Conditions: Chlamydia Trachomatis Infection
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 860
Healthy volunteers: yes

Brief summary:
Phase 2B double-blind placebo-controlled efficacy trial of EVO100 (previously known as Amphora ® Gel) for the prevention of acquisition of urogenital Chlamydia trachomatis infection

Detailed description:
Primary: To determine if intravaginal EVO100 reduces the risk of urogenital Chlamydia trachomatis (CT) infection.

Secondary: To determine if intravaginal EVO100 reduces the risk of urogenital Neisseria gonorrhoeae (GC) infection.

Exploratory:To determine if EVO100 use rate (subject adherence to instructed use) has an effect on proportion of subjects who experience CT or GC infection during the study intervention period.

Primary Outcome Measures: Proportion of subjects who experience urogenital CT infection during the study intervention period (incident infection of CT).

Secondary Outcome Measures: Proportion of subjects who experience urogenital GC infection during the study intervention period (incident infection of GC).

Exploratory Outcome Measures:

* Compliance with EVO100 usage during study (rate of product use adherence).
* Sensitivity analyses of the primary parameter (proportion of subjects who experience at least one CT or GC infection during the study intervention period) will be performed for the following:
* Subjects with ≥20%, ≥40%, ≥60% and ≥80% product use adherence
* Subject Satisfaction
* Sexual satisfaction

Arms:
arm 1: A pH-buffering, acidity-maintaining gel (pH 3.5), containing three active compounds: lactic acid, citric acid, potassium bitartrate. 5 g intravaginally applied at least one hour prior to vaginal intercourse. arm 2: An isotonic, non-buffering gel, pH adjusted to 4.5, containing 2.7% hydroxyethylcellulose, sorbic acid, sodium hydroxide, sodium chloride and purified water. 5 g intravaginally applied at least one hour prior to vaginal intercourse.

Interventions: intervention 1: EVO100 intervention 2: Placebo
Intervention descriptions: intervention 1: 5 g dose applied up to 1 hour prior to coitus intervention 2: 5 g dose applied up to 1 hour prior to coitus

Protocol document:
Prot_000.pdf: 
AMPHORA® 
Protocol: EVO-003 
Evofem, Inc. v6.0 – 25 January 2019 
 
 
CONFIDENTIAL AND PROPRIETARY 
 
Page 1 of 76 
Phase 2B/3 double-blinded placebo-controlled efficacy trial of  
AMPHORA® gel for the prevention of acquisition of urogenital  
Chlamydia trachomatis infection 
 
Protocol Number: EVO-003 
 
Sponsor:  
Evofem, Inc. 
12400 High Bluff Drive, Suite 600 
San Diego, CA 92130 
 
CRO: 
ICON Government and Public Health Solutions (GPHS) 
1265 Ridge Road 
Hinckley, OH 44233 
 
Investigational Product:  
AMPHORA (L-lactic acid, citric acid and potassium bitartrate)  
Vaginal Gel 1.8%/1%/0.4% 
 
IND Number: 128092 
 
Protocol Version Number: 
Version 6.0 
January 25, 2019 
 


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Statement of Compliance 
 
 
This study will be carried out in accordance with the US Code of Federal Regulations (CFR), 
local regulations, and Good Clinical Practice (GCP) as required by the following:  
 
• 21 CFR 50, 21 CFR 56, and 21 CFR 312 
 
• International Council for Harmonisation (ICH E6); 62 Federal Register 25691 (1997) 
 
All individuals responsible for the design and conduct of this study have completed Human 
Subjects Protection Training and are qualified to be conducting research prior to the enrollment 
of any subjects. CVs for all Investigators and Sub-Investigators participating in this study are on 
file in a central facility (21 CFR 312.23 [a] [6] [iii] [b] edition). 
 
 
 




AMPHORA® 
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Signature Page for the Investigator 
 
Phase 2B/3 double-blinded placebo-controlled efficacy trial of  
AMPHORA® gel for the prevention of acquisition of urogenital  
Chlamydia trachomatis infection 
Protocol Number: 
EVO-003 
The signature below constitutes the approval of this protocol and the attachments and provides 
the necessary assurances that this study 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 state and federal regulations, all other applicable 
local regulatory requirements, and applicable US Food and Drug Administration regulations. 
 
 
 
 
 
 
 
 
 
 
 
 
Organization Name 
 
 
 
 
 
 
 
 
 
 
 
 
 
Investigator Signature  
 
 
 
Date 
 
 
 
 
 
 
 
 
 
Print Name 
 
 


AMPHORA® 
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Evofem, Inc. v6.0 – 25 January 2019 
 
 
CONFIDENTIAL AND PROPRIETARY 
 
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Table of Contents 
Protocol Synopsis ...........................................................................................................................9 
List of Abbreviations ...................................................................................................................15 
1 Background Information and Scientific Rationale .............................................................17 
1.1 
Background Information ...........................................................................................17 
1.2 
Scientific Rationale ...................................................................................................18 
1.3 
Study Objectives .......................................................................................................18 
2 Study Design ...........................................................................................................................20 
2.1 
Study Outcome Measures .........................................................................................21 
2.1.1 Primary Outcome Measures ..........................................................................21 
2.1.2 Secondary Outcome Measures ......................................................................21 
2.1.3 Exploratory Outcome Measures ...................................................................22 
2.2 
Study Population .......................................................................................................22 
2.3 
Study Schedule..........................................................................................................22 
3 Study Enrollment and Retention ..........................................................................................23 
3.1 
Inclusion Criteria ......................................................................................................23 
3.2 
Exclusion Criteria .....................................................................................................24 
3.3 
Prohibited Medications .............................................................................................25 
3.4 
Randomization ..........................................................................................................25 
3.5 
Blinding.....................................................................................................................26 
3.6 
Withdrawal ................................................................................................................26 
3.6.1 Reasons for Withdrawal ................................................................................26 
3.6.2 Handling of Withdrawal ...............................................................................27 
3.6.3 Handling Subjects Lost to Follow-up ...........................................................27 
3.6.4 Replacement of Subjects Lost to Follow-up and Withdrawal ......................28 
3.7 
Subject Completion ...................................................................................................28 
3.8 
Termination of the Study ..........................................................................................28 
4 Study Products .......................................................................................................................29 
4.1 
Study Products Description.......................................................................................29 
4.1.1 Formulation and Packaging ..........................................................................29 
4.1.2 Product Supply ..............................................................................................30 
4.1.3 Product Storage, Stability, and Expiration ....................................................30 
4.1.4 Preparation ....................................................................................................30 
4.1.5 Distribution to Subjects/Return of Unused Product and Used Applicators ..30 
4.1.6 Administration ..............................................................................................30 
5 Study Procedures/Evaluations ..............................................................................................32 
5.1 
Written Informed Consent ........................................................................................32 
5.2 
Inclusion/Exclusion Criteria .....................................................................................32 
5.3 
Evaluation of Eligibility Criteria ..............................................................................32 


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5.4 
Demographics ...........................................................................................................32 
5.5 
Clinical Evaluations ..................................................................................................33 
5.5.1 Medical History ............................................................................................33 
5.5.2 Vital Signs .....................................................................................................33 
5.5.3 Gynecologic Examinations ...........................................................................33 
5.5.4 Concomitant Medications .............................................................................33 
5.5.5 Height and Weight ........................................................................................33 
5.6 
Laboratory Evaluations .............................................................................................34 
5.6.1 Pregnancy Testing .........................................................................................34 
5.6.2 Vaginal pH Testing .......................................................................................34 
5.6.3 Nucleic Acid Amplification Tests for Chlamydia trachomatis/Neisseria 
gonorrhoeae ..................................................................................................34 
5.6.4 Staining of Used Applicators ........................................................................34 
5.7 
Subject eDiaries ........................................................................................................35 
5.8 
Procedures by Visit ...................................................................................................35 
5.8.1 Screening (Visit 0; Weeks -6-0) ...................................................................35 
5.8.2 Rescreening ...................................................................................................36 
5.8.3 Enrollment/Visit 1 (Week 0 ±7 days) ...........................................................36 
5.8.4 Visits 2 Through 4 (Weeks 4-12 ±7 days) ....................................................37 
5.8.5 Visit 5 (Week 16 ±7 days) ............................................................................37 
5.8.6 Post-intervention Follow-up Visit/Visit 6 (Week 20 ±7 days) .....................38 
5.9 
Unscheduled Visit(s) .................................................................................................38 
5.10 
Early Termination .....................................................................................................38 
5.11 
Clinical Laboratory Specimen Preparation, Handling and Storage ..........................38 
6 Safety Reporting and Safety Monitoring .............................................................................40 
6.1 
Responsibilities .........................................................................................................40 
6.2 
Definitions.................................................................................................................40 
6.3 
Safety Reporting Requirements ................................................................................41 
6.3.1 Reporting Interval .........................................................................................41 
6.3.2 Notification of the Sponsor of Serious Adverse Events ...............................42 
6.3.3 Regulatory Reporting for Studies Conducted Under Investigational New 
Drug Application ..........................................................................................42 
6.4 
Investigator’s Assessment of Adverse Events ..........................................................42 
6.4.1 Assessment of Severity .................................................................................43 
6.4.2 Adverse Event Outcome Measures ...............................................................45 
6.5 
Study-related Adverse Events ...................................................................................45 
6.6 
Other Safety Considerations .....................................................................................45 
6.6.1 Follow-up of Adverse Events .......................................................................46 
6.6.2 Pregnancy ......................................................................................................46 
7 Clinical Monitoring/Site Monitoring Plan ...........................................................................48 


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8 Statistical Considerations ......................................................................................................49 
8.1 
Study Hypotheses......................................................................................................49 
8.2 
Sample Size Considerations ......................................................................................49 
8.3 
Final Analysis Plan ...................................................................................................49 
8.3.1 Analysis Populations .....................................................................................49 
8.3.2 Randomization and Stratification .................................................................50 
8.3.3 Procedures for Handling Missing, Unused, and Spurious Data....................50 
8.3.4 General Statistical Considerations ................................................................50 
8.4 
Planned Statistical Methodology ..............................................................................50 
8.4.1 Data Analysis for Efficacy ............................................................................50 
8.4.2 Data Analysis for Safety ...............................................................................51 
8.4.3 Analyses for Exploratory Objectives and Endpoints ....................................51 
9 Data Handling/Recordkeeping/Source Documents ............................................................52 
9.1 
Data Capture Methods ..............................................................................................52 
9.2 
Types of Data ............................................................................................................52 
9.3 
Study Records Retention ...........................................................................................52 
9.4 
Source Documents ....................................................................................................53 
9.5 
Protocol Deviations ...................................................................................................53 
10 Quality Control and Quality Assurance ..............................................................................54 
11 Ethics/Protection of Human Subjects ..................................................................................55 
11.1 
Ethical Standard ........................................................................................................55 
11.2 
Institutional Review Board .......................................................................................55 
12 Informed Consent Process ....................................................................................................56 
12.1 
Subject Confidentiality .............................................................................................56 
13 Confidentiality Policy ............................................................................................................57 
14 Publication Policy...................................................................................................................58 
15 Summary of Changes .............................................................................................................59 
16 Literature References ............................................................................................................62 
17 Appendices ..............................................................................................................................64 
Appendix A. 
Grading of Study-related Adverse Events ...................................................64 
Appendix B. 
Study-related Adverse Events .....................................................................65 
Appendix C. 
Study Product Instructions for Use .............................................................66 
Appendix D. 
Subject Satisfaction with Product ................................................................69 
Appendix E. 
Subject Sexual Satisfaction .........................................................................70 
Appendix F. 
Sexual Function Questionnaire (SFQ).........................................................71 
Appendix G. 
Female Sexual Function Index (FSFI) ........................................................72 
 
 
 
 


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List of Tables 
Table 1 
Schedule of Assessments .............................................................................................. 13 
Table 2 
Study Product Dosing .................................................................................................. 29 
Table 3 
Summary of Changes ................................................................................................... 59 
 
List of Figures 
Figure 1 
Schematic Flow of Study Design ................................................................................. 14 
 
 


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PROTOCOL SYNOPSIS 
 
TITLE OF CLINICAL TRIAL: 
Phase 2B/3 double-blinded placebo-controlled efficacy trial of AMPHORA® gel for the 
prevention of acquisition of urogenital Chlamydia trachomatis infection 
INVESTIGATIONAL PRODUCT(S): 
Eligible subjects will receive: 
AMPHORA vaginal gel, supplied in individually wrapped 5 g single-dose, pre-filled vaginal 
applicators. AMPHORA is a dense, viscous, off white to tan gel of uniform consistency. Its 
active ingredients are L-lactic acid United States Pharmacopeia (USP), citric acid USP, and 
potassium bitartrate USP, with alginic acid and xanthan gum included as viscosity and 
bioadhesive controllers 
CLINICAL PHASE: Phase 2B/3 
CLINICAL TRIAL OBJECTIVES: 
Primary: 
• To determine if intravaginal AMPHORA gel reduces the risk of urogenital Chlamydia 
trachomatis (CT) infection 
Secondary: 
• To determine if intravaginal AMPHORA gel reduces the risk of urogenital Neisseria 
gonorrhoeae (GC) infection 
Exploratory: 
• To determine if AMPHORA gel use rate (subject adherence to instructed use) has an 
effect on proportion of subjects who experience at least one CT or GC infection 
during the study intervention period 
• To assess subject satisfaction (including sexual satisfaction) with AMPHORA gel 
over the course of the clinical study 
OUTCOME MEASURES: 
Primary: 
• Proportion of subjects who experience at least one urogenital CT infection during the 
study intervention period (incident infection of CT) 
Secondary: 
• Proportion of subjects who experience at least one urogenital GC infection during the 
study intervention period (incident infection of GC) 


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Exploratory: 
• Compliance with AMPHORA usage during study (rate of product use adherence)  
• Sensitivity analyses of the primary parameter (proportion of subjects who experience 
at least one CT or GC infection during the study intervention period) will be 
performed for the following: 
o Subjects with ≥20%, ≥40%, ≥60%, ≥80% and 100% product use adherence 
• Subject satisfaction  
• Sexual satisfaction 
CLINICAL TRIAL DESIGN: 
This is a Phase 2B/3 double-blind, placebo-controlled study in approximately 50 sites in the 
United States (US) over approximately 16 weeks of use in women aged 18 to 45 years who 
are at risk of urogenital re-infection  
TREATMENT DURATION: 
After a screening period of up to 45 days, women will be randomized to receive either 
AMPHORA or placebo. Each woman will participate in the study until after she has 
completed 16 weeks of treatment. The final visit to the clinical site will take place 4 weeks 
after the end of treatment even if the subject discontinues treatment prematurely 
SAMPLE SIZE: 
A sample of approximately 844 women will receive AMPHORA or placebo 
STUDY POPULATION: 
Study Sites: 
The study will be conducted at up to 50 clinical sites in the US. Subjects will be selected for 
the study according to the eligibility criteria detailed below 
Inclusion Criteria: 
1. Healthy female subjects between 18 and 45 years of age, inclusive 
2. Ability to understand the consent process and procedures 
3. Subjects agree to be available for all study visits 
4. Written informed consent in accordance with institutional guidelines 
5. Negative pregnancy test 
6. Negative CT and GC nucleic acid amplification test (NAAT) at screening or positive 
CT or GC NAAT and receives standard of care (SOC) treatment prior to enrollment  
7. Agree to use a woman-controlled method of contraception that is not directly 
delivered to the vaginal mucosa (with the exception of a vaginal ring) throughout the 
duration of the study, such as oral contraceptives, birth control implants, intrauterine 
devices (IUDs), or tubal ligation. Condom use only is not an acceptable form of 
contraception for this study 
8. Able and willing to comply with all study procedures 


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9. Documented (as part of a retrievable medical record) diagnosis of CT or GC infection 
within 16 weeks prior to enrollment. Acceptable documentation will include:   
• Lab reports confirming CT/GC infection OR 
• Third party clinic note confirming previous CT/GC infection and indicating 
the date of diagnosis and/or date of treatment 
10. Reports vaginal sexual intercourse with a male partner at least three times per month 
in the previous month and anticipates vaginal sexual intercourse regularly for the 
duration of the study 
11. Agree to abstain from douching or any form of vaginal suppository use (other than 
investigational product) during course of study  
Exclusion Criteria: 
1. Participation in any study with an investigational compound or device within 30 days 
prior to signing informed consent 
2. In the opinion of the Investigator, has a history of substance or alcohol abuse in the 
last 12 months 
3. In the opinion of the Investigator, has issues, conditions, or concerns that may 
compromise the safety of the subject, impact the subject’s compliance with the 
protocol requirements, or confound the reliability of the data acquired 
4. Is an Evofem, ICON GPHS, or clinical site employee regardless of direct 
involvement in research activities, or their close relative 
5. Pregnant (or actively trying to become pregnant), or breastfeeding 
6. Women who have undergone a total hysterectomy (had uterus and cervix removed)  
7. Inability to provide informed consent 
8. Has a history or expectation of noncompliance with medications or intervention 
protocol  
9. Have engaged in sexual vaginal intercourse or douching, or used of any form of 
vaginal suppository or intravaginal device (with the exception of contraceptive 
vaginal ring or tampons) for 24 hours prior to enrollment (may be enrolled at a later 
date if all other criteria are met) 
10. Menstruating at enrollment (may be enrolled at a later date if all other criteria are 
met) 
11. Is currently being treated, or have been treated, for a period of 21 days prior to 
enrollment, with specific antibiotics known to be used for the treatment of CT or GC: 
• Azithromycin 
• Erythromycin 
• Tetracycline 
• Minocycline 
• Doxycycline 
• Levofloxacin 


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• Ofloxacin 
• Ceftriaxone 
• Cefixime 
12. In the opinion of the Investigator, has signs/symptoms that indicate persistence of 
chlamydia or gonorrhea infection diagnosed at screening, new interval infection, 
and/or a failure to comply with or complete the prescribed treatment regimen 
following a positive screening NAAT 
13. Women who regularly use douches, vaginal medications, products, or suppositories  
14. Women who are currently using contraceptive products that are directly delivered to 
the vaginal mucosa (with the exception of contraceptive vaginal ring), such as 
diaphragms, spermicides, or any vaginally applied or inserted products containing 
nonoxynol-9 (N-9) 
15. Children, pregnant women, prisoners, and other vulnerable populations 
 
 
 


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Table 1 
Schedule of Assessments 
(1)Screening period may be up to 45 days. Subjects will be asked to return 7 days after Screening Visit. If subjects 
NAAT results are positive, they will be first treated by SOC then will return 3-4 weeks after Screening Visit (at least 
21 days after treatment) for Enrollment/Visit 1. If the screening period extends past 45 days, subjects will not be 
enrolled and will need to be rescreened. 
(2) Subjects must be asked to abstain from vaginal intercourse in the 24 hours preceding Study Visits 2 through 5. 
 
 
Intervention Period;  
AMPHORA gel N=422, Placebo 
gel N=422 
 
Study Visit (V) 
Screening (1) 
Enrollment/ 
Visit 1 (2) 
Visit 2 (2) 
Visit 3 (2) 
Visit 4 (2) 
Visit 5/Early 
Termination (2,3) 
Post-Intervention 
Follow-up/Visit 6 
Study Week 
-6-0 
(-45-0 days) 
0(4) 
4(4) 
8(4) 
12(4) 
16(4) 
20 
Investigational Product Dispensed 
 
X 
X 
X 
X 
 
 
Informed Consent/HIPAA 
X 
 
 
 
 
 
 
Inclusion/Exclusion 
X 
X 
 
 
 
 
 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
AE Assessment 
 
X 
X 
X 
X 
X 
X 
Medical/Sexual History 
X 
X 
 
 
 
 
 
Last Menstrual Period  
 
X 
 
 
 
 
 
Physical Exam 
 
X 
 
 
 
 
 
Targeted Physical Exam 
 
 
[X] 
[X] 
[X] 
[X] 
[X] 
Body Weight/Height 
 
X 
 
 
 
 
 
Vital Signs 
 
X 
 
 
 
 
 
Gynecologic Exam 
 
X 
 
 
 
 
 
Urine HCG (females) 
 
X 
X 
X 
X 
X 
X 
Vaginal pH 
 
X 
 
 
 
 
 
Self-collected CT/GC NAAT 
X 
 
X 
X 
X 
X 
X3 
Clinician-collected CT/GC NAAT 
 
X 
 
 
 
 
 
eDiary Setup 
 
X 
 
 
 
 
 
eDiary Review 
 
 
X 
X 
X 
X 
X 
Inspection of Returned Investigational 
Product 
 
 
X 
X 
X 
X 
 
Staining of Used Applicators 
 
 
X 
X 
X 
X 
 
Subject Satisfaction with Product 
 
 
 
 
 
X 
 
Subject Sexual Satisfaction 
 
 
 
 
 
X 
 
Female Sexual Function Index (FSFI) 
 
X 
 
 
 
X 
 
Sexual Function Questionnaire  
 
X 
 
 
 
X 
 


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(3) CT/GC NAAT testing is not required at this visit if subject was discontinued due to positive NAAT. For early 
termination, procedures for V5 should be followed with CT/GC NAAT testing required. 
(4) Subjects will be asked to return ± 7 days within each visit window. 
 
Figure 1 
Schematic Flow of Study Design 
 
Screening 
Visit 0 
Week -6-0 
Intervention Period 
Visits 1-5 
Weeks 0-16 
Follow-up 
Visit 6 
Week 20 
Enrollment 
Eligibility Criteria 
Visit 1 Assessments/Procedures/CT/GC NAAT 
Visit 6 Assessments/Procedures 
Informed Consent 
CT/GC NAAT 
Visits 2-5 Assessments/Procedures 
CT/GC NAAT  
Results 
NEGATIVE 
POSITIVE 
SOC Treatment 
Placebo Gel 
n=422 
AMPHORA 
Gel n=422 
Randomization 


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LIST OF ABBREVIATIONS 
ADL 
Activities of daily living 
AE 
Adverse event 
BV 
Bacterial vaginosis 
CFR 
US Code of Federal Regulations 
CQMP 
Clinical Quality Management Plan 
CRA 
Clinical Research Associate 
CRF 
Case report form 
CRO 
Contract research organization 
CT 
Chlamydia trachomatis 
CTCAE 
Common Terminology Criteria for Adverse Events 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
eDiary 
Electronic diary 
FDA 
US Food and Drug Administration 
FDAAA 
US Food and Drug Administration Amendments Act 
FSFI 
Female Sexual Function Index 
G (g) 
Gram 
GC 
Neisseria gonorrhoeae 
GCP 
Good Clinical Practice 
GPHS 
ICON Government and Public Health Solutions 
HDPE 
High-density polyethylene 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
Human immunodeficiency virus 
ICH 
International Conference on Harmonisation 
IFU 
Inclusion forming units 
IND 
Investigational New Drug Application 
IRB 
Institutional review board 
ITT 
Intention-to-treat 
IUD 
Intrauterine device 
IWRS 
Interactive Web Response System 
LB 
Lactobacillus species 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
Modified Intention-to-Treat 
MOP 
Manual of Procedures 
N-9 
Nonoxynol-9 
N 
Number (typically refers to subjects) 


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NAAT 
Nucleic acid amplification test 
NCI 
National Cancer Institute 
PID 
Pelvic inflammatory disease 
Placebo 
Inactive substance which may resemble an active agent but has no 
medical value 
QA 
Quality assurance 
QC 
Quality control 
SAE 
Serious adverse event 
SAS 
Statistical analysis software 
SFQ 
Sexual Function Questionnaire 
SOC 
Standard of care 
SOP 
Standard operating procedure 
STI 
Sexually transmitted infection 
TEAE 
Treatment-emergent adverse event 
uHCG 
Urine β-human chorionic gonadotropin 
UMC 
Uppsala Monitoring Centre 
UPG 
Universal placebo gel 
US 
United States 
USP 
United States Pharmacopeia 
WHO 
World Health Organization 
 


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1 
Background Information and Scientific Rationale 
1.1 
Background Information 
Chlamydia trachomatis (CT) infection remains the most frequently reported infectious disease in 
the United States (US) (1). Several sequelae can result from CT infection in women, the most 
serious of which include pelvic inflammatory disease (PID) and scarring of the fallopian tubes, 
ovaries, endometrial lining, and occasionally, adjacent perineum, which increases the risk of 
future ectopic pregnancy and tubal infertility. These consequences are the main reason that CT 
infection is estimated to be the costliest of all non-viral sexually transmitted infections (STIs) 
(2). 
An acidic vaginal pH and colonization with Lactobacillus species (LB) are two proven 
components of the multiple defense mechanisms active against infection in the lower female 
genital tract (3). These species are thought to play key protective roles by producing various 
bacteriostatic and bactericidal compounds (4), (5), (6). A lower vaginal pH may inhibit STIs, 
including CT infection (7). In vitro studies have shown that exposure to vaginal secretions at 
lower pH significantly inhibits CT replication (7), (8). In another experiment, the growth of CT 
within epithelial cells was inhibited by acidic pH (9). 
 
A prospective case-controlled study found an association between CT infection and higher 
vaginal pH (median pH of 4.5 in CT and 4.0 in controls, respectively), independent of any other 
factors (10). The study included 144 cases of CT infections and 145 controls. Sixty-two (62) of 
the women with CT were diagnosed with concurrent STIs (bacterial vaginosis [BV], genital 
warts, Neisseria gonorrhoeae [GC], trichomoniasis, and candidiasis). However, even when the 
analyses were restricted to the 82 cases that did not have any other concurrent STI, vaginal pH 
remained higher in those cases than in the controls. In univariate analyses, cases were over six 
times as likely as controls to have a pH >4.5. This study, in itself, was unable to answer whether 
lower vaginal pH reduces risk of acquisition of urogenital CT infection, and further study is 
needed. However, the results of this study lead to the hypothesis that reduction of vaginal pH 
(through treatment) in asymptomatic women with conditions that are known to increase vaginal 
pH (such as BV), may help to prevent CT infection, particularly in those at increased risk of 
infection.  
 
A recent study of 61 women exposed to GC through an infected partner was conducted at the 
Baltimore City Health Department STI clinics and showed that 100% of the women whose 
vaginal pH was ≥5.0 were subsequently infected with GC versus 40% of the women whose pH 
was <5.0 (when measured within 5 days of GC exposure) (11). Additionally, pH-dependent risk 
was independent of BV as diagnosed by Amsel criteria. These data suggest that modification of 
vaginal pH could be used clinically to reduce risk of GC infection in women.  


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In summary, the interplay between vaginal pH and the naturally occurring human vaginal 
microbiota represents an important relationship which has been linked to increased risk for STIs, 
including CT and GC (12), (13), (14), (15), (16), (17), (18), (19), (20), (21).  
1.2 
Scientific Rationale 
AMPHORA is an acid-buffering vaginal gel (pH 3.5) containing three active ingredients 
(L-lactic acid, citric acid, and potassium bitartrate). It is currently in development as a 
contraceptive to be applied intravaginally before sexual intercourse. During development, it was 
found to have in vitro activity against GC, as well as BV-associated microbes, without having a 
detrimental effect on beneficial native LB and to inhibit Trichomonas vaginalis under both 
aerobic and anaerobic conditions (Investigator’s Brochure, 2016). This has led to further 
development as a microbicide to lessen the risk of, or prevent acquisition of, STIs. 
Subsequent studies done on AMPHORA in the animal model support further in vivo microbicide 
research. AMPHORA with and without nonoxynol-9 (N-9) was applied vaginally to Swiss 
Webster mice before inoculation of 15 µL 104 or 105 inclusion forming units [IFU] CT. 
AMPHORA was found to provide protection against upper genital tract infection in 88% to 
100% of the animals, whereas the other four vaginal gel products tested protected only 0% to 
38% of the animals. It was also determined that the addition of 5% N-9 to AMPHORA did not 
enhance its protective effect at the usual challenge inoculum (22). 
In another murine study, AMPHORA displayed significant protection against transmission of 
GC with only one of 17 mice treated having positive culture results compared with 13 of 15 
untreated control mice. Of the six topical microbicide agents tested, AMPHORA was the most 
highly active against GC in vitro; a 0.625% solution of this product inhibited six of the seven GC 
strains (23). 
Low adherence to product use is an ongoing challenge in vaginal microbicide studies, though 
recent analysis of study data has produced baseline predictors of high adherence (24). A recent 
prospective study on sexual risk behavior and incident STIs included a substudy that showed use 
of cell phone-based e-diaries assisted in achieving an enhanced subject compliance rate of 89.7% 
(25).  
1.3 
Study Objectives 
Primary: To determine if intravaginal AMPHORA reduces the risk of urogenital Chlamydia 
trachomatis (CT) infection  
Secondary: To determine if intravaginal AMPHORA reduces the risk of urogenital Neisseria 
gonorrhoeae (GC) infection 
 


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Exploratory:  
• To determine if AMPHORA use rate (subject adherence to instructed use) has an effect 
on proportion of subjects who experience at least one CT or GC infection during the 
study intervention period 
• To assess subject satisfaction (including sexual satisfaction) with AMPHORA over the 
course of the clinical study 


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2 
Study Design 
Eight hundred forty-four (844) women, ages 18 to 45, who have had a documented urogenital 
chlamydia or gonorrhea infection at any time over the 16 weeks preceding the Enrollment Visit, 
or found to be positive at Screening Visit will be enrolled. A high prevalence of Chlamydia 
trachomatis infection has been observed in those who were treated for urogenital chlamydial 
infection during the preceding several months. The second infection may result from re-infection 
through an untreated partner or exposure through a new partner. By including only women who 
have had a CT infection within the past 16 weeks, this study targets those at high risk for 
infection (1), (26).  
Regardless of whether a potential subject agrees to participate in the study, subjects should be 
treated according to each site’s routine standard of care (SOC) for STI prevention which should 
follow the prevention strategies recommended by the Centers for Disease Control and Prevention 
(https://www.cdc.gov/std/tg2015/clinical.htm). These strategies include client-centered STI 
prevention counseling addressing subject’s individual risk factors and advice on the correct and 
consistent use of male condoms to prevent STIs and human immunodeficiency virus (HIV), as 
well as condom provision if part of the site’s SOC. Those who agree to participate (ie, subjects 
who provide informed consent) should be treated according to SOC prior to and throughout the 
study period as necessary. 
Subjects will be tested for current GC/CT infection by nucleic acid amplification test (NAAT) 
via vaginal swab. Those negative for current infection will be enrolled. Those who test positive 
for CT/GC infection will receive SOC treatment. To meet eligibility criteria, these subjects will 
not be enrolled until 3 to 4 weeks after screening (at least 21 days after treatment). 
Eligible participants will be enrolled and randomized 1:1 (422 subjects per treatment arm) to 
either AMPHORA or placebo; 5 g of AMPHORA or placebo will be supplied in pre-filled, 
single-dose applicators. A baseline vaginal pH and a full gynecologic exam (speculum) will be 
obtained at enrollment.  
Subjects are instructed to apply AMPHORA or placebo gel immediately before or up to one hour 
prior to coitus for the duration of the 16-week intervention period. AMPHORA or placebo is to be 
re-applied in the same manner for each occurrence of sexual intercourse. Subjects will keep an 
electronic diary (eDiary) to document and track sexual activity and product use. 
Every 4 weeks (5 visits), all subjects will return to the clinic for repeat CT/GC NAAT (vaginal 
swab), urine pregnancy (urinary human chorionic gonadotrophin [uHCG]) testing, eDiary review, 
and return of used and unused investigational product. Applicators will be visually inspected for 
use and staining will be performed to confirm vaginal insertion of used (empty) applicators. At 
Visits 2 to 4, subjects will be re-supplied with AMPHORA or placebo gel. At Visit 5, subjects will 


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return used and unused investigational product and continue to use their eDiaries but will not be 
resupplied with AMPHORA or placebo gel.  
Subjects will return for a follow-up visit 4 weeks after the intervention period. At this time, CT/GC 
NAAT (vaginal swab), pregnancy (uHCG) testing, and eDiary review will be performed. 
Screening and Eligibility 
Subjects who consent may be screened if they have a known case of CT or GC within 16 weeks 
of enrollment, or suspicion of current CT or GC infection (subsequently confirmed with NAAT 
test at Screening Visit). Subjects randomized within 45 days of initial screening do not need to 
be re-screened. 
Intervention and Follow-up Period 
The intervention period is defined as Visits 1 to 5. There is one follow-up visit (Visit 6) 4 weeks 
after the last intervention visit. These periods are outlined in the Schedule of Assessments (Table 
1). The protocol-defined period of observation is 20 weeks. 
Safety Follow-up After Protocol-defined Period of Observation 
This period includes safety follow-up as required by Good Clinical Practice (GCP) and standard 
clinical study practice. Adverse events (AEs) determined to be at least possibly related to the 
investigational product continuing after the final study visit (Visit 6) will be followed until 
resolution or stable status as determined by the Investigator. Applicable information is found in 
Section 6.3.  
2.1 
Study Outcome Measures 
2.1.1 Primary Outcome Measures 
The primary objective of this study is to demonstrate the superior efficacy of AMPHORA 
compared with placebo for the prevention of urogenital CT infection. The primary efficacy 
endpoint is the proportion of subjects who experience at least one CT infection during the study 
intervention period (incident infection of CT).  
2.1.2 Secondary Outcome Measures 
The secondary outcome will measure the proportion of subjects who experience at least one 
urogenital GC infection during the study intervention period (incident infection of GC). 


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2.1.3 Exploratory Outcome Measures 
Exploratory assessments include: 
• AMPHORA usage during the study (rate of product use adherence) and sensitivity 
analyses of the primary parameter (proportion of subjects who experience at least one CT 
or GC infection during the study intervention period) and subjects with ≥20%, ≥40%, 
≥60%, ≥80%, and 100% product use adherence 
• Assessing subject satisfaction (including sexual satisfaction) with AMPHORA over the 
course of the clinical study 
2.2 
Study Population 
Approximately 1055 women who have had a documented CT or GC vaginal infection at any 
time over the 16 weeks preceding enrollment, or suspicion of current CT or GC infection 
(subsequently confirmed with NAAT test at Screening Visit), will be screened to identify 844 
healthy female subjects who are eligible to participate.  
2.3 
Study Schedule 
Schedule for individual subjects: Individual subjects will participate in the study for up to 24 
weeks. The study Schedule of Assessments (Table 1) and the description of procedures involving 
study subjects, by study visit, is provided in Section 5.8. 


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3 
Study Enrollment and Retention 
No study procedures will be performed until informed consent is obtained. Eight hundred forty-
four (844) healthy female subjects, ages 18 to 45, will be enrolled.  
Subjects will be recruited through institutional review board (IRB)-approved materials, database 
queries, and word of mouth. Children, pregnant women, prisoners, and other vulnerable 
populations will not be enrolled.  
Screening will begin with the Investigator or designee providing an overview of the study to the 
potential subject. Subjects will be excluded if they do not understand the protocol and 
participation requirements and/or if they are unable, unlikely, or unwilling to comply with gel 
application as directed, eDiary recording, or follow-up visit attendance. All subjects who consent 
will be assigned a screening number. 
All eligibility criteria must be met for inclusion into the study; no waivers will be granted. 
In this study, subjects will be encouraged to strive for 100% product use adherence; however, 
emphasis will be placed on accurate and forthright eDiary recording of each coital event noting 
use or non-use of the product and any circumstance that may have impacted their decision to use 
or not use as directed under the study. Adherence to product use will be measured using a 
combination of eDiary reporting and number/inspection/staining of returned investigational 
product/gel applicators.  
Study retention strategies will include clear explanations during enrollment of the study schedule 
and procedures and financial payment and/or reimbursements. Study staff will be actively 
involved in engaging subjects and implementing systems for appointment reminders and follow-
up with missed visits.  
3.1 
Inclusion Criteria 
1. Healthy female subjects between 18 and 45 years of age, inclusive 
2. Ability to understand the consent process and procedures 
3. Subjects agree to be available for all study visits 
4. Written informed consent in accordance with institutional guidelines 
5. Negative pregnancy test 
6. Negative CT and GC NAAT at screening or positive CT or GC NAAT and receives 
SOC treatment prior to enrollment  
7. Agree to use a woman-controlled method of contraception that is not directly 
delivered to the vaginal mucosa (with the exception of a vaginal ring) throughout the 
duration of the study, such as oral contraceptives, birth control implants, intrauterine 


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devices (IUDs), or tubal ligation. Condom use only is not an acceptable form of 
contraception for this study 
8. Able and willing to comply with all study procedures 
9. Documented (as part of a retrievable medical record) CT or GC infection within 16 
weeks prior to enrollment. Acceptable documentation will include:   
• Lab reports confirming CT/GC infection OR 
• Third party clinic note confirming previous CT/GC infection and indicating the 
date of diagnosis and/or date of treatment 
10. Reports vaginal sexual intercourse with a male partner at least three times per month 
in the previous month and anticipates vaginal sexual intercourse regularly for the 
duration of the study 
11. Agree to abstain from douching or any form of vaginal suppository use (other than 
investigational product) during course of study  
3.2 
Exclusion Criteria 
1. Participation in any study with an investigational compound or device within 30 days 
prior to signing informed consent  
2. In the opinion of the Investigator, has a history of substance or alcohol abuse in the 
last 12 months 
3. In the opinion of the Investigator, has issues, conditions, or concerns that may 
compromise the safety of the subject, impact the subject’s compliance with the 
protocol requirements, or confound the reliability of the data acquired 
4. Is an Evofem, ICON GPHS, or clinical site employee regardless of direct 
involvement in research activities, or their close relative 
5. Pregnant (or actively trying to become pregnant), or breastfeeding 
6. Women who have undergone a total hysterectomy (had uterus and cervix removed)  
7. Inability to provide informed consent 
8. Has a history or expectation of noncompliance with medications or intervention 
protocol  
9. Has engaged in sexual vaginal intercourse or douching, or used any form of vaginal 
suppository or intravaginal device (with the exception of contraceptive vaginal ring or 
tampons) for 24 hours prior to enrollment (may be enrolled at a later date if all other 
criteria are met) 
10. Menstruating at enrollment (may be enrolled at a later date if all other criteria are 
met) 
11. Is currently being treated, or have been treated, for a period of 21 days prior to 
enrollment, with specific antibiotics known to be used for the treatment of CT or GC: 
• Azithromycin 


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• Erythromycin 
• Tetracycline 
• Minocycline 
• Doxycycline 
• Levofloxacin 
• Ofloxacin 
• Ceftriaxone 
• Cefixime 
12. In the opinion of the Investigator, has signs/symptoms that indicate persistence of 
chlamydia or gonorrhea infection diagnosed at screening, new interval infection 
and/or a failure to comply with or complete the prescribed treatment regimen 
following a positive screening NAAT 
13. Women who regularly use douches, vaginal medications, products, or suppositories  
14. Women who are currently using contraceptive products that are directly delivered to 
the vaginal mucosa, such as diaphragms, spermicides, or any vaginally applied or 
inserted products containing N-9  
15. Children, pregnant women, prisoners, and other vulnerable populations 
3.3 
Prohibited Medications 
Subjects must not be currently taking or applying, or have taken or applied, for a period of 21 
days prior to enrollment, antibiotics with activity against CT or GC. The following antibiotics 
meet these criteria: 
• Azithromycin 
• Erythromycin 
• Tetracycline 
• Minocycline 
• Doxycycline 
• Levofloxacin 
• Ofloxacin 
• Ceftriaxone 
• Cefixime 
3.4 
Randomization 
This is a Phase 2B/3 placebo-controlled randomized study with 422 subjects per intervention 
arm, for a total of 844 subjects. The 844 subjects will be randomized using an Interactive Web 
Response System (IWRS) in a 1:1 fashion across the two intervention groups, AMPHORA or 


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placebo. Randomization will be stratified by site, and all documentation of this procedure and 
output will be saved with the IWRS vendor until the end of the study. Randomization will occur 
following enrollment and prior to issuance of investigational product to subjects.  
3.5 
Blinding 
Investigators and subjects in both intervention groups will remain blinded to their intervention 
assignment (AMPHORA or placebo) over the entire duration of the study (double-blind). The 
Sponsor, Evofem, Inc., will prepare the investigational product as well as placebo and supply 
these products in ready-to-dispense status.  
Any request from the Investigator for information about treatment administered to study subjects 
must be approved by the Medical Monitor. 
If the code must be broken in the case of an emergency for subsequent management of a subject, 
the Investigator must provide a written request with record of the circumstances surrounding the 
event, including the purpose, date, and personnel involved. Emergency unblinding will be 
available by using the IWRS. An emergency treatment disclosure is a reportable event that must 
be reported to the Medical Monitor within 24 hours of the event.  
Otherwise, blinding will not be broken until all subjects have completed the final study visit and 
the database has been locked and approved.  
3.6 
Withdrawal 
3.6.1 Reasons for Withdrawal 
A study subject will be discontinued from participation in the study for: 
• Development of any exclusion criteria  
• Positive GC/CT NAAT testing at enrollment 
• Pregnancy or breastfeeding 
• Request by subject to terminate participation 
• Subject is no longer sexually active on a regular basis, ie, records no sexual activity for 
two or more cycles 
• Requirement for prohibited treatment (see exclusion criteria) during the intervention 
period 
• Intervention-related toxicity 
• Lost to follow-up 
• Request of primary care provider 


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• Request of the IRB/ethics committee, US Food and Drug Administration (FDA), or 
Sponsor 
• Subject is no longer able to attend study visits and/or comply with study procedures 
• The subject’s well-being, based on the opinion of the Investigator  
3.6.2 Handling of Withdrawal 
If a subject is withdrawn from participation, the reason(s) for discontinuation must be 
documented in the source documents and electronic case report forms (eCRFs). The procedures 
for Visit 5 should be followed for the Early Termination Visit. Subjects who withdraw or are 
withdrawn from the study who received any amount of the investigational product will be 
encouraged to return to the clinic for a final visit to complete the post-intervention follow-up 
visit (all procedures from Visit 6). If an AE or serious adverse event (SAE) has occurred, every 
effort will be made to undertake protocol-specified safety follow-up procedures, and the subject 
will be encouraged to receive appropriate care under medical supervision until the symptoms of 
any AE resolve or the subject’s condition becomes stable.  
3.6.3 Handling Subjects Lost to Follow-up  
The study design has incorporated primary, secondary, and tertiary strategies for reducing the 
number of subjects lost to follow-up. Primary strategies include having sites: 1) fully inform 
subjects of study visit details prior to randomization, 2) addressing subjects’ expectations on 
study participation, 3) motivating subjects to adhere to follow-up visits and research protocols, 
and 4) utilizing eDiaries for data entry and review. Secondary strategies include: 1) scheduling 
all visits around subjects’ availability which are within the visit window, 2) providing a visit 
reminder ahead of time, and 3) reviewing data for missed and overdue follow-up visits. Tertiary 
strategies include: 1) discussing subjects’ difficulty in adhering to study protocol and answering 
any questions they might have and 2) continuing attempts to reach subjects lost to follow-up and 
recording all contact attempts.  
A subject will be considered as lost to follow-up if participation in study activities is not 
continued after: 
• Three attempts at telephone contact without success following missed study assessment 
timepoint, followed by 
• Issuance of a certified letter to last documented address of subject, and no response 
within 7 days of mailing 
Documentation of lost to follow-up status will be maintained in the subject’s case report form 
(CRF) and in source documents. The reason(s) for the lost to follow-up, if known, and the 
appropriate timelines for subject-study site correspondence will be captured along with the study 
site’s attempts to reach the subject. Lastly, all proper procedures of sending certified letter of 


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discontinuation from study based on lost to follow-up status and a recommendation to come in 
for a discontinuation visit to determine safety of the subject will be followed by the study site. 
The conditions and plans for replacement of subjects lost to follow-up are described in 
Section 3.6.3.  
3.6.4 Replacement of Subjects Lost to Follow-up and Withdrawal 
An enrolled subject will be considered lost to follow-up or withdrawn as described in 
Section 3.6.3 at any point prior to Visit 6 (post-intervention follow-up visit). Subjects will not be 
replaced in this study. 
3.7 
Subject Completion 
An enrolled subject will be considered a study completer once any of the following three 
criterion is met: 
1. Finishes all study visits without experiencing a urogenital CT or GC infection 
2. Experiences urogenital CT infection 
3. Experiences urogenital GC infection 
3.8 
Termination of the Study 
The study may be terminated at the discretion of the Sponsor. The study may also be terminated 
at a study site after discussion with the Sponsor. The reason for termination will be documented. 


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4 
Study Products 
4.1 
Study Products Description 
There are two study products used over the course of the intervention period for this study: 
1) AMPHORA and 2) placebo. 
 
AMPHORA  
AMPHORA is in development as a vaginally administered contraceptive gel and microbicidal 
agent. AMPHORA is an acid-buffering gel (pH 3.5) containing three active ingredients (L-lactic 
acid 1.8%, citric acid 1%, and potassium bitartrate 0.4%) and the following non-active 
ingredients: benzoic acid, alginic acid, xanthan gum, glycerin, and water.  
 
Placebo (Universal Placebo Gel) 
The placebo used in this study is universal placebo gel (UPG). UPG is an isotonic non-buffering 
gel, with pH adjusted to 4.5 and containing 2.7% hydroxyethylcellulose, sorbic acid, sodium 
hydroxide, sodium chloride, and purified water. In clinical studies, UPG has been proven safe 
and acceptable when used up to twice daily for 14 days (27). 
Table 2 
Study Product Dosing 
Intervention Group 
AMPHORA 
Placebo 
Group A 
422 subjects, 5 g dose applied up 
to 1 hour prior to coitus 
N/A 
Group B 
N/A 
422 subjects, 5 g dose applied up 
to 1 hour prior to coitus 
4.1.1 Formulation and Packaging  
For this study, pre-filled, single-use applicators will be used. The AMPHORA and placebo gels 
will be filled (5 g) into identical single-dose applicators consisting of an injection molded opaque 
white high-density polyethylene (HDPE) barrel with a rounded distal end for easy insertion. A 
thermoplastic rubber piston will be inserted at the opposite end of the barrel. This component 
will seal the end of the barrel to keep the contents stable over time and also functions as the 
applicator piston when in use. A HDPE plunger rod will be packaged alongside of the barrel 
within an aluminum overwrap. Product will be dispensed as a box of 10 overwrapped applicators 
with used applicator return bags and instructions for use. 


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4.1.2 Product Supply 
AMPHORA and placebo will be supplied by the Sponsor, Evofem, Inc., 12400 High Bluff 
Drive, Suite 600, San Diego, CA 92130. 
4.1.3 Product Storage, Stability, and Expiration  
The investigational product should be stored at room temperature (15oC-30oC). The 
investigational product will be maintained and dispensed by site research staff. 
4.1.4 Preparation 
The investigational product is supplied ready for use. No preparation is necessary. 
4.1.5 Distribution to Subjects/Return of Unused Product and Used Applicators 
Following screening, enrollment, and randomization, subjects will be issued a 4-week supply of 
investigational product based on the individual subject’s projected usage. Each investigational 
product box contains 10 applicators. A subject could receive up to three boxes at a study visit 
during the intervention period. Subjects will be asked how many prefilled applicators they need, 
based on their number of sexual encounters per 4 weeks. At Visits 2 to 4 each, during the 
intervention period, subjects will return all unused product and used applicators packaged 
individually in plastic return bags provided and will be issued a new 4-week supply of 
investigational product based on projected usage. Unopened kits may be redispensed to the same 
subject, as appropriate. Subjects may be issued additional investigational product, as needed, 
should their supply be exhausted prior to the next study visit; however, excessive product usage 
should be brought to the attention of the Investigator and Sponsor. At Visit 5, subjects will return 
all unused product and used applicators. 
4.1.6 Administration  
AMPHORA and placebo will be intravaginally administered by the subject in exactly the same 
manner. To administer, the plunger rod is inserted into the piston end of the barrel engaging the 
piston. The cap is removed from the distal end of the barrel; the barrel is then inserted into the 
subject’s vagina (distal end first). The plunger rod is pushed into the barrel, subsequently moving 
the piston and gel toward the open end of the barrel. Only the gel will leave the barrel.  
Detailed instructions for administration are included as Appendix C and supplied to the subject 
with the investigational product. Subjects will be trained in investigational product application 
prior to issuance. 


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4.1.7 Product Accountability 
The Investigator will keep a record of the dates and amounts of investigational product received, 
the amount dispensed to study subjects, the amount returned from subjects at each visit (unused 
and used applicators) and the amount in inventory (not issued). These records should include the 
dates, quantities, and batch/serial numbers or kit numbers. 
 
The Investigator will record drug accountability on a Drug Disposition Log, which will be 
monitored and confirmed by the Clinical Research Associate (CRA). Upon completion of the 
study and final drug accountability monitoring visit, all unused study medication will be returned 
to Evofem, Inc., or, if instructed by Evofem, Inc., unused investigational product may be 
destroyed onsite according to the site’s standard operating procedures (SOPs). 
 


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5 
Study Procedures/Evaluations 
Subjects will undergo the following study procedures as indicated in this section and according 
to the Schedule of Assessments (Table 1). All equipment used should be calibrated and undergo 
routine calibration, as appropriate.  
5.1 
Written Informed Consent 
A written informed consent will be obtained from all study participants before start of any study 
activities. The Informed Consent specifies, in lay and culturally appropriate language, all 
expectations from the participant including duration of study, number of doses and visits, 
procedures at each visit, safety documentation (including subject diary), use of contraceptives, 
restrictions on intravaginal product or device use, sampling plan, potential risks, stipend for 
participation in study, and relevant research scope.  
 
All study-related questions by the subject should be responded to before completion of the 
Informed Consent. The subject will be provided ample time to consider their potential 
participation, including time to consult with friends, family, and primary care provider if desired. 
The completed Informed Consent form will be verified for its proper completion. A signed copy 
of the Informed Consent will be provided to the subject and the original will be kept on file in 
the subject’s study file.  
5.2 
Inclusion/Exclusion Criteria 
Participants will meet all the stated inclusion criteria and not possess any of the exclusion criteria 
to be eligible to participate in this study. Only subjects that are eligible based on the study 
inclusion and exclusion criteria will be enrolled in the study.  
5.3 
Evaluation of Eligibility Criteria 
The Investigator will evaluate whether a subject meets the study’s inclusion/exclusion criteria at 
screening and enrollment and before administering any study product. The Investigator will be 
responsible for ensuring that the evaluation of eligibility criteria is addressed for all subjects 
enrolled in the study.  
5.4 
Demographics  
Demographics data will be collected from all study participants, including date of birth, race, and 
ethnicity.  


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5.5 
Clinical Evaluations 
All clinical procedures summarized in this section will be performed according to the site’s SOC 
SOPs.  
5.5.1 Medical History  
A detailed medical/surgical/gynecologic/sexual history will be obtained. Changes in medical 
history, if applicable, will be reviewed at each visit. 
A review of body systems will be performed by the Investigator to screen for exclusion criteria. 
Subjects will be asked about current drug and alcohol use by the Investigator for evaluating 
eligibility. 
5.5.2 Vital Signs  
Vital signs, including blood pressure, heart rate, and body temperature, will be measured and 
recorded. Vital sign measurements will be obtained after the subject has been sitting quietly for 
at least 5 minutes. When taking an oral temperature, assure the subject has not had any recent hot 
or cold beverages or has recently smoked, including e-cigarettes. The Investigator should use 
clinical judgment when characterizing bradycardia among health subjects, eg, conditioned 
athletes.  
5.5.3 Gynecologic Examinations  
A full gynecologic examination (speculum) will be performed after swab for vaginal pH is 
collected. 
Targeted physical and/or gynecologic examination (speculum), will be performed at any 
subsequent or unscheduled visit if necessary due to an AE.  
5.5.4 Concomitant Medications 
Concomitant medications that will be taken during the study, including all over-the-counter 
medications, vitamins, and nutritional supplements, will be recorded and should include at a 
minimum: start date, stop date or continuing, and indication/reason. 
5.5.5 Height and Weight  
Body weight and height will be recorded.  


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5.6 
Laboratory Evaluations  
Specimens collected for NAATs will be processed by the sites and shipped to a central 
laboratory for testing. All other laboratory testing and staining of used applicators will be 
performed onsite. 
5.6.1 Pregnancy Testing  
Subjects of reproductive potential, including those with history of tubal ligation, will be required 
to provide a urine specimen to be tested for uHCG. This test will be performed at each site using 
the SOC testing materials and procedure. 
Negative results must be obtained prior to dosing. Women who test positive for pregnancy will 
be excluded from participating in this study and be referred for follow-up as per clinic protocol 
(see Section 6.6.2 Pregnancy). 
5.6.2 Vaginal pH Testing 
Swab for vaginal pH reading is collected prior to introduction of speculum for gynecologic 
exam. Specimen collection and vaginal pH testing procedures is detailed in the Manual of 
Procedures (MOP). 
5.6.3 Nucleic Acid Amplification Tests for Chlamydia trachomatis/Neisseria gonorrhoeae 
All women will have vaginal swabs collected all visits (screening, enrollment, and each 
intervention visit and follow-up visit) for NAATs. Swabs will be collected by clinician when 
speculum exams are performed; otherwise vaginal swabs will be self-collected by subject while 
in clinic. Specimens will be collected using the specific collection/transport kit materials and 
package insert instructions as designated by the central laboratory. Specimens will be shipped to 
the central laboratory according to procedure and as included in the MOP. All positive results 
will be reported to the study site for follow-up. 
5.6.4 Staining of Used Applicators 
Sites will collect returned unused product and used applicators at each study visit. Site staff is 
responsible to visually inspect unused study product to confirm package seal is intact/not broken. 
If the seal is broken the applicator should be assessed for use (appears full of gel and unused). 
The used applicators will be tested onsite to validate vaginal insertion by using staining with 
trypan blue. Staff performing staining procedures will be trained and procedures will be detailed 
in the MOP. 


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5.7 
Subject eDiaries 
Each subject will be provided with a secure validated eDiary software application downloaded to 
their personal cellular telephone or tablet to collect, at minimum, subject-reported sexual activity 
and study product use data. The eDiary application will be de-identified using the subject 
number assigned at the time of screening; research staff will receive, and review data identified 
only by the subject number throughout the course of the study.  
The Investigator or designee will ensure each subject is trained in the importance of the eDiary 
and on its use. The instruction on maintaining the eDiary should include fields that must be 
completed and how the subject should record data within them. All eDiary entries will be 
reviewed on a regular basis, with subjects at each follow-up visit. Study sites must encourage 
eDiary recording by subjects via text messaging or direct contact with subjects. All eDiary 
entries will become part of the subjects’ study record. 
5.8 
Procedures by Visit 
5.8.1 Screening (Visit 0; Weeks -6-0) 
Subjects who wish to participate in the study will be asked to sign and date the Informed Consent 
and HIPAA forms prior to any study-specific procedures. All subjects will be provided with a 
copy of their own signed and dated Informed Consent form. The Investigator must keep a subject 
screening log, subject enrollment log, and subject identification log for identifying all subjects 
having signed Informed Consent and HIPAA forms.  
The following will be recorded by research staff in the source documents and CRF, as required: 
1. Informed consent and HIPAA forms completed 
2. Demographic data 
3. Evaluation of inclusion and exclusion criteria 
4. Medical/surgical/gynecologic/sexual history 
5. Concomitant medication: all medications taken will be recorded in standard data 
collection forms with attention to drug route, daily dose, duration, start date, stop 
date, and indications 
6. Self-collected vaginal swab for CT and GC NAATs 
Subjects will be asked to return to the clinic after receipt of negative CT and GC NAAT results, 
preferably in 1 week ±7 days for enrollment. Enrollment must be completed within 45 days of 
screening.  
If NAAT results are positive, subjects must be treated according to SOC prior to enrollment. To 
meet eligibility criteria, these subjects will not be enrolled until 3 to 4 weeks after screening (at 
least 21 days after treatment). 


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5.8.2 Rescreening 
Subjects do not need to be rescreened if enrollment is within 45 days of initial screening. If more 
than 45 days, Informed Consent and Screening Visit assessments/procedures should be repeated. 
5.8.3 Enrollment/Visit 1 (Week 0 ±7 days) 
Subjects must be asked to abstain from vaginal intercourse in the 24 hours preceding Study 
Visit 1. The following will be recorded by research staff in the source documents and CRF: 
1. Evaluation of inclusion and exclusion criteria 
2. Evaluation of eligibility criteria 
3. Demographic data 
4. Completed Female Sexual Function Index (FSFI) and Sexual Function Questionnaire 
(SFQ) 
5. Updated Medical/surgical/gynecologic/sexual history 
6. Last menstrual period (date, if known) 
7. Concomitant medication: all medications taken will be recorded in standard data 
collection forms with attention to drug route, daily dose, duration, start date, stop date 
and indications 
8. Body height and weight 
9. Vital sign measurements (blood pressure, heart rate, temperature)  
10. Physical exam 
11. Pregnancy test (urine) 
12. Vaginal pH* 
13. Clinician-collected vaginal swab for CT and GC NAATs 
14. Gynecologic examination* (speculum, performed by clinician)  
15. Randomization and issuance of study product (4-week supply based subject 
estimation of projected use) 
16. Instructions on eDiary setup and use 
*Swab for vaginal pH reading is collected prior to introduction of speculum for gynecologic 
exam.  
Should subject be menstruating at time of scheduled visit, the visit may be rescheduled during 
the 7-day visit window, if possible. 
Randomization, training, and verification of subject understanding, competency, and willingness 
to administer study product as directed is documented prior to issuance of study product. 
If a subject’s CT/GC NAAT results are positive at the enrollment visit, the subject should be 
immediately terminated from the study, IP accountability conducted, and all used/unused kits 


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returned to the clinic. An Early Termination Visit should be performed to complete all 
procedures indicated for Visit 5 with the exception of repeat GC/CT NAAT testing. The subject 
should have SOC treatment for the infection and should be encouraged to return for a post-
intervention follow-up visit approximately 4 weeks ±7 days from Early Termination Visit or last 
IP use.    
5.8.4 Visits 2 Through 4 (Weeks 4-12 ±7 days)  
Subjects must be asked to abstain from vaginal intercourse in the 24 hours preceding Study 
Visits 2 through 4. The following will be performed, and research staff will record results in the 
source documents and CRF: 
1. Changes in the following since Screening Visit: 
a. AEs  
b. Concomitant medications  
2. Pregnancy test (urine) 
3. Self-collected vaginal swab for CT and GC NAATs 
4. Targeted physical exam, if needed based on symptoms 
5. Subject diary review (sexual activity, product use since last visit) 
6. Return of all unused study product and used applicators 
7. Issuance of additional study product (4-week supply based on prior month’s usage or 
per subject estimation of projected use) 
5.8.5 Visit 5 (Week 16 ±7 days) 
Subjects must be asked to abstain from vaginal intercourse in the 24 hours preceding Study 
Visit 5. The following will be performed, and research staff will record results in the source 
documents and CRF: 
1. Changes in the following since last visit: 
a. AEs  
b. Concomitant medications  
2. Pregnancy test (urine)  
3. Self-collected vaginal swab for CT and GC NAATs 
4. Targeted physical exam, as needed, based on symptoms 
5. Subject diary review (sexual activity, product use since last visit) 
6. Completed FSFI, SFQ, subject satisfaction with product, and subject sexual 
satisfaction questionnaires 


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7. Return of all unused study product and used applicators 
5.8.6 Post-intervention Follow-up Visit/Visit 6 (Week 20 ±7 days) 
The following will be performed, and research staff will record results in the source 
documents and CRF: 
1. Changes in the following since last visit: 
a. AEs  
b. Concomitant medications  
2. Pregnancy test (urine) 
3. Self-collected vaginal swab for CT and GC NAATs. This is not required for subjects 
who were withdrawn due to positive CT or GC NAAT 
4. Targeted physical exam, as needed based on symptoms 
5. Subject diary review (sexual activity since last visit) 
5.9 
Unscheduled Visit(s) 
The subject will be asked to return to the study site for evaluation if she develops symptoms or 
signs of illness and needs to be evaluated between scheduled visits. A targeted physical 
examination, as dictated by the symptoms, will be performed. Safety or other laboratory tests 
will be obtained as deemed necessary by the Investigator. Findings will be documented in the 
source documents and eCRF for unscheduled visits. AE assessment (including SAEs) will be 
recorded in the source documents and eCRF.  
Subjects will be asked to contact the study site to obtain additional study product should their 
monthly supply be depleted in advance of their next scheduled visit. 
5.10 
Early Termination  
If a subject who has received study product withdraws or is withdrawn, an early termination visit 
will be conducted if the subject is willing. All activities listed for Visit 5 will be carried out 
unless medically contraindicated. CT and GC NAAT is not required at the Early Termination 
Visit if subject is being withdrawn due to positive GC or CT NAAT. 
5.11 
Clinical Laboratory Specimen Preparation, Handling and Storage 
All laboratory specimens collected during study visits will be collected and processed by a 
trained study research team member, following site SOPs, MOPs, and all applicable site and 
local safety committee safety guidelines. All samples collected for uHCG will be tested onsite.  


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Vaginal swab specimens collected for NAATs will be processed, stored, and shipped to the 
central laboratory for testing as described in the MOP. 
Returned applicators will be collected from subjects at each visit. Trained study staff will 
perform staining on used applicators onsite as described in the MOP. 


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6 
Safety Reporting and Safety Monitoring 
Since this clinical study is being conducted exclusively in the US, FDA regulations including 
safety monitoring and reporting responsibilities of Sponsor and Investigators must be followed to 
ensure the safety and protection of human subjects and accuracy of the data collected. 
6.1 
Responsibilities 
Investigators participating in this clinical study are required to: 
• Evaluate subject safety including assessment of AEs for seriousness, severity, and 
causality 
• Notify the ICON GPHS Medical Monitor of SAEs within 24 hours of becoming 
aware of them 
• Provide detailed written reports, including necessary documentation requested by the 
Sponsor or IRB, promptly following immediate initial reports 
• Inform the IRB of AEs as required by applicable regulatory requirements 
6.2 
Definitions 
Adverse Event (AE)  
Any untoward medical occurrence in a clinical investigation subject who has received a study 
product intervention and that does not necessarily have to have a causal relationship with the 
study product. An AE can, therefore, be any unfavorable and unintended sign (including an 
abnormal laboratory finding, for example), symptom, or disease temporally associated with the 
use of a study medicinal product, whether or not considered related to the study medicinal 
product.  
Serious Adverse Event (SAE)  
An SAE is any adverse event that results in any of the following outcomes: 
• Death 
• Life-threatening (immediate risk of death) 
• Inpatient hospitalization or prolongation of existing hospitalization 
• Persistent or significant disability or incapacity 
• Congenital anomaly/birth defect 


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• Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered an SAE when, based upon appropriate medical 
judgment, they may jeopardize the subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition  
The term “life-threatening” in the definition of SAE refers to an event in which the subject was 
at risk of death at the time of the event. It does not refer to an event which hypothetically might 
have caused death if it were more severe. 
The term “hospitalization” describes a period of at least 24 hours. Overnight stay for observation, 
treatment at an emergency room or treatment on an outpatient basis does not constitute a 
hospitalization. However, medical judgment must always be exercised and when in doubt the 
case should be considered serious. 
Non-serious Adverse Event 
A non-serious AE is any AE which does not fulfill the definition of an SAE. 
Treatment-emergent Adverse Event (TEAE) 
A TEAE is any AE occurring after the application of the study product and within the time of 
residual product effect, or pre-existing medical condition that worsens in intensity after the 
application of study product and within the time of residual product effect. The time of residual 
product effect is 7 days after the dose of the study product, when the effect of the product is still 
considered to be present based on change of vaginal pH from baseline. 
Unexpected Adverse Reaction 
An adverse reaction, the nature or severity of which is not consistent with the applicable product 
information (eg, Investigational New Drug (IND) Safety Data; see Investigator’s Brochure). 
6.3 
Safety Reporting Requirements 
6.3.1 Reporting Interval 
All AEs and SAEs will be collected and recorded following randomization.  
The Investigators will follow all AEs that are deemed at least possibly related to investigational 
product and SAEs until resolution (return to pre-intervention status or stabilization of conditions 
deemed as chronic), even if this extends beyond the study-reporting period.  


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A subject will be considered as lost to follow-up if participation in AE assessment is not 
continued after: 
• Three unsuccessful attempts at telephone contact (separated by at least 24 hours) 
following missed AE assessment visit or telephone consultation; followed by 
• Issuance of a certified letter to last documented address of subject, and no response 
within 7 days of mailing 
At any time after the completion of the study, if an Investigator becomes aware of an SAE that is 
suspected to be related to the investigational product, the Investigator will report the event to 
ICON GPHS within 24 hours of awareness. The Investigator will ensure that the appropriate IRB 
has been notified of the reported SAE in a timely manner per internal IRB reporting 
requirements. 
6.3.2 Notification of the Sponsor of Serious Adverse Events 
Any AE that meets a protocol-defined serious criterion, must be submitted within 24 hours of 
site awareness. 
The Medical Monitor will review and assess the SAE for regulatory reporting and potential 
impact on study subject safety and protocol conduct. 
Other supporting documentation of the event requested by the Medical Monitor should be 
provided. 
The Sponsor will be notified of any unexpected SAE with suspicion of being related to study 
drug. In addition, the Sponsor will be informed of any study procedure-related SAE which may 
warrant a change of any study procedure or halting of the study. 
6.3.3 Regulatory Reporting for Studies Conducted Under Investigational New Drug 
Application 
The Sponsor is responsible to report both serious and unexpected events that are associated with 
investigational product(s) to the FDA within the required timelines as specified in 21 CFR 
312.32 (fatal and life-threatening events within 7 calendar days by phone or fax and all other 
SAEs in writing within 15 calendar days). All serious events designated as “not associated” to 
investigational product(s) will be reported to the FDA at least annually in a summary format.  
6.4 
Investigator’s Assessment of Adverse Events  
The determination of seriousness, severity, and causality will be made by a site Investigator.  


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6.4.1 Assessment of Severity 
Each AE will be assessed by the Investigator with regard to the following categories: 
Seriousness 
An SAE is defined as any untoward medical occurrence that at any dose: 
• 
Results in death 
• 
Is life-threatening; this means that the subject is at risk of death at the time of the event, 
and it does not mean that the event hypothetically might have caused death if it were 
more severe 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization 
• 
Results in persistent or significant disability or incapacity 
• 
Is a congenital anomaly or birth defect 
• 
Is an important medical event that may not be immediately life-threatening or result in 
death or hospitalization but that may jeopardize the subject or require intervention to 
prevent one of the above outcomes; examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions 
that do not result in hospitalization, or development of drug dependency or drug abuse 
Medical and scientific judgment should be exercised in deciding whether a case is serious and 
whether expedited reporting is appropriate. 
 
Intensity 
Investigators should assess the severity of AEs according to Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.03. In general, CTCAE severity grades are: 
• 
Grade 1: mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated 
• 
Grade 2: moderate; minimal, local, or noninvasive intervention indicated; limiting age-
appropriate instrumental activities of daily living (ADL) (instrumental ADL refer to 
preparing meals, shopping for groceries or clothes, using the telephone, managing 
money, etc) 
• 
Grade 3: severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care 
ADL (self-care ADL refer to bathing, dressing and undressing, feeding self, using the 
toilet, taking medications, and not bedridden) 
• 
Grade 4: life-threatening consequences; urgent intervention indicated 


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• 
Grade 5: death related to AE 
 
Causality 
The Investigator will assess the causality/relationship between the study drug and the AE and 
record that assessment in the electronic data capture (EDC) system. The most likely cause of an 
AE (eg, concomitant disease, concomitant medication, other) will be indicated in the EDC 
system with details of the concomitant disease or medication or other cause. 
The causal relationship of the AE to study drug will be described per World Health Organization 
(WHO) Uppsala Monitoring Centre (UMC) causality categories:  
• Certain 
o Event or laboratory test abnormality, with plausible time relationship to drug intake 
o Cannot be explained by disease or other drugs 
o Response to withdrawal plausible (pharmacologically, pathologically) 
o Event definitive pharmacologically or phenomenologically (ie, an objective and 
specific medical disorder or a recognized pharmacological phenomenon) 
o Rechallenge satisfactory, if necessary 
• 
Probable/Likely:  
o Event or laboratory test abnormality, with reasonable time relationship to drug intake 
o Unlikely to be attributed to disease or other drugs 
o Response to withdrawal clinically reasonable 
o Rechallenge not required 
• 
Possible:  
o Event or laboratory test abnormality, with plausible time relationship to drug intake 
o Could also be explained by disease or other drugs 
o Information on drug withdrawal may be lacking or unclear 
• 
Unlikely: 
o Event or laboratory test abnormality, with a time to drug intake that makes a 
relationship improbable (but not impossible) 
o Disease or other drugs provide plausible explanations 
• 
Conditional/Unclassified: 
o Event or laboratory test abnormality 
o More data for proper assessment needed, or 
o Additional data under examination 


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• 
Unassessable/Unclassifiable: 
o Report suggesting an adverse reaction 
o Cannot be judged because information is insufficient or contradictory 
o Data cannot be supplemented or verified 
6.4.2 Adverse Event Outcome Measures 
The outcome of all AEs will be reported based on the following definitions, independent of 
whether they are serious or non-serious AEs, their severity, or their relationship to the 
investigational product:  
• Recovered: fully recovered, or by medical or surgical treatment the condition has 
returned to the level observed at the first study-related activity after the subject signed the 
informed consent 
• Recovering: the condition is improving and the subject is expected to recover from the 
event. This term should only be used when the subject has completed the study 
• Recovered with sequelae: as a result of the AE, the subject suffered persistent and 
significant disability/incapacity (eg, became blind, deaf, paralyzed). Any AE recovered 
with sequelae should be rated as an SAE 
• Not recovered 
• Fatal 
• Unknown: this term should only be used in cases where the subject is lost to follow-up 
6.5 
Study-related Adverse Events 
See Appendix A for descriptions and grading criteria for anticipated study-related AEs. All AEs 
will be documented on the standard AE forms. AE forms for cutaneous AE grade 3 or higher will 
be sent to the Medical Monitor within 24 hours of awareness (non-serious or serious).    
The reporting of an AE grade 3 or higher will prompt follow-up diagnostic work-up (eg, physical 
examinations, vital signs, descriptive assessment, subject diary, and clinical laboratory work). If 
the cutaneous AE is grade 3, subjects will be seen twice weekly until the severity is reduced to 
grade 2 or less at two consecutive follow-up visits (1 week) and not getting worse.  
6.6 
Other Safety Considerations 
Any significant worsening or new findings noted during post-intervention follow-up visit or any 
other potential safety assessments performed during the study, whether or not they are required 
by the protocol, should be recorded on the appropriate AE form. 


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6.6.1 Follow-up of Adverse Events 
During and following a subject’s participation in a clinical study, the Investigator should ensure 
that adequate medical care is provided to the subject for any AEs, including clinically significant 
laboratory values related to the study. The Investigator should inform the subject when medical 
care is needed for AEs. 
The period for reporting new AEs will continue until the post-intervention follow-up visit (final 
study visit).  
All non-serious AEs classified as possibly/probably related to the investigational product must be 
followed until the subject has recovered and all queries have been resolved. However, cases of 
chronic conditions can be closed if determined by clinician as stable, with an outcome of 
“recovering” or “not recovered.” If a subject died from another event, these cases can be closed 
with an outcome of “not recovered.” 
All other non-serious AEs must be followed until the outcome of the event is “recovering” (for 
chronic conditions), or until the end of the post-intervention follow-up stated in the protocol, 
whichever comes first, and until all queries related to these AEs have been resolved. If a subject 
died from another event, these cases can be closed with an outcome of “not recovered.” 
The Investigator must enter follow-up information about non-serious AEs on the AE form within 
the CRF. 
Queries or follow-up requests from ICON GPHS should be responded to within 14 calendar 
days, unless otherwise specified. The Investigator must forward follow-up information on SAEs 
to the requestor within 5 calendar days of obtaining the request for follow-up information. 
All SAEs must be followed until the outcome of the event is recovered, recovered with sequelae, 
or fatal and until all queries have been resolved. For cases of chronic conditions and cancer or if 
the subject dies from another event, follow-up until the outcome categories are “recovered,” 
“recovered with sequelae,” or “fatal” is not required, as these cases can be closed with an 
outcome of “recovering” or “not recovered.” 
6.6.2 Pregnancy 
While women of childbearing potential are eligible for the study, they must agree to use an 
approved form of birth control (see Section 3.1 Inclusion Criteria) over the duration of the study 
period. Women of childbearing potential are defined as any female who has experienced 
menarche and who is NOT permanently sterile or postmenopausal. Postmenopausal is defined as 
12 consecutive months with no menses without an alternative medical cause. If there is any 


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question that a subject will not be reliable in the adherence to this requirement, they should not 
be entered into the study. 
Study subjects must be instructed to notify the study site Investigator immediately if they suspect 
pregnancy during the course of the study and for a period of 4 weeks following study discharge. 
Subjects who become pregnant will be instructed to immediately discontinue study product. The 
Investigator must report any pregnancy during the study to the Medical Monitor within 14 
calendar days of obtaining the information using the Pregnancy Form and the Pregnancy 
Follow-up Form, respectively. Pregnancy complications must be recorded as AEs or SAEs if 
meets criteria. If the infant has a congenital anomaly or birth defect, the anomaly or defect must 
be reported and followed as an SAE. 


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7 
Clinical Monitoring/Site Monitoring Plan  
Monitoring will be conducted to ensure that human subject rights and well-being are protected, 
data are accurate, complete, and verifiable from source documents, and the study complies with 
the protocol/amendment(s), and applicable regulatory requirements.  
In order to ensure protocol compliance, monitoring visits will occur at scheduled intervals prior 
to, during, and at study completion. The visit frequency will be defined in a monitoring plan and 
communicated to the Investigators. 
A separate study-specific monitoring plan will define the monitoring details such as the 
frequency of monitoring visits and percentage and selection of charts/source documentation to be 
monitored. An ICON GPHS CRA will be responsible for the clinical monitoring at the study 
sites. The CRA will operate independently from the study sites and will comply with ICON 
GPHS SOPs. The CRA will ensure that the Investigators understand the investigational status of 
the study product, all requirements of the protocol, and his/her regulatory responsibilities as an 
Investigator. The CRA will visit the clinical site in accordance with the monitoring plan to assess 
compliance with the protocol, verify accuracy and completeness of the data, perform 
accountability of study product, and review essential regulatory documents. 
The investigational sites will provide direct access to all study-related documents and records 
maintained by the Investigators, including but not limited to study-related source data for the 
participants in this study.  
The Investigators are ultimately responsible for ensuring that the CRA’s findings are addressed.  


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8 
Statistical Considerations 
This section outlines the basic statistical approach for the study. A final statistical analysis plan 
will be written and approved before the database lock. This plan will specify all statistical 
methods and plans for analysis.  
8.1 
Study Hypotheses 
The hypothesis to be tested in this study is that AMPHORA will prevent the sexual transmission 
of CT. As noted above, CT infection in women is associated with higher vaginal pH (pH >4.5) 
(10). This finding is supported by other reports in the literature (7). In addition, a higher vaginal 
pH has been associated with increased transmission of GC (28). AMPHORA also contains a 
relatively high concentration of lactic acid (1.8% w/v). Lactobacilli inactivate CT through the 
production of lactic acid (29). Thus, AMPHORA should reinforce the ability of lactobacilli to 
maintain healthy levels as well as provide additional lactic acid that may act directly in 
preventing CT infection. 
8.2 
Sample Size Considerations 
The primary analysis is a comparison between proportion of subjects who experience at least one 
CT infection among the intervention groups (AMPHORA or placebo).  
It is assumed that the proportion of subjects experiencing at least one infection of CT during the 
study period (incident infection of CT) up to Week 16 under placebo will be 22.5%. An incident 
infection of CT of 13% in the subjects receiving active treatment (ie, a treatment difference of 
9.5%) is considered clinically relevant for AMPHORA versus placebo. Using a Chi-square test 
for the primary endpoint, 253 analyzable subjects per treatment group (506 subjects total in the 
ITT population) will yield approximately 80% power to detect 9.5% treatment difference with a 
2-sided 5% type I error rate (SAS 9.3 PROC POWER). Assuming that 20% of the total enrolled 
subjects will be lost to follow-up, 15% will be re-infected with GC (making them ineligible for 
the primary endpoint analysis), and 5% will be deemed ineligible for analysis due to antibiotic 
use, the total sample size planned for this study is 844 subjects.  
8.3 
Final Analysis Plan 
8.3.1 Analysis Populations 
This study will utilize three analysis populations: Intention-to-Treat (ITT), modified Intention-to-
Treat (mITT), and safety. 
The ITT population will consist of all randomized subjects. The mITT population will consist of 
all randomized subjects who are negative for chlamydia and gonorrhea at enrollment and report 


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use of study product prior to at least one coital event. Lastly, the safety population will be based 
on subjects who applied any amount of study product. 
Analyses using the ITT and mITT populations will be performed based on the treatment 
randomized. Meanwhile, safety analyses will be based on the treatment received.  
8.3.2 Randomization and Stratification 
A randomized study group assignment schema, stratified by study site, will be developed using 
SAS, release 9.3 or higher. 
8.3.3 Procedures for Handling Missing, Unused, and Spurious Data 
All analyses will be based on data as observed in the study. No imputations will be performed for 
data that are missing or spurious. 
Given the need to provide treatment to subjects who become infected with CT and/or GC, not all 
subjects will be evaluable for each endpoint since the use of antibiotics would treat both possible 
infections. Therefore, the subjects analyzed for the primary efficacy endpoint are those that are 
infected with CT or who complete the study with no re-infections. Likewise, the subjects 
analyzed for the secondary efficacy endpoint are those that are infected with GC or who 
complete the study with no re-infections. 
8.3.4 General Statistical Considerations 
All subjects that enter the study will be accounted for in the final clinical report, whether or not 
they are included in the analysis. All reasons for exclusion will be documented for those 
subjects. 
For continuous variables, descriptive statistics will include the number of non-missing values, 
mean, standard deviation, median, minimum, and maximum. For categorical variables, 
descriptive statistics will include counts and percentages per category. 
Baseline values for all parameters will be the most recent value prior to administration of study 
product or speculum exam. 
8.4 
Planned Statistical Methodology 
8.4.1 Data Analysis for Efficacy 
For the primary analysis, the proportion of subjects who experience at least one CT infection will 
be compared between the intervention groups (AMPHORA or placebo) using a Chi-square test. 


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The primary efficacy analysis will be completed using the subjects deemed analyzable (see 
Section 8.2) from the mITT population.  
The primary statistical hypothesis being tested is that there is no difference in the proportion of 
subjects with CT infections in the AMPHORA intervention group versus placebo. In statistical 
terms:  
H0: pAMPHORA = pplacebo, HA: pAMPHORA ≠ pplacebo 
 
where pAMPHORA and pplacebo denote the proportion of subjects with CT infections during the 
study while on AMPHORA or placebo, respectively. Denominators for percentages are number 
of subjects in the mITT population in each intervention group. To test superiority over placebo, 
the incident infection of CT will be compared against placebo based on a Chi-square test. The 
estimated difference in proportions, 95% confidence interval, and p-value will be presented. A 
two-sided 5% type I error rate (α=0.05) will be used. 
Similar analyses will be performed for incident infection of GC.  
8.4.2 Data Analysis for Safety  
All AEs will be coded using the Medical Dictionary for Regulatory Activities® (MedDRA) v17.0 
or higher. The incidence of AEs (new or worsened) will be summarized by primary system organ 
class, preferred term, severity, and relationship to study intervention. The incidence of death, 
SAEs, and AEs leading to discontinuation will be summarized separately by primary system 
organ class and preferred term.  
8.4.3 Analyses for Exploratory Objectives and Endpoints 
Adherence with AMPHORA usage during study (rate of product use adherence) will be 
measured by inspection/analysis of returned gel applicators and eDiary data. Summary statistics 
of adherence overall and by intervention group will be provided.  
Based on the adherence rate for each subject, sensitivity analyses will be conducted in the same 
manner as the primary and secondary endpoint analyses to examine if the level of re-infection 
between treatment groups differs for ≥20%, ≥40%, ≥60%, ≥80%, and 100% adherence rates. 
These sensitivity analyses will be performed on the mITT population. 
Subject satisfaction with the study drug (including sexual satisfaction in Appendix E) will be 
summarized using frequency and percentage.  
Subject sexual satisfaction will be measured utilizing baseline and follow-up questions on the 
impact of study drug on sexual function with the SFQ and item 10 on the FSFI. These scores and 
responses will be summarized using frequency and percentage.  


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9 
Data Handling/Recordkeeping/Source Documents 
It is each Investigator’s responsibility to ensure that all team members appropriately handle all 
data and related documentation. All subject information, including source documents and 
laboratory reports, must be reviewed by the Investigator and clinical team and submitted to the 
ICON GPHS Data Management Team via eCRF. ICON GPHS Data Management will work with 
the Investigators and CRAs to develop a data management plan, including eCRF creation and 
instructions for the study to establish, maintain, and update the study data effectively. Clinical 
data will be entered directly from the source documents to the data management system within 
72 hours of study activity to maintain up-to-date information on all clinical and laboratory data. 
There will be ongoing processing of data and quality checks. CRAs will be responsible for 
source verification of the eCRFs.  
Data security is of paramount concern. A comprehensive IT Systems Security Plan with a 
disaster recovery plan is in place to safeguard data systems related to this clinical study. 
9.1 
Data Capture Methods 
Clinical data (including AEs and concomitant medications) will be entered into the Clinical 
Studio EDC system. This system is a 21 CFR 11-compliant internet data entry system provided 
by the ICON GPHS Data Coordinating Center. Only those who are trained and delegated the 
responsibility by the Investigator (with delegation documented on the signature delegation log) 
will collect and enter data. The data system includes password protection and internal quality 
checks, such as heuristic checks, to identify data that appear inconsistent, incomplete, or 
inaccurate.  
9.2 
Types of Data 
Data for this study will include reported symptoms, AEs, clinical laboratory data, adherence with 
AMPHORA usage from eDiary data and applicator staining, and clinician-obtained baseline pH 
values.  
Clinical data will be entered directly from the source documents. CRAs will perform source 
verification and query generation. CRAs will work with the Data Manager and site personnel to 
freeze data prior to analysis. AEs, medical history, and medications will be coded using 
MedDRA v17.0 (or higher) and WHO drug dictionaries.  
9.3 
Study Records Retention  
Each study site will maintain appropriate medical and research records for this study, in 
compliance with ICH E6 R1 Section 4.9, regulatory and institutional requirements for the 


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protection of confidentiality of subjects. The study site will permit authorized representatives of 
Evofem, Inc., ICON GPHS, and regulatory agencies to examine (and when required by 
applicable law, copy) clinical records for the purposes of clinical site monitoring, quality 
assurance reviews, audits, and evaluation of the study safety and progress. A site master file will 
be maintained to include essential documents.  
Study documents will be retained for a minimum of two years after the last marketing 
application approval or two years from the formal discontinuation of clinical development of the 
investigational product. These documents will be retained for a longer period, if required by local 
regulations. No record will be destroyed without the written consent of Evofem, Inc. 
9.4 
Source Documents 
The source document is defined as the first place the data are recorded, eg, hard copy paper 
and/or electronic forms, laboratory printouts, and medical records. The study sites may use 
study-specific paper data collection forms that mirror each EDC form to enter data from the 
source (the subject’s chart, eDiary data, or other medical records) onto the form provided. 
Clinical and research laboratory reports will be printed from the laboratory system and utilized as 
source documents. Clinical data will be entered directly from the source documents to the data 
management system within 72 hours of study activity to maintain up-to-date information on all 
clinical and laboratory data protocol deviations. 
9.5 
Protocol Deviations 
A protocol deviation is any noncompliance with the clinical study protocol or GCP requirements. 
The noncompliance may be either on the part of the subject, the Investigator, or the study site 
staff. As a result of deviations, corrective actions are to be developed by the site and 
implemented promptly.  
Investigation of the protocol deviations will be conducted by the study team, especially the 
Investigator, to assess whether the deviation is due to a subject-specific issue, or whether there is 
an underlying structural or operational aspect of the research process and protocol which may 
require correction or revision. 
It is the responsibility of the Investigator to use continuous vigilance to identify and report 
deviations by entering the information into the clinical database within three working days of 
identification of the protocol deviation or of the scheduled protocol-required activity. 
Appropriate reporting forms must be maintained in the regulatory file as well as in the subject’s 
source document. The Investigator is responsible for ensuring all study staff understand the IRB 
reporting guidelines and adhere to all related requirements and documentation. A cumulative list 
of protocol deviations will be reported in the clinical study report. 
Refer also to Section 10 Quality Control and Quality Assurance. 


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10 
Quality Control and Quality Assurance 
The Clinical Quality Management Plan (CQMP) is developed by ICON GPHS. The CQMP 
outlines quality control (QC) and quality assurance (QA) processes to be applied to protocol 
activities at the clinical sites.  
The ICON GPHS QA Specialist will develop, implement, and oversee all functions of the 
CQMP. The Investigators are responsible for the oversight and implementation of the CQMP at 
their respective clinical sites. The site roles and responsibilities are to submit protocol deviation 
logs, AE/SAEs, and screening and enrollment logs within required time intervals. 
The QC of study-related records will be performed by the site’s clinical staff. Prior to data entry, 
study visit documentation will be reviewed for accuracy and completeness.  
Through periodic verification of data collected for this protocol, ICON GPHS QA activities 
document compliance with GCP standards, human subjects’ protections, and applicable federal 
regulations governing the use of investigational products. Key quality indicators, as detailed in 
the CQMP and applicable to the protocol, will be examined in each subject record selected for 
QA review.  
Study records will remain onsite in a secure location. The clinical site will permit ICON GPHS, 
the Sponsor, and other applicable regulatory authorities access to study-related records.  


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11 
Ethics/Protection of Human Subjects 
11.1 
Ethical Standard 
The study sites will ensure compliance with the legal and ethical obligations for the conduct of 
clinical research involving human subjects, with the key regulations and ethical standards 
implemented as follows: 
• Title 21 CFR 50, Subpart A: General Provisions and Subpart B: Informed Consent, FDA 
• Title 21 CFR 56, Subparts A-E: Institutional Review Boards  
• FDA Information Sheets: Guidance for IRBs and Clinical Investigators, 1998 Update 
• International Conference on Harmonisation GCP (ICH E6 R1): Consolidated Guideline, 
June 1996 
• The Belmont Report 
11.2 
Institutional Review Board 
Prior to initiation of the study, the study protocol, investigator brochure, sample informed 
consent form, and any other documents that pertain to subject information and recruitment 
methods such as advertisements, will be submitted to a centralized and/or local IRB. Any other 
information that may be requested by the IRB for review and approval will also be submitted.  
Approval from the IRB for all subsequent protocol amendments and changes to the informed 
consent form will be obtained. The IRB will be notified of protocol deviations as well as AEs 
and SAEs occurring at the site, in accordance with regulatory requirements. 
Each IRB will review and approve the study protocol and subject informed consent form. After 
approval by the committee, the following documentation must be sent to the study manager or 
designee before the study commences: 
• Confirmation of IRB approval of the protocol 
• Confirmation of IRB approval of the informed consent form and applicable addenda 
• A list of IRB members, their representative capacity, and their affiliation (a Health and 
Human Services General Assurance number will suffice) 


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12 
Informed Consent Process 
The informed consent process will be initiated before a volunteer agrees to participate in the 
study and should continue throughout the individual’s study participation. The subject will sign 
the informed consent document before any procedures are undertaken for the study. A copy of 
the signed informed consent/assent document will be given to the subject or the legal guardian 
for their records. The consent will explain that subjects may withdraw consent at any time 
throughout the course of the study. Extensive explanation and discussion of risks and possible 
benefits of this investigation will be provided to the subjects in understandable language. 
Adequate time will be provided to ensure that the subject has time to consider and discuss 
participation in the protocol.  
The consent forms will describe in detail the study interventions/products/procedures and 
risks/benefits associated with participation in the study. The rights and welfare of the subjects 
will be protected by emphasizing that their access to and the quality of medical care will not be 
adversely affected if they decline to participate in this study. 
12.1 
Subject Confidentiality 
Subject confidentiality is strictly held in trust by the participating Investigators, their staff, and 
the Sponsor and their agents. This confidentiality includes documentation, investigation data, 
subject’s clinical information, and all other information generated during participation in the 
study. 
No information concerning the study or the data generated from the study will be released to any 
unauthorized third party without prior written approval of the Sponsor and the subject. 
The study monitor or other authorized representatives of the Sponsor or governmental regulatory 
agencies may inspect all documents and records required to be maintained by the Investigators, 
including but not limited to, medical records (office, clinic, or hospital) for the subjects in this 
study. The clinical study site will permit access to such records. 


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13 
Confidentiality Policy  
The information obtained during the conduct of this study is considered confidential and can be 
used by Evofem, Inc., for regulatory purposes and for the general development of the 
investigational product. All information supplied by Evofem, Inc., in connection with this study 
shall remain the sole property of Evofem, Inc., and is to be considered confidential information. 
No confidential information shall be declared to others without prior written consent from 
Evofem, Inc. Such information shall not be used except in the performance of this study. The 
information obtained during this study may be made available to other physicians who are 
conducting other clinical studies with the investigational product, if deemed necessary by 
Evofem, Inc. 


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14 
Publication Policy  
Evofem, Inc., is the IND Sponsor. Evofem, Inc., will assume responsibility for registering the 
study in the National Library of Medicine registry (https://www.clinicaltrials.gov). In 
compliance with Public Law 110-85, the FDA Amendments Act of 2007 (FDAAA), 
Evofem, Inc., will also post results of the study. 


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15 
Summary of Changes 
Table 3 
Summary of Changes 
Version 
Number 
Effective 
Date 
Summary of Changes 
1.0 
24 Mar 2017 
Original protocol 
2.0 
19 Sep 2017 
Editorial changes and additional detail added throughout 
Title Page – added CRO information, updated AMPHORA name 
Signature page for the Investigator added 
Original Section 2 – Protocol Summary changed to Protocol 
Synopsis, updated, and moved to front for easier reference 
Original section 3 – removed (included elsewhere in study 
documentation) 
Original Section 4.3 – removed (included in Investigator’s 
Brochure) 
Sections renumbered 
Original Section 5; new Section 2 – added requirement for 
subjects to be treated to the clinical site’s standard of care for STI 
prevention including condom provision 
Original Section 6.2; new Section 3.2 – added/revised exclusion 
criteria 2, 3, 4, 5, 13, 16 
Original Section 6.4; new section 3.4 – revised randomization 
scheme to include IWRS 
Original Section 6.6.1; new Section 3.6.1 – clarified/expanded 
reason for withdrawal 
New Section 3.7 – added completer criteria 
Original Section 7.1; new section 4.1 – updated the description of 
AMPHORA, removed intellectual property information 
Original Section 7.1.5; new Section 4.1.5 – clarified amount of 
study product to be dispensed at each visit 
Original Section 8.8; new Section 5.8.1 – revised list of 
procedures performed 
Original Section 8.8; new Section 5.8.3, 5.8.4, 5.8.5 – added 
requirement for subjects to abstain from intercourse 24 hours prior 
to the visit; removed condom issuance 
Original Section 9.2; new Section 6.2; removed “Pre-intervention 
adverse event” definition 
Original Section 9.4.1 – removed (duplicative) 


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Version 
Number 
Effective 
Date 
Summary of Changes 
Original Section 9.6.2; new Section 6.6.2 – clarified pregnancy 
reporting process 
Original Section 7 – removed (not necessary due to extensive 
prior clinical testing) 
Original Section 11.2; new Section 8.2 – increased sample size to 
844 subjects 
Original Section 11.3 – removed (not necessary) 
Original Section 11.4.3; new Section 8.3.3 – clarified evaluable 
subjects 
Original Section 11.5.3; new Section 8.4.3 – clarified exploratory 
analyses 
Appendix A – Schedule of Events changed to Schedule of 
Assessments, updated, and moved to front for easier reference 
Appendix B – removed (included in Investigator’s Brochure) 
2.1 
10 Oct 2017 
Inclusion criterion #7 and exclusion criterion # 15 were updated to 
provide clarity on acceptable forms of contraception 
Section 5.1 – removed statement regarding ICH GCP 
Section 6.6.2 – included definition of women of childbearing 
potential 
3.0 
11 Oct 2017 
Inclusion criterion #7 and exclusion criterion #15 were updated to 
provide clarity on acceptable forms of contraception 
Section 5.1 – removed statement regarding ICH GCP 
Section 6.6.2 – included definition of women of childbearing 
potential 
4.0 
15 Mar 2018 
Inclusion criterion #1, age increased from 18-35 to 18-45 
Exclusion criterion #2 (consume on average more than three 
drinks of an alcoholic beverage…) was merged with exclusion 
criterion #3 (in the opinion of the investigator, has a history of 
substance or alcohol abuse within that last 12 months 
Inclusion criterion #7 modified 
Exclusion criterion #15 may use NuvaRing 
Screening period increased from to 30-45 days 
Sites increased to 50 
Addition of exploratory measures (subject satisfaction, sexual 
satisfaction, SFQ, FSFI) 
 


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Version 
Number 
Effective 
Date 
Summary of Changes 
5.0 
13 Aug 2018 
Exclusion criterion #11, antibiotic treatment increased to 21 days 
prior to enrollment to provide consistency throughout the protocol 
Screening eligibility, increase from 30-45 days modified for 
consistency 
Study schedule, location of Schedule of Assessments table 
clarified 
Inclusion Criterion #7 modified for consistency throughout the 
protocol 
Exclusion Criterion #9 modified for consistency throughout the 
protocol 
Prohibited medications, antibiotic treatment increased to 21 days 
to provide consistency throughout the protocol 
Appendix D, extra page removed 
6.0 
21 Jan 2019 
Table 1 Schedule of Assessments and Section 3.6.2, clarified that 
procedures for V5 should be followed for Early Termination. 
Added CT/GC NAAT testing is not required at V5/Early 
Termination if termination from the study is due to positive 
CT/GC NAAT test. 
Inclusion Criterion #9 clarified and formatting/numbering 
corrected.  
Section 3.6 clarified that positive CT/GC NAAT test at enrollment 
is a reason for withdrawal. 
Section 5.8.3 updated Termination Visit procedures for positive 
CT/CG testing at enrollment. 
Section 5.8.6 updated self-collected vaginal swab for CT and GC 
NAATs not required for Post-Intervention Follow-up Visit if 
termination of study is due to positive CT/GC NAAT test.  
Section 6.4.1 SAE causality – returned to original language. 
Safety CRO changed to ICON GPHS throughout.   


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16 
Literature References 
1. Centers for Disease Control and Prevention. Sexually Transmitted Disease Treatment 
Guidelines, 2015. MMWR Recomm Rep. 2015 June 15; 64(3). 
2. Owusu-Edusei KJ,HW,TL,ea. The Estimated Direct Medical Cost of Selected Sexually 
Transmitted Infections in the United States, 2008. Sexually Transmitted Diseases. 2013 
Mar; 40(3): p. 197-201. 
3. Linhares IM SPLBGPWS. Contemporary perspectives on vaginal pH and lactobacilli. Am J 
Obstet Gynecol. 2011 Feb; 204(2): p. 120.e1-e5. 
4. Boskey E, Cone R, Whaley K, Moench T. Origins of vaginal acidity: High D/L lactate ratio 
is consistent with bacteria being the primary source. Hum Reprod. 2001; 16: p. 1809-1813. 
5. Kaewsrichan J, Peeyananjarassri K, Kongprasertkit J. Selection and identification of 
anaerobic lactobacilli producing inhibitory compounds against vaginal pathogens. FEMS 
Imm Med Microbiol. 2006; 8: p. 75-83. 
6. Klebanoff J, Hillier L, Eschenbach D. Control of the Microbial Flora of the Vagina by 
H2O2-Generating Lactobacilli. The Journal of Infectious Disease. 1991; 164: p. 94-100. 
7. Yasin B, Pang M, Wagar E, Lehrer R. Examination of Chlamydia trachomatis Infection in 
Environments Mimicking Normal and Abnormal Vaginal pH. American Sexually 
Transmitted Diseases Association. 2002; 29(9): p. 514-519. 
8. Mahmoud E, Svenssen LO, Olsson SE, Mardh PA. Antichlamydial activity of vaginal 
secretion. Am J Obstet Gynecol. 1995; 172: p. 1268-72. 
9. Schramm N, Bagnell C, Wyrick P. Vesicles Containing Chlamydia trachomatis Serovar L2 
Remain above pH 6 within HEC-1B Cells. Infection and Immunity. 1996 Apr; 64(4): p. 
1208-14. 
10. Das S SCAS. Higher vaginal pH is associated with Chlamydia trachomatis infection in 
women: a prospective case-controlled study. International Journal of STD & AIDS. 2005 
Apr; 16(4): p. 290-293. 
11. McLaughlin S, Zenilman J, Ghanem K, Griffiss J. An Algorithim to Identify Neisseria 
gonorrhoeae Infection in Exposed Women. Poster. ; 2016. 
12. Donders G, Bosmans E, Dekeersmaecker A. Pathogenesis of abnormal vaginal bacterial 
flora. Am J Obstet Gynecol. 2000 Apr; 182(4): p. 872-878. 
13. Gupta K, Stapleton A, Hooton T, Roberts P, Fennell C, Stamm W. Inverse Association of 
H2O2-Producing Lactobacilli and Vaginal Escherichia coli Colonization in Women with 
Recurrent Urinary Tract Infections. The Journal of Infectious Diseases. 1998; 178: p. 446-
50. 
14. Pybus V, Onderdonka A. Microbial interactions in the vaginal ecosystem, with emphasis on 
the pathogenesis of bacterial vaginosis. Microbes and Infection. 1999;: p. 285-292. 
15. Cherpes T, Meyn L, Krohn M, Lurie J, Hillier S. Association between Acquisition of 
Herpes Simplex Virus Type 2 in Women and Bacterial Vaginosis. Clinical Infectious 
Disease. 2003 Aug; 37: p. 319-25. 


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16. Martin Jr. H, Richardson B, Nyange P, Lavreys L, Hillier S, Chohan B, et al. Vaginal 
Lactobacilli, Microbial Flora, and Risk of Human Immunodeficiency Virus Type 1 and 
Sexually Transmitted Disease Acquisition. The Journal of Infectious Diseases. 1990; 180: p. 
1863-8. 
17. Sobel J. Is There a Protective Role for Vaginal Flora? Current Infectious Disease Reports. 
1990; 1: p. 379-383. 
18. Watts D, Fazarri M, Minkoff H, Hillier S, Sha B, Glesby M, et al. Effects of Bacterial 
Vaginosis and Other Genital Infections on the Natural History of Human Papillomavirus 
Infection in HIV-1–Infected and High-Risk HIV-1–Uninfected Women. The Journal of 
Infectious Diseases. 2005; 191: p. 1129-39. 
19. Wiesenfeld H, Hillier S, Krohn M, Landers D, Sweet R. Bacterial Vaginosis Is a Strong 
Predictor of Neisseria gonorrhoeae and Chlamydia trachomatis Infection. Clinical Infectious 
Diseases. 2003; 36: p. 663-668. 
20. Lai S, Hida K, Shukair S, Wang Y, Figueiredo A, Conoe R, et al. Human Immunodeficiency 
Virus Type 1 Is Trapped by Acidic but Not by Neutralized Human Cervicovaginal Mucus. 
Journal of Virology. 2009 Nov; 83(21): p. 11196-11200. 
21. Taha T, Hoover D, Dallabetta G, Kumwenda N, Mtimavayle L, Yang LP, et al. Bacterial 
vaginosis and disturbances of vaginal flora: association with increased acquisition of HIV. 
AIDS. 1998; 12: p. 1699-1706. 
22. Pilipenko V, Bourne N, Zaneveld L, Garg S, Waller D, Stanberry L. New Nonoxynol-9 
Formulation (ACIDFORM) Significantly Impacts Experimental Genital Chlamydia 
Infection in a Mouse Model. In ; 1999; Denver. 
23. Spencer S, Valentin-Bon I, Whaley K, Jerse A. Inhibition of Neisseria gonorrhoeae genital 
tract infection by leading-candidate topical microbicides in a mouse model. J Infect Dis. 
2004 Feb; 189: p. 410-419. 
24. Friedland B, Stoner M, Chau M, Plagianos M, Govender S, Moror N, et al. Baseline 
Predictors of High Adherence to a Coitally Dependent Microbicide Gel Based on an 
Objective Marker of Use: Findings from the Carraguard Phase 3 Trial. In ; 2016. p. 2565-
2577. 
25. Hensel D, Fortenberry J, Harezlak J, Craig D. The feasibility of cell phone based electronic 
diaries for STI/HIV research. BMC Med Res Meth. 2012; 12: p. 75. 
26. Hosenfeld C, Workowski K, Berman S, Zaidi A, Dysoon J, Mosure D, et al. Repeat 
Infection With Chlamydia and Gonorrhea Among Females: A Systematic Review of the 
Literature. Sexually Transmitted Diseases. 2009 Aug; 36(8): p. 478-489. 
27. Schwartz J, Ballagh S, Kwok C, Mauck C, Weiner D, Rencher W, et al. Fourteen-day safety 
and acceptability study of the universal placebo gel. Contraception. 2007;: p. 136-141. 
28. Das S, Allan S. Higher Vaginal pH Is Associated With Neisseria gonorrhoeae and 
Chlamydia trachomatis Infection in a Predominantly White Population. Sexually 
Transmitted Diseases. 2006 Aug; 33(8): p. 527-528. 
29. Gong Z, Luna Y, Yu P, Fan H. Lactobacilli Inactivate Chlamydia trachomatis through 
Lactic Acid but Not H2O2. PLoS ONE. 2014; 9(9). 
 


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17 
Appendices 
Appendix A. Grading of Study-related Adverse Events 
The table referenced below is a modification of the NCI Common Terminology Criteria for 
Adverse Events (v4.03, May 2009) tables, adjusted to display common AEs applicable to this 
study. A grading (severity) scale is provided for each AE term. A brief definition is provided to 
clarify the meaning of each AE term. Any clinical event deemed by the clinician to be serious or 
life threatening should be considered a Grade 4 event.  
A semi-colon indicates ‘or’ within the description of the grade; a single dash (-) indicates a grade 
is not available. ADL = Activities of Daily Living. 
ESTIMATING SEVERITY GRADE 
For abnormalities NOT found elsewhere in the tables use the scale below to estimate grade of 
severity: 
GRADE 1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated 
GRADE 2 
Moderate; minimal, local or noninvasive intervention indicated; limiting age-
appropriate instrumental ADL*. 
GRADE 3 
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting 
self-care ADL**. 
GRADE 4 
Life-threatening consequences; urgent intervention indicated. 
GRADE 5 
(Death) is not appropriate for some AEs and therefore is not an option. 
*Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the 
telephone, managing money, etc. 
**Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking 
medications, and not bedridden. 
 
 


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Appendix B. Study-related Adverse Events 
 
Adverse Event 
GRADE 1 
GRADE 2 
GRADE 3 
GRADE 4 
GRADE 5 
Vaginal inflammation 
Definition: A disorder 
characterized by inflammation 
involving the vagina.  
Mild discomfort 
or pain with 
edema or redness 
Moderate 
discomfort or 
pain with edema, 
redness; limiting 
instrumental ADL 
Severe discomfort 
or pain and edema, 
or redness; limiting 
self-care ADL; 
small areas of 
mucosal ulceration 
Widespread areas 
of mucosal 
ulceration; life-
threatening 
consequences; 
urgent 
intervention 
indicated 
Death 
 
Vaginal pain  
Definition: A disorder 
characterized by a sensation of 
marked discomfort in the vagina. 
Mild pain 
Moderate pain; 
limiting 
instrumental ADL 
Severe pain; 
limiting self-care 
ADL 
- 
- 
Vaginal burning 
Definition: A disorder 
characterized by a sensation of 
marked burning in the vagina. 
Mild burning 
Moderate 
burning; limiting 
instrumental ADL 
Severe burning; 
limiting self-care 
ADL 
 
 
Vaginal pruritus 
Definition: A disorder 
characterized by an 
uncomfortable feeling of itching 
and burning in the vagina. 
Mild  
Intense; 
intermittent; 
limiting 
instrumental ADL 
Intense; constant; 
limiting self-care 
ADL or sleep; oral 
corticosteroid or 
immunosuppressive 
therapy indicated  
- 
- 


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Appendix C. Study Product Instructions for Use 
 
 
How to Use the Study Drug 
 
Description 
• 
Each single-use foil pouch contains a pre-filled applicator with a pink cap and a 
plunger rod (Figure 1). 
 
Important Use Information 
• 
During your entire time in this study, use the Study Drug every time you have 
vaginal sex regardless of the time of the last application or even if you have sex more 
than once in a day. The Study Drug can be used immediately before or up to one 
hour before vaginal sex. 
• 
If you or your partner develop burning or irritation of the vagina or penis or 
experience difficult or painful urination, discontinue use and consult your clinical site 
staff. 
 
Instructions for Using the Study Drug 
1. 
• 
Wash your hands with soap and water before opening the foil pouch. 
• 
Remove the pre-filled applicator and plunger from the foil pouch. 
 
2. Gently insert the pointed end of the plunger into the opening inside the pre-filled applicator 
until the plunger lightly snaps in place (Figure 2). Be careful not to push the plunger farther 
after it snaps in place to avoid the release of any Study Drug into the cap. 
 
 
 
 
 
 
Figure 2 


AMPHORA® 
Protocol: EVO-003 
Evofem, Inc. v6.0 – 25 January 2019 
 
 
CONFIDENTIAL AND PROPRIETARY 
 
Page 67 of 76 
 
3. 
• 
Remove the pink cap from the pre-filled applicator (Figure 3). The pre-filled 
applicator is now ready for use. 
• 
NOTE – space between the Study Drug and end of the applicator is normal. 
 
 
 
4. 
• 
Hold the applicator at the grooved area closest to the plunger. Gently place the 
applicator into the opening of your vagina pushing it as far as it will comfortably go, 
similar to the placement of a tampon (Figure 4). 
• 
NOTE - Lying on your back with your knees up may help with this step. 
 
 
5. Using your index finger, push the plunger all the way into the barrel of the pre-filled 
applicator until it stops to ensure all the Study Drug has been applied (Figure 5). 
 
 
 


AMPHORA® 
Protocol: EVO-003 
Evofem, Inc. v6.0 – 25 January 2019 
 
 
CONFIDENTIAL AND PROPRIETARY 
 
Page 68 of 76 
 
6. 
• Gently withdraw the pre-filled applicator (Figure 6). Do not reuse the empty applicator 
or plunger. Place the used applicator in the resealable plastic bag provided (only one 
applicator per bag) and return along with all other used and unused applicators to next 
scheduled visit. 
• The Study Drug gel is effective immediately after insertion. Vaginal sex should occur 
within one hour after insertion. 
 
 
 
 


AMPHORA® 
Protocol: EVO-003 
Evofem, Inc. v6.0 – 25 January 2019 
 
 
CONFIDENTIAL AND PROPRIETARY 
 
Page 69 of 76 
Appendix D. Subject Satisfaction with Product 
 
 
STUDY VISIT 5 
  
1. How satisfied are you with the study product?  
a. Very satisfied  
b. Satisfied  
c. Somewhat satisfied 
d. Somewhat dissatisfied  
e. Dissatisfied  
2. How likely is it that you would recommend this study product to a friend who is 
considering such a product?  
a. Very likely  
b. Likely 
c. Somewhat likely  
d. Somewhat unlikely  
e. Unlikely  
3. If you were still considered to be at risk of an infection, how likely would you be to 
continue with the use of this product if it were available after the study?  
a. Very likely  
b. Likely  
c. Somewhat likely  
d. Somewhat unlikely  
e. Unlikely  
 
 
 


AMPHORA® 
Protocol: EVO-003 
Evofem, Inc. v6.0 – 25 January 2019 
 
 
CONFIDENTIAL AND PROPRIETARY 
 
Page 70 of 76 
Appendix E. Subject Sexual Satisfaction 
 
 
Study Visit 5 
 
What impact has the study product had on your sex life since your last study visit? 
a. My sex life is a lot better than before  
b. My sex life is a little better than before  
c. My sex life is no different than before  
d. My sex life is a little worse than before  
e. My sex life is a lot worse than before


AMPHORA® 
Protocol: EVO-003 
Evofem, Inc. v6.0 – 25 January 2019 
 
 
CONFIDENTIAL AND PROPRIETARY 
 
Page 71 of 76 
Appendix F. Sexual Function Questionnaire (SFQ) 
 
 
How frequently in the PAST MONTH have you had the problems listed below?* 
ALSO, MARK THE BOX IN THE LAST COLUMN if the problem stops your sexual activity. 
 
 
 
Not 
at all 
Seldom,  
<25% of 
the time 
Sometimes, 
about 50% 
of the time 
Usually, 
about 
75% of 
the time 
Always 
MARK THE 
BOX IF THE 
PROBLEM 
STOPS 
YOUR 
SEXUAL 
ACTIVITY 
a. 
Vaginal dryness 
during sexual 
activity 
1 
2 
3 
4 
5 
☐ 
b. 
Lack of sexual 
interest or desire 
1 
2 
3 
4 
5 
☐ 
c. 
Vaginal tightness 
1 
2 
3 
4 
5 
☐ 
d. 
Pain during 
penetration or 
intercourse 
1 
2 
3 
4 
5 
☐ 
e. 
Anxiety about your 
sexual performance 
1 
2 
3 
4 
5 
☐ 
f. 
Unable to orgasm 
1 
2 
3 
4 
5 
☐ 
g. 
Vaginal bleeding or 
irritation from 
penetration or 
intercourse 
1 
2 
3 
4 
5 
☐ 
h. 
Increased sensitivity 
of your skin to 
intimate touching 
1 
2 
3 
4 
5 
☐ 
i. 
Sharp pain inside or 
outside your vagina 
1 
2 
3 
4 
5 
☐ 
j. 
Other problem with 
sexuality;  
Please specify: 
1 
2 
3 
4 
5 
☐ 
*Source: Question 10, Sexual Function Questionnaire, Fred Hutchinson Cancer Research Center.


AMPHORA® 
Protocol: EVO-003 
Evofem, Inc. v6.0 – 25 January 2019 
 
 
CONFIDENTIAL AND PROPRIETARY 
 
Page 72 of 76 
Appendix G. Female Sexual Function Index (FSFI) 
 
 


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Protocol: EVO-003 
Evofem, Inc. v6.0 – 25 January 2019 
 
 
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Protocol: EVO-003 
Evofem, Inc. v6.0 – 25 January 2019 
 
 
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Protocol: EVO-003 
Evofem, Inc. v6.0 – 25 January 2019 
 
 
CONFIDENTIAL AND PROPRIETARY 
 
Page 75 of 76 
 


AMPHORA® 
Protocol: EVO-003 
Evofem, Inc. v6.0 – 25 January 2019 
 
 
CONFIDENTIAL AND PROPRIETARY 
 
Page 76 of 76 
 

SAP_001.pdf: 
 
 
Statistical Analysis Plan (SAP) 
 
Statistical Analysis Plan 
Protocol Number: EVO-003 
Version: 2.0, Date: 24SEP2019                                             
Page 1 of 25 
 
Protocol Title: 
Phase 2B/3 double-blinded placebo-controlled efficacy trial of 
AMPHORA® gel for the prevention of acquisition of urogenital 
Chlamydia trachomatis infection 
Protocol Number: 
EVO-003  
Protocol Version, Date 
Version 6.0, 25JAN2019 
ICON ID:  
3853/0001 
Document Version, Date: 
2.0, 24SEP2019 
 
 
 
 
 
Prepared by:  
ICON Clinical Research Services 
 
On behalf of: 
Evofem, Inc. 
 
 
 


 
 
Statistical Analysis Plan (SAP) 
 
Statistical Analysis Plan 
Protocol Number: EVO-003 
Version: 2.0, Date: 24SEP2019                                             
Page 2 of 25 
 
 
Confidentiality statement: 
 
The information provided in this document is strictly confidential.  
 
The recipients of the SAP must not disclose the confidential information 
contained within this document or any related information to other persons 
without the permission of the sponsor. 
 
In addition, the recipients of the SAP must keep this confidential document in a 
controlled environment which prevents unauthorized access to the document. 
 
 
 
 
SIGNATURE PAGE 
 
 
Prepared at ICON Clinical Research by:  
 
 
 
 
 
 
Scott Mollan, Principal Biostatistician 
 
Date  
(DD 
Mmm 
YYYY) 
 
 
 
 
 
Reviewed at ICON Clinical Research by:  
 
 
 
 
 
 
 
 
Aaron Camp, Director,  Biostatistics 
 
Date  
(DD 
Mmm 
YYYY) 
 
 
 
 
 
 


 
 
Statistical Analysis Plan (SAP) 
 
Statistical Analysis Plan 
Protocol Number: EVO-003 
Version: 2.0, Date: 24SEP2019                                             
Page 3 of 25 
 
 
Approved at Evofem, Inc. by: 
 
 
 
 
 
 
 
 
 
Kelly Culwell, MD, Chief Medical Officer 
 
Date  
(DD 
Mmm 
YYYY) 
 
 
 


 
 
Statistical Analysis Plan (SAP) 
 
Statistical Analysis Plan 
Protocol Number: EVO-003 
Version: 2.0, Date: 24SEP2019
Page 4 of 25
 
REVISION HISTORY 
Version/Date 
Version name 
Section 
Changes implemented 
Version 0.1/ 
01-Mar-2017 
Initial draft 
version 
N/A 
N/A 
Version 0.2/ 
20-Mar-2017 
Version 0.2 
Cover page 
Updated protocol title according to the protocol update 
 
 
Section 2 
Removed the incidence of Trichomonas vaginalis (Trich) infection 
from exploratory objectives  
 
 
Section 3 
Updated the study design  
Removed the randomization replacement 
 
 
Section 4                                           Removed proportion of subjects who experience at least one Trich 
infection during the study and safety endpoints 
 
 
Section 5 
The dropout rate is changed from 10% to 20%. The total sample 
size was adjusted accordingly. 
 
 
Section 8.4.3 
Added the summary of  surgical/gynecologic/sexual health history 
per protocol update 
 
 
Section 8.7.3 
Removed assessment of vaginal irritation per protocol update. 
Version 0.3/ 
19-Jan-2018 
Version 0.3 
Entire Document 
Revisions throughout document to reflect protocol version 3 
Version 
0.4/ 
02-Feb-2018 
Version 0.4 
Sections 8 & 9 
Adherence rate analyses are clarified.  Condom usage statistics 
were presented and testing for an effect of condom use on re-
infection rates by treatment group was added.  A section 
summarizing analyses added post-protocol was included. 
Version 
0.5/ 
23-Apr-2018 
Version 0.5 
Section 2.3, section 4.3 and section 
8.8.4 
Add  Exploratory endpoints 
Version 0.6/ 
19-OCT-2018 
Version 0.6 
 
Updating to reflect new protocol version.   
Version 1.0/ 
04-DEC-2018 
Version 1.0 
 
Reflects SAP signoff 


 
 
Statistical Analysis Plan (SAP) 
 
Statistical Analysis Plan 
Protocol Number: EVO-003 
Version: 2.0, Date: 24SEP2019
Page 5 of 25
 
 
Version 2.0/ 
xx-SEP-2019 
Version 2.0 
 
Clarified eligibility rules for CT & GC re-infection analyses.  
Added re-infection rate by visit analysis.  Added AE by relationship 
classification analysis.  Added GU adverse event summary to 
overall AE table.  Added sensitivity analysis.  Addressed the 
handling of subjects who enrolled into the study more than once.  
Revised TLF shells to reflect said updates. 


 
Statistical Analysis Plan (SAP) 
 
Statistical Analysis Plan 
Protocol Number: EVO-003 
Version: 2.0, Date: 24SEP2019
                                                                     Page 6 of 25 
 
TABLE OF CONTENTS 
 
SIGNATURE PAGE ............................................................................................................. 2 
REVISION HISTORY .......................................................................................................... 4 
TABLE OF CONTENTS ...................................................................................................... 6 
LIST OF ABBREVIATIONS ............................................................................................... 8 
1 INTRODUCTION ........................................................................................................... 9 
2 STUDY OBJECTIVES ................................................................................................. 10 
2.1 Primary objective .................................................................................................. 10 
2.2 Secondary objective .............................................................................................. 10 
2.3 Exploratory objective ........................................................................................... 10 
3 STUDY DESIGN .......................................................................................................... 11 
3.1 General study design ............................................................................................ 11 
3.2 Randomization and blinding ................................................................................. 12 
3.3 Study treatments and assessments ........................................................................ 12 
4 STUDY ENDPOINTS ................................................................................................... 14 
4.1 Primary efficacy endpoint .................................................................................... 14 
4.2 Secondary efficacy endpoint ................................................................................ 14 
4.3 Exploratory endpoints .......................................................................................... 14 
5 SAMPLE SIZE AND POWER ..................................................................................... 15 
6 ANALYSIS POPULATIONS ....................................................................................... 16 
6.1 Intention-To-Treat population (ITT) .................................................................... 16 
6.2 Modified Intention-To-Treat population (mITT) ................................................. 16 
6.3 Safety population (Safety) .................................................................................... 16 
6.4 Protocol deviations/violations and exclusions from analysis sets ........................ 16 
7 Statistical Considerations and analysis .......................................................................... 17 
7.1 Derived Variables ................................................................................................. 17 
7.2 Handling of missing data and outliers .................................................................. 17 
7.3 Analysis Eligible Subjects .................................................................................... 18 
8 STATISTICAL METHODS.......................................................................................... 19 
8.1 General statistical conventions ............................................................................. 19 
8.2 Subject disposition ................................................................................................ 19 
8.3 Protocol deviations ............................................................................................... 19 
8.4 Demographics and baseline characteristics .......................................................... 20 
8.5 Medical history ..................................................................................................... 20 
8.6 Concomitant medications ..................................................................................... 20 
8.7 Treatment adherence............................................................................................. 20 
8.8 Efficacy analyses .................................................................................................. 21 
8.8.1 Analysis of primary efficacy endpoint ..................................................... 21 
8.8.2 Analysis of secondary efficacy endpoint .................................................. 21 
8.8.3 Analysis of exploratory endpoints ............................................................ 22 
8.8.4 Other Analysis .......................................................................................... 22 


 
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Statistical Analysis Plan 
Protocol Number: EVO-003 
Version: 2.0, Date: 24SEP2019
                                                                     Page 7 of 25 
 
8.9 Safety analyses ..................................................................................................... 23 
8.9.1 Adverse events .......................................................................................... 23 
8.9.2 Clinical laboratory evaluations ................................................................. 23 
8.10 Interim analysis .................................................................................................... 23 
9 Analysis changes from the protocol .............................................................................. 24 
10 REFERENCES .............................................................................................................. 25 
 
 


 
Statistical Analysis Plan (SAP) 
 
Statistical Analysis Plan 
Protocol Number: EVO-003 
Version: 2.0, Date: 24SEP2019
                                                                     Page 8 of 25 
 
LIST OF ABBREVIATIONS 
The following abbreviations will be used within this SAP. 
AE 
Adverse Event/Adverse Experience 
ATC 
Anatomical Therapeutic Chemical 
BP 
Blood Pressure 
BMI 
Body Mass Index 
CRF 
Case Report Form 
CI 
Confidence Intervals 
CT 
Chlamydia trachomatis 
CSR 
Clinical Study Report 
eCRF 
Electronic Case Report Form 
g 
Gram 
GC 
Neisseria gonorrhoeae 
GCP 
Good Clinical Practice 
uHCG 
(urine) Human Chorionic Gonadotropin 
HIPAA 
Health Insurance Portability and Accountability Act 
HR 
Heart Rate 
ICH 
International Conference on Harmonisation 
ITT 
Intent to Treat 
MedDRA 
Medical Dictionary for Regulatory Activities 
N 
Number (typically refers to subjects) 
PP 
Per Protocol 
SAE 
Serious Adverse Event/Serious Adverse Experience 
SMC 
Safety Monitoring Committee 
SOC 
System Organ Class 
TEAE 
Treatment Emergent Adverse Event 
TOC 
Test of Cure 
WHO 
World Health Organization 
 
 
 
 
 


 
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Statistical Analysis Plan 
Protocol Number: EVO-003 
Version: 2.0, Date: 24SEP2019
                                                                     Page 9 of 25 
 
1 
INTRODUCTION 
The purpose of this Statistical Analysis Plan (SAP) is to provide detailed descriptions of the 
statistical methods, data derivations and data displays for study protocol EVO-003 Version 6.0 
“Phase 2B/3 double-blinded placebo-controlled efficacy trial of AMPHORA® gel for the 
prevention of acquisition of urogenital Chlamydia trachomatis infection” dated 25JAN2019 for 
CSR analysis. The table of contents and templates for the TFLs will be produced in a separate 
document. 
Any deviations from this SAP will be described and justified in the Clinical Study Report (CSR). 
The preparation of this SAP has been based on International Conference on Harmonisation (ICH) 
E9. 
All data analyses and generation of TFLs will be performed using SAS version 9.4 or higher on the 
SAS Grid. 


 
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Protocol Number: EVO-003 
Version: 2.0, Date: 24SEP2019
                                                                     Page 10 of 25 
 
2 
STUDY OBJECTIVES 
2.1 
Primary objective 
To determine if intravaginal AMPHORA gel reduces the risk of urogenital Chlamydia trachomatis 
(CT) infection. 
2.2 
Secondary objective 
To determine if intravaginal AMPHORA gel reduces the risk of urogenital Neisseria gonorrhoeae 
(GC) infection. 
2.3 
Exploratory objective 
To determine if AMPHORA gel use rate (subject adherence to instructed use) has an effect on 
proportion of subjects who experience at least one CT or GC infection during the study 
intervention period. 
To assess subject satisfaction (including sexual satisfaction) with AMPHORA gel over the course 
of the clinical trial.  
 


 
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Protocol Number: EVO-003 
Version: 2.0, Date: 24SEP2019
                                                                     Page 11 of 25 
 
3 
STUDY DESIGN 
3.1 
General study design 
Eight hundred forty-four (844) women, ages 18-45, who have had a documented urogenital 
infection at any time over 16 weeks (up  to 118 days) preceding the enrollment visit, or found to be 
positive at screening visit will be enrolled.  Subjects will be tested for current GC/CT infection by 
NAAT (vaginal swab).  
A baseline vaginal pH and a full gynecologic exam (speculum) will be obtained at enrollment. 
Those who test positive for CT/GC infection at screening will receive standard of care (SOC) 
treatment.  To meet eligibility criteria, these subjects will not be enrolled until 3-4 weeks after 
screening (at least 21 days after treatment).  
Subjects are instructed to apply AMPHORA or placebo gel up to one hour prior to coitus for the 
duration of the 16-week intervention period.  AMPHORA or placebo is to be reapplied in the same 
manner for each occurrence of sexual intercourse. Subjects will keep an electronic diary (eDiary) to 
document and track sexual activity and product use and condom use.  
Every 4 weeks (5 visits) all subjects will return to the clinic for repeat CT/GC NAAT (vaginal 
swab), urine pregnancy (uHCG) testing, eDiary review, and return of used and unused study 
product. Applicators will be visually inspected for use and staining will be performed to confirm 
vaginal insertion of used (empty) applicators. At each Visit 2-4, subjects will be re-supplied with 
AMPHORA or placebo gel.  At Visit 5, subjects will return used and unused study product and 
continue to use their e-diaries but will not be resupplied with AMPHORA or placebo gel.   
Subjects will return for a follow-up visit four weeks after the intervention period.  At this time, a 
repeat CT/GC NAAT (vaginal swab), pregnancy (uHCG) testing and eDiary review will be 
performed. 
Screening and Eligibility 
Subjects who consent may be screened if they have a known case of CT or GC within 16 weeks of 
enrollment, or suspicion of current CT or GC infection (subsequently confirmed with NAAT test at 
screening visit).  Subjects randomized within 45 days of initial screening do not need to be re-
screened.    
Intervention and Follow-up Period 
The Intervention Period is defined as Visit 1 through Visit 5.  There is one follow-up visit (Visit 6), 
four weeks after the last intervention visit.  These periods are outlined in the Schedule of 
Assessments.  The protocol defined period of observation is 20 weeks.  
Safety Follow-up After Protocol Defined Period of Observation 
This period includes safety follow-up as required by Good Clinical Practice and standard clinical 
trial practice. Adverse events determined to be at least possibly related to the study product 


 
Statistical Analysis Plan (SAP) 
 
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Protocol Number: EVO-003 
Version: 2.0, Date: 24SEP2019
                                                                     Page 12 of 25 
 
continuing after the final study visit (Visit 6) will be followed until resolution or stable status as 
determined by the Investigator.  
3.2 
Randomization and blinding 
This is a Phase 2B/3 placebo-controlled randomized trial, with 422 subjects per intervention arm; 
for a total of 844 subjects to be enrolled. The 844 subjects will be randomized using an Interactive 
Web Interactive System (IWRS), in a 1:1 fashion across the two intervention groups, IP or placebo. 
Simple randomization will be stratified by site and all documentation of this procedure will be 
saved with the IWRS vendor until the end of the study. Randomization will occur following 
enrollment and prior to issuance of study product to subjects.  
On completion of the trial, after data entry is complete and the data is considered to be clean, the 
final database will be locked and the study will be fully unblinded. 
3.3 
Study treatments and assessments 
Approximately 24 weeks: Screening, five intervention period visits (one every 4 weeks) and one 
post-intervention follow-up visit (4 weeks after the last intervention period visit).  Following 
screening, enrollment and randomization, subjects will be issued a 4-week supply of study product 
based on the individual subject’s projected usage.  During the Intervention Period, subjects will 
return all unused product and used applicators packaged individually in plastic return bags 
provided, and be issued a new 4-week supply of study product based on projected usage. Subjects 
may be issued additional study product, as needed, should their supply be exhausted prior to the 
next study visit; however, excessive product usage should be brought to the attention of the 
Investigator and Sponsor. At Visit 5, subjects will return all unused product and used applicators. 
Table 1 shows the study dosing for each intervention group. 
Table 1: Investigational Product Dosing 
Intervention Group 
IP:  AMPHORA gel* 
Placebo: 
Universal Placebo Gel* 
Group A 
422 subjects, 5 g dose 
applied up to 1 hour prior 
to coitus** 
N/A 
Group B 
N/A 
422 subjects, 5 g dose applied up 
to 1 hour prior to coitus** 
*The dosage of study product is 5 g (as described for each intervention group) in a pre-filled 
vaginal applicator.  
**A detailed description of procedures and assessments to be conducted during this study is 
summarized in the Scheduled of Study Assessments in Table 2 below. 


 
Statistical Analysis Plan (SAP) 
 
Statistical Analysis Plan 
Protocol Number: EVO-003 
Version: 2.0, Date: 24SEP2019
                                                                     Page 13 of 25 
 
 
Table 2: Schedule of Study Assessments 
  
Intervention Period;  
AMPHORA gel N=422, Placebo gel N=422 
  
Study Visit (V) 
Screening(1) 
Enrollment/ 
Visit 1(2) 
Visit 2(2) 
Visit 3(2) 
Visit 4(2) 
Visit 5(2) 
Post-Intervention 
Follow-up/Visit 6 
Study Week 
-4 – 0 
(-30 – 0 days) 
0 
4 
8 
12 
16 
20 
Study Product Dispensed 
X 
X 
X 
X 
Informed Consent/HIPAA 
X 
Inclusion/Exclusion 
X 
X 
Concomitant Meds 
X 
X 
X 
X 
X 
X 
X 
AE Assessment 
X 
X 
X 
X 
X 
X 
Medical/Sexual History 
X 
X 
Last Menstrual Period 
 
X 
 
 
 
 
 
Physical Exam 
X 
Targeted Physical Exam 
[X] 
[X] 
[X] 
[X] 
[X] 
Body Weight/Height 
X 
Vital Signs 
X 
Gynecologic Exam 
X 
Urine HCG (females) 
X 
X 
X 
X 
X 
X 
Vaginal pH 
X 
Self-collected CT/GC NAAT 
X 
X 
X 
X 
X 
X 
Clinician-collected CT/GC NAAT 
 
X 
 
 
 
 
 
eDiary Set-up 
X 
eDiary Review 
X 
X 
X 
X 
X 
Inspection of Returned Study Product 
 
 
X 
X 
X 
X 
 
Staining of Used Applicators 
X 
X 
X 
X 
Subject Satisfaction With Product 
 
 
 
 
 
X 
 
Subject Sexual Satisfaction 
 
 
 
 
 
X 
 
Female Sexual Function Index (FSFI) 
 
X 
 
 
 
X 
 
Sexual Function Questionnaire 
 
X 
 
 
 
X 
 
(1) Screening period may be up to 45 days.  Subjects will be asked to return 7 days +/- 7 days after 
Screening Visit.  If subjects NAAT results are positive, they will be first treated by SOC then will 
return 3 – 4 weeks after screening visit (at least 21 days after treatment) for Enrollment/Visit 1.  If 
the screening period extends past 45 days, subjects will not be enrolled and will need to be re-
screened. 
(2) Patients must be asked to abstain from vaginal intercourse in the 24 hours preceding study visits 
2 through 5. 


 
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Protocol Number: EVO-003 
Version: 2.0, Date: 24SEP2019
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4 
STUDY ENDPOINTS 
4.1 
Primary efficacy endpoint 
The primary efficacy endpoint is the proportion of subjects who experience at least one urogenital 
CT infection during the study intervention period (incident infection of CT). 
4.2 
Secondary efficacy endpoint 
The secondary efficacy endpoint is the proportion of subjects who experience at least one 
urogenital GC infection during the study intervention period (incident infection of GC). 
4.3 
Exploratory endpoints 
Exploratory endpoints will comprise: 
• 
Adherence with AMPHORA gel usage during study (rate of product use adherence). 
• 
Sensitivity analyses of the primary and secondary parameters will be performed for the 
following: 
o mITT Subjects with ≥20%, ≥40%, ≥60%, ≥80%, and 100% product use adherence. 
o Re-infection rate analysis with alternative definition of no re-infection 
• 
Subject satisfaction 
• 
Sexual satisfaction 
 
 


 
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Statistical Analysis Plan 
Protocol Number: EVO-003 
Version: 2.0, Date: 24SEP2019
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5 
SAMPLE SIZE AND POWER 
The primary analysis is a comparison between proportion of subjects who experience at least one 
CT infection among the intervention groups (AMPHORA or placebo).   
It is assumed that the proportion of patients experiencing at least one infection of CT during the 
study period (incident infection of CT) up to week 16 under placebo will be 22.5%.  An incident 
infection of CT of 13% in the patients receiving active treatment (i.e., a treatment difference of 
9.5%) is considered clinically relevant for AMPHORA versus placebo. Using a Chi-Square Test 
for the primary endpoint, 253 analyzable patients per treatment group (506 patients total in the ITT 
population) will yield approximately 80% power to detect 9.5% treatment difference with a 2-sided 
5% type I error rate (SAS 9.3 PROC POWER). Assuming that 20% of the total enrolled patients 
will be lost to follow-up, 15% will be re-infected with GC (making them ineligible for the primary 
endpoint analysis), and 5% will be deemed ineligible for analysis due to antibiotic use, the total 
sample size planned for this study is 844 patients. 
 
 


 
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Protocol Number: EVO-003 
Version: 2.0, Date: 24SEP2019
                                                                     Page 16 of 25 
 
6 
ANALYSIS POPULATIONS 
This study will utilize three analysis populations:  Intention-to-Treat (ITT), modified Intention-to-
Treat (mITT), and safety. 
6.1 
Intention-To-Treat population (ITT) 
The ITT population is defined as all randomized subjects. Analyses with this population will be 
performed based on the treatment randomized.   
6.2 
Modified Intention-To-Treat population (mITT) 
The modified ITT population is defined as all randomized subjects who report use of study product 
(IP or UPG) and have negative GC/CT test result at enrollment. Analyses with this population will 
be performed based on the treatment randomized.   
6.3 
Safety population (Safety) 
All randomized subjects who applied any amount of study product will be included in the Safety 
population.  Analysis with this population will be performed based on the treatment actually 
received. 
6.4 
Protocol deviations/violations and exclusions from analysis sets 
A cumulative list of protocol deviations will be reported in the Clinical Study Report. 
 
 


 
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Statistical Analysis Plan 
Protocol Number: EVO-003 
Version: 2.0, Date: 24SEP2019
                                                                     Page 17 of 25 
 
7 
STATISTICAL CONSIDERATIONS AND ANALYSIS 
7.1 
Derived Variables 
The below table provides a list of derived variables for demographic and baseline characteristics. 
Variables 
Formula 
Demographic and Baseline characteristics 
Age at informed consent (in 
years) 
integer ((date of informed consent – date of birth + 1)/ 365.25) 
Body mass index (BMI) (kg/m2)   weight (kg)/[height (m)]^2 
 
7.2 
Handling of missing data and outliers 
No imputations will be performed for data that is missing or spurious. All analyses will be based on 
data as observed in the study with the exception of the following subjects that have been identified 
as attempting to enroll and/or successfully enrolling in the study multiple times: 
1) 840-034-016/840-038-008/840-032-049 
2) 840-095-013/840-097-001 
3) 840-032-007/840-034-001 
4) 840-075-001/840-038-003 
5) 840-066-020/840-004-020 
6) 840-032-048/840-034-017 
7) 840-032-047/840-038-009 
8) 840-075-002/840-034-005 
9) 840-066-079/840-004-001 
For these subjects, the following data handling rules will be applied: 
1) If the subject was ultimately randomized only once, then their efficacy and applicable 
safety data will be counted and associated with the planned and actual treatment like any 
other subject. 
2) To account for the presumed negligible impact of subjects were randomized multiple times 
the following will be done: 
a. Analyses will be run for the primary efficacy and overall AE summary table 
including all records associated with these subjects and will treat them as 
independent observations using their planned & actual treatment assignments for 
efficacy and safety, respectively. 
b. Analyses will be run for the primary efficacy and overall AE summary excluding 


 
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these subjects altogether from the analysis. 
7.3 
Analysis Eligible Subjects 
When considering subjects for inclusion in the re-infection analyses, it becomes apparent that some 
are not appropriate for consideration.  As an example, if a subject is treated with an antibiotic for an 
illness and this antibiotic also treats GC and/or CT, then it is not possible to get a true reflection as 
to the re-infection prevention abilities of the product under investigation.  Likewise, if a subject is 
found to be infected with GC and needs to be treated, the ability to later detect a CT infection is 
compromised.  As such, for subjects to be eligible for CT (or GC) re-infection analyses, we require 
the following:   
1) Known re-infection status through the end of the treatment phase (i.e., a determination of 
positive or negative re-infection can be definitively made per definitions below), 
2) No use of prohibited antibiotic medications, and 
3) No GC (or CT) re-infection, unless it is identified at the same time as the CT (or GC) re-
infection. 
 
 


 
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8 
STATISTICAL METHODS 
8.1 
General statistical conventions 
All statistical procedures will be completed using SAS version 9.4 or higher on the SAS Grid. 
Unless otherwise stated, all statistical testing will be two-sided and will be performed using a 
significance (alpha) level of 0.05. Two-sided 95% confidence intervals (CI) will be provided when 
relevant. 
For continuous variables, descriptive statistics will include the number of non-missing values, 
mean, standard deviation, median, minimum, and maximum. For categorical variables, descriptive 
statistics will include counts and percentages per category. All summaries will be presented by 
treatment group, unless otherwise specified. 
Baseline values for all parameters will be the most recent value prior to administration of study 
product or speculum exam. 
All subject data will be presented in individual subject data listings. Unless otherwise stated, 
unscheduled visit results will be included in date/time chronological order, within patient listings 
only. All listings will be sorted by investigational site, patient number, and visit. The treatment 
group (AMPHORA, Placebo) as well as patient’s age and sex (if available) will be stated on each 
listing.  With respect to study tables, the mITT population will be used for efficacy analyses; safety 
population will be used for safety analyses.  
8.2 
Subject disposition 
Subject disposition information will be summarized by treatment group and overall. The number 
and percent of subjects who are randomized, who are randomized as replacement, who complete 
the study and who withdraw early from the study will be presented. 
The primary reason for early withdrawal will also be tabulated. 
The number of subjects randomized will be used as the denominator for the percentage calculation.  
The number and percent of subjects in each analysis set and the mITT CT & GC analysis eligible 
subjects will also be tabulated. 
Subject disposition will be listed. 
8.3 
Protocol deviations 
The number of patients excluded from ITT, mITT, Safety analyses sets and reasons for exclusion 
will be summarized by treatment group and overall.  Similarly, summaries of CT & GC analysis 
eligible patients within mITT will be presented with reasons for exclusion summarized by treatment 
group and overall. 


 
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All protocol deviations identified will be summarized by treatment group and overall. 
A listing will include the inclusion/exclusion criteria violated at Screening and Enrollment Visits as 
well as other protocol deviations identified.  
8.4 
Demographics and baseline characteristics 
Continuous measures (e.g., age, race, ethnicity, height, weight, BMI, vital signs, etc.) will be 
summarized treatment group and overall using descriptive statistics (n, mean median, standard 
deviation, 25th percentile, 75th percentile, min, and max).  Meanwhile, categorical baseline 
characteristics will be summarized by treatment group and overall using frequency counts and 
percentages.   All demographic & baseline information will also be in subject-level listings. 
8.5 
Medical history 
A summary of medical/surgical/gynecologic/sexual health history will be presented by system 
organ class (SOC) and preferred term (PT) using Medical Dictionary for Regulatory Affairs® 
(MedDRA) Version 20.1 or higher. Medical history will be listed. 
8.6 
Concomitant medications 
Concomitant medications will be assessed and includes any medication that would be taken during 
the study including all over the counter medications, vitamins and nutritional supplements. 
Medications used in this study will be coded by using WHO drug dictionaries. 
Concomitant medications will be summarized descriptively using frequency tables by ATC class 
and preferred name by treatment group. Concomitant medications will be listed. 
8.7 
Treatment adherence 
Adherence with AMPHORA gel usage during study (rate of product use adherence) is defined 
using the gel applicators and e-diary data. Specifically, adherence will be determined using 2 
methods.  Method 1:  adherence = # of times product is properly used as noted in the e-diary / # of 
coital events noted during the treatment phase in the e-diary.  Method 2:  adherence = # of times 
product is used as determined by Trypan Blue staining / # of coital events during the treatment 
phase noted in the e-diary.  Summary statistics of adherence by method will be presented overall 
and by treatment group. 
Study product adherence will be calculated as: 100x[adherence ratio calculated via Method 1 (or 
2)]. The maximum percentage of doses used will be 100%. 
Study drug compliance, times of product use (determined via e-diary & dye staining), and times of 
coital event will be summarized by treatment group by the number of subjects (n), mean, std dev, 
std error, median, min, and max.  


 
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Study drug compliance will be summarized in categories “≥20%”, “≥40%”, “≥60%”,  “≥80%”, and 
“100%”  using frequency tables.  For the purposes of the frequency table, each compliance group 
will be deemed mutually exclusive (e.g., compliance rate of 41% would be in the ≥40% category 
only and would not be counted in the ≥20% category). 
Treatment compliance data will be listed. 
8.8 
Efficacy analyses 
This section addresses separately the analyses to be conducted on the primary, secondary and 
exploratory efficacy endpoints. 
 
8.8.1 Analysis of primary efficacy endpoint 
The primary objective of this trial is to demonstrate the efficacy of AMPHORA compared to 
placebo for the prevention of urogenital CT infection.  The primary efficacy endpoint is the 
proportion of subjects who experience at least one urogenital CT infection during the study 
intervention period (incident infection of CT).   
The primary statistical hypothesis being tested is that: There is no difference in the proportion of 
subjects with CT infections in the AMPHORA intervention group versus placebo.  In statistical 
terms:  
H0: p AMPHORA = pplacebo, HA: p AMPHORA ≠ pplacebo  
where p AMPHORA and pplacebo denote the proportion of subjects with CT infections during the study in 
the AMPHORA and placebo groups, respectively.   
Denominators for each proportion are the number of subjects in the mITT population in each 
intervention group’s analysis eligible subset. To test for superiority over the placebo, the incidence 
of infection of CT will be compared against placebo based on a Chi-Square test. The estimate of 
difference in proportions, 95% confidence interval and p-value will be presented. A two-sided 5% 
type I error rate (α=0.05) will be used.  Note:  for a subject to be considered re-infected with CT 
any positive NAAT test during the treatment phase (visits 1-5) will constitute re-infection.  For a 
subject to be considered not re-infected, a subject with a negative NAAT at visits 1 & 5 with no 
positive NAATs in between is deemed not re-infected. 
As a complementary analysis, tables will be created which also summarize re-infection by each 
scheduled visit.  
CT infection information will be listed.   
8.8.2 Analysis of secondary efficacy endpoint 
Similar to the primary endpoint analysis, the incidence of urogenital GC infection will be described 


 
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using frequencies and percentages with the difference between treatment groups analysed using a 
Chi-Square test.  Note:  for a subject to be considered re-infected with GC any positive NAAT test 
during the treatment phase (visits 1-5) will constitute re-infection utilized.  For a subject to be 
considered not re-infected, a subject with a negative NAAT at visits 1 & 5 with no positive NAATs 
in between is deemed not re-infected. 
As a complementary analysis, tables will be created which also summarize re-infection by each 
scheduled visit. 
GC infection information will be listed.   
8.8.3 Analysis of exploratory endpoints 
Exploratory endpoints include: 
• 
Adherence with AMPHORA gel usage during study (see section 8.7 for more details).  
• 
Sensitivity analyses of the primary and secondary endpoints will be performed for 
mITT population subjects with ≥20%,  ≥40%,  ≥60%, ≥80%, and 100% product 
use adherence (as determined via Method 1 & 2).  
• 
Re-infection rate analysis with alternative definition of no re-infection 
• 
Subject satisfaction, sexual satisfaction, Female Sexual Function Index and Sexual 
Function Questionnaire 
The proportion of subjects who experience at least one CT infection during the study intervention 
period will be summarized by treatment group using the mITT populations and subject adherence 
rates. Treatment differences between AMPHORA and placebo will be tested by using Chi-square 
test (or Fisher Exact test, if necessary).  A similar analysis will be conducted regarding GC 
infections.  For the re-infection rate analysis with alternative definition of no re-infection, the 
primary & secondary endpoints will be analyzed as before with the exception that no re-infection 
will require negative NAAT results at Visits 1, 5 and at least 1 other schedule visit (i.e., Visits 2, 3, 
or 4).  For satisfaction and sexual function questionnaires, descriptive statistics will be calculated 
for the AMPHORA group only.  Listings will be provided with details for both treatment groups. 
 
8.8.4 Other Analysis 
Condom usage rates and their effect on urogenital CT re-infection rates will be explored.  The rate 
of condom usage will be defined as # of coital acts where male condom usage is noted in the e-
diary (over the course of the treatment phase) / total # of coital acts during the treatment phase.   


 
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To assess the usage rate of condoms during the study, a summary will be presented using 
descriptive statistics for subjects displayed by treatment group.  Additionally, a summary of re-
infection rates by treatment group and condom usage (none, low, high) will be presented.  For the 
purposes of this display, low condom use will be defined as subjects that have a rate that is less 
than or equal to the 50th percentile of subjects using condoms (i.e., no condom use will not be used 
for the 50th percentile calculation). 
8.9 
Safety analyses 
All safety data will be summarized by intervention group. Safety analyses will be conducted on the 
Safety Analyses Set and will be performed for all safety variables specified below. 
No statistical tests will be performed. 
8.9.1 Adverse events 
A summary of all adverse events that were reported will be presented by Medical Dictionary for 
Regulatory Activities® (MedDRA®-version 20.1 or higher) coding (System Organ Class and 
Preferred Term) by highest severity (one report by highest severity for each subject for that adverse 
event).  
The incidence of adverse events (new or worsened) will be summarized by system organ class, 
preferred term, severity, and relationship to study intervention. The incidence of death, SAEs, and 
AEs leading to discontinuation will be summarized separately by system organ class and preferred 
term.  Lastly, a summary of AEs by system organ class and relationship to study interventions will 
be provided.  
An overall AE table will also be provided which provides a high-level of AE findings.  As a part of 
this summary, subject & event counts for genitourinary events of FDA interest will be noted. 
All adverse events will be listed. 
8.9.2 Clinical laboratory evaluations 
Specimens collected for NAATs will be processed by the sites and shipped to a central laboratory 
for testing. All other laboratory testing and staining of used applicators will be performed on-site.  
Vaginal pH, NAATs for CT/GC, staining of used applicators, and urine β-human chorionic 
gonadotropin (uHCG) will be summarized by visit for each treatment group.  Listings will be 
provided as well. 
8.10 Interim analysis 
There are no interim analyses planned.  
 


 
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9 
ANALYSIS CHANGES FROM THE PROTOCOL 
The following changes to the analysis plan have changed since the approval of the protocol: 
1) Male condom usage summary statistics. 
2) Assessing the effect of male condom usage on re-infection rates. 
3) The data handling rules associated with subjects who enrolled multiple times in the study. 
4) CT/GC re-infection rate sensitivity analysis 
5) CT/GC re-infection rate summaries by timepoint 
6) GU events summary added to the overall AE summary table 
7) The mITT population has been relaxed to allow any randomized subject who uses product, 
whether or not there is coitus, and has negative CT/GC NAATs at baseline. 


 
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10 
REFERENCES 
 
1. 
ICH Topic E3: Structure and Content of Clinical Study Reports (CPMP/ICH/137/95- 
adopted December 1995). 
2. 
ICH Topic E9: Statistical Principles for Clinical Trials (CPMP/ICH/363/96 – adopted March 
1998). 
3. 
EVO-003 Protocol Version 6.0, 25JAN2019.