A Study of the Safety and Acceptability of a Placebo Vaginal Film: FAME101
Phase: NA
Conditions: Safety of Vaginal Film Use
Sponsor: Katherine Bunge

 
   
 
A STUDY OF THE SAFETY AND ACCEPTABILITY OF A PLACEBO VAGINAL FILM: 
FAME 101 
 
DAIDS-ES # 38322 
 
 
Funding Agency: 
Division of AIDS, US National Institute of Allergy and Infectious Diseases 
US National Institutes of Health 
 
Grant Number: 1U19AI120249 
 
Protocol Chair: 
Katherine Bunge, MD MPH 
University of Pittsburgh 
Pittsburgh, PA USA 
 
 
Protocol Co-Chair 
Sharon Hillier, PhD 
University of Pittsburgh 
Pittsburgh, PA USA 
 
 
Study Site: 
Magee-Womens Hospital 
University of Pittsburgh Medical Center 
Pittsburgh, PA 
Phone:  412-641-6435 
Fax:  412-641-1133 
 
20September2017 
Version 1.0
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

FAME-101 version 1.0 20September2017 
 
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A study of the safety and acceptability of a placebo vaginal film: 
 FAME 101  
Table of Contents 
LIST OF ABBREVIATIONS AND ACRONYMS ......................................................................... 5 
PROTOCOL TEAM ROSTER .................................................................................................... 6 
PROTOCOL SUMMARY ........................................................................................................... 8 
1 
KEY ROLES .....................................................................................................................10 
1.1 
Protocol Identification ...................................................................................... 10 
1.2 
Funding ........................................................................................................... 10 
1.3 
Monitor Identification ....................................................................................... 10 
1.4 
Protocol Chair ................................................................................................. 10 
1.5 
Laboratory ....................................................................................................... 10 
2 
INTRODUCTION ...............................................................................................................12 
2.1 
HIV prevention and microbicides .................................................................... 12 
2.2 
Integrated Preclinical/Clinical Program ........................................................... 12 
2.3 
Rationale ......................................................................................................... 13 
2.4 
Safety Data: Placebo Film............................................................................... 13 
2.5 
Summary......................................................................................................... 15 
3 
OBJECTIVES ...................................................................................................................15 
3.1 
Primary Objectives .......................................................................................... 15 
3.2 
Secondary Objectives ..................................................................................... 15 
3.3 
Exploratory Objectives .................................................................................... 15 
4 
STUDY DESIGN ...............................................................................................................15 
4.1 
Identification of Study Design .......................................................................... 15 
4.2 
Summary of Major Endpoints .......................................................................... 15 
4.3 
Description of Study Population ...................................................................... 15 
4.4 
Time to Complete Accrual ............................................................................... 15 
4.5 
Study Groups .................................................................................................. 16 
4.6 
Expected Duration of Participation .................................................................. 16 
4.7 
Site .................................................................................................................. 16 
5 
STUDY POPULATION ......................................................................................................16 
5.1 
Selection of the Study Population ................................................................... 16 
5.2 
Recruitment ..................................................................................................... 16 
5.3 
Retention......................................................................................................... 16 
5.4 
Inclusion Criteria ............................................................................................. 16 
5.5 
Exclusion Criteria ............................................................................................ 17 
6 
STUDY PRODUCT ...........................................................................................................18 
6.1 
Regimen.......................................................................................................... 18 
6.2 
Administration ................................................................................................. 18 
6.3 
Study Product Formulation.............................................................................. 18 
6.4 
Study Product Supply and Accountability ....................................................... 18 
6.5 
Study Product Dispensing ............................................................................... 19 
6.6 
Concomitant Medications ................................................................................ 19 
7 
STUDY PROCEDURES ....................................................................................................19 
7.1 
Pre-Screening ................................................................................................. 19 
7.2 
Visit 1: Screening Visit .................................................................................... 19 
7.3 
Visit 2: Enrollment ........................................................................................... 20 
7.4 
Visit 3: Follow-Up Visit .................................................................................... 22 
7.5 
Visit 4: Follow-Up Visit 21 Days Post Enrollment ............................................ 23 

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7.6 
Participants Who Become Pregnant ............................................................... 23 
7.7 
Interim Visits ................................................................................................... 23 
7.8 
Clinical Evaluations and Procedures ............................................................... 24 
7.9 
Laboratory Evaluations ................................................................................... 24 
7.10 
Specimen Collection and Processing .............................................................. 25 
7.11 
Biohazard Containment .................................................................................. 25 
8 
ASSESSMENT OF SAFETY AND CLINICAL MANAGEMENT ........................................26 
8.1 
Safety Monitoring ............................................................................................ 26 
8.2 
Clinical Data Safety Review ............................................................................ 26 
8.3 
Adverse Events Definitions ............................................................................. 27 
8.4 
Expedited Adverse Event Reporting Requirements ........................................ 28 
8.4.1 Expedited Adverse Event Reporting to DAIDS .......................................................... 28 
8.4.2 Reporting of Critical Events to DAIDS ....................................................................... 29 
8.5 
Clinical Management of Adverse Events ........................................................ 29 
8.5.1 Product Hold ................................................................................................................ 29 
8.6 
Criteria for Early Termination of Study Participation ....................................... 29 
9 
STATISTICAL CONSIDERATIONS ..................................................................................30 
9.1 
Review of Study Design .................................................................................. 30 
9.2 
Sample Size and Accrual ................................................................................ 30 
9.3 
Study Endpoints .............................................................................................. 31 
9.3.1 Primary Endpoint ......................................................................................................... 31 
9.3.2 Secondary Endpoints ................................................................................................... 31 
9.4 
Blinding ........................................................................................................... 32 
9.5 
Random Assignment ....................................................................................... 32 
9.6 
Data Monitoring and Analysis ......................................................................... 32 
9.6.1 Data Monitoring ........................................................................................................... 32 
9.6.2 Primary Endpoint Analysis .......................................................................................... 32 
9.6.3 Secondary Endpoint Analysis ...................................................................................... 32 
9.6.4 Analysis Cohort ........................................................................................................... 33 
10 
HUMAN SUBJECTS CONSIDERATIONS ........................................................................34 
10.1 
Special Populations ........................................................................................ 34 
10.1.1 Men ............................................................................................................................ 34 
10.1.2 Children...................................................................................................................... 34 
10.1.3 Prisoners ..................................................................................................................... 34 
10.1.4 Pregnant women......................................................................................................... 34 
10.2 
Informed Consent Process.............................................................................. 35 
10.2.1 Risk/Benefit Statement .............................................................................................. 35 
10.3 
Incentives ........................................................................................................ 35 
10.4 
Participant Confidentiality................................................................................ 36 
10.5 
Communicable Disease Reporting .................................................................. 36 
10.6 
Study Discontinuation ..................................................................................... 36 
11 
LABORATORY SPECIMENS AND BIOHAZARD CONTAINMENT .................................36 
11.1 
Laboratory Specimens .................................................................................... 36 
11.1.1 Urine Samples ............................................................................................................ 37 
11.1.2 Vaginal Samples ........................................................................................................ 37 
11.1.3 Cervical Swabs........................................................................................................... 37 
11.1.4 Cervicovaginal Lavage Samples ................................................................................ 37 
11.2 
Quality Control and Quality Assurance Procedures ........................................ 38 
11.3 
Specimen Storage and Possible Future Research Testing ............................. 38 
11.4 
Biohazard Containment .................................................................................. 38 
12 
ADMINISTRATIVE PROCEDURES ..................................................................................38 

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12.1 
Protocol Registration ....................................................................................... 38 
12.2 
Study Coordination ......................................................................................... 39 
12.3 
Study Monitoring ............................................................................................. 39 
12.4 
Protocol Compliance ....................................................................................... 39 
12.5 
Investigator’s Records .................................................................................... 39 
12.6 
Use of Information and Publications ............................................................... 40 
12.7 
Training Procedures ........................................................................................ 40 
REFERENCES .........................................................................................................................41 
APPENDIX I:  SCHEDULE OF STUDY VISITS AND PROCEDURES ......... Error! Bookmark not 
defined. 
APPENDIX II:  HIV TESTING AGORITHIM ..............................................................................43 
APPENDIX III: SAMPLE INFORMED CONSENT .....................................................................44 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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A study of the safety and acceptability of a placebo vaginal film: 
 FAME 101 
LIST OF ABBREVIATIONS AND ACRONYMS 
 
ACHD  
 
Allegheny County Health Department 
AE 
 
 
Adverse event 
AIDS  
 
Acquired Immunodeficiency Syndrome 
BV 
 
 
Bacterial vaginosis 
CVL 
 
 
Cervicovaginal lavage 
CT 
 
 
Chlamydia trachomatis 
DAIDS  
 
Division of AIDS 
EAE 
 
 
Expedited adverse event 
GC 
 
 
Neisseria gonorrhoeae 
HEC 
 
 
Hydroxyethylcellulose 
HIV 
 
 
Human Immunodeficiency Virus 
HSV-1, HSV-2 
Herpes Simplex Virus type 1, type 2 
IRB 
 
 
Institutional Review Board 
ITT 
 
 
Intent-to-treat 
N-9 
 
 
Nonoxynol-9 
NIAID  
 
National Institute of Allergy and Infectious Disease 
NIH 
 
 
National Institutes of Health 
NRTI  
 
Nucleoside reverse transcriptase inhibitor 
PCR 
 
 
Polymerase chain reaction 
PSRT  
 
Protocol Safety Review Team 
RSC 
 
 
Regulatory Support Center 
RT 
 
 
Reverse transcriptase 
SOP 
 
 
Standard operating procedure(s) 
STI 
 
 
Sexually transmitted infection 

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A study of the safety and acceptability of a placebo vaginal film: 
 FAME 101  
 PROTOCOL TEAM ROSTER 
 
Katherine Bunge, MD MPH 
Protocol Chair 
Department of Obstetrics,  
Gynecology and Reproductive Sciences 
University of Pittsburgh School of Medicine 
300 Halket Street 
Pittsburgh, PA 15213 USA 
Phone: 412-641-6967 
Fax: 412-641-1133 
Email: kbunge@mail.magee.edu  
 
Sharon Hillier, PhD 
Protocol Co-Chair 
Department of Obstetrics,  
Gynecology and Reproductive Sciences 
University of Pittsburgh School of Medicine 
204 Craft Avenue 
Pittsburgh, PA 15213 USA 
Phone: 412-641-8933 
Fax: 412-641-6170 
Email: shillier@mail.magee.edu 
 
Lisa Rohan, PhD 
Co-investigator 
Department of Pharmaceutical Sciences 
University of Pittsburgh School of Medicine 
204 Craft Avenue 
Pittsburgh, PA 15213 
Phone: 412-641-6108 
Fax: 12-641-6170 
Email:  lrohan@mwri.magee.edu 
 
Charlene S. Dezzutti, PhD 
Co-investigator 
Department of Obstetrics,  
Gynecology and Reproductive Sciences 
University of Pittsburgh School of Medicine 
204 Craft Avenue 
Pittsburgh, PA 15213 USA 
Phone: 412-641-3462 
Fax: 412-641-6170 
Email: dezzuttics@upmc.edu 
 
 
 
 
 
 
 
Bernard Moncla, PhD  
Co-investigator 
Department of Obstetrics, Gynecology and 
Reproductive Sciences 
Magee-Womens Research Institute 
204 Craft Avenue 
Pittsburgh, PA 15213 
Phone: 412-641-6025 
Fax: 412-641-6170 
Email:  bmoncla@mwri.magee.edu 
 
Leslie Meyn, PhD 
Biostatistician/Epidemiologist 
Department of Obstetrics,  
Gynecology and Reproductive Sciences 
University of Pittsburgh School of Medicine 
204 Craft Avenue 
Pittsburgh, PA 15213 
Phone:  42-641-4233 
Fax: 412-641-1133 
Email:  lmeyn@mail.magee.edu  
 
Lara K. Mahal, PhD  
Co-investigator 
Department of Chemistry 
New York University 
100 Washington Square East  Room 1001 
New York, NY 10003 
Phone:  212-998-3533 
Fax:  212-995-4475 
Email:  lkmahal@nyu.edu 
 
Peter L. Anderson, PharmD 
Co-investigator 
Department of Pharmaceutical Sciences 
Skaggs School of Pharmacy and Pharmaceutical 
Sciences 
University of Colorado Anschutz Medical Campus 
V20-C238, Room 4101 
12850 E. Montview Blvd.  
Aurora, CO 80045 
Phone:  303-724-6128 
Fax:  303-724-6135 
Email:  Peter.Anderson@ucdenver.edu  
 
 
 
 
 

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Julie S. Downs, PhD 
Co-investigator 
Dept. of Social and Decision Sciences 
Carnegie Mellon University 
208 Porter Hall (SDS) 
Pittsburgh, PA 15213-3890 
Office:  219-C Porter Hall 
Phone:  412-268-1862 
Fax:  412-268-6938 
Email:  downs@cmu.edu 
 
NIH 
Hans M.L. Spiegel, MD 
Sr. Medical Officer, PMPRB/Prevention 
Sciences Program,  
Contractor, Kelly Government Solutions 
DAIDS, NIAID, NIH 
5601 Fishers Lane  
Room 8B51A 
Rockville, MD 20852 
Tel:  240-292-4633 
Fax: 240-627-3465 
Email: hans.spiegel@nih.gov 
 
 
 
Jim A. Turpin, PhD  
Branch Chief 
Preclinical Microbicides and Prevention Research 
Branch (PMPRB)  
NIAID/DAIDS  
Room 8B31/MSC 9831 
5601 Fishers Lane 
Rockville, MD 20852-9831 
Phone   (301) 451-2732 
Fax (240) 627-3465 
Email: jturpin@niaid.nih.gov  
 
 
Cherlynn Mathias, RN, BSN 
Program Officer/Nurse Consultant 
Prevention Science Program, NIH/DAIDS/PSP 
5601 Fishers Lane, 8B51B MSC 9831 
Rockville, MD 20852 
Phone: 240-292-4791 
Fax: 240-627-3465 
Email: cmathias@niaid.nih.gov  
 
Jeanna Piper, MD 
Sr. Medical Officer 
Clinical Microbicide Research Branch 
PSP/DAIDS/NIAID/NIH 
5601 Fishers Lane 
Room 8B68 
Rockville, MD 20852 
Tel: 240-292-4798 
E-mail: piperj@niaid.nih.gov 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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A study of the safety and acceptability of a placebo vaginal film: 
 FAME 101  
PROTOCOL SUMMARY 
 
Short Title: 
 
      FAME 101 
 
Protocol Chair: 
Katherine Bunge, MD MPH  
 
Protocol Co-chair: 
Sharon Hillier, PhD 
 
Sample Size: 
Approximately 64  
 
Study Population:  
HIV-uninfected women, 18 – 45 years old 
 
Study Sites: 
Magee-Womens Hospital of UPMC, Pittsburgh, PA 
 
 
Study Design: 
A phase I, 4 arm, single site, open label placebo trial with 
randomization to  timing of follow-up 
 
 
 
 
 
 
 
 
 
 
 
 
Study Duration: 
Accrual of approximately 64 participants is expected to take 6 months. 
The expected duration of study participation for each participant will be 
approximately 5 to 11 weeks. This includes the screening period. After 
enrollment, the study duration is 3 weeks. 
 
 Study Products: 
Vaginal Film 
 
 
 
One dose placebo vaginal film (2” x 2” size) 
 
 
 
 
  
Study Regimen: 
All participants will receive a single dose of vaginal placebo film that will 
be self-administered  
 
 
Primary Objective: 
 
• 
To assess the safety of a single dose of a placebo film which is intended for extended 
release of antiretroviral drugs. 
 
Primary Endpoint: 
 
• 
Grade 2 or higher Adverse Events 
 
 
Visit 1 
Visit 2  
Visit 3 
 
Visit 4 
  
_______________________________________________________ 
-45 days 
Day 0              Day 3,7,10 or 14* 
Day 21 
 
*Randomized to timing of Visit 3  

FAME-101 version 1.0 20September2017 
 
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Secondary Objectives: 
 
• 
Acceptability 
 
o To describe the acceptability of the placebo vaginal film and identify qualities 
associated with higher or lower degrees of acceptability 
 
Secondary Endpoint: 
 
• 
Acceptability 
 
o Self-reported assessment of qualities of the experience with the film drawn from 
existing survey on microbicidal films, and general acceptability ratings drawn from 
market research methodology 
 
 
Exploratory Objectives: 
 
 
• 
Vaginal Microenvironment 
 
o  To compare the effects of the placebo film on the vaginal microbiota and glycome 
pre and post study product use 
 
 
• 
Persistence 
 
o To describe the persistence of the film at 3,7,10 and 14 days after insertion  
 
Exploratory Endpoints: 
 
• 
Vaginal Microenvironment 
 
o Cervicovaginal lavage (CVL) 
o Levels of anti-viral activity  
o Lectin microarray 
o Levels of glycoproteins and mucins  
o Levels of cytokine and innate immunity factors 
 
o Vaginal    
o Quantitative vaginal cultures and quantitative PCR for selected microbiota 
o Nugent score 
 
 
• 
Persistence 
 
o  Eudragit ®levels in CVL 

FAME-101 version 1.0 20September2017 
 
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1 
KEY ROLES 
 
1.1 Protocol Identification 
Protocol Title: 
A study of the safety and acceptability of a placebo vaginal film: 
 
Short Title: 
FAME 101 
  
Date:  
September 20, 2017  
 
1.2 Funding 
Funding Agency: 
DAIDS/NIAID/NIH 
 
 
            5601 Fishers Lane 
                                   Rockville, MD 20892-9831 
 
 
1.3 Monitor Identification 
Monitor: 
 
Pharmaceutical Product Development (PPD), Inc.  
 
 
 
929 North Front Street  
Wilmington, NC 28401-3331 USA 
 
 
 
1.4 Protocol Chair 
Protocol Chair: 
Katherine Bunge, MD MPH 
Department of Obstetrics,  
Gynecology and Reproductive Sciences 
University of Pittsburgh School of Medicine 
300 Halket Street 
Pittsburgh, PA 15213 USA 
Phone: 412-641-6967 
Fax: 412-641-1133 
Email: kbunge@mail.magee.edu  
 
 
Protocol Co-Chair: 
Sharon L. Hillier, PhD 
 
 
 
University of Pittsburgh School of Medicine 
 
 
 
Magee-Womens Hospital 
 
 
 
300 Halket Street 
 
 
 
Pittsburgh, PA 15213 
 
 
 
Phone: 412-641-6435 
 
 
 
Fax: 412-641-1133 
 
 
 
Email:  shillier@mail.magee.edu 
  
1.5 Laboratory 
Safety Labs: 
Magee-Womens Hospital Laboratory 
 
 
300 Halket Street 
 
 
Pittsburgh, PA 15213 USA 
 

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Pharmacology: 
Anderson Laboratory 
 
 
 
12850 E. Montview Blvd.  
Aurora, CO 80045 
 
Anti-viral 
Studies: 
Dezzutti Laboratory 
 
 
204 Craft Avenue 
 
 
Pittsburgh, PA 15213 USA 
 
Microbiology 
Studies: 
Hillier Laboratory 
 
 
204 Craft Avenue 
 
 
Pittsburgh, PA 15213 USA 
 
 
Glycome 
Moncla Laboratory 
Studies: 
204 Craft Avenue 
 
 
Pittsburgh, PA 15213 USA 
 
 
 
                                     Mahal Laboratory 
                                     100 Washington Square East Room 1001 
                                     New York, New York 10003 USA 
 

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2 
INTRODUCTION 
 
2.1 HIV prevention and microbicides 
Since 1981, HIV has directly or indirectly resulted in the deaths of 25 million people1. Each year 
millions of people worldwide are newly infected with HIV, most recently 2.7 million people in 
20082. Sexual transmission accounts for the majority of new HIV infections worldwide. While 
most cases of sexual transmission involve both a male partner and a female partner, women 
are disproportionately impacted by the sexual transmission of HIV 2. This disproportionate 
impact arises from a combination of biologic, social, and economic factors 2.   Women at risk 
face formidable challenges in protecting themselves from HIV infection, including power 
differentials, gender norms, and economic dependence.  
 
 
Topical microbicides are agents designed to prevent or at least substantially reduce the 
acquisition and transmission of HIV when applied to the genital or gastrointestinal mucosa. In 
addition to preventing HIV infection, topical microbicides may satisfy two critical needs: 
affordability and female control. Topical microbicides also have the potential for high 
acceptability for both male and female partners. Acceptability and utility of topical microbicides 
can be maximized by the development of an array of dosing formulations. For all dosing 
formulations, safety, stability, and efficacy must be established. 
 
Vaginal films are an attractive dosing option for several reasons. In terms of manufacturing, 
films are inexpensive, scalable, physically and chemically stable, uniform with regards to 
product content, and amenable to combinations of active ingredients. In terms of use, films are 
discreet, portable, and easy to store. Vaginal films can deliver fixed doses of microbicidal agents 
with minimal mess and without an applicator. The small volume of vaginal films may also result 
in less dilution of endogenous antiviral or antibacterial properties of vaginal fluids compared to 
vaginal gels. In studies of spermicidal film, women have found vaginal films to be acceptable3-5. 
When Vaginal Contraceptive Film (VCF) was compared to foaming tablets containing 
nonoxynol-9 (N-9), contraceptive film was preferred in three different countries 3. Ninety-seven 
percent of 59 Mexican women, 60 percent of 52 Dominican women, and 86 percent of 51 
Kenyan women reported liking contraceptive film.  In particular, they cited the following 
favorable characteristics: ease of use, general feel or comfort, additional lubrication, and lack of 
side effects 3. Over eighty percent of Cameroonian sex workers, who participated in a large 
randomized placebo-controlled trial of N-9 film, reported that they would use the film were it 
found to be effective against HIV4. In Zambian focus groups, placebo vaginal film was preferred 
over placebo vaginal tablets and soft-gel capsules after each product was used once daily for 
one week 6. In a study evaluating the acceptability of placebo microbicidal film, soft gel capsule 
and tablet, African women were instructed to use each of the three products once daily for 7 
consecutive days. The film and soft-gel capsule were chosen significantly more often than the 
tablet as the preferred dosage form (39%, 37% and 25%, respectively). In this particular study, 
film and soft gel were preferred because of faster dissolving time and easier insertion.7 In other 
studies, participants found vaginal films to be neater than foaming tablets and gel3,8.   
 
 
2.2 Integrated Preclinical/Clinical Program  
 
The Film Antiretroviral Microbicide Evaluation (FAME) program brings together an inter-
disciplinary group of research scientists from four academic institutions: University of Pittsburgh, 
University of Washington, Carnegie Mellon University, New York University and the University of 
Colorado The long term goal of the program is to develop and evaluate an extended delivery 
vaginal film containing an integrase inhibitor which could provide protection from HIV for one 
week or more following a single application. The first iteration of the FAME IPCP established 
proof of concept that vaginal films containing the antiretrovirals (ARVs) dapivirine and tenofovir 
can deliver drug to target tissues as effectively as gel formulations of those same ARVs. The 

FAME-101 version 1.0 20September2017 
 
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second iteration, of which this is the first clinical trial, strives to develop an extended release 
formulation of an integrase inhibitor MK-2048 which will provide coverage for 7 days after each 
use.  
 
2.3 Rationale   
This is a phase I randomized trial assessing the safety of a single vaginal placebo film 
application.  In order to develop a vaginal film which can provide extended release of an ARV, 
the film polymers and formulation have been altered from the cellulose and polyvinyl alcohol 
films used to deliver dapivirine and tenofovir in previous trials. Therefore, the proposed study 
will evaluate the safety and persistence of these film polymers when applied vaginally.    
 
HIV-negative women will be randomized to the timing of the follow up visit prior to administration 
of the placebo vaginal film and. Women will be randomized to return for a clinical evaluation 
either three days, seven days, ten days, or fourteen days after study product insertion. In 
addition to safety, the acceptability of this vaginal film intended for extended release of ARVs 
will be assessed, as will its impact on the vaginal microenvironment.   Cervicovaginal lavage 
and vaginal fluid (as sampled by absorptive material, such as sponge or wick) will be used to 
assess the impact of the film on the on the vaginal microbiota and glycome. The film’s impact on 
cellular immunity and inflammation will also be assessed, and the CVL samples will be 
assessed for changes to the innate anti-HIV activity. 
 
 
The film is intended to provide HIV protection for a week after a single application. 
Understanding how long the film remains in the vagina will be an integral part of this study. Dr. 
Anderson’s lab has developed an assay to detect the polymer Eudragit® in cervical vaginal 
fluid. Genital samples from Visit 1,  Visit 3 and Visit 4 will be evaluated for the presence of 
Eudragit.®.  Eudragit was chosen over the other polymers because of technical feasibility for the 
assay. The other polymers in the film are cellulose based, and it would be very difficult to 
differentiate between the polymers in a biologic sample. Eudragit, on the other hand has a 
unique structure. Of note, all of the visible film will be removed with the CVL performed at Visit 
3; therefore, no Eudragit® should be detectable at Visit 4. 
   
This study has been designed to add to our knowledge about film application challenges. 
Product misplacement was noted in the three clinical trials of vaginal film previously conducted 
at the University of Pittsburgh. While most participants could successfully insert the vaginal 
films, incorrect film placement was noted for some. In some instances, the vaginal film stuck to 
the finger after attempted insertion and in other instances the film was visualized on the external 
genitalia. Because the primary objective of this study is to assess safety and persistence, 
administration error will be noted immediately after the participant attempts to insert the film. If 
most the film is noted to be external to the vaginal introitus, the film will be removed by the 
clinician and a new vaginal film will be placed inside the vagina by the clinician. This will ensure 
the integrity of the primary objective. 
  
2.4 Safety Data: Placebo Film 
The placebo film consists of ingredients with a proven safety record.  Table 1 outlines 
documented usage with film excipients per the FDA database for inactive ingredients in 
approved drug products. 
 

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Table 1: Placebo Film Excipients 
 
Excipient 
Use 
Concentration* 
History of Vaginal Use 
Hydroxypropyl 
methyl cellulose 
(HPMC) or 
Hypromellose**, 
USP 
Film Forming Polymer 
Vaginal; gel 3.5% 
Vaginal; tablet  5 mg 
Rectal; gel 4.35% 
(listed as 
hypromelloses**) 
ESTRACE® Cream and 
VAGIFEM® vaginal tablets, 
tenofovir and dapvirine 
vaginal films 
Propylene glycol 
(PG), USP 
Plasticizer/Dispersant 
Vaginal; emulsion, 
cream 20% 
Vaginal; gel 3% 
Vaginal; suppository 
252 mg 
VCF dissolving vaginal 
lubricant film (5%)35 
Hydroxyethyl 
cellulose, NF  
Film Forming Polymer 
Buccal ; film 54.92 mg 
Oral; tablet, extended 
release 400mg 
Topical; gel 1.75%w/w 
Tenofovir vaginal film, 
tenofovir and dapvirine 
vaginal gels 
Polyethylene glycol 
400, NF 
Plasticizer/Dispersant 
Rectal; suppository 
24.8% 
Topical; cream 1.5%w/w 
Topical; cream, 
emulsion, sustained 
release 7.5%w/w 
Vaginal suppository 
Ammonio 
Methacrylate 
Copolymer Type B 
(Eudragit®), NF 
Extended Release 
Polymer  
Oral; capsule, extended 
release 35.7mg 
Oral;tablet, extended 
release 11.05mg 
Tablet, film coated 8mg 
* 
Hydroxypropyl 
cellulose, NF 
Film Forming Polymer 
Buccal; film 100.04mg 
Topical; patch 
Transdermal; film 
controlled release 19mg 
Oral; tablet 
(immed./comp. 
Release), film coated 
24mg 
* 
  
*Although there is not a history of vaginal use, these excipients have been used extensively in other pharmaceutical 
products such as buccal films, oral tablets, and in transdermal and topical films and patches.  
 
Safety evaluation of the extended release placebo film was performed in a nonhuman primate 
model.  Six pigtailed macaques were exposed to two films per week for two weeks, which is 
double the proposed human dosing (intended dosing is one film per week). In total, four films 
were delivered to each macaque over fourteen days. The vaginal microbiota, vaginal pH, and 
number of PMNs on gram stained vaginal smears were assessed before the first film placement 
and after the fourth film placement.  The integrity of the cervicovaginal tissues was assessed by 
colposcopy at each film placement. Of note, there was visible film in the vagina with each film 
placement. No adverse events were noted by colposcopy; microbiota remained stable with no 
effect noted on the beneficial H202 producing microorganisms; vaginal pH remained within 
normal range; and PMN counts remained within the normal range even after more frequent 
administration than intended for use (Patton, personal communication). The entire study report 
is presented in Appendix IV. 
 
Though the films used had different excipients, the tenofovir and dapivirine vaginal films used in 
FAME-02 and FAME-04 were found to be safe with no Grade 3 or higher Adverse Events 
attributed to study product and no changes in the vaginal microenvironment noted. The 
macaque exposure model utilized for this protocol provided the initial assurances of safety for 
those studies as well. 

FAME-101 version 1.0 20September2017 
 
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2.5 Summary 
It is appropriate to advance this placebo film into a clinical trial for safety for the following 
reasons: 
• 
The individual ingredients used in the film have a history of safe use in mucosal 
compartments (gastrointestinal and/or vaginal). 
• 
The same film was found to be safe in macaques without evidence of epithelial 
disruption despite twice weekly dosing, twice the frequency of intended human use.   
  
3 
OBJECTIVES 
 
3.1 Primary Objectives 
 
o To assess the safety of a single dose of a placebo film which is intended for 
extended release of antiretroviral drugs 
 
3.2 Secondary Objectives 
 
• 
Acceptability 
 
To describe the acceptability of the placebo vaginal film and how different qualities 
are associated with higher or lower degrees of acceptability  
 
3.3 Exploratory Objectives 
 
• 
Vaginal Microenvironment 
 
o To compare the effects of the placebo film on the vaginal microbiota and glycome 
pre and post study product use.  
 
• 
Persistence 
 
o To describe the persistence of the placebo vaginal film at 3, 7, 10 and 14 days after 
insertion 
4 
STUDY DESIGN 
 
4.1 Identification of Study Design 
This is, single site, open label placebo trial with randomized timing of follow-up  
 
4.2 Summary of Major Endpoints 
Grade 2 or higher Adverse Events deemed related to study product 
 
4.3 Description of Study Population 
The study population will be HIV-uninfected women who meet criteria outlined in Section 5. 
 
4.4 Time to Complete Accrual 
Accrual is expected to be completed in approximately 6 months. 
 

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4.5 Study Groups 
All participants will receive a single dose of the vaginal film. They will be randomized at 
enrollment to the timing of Visit 3. In total, there will be four groups: 
 
• 
Visit 3 at Day 3 (range days 2-4) 
• 
Visit 3 at Day 7 (range days 6-8) 
• 
Visit 3 at Day 10 (range days 9-11) 
• 
Visit 3 at Day 14 (range days12-16)  
 
4.6 Expected Duration of Participation 
The duration of study participation per woman is expected to be approximately 5-11 weeks. This 
includes the screening period. 
 
4.7 Site 
There is a single study site: Magee-Womens Hospital, Pittsburgh, PA.   
 
 
5 
STUDY POPULATION 
 
5.1 Selection of the Study Population 
The inclusion and exclusion criteria in this section will be utilized to ensure the appropriate 
selection of study participants.  
 
5.2 Recruitment 
Participants will be recruited from a variety of sources including the ambulatory clinic of Magee-
Womens Hospital and the surrounding population. Participants will also be referred to the study 
from other local research projects and other health and social service providers serving the 
target study population.  Recruitment materials will be approved by the University of Pittsburgh 
Institutional Review Board. 
 
5.3 Retention 
Once a participant is enrolled, the study site will make every effort to retain her in follow-up to 
minimize possible bias associated with loss-to-follow-up. The site will implement the following 
procedures to enhance retention:    
 
• 
Thorough explanation of the study visit schedule and procedural requirements during the 
informed consent process and re-emphasis at each study visit.      
• 
Thorough explanation of the importance of all 4 study groups to the overall success of the 
study. 
• 
Collection of detailed locator information at the study screening visits, and active review and 
updating of this information at each subsequent visit. 
• 
Use of appropriate and timely visit reminder mechanisms. 
• 
Immediate follow-up on missed visits. 
 
Study sites will use a participant tracking mechanism to facilitate visit scheduling and timely 
identification and follow-up on missed visits.   
 
5.4 Inclusion Criteria 
Women must meet all the following criteria to be eligible for inclusion in the study: 
 
1) Age 18 through 45 years (inclusive) at screening 
 
2) Able and willing to provide written informed consent to be screened for and to take part in 
the study. 

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3) Able and willing to provide adequate locator information  
 
4) HIV-uninfected based on testing performed by study staff at screening (per algorithm in 
Appendix II) 
 
5) In general good health as determined by the site clinician 
 
6) Agree to be sexually abstinent for 48 hours prior to each visit and from Visit 2 to seven 
days after Visit 3   
 
7) At screening, agrees to abstain from any other intravaginal product or penetration 
(including sex toys, excluding tampons) for 48 hours prior to each visit and between Visit 2 
and 3. 
 
8)  Willingness to undergo all study-related assessments and follow all study-related 
procedures 
 
9) At screening and enrollment, agrees not to participate in other research studies involving 
drugs, medical devices, or vaginal products while enrolled in this trial 
 
5.5 Exclusion Criteria 
Women who meet any of the following criteria by participant report will be excluded from the 
study. Of note, the study is limited to premenopausal women with an intact uterus because the 
mucosal immune environment differs substantially between pre- and post- menopausal women. 
Therefore, inclusion of post-menopausal women would introduce heterogeneity into the 
population. 
 
1.) Menopause (as defined as amenorrhea for one year or more without an alternative 
etiology) 
 
2.) Hysterectomy 
 
3.) Participant report of any of the following: 
a) Known adverse reaction to any of the study products (ever) 
b) Known adverse reaction to latex (ever) 
c) Non- therapeutic injection drug use in the 12 months prior to Screening 
d) Surgical procedure involving the pelvis in the 90 days prior to enrollment (includes 
dilation and curettage or evacuation, and cryosurgery; does not include cervical 
biopsy for evaluation of an abnormal pap smear)   
e) Participation in a drug, spermicide and/or microbicide study in the 30 days prior to 
enrollment or anticipated participation in an investigational drug study until 
completion of the study 
f) Currently pregnant or pregnancy within 42 days prior to enrollment  
g) Currently lactating 
h) Use of a diaphragm, NuvaRing®, or spermicide for contraception 
i) Internal vaginal use of any device or product (except tampons) in the 48 hours prior 
to enrollment  
 
4.) Urogenital infection or suspected infection within 14 days of enrollment including: 
symptomatic candidiasis, trichomonas vaginalis, and symptomatic bacterial vaginosis; or 
cervical infection, including N. gonorrhoeae (GC), C. trachomatis (CT), or mucopurulent 
cervicitis; syphilis; HSV lesions, or other sores (Note: seropositive HSV without active 
lesions will not be excluded); acute pelvic inflammatory disease; urinary tract infection; 
recent exposure to a partner with GC, CT, Trichomonas, syphilis, or NGU 

FAME-101 version 1.0 20September2017 
 
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5.) Antibiotic or antifungal therapy (vaginal or systemic) within 14 days of enrollment 
 
6.) As determined by the PI, has any significant uncontrolled active or chronic cardiovascular, 
renal, liver, hematologic, neurologic, gastrointestinal, psychiatric, endocrine, respiratory, 
immunologic disorder or infectious disease 
 
7.) Menses-like bleeding at the time of the Enrollment visit* or expected menses-like bleeding 
within 14 days of the Enrollment visit 
(*Women who have vaginal bleeding at the scheduled Enrollment Visit may return at a 
different date to be re-examined and possibly enrolled provided they are still within the 
screening window and meet all criteria.) 
 
8.) Any condition that, in the opinion of the Investigator, would preclude provision of consent, 
make participation in the study unsafe, complicate interpretation of study outcome data, or 
otherwise interfere with achieving the study objectives 
 
6 
STUDY PRODUCT 
 
6.1 Regimen 
Each participant will receive one vaginal film. 
 
6.2 Administration 
After eligibility is confirmed, site staff will randomize the participant to the timing of Visit 3 and 
retrieve the study product from the Pharmacy. Participants will be counselled thoroughly on 
product administration and then handed the film in its packaging. The participant will attempt to 
insert the film while a site staff member stands behind a curtain to maintain privacy. Should the 
participant have any concerns or questions, the site staff member will be readily available.  
Immediately after the participant attempts insertion, the site clinician will do a quick inspection of 
the external genitalia to assess for proper placement. If the film is visible outside of the vaginal 
introitus, the clinician will return to the pharmacy to retrieve a second dose of the vaginal film. 
The clinician will then remove visible film, insert a speculum, remove visible film from inside the 
vagina, and place a second film in the proximal third of the vagina using a forceps instrument.  
 
6.3 Study Product Formulation   
A two inch by two inch (2” x 2”) film containing no active pharmaceutical ingredient will be used. 
This placebo film is a cellulose based film containing hydroxypropyl methyl cellulose (HPMC) 
(E5 and K4M), hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), Eudragit® 
(Ammonio Methacrylate Copolymer Type B), propylene glycol and polyethylene glycol 400.  
Placebo films will be manufactured by CMO under cGMP using hot melt extrusion and clinical 
trial material will be subjected to GMP stability program by the contract manufacturer. 
 
6.4 Study Product Supply and Accountability 
Packaged study product is being provided to the Magee-Womens Hospital Pharmacy.  All study 
product will be available to the study staff through the Magee Pharmacy. 
 
The Magee research pharmacist will maintain complete records of all study products received 
for this protocol and dispensed to participants.  Additional documentation will be required for 
study product returns, destruction (if applicable) and other related issues as outlined in 
instructions for DAIDS clinical trials. All unused study products must be returned to the 
Pharmacy.   
 

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The film is packaged into a foil-lined pouch and stored at room temperature. Product has R&D 
stability for 6 months. 
 
6.5 Study Product Dispensing  
Study products will be dispensed only to enrolled participants upon receipt of a written 
prescription signed by an authorized prescriber.   
 
6.6 Concomitant Medications  
Enrolled study participants may use concomitant medications during study participation.  All 
concomitant medications, over-the-counter preparations, vitamins and nutritional supplements, 
recreational drugs, and herbal preparations will be recorded on the concomitant medications log 
form.  
 
All participants will be counseled to avoid the use of spermicide and other non-study vaginal 
products (other than tampons during menstruation and female condoms) while participating in 
the study.  Participants who report use of these products will be counseled regarding the use of 
alternative methods, but reported use of these products does not require any change in study 
product administration or follow-up procedures.  Condoms provided by study staff will not be 
coated with any type of spermicide.   
 
7 
STUDY PROCEDURES 
This section describes visit-specific study procedures.     
 
7.1 Pre-Screening  
As part of participant outreach and recruitment strategies, study staff may pre-screen potential 
study participants (e.g. via telephone). During these interactions, study staff may explain the 
study to participants and ascertain elements of presumptive eligibility, to be confirmed at an on-
site screening visit. If the participant is eligible based on a screening script her name and 
appointment time will be placed on the script.  If she signs consent, the telephone script will then 
become part of her research record. If she does not sign consent, the form will be de-identified. 
 
7.2 Visit 1: Screening Visit 
Screening may take place up to 45 days prior to Enrollment.  Screening procedures may occur 
over several visits. A combined written informed consent for screening and enrollment will be 
obtained before any screening procedures are initiated.  For participants who do not meet the 
eligibility criteria, screening will be discontinued once ineligibility is determined. 
 
The table below outlines procedure to take place at the Screening Visit.  

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   Table 2:  Visit 1 Procedures 
VISIT 1:  SCREENING VISIT 
Component 
Procedure/Analysis 
 
 
 
 
 
 
 
ADMINISTRATIVE 
• 
Written Informed Consent 
• 
Assign Study Number (PTID) 
• 
Review Eligibility 
• 
Collect Contact Information 
• 
Visit Questionnaire 
• 
HIV Pre-/Post-Test Counseling 
• 
Screening Results 
• 
Abstinence/Condom Counseling (& distribution prn) 
• 
Schedule Next Study Visit, prn 
• 
Participant Reimbursement 
 
URINE 
• 
Pregnancy test 
• 
Urine dipstick, as clinically indicated 
SALIVA 
• 
Rapid HIV 
BLOOD 
• 
Confirmatory HIV, as clinically indicated 
 
VAGINAL 
• 
pH 
• 
Wet Mount, as clinically indicated 
• 
Trichomonas (NAAT) 
• 
Future Use 
 
CERVICAL 
• 
GC/CT (NAAT) 
• 
Future Use 
 
 
CVL 
• 
Levels of antiviral activity 
• 
Lectin microarray 
• 
Levels of glycoproteins and mucins 
• 
Levels of cytokines & innate immunity factors 
• 
Eudragit® level 
 
 
PHYSICAL EXAM 
 
• 
Physical Exam 
• 
Vital Signs (BP) 
• 
Height & Weight 
 
PELVIC EXAM 
• 
Bimanual Exam, as clinically indicated 
• 
External Genital & Speculum Exam 
       
7.3  Visit 2: Enrollment 
Subjects who meet the inclusion and exclusion criteria following the Screening Visit may 
schedule an Enrollment Visit.  Care will be taken to schedule the Enrollment visit at a time when 
the participant is not expecting to be actively bleeding or anticipating her menses within 14 
days.  
 
Before performing any enrollment procedures, study staff will confirm eligibility.  The participant 
will undergo a pelvic examination. Pelvic specimens as described below will be collected and 
the study staff will assess for bleeding.  If no bleeding or other exclusionary findings are evident, 
the participant will then be randomized to the timing of Visit 3. The act of randomization is 
considered the act of enrollment for this study. Subjects with menses like vaginal bleeding at the 
Enrollment visit will not be randomized/enrolled at that time.  These subjects may be 
rescheduled if vaginal bleeding resolves before 45 days from Screening have elapsed. If vaginal 

FAME-101 version 1.0 20September2017 
 
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bleeding does not resolve during the window period, and the subject expresses interest in 
enrollment for the study, she may be offered a rescreening attempt.   
 
After eligibility is confirmed, the clinician will go to the Pharmacy to obtain the study product. 
Participants will be counselled thoroughly on product administration and then handed the film in 
its packaging. The participant will attempt to insert the film while a site staff member stands 
behind a curtain to maintain privacy. Should the participant have any concerns or questions, the 
site staff member will be readily available.  Immediately after the participant attempts insertion, 
the site clinician will do a quick inspection of the external genitalia to assess for proper 
placement. If the majority of the film is visible outside of the vaginal introitus, the clinician will 
return to the pharmacy to retrieve a second dose of the vaginal film. The clinician will then 
remove visible film, insert a speculum, remove visible film from inside the vagina, and place a 
second film in the proximal third of the vagina using a forceps instrument. After film placement, 
participants will be scheduled for Visit 3. When Visit 3 occurs will be determined by 
randomization (3, 7, 10 or 14 days).    
 
   Table 3:  Visit 2 Procedures 
VISIT 2:  ENROLLMENT – DAY 0 (Day 1 of Product Use) 
Component 
Procedure/Analysis 
 
 
 
ADMINISTRATIVE 
• 
Review/Confirm Eligibility 
• 
Collect/Update Contact Information 
• 
Visit Questionnaire 
• 
Screening Results 
• 
Abstinence/Condom Counseling (& distribution prn) 
• 
Assess/Document Adverse Events 
• 
Schedule Next Study Visit 
• 
Participant Reimbursement 
ACCEPTABILITY 
• 
Acceptability Questionnaire 
 
URINE 
• 
Pregnancy test 
• 
Urine dipstick, as clinically indicated 
 
 
VAGINAL 
• 
pH 
• 
Wet Mount, as clinically indicated 
• 
Gram Stain 
• 
Quantitative Vaginal Culture 
• 
Quantitative PCR for microbiota 
• 
Future Use 
 
CERVICAL 
• 
Future Use 
 
 
PHYSICAL EXAM 
 
• 
Physical Exam, as clinically indicated 
• 
Vital Signs (BP) 
 
PELVIC EXAM 
• 
Bimanual Exam, as clinically indicated 
• 
External Genital & Speculum Exam 
• 
Post-insertion External Genital Exam 
• 
Repeat Speculum Exam, prn 
RANDOMIZATION 
• 
Randomization to timing of V3 
 
 
STUDY PRODUCT 
• 
Study Product Distribution 
• 
Participant Self-Inserted (1st attempt) 
• 
Clinician-inserted (2nd attempt), prn 
 

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7.4 Visit 3: Follow-Up Visit 
The timing of Visit 3 will be determined through the randomization process. All participants will 
be randomized to return either 3,7,10, or 14 days after film insertion. Visit 3 procedures are 
outlined in Table 4.  The windows around these study visits are as follows:  
Day 3 (days 2-4) 
Day 7 (days 6-8) 
Day 10 (days 9-11) 
Day 14 (days 12-16)  
 
   Table 4:  Visit 3 Procedures 
VISIT 3:  FOLLOW-UP VISIT – 3, 7, 10, 14 DAYS POST FILM INSERTION 
Component 
Procedure/Analysis 
 
 
ADMINISTRATIVE 
• 
Collect/Update Contact Information 
• 
Visit Questionnaire 
• 
Abstinence/Condom Counseling (& distribution prn) 
• 
Assess/Document Adverse Events 
• 
Schedule Next Study Visit 
• 
Participant Reimbursement 
ACCEPTABILITY 
• 
Acceptability Questionnaire 
 
URINE 
• 
Pregnancy test 
• 
Urine dipstick, as clinically indicated 
 
 
VAGINAL 
• 
pH 
• 
Wet Mount, prn 
• 
Trichomonas (NAAT), as clinically indicated 
• 
Gram Stain 
• 
Quantitative Vaginal Culture 
• 
Quantitative PCR for microbiota 
• 
Future Use 
 
CERVICAL 
• 
GC/CT (NAAT), as clinically indicated 
• 
Future Use 
 
 
CVL 
• 
Levels of antiviral activity 
• 
Lectin microarray 
• 
Levels of glycoproteins and mucins 
• 
Levels of cytokines & innate immunity factors 
• 
Eudragit® level 
 
 
PHYSICAL EXAM 
 
• 
Physical Exam, as clinically indicated 
• 
Vital Signs (BP) 
 
PELVIC EXAM 
• 
Bimanual Exam, as clinically indicated 
• 
External Genital & Speculum Exam 
 
 
 
 
 
 
 
 
 
 

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7.5 Visit 4: Follow-Up Visit 21 Days Post Enrollment 
The final scheduled visit will be 21 (18-25) days after the Enrollment Visit. 
 
   TABLE 5:  Visit 4 Procedures 
VISIT 4:  FOLLOW-UP VISIT 
Component 
Procedure/Analysis 
 
 
ADMINISTRATIVE 
• 
Collect/Update Contact Information 
• 
Visit Questionnaire 
• 
Abstinence/Condom Counseling (& distribution prn) 
• 
Assess/Document Adverse Events 
• 
Participant Reimbursement 
ACCEPTABILITY 
• 
Acceptability Questionnaire 
 
URINE 
• 
Pregnancy test 
• 
Urine dipstick, as clinically indicated  
 
 
 
VAGINAL 
• 
pH 
• 
Wet Mount, as clinically indicated 
• 
Trichomonas (NAAT), as clinically indicated 
• 
Gram Stain 
• 
Quantitative Vaginal Culture 
• 
Quantitative PCR for microbiota 
• 
Future Use 
 
CERVICAL 
• 
GC/CT (NAAT), as clinically indicated 
• 
Future Use 
 
 
CVL 
• 
Levels of antiviral activity 
• 
Lectin microarray 
• 
Levels of glycoproteins and mucins 
• 
Levels of cytokines & innate immunity factors 
• 
Eudragit® level 
 
 
PHYSICAL EXAM 
 
• 
Physical Exam, as clinically indicated 
• 
Vital Signs (BP) 
 
PELVIC EXAM 
• 
Bimanual Exam, as clinically indicated 
• 
External Genital & Speculum Exam 
 
7.6 Participants Who Become Pregnant 
Urine pregnancy tests will be performed at screening, enrollment, Visit 3, the last study visit, and 
as clinically indicated. Participants who become pregnant will be referred for care. Should the 
pregnancy be diagnosed during study follow-up, pelvic exams will only be performed to evaluate 
a participant's reported symptom. No genital specimens will be collected in a pregnant 
participant. 
 
Of note, the participant will be encouraged to continue in the study so that safety data might be 
collected. Participants who are pregnant at the final study visit will be contacted after their study 
participation to ascertain the pregnancy outcome. 
 
7.7 Interim Visits 
Interim visits may be performed at any time during the study (and study procedures repeated as 
clinically indicated), for the following or other reasons: 
 
• 
For administrative reasons, e.g., a participant may have questions for study staff, or may 
need to re-schedule a follow-up visit. 

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• 
In response to AEs.  When interim contacts or visits are completed in response to 
participant reports of AEs, study staff will assess the reported event clinically and 
provide or refer the participant to appropriate medical care.   
• 
In the event of laboratory processing issues (i.e. inconclusive STD testing, lost or 
inadequate sample 
• 
For other reasons at participant request. 
 
 Details of the interim visit will be recorded in the chart notes. 
 
7.8 Clinical Evaluations and Procedures 
Physical exams will include the following assessments:   
 
• 
Vital signs: 
o Blood pressure 
 
• 
Measurements of: 
o Weight (at Screening only) 
o Height (at Screening only) 
  
• 
Focused physical exam (at Screening only): 
o General appearance 
o Cardiac exam   
o Respiratory exam   
o Abdomen  
 
Additional assessments may be performed at the discretion of the examining clinician in 
response to symptoms or illnesses present at the time of the exam. 
 
7.9    Laboratory Evaluations 
 
Clinical Local Laboratory 
Urine pregnancy test  
Rapid saliva HIV test  
Wet mount if clinically indicated 
Vaginal pH 
Dipstick urinalysis 
Confirmatory HIV testing if indicated 
 
MWRI Laboratories 
 
Cervical NAAT for chlamydia, gonorrhea 
Vaginal NAAT for trichomonas 
Vaginal Gram stain  
Quantitative vaginal cultures 
Quantitative PCR for selected microbiota 
Levels of cytokines and innate immunity factors from CVL 
Anti-viral activity from CVL 
 
New York University Laboratory (Mahal) and/or MWRI Laboratory 
Levels of glycoproteins and mucin in CVL 
Lectin microarray in CVL 
 
 
University of Colorado Lab 

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Eudragit® levels in CVL and vaginal fluid   
 
7.10 Specimen Collection and Processing 
The site will adhere to the standards of good clinical laboratory practice and site standard 
operating procedures for proper collection, processing, labeling, handling, transport, and 
storage of specimens.  In cases where laboratory results are not available due to administrative 
or laboratory error, sites are permitted to re-draw and/or re-collect specimens. 
 
7.11 Biohazard Containment 
As the transmission of HIV and other blood-borne pathogens can occur through contact with 
contaminated needles, blood, and blood products, appropriate blood and secretion precautions 
will be employed by all personnel in the drawing of blood and shipping and handling of all 
specimens for this study as recommended by the CDC and NIH.  All biological specimens sent 
to the University of Colorado lab will be transported using packaging mandated by CFR 42 Part 
72.  Biohazardous waste will be contained according to institutional, transportation/carrier, and 
all other applicable regulations.   
 

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8 
ASSESSMENT OF SAFETY AND CLINICAL MANAGEMENT 
 
8.1 Safety Monitoring 
The study site investigators are responsible for continuous close safety monitoring of all study 
participants, and for alerting the Protocol Team if unexpected concerns arise. A sub-group of 
the Protocol Team, including the Protocol Chair or designee, the DAIDS Medical Officer, and 
the External Safety Monitor will serve as the Protocol Safety Review Team (PSRT). Close 
cooperation among the PSRT and the study site will be necessary to monitor participant safety 
and respond to occurrences of toxicity in a timely manner. Appropriate safety monitoring will be 
contingent upon excellent communication between study participants and study staff, and upon 
cooperation among study staff, investigators, the External Safety Monitor, and the DAIDS 
Medical Officer.  
 
8.2 Clinical Data Safety Review 
An External Safety Monitor who is familiar with the pertinent scientific literature related to the 
study product will be responsible for the first review of data and safety monitoring.  This 
physician, independent of the study sponsor, will be available to monitor data from this site.  
His/her minimum qualifications will include experience as a physician and experience in the 
conduct of clinical research. This individual will not receive salary or other support from the 
grant. The External (Independent) Safety Monitor model has been used successfully for other 
Magee-Womens Hospital Reproductive Infectious Disease studies involving investigational 
products. The proposed individual will meet the qualifications outlined above and have training 
in the importance of the objective treatment of clinical safety data.   
 
The Data Management team for this site will generate data summaries for the Protocol Chair, 
the External Safety Monitor, and the DAIDS Medical Officer on an at least monthly basis. More 
frequent ad hoc safety reviews can be implemented during the initial enrollment and throughout 
the study as needed. These data summaries will include adverse event, accrual and retention 
data. The External Safety Monitor will evaluate adverse event data independently as well to 
determine whether the study protocol should continue as originally designed, should be 
changed, or should be terminated.   
 
Approximately once a month the PSRT will convene via email or telephone to review adverse 
event data. Only masked safety data will be reviewed by the PSRT.  If more urgent safety 
matters arise, telephone calls can occur more frequently.    
 
The IRB will be notified of any serious and unexpected adverse events according to the policies 
outlined in the University of Pittsburgh IRB Policy and Procedure Manual9. 
 
The following information will be submitted to the University of Pittsburgh IRB at the time of 
renewal of a research protocol, as required by the IRB guidelines: 
 
• 
The frequency of monitoring during the renewal interval, including the dates of data and 
safety monitoring; 
• 
A summary of any assessment performed to evaluate external factors or other relevant 
information that may have an impact on the safety of study volunteers or the ethics of 
the research study; 
• 
A summary of the outcome of procedural reviews conducted to ensure subject privacy 
and research data confidentiality; 
• 
Any conclusions regarding changes to the anticipated benefit-to-risk ratio of study 
participation and final recommendations related to continuing, changing, or terminating 
the study, with accompanying rationales as appropriate. 
 

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8.3 Adverse Events Definitions   
An AE is defined as any untoward medical occurrence in a clinical research participant 
administered an investigational product and which does not necessarily have a causal 
relationship with the investigational product.  As such, an AE can be an unfavorable or 
unintended sign (including an abnormal laboratory finding, for example), symptom or disease 
temporally associated with the use of an investigational product, whether or not considered 
related to the product.  This definition is applied to all groups beginning from the time of 
randomization.   
 
Study participants will be provided instructions for contacting the study site to report any 
untoward medical occurrences they may experience, except for possible life-threatening events, 
for which they will be instructed to seek immediate emergency care.  Where feasible and 
medically appropriate, participants will be encouraged to seek evaluation at Magee-Womens 
Hospital of UPMC, where the study clinicians are based, and to request that a study clinician be 
contacted upon their arrival.  All participants reporting a clinically significant untoward medical 
occurrence will be followed either in person or by phone until the occurrence resolves (returns to 
baseline) or stabilizes over a four week period. 
 
Study site staff will document in source documents all AEs reported by or observed in enrolled 
study participants regardless of severity and presumed relationship to study product.   
 
For each study participant, AE documentation and reporting will be undertaken throughout the 
scheduled duration of follow-up, i.e., through Visit 4.  
 
The PI/designee will grade the severity of each AE and the relationship of the AE to study 
product:   
 
AE severity will be graded per the DAIDS Table for Grading Adult and Pediatric Adverse Events, 
Version 2.1, July 2017 and the Female Genital Grading Table for Use in Microbicide Studies 
(Appendix 1, version 1.0, November 2007) except that asymptomatic BV will not be considered 
an AE. AEs not included in the Female Genital Grading Table will be graded by the DAIDS AE 
Grading Table Version 2.1, July 2017.  In cases where a genital AE is covered in both tables, 
the Female Genital Grading Table for Use in Microbicide Studies will be the grading scale 
utilized.   
 
The relationship of all reported AEs will be assessed based on the Manual for Expedited 
Reporting of Adverse Events to DAIDS (Version 2.0, dated January 2010) and the clinical 
judgment of the PI/designee.   
 
Per the Manual for Expedited Reporting of Adverse Events to DAIDS, the relationship 
categories that will be used for this study are:  
Related: There is a reasonable possibility that the AE may be related to the study agent(s)  
Not related: There is not a reasonable possibility that the AE is related to the study agent(s)  
The study products that must be considered when AE relationships are assigned are the 
placebo film.   
 
The DAIDS Table for Grading Adult and Pediatric Adverse Events, the Female Genital Grading 
Table for Use in Microbicide Studies, and Version 2.0 of the Manual for Expedited Reporting of 
Adverse Events to DAIDS are available on the DAIDS Regulatory Support Center (RSC) web 
site:   http://rsc.tech-res.com/ 
 
All AEs will be captured on an AE log form.  The form should be reviewed at each study visit 
and updated as needed.  For any serious or expedited AEs (SAEs/EAEs) that are continuing at 

FAME-101 version 1.0 20September2017 
 
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a participant’s study exit visit, the PI/designee must establish a clinically appropriate follow-up 
plan for the AE and review with the DAIDS Medical Officer.  At a minimum, the AE must be re-
assessed by study staff at least 2 weeks after the participant’s study exit visit (Visit 4); additional 
evaluations also may take place at the discretion of the PI/designee.  The same approach must 
be taken for any AEs deemed related to study product that are found to have increased in 
severity at the study exit visit (Visit 4).  For those AEs requiring re-assessment, if the AE has not 
resolved or stabilized at the time of re-assessment, study staff will continue to re-assess the 
participant at least once per month while the study is ongoing.  After the study has ended, all 
AEs requiring re-assessment will be re-assessed at least once within the 30-60 days after the 
study end date.   
 
8.4 Expedited Adverse Event Reporting Requirements 
8.4.1 Expedited Adverse Event Reporting to DAIDS 
Requirements, definitions and methods for expedited reporting of Adverse Events (AEs) are 
outlined in Version 2.0 of the DAIDS EAE Manual, which is available on the DAIDS RSC 
website at http://rsc.tech-res.com/clinical-research-sites/safety-reporting/manual. 
 
The DAIDS Adverse Experience Reporting System (DAERS), an internet-based reporting 
system, must be used for expedited AE reporting to DAIDS. In the event of system outages or 
technical difficulties, expedited AEs may be submitted via the DAIDS EAE Form. This form is 
available on the DAIDS RSC website at http://rsc.tech-res.com/clinical-research-sites/safety-
reporting/daids/paper-eae-reporting.  
 
For 
questions 
about 
DAERS, please 
contact 
NIAID 
CRMS 
Support 
at 
CRMSSupport@niaid.nih.gov.  Please note that site queries may also be sent from within the 
DAERS application itself.   
 
For questions about expedited reporting, please contact the DAIDS RSC Safety Office at 
(DAIDSRSCSafetyOffice@tech-res.com).  
 
EAE reporting procedures specific to this protocol are that once the site has submitted EAEs via 
DAERS (as above), the RSC Safety Office will also prepare the draft safety reports and send 
them to the DAIDS Medical Officers for review. The study site will be contacted by the DAIDS 
Medical Officer if any further information or clarification is needed after the report is evaluated.  
 
For all EAEs submitted, sites must file an RSC update with the final or stable outcome 
unless the initial EAE submitted had a final or stable outcome noted already. 
 
 
EAE Reporting Level 
This study uses SAE category of expedited AE reporting as defined in the DAIDS EAE Manual.   
 
Study Agents for Expedited Reporting to DAIDS 
The study agent that must be considered in determining relationships of AEs requiring 
expedited reporting to DAIDS is the placebo film.  
 
Reporting Period 
AEs must be reported on an expedited basis during the entire study duration for an individual 
subject (from study enrollment until study completion or discontinuation of the subject from 
study participation for any reason).  After the protocol-defined AE reporting period, unless 
otherwise noted, only suspected unexpected serious adverse reactions (SUSARs as defined in 
Version 2.0 of the EAE Manual) will be reported to DAIDS if the study staff become aware of the 
events on a passive basis (from publicly available information). 
 

FAME-101 version 1.0 20September2017 
 
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8.4.2 Reporting of Critical Events to DAIDS 
 
Protocol violations and unanticipated problems must be reported to DAIDS as critical events. 
The following information about the critical event will be submitted to DAIDS MO and Clinical 
Operations Officer: 
 
A detailed description of the problem;  
Actions the study site is taking or plans to take to address the problem, such as suspending 
participant enrollment, termination of research, revising study protocol or informed consent 
documents, increasing monitoring of the study participant, etc. Any revisions to the study 
protocol and informed consent must be reviewed and approved by the DAIDS MO and study 
site IRB prior to implementation.  
 
Serious or continuing noncompliance and suspension/termination of IRB approval must be 
reported as critical events as well. 
 
 
8.5 Clinical Management of Adverse Events   
By definition, an adverse event can be either new finding or symptom or a worsening of a pre-
existing condition. In order to accurately capture adverse events in follow-up, a thorough 
baseline history will be obtained at Visit 1 and Visit 2.  For example, for participants who 
endorse a history of headache, site staff will probe for and record details surrounding the 
condition such as frequency, location, duration, medication use, triggers, etc. Only by eliciting a 
full description will study staff be equipped to determine whether a subsequent event in follow-
up is a clinically distinct event or not. 
 
Adverse events will be elicited at each follow-up visit. Referral to appropriate care will be offered 
to participants as needed. Vaginitis and some sexually transmitted infections can be treated in 
the study clinic. The PI/designee should manage STI/RTI per CDC guidelines, available at 
http://www.cdc.gov.  Observed single dose treatment should be provided whenever possible.  
Vaginally applied medications should not be used if possible.  
 
8.5.1 Product Hold 
In the unlikely event that a participant is intolerant of the study product immediately after 
placement, the site clinician will perform a pelvic exam to remove all visible product. 
 
 
8.6 Criteria for Early Termination of Study Participation 
Participants may voluntarily withdraw from the study for any reason at any time.  The Site 
PI/designee also may withdraw participants from the study to protect their safety and/or if they 
are unwilling or unable to comply with required study procedures. Participants also may be 
withdrawn if the study sponsors, government or regulatory authorities, including the Office of 
Human Research Protections (OHRP), or site IRBs/ECs terminate the study prior to its planned 
end date.  Every reasonable effort is made to complete a final evaluation of participants who 
withdraw or are withdrawn from the study prior to completing follow-up.  Study staff members 
will record the reason(s) for all withdrawals in participants’ study records.   

FAME-101 version 1.0 20September2017 
 
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9 
STATISTICAL CONSIDERATIONS 
 
9.1 Review of Study Design 
The primary aim of this study is to assess the safety of a single dose of placebo film.  
Urogenital, systemic and menstrual symptoms will be collected via symptom review with 
participants.  Testing for sexually transmitted infections and vaginitis will occur at the screening 
visit to rule out other potential causes of reproductive tract inflammation and epithelial 
disruption.  This testing will be repeated during subsequent examinations if clinically indicated.  
Data on epithelial inflammation and disruption will be collected during visual examination of the 
reproductive tract. Pharmacokinetic measures will assess persistence following a single 
exposure.  
 
9.2 Sample Size and Accrual 
The primary aim of the study is to assess the local and systemic safety of a single dose of 
placebo vaginal film. The primary endpoint is the proportion of participants who experience a 
Grade 2 or higher adverse event. The proposed total sample size is N=64 divided into 4 arms 
(placebo film with follow up at days 3, 7, 10, or 14 assigned at a 1:1:1:1 ratio).  Based on 
previous studies of vaginal products conducted at the study site, the accrual of 64 eligible 
subjects with normal reproductive tracts is expected to require the screening of approximately 
150 volunteers.  Since unevaluable participants will be replaced, it is anticipated that 64 women 
exposed to study product will complete study visit 3.   
 
The sample size is based on the exact binomial probability of observing at least two Grade 2 or 
higher Adverse Events. For a given arm, if the true rate of a given toxicity endpoint is 5%, 16 
women per arm provide 80% power to exclude toxicity endpoint rates greater than 27% (the 
probability of observing zero or one event is less than 0.05 when the true rate is 27%). 
 
 
Table 6:  Power Calculations for FAME 101  
 
Event 
Rate 
P(No events | 
n=16) 
P(1 or more events | 
n=16) 
P(2 or more events | n=16) 
1% 
0.851 
0.149 
0.011 
5% 
0.440 
0.560 
0.189 
10% 
0.185 
0.815 
0.485 
15% 
0.074 
0.926 
0.716 
20% 
0.028 
0.972 
0.859 
25% 
0.010 
0.990 
0.937 
27% 
0.007 
0.993 
0.955 
30% 
0.003 
0.997 
0.974 
35% 
0.001 
0.999 
0.990 
 
 
In previous studies of two different placebo film products the combined frequency of Grade 2 or 
higher Adverse Events was 19%. Assuming a similar frequency in the current study, a sample 
size of 64 women will assure that a 95% confidence interval for the Grade 2 or higher Adverse 
Events rate has an upper limit of no greater than 30%. 
 
 

FAME-101 version 1.0 20September2017 
 
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9.3 Study Endpoints 
9.3.1 Primary Endpoint   
Grade 2 Adverse Events 
The safety/toxicity endpoint is clinical or laboratory evidence of a Grade 2 or higher Adverse 
Event as defined by the DAIDS Table for Grading Adult and Pediatric Adverse Events, Version 
2.1, July 2017 and the Female Genital Grading Table for Use in Microbicide Studies (Appendix 
1 to the DAIDS Table for Grading Adult and Pediatric Adverse Events, (Dated November 2007). 
9.3.2 Secondary and Exploratory Endpoints 
The secondary and exploratory endpoints of this study are as follows: 
 
Secondary: Acceptability 
Reports of overall acceptability of the film and qualities of the experience with the film will be 
measured using a self-report survey drawing items from two sources. Overall acceptability is 
measured using standard language in market research methodology, each using a 5-point 
agreement scale followed by an open-ended explanation. Assessment of film-specific qualities 
of the experience is assessed by a 9-item scale drawn from previous research with participant-
inserted films. Questions assess perceptions of leaking, vaginal dryness, and sensation of the 
film inside the vagina during and after insertion. 
Exploratory: Vaginal Microenvironment 
Given that there is no non-product use arm, participants will serve as their own control. 
Assessment of baseline microenvironment will take place during the enrollment visit with the 
exception of CVL properties. CVL will be obtained at the screening visit so that the 
microenvironment can recover prior to study product administration at the enrollment visit.  
 
Levels of lectin binding and mucins measured in CVL samples 
Endogenous and exogenous glycolytic enzymes, formulated microbicide products, and 
microbial flora interact with mucins and may alter their structure and function. These alterations 
may be detected with lectins, which are sugar specific binding molecules, and can be bound to 
reporter molecules (such as horseradish peroxidase) in an ELISA type assay.  
 
Changes in the Glycome 
Lectin microarray will be used to assess changes in the glycome. 
 
Nugent Score 
Clinically significant changes in vaginal flora will be evaluated by a change in the Nugent score 
baseline (Visit 2, pre-exposure) to Visit 5.  The Nugent score is graded 1 to 10 as follows: 
Normal, 0 to 3 
Intermediate, 4 to 6 
BV, 7-10 
 
Any shift from normal at baseline to intermediate or BV at Visit 3 or 4, or shift from intermediate 
or BV to normal at Visit 3 or 4 will be considered a scientifically meaningful change in vaginal 
microbiota.   
 
Quantitative vaginal cultures and quantitative PCR 
Meaningful changes will be defined by greater than or equal to 1 log changes in dominant 
members of the microbiota, including Lactobacillus species, Gardnerella vaginalis, key 
anaerobic microorganisms, Enterococcus species, Escherichia coli, Staphylococcus aureus, 
Group B Streptococcus, and Candida species. 
 
Levels of anti-viral activity   in CVL 
In-vitro anti-HIV activity will be determined by the TZM-bl assay. 

FAME-101 version 1.0 20September2017 
 
Page 32 
 
The TZM-bl assay will determine HIV-1 infection by luciferase for single round of replication. To 
assess the potency of the CVL, serial dilutions will be made and tested to determine the IC50. 
 
Levels of cytokine and innate immunity factors 
Changes in cervical cytokine expression and innate immunity factors in cervicovaginal lavage  
will be assessed.  Changes within each group will be reported. 
Exploratory: Pharmacokinetic (PK)/ Persistence of Eudragit® in CVL 
Persistence of polymer will be determined as detected levels of polymer in vaginal fluid 
collected through cervicovaginal lavage.  
 
9.4 Blinding 
All participants will receive a single dose of the vaginal film. They will be randomized to the 
timing of Visit 3. This will not be blinded. 
 
9.5 Random Assignment 
The randomization scheme will be generated and maintained by a member of the Data 
Management Division at the study site.  Women will be randomized to one of the four arms at a 
1:1:1:1 ratio using a permuted block design with random block sizes of 4 and 8.  In order to 
minimize bias in group assignment, participants will be given study identification numbers.  A 
study staff member will allot the identification numbers in sequential order as participants 
become eligible to enroll in the study.  These numbers will be randomly assigned with timing of 
Visit 3. The randomization scheme will be created for a total of 72 participants; the overage will 
be created to compensate for participant withdrawals or unusable products.   
 
9.6 Data Monitoring and Analysis 
9.6.1 Data Monitoring 
This clinical trial will be conducted in compliance with the protocol, GCP guidelines, and 
applicable regulatory requirements.  All research charts are maintained in locked files in a 
locked room. The research staff, under the direction of the primary investigator, will create and 
maintain an electronic database on the hospital system on the computers in the Reproductive 
Infectious Diseases research offices. The database will be backed up every night onto the 
server’s back-up system, and weekly onto an external storage device.  Appropriate firewall and 
virus scanning software are installed and updated routinely by the hospital support staff. 
 
This study will utilize electronic data capture. Once the source documents are ready for 
computer entry, site staff will enter data into a data entry system.  Study data management staff 
will review the electronic data elements for completeness and accuracy.  If there are any 
responses that are incomplete, unclear, or inconsistent with related data elements, the staff 
person will speak with the clinician in question as soon as possible to resolve the problem.  If 
necessary, the study staff will make the appropriate change in the electronic database which 
tracks time and date a change is made.   
 
9.6.2 Primary Endpoint Analysis 
The number of adverse events will be summarized by severity, body system, and relationship to 
study product using frequencies, percent, and 95% confidence intervals. Individual participants 
will contribute once to the calculation of event rates.  
9.6.3 Secondary and Exploratory Endpoint Analysis 
Summary statistics of frequencies, percentages, and 95% confidence intervals will be provided 
for categorical data.  Means, standard deviations, medians, ranges and 95% confidence 

FAME-101 version 1.0 20September2017 
 
Page 33 
intervals will be provided for continuous data. Methods for the analyses of the secondary 
endpoints are described below.  
 
One-way analysis of variance (ANOVA) and Kruskal-Wallis tests will be used, where 
appropriate, to evaluate differences in the following continuous variables between the study 
arms: levels of glycoproteins and mucins in CVL, levels of cytokines and innate immunity 
factors, and antiviral activity in CVL. Between groups, pre- to post-exposure changes in the 
above endpoints will also be evaluated using ANOVA and Kruskal-Wallis  tests, where 
appropriate, while paired Student’s t- and Wilcoxon signed-rank tests will be used to evaluate 
these changes within each study arm. Mixed effects linear regression will be used to evaluate 
associations between days of exposure to study product and these outcomes.  
 
Nugent score will be categorized as follows: normal (score 0-3), intermediate (score 4-6), and 
bacterial vaginosis (score 7-10). Differences in the categorized Nugent score pre and post 
exposure levels will be evaluated using Fisher’s exact, while McNemar’s tests will be used to 
evaluate pre- to post-exposure shifts between normal (score 0-3) and abnormal (score 4-10) 
vaginal microflora within each study arm.  
 
Prevalence of microorganisms at each visit will be compared between the study arms using 
Fisher’s exact tests, while pre- to post-exposure shifts will be evaluated within each group using 
McNemar’s tests. Differences between the study arms in the quantity of microorganisms at each 
visit, as well as the change in quantity, will be evaluated using Mann-Whitney U tests. 
Meaningful changes will be defined by greater than  or equal to 1 log changes in dominant 
members of the microflora, including Lactobacillus (H2O2 positive and negative strains), 
anaerobic gram negative rods, Gardnerella vaginalis, Candida species, facultative gram 
negative rods, Streptococci and facultative gram positive cocci and rods. Fisher’s exact tests will 
be used to evaluate differences in these changes between study arms.  Mixed effects linear 
regression (for continuous outcomes) and generalized estimating equations (for binary 
outcomes) will be used to evaluate associations between days of exposure to study product and 
these outcomes. 
 
 
Time since last menstrual period will be included as a potential confounder in these analyses. 
  
9.6.4 Analysis Cohort 
The cohort will be defined as participants who are randomized.  It will be used for analyses of 
baseline characteristics, protocol deviations and violations, and trial conduct.  The intent-to-treat 
cohort (ITT) will be defined as those who were randomized.  The evaluable cohort (Eval) is a 
subset of ITT participants. Evaluable participants will be defined as participants who complete 
the Screening and Enrollment Visits and return for their Visit 3 within the window.  Non-
evaluable participants will be replaced.   
 
Table 7: Statistical Analysis Plan 
Endpoint 
Variable 
Statistics 
Primary 
 
Adverse Events 
Frequency, Percent, 95% 
Confidence Interval 
Exploratory 
 
Persistence of Eudragit® in CVL 
Frequency, Percent, 95% 
Confidence Interval 
Levels of glycoproteins and mucins, 
in CVL 
Mean, SD, Median, Range, 
95% Confidence Interval 
Antiviral activity in CVL 
Mean, SD, Median, Range, 
95% Confidence Interval 

FAME-101 version 1.0 20September2017 
 
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Change in vaginal flora (Nugent 
score) 
Frequency, Percent, 95% 
Confidence Interval 
 
 
Culture/qPCR results from vaginal 
organisms 
Frequency, Percent, 95% 
Confidence Interval 
Mean, SD, Median, Range, 
95% Confidence Interval 
 
Change in cytokine and innate 
immunity factors  
Mean, SD, Median, Range, 
95% Confidence Interval 
Lectin Microarray to assess changes 
in gylcome 
Mean, SD, Median, Range, 
95% Confidence Interval 
10 HUMAN SUBJECTS CONSIDERATIONS 
 
The investigators will make efforts to minimize risks of these products to human subjects.  
Volunteers will take part in a thorough informed consent process throughout their participation in 
the study.  Before beginning the study, the investigators will have obtained IRB approval. The 
investigators will permit audits by the NIH or any of their appointed agents. 
  
10.1 Special Populations 
Study staff will offer screening to eligible women of all ethnic and racial groups.  Members of the 
study staff are not seeking the screening or enrollment of women in special or vulnerable 
populations.  The following section also discusses special considerations for male partners of 
participants. 
 
10.1.1 Men  
Men are not included as subjects in the study because the study is testing a vaginal application 
of the study product.  The male sexual partners of women participating in this study will not be 
consented or monitored for several reasons.  Protocol-specified guidelines for abstinence and 
condom use are expected to protect male partners from exposure to the study product.  In 
addition, based on preclinical data, no toxicity is anticipated from the study product.   
 
10.1.2 Children 
The NIH has mandated that children be included in research trials when appropriate.  This study 
will enroll women aged 18 to 20 who are able to give informed consent.  This study meets 
“Justifications for Exclusion” criteria for younger children as set forth by the NIH.  Specifically, 
"the research topic to be studied is irrelevant to (young) children" and "a separate, age-specific 
study in (adolescent) children is warranted and preferable" at a later time. 
 
10.1.3 Prisoners 
Prisoners will not be included in this study (for screening or enrollment).  Any participants 
incarcerated during the course of participation in the trial will not be followed during their 
incarceration, and will be discontinued from the study.  Participants who have been released 
from incarceration will be permitted to return for any protocol specified follow-up or safety visits 
per the guidelines of the local IRB. 
 
10.1.4 Pregnant women 
Pregnancy is an exclusion criterion as the vaginal microenvironment in pregnancy differs 
substantially from the non-pregnant state. Including pregnant participants would make the 
interpretation of study results difficult. Women who become pregnant during the study period 
following randomization will not be excluded from analysis. Participants who become pregnant 

FAME-101 version 1.0 20September2017 
 
Page 35 
during the course of the study will be contacted periodically after study termination in order to 
determine the pregnancy outcome. 
 
 
10.2 Informed Consent Process 
Written informed consent will be obtained from all potential study participants prior to the 
initiation of any study-related procedures.  The informed consent process will give individuals all 
of the relevant information they need in order to decide whether to participate, or to continue 
participation, in this study.  Potential research participants will be permitted to ask questions and 
to exchange information freely with the study investigators.  Only listed study investigators may 
obtain informed consent from potential study participants.  The investigators will keep research 
participants fully informed of any new information that could affect their willingness to continue 
study participation.   
 
10.2.1 Risk/Benefit Statement 
Risks 
It is not expected that this trial will expose human subjects to unreasonable risk.  The 
intervention used in this study is unlikely to cause uncomfortable side effects and is only given 
once. However, there may be unknown risks or side effects associated with the use of the 
vaginal film.  Some women who used the film in other studies have reported vaginal discharge, 
and irritation and discomfort.   
 
Having genital exams may cause some discomfort from placing the speculum.  It is unlikely that 
collection of genital samples will cause discomfort.  Cervicovaginal lavage has been associated 
with mild discomfort secondary to the introduction of sterile fluid into the vagina and its removal. 
Standard study procedures do not include a blood draw; however, a blood draw is required if a 
confirmatory HIV test needs to be run. Phlebotomy may lead to discomfort, feelings of dizziness 
or faintness, and/or bruising, swelling and/or infection. 
 
Disclosure of sexually transmitted infection (STI) may cause sadness or depression in 
volunteers.  Disclosure of HIV-positive status has been associated with depression, suicidal 
ideation, and denial as well as social isolation.  Participation in clinical research includes the 
risks of loss of confidentiality and discomfort with personal nature of questions.  
 
Benefits 
Participation in this trial likely will have no direct benefit to volunteers.  Some volunteers may 
have the opportunity to access expedient treatment and decreased morbidity due to early 
diagnosis and treatment of a cervical and/or vaginal abnormality with expedient referral if an 
abnormality is detected.  Lastly, the participant may appreciate the opportunity to contribute to 
the body of knowledge in the field of microbicide research.  However, there is no guarantee that 
volunteers will receive any of these benefits. 
 
10.3 Incentives 
Volunteers will not be charged for any of the study visits, study supplies or examinations.  There 
are no costs to participants in this study other than their time.  Pending IRB approval of these 
compensation guidelines, women will be compensated for their time and inconvenience and for 
their travel needs while participating in the protocol.  The approved amounts of compensation 
will be given out at each visit.  The visits will be prorated and partial payment given in the event 
that the participant only completes a portion of the study visits.  The following proposed 
compensation amounts were created based on common institutional practice for studies 
investigating vaginal products, as well as studies utilizing observation periods in the Clinical  
Translational Research Center.   
 
 
Visit 1  
 
$50 

FAME-101 version 1.0 20September2017 
 
Page 36 
 
Visit 2  
 
$50 
 
Visit 3  
 
$100 (if evaluable and compliant with date/time) 
 
Visit 4  
 
$50 
 
 
In addition a parking pass or a bus pass will be provided to participants as needed.  
 
10.4 Participant Confidentiality 
Members of the study staff are all trained in patient confidentiality.  The log of study subject 
names and other protected health information is kept in a locked area.  All computer information 
about study volunteers is kept on a computer with log-on passwords.  Laboratory specimens are 
labeled with study numbers and date, and are delivered by study staff.   In addition to the 
research study staff, the NIH, study monitors, University of Pittsburgh Research Conduct and 
Compliance Office, the Office of Human Research Protections, and/or the University of 
Pittsburgh IRB may have access to participant’s health information. Each member of the staff 
has log-on identification and password, logs off before leaving a computer screen unattended, 
and closes their office door when out of the office.  All research records will be kept for a 
minimum of seven years following closure of this study (per University of Pittsburgh policy).    
 
10.5 Communicable Disease Reporting 
Study staff members will comply with all local requirements to report communicable diseases 
including chlamydia, gonorrhea, and HIV identified among study participants to the Allegheny 
County Health Department.  Study investigators will include discussion of mandated reporting 
during the study informed consent process. 
 
10.6 Study Discontinuation 
NIAID or the University of Pittsburgh Institutional Review Board may discontinue this study at 
any time.  Ongoing safety monitoring will track the incidence of AEs and EAEs.  In the event of 
an abnormal number of reported AEs and/or EAEs judged to be related to study product the 
External Safety Monitor will contact the Principal Investigator to initiate a temporary hold on 
further enrollment. 
11 LABORATORY SPECIMENS AND BIOHAZARD CONTAINMENT 
 
11.1 Laboratory Specimens 
Laboratory specimens will be handled in a manner consistent with institutional, OSHA, and GLP 
guidelines.  Study staff members are trained in the appropriate handling of laboratory 
specimens.  Samples such as urine that will be divided for multiple analyses will be divided 
according to site SOP. 
   Table 8:  Laboratory Test Methods 
SAMPLE 
METHOD 
LABORATORY 
 
URINE 
Pregnancy test 
Clinical Research Center 
CLIA #39D1031322 
Urine dipstick 
 
SALIVA 
Rapid HIV 
Clinical Research Center 
CLIA #39D1031322 
 
BLOOD 
Confirmatory HIV 
UPMC Presbyterian Shadyside CP PUH 
CLIA# 39D0911193 
 
 
VAGINAL* 
pH 
Clinical Research Center 
CLIA #39D1031322 
Wet Mount 
Trichomonas (NAAT) 
 
Magee-Womens Research Institute 
CLIA #39D1004688 
Gram Stain 
Quantitative Vaginal Culture 
Quantitative PCR for 
microbiota 

FAME-101 version 1.0 20September2017 
 
Page 37 
 
CERVICAL* 
 
GC/CT (NAAT) 
Magee-Womens Research Institute 
CLIA #39D1004688 
 
 
 
 
CVL 
Levels of antiviral activity 
Magee-Womens Research Institute/Dezzutti 
Laboratory 
(non-diagnostic laboratory) 
Lectin microarray 
Magee-Womens Research Institute/Moncla 
Laboratory 
(non-diagnostic laboratory) and/or 
New York University (Mahal Laboratory) 
Levels of glycoproteins and 
mucins 
Levels of cytokines & innate 
immunity factors 
Magee-Womens Research Institute/Moncla 
Laboratory  
(non-diagnostic laboratory) 
Eudragit® level 
University of Colorado  
(non-diagnostic laboratory) 
      *Future Use Samples will be stored at Magee-Womens Research Institute; use and processing lab to 
be determined 
11.1.1 Urine Samples 
Study staff at the clinical site will utilize dipstick urinalysis to screen for possible urinary tract 
infection as clinically indicated.  Urine will be tested for HCG via the Sure-Vue® test. 
 
11.1.2 Vaginal Samples 
The assessment of vaginal flora will be based on the Nugent Scoring System for Gram Stained 
Vaginal Smears as well as assessment of several groups of organisms by cultivation (culture) 
based methods.  In addition, selected microbiota will be detected using a quantitative 
polymerase chain reaction (qPCR) test which has been developed and validated within the 
laboratory.  Gram stained vaginal smears will have neutrophils quantified according to site 
laboratory SOP.    Collection will be done as gently and carefully as possible so as to collect an 
adequate sample that is unlikely to disturb the mucosa or overall vaginal microenvironment.  
Trichomonas vaginalis will be detected using an amplified DNA assay and handled according to 
policies outlined in SOPs for this study. 
11.1.3 Cervical Swabs 
C. trachomatis and N. gonorrhoeae  will be detected using an amplified DNA assay and handled 
according to policies outlined in SOPs for this study.   
11.1.4 Cervicovaginal Lavage Samples 
Eudragit® Content in CVL 
Aliquots of lavage samples will be tested for polymer levels (according to SOP).   
 
Anti-viral Activity in CVL 
Aliquots of lavage samples will be tested for anti-viral and antibacterial activity as outlined in the 
site SOPs.  
 
Cervical Cytokines and Innate Factors in CVL 
Cytokines (for example, IL-1β and TNFα) along with innate immune factors (for example, 
antiproteases) that could contribute to a proinflammatory milieu or changes in the glycomic 
signatures may be evaluated.” 
 
Glycome Studies 
Aliquots of lavage samples will be tested for glycoproteins, mucins and lectin microarray.   
 
 

FAME-101 version 1.0 20September2017 
 
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11.2 Quality Control and Quality Assurance Procedures 
Dr. Sharon Hillier, who completed a training program in clinical and public health microbiology 
certified by the American Board of Medical Microbiology (ABMM), directs the Infectious Disease 
Research Laboratory at Magee-Womens Research Institute.  This laboratory is CLIA-inspected 
and maintains its own CLIA license.  Thus, all testing done in this research laboratory is 
performed with the same level of quality control as required in a licensed clinical laboratory.   
 
11.3 Specimen Storage and Possible Future Research Testing 
Part of the consent form will include an explanation of future use of vaginal and cervical 
specimens and blood samples.  Any future use or residual samples will be stored at Magee-
Womens Research Institute, Microbiology Laboratory, 5th floor for an indefinite period of time.  
The principal investigator will assume primary responsibility for control of this area. 
 
Any results from research done on future use or leftover specimens will not be placed in health 
records and will be kept confidential. The language and format employed in the consent for 
these purposes are an IRB-approved means commonly employed in studies performed at this 
and other study sites within our institution to obtain permission for use of stored samples.  All 
primary study endpoints, protocol-specified testing, and QA/QC testing will be ascertained prior 
to any additional testing of stored specimens.   
 
11.4 Biohazard Containment 
Biohazardous waste will be contained according to institutional and all other applicable 
regulations. 
 
12 ADMINISTRATIVE PROCEDURES 
The study proposal for funding, this protocol, the informed consent document, data collection 
forms, and advertising flyers are all reviewed by the University of Pittsburgh Institutional Review 
Board prior to enrollment of participants in the study. 
 
12.1 Protocol Registration 
Prior to implementation of this protocol, and any subsequent full version amendments, the site 
will have the protocol and the consent form approved, as appropriate, by their local institutional 
review board (IRB)/ethics committee (EC) and any other applicable regulatory entity (RE). Upon 
receiving final approval, the site will submit all required protocol registration documents to the 
DAIDS Protocol Registration Office (DAIDS PRO) at the Regulatory Support Center (RSC). The 
DAIDS PRO will review the submitted protocol registration packet to ensure that all of the 
required documents have been received.  
             
The site will receive an Initial Registration Notification when the DAIDS PRO receives a 
complete registration packet. Receipt of an Initial Registration Notification indicates successful 
completion of the protocol registration process. Sites will not receive any additional notifications 
from the DAIDS PRO for the initial protocol registration. A copy of the Initial Registration 
Notification should be retained in the site's regulatory files. 
 
Upon receiving final IRB/EC and any other applicable RE approvals for an amendment, the site 
should implement the amendment immediately. The site is required to submit an amendment 
registration packet to the DAIDS PRO at the RSC. The DAIDS PRO will review the submitted 
protocol registration packet to ensure that all the required documents have been received. The 
site will receive an Amendment Registration Site-specific ICF (s) WILL NOT be reviewed and 
approved by the DAIDS PRO and sites will receive an Amendment Registration Notification 
when the DAIDS PRO receives a complete registration packet A copy of the Amendment 
Registration Notification should be retained in the site's regulatory files. 
 

FAME-101 version 1.0 20September2017 
 
Page 39 
For additional information on the protocol registration process and specific documents required 
for initial and amendment registrations, refer to the current version of the DAIDS Protocol 
Registration Manual. 
 
 
12.2 Data Coordination 
Data management responsibilities will reside with the Data Management staff at Magee-
Womens Hospital. 
 
12.3 Study Monitoring 
Monitoring will be carried out by Pharmaceutical Product Development Inc., (PPD, Wilmington, 
NC).  Site monitoring visits will be conducted to assess overall study compliance, as required 
per Requirements for On-Site Monitoring of DAIDS Funded and/or Sponsored Clinical Trials, 
GCP, and FDA regulations 21 CFR Part 312:  
 
http://www.niaid.nih.gov/LabsAndResources/resources/DAIDSClinRsrch/Documents/onsitemoni
tor_reqs.pdf  
 
Study monitors will visit the site to complete the following: 
 
• 
Assess compliance with the study protocol, Good Clinical Practices (GCP) guidelines, 
and applicable regulatory requirements, including US CFR Title 45 Part 46 and Title 21 
Parts 50, 56, and 312 
• 
Review informed consent forms, procedures, and documentation 
• 
Perform data verification to ensure the accuracy and completeness of study data as 
applicable  
• 
Verify proper collection and storage of biological specimens 
• 
Verify proper storage, dispensing, and accountability for investigational study products 
• 
Assess implementation and documentation of internal site quality management 
procedures 
• 
Assess site staff training needs 
 
Site investigators will allow study monitors to inspect study facilities and documentation (e.g., 
informed consent forms, clinic and laboratory records, other source documents, case report 
forms), as well as observe the performance of study procedures.  Investigators also will allow 
inspection of all study-related documentation by authorized representatives of the DAIDS, 
Sponsor and US regulatory authorities.  A site visit log will be maintained at the study sites to 
document all visits. The outcomes of the monitoring visits and the subsequent reports of 
resolutions of any identified problems will be provided to the Sponsor. 
 
 
12.4 Protocol Compliance 
All protocol amendments will be submitted to and approved by the University of Pittsburgh IRB 
and  DAIDS prior to the implementation of an amendment. 
 
12.5 Investigator’s Records 
The investigator will maintain, and store securely, complete, accurate and current study records 
throughout the study.  Study records will not be destroyed prior to receiving approval for record 
destruction from the Principal Investigator and they will be maintained for a minimum of seven 
years following completion of the study, per the University of Pittsburgh IRB policy.  Applicable 
records include source documents, site registration documents and reports, correspondence, 
informed consent forms, and notations of all contacts with the participant.   

FAME-101 version 1.0 20September2017 
 
Page 40 
 
12.6 Use of Information and Publications 
Publication of study results will be governed by DAIDS policies.  The investigators will submit 
any presentation, abstract, or manuscript to DAIDS for review prior to submission.  
 
12.7 Training Procedures 
Only study staff trained and experienced in HIV pre-test and post-test counseling and who are 
investigators on this study will provide these study procedures.  Approved written materials 
consistent with the local clinical standard of care will support pre-test and post-test counseling.   

FAME-101 version 1.0 20September2017 
 
Page 41 
 REFERENCES 
1. 
UNAIDS. Report on the global HIV/AIDS epidemic 2008. 
2. 
UNAIDS. AIDS epidemic update: November 2009. 
3. 
Buffa V, Stieh D, Mamhood N, Hu Q, Fletcher P, Shattock RJ. Cyanovirin-N potently 
inhibits human immunodeficiency virus type 1 infection in cellular and cervical explant models. J 
Gen Virol 2009;90:234-43. 
4. 
Gupta P, Collins KB, Ratner D, et al. Memory CD4(+) T cells are the earliest detectable 
human immunodeficiency virus type 1 (HIV-1)-infected cells in the female genital mucosal tissue 
during HIV-1 transmission in an organ culture system. J Virol 2002;76:9868-76. 
5. 
Collins KB, Patterson BK, Naus GJ, Landers DV, Gupta P. Development of an in vitro 
organ culture model to study transmission of HIV-1 in the female genital tract. Nat Med 
2000;6:475-9. 
6. 
Cummins JE, Jr., Guarner J, Flowers L, et al. Preclinical testing of candidate topical 
microbicides for anti-human immunodeficiency virus type 1 activity and tissue toxicity in a 
human cervical explant culture. Antimicrob Agents Chemother 2007;51:1770-9. 
7. 
Anton P, Elliott J, Tanner K, et al. Strong Suppression of HIV-1 Infection of Colorectal 
Explants following in vivo Rectal Application of UC781 Gel: A Novel Endpoint in a Phase I Trial. 
In: 16th Conference on Retroviruses and Opportunistic Infections. Montreal; 2009. 
8. 
Anton P CR, Carballo-Diequez A, Kashuba A, Khanukhova E, Elliott J, Janocko L, 
Cumberland W, Mauck C, McGowan I. RMP-02/MTN-006: A Phase 1 Placebo-controlled Trial of 
Rectally Applied 1% Vaginal TFV Gel with Comparison to Oral TDF. 18th Conference on 
Retroviruses and Opportunistic Infections, Boston MA 2011. 
9. 
Steiner M, Spruyt A, Joanis C, et al. Acceptability of Spermicidal Film and Foaming 
Tablets Among Women in Three Countries. International Family Planning Perspectives 
1995;21:104-7. 
10. 
Visness CM, Ulin P, Pfannenschmidt S, Zekeng L. Views of Cameroonian sex workers 
on a woman-controlled method of contraception and disease protection. Int J STD AIDS 
1998;9:695-9. 
11. 
Raymond E, Alvarado G, Ledesma L, et al. Acceptability of two spermicides in five 
countries. Contraception 1999;60:45-50. 
12. 
Schley A. IPM Product Acceptability Study II (PAS II). In: International Partnership for 
Microbicides; 2009. 
13. 
Nel AM, Mitchnick LB, Risha P, Muungo LT, Norick PM. Acceptability of vaginal film, 
soft-gel capsule, and tablet as potential microbicide delivery methods among African women. J 
Womens Health (Larchmt) 2011;20:1207-14. 
14. 
Raymond EG, Chen PL, Condon S, et al. Acceptability of five nonoxynol-9 spermicides. 
Contraception 2005;71:438-42. 
15. 
Pittsburgh Uo. Institutional Review Board Manual. http://wwwirbpittedu/manual/. 
 
 
 
 
 
 
 
 
 
 
 
 
 
    

FAME-101 version 1.0 20September2017 
 
Page 42 
APPENDIX 1:  SCHEDULE OF STUDY VISITS AND PROCEDURES* 
Component 
Procedure/Analysis 
V1:  
Screening 
V2:  
Enrollment 
V3: 
3, 7, 10 
or 14 
Day FU 
V4: 
21 
Day 
FU 
 
 
 
 
 
 
ADMINISTRATIVE 
Written Informed Consent 
X 
 
 
 
Assign Study Number (PTID) 
X 
 
 
 
Review/Confirm Eligibility 
X 
X 
 
 
Collect/Update Contact Information 
X 
X 
X 
X 
Visit Questionnaire 
X 
X 
X 
X 
HIV Pre-/Post-Test Counseling 
X 
 
 
 
Screening Results 
X 
X 
 
 
Abstinence/Condom Counseling (& 
distribution prn) 
X 
X 
X 
X 
Assess/Document Adverse Events 
 
X 
X 
X 
Schedule Next Study Visit 
X 
X 
X 
 
Participant Reimbursement 
X 
X 
X 
X 
ACCEPTABILITY 
Acceptability Questionnaire 
 
X 
X 
X 
 
URINE 
Pregnancy test 
X 
X 
X 
X 
Urine dipstick 
^ 
^ 
^ 
^ 
SALIVA 
Rapid HIV 
X 
 
 
 
BLOOD 
Confirmatory HIV 
^ 
 
 
 
 
 
VAGINAL 
(SWAB) 
pH 
X 
X 
X 
X 
Wet Mount 
^ 
^ 
^ 
^ 
Trichomonas (NAAT) 
X 
 
^ 
^ 
Gram Stain 
 
X 
X 
X 
Quantitative Vaginal Culture 
 
X 
X 
X 
Quantitative PCR for microbiota 
 
X 
X 
X 
Future Use 
X 
X 
X 
X 
 
CERVICAL 
GC/CT (NAAT) 
X 
 
^ 
^ 
Future Use 
X 
X 
X 
X 
 
 
CVL 
Levels of antiviral activity 
X 
 
X 
X 
Lectin microarray 
X 
 
X 
X 
Levels of glycoproteins and mucins 
X 
 
X 
X 
Levels of cytokines & innate immunity 
factors 
X 
 
X 
X 
Eudragit® level 
X 
 
X 
X 
 
PHYSICAL 
EXAM 
Physical Exam 
X 
^ 
^ 
^ 
Vital Signs (BP) 
X 
X 
X 
X 
Height & Weight 
X 
 
 
 
 
 
PELVIC  
EXAM 
Bimanual Exam 
^ 
^ 
^ 
^ 
External Genital & Speculum Exam 
X 
X 
X 
X 
Post-insertion External Genital Exam 
 
X 
 
 
Repeat Speculum Exam 
 
^ 
 
 
RANDOMIZATION 
Randomization to timing of V3 
 
X 
 
 
 
STUDY 
PRODUCT 
Study Product Distribution 
 
X 
 
 
Participant Self-Inserted (1st attempt) 
 
X 
 
 
Clinician-inserted (2nd attempt) 
 
^ 
 
 
      X Required  
 
      ^ PRN/as clinically indicated 
*Safety Follow-up may extend beyond V4 to include AE Collection and any procedure deemed        
clinically indicated  
 

FAME-101 version 1.0 20September2017 
 
Page 43 
 
 
 
APPENDIX II:  HIV TESTING AGORITHIM 
 
 
 
START 
SAMPLE 1 
OraQUICK® Rapid 
HIV Test 
IF 
NEGATIVE 
→ 
STOP 
REPORT AS HIV-
UNINFECTED; 
ENROLL IN STUDY 
 
 
 
IF POSITIVE 
 
 
 
 
 
 
↓ 
 
REPORT AS 
INDETERMINATE, 
REQUIRES 
ADDITIONAL 
TESTING 
IF  
INDET. 
← 
SAMPLE 2 
HIV Ab/Ag Plasma 
Testing 
IF 
NEGATIVE 
 
 
 
 
IF POSITIVE 
 
 
 
 
↓ 
 
 
 
 
REPORT AS HIV-
POSITIVE, 
REQUIRES 
CONFIRMATORY 
TESTING 
 
 
 
 
 
↓ 
 
 
 
 
REFERRALFOR 
CARE 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

FAME-101 version 1.0 20September2017 
 
Page 44 
 APPENDIX III: SAMPLE INFORMED CONSENT 
 
 
 
CONSENT TO ACT AS A PARTICIPANT IN A RESEARCH STUDY 
 
Title:  A Study of the Safety and Acceptability of a Placebo Vaginal Film 
Short Title:  FAME 101 
Consent Version:  0.7, 13September2017   
 
Principal Investigators: 
Magee-Womens Hospital of UPMC  
Department of OB/GYN/RS  
Pittsburgh, PA  15213 
Phone:  412-641-5403 
Katherine Bunge MD, MPH, Assistant Professor 
Sharon Hillier, PhD, Professor 
 
Reproductive ID Research Staff 
412-641-4242 
 
 
Funding Agency:  Division of AIDS, US National Institute of Allergy and Infectious Diseases, 
US National Institutes of Health 
 
You are being asked to take part in this research study because you are a woman between the 
ages of 18 and 45 years.  Approximately 64 women will participate in this study. The product 
being used in this study is a placebo (i.e. blank, inactive, no drug) vaginal film (similar to 
Listerine® breath strips).  The person in charge of this study is Katherine Bunge, MD.  Before 
you decide if you want to join this study, we want you to know about the study.  This consent 
form gives you information about this study.  The study staff will talk with you about it and 
answer your questions about this study.  You may decide to withdraw from the study at any 
time.   
 
YOUR PARTICIPATION IS VOLUNTARY 
Once you read, discuss, and understand the consent form, and if you agree to take part, you 
will be asked to sign your name on this form.  You will be offered a copy of this form to keep.  
 
 
PURPOSE OF THE STUDY  
This research study will involve the use of a placebo vaginal film.  Investigators want to evaluate 
the safety of the film and understand the acceptability and length of time for the film to dissolve 
once inserted into the vagina.  In future studies, this film may have medication added to it to 
deliver medication over an extended period of time (i.e. extended release).  
 
STUDY PRODUCTS 
This placebo film has not been used in humans before, but it is made from ingredients with a 
proven safety record.  The same film was found to be safe in monkey models.  
 
STUDY GROUPS   
All of the eligible women will be randomized (distributed by chance, like rolling a dice) at the 
Enrollment Visit to one of four study groups.  The groups will specify what day Visit 3 will be 
performed. 

FAME-101 version 1.0 20September2017 
 
Page 45 
 
Group 
Study Product 
Follow-up Schedule # of participants 
1 
Placebo film 
Visit 3 at Day 3 
16 
2 
Placebo film 
Visit 3 at Day 7 
16 
3 
Placebo film 
Visit 3 At Day 10 
16 
4 
Placebo film 
Visit 3 at Day 14 
16 
  
You have an equal likelihood of being in any one of the four groups.  Neither you nor the study 
staff can choose your group or can change the group you have been placed into.  Regardless 
of which group you are in, you will use the film once during the study.  Women in all of the study 
groups will have the same study visit schedule except for the timing of Visit 3.  All of the study 
groups are important to this study.   
 
FAME 101 STUDY PATICIPATION VISIT REQUIREMENTS 
 
Screening Visit: 
Your first visit will happen after you read, discuss, understand and sign this form.  The 
procedures done at this visit will take about an hour.  
Study staff will ask you where you live and other questions about you, your medical health 
(including what medications you are taking), menstrual history, your sexual practices and your 
understanding of the study requirements.   
Study staff will: 
Perform a physical exam, including height, weight and blood pressure.  
Talk with you about the requirements of the study.  
Perform condom counseling and provide condoms if you need them.   
Test your urine  
A urine pregnancy test will be performed.  If you are pregnant you cannot join this study.   
If necessary, a urinalysis (urine dipstick) will be performed. 
Perform a rapid HIV test using blood or saliva. 
You will be told your HIV test result as soon as it is available, approximately 20 minutes.  You 
will talk with the study staff about the meaning of your result, how you feel about it, and ways to 
prevent HIV and other sexually transmitted infections.  Your sample will be tested for the 
antibody to HIV. An antibody is a substance that blood cells make to fight infection. Exposure 
(contact) to the HIV virus produces antibodies. Sometimes HIV test results are not clearly 
positive, but also not clearly negative.  In that case, we will do more tests until we know your 
status for sure.  You must receive your HIV test results to be in the study.  If the test shows you 
have HIV, you cannot join the study.  We will refer you to available sources of medical care and 
other services you may need.  Your partner(s) may have access to free HIV counseling and 
testing, if needed.   
Perform a pelvic examination: 
The study doctor or research clinician will use a speculum, a plastic or metal instrument used to 
separate the walls of the vagina.  The study clinician will check your vagina and cervix for signs 
of infection, and other problems.  They will also take some fluids to test for sexually transmitted 
infections or diseases (commonly known as STIs or STDs, including gonorrhea, chlamydia, and 
trichomonas) and other possible problems if they feel it is necessary.  
The study clinician will perform a cervicovaginal lavage (CVL). This involves putting saline (salt 
water) into your vagina and using a pipette (or suction bulb) to draw up the fluid and wash the 
walls of your vagina and the cervix. The washing lasts for one minute. The purpose of collecting 
this lavage fluid is to use it to compare future fluid collected during the course of the study after 
you have been using the study product if you are enrolled into the study. 

FAME-101 version 1.0 20September2017 
 
Page 46 
Provide you with the results of your tests, if available. 
If necessary, this visit can occur over more than one visit. 
Schedule your next visit to enroll in this study, if you are willing and eligible, within 45 days of 
this visit.  This visit will be scheduled when you are not expecting to be bleeding or anticipating 
menses within 14 days of the visit.  
 
You must agree to periods of abstinence (no sex) during the study and agree not to use vaginal 
products throughout the study.  The details will be discussed with you.   
 
If you are eligible and decide to enroll, the following may happen at every additional visit:  
Your contact information will be reviewed and updated as needed 
Your medical history and medication use will be reviewed and updated as needed 
You will be asked to complete a study questionnaire 
You will have your blood pressure taken and a urine pregnancy test performed 
A bimanual exam (to feel uterus and ovaries) will be done as part of the pelvic exam only as 
clinically indicated 
A physical exam may be performed as needed 
You will be reminded of abstinence requirements and of the importance of not using other 
vaginal products throughout the study 
Condoms and protocol counseling will be reviewed; condoms will be provided if you need them 
The next study visit will be scheduled 
You will be provided of results of tests that would impact your care (i.e. STD testing results, 
results of evaluations as a result of vaginal complaints, pregnancy test results).  You will not be 
given the results of the tests that are done for research purposes (i.e. vaginal fluid and CVL).   
You may be offered treatment for infections diagnosed during the study or you will be referred 
for treatment 
 
Visit 2 (Enrollment; Day 0):  Duration of visit = approx. 1 ½ hours 
At this visit, you will:  
Answer acceptability questions related to the vaginal film. 
Have a pelvic examination, including a visual examination of the outside of your vagina, and a 
speculum examination.  The study clinician will check your vagina and cervix for signs of 
infection or any problems.  Vaginal and cervical fluids will be collected to test for bacteria, 
organisms and baseline tests.   If an infection is present you may be offered treatment or 
referred for treatment as needed.  
If you are bleeding, the visit will need to be re-scheduled within 45 days of the screening.   
Be randomly assigned by study staff to one of the four study groups.   
The film will be obtained from the pharmacy and given to you with verbal/written instructions on 
how to insert it.  A researcher will remain in the room, behind a curtain while you attempt to 
insert it in case you have questions and to time the insertion. 
Following insertion, the clinician will do a quick look at the outside genital area to be sure she 
cannot see the film.   
   
If the film is seen outside or if you are unable to get the film in, a new film will be dispensed from 
the pharmacy and will be inserted by the clinician using a speculum.  
You will be asked to return for Visit 3 according to your randomized assignment.   
 
 
Visit 3 (Day 3, 7, 10 or 14)  Duration of visit = up to 45 minutes 
At this visit, you will: 

FAME-101 version 1.0 20September2017 
 
Page 47 
Answer acceptability questions related to the vaginal film. 
Have a pelvic examination performed by a study clinician that will include a check of the 
external genital area and vagina and cervix (using a speculum) for signs of an infection or 
problem.  Vaginal and cervical fluids will be collected to test for bacteria and organisms, 
changes that may have occurred during the use of study products and, if necessary, look for 
any other problems. A CVL wash will be repeated. This fluid will be used for additional testing of 
the effect of the study film. 
 
Visit 4 (Day 21) Duration of Visit = up to 45 minutes 
During this visit, you will:   
Answer acceptability questions related to the vaginal film. 
Have a pelvic examination including a visual examination of the outside of your vagina and a 
speculum examination.  The study clinician will check your vagina and cervix for signs of 
infection or any problems.  Vaginal and cervical fluids will be collected to test for bacteria and 
organisms.  A CVL wash will be repeated. This fluid will be used for additional testing of the 
effect of the study film. 
Your study participation will end at this visit. 
 
Interim Visits 
It may be necessary for additional visit(s) during your participation in this study to have any of 
the study procedures listed above repeated in the event of unforeseen or unanticipated 
abnormal results; difficulties in sample delivery, processing, or testing; and/or if you experience 
any vaginal symptoms.  Additional relevant testing may be done as determined by a study 
clinician (i.e. urine dip to test for infection, herpes culture, etc.). 
 
It may also be necessary for the study staff to call you after your last study visit if you have any 
side effects that need to be followed.  In the rare event you become pregnant while participating 
in the study, the study staff will refer you for appropriate care.  The investigator would 
encourage you to stay in the study so that safety data could be collected.  Additional genital 
samples will not be collected and a pelvic exam will not be performed unless you are 
experiencing vaginal symptoms that the investigator feels needs to be evaluated.   Study staff 
would need to follow up with you by telephone until the outcome of your pregnancy is known. 
 
RISKS AND/OR DISCOMFORTS  
 
Blood draw 
You may have excessive bleeding, discomfort, dizziness, fainting, a small blood clot, bruising, 
swelling or infection.  
 
Pelvic Exam and Sample Collection 
During pelvic exams and sample/fluid collection, you may feel discomfort or pressure in your 
vagina and/or pelvis.     
 
Vaginal Film 
The vaginal film may cause some side effects.  We do not yet know all the side effects of the 
film.  Some, but not all women who used film in other studies have had: 
Discharge from the vagina 
Irritation and discomfort 
 
Discussing Sexual Practices, Being tested for STDs and Waiting for Test Results 

FAME-101 version 1.0 20September2017 
 
Page 48 
You may become embarrassed and/or worried when discussing your sexual practices, ways to 
protect against HIV and other infections passed through sex, and your test results.  You may be 
worried while waiting for your test results.  If you have HIV or other STDs, learning this could 
make you worried.  Trained study staff will help you deal with any feelings or questions you 
have. Finding out your HIV status could also cause problems between you and your partner.  If 
you have any problems, study staff will talk with you and/or your partner to try to help resolve 
them. 
 

FAME-101 version 1.0 20September2017 
 
Page 49 
Breach of Confidentiality 
We will make every effort to protect your privacy and confidentiality during the study visits.  Your 
visits will take place in private.  However, it is possible that others may learn of your 
participation here and, because of this, may treat you unfairly or discriminate against you.  For 
example, you could have problems getting or keeping a job, or being accepted by your family or 
community.   
 
You could have these side effects or other side effects that we do not know about. 
 
BENEFITS 
You may get no benefit from participating in this study.  Information learned from this study may 
help in the development of vaginal products for women.   
 
You will have exams and HIV/STI testing as part of your participation in this study.  You may 
receive treatment for certain STIs as explained above or you will be referred for treatment.     
 
NEW INFORMATION 
You will be told any new information learned during this study that might affect your willingness 
to stay in the study.   
 
STOPPING STUDY DRUG OR BEING WITHDRAWN EARLY 
A study doctor may need to remove you from the study early without your permission if: 
The study is stopped or cancelled  
You are not able to keep appointments 
Other reasons that may prevent you from completing the study successfully 
Participants who withdraw or who are withdrawn from the study prior to completing follow up 
may be asked to complete a final study visit.   
 
COSTS TO YOU 
There is no cost to you for study related visits, the vaginal film, physical examinations, 
laboratory tests or other study procedures.  Treatments available to you from the study site for 
infections passed through sex may be given at no cost to you or you may be referred for 
available treatment while you are in the study. 
 
REIMBURSEMENT 
You will receive compensation for your time, effort, and travel at the end of each study visit if all 
study procedures were completed.  
   Visit 1 (Screening): 
 
$50 
   Visit 2 (Enrollment):    
 
$50 
   Visit 3 (Randomized Visit):      $100 (if compliant with appointment day/time) 
   Visit 4 (Final Visit) : 
 
$50 
 
You will receive male condoms as needed at no cost to you.   Parking passes will be provided 
as needed.  
 
CONFIDENTIALITY 
Every effort will be made to keep your information confidential.  However, it is not possible to 
guarantee confidentiality.  Your personal information may be disclosed if required by law.  The 
study staff may use your personal information to verify that you are not in any other research 

FAME-101 version 1.0 20September2017 
 
Page 50 
studies.  This includes studies conducted by other researchers about which study staff know.  
Any publication of this study will not use your name or identify you personally. 
 
Your records may be reviewed by: 
NIH, and/or contractors of NIH 
Study monitors 
University of Pittsburgh Research Conduct and Compliance Office 
Study staff 
 
If you test positive for gonorrhea, chlamydia, or HIV, the Commonwealth of Pennsylvania 
requires that your name be given to the Allegheny County Health Department.  You may be 
contacted and asked questions about your sexual partner(s). 
 
The investigators may use or disclose, for purposes described above, identifiable information 
(which may include identifiable medical information) related to your being in this study for a 
minimum of 7 years and for as long (indefinite) as it may take to complete this study. 
 
A description of this clinical trial will be available on http://www.clinicaltrials.gov.. This website 
will not include information that can identify you. At most, the website will include a summary of 
the results. You can search this website at any time. 
 
FUTURE USE OF STUDY SAMPLES 
 
By participating in this study, you allow the researchers to use any leftover study samples (i.e. 
vaginal swabs, cervical or vaginal fluid) -- identified only by your unique research number – for 
future use on the female genital tract. and how the body responds to infections.  You would not 
be told or learn of the results.  Your specimens used in this research study may contribute to a 
new discovery or treatment.  In some instances, these discoveries or treatments may be of 
commercial value and may be sold, patented, or licensed by the investigators and the University 
of Pittsburgh for use in other research or the development of new products.  You will not retain 
any property rights nor will you share in any money that the investigators, the University of 
Pittsburgh, or their agents may realize. 
 
RESEARCH-RELATED INJURY 
If you believe that the research procedures have resulted in an injury to you, immediately 
contact the Principal Investigator who is listed on the first page of this form.  Emergency 
medical treatment for injuries solely and directly related to your participation in this research 
study will be provided to you by the hospitals of UPMC.  Your insurance provider may be billed 
for the costs of this emergency treatment, but none of those costs will be charged directly to 
you.  If your research related injury requires medical care beyond this emergency treatment, 
you will be responsible for the costs of this follow-up care.  At this time, there is no plan for any 
additional financial compensation.  The US National Institutes of Health (NIH) does not have a 
mechanism to provide compensation for research related injury.   
 
YOUR RIGHTS AS A RESEARCH PARTICIPANT/VOLUNTEER 
Taking part in this study is completely voluntary.  You may choose not to take part in this study 
or leave this study at any time.  If you choose not to participate or to leave the study, you will 
not lose the benefit of services to which you would otherwise be entitled at this clinic.  If you 
want the results of the study after the study is over, let the study staff members know. 
 
PROBLEMS OR QUESTIONS 

FAME-101 version 1.0 20September2017 
 
Page 51 
If you ever have any questions about the study, or if you have a research-related injury, you 
should contact Katherine Bunge, MD or the research staff at (412) 641-4242. If you ever have 
any questions about your rights as a research participant, you can contact the University of 
Pittsburgh IRB at 1-866-212-2668.   
 
VOLUNTARY CONSENT 
The above information has been explained to me and all of my current questions have been 
answered.  I understand that I am encouraged to ask questions, voice concerns or complaints 
about any aspect of this research study during the course of this study, and that such future 
questions, concerns or complaints will be answered by a qualified member of the research team 
or by the principal investigator listed on the first page.  I understand that I may always request 
that my questions, concerns or complaints be addressed by the Principal Investigator.  At any 
time I may also contact the Human Subjects Protection Advocate of the IRB Office, University of 
Pittsburgh (1-866-212-2668) to discuss problems, concerns and questions; obtain information; 
offer input; or discuss situations in the event that the research team is unavailable.  By signing 
this form I agree to participate in this research study for the purposes described above.  A copy 
of this consent form will be offered to me. 
 
 
___________________________________   
Printed Name of Participant 
 
 
 
 
___________________________________ 
______________ 
______________ 
Participant Signature 
 
 
 
Date  
 
Time (am/pm) 
 
 
 
 
CERTIFICATION OF INFORMED CONSENT:  I certify that I have explained the nature and 
purpose of this research to the above individual and I have discussed the potential benefits and 
possible risks of study participation.  Any questions the individual has about this study have 
been answered, and we will always be available to address future questions as they arise.  I 
further certify that no research component of this protocol was begun until after this consent 
form was signed. 
 
 
________________________________________ 
 
____________________ 
Printed Name of Person Obtaining Consent 
 
 
Role in Research Study 
 
 
________________________________________ 
 
____________________ 
Signature of Person Obtaining Consent  
 
 
Date 
 
 
 
 
 

FAME-101 version 1.0 20September2017 
 
Page 52 
APPENDIX IV 
Study summary for F2‐5.1: Placebo (Extended release film): super‐dosing SAFETY STUDY 
 
 
Background: A vaginal film platform has been designed to provide extended release of an API over (at least) 
seven days. The film is optimized for Appearance, Dissolution, Disintegration and Manufacturability. Placebo 
films with excipients expected to tolerate MK‐2048 drug loading have been provided for pre‐clinical testing. 
Purpose: This safety study will assess responses in the cervicovaginal environment with placebo film “super‐ 
dosing.” Rather than once a week dosing, we will expose macaques to two films per week for two weeks. 
We will assess the vaginal microflora, pH, PMN influx, and surface tissues after four film placements over two 
weeks. Additionally, we will detect the level of one of the film platform polymers using PK analysis, as an indicator 
of residual film presence on day 14 of the study. 
Design: 
 
 
 
Vaginal Flora: Two Vaginal swabs (dacron) collected from mid‐depth vaginal canal and placed in MaxV 
transporter tubes for overnight delivery to MWRI (Pittsburgh, PA) for semi‐quantitative microbiologic 
assessment. 
Vaginal pH/smear: Vaginal pH: Dab head of a Dacron tipped swab onto a pH indicator strip (resolution 0.5 pH 
units) to document vaginal pH. Vaginal smear‐Gram stain: Roll the Dacron tipped swab of vaginal exudate on a 
glass microscope slide. The smear is air dried and subsequently Gram stained for identification and 
quantification of polymorphonuclear cells. 
Colposcopy: Colposcopy to take place after vaginal secretion collections. If vaginal exudate/product remnant 
obscures the cervix, save images of the cervicovaginal site prior to clearing out vaginal exudate. Then clear area 
and continue with colposcopy. Note observations and document with digital photography. Adverse findings 
include any break in the integrity of the epithelial layer, deeply erythematous or friable tissues, and microulcers.  
Note: Limited colposcopic exams and photos were additionally collected just prior to and immediately            after 
each film placement. Remnant film product was noted, but not removed at these visits. 

FAME-101 version 1.0 20September2017 
 
Page 53 
CVL: Collect two 2mL saline CVLs: (“‐1”) before cleaning the site for colposcopy if necessary, and again (“‐2”) 
after conducting colposcopy. Split the recovery fluid from each CVL into two cryovials and freeze (‐80C) for 
future PK analysis [UCD]. 
Film placement: Administer test film to the vaginal fornix. 
 
 
RESULTS 
 
 
 
Vaginal Microflora: 
Placebo Films had no effect on beneficial (H2O2 producers) microorganisms after repeated exposures: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Shifts in potentially harmful microorganisms after super‐dosing: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
There was a low prevalence of E. coli and G. vaginalis organisms, neither of which increased after film use. 
Other potentially deleterious organisms S. aureus and enterococcus were not cultured from any specimens. 
Day 0 
Day 3 
Day 7 
Day 10 
Day 14 
Vaginal Microflora 
√ 
√ 
8
7
6
5
4
3
2
1
0
DAY 0 
DAY 14 
H2O2 +  Lactobacilli 
H2O2 +  Viridans 
7
6
5
4
3
2
1
0
DAY 0 
DAY 14 
G. vaginalis 
E. coli 
Number of macaques with 
organism cultured 
Number of macaques with 
organism cultured 

FAME-101 version 1.0 20September2017 
 
Page 54 
Prevalence of each microorganism detected in vaginal swabs remained quite stable after super‐dosing with the 
placebo film platform for extended release API. 
 
 
Compiled PREVALENCE: Super-Dosing Placebo 
for Extended Release API 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
n=7 macaques 
 
 
 
 
 
A data table displaying semi‐quantitative scores for each sample is appended under Raw Data. 
Day 0 
Pre- 
Exposure 
Day 14 
H2O2 +  Lactobacilli 
6 
6 
H2O2 - Lactobacilli 
1 
1 
H2O2 +  Viridans 
5 
5 
H2O2 - Viridans 
7 
5 
G. vaginalis 
1 
1 
S. aureus 
0 
0 
coagulase-negative Staph 
6 
5 
group B Strep 
0 
0 
group C Strep 
0 
0 
group F Strep 
1 
0 
group G Strep 
0 
0 
non-groupable Beta-Strep 
0 
0 
diptheroids 
7 
7 
E. coli 
2 
0 
enterococcus 
0 
0 
black anaerobic Gram Negative Rods 
7 
7 
non-pigmented anaerobic GNR 
7 
7 
other anaerobic GNR 
0 
0 
micrococcus 
0 
0 
proteus 
0 
0 
bacillus 
0 
0 
aerobic Gram-positive rods 
6 
5 
aerobic Gram-positive cocci 
1 
2 

FAME-101 version 1.0 20September2017 
 
Page 55 
 
 
 
 
Vaginal PMN response after cumulative exposures to the extended release Film Platform (as noted by Gram 
stained vaginal smears): 
Gram stained vaginal smears were assessed for presence of red blood cells (RBC) and polymorphonuclear cells 
(PMN) as indicators of a white blood cell infiltrate. RBC are generally associated with menses. In a population of 
120 control pigtail macaques to date, we have calculated a normal range of PMNs to fall between 0 and 15 PMNs 
per high power field (unpublished). This normal range appears lightly shaded in the line graph below. 
The graph below plots the mean values (from 5 high power non‐adjacent fields) of PMN counts for each macaque 
at baseline and on day 14. Both of the macaques with elevated PMN counts on Day 0 were menstruating, as was 
T02319 on Day 14. Clearly this film platform does not elicit a PMN response even when administered more 
frequently than intended. Raw data is appended. 
 
 
 
PMN counts: PLACEBO FILM 
40
35
30
25
20
15
10
Normal range 
5
0
Day 0 
Day 14 
A07101 
A10010 
A10200 
K05007 
T02319 
W04064 
Z08187 
Day 0 
Day 3 
Day 7 
Day 10 
Day 14 
Vaginal fluid PMNs 
√ 
√ 

FAME-101 version 1.0 20September2017 
 
Page 56 
 
 
 
 
Vaginal pH Super dosing with extended release vaginal films did not have a deleterious effect on vaginal pH, 
which normally measures 5.0‐8.5 in pigtail macaques. Of four samples that measured pH 7.0 or higher in this 
study, three were collected during menses. 
 
 
 
 
 
 
 
The weight and temperature of each animal also remained within normal ranges. No indication of adverse 
health responses to multiple film exposures were noted. 
Vaginal pH: PLACEBO FILM 
9 
8.5
8 
7.5
7 
6.5
6 
5.5
5 
4.5
4 
D0 
D14 
A07101 
A10010 
A10200 
K05007 
T02319 
W04064 
Z08187 
Day 0 
Day 3 
Day 7 
Day 10 
Day 14 
Vaginal pH 
√ 
√ 

FAME-101 version 1.0 20September2017 
 
Page 57 
 
 
 
 
Cervicovaginal Lavage samples were stored at ‐80oC in the Patton Laboratory, then shipped to UC Denver (Core 
C). They will be assessed by PK analysis for polymer detection as a marker for film presence in the macaque 
vagina. Optimizing the conditions for PK detection of the polymer will allow future studies to include drug 
deposition and film platform presence to be distinguished from each other. 
Two CVL samples were collected from each macaque on study day 14. One (CVL‐1) was collected prior to clearing 
residual film for colposcopy; the second (CVL‐2) was collected after removing residual film product. In addition to 
CVL, a sample of residual film from two macaques was frozen and provided to the PK lab. 
The data from these samples will be reported separately, and are not expected to impact the safety findings. 
Day 0 
Day 3 
Day 7 
Day 10 
Day 14 
Cervicovaginal Lavage (PK) 
√ 

FAME-101 version 1.0 20September2017 
 
Page 58 
 
 
 
 
Colposcopy No adverse findings were noted by colposcopy. Residual film was frequently noted. When an 
animal was menstruating, the residual took on a brown to red tone as seen in photos. Otherwise the residual 
appeared white. No formulation induced changes to the cervicovaginal tissues were noted. 
 
 
Colposcopy photo plates follow. 
Day 0 
Day 3 
Day 7 
Day 10 
Day 14 
Colposcopy 
√ 
√ 
√ 
√ 
√ 

F2‐5.1 Extended Release Film Platform: Super Dosing Safety Study 
Framed 
photos 
indicate time 
points when 
specimens 
M :Menses 
 
 
 
 
 
A07101 
 
Prior to 
Film 
Placement 
 
 
Film 
placed 
Film 1 
 
 
 
 
 
 
M 
Film 2 
Film 3 
Film 4 
 
 
 
 
 
A10010 
 
Prior to 
Film 
placement 
 
 
Film 
placed 
Baseline 
appearance 
(menses) 
Residual film 
appears white 
+ menses 
Residual film 
+ exudate 
Residual film 
+ exudate 
Residual film 
+ exudate 
 
 
 
Baseline appearance. 
Edema 
Some residual 
film noted in 
exudate 
Focal 
erythema 
(normal near 
menses), 
Residual film 
Residual film 
+ menses 
Residual film 
+ exudate 
Day 0 
Day 3 
Day 7 
Day 10 
Day 14 
M
M

F2‐5.1 Extended Release Film Platform: Super Dosing Safety Study 
Framed 
photos 
indicate time 
points when 
specimens 
M :Menses 
 
 
 
 
 
A10200 
 
Prior to 
Film 
placement 
 
 
 
Film 
placed 
Film 1 
Film 2 
Film 3 
Film 4 
 
 
Baseline appearance 
 
K05007 
 
Prior to 
Film 
Placement 
 
 
Film 
placed 
Residual film 
appears white 
Residual film + 
menses 
Residual film 
post‐menses 
Residual film 
 
 
 
Baseline appearance 
Residual film 
appears 
white/yellow 
Residual film 
(suspected 
end of 
menses) 
Residual film 
Residual film 
+ exudate 
Day 0 
Day 3 
Day 7 
Day 10 
Day 14 
M

F2‐5.1 Extended Release Film Platform: Super Dosing Safety Study 
Framed 
photos 
indicate time 
points when 
specimens 
M :Menses 
 
 
 
 
 
T02319 
 
Prior to 
Film 
placement 
 
 
Film 
placed 
Film 1 
Film 2 
Film 3 
Film 4 
 
 
 
 
 
 
W04064 
 
Prior to 
Film 
placement 
 
 
 
Film 
placed 
Baseline 
appearance 
Residual film is 
white & 
original shape 
Residual film is 
white. 
Petechiae 
Residual film 
appears white 
Residual film 
+ menses 
 
 
Baseline appearance 
(menses) 
Residual film 
appears white. 
Focal erythema. 
Residual film 
Residual film 
Residual film 
in pieces 
Day 0 
Day 3 
Day 7 
Day 10 
Day 14 
M
M 

F2‐5.1 Extended Release Film Platform: Super Dosing Safety Study 
 
 
 
 
Z08187 
 
Prior to 
Film 
Placement 
Film 1 
Film 2 
Film 3 
Film 4 
 
 
Film 
placed 
 
 
 
Baseline appearance. 
Edema 
Residual film 
appears white 
+ exudate 
Residual film 
Residual film 
Residual film 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Framed photos 
indicate time 
points when 
specimens 
were collected. 
Day 0 
Day 3 
Day 7 
Day 10 
Day 14 

 
Raw data 
Vaginal Flora: Semi‐quantitative results (0‐4, denoting organism growth on quadrants of a plate) were reported for 
each organism listed. 
 
 
 
 
 
 
N=7 Mn 
A07101 
A10010 
A10200 
K05007 
T02319 
W04064 
Z08487 
Day 
0 
Day 
14 
Day 
0 
Day 
14 
Day 
0 
Day 
14 
Day 
0 
Day 
14 
Day 
0 
Day 
14 
Day 
0 
Day 
14 
Day 
0 
Day 
14 
H2O2 +  Lactobacilli 
1 
1 
4 
1 
1 
3 
3 
4 
0 
0 
3 
4 
1 
1 
H2O2 - Lactobacilli 
0 
3 
0 
0 
0 
0 
2 
0 
0 
0 
0 
0 
0 
0 
H2O2 +  Viridans 
2 
4 
2 
2 
4 
4 
0 
0 
0 
0 
3 
4 
3 
4 
H2O2 - Viridans 
3 
2 
4 
0 
2 
3 
3 
0 
4 
3 
3 
4 
3 
4 
G. vaginalis 
0 
0 
0 
0 
0 
0 
4 
4 
0 
0 
0 
0 
0 
0 
S. aureus 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
coagulase-negative 
Staph 
2 
0 
2 
2 
0 
2 
2 
3 
4 
2 
3 
0 
2 
3 
group B Strep 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
group C Strep 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
group F Strep 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
3 
0 
0 
0 
group G Strep 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
non-groupable Beta- 
Strep 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
diptheroids 
3 
4 
4 
4 
4 
4 
3 
1 
4 
4 
3 
4 
3 
4 
E. coli 
0 
0 
0 
0 
0 
0 
3 
0 
0 
0 
2 
0 
0 
0 
enterococcus 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
black anaerobic 
Gram Negative Rods 
3 
4 
4 
4 
4 
4 
3 
4 
4 
4 
4 
4 
3 
4 
non-pigmented 
anaerobic GNR 
2 
4 
4 
4 
3 
4 
4 
4 
3 
4 
4 
4 
3 
4 
other anaerobic GNR 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
micrococcus 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
proteus 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
bacillus 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
aerobic Gram- 
positive rods 
3 
4 
3 
4 
4 
2 
0 
0 
4 
4 
3 
0 
2 
3 
aerobic Gram- 
positive cocci 
0 
4 
0 
0 
0 
0 
0 
0 
0 
0 
3 
0 
0 
2 

 
FAME 101-version 1.0 
64  
20Sep17 
Vaginal pH: Vaginal fluid transferred to pH indicator strips (resolution 0.5 pH units) by dabbing VF swab. pH 
measures are noted for Day 0 and Day 14. 
 
Vaginal pH 
D0 
D14 
A07101 
7.5* 
6.5 
A10010 
5.5 
6.5 
A10200 
6.5 
7.5 
K05007 
6.5 
6.5 
T02319 
6 
7* 
W04064 
7* 
6.5 
Z08187 
6.5 
6.5 
*menses 
 
 
Gram stain PMN count from vaginal smear: Polymorphonuclear (PMN) cells were counted in 5 representative 
non‐adjacent high power fields. Presence of red blood cells (RBC) was also noted. 
 
Polymorphonuclear (PMN) Cell Counts 
Animal 
ID 
Study 
Day 
Field 1 Field 2 Field 3 Field 4 Field 5 Total Avg 
RBC Comments 
A07101 
0 
10 
14 
15 
9 
7 
55 
11 
4 
Macaque menstruating 
14 
1 
3 
0 
0 
0 
4 
0.8 
0 
A10010 
0 
1 
1 
1 
1 
1 
5 
1 
0 
14 
0 
0 
0 
0 
0 
0 
0 
0 
A10200 
0 
0 
0 
0 
0 
3 
3 
0.6 
0 
14 
0 
0 
0 
0 
0 
0 
0 
0 
K05007 
0 
0 
1 
0 
1 
1 
3 
0.6 
0 
14 
0 
0 
0 
0 
0 
0 
0 
0 
T02319 
0 
0 
0 
0 
0 
0 
0 
0 
0 
14 
2 
1 
5 
1 
1 
10 
2 
0 
Macaque menstruating 
W04064 
0 
22 
32 
30 
20 
30 
134 
26.8 
0 
Macaque menstruating; 
WBC seen in cervical mucus 
14 
0 
0 
0 
0 
0 
0 
0 
0 
Z08187 
0 
2 
1 
1 
0 
0 
4 
0.8 
0 
14 
4 
3 
0 
0 
0 
7 
1.4 
0 
RBC   0 = none 
1+ =less than one per field 
2+ =1‐4 per field 
3+ =5‐30 per field 
4+ = greater than 30 per field 

 
FAME 101-version 1.0 
65  
20Sep17 
CVL: Fourteen frozen samples (2/macaque on Day 14) were batch shipped to PK lab at UC Denver. (11/14/2017) 
 
 
Colposcopy: Colposcopy was conducted prior to each film administration, and on study day 14. Common 
findings include edema, erythema, petechiae and ecchymoses. These are routinely noted in cycling macaques 
regardless of vaginal product use. In this study, tissue edema and erythema were noted by quartile of tissue 
coverage (0, 25%. 50%, 75% or 100%). Petechiae and ecchymoses were noted if present. Adverse findings would 
include any break in the integrity of the epithelial layer, deeply erythematous or friable tissues, and 
micro‐ulcers. No adverse findings were noted in this study. The raw colposcopic data is compiled in the 
following table. 
 

 
FAME 101-version 1.0 
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FAME 101-version 1.0 
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20Sep17 
1. 
UNAIDS. Report on the global HIV/AIDS epidemic 2008. 
2. 
UNAIDS. AIDS epidemic update: November 2009. 
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Steiner M, Spruyt A, Joanis C, et al. Acceptability of Spermicidal Film and Foaming Tablets 
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Visness CM, Ulin P, Pfannenschmidt S, Zekeng L. Views of Cameroonian sex workers on a 
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Raymond E, Alvarado G, Ledesma L, et al. Acceptability of two spermicides in five countries. 
Contraception 1999;60:45-50. 
6. 
Schley A. IPM Product Acceptability Study II (PAS II). International Partnership for 
Microbicides; 2009. 
7. 
Nel AM, Mitchnick LB, Risha P, Muungo LT, Norick PM. Acceptability of vaginal film, soft-
gel capsule, and tablet as potential microbicide delivery methods among African women. J Womens 
Health (Larchmt) 2011;20:1207-14. 
8. 
Raymond EG, Chen PL, Condon S, et al. Acceptability of five nonoxynol-9 spermicides. 
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9. 
Pittsburgh Uo. Institutional Review Board Manual. http://wwwirbpittedu/manual/.