
interference with usual 
social & functional 
activities 
Symptoms causing inability to perform usual social & 
functional activities OR Symptoms causing inability 
to perform basic self-care functions OR 
Hospitalization indicated (other than emergency 
room visit) OR Headache with significant impairment 
of alertness or other neurologic function 
Insomnia 
NA 
Difficulty sleeping 
causing greater than 
minimal interference 
with usual social & 
functional activities 
Difficulty sleeping causing inability to perform usual 
social & functional activities OR Disabling insomnia 
causing inability to perform basic self-care functions 
Neuromuscular 
weakness (including 
myopathy & 
neuropathy) 
Asymptomatic with 
decreased strength on 
exam OR Minimal 
muscle weakness 
causing no or minimal 
interference with usual 
social & functional 
activities 
Muscle weakness 
causing greater than 
minimal interference 
with usual social & 
functional activities 
Muscle weakness causing inability to perform usual 
social & functional activities OR Disabling muscle 
weakness causing inability to perform basic self-care 
functions OR Respiratory muscle weakness 
impairing ventilation 
  
 


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APPENDIX C 
DIVISION OF AIDS TABLE FOR GRADING THE SEVERITY OF 
ADULT AND PEDIATRIC ADVERSE EVENTS  
VERSION 1.0, DECEMBER, 2004; CLARIFICATION AUGUST 2009  
Basic Self-care Functions – Adult: Activities such as bathing, dressing, toileting, transfer/movement, continence, and feeding. 
Basic Self-care Functions – Young Children: Activities that are age and culturally appropriate (e.g., feeding self with culturally appropriate eating 
implement). 
Usual Social & Functional Activities – Adult: Adaptive tasks and desirable activities, such as going to work, shopping, cooking, use of 
transportation, pursuing a hobby, etc. 
Usual Social & Functional Activities – Young Children: Activities that are age and culturally appropriate (e.g., social interactions, play activities, 
learning tasks, etc.). 
 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
Neurosensory alteration 
(including paresthesia 
and painful neuropathy) 
Asymptomatic with 
sensory alteration on 
exam or minimal 
paresthesia causing no 
or minimal interference 
with usual social & 
functional activities 
Sensory alteration or 
paresthesia causing greater 
than minimal interference with 
usual social & functional 
activities 
Sensory alteration or paresthesia 
causing inability to perform usual social 
& functional activities OR Disabling 
sensory alteration or paresthesia 
causing inability to perform basic self-
care functions 
Seizure: (new onset) 
NA 
1 seizure 
> 1 seizure 
– Adult ≥ 18 years 
See also Seizure: 
(known pre-existing 
seizure disorder) 
Seizure: (known pre- 
existing seizure disorder) 
– Adult ≥ 18 years For 
worsening of existing 
epilepsy the grades 
should be based on an 
increase from previous 
level of control to any of 
these levels. 
NA 
Increased frequency of pre-
existing seizures (non-
repetitive) without change in 
seizure character OR 
Infrequent break- through 
seizures while on stable 
medication in a previously 
controlled seizure disorder 
Change in seizure character from 
baseline either in duration or quality 
(e.g., severity or focality) OR Seizures of 
any kind which are prolonged, repetitive 
(e.g., status epilepticus), or difficult to 
control (e.g., refractory epilepsy) 
Seizure 
Seizure, generalized 
Seizure, generalized 
Seizure, generalized onset with or 
without secondary generalization, lasting 
> 20 minutes OR Seizure, generalized 
onset with or without secondary 
generalization, requiring intubation and 
sedation 
– Pediatric < 18 
onset with or without 
onset with or without 
years 
secondary 
generalization, lasting < 
5 minutes with < 24 
hours post ictal state 
secondary generalization, 
lasting 5 – 20 minutes with < 24 
hours post ictal state 
Syncope (not associated 
with a procedure) 
NA 
Present 
NA 
Vertigo 
Vertigo causing no or 
minimal interference with 
usual social & functional 
activities 
Vertigo causing greater than 
minimal interference with usual 
social & functional activities 
Vertigo causing inability to perform usual 
social & functional activities OR 
Disabling vertigo causing inability to 
perform basic self-care functions 
 
 


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Version 1.0/Clarification 1 
 
 
DMID14-0029 
 
Version 3.0 
 
February 19, 2016 
____________________________________________________________________________________________  
APPENDIX C 
DIVISION OF AIDS TABLE FOR GRADING THE SEVERITY OF 
ADULT AND PEDIATRIC ADVERSE EVENTS  
VERSION 1.0, DECEMBER, 2004; CLARIFICATION AUGUST 2009  
Basic Self-care Functions – Adult: Activities such as bathing, dressing, toileting, transfer/movement, continence, and feeding. 
Basic Self-care Functions – Young Children: Activities that are age and culturally appropriate (e.g., feeding self with culturally appropriate eating 
implement). 
Usual Social & Functional Activities – Adult: Adaptive tasks and desirable activities, such as going to work, shopping, cooking, use of 
transportation, pursuing a hobby, etc. 
Usual Social & Functional Activities – Young Children: Activities that are age and culturally appropriate (e.g., social interactions, play activities, 
learning tasks, etc.). 
 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
RESPIRATORY 
Bronchospasm (acute) 
FEV1 or peak flow reduced 
to 70 – 80% 
FEV1 or peak flow 50 – 69% 
FEV1 or peak flow 25 – 49% OR 
Cyanosis OR FEV1 or peak flow 
< 25% OR Intubation 
Dyspnea or respiratory distress 
Adult ≥ 14 years 
Dyspnea on exertion with no 
or minimal interference with 
usual social & functional 
activities 
Dyspnea on exertion causing 
greater than minimal 
interference with usual social & 
functional activities 
Dyspnea at rest causing inability 
to perform usual social & 
functional activities OR 
Respiratory failure with ventilatory 
support indicated 
Pediatric < 14 years 
Wheezing OR minimal 
increase in respiratory rate 
for age 
Nasal flaring OR Intercostal 
retractions OR Pulse oximetry 
90 – 95% 
Dyspnea at rest causing inability 
to perform usual social & 
functional activities OR Pulse 
oximetry < 90% OR Respiratory 
failure with ventilatory support 
indicated 
 MUSCULOSKELETAL 
Arthralgia See also 
Arthritis 
Joint pain causing no or 
minimal interference with 
usual social & functional 
activities 
Joint pain causing greater than 
minimal interference with usual 
social & functional activities 
Joint pain causing inability to 
perform usual social & functional 
activities OR Disabling joint pain 
causing inability to perform basic 
self-care functions 
Arthritis See also 
Arthralgia 
Stiffness or joint swelling 
causing no or minimal 
interference with usual social 
& functional activities 
Stiffness or joint swelling 
causing greater than minimal 
interference with usual social & 
functional activities 
Stiffness or joint swelling causing 
inability to perform usual social & 
functional activities OR Disabling 
joint stiffness or swelling causing 
inability to perform basic self-care 
functions 
Bone Mineral Loss 
Adult ≥ 21 years 
BMD t-score -2.5 to -1.0 
BMD t-score < -2.5 
Pathological fracture (including 
loss of vertebral height) OR 
Pathologic fracture causing life-
threatening consequences 
Pediatric < 21 years 
BMD z-score -2.5 to -1.0 
BMD z-score < -2.5 
Pathological fracture (including 
loss of vertebral height) OR 
Pathologic fracture causing life-
threatening consequences 
 


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Version 1.0/Clarification 1 
 
 
DMID14-0029 
 
Version 3.0 
 
February 19, 2016 
____________________________________________________________________________________________  
APPENDIX C 
DIVISION OF AIDS TABLE FOR GRADING THE SEVERITY OF 
ADULT AND PEDIATRIC ADVERSE EVENTS  
VERSION 1.0, DECEMBER, 2004; CLARIFICATION AUGUST 2009  
Basic Self-care Functions – Adult: Activities such as bathing, dressing, toileting, transfer/movement, continence, and feeding. 
Basic Self-care Functions – Young Children: Activities that are age and culturally appropriate (e.g., feeding self with culturally appropriate eating 
implement). 
Usual Social & Functional Activities – Adult: Adaptive tasks and desirable activities, such as going to work, shopping, cooking, use of 
transportation, pursuing a hobby, etc. 
Usual Social & Functional Activities – Young Children: Activities that are age and culturally appropriate (e.g., social interactions, play activities, 
learning tasks, etc.). 
 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
Myalgia (non-injection site) 
Muscle pain causing no 
or minimal interference 
with usual social & 
functional activities 
Muscle pain causing 
greater than minimal 
interference with usual 
social & functional 
activities 
Muscle pain causing inability to perform 
usual social & functional activities OR 
Disabling muscle pain causing inability to 
perform basic self-care functions 
Osteonecrosis 
NA 
Asymptomatic with 
radiographic findings 
AND No operative 
intervention indicated 
Symptomatic bone pain with radiographic 
findings OR Operative intervention 
indicated OR Disabling bone pain with 
radiographic findings causing inability to 
perform basic self-care functions 
GENITOURINARY 
Cervicitis (symptoms) (For use in 
studies evaluating topical study 
agents) For other cervicitis see 
Infection: Infection (any other 
than HIV infection) 
Symptoms causing no 
or minimal interference 
with usual social & 
functional activities 
Symptoms causing 
greater than minimal 
interference with usual 
social & functional 
activities 
Symptoms causing inability to perform 
usual social & functional activities and 
basic self-care functions. 
Cervicitis (clinical exam) (For 
use in studies evaluating topical 
study agents) For other cervicitis 
see Infection: Infection (any 
other than HIV infection) 
Minimal cervical 
abnormalities on 
examination (erythema, 
mucopurulent 
discharge, or friability) 
OR Epithelial disruption 
< 25% of total surface 
Moderate cervical 
abnormalities on 
examination (erythema, 
mucopurulent discharge, 
or friability) OR Epithelial 
disruption of 25 – 49% 
total surface 
Severe cervical abnormalities on 
examination (erythema, mucopurulent 
discharge, or friability) OR Epithelial 
disruption > 50% total surface 
Inter-menstrual bleeding (IMB) 
Spotting observed by 
participant OR Minimal 
blood observed during 
clinical or colposcopic 
examination 
Inter-menstrual bleeding 
not greater in duration or 
amount than usual 
menstrual cycle 
Inter-menstrual bleeding greater in duration 
or amount than usual menstrual cycle OR 
Hemorrhage with life-threatening 
hypotension OR Operative intervention 
indicated 
Urinary tract obstruction (e.g., 
stone) 
NA 
Signs or symptoms of 
urinary tract obstruction 
without hydronephrosis 
or renal dysfunction 
Signs or symptoms of urinary tract 
obstruction with hydronephrosis or renal 
dysfunction OR Obstruction causing life-
threatening consequences 
  
 


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Version 1.0/Clarification 1 
 
 
DMID14-0029 
 
Version 3.0 
 
February 19, 2016 
____________________________________________________________________________________________  
APPENDIX C 
DIVISION OF AIDS TABLE FOR GRADING THE SEVERITY OF 
ADULT AND PEDIATRIC ADVERSE EVENTS  
VERSION 1.0, DECEMBER, 2004; CLARIFICATION AUGUST 2009  
Basic Self-care Functions – Adult: Activities such as bathing, dressing, toileting, transfer/movement, continence, and feeding. 
Basic Self-care Functions – Young Children: Activities that are age and culturally appropriate (e.g., feeding self with culturally appropriate eating 
implement). 
Usual Social & Functional Activities – Adult: Adaptive tasks and desirable activities, such as going to work, shopping, cooking, use of 
transportation, pursuing a hobby, etc. 
Usual Social & Functional Activities – Young Children: Activities that are age and culturally appropriate (e.g., social interactions, play activities, 
learning tasks, etc.). 
 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
Vulvovaginitis (symptoms) 
(Use in studies evaluating 
topical study agents) For other 
vulvovaginitis see Infection: 
Infection (any other than HIV 
infection)
Symptoms causing no or 
minimal interference with 
usual social & functional 
activities 
Symptoms causing 
greater than minimal 
interference with usual 
social & functional 
activities 
Symptoms causing inability to perform 
usual social & functional activities OR 
basic self-care functions 
Vulvovaginitis (clinical exam) 
(Use in studies evaluating 
topical study agents) For other 
vulvovaginitis see Infection: 
Infection (any other than HIV 
infection) 
Minimal vaginal 
abnormalities on 
examination OR Epithelial 
disruption < 25% of total 
surface 
Moderate vaginal 
abnormalities on 
examination OR Epithelial 
disruption of 25 - 49% 
total surface 
Severe vaginal abnormalities on 
examination OR Epithelial disruption 
>50% total surface 
 OCULAR/VISUAL 
Uveitis 
Asymptomatic but 
detectable on exam 
Symptomatic anterior 
uveitis OR Medical 
intervention indicated 
Posterior or pan-uveitis OR Operative 
intervention indicated OR Disabling 
visual loss in affected eye(s) 
Visual changes (from 
baseline) 
Visual changes causing no 
or minimal interference 
with usual social & 
functional activities 
Visual changes causing 
greater than minimal 
interference with usual 
social & functional 
activities 
Visual changes causing inability to 
perform usual social & functional 
activities OR Disabling visual loss in 
affected eye(s) 
 ENDOCRINE/METABOLIC 
Abnormal fat accumulation 
(e.g., back of neck, breasts, 
abdomen) 
Detectable by study 
participant (or by caregiver 
for young children and 
disabled adults) 
Detectable on physical 
exam by health care 
provider 
Disfiguring OR Obvious changes on 
casual visual inspection 
Diabetes mellitus 
NA 
New onset without need 
to initiate medication OR 
Modification of current 
medications to regain 
glucose control 
New onset with initiation of medication 
indicated OR Diabetes uncontrolled 
despite treatment modification OR 
Life-threatening consequences (e.g., 
ketoacidosis, hyperosmolar non- 
ketotic coma) 
  
 


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Version 1.0/Clarification 1 
 
 
DMID14-0029 
 
Version 3.0 
 
February 19, 2016 
____________________________________________________________________________________________  
APPENDIX C 
DIVISION OF AIDS TABLE FOR GRADING THE SEVERITY OF 
ADULT AND PEDIATRIC ADVERSE EVENTS  
VERSION 1.0, DECEMBER, 2004; CLARIFICATION AUGUST 2009  
Basic Self-care Functions – Adult: Activities such as bathing, dressing, toileting, transfer/movement, continence, and feeding. 
Basic Self-care Functions – Young Children: Activities that are age and culturally appropriate (e.g., feeding self with culturally appropriate eating 
implement). 
Usual Social & Functional Activities – Adult: Adaptive tasks and desirable activities, such as going to work, shopping, cooking, use of 
transportation, pursuing a hobby, etc. 
Usual Social & Functional Activities – Young Children: Activities that are age and culturally appropriate (e.g., social interactions, play activities, 
learning tasks, etc.). 
 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
Gynecomastia 
Detectable by study 
participant or caregiver (for 
young children and disabled 
adults) 
Detectable on physical exam 
by health care provider 
Disfiguring OR Obvious on 
casual visual inspection 
Hyperthyroidism 
Asymptomatic 
Symptomatic causing greater 
than minimal interference with 
usual social & functional 
activities OR Thyroid 
suppression therapy indicated 
Symptoms causing inability to 
perform usual social & 
functional activities OR 
Uncontrolled despite treatment 
modification OR Life-
threatening consequences 
(e.g., thyroid storm) 
Hypothyroidism 
Asymptomatic 
Symptomatic causing greater 
than minimal interference with 
usual social & functional 
activities OR Thyroid 
replacement therapy indicated 
Symptoms causing inability to 
perform usual social & 
functional activities OR 
Uncontrolled despite treatment 
modification OR Life-
threatening consequences 
(e.g., myxedema coma) 
Lipoatrophy 
(e.g., fat loss from the face, 
extremities, buttocks) 
Detectable by study 
participant (or by caregiver for 
young children and disabled 
adults) 
Detectable on physical exam 
by health care provider 
Disfiguring OR Obvious on 
casual visual inspection 
 


 
DMID14-0029 
 
Version 3.0 
 
February 19, 2016 
 ____________________________________________________________________________________________ 
APPENDIX C 
DAIDS Toxicity Table for Grading the Severity of Adult and Pediatric Adverse Events,  
Version 1.0 - December 2004 (Clarification dated August 2009) 
 
NOTE: For protocols utilizing this Addendum, when the same parameter appears in both this Female 
Genital Grading Table and the main DAIDS AE Grading Table, use the grading scheme in this 
table. 
 
 
 
Page 1 of 6 
 
LABORATORY 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
HEMATOLOGY 
Standard International Units are listed in italics 
Absolute CD4+ count – Adult 
and Pediatric > 13 years 
(HIV NEGATIVE ONLY) 
300 – 400/mm3 300 – 400/µL 
200 – 299/mm3 200 – 299/µL 
< 199/mm3 < 199/µL 
Absolute lymphocyte count – 
Adult and Pediatric > 13 
years (HIV NEGATIVE ONLY) 
600 – 650/mm3 0.600 x 109 – 
0.650 x 10
9/L 
500 – 599/mm3 0.500 x 109 – 
0.599 x 10
9/L 
< 499/mm3 < 0.499 x 10
9/L 
Comment:  Values in children ≤ 13 years are not given for the two parameters above because the absolute counts are variable. 
Absolute neutrophil count (ANC) 
Adult and Pediatric, > 7 days 1,000 – 1,300/mm3 1.000 x 
109 – 1.300 x 109/L 
750 – 999/mm3 0.750 x 109 – 
0.999 x 109/L 
< 749/mm3 < 0.749 x 109/L 
Infant∗†, 2 – ≤ 7 days 
1,250 – 1,500/mm3 1.250 x 
109 – 1.500 x 109/L 
1,000 – 1,249/mm3 1.000 x 
109 – 1.249 x 109/L 
< 999/mm3 < 0.999 x 109/L 
Infant∗†, ≤1 day 
4,000 – 5,000/mm3 4.000 x 
109 – 5.000 x 109/L 
3,000 – 3,999/mm3 3.000 x 
109 – 3.999 x109/L 
< 2,999/mm3 < 2.999 x 109/L 
Comment:  Parameter changed from “Infant, < 1 day” to “Infant, ≤1 day” 
Fibrinogen, decreased 
100 – 200 mg/dL 1.00 – 2.00 
g/L OR 0.75 – 0.99 x LLN 
75 – 99 mg/dL 0.75 – 0.99 g/L 
OR 0.50 – 0.74 x LLN 
< 74 mg/dL < 0.74 g/L OR < 
0.49 x LLN OR Associated 
with gross bleeding 
 
 
 


 
DMID14-0029 
 
Version 3.0 
 
February 19, 2016 
 ____________________________________________________________________________________________  
APPENDIX C (Cont'd) 
DAIDS Toxicity Table for Grading the Severity of Adult and Pediatric Adverse Events,  
Version 1.0 - December 2004 (Clarification dated August 2009) 
Page 2 of 6 
LABORATORY 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
Hemoglobin (Hgb) 
Comment: The Hgb values in mmol/L have changed because the conversion factor used to convert g/dL to mmol/L has been 
changed from 0.155 to 0.6206 (the most commonly used conversion factor). For grading Hgb results obtained by an analytic 
method with a conversion factor other than 0.6206, the result must be converted to g/dL using the appropriate conversion factor 
for that lab. 
Adult and Pediatric ≥ 57 
days (HIV POSITIVE ONLY) 
8.5 – 10.0 g/dL 5.24 – 6.23 
mmol/L 
7.5 – 8.4 g/dL 4.62–5.23 
mmol/L 
< 7.4 g/dL < 4.61 mmol/L 
Adult and Pediatric ≥ 57 
days (HIV NEGATIVE ONLY) 
10.0 – 10.9 g/dL 6.18 – 6.79 
mmol/L OR Any decrease 2.5 
– 3.4 g/dL 1.58 – 2.13 mmol/L 
9.0 – 9.9 g/dL 5.55 - 6.17 
mmol/L OR Any decrease 3.5 
– 4.4 g/dL 2.14 – 2.78 mmol/L 
< 8.9 g/dL < 5.54 mmol/L OR 
Any decrease ≥ 4.5 g/dL > 
2.79 mmol/L 
Comment:  The decrease is a decrease from baseline 
Infant∗†, 36 – 56 days (HIV 
POSITIVE OR NEGATIVE) 
8.5 – 9.4 g/dL 5.24 – 5.86 
mmol/L 
7.0 – 8.4 g/dL 4.31 – 5.23 
mmol/L 
< 6.9 g/dL < 4.30 mmol/L 
Infant∗†, 22 – 35 days (HIV 
POSITIVE OR NEGATIVE) 
9.5 – 10.5 g/dL 5.87 - 6.54 
mmol/L 
8.0 – 9.4 g/dL 4.93 – 5.86 
mmol/L 
< 7.9 g/dL < 4.92 mmol/L 
Infant∗†, ≤ 21 days (HIV 
POSITIVE OR NEGATIVE) 
12.0 – 13.0 g/dL 7.42 – 8.09 
mmol/L 
10.0 – 11.9 g/dL 6.18 – 7.41 
mmol/L 
< 9.9 g/dL < 6.17 mmol/L 
Correction: Parameter changed from “Infant < 21 days” to “Infant ≤ 21 days” 
International Normalized Ratio 
of prothrombin time (INR) 
1.1 – 1.5 x ULN 
1.6 – 2.0 x ULN 
> 2.1 x ULN 
Methemoglobin 
5.0 – 10.0% 
10.1 – 15.0% 
> 15.1% 
Prothrombin Time (PT) 
1.1 – 1.25 x ULN 
1.26 – 1.50 x ULN 
> 1.51 x ULN 
Partial Thromboplastin Time 
(PTT) 
1.1 – 1.66 x ULN 
1.67 – 2.33 x ULN 
> 2.34 x ULN 
Platelets, decreased 
100,000 – 124,999/mm3 
100.000 x 109 – 124.999 x 
109/L 
50,000 – 99,999/mm3 50.000 x 
109 – 99.999 x 109/L 
< 49,999/mm3 <  49.999 x 
109/L 
WBC, decreased 
2,000 – 2,500/mm3 2.000 x 
109 – 2.500 x 109/L 
1,500 – 1,999/mm3 1.500 x 
109 – 1.999 x 109/L 
< 1,499/mm3 < 1.499 x 109/L 
 
 
 


 
DMID14-0029 
 
Version 3.0 
 
February 19, 2016 
 ____________________________________________________________________________________________  
APPENDIX C (Cont'd) 
DAIDS Toxicity Table for Grading the Severity of Adult and Pediatric Adverse Events,  
Version 1.0 - December 2004 (Clarification dated August 2009) 
Page 3 of 6 
LABORATORY 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
CHEMISTRIES 
Standard International Units are listed in italics 
Acidosis 
NA 
pH < normal, but ≥ 7.3 
pH < 7.3  
Albumin, serum, low 
3.0 g/dL – < LLN 
30 g/L – < LLN 
2.0 – 2.9 g/dL 
20 – 29 g/L 
< 2.0 g/dL 
< 20 g/L 
Alkaline Phosphatase 
1.25 – 2.5 x ULN† 
2.6 – 5.0 x ULN† 
> 5.1 – 10.0 x ULN† 
Alkalosis 
NA 
pH > normal, but ≤ 7.5 
pH > 7.5  
ALT (SGPT) 
1.25 – 2.5 x ULN 
2.6 – 5.0 x ULN 
> 5.1 x ULN 
AST (SGOT) 
1.25 – 2.5 x ULN 
2.6 – 5.0 x ULN 
> 5.1 x ULN 
Bicarbonate, serum, low 
16.0 mEq/L – < LLN 
16.0 mmol/L – < LLN 
11.0 – 15.9 mEq/L 
11.0 – 15.9 mmol/L 
> 8.0 mEq/L 
> 8.0 mmol/L 
Comment:  Some laboratories will report this value as Bicarbonate (HCO3) and others as Total Carbon Dioxide (CO2). These 
are the same tests; values should be graded according to the ranges for Bicarbonate as listed above. 
Bilirubin (Total) 
 
Adult and Pediatric > 
14 days 
1.1 – 1.5 x ULN 
1.6 – 2.5 x ULN 
> 2.6 x ULN 
 
Infant∗†, ≤ 14 days 
(non-hemolytic) 
NA 
20.0 – 25.0 mg/dL 
342 – 428 µmol/L 
> 25.1 mg/dL 
> 429 µmol/L 
 
Infant∗†, ≤ 14 days 
(hemolytic) 
NA 
NA 
> 20.0 mg/dL 
> 342 µmol/L 
Calcium, serum, high 
 
Adult and Pediatric 
≥ 7 days 
10.6 – 11.5 mg/dL 
2.65 – 2.88 mmol/L 
11.6 – 12.5 mg/dL 
2.89 – 3.13 mmol/L 
> 12.6 mg/dL 
> 3.14 mmol/L 
 
Infant∗†, < 7 days 
11.5 – 12.4 mg/dL 
2.88 – 3.10 mmol/L 
12.5 – 12.9 mg/dL 
3.11 – 3.23 mmol/L 
> 13.0 mg/dL 
> 3.245 mmol/L 
Calcium, serum, low 
 
Adult and Pediatric 
≥ 7 days 
7.8  – 8.4 mg/dL 
1.95 – 2.10 mmol/L 
7.0  – 7.7 mg/dL 
1.75 – 1.94 mmol/L 
< 6.1 mg/dL 
< 1.53 mmol/L 
 
Infant∗†, < 7 days 
6.5 – 7.5 mg/dL 
1.63 – 1.88 mmol/L 
6.0 – 6.4 mg/dL 
1.50 – 1.62 mmol/L 
< 5.50 mg/dL 
< 1.38 mmol/L 
Comment:  Do not adjust Calcium, serum, low or Calcium, serum, high for albumin 
 


 
DMID14-0029 
 
Version 3.0 
 
February 19, 2016 
 ____________________________________________________________________________________________  
APPENDIX C (Cont'd) 
DAIDS Toxicity Table for Grading the Severity of Adult and Pediatric Adverse Events,  
Version 1.0 - December 2004 (Clarification dated August 2009) 
Page 4 of 6 
LABORATORY 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
Cardiac troponin I (cTnI) 
NA 
NA 
Levels consistent with 
myocardial infarction or 
unstable angina as defined by 
the manufacturer 
Cardiac troponin T (cTnT) 
NA 
NA 
≥ 0.20 ng/mL 
OR 
Levels consistent with 
myocardial infarction or 
unstable angina as defined by 
the manufacturer 
Cholesterol (fasting) 
Adult ≥ 18 years 
200 – 239 mg/dL 
5.18 – 6.19 mmol/L 
240 – 300 mg/dL 
6.20 – 7.77 mmol/L 
> 300 mg/dL 
> 7.77 mmol/L 
Pediatric < 18 years 
170 – 199 mg/dL 
4.40 – 5.15 mmol/L 
200 – 300 mg/dL 
5.16 – 7.77 mmol/L 
> 300 mg/dL 
> 7.77 mmol/L 
Creatine Kinase 
3.0 – 5.9 x ULN† 
6.0 – 9.9 x ULN† 
> 10.0 x ULN† 
Creatinine 
1.1 – 1.3 x ULN† 
1.4 – 1.8 x ULN† 
> 1.9 x ULN† 
Glucose, serum, high 
Nonfasting 
116 – 160 mg/dL 
6.44 – 8.88 mmol/L 
161 – 250 mg/dL 
8.89 – 13.88 mmol/L 
> 251 mg/dL 
> 13.89 mmol/L 
Fasting 
110 – 125 mg/dL 
6.11 – 6.94 mmol/L 
126 – 250 mg/dL 
6.95 – 13.88 mmol/L 
> 251 mg/dL 
> 13.89 mmol/L 
Glucose, serum, low 
Adult and Pediatric 
≥ 1 month 
55 – 64 mg/dL 
3.05 – 3.55 mmol/L 
40 – 54 mg/dL 
2.22 – 3.06 mmol/L 
< 40 mg/dL 
< 2.21 mmol/L 
Infant∗†, < 1 month 
50 – 54 mg/dL 
2.78 – 3.00 mmol/L 
40 – 49 mg/dL 
2.22 – 2.77 mmol/L 
< 40 mg/dL 
< 2.21 mmol/L  
Lactate 
ULN - < 2.0 x ULN 
without acidosis 
≥ 2.0 x ULN without 
acidosis 
Increased lactate with pH < 
7.3  
 
 


 
DMID14-0029 
 
Version 3.0 
 
February 19, 2016 
 ____________________________________________________________________________________________  
APPENDIX C (Cont'd) 
DAIDS Toxicity Table for Grading the Severity of Adult and Pediatric Adverse Events,  
Version 1.0 - December 2004 (Clarification dated August 2009) 
Page 5 of 6 
LABORATORY
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
Comment: Added ULN to Grade 1 parameter 
LDL cholesterol (fasting) 
Adult ≥ 18 years 
130 – 159 mg/dL 
3.37 – 4.12 mmol/L 
160 – 190 mg/dL 
4.13 – 4.90 mmol/L 
>190 mg/dL 
> 4.91 mmol/L 
Pediatric > 2 - < 18 years 
110 – 129 mg/dL 
2.85 – 3.34 mmol/L 
130 – 189 mg/dL 
3.35 – 4.90 mmol/L 
≥ 190 mg/dL 
≥ 4.91 mmol/L 
Lipase 
1.1 – 1.5 x ULN OR 
Refers to ULN 
1.6 – 3.0 x ULN 
> 3.1 x ULN 
Magnesium, serum, low 
1.2  – 1.4 mEq/L 
0.60 – 0.70 mmol/L 
0.9 – 1.1 mEq/L 
0.45 – 0.59 mmol/L 
< 0.89 mEq/L 
< 0.44 mmol/L 
Pancreatic amylase 
1.1 – 1.5 x ULN 
1.6 – 2.0 x ULN 
> 2.1 x ULN 
Phosphate, serum, low 
Adult and Pediatric 
> 14 years 
2.5 mg/dL – < LLN 
0.81 mmol/L – < LLN 
2.0 – 2.4 mg/dL 
0.65 – 0.80 mmol/L 
< 1.9 mg/dL 
< 0.64 mmol/L 
Pediatric 1 year – 14 years 
3.0 – 3.5 mg/dL 
0.97 – 1.13 mmol/L 
2.5 – 2.9 mg/dL 
0.81 – 0.96 mmol/L 
< 2.4 mg/dL 
< 0.80 mg/dL 
< 2.21 mmol/L 0.80 mmol/L 
Pediatric < 1 year 
3.5 – 4.5 mg/dL 
1.13 – 1.45 mmol/L 
2.5 – 3.4 mg/dL 
0.81 – 1.12 mmol/L 
< 2.4 mg/dL 
< 0.80 mmol/L 
Potassium, serum, high 
5.6 – 6.0 mEq/L 
5.6 – 6.0 mmol/L 
6.1 – 6.5 mEq/L 
6.1 – 6.5 mmol/L 
> 6.6 mEq/L 
> 6.6 mmol/L 
Potassium, serum, low 
3.0 – 3.4 mEq/L 
3.0 – 3.4 mmol/L 
2.5 – 2.9 mEq/L 
2.5 – 2.9 mmol/L 
< 2.4 mEq/L 
< 2.4 mmol/L 
Sodium, serum, high 
146 – 150 mEq/L 
146 – 150 mmol/L 
151 – 154 mEq/L 
151 – 154 mmol/L 
> 155 mEq/L 
> 155 mmol/L 
Sodium, serum, low 
130 – 135 mEq/L 
130 – 135 mmol/L 
125 – 129 mEq/L 
125 – 129 mmol/L 
< 121 mEq/L 
< 121 mmol/L
Triglycerides (fasting) 
NA 
500 – 750 mg/dL 
5.65 – 8.48 mmol/L 
> 751 mg/dL 
> 8.49 mmol/L 
 
 
 


 
DMID14-0029 
 
Version 3.0 
 
February 19, 2016 
 ____________________________________________________________________________________________  
APPENDIX C (Cont'd) 
DAIDS Toxicity Table for Grading the Severity of Adult and Pediatric Adverse Events,  
Version 1.0 - December 2004 (Clarification dated August 2009) 
Page 6 of 6 
 
LABORATORY 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
Uric acid 
7.5 – 10.0 mg/dL 
0.45 – 0.59 mmol/L 
10.1 – 12.0 mg/dL 
0.60 – 0.71 mmol/L 
> 12.1 mg/dL 
> 0.72 mmol/L 
URINALYSIS 
Standard International Units are listed in italics 
Hematuria (microscopic) 
6 – 10 RBC/HPF 
> 10 RBC/HPF 
Gross, with or without clots OR with RBC casts 
Proteinuria, random 
collection 
1 + 
2 – 3 + 
4 + 
Proteinuria, 24 hour collection 
Adult and Pediatric 
≥ 10 years 
200 – 999 mg/24 h 
0.200 – 0.999 g/d 
1,000 – 1,999 mg/24 h 
1.000 – 1.999 g/d 
> 2,000 mg/24 h 
> 2.000 g/d 
Pediatric > 3 mo - 
< 10 years 
201 – 499 mg/m2/24 h 
0.201 – 0.499 g/d 
500 – 799 mg/m2/24 h 
0.500 – 0.799 g/d 
> 800 mg/m2/24 h 
> 0.800 g/d 
 
 

SAP_001.pdf: 
CLINICAL RESEARCH IN INFECTIOUS DISEASES 
 
 
 
STATISTICAL ANALYSIS PLAN 
for 
DMID Protocol: 14-0029 
Study Title: 
Phase II-b Randomized Double-Blind Placebo-Controlled Trial of 
Lactobacillus crispatus CTV-05 (LACTIN-V) to Prevent the Recurrence of 
Bacterial Vaginosis 
 
NCT02766023 
 
Version 1.0 
 
DATE: 11-MAY-2018 
 
 
THIS COMMUNICATION IS PRIVILEGED AND CONFIDENTIAL  
 


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Study Title 
Protocol Number Code: 
DMID Protocol: 14-0029 
Development Phase: 
Phase 2b 
Products: 
LACTIN-V 
Form/Route: 
Intravaginally 
Indication Studied: 
Bacterial Vaginosis 
Sponsor: 
Division of Microbiology and Infectious Diseases 
National Institute of Allergy and Infectious Diseases 
National Institutes of Health 
Clinical Trial Initiation Date: 
28APR2018 
Clinical Trial Completion Date: 
TBD 
Date of the Analysis Plan: 
11MAY2018 
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. 
 


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TABLE OF CONTENTS 
TABLE OF CONTENTS ...............................................................................................................III 
LIST OF ABBREVIATIONS ....................................................................................................... VI 
1. 
PREFACE .....................................................................................................................1 
2. 
INTRODUCTION ........................................................................................................2 
2.1. 
Purpose of the Analyses ................................................................................................3 
3. 
STUDY OBJECTIVES AND ENDPOINTS ................................................................4 
3.1. 
Study Objectives ...........................................................................................................4 
3.1.1. 
Primary Objectives .......................................................................................................4 
3.1.2. 
Secondary Objectives ...................................................................................................4 
3.1.3. 
Exploratory Objectives .................................................................................................4 
3.2. 
Endpoints ......................................................................................................................4 
3.2.1. 
Primary Efficacy Outcome Measure ............................................................................4 
3.2.2. 
Primary Safety Outcome Measure ................................................................................4 
3.2.3. 
Secondary Outcome Measures .....................................................................................4 
3.2.4. 
Exploratory Outcome Measures ...................................................................................5 
3.3. 
Study Definitions and Derived Variables .....................................................................5 
3.3.1. 
BV Diagnosis ................................................................................................................5 
3.3.2. 
Recurrent BV ................................................................................................................5 
3.3.3. 
Successful Colonization of L. crispatus ........................................................................6 
3.3.4. 
Baseline Value ..............................................................................................................6 
3.3.5. 
Treatment Compliance ..................................................................................................6 
4. 
INVESTIGATIONAL PLAN .......................................................................................7 
4.1. 
Overall Study Design and Plan .....................................................................................7 
4.2. 
Discussion of Study Design, Including the Choice of Control Groups ........................7 
4.3. 
Selection of Study Population ......................................................................................8 
4.4. 
Treatments ..................................................................................................................10 
4.4.1. 
Treatments Administered ............................................................................................10 
4.4.2. 
Method of Assigning Subjects to Treatment Groups (Randomization) .....................10 
4.4.3. 
Selection and Timing of Dose for Each Subject .........................................................11 
4.4.4. 
Blinding ......................................................................................................................12 


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4.4.5. 
Prior and Concomitant Therapy ..................................................................................13 
4.4.6. 
Treatment Compliance ................................................................................................13 
4.5. 
Efficacy and Safety Variables ....................................................................................13 
4.5.1. 
Safety Variables ..........................................................................................................13 
4.5.2. 
Efficacy Variables ......................................................................................................14 
5. 
SAMPLE SIZE CONSIDERATIONS .......................................................................15 
6. 
GENERAL STATISTICAL CONSIDERATIONS ....................................................16 
6.1. 
General Principles .......................................................................................................16 
6.1.1. 
Pseudo Code ...............................................................................................................16 
6.2. 
Timing of Analyses .....................................................................................................18 
6.3. 
Analysis Populations ..................................................................................................18 
6.3.1. 
Safety Analyses ..........................................................................................................18 
6.3.2. 
Efficacy Analyses .......................................................................................................18 
6.3.2.1. 
Intent-to-Treat Analysis (ITT) Population ..................................................................18 
6.3.2.2. 
Modified Intent-to-Treat (mITT) Population ..............................................................18 
6.3.2.3. 
Complete Case (CC) Population .................................................................................19 
6.3.2.4. 
Per Protocol (PP) Population ......................................................................................19 
6.3.2.5. 
Blinded Review of Efficacy Analysis Population Eligibilities ...................................19 
6.3.2.6. 
Analysis Population Summaries .................................................................................20 
6.4. 
Covariates and Subgroups ..........................................................................................20 
6.5. 
Missing Data ...............................................................................................................20 
6.6. 
Interim Analyses and Data Monitoring ......................................................................20 
6.7. 
Multicenter Studies .....................................................................................................21 
6.8. 
Multiple Comparisons/Multiplicity ............................................................................21 
7. 
STUDY SUBJECTS ...................................................................................................22 
7.1. 
Disposition of Subjects ...............................................................................................22 
7.2. 
Protocol Deviations ....................................................................................................22 
8. 
EFFICACY EVALUATION ......................................................................................23 
8.1. 
Primary Efficacy Analysis ..........................................................................................23 
8.2. 
Secondary Efficacy Analyses .....................................................................................23 
8.3. 
Exploratory Efficacy Analyses ...................................................................................26 
9. 
SAFETY EVALUATION ..........................................................................................28 
9.1. 
Demographic and Other Baseline Characteristics ......................................................28 


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9.1.1. 
Prior and Concurrent Medical Conditions ..................................................................28 
9.1.2. 
Prior and Concomitant Medications ...........................................................................28 
9.2. 
Measurements of Treatment Compliance ...................................................................28 
9.3. 
Adverse Events ...........................................................................................................28 
9.3.1. 
Solicited Events and Symptoms .................................................................................29 
9.3.2. 
Unsolicited Adverse Events ........................................................................................29 
9.4. 
Deaths, Serious Adverse Events and other Significant Adverse Events ....................30 
9.5. 
Pregnancies .................................................................................................................31 
9.6. 
Clinical Laboratory Evaluations .................................................................................31 
9.7. 
Vital Signs and Physical Evaluations .........................................................................31 
9.8. 
Concomitant Medications ...........................................................................................31 
10. 
OTHER ANALYSES .................................................................................................32 
11. 
REPORTING CONVENTIONS ................................................................................33 
12. 
TECHNICAL DETAILS ............................................................................................34 
13. 
SUMMARY OF CHANGES IN THE CONDUCT OF THE STUDY OR 
PLANNED ANALYSES ............................................................................................35 
14. 
REFERENCES ...........................................................................................................36 
15. 
LISTING OF TABLES, FIGURES, AND LISTINGS ..............................................37 
APPENDIX 1. TABLE MOCK-UPS..........................................................................................38 
Narratives of Deaths, Other Serious and Significant Adverse Events (not included in 
SAP, but will be included in the CSR) .....................................................................127 
APPENDIX 2. FIGURE MOCK-UPS ......................................................................................130 
APPENDIX 3. LISTINGS MOCK-UPS ...................................................................................149 
 


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LIST OF ABBREVIATIONS 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase 
BP 
Blood Pressure  
BUN 
Blood Urea Nitrogen 
C 
Celsius 
CI 
Confidence Interval 
CRF 
Case Report Form 
DMID 
Division of Microbiology and Infectious Diseases 
DSMB 
Data and Safety Monitoring Board 
EDC 
Electronic Data Capture 
ELISA 
Enzyme-linked Immunosorbent Assay 
ER 
Emergency Room 
F 
Fahrenheit 
GGT 
Gamma Glutamyl Transferase 
GMT 
Geometric Mean Titer 
GMFR 
Geometric Mean Fold Rise 
ICH 
International Conference on Harmonisation 
IRB 
Institutional Review Board 
ITT 
Intention to Treat 
L 
Liter 
LLN 
Lower Limit of Normal 
mcg 
Microgram 
MedDRA® 
Medical Dictionary for Regulatory Activities  
mEq 
Milliequivalent 
mg 
Milligram 
mITT 
Modified Intention to Treat 
mL 
Milliliter 
MAR 
Missing at Random 
MCAR 
Missing Completely at Random 
MNAR 
Missing Not at Random 


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N 
Number (typically refers to subjects) 
NIH 
National Institutes of Health 
PI 
Principal Investigator 
PP 
Per Protocol 
PT 
Preferred Term 
RBC 
Red Blood Cell 
RCD 
Reverse Cumulative Distribution  
SAE 
Serious Adverse Event 
SD 
Standard Deviation 
SDCC 
Statistical and Data Coordinating Center 
SMC 
Safety Monitoring Committee 
SOC  
System Organ Class 
SOP 
Standard Operating Procedures 
U 
Units 
ULN 
Upper Limit of Normal 
WBC 
White Blood Cell 
WHO 
World Health Organization 
 


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1. 
PREFACE 
The Statistical Analysis Plan (SAP) for “Phase II-b Randomized Double-Blind Placebo-Controlled Trial of 
Lactobacillus crispatus CTV-05 (LACTIN-V) to Prevent the Recurrence of Bacterial Vaginosis” (DMID 
protocol 14-0029) 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, listings, and figures planned for the final analyses. Regarding the final analyses 
and Clinical Study Report (CSR), this SAP follows the International Conference on Harmonisation of 
Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) Guidelines, as indicated in 
Topic E3 (Structure and Content of Clinical Study Reports), and more generally is consistent with Topic E8 
(General Considerations for Clinical Trials) and Topic E9 (Statistical Principles for Clinical Trials). The 
structure and content of the SAP provides sufficient detail to meet the requirements identified by the FDA and 
ICH, while all work planned and reported for this SAP will follow internationally accepted guidelines 
published by the American Statistical Association and the Royal Statistical Society for statistical practice.  
This document contains four sections: (1) a review of the study design, (2) general statistical considerations, 
(3) comprehensive statistical analysis methods for efficacy and safety outcomes, and (4) a list of proposed 
tables and figures. 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 
Bacterial vaginosis (BV), characterized by an imbalanced vaginal flora deficient in naturally occurring acid-
producing lactobacilli, is one of the most frequent vaginal infections and affects about 15–50% of 
reproductive aged women globally [1]. Following standard antibiotic treatment of BV, 20–75% of women 
relapse within 1–3 months [2, 3]. The high risk of recurrence and sequelae suggests that investigational 
studies of new agents like live biotherapeutic products [4] may be effective for the improved treatment and 
prevention of BV.  
Reconstituting a normal, Lactobacillus-predominant vaginal flora has been promoted for many years as a 
microbial defense against pathogens. The vaginal live biotherapeutic product Lactobacillus (L.) crispatus 
CTV-05 (LACTIN-V) was developed by Osel, Inc. in Mountain View, California, and is designed to 
replenish the vaginal lactobacilli population following conventional antibiotic treatment with MetroGel® 
(topical metronidazole gel 0.75%). The product contains a naturally occurring vaginal strain of L. crispatus 
CTV-05, preserved as a powder applied by a vaginal applicator. Since the Lactobacillus strain used in 
LACTIN-V is a commensal organism normally present in the vagina associated with vaginal health, the 
product has an excellent pre-clinical and clinical safety profile. 
Early studies of LACTIN-V administered the product in gelatin-coated capsules. The University of California, 
San Francisco (UCSF) and Osel hypothesized that the efficacy of LACTIN-V to prevent BV recurrence could 
be improved by increasing the vaginal colonization rate of L. crispatus CTV-05. In order to achieve this, a 
vaginal applicator was developed capable of delivering a higher dose of LACTIN-V powder (up to 2 x 109 
cfu/dose) directly to the vagina without the impediment of a gelatin capsule, which was found to dissolve 
slowly in the vaginal environment. 
Collecting a larger body of data on colonization and efficacy of unmodified Lactobacillus strains to prevent 
BV recurrence will greatly contribute to the efforts of developing unmodified as well as genetically modified 
Lactobacillus strains as a multipurpose technology for the prevention of HIV-1 and other genital tract 
infections. 
CTV-05 is a strain of L. crispatus, a gram-positive rod isolated from the vagina of a healthy woman. 
L.crispatus is found naturally in the vaginas of healthy women and is commonly found as a component of the 
natural human intestinal flora.  Unlike most commercially available strains of Lactobacillus, CTV-05 adheres 
well to vaginal epithelial cells and is capable of colonizing the vaginal epithelium.   
LACTIN-V administered as a capsule has been tested in four trials (LV 001-004) with a dose level up to 5 x 
108 cfu/capsule. Since the dose of 5 x 108 cfu/capsule resulted in colonization rates lower than desired, several 
changes to the study product were made. The higher dose of 2 x 109 cfu/dose delivered via vaginal applicator 
as dried powder directly into the upper vaginal vault has been tested in a Phase 1 trial (LV-005) in 12 healthy 
women and subsequently in a Phase II-a trial (LV-006) in 24 women with BV. 
Based on the achieved colonization rate of L. crispatus CTV-05 at 2 x 109 cfu/dose of LACTIN-V, coupled 
with prior data from the Phase II-a clinical trial suggesting that vaginal colonization with L. crispatus CTV-05 
was associated with a reduced risk of BV recurrence, this Phase II-b trial is designed to provide a screening 
evaluation for the hypothesis that, following a 5-day course of MetroGel to treat BV, LACTIN-V 
administered at 2 x 109 cfu/dose using a vaginal applicator reduces the 12-week incidence of BV recurrence 
by ≥50% when compared to placebo. This study follows the 2015 CDC Sexually Transmitted Diseases 
Treatment Guidelines as well as the 2013 Food and Drug Administration (FDA) draft guidance for the use of 
metronidazole gel and the 2016 FDA draft guidance for BV and uses a combined requirement of at least 3 of 
4 Amsel criteria and a Nugent score of 4-10.  


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2.1. 
Purpose of the Analyses 
These analyses will assess the efficacy and safety of repeated doses of LACTIN-V in comparison with the 
placebo 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 Objectives 
1. To estimate the efficacy of repeated doses of LACTIN-V (2 x 109 cfu/dose) as compared to placebo in 
preventing BV recurrence by 12 weeks following treatment of BV with MetroGel. 
2. To assess the safety of LACTIN-V over 24 weeks by comparing the incidence of adverse events (AEs) 
between individuals randomized to LACTIN-V or placebo. 
3.1.2. 
Secondary Objectives 
1. To investigate the colonization of LACTIN-V (presence of L. crispatus CTV-05 in the vaginal 
specimen) and fluctuations over 12 weeks, in relation to menses and sexual intercourse. 
2. To evaluate user acceptability and tolerability of LACTIN-V over 12 weeks, including perceptions 
around method of delivery and dosing. 
3. To measure long-term colonization of LACTIN-V at 24 weeks (12 weeks after last dosing). 
4. To estimate the long-term efficacy of repeated doses of LACTIN-V (2 x 109 cfu/dose) as compared to 
placebo in preventing BV recurrence at 24 weeks (12 weeks after last dosing). 
3.1.3. 
Exploratory Objectives 
1. To estimate the efficacy of repeated doses of LACTIN-V (2 x 109 cfu/dose) as compared to placebo in 
preventing repeated (more than one) episodes of BV recurrence up to 12 weeks following treatment of 
BV with MetroGel. 
3.2. 
Endpoints 
3.2.1. 
Primary Efficacy Outcome Measure 
1. The proportion of subjects with a positive BV diagnosis in each study arm by Visit 4 (Week 12, 
Day 84). 
3.2.2. 
Primary Safety Outcome Measure 
1. The proportion of subjects reporting product-related AEs and SAEs in each study arm through Visit 7 
(Week 24, Day 168). 
3.2.3. 
Secondary Outcome Measures 
1. The proportion of subjects experiencing successful colonization with L. crispatus CTV-05 following 
dose of study product through Visit 4 (Week 12, Day 84) in the LACTIN-V arm, overall and by 
occurrence of menses and intercourse. 
2. (Acceptability of LACTIN-V and the applicator):  The proportion of subjects who are compliant with 
the complete dose regimen in each study arm as assessed by subject reporting and applicator staining. 
3. (Tolerability of LACTIN-V and the applicator): The proportion of subjects who discontinue study 
product early in each study arm due to adverse events. 


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4. (Acceptability of LACTIN-V and the applicator): Self-administered questionnaires about acceptability 
of the study product in each study arm. 
5. The proportion of subjects experiencing successful colonization with L. crispatus CTV-05 following 
dose of study product at Visit 7 (Week 24, Day 168) in the LACTIN-V arm, overall and by occurrence 
of menses and intercourse. 
6. The proportion of subjects with a positive BV diagnosis in each study arm by Visit 7 (Week 24, 
Day 168). 
3.2.4. 
Exploratory Outcome Measures 
1. The number of BV recurrences per 12 weeks of follow-up. 
2. The probability of BV recurrence during the 12 weeks of follow-up. 
3.3. 
Study Definitions and Derived Variables  
3.3.1. 
BV Diagnosis 
The Amsel criteria and Nugent score will be used to diagnose BV. 
During a pelvic examination, presence of the following Amsel criteria will be determined: 
a. Homogeneous, thin, grayish-white discharge that smoothly coats the vaginal walls  
b. Vaginal pH > 4.5  
c. Positive whiff-amine test, defined as the presence of a fishy odor when a drop of 10% potassium 
hydroxide (KOH) is added to a sample of vaginal discharge  
d. Presence of clue cells (>20%) on microscopy 
A vaginal swab for assessment of BV by Nugent criteria will be performed. The Nugent score utilized a 0-10-
point scale for evaluation of vaginal flora. The Nugent score is interpreted as follows:  
• 0-3 Normal  
• 4-6 Intermediate 
• 7-10 BV 
A positive diagnosis of BV is defined by the presence of at least three of the Amsel criteria and a Nugent 
score of 4 or greater.   
3.3.2. 
Recurrent BV 
By standard definition, a treatment of BV is only considered to have failed if Amsel criteria or Nugent score 
on Gram stain diagnose BV to persist at 22-30 days after the initiation of the antibiotic treatment. As a result, 
women who continue to have BV during the enrollment visit will not be re-treated with MetroGel at the time 
of enrollment, as additional time is needed for BV to resolve after antibiotic treatment. Thus, they are not 
considered treatment failures at this time (approximately 2 days after termination of antibiotic treatment). All 
BV diagnoses following enrollment are considered incident, as they occur at least 22-30 days after the 
commencement of MetroGel treatment and consequently are treatment failures or new infections. And so, a 
positive diagnosis of BV at any visit after the enrollment visit will be considered a recurrence of BV (i.e. there 


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is no distinction between treatment failure and new infection). A positive diagnosis of BV at the enrollment 
visit will not be considered a recurrence of BV. 
3.3.3. 
Successful Colonization of L. crispatus 
Colonization of L. crispatus will be determined from the concentrations of L. crispatus species and L. 
crispatus CTV-05 obtained from qPCR. Successful colonization is defined as follows: 
• If CTV-05 concentration is above the lower limit of detection (LLOD) and the L. crispatus is above 
the LLOD, then successful colonization has occurred. 
• If either CTV-05 or L. crispatus concentration is below LLOD or indeterminate, then successful 
colonization has not occurred. 
The LLOD for CTV-05 is 660 copies/mL and the LLOD for L. crispatus is 953 copies/mL. 
3.3.4. 
Baseline Value 
The baseline value for most variables will be defined as the last value obtained prior to the first dose of 
LACTIN-V or placebo. As noted in Section 3.3.2, for BV recurrence, the baseline BV diagnosis will be the 
diagnosis at the screening visit. 
3.3.5. 
Treatment Compliance 
All subjects are to receive a total of 25 doses of study product. The first dose is administered in clinic and the 
remaining doses will be administered by the subject at home. A subject is compliant with the assigned study 
product if she takes at least 75% of the scheduled doses prior to the first diagnosis of BV or through Visit 4 
(Week 12, Day 84), whichever occurs first. Compliance will be assessed by applicator staining of the returned 
kit. If a kit is not returned, compliance will be assessed by the subject’s self-report (e.g. via the memory aid). 
If an incomplete kit is returned or staining results are indeterminate, the subject’s self-report will be used in 
conjunction with the count of stained applicators to determine subject compliance. 
Compliance is assessed on a weekly basis, so for subjects who are not compliant per the definition above, the 
time (week) at which the subject became non-compliant will be determined. The time of non-compliance will 
be defined as the first week at which the cumulative proportion of doses taken drops below 75% of the 
scheduled doses up to that week. 


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4. 
INVESTIGATIONAL PLAN 
4.1. 
Overall Study Design and Plan 
This is a Phase II-b multicenter randomized double-blind placebo-controlled trial to assess the efficacy of 
repeated doses of LACTIN-V compared to placebo in preventing BV recurrence in women diagnosed with 
BV. The study will also assess the safety of LACTIN-V by comparing the incidence of AEs between women 
randomized to LACTIN-V or placebo. The study plans to enroll 228 sexually-experienced, pre-menopausal 
women age 18 to 45 years. Women will be randomized 2:1 to receive LACTIN-V or placebo. Women will be 
consented and will have a history and physical examination to include a pelvic exam with STI diagnostics and 
testing for BV.  Potentially eligible women with Amsel criteria ≥3 will have a vaginal smear sent to a central 
laboratory for Gram stain evaluation by Nugent score. Blood will be obtained for HIV and syphilis serologies, 
a vaginal swab for gonorrhea, chlamydia and trichomonas molecular testing, and urine for βhCG. Potentially 
eligible women will start a standard 5-day course of MetroGel. Table 1 provides the study schematic. 
Women will return to the study clinic within 2 days after completing the 5-day course of MetroGel to re-
evaluate eligibility criteria and review the BV test results from the screening visit. Women with Amsel criteria 
≥3 and Nugent score 4-10 will be randomized and instructed to administer the LACTIN-V or placebo at home 
for 5 consecutive days and then twice weekly for 10 weeks.   
LACTIN-V (or placebo) will be administered at 2 x 109 cfu/dose using a vaginal applicator. Women will 
complete a memory aid to record times of product application, menses, sexual intercourse, concomitant 
medications, condom use and any AEs. Reminders will be sent to women in order to increase adherence with 
all doses and prior to scheduled follow-up visits. Women will complete either a paper or electronic memory 
aid. If the electronic version of the memory aid is utilized by the subject, the study clinic will be alerted of any 
potential AEs reported by the subject for subsequent clinical evaluation, follow-up and reporting as deemed 
necessary. 
Follow-up visits are scheduled 4, 8, 12, and 24 weeks after enrollment. A memory aid to gauge symptoms and 
AEs will be reviewed, a questionnaire to collect clinical, including AEs, data will be administered and a 
pelvic exam will be performed to detect genital tract AEs. Vaginal swabs for wet mount evaluation (Amsel 
criteria) and Gram stain evaluation (Nugent score) will be collected. A vaginal swab for L. crispatus 
(including CTV-05) identification will be collected. Vaginal applicators will be collected at Visits 2, 3, and 4 
and stained with Trypan Blue upon return to the site as a proxy for product use. Telephone interviews will be 
scheduled between the 12 and 24 week visits, at 16 and 20 weeks after enrollment. Table 2 presents the 
schedule of events for each visit. 
The DSMB met on 02JUN2017 after one-third of the 228 subjects completed Study Visit 2 (Week 4) to 
review aggregate safety data for increased rate of occurrence of serious suspected adverse reactions. The 
DSMB will also meet annually to assess safety data on each arm of the study. There are no formal planned 
interim analyses of efficacy. 
4.2. 
Discussion of Study Design, Including the Choice of Control Groups 
This Phase II-b trial is designed to provide a screening evaluation for the hypothesis that, following a 5-day 
course of MetroGel to treat BV, LACTIN-V administered at 2 x 109 cfu/dose using a vaginal applicator 
reduces the 12-week incidence of BV recurrence by ≥50% when compared to placebo. Based on the achieved 
colonization rate of L. crispatus CTV-05 at 2 x 109 cfu/dose of LACTIN-V, coupled with prior data from the 


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Phase II-a clinical trial suggesting that vaginal colonization with L. crispatus CTV-05 was associated with a 
reduced risk of BV recurrence, the next logical step is to perform a larger Phase II-b trial. A placebo is used 
since MetroGel alone is the standard antibiotic treatment. 
4.3. 
Selection of Study Population 
Subjects must meet all the inclusion criteria in order to be eligible to participate in the study: 
1. Capable of reading and writing English and voluntarily provide written informed consent to participate 
in the study and comply with all study procedures 
2. Untreated BV (asymptomatic or symptomatic) as diagnosed during the screening visit defined by >3 
Amsel criteria  
Note: Amsel criteria include the following:  
• Homogeneous, thin, grayish-white discharge that smoothly coats the vaginal walls;  
• Vaginal pH >4.5;  
• Positive whiff-amine test, defined as the presence of a fishy odor when a drop of 10% potassium 
hydroxide (KOH) is added to a sample of vaginal discharge;  
• Presence of clue cells (>20% on microscopy). 
3. Untreated BV (asymptomatic or symptomatic) as confirmed in the laboratory using the Nugent scoring 
system (Nugent Score ≥4) 
4. Otherwise healthy pre-menopausal women 18–45 years of age on the day of screening 
5. Regular predictable menstrual cycles or amenorrheic for at least 3 months due to use of a long-acting 
progestin or continuous use of oral contraceptives 
6. Willing to be asked questions about personal medical health and sexual history 
7. Willing to apply study agent vaginally and comply with study examinations 
8. Agree to abstain from sexual intercourse during the first 5 consecutive days of study product 
administration, 12 hours prior to study visits and for 12 hours after each study product application  
9. Agree to abstain from the use of any other intravaginal product throughout the trial period from the 
time of screening through Visit 7 (Week 24, Day 168)  
Note: Intravaginal products include contraceptive creams such as Gynol II, gels, foams, sponges, 
lubricants not approved by the study investigators, and douches.   Limit use of tampons during 
menstruation to unscented products. 
10. Must be of non-childbearing potential or if of childbearing potential, must agree to use a reliable 
method of birth control for the duration of the study  
Note: Reliable methods of birth control include tubal ligation, male partner with a vasectomy, a 
steroidal contraceptive (oral, patch, injectable or implantable), IUD, condoms or abstinence. 
Subjects meeting any of the following criteria at screening, or when assessed at the enrollment visit, will be 
excluded from the study: 
1. Urogenital infection at screening 


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Note: Urogenital infection includes urinary tract infection, Trichomonas (T.) vaginalis, Neisseria (N.) 
gonorrhoeae, Chlamydia (C.) trachomatis, Treponema (T.) pallidum, or vulvo-vaginal candidiasis.  
2. Diagnosis of two or more outbreaks of N. gonorrhoeae, C. trachomatis, T. pallidum, T. vaginalis, or 
herpes simplex virus (herpes genitalis) within 6 months prior to screening 
3. Positive for syphilis or HIV at screening 
4. Current pregnancy or within 2 months of last pregnancy and/or currently breastfeeding** 
5. Vaginal or systemic antibiotic or antifungal therapy (other than MetroGel given as part of study 
procedures) within 21 days of screening or within 30 days of enrollment**  
6. Use of disulfiram within past 2 weeks or other contraindication to use of MetroGel** 
7. Any condition requiring regular periodic use of systemic antibiotics during participation in the trial 
8. Active genital herpes lesion (if not resolved by enrollment)** 
9. Investigational drug use other than LACTIN-V within 30 days or 10 half-lives of the drug, whichever 
is longer, of enrollment visit**  
10. Other planned participation in an investigational drug study while participating in this study** 
11. Menopause defined as more than 12 consecutive months of amenorrhea without another known cause 
including pregnancy  
12. IUD insertion or removal, pelvic surgery, cervical cryotherapy or cervical laser treatment within the 
last 2 months prior to screening 
13. Use of vaginal ring (eg, NuvaRing) within 3 days of screening or during the course of the study** 
14. Failure to complete 5 days of MetroGel with the last dose taken no later than 48 hours prior to 
randomization*** 
15. Use of new long-acting hormonal treatments. Subject may be enrolled if stable (>3 months) on 
existing therapy as determined by the principal investigator** 
16. Known allergy to any component of LACTIN-V/placebo or MetroGel or to nitroimidazole derivatives 
or latex (condoms) 
17. Any social, medical, or psychiatric condition, including history of drug or alcohol abuse, that in the 
opinion of the investigator would make it unlikely for the subject to comply with the study 
** Note: Criteria will be assessed at screening and enrollment. 
*** Note: Criteria will be assessed at enrollment. 
Subjects may withdraw or be withdrawn for any of the reasons given below.  The reason for withdrawal will 
be recorded on the corresponding data collection form.  
• Subject withdraws consent 
• Pregnancy or breastfeeding 
• Adverse event which requires discontinuation of the treatment regimen or results in inability to 
comply with study procedures 
• 
Discretionary decision by the site investigator  


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• At the discretion of the IRB, FDA, NIH, or other government agencies as part of their duties to 
ensure that research subjects are protected, or the industry supporter or its designee 
• Study is terminated 
Subjects who receive MetroGel, but do not complete the full MetroGel treatment, do not return for the 
Enrollment visit, or are otherwise found ineligible to be randomized to study treatment will not be enrolled 
into the study and will not be followed for safety or for AEs. 
All randomized subjects who are discontinued from receiving further study product will continue to be 
followed through Visit 7 (Week 24, Day 168). 
If withdrawal of consent or study product discontinuation occurs after study treatment is initiated, the subject 
will be asked to continue scheduled study procedures including safety evaluations, if possible, and be given 
appropriate care under medical supervision if symptoms of any AE related to participation in the study are 
continuing.  The subject will be followed until the AE is resolved or until the subject’s condition becomes 
stable. 
Subjects who withdraw their consent for further participation in the study after their study treatment ends or 
discontinue study product early will be reminded of the importance of continuing in the study for safety 
evaluations. Subjects will be encouraged to complete the Early Termination evaluations if they choose not to 
complete the remaining study visits.   
Subjects who enroll in the study but do not return for study visits after a minimum of three attempts to contact 
them over a 2-week period will be considered lost to follow-up. 
4.4. 
Treatments 
4.4.1. 
Treatments Administered  
Each subject will receive one box of MetroGel vaginal gel sufficient for the 5-day course of treatment. 
Women will return to the study clinic within 2 days after completing the 5-day course of MetroGel to re-
evaluate eligibility criteria and review the BV test results from the screening visit. Women with Amsel criteria 
≥3 and Nugent score 4-10 will be randomized.   
Subjects will administer the first dose of LACTIN-V or Placebo under direct supervision by the study 
clinician before leaving the clinic (Day 1). Subjects will be instructed to administer one dose once a day at 
bedtime for the next 4 days (beginning on Day 2), and then two times a week for 10 weeks. The remaining 20 
applicators will be used for the two doses each week during weeks 2 through 11. 
The dates of first treatment are presented for subjects in the Safety population by site in Table 3 and actual 
treatment group in Table 4.  
4.4.2. 
Method of Assigning Subjects to Treatment Groups (Randomization) 
Women will be randomized at the enrollment visit (Visit 1) upon completion of the initial standardized 
antibiotic treatment with 0.75% topical MetroGel.  Enrollment of subjects is done online using the enrollment 
module of AdvantageEDCSM. Subjects are randomly assigned to LACTIN-V or placebo in a 2:1 ratio. The 
study uses a permuted blocked randomization scheme. Permuted block randomization is used to avoid the 
potential for serious imbalance in the number of subjects assigned to each group during the study, an 
imbalance that can occur in the simple randomization procedures.  


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The randomization is prepared by statisticians at the Statistical and Data Coordinating Center (SDCC) and 
included in the enrollment module for the trial. AdvantageEDC assigns each subject to a treatment group after 
the demographic and eligibility data have been entered into the system.  
4.4.3. 
Selection and Timing of Dose for Each Subject 
Subjects will be instructed to administer one dose of MetroGel vaginal gel once a day at bedtime for 5 days, 
initiated as soon as possible (ideally within 5 days of diagnosis at the screening or follow-up visit for 
symptomatic subjects, or within 24 days of the screening visit for asymptomatic subjects). 
Each subject will self-administer a 5-day course of MetroGel, applied vaginally once daily in the evening for 
5 consecutive days. Timing of MetroGel administration will be based on each subject’s menstrual cycle. 
If a subject misses a dose, she may take the missed dose on the sixth day after initiation of MetroGel 
treatment. A second dose may be taken on the seventh day. No more than 2 missed doses may be added. All 5 
doses must be taken within 7 days after initiation of MetroGel treatment. If the duration of MetroGel 
treatment is longer than 5 days, the subject’s enrollment visit may be rescheduled to ensure a 12-48 hour 
interval between completion of MetroGel treatment and the enrollment visit. At the screening visit (Visit 0), 
the woman's menstrual cycle history will be evaluated to ensure regular menstrual cycles (or amenorrhea due 
to long-acting contraceptives). Depending on the timing of her menstrual cycle, the screening procedure will 
be as follows: 
1. If she has just finished her menstrual cycle or is within the first half of her cycle with 12 days or more 
expected until the onset of the next menstrual cycle, (latest screening visit on the 16th day of a regular 
28-day cycle), she will proceed with screening, and will be able to complete screening, the treatment 
course of BV with 5 days of topical metronidazole (MetroGel), the enrollment visit (Visit 1) (in case 
of eligibility confirmed by the laboratory results of the screening visit) within 48 hours of her last 
MetroGel administration, and the 5 days of continuous treatment use starting during the enrollment 
visit. In this case, MetroGel treatment should be started on the evening of the screening visit.  
2. If she is menstruating at the time of the screening visit, she will be asked to reschedule and return for 
the screening visit as soon as possible after her menstrual cycle ends.  
3. If she is in the second half of her cycle with less than 12 days expected before the onset of the next 
menstrual bleeding, she will proceed with screening, but would be instructed to wait until after her 
next period before starting the 5-day course of MetroGel treatment. The screening visit must also be 
timed depending on her availability to return for the enrollment visit within 12-48 hours after the 
termination of the 5-day course of MetroGel.  
MetroGel treatment for women with symptomatic BV needs to be initiated as soon as possible (ideally within 
5 days of diagnosis at the screening visit). For women diagnosed with asymptomatic BV at the screening visit, 
MetroGel needs to be initiated according to her menstrual cycle and within 24 days of the screening visit to 
ensure the time window between screening and enrollment is not more than 30 days. 
Women must start MetroGel treatment on a Sunday, Tuesday, Wednesday, Thursday, Friday or Saturday 
(NOT Monday) in order to return for enrollment within 12-48 hours after the fifth dose of her MetroGel 
treatment on the subsequent weekday, Monday –Friday. See the table below for a summary of the course of 
MetroGel treatment. 


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Subjects will administer the first dose under direct supervision by the study clinician before leaving the clinic 
(Day 1). Subjects will be instructed to administer one dose once a day at bedtime for the next 4 days 
(beginning on Day 2). 
Should the subject forget or is not able to take the study treatment on a day within the 5-day treatment and 
she notices before 8 hours of the next scheduled dose, she is advised to take the missed dose as soon as she 
remembers. If she notices only within 8 hours of the next scheduled dose, she is advised to skip this dose. 
Instead, she will be instructed to apply the missed dose on Day 6 instead. A second missed dose can be taken 
on Day 7. No more than two missed doses can be added after the 5-day study treatment administration. 
The remaining 20 doses will be self-administered twice weekly for 10 weeks (only one dose at bedtime on the 
first day of administration). 
Subjects will choose two fixed days of the week that are 72- 96 hours apart (e.g. Mondays and Thursdays, 
Tuesdays and Fridays, Wednesdays and Saturdays, or Thursdays and Sundays). If the subject cannot 
administer a weekly dose on a scheduled day because of menstruation, she should take the missed dose as 
soon as the menstrual blood flow subsides and return to the schedule for the next dose. If the subject forgets to 
take a weekly dose on a scheduled day, wishes to have sex that particular night, or is away from home, she 
should take the missed dose the next day or as soon as possible and return to the schedule for the next dose. 
If subject is unable to make up all missed doses after Week 11, leftover doses should not be taken and unused 
doses should be returned by the subject.  
If the subject takes more than the required number of doses, she should be provided additional doses to 
continue dosing twice weekly through Week 11. 
The minimum time gap between the applications should be about 48 hours, the maximum time gap 96 hours. 
No dose should be taken for at least 48 hours before each study visit. 
4.4.4. 
Blinding 
At the time of enrollment, the site pharmacist will select the next available box of study product applicators 
(per the kit number on the label of the box) in sequential order and will distribute to blinded study personnel 
with no labels that identify the product or applicators as LACTIN-V or placebo. No blinding procedures are 
required for the MetroGel.   
The site pharmacist, subjects, study personnel who perform study assessments, data entry personnel at the 
sites, and laboratory personnel will be blinded to treatment assignment. 
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The protocol contains no explicit provisions for emergency unblinding. According to DMID policy, the study 
medical monitor responds to requests for emergency unblinding, and instructs the SDCC to release treatment 
codes only if necessary to ensure that the subject receives appropriate clinical care. 
4.4.5. 
Prior and Concomitant Therapy  
The following drugs and procedures are prohibited during the specified time periods as they may affect 
efficacy assessments: 
• Vaginal or systemic antibiotic or antifungal therapy (other than MetroGel given as part of study 
procedures) within 21 days of screening or within 30 days of enrollment; 
• Use of new long-acting hormonal treatments; 
• Investigational drug use other than LACTIN-V within 30 days or 10 half-lives of the drug; 
• Use of disulfiram within past 2 weeks or other contraindication to use of MetroGel; 
• IUD insertion or removal, pelvic surgery, cervical cryotherapy or cervical laser treatment within 
the last 2 months prior to screening 
• Use of vaginal ring (eg, NuvaRing) within 3 days of screening or during the course of the study. 
Prior to unblinding, a blinded case review committee will review subjects with a reported concomitant 
infection/disease/procedure that may interfere with study product, use of concomitant medications or products 
that may interfere with study product, significant protocol deviations, and other events that may impact study 
product effectiveness or study analyses.   
4.4.6. 
Treatment Compliance 
All subjects are to receive a total of 25 doses of study product. The first dose is administered in clinic and the 
remaining doses will be administered by the subject at home. Compliance will be assessed by applicator 
staining of the returned kits. If a kit is not returned, compliance will be assessed by the subject’s self-report on 
the memory aid. See Section 3.3.5 for a definition of treatment compliance. Treatment compliance will be part 
of the review of the blinded case review committee. 
4.5. 
Efficacy and Safety Variables 
For safety and efficacy analyses, multiple observations within specific visit period are accepted. In the case of 
multiple observations within a specific window, the assessment value that is closest to the scheduled visit 
window will be used in the analyses for the post-baseline records. The last observed value prior to 
administration of LACTIN-V or placebo will be used as the baseline value. 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. 
Safety Variables 
Solicited local and systemic events are captured on a memory aid starting on Day 1, the first day of dosing 
daily through Week 1 and then weekly, continuing through Visit 7 (Week 24, Day 168). The subject is to 
record the presence and intensity of solicited events on the memory aid. Any event that is present at the time 
that the subject is screened should be considered as baseline and not reported as a solicited urogenital AE. 
However, if the symptom deteriorates at any time during the study, it is recorded as an AE. If a symptom is 
reported that is not present at baseline, it too is recorded as an AE. Solicited local events include vaginal 
bleeding other than menstruation, abnormal vaginal discharge, abnormal vaginal odor, genital itching, genital 


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burning, external genital irritation, external genital swelling, and genital rash. Solicited systemic events include 
nausea, vomiting, abdominal pain/cramps, diarrhea, constipation, pain/burning with urination, frequent 
urination, blood in urine, and headache. 
Severity of solicited events symptoms are graded according to the tables in Appendix B and Appendix C in the 
protocol. Symptoms not specifically mentioned will be graded using the following scale:  
• Mild:  Events require minimal or no treatment and do not interfere with the subject’s daily 
activities. 
• Moderate:  Events result in a low level of inconvenience or concern with the therapeutic measures. 
Moderate events may cause some interference with functioning. 
• Severe:  Events interrupt a subject’s usual daily activity and may require systemic drug therapy or 
other treatment. Severe events are usually incapacitating. 
Tolerability of LACTIN-V will be measured by identifying subjects who discontinue study product early due 
to adverse events.   
4.5.2. 
Efficacy Variables 
See Section 3.3 for efficacy variable definitions. BV recurrence is the primary efficacy variable.  Amsel 
criteria and Nugent scores will be determined at each follow-up visit to diagnose BV according to the 
definition in Section 3.3.1. BV diagnosis at the screening visit will be used as the baseline BV diagnosis (see 
Section 3.3.2). Vaginal specimens will be analyzed for vaginal colonization with L. crispatus using qPCR 
assays and will be performed by a central laboratory. Concentrations of L. crispatus will be collected and used 
to determine the presence or absence of colonization. Acceptability of LACTIN-V will be measured by 
treatment compliance and responses to the self-administered questionnaire. 


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5. 
SAMPLE SIZE CONSIDERATIONS 
Sample size calculations are based on the assumption of detecting a 50% reduction in the cumulative 
proportion of subjects who experience BV recurrence by 12 weeks post-administration of study product 
among subjects receiving LACTIN-V compared to those receiving placebo in a complete case analysis at the 
0.05 significance level. The proportion of subjects among controls who will experience BV recurrence at 12 
weeks is assumed to be 30%. We assume a LACTIN-V to placebo allocation ratio of 2:1 and 10% of subjects 
drop-out from the Complete Case population.  Given logistical and feasibility constraints on the sample size 
and that this is a Phase II-b trial, which will provide screening evidence about safety and efficacy for a 
subsequent Phase III trial, this trial is powered at the 70% level. Given the assumptions above, a sample size 
of 228 subjects is required to detect a 50% reduction in the cumulative proportion of subjects experiencing 
recurrence in the Complete Case population with 70% power using the Pearson Chi-Square test. 


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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. Wilson confidence intervals for binomial proportions and differences in binomial 
proportions will be computed for efficacy variables.  Blaker confidence intervals for binomial proportions and 
differences in binomial proportions will be computed for safety variables. For the hypothesis tests comparing 
treatment groups with respect to safety outcomes, the two-sided Fisher’s Exact test will be used.  For the 
hypothesis tests comparing treatment groups with respect to efficacy outcomes, the two-sided Chi-Square test 
will be used.  For all tests, a 5% two-sided significance level will be used.  
For all efficacy outcome measures, the Complete Case population (see Section 6.3) will be used as the 
primary analysis population and the Per Protocol, modified Intent-to-Treat, and Intent-to-Treat populations 
will be used as secondary analysis populations.  For all safety analyses, the Safety population will be used as 
the analysis population. 
All summary tables will be structured with a column/sub-table for each treatment group (LACTIN-V, 
Placebo, and All Subjects). In general, all data will be listed by treatment group and/or subject, and when 
appropriate by visit number within subject. The total population size relevant to that table/column if 
applicable, including any missing observations will be displayed in the tables. 
Note that in the data listings, Subject ID is the unique subject identifier, not the Study ID used on study and 
dates will not be included, only Study Day. Study Day 1 will be the day of the first dose of treatment. 
6.1.1. 
Pseudo Code 
The following SAS® pseudo code will be used to calculate the following: 
Chi-Square test at 5% two-sided significance level and odds ratio (and 95% asymptotic CI) from 2x2 table: 
proc freq; 
   
Table treatment*analysis_variable / chisq; 
    
ods output ChiSq=outputdsn1; 
 
ods output RelativeRisks=outputdsn2; 
run; 
Fisher's Exact test at 5% two-sided significance level: 
proc freq; 
   
Table treatment*analysis_variable / exact; 
    
ods output FishersExact=outputdsn; 
run; 
 
95% Wilson CI for proportions/percentages: 
proc freq; 
Table treatment*analysisvariable / binomial(wilson); 
    
ods output binomialcls=outputdsn; 
run; 
 
95% Wilson CI for difference in proportions (produces Newcombe CI): 


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proc freq; 
   
Table treatment*analysisvariable / riskdiff(cl=Wilson); 
   
Exact Riskdiff; 
    
ods output pdiffcls=outputdsn; 
run; 
 
95% Exact Blaker CI for proportions/percentages: 
proc freq; 
Table treatment*analysisvariable / binomial(blaker); 
ods output binomialcls=outputdsn; 
run; 
 
Time to event analysis to estimate number of events, median (and other quartiles) time to event, and Kaplan-
Meier curves: 
 
ods output CensoredSummary =_censorsum Quartiles =_quartiles;  
proc lifetest plots=survival; 
 
time studyday*eventstatus(0); 
 
strata treatment; 
run; 
 
Poisson regression analysis to estimate event rate in each treatment group and rate ratio between treatment 
groups (with associated 95% CIs): 
 
proc genmod; 
class treatment; 
      model eventcount = treatment / dist=poisson link=log offset=logfollowuptime; 
      lsmeans treatment / ilink diff cl; 
run; 
 
Repeated measures logistic regression analysis using Generalized Estimating Equations to estimate odds of 
event in each treatment group and odds ratio between treatment groups (with associated 95% CIs): 
 
proc genmod; 
    
class subjectid treatment other_covariates / param=glm; 
    
model outcome=treatment other_covariates / dist=bin; 
    
repeated subject=subjectid / type=ind/un/exch/ar(1); 
   
lsmeans treatment / ilink exp diff cl; 
run; 
 
Smoothing spline regression with different curves for each treatment group (with 95% confidence bands): 
 
proc transreg; 
model identity(outcome) = class(treatment / zero=none) | spline(day / knots=0 to 
max_day by 1); 
run; 


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6.2. 
Timing of Analyses 
The final analysis will be performed after database lock when all subjects have been followed through Visit 7 
(Week 24), the final study visit, at Day 168 (Window: Days 161-175). 
6.3. 
Analysis Populations 
6.3.1. 
Safety Analyses 
All safety analyses will be performed in the safety analysis population.  The safety population includes all 
randomized subjects who received at least one dose of study product. In the unlikely event of an error in 
randomization or study product administration (i.e., incorrect product), subjects will be grouped by the 
product they actually received. 
6.3.2. 
Efficacy Analyses 
All efficacy analyses will be performed in the Intent-to-Treat, Modified Intent-to-Treat, Complete Case, and 
Per Protocol analysis populations.  For analyses of cumulative BV recurrence at Visit 4 or Visit 7 in all 
efficacy populations, subjects who withdraw or are withdrawn from study participation prior to the visit of 
interest and the reason for withdrawal recorded on the CRF is lack of treatment effect are included in the 
analysis population as experiencing recurrent BV at the point in time of the withdrawal. Likewise, for 
analyses of cumulative BV recurrence at Visit 4 or Visit 7 in all efficacy populations, subjects who 
discontinue study product prior to the visit of interest and the reason for discontinuation recorded on the CRF 
is lack of treatment effect or begin other treatment for BV prior to the visit of interest are included in the 
analysis population as experiencing recurrent BV at the point in time of the discontinuation or commencement 
of the other treatment. 
See Section 6.5 for the imputation methods that will be used in the efficacy analyses. 
6.3.2.1. 
Intent-to-Treat Analysis (ITT) Population 
The ITT analysis population includes all randomized subjects, regardless of whether they received study 
treatment or were compliant with the administration procedures or schedule. In the unlikely event of an error 
in randomization or study product administration (i.e., incorrect product), subjects will be grouped by their 
intended randomized assignment. 
6.3.2.2. 
Modified Intent-to-Treat (mITT) Population 
The mITT population includes all randomized subjects who did not have any concomitant vaginal or cervical 
infections at screening or enrollment, received at least one dose of study product, and returned for at least one 
post-baseline visit prior to or including the visit of interest. In the unlikely event of an error in randomization 
or study product administration (i.e., incorrect product), subjects will be grouped by their intended 
randomized assignment. 
Note this differs from what is stated in Section 11.6.2 of the protocol. See Section 13 for more details. 
For efficacy analyses at Visit 4 (Week 12), subjects who discontinue prior to Visit 4, as well as subjects with a 
missing or non-evaluable Amsel or Nugent result at Visit 4 with no positive result at another visit, are 
included in the mITT population using imputation methods noted in Section 6.5. 


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For efficacy analyses at Visit 7 (Week 24), subjects who discontinue prior to Visit 7, as well as subjects with a 
missing or non-evaluable Amsel or Nugent result at Visit 7 with no positive result at another visit, are 
included in the mITT population using imputation methods noted in Section 6.5. 
6.3.2.3. 
Complete Case (CC) Population 
For efficacy analyses at Visit 4 (Week 12), the CC population includes all subjects who did not have any 
concomitant vaginal or cervical infections at screening or enrollment, received study product, and were 
followed up until the first diagnosis of BV or through Visit 4 (Week 12).   
Note this differs from what is stated in Section 11.6.2 of the protocol. See Section 13 for more details. 
For efficacy analyses at Visit 7 (Week 24), the CC population includes all subjects who did not have any 
concomitant vaginal or cervical infections at screening or enrollment, received study product, and were 
followed up until the first diagnosis of BV or through Visit 7 (Week 24).   
In the unlikely event of an error in randomization or study product administration (i.e., incorrect product), 
subjects will be grouped by the product they actually received. 
Subjects who terminate early prior to the visit of interest for reasons other than lack of treatment effect with 
no positive result at another visit, as well as subjects with a missing or non-evaluable Amsel or Nugent result 
with no positive result at another visit, are excluded from the CC population. 
6.3.2.4. 
Per Protocol (PP) Population 
For the analyses at Visit 4 (Week 12), the PP population includes all randomized subjects who met all 
inclusion/exclusion criteria at enrollment, complied with the assigned study product, and were followed up 
until the first diagnosis of BV or through Visit 4 (Week 12).  
For the analyses at Visit 7 (Week 24), the PP population includes all randomized subjects who met all 
inclusion/exclusion criteria at enrollment, complied with the assigned study product, and were followed up 
until the first diagnosis of BV or through Visit 7 (Week 24).  
In the unlikely event of an error in randomization or study product administration (i.e., incorrect product), 
subjects will be grouped by the product they actually received. 
Subjects who terminate early prior to the visit of interest for reasons other than lack of treatment effect with 
no positive result at another visit, as well as subjects with a missing or non-evaluable Amsel or Nugent result 
with no positive result at another visit, are excluded from the PP population. 
6.3.2.5. 
Blinded Review of Efficacy Analysis Population Eligibilities 
Prior to unblinding, a blinded case review committee will review subjects with a reported concomitant 
infection/disease/procedure that may interfere with study product, use of concomitant medications or products 
that may interfere with study product, significant protocol deviations, and other events that may impact study 
product effectiveness or study analyses. On a case-by-case basis, the case review committee will determine if 
each subject will be included in the various efficacy analysis populations, if and when a subject should be 
censored or removed from any analyses, and/or any other analytical requirements for the subject. The 
committee will be blinded to both treatment assignment as well as BV outcome status. The protocol denotes 
that the committee will only review subjects for inclusion into the PP population, however all efficacy 
populations will be considered. 


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6.3.2.6. 
Analysis Population Summaries 
Table 5 summarizes the ITT and mITT analysis population eligibilities by randomized treatment group and 
reasons excluded. Table 6 summarizes the Safety, CC, and PP analysis population eligibilities by actual 
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 
“Excluded from…” counts may be less than the sum of the individual reason counts. A listing of the subjects 
excluded from each of the analysis populations and the reasons for exclusion will be provided (Listing 1). A 
listing of subjects whose assigned treatment group does not match their randomized treatment group will be 
provided in Listing 2. 
6.4. 
Covariates and Subgroups 
The protocol does not define any formal subgroup hypothesis tests, and the study is not adequately powered to 
perform formal subgroup hypothesis testing.  However, safety and enrollment summaries will be presented by 
clinical site. In addition, summaries of colonization will be presented by subgroups defined by menses and 
sexual intercourse variables (see Section 8.2). 
6.5. 
Missing Data 
The primary efficacy outcome measure of BV recurrence will be assessed in the CC population. Use of the 
mITT population has previously been recommended by the FDA where missing values from subjects who 
drop out early are imputed using Last Observation Carried Forward (LOCF) [6]. However, this includes 
subjects who dropped out after completing at least one-follow-up visit, and/or before their first positive 
diagnosis.  LOCF would classify such subjects as ‘not recurrent.’ Thus, it is possible that the estimated 
proportions of treatment successes in a study arm could, in reality, be larger than expected. Thus, LOCF could 
result in an over-optimistic estimate of treatment effect, conflicting with the following rational for using an 
ITT analysis population stated in ICH E9 [7]: “[ITT analysis] tends to avoid over-optimistic estimates of 
efficacy resulting from a per protocol analysis, since the non-compliers included in the [ITT] analysis set will 
generally diminish the estimated treatment effect.” In addition, simulation studies suggest that CC analysis 
leads to slightly less biased estimates of the difference in cure proportions (LACTIN-V vs. placebo) compared 
to the mITT analysis using LOCF. 
To assess the effect of the choice of analysis population on the primary analysis, the analysis will be repeated 
as a secondary analysis in the ITT, mITT, and PP populations.  The following imputation methods will be 
used for BV recurrence by Visit 4 and BV recurrence by Visit 7 in the ITT and mITT populations: 
• LOCF 
• Worst-Case Scenario – impute missing/unevaluable values in the LACTIN-V group as treatment 
failures and missing values in the Placebo group as treatment successes. 
For summaries of recurrence in “by study day” displays, missing data will not be imputed. 
For the secondary analyses of successful L. crispatus colonization by Visit 4 and by Visit 7, missing or 
unevaluable colonization data at a visit will imputed as unsuccessful colonization. For summaries of 
colonization in “by study day” displays, missing data will not be imputed. 
6.6. 
Interim Analyses and Data Monitoring 
The study is monitored to determine if any of the safety halting rules are met. 


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1. One or more subjects experience a treatment-related SAE. 
2. Two or more subjects experience treatment-related vulvar and/or vaginal ulceration, abscess, or 
necrosis.  
3. Four or more subjects experience a treatment-related severe (Grade 3) systemic adverse event.  
4. An overall pattern of symptomatic, clinical, or laboratory events that the DMID, medical monitor, or 
DSMB consider associated with study product and that may collectively represent a serious potential 
concern for safety. 
If any of the halting rules are met, the study will not continue with the remaining enrollments or study 
treatments without a review by and recommendation from the DSMB to proceed. A summary of halting rules 
is provided in Table 7. 
The DSMB met to review aggregate safety data on 02JUN2017 after one third of the 228 subjects completed 
Study Visit 2 (Week 4). The DSMB may also review study progress and subject safety data at other specified 
times during the course of the study and hold a study closeout meeting, as defined in the DSMB Charter.  No 
interim analyses of efficacy data are planned and this Statistical Analysis Plan does not cover the interim safety 
analyses. 
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. See Sections 8 and 
9 for more details. 
6.8. 
Multiple Comparisons/Multiplicity 
As this trial is designed to provide screening evidence about safety and efficacy for a subsequent Phase III 
trial and is not a confirmatory trial, no adjustments for multiplicity are planned. 


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7. 
STUDY SUBJECTS 
7.1. 
Disposition of Subjects 
The disposition of subjects in the study will be tabulated by randomized treatment group and all subjects. 
Table 8 shows the number of subjects who are screen failures and the number of subjects that met each 
inclusion/exclusion criterion. The number of enrolled subjects in the study completing study milestones will 
be tabulated separately by randomized treatment group. Table 9 shows the total number of subjects enrolled, 
randomized, treated, complying with treatment, and completing each visit (Visit 1 through Visit 7). A listing 
of subjects who completed the study, terminated early from study, or discontinued treatment and the reason 
for early termination or treatment discontinuation is included in Listing 3. 
Figure 1 is a flowchart showing the disposition of study subjects in the safety and efficacy analyses, adapted 
from the CONSORT statement. It shows the number of subjects eligible, enrolled and randomized, lost to 
follow-up, and analyzed for the safety and efficacy analyses, overall and by treatment group. 
7.2. 
Protocol Deviations 
A summary of subject-specific protocol deviations will be presented by the deviation category, the type of 
deviation, and randomized treatment group for all enrolled subjects (Table 10). All subject-specific protocol 
deviations and non-subject-specific protocol deviations will be included in Appendix III as data listings 
(Listing 4 and Listing 5, respectively). 


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8. 
EFFICACY EVALUATION 
8.1. 
Primary Efficacy Analysis 
For the primary analysis, the cumulative proportion of BV recurrence by Visit 4 (Week 12) will be 
summarized by treatment group. A formal hypothesis test will be performed with null hypothesis that the 
cumulative proportion of BV recurrence by Visit 4 (Week 12) in the LACTIN-V group is equal to that in the 
placebo group and alternative hypothesis that they are not equal. Cumulative proportion of BV recurrence is 
defined as follows: the numerator is the number of subjects who experience recurrence at least once through 
Visit 4 in the particular analysis population and the denominator is the number of subjects included in the 
particular analysis population. Table 11 will present the cumulative proportion of BV recurrence by Visit 4 
(Week 12) (and 95% Wilson confidence interval) in each treatment group along with the odds ratio of BV 
recurrence proportions between treatment groups (and 95% asymptotic confidence interval). The p-value from 
the Chi-Square test will be presented. The summaries will be calculated in the ITT, mITT, CC, and PP 
populations, where the ITT and mITT summaries will be replicated using the imputation methods described in 
Section 6.5. Listing 6 will present individual efficacy data for all subjects. 
8.2. 
Secondary Efficacy Analyses 
Table 12 will present the cumulative proportion of BV recurrence by Visit 7 (Week 24) (and 95% Wilson 
confidence interval) in each treatment group along with the odds ratio of BV recurrence proportions between 
treatment groups (and 95% asymptotic confidence interval). A formal hypothesis test will be performed with 
null hypothesis that the cumulative proportion of BV recurrence by Visit 7 (Week 24) in the LACTIN-V 
group is equal to that in the placebo group and alternative hypothesis that they are not equal.  The p-value 
from the Chi-Square test will be presented. The summaries will be calculated in the ITT, mITT, CC, and PP 
populations, where the ITT and mITT summaries will be replicated using the imputation methods described in 
Section 6.5. Table 13, Table 14, Table 15, and Table 16 will present BV recurrence by study visit (Day 28, 
56, 86, and 168). For the by-visit summaries, the proportions of subjects with BV recurrence at a visit is 
defined as follows: the numerator is the number of subjects who experience recurrence at the particular visit 
and the denominator of the proportion of subjects with BV recurrence is the number of subjects in the analysis 
population who returned for the visit. The 95% Wilson confidence interval for the proportion in each 
treatment group along with the odds ratio of BV recurrence proportions between treatment groups (and 95% 
asymptotic confidence interval) and the p-value from the Chi-Square test will also be presented. 
As an additional analysis of the outcome measures of BV recurrence by Visit 4 and by Visit 7, the median 
time to BV recurrence (from randomization) will be estimated by treatment group using Kaplan-Meier 
estimates (Table 17 and Table 18). In addition, the median 95% confidence interval, minimum, first quartile, 
third quartile, and maximum estimates of time to BV recurrence will be presented.  For subjects who 
experience BV recurrence by Visit 4 (Week 12), 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 subjects without BV recurrence at or before Visit 4, the BV recurrence endpoint will be coded as 
censored, with time to recurrence defined as the elapsed time from the first dose of study product, to the Visit 
4 time point, or to the first occurrence of loss to follow-up or the time-point at which the subject became 
ineligible for the particular analysis population. Time to BV recurrence by Visit 7 (Week 24) will be defined 
similarly. The analyses will be performed in the ITT, mITT, CC, and PP populations, where the ITT and 
mITT summaries will be replicated using the imputation methods described in Section 6.5. Kaplan-Meier 
curves for BV recurrence will also be generated for each analysis population by Visit 4 (Week 12) and by 
Visit 7 (Week 24), respectively (Figure 2 and Figure 3). 


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As a sensitivity analysis of the outcome measures of BV recurrence by Visit 4 and by Visit 7, the cumulative 
proportion of BV recurrence analyses will be repeated in the mITT and CC populations after removing the 
subjects who received additional treatment for BV as documented in the concomitant medications CRF after 
the beginning of administration of LACTIN-V or placebo and before Visit 4 and before Visit 7, respectively 
(Table 19 and Table 20). 
Table 21 will present the proportion of subjects who experience successful L. crispatus colonization at any 
time post-baseline through Visit 4 (Week 12) (and 95% Wilson confidence interval) in each treatment group 
along with the odds ratio of L. crispatus colonization (and 95% asymptotic confidence interval). A formal 
hypothesis test will be performed with null hypothesis that the proportion subjects who experience successful 
L. crispatus colonization through Visit 4 (Week 12) in the LACTIN-V group is equal to that in the placebo 
group and alternative hypothesis that they are not equal. The p-value from the Chi-Square test will be 
presented.  The analyses will be performed in the ITT, mITT, CC, and PP populations, where the ITT and 
mITT summaries will use the imputation methods described in Section 6.5. Table 22 presents the same 
summaries for successful L. crispatus colonization at Visit 7 (Week 24). Table 23, Table 24, Table 25, and 
Table 26 present L. crispatus colonization by study visit (and 95% Wilson confidence interval) in each 
treatment group along with the odds ratio of L. crispatus colonization (and 95% asymptotic confidence 
interval). A formal hypothesis test will be performed with null hypothesis that the proportion of subjects who 
experience successful L. crispatus colonization through each visit in the LACTIN-V group is equal to that in 
the placebo group and alternative hypothesis that they are not equal. The p-value from the Chi-Square test will 
be presented. Table 27, Table 28, Table 29, and Table 30 presents summary statistics of the concentration of 
L. crispatus CTV-05 by study visit.   
Table 31, Table 32, Table 33, and Table 34 will present L. crispatus colonization by study day, treatment 
group, and number of condom-less sexual intercourse acts for each analysis population. The proportion of 
subjects with colonization along with the 95% Wilson confidence intervals will also be presented. Number of 
condom-less sexual intercourse acts will be broken up by quartiles from data obtained from the sexual history 
interview. If the distribution of sexual intercourse acts is such that the use of quartiles does not lead to distinct 
intervals of values, other cutpoints will be examined (e.g. tertiles, above/below median). Figure 10, Figure 11, 
Figure 12, and Figure 13 will present L. crispatus CTV-05 concentration by study visit, treatment group, 
number of condom-less sexual intercourse acts, and analysis population. 
Table 35, Table 36, Table 37, and Table 38 will present L. crispatus colonization by study day, treatment 
group, and number of partners for each analysis population. Number of partners will be categorized as “No 
partners,” “1 Partner,” and “>1 Partner” from data obtained from the sexual history interview. Depending on 
the distribution of number of partners, other cutpoints may be examined. Figure 14, Figure 15, Figure 16, and 
Figure 17 will present L. crispatus CTV-05 concentration by study visit, treatment group, number of partners, 
and analysis population. 
Summaries of days since last dose (mean, median, standard deviation, range) will be presented by L. crispatus 
colonization status will be presented in Table 39, Table 40, Table 41, and Table 42. L. cripastus CTV-05 
concentration and time since last dose will be presented graphically for each visit, treatment group, and 
analysis population in Figure 6, Figure 7, Figure 8, and Figure 9. A smoothing spline regression model will be 
fit with treatment group as an independent variable. The fitted curves with 95% confidence bans will be 
included in the figures. Model fit and inference of the parameters will be commented on in the final report but 
not included in a table. 
L. crispatus colonization will be presented by treatment compliance status in Table 43, Table 44, and 
Table 45. Treatment compliance will be categorized as “Compliant” or “Not compliant,” and will be assessed 
from the start of treatment administration up until the visit listed. See Section 9.2 for measurements of 


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treatment compliance. Box plots of L. crispatus CTV-05 concentration by treatment compliance status are 
provided for each treatment group, visit, and analysis population in Figure 18, Figure 19, and Figure 20.  
Summaries of days since the last day of the last menstrual period (mean, median, standard deviation, range) 
by L. crispatus colonization status will be presented in Table 46, Table 47, Table 48, and Table 49. 
Occurrence of menses will be captured on the memory aid. L. cripastus CTV-05 concentration and time since 
last day of the last menstrual period will be presented graphically for each visit, treatment group, and analysis 
population in Figure 21, Figure 22, Figure 23, and Figure 24. A smoothing spline regression model will be fit 
with treatment group as an independent variable.  The fitted curves with 95% confidence bans will be 
included in the figures. Model fit and inference of the parameters will be commented on in the final report but 
not included in a table. 
L. crispatus colonization will be also be presented by occurrence of menses after the last dose taken in 
Table 50, Table 51, Table 52, and Table 53. Subjects will be categorized as menstruating after their last dose 
taken before the visit presented, or not menstruating after the last dose taken before the specified visit. If there 
are less than three subjects in either treatment group who had menses since their last dose for a specified visit, 
that visit will be excluded from the table. Box plots of L. crispatus CTV-05 concentration by occurrence of 
menses are provided for each treatment group, visit, and analysis population in Figure 25, Figure 26, 
Figure 27, and Figure 28.  
For all by-visit summaries, the proportions of subjects with colonization at a visit is defined as follows:  the 
numerator is the number of subjects who experience recurrence at the specified visit and the denominator of 
the proportion of subjects with BV recurrence is the number of subjects in the analysis population and 
subgroup who returned for that visit. 
As an additional analysis of the colonization analyses, the median time to colonization (from randomization) 
will be estimated by treatment group using Kaplan-Meier estimates (Table 54). In addition, the median 95% 
confidence interval, minimum, first quartile, third quartile, and maximum Kaplan-Meier estimates of time to 
BV recurrence will be presented.  For subjects who experience colonization by Visit 4 (Week 12), the time of 
colonization will be defined as the midpoint between the earliest time point of colonization (post-baseline) 
and the previous observed time point. For subjects without colonization at or before Visit 4, the colonization 
endpoint will be coded as censored, with time to colonization defined as the elapsed time from the first dose 
of study product, to the Visit 4 time point, or to the first occurrence of loss to follow-up or the time-point at 
which the subject became ineligible for the particular analysis population. Time to colonization by Visit 7 
(Week 24) will be defined similarly.  Kaplan-Meier curves for colonization will also be generated (Figure 4 
and Figure 5). 
Table 55 will present the proportion of subjects who were compliant (See Section 3.3.5) with the dose 
regimen through their first BV recurrence or through Visit 4 (Week 12) (and 95% Wilson confidence interval) 
in each treatment group with difference in compliance proportions between treatment groups (and 95% 
Wilson confidence interval). The summaries will be presented in the ITT, mITT, and CC populations. The p-
value from the Chi-Square test will also be presented. Table 56, Table 57, Table 58, Table 59, Table 60, 
Table 61, and Table 62 will present summaries of product administration via subject report, returned 
applicators, and staining for each week. Summaries will be presented by clinical site and treatment group.  
Listing 7 and Listing 8 will present individual dosing data. 
The responses to the acceptability questionnaire at screening and at Visit 4 (Week 12) will be summarized by 
treatment group. For categorical responses, the proportion of subjects with the particular response and its 
associated 95% Wilson confidence interval will be used (Table 63 and Table 64). For continuous or discrete 
responses, the mean, standard deviation, median, and range of responses will be used (Table 65 and Table 66). 


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The analyses will be performed in the ITT, mITT, CC, and PP populations. Individual responses will be 
included in Listing 9. 
8.3. 
Exploratory Efficacy Analyses 
A Poisson regression model will be fit to estimate the rate of positive BV diagnoses through Visit 4 (Week 
12) in each of the treatment arms and to compare the rate in the LACTIN-V arm to that in the placebo arm.  
The outcome of the model will be the number of positive BV diagnosis after enrollment and through Visit 4 
and the model will include a covariate for treatment group and an offset term of log(follow-up time).  The 
offset is included in the model as not all subjects will be followed up through Visit 4 (e.g. subjects who are 
lost to follow-up prior to Visit 4) and so subjects will have variable follow-up times. The follow-up time 
variable in the model will be the elapsed time (in days) from randomization to the earliest of the following: 
Visit 4 date, date of censoring from the particular analysis population, or the termination date. Table 67 will 
present the treatment group-specific rates of BV (and 95% confidence interval) along with the rate ratio 
between treatment groups (and 95% confidence interval). 
A repeated measures logistic regression model will be fit to estimate the odds of a positive BV diagnosis 
through Visit 4 (Week 12) in each of the treatment arms and to compare the odds of a BV diagnosis in the 
LACTIN-V arm to that in the placebo arm. The marginal model to be used will have covariates for treatment 
group, time, and a treatment by time interaction, i.e. the model is of the form: 
𝑔𝑔(𝐸𝐸[𝑌𝑌𝑖𝑖𝑖𝑖]) = 𝛽𝛽0 + 𝛿𝛿𝑖𝑖𝛽𝛽1 + 𝑡𝑡𝑖𝑖𝑖𝑖𝛽𝛽2 + 𝛿𝛿𝑖𝑖𝑡𝑡𝑖𝑖𝑖𝑖𝛽𝛽3 + 𝜖𝜖𝑖𝑖𝑖𝑖  
 
where g(.) is the logit function, 𝑌𝑌𝑖𝑖𝑗𝑗 is the BV diagnosis status of subject i at visit j, 𝛿𝛿𝑖𝑖 is the indicator function 
for the treatment group of subject i (𝛿𝛿𝑖𝑖= 1 for LACTIN-V and 𝛿𝛿𝑖𝑖= 0 for Placebo), and 𝑡𝑡𝑖𝑖𝑖𝑖 is time (in study 
days) at which visit j occurred for subject i. The visits included in the model will be Visit 2 (Week 4) through 
Visit 4 (Week 12) and each subject will be included from the time of the first administration of study product 
to the earliest of the following: Visit 4 date, date of exclusion from the particular analysis population, or the 
termination date. Generalized Estimating Equations will be used to fit the model and estimate its parameters. 
The following working correlation structures will be explored for the assumed covariance among responses 
within a subject: independent, exchangeable, unstructured, and first-order autoregressive. Model estimates 
will be compared informally to assess robustness of the estimates with respect to choice of correlation 
structure. QIC will be also be used to assess model fit with regard to the correlation structure. The model with 
the lowest QIC will be reported.  If inferential differences between the models, this will be noted in the CSR. 
Table 68 will present the treatment group-specific odds of BV (and 95% confidence interval) along with the 
odds ratio between treatment groups (and 95% confidence interval). 
Select outcome measures will be further broken down by race as an exploratory analysis. Race will be 
categorized as Black/African American, White, and Other. The following summaries will be generated: 
• BV recurrence by Visit 4 (Week 12) by analysis population, treatment group, and race (Table 69). 
Analyses will follow those for Table 11. 
• BV recurrence by Visit 7 (Week 24) by analysis population, treatment group, and race (Table 70). 
Analysis will follow those for Table 12. 
• L. crispatus colonization through Visit 4 (Week 12) by analysis population, treatment group, and race 
(Table 71). Analysis will follow those for Table 21. 


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• L. crispatus colonization at Visit 7 (Week 24) by analysis population, treatment group, and race 
(Table 72). Analyses will follow those for Table 22. 
• L. crispatus CTV-05 concentration by study day, treatment group, and race (Table 73, Table 74, 
Table 75, and Table 76). Analysis will follow those for Tables 27 – 30. 
Additional summaies of the L. crispatus colonization and CTV-05 concentration will be generated as 
exploratory analyses.  Figures of CTV-05 concentration by L. crispatus concentration will be generated for 
each treatment group and study day (Figure 29, Figure 30, Figure 31, and Figure 32). CTV-05 concentration 
and L. crispatus colonization will be further broken down by Amsel criteria and Nugent score. Summaries L. 
crispatus colonization (Yes/No) will be presented by Amsel criteria status (Positive/Negative) (Table 77, 
Table 78, Table 79, and Table 80) and Nugent score category (Normal/Indeterminate/BV) (Table 81, 
Table 82, Table 83, and Table 84), following the analyses for Tables 23 - 26. See Section 3.3.1 for Amsel 
criteria and Nugent score category definitions. Similar summaries will be generated for L. crispatus CTV-05 
concentration (Table 85, Table 86, Table 87, Table 88, Table 89, Table 90, and Table 91). Boxplots of L. 
crispatus CTV-05 concentration by Amsel Criteria/Nugent Score will be generated for each treatment group 
and study day (Figure 33, Figure 34, Figure 35, Figure 36, Figure 37, Figure 38, Figure 39, and Figure 40 ). 
Listing 6 will provide a listing individual efficacy data. 


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9. 
SAFETY EVALUATION 
9.1. 
Demographic and Other Baseline Characteristics 
Demographic and other baseline characteristics will be summarized for all randomized subjects (ITT 
population). Ethnicity and race will be summarized by site (Table 92) and by randomized treatment group 
(Table 93). Ethnicity is categorized as Hispanic or Latino, or Not Hispanic or Latino. Race is categorized as 
American Indian or Alaska Native, Asian, Native Hawaiian or Other Pacific Islander, Black or African 
American, White, Multi-Racial, or Unknown 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. Age will be summarized by site 
(Table 94) and by randomized treatment (Table 95).  
Baseline sexual history will be summarized for all randomized subjects (ITT population). Categorical sexual 
history questions will be summarized by treatment group (Table 96) and continuous sexual history questions 
will be summarized by treatment group (Table 97). 
Individual subject listings will be presented for all demographics, baseline and follow-up sexual history, and 
baseline pregnancy history (Listing 10, Listing 11, Listing 12, Listing 13, Listing 14, and Listing 15). 
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 20.1 or higher. Summaries of subjects’ pre-existing and concurrent medical conditions will 
be presented by randomized treatment group for all sites and by each site in the ITT population (Table 98, 
Table 99, Table 100, Table 101, and Table 102). 
Individual subject listings will be presented for all medical conditions (Listing 16). 
9.1.2. 
 Prior and Concomitant Medications  
Summaries of medications that were started prior to dosing and continuing at the time of dosing as well as 
medications that were starting during dosing or during follow up will be presented by WHO Drug Anatomical 
codes (ATC) Level 1 and Level 2 and actual treatment group for subjects in the Safety population (Table 103, 
Table 104, Table 105, Table 106, and Table 107). 
Individual subject listings will be presented for all concomitant medications (Listing 17). 
9.2. 
Measurements of Treatment Compliance 
All subjects are to receive a total of 25 doses of study product. The first dose is administered in clinic and the 
remaining doses will be administered by the subject at home. See Section 3.3.5 for the definition of 
compliance that will be used for analyses. 
The number of subjects not compliant with study treatment will be presented by treatment group as part of the 
subject disposition table (Table 6). Treatment compliance is also a secondary outcome measure of the study; 
analyses and summaries are described in Section 8.2. 
9.3. 
Adverse Events 
When calculating the incidence of adverse events (i.e., on a per subject basis), each subject will only be 
counted once and any repetitions of adverse events within a subject will be ignored; the denominator will be 
the total safety population using the actual treatment group. All adverse events reported will be included in the 


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summaries and analyses. All analyses in Section 9.3 will be performed in the safety analysis population using 
the actual treatment received. 
9.3.1. 
Solicited Events and Symptoms 
Solicited local and systemic events will be captured on a memory aid starting on Day 1, the first day of 
therapy continuing through Visit 7 (Week 24, Day 168) and graded on a scale of 0 (absent), 1 (mild), 2 
(moderate) and 3 (severe). Solicited local events include vaginal bleeding other than menstruation, abnormal 
vaginal discharge, abnormal vaginal odor, genital itching, genital burning, external genital irritation, external 
genital swelling, and genital rash. Solicited systemic events include nausea, vomiting, abdominal pain/cramps, 
diarrhea, constipation, pain/burning with urination, frequent urination, blood in urine, and headache. 
Any symptom that is present at the time that the subject is screened or enrolled should be considered as 
baseline and not reported as a solicited AE. However, if it deteriorates at any time during the study, it will be 
recorded as a solicited AE. If a symptom is reported that was not present at baseline, it will also be recorded 
as a solicited AE. Treatment-emergent solicited adverse events will be identified by comparing the severity of 
the baseline solicited symptoms with the severity of the post-baseline solicited symptoms. If the severity 
increases post-baseline or the symptoms appear post-baseline when it was 'None' at baseline, then the 
symptom will be considered to be treatment-emergent. 
The number and percent of subjects reporting at least one treatment-emergent solicited adverse event will be 
summarized for each solicited adverse event and any solicited adverse event along with the 95% Blaker CI 
and presented in Table 108. Section 6.1 provides pseudo SAS code to use for calculating confidence intervals. 
For each treatment-emergent solicited adverse event, the maximum severity over 24 weeks after the first dose 
will be summarized for the Safety population. The number and percentage of subjects reporting each solicited 
adverse event will be summarized by the maximum severity and actual treatment group along with the 95% 
Blaker CIs. For each event, the denominator is the number of subjects with non-missing data for the solicited 
adverse event being summarized. See Table 109, Table 110, Table 111, and Table 112 and Figure 41 and 
Figure 42.  
The number of subjects reporting a solicited symptom will be summarized for each week for all subjects and 
separately for each treatment group (Table 113, Table 114, Table 115, Table 116, Table 117, Table 118, 
Table 119, Table 120, Table 121, Table 122, Table 123, and Table 124) and graphically in a bar chart 
(Figure 43 and Figure 44).  
Solicited symptoms by subject will be presented in Listing 18 and Listing 19. 
9.3.2. 
Unsolicited Adverse Events 
The primary safety endpoint is the proportion of subjects reporting product-related AEs and SAEs in each 
study arm following the first dose of study product through Visit 7 (Week 24, Day 168). The number of 
subjects, the proportion of subjects who experienced unsolicited AEs and SAEs following the first dose of the 
study product through Visit 7 (Week 24, Day 168), and the 95% Blaker CIs for the proportion of subjects who 
experienced unsolicited AEs and SAEs related to study product through Visit 7 will be presented for the 
safety population and actual treatment group. In addition, the difference in proportions between the LACTIN-
V arm and the Placebo arm and 95% Blaker CIs will be presented in Table 125. The proportion of subjects in 
each treatment group who experience product-related AEs following the first dose of the study product through 
Visit 7 (Week 24 Day 168) will be tested using a Fisher’s exact test at the 5% two-sided level of significance 
level without adjustment for multiplicity in the safety analysis population. See Section 6.1 for pseudocode for 
calculating p-values and CIs. 


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The proportion of subjects reporting at least one unsolicited adverse event will be summarized by MedDRA 
system organ class and preferred term for all subjects and each actual treatment group. Denominators for 
percentages are the number of subjects who received the study product being summarized. A 95% Blaker CI 
will be presented for each MedDRA system organ class and preferred term (Table 126). Adverse events by 
subject will be presented in Listing 20. 
The following summaries for unsolicited adverse events will be presented by MedDRA system organ class, 
preferred term, and treatment group: 
• Incidence and percentage of subjects by maximum severity and maximum relationship to study 
product, including Frequency (Event level) of events for all subjects and by actual treatment received 
(Table 127 and Table 128); 
• The number of adverse events occurring in 5% of subjects in any treatment group will be presented by 
MedDRA system organ class, preferred term, and treatment group in Table 129; 
• The number of subjects reporting adverse events occurring in 5% of subjects in any treatment group 
will be presented by MedDRA system organ class, preferred term and treatment group in Table 130; 
• Subject listing of non-serious adverse events of moderate or greater severity (Table 131); 
• Bar chart of total frequency of adverse events by severity and MedDRA system organ class 
(Figure 45); 
• Bar chart of subject incidence of adverse events by severity and MedDRA system organ class 
(Figure 46); 
• Bar chart of total frequency of adverse events by relationship to study product and MedDRA system 
organ class (Figure 47); 
• Bar chart of subject incidence of adverse events by relationship to study product and MedDRA system 
organ class (Figure 48). 
9.4. 
Deaths, Serious Adverse Events and other Significant Adverse Events 
The primary safety endpoint is the proportion of subjects reporting product-related AEs and SAEs in each 
study arm following the first dose of study product through Visit 7 (Week 24, Day 168). The number of 
subjects, the proportion of subjects who experienced product-related AEs and SAEs, and the 95% Blaker 
confidence interval for the proportion of subjects who experienced product-related SAEs will be presented for 
each analysis population, actual treatment group, and study visit. In addition, the difference in proportions 
between the LACTIN-V arm and the Placebo arm and 95% Blaker confidence intervals will be presented. As 
noted in Section 9.3.2, the proportion of subjects in each treatment group who experience product-related AEs 
and SAEs following the first dose of the study product through Visit 7 (Week 24 Day 168) will be tested using 
a Fisher’s exact test at the 5% two-sided level of significance level without adjustment for multiplicity in the 
safety analysis population (Table 125). See Section 6.1 for pseudocode for calculating p-values and CIs. 
A listing of deaths and serious adverse events will be presented, which will include Subject ID, treatment 
group, Adverse Event Description, Study Day the Event became Serious, Reason Reported as an SAE, 
Relationship to Treatment, Alternate Etiology if Not Related, Outcome, and Duration of Event in days 
(Table 132). 


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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 21, 
Listing 22, Listing 23, Listing 24, and Listing 25). 
9.6. 
Clinical Laboratory Evaluations 
Various clinical laboratory parameters are collected during follow-up, if indicated.  The evaluations are: clean 
catch urine dipstick, urinalysis, rapid urine βhCG pregnancy test, HIV and syphilis serology, and vaginal 
swab for N. gonorrhoeae, C. trachomatis, and T. vaginalis.  Since the laboratory evaluations are only 
performed if indicated, subject listings of the clinical laboratory results will be provided (Listing 26 and 
Listing 27). Trichomoniasis and yeast vaginitis wet mount results will be provided in Listing 28. 
9.7. 
Vital Signs and Physical Evaluations 
A complete physical examination, assessment of vital signs, and a pelvic examination will be performed at 
screening and symptom-directed examinations will be performed at all subsequent visits.  Vital sign 
measurements include systolic blood pressure, diastolic blood pressure, pulse, respiration, oral temperature, 
height, and weight. Since the evaluations are symptom-driven from enrollment to the end of follow-up, 
subject listings will be provided for vital signs (Listing 29), physical exam findings (Listing 30), and pelvic 
exam findings (Listing 31). Abnormal discharge and cervical mucus characteristics are displayed by visit and 
treatment group in Table 133, Table 134, and Table 135. Subject listings will be provided for abnormal 
discharge (Listing 32), and cervical mucus characteristics (Listing 33). 
9.8. 
Concomitant Medications 
Summaries of medications that were started prior to dosing and continuing at the time of dosing, as well as 
medications that were started during dosing or during follow up will be presented by WHO Drug Anatomical 
Codes (ATC) Level 1 and Level 2 and actual treatment group for subjects in the Safety population (See 
Section 9.1.2 and Table 98, Table 99, Table 100, Table 101, and Table 102). 
Individual subject listings will be presented for all concomitant medications (See Section 9.1.2 and Listing 
17). 


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10. 
OTHER ANALYSES 
No other analyses are planned. 


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11. 
REPORTING CONVENTIONS 
P-values ≥0.001 and ≤0.999 will be reported to three decimal places; p-values less than 0.001 will be reported 
as “<0.001”; p-values greater than 0.999 will be reported as “> 0.999”. The mean, median, standard deviation, 
and any other statistics other than quantiles, will be reported to one decimal place greater than the original 
data. Quantiles other than the median will use the same number of decimal places as the original data. 
Proportions will be presented to two decimal places; values <0.01 will be presented as “<0.01”. Percentages 
will be reported to the nearest whole number; values < 1% will be presented as “<1”. Estimated parameters, 
not on the same scale as raw observations (e.g. regression coefficients) will be reported to three significant 
figures. 


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12. 
TECHNICAL DETAILS 
SAS version 9.4 or above will be used to generate all tables, figures, and listings. 


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13. 
SUMMARY OF CHANGES IN THE CONDUCT OF THE STUDY OR 
PLANNED ANALYSES 
This SAP denotes that ITT efficacy analyses will be performed, though the protocol did not specify that ITT 
analyses would be performed. 
Section 11.6.2 of the protocol states the mITT and CC populations will include subjects who met all 
inclusion/exclusion criteria. Section 6.4 of this analysis plan clarifies that rather than including subjects who 
met all inclusion/exclusion criteria, the mITT and CC analysis populations will exclude subjects who were 
positive for concomitant vaginal or cervical infections at screening and enrollment to better align with the 
analysis population definitions in the July 2016 FDA guidance for BV. 


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14. 
REFERENCES 
1. Allsworth JE and Peipert JF. Prevalence of bacterial vaginosis: 2001-2004 National Health and Nutrition 
Examination Survey data. Obstet Gynecol 2007;109(1):114-20. 
2. Eschenbach DA, Hillier S, Critchlow C, et al. Diagnosis and clinical manifestations of bacterial vaginosis. 
Am J Obstet Gynecol 1988;158(4):819-28. 
3. Hillier SL, Kiviat NB, Hawes SE, et al. Role of bacterial vaginosis-associated microorganisms in 
endometritis. Am J Obstet Gynecol 1996;175(2):435-41. 
4. Watts DH, Krohn MA, Hillier SL, et al. Bacterial vaginosis as a risk factor for post-cesarean endometritis. 
Obstet Gynecol 1990;75(1):52-8. 
5. Soper DE. Bacterial vaginosis and postoperative infections. Am J Obstet Gynecol. 1993 Aug;169(2 Pt 
2):467-9. 
6. FDA Draft Guidance for the Use of Metronidazole Gel. 
https://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm345807.p
df 
7. International Conference on Harmonisation (ICH) E9. 
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E9/Step4/E9_Guidelin
e.pdf 


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15. 
LISTING OF TABLES, FIGURES, AND LISTINGS  
Table, figure, and listing shells are presented in Appendices 1, 2, and 3, respectively. 


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APPENDIX 1. TABLE MOCK-UPS 
Table 1: 
Study Design ...............................................................................................................46 
Table 2: 
Schedule of Study Procedures ....................................................................................47 
Table 3: 
Dates of First Treatment by Site – Safety Population ................................................50 
Table 4: 
Dates of First Treatment by Treatment Group - Safety Population ............................51 
Table 5: 
Intent-to-Treat and Modified Intent-to-Treat Analysis Populations for 
Primary Analysis by Treatment Group .......................................................................52 
Table 6: 
Safety, Complete Case, and Per Protocol Analysis Populations for Safety 
and Primary Analysis by Treatment Group ................................................................53 
Table 7: 
Summary of Halting Rules - Safety Population .........................................................54 
Table 8: 
Ineligibility Summary of Screen Failures ...................................................................55 
Table 9: 
Subject Disposition by Treatment Group - All Enrolled Subjects .............................56 
Table 10: Distribution of Protocol Deviations by Category, Type, and Treatment 
Group—All Enrolled Subjects ....................................................................................57 
Table 11: BV Recurrence by Visit 4 (Week 12) by Analysis Population and Treatment 
Group ..........................................................................................................................59 
Table 12: BV Recurrence by Visit 7 (Week 24) by Analysis Population and Treatment 
Group ..........................................................................................................................59 
Table 13: BV Recurrence by Study Day and Treatment Group – ITT Population .....................60 
Table 14: BV Recurrence by Study Day and Treatment Group – mITT Population .................60 
Table 15: BV Recurrence by Study Day and Treatment Group – CC Population .....................60 
Table 16: BV Recurrence by Study Day and Treatment Group – PP Population ......................60 
Table 17: Time to BV Recurrence by Analysis Population and Treatment Group – By 
Visit 4 (Week 12) ........................................................................................................61 
Table 18: Time to BV Recurrence by Analysis Population and Treatment Group – By 
Visit 7 (Week 12) ........................................................................................................61 
Table 19: BV Recurrence by Visit 4 (Week 12) by Analysis Population and Treatment 
Group – Excluding Subjects Receiving Additional BV Treatment ............................62 
Table 20: BV Recurrence by Visit 7 (Week 24) by Analysis Population and Treatment 
Group – Excluding Subjects Receiving Additional BV Treatment ............................62 
Table 21: L. crispatus Colonization through Visit 4 (Week 12) by Analysis Population 
and Treatment Group ..................................................................................................63 
Table 22: L. crispatus Colonization at Visit 7 (Week 24) by Analysis Population and 
Treatment Group .........................................................................................................63 


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Table 23: L. crispatus Colonization by Study Day and Treatment Group – ITT 
Population ...................................................................................................................64 
Table 24: L. crispatus Colonization by Study Day and Treatment Group – mITT 
Population ...................................................................................................................64 
Table 25: L. crispatus Colonization by Study Day and Treatment Group – CC 
Population ...................................................................................................................64 
Table 26: L. crispatus Colonization by Study Day and Treatment Group – PP 
Population ...................................................................................................................64 
Table 27: L. crispatus CTV-05 Concentration by Study Day and Treatment Group – 
ITT Population ............................................................................................................65 
Table 28: L. crispatus CTV-05 Concentration by Study Day and Treatment Group – 
mITT Population .........................................................................................................65 
Table 29: L. crispatus CTV-05 Concentration by Study Day and Treatment Group – 
CC Population .............................................................................................................65 
Table 30: L. crispatus CTV-05 Concentration by Study Day and Treatment Group – PP 
Population ...................................................................................................................65 
Table 31: L. crispatus Colonization by Study Day, Treatment Group, and Number of 
Condom-less Sexual Intercourse Acts – ITT Population ...........................................66 
Table 32: L. crispatus Colonization by Study Day, Treatment Group, and Number of 
Condom-less Sexual Intercourse Acts – mITT ...........................................................68 
Table 33: L. crispatus Colonization by Study Day, Treatment Group, and Number of 
Condom-less Sexual Intercourse Acts – CC Population ............................................68 
Table 34: L. crispatus Colonization by Study Day, Treatment Group, and Number of 
Condom-less Sexual Intercourse Acts – PP Population .............................................68 
Table 35: L. crispatus Colonization by Study Day, Treatment Group, and Number of 
Partners – ITT Population ...........................................................................................69 
Table 36: L. crispatus Colonization by Study Day, Treatment Group, and Number of 
Partners– mITT ...........................................................................................................70 
Table 37: L. crispatus Colonization by Study Day, Treatment Group, and Number of 
Partners – CC Population............................................................................................70 
Table 38: L. crispatus Colonization by Study Day, Treatment Group, and Number of 
Partners – PP Population ............................................................................................70 
Table 39: Days Since Last Dose by Study Day, Treatment Group, and L. crispatus 
Colonization Status – ITT Population ........................................................................71 
Table 40: Days Since Last Dose by Study Day, Treatment Group, and L. crispatus 
Colonization Status – mITT Population .....................................................................71 
Table 41: Days Since Last Dose by Study Day, Treatment Group, and L. crispatus 
Colonization Status – CC Population .........................................................................71 


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Table 42: Days Since Last Dose by Study Day, Treatment Group, and L. crispatus 
Colonization Status – PP Population ..........................................................................71 
Table 43: L. crispatus Colonization by Study Day, Treatment Group, and Treatment 
Compliance – ITT Population ....................................................................................72 
Table 44: L. crispatus Colonization by Study Day, Treatment Group, and Treatment 
Compliance – mITT Population .................................................................................73 
Table 45: L. crispatus Colonization by Study Day, Treatment Group, and Treatment 
Compliance – CC Population .....................................................................................73 
Table 46: Days Since Last Day of Last Menstrual Period by Study Day, Treatment 
Group, and L. crispatus Colonization Status – ITT Population ..................................74 
Table 47: Days Since Last Day of Last Menstrual Period by Study Day, Treatment 
Group, and L. crispatus Colonization Status – mITT Population...............................74 
Table 48: Days Since Last Day of Last Menstrual Period by Study Day, Treatment 
Group, and L. crispatus Colonization Status – CC Population...................................74 
Table 49: Days Since Last Day of Last Menstrual Period by Study Day, Treatment 
Group, and L. crispatus Colonization Status – PP Population ...................................74 
Table 50: L. crispatus Colonization by Study Day, Treatment Group, and Occurrence 
of Menses After Last Dose Taken – ITT Population ..................................................75 
Table 51: L. crispatus Colonization by Study Day, Treatment Group, and Occurrence 
of Menses After Last Dose Taken – mITT Population ...............................................76 
Table 52: L. crispatus Colonization by Study Day, Treatment Group, and Occurrence 
of Menses After Last Dose Taken – CC Population ...................................................76 
Table 53: L. crispatus Colonization by Study Day, Treatment Group, and Occurrence 
of Menses After Last Dose Taken – PP Population ...................................................76 
Table 54: Time to L. crispatus Colonization by Analysis Population and Treatment 
Group ..........................................................................................................................77 
Table 55: Treatment Compliance by Treatment Group and Analysis Population ......................78 
Table 56: Product Administration by Week, Dose Number, and Method of Assessment 
- Safety Population .....................................................................................................79 
Table 57: Product Administration by Site, Week, Dose Number, and Method of 
Assessment - Safety Population- San Francisco General Hospital ............................80 
Table 58: Product Administration by Site, Week, Dose Number, and Method of 
Assessment - Safety Population- Stroger Hospital of Cook County ..........................80 
Table 59: Product Administration by Site, Week, Dose Number, and Method of 
Assessment - Safety Population- University of California San Diego .......................80 
Table 60: Product Administration by Site, Week, Dose Number, and Method of 
Assessment - Safety Population- Washington University in St. Louis ......................80 


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Table 61: Product Administration by Treatment Group, Week, Dose Number, and 
Method of Assessment - Safety Population- LACTIN-V ...........................................80 
Table 62: Product Administration by Site, Week, Dose Number, and Method of 
Assessment - Safety Population- Placebo...................................................................80 
Table 63: Categorical Responses to Acceptability Questionnaire by Treatment Group – 
Screening Visit ............................................................................................................81 
Table 64: Categorical Responses to Acceptability Questionnaire by Treatment Group –
Visit 4 (Week 12) ........................................................................................................81 
Table 65: Continuous/Discrete Responses to Acceptability Questionnaire by Treatment 
Group – Screening Visit .............................................................................................82 
Table 66: Continuous/Discrete Responses to Acceptability Questionnaire by Treatment 
Group – Visit 4 (Week 12) .........................................................................................82 
Table 67: Model-Based Rate of Positive BV Diagnoses by Visit 4 (Week 12) by 
Analysis Population and Treatment Group .................................................................83 
Table 68: Model-Based Odds of Positive BV Diagnoses by Visit 4 (Week 12) by 
Analysis Population and Treatment Group .................................................................84 
Table 69: BV Recurrence by Visit 4 (Week 12) by Analysis Population, Treatment 
Group, and Race .........................................................................................................85 
Table 70: BV Recurrence by Visit 7 (Week 24) by Analysis Population, Treatment 
Group, and Race .........................................................................................................85 
Table 71: L. crispatus Colonization through Visit 4 (Week 12) by Analysis Population, 
Treatment Group, and Race ........................................................................................86 
Table 72: L. crispatus Colonization at Visit 7 (Week 24) by Analysis Population, 
Treatment Group, and Race ........................................................................................86 
Table 73: L. crispatus CTV-05 Concentration by Study Day, Treatment Group, and 
Race – ITT Population ................................................................................................87 
Table 74: L. crispatus CTV-05 Concentration by Study Day, Treatment Group, and 
Race – mITT Population .............................................................................................87 
Table 75: L. crispatus CTV-05 Concentration by Study Day, Treatment Group, and 
Race – CC Population .................................................................................................87 
Table 76: L. crispatus CTV-05 Concentration by Study Day, Treatment Group, and 
Race – PP Population..................................................................................................87 
Table 77: L. crispatus Colonization by Study Day, Treatment Group, and Amsel 
Critera – ITT Population .............................................................................................88 
Table 78: L. crispatus Colonization by Study Day, Treatment Group, and Amsel 
Critera – mITT Population ..........................................................................................88 
Table 79: L. crispatus Colonization by Study Day, Treatment Group, and Amsel 
Critera – CC Population ..............................................................................................88 


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Table 80: L. crispatus Colonization by Study Day, Treatment Group, and Amsel 
Critera – PP Population ..............................................................................................88 
Table 81: L. crispatus Colonization by Study Day, Treatment Group, and Nugent 
Score – ITT Population ...............................................................................................89 
Table 82: L. crispatus Colonization by Study Day, Treatment Group, and Nugent 
Score – mITT Population ............................................................................................89 
Table 83: L. crispatus Colonization by Study Day, Treatment Group, and Nugent 
Score – CC Population................................................................................................89 
Table 84: L. crispatus Colonization by Study Day, Treatment Group, and Nugent 
Score – PP Population ................................................................................................89 
Table 85: L. crispatus CTV-05 Concentration by Study Day, Treatment Group, and 
Amsel Criteria – ITT Population ................................................................................90 
Table 86: L. crispatus CTV-05 Concentration by Study Day, Treatment Group, and 
Amsel Criteria – mITT Population .............................................................................90 
Table 87: L. crispatus CTV-05 Concentration by Study Day, Treatment Group, and 
Amsel Criteria – CC Population .................................................................................90 
Table 88: L. crispatus CTV-05 Concentration by Study Day, Treatment Group, and 
Amsel Criteria – PP Population ..................................................................................90 
Table 89: L. crispatus CTV-05 Concentration by Study Day, Treatment Group, and 
Nugent Score – mITT Population ...............................................................................90 
Table 90: L. crispatus CTV-05 Concentration by Study Day, Treatment Group, and 
Nugent Score – CC Population ...................................................................................90 
Table 91: L. crispatus CTV-05 Concentration by Study Day, Treatment Group, and 
Nugent Score – PP Population ....................................................................................90 
Table 92: Summary of Categorical Demographic and Baseline Characteristics by Site - 
All Enrolled Subjects ..................................................................................................91 
Table 93: Summary of Categorical Demographic and Baseline Characteristics by 
Treatment Group—ITT Population ............................................................................92 
Table 94: Summary of Continuous Demographic and Baseline Characteristics by 
Site—All Enrolled Subjects ........................................................................................93 
Table 95: Summary of Continuous Demographic and Baseline Characteristics by 
Treatment Group - ITT Population .............................................................................94 
Table 96: Summary of Baseline* Categorical Sexual History by Treatment Group - 
ITT Population ............................................................................................................95 
Table 97: Summary of Baseline* Continuous Sexual History by Treatment Group - 
ITT Population ............................................................................................................96 
Table 98: Summary of Subjects with Pre-Existing Medical Conditions by MedDRA 
System Organ Class and Treatment Group - ITT Population – All Sites ...................98 


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Table 99: Summary of Subjects with Pre-Existing Medical Conditions by MedDRA 
System Organ Class and Treatment Group - ITT Population – San Francisco 
General Hospital .........................................................................................................98 
Table 100: Summary of Subjects with Pre-Existing Medical Conditions by MedDRA 
System Organ Class and Treatment Group - ITT Population – Stroger 
Hospital of Cook County ............................................................................................98 
Table 101: Summary of Subjects with Pre-Existing Medical Conditions by MedDRA 
System Organ Class and Treatment Group - ITT Population – University of 
California, San Diego .................................................................................................98 
Table 102: Summary of Subjects with Pre-Existing Medical Conditions by MedDRA 
System Organ Class and Treatment Group - ITT Population – Washington 
University in St. Louis ................................................................................................98 
Table 103: Number and Percentage of Subjects with Prior and Concurrent Medications 
by WHO Drug Classification and Treatment Group - Safety Population - All 
Subjects .......................................................................................................................99 
Table 104: Number and Percentage of Subjects with Prior and Concurrent Medications 
by WHO Drug Classification and Treatment Group-Safety Population-San 
Francisco General Hospital .........................................................................................99 
Table 105: Number and Percentage of Subjects with Prior and Concurrent Medications 
by WHO Drug Classification and Treatment Group-Safety Population-
Stroger Hospital of Cook County ...............................................................................99 
Table 106: Number and Percentage of Subjects with Prior and Concurrent Medications 
by WHO Drug Classification and Treatment Group-Safety Population-
University of California, San Diego ...........................................................................99 
Table 107: Number and Percentage of Subjects with Prior and Concurrent Medications 
by WHO Drug Classification and Treatment Group-Safety Population-
Washington University in St. Louis ............................................................................99 
Table 108: Number and Percentage of Subjects Experiencing Solicited Events with 95% 
Confidence Intervals by Symptom and Treatment Group—Safety Population .......100 
Table 109: Number and Percentage of Subjects Experiencing Solicited Local Events by 
Symptom and Maximum Severity - Safety Population - All Subjects .....................101 
Table 110: Number and Percentage of Subjects Experiencing Solicited Local Events by 
Symptom, Maximum Severity, and Treatment Group - Safety Population .............103 
Table 111: Number and Percentage of Subjects Experiencing Solicited Systemic Events 
by Symptom and Maximum Severity—Safety Population—All Subjects ...............105 
Table 112: Number and Percentage of Subjects Experiencing Solicited Local Events by 
Symptom, Maximum Severity, and Treatment Group—Safety Population .............107 
Table 113: Number and Percentage of Subjects Experiencing Solicited Local Events by 
Symptom, Severity, Week, and Treatment Group - Safety Population - All 
Subjects - Weeks 1-6 ................................................................................................109 


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Table 114: Number and Percentage of Subjects Experiencing Solicited Local Events by 
Symptom, Severity, Week, and Treatment Group - Safety Population - All 
Subjects - Weeks 7-24 ..............................................................................................111 
Table 115: Number and Percentage of Subjects Experiencing Solicited Local Events by 
Symptom, Severity, Week, and Treatment Group—Safety Population—
LACTIN-V—Weeks 1-6 ..........................................................................................113 
Table 116: Number and Percentage of Subjects Experiencing Solicited Local Events by 
Symptom, Severity, Week, and Treatment Group—Safety Population—
LACTIN-V—Weeks 7-24 ........................................................................................113 
Table 117: Number and Percentage of Subjects Experiencing Solicited Local Events by 
Symptom, Severity, Week, and Treatment Group—Safety Population—
Placebo—Weeks 1-6 ................................................................................................113 
Table 118: Number and Percentage of Subjects Experiencing Solicited Local Events by 
Symptom, Severity, Week, and Treatment Group—Safety Population—
Placebo—Weeks 7-24 ..............................................................................................113 
Table 119: Number and Percentage of Subjects Experiencing Solicited Systemic Events 
by Symptom, Severity, Week, and Treatment Group - Safety Population - 
All Subjects - Weeks 1-6 ..........................................................................................114 
Table 120: Number and Percentage of Subjects Experiencing Solicited Systemic Events 
by Symptom, Severity, Week, and Treatment Group—Safety Population—
All Subjects—Weeks 7-24 .......................................................................................116 
Table 121: Number and Percentage of Subjects Experiencing Solicited Local Events by 
Symptom, Severity, Week, and Treatment Group—Safety Population—
LACTIN-V—Weeks 1-6 ..........................................................................................118 
Table 122: Number and Percentage of Subjects Experiencing Solicited Local Events by 
Symptom, Severity, Week, and Treatment Group—Safety Population—
LACTIN-V—Weeks 7-24 ........................................................................................118 
Table 123: Number and Percentage of Subjects Experiencing Solicited Local Events by 
Symptom, Severity, Week, and Treatment Group—Safety Population—
Placebo—Weeks 1-6 ................................................................................................118 
Table 124: Number and Percentage of Subjects Experiencing Solicited Local Events by 
Symptom, Severity, Week, and Treatment Group—Safety Population—
Placebo—Weeks 7-24 ..............................................................................................118 
Table 125: Proportion of Subjects Reporting Product Related Unsolicited Adverse 
Events Following the First Dose of Study Product through Visit 7 by 
Treatment Group –  Safety Population .....................................................................119 
Table 126: Number and Percentage of Subjects Experiencing Unsolicited Adverse 
Events with 95% Confidence Intervals by MedDRA System Organ Class 
and Preferred Term, Dose Number, and Treatment Group - Safety 
Population .................................................................................................................120 


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Table 127: Number and Percentage of Subjects Experiencing Unsolicited Adverse 
Events by MedDRA System Organ Class and Preferred Term, Maximum 
Severity and Relationship—Safety Population ........................................................121 
Table 128: Number and Percentage of Subjects Experiencing Unsolicited Adverse 
Events by MedDRA System Organ Class and Preferred Term, Maximum 
Severity, Relationship, and Treatment Group - Safety Population ..........................122 
Table 129: Number of Adverse Events Occurring in 5% of Subjects in Any Treatment 
Group by MedDRA System Organ Class and Preferred Term, and Treatment 
Group - Safety Population ........................................................................................123 
Table 130: Subjects Reporting Adverse Events Occurring in 5% Subjects in Any 
Treatment Group by MedDRA System Organ Class and Preferred Term, and 
Treatment Group - Safety Population .......................................................................124 
Table 131: Listing of Non-Serious, Unsolicited, Moderate or Severe Adverse Events .............125 
Table 132: Listing of Serious Adverse Events ...........................................................................126 
Table 133: Abnormal Discharge and Cervical Mucus Characteristics by Visit and 
Treatment Group - Safety Population .......................................................................128 
Table 134: Abnormal Discharge and Cervical Mucus Characteristics by Visit and 
Treatment Group - Safety Population - LACTIN-V .................................................129 
Table 135: Abnormal Discharge and Cervical Mucus Characteristics by Visit and 
Treatment Group - Safety Population - Placebo .......................................................129 
 


Statistical Analysis Plan - DMID Protocol: 14-0029  
Version 1.0 
11MAY2018 
- 46 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Table 1: 
Study Design 
 
 
 


Statistical Analysis Plan - DMID Protocol: 14-0029  
Version 1.0 
11MAY2018 
- 47 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Table 2: 
Schedule of Study Procedures 
 
Study Treatment 
 
Study Follow Up  
 
Evaluation 
Screening 
Visit 0 
Day -30 to -5 
Enrollment Visit 1 
Day 1 
Study Visit 2  
Day 28 (Week 4) 
Study Visit 3  
Day 56 (Week 8) 
Study Visit 4  
Day 84 (Week 12) 
Phone Visit 5   
Day 112 
 (Week 16) 
Phone Visit 6   
Day 140  
(Week 20) 
Study Visit 7   
Day 168  
(Week 24) 
Unscheduled Visit 
Study Product  
Discontinuation 
Early  Termination 
Visit 
Visit window 
 
 
 
± 1 week 
 
Signed consent form 
X 
X 
 
 
 
 
 
 
 
 
 
Assessment of eligibility criteria 
X 
X 
 
 
 
 
 
 
 
 
 
Demographics 
X 
X 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
Detailed medical, gynecological 
and sexual history 
X 
 
 
 
 
 
 
 
 
 
 
Dispense MetroGel  
X 
 
(X) 
(X) 
(X) 
 
 
 
 
 
 
Dispense LACTIN-V/placebo 
and applicators 
 
X 
(X) 
(X) 
 
 
 
 
 
 
 
Dispense condoms 
X 
X 
X 
X 
X 
 
 
 
X 
X 
 
Dispense memory aid or 
instructions on using web based 
memory aid 
 
X 
 
 
 
 
 
 
 
 
 
Brief  medical, gynecological 
and sexual history 
 
X 
X 
X 
X 
 
 
X 
X 
X 
X 
Review of concomitant 
medications  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study intervention 
 
X 
X 
X 
X 
 
 
 
 
 
 
Physical 
Examination 
Complete 
X 
 
 
 
 
 
 
 
 
 
 
Symptom-directed 
 
X 
X 
X 
X 
 
 
X 
X 
X 
X 
Vital signs 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
X 
Pelvic examination 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
X 
Review memory aid and 
symptoms 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 


Statistical Analysis Plan - DMID Protocol: 14-0029  
Version 1.0 
11MAY2018 
- 48 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
 
Study Treatment 
 
Study Follow Up  
 
Evaluation 
Screening 
Visit 0 
Day -30 to -5 
Enrollment Visit 1 
Day 1 
Study Visit 2  
Day 28 (Week 4) 
Study Visit 3  
Day 56 (Week 8) 
Study Visit 4  
Day 84 (Week 12) 
Phone Visit 5   
Day 112 
 (Week 16) 
Phone Visit 6   
Day 140  
(Week 20) 
Study Visit 7   
Day 168  
(Week 24) 
Unscheduled Visit 
Study Product  
Discontinuation 
Early  Termination 
Visit 
Reminder to abstain from sexual 
intercourse 
 
X 
X 
X 
X 
X 
X 
 
X 
 
 
Reminder not to use vaginal 
products 
 
X 
X 
X 
X 
X 
X 
 
X 
 
 
Reminder to collect and return 
used applicators 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
Assessment of adverse events 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Clinical 
Laboratory 
Clean catch urine 
dipstick 
X 
(X) 
(X) 
(X) 
(X) 
 
 
(X) 
(X) 
(X) 
(X) 
Urinalysis 
(X) 
(X) 
(X) 
(X) 
(X) 
 
 
(X) 
(X) 
(X) 
(X) 
Rapid urine βhCG 
pregnancy test 
X 
X 
(X) 
(X) 
(X) 
 
 
(X) 
(X) 
(X) 
(X) 
HIV and syphilis 
serology (total blood 
required is 
approximately 
15mL (3 teaspoons)  
X 
 
 
 
 
 
 
 
 
 
 
Vaginal swab for N. 
gonorrhoeae, C. 
trachomatis, T. 
vaginalis 
X 
(X) 
(X) 
(X) 
(X) 
 
 
(X) 
(X) 
(X) 
(X) 
Research 
Laboratory 
Vaginal swab for pH 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
X 
Vaginal swab for 
wet mount, amine 
test 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
X 
Vaginal swab for 
Gram stain  
X 
X 
X 
X 
X 
 
 
X 
X 
X 
X 


Statistical Analysis Plan - DMID Protocol: 14-0029  
Version 1.0 
11MAY2018 
- 49 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
 
Study Treatment 
 
Study Follow Up  
 
Evaluation 
Screening 
Visit 0 
Day -30 to -5 
Enrollment Visit 1 
Day 1 
Study Visit 2  
Day 28 (Week 4) 
Study Visit 3  
Day 56 (Week 8) 
Study Visit 4  
Day 84 (Week 12) 
Phone Visit 5   
Day 112 
 (Week 16) 
Phone Visit 6   
Day 140  
(Week 20) 
Study Visit 7   
Day 168  
(Week 24) 
Unscheduled Visit 
Study Product  
Discontinuation 
Early  Termination 
Visit 
Vaginal swab for 
storage and future 
identification of 
vaginal bacteria  
X 
X 
X 
X 
X 
 
 
X 
X 
X 
X 
Vaginal swab for 
qPCR (L. crispatus 
identification) 
 
X 
X 
X 
X 
 
 
X 
X 
X 
X 
Other 
Procedures 
Acceptability 
questionnaire 
X 
 
 
 
X 
 
 
 
 
X 
X 
Staining of used 
applicators 
 
 
X* 
 
 
 
 
 
 
Telephone interview 
 
 
 
 
 
X 
X 
 
 
 
 
 


Statistical Analysis Plan - DMID Protocol: 14-0029  
Version 1.0 
11MAY2018 
- 50 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Table 3: 
Dates of First Treatment by Site – Safety Population 
[Note:  Dates will be categorized by breaking the calendar year into quarters.]  
Dates of Dosing 
San Francisco 
General Hospital 
(N = X) 
Stroger Hospital of 
Cook County 
(N = X) 
University of 
California, San 
Diego 
(N = X) 
Washington 
University in St. 
Louis 
(N = X) 
All Subjects 
(N = X) 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
DDMMMYYYY-
DDMMMYYYY 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
DDMMMYYYY-
DDMMMYYYY 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
DDMMMYYYY-
DDMMMYYYY 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
DDMMMYYYY-
DDMMMYYYY 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Note: N=Number of subjects in the safety population 


Statistical Analysis Plan - DMID Protocol: 14-0029  
Version 1.0 
11MAY2018 
- 51 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Table 4: 
Dates of First Treatment by Treatment Group - Safety Population 
[Note:  Dates will be categorized by breaking the calendar year into quarters.]  
Dates of Dosing 
LACTIN-V 
(N = X) 
Placebo  
(N = X) 
All Subjects 
(N = X) 
n 
% 
n 
% 
n 
% 
DDMMMYYYY-DDMMMYYYY 
x 
x 
x 
x 
x 
x 
DDMMMYYYY-DDMMMYYYY 
x 
x 
x 
x 
x 
x 
DDMMMYYYY-DDMMMYYYY 
x 
x 
x 
x 
x 
x 
DDMMMYYYY-DDMMMYYYY 
x 
x 
x 
x 
x 
x 
Note: N=Number of subjects in the safety population 


Statistical Analysis Plan - DMID Protocol: 14-0029  
Version 1.0 
11MAY2018 
- 52 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Table 5: 
Intent-to-Treat and Modified Intent-to-Treat Analysis Populations for Primary Analysis by Treatment Group 
 
 
LACTIN-V 
(N=X) 
Placebo  
(N=X) 
All Subjects 
(N=X) 
Analysis Population 
Eligibility Category 
Reason Subjects Excluded 
n 
% 
n 
% 
n 
% 
Intent-to-Treat (ITT) Analysis Population 
Eligible for ITT 
 
x 
x 
x 
x 
x 
x 
Modified Intent-to-Treat (mITT) Analysis 
Eligible for mITT 
 
x 
x 
x 
x 
x 
x 
Excluded from mITT  
Any Reason 
x 
x 
x 
x 
x 
x 
Did not meet inclusion/exclusion criteria  
x 
x 
x 
x 
x 
x 
Did not receive study product   
x 
x 
x 
x 
x 
x 
Did not return for at least one post-baseline visit  
x 
x 
x 
x 
x 
x 
Notes: N=number of enrolled subjects. 
Treatment group is the treatment group to which a subject was randomized. 


Statistical Analysis Plan - DMID Protocol: 14-0029  
Version 1.0 
11MAY2018 
- 53 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Table 6: 
Safety, Complete Case, and Per Protocol Analysis Populations for Safety and Primary Analysis by Treatment Group 
 
 
LACTIN-V 
(N=X) 
Placebo  
(N=X) 
All Subjects 
(N=X) 
Analysis Population 
Eligibility Category 
Reason Subjects Excluded 
n 
% 
n 
% 
n 
% 
Safety Analysis Population 
Eligible for Safety 
x 
x 
x 
x 
x 
x 
Excluded from Safety 
Any Reason 
x 
x 
x 
x 
x 
x 
Did not receive study product 
x 
x 
x 
x 
x 
x 
Complete Case (CC) Analysis 
Population 
Eligible for CC 
x 
x 
x 
x 
x 
x 
Excluded from CC 
Any Reason 
x 
x 
x 
x 
x 
x 
Did not meet inclusion/exclusion criteria  
x 
x 
x 
x 
x 
x 
Did not receive study product   
x 
x 
x 
x 
x 
x 
Was not followed up until the first diagnosis of BV or through 
Visit 4 (Week 12, Day 84) 
x 
x 
x 
x 
x 
x 
Per-Protocol (PP) Analysis 
Population 
Eligible for PP 
x 
x 
x 
x 
x 
x 
Excluded from PP 
Any Reason 
x 
x 
x 
x 
x 
x 
Did not meet inclusion/exclusion criteria  
x 
x 
x 
x 
x 
x 
Was not compliant with study product 
x 
x 
x 
x 
x 
x 
Was not followed up until the first diagnosis of BV or through 
Visit 4 (Week 12, Day 84) 
x 
x 
x 
x 
x 
x 
Notes: N=number of enrolled subjects. 
Treatment group is the actual treatment a subject received 


Statistical Analysis Plan - DMID Protocol: 14-0029  
Version 1.0 
11MAY2018 
- 54 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Table 7: 
Summary of Halting Rules - Safety Population 
Halting Rules  
Number of 
Subjects 
One or more subjects experiences a treatment-related SAE 
x 
Two or more subjects experience treatment-related vulvar and/or vaginal ulceration, abscess, or necrosis 
x  
Four or more subjects experience a treatment-related severe (Grade 3) systemic adverse event   
x 
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 
x 


Statistical Analysis Plan - DMID Protocol: 14-0029  
Version 1.0 
11MAY2018 
- 55 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Table 8: 
Ineligibility Summary of Screen Failures 
Inclusion/Exclusion Category 
Inclusion/Exclusion Criterion 
Number of Subjectsa 
Inclusion and Exclusion 
Any Criterion 
x 
Inclusion 
Any inclusion criterion 
x 
 
[inclusion criterion 1] 
x 
 
[inclusion criterion 2] 
x 
 
[inclusion criterion 3] 
x 
Exclusion 
Any exclusion criterion 
x 
 
[exclusion criterion 1] 
x 
 
[exclusion criterion 2] 
x 
 
[exclusion criterion 3] 
x 
Declined Enrollment 
Any Reason 
x 
 
Time commitment 
x 
 
Concern of potential risks 
x 
 
Number of procedures 
x 
 
Unable to contact subject 
x 
 
Other 
x 
Note: aMore than one criterion may be marked per subject. 


Statistical Analysis Plan - DMID Protocol: 14-0029  
Version 1.0 
11MAY2018 
- 56 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Table 9: 
Subject Disposition by Treatment Group - All Enrolled Subjects 
Subject 
Disposition  
LACTIN-V 
(N=X) 
Placebo  
(N=X) 
All Subjects 
(N=X) 
n 
% 
n 
% 
n 
% 
Screened 
x 
-- 
x 
-- 
x 
-- 
Enrolled/Randomized 
x 
100 
x 
100 
x 
100 
Received Treatment 
x 
x 
x 
x 
x 
x 
Complied with Treatmenta, b 
x 
x 
x 
x 
x 
x 
Completed Visit 2, Week 4 (Day 28 ±7)  
x 
x 
x 
x 
x 
x 
Completed Visit 3, Week 8 (Day 56 ±7)  
x 
x 
x 
x 
x 
x 
Completed Visit 4, Week 12 (Day 84 ±7)  
x 
x 
x 
x 
x 
x 
Completed Visit 5, Week 16 (Day 112 ±7) – Telephone 
Interview* 
x 
x 
x 
x 
x 
x 
Completed Visit 6, Week 20 (Day 140 ±7) – Telephone 
Interview* 
x 
x 
x 
x 
x 
x 
Completed Visit 7, Week 24 (Study Day 168 ±7) 
x 
x 
x 
x 
x 
x 
Notes: N=Number of enrolled subjects. 
aRefer to Listing 16.2.1 for reasons subjects discontinued or terminated early. 
b Refer to 16.2.5.1 and 16.2.5.2 for treatment compliance. 
*Includes subjects who completed their visits in clinic. 


Statistical Analysis Plan - DMID Protocol: 14-0029  
Version 1.0 
11MAY2018 
- 57 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Table 10: 
Distribution of Protocol Deviations by Category, Type, and Treatment Group—All Enrolled Subjects 
Category 
Deviation Type 
LACTIN-V 
(N=X) 
Placebo  
(N=X) 
All Subjects 
(N=X) 
# of 
Subj. 
% 
# of 
Dev. 
# of 
Subj. 
% 
# of 
Dev. 
# of 
Subj. 
% 
# of 
Dev. 
Eligibility/enrollment 
Any type 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Did not meet inclusion criterion 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Met exclusion criterion 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
ICF not signed prior to study procedures 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Other 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Treatment administration schedule 
Any type 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Out of window visit 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Missed visit/visit not conducted 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Missed treatment administration 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Delayed treatment administration 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Other 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Follow-up visit schedule 
Any type 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Out of window visit 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Missed visit/visit not conducted 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Other 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Protocol procedure/assessment 
Any type 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Incorrect version of ICF signed 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Blood not collected 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Urine not collected 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Other specimen not collected 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Specimen result not obtained 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Required procedure not conducted 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Required procedure done incorrectly 
x 
x 
x 
x 
x 
x 
x 
x 
x 


Statistical Analysis Plan - DMID Protocol: 14-0029  
Version 1.0 
11MAY2018 
- 58 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Category 
Deviation Type 
LACTIN-V 
(N=X) 
Placebo  
(N=X) 
All Subjects 
(N=X) 
# of 
Subj. 
% 
# of 
Dev. 
# of 
Subj. 
% 
# of 
Dev. 
# of 
Subj. 
% 
# of 
Dev. 
 
Study product temperature excursion 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Specimen temperature excursion 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Prohibited use of vaginal products 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Other 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Treatment administration 
Any type 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Required procedure done incorrectly 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Study product temperature excursion 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Other 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Blinding policy/procedure 
Any type 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Treatment unblinded 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Other 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Notes: N=Number of enrolled subjects. Treatment group is the treatment to which the subject was randomized. 
 


Statistical Analysis Plan - DMID Protocol: 14-0029  
Version 1.0 
11MAY2018 
- 59 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Table 11: 
BV Recurrence by Visit 4 (Week 12) by Analysis Population and Treatment Group 
Analysis Population 
Treatment 
Group 
Number of 
Subjects with BV 
Recurrence 
n 
Number of 
Subjects 
N 
Proportion of 
Subjects with 
BV Recurrence 
BV Recurrence 
95% CI1 
Odds of BV Recurrence 
in LACTIN-V Group 
Compared to Placebo 
Group 
Odds of BV Recurrence in 
LACTIN-V Group Compared to 
Placebo Group 
95% CI2 
p-value3 
ITT 
(LOCF) 
LACTIN-V 
x 
x 
0.xx 
0.xx, 0.xx 
x.xx 
x.xx, x.xx 
0.xxx 
Placebo 
x 
x 
0.xx 
0.xx, 0.xx 
-- 
-- 
 
All Subjects 
x 
x 
0.xx 
0.xx, 0.xx 
-- 
-- 
 
mITT (LOCF) 
LACTIN-V 
x 
x 
0.xx 
0.xx, 0.xx 
x.xx 
x.xx, x.xx 
0.xxx 
Placebo 
x 
x 
0.xx 
0.xx, 0.xx 
-- 
-- 
 
All Subjects 
x 
x 
0.xx 
0.xx, 0.xx 
-- 
-- 
 
ITT 
(Worst Case) 
LACTIN-V 
x 
x 
0.xx 
0.xx, 0.xx 
x.xx 
x.xx, x.xx 
0.xxx 
Placebo 
x 
x 
0.xx 
0.xx, 0.xx 
-- 
-- 
 
All Subjects 
x 
x 
0.xx 
0.xx, 0.xx 
-- 
-- 
 
mITT 
(Worst Case) 
LACTIN-V 
x 
x 
0.xx 
0.xx, 0.xx 
x.xx 
x.xx, x.xx 
0.xxx 
Placebo 
x 
x 
0.xx 
0.xx, 0.xx 
-- 
-- 
 
All Subjects 
x 
x 
0.xx 
0.xx, 0.xx 
-- 
-- 
 
CC 
LACTIN-V 
x 
x 
0.xx 
0.xx, 0.xx 
x.xx 
x.xx, x.xx 
0.xxx 
Placebo 
x 
x 
0.xx 
0.xx, 0.xx 
-- 
-- 
 
All Subjects 
x 
x 
0.xx 
0.xx, 0.xx 
-- 
-- 
 
PP 
LACTIN-V 
x 
x 
0.xx 
0.xx, 0.xx 
x.xx 
x.xx, x.xx 
0.xxx 
Placebo 
x 
x 
0.xx 
0.xx, 0.xx 
-- 
-- 
 
All Subjects 
x 
x 
0.xx 
0.xx, 0.xx 
-- 
-- 
 
Note: The denominator for rate estimates is based on the number of subjects in the respective treatment group and analysis population. 
1: 95% CI= 95% Wilson confidence interval 
2: Difference in 95% CI=asymptotic 95% CI from a Chi-Square test 
3: p-value calculated from the Chi Square Test. 
 
Table with similar format: 
Table 12: 
BV Recurrence by Visit 7 (Week 24) by Analysis Population and Treatment Group 


Statistical Analysis Plan - DMID Protocol: 14-0029  
Version 1.0 
11MAY2018 
- 60 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Table 13: 
BV Recurrence by Study Day and Treatment Group – ITT Population 
Study Day 
(Week) 
Treatment Group 
Number of 
Subjects with 
BV Recurrence 
n 
Number of 
Subjects 
N 
Proportion of 
Subjects with 
BV Recurrence 
BV Recurrence 
95% CI1 
Odds of BV Recurrence in 
LACTIN-V Group Compared 
to Placebo Group 
Odds of BV Recurrence in 
LACTIN-V Group Compared to 
Placebo Group 
95% CI2 
p-value3 
Day 1 
LACTIN-V 
x 
x 
0.xx 
0.xx, 0.xx 
x.xx 
x.xx, x.xx 
0.xxx 
Placebo 
x 
x 
0.xx 
0.xx, 0.xx 
-- 
-- 
 
All Subjects 
x 
x 
0.xx 
0.xx, 0.xx 
-- 
-- 
 
Day 28 
(Week 4) 
LACTIN-V 
x 
x 
0.xx 
0.xx, 0.xx 
x.xx 
x.xx, x.xx 
0.xxx 
Placebo 
x 
x 
0.xx 
0.xx, 0.xx 
-- 
-- 
 
All Subjects 
x 
x 
0.xx 
0.xx, 0.xx 
-- 
-- 
 
Day 56 
(Week 8) 
LACTIN-V 
x 
x 
0.xx 
0.xx, 0.xx 
x.xx 
x.xx, x.xx 
0.xxx 
Placebo 
x 
x 
0.xx 
0.xx, 0.xx 
-- 
-- 
 
All Subjects 
x 
x 
0.xx 
0.xx, 0.xx 
-- 
-- 
 
Day 84 
(Week 12) 
LACTIN-V 
x 
x 
0.xx 
0.xx, 0.xx 
x.xx 
x.xx, x.xx 
0.xxx 
Placebo 
x 
x 
0.xx 
0.xx, 0.xx 
-- 
-- 
 
All Subjects 
x 
x 
0.xx 
0.xx, 0.xx 
-- 
-- 
 
Day 168 
(Week 24) 
LACTIN-V 
x 
x 
0.xx 
0.xx, 0.xx 
x.xx 
x.xx, x.xx 
0.xxx 
Placebo 
x 
x 
0.xx 
0.xx, 0.xx 
-- 
-- 
 
All Subjects 
x 
x 
0.xx 
0.xx, 0.xx 
-- 
-- 
 
Note: The denominator for rate estimates is based on the number of subjects in the respective treatment group and analysis population with BV diagnosis data available at the specified visit. 
1: 95% CI= 95% Wilson confidence interval 
2: Difference in 95% CI=asymptotic 95% CI from a Chi-Square test 
3: p-value calculated from the Chi Square Test. 
 
Tables with similar format: 
Table 14: 
BV Recurrence by Study Day and Treatment Group – mITT Population 
Table 15: 
BV Recurrence by Study Day and Treatment Group – CC Population 
Table 16: 
BV Recurrence by Study Day and Treatment Group – PP Population


Statistical Analysis Plan - DMID Protocol: 14-0029  
Version 1.0 
11MAY2018 
- 61 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Table 17: 
Time to BV Recurrence by Analysis Population and Treatment Group – By Visit 4 (Week 12) 
 
ITT 
mITT 
CC 
PP 
 
LACTIN-V 
(N = xxx) 
Placebo 
(N = xxx) 
All Subjects 
(N = xxx) 
LACTIN-V 
(N = xxx) 
Placebo 
(N = xxx) 
All Subjects 
(N = xxx) 
LACTIN-V 
(N = xxx) 
Placebo 
(N = xxx) 
All Subjects 
(N = xxx) 
LACTIN-V 
(N = xxx) 
Placebo 
(N = xxx) 
All Subjects 
(N = xxx) 
Number (%) of subjects 
with BV Recurrence 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
Median Time (days) 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
Median Time (days) 95% 
CI 
x.x, x.x 
x.x, x.x 
x.x, x.x 
x.x, x.x 
x.x, x.x 
x.x, x.x 
x.x, x.x 
x.x, x.x 
x.x, x.x 
x.x, x.x 
x.x, x.x 
x.x, x.x 
Minimum (days) 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Q1 (days) 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Q3 (days) 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Maximum (days) 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Notes: Median time and median time 95% CI comes from Kaplan-Meier estimates 
 
Tables with similar format: 
Table 18: 
Time to BV Recurrence by Analysis Population and Treatment Group – By Visit 7 (Week 12) 
 


Statistical Analysis Plan - DMID Protocol: 14-0029  
Version 1.0 
11MAY2018 
- 62 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Table 19: 
BV Recurrence by Visit 4 (Week 12) by Analysis Population and Treatment Group – Excluding Subjects Receiving Additional BV 
Treatment 
Analysis Population 
Treatment 
Group 
Number of 
Subjects with BV 
Recurrence 
n 
Number of 
Subjects 
N 
Proportion of 
Subjects with BV 
Recurrence 
BV Recurrence 
95% CI1 
Odds of BV 
Recurrence in 
LACTIN-V Group 
Compared to Placebo 
Group 
Odds of BV Recurrence 
in LACTIN-V Group 
Compared to Placebo 
Group 
95% CI2 
p-value3 
CC 
LACTIN-V 
x 
x 
0.xx 
0.xx, 0.xx 
x.xx 
x.xx, x.xx 
0.xxx 
Placebo 
x 
x 
0.xx 
0.xx, 0.xx 
-- 
-- 
 
All Subjects 
x 
x 
0.xx 
0.xx, 0.xx 
-- 
-- 
 
PP 
LACTIN-V 
x 
x 
0.xx 
0.xx, 0.xx 
x.xx 
x.xx, x.xx 
0.xxx 
Placebo 
x 
x 
0.xx 
0.xx, 0.xx 
-- 
-- 
 
All Subjects 
x 
x 
0.xx 
0.xx, 0.xx 
-- 
-- 
 
Note: The denominator for rate estimates is based on the number of subjects in the respective treatment group and analysis population. 
1: 95% CI= 95% Wilson confidence interval 
2: Difference in 95% CI=asymptotic 95% CI from a Chi-Square test 
3: p-value calculated from the Chi Square Test. 
 
Table with similar format: 
Table 20: 
BV Recurrence by Visit 7 (Week 24) by Analysis Population and Treatment Group – Excluding Subjects Receiving Additional BV 
Treatment 


Statistical Analysis Plan - DMID Protocol: 14-0029  
Version 1.0 
11MAY2018 
- 63 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Table 21: 
L. crispatus Colonization through Visit 4 (Week 12) by Analysis Population and Treatment Group 
Analysis 
Population 
Treatment Group 
Number of Subjects 
with Colonization 
n 
Number of 
Subjects 
N 
Proportion of 
Subjects with 
Colonization 
Colonization 
95% CI 
Odds of Colonization in 
LACTIN-V Group 
Compared to Placebo 
Group 
Odds of Colonization in 
LACTIN-V Group 
Compared to Placebo 
Group 
95% CI 
p-value1 
ITT 
LACTIN-V 
x 
x 
0.xx 
0.xx, 0.xx 
x.xx 
x.xx, x.xx 
0.xxx 
Placebo 
x 
x 
0.xx 
0.xx, 0.xx 
-- 
-- 
 
All Subjects 
x 
x 
0.xx 
0.xx, 0.xx 
-- 
-- 
 
mITT 
LACTIN-V 
x 
x 
0.xx 
0.xx, 0.xx 
x.xx 
x.xx, x.xx 
0.xxx 
Placebo 
x 
x 
0.xx 
0.xx, 0.xx 
-- 
-- 
 
All Subjects 
x 
x 
0.xx 
0.xx, 0.xx 
-- 
-- 
 
CC 
LACTIN-V 
x 
x 
0.xx 
0.xx, 0.xx 
x.xx 
x.xx, x.xx 
0.xxx 
Placebo 
x 
x 
0.xx 
0.xx, 0.xx 
-- 
-- 
 
All Subjects 
x 
x 
0.xx 
0.xx, 0.xx 
-- 
-- 
 
PP 
LACTIN-V 
x 
x 
0.xx 
0.xx, 0.xx 
x.xx 
x.xx, x.xx 
0.xxx 
Placebo 
x 
x 
0.xx 
0.xx, 0.xx 
-- 
-- 
 
All Subjects 
x 
x 
0.xx 
0.xx, 0.xx 
-- 
-- 
 
Note: The denominator for rate estimates is based on the number of subjects in the respective treatment group and analysis population. 
1: 95% CI= 95% Wilson confidence interval 
2: Difference in 95% CI=asymptotic 95% CI from a Chi-Square test 
3: p-value calculated from the Chi Square Test. 
 
Tables with similar format: 
Table 22: 
L. crispatus Colonization at Visit 7 (Week 24) by Analysis Population and Treatment Group 
 


Statistical Analysis Plan - DMID Protocol: 14-0029  
Version 1.0 
11MAY2018 
- 64 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Table 23: 
L. crispatus Colonization by Study Day and Treatment Group – ITT Population 
Study Day 
(Week) 
Treatment Group 
Number of Subjects 
with Colonization 
n 
Number of 
Subjects 
N 
Proportion of 
Subjects with 
Colonization 
Colonization 
95% CI1 
Odds of Colonization in 
LACTIN-V Group 
Compared to Placebo 
Group 
Odds of Colonization in 
LACTIN-V Group Compared to 
Placebo Group 
95% CI2 
p-value3 
Day 1 
LACTIN-V 
x 
x 
0.xx 
0.xx, 0.xx 
x.xx 
x.xx, x.xx 
0.xxx 
Placebo 
x 
x 
0.xx 
0.xx, 0.xx 
-- 
-- 
 
All Subjects 
x 
x 
0.xx 
0.xx, 0.xx 
-- 
-- 
 
Day 28 
(Week 4) 
LACTIN-V 
x 
x 
0.xx 
0.xx, 0.xx 
x.xx 
x.xx, x.xx 
0.xxx 
Placebo 
x 
x 
0.xx 
0.xx, 0.xx 
-- 
-- 
 
All Subjects 
x 
x 
0.xx 
0.xx, 0.xx 
-- 
-- 
 
Day 56 
(Week 8) 
LACTIN-V 
x 
x 
0.xx 
0.xx, 0.xx 
x.xx 
x.xx, x.xx 
0.xxx 
Placebo 
x 
x 
0.xx 
0.xx, 0.xx 
-- 
-- 
 
All Subjects 
x 
x 
0.xx 
0.xx, 0.xx 
-- 
-- 
 
Day 84 
(Week 12) 
LACTIN-V 
x 
x 
0.xx 
0.xx, 0.xx 
x.xx 
x.xx, x.xx 
0.xxx 
Placebo 
x 
x 
0.xx 
0.xx, 0.xx 
-- 
-- 
 
All Subjects 
x 
x 
0.xx 
0.xx, 0.xx 
-- 
-- 
 
Day 168 
(Week 24) 
LACTIN-V 
x 
x 
0.xx 
0.xx, 0.xx 
x.xx 
x.xx, x.xx 
0.xxx 
Placebo 
x 
x 
0.xx 
0.xx, 0.xx 
-- 
-- 
 
All Subjects 
x 
x 
0.xx 
0.xx, 0.xx 
-- 
-- 
 
Note: The denominator for rate estimates is based on the number of subjects in the respective treatment group and analysis population with colonization data available at the specified visit. 
1: 95% CI= 95% Wilson confidence interval 
2: Difference in 95% CI=asymptotic 95% CI from a Chi-Square test 
3: p-value calculated from the Chi Square Test. 
 
Tables with similar format: 
Table 24: 
L. crispatus Colonization by Study Day and Treatment Group – mITT Population 
Table 25: 
L. crispatus Colonization by Study Day and Treatment Group – CC Population 
Table 26: 
L. crispatus Colonization by Study Day and Treatment Group – PP Population 
 


Statistical Analysis Plan - DMID Protocol: 14-0029  
Version 1.0 
11MAY2018 
- 65 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Table 27: 
L. crispatus CTV-05 Concentration by Study Day and Treatment Group – ITT 
Population 
Study Day (Week) 
Treatment Group 
Number of 
Subjects1 
Mean (SD) 
Median 
Range 
Day 1 
LACTIN-V 
x 
x.xx (x.xx) 
x.xx 
x.xx, x.xx 
Placebo 
x 
x.xx (x.xx) 
x.xx 
x.xx, x.xx 
All Subjects 
x 
x.xx (x.xx) 
x.xx 
x.xx, x.xx 
Day 28 (Week 4) 
LACTIN-V 
x 
x.xx (x.xx) 
x.xx 
x.xx, x.xx 
Placebo 
x 
x.xx (x.xx) 
x.xx 
x.xx, x.xx 
All Subjects 
x 
x.xx (x.xx) 
x.xx 
x.xx, x.xx 
Day 56 (Week 8) 
LACTIN-V 
x 
x.xx (x.xx) 
x.xx 
x.xx, x.xx 
Placebo 
x 
x.xx (x.xx) 
x.xx 
x.xx, x.xx 
All Subjects 
x 
x.xx (x.xx) 
x.xx 
x.xx, x.xx 
Day 84 (Week 12) 
LACTIN-V 
x 
x.xx (x.xx) 
x.xx 
x.xx, x.xx 
Placebo 
x 
x.xx (x.xx) 
x.xx 
x.xx, x.xx 
All Subjects 
x 
x.xx (x.xx) 
x.xx 
x.xx, x.xx 
Day 168 (Week 24) 
LACTIN-V 
x 
x.xx (x.xx) 
x.xx 
x.xx, x.xx 
Placebo 
x 
x.xx (x.xx) 
x.xx 
x.xx, x.xx 
All Subjects 
x 
x.xx (x.xx) 
x.xx 
x.xx, x.xx 
1: The number of subjects in the respective treatment group and analysis population with concentration data available at the specified visit. 
 
Tables with similar format: 
Table 28: 
L. crispatus CTV-05 Concentration by Study Day and Treatment Group – mITT 
Population 
Table 29: 
L. crispatus CTV-05 Concentration by Study Day and Treatment Group – CC Population 
Table 30: 
L. crispatus CTV-05 Concentration by Study Day and Treatment Group – PP Population 
 


Statistical Analysis Plan - DMID Protocol: 14-0029  
Version 1.0 
11MAY2018 
- 66 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Table 31: 
L. crispatus Colonization by Study Day, Treatment Group, and Number of Condom-less 
Sexual Intercourse Acts – ITT Population 
Study Day 
(Week) 
Treatment 
Group 
Number of Condom-less Sex 
Acts Since the Previous Visit 
Number of Subjects 
with Colonization 
n 
Number of 
Subjects 
N 
Proportion of Subjects 
with Colonization 
Colonization 
95% CI1 
Day 1* 
LACTIN-V 
1st Quartile 
x 
x 
0.xx 
0.xx, 0.xx 
2nd Quartile 
x 
x 
0.xx 
0.xx, 0.xx 
3rd Quartile 
x 
x 
0.xx 
0.xx, 0.xx 
4th Quartile 
x 
x 
0.xx 
0.xx, 0.xx 
Placebo 
1st Quartile 
x 
x 
0.xx 
0.xx, 0.xx 
2nd Quartile 
x 
x 
0.xx 
0.xx, 0.xx 
3rd Quartile 
x 
x 
0.xx 
0.xx, 0.xx 
4th Quartile 
x 
x 
0.xx 
0.xx, 0.xx 
All Subjects 
1st Quartile 
x 
x 
0.xx 
0.xx, 0.xx 
2nd Quartile 
x 
x 
0.xx 
0.xx, 0.xx 
3rd Quartile 
x 
x 
0.xx 
0.xx, 0.xx 
4th Quartile 
x 
x 
0.xx 
0.xx, 0.xx 
Day 28 
(Week 4) 
LACTIN-V 
1st Quartile 
x 
x 
0.xx 
0.xx, 0.xx 
2nd Quartile 
x 
x 
0.xx 
0.xx, 0.xx 
3rd Quartile 
x 
x 
0.xx 
0.xx, 0.xx 
4th Quartile 
x 
x 
0.xx 
0.xx, 0.xx 
Placebo 
1st Quartile 
x 
x 
0.xx 
0.xx, 0.xx 
2nd Quartile 
x 
x 
0.xx 
0.xx, 0.xx 
3rd Quartile 
x 
x 
0.xx 
0.xx, 0.xx 
4th Quartile 
x 
x 
0.xx 
0.xx, 0.xx 
All Subjects 
1st Quartile 
x 
x 
0.xx 
0.xx, 0.xx 
2nd Quartile 
x 
x 
0.xx 
0.xx, 0.xx 
3rd Quartile 
x 
x 
0.xx 
0.xx, 0.xx 
4th Quartile 
x 
x 
0.xx 
0.xx, 0.xx 
Day 56 
(Week 8) 
LACTIN-V 
1st Quartile 
x 
x 
0.xx 
0.xx, 0.xx 
2nd Quartile 
x 
x 
0.xx 
0.xx, 0.xx 
3rd Quartile 
x 
x 
0.xx 
0.xx, 0.xx 
4th Quartile 
x 
x 
0.xx 
0.xx, 0.xx 
Placebo 
1st Quartile 
x 
x 
0.xx 
0.xx, 0.xx 
2nd Quartile 
x 
x 
0.xx 
0.xx, 0.xx 
3rd Quartile 
x 
x 
0.xx 
0.xx, 0.xx 
4th Quartile 
x 
x 
0.xx 
0.xx, 0.xx 
All Subjects 
1st Quartile 
x 
x 
0.xx 
0.xx, 0.xx 
2nd Quartile 
x 
x 
0.xx 
0.xx, 0.xx 
3rd Quartile 
x 
x 
0.xx 
0.xx, 0.xx 


Statistical Analysis Plan - DMID Protocol: 14-0029  
Version 1.0 
11MAY2018 
- 67 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Study Day 
(Week) 
Treatment 
Group 
Number of Condom-less Sex 
Acts Since the Previous Visit 
Number of Subjects 
with Colonization 
n 
Number of 
Subjects 
N 
Proportion of Subjects 
with Colonization 
Colonization 
95% CI1 
4th Quartile 
x 
x 
0.xx 
0.xx, 0.xx 
Day 84 
(Week 12) 
LACTIN-V 
1st Quartile 
x 
x 
0.xx 
0.xx, 0.xx 
2nd Quartile 
x 
x 
0.xx 
0.xx, 0.xx 
3rd Quartile 
x 
x 
0.xx 
0.xx, 0.xx 
4th Quartile 
x 
x 
0.xx 
0.xx, 0.xx 
Placebo 
1st Quartile 
x 
x 
0.xx 
0.xx, 0.xx 
2nd Quartile 
x 
x 
0.xx 
0.xx, 0.xx 
3rd Quartile 
x 
x 
0.xx 
0.xx, 0.xx 
4th Quartile 
x 
x 
0.xx 
0.xx, 0.xx 
All Subjects 
1st Quartile 
x 
x 
0.xx 
0.xx, 0.xx 
2nd Quartile 
x 
x 
0.xx 
0.xx, 0.xx 
3rd Quartile 
x 
x 
0.xx 
0.xx, 0.xx 
4th Quartile 
x 
x 
0.xx 
0.xx, 0.xx 
Day 168 
(Week 24) 
LACTIN-V 
1st Quartile 
x 
x 
0.xx 
0.xx, 0.xx 
2nd Quartile 
x 
x 
0.xx 
0.xx, 0.xx 
3rd Quartile 
x 
x 
0.xx 
0.xx, 0.xx 
4th Quartile 
x 
x 
0.xx 
0.xx, 0.xx 
Placebo 
1st Quartile 
x 
x 
0.xx 
0.xx, 0.xx 
2nd Quartile 
x 
x 
0.xx 
0.xx, 0.xx 
3rd Quartile 
x 
x 
0.xx 
0.xx, 0.xx 
4th Quartile 
x 
x 
0.xx 
0.xx, 0.xx 
All Subjects 
1st Quartile 
x 
x 
0.xx 
0.xx, 0.xx 
2nd Quartile 
x 
x 
0.xx 
0.xx, 0.xx 
3rd Quartile 
x 
x 
0.xx 
0.xx, 0.xx 
4th Quartile 
x 
x 
0.xx 
0.xx, 0.xx 
Note: The denominator for rate estimates is based on the number of subjects in the respective treatment group and analysis population with 
colonization and condomless sex act data available at the specified visit. 
*Number of condom-less sexual intercourse acts in the last 30 days 
1: 95% CI= 95% Wilson confidence interval  
Implementation note: Quartiles will be filled in with the actual ranges 
 
 


Statistical Analysis Plan - DMID Protocol: 14-0029  
Version 1.0 
11MAY2018 
- 68 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
 
Tables with similar format: 
Table 32: 
L. crispatus Colonization by Study Day, Treatment Group, and Number of Condom-less 
Sexual Intercourse Acts – mITT  
Table 33: 
L. crispatus Colonization by Study Day, Treatment Group, and Number of Condom-less 
Sexual Intercourse Acts – CC Population 
Table 34: 
L. crispatus Colonization by Study Day, Treatment Group, and Number of Condom-less 
Sexual Intercourse Acts – PP Population 


Statistical Analysis Plan - DMID Protocol: 14-0029  
Version 1.0 
11MAY2018 
- 69 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Table 35: 
L. crispatus Colonization by Study Day, Treatment Group, and Number of Partners – 
ITT Population 
Study Day 
(Week) 
Treatment 
Group 
Number of Partners 
Since the Previous Visit 
Number of Subjects 
with Colonization 
n 
Number of 
Subjects 
N 
Proportion of Subjects 
with Colonization 
Colonization 
95% CI1 
Day 1* 
LACTIN-V 
No Partners 
x 
x 
0.xx 
0.xx, 0.xx 
1 Partner 
x 
x 
0.xx 
0.xx, 0.xx 
>1 Partner 
x 
x 
0.xx 
0.xx, 0.xx 
Placebo 
No Partners 
x 
x 
0.xx 
0.xx, 0.xx 
1 Partner 
x 
x 
0.xx 
0.xx, 0.xx 
>1 Partner 
x 
x 
0.xx 
0.xx, 0.xx 
All Subjects 
No Partners 
x 
x 
0.xx 
0.xx, 0.xx 
1 Partner 
x 
x 
0.xx 
0.xx, 0.xx 
>1 Partner 
x 
x 
0.xx 
0.xx, 0.xx 
Day 28 
(Week 4) 
LACTIN-V 
No Partners 
x 
x 
0.xx 
0.xx, 0.xx 
1 Partner 
x 
x 
0.xx 
0.xx, 0.xx 
>1 Partner 
x 
x 
0.xx 
0.xx, 0.xx 
Placebo 
No Partners 
x 
x 
0.xx 
0.xx, 0.xx 
1 Partner 
x 
x 
0.xx 
0.xx, 0.xx 
>1 Partner 
x 
x 
0.xx 
0.xx, 0.xx 
All Subjects 
No Partners 
x 
x 
0.xx 
0.xx, 0.xx 
1 Partner 
x 
x 
0.xx 
0.xx, 0.xx 
>1 Partner 
x 
x 
0.xx 
0.xx, 0.xx 
Day 56 
(Week 8) 
LACTIN-V 
No Partners 
x 
x 
0.xx 
0.xx, 0.xx 
1 Partner 
x 
x 
0.xx 
0.xx, 0.xx 
>1 Partner 
x 
x 
0.xx 
0.xx, 0.xx 
Placebo 
No Partners 
x 
x 
0.xx 
0.xx, 0.xx 
1 Partner 
x 
x 
0.xx 
0.xx, 0.xx 
>1 Partner 
x 
x 
0.xx 
0.xx, 0.xx 
All Subjects 
No Partners 
x 
x 
0.xx 
0.xx, 0.xx 
1 Partner 
x 
x 
0.xx 
0.xx, 0.xx 
>1 Partner 
x 
x 
0.xx 
0.xx, 0.xx 
Day 84 
(Week 12) 
LACTIN-V 
No Partners 
x 
x 
0.xx 
0.xx, 0.xx 
1 Partner 
x 
x 
0.xx 
0.xx, 0.xx 
>1 Partner 
x 
x 
0.xx 
0.xx, 0.xx 
Placebo 
No Partners 
x 
x 
0.xx 
0.xx, 0.xx 
1 Partner 
x 
x 
0.xx 
0.xx, 0.xx 
>1 Partner 
x 
x 
0.xx 
0.xx, 0.xx 
All Subjects 
No Partners 
x 
x 
0.xx 
0.xx, 0.xx 
1 Partner 
x 
x 
0.xx 
0.xx, 0.xx 
>1 Partner 
x 
x 
0.xx 
0.xx, 0.xx 


Statistical Analysis Plan - DMID Protocol: 14-0029  
Version 1.0 
11MAY2018 
- 70 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Study Day 
(Week) 
Treatment 
Group 
Number of Partners 
Since the Previous Visit 
Number of Subjects 
with Colonization 
n 
Number of 
Subjects 
N 
Proportion of Subjects 
with Colonization 
Colonization 
95% CI1 
Day 168 
(Week 24) 
LACTIN-V 
No Partners 
x 
x 
0.xx 
0.xx, 0.xx 
1 Partner 
x 
x 
0.xx 
0.xx, 0.xx 
>1 Partner 
x 
x 
0.xx 
0.xx, 0.xx 
Placebo 
No Partners 
x 
x 
0.xx 
0.xx, 0.xx 
1 Partner 
x 
x 
0.xx 
0.xx, 0.xx 
>1 Partner 
x 
x 
0.xx 
0.xx, 0.xx 
All Subjects 
No Partners 
x 
x 
0.xx 
0.xx, 0.xx 
1 Partner 
x 
x 
0.xx 
0.xx, 0.xx 
>1 Partner 
x 
x 
0.xx 
0.xx, 0.xx 
Note: The denominator for rate estimates is based on the number of subjects in the respective treatment group and analysis population with 
colonization and sexual partner data available at the specified visit. 
*Number of male and female partners in the last 6 months 
1: 95% CI= 95% Wilson confidence interval 
 
Tables with similar format: 
Table 36: 
L. crispatus Colonization by Study Day, Treatment Group, and Number of Partners– 
mITT  
Table 37: 
L. crispatus Colonization by Study Day, Treatment Group, and Number of Partners – CC 
Population 
Table 38: 
L. crispatus Colonization by Study Day, Treatment Group, and Number of Partners – PP 
Population 
 


Statistical Analysis Plan - DMID Protocol: 14-0029  
Version 1.0 
11MAY2018 
- 71 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Table 39: 
Days Since Last Dose by Study Day, Treatment Group, and L. crispatus Colonization 
Status – ITT Population 
Study Day (Week) 
Treatment Group 
Colonization 
Status 
Number of 
Subjects1 
Mean (SD) 
Median 
Range 
Day 28 (Week 4) 
LACTIN-V 
Yes 
x 
x.xx (x.xx) 
x.xx 
x.xx, x.xx 
No 
x 
x.xx (x.xx) 
x.xx 
x.xx, x.xx 
Placebo 
Yes 
x 
x.xx (x.xx) 
x.xx 
x.xx, x.xx 
No 
x 
x.xx (x.xx) 
x.xx 
x.xx, x.xx 
All Subjects 
Yes 
x 
x.xx (x.xx) 
x.xx 
x.xx, x.xx 
 
No 
x 
x.xx (x.xx) 
x.xx 
x.xx, x.xx 
Day 56 (Week 8) 
LACTIN-V 
Yes 
x 
x.xx (x.xx) 
x.xx 
x.xx, x.xx 
No 
x 
x.xx (x.xx) 
x.xx 
x.xx, x.xx 
Placebo 
Yes 
x 
x.xx (x.xx) 
x.xx 
x.xx, x.xx 
No 
x 
x.xx (x.xx) 
x.xx 
x.xx, x.xx 
All Subjects 
Yes 
x 
x.xx (x.xx) 
x.xx 
x.xx, x.xx 
No 
x 
x.xx (x.xx) 
x.xx 
x.xx, x.xx 
Continue for Day 84 (Week 12) and Day 168 (Week 24) 
1: The number of subjects in the respective treatment group and analysis population with concentration and dosing data available at the specified 
visit. 
 
Tables with similar format: 
Table 40: 
Days Since Last Dose by Study Day, Treatment Group, and L. crispatus Colonization 
Status – mITT Population 
Table 41: 
Days Since Last Dose by Study Day, Treatment Group, and L. crispatus Colonization 
Status – CC Population 
Table 42: 
Days Since Last Dose by Study Day, Treatment Group, and L. crispatus Colonization 
Status – PP Population 
 


Statistical Analysis Plan - DMID Protocol: 14-0029  
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Table 43: 
L. crispatus Colonization by Study Day, Treatment Group, and Treatment Compliance – ITT Population 
Study 
Day 
(Week) 
Treatment 
Group 
Treatment 
Compliance 
Status 
Number of Subjects 
with Colonization 
n 
Number of 
Subjects 
N 
Proportion of 
Subjects with 
Colonization 
Colonization 
95% CI1 
Odds of Colonization in 
Compliant Group Compared to 
Not Compliant Group 
Odds of Colonization in Compliant Group 
Compared to Not Compliant Group 
95% CI2 
Day 28 
(Week 4) 
LACTIN-V 
Compliant 
x 
x 
0.xx 
0.xx, 0.xx 
x.xx 
x.xx, x.xx 
Not Compliant 
x 
x 
0.xx 
0.xx, 0.xx 
-- 
-- 
Placebo 
Compliant 
x 
x 
0.xx 
0.xx, 0.xx 
x.xx 
x.xx, x.xx 
Not Compliant 
x 
x 
0.xx 
0.xx, 0.xx 
-- 
-- 
All Subjects 
Compliant 
x 
x 
0.xx 
0.xx, 0.xx 
x.xx 
x.xx, x.xx 
Not Compliant 
x 
x 
0.xx 
0.xx, 0.xx 
-- 
-- 
Day 56 
(Week 8) 
LACTIN-V 
Compliant 
x 
x 
0.xx 
0.xx, 0.xx 
x.xx 
x.xx, x.xx 
Not Compliant 
x 
x 
0.xx 
0.xx, 0.xx 
-- 
-- 
Placebo 
Compliant 
x 
x 
0.xx 
0.xx, 0.xx 
x.xx 
x.xx, x.xx 
Not Compliant 
x 
x 
0.xx 
0.xx, 0.xx 
-- 
-- 
All Subjects 
Compliant 
x 
x 
0.xx 
0.xx, 0.xx 
x.xx 
x.xx, x.xx 
Not Compliant 
x 
x 
0.xx 
0.xx, 0.xx 
-- 
-- 
Day 84 
(Week 12) 
LACTIN-V 
Compliant 
x 
x 
0.xx 
0.xx, 0.xx 
x.xx 
x.xx, x.xx 
Not Compliant 
x 
x 
0.xx 
0.xx, 0.xx 
-- 
-- 
Placebo 
Compliant 
x 
x 
0.xx 
0.xx, 0.xx 
x.xx 
x.xx, x.xx 
Not Compliant 
x 
x 
0.xx 
0.xx, 0.xx 
-- 
-- 
All Subjects 
Compliant 
x 
x 
0.xx 
0.xx, 0.xx 
x.xx 
x.xx, x.xx 
Not Compliant 
x 
x 
0.xx 
0.xx, 0.xx 
-- 
-- 
Day 168 
(Week 24) 
LACTIN-V 
Compliant 
x 
x 
0.xx 
0.xx, 0.xx 
x.xx 
x.xx, x.xx 
Not Compliant 
x 
x 
0.xx 
0.xx, 0.xx 
-- 
-- 
Placebo 
Compliant 
x 
x 
0.xx 
0.xx, 0.xx 
x.xx 
x.xx, x.xx 
Not Compliant 
x 
x 
0.xx 
0.xx, 0.xx 
-- 
-- 
All Subjects 
Compliant 
x 
x 
0.xx 
0.xx, 0.xx 
x.xx 
x.xx, x.xx 
Not Compliant 
x 
x 
0.xx 
0.xx, 0.xx 
-- 
-- 
Note: The denominator for rate estimates is based on the number of subjects in the respective treatment group and analysis population with colonization and compliance data available at the specified 
visit. 
Treatment compliance is assessed up until the respective visit 
1: 95% CI= 95% Wilson confidence interval 
2: Difference in 95% CI=asymptotic 95% CI from a Chi-Square test 
 


Statistical Analysis Plan - DMID Protocol: 14-0029  
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Tables with similar format: 
Table 44: 
L. crispatus Colonization by Study Day, Treatment Group, and Treatment Compliance – mITT Population 
Table 45: 
L. crispatus Colonization by Study Day, Treatment Group, and Treatment Compliance – CC Population 


Statistical Analysis Plan - DMID Protocol: 14-0029  
Version 1.0 
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Table 46: 
Days Since Last Day of Last Menstrual Period by Study Day, Treatment Group, and L. 
crispatus Colonization Status – ITT Population 
Study Day (Week) 
Treatment Group 
Colonization 
Status 
Number of 
Subjects1 
Mean (SD) 
Median 
Range 
Day 28 (Week 4) 
LACTIN-V 
Yes 
x 
x.xx (x.xx) 
x.xx 
x.xx, x.xx 
No 
x 
x.xx (x.xx) 
x.xx 
x.xx, x.xx 
Placebo 
Yes 
x 
x.xx (x.xx) 
x.xx 
x.xx, x.xx 
No 
x 
x.xx (x.xx) 
x.xx 
x.xx, x.xx 
All Subjects 
Yes 
x 
x.xx (x.xx) 
x.xx 
x.xx, x.xx 
 
No 
x 
x.xx (x.xx) 
x.xx 
x.xx, x.xx 
Day 56 (Week 8) 
LACTIN-V 
Yes 
x 
x.xx (x.xx) 
x.xx 
x.xx, x.xx 
No 
x 
x.xx (x.xx) 
x.xx 
x.xx, x.xx 
Placebo 
Yes 
x 
x.xx (x.xx) 
x.xx 
x.xx, x.xx 
No 
x 
x.xx (x.xx) 
x.xx 
x.xx, x.xx 
All Subjects 
Yes 
x 
x.xx (x.xx) 
x.xx 
x.xx, x.xx 
No 
x 
x.xx (x.xx) 
x.xx 
x.xx, x.xx 
Continue for Day 84 (Week 12), and Day 168 (Week 24) 
1: The number of subjects in the respective treatment group and analysis population with concentration and menses data available at the specified 
visit. 
 
Tables with similar format: 
Table 47: 
Days Since Last Day of Last Menstrual Period by Study Day, Treatment Group, and L. 
crispatus Colonization Status – mITT Population 
Table 48: 
Days Since Last Day of Last Menstrual Period by Study Day, Treatment Group, and L. 
crispatus Colonization Status – CC Population 
Table 49: 
Days Since Last Day of Last Menstrual Period by Study Day, Treatment Group, and L. 
crispatus Colonization Status – PP Population 


Statistical Analysis Plan - DMID Protocol: 14-0029  
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Table 50: 
L. crispatus Colonization by Study Day, Treatment Group, and Occurrence of Menses After Last Dose Taken – ITT Population 
Study Day 
(Week) 
Treatment Group 
Occurrence of 
Menses 
Number of 
Subjects with 
Colonization 
n 
Number of 
Subjects 
N 
Proportion of 
Subjects with 
Colonization 
Colonization 
95% CI1 
Odds of Colonization in 
Subjects with Menses 
Compared to Subjects with 
No Menses 
Odds of Colonization in 
Subjects with Menses 
Compared to Subjects with 
No Menses 
95% CI2 
Day 28 
(Week 4) 
LACTIN-V 
Menses since last dose  
x 
x 
0.xx 
0.xx, 0.xx 
x.xx 
x.xx, x.xx 
No menses since last 
dose 
x 
x 
0.xx 
0.xx, 0.xx 
-- 
-- 
Placebo 
Menses since last dose  
x 
x 
0.xx 
0.xx, 0.xx 
x.xx 
x.xx, x.xx 
No menses since last 
dose 
x 
x 
0.xx 
0.xx, 0.xx 
-- 
-- 
Day 56 
(Week 8) 
LACTIN-V 
Menses since last dose  
x 
x 
0.xx 
0.xx, 0.xx 
x.xx 
x.xx, x.xx 
No menses since last 
dose 
x 
x 
0.xx 
0.xx, 0.xx 
-- 
-- 
Placebo 
Menses since last dose  
x 
x 
0.xx 
0.xx, 0.xx 
x.xx 
x.xx, x.xx 
No menses since last 
dose 
x 
x 
0.xx 
0.xx, 0.xx 
-- 
-- 
Day 84 
(Week 12) 
LACTIN-V 
Menses since last dose  
x 
x 
0.xx 
0.xx, 0.xx 
x.xx 
x.xx, x.xx 
No menses since last 
dose 
x 
x 
0.xx 
0.xx, 0.xx 
-- 
-- 
Placebo 
Menses since last dose  
x 
x 
0.xx 
0.xx, 0.xx 
x.xx 
x.xx, x.xx 
No menses since last 
dose 
x 
x 
0.xx 
0.xx, 0.xx 
-- 
-- 
Day 168 
(Week 24) 
LACTIN-V 
Menses since last dose  
x 
x 
0.xx 
0.xx, 0.xx 
x.xx 
x.xx, x.xx 
No menses since last 
dose 
x 
x 
0.xx 
0.xx, 0.xx 
-- 
-- 
Placebo 
Menses since last dose  
x 
x 
0.xx 
0.xx, 0.xx 
x.xx 
x.xx, x.xx 
 
 
No menses since last 
dose 
x 
x 
0.xx 
0.xx, 0.xx 
-- 
-- 
Note: The denominator for rate estimates is based on the number of subjects in the respective treatment group and analysis population witih colonization and menses data available at the specified visit. 
1: 95% CI= 95% Wilson confidence interval 
2: Difference in 95% CI=asymptotic 95% CI from a Chi-Square test 


Statistical Analysis Plan - DMID Protocol: 14-0029  
Version 1.0 
11MAY2018 
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PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
 
Tables with similar format: 
Table 51: 
L. crispatus Colonization by Study Day, Treatment Group, and Occurrence of Menses After Last Dose Taken – mITT Population 
Table 52: 
L. crispatus Colonization by Study Day, Treatment Group, and Occurrence of Menses After Last Dose Taken – CC Population 
Table 53: 
L. crispatus Colonization by Study Day, Treatment Group, and Occurrence of Menses After Last Dose Taken – PP Population 


Statistical Analysis Plan - DMID Protocol: 14-0029  
Version 1.0 
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PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Table 54: 
Time to L. crispatus Colonization by Analysis Population and Treatment Group 
 
ITT 
mITT 
CC 
PP 
 
LACTIN-V 
(N = xxx) 
Placebo 
(N = xxx) 
All Subjects 
(N = xxx) 
LACTIN-V 
(N = xxx) 
Placebo 
(N = xxx) 
All Subjects 
(N = xxx) 
LACTIN-V 
(N = xxx) 
Placebo 
(N = xxx) 
All Subjects 
(N = xxx) 
LACTIN-V 
(N = xxx) 
Placebo 
(N = xxx) 
All Subjects 
(N = xxx) 
Number (%) of subjects 
with Colonization 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
Median Time (days) 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
Median Time (days) 95% 
CI 
x.x, x.x 
x.x, x.x 
x.x, x.x 
x.x, x.x 
x.x, x.x 
x.x, x.x 
x.x, x.x 
x.x, x.x 
x.x, x.x 
x.x, x.x 
x.x, x.x 
x.x, x.x 
Minimum (days) 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Q1 (days) 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Q3 (days) 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Maximum (days) 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Notes: Median time and median time 95% CI comes from Kaplan-Meier estimates 
 


Statistical Analysis Plan - DMID Protocol: 14-0029  
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11MAY2018 
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PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Table 55: 
Treatment Compliance by Treatment Group and Analysis Population 
Analysis Population 
Treatment Group 
Number of 
Subjects 
Compliant with 
Dose Regimen 
n 
Number of 
Subjects 
N 
Proportion of 
Subjects 
Compliant with 
Dose Regimen 
Compliant 
95% CI1 
Difference in Proportion of 
Subjects Compliant with 
Dose Regimen between 
LACTIN-V Group and 
Placebo Group 
Difference in Proportion of 
Subjects Compliant with 
Dose Regimen between 
LACTIN-V Group and 
Placebo Group 
95% CI2 
p-value3 
ITT 
LACTIN-V 
x 
x 
0.xx 
0.xx, 0.xx 
0.xx 
0.xx, 0.xx 
0.xxx 
 
Placebo 
x 
x 
0.xx 
0.xx, 0.xx 
-- 
-- 
 
 
All Subjects 
x 
x 
0.xx 
0.xx, 0.xx 
-- 
-- 
 
mITT 
LACTIN-V 
x 
x 
0.xx 
0.xx, 0.xx 
0.xx 
0.xx, 0.xx 
0.xxx 
 
Placebo 
x 
x 
0.xx 
0.xx, 0.xx 
-- 
-- 
 
 
All Subjects 
x 
x 
0.xx 
0.xx, 0.xx 
-- 
-- 
 
CC 
LACTIN-V 
x 
x 
0.xx 
0.xx, 0.xx 
0.xx 
0.xx, 0.xx 
0.xxx 
 
Placebo 
x 
x 
0.xx 
0.xx, 0.xx 
-- 
-- 
 
 
All Subjects 
x 
x 
0.xx 
0.xx, 0.xx 
-- 
-- 
 
Note: The denominator for rate estimates is based on the number of subjects in the respective treatment group. 
1: 95% CI= 95% Wilson confidence interval 
2: Difference in 95% CI=asymptotic 95% CI from a Chi-Square test 
3: p-value calculated from the Chi Square Test. 


Statistical Analysis Plan - DMID Protocol: 14-0029  
Version 1.0 
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PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Table 56: 
Product Administration by Week, Dose Number, and Method of Assessment - Safety 
Population 
All Subjects (N=X) 
 
Subject Report 
Clinic Assessment of Product 
Accountability 
Staining Results 
Dose  
Dose Taken 
n (%) 
Dose Not 
Taken 
n (%) 
Used Applicators 
Returned 
Mean (Std) 
Unused Applicators 
Returned 
Mean (Std) 
Used Mean 
(Std) 
Unused 
Mean (Std) 
Indeterminate 
Mean (Std) 
Week 1 
1 
x (x) 
x (x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
2 
x (x) 
x (x) 
3 
x (x) 
x (x) 
4 
x (x) 
x (x) 
5 
x (x) 
x (x) 
Week 2 
1 
x (x) 
x (x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
2 
x (x) 
x (x) 
Week 3 
1 
x (x) 
x (x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
2 
x (x) 
x (x) 
Week 4 
1 
x (x) 
x (x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
2 
x (x) 
x (x) 
Week 5 
1 
x (x) 
x (x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
2 
x (x) 
x (x) 
Week 6 
1 
x (x) 
x (x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
2 
x (x) 
x (x) 
Week 7 
1 
x (x) 
x (x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
2 
x (x) 
x (x) 
Week 8 
1 
x (x) 
x (x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
2 
x (x) 
x (x) 
Week 9 
1 
x (x) 
x (x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
2 
x (x) 
x (x) 
Week 10 
1 
x (x) 
x (x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 


Statistical Analysis Plan - DMID Protocol: 14-0029  
Version 1.0 
11MAY2018 
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PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
 
Tables with similar format: 
Table 57: 
Product Administration by Site, Week, Dose Number, and Method of Assessment - Safety 
Population- San Francisco General Hospital 
Table 58: 
Product Administration by Site, Week, Dose Number, and Method of Assessment - Safety 
Population- Stroger Hospital of Cook County 
Table 59: 
Product Administration by Site, Week, Dose Number, and Method of Assessment - Safety 
Population- University of California San Diego 
Table 60: 
Product Administration by Site, Week, Dose Number, and Method of Assessment - Safety 
Population- Washington University in St. Louis 
Table 61: 
Product Administration by Treatment Group, Week, Dose Number, and Method of 
Assessment - Safety Population- LACTIN-V 
Table 62: 
Product Administration by Site, Week, Dose Number, and Method of Assessment - Safety 
Population- Placebo 
 
2 
x (x) 
x (x) 
Week 11 
1 
x (x) 
x (x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
x.x (x.x) 
2 
x (x) 
x (x) 
Note: Denominator of percentages is the number of subjects in the Safety Population. 


Statistical Analysis Plan - DMID Protocol: 14-0029  
Version 1.0 
11MAY2018 
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PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Table 63: 
Categorical Responses to Acceptability Questionnaire by Treatment Group – Screening Visit 
Questionnaire Item 
Response 
LACTIN-V 
(N = x) 
Placebo 
(N = x) 
Number of 
Subjects with 
Response 
n 
Number of 
Subjects 
Queried 
N 
Proportion of 
Subjects with 
Response 
Response 
95% CI1 
Number of 
Subjects with 
Response 
n 
Number of 
Subjects 
Queried 
N 
Proportion of 
Subjects with 
Response 
Response 
95% CI1 
How many episodes of BV have 
you experienced in your life? 
None 
x 
x 
0.xx 
0.xx, 0.xx 
x 
x 
0.xx 
0.xx, 0.xx 
1-2 
x 
x 
0.xx 
0.xx, 0.xx 
x 
x 
0.xx 
0.xx, 0.xx 
3-4 
x 
x 
0.xx 
0.xx, 0.xx 
x 
x 
0.xx 
0.xx, 0.xx 
5 or more 
x 
x 
0.xx 
0.xx, 0.xx 
x 
x 
0.xx 
0.xx, 0.xx 
Unknown 
x 
x 
0.xx 
0.xx, 0.xx 
x 
x 
0.xx 
0.xx, 0.xx 
If you have had BV in the past, 
what have you used for treatment? 
Nothing 
x 
x 
0.xx 
0.xx, 0.xx 
x 
x 
0.xx 
0.xx, 0.xx 
Antibiotics 
x 
x 
0.xx 
0.xx, 0.xx 
x 
x 
0.xx 
0.xx, 0.xx 
Probiotics 
x 
x 
0.xx 
0.xx, 0.xx 
x 
x 
0.xx 
0.xx, 0.xx 
Home remedies 
x 
x 
0.xx 
0.xx, 0.xx 
x 
x 
0.xx 
0.xx, 0.xx 
Other 
x 
x 
0.xx 
0.xx, 0.xx 
x 
x 
0.xx 
0.xx, 0.xx 
Unknown 
x 
x 
0.xx 
0.xx, 0.xx 
x 
x 
0.xx 
0.xx, 0.xx 
If you ever had BV and treated it, 
how would you reply to the 
following statement: “I believe the 
treatment I have previously used 
are effective in treating BV”. 
Strongly Agree 
x 
x 
0.xx 
0.xx, 0.xx 
x 
x 
0.xx 
0.xx, 0.xx 
Agree 
x 
x 
0.xx 
0.xx, 0.xx 
x 
x 
0.xx 
0.xx, 0.xx 
Neutral 
x 
x 
0.xx 
0.xx, 0.xx 
x 
x 
0.xx 
0.xx, 0.xx 
Disagree 
x 
x 
0.xx 
0.xx, 0.xx 
x 
x 
0.xx 
0.xx, 0.xx 
Strongly Disagree 
x 
x 
0.xx 
0.xx, 0.xx 
x 
x 
0.xx 
0.xx, 0.xx 
Etc. 
Notes: 
Denominator of percentages is the number of subjects in the Safety Population in the respective treatment group 
1: 95% CI= 95% Wilson confidence interval 
 
Tables with similar format: 
Table 64: 
Categorical Responses to Acceptability Questionnaire by Treatment Group –Visit 4 (Week 12) 
 


Statistical Analysis Plan - DMID Protocol: 14-0029  
Version 1.0 
11MAY2018 
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PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Table 65: 
Continuous/Discrete Responses to Acceptability Questionnaire by Treatment Group – Screening Visit 
Questionnaire Item 
Questionnaire Sub-Item 
LACTIN-V 
(N = x) 
Placebo 
(N = x) 
Mean (SD) 
Median 
Range 
Mean (SD) 
Median 
Range 
On a scale of 0 to 10, with 0 being “not at all 
bothersome” to 10 being “extremely 
bothersome”, I found the following symptoms 
of BV: 
Increase vaginal discharge 
xx.x (xx.xx) 
xx.xx 
xx.x, xx.x 
xx.x (xx.xx) 
xx.xx 
xx.x, xx.x 
Vaginal odor 
xx.x (xx.xx) 
xx.xx 
xx.x, xx.x 
xx.x (xx.xx) 
xx.xx 
xx.x, xx.x 
Vaginal irritation and itching 
xx.x (xx.xx) 
xx.xx 
xx.x, xx.x 
xx.x (xx.xx) 
xx.xx 
xx.x, xx.x 
Pain with urination 
xx.x (xx.xx) 
xx.xx 
xx.x, xx.x 
xx.x (xx.xx) 
xx.xx 
xx.x, xx.x 
Other 
xx.x (xx.xx) 
xx.xx 
xx.x, xx.x 
xx.x (xx.xx) 
xx.xx 
xx.x, xx.x 
On a scale of 0 to 10, with 0 being “not at all 
important” to 10 being “extremely important”, I 
would find the following characteristics 
important about such a product: 
Effective to treat BV 
xx.x (xx.xx) 
xx.xx 
xx.x, xx.x 
xx.x (xx.xx) 
xx.xx 
xx.x, xx.x 
Comfortable 
xx.x (xx.xx) 
xx.xx 
xx.x, xx.x 
xx.x (xx.xx) 
xx.xx 
xx.x, xx.x 
Easy to use 
xx.x (xx.xx) 
xx.xx 
xx.x, xx.x 
xx.x (xx.xx) 
xx.xx 
xx.x, xx.x 
Improved vaginal prescription 
xx.x (xx.xx) 
xx.xx 
xx.x, xx.x 
xx.x (xx.xx) 
xx.xx 
xx.x, xx.x 
Availability without prescription 
xx.x (xx.xx) 
xx.xx 
xx.x, xx.x 
xx.x (xx.xx) 
xx.xx 
xx.x, xx.x 
All-natural ingredients of the product 
xx.x (xx.xx) 
xx.xx 
xx.x, xx.x 
xx.x (xx.xx) 
xx.xx 
xx.x, xx.x 
Partner’s approval of the product 
xx.x (xx.xx) 
xx.xx 
xx.x, xx.x 
xx.x (xx.xx) 
xx.xx 
xx.x, xx.x 
Other 
xx.x (xx.xx) 
xx.xx 
xx.x, xx.x 
xx.x (xx.xx) 
xx.xx 
xx.x, xx.x 
Etc. 
Note: N= number of subjects in the Safety Population in the respective treatment group 
 
Tables with similar format: 
Table 66: 
Continuous/Discrete Responses to Acceptability Questionnaire by Treatment Group – Visit 4 (Week 12) 
 


Statistical Analysis Plan - DMID Protocol: 14-0029  
Version 1.0 
11MAY2018 
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PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Table 67: 
Model-Based Rate of Positive BV Diagnoses by Visit 4 (Week 12) by Analysis Population 
and Treatment Group 
Analysis 
Population 
Treatment Group 
Number of 
Subjects 
N 
Rate of BV 
Diagnoses 
n 
BV 
Diagnosis 
Rate 
95% CI 
BV Diagnosis Rate Ratio 
between LACTIN-V 
Group and Placebo 
Group 
BV Diagnosis Rate Ratio 
between LACTIN-V 
Group and Placebo Group 
95% CI 
ITT 
LACTIN-V 
x 
x.xx 
x.xx, x.xx 
x.xx 
x.xx, x.xx 
Placebo 
x 
x.xx 
x.xx, x.xx 
-- 
-- 
All Subjects 
x 
x.xx 
x.xx, x.xx 
-- 
-- 
mITT 
LACTIN-V 
x 
x.xx 
x.xx, x.xx 
x.xx 
x.xx, x.xx 
Placebo 
x 
x.xx 
x.xx, x.xx 
-- 
-- 
All Subjects 
x 
x.xx 
x.xx, x.xx 
-- 
-- 
CC 
LACTIN-V 
x 
x.xx 
x.xx, x.xx 
x.xx 
x.xx, x.xx 
Placebo 
x 
x.xx 
x.xx, x.xx 
-- 
-- 
All Subjects 
x 
x.xx 
x.xx, x.xx 
-- 
-- 
PP 
LACTIN-V 
x 
x.xx 
x.xx, x.xx 
x.xx 
x.xx, x.xx 
Placebo 
x 
x.xx 
x.xx, x.xx 
-- 
-- 
All Subjects 
x 
x.xx 
x.xx, x.xx 
-- 
-- 
 


Statistical Analysis Plan - DMID Protocol: 14-0029  
Version 1.0 
11MAY2018 
- 84 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Table 68: 
Model-Based Odds of Positive BV Diagnoses by Visit 4 (Week 12) by Analysis Population 
and Treatment Group 
Analysis 
Population 
Treatment Group 
Number of 
Subjects 
N 
Odds of BV 
Diagnoses 
n 
BV 
Diagnosis 
Odds 
95% CI 
BV Diagnosis Odds Ratio 
between LACTIN-V 
Group and Placebo 
Group 
BV Diagnosis Odds Ratio 
between LACTIN-V 
Group and Placebo Group 
95% CI 
ITT 
LACTIN-V 
x 
x.xx 
x.xx, x.xx 
x.xx 
x.xx, x.xx 
Placebo 
x 
x.xx 
x.xx, x.xx 
-- 
-- 
All Subjects 
x 
x.xx 
x.xx, x.xx 
-- 
-- 
mITT 
LACTIN-V 
x 
x.xx 
x.xx, x.xx 
x.xx 
x.xx, x.xx 
Placebo 
x 
x.xx 
x.xx, x.xx 
-- 
-- 
All Subjects 
x 
x.xx 
x.xx, x.xx 
-- 
-- 
CC 
LACTIN-V 
x 
x.xx 
x.xx, x.xx 
x.xx 
x.xx, x.xx 
Placebo 
x 
x.xx 
x.xx, x.xx 
-- 
-- 
All Subjects 
x 
x.xx 
x.xx, x.xx 
-- 
-- 
PP 
LACTIN-V 
x 
x.xx 
x.xx, x.xx 
x.xx 
x.xx, x.xx 
Placebo 
x 
x.xx 
x.xx, x.xx 
-- 
-- 
All Subjects 
x 
x.xx 
x.xx, x.xx 
-- 
-- 


Statistical Analysis Plan - DMID Protocol: 14-0029  
Version 1.0 
11MAY2018 
- 85 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Table 69: 
BV Recurrence by Visit 4 (Week 12) by Analysis Population, Treatment Group, and Race 
Analysis Population 
Treatment 
Group 
Race 
Number of 
Subjects with 
BV Recurrence 
n 
Number of 
Subjects 
N 
Proportion of 
Subjects with 
BV Recurrence 
BV Recurrence 
95% CI1 
Odds of BV 
Recurrence in 
LACTIN-V Group 
Compared to 
Placebo Group 
Odds of BV 
Recurrence in 
LACTIN-V Group 
Compared to Placebo 
Group 
95% CI2 
p-value3 
ITT 
(LOCF) 
LACTIN-V 
Black/African 
American 
x 
x 
0.xx 
0.xx, 0.xx 
x.xx 
x.xx, x.xx 
0.xxx 
White 
x 
x 
0.xx 
0.xx, 0.xx 
x.xx 
x.xx, x.xx 
0.xxx 
Other 
x 
x 
0.xx 
0.xx, 0.xx 
x.xx 
x.xx, x.xx 
0.xxx 
Placebo 
Black/African 
American 
x 
x 
0.xx 
0.xx, 0.xx 
-- 
-- 
 
White 
x 
x 
0.xx 
0.xx, 0.xx 
-- 
-- 
 
Other 
x 
x 
0.xx 
0.xx, 0.xx 
-- 
-- 
 
All Subjects 
Black/African 
American 
x 
x 
0.xx 
0.xx, 0.xx 
-- 
-- 
 
 
White 
x 
x 
0.xx 
0.xx, 0.xx 
-- 
-- 
 
 
Other 
x 
x 
0.xx 
0.xx, 0.xx 
-- 
-- 
 
Continue for mITT (LOCF), ITT (Worst Case), mITT (Worst Case), CC, and PP populations 
Note: The denominator for rate estimates is based on the number of subjects in the respective treatment group, race group, and analysis population. 
1: 95% CI= 95% Wilson confidence interval 
2: Difference in 95% CI=asymptotic 95% CI from a Chi-Square test 
3: p-value calculated from the Chi Square Test. 
 
Table with similar format: 
Table 70: 
BV Recurrence by Visit 7 (Week 24) by Analysis Population, Treatment Group, and Race 


Statistical Analysis Plan - DMID Protocol: 14-0029  
Version 1.0 
11MAY2018 
- 86 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Table 71: 
L. crispatus Colonization through Visit 4 (Week 12) by Analysis Population, Treatment Group, and Race 
Analysis 
Population 
Treatment Group 
Race 
Number of 
Subjects with 
Colonization 
n 
Number of 
Subjects 
N 
Proportion of 
Subjects with 
Colonization 
Colonization 
95% CI 
Odds of Colonization 
in LACTIN-V Group 
Compared to Placebo 
Group 
Odds of Colonization in 
LACTIN-V Group 
Compared to Placebo 
Group 
95% CI 
p-value1 
ITT 
LACTIN-V 
Black/African 
American 
x 
x 
0.xx 
0.xx, 0.xx 
x.xx 
x.xx, x.xx 
0.xxx 
White 
x 
x 
0.xx 
0.xx, 0.xx 
x.xx 
x.xx, x.xx 
0.xxx 
Other 
x 
x 
0.xx 
0.xx, 0.xx 
x.xx 
x.xx, x.xx 
0.xxx 
Placebo 
Black/African 
American 
x 
x 
0.xx 
0.xx, 0.xx 
-- 
-- 
 
White 
x 
x 
0.xx 
0.xx, 0.xx 
-- 
-- 
 
Other 
x 
x 
0.xx 
0.xx, 0.xx 
-- 
-- 
 
All Subjects 
Black/African 
American 
x 
x 
0.xx 
0.xx, 0.xx 
-- 
-- 
 
 
White 
x 
x 
0.xx 
0.xx, 0.xx 
-- 
-- 
 
 
Other 
x 
x 
0.xx 
0.xx, 0.xx 
-- 
-- 
 
Continue for mITT, CC, and PP populations 
Note: The denominator for rate estimates is based on the number of subjects in the respective treatment group, race group, and analysis population. 
1: 95% CI= 95% Wilson confidence interval 
2: Difference in 95% CI=asymptotic 95% CI from a Chi-Square test 
3: p-value calculated from the Chi Square Test. 
 
Tables with similar format: 
Table 72: 
L. crispatus Colonization at Visit 7 (Week 24) by Analysis Population, Treatment Group, and Race 
 


Statistical Analysis Plan - DMID Protocol: 14-0029  
Version 1.0 
11MAY2018 
- 87 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Table 73: 
L. crispatus CTV-05 Concentration by Study Day, Treatment Group, and Race – ITT Population 
Study Day (Week) 
Treatment Group 
Race 
Number of Subjects1 
Mean (SD) 
Median 
Range 
Day 1 
LACTIN-V 
Black/African American 
x 
x.xx (x.xx) 
x.xx 
x.xx, x.xx 
White 
x 
x.xx (x.xx) 
x.xx 
x.xx, x.xx 
Other 
x 
x.xx (x.xx) 
x.xx 
x.xx, x.xx 
Placebo 
Black/African American 
x 
x.xx (x.xx) 
x.xx 
x.xx, x.xx 
White 
x 
x.xx (x.xx) 
x.xx 
x.xx, x.xx 
Other 
x 
x.xx (x.xx) 
x.xx 
x.xx, x.xx 
All Subjects 
Black/African American 
x 
x.xx (x.xx) 
x.xx 
x.xx, x.xx 
 
White 
x 
x.xx (x.xx) 
x.xx 
x.xx, x.xx 
 
Other 
x 
x.xx (x.xx) 
x.xx 
x.xx, x.xx 
Continue for Day 28 (Week 4), Day 56 (Week 8), Day 84 (Week 12), and Day 168 (Week 24) 
1: The number of subjects in the respective treatment group, race group, and analysis population with concentration data available at the specified visit. 
 
Tables with similar format: 
Table 74: 
L. crispatus CTV-05 Concentration by Study Day, Treatment Group, and Race – mITT Population 
Table 75: 
L. crispatus CTV-05 Concentration by Study Day, Treatment Group, and Race – CC Population 
Table 76: 
L. crispatus CTV-05 Concentration by Study Day, Treatment Group, and Race – PP Population 


Statistical Analysis Plan - DMID Protocol: 14-0029  
Version 1.0 
11MAY2018 
- 88 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Table 77: 
L. crispatus Colonization by Study Day, Treatment Group, and Amsel Critera – ITT Population  
Study Day 
(Week) 
Treatment Group 
Amsel Criteria 
Number of 
Subjects with 
Colonization 
n 
Number of 
Subjects 
N 
Proportion of 
Subjects with 
Colonization 
Colonization 
95% CI 
Odds of Colonization 
in LACTIN-V Group 
Compared to Placebo 
Group 
Odds of Colonization in 
LACTIN-V Group 
Compared to Placebo 
Group 
95% CI 
p-value1 
Day 1 
LACTIN-V 
Positive 
x 
x 
0.xx 
0.xx, 0.xx 
x.xx 
x.xx, x.xx 
0.xxx 
Negative 
x 
x 
0.xx 
0.xx, 0.xx 
x.xx 
x.xx, x.xx 
0.xxx 
Placebo 
Positive 
x 
x 
0.xx 
0.xx, 0.xx 
-- 
-- 
 
Negative 
x 
x 
0.xx 
0.xx, 0.xx 
-- 
-- 
 
All Subjects 
Positive 
x 
x 
0.xx 
0.xx, 0.xx 
-- 
-- 
 
 
Negative 
x 
x 
0.xx 
0.xx, 0.xx 
-- 
-- 
 
Continue for Day 28 (Week 4), Day 56 (Week 8), Day 84 (Week 12), and Day 168 (Week 24) 
Note: The denominator for rate estimates is based on the number of subjects in the respective treatment group and analysis population. 
1: 95% CI= 95% Wilson confidence interval 
2: Difference in 95% CI=asymptotic 95% CI from a Chi-Square test 
3: p-value calculated from the Chi Square Test. 
 
Tables with similar format: 
Table 78: 
L. crispatus Colonization by Study Day, Treatment Group, and Amsel Critera – mITT Population 
Table 79: 
L. crispatus Colonization by Study Day, Treatment Group, and Amsel Critera – CC Population 
Table 80: 
L. crispatus Colonization by Study Day, Treatment Group, and Amsel Critera – PP Population 
 


Statistical Analysis Plan - DMID Protocol: 14-0029  
Version 1.0 
11MAY2018 
- 89 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Table 81: 
L. crispatus Colonization by Study Day, Treatment Group, and Nugent Score – ITT Population  
Study Day 
(Week) 
Treatment Group 
Nugent Score 
Category 
Number of 
Subjects with 
Colonization 
n 
Number of 
Subjects 
N 
Proportion of 
Subjects with 
Colonization 
Colonization 
95% CI 
Odds of Colonization 
in LACTIN-V Group 
Compared to Placebo 
Group 
Odds of Colonization in 
LACTIN-V Group 
Compared to Placebo 
Group 
95% CI 
p-value1 
Day 1 
LACTIN-V 
Normal 
x 
x 
0.xx 
0.xx, 0.xx 
x.xx 
x.xx, x.xx 
0.xxx 
Intermediate 
x 
x 
0.xx 
0.xx, 0.xx 
x.xx 
x.xx, x.xx 
0.xxx 
BV 
x 
x 
0.xx 
0.xx, 0.xx 
x.xx 
x.xx, x.xx 
0.xxx 
Placebo 
Normal 
x 
x 
0.xx 
0.xx, 0.xx 
-- 
-- 
 
Intermediate 
x 
x 
0.xx 
0.xx, 0.xx 
-- 
-- 
 
BV 
x 
x 
0.xx 
0.xx, 0.xx 
-- 
-- 
 
All Subjects 
Normal 
x 
x 
0.xx 
0.xx, 0.xx 
-- 
-- 
 
 
Intermediate 
x 
x 
0.xx 
0.xx, 0.xx 
-- 
-- 
 
 
BV 
x 
x 
0.xx 
0.xx, 0.xx 
-- 
-- 
 
Continue for Day 28 (Week 4), Day 56 (Week 8), Day 84 (Week 12), and Day 168 (Week 24) 
Note: The denominator for rate estimates is based on the number of subjects in the respective treatment group and analysis population. 
1: 95% CI= 95% Wilson confidence interval 
2: Difference in 95% CI=asymptotic 95% CI from a Chi-Square test 
3: p-value calculated from the Chi Square Test. 
 
Tables with similar format: 
Table 82: 
L. crispatus Colonization by Study Day, Treatment Group, and Nugent Score – mITT Population 
Table 83: 
L. crispatus Colonization by Study Day, Treatment Group, and Nugent Score – CC Population 
Table 84: 
L. crispatus Colonization by Study Day, Treatment Group, and Nugent Score – PP Population 
 


Statistical Analysis Plan - DMID Protocol: 14-0029  
Version 1.0 
11MAY2018 
- 90 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Table 85: 
L. crispatus CTV-05 Concentration by Study Day, Treatment Group, and Amsel Criteria – ITT Population 
Study Day (Week) 
Treatment Group 
Amsel Criteria 
Number of Subjects1 
Mean (SD) 
Median 
Range 
Day 1 
LACTIN-V 
Positive 
x 
x.xx (x.xx) 
x.xx 
x.xx, x.xx 
Negative 
x 
x.xx (x.xx) 
x.xx 
x.xx, x.xx 
Placebo 
Positive 
x 
x.xx (x.xx) 
x.xx 
x.xx, x.xx 
Negative 
x 
x.xx (x.xx) 
x.xx 
x.xx, x.xx 
All Subjects 
Positive 
x 
x.xx (x.xx) 
x.xx 
x.xx, x.xx 
 
Negative 
x 
x.xx (x.xx) 
x.xx 
x.xx, x.xx 
Continue for Day 28 (Week 4), Day 56 (Week 8), Day 84 (Week 12), and Day 168 (Week 24) 
1: The number of subjects in the respective treatment group and analysis population with concentration and Amsel data available at the specified visit. 
 
 
Tables with similar format: 
Table 86: 
L. crispatus CTV-05 Concentration by Study Day, Treatment Group, and Amsel Criteria – mITT Population 
Table 87: 
L. crispatus CTV-05 Concentration by Study Day, Treatment Group, and Amsel Criteria – CC Population 
Table 88: 
L. crispatus CTV-05 Concentration by Study Day, Treatment Group, and Amsel Criteria – PP Population 
Table 89: 
L. crispatus CTV-05 Concentration by Study Day, Treatment Group, and Nugent Score – mITT Population 
Table 90: 
L. crispatus CTV-05 Concentration by Study Day, Treatment Group, and Nugent Score – CC Population 
Table 91: 
L. crispatus CTV-05 Concentration by Study Day, Treatment Group, and Nugent Score – PP Population 
 


Statistical Analysis Plan - DMID Protocol: 14-0029  
Version 1.0 
11MAY2018 
- 91 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Table 92: 
Summary of Categorical Demographic and Baseline Characteristics by Site - All Enrolled Subjects 
Variable 
Characteristic 
San Francisco 
General Hospital 
(N = X) 
Stroger Hospital 
of Cook County 
(N = X) 
University of California, San 
Diego 
(N = X) 
Washington University in 
St. Louis 
(N = X) 
All Subjects 
(N=X) 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Sex 
Female 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Ethnicity  
Not Hispanic or Latino 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Hispanic or Latino 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Not Reported 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Unknown 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Race  
American Indian or Alaska Native 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Asian 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Native Hawaiian or Other Pacific 
Islander 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Black or African American 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
White 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Multi-Racial 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Unknown 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Notes: N=number of enrolled subjects 
 
 
 


Statistical Analysis Plan - DMID Protocol: 14-0029  
Version 1.0 
11MAY2018 
- 92 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Table 93: 
Summary of Categorical Demographic and Baseline Characteristics by Treatment 
Group—ITT Population 
Variable 
Characteristic 
LACTIN-V 
(N=X) 
Placebo 
(N=X) 
All Subjects 
(N=X) 
n 
% 
n 
% 
n 
% 
Sex 
Female 
x 
x 
x 
x 
x 
x 
Ethnicity  
Not Hispanic or Latino 
x 
x 
x 
x 
x 
x 
 
Hispanic or Latino 
x 
x 
x 
x 
x 
x 
 
Not Reported 
x 
x 
x 
x 
x 
x 
 
Unknown 
x 
x 
x 
x 
x 
x 
Race  
American Indian or Alaska Native 
x 
x 
x 
x 
x 
x 
 
Asian 
x 
x 
x 
x 
x 
x 
 
Native Hawaiian or Other Pacific Islander 
x 
x 
x 
x 
x 
x 
 
Black or African American 
x 
x 
x 
x 
x 
x 
 
White 
x 
x 
x 
x 
x 
x 
 
Multi-Racial 
x 
x 
x 
x 
x 
x 
 
Unknown 
x 
x 
x 
x 
x 
x 
Note: N=Number of Subjects in the ITT population 
 


Statistical Analysis Plan - DMID Protocol: 14-0029  
Version 1.0 
11MAY2018 
- 93 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Table 94: 
Summary of Continuous Demographic and Baseline Characteristics by Site—All Enrolled Subjects 
Variable 
Statistic 
San Francisco 
General Hospital 
(N = X) 
Stroger Hospital of Cook 
County 
(N = X) 
University of California, 
San Diego 
(N = X) 
Washington University in 
St. Louis 
(N=X) 
All Subjects 
(N=X) 
Age 
Mean 
x.x 
x.x 
x.x 
x.x 
x.x 
 
Standard Deviation 
x.x 
x.x 
x.x 
x.x 
x.x 
 
Median 
x.x 
x.x 
x.x 
x.x 
x.x 
 
Minimum 
x 
x 
x 
x 
x 
 
Maximum 
x 
x 
x 
x 
x 
Notes: N=number of enrolled subjects 
 


Statistical Analysis Plan - DMID Protocol: 14-0029  
Version 1.0 
11MAY2018 
- 94 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Table 95: 
Summary of Continuous Demographic and Baseline Characteristics by Treatment Group - ITT Population 
Variable 
Statistic 
LACTIN-V 
(N=X) 
Placebo 
(N=X) 
All Subjects 
(N=X) 
Age 
Mean 
x.x 
x.x 
x.x 
 
Standard Deviation 
x.x 
x.x 
x.x 
 
Median 
x.x 
x.x 
x.x 
 
Minimum 
x 
x 
x 
 
Maximum 
x 
x 
x 
Note: N=Number of subjects in the ITT population 


Statistical Analysis Plan - DMID Protocol: 14-0029  
Version 1.0 
11MAY2018 
- 95 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Table 96: 
Summary of Baseline* Categorical Sexual History by Treatment Group - ITT Population 
Gynecological and Sexual History Interview Question 
Value 
LACTIN-V 
(N=X) 
Placebo  
(N=X) 
All Subjects 
(N=X) 
n 
% 
n 
% 
n 
% 
Have you been amenorrheic for at least 3 months due to use 
of a long-acting progestin or continuous use of oral 
contraceptives? 
Yes 
x 
x 
x 
x 
x 
x 
No 
x 
x 
x 
x 
x 
x 
In the past 3 months, have you had any abnormal menstrual 
cycles? 
Yes 
x 
x 
x 
x 
x 
x 
No 
x 
x 
x 
x 
x 
x 
Cycle length less than 21 days? 
Yes 
x 
x 
x 
x 
x 
x 
No 
x 
x 
x 
x 
x 
x 
Cycle length less than 35 days? 
Yes 
x 
x 
x 
x 
x 
x 
No 
x 
x 
x 
x 
x 
x 
Intermenstrual bleeding/spotting? 
Yes 
x 
x 
x 
x 
x 
x 
No 
x 
x 
x 
x 
x 
x 
What sanitary products do you use during your period? 
Pads 
x 
x 
x 
x 
x 
x 
Cups 
x 
x 
x 
x 
x 
x 
Tampons 
x 
x 
x 
x 
x 
x 
Other 
x 
x 
x 
x 
x 
x 
Have you ever douched or used vaginal preparations or 
drying agents? 
Yes 
x 
x 
x 
x 
x 
x 
No 
x 
x 
x 
x 
x 
x 
Do you have any children born with congenital anomalies? 
Yes 
x 
x 
x 
x 
x 
x 
No 
x 
x 
x 
x 
x 
x 
What is your current relationship status? 
Married 
x 
x 
x 
x 
x 
x 
Divorced/Separated 
x 
x 
x 
x 
x 
x 
Single (never married) 
x 
x 
x 
x 
x 
x 
Widowed 
x 
x 
x 
x 
x 
x 
Steady partner, cohabitating 
x 
x 
x 
x 
x 
x 
Steady partner, not cohabitating 
x 
x 
x 
x 
x 
x 
Casual partner 
x 
x 
x 
x 
x 
x 
Have you had sex in the past 30 days? 
Yes 
x 
x 
x 
x 
x 
x 
No 
x 
x 
x 
x 
x 
x 
If you had sex with a man, did your partner use a condom 
each time? 
Yes 
x 
x 
x 
x 
x 
x 
No 
x 
x 
x 
x 
x 
x 
Notes: N=Number of subjects in the ITT population  
*Visit 1 Day 1 


Statistical Analysis Plan - DMID Protocol: 14-0029  
Version 1.0 
11MAY2018 
- 96 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Table 97: 
Summary of Baseline* Continuous Sexual History by Treatment Group - ITT Population 
Gynecological and Sexual History Interview Question 
Value 
LACTIN-V 
(N=X) 
Placebo  
(N=X) 
All Subjects 
(N=X) 
n 
% 
n 
% 
n 
% 
How many days does your period last? 
Mean (Standard Deviation) 
x.x 
(x.x) 
x x.x 
(x.x) 
x.x 
(x.x) 
x x.x 
(x.x) 
x.x 
(x.x) 
x x.x 
(x.x) 
Median 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
Minimum, Maximum 
x, x 
x, x 
x, x 
x, x 
x, x 
x, x 
In the last 30 days how many times have you douched or 
used vaginal preparations or drying agents? 
Mean (Standard Deviation) 
x.x 
(x.x) 
x x.x 
(x.x) 
x.x 
(x.x) 
x x.x 
(x.x) 
x.x 
(x.x) 
x x.x 
(x.x) 
Median 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
Minimum, Maximum 
x, x 
x, x 
x, x 
x, x 
x, x 
x, x 
How many days has it been since you last douched or 
vaginally inserted anything other than the study applicator 
or MetroGel 
Mean (Standard Deviation) 
x.x 
(x.x) 
x x.x 
(x.x) 
x.x 
(x.x) 
x x.x 
(x.x) 
x.x 
(x.x) 
x x.x 
(x.x) 
Median 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
Minimum, Maximum 
x, x 
x, x 
x, x 
x, x 
x, x 
x, x 
How many times have you douched or vaginally inserted 
anything other than the study applicator or MetroGel? 
Mean (Standard Deviation) 
x.x 
(x.x) 
x x.x 
(x.x) 
x.x 
(x.x) 
x x.x 
(x.x) 
x.x 
(x.x) 
x x.x 
(x.x) 
Median 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
Minimum, Maximum 
x, x 
x, x 
x, x 
x, x 
x, x 
x, x 
How many times have you been pregnant? 
Mean (Standard Deviation) 
x.x 
(x.x) 
x x.x 
(x.x) 
x.x 
(x.x) 
x x.x 
(x.x) 
x.x 
(x.x) 
x x.x 
(x.x) 
Median 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
Minimum, Maximum 
x, x 
x, x 
x, x 
x, x 
x, x 
x, x 
How many pregnancies resulted in live birth? 
Mean (Standard Deviation) 
x.x 
(x.x) 
x x.x 
(x.x) 
x.x 
(x.x) 
x x.x 
(x.x) 
x.x 
(x.x) 
x x.x 
(x.x) 
Median 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
Minimum, Maximum 
x, x 
x, x 
x, x 
x, x 
x, x 
x, x 
How many pregnancies resulted in stillborn birth? 
Mean (Standard Deviation) 
x.x 
(x.x) 
x x.x 
(x.x) 
x.x 
(x.x) 
x x.x 
(x.x) 
x.x 
(x.x) 
x x.x 
(x.x) 
Median 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
Minimum, Maximum 
x, x 
x, x 
x, x 
x, x 
x, x 
x, x 
How many pregnancies resulted in spontaneous abortion? 
Mean (Standard Deviation) 
x.x 
(x.x) 
x x.x 
(x.x) 
x.x 
(x.x) 
x x.x 
(x.x) 
x.x 
(x.x) 
x x.x 
(x.x) 
Median 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
Minimum, Maximum 
x, x 
x, x 
x, x 
x, x 
x, x 
x, x 
How many pregnancies resulted in elective abortion? 
Mean (Standard Deviation) 
x.x 
(x.x) 
x x.x 
(x.x) 
x.x 
(x.x) 
x x.x 
(x.x) 
x.x 
(x.x) 
x x.x 
(x.x) 
Median 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
Minimum, Maximum 
x, x 
x, x 
x, x 
x, x 
x, x 
x, x 
How many pregnancies resulted in ectopic pregnancy? 
Mean (Standard Deviation) 
x.x 
(x.x) 
x x.x 
(x.x) 
x.x 
(x.x) 
x x.x 
(x.x) 
x.x 
(x.x) 
x x.x 
(x.x) 
Median 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
Minimum, Maximum 
x, x 
x, x 
x, x 
x, x 
x, x 
x, x 


Statistical Analysis Plan - DMID Protocol: 14-0029  
Version 1.0 
11MAY2018 
- 97 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Gynecological and Sexual History Interview Question 
Value 
LACTIN-V 
(N=X) 
Placebo  
(N=X) 
All Subjects 
(N=X) 
n 
% 
n 
% 
n 
% 
How many male partners have you had in the past 6 
months? 
Mean (Standard Deviation) 
x.x 
(x.x) 
x x.x 
(x.x) 
x.x 
(x.x) 
x x.x 
(x.x) 
x.x 
(x.x) 
x x.x 
(x.x) 
Median 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
Minimum, Maximum 
x, x 
x, x 
x, x 
x, x 
x, x 
x, x 
How many female partners have you had in the past 6 
months? 
Mean (Standard Deviation) 
x.x 
(x.x) 
x x.x 
(x.x) 
x.x 
(x.x) 
x x.x 
(x.x) 
x.x 
(x.x) 
x x.x 
(x.x) 
Median 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
Minimum, Maximum 
x, x 
x, x 
x, x 
x, x 
x, x 
x, x 
How many times did you have sex since the last visit? 
Mean (Standard Deviation) 
x.x 
(x.x) 
x x.x 
(x.x) 
x.x 
(x.x) 
x x.x 
(x.x) 
x.x 
(x.x) 
x x.x 
(x.x) 
Median 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
Minimum, Maximum 
x, x 
x, x 
x, x 
x, x 
x, x 
x, x 
How many times did you have unprotected sex since the last 
visit? 
Mean (Standard Deviation) 
x.x 
(x.x) 
x x.x 
(x.x) 
x.x 
(x.x) 
x x.x 
(x.x) 
x.x 
(x.x) 
x x.x 
(x.x) 
Median 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
Minimum, Maximum 
x, x 
x, x 
x, x 
x, x 
x, x 
x, x 
How many times did you have unprotected sex since the last 
visit? 
Mean (Standard Deviation) 
x.x 
(x.x) 
x x.x 
(x.x) 
x.x 
(x.x) 
x x.x 
(x.x) 
x.x 
(x.x) 
x x.x 
(x.x) 
Median 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
Minimum, Maximum 
x, x 
x, x 
x, x 
x, x 
x, x 
x, x 
How many new partners did you have? 
Mean (Standard Deviation) 
x.x 
(x.x) 
x x.x 
(x.x) 
x.x 
(x.x) 
x x.x 
(x.x) 
x.x 
(x.x) 
x x.x 
(x.x) 
Median 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
Minimum, Maximum 
x, x 
x, x 
x, x 
x, x 
x, x 
x, x 
How many days has it been since the last time you had sex? 
Mean (Standard Deviation) 
x.x 
(x.x) 
x x.x 
(x.x) 
x.x 
(x.x) 
x x.x 
(x.x) 
x.x 
(x.x) 
x x.x 
(x.x) 
Median 
x.x 
x.x 
x.x 
x.x 
x.x 
x.x 
Minimum, Maximum 
x, x 
x, x 
x, x 
x, x 
x, x 
x, x 
Notes: N=Number of subjects in the ITT population  
*Visit 1 Day 1 


Statistical Analysis Plan - DMID Protocol: 14-0029  
Version 1.0 
11MAY2018 
- 98 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Table 98: 
Summary of Subjects with Pre-Existing Medical Conditions by MedDRA System Organ Class and Treatment Group - 
ITT Population – All Sites 
MedDRA System Organ Class 
LACTIN-V 
(N=X) 
Placebo 
(N=X) 
All Subjects 
(N=X) 
n 
% 
n 
% 
n 
% 
Any SOC 
x 
x 
x 
x 
x 
x 
[SOC 1] 
x 
x 
x 
x 
x 
x 
[SOC 2] 
x 
x 
x 
x 
x 
x 
Notes: N=number of subjects in the ITT population. 
n = Number of subjects reporting medical history within the specified SOC. 
A subject is only counted once per SOC. 
 
Tables with Similar Format: 
Table 99: 
Summary of Subjects with Pre-Existing Medical Conditions by MedDRA System Organ Class and Treatment Group - 
ITT Population – San Francisco General Hospital 
Table 100: 
Summary of Subjects with Pre-Existing Medical Conditions by MedDRA System Organ Class and Treatment Group - 
ITT Population – Stroger Hospital of Cook County 
Table 101: 
Summary of Subjects with Pre-Existing Medical Conditions by MedDRA System Organ Class and Treatment Group - 
ITT Population – University of California, San Diego 
Table 102: 
Summary of Subjects with Pre-Existing Medical Conditions by MedDRA System Organ Class and Treatment Group - 
ITT Population – Washington University in St. Louis 
 


Statistical Analysis Plan - DMID Protocol: 14-0029  
Version 1.0 
11MAY2018 
- 99 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Table 103: 
Number and Percentage of Subjects with Prior and Concurrent Medications by WHO Drug Classification and Treatment Group 
- Safety Population - All Subjects 
All Subjects (N=X) 
WHO Drug Code 
Level 1, Anatomic Group 
WHO Drug Code 
Level 2, Therapeutic Subgroup 
LACTIN-V 
(N=X) 
Placebo  
(N=X) 
All Subjects 
(N=X) 
n 
% 
n 
% 
n 
% 
Any Level 1 Codes 
Any Level 2 Codes 
x 
x 
x 
x 
x 
x 
[ATC Level 1 - 1] 
Any  
x 
x 
x 
x 
x 
x 
 
[ATC 2 - 1] 
x 
x 
x 
x 
x 
x 
 
[ATC 2 - 2] 
x 
x 
x 
x 
x 
x 
 
[ATC 2 - 3] 
x 
x 
x 
x 
x 
x 
[ATC Level 1 – 2] 
Any 
x 
x 
x 
x 
x 
x 
 
[ATC 2 - 1] 
x 
x 
x 
x 
x 
x 
 
[ATC 2 - 2] 
x 
x 
x 
x 
x 
x 
 
[ATC 2 - 3] 
x 
x 
x 
x 
x 
x 
Notes: N= Number of subjects in the Safety population 
n=Number of subjects reporting taking at least one medication in the specific WHO Drug Class. 
 
Tables with Similar Format: 
Table 104: 
Number and Percentage of Subjects with Prior and Concurrent Medications by WHO Drug Classification and Treatment Group-
Safety Population-San Francisco General Hospital 
Table 105: 
Number and Percentage of Subjects with Prior and Concurrent Medications by WHO Drug Classification and Treatment Group-
Safety Population-Stroger Hospital of Cook County 
Table 106: 
Number and Percentage of Subjects with Prior and Concurrent Medications by WHO Drug Classification and Treatment Group-
Safety Population-University of California, San Diego 
Table 107: 
Number and Percentage of Subjects with Prior and Concurrent Medications by WHO Drug Classification and Treatment Group-
Safety Population-Washington University in St. Louis 


Statistical Analysis Plan - DMID Protocol: 14-0029  
Version 1.0 
11MAY2018 
- 100 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Table 108: 
Number and Percentage of Subjects Experiencing Solicited Events with 95% Confidence Intervals by Symptom and Treatment 
Group—Safety Population 
Category 
Solicited Adverse Event 
LACTIN-V 
(N=X) 
Placebo  
(N=X) 
All Subjects 
(N=X) 
n 
% 
95% CI 
n 
% 
95% CI 
n 
% 
95% CI 
Solicited Adverse Events 
Any Solicited Adverse Event 
x 
x 
x, x 
x 
x 
x, x 
x 
x 
x, x 
Solicited Local Adverse Events 
Any Local Adverse Event 
x 
x 
x, x 
x 
x 
x, x 
x 
x 
x, x 
 
Vaginal Bleeding 
x 
x 
x, x 
x 
x 
x, x 
x 
x 
x, x 
 
Abnormal Vaginal Discharge 
x 
x 
x, x 
x 
x 
x, x 
x 
x 
x, x 
 
Abnormal Vaginal Odor 
x 
x 
x, x 
x 
x 
x, x 
x 
x 
x, x 
 
Genital Itching 
x 
x 
x, x 
x 
x 
x, x 
x 
x 
x, x 
 
Genital Burning 
x 
x 
x, x 
x 
x 
x, x 
x 
x 
x, x 
 
External Genital Irritation 
x 
x 
x, x 
x 
x 
x, x 
x 
x 
x, x 
 
External Genital Swelling 
x 
x 
x, x 
x 
x 
x, x 
x 
x 
x, x 
 
Genital Rash 
x 
x 
x, x 
x 
x 
x, x 
x 
x 
x, x 
Solicited Systemic Adverse Events 
Any Systemic Adverse Event 
x 
x 
x, x 
x 
x 
x, x 
x 
x 
x, x 
 
Nausea 
x 
x 
x, x 
x 
x 
x, x 
x 
x 
x, x 
 
Vomiting 
x 
x 
x, x 
x 
x 
x, x 
x 
x 
x, x 
 
Abdominal Pain/Cramps 
x 
x 
x, x 
x 
x 
x, x 
x 
x 
x, x 
 
Diarrhea 
x 
x 
x, x 
x 
x 
x, x 
x 
x 
x, x 
 
Constipation 
x 
x 
x, x 
x 
x 
x, x 
x 
x 
x, x 
 
Pain/Burning with Urination 
x 
x 
x, x 
x 
x 
x, x 
x 
x 
x, x 
 
Blood in Urine 
x 
x 
x, x 
x 
x 
x, x 
x 
x 
x, x 
 
Headache 
x 
x 
x, x 
x 
x 
x, x 
x 
x 
x, x 
Notes: N = number of subjects in the Safety Analysis Population who received the specified treatment. 
This table presents number and percentage of subjects. 
A subject is only counted once per solicited adverse event. 
95% CI= 95% Blaker Confidence Interval 


Statistical Analysis Plan - DMID Protocol: 14-0029  
Version 1.0 
11MAY2018 
- 101 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Table 109: 
Number and Percentage of Subjects Experiencing Solicited Local Events by Symptom 
and Maximum Severity - Safety Population - All Subjects 
 
All Subjects 
(N=X) 
Solicited Adverse Event 
Severity1 
n 
% 
95% CI 
Any Solicited Local Event 
None 
x 
x 
x,x 
Mild 
x 
x 
x,x 
Moderate 
x 
x 
x,x 
Severe 
x 
x 
x,x 
Vaginal bleeding other than menstruation 
None 
x 
x 
x,x 
Mild 
x 
x 
x,x 
Moderate 
x 
x 
x,x 
Severe 
x 
x 
x,x 
Abnormal vaginal discharge 
None 
x 
x 
x,x 
Mild 
x 
x 
x,x 
Moderate 
x 
x 
x,x 
Severe 
x 
x 
x,x 
Abnormal vaginal odor 
None 
x 
x 
x,x 
Mild 
x 
x 
x,x 
Moderate 
x 
x 
x,x 
Severe 
x 
x 
x,x 
Genital itching 
None 
x 
x 
x,x 
Mild 
x 
x 
x,x 
Moderate 
x 
x 
x,x 
Severe 
x 
x 
x,x 
Genital burning 
None 
x 
x 
x,x 
Mild 
x 
x 
x,x 
Moderate 
x 
x 
x,x 
Severe 
x 
x 
x,x 
External genital irritation 
None 
x 
x 
x,x 
Mild 
x 
x 
x,x 
Moderate 
x 
x 
x,x 
Severe 
x 
x 
x,x 
External genital swelling 
None 
x 
x 
x,x 
Mild 
x 
x 
x,x 
Moderate 
x 
x 
x,x 
Severe 
x 
x 
x,x 


Statistical Analysis Plan - DMID Protocol: 14-0029  
Version 1.0 
11MAY2018 
- 102 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
 
All Subjects 
(N=X) 
Solicited Adverse Event 
Severity1 
n 
% 
95% CI 
Genital rash 
None 
x 
x 
x,x 
Mild 
x 
x 
x,x 
Moderate 
x 
x 
x,x 
Severe 
x 
x 
x,x 
Notes: Denominator for percentages is the number of subjects in the Safety Population (N) with solicited adverse event data available after the 
first dose of study product. 
1Each subject's maximum severity is reported for each solicited adverse event across all doses. 
95% CI= 95% Blaker Confidence Interval 


Statistical Analysis Plan - DMID Protocol: 14-0029  
Version 1.0 
11MAY2018 
- 103 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Table 110: 
Number and Percentage of Subjects Experiencing Solicited Local Events by Symptom, 
Maximum Severity, and Treatment Group - Safety Population 
 
LACTIN-V 
(N=X) 
Placebo 
(N=X) 
Solicited Adverse Event 
Severity1 
n 
% 
95% CI 
n 
% 
95% CI 
Any Solicited Local Event 
None 
x 
x 
x,x 
x 
x 
x,x 
Mild 
x 
x 
x,x 
x 
x 
x,x 
Moderate 
x 
x 
x,x 
x 
x 
x,x 
Severe 
x 
x 
x,x 
x 
x 
x,x 
Vaginal bleeding other than menstruation 
None 
x 
x 
x,x 
x 
x 
x,x 
Mild 
x 
x 
x,x 
x 
x 
x,x 
Moderate 
x 
x 
x,x 
x 
x 
x,x 
Severe 
x 
x 
x,x 
x 
x 
x,x 
Abnormal vaginal discharge 
None 
x 
x 
x,x 
x 
x 
x,x 
Mild 
x 
x 
x,x 
x 
x 
x,x 
Moderate 
x 
x 
x,x 
x 
x 
x,x 
Severe 
x 
x 
x,x 
x 
x 
x,x 
Abnormal vaginal odor 
None 
x 
x 
x,x 
x 
x 
x,x 
Mild 
x 
x 
x,x 
x 
x 
x,x 
Moderate 
x 
x 
x,x 
x 
x 
x,x 
Severe 
x 
x 
x,x 
x 
x 
x,x 
Genital itching 
None 
x 
x 
x,x 
x 
x 
x,x 
Mild 
x 
x 
x,x 
x 
x 
x,x 
Moderate 
x 
x 
x,x 
x 
x 
x,x 
Severe 
x 
x 
x,x 
x 
x 
x,x 
Genital burning 
None 
x 
x 
x,x 
x 
x 
x,x 
Mild 
x 
x 
x,x 
x 
x 
x,x 
Moderate 
x 
x 
x,x 
x 
x 
x,x 
Severe 
x 
x 
x,x 
x 
x 
x,x 
External genital irritation 
None 
x 
x 
x,x 
x 
x 
x,x 
Mild 
x 
x 
x,x 
x 
x 
x,x 
Moderate 
x 
x 
x,x 
x 
x 
x,x 
Severe 
x 
x 
x,x 
x 
x 
x,x 
External genital swelling 
None 
x 
x 
x,x 
x 
x 
x,x 
Mild 
x 
x 
x,x 
x 
x 
x,x 
Moderate 
x 
x 
x,x 
x 
x 
x,x 
Severe 
x 
x 
x,x 
x 
x 
x,x 


Statistical Analysis Plan - DMID Protocol: 14-0029  
Version 1.0 
11MAY2018 
- 104 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
 
LACTIN-V 
(N=X) 
Placebo 
(N=X) 
Solicited Adverse Event 
Severity1 
n 
% 
95% CI 
n 
% 
95% CI 
Genital rash 
None 
x 
x 
x,x 
x 
x 
x,x 
Mild 
x 
x 
x,x 
x 
x 
x,x 
Moderate 
x 
x 
x,x 
x 
x 
x,x 
Severe 
x 
x 
x,x 
x 
x 
x,x 
Notes: Denominator for percentages is the number of subjects in the Safety Population (N) with solicited adverse event data available after the 
first dose of study product. 
1Each subject's maximum severity is reported for each solicited adverse event across all doses. 
95% CI= 95% Blaker Confidence Interval 
 


Statistical Analysis Plan - DMID Protocol: 14-0029  
Version 1.0 
11MAY2018 
- 105 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Table 111: 
Number and Percentage of Subjects Experiencing Solicited Systemic Events by Symptom 
and Maximum Severity—Safety Population—All Subjects 
 
All Subjects 
(N=X) 
Solicited Adverse Event 
Severity1 
n 
% 
95% CI 
Any Solicited Systemic Event 
None 
x 
x 
x,x 
Mild 
x 
x 
x,x 
Moderate 
x 
x 
x,x 
Severe 
x 
x 
x,x 
Nausea 
None 
x 
x 
x,x 
Mild 
x 
x 
x,x 
Moderate 
x 
x 
x,x 
Severe 
x 
x 
x,x 
Vomiting 
None 
x 
x 
x,x 
Mild 
x 
x 
x,x 
Moderate 
x 
x 
x,x 
Severe 
x 
x 
x,x 
Abdominal pain/cramps 
None 
x 
x 
x,x 
Mild 
x 
x 
x,x 
Moderate 
x 
x 
x,x 
Severe 
x 
x 
x,x 
Diarrhea 
None 
x 
x 
x,x 
Mild 
x 
x 
x,x 
Moderate 
x 
x 
x,x 
Severe 
x 
x 
x,x 
Constipation 
None 
x 
x 
x,x 
Mild 
x 
x 
x,x 
Moderate 
x 
x 
x,x 
Severe 
x 
x 
x,x 
Pain/burning with urination 
None 
x 
x 
x,x 
Mild 
x 
x 
x,x 
Moderate 
x 
x 
x,x 
Severe 
x 
x 
x,x 
Frequent urination 
None 
x 
x 
x,x 
Mild 
x 
x 
x,x 
Moderate 
x 
x 
x,x 
Severe 
x 
x 
x,x 


Statistical Analysis Plan - DMID Protocol: 14-0029  
Version 1.0 
11MAY2018 
- 106 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
 
All Subjects 
(N=X) 
Solicited Adverse Event 
Severity1 
n 
% 
95% CI 
Blood in urine 
None 
x 
x 
x,x 
Mild 
x 
x 
x,x 
Moderate 
x 
x 
x,x 
Severe 
x 
x 
x,x 
Notes: Denominator for percentages is the number of subjects in the Safety Population (N) with solicited adverse event data available after the 
first dose of study product. 
1Each subject's maximum severity is reported for each solicited adverse event across all doses. 
95% CI= 95% Blaker Confidence Interval 
 


Statistical Analysis Plan - DMID Protocol: 14-0029  
Version 1.0 
11MAY2018 
- 107 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Table 112: 
Number and Percentage of Subjects Experiencing Solicited Local Events by Symptom, 
Maximum Severity, and Treatment Group—Safety Population 
 
LACTIN-V 
(N=X) 
Placebo 
(N=X) 
Solicited Adverse Event 
Severity1 
n 
% 
95% CI 
n 
% 
95% CI 
Any Solicited Systemic Event 
None 
x 
x 
x,x 
x 
x 
x,x 
Mild 
x 
x 
x,x 
x 
x 
x,x 
Moderate 
x 
x 
x,x 
x 
x 
x,x 
Severe 
x 
x 
x,x 
x 
x 
x,x 
Nausea 
None 
x 
x 
x,x 
x 
x 
x,x 
Mild 
x 
x 
x,x 
x 
x 
x,x 
Moderate 
x 
x 
x,x 
x 
x 
x,x 
Severe 
x 
x 
x,x 
x 
x 
x,x 
Vomiting 
None 
x 
x 
x,x 
x 
x 
x,x 
Mild 
x 
x 
x,x 
x 
x 
x,x 
Moderate 
x 
x 
x,x 
x 
x 
x,x 
Severe 
x 
x 
x,x 
x 
x 
x,x 
Abdominal pain/cramps 
None 
x 
x 
x,x 
x 
x 
x,x 
Mild 
x 
x 
x,x 
x 
x 
x,x 
Moderate 
x 
x 
x,x 
x 
x 
x,x 
Severe 
x 
x 
x,x 
x 
x 
x,x 
Diarrhea 
None 
x 
x 
x,x 
x 
x 
x,x 
Mild 
x 
x 
x,x 
x 
x 
x,x 
Moderate 
x 
x 
x,x 
x 
x 
x,x 
Severe 
x 
x 
x,x 
x 
x 
x,x 
Constipation 
None 
x 
x 
x,x 
x 
x 
x,x 
Mild 
x 
x 
x,x 
x 
x 
x,x 
Moderate 
x 
x 
x,x 
x 
x 
x,x 
Severe 
x 
x 
x,x 
x 
x 
x,x 
Pain/burning with urination 
None 
x 
x 
x,x 
x 
x 
x,x 
Mild 
x 
x 
x,x 
x 
x 
x,x 
Moderate 
x 
x 
x,x 
x 
x 
x,x 
Severe 
x 
x 
x,x 
x 
x 
x,x 
Frequent urination 
None 
x 
x 
x,x 
x 
x 
x,x 
Mild 
x 
x 
x,x 
x 
x 
x,x 
Moderate 
x 
x 
x,x 
x 
x 
x,x 
Severe 
x 
x 
x,x 
x 
x 
x,x 


Statistical Analysis Plan - DMID Protocol: 14-0029  
Version 1.0 
11MAY2018 
- 108 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
 
LACTIN-V 
(N=X) 
Placebo 
(N=X) 
Solicited Adverse Event 
Severity1 
n 
% 
95% CI 
n 
% 
95% CI 
Blood in urine 
None 
x 
x 
x,x 
x 
x 
x,x 
Mild 
x 
x 
x,x 
x 
x 
x,x 
Moderate 
x 
x 
x,x 
x 
x 
x,x 
Severe 
x 
x 
x,x 
x 
x 
x,x 
Notes: Denominator for percentages is the number of subjects in the Safety Population (N) with solicited adverse event data available after the 
first dose of study product. 
1Each subject's maximum severity is reported for each solicited adverse event across all doses. 
95% CI= 95% Blaker Confidence Interval 
 


Statistical Analysis Plan - DMID Protocol: 14-0029  
Version 1.0 
11MAY2018 
- 109 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Table 113: 
Number and Percentage of Subjects Experiencing Solicited Local Events by Symptom, Severity, Week, and Treatment Group - 
Safety Population - All Subjects - Weeks 1-6 
Treatment Group=All (N=X) 
 
Week 1 
(N=X) 
Week 2 
(N=X) 
Week 3 
(N=X) 
Week 4 
(N=X) 
Week 5 
(N=X) 
Week 6 
(N=X) 
Solicited Adverse Event 
Severity1 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Any Solicited Local Event 
None 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Mild 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Moderate 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Severe 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Vaginal bleeding other than menstruation 
None 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Mild 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Moderate 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Severe 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Abnormal vaginal discharge 
None 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Mild 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Moderate 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Severe 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Abnormal vaginal odor 
None 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Mild 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Moderate 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Severe 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Genital itching 
None 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Mild 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Moderate 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Severe 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 


Statistical Analysis Plan - DMID Protocol: 14-0029  
Version 1.0 
11MAY2018 
- 110 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Treatment Group=All (N=X) 
 
Week 1 
(N=X) 
Week 2 
(N=X) 
Week 3 
(N=X) 
Week 4 
(N=X) 
Week 5 
(N=X) 
Week 6 
(N=X) 
Solicited Adverse Event 
Severity1 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Genital burning 
None 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Mild 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Moderate 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Severe 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
External genital irritation 
None 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Mild 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Moderate 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Severe 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
External genital swelling 
None 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Mild 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Moderate 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Severe 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Genital rash 
None 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Mild 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Moderate 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Severe 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Notes: Denominator for percentages is the number of subjects in the Safety Population (N) completing memory aid that week. 
1The maximum severity of any solicited adverse event is summarized.  A subject is only counted once at the maximum severity. 


Statistical Analysis Plan - DMID Protocol: 14-0029  
Version 1.0 
11MAY2018 
- 111 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Table 114: 
Number and Percentage of Subjects Experiencing Solicited Local Events by Symptom, Severity, Week, and Treatment Group - 
Safety Population - All Subjects - Weeks 7-24 
Treatment Group=All (N=X) 
 
Week 7 
(N=X) 
Week 8 
(N=X) 
Week 9 
(N=X) 
Week 10 
(N=X) 
Week 11 
(N=X) 
Weeks 12-18 
(N=X) 
Weeks 19-24 
(N=X) 
Solicited Adverse Event 
Severity1 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Any Solicited Local Event 
None 
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 
Moderate 
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 
Vaginal bleeding other than menstruation 
None 
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 
Moderate 
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 
Abnormal vaginal discharge 
None 
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 
Moderate 
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 
Abnormal vaginal odor 
None 
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 
Moderate 
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 
Genital itching 
None 
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 
Moderate 
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 


Statistical Analysis Plan - DMID Protocol: 14-0029  
Version 1.0 
11MAY2018 
- 112 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Treatment Group=All (N=X) 
 
Week 7 
(N=X) 
Week 8 
(N=X) 
Week 9 
(N=X) 
Week 10 
(N=X) 
Week 11 
(N=X) 
Weeks 12-18 
(N=X) 
Weeks 19-24 
(N=X) 
Solicited Adverse Event 
Severity1 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Genital burning 
None 
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 
Moderate 
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 
External genital irritation 
None 
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 
Moderate 
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 
External genital swelling 
None 
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 
Moderate 
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 
Genital rash 
None 
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 
Moderate 
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 
Notes: Denominator for percentages is the number of subjects in the Safety Population (N) completing memory aid that week. 
1The maximum severity of any solicited adverse event is summarized.  A subject is only counted once at the maximum severity. 
 


Statistical Analysis Plan - DMID Protocol: 14-0029  
Version 1.0 
11MAY2018 
- 113 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Tables with Similar Format: 
Table 115: 
Number and Percentage of Subjects Experiencing Solicited Local Events by Symptom, Severity, Week, and Treatment Group—
Safety Population—LACTIN-V—Weeks 1-6 
Table 116: 
Number and Percentage of Subjects Experiencing Solicited Local Events by Symptom, Severity, Week, and Treatment Group—
Safety Population—LACTIN-V—Weeks 7-24 
Table 117: 
Number and Percentage of Subjects Experiencing Solicited Local Events by Symptom, Severity, Week, and Treatment Group—
Safety Population—Placebo—Weeks 1-6 
Table 118: 
Number and Percentage of Subjects Experiencing Solicited Local Events by Symptom, Severity, Week, and Treatment Group—
Safety Population—Placebo—Weeks 7-24 


Statistical Analysis Plan - DMID Protocol: 14-0029  
Version 1.0 
11MAY2018 
- 114 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Table 119: 
Number and Percentage of Subjects Experiencing Solicited Systemic Events by Symptom, Severity, Week, and Treatment Group 
- Safety Population - All Subjects - Weeks 1-6 
Treatment Group= All (N=X) 
 
Week 1 
(N=X) 
Week 2 
(N=X) 
Week 3 
(N=X) 
Week 4 
(N=X) 
Week 5 
(N=X) 
Week 6 
(N=X) 
Solicited Adverse Event 
Severity1 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Any Solicited Systemic Event 
None 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Mild 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Moderate 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Severe 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Nausea* 
None 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Mild 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Moderate 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Severe 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Vomiting* 
None 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Mild 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Moderate 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Severe 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Abdominal pain/cramps* 
None 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Mild 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Moderate 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Severe 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Diarrhea* 
None 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Mild 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Moderate 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Severe 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 


Statistical Analysis Plan - DMID Protocol: 14-0029  
Version 1.0 
11MAY2018 
- 115 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Treatment Group= All (N=X) 
 
Week 1 
(N=X) 
Week 2 
(N=X) 
Week 3 
(N=X) 
Week 4 
(N=X) 
Week 5 
(N=X) 
Week 6 
(N=X) 
Solicited Adverse Event 
Severity1 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Constipation* 
None 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Mild 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Moderate 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Severe 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Pain/burning with urination 
None 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Mild 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Moderate 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Severe 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Frequent urination 
None 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Mild 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Moderate 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Severe 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Blood in urine* 
None 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Mild 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Moderate 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Severe 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Headache* 
None 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Mild 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Moderate 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Severe 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Notes: Denominator for percentages is the number of subjects in the Safety Population (N) completing memory aid that week. 
*Symptom not collected during weeks 12-24. 
1The maximum severity of any solicited adverse event is summarized.  A subject is only counted once at the maximum severity. 


Statistical Analysis Plan - DMID Protocol: 14-0029  
Version 1.0 
11MAY2018 
- 116 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Table 120: 
Number and Percentage of Subjects Experiencing Solicited Systemic Events by Symptom, Severity, Week, and Treatment 
Group—Safety Population—All Subjects—Weeks 7-24 
Treatment Group=All (N=X) 
 
Week 7 
(N=X) 
Week 8 
(N=X) 
Week 9 
(N=X) 
Week 10 
(N=X) 
Week 11 
(N=X) 
Weeks 12-18 
(N=X) 
Weeks 19-24 
(N=X) 
Solicited Adverse Event 
Severity1 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Any Solicited Systemic Event 
None 
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 
Moderate 
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 
Nausea* 
None 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
- 
- 
- 
- 
Mild 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
- 
- 
- 
- 
Moderate 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
- 
- 
- 
- 
Severe 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
- 
- 
- 
- 
Vomiting* 
None 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
- 
- 
- 
- 
Mild 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
- 
- 
- 
- 
Moderate 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
- 
- 
- 
- 
Severe 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
- 
- 
- 
- 
Abdominal pain/cramps* 
None 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
- 
- 
- 
- 
Mild 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
- 
- 
- 
- 
Moderate 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
- 
- 
- 
- 
Severe 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
- 
- 
- 
- 
Diarrhea* 
None 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
- 
- 
- 
- 
Mild 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
- 
- 
- 
- 
Moderate 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
- 
- 
- 
- 
Severe 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
- 
- 
- 
- 


Statistical Analysis Plan - DMID Protocol: 14-0029  
Version 1.0 
11MAY2018 
- 117 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Treatment Group=All (N=X) 
 
Week 7 
(N=X) 
Week 8 
(N=X) 
Week 9 
(N=X) 
Week 10 
(N=X) 
Week 11 
(N=X) 
Weeks 12-18 
(N=X) 
Weeks 19-24 
(N=X) 
Solicited Adverse Event 
Severity1 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
n 
% 
Constipation* 
None 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
- 
- 
- 
- 
Mild 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
- 
- 
- 
- 
Moderate 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
- 
- 
- 
- 
Severe 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
- 
- 
- 
- 
Pain/burning with urination 
None 
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 
Moderate 
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 
Frequent urination 
None 
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 
Moderate 
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 
Blood in urine* 
None 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
- 
- 
- 
- 
Mild 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
- 
- 
- 
- 
Moderate 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
- 
- 
- 
- 
Severe 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
- 
- 
- 
- 
Headache* 
None 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
- 
- 
- 
- 
Mild 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
- 
- 
- 
- 
Moderate 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
- 
- 
- 
- 
Severe 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
- 
- 
- 
- 
Notes: Denominator for percentages is the number of subjects in the Safety Population (N) completing memory aid that week. 
*Symptom not collected during weeks 12-24. 
1The maximum severity of any solicited adverse event is summarized.  A subject is only counted once at the maximum severity. 
 


Statistical Analysis Plan - DMID Protocol: 14-0029  
Version 1.0 
11MAY2018 
- 118 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Tables with Similar Format: 
Table 121: 
Number and Percentage of Subjects Experiencing Solicited Local Events by Symptom, Severity, Week, and Treatment Group—
Safety Population—LACTIN-V—Weeks 1-6 
Table 122: 
Number and Percentage of Subjects Experiencing Solicited Local Events by Symptom, Severity, Week, and Treatment Group—
Safety Population—LACTIN-V—Weeks 7-24 
Table 123: 
Number and Percentage of Subjects Experiencing Solicited Local Events by Symptom, Severity, Week, and Treatment Group—
Safety Population—Placebo—Weeks 1-6 
Table 124: 
Number and Percentage of Subjects Experiencing Solicited Local Events by Symptom, Severity, Week, and Treatment Group—
Safety Population—Placebo—Weeks 7-24 
 


Statistical Analysis Plan - DMID Protocol: 14-0029  
Version 1.0 
11MAY2018 
- 119 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Table 125: 
Proportion of Subjects Reporting Product Related Unsolicited Adverse Events Following the First Dose of Study Product through 
Visit 7 by Treatment Group –  Safety Population 
Treatment 
Group 
Number of 
Subjects with 
AEs 
n 
Number of 
Subjects 
N 
Proportion of 
Subjects with AEs 
Proportion of 
Subjects with AEs 
95% CI 
Difference in Proportion of Subjects with 
AEs between LACTIN-V and Placebo  
Difference in Proportion of Subjects with 
AEs between LACTIN-V and Placebo  
95% CI 
P-
value* 
LACTIN-V 
x 
x 
0.xx 
0.xx, 0.xx 
0.xx 
0.xx, 0.xx 
0.xxx 
Placebo  
x 
x 
0.xx 
0.xx, 0.xx 
-- 
-- 
-- 
All Subjects 
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 and analysis population. 
*P-value from the Fisher’s exact two-sided test at the .05 level of significance. 
95% CI= 95% Blaker Confidence Interval 
 


Statistical Analysis Plan - DMID Protocol: 14-0029  
Version 1.0 
11MAY2018 
- 120 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Table 126: 
Number and Percentage of Subjects Experiencing Unsolicited Adverse Events with 95% Confidence Intervals by MedDRA 
System Organ Class and Preferred Term, Dose Number, and Treatment Group - Safety Population 
MedDRA System Organ Class 
MedDRA Preferred Term 
LACTIN-V 
(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 treatment. 
This table presents number and percentage of subjects. 
A subject is only counted once per PT/timepoint. 
95% CI= 95% Blaker Confidence Interval 
 


Statistical Analysis Plan - DMID Protocol: 14-0029  
Version 1.0 
11MAY2018 
- 121 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Table 127: 
Number and Percentage of Subjects Experiencing Unsolicited Adverse Events by MedDRA System Organ Class and Preferred 
Term, Maximum Severity and Relationship—Safety Population 
 
 
 
All Subjects 
(N = X) 
Related 
Not Related 
Total 
n 
% 
Freq 
n 
% 
Freq 
n 
% 
Freq 
Any SOC 
Any PT 
Any Severity 
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  
 
 
Moderate 
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  
[SOC 1] 
Any PT 
Any Severity 
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  
 
 
Moderate 
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  
 
[PT 1] 
Any Severity 
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  
 
 
Moderate 
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  
Notes: N = Number of subjects in the Safety Analysis Population 
This table presents number and percentage of subjects as well as number of events. 
For severity, a subject is counted once per preferred term and is summarized according to their highest severity. 


Statistical Analysis Plan - DMID Protocol: 14-0029  
Version 1.0 
11MAY2018 
- 122 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Table 128: 
Number and Percentage of Subjects Experiencing Unsolicited Adverse Events by MedDRA System Organ Class and Preferred 
Term, Maximum Severity, Relationship, and Treatment Group - Safety Population 
 
 
 
LACTIN-V 
(N = X) 
Placebo 
(N = X) 
Related 
Not Related 
Total 
Related 
Not Related 
Total 
n 
% 
Freq 
n 
% 
Freq 
n 
% 
Freq 
n 
% 
Freq 
n 
% 
Freq 
n 
% 
Freq 
Any SOC 
Any PT 
Any Severity 
x  
x.x 
x  
x.x 
x  
x.x 
x  
x.x 
x  
x.x 
x  
x.x 
x  
x.x 
x  
x.x 
x  
x.x 
 
 
Mild 
x  
x.x 
x  
x.x 
x  
x.x 
x  
x.x 
x  
x.x 
x  
x.x 
x  
x.x 
x  
x.x 
x  
x.x 
 
 
Moderate 
x  
x.x 
x  
x.x 
x  
x.x 
x  
x.x 
x  
x.x 
x  
x.x 
x  
x.x 
x  
x.x 
x  
x.x 
 
 
Severe 
x  
x.x 
x  
x.x 
x  
x.x 
x  
x.x 
x  
x.x 
x  
x.x 
x  
x.x 
x  
x.x 
x  
x.x 
[SOC 1] 
Any PT 
Any Severity 
x  
x.x 
x  
x.x 
x  
x.x 
x  
x.x 
x  
x.x 
x  
x.x 
x  
x.x 
x  
x.x 
x  
x.x 
 
 
Mild 
x  
x.x 
x  
x.x 
x  
x.x 
x  
x.x 
x  
x.x 
x  
x.x 
x  
x.x 
x  
x.x 
x  
x.x 
 
 
Moderate 
x  
x.x 
x  
x.x 
x  
x.x 
x  
x.x 
x  
x.x 
x  
x.x 
x  
x.x 
x  
x.x 
x  
x.x 
 
 
Severe 
x  
x.x 
x  
x.x 
x  
x.x 
x  
x.x 
x  
x.x 
x  
x.x 
x  
x.x 
x  
x.x 
x  
x.x 
 
[PT 1] 
Any Severity 
x  
x.x 
x  
x.x 
x  
x.x 
x  
x.x 
x  
x.x 
x  
x.x 
x  
x.x 
x  
x.x 
x  
x.x 
 
 
Mild 
x  
x.x 
x  
x.x 
x  
x.x 
x  
x.x 
x  
x.x 
x  
x.x 
x  
x.x 
x  
x.x 
x  
x.x 
 
 
Moderate 
x  
x.x 
x  
x.x 
x  
x.x 
x  
x.x 
x  
x.x 
x  
x.x 
x  
x.x 
x  
x.x 
x  
x.x 
 
 
Severe 
x  
x.x 
x  
x.x 
x  
x.x 
x  
x.x 
x  
x.x 
x  
x.x 
x  
x.x 
x  
x.x 
x  
x.x 
Notes: N = Number of subjects in the Safety Analysis Population 
This table presents number and percentage of subjects as well as number of events. 
For severity, a subject is counted once per preferred term and is summarized according to their highest severity. 


Statistical Analysis Plan - DMID Protocol: 14-0029  
Version 1.0 
11MAY2018 
- 123 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Table 129: 
Number of 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 
MedDRA Version 
LACTIN-V 
(N=X) 
Placebo 
(N=X) 
All Subjects 
(N=X) 
xxxxxx 
xxxxxxxxxx 
xx.x 
xx 
xx 
xx 
Notes: N = Number of subjects in the Safety Analysis Population 


Statistical Analysis Plan - DMID Protocol: 14-0029  
Version 1.0 
11MAY2018 
- 124 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Table 130: 
Subjects Reporting Adverse Events Occurring in 5% Subjects in Any Treatment Group by MedDRA System Organ Class and 
Preferred Term, and Treatment Group - Safety Population 
Preferred Term 
MedDRA System Organ Class 
MedDRA Version 
LACTIN-V 
(N=X) 
Placebo 
(N=X) 
All Subjects 
(N=X) 
xxxxxx 
xxxxxxxxxx 
xx.x 
xx 
xx 
xx 
Notes: N = Number of subjects in the Safety Analysis Population 
 


Statistical Analysis Plan - DMID Protocol: 14-0029  
Version 1.0 
11MAY2018 
- 125 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Table 131: 
Listing of Non-Serious, Unsolicited, Moderate or Severe Adverse Events 
Adverse 
Event 
Study 
Day 
Severity 
Relationship to Study 
Treatment 
In Not Related, 
Alternative Etiology 
Action Taken with 
Study Treatment 
Subject Discontinued 
Due to AE 
Outcome 
MedDRA 
System Organ 
Class 
MedDRA 
Preferred 
Term 
Subject ID: , Treatment Group: , AE Number:  
xxxxxxx 
xx 
xxxxxx 
xxxxxx 
xxxxx 
xxxxxx 
Y/N 
xxxxx 
xxxxx 
xxxxx 
Comments:xxxxxxxxxxx 
 
 
 
 
 
 
 
 
 
 
Subject ID: , Treatment Group: , AE Number:  
xxxxxxx 
xx 
xxxxxx 
xxxxxx 
xxxxx 
xxxxxx 
Y/N 
xxxxx 
xxxxx 
xxxxx 
Comments:xxxxxxxxxxx 
 


Statistical Analysis Plan - DMID Protocol: 14-0029  
Version 1.0 
11MAY2018 
- 126 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Table 132: 
Listing of Serious Adverse Events 
Adverse 
Event 
Study Day the 
Event Became 
Serious 
Reason 
Reported 
as an SAE 
Severity 
Relationship to Study 
Treatment 
In Not Related, 
Alternative Etiology 
Action Taken with 
Study Treatment 
Subject 
Discontinued 
Due to AE 
Outcome 
MedDRA 
System Organ 
Class 
MedDRA 
Preferred 
Term 
Subject ID: , Treatment Group: , AE Number:  
xxxxxxx 
xx 
xxxxxx 
xxxxxx 
xxxxxx 
xxxxx 
xxxxxx 
Y/N 
xxxxx 
xxxxx 
xxxxx 
Comments: xxxxxxxxxxxxx 
 
 
 
 
 
 
 
 
 
 
 
Subject ID: , Treatment Group: , AE Number:  
xxxxxxx 
xx 
xxxxxx 
xxxxxx 
xxxxxx 
xxxxx 
xxxxxx 
Y/N 
xxxxx 
xxxxx 
xxxxx 
Comments: xxxxxxxxxxxxx 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan - DMID Protocol: 14-0029  
Version 1.0 
11MAY2018 
- 127 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Narratives of Deaths, Other Serious and Significant Adverse Events (not included in SAP, but will be 
included in the CSR) 
 


Statistical Analysis Plan - DMID Protocol: 14-0029  
Version 1.0 
11MAY2018 
- 128 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Table 133: 
Abnormal Discharge and Cervical Mucus Characteristics by Visit and Treatment Group 
- Safety Population 
All Subjects (N=X) 
Category 
Value 
Visit 1 
(N=X) 
Visit 2 
(N=X) 
Visit 3 
(N=X) 
Visit 4 
(N=X) 
n 
% 
n 
% 
n 
% 
n 
% 
Abnormal Discharge 
Source 
Vagina 
x 
x 
x 
x 
x 
x 
x 
x 
Cervix/vagina 
x 
x 
x 
x 
x 
x 
x 
x 
Amount 
Minimal 
x 
x 
x 
x 
x 
x 
x 
x 
Moderate 
x 
x 
x 
x 
x 
x 
x 
x 
Profuse 
x 
x 
x 
x 
x 
x 
x 
x 
Character 
Thin/watery 
x 
x 
x 
x 
x 
x 
x 
x 
Normal 
x 
x 
x 
x 
x 
x 
x 
x 
Thicker than normal 
x 
x 
x 
x 
x 
x 
x 
x 
Color 
White 
x 
x 
x 
x 
x 
x 
x 
x 
Clear 
x 
x 
x 
x 
x 
x 
x 
x 
Yellow 
x 
x 
x 
x 
x 
x 
x 
x 
Brown 
x 
x 
x 
x 
x 
x 
x 
x 
Bloody 
x 
x 
x 
x 
x 
x 
x 
x 
Consistency 
Non-homogenous (normal) 
x 
x 
x 
x 
x 
x 
x 
x 
Homogenous 
x 
x 
x 
x 
x 
x 
x 
x 
Curdy/Plaques 
x 
x 
x 
x 
x 
x 
x 
x 
Frothy 
x 
x 
x 
x 
x 
x 
x 
x 
Other 
x 
x 
x 
x 
x 
x 
x 
x 
Distribution 
Pooled 
x 
x 
x 
x 
x 
x 
x 
x 
Diffuse 
x 
x 
x 
x 
x 
x 
x 
x 
Patches 
x 
x 
x 
x 
x 
x 
x 
x 
Odor 
None 
x 
x 
x 
x 
x 
x 
x 
x 
Foul 
x 
x 
x 
x 
x 
x 
x 
x 
Fishy 
x 
x 
x 
x 
x 
x 
x 
x 
Cervical Mucus 
Amount 
Minimal (to os) 
x 
x 
x 
x 
x 
x 
x 
x 
Moderate (on face) 
x 
x 
x 
x 
x 
x 
x 
x 
Profuse (pools) 
x 
x 
x 
x 
x 
x 
x 
x 
Color 
Clear 
x 
x 
x 
x 
x 
x 
x 
x 
Opaque White 
x 
x 
x 
x 
x 
x 
x 
x 
Translucent White 
x 
x 
x 
x 
x 
x 
x 
x 
Yellow 
x 
x 
x 
x 
x 
x 
x 
x 
Brown 
x 
x 
x 
x 
x 
x 
x 
x 


Statistical Analysis Plan - DMID Protocol: 14-0029  
Version 1.0 
11MAY2018 
- 129 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
All Subjects (N=X) 
Category 
Value 
Visit 1 
(N=X) 
Visit 2 
(N=X) 
Visit 3 
(N=X) 
Visit 4 
(N=X) 
n 
% 
n 
% 
n 
% 
n 
% 
Bloody 
x 
x 
x 
x 
x 
x 
x 
x 
Viscosity 
Thin 
x 
x 
x 
x 
x 
x 
x 
x 
Average 
x 
x 
x 
x 
x 
x 
x 
x 
Thick 
x 
x 
x 
x 
x 
x 
x 
x 
Note: Denominator for percentages are the number of subjects with abnormal discharge that can be evaluated at the respective visit 
 
Tables with similar format: 
Table 134: 
Abnormal Discharge and Cervical Mucus Characteristics by Visit and Treatment Group 
- Safety Population - LACTIN-V 
Table 135: 
Abnormal Discharge and Cervical Mucus Characteristics by Visit and Treatment Group 
- Safety Population - Placebo 


Statistical Analysis Plan - DMID Protocol: 14-0029  
Version 1.0 
11MAY2018 
- 130 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
APPENDIX 2.  FIGURE MOCK-UPS 
This document includes example mock-ups of figures to present efficacy and safety data. 
Figure 1: 
CONSORT Flow Diagram .......................................................................................133 
Figure 2: 
Time to BV Recurrence by Visit 4 (Week 12) by Treatment Group ........................134 
Figure 3: 
Time to BV Recurrence by Visit 7 (Week 24) by Treatment Group ........................134 
Figure 4: 
Time to L. crispatus Colonization by Visit 4 (Week 12) by Treatment Group ........134 
Figure 5: 
Time to L. crispatus Colonization by Visit 7 (Week 24) by Treatment Group ........134 
Figure 6: 
L. crispatus CTV-05 Concentration by Time Since Last Dose, Week, and 
Treatment Group-ITT Population .............................................................................135 
Figure 7: 
L. crispatus CTV-05 Concentration by Time Since Last Dose, Week, and 
Treatment Group-mITT Population ..........................................................................136 
Figure 8: 
L. crispatus CTV-05 Concentration by Time Since Last Dose, Week, and 
Treatment Group-CC Population ..............................................................................136 
Figure 9: 
L. crispatus CTV-05 Concentration by Time Since Last Dose, Week, and 
Treatment Group-PP Population...............................................................................136 
Figure 10: L. crispatus CTV-05 Concentration by Number of Condom-less Sexual 
Intercourse Acts, Week, and Treatment Group-ITT Population ..............................136 
Figure 11: L. crispatus CTV-05 Concentration by Number of Condom-less Sexual 
Intercourse Acts, Week, and Treatment Group-mITT Population ...........................136 
Figure 12: L. crispatus CTV-05 Concentration by Number of Condom-less Sexual 
Intercourse Acts, Week, and Treatment Group-CC Population ...............................136 
Figure 13: L. crispatus CTV-05 Concentration by Number of Condom-less Sexual 
Intercourse Acts, Week, and Treatment Group-PP Population ................................136 
Figure 14: L. crispatus CTV-05 Concentration by Number of Partners, Week, and 
Treatment Group-ITT Population .............................................................................136 
Figure 15: L. crispatus CTV-05 Concentration by Number of Partners, Week, and 
Treatment Group-mITT Population ..........................................................................136 
Figure 16: L. crispatus CTV-05 Concentration by Number of Partners, Week, and 
Treatment Group-CC Population ..............................................................................136 
Figure 17: L. crispatus CTV-05 Concentration by Number of Partners, Week, and 
Treatment Group-PP Population...............................................................................136 
Figure 18: L. crispatus CTV-05 Concentration by Compliance Status, Week, and 
Treatment Group-ITT Population .............................................................................137 
Figure 19: L. crispatus CTV-05 Concentration by Compliance Status, Week, and 
Treatment Group-mITT Population ..........................................................................137 


Statistical Analysis Plan - DMID Protocol: 14-0029  
Version 1.0 
11MAY2018 
- 131 - 
PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Figure 20: L. crispatus CTV-05 Concentration by Compliance Status, Week, and 
Treatment Group-CC Population ..............................................................................137 
Figure 21: L. crispatus CTV-05 Concentration by Day Since Last Day of Last 
Menstrual Period, Week, and Treatment Group - ITT Population ...........................138 
Figure 22: L. crispatus CTV-05 Concentration by Day Since Last Day of Last 
Menstrual Period, Week, and Treatment Group - mITT Population ........................138 
Figure 23: L. crispatus CTV-05 Concentration by Day Since Last Day of Last 
Menstrual Period, Week, and Treatment Group - CC Population ............................138 
Figure 24: L. crispatus CTV-05 Concentration by Day Since Last Day of Last 
Menstrual Period, Week, and Treatment Group - PP Population .............................138 
Figure 25: L. crispatus CTV-05 Concentration by Menses After Last Dose Taken, 
Week, and Treatment Group-ITT Population ...........................................................139 
Figure 26: L. crispatus CTV-05 Concentration by Menses After Last Dose Taken, 
Week, and Treatment Group-mITT Population ........................................................139 
Figure 27: L. crispatus CTV-05 Concentration by Menses After Last Dose Taken, 
Week, and Treatment Group-CC Population ............................................................139 
Figure 28: L. crispatus CTV-05 Concentration by Menses After Last Dose Taken, 
Week, and Treatment Group-PP Population ............................................................139 
Figure 29: CTV-05 Concentration by L. crispatus Concentration, Week, and Treatment 
Group - ITT Population ............................................................................................140 
Figure 30: CTV-05 Concentration by L. crispatus Concentration, Week, and Treatment 
Group - mITT Population .........................................................................................140 
Figure 31: CTV-05 Concentration by L. crispatus Concentration, Week, and Treatment 
Group - CC Population .............................................................................................140 
Figure 32: CTV-05 Concentration by L. crispatus Concentration, Week, and Treatment 
Group - PP Population ..............................................................................................140 
Figure 33: L. crispatus CTV-05 Concentration by Amsel Criteria, Week, and Treatment 
Group-ITT Population ..............................................................................................141 
Figure 34: L. crispatus CTV-05 Concentration by Amsel Criteria, Week, and Treatment 
Group-mITT Population ...........................................................................................141 
Figure 35: L. crispatus CTV-05 Concentration by Amsel Criteria, Week, and Treatment 
Group-CC Population ...............................................................................................141 
Figure 36: L. crispatus CTV-05 Concentration by Amsel Criteria, Week, and Treatment 
Group-PP Population ................................................................................................141 
Figure 37: L. crispatus CTV-05 Concentration by Nugent Score, Week, and Treatment 
Group-ITT Population ..............................................................................................141 
Figure 38: L. crispatus CTV-05 Concentration by Nugent Score, Week, and Treatment 
Group-mITT Population ...........................................................................................141 


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Figure 39: L. crispatus CTV-05 Concentration by Nugent Score, Week, and Treatment 
Group-CC Population ...............................................................................................141 
Figure 40: L. crispatus CTV-05 Concentration by Nugent Score, Week, and Treatment 
Group-PP Population ................................................................................................141 
Figure 41: Maximum Severity of Solicited Local Adverse Events by Symptom and 
Treatment Group - Safety Population .......................................................................142 
Figure 42: Maximum Severity of Solicited Systemic Adverse Events by Symptom and 
Treatment Group - Safety Population .......................................................................143 
Figure 43: Maximum Severity of Solicited Local Adverse Events by Day and 
Treatment Group—Safety Population ......................................................................144 
Figure 44: Maximum Severity of Solicited Systemic Adverse Events by Day and 
Treatment Group—Safety Population ......................................................................144 
Figure 45: Frequency of Adverse Events by MedDRA System Organ Class and 
Severity .....................................................................................................................145 
Figure 46: Incidence of Adverse Events by MedDRA System Organ Class and 
Maximum Severity ...................................................................................................146 
Figure 47: Frequency of Adverse Events by MedDRA System Organ Class and 
Relationship to Treatment .........................................................................................147 
Figure 48: Incidence of Adverse Events by MedDRA System Organ Class and 
Relationship to Treatment .........................................................................................148 
 


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Figure 1: 
CONSORT Flow Diagram 
Implementation notes:  The actual diagram will match the design of this study. 
Allocated to Group 1 (n=x) 
♦Received allocated intervention (n=x) 
♦Did not receive allocated intervention (n=x) 
[Reason 1] (x), [Reason 2] (x) 
Discontinued Intervention (n=x) 
♦[Reason 1] (x), [Reason 2] (x) 
Early Termination (n=32) 
Analysed for efficacy (n=x) 
♦Excluded from efficacy analyses (n=x) 
[Reason 1] (x), [Reason 2] (x) 
Analyzed for safety (n=x) 
♦Excluded from safety analyses (n=x) 
[Reason 1] (x), [Reason 2] (x) 
Assessed for Eligibility (n=x) 
Excluded* (n=x) 
♦   [Reason 1] (n=x) 
♦   Concern of potential risk (n=x) 
Randomized (n=x) 
Allocation 
Analysis 
Follow-Up 
Enrollment 
Allocated to Group 1 (n=x) 
♦Received allocated intervention (n=x) 
♦Did not receive allocated intervention (n=x) 
[Reason 1] (x), [Reason 2] (x) 
Allocated to Group 1 (n=x) 
♦Received allocated intervention (n=x) 
♦Did not receive allocated intervention (n=x) 
[Reason 1] (x), [Reason 2] (x) 
Discontinued Intervention (n=x) 
♦[Reason 1] (x), [Reason 2] (x) 
Early Termination (n=32) 
Discontinued Intervention (n=x) 
♦[Reason 1] (x), [Reason 2] (x) 
Early Termination (n=32) 
Analysed for efficacy (n=x) 
♦Excluded from efficacy analyses (n=x) 
[Reason 1] (x), [Reason 2] (x) 
Analyzed for safety (n=x) 
♦Excluded from safety analyses (n=x) 
[Reason 1] (x), [Reason 2] (x) 
Analysed for efficacy (n=x) 
♦Excluded from efficacy analyses (n=x) 
[Reason 1] (x), [Reason 2] (x) 
Analyzed for safety (n=x) 
♦Excluded from safety analyses (n=x) 
[Reason 1] (x), [Reason 2] (x) 


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Figure 2: 
Time to BV Recurrence by Visit 4 (Week 12) by Treatment Group 
 
 
Figure will be a 2x2 panel plot with each panel displaying one of the analysis populations:  ITT, mITT, CC, 
and PP. 
 
Figures with similar format: 
Figure 3: 
Time to BV Recurrence by Visit 7 (Week 24) by Treatment Group 
Figure 4: 
Time to L. crispatus Colonization by Visit 4 (Week 12) by Treatment Group 
Figure 5: 
Time to L. crispatus Colonization by Visit 7 (Week 24) by Treatment Group 
 


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Figure 6: 
L. crispatus CTV-05 Concentration by Time Since Last Dose, Week, and Treatment 
Group-ITT Population 
 
 


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Figures with similar format: 
Figure 7: 
L. crispatus CTV-05 Concentration by Time Since Last Dose, Week, and Treatment 
Group-mITT Population 
Figure 8: 
L. crispatus CTV-05 Concentration by Time Since Last Dose, Week, and Treatment 
Group-CC Population 
Figure 9: 
L. crispatus CTV-05 Concentration by Time Since Last Dose, Week, and Treatment 
Group-PP Population 
Figure 10: 
L. crispatus CTV-05 Concentration by Number of Condom-less Sexual Intercourse Acts, 
Week, and Treatment Group-ITT Population 
Figure 11: 
L. crispatus CTV-05 Concentration by Number of Condom-less Sexual Intercourse Acts, 
Week, and Treatment Group-mITT Population 
Figure 12: 
L. crispatus CTV-05 Concentration by Number of Condom-less Sexual Intercourse Acts, 
Week, and Treatment Group-CC Population 
Figure 13: 
L. crispatus CTV-05 Concentration by Number of Condom-less Sexual Intercourse Acts, 
Week, and Treatment Group-PP Population 
Figure 14: 
L. crispatus CTV-05 Concentration by Number of Partners, Week, and Treatment 
Group-ITT Population 
Figure 15: 
L. crispatus CTV-05 Concentration by Number of Partners, Week, and Treatment 
Group-mITT Population 
Figure 16: 
L. crispatus CTV-05 Concentration by Number of Partners, Week, and Treatment 
Group-CC Population 
Figure 17: 
L. crispatus CTV-05 Concentration by Number of Partners, Week, and Treatment 
Group-PP Population 


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Figure 18: 
L. crispatus CTV-05 Concentration by Compliance Status, Week, and Treatment Group-
ITT Population 
 
 
Figures with similar format: 
Figure 19: 
L. crispatus CTV-05 Concentration by Compliance Status, Week, and Treatment Group-
mITT Population 
Figure 20: 
L. crispatus CTV-05 Concentration by Compliance Status, Week, and Treatment Group-
CC Population 


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Figure 21: 
L. crispatus CTV-05 Concentration by Day Since Last Day of Last Menstrual Period, 
Week, and Treatment Group - ITT Population 
 
Implementation Note: 
X-axis labels will read “Days Since Last Day of Last Menstrual Period” 
Figures with similar format: 
Figure 22: 
L. crispatus CTV-05 Concentration by Day Since Last Day of Last Menstrual Period, 
Week, and Treatment Group - mITT Population 
Figure 23: 
L. crispatus CTV-05 Concentration by Day Since Last Day of Last Menstrual Period, 
Week, and Treatment Group - CC Population 
Figure 24: 
L. crispatus CTV-05 Concentration by Day Since Last Day of Last Menstrual Period, 
Week, and Treatment Group - PP Population 


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Figure 25: 
L. crispatus CTV-05 Concentration by Menses After Last Dose Taken, Week, and 
Treatment Group-ITT Population 
 
Implementation Note: 
X-axis groups will be “Menses” and “No Menses” 
Figures with similar format: 
Figure 26: 
L. crispatus CTV-05 Concentration by Menses After Last Dose Taken, Week, and 
Treatment Group-mITT Population 
Figure 27: 
L. crispatus CTV-05 Concentration by Menses After Last Dose Taken, Week, and 
Treatment Group-CC Population 
Figure 28: 
L. crispatus CTV-05 Concentration by Menses After Last Dose Taken, Week, and 
Treatment Group-PP Population 


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Figure 29: 
CTV-05 Concentration by L. crispatus Concentration, Week, and Treatment Group - ITT 
Population 
 
Implementation Note: 
Y-axis labels will read “CTV-05 concentration”, X-axis labels will read “L. crispatus concentration”. 
Figures with similar format: 
Figure 30: 
CTV-05 Concentration by L. crispatus Concentration, Week, and Treatment Group - 
mITT Population 
Figure 31: 
CTV-05 Concentration by L. crispatus Concentration, Week, and Treatment Group - CC 
Population 
Figure 32: 
CTV-05 Concentration by L. crispatus Concentration, Week, and Treatment Group - PP 
Population 


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Figure 33: 
L. crispatus CTV-05 Concentration by Amsel Criteria, Week, and Treatment Group-ITT 
Population 
 
Implementation Note: 
X-axis groups will be “Positive” and “Negative” 
Figures with similar format: 
Figure 34: 
L. crispatus CTV-05 Concentration by Amsel Criteria, Week, and Treatment Group-
mITT Population 
Figure 35: 
L. crispatus CTV-05 Concentration by Amsel Criteria, Week, and Treatment Group-CC 
Population 
Figure 36: 
L. crispatus CTV-05 Concentration by Amsel Criteria, Week, and Treatment Group-PP 
Population 
Figure 37: 
L. crispatus CTV-05 Concentration by Nugent Score, Week, and Treatment Group-ITT 
Population 
Figure 38: 
L. crispatus CTV-05 Concentration by Nugent Score, Week, and Treatment Group-mITT 
Population 
Figure 39: 
L. crispatus CTV-05 Concentration by Nugent Score, Week, and Treatment Group-CC 
Population 
Figure 40: 
L. crispatus CTV-05 Concentration by Nugent Score, Week, and Treatment Group-PP 
Population 


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Figure 41: 
Maximum Severity of Solicited Local Adverse Events by Symptom and Treatment Group 
- Safety Population 
 
 


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Figure 42: 
Maximum Severity of Solicited Systemic Adverse Events by Symptom and Treatment 
Group - Safety Population 
 


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Figure 43: 
Maximum Severity of Solicited Local Adverse Events by Day and Treatment Group—
Safety Population 
 
 
Figures with Similar Format: 
Figure 44: 
Maximum Severity of Solicited Systemic Adverse Events by Day and Treatment Group—
Safety Population 
 
 


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Figure 45: 
Frequency of Adverse Events by MedDRA System Organ Class and Severity 
 
 
Implementation Note: 
• Include “Any SOC” bars 
 


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Figure 46: 
Incidence of Adverse Events by MedDRA System Organ Class and Maximum Severity  
 
 
Implementation Note: 
• Include “Any SOC” bars 


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Figure 47: 
Frequency of Adverse Events by MedDRA System Organ Class and Relationship to Treatment 
 
 
Implementation Note: 
• Include “Any SOC” bars 


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Figure 48: 
Incidence of Adverse Events by MedDRA System Organ Class and Relationship to Treatment 
 
 
Implementation Note: 
• Include “Any SOC” bars 


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APPENDIX 3. LISTINGS MOCK-UPS 
This document includes example mock-ups of listings to present subject-level data. 
Listing 1 
Subjects Excluded from Analysis Populations .........................................................152 
Listing 2 
Subjects Whose Assigned Treatment Group Does Not Match Their 
Randomized Treatment Group .................................................................................153 
Listing 3 
Early Terminations or Discontinued Subjects-All Enrolled Subjects ......................154 
Listing 4 
Subject-Specific Protocol Deviations-All Enrolled Subjects ...................................155 
Listing 5 
Non-Subject-Specific Protocol Deviations ...............................................................156 
Listing 6 
Individual Efficacy Response Data ..........................................................................157 
Listing 7 
Compliance Data- All Treated Subjects ...................................................................158 
Listing 8 
Missed Dose Data- All Treated Subjects ..................................................................159 
Listing 9 
Individual Acceptability Questionnaire Responses ..................................................160 
Listing 10 Demographic Data-All Enrolled Subjects ................................................................161 
Listing 11 Screening Gynecological History Interview-All Enrolled Subjects .........................162 
Listing 12 Screening Sexual History Interview-All Enrolled Subjects .....................................163 
Listing 13 Follow-up Gynecological History Interview-All Enrolled Subjects ........................164 
Listing 14 Follow-up Sexual History Interview-All Enrolled Subjects .....................................165 
Listing 15 Screening Pregnancy History Interview-All Enrolled Subjects ...............................166 
Listing 16 Pre-Existing Medical Conditions- All Enrolled Subjects .........................................167 
Listing 17 Concomitant Medications .........................................................................................168 
Listing 18 Solicited Local Events –All Treated Subjects ..........................................................169 
Listing 19 Solicited Systemic Events – Safety Population ........................................................170 
Listing 20 Unsolicited Adverse Events ......................................................................................171 
Listing 21 Pregnancy Reports – Maternal Information .............................................................172 
Listing 22 Pregnancy Reports – Gravida and Para ....................................................................173 
Listing 23 Pregnancy Reports – Live Birth Outcomes ..............................................................174 
Listing 24 Pregnancy Reports – Still Birth Outcomes ...............................................................175 
Listing 25 Pregnancy Reports – Spontaneous, Elective, or Therapeutic Abortion 
Outcomes ..................................................................................................................176 
Listing 26 Clinical Laboratory Results – Urinalysis ..................................................................177 
Listing 27 Clinical Laboratory Results – Serology and STI Testing .........................................178 


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Listing 28 Additional Gynecological Test Results ....................................................................179 
Listing 29 Vital Signs ................................................................................................................180 
Listing 30 Physical Exam Findings ...........................................................................................181 
Listing 31 Pelvic Exam Findings ...............................................................................................182 
Listing 32 Abnormal Discharge .................................................................................................183 
Listing 33 Cervical Mucus .........................................................................................................184 
 
 


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Listing of Subjects Receiving Investigational Product (not included in SAP, but will be included in the 
CSR) 
 


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Listing 1 
Subjects Excluded from Analysis Populations 
Actual Treatment 
Group 
Randomized 
Treatment 
Group 
Subject ID 
Analyses in which 
Subject is Included 
Analyses from which  
Subject is Excluded 
Results Available? 
Reason(s) Subject Excluded 
LACTIN-V/Placebo 
LACTIN-
V/Placebo 
xxxxxx 
[e.g., Safety, ITT, mITT, CC, 
PP] 
[e.g., Safety, ITT, mITT, CC, PP, 
Visit  x] 
Yes/No 
xxxxx 
LACTIN-V/Placebo 
LACTIN-
V/Placebo 
xxxxxx 
[e.g., Safety, ITT, mITT, CC, 
PP] 
[e.g., Safety, ITT, mITT, CC, PP, 
Visit x] 
Yes/No 
xxxxx 
LACTIN-V/Placebo 
LACTIN-
V/Placebo 
xxxxxx 
[e.g., Safety, ITT, mITT, CC, 
PP] 
[e.g., Safety, ITT, mITT, CC, PP, 
Visit x] 
Yes/No 
xxxxx 
Note: “Yes” in the “Results available” column indicates that available data were removed from the analysis. If “Yes” the population in which data were removed will be listed in parenthesis.  “No” indicates that no data were 
available for inclusion in the analysis. 
 
Implementation Notes:   
1. Sort order will be actual treatment group, Subject ID 
2. Reasons Subject Excluded should match the same verbiage that is used on the Analysis population tables 
3. If all subjects received the correct treatment, only display “Treatment Group”. 
 


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Listing 2 
Subjects Whose Assigned Treatment Group Does Not Match Their Randomized Treatment Group 
Subject ID 
Treatment Group at Randomization 
Treatment Actually Received 
xxxxxx 
LACTIN-V/Placebo 
LACTIN-V/Placebo 
xxxxxx 
LACTIN-V/Placebo 
LACTIN-V/Placebo 
 
Implementation Note: 
1. Sort order is Subject ID. 
 


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Listing 3 
Early Terminations or Discontinued Subjects-All Enrolled Subjects 
Actual 
Treatment Group 
Randomized 
Treatment Group 
Subject ID 
Category 
Study Day Corresponding to 
Early Termination/Treatment 
Discontinuation/Completion 
Reason for Early 
Termination/ Treatment 
Discontinuation 
LACTIN-V/Placebo 
LACTIN-V/Placebo 
xxxxxxx 
Early Termination/Treatment 
Discontinuation/Completion 
xx 
xxxxxxxxxxxxxxxxx 
LACTIN-V/Placebo 
LACTIN-V/Placebo 
xxxxxxx 
Early Termination/Treatment 
Discontinuation/Completion 
xx 
--- 
 
Implementation Notes:   
1.  Sort order will be by Actual Treatment Group, Subject ID, Category 
2. Category will be "Early Termination", "Completion" 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. 


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Listing 4 
Subject-Specific Protocol Deviations-All Enrolled Subjects 
Deviation 
Number 
Study 
Day 
Deviation 
Description 
Deviation 
Category 
Reason for 
Deviation 
Deviation 
Affected 
Product 
Stability? 
Deviation 
Resulted in 
AE? 
Deviation 
Resulted in 
Subject 
Termination? 
Deviation 
Resolution 
Comments 
Actual Treatment Group:    ,  Randomized Treatment Group:   ,  Subject ID:    
xx 
xx 
xxxxxxx 
xxxxxxxxxxx 
xxxxxxx 
Yes/No 
Yes/No 
Yes/No 
Yes/No 
xxxxxxxxxxx 
xx 
xx 
xxxxxxx 
xxxxxxxxxxx 
xxxxxxx 
Yes/No 
Yes/No 
Yes/No 
Yes/No 
-- 
Note: Deviation description column will contain all subfields concatenated together 
 
Implementation Notes:   
1. Sort order will be by Actual Treatment Group, Subject ID, Deviation Number 
2. In the Deviation Category column concatenate any specify fields  
3. In the Reason for Deviation column concatenate any specify fields. 


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


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Listing 6 
Individual Efficacy Response Data 
Study 
Day 
(Week) 
Homogeneous, 
thin, grayish-white 
discharge 
Vaginal 
pH 
Amine (“whiff”) test 
on KOH wet mount 
Clue 
Cells 
on wet 
mount 
(%) 
Amsel 
Criteria 
Nugent 
Score 
BV  
Diagnosis 
L. crispatus 
Concentration 
(copies/mL) 
CTV-05 
Concentration 
(copies/mL) 
Lactobacillus 
spp. 
Concentration 
(copies/mL) 
Total Bacteria 
Concentration 
(copies/mL) 
L. crispatus 
Colonization 
Status 
Actual Treatment Group:   , Randomized Treatment Group:   Subject ID:    
x (x) 
Present/ 
Absent/ 
Not Assessed 
xx.x 
Negative/ 
Positive/ 
Not Assessed 
xx 
x 
x 
Positive/ 
Negative/ 
Indeterminate 
x.x E x 
x.x E x 
x.x E x 
x.x E x 
Successful/ 
No 
colonization 
 
Implementation Notes: 
1. Sort order is actual treatment group, Subject ID, Study Day.  
2. If all subjects received the correct treatment, only display “Treatment Group”. 
 


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Listing 7 
Compliance Data- All Treated Subjects 
Actual 
Treatment 
Group 
Subject 
ID 
Week 
Dose 
Dose Taken? 
(Subject Report) 
Study Day of 
Administration 
(Subject Report) 
Time of 
Administration 
(Subject Report) 
Number of 
Applicators 
Returned 
(Used / Unused) 
Staining Assessment 
(Used / Unused / 
Indeterminate) 
Compliance Status 
xxxxxx 
xxxxxx 
1 
1 
Yes/No 
xx 
xx:xx 
x / x 
x / x / x 
Compliant/Non-compliant 
2 
Yes/No 
xx 
xx:xx 
3 
Yes/No 
xx 
xx:xx 
4 
Yes/No 
xx 
xx:xx 
5 
Yes/No 
xx 
xx:xx 
2 
1 
Yes/No 
xx 
xx:xx 
x / x 
x / x / x 
2 
Yes/No 
xx 
xx:xx 
3 
1 
Yes/No 
xx 
xx:xx 
x / x 
x / x / x 
2 
Yes/No 
xx 
xx:xx 
Etc. 
 
Implementation Notes: 
1. Sort order is actual treatment Group, Subject ID. 
2. Total number of doses is 25.  Number of doses not taken will be calculated as 25 - Number of doses taken as scheduled - Number of doses taken out of 
window. 
3. If a subject does not have a record for 'Returned Used Applicators' or 'Returned Unused Applicators', then an 'Unknown' will be placed in those 
columns. 
 


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Listing 8 
Missed Dose Data- All Treated Subjects  
Actual Treatment 
Group  
Randomized Treatment 
Group 
Subject ID  
Dose(s) Missed 
LACTIN-V/Placebo LACTIN-V/Placebo 
xxxxxx 
[e.g., Week 2 Dose 1, Week Dose 2, etc.] 
 
Implementation Notes: 
1. Sort order is Treatment Group, Subject ID. 


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Listing 9 
Individual Acceptability Questionnaire Responses 
Actual 
Treatment 
Group 
 
Questionnaire 
Item 
Questionnaire Sub-
Item 
Screening 
Follow-up 
Subject ID 
Study Day (Week) 
Response 
Study Day (Week) 
Response 
LACTIN-
V/Placebo 
xxxxxx 
1 
- 
x (x) 
xxx 
x (x) 
xxx 
2 
A 
x (x) 
Yes/No 
x (x) 
Yes/No 
B 
x (x) 
Yes/No 
x (x) 
Yes/No 
C 
x (x) 
Yes/No 
x (x) 
Yes/No 
D 
x (x) 
Yes/No 
x (x) 
Yes/No 
E 
x (x) 
Yes/No 
x (x) 
Yes/No 
F 
x (x) 
Yes/No 
x (x) 
Yes/No 
3 
- 
x (x) 
xxx 
x (x) 
xxx 
4 
- 
x (x) 
xxx 
x (x) 
xxx 
5 
- 
x (x) 
xxx 
x (x) 
xxx 
Etc. 
 
Implementation Notes:   
1. Sort order is actual treatment group, Subject ID, Study Day. 
2. If all subjects received the correct treatment, only display “Treatment Group”. 


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Listing 10 
Demographic Data-All Enrolled Subjects 
Actual Treatment Group 
Randomized Treatment Group 
Subject ID 
Age at Enrollment (years) 
Ethnicity 
Race 
LACTIN-V/Placebo 
LACTIN-V/Placebo 
xxxxxx 
xx 
xxxxxx 
xxxxxx 
LACTIN-V/Placebo 
LACTIN-V/Placebo 
xxxxxx 
xx 
xxxxxx 
xxxxxx 
LACTIN-V/Placebo 
LACTIN-V/Placebo 
xxxxxx 
xx 
xxxxxx 
xxxxxx 
 
Implementation Notes:   
1. Sort order will be by Actual Treatment Group, Subject ID 
2. For the Race column, if a subject is Multi-Racial, all races will be listed, separated by a comma 
 
 


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Listing 11 
Screening Gynecological History Interview-All Enrolled Subjects 
Study 
Day 
Have you been 
amenorrheic for at least 3 
months due to use of a 
long-acting progestin or 
continuous use of oral 
contraceptives? 
First Day of 
your last 
menstrual 
period 
 (Study Day) 
How many 
days is your 
average 
menstrual 
cycle? 
How 
many 
days does 
your 
period 
last? 
In the past 3 months, have 
you had any abnormal 
menstrual cycles? 
What sanitary products do you 
use during your period? 
Have you ever 
douched or used 
vaginal 
preparations or 
drying agents? 
In the last 30 days how 
many times have you 
douched or used 
vaginal preparations or 
drying agents? 
Actual Treatment Group:   , Randomized Treatment Group:   Subject ID:    
xx 
Yes/No 
xx 
xx 
 
xx 
 
Yes/No 
[cycle length less than 21 
days/cycle length more than 
35 days/Intermenstrual 
bleeding/spotting] 
Pads/Cups/Tampons/Other 
Yes/No 
[Specify] 
 
xx/NA 
 
Implementation Notes:   
1. Sort order will be by Actual treatment group, Subject ID 
2. For questions that are parented, if the parent question is “No” and the subsequent fields are not required, fill the cell with “—“ 
3. Includes data from Visit 00 
4. If answer to ‘In the past 3 months, have you had any abnormal menstrual cycles?’ is “Yes,” then concatenate the answer to the abnormal cycles that 
were experienced 
5. If answer to ‘Have you ever douched or used vaginal preparations or drying agents?’ is “Yes,” then concatenate answer to the ‘specify’ field. If the 
answer is “No” then there will be no answer. 
 
 


Statistical Analysis Plan - DMID Protocol: 14-0029  
Version 1.0 
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Listing 12 
Screening Sexual History Interview-All Enrolled Subjects 
Study 
Day 
How many male partners 
have you had in the past 6 
months? 
How many female partners 
have you had in the past 6 
months? 
Have you had sex 
in the past 30 
days? 
How many times 
did you have 
sex? 
How many times did 
you have protected sex? 
How many times did you 
have unprotected sex? 
How many days has it 
been since the last time 
you had sex? 
Actual Treatment Group:   , Randomized Treatment Group:   Subject ID:    
xx 
xx 
xx 
Yes/No 
 
xx 
 
xx 
xx 
xx 
 
Implementation Notes:   
1. Sort order will be by actual treatment group, Subject ID 
2. For questions that are parented, if the parent question is “No” and the subsequent fields are not required, fill the cell with “—“ 
3. Includes data from Visit 00 
 


Statistical Analysis Plan - DMID Protocol: 14-0029  
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Listing 13 
Follow-up Gynecological History Interview-All Enrolled Subjects 
Study 
Day 
Have you menstruated 
since your last visit? 
First Day of 
your last 
menstrual 
period 
(Study Day) 
Since your last 
visit, have you 
experienced any 
spotting or 
bleeding other 
than menstrual 
bleeding? 
Since your 
last visit, 
have you 
used 
scented 
tampons? 
Since your last visit, 
have you douched or 
vaginally inserted 
anything other than 
the study applicator 
or MetroGel? 
How many days has it 
been since you last 
douched or vaginally 
inserted  anything other 
than the study applicator 
or MetroGel? 
Since your last visit, how 
many times have you 
douched or vaginally 
inserted anything other than 
the study applicator or 
MetroGel? 
Have you changed 
birth control 
methods or started 
a new method 
since the last visit? 
Actual Treatment Group:   , Randomized Treatment Group:   Subject ID:    
xx 
Yes/No 
xx 
Yes/No 
 
Yes/No/NA 
 
Yes/No 
[specify] 
xx 
xx  
Yes/No/NA 
 
Implementation Notes:   
1. Sort order will be by actual treatment group, subject ID 
2. For questions that are parented, if the parent question is “No” and the subsequent fields are not required, fill the cell with “—“ 
3. Includes data from Visit 0, 02, 03, 04,07 
4. If answer to ‘Since your last visit, have you douched or vaginally inserted anything other than the study applicator or MetroGel?’ is “Yes,” 
concatenate answer to ‘Specify’ field. If the answer is “No” then there will be no answer. 
 


Statistical Analysis Plan - DMID Protocol: 14-0029  
Version 1.0 
11MAY2018 
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Listing 14 
Follow-up Sexual History Interview-All Enrolled Subjects 
Study Day 
Have you had sex since the 
last visit? 
How many times did you 
have sex? 
How many new partners did 
you have? 
How many days has it been since 
the last time you had sex? 
If you had sex with a man, did your partner use 
a condom each time? 
Actual Treatment Group:   , Randomized Treatment Group:   Subject ID:    
xx 
Yes/No 
xx 
xx 
 
xx 
 
Yes/No/NA 
 
Implementation Notes:   
1. Sort order will be by Subject ID 
2. For questions that are parented, if the parent question is “No” and the subsequent fields are not required, fill the cell with “—“ 
3. Includes data from Visit 0, 02, 03, 04,07 
 
 


Statistical Analysis Plan - DMID Protocol: 14-0029  
Version 1.0 
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Listing 15 
Screening Pregnancy History Interview-All Enrolled Subjects 
Study 
Day 
How many times 
have you been 
pregnant? 
Number of 
Live Births 
Number of 
Stillborn 
Births 
Number of 
Spontaneous 
Abortions 
Number of 
Elective 
Abortions 
Number of 
Ectopic 
Pregnancies 
Do you have any 
children born with 
congenital 
anomalies? 
What is your current Relationship Status? 
Actual Treatment Group:   , Randomized Treatment Group:   Subject ID:    
xx 
xx 
xx 
xx 
 
xx 
 
xx 
 
xx 
 
Yes/No 
[Specify] 
 
Married/Divorced/Separated/Single (never 
married)/Widowed/Steads partner, cohabitating/Steady 
partner, not cohabitating/Casual partner 
 
Implementation Notes:   
1. Sort order will be by Actual treatment group, Subject ID 
2. For questions that are parented, if the parent question is “No” and the subsequent fields are not required, fill the cell with “—“ 
3. Includes data from Visit 00 
4. If answer to ‘Do you have any children born with congenital anomalies?’ is yes, then concatenate answer to ‘Describe.’ If the answer is “No” then 
there will be no answer. 
 


Statistical Analysis Plan - DMID Protocol: 14-0029  
Version 1.0 
11MAY2018 
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PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Listing 16 
Pre-Existing Medical Conditions- All Enrolled Subjects 
Actual Treatment Group 
Randomized Treatment Group 
Subject ID 
MH 
Number 
Medical History 
Term 
Condition 
Start Day  
Condition End 
Day 
MedDRA 
System Organ 
Class 
MedDRA 
Preferred Term 
LACTIN-V/Placebo 
LACTIN-V/Placebo 
xxxxxx 
xxx 
xxxxxx 
xx 
xx 
xxxxxx 
xxxxxx 
LACTIN-V/Placebo 
LACTIN-V/Placebo 
xxxxxx 
xxx 
xxxxxx 
xx 
xx 
xxxxxx 
xxxxxx 
 
Implementation Notes: 
1. Sort order is Actual Treatment Group, Subject ID, MH Number. 
2. "Condition Start Day" and "Condition End Day" are relative to enrollment (which is Day 1, day before enrollment is Day -1).  Rather than use exact 
study days, categorize as follows: 
- > 5 years prior to enrollment 
- 1-5 years prior to enrollment 
-1-12 months prior to enrollment 
-Within 1 month of enrollment 
-During Study 
-If Ongoing at the end of the study, display "Ongoing' in the "Condition End Day" column. 
-If ending is unknown at the end of the study, display "Unknown" in the "Condition End Day" column. 
 


Statistical Analysis Plan - DMID Protocol: 14-0029  
Version 1.0 
11MAY2018 
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Listing 17 
Concomitant Medications 
Actual Treatment 
Group 
Randomized 
Treatment Group 
Subject ID 
Concomitant 
Medication 
Number 
Medication 
Medication Start 
Day 
Medication 
End Day 
Indication 
Taken for an AE? 
(AE Description; 
AE Number) 
Taken for a 
condition on Medical 
History? 
(MH Description; 
MH Number) 
LACTIN-V/Placebo 
LACTIN-V/Placebo 
LACTIN-V/Placebo 
xx 
xxxxxx 
xx 
xx 
xxxxxx 
Yes/No 
xxxxx; xx 
Yes/No 
xxxxx; xx 
LACTIN-V/Placebo 
LACTIN-V/Placebo 
LACTIN-V/Placebo 
xx 
xxxxxx 
xx 
xx 
xxxxxx 
Yes/No 
xxxxx; xx 
Yes/No 
xxxxx; xx 
 
Implementation Notes: 
1. Sort order is actual treatment group, Subject ID, concomitant medication number. 
2. 'Medication Start Day' and 'Medication End Day' are relative to enrollment (which is Day 1, day before enrollment is Day -1).   For medication start 
dates that are > 30 days prior to enrollment, rather than use exact days, categorize as follows: 
- > 5 years prior to enrollment 
- 1- 5 years prior to enrollment 
- 1-12 months prior to enrollment. 
- For 'Medication End Day', if medication is Ongoing, display 'Ongoing' in the Medication End Day' column.   
- For 'Medication End Day', if end of medication is unknown, display 'Unknown' in the 'Medication End Day' column.  
3. If a Medication is taken for an AE, then concatenate the conmed with the Advere Events by AENUM and report the AETERM, plus the AE Number.  
4. If a Medication is taken for an MH, then concatenate the conmed with the Medical History event by MHNUM and report the MHTERM, plus the MH 
Number. 
5. Include the birth control information in this dataset.  The birth control information is coming from the RP/SUPPRP or BC1 dataset. 
6. If all subjects received the correct treatment, only display “Treatment Group”.


Statistical Analysis Plan - DMID Protocol: 14-0029  
Version 1.0 
11MAY2018 
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PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Listing 18 
Solicited Local Events –All Treated Subjects 
Week 
Study 
Day 
Vaginal Bleeding 
Other than 
Menstruation 
Abnormal Vaginal 
Discharge 
Abnormal Vaginal 
Odor 
Genital Itching 
Genital Burning 
External Genital 
Irritation 
External Genital 
Swelling 
Genital Rash 
Actual Treatment Group:   , Randomized Treatment Group:   Subject ID:    
x 
x 
[severity] 
[severity] 
[severity] 
[severity] 
[severity] 
[severity] 
[severity] 
[severity] 
x 
x 
[severity] 
[severity] 
[severity] 
[severity] 
[severity] 
[severity] 
[severity] 
[severity] 
 
Implementation Notes: 
1. Sort order is actual treatment group, Subject ID, Study Day. 
2. If a symptom is ongoing after day 5, add a row for Day 6 and for each day until the end date of the symptom.  The severity will be the maximum 
severity reported for that symptom. 
3. Mark all severities with a +, that are considered treatment emergent solicited adverse events. 
4. Severity will be color coded 
5. If all subjects received the correct treatment, only display “Treatment Group”. 


Statistical Analysis Plan - DMID Protocol: 14-0029  
Version 1.0 
11MAY2018 
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Listing 19 
Solicited Systemic Events – Safety Population 
Week 
Study 
Day 
Nausea* 
Vomiting* 
Abdominal 
Pain/Cramps* 
Diarrhea* 
Constipation* 
Pain/Burning with 
Urination 
Frequent 
Urination 
Blood in Urine* 
Headache* 
Actual Treatment Group:   , Randomized Treatment Group:   Subject ID:    
x 
x 
[severity] 
[severity] 
[severity] 
[severity] 
[severity] 
[severity] 
[severity] 
[severity] 
[severity] 
x 
x 
[severity] 
[severity] 
[severity] 
[severity] 
[severity] 
[severity] 
[severity] 
[severity] 
[severity] 
Note: *Symptom not collected during weeks 12-24. 
 
Implementation Notes: 
1. Sort order is actual treatment group, Subject ID, Study Day. 
2. If a symptom is ongoing after day 5, add a row for Day 6 and for each day until the end date of the symptom.  The severity will be the maximum 
severity reported for that symptom. 
3. Mark all severities with a +, that are considered treatment emergent solicited adverse events. 
4. Severity will be color coded 
5. If all subjects received the correct treatment, only display “Treatment Group”.


Statistical Analysis Plan - DMID Protocol: 14-0029  
Version 1.0 
11MAY2018 
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Listing 20 
Unsolicited Adverse Events 
Adverse 
Event 
Study 
Day 
Severity 
SAE? 
Relationship to 
Study Treatment 
In Not Related, 
Alternative Etiology 
Action Taken with 
Study Treatment 
Subject 
Discontinued Due to 
AE 
Outcome 
MedDRA 
System Organ 
Class 
MedDRA 
Preferred 
Term 
Actual Treatment Group: , Randomized Treatment Group: ,  Subject ID:   , AE Number:  
xxxxxxx 
xx 
xxxxxx 
xxxxxx 
xxxxxx 
xxxxx 
xxxxxx 
Y/N 
xxxxx 
xxxxx 
xxxxx 
Comments: xxxxxxxxxxxxx 
 
 
 
 
 
 
 
 
 
 
 
Actual Treatment Group: , Randomized Treatment Group: ,  Subject ID:   , AE Number:  
xxxxxxx 
xx 
xxxxxx 
xxxxxx 
xxxxxx 
xxxxx 
xxxxxx 
Y/N 
xxxxx 
xxxxx 
xxxxx 
Comments: xxxxxxxxxxxxx 
 
 
 
 
 
 
 
 
 
 
 
Note: For additional details about SAEs, see Table X. 
 
 
Implementation Notes: 
1. Sort order is actual treatment group, Subject ID, AE Number. 
2. If all subjects received the correct treatment, only display “Treatment Group”. 
 


Statistical Analysis Plan - DMID Protocol: 14-0029  
Version 1.0 
11MAY2018 
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PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Listing 21 
Pregnancy Reports – Maternal Information 
Actual 
Treatment 
Group  
Actual 
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? 
LACTIN-
V/Placebo 
LACTIN-
V/Placebo 
xxxxxxxx 
xx 
xx 
xxx 
xxx 
xxx 
xxx 
Y/N 
Y/N 
Y/N 
Y Y/N /N 
LACTIN-
V/Placebo 
LACTIN-
V/Placebo 
xxxxxxxx 
xx 
xx 
xxx 
xxx 
xxx 
xxx 
Y/N 
Y/N 
Y/N 
Y Y/N /N 
Note: Maternal Complications are included in the Adverse Event listing. Medications taken during pregnancy are included in the Concomitant Medications Listing. 
 
Implementation Notes: 
1. Sort order is actual treatment group, Subject ID 
2. If all subjects received the correct treatment, only display “Treatment Group”. 
 


Statistical Analysis Plan - DMID Protocol: 14-0029  
Version 1.0 
11MAY2018 
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Listing 22 
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: 14-0029  
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Listing 23 
Pregnancy Reports – Live Birth Outcomes 
Subject 
ID 
Pregnancy 
Number 
Fetus 
Number 
Pregnancy 
Outcome 
(for this 
Fetus) 
Fetal 
Distress 
During 
Labor and 
Delivery? 
Delivery 
Method 
Gestational 
Age at Live 
Birth  
Size for 
Gestational 
Age 
Apgar 
Score, 1 
minute 
Apgar 
Score, 5 
minutes 
Cord 
pH 
Congenital 
Anomalies? 
Illnesses/ 
Hospitalizations 
within 1 Month of 
Birth? 
xxxxxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
Y/N 
xxx 
xxxxxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
Y/N 
xxx 
Note: Congenital Anomalies are included in the Adverse Event listing. 


Statistical Analysis Plan - DMID Protocol: 14-0029  
Version 1.0 
11MAY2018 
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Listing 24 
Pregnancy Reports – Still Birth Outcomes 
Subject 
ID 
Date of 
Initial 
Report 
Fetus 
Number 
Pregnancy 
Outcome (for 
this Fetus) 
Fetal 
Distress 
During 
Labor and 
Delivery? 
Delivery 
Method 
Gestational 
Age at Still 
Birth 
Size for 
Gestational 
Age 
Cord 
pH 
Congenital 
Anomalies? 
Autopsy 
Performed? 
If Autopsy, 
Etiology for 
Still Birth 
Identified? 
xxxxxx 
xx 
xxx 
xxxxxxx 
Y/N 
xxxxxxx 
xxx 
xxx 
xx 
Y/N 
Y/N 
xxxxxxx 


Statistical Analysis Plan - DMID Protocol: 14-0029  
Version 1.0 
11MAY2018 
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Listing 25 
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: 14-0029  
Version 1.0 
11MAY2018 
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PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Listing 26 
Clinical Laboratory Results – Urinalysis 
Study Visit 
Study Day of 
Assessment 
Collection 
Day 
Was Urine 
assessed by 
dipstick? 
UTI Testing 
Result 
Are clean catch urine dipstick results 
acceptable and do not warrant a full 
urinalysis and urine culture to be 
completed? 
Are urinalysis and urine 
culture results acceptable and 
not clinically significant? 
Was a urine 
pregnancy test 
performed? 
Result 
Actual Treatment Group: , Randomized Treatment Group: ,  Subject ID:    
Screening 
Visit (Day -
30) 
xx 
xx 
No/Yes/NA 
Negative/Positive 
Yes/No 
Yes/No 
No/Yes/NA 
Negative/Positive 
Visit 1 (Day 
1) 
xx 
xx 
No/Yes/NA 
Negative/Positive 
Yes/No 
Yes/No 
No/Yes/NA 
Negative/Positive 
Visit 2, Week 
4 (Day 28) 
xx 
xx 
No/Yes/NA 
Negative/Positive 
Yes/No 
Yes/No 
No/Yes/NA 
Negative/Positive 
Visit 3, Week 
8 (Day 56) 
xx 
xx 
No/Yes/NA 
Negative/Positive 
Yes/No 
Yes/No 
No/Yes/NA 
Negative/Positive 
Visit 4, Week 
12 (Day 84) 
xx 
xx 
No/Yes/NA 
Negative/Positive 
Yes/No 
Yes/No 
No/Yes/NA 
Negative/Positive 
Visit 7, Week 
24 (Day 168) 
xx 
xx 
No/Yes/NA 
Negative/Positive 
Yes/No 
Yes/No 
No/Yes/NA 
Negative/Positive 
 
Implementation Notes: 
1. Sort order is actual treatment group, Subject ID, Study Day. 
2. If all subjects received the correct treatment, only display “Treatment Group”. 
 


Statistical Analysis Plan - DMID Protocol: 14-0029  
Version 1.0 
11MAY2018 
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Listing 27 
Clinical Laboratory Results – Serology and STI Testing 
Study Day of Assessment 
HIV Result 
Syphilis Result 
Gonorrhea NAAT Result 
Chlamydia NAAT Result 
Trichomoniasis NAAT Result 
Actual Treatment Group: , Randomized Treatment Group: ,  Subject ID:    
xx 
Negative/Positive 
Negative/Positive 
Negative/Positive 
Negative/Positive 
Negative/Positive 
xx 
Negative/Positive 
Negative/Positive 
Negative/Positive 
Negative/Positive 
Negative/Positive 
xx 
Negative/Positive 
Negative/Positive 
Negative/Positive 
Negative/Positive 
Negative/Positive 
xx 
Negative/Positive 
Negative/Positive 
Negative/Positive 
Negative/Positive 
Negative/Positive 
xx 
Negative/Positive 
Negative/Positive 
Negative/Positive 
Negative/Positive 
Negative/Positive 
xx 
Negative/Positive 
Negative/Positive 
Negative/Positive 
Negative/Positive 
Negative/Positive 
 
Implementation Notes: 
1. Sort order is actual treatment group, Subject ID, Study Day. 
2. If all subjects received the correct treatment, only display “Treatment Group”. 
 
 


Statistical Analysis Plan - DMID Protocol: 14-0029  
Version 1.0 
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Listing 28 
Additional Gynecological Test Results  
Actual Treatment 
Group 
Randomized 
Treatment Group 
Subject ID 
Study Day 
Trichomoniasis Present on Wet Mount? 
Yeast Vaginitis Present on Wet Mount? 
LACTIN-V/Placebo 
LACTIN-V/Placebo 
xxxxxxxx 
xx 
Absent/Present/Not Assessed 
Absent/Present/Not Assessed 
 
Implementation Notes: 
1. Sort order is Actual treatment group, Subject ID, Study Day. 
2. If all subjects received the correct treatment, only display “Treatment Group”. 
 


Statistical Analysis Plan - DMID Protocol: 14-0029  
Version 1.0 
11MAY2018 
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Listing 29 
Vital Signs 
Study Visit 
Study Day of 
Assessment 
Temperature 
(°F) 
Systolic Blood Pressure 
(mmHg) 
Diastolic Blood Pressure 
(mmHg) 
Pulse 
(beats/min) 
Respiratory Rate 
(breaths/min) 
Subject ID:   ,  Randomized Treatment Group:   ,  Actual Treatment Group:    
Screening Visit (Day -30) 
xx 
xx 
xx 
xx 
xx 
xx 
Visit 1 (Day 1) 
xx 
xx 
xx 
xx 
xx 
xx 
Visit 2, Week 4 (Day 28) 
xx 
xx 
xx 
xx 
xx 
xx 
Visit 3, Week 8 (Day 56) 
xx 
xx 
xx 
xx 
xx 
xx 
Visit 4, Week 12 (Day 84) 
xx 
xx 
xx 
xx 
xx 
xx 
Visit 7, Week 24 (Day 168) 
xx 
xx 
xx 
xx 
xx 
xx 
 
Implementation Notes: 
1. Sort order is actual treatment group, Subject ID, Study Day. 
2. If all subjects received the correct treatment, only display “Treatment Group”. 
 


Statistical Analysis Plan - DMID Protocol: 14-0029  
Version 1.0 
11MAY2018 
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PRIVILEGED AND CONFIDENTIAL COMMUNICATION 
Listing 30 
Physical Exam Findings 
Actual 
Treatment 
Group 
Randomized 
Treatment Group 
Subject ID 
Study Day 
Body System 
Abnormal Finding 
Reported as an AE? 
(AE Description; AE 
Number) 
LACTIN-
V/Placebo 
LACTIN-V/Placebo 
xxxxxxx 
xxx 
xxxxxxxx 
xxxxxxxx 
Yes/No 
xxxxxx; xx 
 
Implementation Notes: 
1. Sort order is actual treatment group, Subject ID, Study Day. 
2. If all subjects received the correct treatment, only display “Treatment Group”. 
3. Only abnormal findings will be presented. 
4. If the physical exam was reported as an AE, then concatenate the Physical exam with the Adverse 
Events by AENUM and report the AETERM, plus the AE Number 
 


Statistical Analysis Plan - DMID Protocol: 14-0029  
Version 1.0 
11MAY2018 
182 
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Listing 31 
Pelvic Exam Findings 
Actual 
Treatment 
Group 
Randomized 
Treatment Group 
Subject ID 
Study Day 
Body System 
Abnormal Finding 
Reported as an AE? 
(AE Description; AE 
Number) 
LACTIN-
V/Placebo 
LACTIN-V/Placebo 
xxxxxxxx 
xxx 
xxxxxxxx 
xxxxxxxx 
Yes/No 
xxxxxx; xx 
 
Implementation Notes: 
1. Sort order is actual treatment group, Subject ID, Study Day. 
2. Only abnormal findings will be presented. 
3. If the pelvic exam was reported as an AE, then concatenate the Pelvic exam with the Adverse Events by 
AENUM and report the AETERM, plus the AE Number 
4. If all subjects received the correct treatment, only display “Treatment Group”. 
 


Statistical Analysis Plan - DMID Protocol: 14-0029  
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Listing 32 
Abnormal Discharge 
Study 
Day 
Does the subject have 
abnormal discharge 
that can be evaluated? 
Source of 
Discharge 
Amount of Discharge 
Discharge 
Character 
Discharge Color 
Discharge Consistency 
Discharge 
Distribution 
Discharge 
Odor 
Actual Treatment Group:   ,  Randomized Treatment Group:     , Subject ID: 
xx 
Yes/No 
Vagina/Cervix Minimal/Moderate/Profuse 
Thin watery/ 
Normal/Thicker 
than normal 
White/Clear/Yellow/Brown/Bloody 
Non-homogenous 
(normal/homogenous/ 
Curdy 
plaques/Frothy/Other 
Pooled/Diffuse/Patches None/foul/fishy 
 
Implementation Notes: 
1. Sort order is Actual treatment group, Subject ID, Study Day. 
2. If all subjects received the correct treatment, only display “Treatment Group”. 
 


Statistical Analysis Plan - DMID Protocol: 14-0029  
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Listing 33 
Cervical Mucus  
Actual Treatment 
Group 
Randomized Treatment 
Group 
Subject ID 
Study 
Day 
Amount  
Color 
Viscosity 
LACTIN-
V/Placebo 
LACTIN-V/Placebo 
xxxxxxxx 
xx 
Minimal (to os)/Moderate (on 
face)/Profuse (pools) 
Clear/Opaque White/ Translucent 
White/Yellow/Brown/Bloody 
Thin/Average/Thick 
 
Implementation Notes: 
1. Sort order is Actual treatment group, Subject ID, Study Day. 
2. If all subjects received the correct treatment, only display “Treatment Group”.