Acceptability, Tolerability, and Adherence of Three Rectal Microbicide Placebo Formulations Among HIV Seronegative Cisgender Men, Transgender Men and Transgender Women Who Engage in Receptive Anal Intercourse
Phase: NA
Conditions: HIV Prevention
Sponsor: Microbicide Trials Network

MTN-035 
 
 
 
 
Acceptability, Tolerability, and Adherence of Three Rectal Microbicide Placebo 
Formulations among HIV Seronegative Cisgender Men, Transgender Men and 
Transgender Women Who Engage in Receptive Anal Intercourse 
 
 
 
 
Microbicide Trials Network 
 
 
Funding Agencies: 
Division of AIDS, US National Institute of Allergy and Infectious Diseases 
US Eunice Kennedy Shriver National Institute of  
Child Health and Human Development 
US National Institute of Mental Health 
US National Institutes of Health 
 
 
 
Grant Numbers: 
UM1AI068633, UM1AI068615, UM1AI106707 
 
 
 
DAIDS Protocol ID: 38459 
 
 
 
A Non-IND Study 
 
 
 
Protocol Chair: José A. Bauermeister, PhD, MPH 
 
 
 
Version 1.0 
 
June 15, 2018

 
 
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June 15, 2018 
 
MTN-035 
 
Acceptability, Tolerability, and Adherence of Three Rectal Microbicide Placebo 
Formulations among HIV Seronegative Cisgender Men, Transgender Men and 
Transgender Women Who Engage in Receptive Anal Intercourse 
 
TABLE OF CONTENTS 
 
LIST OF ABBREVIATIONS AND ACRONYMS ..................................................................... 5 
PROTOCOL TEAM ROSTER ............................................................................................... 8 
INVESTIGATOR SIGNATURE FORM ................................................................................ 18 
PROTOCOL SUMMARY ..................................................................................................... 19 
1 KEY ROLES .................................................................................................................. 21 
1.1 
Protocol Identification ............................................................................................ 21 
1.2 
Funding Agencies and Sponsor Identification ....................................................... 22 
1.3 
Medical Officer ...................................................................................................... 22 
1.4 
Clinical Laboratories ............................................................................................. 22 
1.5 
Data Centers ......................................................................................................... 22 
1.6 
Study Implementation ........................................................................................... 23 
2 INTRODUCTION ........................................................................................................... 24 
2.1 
Background of Rectal Microbicide Research and Study Rationale ....................... 24 
2.2 
Description of Study Products ............................................................................... 28 
2.3 
Acceptability of non-gel rectal microbicide formulations ........................................ 31 
2.4 
Practices commonly associated with RAI ............................................................. 33 
2.5 
Study Hypotheses and Rationale for Study Design .............................................. 34 
3 OBJECTIVES................................................................................................................. 35 
3.1 
Primary Objectives ................................................................................................ 35 
3.2 
Exploratory Objective ............................................................................................ 35 
4 STUDY DESIGN ............................................................................................................ 35 
4.1 
Identification of Study Design ................................................................................ 35 
4.2 
Summary of Major Endpoints ................................................................................ 36 
4.3 
Description of Study Population ............................................................................ 36 
4.4 
Time to Complete Accrual ..................................................................................... 36 
4.5 
Study Groups ........................................................................................................ 36 
4.6 
Expected Duration of Participation ........................................................................ 36 
4.7 
Sites ...................................................................................................................... 37 
5 STUDY POPULATION ................................................................................................... 37 
5.1 
Selection of the Study Population ......................................................................... 37 
5.2 
Inclusion Criteria ................................................................................................... 37 
5.3 
Exclusion Criteria .................................................................................................. 38 
5.4 
Co-enrollment Guidelines ..................................................................................... 39 
6 STUDY PRODUCT ........................................................................................................ 40 
6.1 
Regimen................................................................................................................ 40 
6.2 
Administration ....................................................................................................... 40 
6.3 
Study Product Formulation.................................................................................... 41 

 
 
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6.4 
Study Product Supply and Accountability ............................................................. 42 
6.5 
Study Product Dispensing ..................................................................................... 42 
6.6 
Ancillary Study Supplies ....................................................................................... 43 
6.7 
Concomitant Medications and Practices ............................................................... 43 
7 STUDY PROCEDURES ................................................................................................ 43 
7.1 
Pre-screening ........................................................................................................ 44 
7.2 
Screening .............................................................................................................. 44 
7.3 
Enrollment (Day 0) ................................................................................................ 46 
7.4 
Follow-up Visits ..................................................................................................... 47 
7.5 
Follow-up Procedures for Participants Who Permanently Discontinue Study 
Product ................................................................................................................. 50 
7.6 
Protocol Counseling:  Adherence and Study Product Use Counseling ................. 51 
7.7 
Clinical Evaluations and Procedures ..................................................................... 51 
7.8 
Behavioral Evaluations ......................................................................................... 52 
7.9 
Laboratory Evaluations ......................................................................................... 53 
7.10 
Specimen Management ........................................................................................ 54 
7.11 
DAIDS Laboratory Oversight................................................................................. 54 
7.12 
Biohazard Containment ........................................................................................ 55 
8 ASSESSMENT OF SAFETY ......................................................................................... 55 
8.1 
Safety Monitoring .................................................................................................. 55 
8.2 
Clinical Data and Safety Review ........................................................................... 55 
8.3 
Adverse Events Definitions and Reporting Requirements .................................... 56 
8.4 
Pregnancy and Infant Outcomes ........................................................................... 58 
8.5 
Regulatory Requirements ..................................................................................... 58 
8.6 
Social Harms Reporting ........................................................................................ 58 
9 CLINICAL MANAGEMENT ............................................................................................ 58 
9.1 
Grading System .................................................................................................... 59 
9.2 
Dose Modification Instructions .............................................................................. 59 
9.3 
General Criteria for Permanent Discontinuation of Study Product ........................ 59 
9.4 
Follow-up in Response to Observed Adverse Events ........................................... 60 
9.5 
Sexually Transmitted Infection/Reproductive Tract Infection ................................ 60 
9.6 
HIV-1/2 Infection ................................................................................................... 60 
9.7 
Pregnancy ............................................................................................................. 60 
9.8 
Criteria for Early Termination of Study Participation other than HIV-1/2 Infection 
and Pregnancy ...................................................................................................... 61 
10 STATISTICAL CONSIDERATIONS ............................................................................... 61 
10.1 
Overview and General Design .............................................................................. 61 
10.2 
Study Endpoints .................................................................................................... 61 
10.3 
Sample Size and Power ........................................................................................ 62 
10.4 
Randomization Procedures ................................................................................... 63 
10.5 
Participant Accrual and Retention ......................................................................... 63 
10.6 
Data and Safety Monitoring Procedures ............................................................... 63 
10.7 
Data Analyses ....................................................................................................... 64 
10.8 
Missing Data ......................................................................................................... 64 
11 DATA HANDLING AND RECORDKEEPING ................................................................. 65 
11.1 
Data Management Responsibilities ....................................................................... 65 

 
 
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11.2 
Source Documents and Access to Source Data/Documents ................................ 65 
11.3 
Quality Control and Quality Assurance ................................................................. 66 
12 CLINICAL SITE OVERSIGHT ........................................................................................ 66 
13 HUMAN SUBJECTS PROTECTIONS ........................................................................... 66 
13.1 
Institutional Review Boards/Ethics Committees .................................................... 66 
13.2 
Protocol Registration ............................................................................................. 67 
13.3 
Study Coordination ............................................................................................... 68 
13.4 
Risk Benefit Statement ......................................................................................... 68 
13.5 
Informed Consent Process.................................................................................... 70 
13.6 
Participant Confidentiality...................................................................................... 70 
13.7 
Special Populations .............................................................................................. 71 
13.8 
Compensation ....................................................................................................... 72 
13.9 
Communicable Disease Reporting ........................................................................ 72 
13.10 Access to HIV-related Care................................................................................... 72 
13.11 Study Discontinuation ........................................................................................... 72 
14 PUBLICATION POLICY ................................................................................................. 73 
15 APPENDICES ................................................................................................................ 74 
APPENDIX I:  SCHEDULE OF STUDY VISITS AND EVALUATIONS ................................ 75 
APPENDIX II:  ALGORITHM FOR HIV TESTING FOR SCREENING AND FOLLOW-UP . 77 
APPENDIX III: SAMPLE INFORMED CONSENT FORM (SCREENING AND 
ENROLLMENT) .................................................................................................................. 78 
REFERENCES .................................................................................................................... 92 
 
TABLE OF FIGURES 
 
Table 1: MTN-035 Study Product Regimen ......................................................................... 20 
Table 2: Witepsol® H5-based suppository products currently on the market ....................... 31 
Table 3: Study Product Regimen ........................................................................................ 40 
Table 4:  Visit 1- Screening Visit ......................................................................................... 45 
Table 5:  Visit 2- Enrollment Visit ........................................................................................ 46 
Table 6:  Visits 3, 5 and 7 – First, Second and Third PUEV ................................................ 47 
Table 7:  Visits 4 and 6 – Product Switch Visits .................................................................. 48 
Table 8:  Visit 8 – Final/Early Termination Visit ................................................................... 49 
Table 9:  Exact 2-sided 95% Confidence Intervals Based on Various Rates of 
Acceptability or Adherence Endpoints ................................................................................. 63 
Table 10:  Analysis of Safety Event Frequency ................................................................... 63 
 
Figure 1: MTN-035 Study Visit Schedule ............................................................................ 20 
Figure 2: MTN-035 Study Visit Schedule ............................................................................ 43 
 
 

 
 
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MTN-035 
 
Acceptability, Tolerability, and Adherence of Three Rectal Microbicide Placebo 
Formulations among HIV Seronegative Cisgender Men, Transgender Men and 
Transgender Women Who Engage in Receptive Anal Intercourse 
 
LIST OF ABBREVIATIONS AND ACRONYMS 
 
AE 
adverse event 
AIDS 
Acquired Immunodeficiency Syndrome 
AI 
AUC 
anal intercourse 
area under the curve 
BRWG 
Behavioral Research Working Group 
BV 
CASI 
bacterial vaginosis 
computer assisted self-interview 
CBC 
complete blood count 
CDC 
Centers for Disease Control and Prevention 
CFR 
Code of Federal Regulations 
CI 
Confidence Interval 
CRF 
case report form 
CRS 
Clinical Research Site 
CT 
Chlamydia trachomatis, Chlamydia 
CTA 
Clinical Trial Agreement 
CWG 
Community Working Group 
DAIDS 
Division of AIDS 
DAIDS PRO 
DAIDS Protocol Registration Office 
DNA 
deoxyribonucleic acid 
DOD 
directly observed dosing 
ENR 
enrollment 
FDA 
(US) Food and Drug Administration 
FHCRC 
Fred Hutchinson Cancer Research Center 
g 
grams 
GC 
Neisseria gonorrhoeae, gonorrhea 
GCP 
Good Clinical Practices 
GMP 
Good Manufacturing Practices 
HCG 
human chorionic gonadotropin 
HEENT 
Head, Eye, Ear, Nose and Throat Examination 
HHS 
(U.S.) Department of Health and Human Services 
HIV 
Human Immunodeficiency Virus 
HIV-1 
Human Immunodeficiency Virus type 1 
HSV 
herpes simplex virus 
HSV-1/2 
herpes simplex virus type 1/2 
IATA 
International Air Transport Association 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 

 
 
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IDI 
IEC 
In-Depth Interview 
Independent Ethics Committee 
IM 
instant message 
IND 
Investigational New Drug 
IoR 
Investigator of Record 
IRB 
Institutional Review Board 
IUD 
IVR 
intrauterine device 
intravaginal ring 
kg 
kilogram 
LC 
Laboratory Center 
LDMS 
Laboratory Data Management System 
LOC 
Leadership and Operations Center 
μg 
microgram 
MDP 
Microbicides Development Programme 
mg 
milligram 
mL 
milliliter 
mM 
millimolar 
MO 
Medical Officer 
mOsm 
milliosmole 
MSM 
men who have sex with men 
MTN 
Microbicide Trials Network 
n 
number 
N-9 
nonoxynol-9 
NAAT 
nucleic acid amplification test 
NF 
National Formulary 
ng 
nanogram 
nM 
nanomolar 
NIAID 
National Institute of Allergy and Infectious Diseases 
NICHD 
National Institute of Child Health and Human Development 
NIH 
National Institutes of Health 
NIMH 
National Institute of Mental Health 
NL 
network laboratory 
OHRP 
Office for Human Research Protections 
PBS 
phosphate-buffered saline 
PEP 
post-exposure prophylaxis 
PoR 
Pharmacist of Record 
PrEP 
pre-exposure prophylaxis 
PRO 
Protocol Registration Office 
PSP 
Prevention Sciences Program 
PSRT 
Protocol Safety Review Team 
PTID 
PUEV 
participant identification 
product use end visit 
RAI 
receptive anal intercourse 
RE 
Regulatory Entity 
RH 
Relative Humidity 
RNA 
ribonucleic acid 
RSC 
Regulatory Support Center 
RTI 
reproductive tract infection 
SAE 
serious adverse event 

 
 
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SCHARP 
Statistical Center for HIV/AIDS Research & Prevention 
SCR 
screening 
SDMC 
Statistical Data Management Center 
SMC 
Study Monitoring Committee 
SOP 
standard operating procedure 
SMS 
short message service 
SSP 
study specific procedures 
STI 
sexually transmitted infection 
SUSAR 
suspected, unexpected serious adverse reaction 
TGM 
TGW 
transgender men 
transgender women 
UA 
urinalysis 
UNAIDS 
UNGASS 
UPMC 
Joint United Nations Programme on HIV/AIDS 
United Nations General Assembly Special Session 
University of Pittsburgh Medical Center 
USA 
United States of America 
USP 
United States Pharmacopoeia 
UTI 
urinary tract infection 
WHO 
World Health Organization 

 
 
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MTN-035 
 
Acceptability, Tolerability, and Adherence of Three Rectal Microbicide Placebo 
Formulations among HIV Seronegative Cisgender Men, Transgender Men and 
Transgender Women Who Engage in Receptive Anal Intercourse 
PROTOCOL TEAM ROSTER 
 
 
 
Protocol Chair 
 
Jose A. Bauermeister, MPH, PhD 
Protocol Chair 
University of Pennsylvania 
418 Curie Blvd., Suite 222L 
Philadelphia, PA 19104 
Phone: 215-898-9993 
Email: bjose@upenn.edu 
 

 
 
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Site Investigators  
 
University of Pittsburgh Clinical Research Site (CRS) 
 
Ken Ho, MD 
Site Investigator 
UPMC, Keystone Building, Suite 531 
Division of Infectious Diseases 
3520 Fifth Avenue 
Pittsburgh, PA 15213 USA 
Phone: 412-383-7178 
Fax: 412-383-2900 
Email: hok2@upmc.edu 
 
 
Alabama CRS 
 
Craig Hoesley, MD 
Site Investigator 
University of Alabama at Birmingham 
1530 3rd Avenue South, VH 201 
Birmingham, AL 35294 USA 
Phone: 205-934-3365 
Fax: 205-975-3232 
Email: choesley@uab.edu 
 
 
Bridge HIV CRS 
 
Albert Liu, MD, MPH 
Site Investigator 
Clinical Research Director 
Bridge HIV CRS 
San Francisco Department of Public Health 
25 Van Ness Avenue, Suite 100 
San Francisco, CA 94102 USA 
Phone: 415-437-7408 
Fax: 415-431-7029 
Email: albert.liu@sfdph.org 
 
Blantyre CRS 
 
Taha E. Taha, PhD 
CTU PI 
Johns Hopkins University  
Bloomberg School of Public Health,  
615 N. Wolfe Street 
Baltimore, MD 21205 
Phone: 410-614-5255 
Fax: 410-502-0688 
Email: ttaha@jhsph.edu 

 
 
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Noel Kayange, MBBS, MMED 
Site Investigator 
Johns Hopkins University Research Project  
Chipatala Avenue 
P.O. Box 1131  
Blantyre, Malawi  
Phone: 265-1875-129  
Fax: 265-1870-132  
Email: nkayange@jhu.medcol.mw 
 
 
Wits Reproductive Health and HIV Institute (Wits RHI) CRS 
 
Helen Vera Rees, OBE, MBBChir, MA, DRCOG, DCH 
CTU Co-PI 
Wits Reproductive Health and HIV Institute (Wits RHI)  
22 Esselen Street, Hillbrow  
Johannesburg, 2001 South Africa 
Phone: 27-11-358-5300  
Email: hrees@wrhi.ac.za 
 
Thesla Palanee-Phillips, MMed Sci, MSc, PhD  
Site Investigator 
Wits Reproductive Health and HIV Institute (Wits RHI)  
Research Centre  
7 Esselen Street, Hillbrow  
Johannesburg, 2038 South Africa  
Phone: 27-11-358-5471  
Fax: 27-86-554-1093  
Email: tpalanee@whri.ac.za 
 
 
Chiang Mai University (CMU) HIV Prevention CRS 
 
Suwat Chariyalertsak, MD, Dr.PH 
Site Investigator 
Research Institute for Health Sciences  
Chiang Mai University 
P.O. Box 80 CMU,    
Chiang Mai 50202 Thailand  
Phone: 66 53 945055 
Fax:  66 53 221849 
Email: suwat.c@cmu.ac.th 
 
 

 
 
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San Miguel CRS 
 
Pedro Gonzales, MD, MAS 
Site Investigator 
IMPACTA – San Miguel CRS 
Calle Putumayo No.177 
San Miguel, 15088, Peru  
Phone: 51-1- 562-1600 Ext 628 
Fax: 51-1- 562-1600 Ext 128 
Email: pgonzales@impactaperu.org 
 
 
 
 
 

 
 
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US National Institutes of Health (NIH) 
 
Roberta Black, PhD 
Chief, Clinical Microbicide Research Branch 
Division of AIDS (DAIDS), National Institute of Allergy and Infectious Diseases (NIAID), 
National Institutes of Health (NIH) - U.S. Department of Health and Human Services (HHS) 
5601 Fishers Lane, Room 8B62, MSC 9831 
Rockville, MD 20852 USA 
Phone: 301-496-8199 
Email: rblack@niaid.nih.gov 
 
Naana Cleland, MHCA 
Health Specialist, Clinical Microbicide Research Branch (CMRB)  
Prevention Sciences Program (PSP) DAIDS, NIAID  
NIH – U.S. DHHS 
5601 Fishers Lane, Room 8B27, MSC 9831 
Rockville, MD 20852 USA 
Phone: 240-292-4779 
Email: clelandn@niaid.nih.gov   
 
Jeanna Piper, MD 
DAIDS Senior Medical Officer 
DAIDS/NIAID/NIH/HHS 
5601 Fishers Lane, Room 8B68, MSC 9831 
Rockville, MD 20852 USA 
Phone: 240-292-4798 
Email: piperj@niaid.nih.gov  
 
Dianne M. Rausch, PhD 
Director 
Division of AIDS Research, National Institutes of Mental Health (NIMH) 
5601 Fishers Lane Room 8D20, MSC 9831 
Rockville, MD 20852 USA 
Phone: 240-627-3874 
Fax: 240-627-3467 
Email: drausch@mail.nih.gov 
 
Teri Senn, PhD 
Program Chief, Psychosocial Co-morbidities of HIV Prevention and Treatment 
Division of AIDS Research, NIMH 
5601 Fishers Lane Room 9G29 
Rockville, MD 20852 USA 
Phone: 301-761-7852 
Email: teri.senn@nih.gov  
 
 
 

 
 
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Microbicide Trials Network (MTN) Leadership and Operations Center (LOC) – Pitt 
 
Jared Baeten, MD, PhD 
Co-Principal Investigator 
University of Washington 
ICRC, Dept of Global Health 
325 Ninth Avenue, Box 359927 
Seattle, WA  98104 
Phone: 206-520-3808 
Fax: 206-520-3831 
Email: jbaeten@uw.edu 
 
Cindy Jacobson, PharmD 
Director of Pharmacy Affairs 
Microbicide Trials Network 
204 Craft Avenue 
Pittsburgh, PA  15213 USA 
Phone: 412-641-8913 
Fax: 412-641-6170 
Email: cjacobson@mail.magee.edu  
 
 
Katherine Bunge, MD 
Protocol Safety Physician 
Magee-Womens Hospital of UPMC 
300 Halket Street 
Pittsburgh, PA 15213 USA 
Phone: 412-641-3464 
Fax: 412-641-1133 
Email: kbunge@mail.magee.edu  
 
Luis Duran, DrPH, MPIA 
Project Manager 
Microbicide Trials Network 
204 Craft Avenue 
Pittsburgh, PA 15213 USA 
Phone: 412-641-8539 
Fax: 412-641-6170 
Email: duranl2@mwri.magee.edu 
 
 
Sharon A. Riddler, MD, MPH 
Protocol Physician 
UPMC, Keystone Building, Suite 510 
3520 Fifth Avenue 
Pittsburgh, PA 15213 USA 
Phone:  412-383-1741or 412-383-1675 
Fax: 412-383-2900 
Email: riddler@dom.pitt.edu 
 
Devika Singh MD, MPH 
Protocol Safety Physician 
19 Randall Drive 
Jericho, VT 05465  USA 
Phone: 206-920-0975 
Email: devika@mtnstopshiv.org 
Craig Hendrix, MD 
Director, Rectal Microbicide Program and 
Pharmacology LC Principal Investigator 
Johns Hopkins University 
600 North Wolfe Street, Harvey 502 
Baltimore, MD 21287 USA 
Phone: 410-955-9707 
Fax: 410-955-9708 
Email: cwhendrix@jhmi.edu 
 
Sharon Hillier, PhD 
MTN Principal Investigator 
Microbicide Trials Network 
204 Craft Avenue 
Pittsburgh, PA 15213 USA 
Phone: 412-641-8933 
Fax: 412-641-6170 
Email: shillier@mail.magee.edu    
 
Mei Song, PhD 
Protocol Specialist 
Microbicide Trials Network 
204 Craft Avenue 
Pittsburgh, PA 15213 USA 
Phone: 412-641-2282 
Fax: 412-641-6170 
Email: songm4@mail.magee.edu 
 
 
Jennifer Thomas, MSc 
Protocol Development Manager 
Microbicide Trials Network 
204 Craft Avenue 
Pittsburgh, PA 15213 USA 
Phone: 412-641-5579 
Fax: 412-641-6170 
Email: thomasj15@mwri.magee.edu 
 
 

 
 
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MTN Laboratory Center (LC) 
 
Edward Livant, BSMT (ASCP), MPH 
MTN LC Research Manager 
Microbicide Trials Network 
204 Craft Avenue 
Pittsburgh, PA 15213 USA 
Phone: 412-641-3772 
Fax: 412-641-5290 
Email: livantew@upmc.edu 
 
Lisa Rohan, PhD 
LC Representative 
University of Pittsburgh Pharmaceutical Sciences 
Magee-Women’s Research Institute 
204 Craft Avenue, Room B509 
Pittsburgh, PA  15213 USA 
Phone: 412-641-6108 
Fax: 412-641-6170 
Email: lrohan@mwri.magee.edu 
 

 
 
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MTN LOC – FHI 360 
 
Kailazarid Gómez-Feliciano, MPM  
Senior Clinical Research Manager 
FHI 360 
359 Blackwell Street, Suite 200  
Durham, NC  27701 USA 
Phone: 919-544-7040, Ext. 11282 
Fax: 919-544-0207 
Email: kgomez@fhi360.org 
 
Sherri Johnson, MPH 
Senior Clinical Research Manager 
FHI 360 
1825 Connecticut Avenue, NW  
Washington, DC 20009 USA 
Phone: 202-884-8000, Ext. 18677 
Fax: 202-884-8844  
Email: sjohnson@fhi360.org 
 
Jonathan Lucas, MPH 
Senior Community Program Manager 
FHI 360 
359 Blackwell Street, Suite 200 
Durham, NC 27701 USA  
Phone: 919-544-7040, Ext. 11458 
Fax: 919-544-0207 
Email: jlucas@fhi360.org 
 
Nicole Macagna, MA 
Prevention Research Specialist 
FHI 360 
359 Blackwell Street, Suite 200  
Durham, NC  27701 USA 
Phone: 919-544-7040, Ext. 11717 
Email: nmacagna@fhi360.org 
 
 

 
 
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MTN Statistical Data Management Center (SDMC) 
 
Jennifer Berthiaume, MSW, MPH 
Clinical Data Manager 
Fred Hutchinson Cancer Research Center (FHCRC) – Statistical Center for HIV/AIDS Research 
and Prevention (SCHARP) 
1100 Fairview Ave. North, J5-000 
PO Box 19024 
Seattle, WA 98109-1024 USA 
Phone: 206-667-1230  
Email: jberthia@scharp.org 
 
Elizabeth Brown, ScD 
SDMC Principal Investigator 
FHCRC 
1100 Fairview Avenue North, M2-C200 
PO Box 19024 
Seattle, WA 98109-1024 USA 
Phone: 206-667-1731 
Fax: 206-667-4812 
Email: erbrown@fredhutch.org 
 
Holly Gundacker, MS 
Statistical Research Associate  
FHCRC-SCHARP 
1100 Fairview Ave North, M2-C200 
PO Box 19024 
Seattle, WA 98109-1024 USA  
Phone: 206-667-6480 
Email: hgundack@scharp.org 
 
Karen Patterson, MPH 
Program & Portfolio Manager 
FHCRC-SCHARP 
1100 Fairview Avenue North, E3-129 
PO Box 19024 
Seattle, WA  98109-1024 USA 
Phone: 206-667-7052 
Fax: 206-667-4812 
Email: karenp@scharp.org    
 
 
 
 
 
 
 

 
 
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MTN Working Group Representatives 
 
Behavioral Research Working Group (BRWG) 
 
Alex Carballo-Diéguez, PhD 
BRWG Representative 
HIV Center for Clinical and Behavioral Studies 
NYSPI & Columbia University 
1051 Riverside Dr., Unit 15 
New York, NY  10032 USA 
Phone: 646-774-6930 
Fax: 646-774-6955 
Email: ac72@cumc.columbia.edu 
 
 
Community Working Group (CWG) 
 
Daniel Gondwe 
CWG Representative 
Johns Hopkins University Research Project  
Chipatala Avenue 
P.O. Box 1131  
Blantyre, Malawi  
Phone: 265-1875-128  
Fax: 265-1870-132  
Email: dgondwe@jhu.medcol.mw 
 
Matthew Rose 
CWG Co-Chair 
National Minority AIDS Council 
1000 Vermont NW, Suite 200 
Washington, DC 20005 USA 
Phone: 202-277-2777 
Email: mrose@nmac.org 

 
 
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MTN-035 
 
Acceptability, Tolerability, and Adherence of Three Rectal Microbicide Placebo 
Formulations among HIV Seronegative Cisgender Men, Transgender Men and 
Transgender Women Who Engage in Receptive Anal Intercourse 
INVESTIGATOR SIGNATURE FORM 
Version 1.0; June 15, 2018 
A Study of the Microbicide Trials Network 
 
Funded by: 
Division of AIDS (DAIDS), US National Institute of Allergy and Infectious Diseases 
US Eunice Kennedy Shriver National Institute of Child Health and Human Development 
US National Institute of Mental Health 
US National Institutes of Health (NIH) 
 
IND Sponsor: 
A Non-IND Study (DAIDS Protocol ID: 38459) 
 
I, the Investigator of Record, agree to conduct this study in full accordance with the provisions 
of this protocol and all applicable protocol-related documents. I agree to conduct this study 
in compliance with United States (US) Health and Human Service regulations (45 CFR 46); 
standards of the International Council on Harmonisation (ICH) Guideline for Good Clinical 
Practice (E6); Institutional Review Board/Independent Ethics Committee determinations; all 
applicable in-country, state, and local laws and regulations; and other applicable 
requirements (e.g., NIH, DAIDS) and institutional policies. 
 
I agree to maintain MTN study records in accordance with protocol-specified protections of 
participants’ confidentiality and with site IRB/IEC policies and procedures.  Study records 
must be maintained on-site for the entire implementation period of the study and a minimum 
of at least three years after completion of research as per 45 CFR 46.115 (b). . 
DAIDS/designee will inform the investigator/institution as to when these documents no longer 
need to be retained. 
 
I have read and understand the information in this protocol and will ensure that all associates, 
colleagues, and employees assisting in the conduct of the study are informed about the 
obligations incurred by their contribution to the study. 
 
 
___________________________ 
Name of Investigator of Record 
 
 
____________________________ 
______________________________ 
Signature of Investigator of Record  
Date 

 
 
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MTN-035 
 
Acceptability, Tolerability, and Adherence of Three Rectal Microbicide Placebo 
Formulations among HIV Seronegative Cisgender Men, Transgender Men and 
Transgender Women Who Engage in Receptive Anal Intercourse 
 
PROTOCOL SUMMARY 
 
Short Title:  
Rectal Microbicide Acceptability, Tolerability, and Adherence 
 
Funders:  
Division of AIDS, NIAID, NIMH, NICHD, US NIH 
 
Protocol Chair:  
José A. Bauermeister, PhD, MPH 
 
Sample Size: 
MTN-035 will enroll approximately 210 participants 
 
Study Population:  
HIV-uninfected cisgender men, transgender men (TGM) and 
transgender women (TGW) aged 18-35 years who engage in 
receptive anal intercourse (RAI)  
 
Study sites: 
Sites selected by MTN Executive Committee 
 
Study Design: 
Multi-site, 
randomized-sequence, 
three-period, 
open 
label 
crossover study 
 
Study Duration: 
Approximately 3.5 months of follow-up with a projected accrual 
period of 9-12 months 
 
Study Products: 
Placebo rectal insert 
Placebo rectal douche 
Placebo rectal suppository 
 
Study Regimen:  
Participants will be randomized (1:1:1:1:1:1) to study product 
sequences A-F (see Table 1 below). At the start of each 4-week 
product use period, they will receive either rectal inserts, rectal 
douches, or rectal suppositories and be instructed to use their 
assigned study product prior to each RAI encounter during that 
period. Participants who do not have RAI in a given week will be 
asked to use the product without sex. There will be a 1-week 
washout period between each of the three product use periods. 
 
 
 

 
 
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Table 1: MTN-035 Study Product Regimen 
Sequence 
N 
Period 1 
(4 weeks) 
Washout 
period (~1 
week) 
Period 2 
(4 weeks) 
Washout 
period (~1 
week) 
Period 3 
(4 weeks) 
A 
35 
Rectal insert 
-- 
Rectal douche 
-- 
Rectal 
suppository 
B 
35 
Rectal 
douche 
-- 
Rectal 
suppository 
-- 
Rectal insert 
C 
35 
Rectal 
suppository 
-- 
Rectal insert 
-- 
Rectal 
douche 
D 
35 
Rectal insert 
-- 
Rectal 
suppository 
-- 
Rectal 
douche 
E 
35 
Rectal 
douche 
-- 
Rectal insert 
-- 
Rectal 
suppository 
F 
35 
Rectal 
suppository 
-- 
Rectal douche 
-- 
Rectal insert 
 
Figure 1: MTN-035 Study Visit Schedule 
 
 
 
Primary Objectives:  
 
Acceptability and Tolerability 
• 
To evaluate the acceptability and tolerability of each study product when applied rectally 
and used prior to RAI 
o Placebo rectal insert 
o Placebo rectal douche 
o Placebo rectal suppository 
 
Adherence 
• 
To evaluate adherence to each study product prior to RAI over a 4-week-long period 
o Placebo rectal insert 
o Placebo rectal douche 
o Placebo rectal suppository 
 

 
 
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Safety 
• 
To evaluate the safety of each study product when applied rectally and used prior to RAI  
o Placebo rectal insert 
o Placebo rectal douche 
o Placebo rectal suppository 
 
Exploratory Objective:  
 
Relative Acceptability and Tolerability 
• 
To evaluate the relative acceptability and tolerability between study products when 
applied rectally and used prior to RAI 
o Placebo rectal insert 
o Placebo rectal douche 
o Placebo rectal suppository 
 
Primary Endpoints: 
 
Acceptability and Tolerability 
• 
For each study product, participant self-report of likelihood of product use if shown to be 
effective  
 
Adherence 
• 
Per participant report, percentage of occasions when each study product was used as 
instructed (per protocol) 
 
Safety 
• 
Grade 2 or higher related adverse events (AEs) as defined by the Division of AIDS Table 
for Grading the Severity of Adult and Pediatric Adverse Events, Corrected Version 2.1, 
July 2017, and/or Addenda 1, 2 and 3 (Female Genital [Dated November 2007], Male 
Genital [Dated November 2007] and Rectal [Clarification Dated May 2012] Grading 
Tables for Use in Microbicide Studies) 
 
Exploratory Endpoint: 
 
Relative Acceptability and Tolerability 
• 
Conjoint analysis of participant acceptability and tolerability between the three study 
products 
 
1 
KEY ROLES 
 
1.1 Protocol Identification 
 
Protocol Title:   
Acceptability, Tolerability, and Adherence of Three Rectal 
Microbicide Placebo Formulations among HIV Seronegative 

 
 
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June 15, 2018 
 
Cisgender Men, Transgender Men and Transgender Women 
Who Engage in Receptive Anal Intercourse 
 
 
Protocol Number: 
MTN-035 
 
Short Title: 
Rectal Microbicide Acceptability, Tolerability, and Adherence 
 
Date:  
June 15, 2018 
 
1.2 Funding Agencies and Sponsor Identification 
 
Funding Agencies:  
US Division of AIDS (DAIDS)/National Institute of Allergy and 
Infectious Diseases (NIAID) 
National Institutes of Health (NIH) 
5601 Fishers Lane 
Rockville, MD  20852 USA 
 
 
 
 
 
US National Institute of Mental Health (NIMH) 
6001 Executive Boulevard 
Rockville, MD  20852 USA 
 
 
US Eunice Kennedy Shriver National Institute of Child Health 
and Human Development (NICHD)  
 
Maternal and Pediatric Infectious Diseases (MPID) Branch 
6100 Executive Boulevard 
Rockville, MD  20852 USA 
 
Pharmaceutical Company  
Collaborator: 
CONRAD 
 
 
1911 North Fort Myer Drive, Suite 900  
 
 
Arlington, VA 22209 USA 
 
1.3 Medical Officer 
 
Medical Officer: 
 
Jeanna Piper, MD 
DAIDS/NIAID 
5601 Fishers Lane, Room 8B68, MSC 9831 
Rockville, MD 20852 
 
1.4 Clinical Laboratories 
 
Network: 
 
MTN Laboratory Center (LC) 
 
 
 
204 Craft Ave. 
 
 
 
Pittsburgh, PA  15213 USA 
 
1.5 Data Centers 
 

 
 
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Data Center:  
 
MTN Statistical Data and Management Center (SDMC)  
 
 
Statistical Center for HIV/AIDS Research & Prevention 
(SCHARP)/Fred Hutchinson Cancer Research Center 
(FHCRC)  
 
 
 
1100 Fairview Avenue N., LE-400  
 
 
 
PO Box 19024  
 
 
 
Seattle, WA 98109-1024 USA 
 
Qualitative Data Center:     University of Pennsylvania 
418 Curie Blvd. 
Philadelphia, PA 19104 
 
 
1.6 Study Implementation 
 
Study Operations:  
MTN LOC - FHI 360  
 
 
 
359 Blackwell Street, Suite 200  
 
 
 
Durham, NC 27701 USA 
 
 

 
 
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2 
INTRODUCTION 
 
2.1 Background of Rectal Microbicide Research and Study Rationale 
 
Microbicides are products that are designed to be applied to the vaginal or rectal mucosa 
with the intent of preventing the acquisition of sexually transmitted infections (STIs) 
including the human immunodeficiency virus (HIV).1 The original impetus for microbicide 
development was to provide women with options for HIV prevention in settings where 
their partners were unwilling to use condoms for penile-vaginal intercourse. However, 
there is recognition that rectal microbicides are needed for men and women who practice 
receptive anal intercourse (RAI).  
 
RAI is associated with the highest probability for sexual acquisition of HIV infection. 
Unprotected RAI is the sexual behavior with the highest per act risk of HIV acquisition,  
conferring approximately 10 to 20 times more risk than unprotected receptive vaginal 
intercourse (RVI).2,3 Globally, transgender women (TGW) and men who have sex with 
men (MSM) are 19 times more likely to be living with HIV compared with the general 
population.4,5  
 
Despite scaled up prevention efforts and expanding access to antiretroviral (ARV) 
treatment in the last few decades, HIV rates remain disproportionately high among MSM 
throughout the world, with prevalence ranging from a low of 3.0% in the Middle East and 
North Africa to a high of 25.4% in the Caribbean.6 In low and middle income countries in 
Africa, Asia and Latin America, MSM continue to experience high rates of HIV infection.6 
7In European Union/European Economic Areas, HIV diagnoses among MSM declined in 
specific countries, such as the United Kingdom, Belgium, Italy, the Netherlands and 
Spain, but HIV continues to increase among MSM in other EU/EEA countries, with 
substantial increases in Bulgaria, Croatia, Cyprus, Czech Republic, Hungary, Ireland, 
Lithuania, and Malta in recent years.8 In the US, according to CDC, estimated annual HIV 
infections remained stable among all gay and bisexual men during 2010 to 2014, but with 
increase among MSM aged 25 to 34 and Hispanic/Latino MSM.9  As modeled by Stall et 
al (2009), even incidence rates as low as 2-3%, like those observed among MSM in high-
income countries between 1995 and 2005, are likely to yield prevalence rates >40% within 
25 years for a cohort of 15-year old gay males in the US.10 
 
For the most vulnerable MSM populations, the likelihood of HIV infection is even higher. 
For example, black MSM in the US are 15 times more likely to be HIV positive than the 
general population and 8.5 times more likely than other African Americans.11 In African 
countries that criminalize homosexual activity, black MSM are roughly 72 times more 
likely to become infected with HIV than the general population in the US, and over 100 
times more likely than the general population in the UK.11 In South Africa, rates among 
black MSM are much higher than the general population, with 43.6% HIV prevalence 
among gay participants in one study conducted in Johannesburg and Durban, and 49% 
HIV prevalence among gay participants aged 20-24 years old in another study.12 In 

 
 
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Kenya, the only African country with HIV incidence data, annual HIV incidence was 
reported at >20% in Mombasa.6 
 
Another segment of the population facing disproportionately high levels of HIV are 
transgender women (TGW) and transgender men (TGM). One meta-analysis estimated 
that HIV prevalence for TGW was 19.1% worldwide, with 21.6% for TGW in high-income 
countries (including 22% of 2,705 TGW sampled in the US) and 17.7% in middle- and 
lower-income countries.13 The same study found that the risk of HIV infection was 50 and 
46.3 times higher, respectively, among TGW than the general population of reproductive-
aged adults in middle- and lower-income countries and in higher income countries. Of the 
2351 transgender people diagnosed with HIV between 2009 and 2014 in the US, 84% 
were TGW, 15% were TGM, and <1% identified with another gender.14 Similar to MSM, 
a meta-analysis found even higher HIV infection rates (30.8% to 56.3%) among black 
TGW than the general TGW population.15 
 
Transgender sex workers experience even higher HIV infection rates. A systematic 
review found that overall crude HIV prevalence was 27.3% among TGW engaging in sex 
work, compared to 14.7% of those not engaging in sex work.16 This same meta-analysis 
indicated that transgender sex workers experienced significantly higher risk for HIV 
infection in comparison to all other groups (RR=1.46), particularly in comparison to female 
sex workers (RR=4.02). However, little data about HIV prevalence is available for TGM 
or other transgender populations.   
 
The World Health Organization (WHO) developed and encourages the use of a 
combination approach to combat the HIV epidemic in key populations, including the gay 
and transgender communities. It includes: comprehensive condom and lubricant 
programs, harm reduction for injection drug users, behavioral interventions, ARV-related 
prevention and voluntary medical male circumcision (VMMC), HIV testing and 
counselling, HIV treatment and care including prevention of mother-to-child transmission 
(PMTCT), prevention of coinfections like tuberculosis and hepatitis, prevention and 
management of mental health problems, and other general care related to sexual and 
reproductive health and nutrition.17  
 
However, prevention services are often grossly inadequate, even in high-income 
countries. For example, a 2010 cross-European Internet survey estimated that only 25–
50% of MSM were tested for HIV infection the previous year, compared with 60% in 
Australia and 77% in the US.18 In low and middle income countries, prevention needs 
among MSM have also been neglected due to limited resources and inadequate service 
quality, especially in countries where male-to-male sexual activity is stigmatized or 
criminalized.19,20 Based on a UN General Assembly Special Session (UNGASS) report, it 
is estimated that only a third of MSM in the 23 low to middle income countries surveyed 
were reached by HIV prevention programs.21 Furthermore, research suggests that black 
MSM are less likely to have received free condoms and lubricants than other MSM22, less 
likely to be tested for HIV than white MSM23, and reported fewer service locations in their 
neighborhood.24   
 

 
 
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Condoms are highly cost-effective tools for prevention of HIV, STIs and unintended 
pregnancies. But, condoms are not readily available in some countries, especially in sub-
Saharan Africa. The Joint United Nations Programme on HIV/AIDS (UNAIDS) estimated 
the need for male condoms was 6 billion in 47 sub-Saharan countries in 2015, yet only 
an estimated 2.7 billion condoms were distributed in those countries that year. This 
suggests over half the condom need in the region is not being met, with South Africa as 
the only country surpassing the condom needs of its people. And, when condoms are 
accessible, they are not consistently used. UNAIDS also estimated that only three of 104 
countries with available data reported >90% condom use at last sexual intercourse among 
MSM.25 
 
There is little data on condom use among transgender people worldwide, but limited 
evidence shows that condom use in this population is low. A study in Cambodia found 
that consistent condom use by transgender people was higher (40%) with female partners 
than with male partners (20–40%), with the lowest rates of use with male partners when 
buying sex.26 Another study in Thailand found that 46.7% of MSM and 52.3% of 
transgender people used condoms in the past three months.27 
 
Analysis of CDC’s National HIV Behavioral Surveillance (NHBS) data suggests that 
condom use among US MSM declined 20% from 2005 to 2011.28 Increases in 
condomless sex have also been reported in other developed countries.29-31 Research 
suggests that the increase in condomless sex has offset the reduction in HIV incidence 
due to earlier HIV diagnosis and ART among MSM.32,33 In a follow-up analysis of the 
NHBS data with new data from 2014, Paz-Bailey and colleagues investigated if the 
increases in condomless sex were associated with use of other prevention strategies, 
and found that decreased condom use was not explained by serosorting, seropositioning, 
PrEP use or HIV treatment.34 However, another study found that condomless anal 
intercourse (AI) among its MSM and TGW participants decreased during follow-up 
regardless of whether they received PrEP or not.35  
  
There will always be people who either prefer sex without a condom (e.g., due to 
increased sexual pleasure, erectile dysfunction, intimacy, or spontaneity), or who do not 
have the necessary autonomy to negotiate condom use with their partners (e.g., sex 
workers, adolescents and young adults, alcohol and drug users). This is evident from 
various analyses of national survey data suggesting low condom use rates among both 
men and women who engaged in RAI (44% among males and 11% among females for 
most recent RAI encounter, and 26% among males and 13% among females for past 10 
RAI encounters).36-38 This data highlights the unrealistic expectation for consistent 
condom use. HIV prevention alternatives are needed to accommodate all persons at risk 
of HIV infection, particularly persons who engage in disproportionately risky activities like 
RAI.  
 
Currently, there is one biomedical alternative to condoms that is approved for HIV 
prevention, the Truvada oral tablet. Truvada for oral pre-exposure prophylaxis (PrEP), 
when used consistently and as indicated, significantly reduces the risk of HIV acquisition 
and is generally safe.39 Also, treating the infected partner in an HIV-serodiscordant couple 

 
 
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June 15, 2018 
 
with combination antiretroviral therapy (ART) including Truvada can reduce HIV 
transmission by up to 96%.40 Furthermore, studies have consistently found no association 
between PrEP use and changes in risky sexual behavior41 or hormonal contraception 
effectiveness.42,43 
 
In the iPrEx study, self-reported oral PrEP adherence among MSM and TGW was high 
(≥89% at week 4), but drug concentrations in participants suggested that actual 
adherence was probably lower.44 Another open-label study found that PrEP uptake and 
adherence among MSM and TGW was high when participants had access to PrEP free 
of charge from experienced health providers.35 In contrast, however, population surveys 
of MSM suggest that overall PrEP use levels are still low45,46, with reported barriers such 
as low PrEP awareness46 and lack of knowledge and prescribing experience among 
health providers.47 
 
Although oral PrEP holds great promise for HIV prevention, its scale and coverage remain 
limited outside the US. UNAIDS estimates that 60,000 people were taking oral PrEP in 
2016, with most of them in the US, though this estimate does not include those who 
access PrEP through less regulated channels like the Internet. In Africa, UNAIDS 
identified several barriers to scaling up PrEP use, including cost, limited awareness, 
limited regulatory approval (currently approved in only seven countries worldwide), and 
limited availability of both PrEP and the ancillary clinical services needed to support its 
successful implementation.25   
 
While generally effective for use as oral PrEP, Truvada tablets require a daily dosage 
schedule to maintain protective levels over time.39,48 Also, while Truvada is generally safe 
for use as oral PrEP, systemic delivery of a drug increases the risk and severity of its 
possible side effects relative to more localized drug delivery alternatives like microbicides. 
Lastly, behaviorally and conceptually linking the taking of pills (a daily prevention strategy) 
with sexual activity (an episodic occurrence) could be difficult for those who would find a 
pericoital prevention strategy more feasible and/or preferable. Therefore, even if readily 
available to everyone, such product characteristics could lead to acceptability and 
adherence challenges for many, and do not address other STIs that can still be passed 
via unprotected RAI. 
 
It is important to develop a range of HIV prevention products that can serve as viable 
alternatives and/or complements to consistent condom use and oral PrEP, including 
formulations able to deliver multiple drugs (e.g., anti-HIV-1 and anti-HSV-2) in 
combination. There are many other drugs being developed for HIV prevention in various 
formulations, including intravaginal rings (IVR), topical gels, film inserts, and 
injectables.1,49,50 However, as past PrEP and microbicide studies have shown, drug 
efficacy translates to drug effectiveness only when people use the drug as intended.51-53  
 
MSM have expressed a preference for topical gel microbicides over other rectal 
microbicide formulations because similarities to personal lubricants would mean that a 
gel microbicide could potentially be readily incorporated into their usual sexual 
practices.33,54,55 Unfortunately, microbicide gel formulations tested thus far have required 

 
 
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June 15, 2018 
 
the use of an applicator which could present acceptability and adherence challenges for 
long-term use.56 Although a lubricant rectal microbicide product would seem an ideal drug 
delivery mechanism from an acceptability and adherence standpoint, it is unclear if topical 
gels could be developed to deliver protective levels of HIV prevention drugs when used 
without an applicator. 
 
It is crucial for drugs to be designed so that they can be delivered via mechanisms that 
not only deliver enough drug to block HIV transmission, but are also a good behavioral fit 
with the drug’s intended end-users. MTN-035 will evaluate the acceptability of three 
potential rectal microbicide formulations – an insert, a douche, and a suppository – that 
could be used prior to RAI and could potentially deliver enough anti-HIV drug locally to 
prevent HIV infection during RAI. It is believed these drug delivery mechanisms would be 
congruent with cleansing practices and behaviors regarded as normal preparations prior 
to engaging in RAI or participating in activities where the probability of engaging in RAI is 
high.57,58 
 
2.2 Description of Study Products 
 
 
2.2.1 
Placebo rectal insert  
 
The placebo rectal insert is formulated as a white to off-white solid dosage form. The 
insert is small (about 1.5 cm [2/3 of an inch] long and about 0.7 cm [1/3 of an inch] wide) 
and bullet-shaped. The rectal insert evaluated in this study will be a placebo product 
intended for use without an applicator. 
 
Safety of placebo rectal insert 
 
Rapidly disintegrating topical inserts offer many advantages as on-demand drug dosage 
forms: inexpensive, portable, easy to apply, discreet, user-initiated, and suitable for both 
vaginal and rectal application. CONRAD developed four placebo insert prototypes with 
varied preparations, formulations, weights, and shapes, including the placebo insert being 
evaluated in this study.59 
 
Toxicity studies were conducted with rabbits and with the EpiVaginal VEC-100-FT human 
tissue model to evaluate the potential for local irritation of various active and placebo 
inserts, including the placebo insert being evaluated in this study. Following once-daily 
rectal application in rabbits for 14 days, there were no definitive article-related effects 
observed for any of the test parameters: bodyweight, clinical observations, macroscopic 
or microscopic tissue pathology. All observed effects were deemed to be procedural in 
origin, not due to the test articles. The average rectal irritation index for the placebo insert 
was <1, indicating no local irritation. Following a 24-hour exposure to the placebo insert 
in the EpiVaginal human tissue model, histopathology results showed there were no 
significant changes to tissue morphology, with only a thinning of the epithelium while the 
basal and parabasal cell layers remained intact. The placebo insert did not induce any 
noticeable effects on tissue viability (110% by MTT assay), barrier integrity (transepithelial 
electrical resistance [TEER] = 95.3%), or tissue structure.59 

 
 
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There are no human data for rectal use of the CONRAD placebo insert. The CONRAD 
134 study tested the safety, stability, and disintegration profile of four inserts when 
administered vaginally by healthy women aged 18-50. All four placebo inserts were found 
to be safe during 1 or 2 uses, with only one mild AE reported which was assessed as 
unrelated to study product. The four placebo inserts also disintegrated faster, had less 
residue leakage, and were more acceptable than the first-generation placebo inserts 
previously used in CONRAD 117, a Phase 1 safety and PK study of TFV, FTC, and 
TFV/FTC vaginal inserts. Of the four products tested in CONRAD 134, Placebo Insert C 
was selected for evaluation in this study.59 The selection of Placebo Insert C was based 
on the following criteria as evaluated in the CONRAD-134 study: disintegration, 
acceptability, physiochemical stability, and preliminary cost-of-goods analysis. As 
compared to Placebo Inserts A, B, and D, Placebo Insert C had favorable results for all 
study benchmarks: it achieved improved disintegration and acceptability rates as 
compared to first generation inserts, showed no changes in appearance or hardness at 
accelerated storage conditions (40˚C/75%RH), and achieved feasibility of meeting price 
targets. (Personal communication with CONRAD, March 23, 2018) 
 
Initial disintegration of the placebo insert in CONRAD 134 occurred quickly, with median 
values of 7.5 minutes for Placebo Insert C. At 60 minutes, 67% (8/12) of Placebo Insert 
C users had less than half the insert visible on exam. At 45 minutes, 25% (3/12) had less 
than half visible on exam. It is expected the insert will disintegrate faster during rectal use 
with the addition of intercourse, somewhere between the results seen in CONRAD 134 
and the results from in-vitro dissolution testing. In in-vitro dissolution testing at 37°C, 
approximately 42% of the insert dissolved by 5 minutes, approximately 94% of the insert 
dissolved by 15 minutes, and approximately 98% of the insert had dissolved by 60 
minutes. 
 
2.2.2 
Placebo rectal douche 
 
The rectal douche evaluated in this study will consist of approximately 120 mL of water 
administered rectally via a disposable, commercially available 125 mL enema bottle. 
 
Safety of rectal douches 
 
Rectal enemas have long been used clinically as bowel preparations before procedures 
and therapeutically for constipation and intussusception. Investigators at the University of 
Washington studied the rectal mucosal safety of various enema preparations, including 
Fleet’s Phospho-Soda, Bisacodyl (Dulcolax), and a 500 mL 0.9% (iso-osmolar, normal) 
saline enema.60 The study evaluated proctoscopic appearance, light microscopic 
appearance, and scanning and transmission electron microscopy of rectal biopsies 
obtained via sigmoidoscopy 5 to 10 cm proximal to the anus, within 10 minutes after the 
various enema agents were administered and expelled. Proctoscopically, there were no 
abnormal findings after the saline enema, but some vascular disruption was grossly 
observed after Fleet's or Bisacodyl enema in all subjects. On light microscopy, only 3 of 
21 (14%) subjects who were given the saline enema were seen to have abnormalities at 

 
 
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the epithelial surface, but no abnormalities were observed in the epithelial crypt or lamina 
propria, whereas much greater microscopic epithelial disruption was observed after 
Fleet's enema (81%, or 17 of 21 biopsies) and Bisacodyl enema (84%, or 21 of 25 
biopsies). Of the 3 of 21 (14%) biopsies after saline enema that were observed to have 
an absent superficial epithelial layer, the appearance was consistent with an abrasion 
possibly caused by either sigmoidoscope or enema tip. When the biopsies were 
evaluated by scanning electron microscopy, all 5 biopsies from subjects who had received 
the saline enema had a normal appearance, whereas the biopsies from individuals who 
had received Fleet's enema had absent goblet cells, abnormal microvilli, or disrupted 
surface in 6 of 7 (86%) cases. Overall, the proctoscopic and scanning electron 
microscopic appearance of rectal mucosa after saline enema was no different than that 
observed in control participants.  
 
Integrated Preclinical/Clinical Program (IPCP) Microbicide Development Program’s 
(MDP) Project 5/Aim 161 studied the safety and acceptability of three enema microbicide 
vehicles and was performed to elucidate the preferred osmolarity of a rectal tenofovir 
enema. In this study, investigators assessed the distribution, safety, and acceptability of 
three enema formulations: hyper-osmolar (Fleet), hypo-osmolar (distilled water), and iso-
osmolar (Normosol-R), using a crossover design. For Project 5/Aim 1, SPECT/CT 
imaging was performed after administration of radiolabeled enema product. This imaging 
showed that the iso-osmolar enema had greater colonic distribution (up to the splenic 
flexure) and greater luminal and colonic tissue concentrations of radiolabeled product 
compared to the other 2 enema formulations (p<0.01). Colonic biopsies were also 
performed, and demonstrated that colonic epithelial sloughing was induced only by the 
hyper-osmolar enema (p<0.05) and not by the other two enema products. Lastly, in 
permeability studies of the radiolabeled diethylenetriaminepentaacetic acid (DTPA) 9 
used primarily for luminal imaging, the hypo-osmolar enema resulted in the highest 
plasma area under the concentration-time curve (AUC) and peak concentration of 
radiolabeled enema out of the three enema types. 
 
The rectal douche evaluated in this study, an enema filled with bottled or tap water, is 
expected to be as safe as the distilled water and saline enemas described above.61,62 
 
2.2.3 
Placebo rectal suppository 
 
The rectal suppository evaluated in this study will be a 2 g, 3-3.8 cm (1.2-1.5 inches) long, 
fat-based, fast-release suppository intended for use without an applicator.  
 
Safety of placebo rectal suppositories 
 
The suppository will consist of Witepsol® H5 (IOI Oleocehmical), a commonly used 
suppository base. Witepsol® H5 is a hard fat suppository base majorly composed of 
triglycerides with 15% diglyceride and not more than 1% monoglyceride content. 
Witepsol® suppository bases are commonly utilized in several marketed products by 
various manufacturers. The table below lists the Witepsol®-based suppository products 
currently on the market63: 

 
 
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Table 2: Witepsol® H5-based suppository products currently on the market 
Brand Name 
Active ingredients 
Manufacturer 
Alvedon 
Paracetamol 
GSK (producer Kemwell) 
Anodesyn 
Lidocaine + Allantoin 
Thornton & Ross = Stada 
Asacol 
Mesalazine 
Warner Chilcott Actavis 
Bisacodyl 
Bisacodyl 
Petrus Australia 
Bismuth 
Bismuth Subgallate 
Martindale 
Boots Haemorrhoid 
Allantoin, Lidocaine 
Boots 
Doloproct/Ultraproct 
Fluocortolon + Lidocaine 
Bayer 
Dulcolax 
Bisacodyl 
Boehringer Ingelheim 
Canasa 
Mesalamine 
Allergan/Aptalis 
Eucalyptine 
Codein + Eucalyptol 
Medgenix 
Febricet 
Paracetamol 
Hemopharm 
Flagyl 
Metronidazole 
Zentiva 
Germoloids 
Zinc Oxide, Lidocaine 
Bayer 
Imigran 
Sumatriptan 
GSK 
Jelliproct 
Fluocinonid + Lidocaine 
Teofarma 
Kortos 
Hydrocortisone 
Embil 
Mesasal 
Mesalazine 
Sanofi 
Morphine Sulphate 
Morphine 
Aurum UK 
Nurofen Junior 
Ibuprofen 
Reckitt Benckiser (Famar) 
Procto‐Glyvenol 
Tribenoside, Lidocaine 
Recordati 
Salazopyrin 
Sulfasalazine 
Pfizer 
Tramadol Stada 
Tramadol 
Stada 
Uniroid HC 
Hydrocortisone 
+ 
Cinchocaine 
Chemidex (Famar) 
Voltaren 
Diclofenac 
Novartis 
Vomacur 
Dimenhydrinate 
Hexal 
Zofran 
Ondansetron 
GSK 
 
2.3 Acceptability of non-gel rectal microbicide formulations  
 
2.3.1 
Rectal inserts/suppositories 
 
There is little data available on the use of rectal inserts or suppositories specifically by 
cisgender men, TGM and TGW. One study assessing rectal health and behaviors among 
896 HIV positive and negative men and women in Los Angeles and Baltimore found that 
38% (101/263) of male and 40% (85/211) of female participants reported ever using a 
rectal suppository.64 
 
Studies have been conducted with MSM in various countries to assess potential users’ 
preference and acceptability for various rectal microbicide delivery methods, including 
gel, cream, suppository and enema. One qualitative study in India found that gel was the 
preferred formulation among focus group participants, consistent with participants’ use of 
water-based lubricants.65 One survey study in Thailand (n = 408) found that young MSM 
and TGW preferred the gel formulation over suppository (odds ratio = 1.4, p <0.01).66 

 
 
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Similarly, one randomized trial in the US found higher acceptability for a gel microbicide 
formulation over rectal suppository (75% vs. 25%, p<0.001, n=77).55 Lastly, a survey 
study (n = 350) assessing rectal microbicide acceptability among MSM in Tianjin, China 
found the highest acceptability for a formulation that “makes your rectum wetter than 
normal during sex”, while a tablet or suppository formulation was viewed as more 
acceptable than a “jelly-like” formulation.67     
   
Though suppositories are viewed as less desirable than other formulations, they are still 
viewed as a viable rectal microbicide delivery method.56 Suppositories are very effective 
in delivering medication to the rectum. Brown et al (1997) compared suppositories against 
enemas and foams in their delivery of mesalazine, and only with suppositories was the 
spread of mesalazine confined to the rectum during 4 hours of gamma scintigraphy, while 
enemas and foams both spread the drug outside the rectum to the colon.68 Also, there 
have been no studies evaluating suppositories specifically formulated to deliver rectal 
microbicides. For example, the suppository used in the randomized US trial mentioned 
earlier55 was much larger (8 g, 6.4 cm [2.5 inches] long) than the average adult 
suppository in the market (2 g, 3 cm [1.2 inches] long) or the suppository planned for this 
study (2 g, 3-3.8 cm [1.2-1.5 inches] long). It is expected that suppositories which are 
smaller, dissolve more readily and/or are easier to insert may result in different 
acceptability ratings. 
 
2.3.2 
Rectal douches 
 
Rectal douching is a common cleansing practice for cisgender men, TGM and TGW who 
engage in RAI (see Section 2.4 for a review of AI-related douching practices). Most MSM 
who douche rectally use water or other homemade solutions, and most of those who use 
commercial products tend to use saline-based solutions.57,69,70 In a survey conducted in 
the US, the type of douching solution used varied between racial/ethnic groups, with water 
being most commonly reported by White participants before (73.8%) and after (64.5%) 
AI, whereas water added with salt, soap, or some other antibacterial product was most 
commonly reported by Hispanic participants before and after AI, and commercially-
prepared saline solution was most commonly reported by Black participants.70 Likewise, 
a wide range of devices were used for rectal douching, including showerheads, plastic 
soda bottles, hair dye bottles, commercial enema kits and syringes.71,72 
 
A few studies have explored the acceptability of rectal douches among MSM in different 
countries. In one US study, 63% of the male couples surveyed (n = 333 couples) indicated 
a willingness to use rectal microbicides in the form of a douche before AI if proven 
effective for HIV prevention, and this willingness did not differ significantly by HIV status.73 
A French study also found that 58.5% of MSM who reported recent rectal douche use 
were likely or very likely to use a hypothetical rectal microbicide douche for HIV 
prevention, compared to 49.2% of MSM who did not report recent rectal douche use.74 
Similar support for rectal microbicide douche formulations has been reported in 
developing countries. Galea et al (2014) conducted a focus group study with MSM in Peru 
and Ecuador (n = 140), where participants voiced support for a douche-based rectal 
microbicide because it could serve as both a cleansing and HIV prevention tool. They 

 
 
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also felt that a douche would provide greater protection than a lubricant as it could go 
deeper into the body, and proposed potential drawbacks to a rectal microbicide douche 
formulation including possible discomfort from an internal cleansing, lack of time to use 
the douche prior to sex, and the inconvenience of carrying the douche around.69 
 
2.4 Practices commonly associated with RAI 
 
One common practice associated with AI is the use of lubricant during sex. An 
international Internet-based survey found that over 59% of respondents (n = 6124) 
reported consistent lubricant use75, while a US-based study found that 94% of MSM 
surveyed (n = 307) used lubricant when they had anal sex and 74% used lubricant at 
least in 80% of anal sex occasions.76 In another US-based study, among young MSM 
who reported lubricant use (n = 91), 88% of participants used water-based products, 33% 
used silicone-based products and 14% used oil-based products.77 Water-based 
lubricants are compatible with condoms and may provide additional prevention against 
STIs and HIV because they reduce condom breakage and rectal trauma.78 However, men 
without access to water-based lubricants may sometimes use saliva, body cream or 
petroleum jelly, which increase the risk of condom failure and viral transmission.79 Using 
lubricant without condoms has also been linked to an increased risk of STIs.80 
 
Rectal douching is another common practice for cisgender men, TGM and TGW who 
engage in RAI. One recent international study found that 62% of participants (n = 1725) 
who had ever engaged in AI douched for cleansing purposes, and 83% of those (n = 
1070) douched always or most of the time before AI.57 Another study found that 52% of 
US MSM surveyed (n = 4992) had douched at least once in their lifetime, with 35% of 
respondents having douched in the last three months.70 For those who had douched at 
least once in their lifetime (n = 2597), that same study found no significant difference 
across racial/ethnic groups in prevalence of douching before RAI, but among those who 
reported douching after RAI (n = 711), there was a 2-3-fold higher likelihood of non-White 
MSM douching after RAI than White MSM (43%-56% vs. 19%, p<0.001). In their survey 
of Peruvian MSM and TGW, Galea and colleagues found that 18% of participants (n = 
415) reported rectal douching in the previous 6 months.71 In France, 54.3% of MSM 
surveyed (n = 580) reported using a rectal douche in the past 3 months74, while in Brazil, 
53.4% of gay and transgender persons interviewed who engaged in AI in the previous 3 
months (n = 369) used a rectal douche.72  
 
One study of MSM living in New York City (n = 105) found that the average age of onset 
for douching before AI was 25 years old, and that higher proportions of HIV-positive vs. 
HIV-negative MSM douched before AI (96% [26/27] vs. 53% [41/78]) and after AI (44% 
[12/27] vs. 27% [21/78]).58 Multiple studies have identified significant associations 
between engaging in rectal douching and having HIV and/or an STI57,70,74, using 
substances during sex57, participating in group sex74, and being “versatile”, i.e., engaging 
in both insertive and receptive AI.71 
 
Reasons for douching before RAI include: a desire to maintain personal hygiene, a desire 
to adhere to a sexual partner’s request, a desire to prepare or get excited for RAI, and a 

 
 
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belief that douching enhances pleasure during RAI.57,58,69,70,81 Reasons for douching after 
sex include: a belief that the practice may help protect them against STIs, a belief that 
douching following RAI enhances pleasure, a desire to maintain personal hygiene, a 
desire to transition from sex, and a desire to adhere to a sexual partner’s request.58,69,70,81 
MSM typically report douching about one hour prior to an expected RAI encounter and 
about thirty minutes following RAI.70,81 
 
No data exists regarding the use of suppositories or inserts prior to RAI. MTN-035 will be 
the first study to assess those two formulations in this context, and study staff will 
document RAI practices in fine detail as part of this assessment. One topic of exploration 
will be what participants do before and after administering the suppositories or inserts, 
including whether participants douche prior to administering these two formulations. 
These findings will allow researchers to develop evidence-based product use 
recommendations and restrictions in the event the development of these formulations 
moves into safety trials. 
 
2.5 Study Hypotheses and Rationale for Study Design 
 
2.5.1 
Study Primary Hypotheses 
 
It is hypothesized that the placebo rectal insert, the rectal douche, and the rectal 
suppository will be safe, acceptable and tolerable to participants when administered 
rectally and used prior to engaging in RAI. It is also hypothesized that participants will use 
the placebo rectal insert, the rectal douche, and the rectal suppository as instructed during 
the 4 weeks they are assigned to use each product. 
 
2.5.2 
Rationale for Study Design 
 
Rectal microbicides are needed for individuals at risk of acquiring HIV infection through 
RAI, particularly young gay men and TGW. It is important to expand the rectal microbicide 
pipeline through the addition of products from different classes that are delivered through 
various mechanisms, including formulations able to deliver multiple drugs in combination. 
Many people who engage in RAI also engage in a variety of cleansing and preparatory 
practices around RAI encounters. Furthermore, intermittent pericoital dosing of rectal 
microbicides associated with sexual activity may be a more feasible long-term HIV 
prevention strategy for some people than daily dosing with oral tablets. Therefore, the 
use of on-demand rectal microbicides like the insert, douche and suppository have the 
potential advantage of both familiarity and context. Data are needed on the acceptability, 
tolerability, and adherence to these three formulations and to this dosing schedule among 
cisgender men, TGM and TGW.  
 
MTN-035 participants will be randomized to one of six sequences of a rectal insert, a 
rectal suppository, and a rectal douche as per Table 1.  Each study product will be 
administered prior to RAI for four weeks, with a one-week washout period between the 
three product use periods.  This crossover design allows for the comparison of 
acceptability, tolerability and adherence data within individuals who have been exposed 

 
 
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to each of the three study products when applied rectally and used prior to RAI. 
 
 
3 
OBJECTIVES  
 
3.1 Primary Objectives 
 
Acceptability and Tolerability 
• 
To evaluate the acceptability and tolerability of each study product when applied 
rectally and used prior to RAI 
o Placebo rectal insert 
o Placebo rectal douche 
o Placebo rectal suppository 
 
Adherence 
• 
To evaluate adherence to each study product prior to RAI over a 4-week-long period 
o Placebo rectal insert 
o Placebo rectal douche 
o Placebo rectal suppository 
 
Safety 
• 
To evaluate the safety of each study product when applied rectally and used prior to 
RAI  
o Placebo rectal insert 
o Placebo rectal douche 
o Placebo rectal suppository 
 
3.2 Exploratory Objective 
 
Relative Acceptability and Tolerability 
• 
To evaluate the relative acceptability and tolerability between study products when 
applied rectally and used prior to RAI 
o Placebo rectal insert 
o Placebo rectal douche 
o Placebo rectal suppository 
 
 
4 
STUDY DESIGN 
 
4.1 Identification of Study Design 
 
MTN-035 is a multi-site, randomized-sequence, three-period, open label crossover study. 
 

 
 
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4.2 Summary of Major Endpoints 
 
Primary Endpoints: 
 
Acceptability and Tolerability 
• 
For each study product, participant self-report of likelihood of product use if shown to 
be effective  
 
Adherence 
• 
Per participant report, percentage of occasions when each study product was used as 
instructed (per protocol) 
 
Safety 
• 
Grade 2 or higher related adverse events (AEs) as defined by the Division of AIDS 
Table for Grading the Severity of Adult and Pediatric Adverse Events, Corrected 
Version 2.1, July 2017, and/or Addenda 1, 2 and 3 (Female Genital [Dated November 
2007], Male Genital [Dated November 2007] and Rectal [Clarification Dated May 
2012] Grading Tables for Use in Microbicide Studies) 
 
Exploratory Endpoint: 
 
Relative Acceptability and Tolerability 
• 
Conjoint analysis of participant acceptability and tolerability between the three study 
products 
 
4.3 Description of Study Population 
 
The study population will consist of HIV-uninfected cisgender men, TGM and TGW aged 
18-35 who engage in RAI and meet the criteria outlined in Sections 5.2 and 5.3. 
 
4.4 Time to Complete Accrual 
 
The time to complete accrual is anticipated to be approximately 9-12 months.   
 
4.5 Study Groups  
 
MTN-035 will enroll approximately 210 participants randomized (1:1:1:1:1:1) to one of six 
sequences of rectal microbicide product application. 
 
4.6 Expected Duration of Participation 
 
Each participant will be in the study for approximately three and a half months.  The total 
duration of the study will be approximately 13-16 months. 
 

 
 
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4.7 Sites 
 
Sites selected by the MTN Executive Committee. 
 
5 
STUDY POPULATION 
 
5.1 Selection of the Study Population 
 
The inclusion and exclusion criteria in Sections 5.2 and 5.3 will be used to ensure the 
appropriate selection of study participants.  
 
5.1.1 
Recruitment 
 
Participants will be recruited from a variety of sources, including outpatient clinics, 
universities, community-based locations, online websites and social networking 
applications.  In addition, participants may be referred to the study from other local 
research projects and other health and social service providers.  Recruitment materials 
will be approved by site Institutional Review Boards/Independent Ethics Committees 
(IRBs/IECs) prior to use.  Advice regarding these materials will be sought from site 
community representatives before they are submitted to the site IRB/IEC for review. 
 
5.1.2 
Retention 
 
Once a participant is enrolled and randomized in MTN-035, the study site will make every 
effort to retain the participant in follow-up to minimize possible bias associated with loss-
to-follow-up. A retention rate of 95% will be targeted. The site will be responsible for 
developing and implementing local Standard Operating Procedures (SOPs) to target and 
ensure high rates of retention. 
 
5.2 Inclusion Criteria 
 
Individuals who meet the following criteria are eligible for study inclusion: 
 
1. Men (cis or transgender) and TGW who are 18-35 years old at Screening, verified 
per site SOP 
 
2. Able and willing to provide written informed consent 
 
3. HIV-1/2 uninfected at Screening and Enrollment, per applicable algorithm in 
Appendix II and willing to receive HIV test results 
 
4. Able and willing to provide adequate locator information, as defined in site SOP 
 
5. Available to return for all study visits and willing to comply with study participation 
requirements 
 

 
 
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6. In general good health at Screening and Enrollment, as determined by the site 
Investigator of Record (IoR) or designee 
 
7. At Screening, history of consensual RAI at least three times in the past three 
months and expecting to maintain at least this frequency of RAI during study 
participation per participant report 
 
8. Willing to not take part in other research studies involving drugs, medical devices, 
genital or rectal products, or vaccines for the duration of study participation 
(including the time between Screening and Enrollment) 
 
9. For individuals who can get pregnant (i.e., TGM with a female reproductive 
system): a negative pregnancy test at Screening and Enrollment 
 
10. For individuals who can get pregnant: Per participant report at Enrollment, using 
an effective method of contraception for at least 30 days (inclusive) prior to 
Enrollment and intending to use an effective method for the duration of study 
participation; effective methods include: 
a) Hormonal methods 
b) Intrauterine device (IUD) inserted at least 30 days prior to Enrollment 
(but not past the maximum length of recommended usage according to 
package instructions)  
c) Sterilization (of participant or, if in a monogamous relationship, of 
partner, as defined in site SOPs)  
d) Abstinence from RVI for 90 days prior to Enrollment, and intention to 
abstain from RVI for the duration of study participation 
 
5.3 Exclusion Criteria 
 
Individuals who meet any of the following criteria will be excluded from the study:   
 
1. At Screening: 
a) History of inflammatory bowel disease   
b) Current anorectal condition that would impede product placement or 
assessment of tolerability by participant report or exam 
 
2. Anticipated use and/or unwillingness to abstain from using non-study rectally-
administered medications and products during study participation, including 
personal lubricants containing nonoxynol-9 (N-9) 
 
Note: The use of non-study personal lubricants and usual pre-RAI douches that do not 
contain N-9 is permitted during study participation. 
 
3. Known adverse reaction to any of the components of the study products 
 
4. Participation in research studies involving drugs, medical devices, genital 
products, or vaccines within 30 days of the Enrollment Visit 
 
5. Participation in research studies involving rectal products (ever) 
 

 
 
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6. Per participant report, use of post-exposure prophylaxis (PEP) for potential HIV 
exposure within the 3 months prior to Enrollment 
 
7. In the 3 months prior to Enrollment, participant engagement in condomless RAI or 
RVI while not on PrEP with a partner who is HIV-positive and either not on ART or 
of unknown ART use status (by self-report) 
 
8. In the month prior to Enrollment, participant engagement in condomless RAI or RVI 
while not on PrEP with a partner who is of unknown HIV status and unknown 
PrEP/ART use status (by self-report) 
 
9. Non-therapeutic injection drug use in the 12 months prior to Enrollment 
 
10. At either Screening or Enrollment, participant-reported symptoms and/or clinical or 
laboratory diagnosis of active anorectal or reproductive tract infection (RTI) 
requiring 
treatment 
per 
current 
WHO 
guidelines 
(http://www.who.int/hiv/pub/sti/pub6/en/), or symptomatic urinary tract infection 
(UTI). Infections requiring treatment include Neisseria gonorrhea (GC), Chlamydia 
trachomatis (CT), syphilis, active herpes simplex virus (HSV) lesions, anogenital 
sores or ulcers, or symptomatic genital warts, chancroid, pelvic inflammatory 
disease (PID), symptomatic bacterial vaginosis (BV), symptomatic vaginal 
candidiasis, and trichomoniasis. 
 
Note: Otherwise eligible participants with a symptomatic UTI or an STI/RTI requiring 
treatment per current WHO guidelines may be re-tested during the screening process and 
if treatment is completed and symptoms have resolved within the screening window the 
participant may be enrolled. 
 
Note: HSV-1 or HSV-2 seropositive diagnosis with no active lesions is permitted since 
treatment is not required. 
 
11. For individuals who can get pregnant: Pregnant or breastfeeding at either 
Screening or Enrollment or planning to become pregnant during study participation 
 
12. For individuals who can get pregnant: Last pregnancy outcome 90 days or less 
prior to Screening 
 
13. Has any other condition that, in the opinion of the IoR/designee, would preclude 
informed consent, make study participation unsafe, complicate interpretation of 
study outcome data, or otherwise interfere with achieving study objectives. 
 
5.4 Co-enrollment Guidelines 
 
As indicated in Sections 5.2 and 5.3, participants must not take part in other research 
studies involving drugs, medical devices, genital or rectal products, or vaccines after the 
Screening Visit and while taking part in MTN-035 unless approved by the Protocol Safety 
Review Team (PSRT).  Participation in the following types of studies may be allowed at 
the discretion of the IoR/designee: 
 

 
 
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• Participants may take part in ancillary studies if approved by MTN-035 PSRT  
• Participants who become infected with HIV may take part in observational and/or 
interventional studies for HIV-positive persons 
 
Should any participant report concurrent participation in contraindicated studies after 
enrolling in MTN-035, the IoR/designee will consult the PSRT regarding ongoing product 
use and other potential safety considerations associated with co-enrollment. 
 
 
6 
STUDY PRODUCT 
 
6.1 Regimen 
 
Participants will be randomized to one of six study product administration sequences 
(Sequence A-F).  Each sequence will consist of three four-week periods of study product 
administration, with one week between each four-week period.  The duration of product 
administration including the two washout periods is approximately 14 weeks.   
 
Table 3: Study Product Regimen 
Sequence 
N 
Period 1 
(4 weeks) 
Washout 
period (~1 
week) 
Period 2 
(4 weeks) 
Washout 
period (~1 
week) 
Period 3 
(4 weeks) 
A 
35 
Rectal 
insert 
-- 
Rectal douche 
-- 
Rectal 
suppository 
B 
35 
Rectal 
douche 
-- 
Rectal 
suppository 
-- 
Rectal insert 
C 
35 
Rectal 
suppository 
-- 
Rectal insert 
-- 
Rectal douche 
D 
35 
Rectal 
insert 
-- 
Rectal 
suppository 
-- 
Rectal douche 
E 
35 
Rectal 
douche 
-- 
Rectal insert 
-- 
Rectal 
suppository 
F 
35 
Rectal 
suppository 
-- 
Rectal douche 
-- 
Rectal insert 
 
6.2 Administration 
 
Each participant will receive study product that includes placebo inserts, placebo 
suppositories, and placebo (water) douches for pericoital rectal administration.  The 
products will be administered in order of the assigned sequence. It is recommended that 
participants insert one dose of the study product between 30 minutes and 3 hours prior 
to RAI, and that they not insert more than one dose in 24 hours. The study product should 
be administered following the participant’s usual pre-RAI practices. If a participant does 
not engage in RAI in a given week, they will be asked to insert a dose of the product in 
the absence of RAI. Participants will self-administer the first dose of each product in the 
clinic to ensure correct administration and tolerability. 

 
 
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6.2.1 
Placebo inserts and suppositories 
 
Participants will be instructed to insert in the rectum a placebo insert or suppository prior 
to RAI.  If a dose is missed, participants will be instructed to wait to take a dose at the 
next occurrence of RAI. Furthermore, if no RAI activity occurs at all in a given 7-day 
period, participants will be instructed to take a dose on the seventh day in the absence of 
RAI.  Participants will be provided instructions on proper insertion of the insert and 
suppository. 
 
6.2.2 
Placebo rectal douche 
 
Participants will be instructed to insert in the rectum a placebo douche prior to RAI.  If a 
dose is missed, participants will be instructed to wait to take a dose at the next occurrence 
of RAI, or if no other RAI activity occurs in that 7-day period, to take a dose in the absence 
of RAI. Furthermore, if no RAI activity occurs at all in a given 7-day period, participants 
will be instructed to take a dose on the seventh day in the absence of RAI.  Participants 
will be provided instructions on preparation and proper insertion of the douche. 
 
6.3 Study Product Formulation  
 
Study products should be stored at controlled room temperature 20° - 25°C (68° - 77°F) 
until dispensed for use.  Excursions between 15° – 30°C (59° – 86°F) are allowed. 
 
6.3.1 
Placebo rectal insert 
 
The placebo rectal insert is formulated into white to off-white uncoated solid dosage forms 
in a bullet shape. The insert contains the following inactive excipients: isomalt, xylitol, 
sodium CMC, povidone, hydroxypropyl methylcellulose, poloxamer 188, sodium stearyl 
fumarate and magnesium stearate. The insert is 1.5 cm (0.6 inches) long, 0.7 cm (0.28 
inches) wide, 0.6 cm (0.23 inches) in height, and approximately 500 mg in weight. The 
rectal insert is manufactured under current Good Manufacturing Practice (cGMP) under 
CONRAD oversight. The insert is stored in a white induction-sealed HDPE bottle along 
with polyester coil and a desiccant at controlled room temperature (see temperature 
details above).  
 
6.3.2 
Placebo rectal douche 
 
Participants will fill the enema bottle with approximately 120 mL of clean tap water or 
bottled water. The enema bottles used in this study are commercially available 125 mL 
enema bottles that meet US Pharmacopeia (USP) standards and contain no heavy 
metals, no phthalates, and are bisphenol A (BPA) free. 
 

 
 
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6.3.3 
Placebo rectal suppository 
 
The rectal suppository is approximately 3-3.8 cm (1.2-1.5 inches) long and 2 grams in 
weight. The placebo rectal suppository consists of a Witepsol® H5 (IOI Oleochemical) 
base and contains 15% diglyceride and not more than 1% monoglyceride content. The 
rectal suppository will be manufactured under current Good Manufacturing Practice 
(cGMP). The suppository is stored at controlled room temperature (see temperature 
details above). 
 
6.4 Study Product Supply and Accountability 
 
6.4.1 
Study Product Supply 
 
Placebo Rectal Insert 
 
CONRAD will oversee the manufacture of the placebo inserts by CoreRx (Clearwater, 
FL)  
 
Placebo Rectal Douche 
 
Participants will be provided commercially available 125 mL enema bottles with pre-
lubricated tips. Bottled water or clean tap water will be used for the rectal douches. Bottled 
water will be provided by the sites for participants who are unable to obtain clean tap 
water. Supplies and instructions for preparing the rectal douches will be provided to the 
study participants.  
 
Placebo Rectal Suppository 
 
The MTN will oversee the manufacture of the placebo suppositories by CoreRx 
(Clearwater, FL). 
 
6.4.2 
Study Product Accountability 
 
The Clinical Research Site (CRS) Pharmacist of Record (PoR) is required to maintain 
complete records of the study products received and subsequently dispensed. All unused 
study products must be returned to the MTN LOC Pharmacist after the study is complete 
unless otherwise instructed by the MTN LOC Pharmacist. 
 
6.5 Study Product Dispensing  
 
Study products will be dispensed by the pharmacist to study staff upon receipt of a written 
prescription from an authorized prescriber. An authorized prescriber includes the IoR or 
a licensed clinician directly responsible to the IoR as noted on the DAIDS IoR Form. Study 
product will be dispensed at the beginning of each product use period including 
Enrollment (Day 0), Visit 4 (Day 35), and Visit 6 (Day 70). If additional supplies are needed 
between study visits, participants will be instructed to contact the study site. 

 
 
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6.6 Ancillary Study Supplies 
 
Participants will be offered male condoms at all visits. The condoms will be made 
available in the clinic and will be dispensed by the clinic staff. Participants will be provided 
lubricant approved for use during the product administration periods to facilitate insertion. 
At all other visits, clinical staff will offer participants lubricant (not containing N-9) as per 
local standard of care.   
 
6.7 Concomitant Medications and Practices 
 
Enrolled study participants may use concomitant medications during study 
participation. All concomitant medications reported throughout the course of the study will 
be recorded in the study database. Concomitant medications include all prescription 
medications, over-the-counter preparations, vitamins, nutritional supplements, and herbal 
preparations.  
 
Use of rectally-administered non-study medications and products is prohibited, including 
any products containing N-9. 
 
Note: The use of non-study personal lubricants and usual pre-RAI douches that do not contain N-
9 is permitted during study participation 
 
 
7 
STUDY PROCEDURES 
 
An overview of the study visit and evaluations schedule is presented in Appendix I.  
Presented in this section is additional information on visit-specific study procedures.  
Detailed instructions to guide and standardize procedures as well as information 
regarding the study visit windows are provided in the MTN-035 SSP Manual available at 
http://www.mtnstopshiv.org/research/studies. 
 
Figure 2: MTN-035 Study Visit Schedule 
 
  

 
 
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7.1 Pre-screening 
 
As part of participant outreach and recruitment strategies, study staff can pre-screen 
potential study participants at either on-site or off-site locations. During these interactions, 
study staff may explain the study to potential participants and ascertain elements of 
presumptive eligibility (e.g., willingness to use the study products, willingness to adhere 
to the study requirements, etc.), to be confirmed at an on-site screening visit. Process 
information (e.g., number of potential participants contacted, number presumptively 
eligible) may be recorded and stored at the study site in the absence of written informed 
consent from potential participants, provided the information is collected in such a manner 
that it cannot be linked to participant identifiers, unless a waiver is granted from the local 
IRB/IEC. Procedures and documentation will comply with local IRB/IEC requirements.  
 
7.2 Screening  
 
A Screening Visit will take place up to 45 days prior to the Enrollment Visit (Day 0).  
Multiple visits may be conducted to complete all required screening procedures, if 
necessary. Written informed consent for Screening/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.   
 
Note:  If a participant is ineligible based upon a behavioral criterion, the behavioral eligibility 
assessment may be completed in its entirety, to avoid socially desirable reporting. 
 

 
 
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Table 4:  Visit 1- Screening Visit 
Visit 1-Screening Visit 
Component 
Procedures 
Administrative and 
Regulatory 
• 
Obtain written informed consent 
• 
Assess consent form comprehension 
• 
Assign a unique Participant Identification (PTID) number 
• 
Assess eligibility 
• 
Collect demographic information 
• 
Collect locator information 
• 
Provide reimbursement 
• 
Schedule next visit/contact* 
Behavioral/Counseling 
• 
HIV pre- and post-test counseling 
• 
HIV/STI risk reduction counseling 
• 
Protocol counseling 
Clinical 
• 
Collect medical history 
• 
Collect concomitant medications 
• 
Perform physical examination 
• 
Perform rectal examination 
• 
Disclose available test results  
• 
Treat or prescribe treatment for RTI/UTI, or STIs* 
Laboratory 
 
Pharyngeal 
• 
Nucleic acid amplification test (NAAT) for GC/CT 
Urine 
• 
NAAT for GC/CT/Trichomonas 
• 
Urine dipstick/culture* 
• 
Pregnancy test ϕ 
Blood 
• 
HIV-1/2 test 
• 
Syphilis serology 
Pelvic 
• 
NAAT for GC/CT and Trichomonas¤ 
Anorectal 
• 
NAAT for GC/CT 
• 
HSV 1/2 detection* (at sites with capacity) 
Study Product/Supplies 
• 
Offer condoms 
• 
Offer lubricant ** 
* If indicated and/or per local standard of care, ** Lubricant will be provided at product administration visits and as per  
  local standard of care at other visits, ϕ Individuals who can get pregnant, ¤ Individuals with a vagina or neovagina 
 

 
 
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7.3 Enrollment (Day 0) 
 
The Enrollment Visit occurs up to 45 days after the Screening Visit. Participants will be 
randomized to study product application sequence and begin using study product at the 
clinic during this visit. 
 
Table 5:  Visit 2- Enrollment Visit 
Visit 2- Enrollment Visit 
Component 
Procedures 
Administrative and Regulatory 
• 
Review informed consent/ confirm participant’s willingness 
to participate in study 
• 
Assess and confirm eligibility 
• 
Review/update locator information 
• 
Provide reimbursement 
• 
Schedule next visit/contact* 
• 
Randomization 
Behavioral/Counseling 
• 
HIV pre- and post-test counseling 
• 
HIV/STI risk reduction counseling 
• 
Protocol counseling 
• 
Training in short message service (SMS)/instant message 
(IM) Reporting System 
• 
Baseline behavioral assessment 
Clinical 
• 
Review/update medical history 
• 
Review/update concomitant medications 
• 
Perform targeted physical examination 
• 
Perform rectal examination 
• 
Disclose available test results  
• 
Treat or prescribe treatment for RTI/UTI, or STIs* 
Laboratory 
 
Pharyngeal 
• 
NAAT for GC/CT* 
Urine 
• 
NAAT for GC/CT/Trichomonas* 
• 
Urine dipstick/culture* 
• 
Pregnancy test ϕ 
Blood 
• 
HIV-1/2 test 
• 
Plasma for archive 
• 
Syphilis serology* 
Pelvic 
• 
NAAT for GC/CT/Trichomonas*¤ 
Anorectal 
• 
NAAT for GC/CT* 
• 
HSV 1/2 detection* (at sites with capacity) 
Study Product/Supplies 
• 
Provide study product and study product use counseling 
• 
First study product application at the clinic 
• 
Offer condoms 
• 
Offer lubricant** 

 
 
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* If indicated and/or per local standard of care, ** Lubricant will be provided at product administration visits and as per  
  local standard of care at other visits, ϕ Individuals who can get pregnant, ¤ Individuals with a vagina or neovagina 
 
7.4 Follow-up Visits 
 
7.4.1 Visits 3, 5 and 7 – First, Second and Third Product Use End Visits (PUEV) 
 
Visit 3 – First PUEV should occur 4 weeks (approximately 28 days) after the Enrollment 
Visit.  Visit 5 – Second PUEV should occur 4 weeks (approximately 28 days) after Visit 4 
– Product Switch Visit. Visit 7 – Third PUEV should occur 4 weeks (approximately 28 
days) after Visit 6 – Product Switch Visit. The PSRT must be consulted regarding 
progression into the next dosing period prior to the initiation of study product for Periods 
2 and 3, for any participant who has unresolved pelvic, genital or anorectal AEs of Grade 
≥3, and any other AE that in the opinion of the investigator would preclude the participant 
from continuing to the next product use period. 
 
Participants will complete brief, weekly short SMS/IM assessments about their product 
use and RAI behaviors during each 4-week product use period.  Behavioral evaluations 
will be completed at the end of each product use period at Visits 3, 5, and 7, including a 
brief in-depth interview (IDI) during the visit to review their SMS/IM reports. 
 
Table 6:  Visits 3, 5 and 7 – First, Second and Third PUEV 
Visits 3, 5 and 7 – First, Second and Third PUEV 
Component 
Procedures 
Administrative and Regulatory 
• 
Review/update locator information 
• 
Provide reimbursement 
• 
Schedule next visit/contact 
Behavioral/Counseling 
• 
HIV pre- and post-test counseling* (Required at Visit 7) 
• 
HIV/STI risk reduction counseling* (Required at Visit 7) 
• 
Protocol counseling 
• 
Behavioral assessment 
• 
Brief in-depth interview (IDI) 
Clinical 
• 
Review/update medical history 
• 
Review/update concomitant medications 
• 
Perform targeted physical examination* 
• 
Perform rectal examination 
• 
Disclose available test results 
• 
Record/update AEs  
• 
Treat or prescribe treatment for RTI/UTI, or STIs* 
Laborator
y 
Pharyngeal 
• 
NAAT for GC/CT* (Required at Visit 7) 
Urine 
• 
Urine dipstick/culture* 
• 
NAAT for GC/CT/Trichomonas* (Required at Visit 7) 
• 
Pregnancy test* ϕ 

 
 
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Visits 3, 5 and 7 – First, Second and Third PUEV 
Component 
Procedures 
Blood 
• 
HIV-1/2 test* (Required at Visit 7) 
• 
Syphilis serology* (Required at Visit 7) 
Pelvic 
• 
NAAT for GC/CT/Trichomonas*¤ (Required at Visit 7) 
Anorectal 
• 
NAAT for GC/CT* (Required at Visit 7) 
• 
HSV 1/2 detection* (at sites with capacity) 
Study Product/Supplies 
• 
Offer condoms 
• 
Offer lubricant** 
* If indicated and/or per local standard of care, ** Lubricant will be provided at product administration visits and as per  
  local standard of care at other visits, ϕ Individuals who can get pregnant, ¤ Individuals with a vagina or neovagina 
 
7.4.2 Visits 4 and 6 – Product Switch Visits 
 
The Visit 4 – Product Switch Visit should occur 1 week (approximately 7 days) after Visit 
3 – First PUEV. The Visit 6 – Product Switch Visit should occur 1 week (approximately 7 
days) after Visit 5 – Second PUEV. 
 
Table 7:  Visits 4 and 6 – Product Switch Visits 
Visits 4 and 6 – Product Switch Visits 
Component 
Procedures 
Administrative and Regulatory 
• 
Review/update locator information 
• 
Provide reimbursement 
• 
Schedule next visit/contact 
Behavioral/Counseling 
• 
HIV pre- and post-test counseling* 
• 
HIV/STI risk reduction counseling* 
• 
Protocol counseling 
Clinical 
• 
Review/update medical history 
• 
Review/update concomitant medications 
• 
Perform targeted physical examination* 
• 
Perform rectal examination* 
• 
Disclose available test results 
• 
Record/update AEs  
• 
Treat or prescribe treatment for RTI/UTI, or STIs* 
Laboratory 
 
Pharyngeal 
• 
NAAT for GC/CT* 
Urine 
• 
Urine dipstick/culture* 
• 
NAAT for GC/CT/Trichomonas* 
• 
Pregnancy test* ϕ 
Blood 
• 
HIV-1/2 test* 
• 
Syphilis serology* 
Pelvic 
• 
NAAT for GC/CT/Trichomonas*¤ 
Anorectal 
• 
NAAT for GC/CT* 
• 
HSV 1/2 detection* (at sites with capacity) 

 
 
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Visits 4 and 6 – Product Switch Visits 
Component 
Procedures 
Study Product/Supplies 
• 
Provide study product and study product use counseling 
• 
Study product application at the clinic 
• 
Offer condoms 
• 
Offer lubricant** 
* If indicated and/or per local standard of care, ** Lubricant will be provided at product administration visits and as per  
  local standard of care at other visits, ϕ Individuals who can get pregnant, ¤ Individuals with a vagina or neovagina 
 
7.4.3 Visit 8 – Final/Early Termination Visit 
 
The Visit 8 – Final Visit should occur 1 week (approximately 7 days) after Visit 7 – Third 
PUEV. This visit will serve as the participant’s study termination. 
 
During their Final or Early Termination Visit, participants will complete a conjoint analysis 
assessment to compare among the study products. Also, a subset of participants 
(approximately 10 per site) will be selected to complete an IDI during this visit to further 
explore participants’ acceptability of the study products. 
 
Table 8:  Visit 8 – Final/Early Termination Visit 
Visit 8 – Final/Early Termination Visit 
Component 
Procedures 
Administrative and Regulatory 
• 
Review/update locator information 
• 
Provide reimbursement 
Behavioral/Counseling 
• 
HIV pre- and post-test counseling* 
• 
HIV/STI risk reduction counseling* 
• 
Behavioral assessment 
• 
IDI (subset) 
Clinical 
• 
Review/update medical history 
• 
Review/update concomitant medications 
• 
Perform targeted physical examination* 
• 
Perform rectal examination* 
• 
Disclose available test results 
• 
Record/update AEs  
• 
Treat or prescribe treatment for RTI/UTI, or STIs* 
Laboratory 
 
Pharyngeal 
• 
NAAT for GC/CT* 
Urine 
• 
Urine dipstick/culture* 
• 
NAAT for GC/CT/Trichomonas* 
• 
Pregnancy test ϕ  
Blood 
• 
HIV-1/2 test* 
• 
Syphilis serology* 
Pelvic 
• 
NAAT for GC/CT/Trichomonas*¤ 
Anorectal 
• 
NAAT for GC/CT* 
• 
HSV 1/2 detection* (at sites with capacity) 

 
 
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Visit 8 – Final/Early Termination Visit 
Component 
Procedures 
Study Product/Supplies 
• 
Offer condoms 
• 
Offer lubricant** 
* If indicated and/or per local standard of care, ** Lubricant will be provided at product administration visits and as per  
  local standard of care at other visits, ϕ Individuals who can get pregnant, ¤ Individuals with vagina or neovagina 
 
7.5 Follow-up Procedures for Participants Who Permanently Discontinue Study 
Product 
 
7.5.1 Participants Who Become Infected with HIV-1/2 
 
If a participant tests positive for HIV-1/2 after the Enrollment Visit, s/he will be referred to 
local care and treatment services and may return to the research clinic for additional 
counseling and other support services, as needed. Continued study participation would 
be of no added benefit; thus follow-up visits will be discontinued and the participant will 
be considered terminated from the study.  An Early Termination Visit will be conducted, if 
the participant is willing. Participants who are taking oral PrEP for HIV prevention while 
on study and seroconvert after randomization may be offered additional laboratory testing 
(such as HIV RNA and HIV drug resistance testing), as clinically indicated, per 
discussions between the site IoR and LC.  Please reference the MTN-035 SSP Manual 
for additional details (www.mtnstopshiv.org/research/studies). 
 
7.5.2 Participants Who Become Pregnant 
 
Any participant who becomes pregnant will be referred to local health care services and 
may return to the research clinic for additional counseling, as needed. Continued study 
participation would be of no added benefit to the participant, thus follow-up visits and 
procedures will be discontinued and the participant will be considered terminated from 
the study.  An Early Termination Visit will be conducted, if the participant is willing. See 
Section 9.7 for additional details.  
 
7.5.3 Participants Who Permanently Discontinue Study Product for Other 
Reasons 
 
For participants who permanently discontinue use of one of the study products for any 
clinician-initiated reason, the PSRT should be consulted regarding continued study 
participation and progression to other study products. For participants terminated from 
the study after PSRT consult, an Early Termination Visit will be conducted, if the 
participant is willing. See Section 9 for additional details regarding clinical follow-up of 
AEs unresolved at the time of study termination. 
 
Participants who permanently discontinue use of one of the study products for any self-
initiated reason during the first or second product use period will be allowed to continue 
in the study and progress to the other study product(s), if they are willing. Participants 
who permanently discontinue study product use for any self-initiated reason during the 

 
 
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third product use period will be terminated from the study, and an Early Termination Visit 
will be conducted, if the participant is willing. See Section 9.8 for additional details.    
 
7.5.4 Interim Visits 
 
Interim visits may be performed at any time during the study, 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 or to perform missed procedures. 
• In response to AEs and/or SAEs.  When interim contacts or visits are completed 
in response to participant reports of AEs and/or SAEs, study staff will assess the 
reported event clinically and provide or refer the participant to appropriate medical 
care (see also Section 9). 
• For interim STI counseling and testing in response to STI symptoms. 
• For interim HIV counseling and testing in response to participant report of 
symptoms consistent with acute infection or presumed exposure to HIV. 
• To provide participants with the results of confirmatory HIV test results, per the 
algorithm in Appendix II. 
• For other reasons at participant request, e.g., social harm, to get additional study 
product. 
 
All interim contacts and visits will be documented in participants' study records. 
 
7.6 Protocol Counseling:  Adherence and Study Product Use Counseling 
 
At the Enrollment and Product Switch Visits, participants will receive study product and 
study product use counseling appropriate to the visit.  Study staff will document 
dispensation of study product and that the counseling was provided.  Protocol adherence 
counseling will be provided to study participants upon enrollment into the study.  
Counseling will be provided in accordance with standard study methods.  Counseling also 
will include reminders regarding concomitant medication and behavioral restrictions for 
the duration of the trial.   
 
7.7 Clinical Evaluations and Procedures 
 
Physical Examination  
The physical examination will include the following assessments:  
• General appearance 
• Weight*  
• Vital signs 
 Temperature 
 Pulse  
 Blood pressure 
 Respirations 

 
 
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• Height* 
• Oral mucosa* 
• Abdomen*  
• Head, Eye, Ear, Nose and Throat (HEENT) Examination* 
• Lymph nodes*  
• Neck*  
• Heart* 
• Lungs*  
• Extremities* 
• Skin*  
• Neurological* 
• Pelvic Examination (for individuals with a vagina or neovagina only)** 
o Visual exam 
o Speculum exam 
o Bimanual exam 
• Genital Examination (for individuals with a penis or neopenis only)** 
o Entire penile surface 
 Glans 
 Urethral meatus 
 Internal and external foreskin (if present) 
 Shaft 
o Scrotum 
o Inguinal lymph nodes 
 
 
 
 
 
 * = May be omitted after Screening Visit 
** = May be omitted if not clinically indicated 
 
Anorectal Examination 
The anorectal examination may include the following:  
• Visual exam 
• Digital exam 
• Anoscopy  
 
Note:  Detailed information regarding the pelvic, genital, and rectal examination, as well as 
associated procedures, can be found in the MTN-035 SSP Manual. 
 
Additional clinical assessments may be performed at the discretion of the examining 
clinical staff in response to symptoms or illnesses present at the time of the exam.  
 
7.8 Behavioral Evaluations 
 
All participants will respond to computer assisted self-interviews (CASI) at the Enrollment 
Visit (Visit 2) and at the three PUEVs (Visits 3, 5 and 7), and to a conjoint analysis 
assessment at the Final Visit (Visit 8). The assessment done at enrollment will include, 
among other topics, questions on participants’ prior experiences and comfort using rectal 
products, as well as douching or other rectal hygiene practices. The follow-up 

 
 
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assessments will explore reactions to each study product and administration method, 
including participants’ perceptions of their partners’ reactions. These assessments will 
allow investigators to identify product attributes likely to challenge and/or facilitate future 
sustained use when applied rectally by participants. Suggestions for product 
improvement will also be collected. The conjoint analysis assessment will compare 
between the three study products, including questions on participant preferences 
regarding the different formulations. 
  
Participants will also complete a brief weekly report of product use via SMS/IM for each 
study product. A brief IDI is planned for all participants at the three PUEVs (Visits 3, 5 
and 7). These IDIs will review and explore participants’ responses to acceptability, 
tolerability, and adherence questions asked via SMS/IM during each product use period.  
 
Based on Behavioral Research Working Group (BRWG) review of SMS/IM data, 
approximately 10 participants per site will be selected and invited to complete a longer 
IDI at the Final Visit (Visit 8). This IDI will include questions comparing user acceptability 
of the study products, user-centered suggestions for product design and delivery, 
acceptability and factors influencing product use, douching history and education, and 
experiences with the application methods, among other topics. Suggestions for product 
improvement will also be collected. The audio from the IDI will be recorded and 
transcribed for analysis. The interview notes, recording and transcript will be considered 
as source documentation.  
 
Major components of both CASI and IDI assessments have been used successfully and 
validated in prior rectal microbicide trials (e.g., MTN-006, MTN-007, MTN-017) and are 
being implemented/planned as part of MTN-026, MTN-033 and MTN-037. 
 
7.9 Laboratory Evaluations 
 
Local Laboratory 
The local laboratory will run the following, as indicated: 
 
• Pharyngeal specimens at sites with capacity 
 NAAT for GC/CT 
• Urine specimens 
 Human chorionic gonadotropin (hCG) 
 NAAT for GC/CT/Trichomonas 
 Dipstick/culture 
• Blood specimens 
 HIV-1/2 testing, with confirmatory testing as needed 
 Syphilis serology 
• Vaginal specimens (fluid) 
 NAAT for GC/CT/Trichomonas 
• Anorectal specimens (rectal fluid) at sites with capacity 
 NAAT for GC/CT  

 
 
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 HSV 1/2 detection 
 
Laboratory Center (LC) 
•  Blood specimens 
 Plasma archive 
• Pharyngeal specimens from sites without local capacity 
 NAAT for GC/CT 
• Anorectal specimens (rectal fluid) from sites without local capacity 
 NAAT for GC/CT 
 
Once all required study analyses of collected specimens are complete, any remaining 
sample may be shipped to the MTN LC for use in study-related quality assurance and 
quality control testing. If study samples will be used for assay validation or proficiency 
testing that is not study related, all participant identifiers (PTID) will be removed from the 
samples prior to use. 
 
7.10 Specimen Management 
 
The study site will adhere to the standards of good clinical laboratory practice 
(https://www.niaid.nih.gov/sites/default/files/gclp.pdf), in accordance with current DAIDS 
Laboratory 
Requirements, 
MTN-035 
SSP 
Manual 
(http://www.mtnstopshiv.org/research/studies and site SOPs for proper collection, 
processing, 
labeling, 
transport, 
and 
storage 
of 
specimens 
to 
standardize 
procedures. Specimen collection, testing, and storage at the site laboratories will be 
documented when applicable using the Laboratory Data Management System (LDMS). In 
cases where laboratory results are not available due to administrative or laboratory error, 
the site is permitted to re-draw specimens. Further, as part of quality control, researchers 
may need to look at short pieces of non-coding repetitive DNA sequence (3-7 base pairs) 
from blood in the event of sample mix-up. This test will only let researchers know the 
number of times this short segment is repeated and not specific genes or specific 
sequences of base pairs. This sequence element does not contain any information about 
genes, therefore researchers will not be able to identify if participants are predisposed to 
specific diseases or any other genetic information based on this information. This test will 
be an important tool for distinguishing whether two samples collected at the same or 
different time points are likely from the same person. The test will only be used as part of 
a sample investigation with the knowledge of the site in situations where a known or 
suspected sample mix-up has occurred. No genetic testing (limited or genome-wide) is 
planned and all leftover samples will be destroyed after all testing related to this study is 
completed. 
 
7.11 DAIDS Laboratory Oversight 
 
All laboratories participating in DAIDS Sponsored and/or Funded Laboratories in Clinical 
Trials will adhere to the DAIDS Laboratory Policy. 
(https://www.niaid.nih.gov/research/daids-clinical-research-policies-us-labs) 
 

 
 
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7.12 Biohazard Containment 
 
As the acquisition 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 National 
Institutes of Health (NIH). All biological specimens will be transported using packaging 
mandated by Code of Federal Regulations (CFR) 42 Part 72. All dangerous goods 
materials, including diagnostic specimens and infectious substances, must be 
transported according to instructions detailed in the International Air Transport 
Association (IATA) Dangerous Goods Regulations. Biohazardous waste will be contained 
according to institutional, transportation/carrier, and all other applicable regulations. 
 
 
8 
ASSESSMENT OF SAFETY 
 
8.1 Safety Monitoring 
 
The site IoR is 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, DAIDS Medical Officer, representative(s) 
from CONRAD, and Protocol Safety Physicians will serve as the PSRT. The MTN 
Statistical Data Management Center (SDMC) prepares routine AE and clinical data 
reports for review by the PSRT, which meets via conference call approximately once per 
month or as needed throughout the period of study implementation to review safety data, 
discuss product use management, and address any potential safety concerns.  
 
8.2 Clinical Data and Safety Review 
 
A multi-tiered safety review process will be followed for the duration of this study. The 
study site investigators are responsible for the initial evaluation and reporting of safety 
information at the participant level and for alerting the PSRT if unexpected concerns arise. 
Participant safety is also monitored at the Network level through a series of routine 
reviews conducted by the SDMC and the PSRT. Additional reviews may be conducted at 
each of these levels as dictated by the occurrence of certain events. 
 
MTN SDMC staff will review incoming safety data on an ongoing basis. Events identified 
as questionable, inconsistent, or unexplained will be queried for verification. 
 
The PSRT will meet approximately every month via conference call to review clinical data 
reports generated by the MTN SDMC. The content, format and frequency of the clinical 
data reports will be agreed upon by the PSRT and the SDMC in advance of study 
implementation. In addition to the routine safety data reviews, the PSRT will convene on 
an ad hoc basis to make decisions regarding the handling of any significant safety 
concerns. If necessary, experts external to the MTN representing expertise in the fields 

 
 
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of microbicides, biostatistics, HIV acquisition and medical ethics may be invited to join the 
PSRT safety review. A recommendation to pause or stop the trial may be made by the 
PSRT at this time or at any such time that the team agrees that an unacceptable type 
and/or frequency of AEs has been observed. 
 
The Study Monitoring Committee (SMC) will review participant safety data as part of its 
regular reviews (see Section 10.6), since no Data and Safety Monitoring Board oversight 
is planned for MTN-035. The SMC may recommend that the study proceed as designed, 
proceed with design modifications, or be discontinued. Members of the SMC will be 
independent investigators with no interest (financial or otherwise) in the outcomes of this 
study. If at any time a decision is made to discontinue enrollment and/or study product 
use in all participants, the Site IoR(s) will notify the responsible IRB(s)/IEC(s) 
expeditiously. 
 
In addition to the safety monitoring, the MTN SMC will conduct interim reviews of study 
progress, including rates of participant accrual, retention, completion of primary and main 
secondary endpoint assessments, and study or lab issues.  These reviews will take place 
approximately every 4-6 months, or as needed. At the time of these reviews, or at any 
other time, the SMC may recommend that the study proceed as designed, proceed with 
design modifications, or be discontinued. 
 
8.3 Adverse Events Definitions and Reporting Requirements 
 
8.3.1 
Adverse Events 
 
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 at the 
time of enrollment (i.e., once a participant is randomized) through to the termination visit. 
The term “investigational product” for this study refers to the placebo rectal insert, the 
placebo (water) rectal douche, and the placebo rectal suppository.  
 
Study participants will be provided instructions for contacting the study site to report any 
untoward medical occurrences they may experience. In cases of potentially life-
threatening events, participants will be instructed to seek immediate emergency care. 
Where feasible and medically appropriate, participants will be encouraged to seek 
evaluation where a study clinician is based, and to request that the clinician be contacted 
upon their arrival. Records from all non-study medical providers related to untoward 
medical occurrences will be obtained whenever possible and with appropriate permission 
of the participant, and required data elements will be captured in the study database. All 
participants reporting an untoward medical occurrence considered related to product use 
will be followed clinically until the occurrence resolves (returns to baseline) or stabilizes. 
 

 
 
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Study site staff will document in source documents and in the study database all AEs 
reported by or observed in enrolled study participants regardless of severity and 
presumed relationship to study product. AE severity will be graded per the DAIDS Table 
for Grading Adult and Pediatric Adverse Events, Corrected Version 2.1, July 2017 and/or 
Addenda 1, 2 and 3 (Female Genital [Dated November 2007], Male Genital [Dated 
November 2007] and Rectal [Clarification Dated May 2012] Grading Tables for Use in 
Microbicide Studies), available on the DAIDS Regulatory Support Center (RSC) website 
at http://rsc.tech-res.com/clinical-research-sites/safety-reporting/daids-grading-tables. 
 
For individuals with a vagina or neovagina, please note: 
• 
Asymptomatic BV and asymptomatic candida will not be reportable AEs, but will 
be captured on the STI CRF. 
 
For individuals who can get pregnant, please note: 
• Fetal losses (e.g., spontaneous abortions, spontaneous fetal deaths, stillbirths) will 
not be reported as AEs, but will be captured on the Pregnancy Outcome CRF. 
• Untoward maternal conditions that either result in or result from fetal losses are 
reported as reproductive system AEs. 
 
Fecal urgency, bloating, flatulence and bleeding associated with rectal procedures 
deemed to be within the range of what is normally expected will not be reportable as AEs. 
Bleeding of greater quantity or longer duration than what is typical, per clinician 
assessment, will be reportable as an AE. 
 
8.3.2 
Serious Adverse Events 
 
An SAE will be defined by the Manual for Expedited Reporting of Adverse Events to 
DAIDS (Version 2.0, January 2010), which is available on the DAIDS RSC website at 
http://rsc.tech-res.com/clinical-research-sites/safety-reporting/manual, as an AE that:  
 
• Results in death 
• Is life-threatening  
• Results in persistent or significant disability/incapacity  
• Is a congenital anomaly/birth defect 
• Requires inpatient hospitalization or prolongation of existing hospitalization 
 
Note: Per ICH SAE definition, hospitalization itself is not an AE, but is an outcome of the 
event. Thus, hospitalization in the absence of an AE is not regarded as an AE. The 
following are examples of hospitalization that are not considered to be AEs: 
o Protocol-specified admission (e.g., for procedure required by study protocol) 
o Admission for treatment of target disease of the study, or for pre-existing condition 
(unless it is a worsening or increase in frequency of hospital admissions as judged 
by the clinical investigator) 
o Diagnostic admission (e.g., for a work-up of an existing condition such as 
persistent pretreatment lab abnormality) 
o Administrative admission (e.g., for annual physical) 
o Social admission (e.g., placement for lack of place to sleep) 

 
 
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o Elective admission (e.g., for elective surgery) 
 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered an SAE when, based upon appropriate medical 
judgment, they may jeopardize the patient or subject and may require medical or surgical 
intervention to prevent one of the outcomes listed above.   
 
8.3.3 
Adverse Event Relationship to Study Product 
 
Relatedness is an assessment made by a study clinician of whether or not the event is 
related to the study agent. Degrees of relatedness will be categorized according to current 
DAIDS-approved guidelines. Per the Manual for Expedited Reporting of Adverse Events 
to DAIDS (Version 2.0, January 2010), 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) 
 
8.4 Pregnancy and Infant Outcomes 
 
Pregnant persons are excluded from this study. 
 
8.5 Regulatory Requirements 
 
Information on all reported AEs will be included in reports to all applicable government 
and regulatory authorities. Site IoRs/designees will submit AEs and any relevant safety 
information in accordance with local regulatory requirements. 
 
8.6 Social Harms Reporting 
 
Although the study site will make every effort to protect participant privacy and 
confidentiality, it is possible that participants’ involvement in the study could become 
known to others and that social harms may result. Social harms that are judged by the 
IoR/designee to be serious or unexpected will be reported to the PSRT and responsible 
site IRBs/IECs according to their individual requirements. 
 
 
9 
CLINICAL MANAGEMENT 
 
Guidelines 
for 
clinical 
management 
and 
temporary 
product 
hold/permanent 
discontinuation of each study product are outlined in this section. In general, the 
IoR/designee has the discretion to hold use of the study product(s) at any time if s/he 

 
 
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feels that continued product use would be harmful to the participant or interfere with 
treatment deemed clinically necessary. Unless otherwise specified below, the 
IoR/designee must immediately consult the PSRT for further guidance on resuming use 
of the study product(s), continuing the hold temporarily, or progressing to permanent 
discontinuation of the study product(s). The IoR/designee will document all temporary 
product holds and permanent discontinuations on applicable CRFs. 
 
Participants reporting any unresolved AEs considered related to product use at the time 
of study termination will be followed clinically until the occurrence resolves (returns to 
baseline) or stabilizes, and this information will be documented. 
 
9.1 Grading System 
 
AE severity grading is described in Section 8.3. 
 
9.2 Dose Modification Instructions 
 
No dose modifications will be undertaken in this study. 
 
9.3 General Criteria for Permanent Discontinuation of Study Product 
 
A participant will be permanently discontinued from all study product use by the 
IoR/designee for any of the following reasons: 
• Acquisition of HIV infection; for those who acquire HIV, study product should be 
held beginning immediately upon recognition of the first positive/reactive HIV test 
• Pregnancy 
• Reported use of non-study rectal medications or products, including personal 
lubricants and usual pre-RAI douches containing N-9  
 
Note: Non-study personal lubricants and usual pre-RAI douches that do not contain N-9 
are permitted 
 
• Participant is unable or unwilling to comply with required study procedures, or 
otherwise might be put at undue risk to their safety and well-being by continuing 
product use, according to the judgment of the IoR/designee 
 
A participant will be temporarily discontinued from all study product use by the 
IoR/designee and a PSRT query submitted for any of the following reasons: 
• Acquisition of an anorectal STI 
 
The IoR/designee must consult the PSRT once the temporary hold is initiated. Together, 
the IoR/designee and the PSRT will discuss resuming product use, continuing the 
temporary hold, or progressing to permanent discontinuation. 
 

 
 
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9.4 Follow-up in Response to Observed Adverse Events 
 
Grade 1 or 2  
In general, a participant who develops a Grade 1 or 2 AE as defined by the Division of 
AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, Corrected 
Version 2.1, July 2017 or Addenda 1, 2 and 3 (Female Genital [Dated November 2007], 
Male Genital [Dated November 2007] and Rectal [Clarification Dated May 2012] Grading 
Tables for Use in Microbicide Studies), regardless of relationship to study product, may 
continue product use. If the IoR/designee opts to discontinue study product, the PSRT 
must be notified. 
 
 
Grade 3 or 4 
For participants who develop a Grade 3 or 4 AE as defined by the Division of AIDS Table 
for Grading the Severity of Adult and Pediatric Adverse Events, Corrected Version 2.1, 
July 2017 or Addenda 1, 2 and 3 (Female Genital [Dated November 2007], Male Genital 
[Dated November 2007] and Rectal [Clarification Dated May 2012] Grading Tables for 
Use in Microbicide Studies), study product must be held and the IoR must consult with 
PSRT regarding continued use of that study product and progression to other study 
products.    
 
9.5 
Sexually Transmitted Infection/Reproductive Tract Infection 
 
The IoR/designee must manage STI/RTI per current WHO guidelines, available at 
http://www.who.int/hiv/pub/sti/pub6/en/.   
 
Per Section 9.3, acquisition of an anorectal STI will lead to a temporary product hold. 
Product use need not be held in the event of other types of STI/RTI requiring treatment, 
unless other temporary product hold/permanent discontinuation guidelines described 
elsewhere in Section 9 apply.  Should the IoR/designee determine that a temporary 
product hold is warranted due to an STI or RTI, consultation with the PSRT is required. 
 
9.6 HIV-1/2 Infection 
 
Participants who test positive for HIV-1/2 must have study product held immediately by 
the IoR/designee.  A participant who is confirmed to be HIV-1/2 positive during the course 
of the study will have study product discontinued, all follow-up visits will be discontinued 
and the participant will be considered terminated from the study, as per Section 7.5.1. 
Guidance regarding management and referral for participants confirmed to be HIV-
positive is located in Section 13.10. 
 
9.7 Pregnancy 
 
Participants who can get pregnant will be encouraged to report all signs or symptoms of 
pregnancy to study staff. The IoR/designee will counsel any participant who becomes 
pregnant regarding possible risks to the fetus according to site SOPs. The IoR/designee 

 
 
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also will refer the participant to all applicable services; however, sites will not be 
responsible for paying for pregnancy-related care.  
 
A participant who becomes pregnant during the study will have study product 
discontinued and will be terminated from the study, as per Section 7.5.2. 
 
9.8 Criteria for Early Termination of Study Participation other than HIV-1/2 
Infection and Pregnancy 
 
Participants may voluntarily withdraw from the study for any reason at any time. The 
IoR/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, after consultation 
with the PSRT. Participants also may be withdrawn if NIAID, MTN, government or 
regulatory authorities including the Office for Human Research Protections (OHRP), or 
site IRBs/IECs 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 (see details regarding the Early Termination Visit 
in Section 7.4.3). Study staff members will record the reason(s) for all withdrawals in 
participants’ study records. 
 
  
10 
STATISTICAL CONSIDERATIONS 
 
10.1 Overview and General Design 
 
This is a multi-site, randomized-sequence, three-period, open label crossover study 
designed to compare acceptability, tolerability, safety, and adherence data within 
individuals who have been exposed to an insert, a douche and a suppository applied 
rectally and used prior to RAI. Approximately 210 HIV-uninfected participants will be 
randomized to receive one of six study product application sequences. In the first product 
use period, participants will use either the rectal insert, the rectal douche, or the rectal 
suppository prior to RAI during a 4-week-long period. After a 1-week washout period, they 
will use one of the other two study products prior to RAI during the second 4-week-long 
study product use period. After another 1-week washout period, they will use the 
remaining study product prior to RAI during the third 4-week-long study product use 
period.  
 
10.2 Study Endpoints 
 
Consistent with the primary study objective to evaluate the acceptability and tolerability 
of a placebo insert, a placebo douche, and a placebo suppository when applied rectally 
and used prior to RAI, the following endpoints will be assessed on a scale of 1 to 10 for 
each study product: 
 

 
 
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• 
Participant self-report of likelihood of product use if shown to be effective 
 
Consistent with the primary study objective to evaluate adherence to a placebo insert, a 
placebo douche, and a placebo suppository when applied rectally and used prior to RAI 
over a 4-week-long period, the following endpoints will be assessed for each study 
product: 
 
• 
Per participant report, percentage of occasions when study product was used as 
instructed (per protocol) 
 
Consistent with the primary study objective to evaluate the safety of a placebo insert, a 
placebo douche, and a placebo suppository when applied rectally and used prior to RAI, 
the following endpoints will be assessed for each study product: 
 
• 
Grade 2 or higher related AEs as defined by the Division of AIDS Table for Grading 
the Severity of Adult and Pediatric Adverse Events, Corrected Version 2.1, July 2017, 
and/or Addenda 1, 2 and 3 (Female Genital [Dated November 2007], Male Genital 
[Dated November 2007] and Rectal [Clarification Dated May 2012] Grading Tables for 
Use in Microbicide Studies) 
 
10.3 Sample Size and Power 
 
There is no control group for comparison in this study. The goal is not to compare each 
product to some standard but instead to estimate overall rates of acceptability, adherence 
and safety. 
 
10.3.1 Primary Endpoints – Acceptability/Tolerability and Adherence 
 
Based on previous studies we expect to observe a high rate of acceptability (>80%) which 
equates to 20% of participants reporting a low likelihood of using the product in the future 
(3 on the rating scale). Likewise, we expect to observe a high rate of participants 
reporting taking at least 90% of expected doses. 
 
The table below shows the exact confidence intervals for acceptability and adherence, 
assuming α=0.05 based on the Binomial distribution and varying rates of acceptability 
and adherence. The power to rule out <50% and <70% acceptability or adherence given 
the rates is also shown. Calculations assume the outcomes are observed in 200 of the 
participants (5% loss to follow-up). For example, if the true acceptability or adherence 
rate is 90%, we have 100% power to rule out a true acceptability or adherence rate of 
75% or lower. If we observe an 80% acceptability or adherence rate, the corresponding 
95% confidence interval (CI) will be (74%, 85%). 
 

 
 
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Table 9:  Exact 2-sided 95% Confidence Intervals Based on Various Rates of Acceptability or 
Adherence Endpoints 
Acceptability rate 
/ adherence rate 
95% CI if rate 
is observed 
Power to rule out 
50% if rate is true 
Power to rule out 
70% if rate is true 
Power to rule out 
75% if rate is true 
95% 
(91, 98) 
100% 
100% 
100% 
90% 
(85, 94) 
100% 
100% 
100% 
85% 
(79, 90) 
100% 
100% 
93% 
80% 
(74, 85) 
100% 
90% 
35% 
 
10.3.2 Primary Endpoint – Safety 
 
To characterize the statistical properties of the safety endpoint, the table below presents 
the probability of observing zero, at least one, and two or more safety endpoints among 
200 participants (allowing for the possibility of 5% dropout) assuming various “true” event 
rates. By assuming that we may only have safety evaluations on 200 participants, these 
calculations are conservative. However, safety analyses will include all enrolled 
participants.  
 
Table 10:  Analysis of Safety Event Frequency 
Event Rate 
P(0 events | n=200) 
P(1 event | n=200) 
P(5 events | 
n=200) 
P(10 events | 
n=200) 
0.1% 
82% 
18% 
0% 
0% 
0.5% 
37% 
63% 
0% 
0% 
1% 
13% 
87% 
5% 
0% 
2% 
2% 
98% 
37% 
1% 
5% 
0% 
100% 
97% 
55% 
 
10.4 Randomization Procedures 
 
Participants will be randomly assigned with the ratio 1:1:1:1:1:1 to one of six study product 
application sequences. The randomized assignments will be in blocks to keep the balance 
of equal allocation. The randomization scheme, including enrollment of replacement 
participants, will be generated and maintained by the MTN SDMC.   
 
10.5 Participant Accrual and Retention 
 
The accrual period is expected to require approximately 9-12 months. The study will enroll 
approximately 210 participants. 
 
The target retention rate for each study visit is 95%. Therefore, once a participant is 
enrolled in the study, the study site will make every reasonable effort to retain the 
participant for the entire study duration so that the participant is evaluable. 
 
10.6 Data and Safety Monitoring Procedures 
 
No Data and Safety Monitoring Board oversight is planned for this study. The MTN Study 
Monitoring Committee (SMC) will conduct interim reviews of study progress, including 

 
 
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rates of participant accrual, retention, completion of primary endpoint assessments, and 
study or lab issues by arm of the study. These reviews will take place approximately every 
4-6 months, or as needed.  Reviews may also be conducted on an as needed basis. At 
the time of this review, or at any other time, the SMC may recommend that the study 
proceed as designed, proceed with design modifications, or be discontinued. 
 
10.7 Data Analyses 
 
10.7.1 Primary Analyses on Acceptability/Tolerability and Adherence Measures 
 
All primary analyses will be based on data from the participants with data in all three 
periods of study (participants who complete each period of the study). Baseline values 
between these participants and those participants lost to follow-up will be described and 
used to interpret the generalizability of the results. Additionally, secondary analyses will 
analyze endpoints among all participants. The adherence and acceptability/tolerability 
endpoints (defined in Section 10.3.1) will be reported with 95% CI. The purpose of this 
protocol is not to compare the placebo products; therefore, we do not plan on doing 
comparisons between products in the primary analysis. Logistic regression models will 
be used to assess the order of product use (period effect) on acceptability/tolerance and 
adherence.  
 
10.7.2 Primary Analysis on Safety Measures 
 
All visits in which a participant has been exposed to the study product will be included in 
the primary analyses of safety. Secondary analyses including the washout period may 
also be performed. The number and the percentages of participants experiencing each 
safety endpoint (see Section 10.2) will be tabulated by study arm. Each participant will 
contribute once in each category (i.e., only for highest severity AE for each participant) 
for the calculation of event rates. Exact binomial confidence intervals will be calculated 
for each safety endpoint for each arm and Fisher’s Exact test will be used to test for 
differences in event rates between the arms. Logistic and Poisson regression models will 
be used to assess the order of product use (period effect) on safety endpoints. 
 
10.8 Missing Data 
 
A retention rate of 95% is targeted.  Based on previous MTN trials, minimal missing data 
is expected.  If missing data rates are higher than anticipated (over 10%), sensitivity 
analyses will be conducted to assess the impact of missing data on trial inference. 
Assuming missing data are ignorable, we will use multiple imputation based on all 
available baseline predictors and available trial outcomes. 
 
 

 
 
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11 
DATA HANDLING AND RECORDKEEPING 
 
11.1 Data Management Responsibilities 
 
Data collection tools will be developed by the MTN SDMC in conjunction with the protocol 
team. Quality control queries will be routinely generated for study site verification and 
resolution. As part of the study activation process, the study site must identify all CRFs to 
be used as source documents. Study CRF data will be entered and cleaned using the 
Medidata Rave EDC tool, a data management system compliant with the International 
Council on Harmonization (ICH) Good Clinical Practices (GCP) and US CFR guidelines 
for electronic data capture. 
 
Audio files generated by the in-depth interviews will be transcribed and translated into 
English by the interviewers at Columbia University. Once the transcripts are cleaned and 
final, both the transcripts and the interview summary sheets will be electronically 
transferred to the central study team at the University of Pennsylvania using a secure File 
Transfer Protocol site, where they will be uploaded and managed using a qualitative 
software package. The qualitative data from MTN-035 will include the IDI transcripts and 
the summary sheets detailing major points of interest regarding acceptability and 
adherence from each interview. The research team at the University of Pennsylvania will 
manage all qualitative data for the study. A convention for file naming will be developed, 
and all data will be labeled according to this process. The research team will save all 
versions of the files on a secure, password-protected server. 
 
11.2 Source Documents and Access to Source Data/Documents 
 
All study sites will maintain source data/documents in accordance with Requirements for 
Source Documentation in DAIDS Funded and/or Sponsored Clinical Trials 
(https://www.niaid.nih.gov/sites/default/files/daids-sourcedocpolicy.pdf) and the relevant 
appendix 
regarding 
source 
documentation 
(https://www.niaid.nih.gov/sites/default/files/sourcedocappndx.pdf). 
 
Each IoR/designee will maintain, and store securely, complete, accurate and current 
study records throughout the study. The IoR/designee will maintain all study 
documentation for a minimum of three years after submission of the site’s final Financial 
Status Report to DAIDS, unless otherwise specified by DAIDS or the MTN LOC. These 
documents should be retained for a longer period, however, if required by the applicable 
regulatory requirements or by an agreement with the sponsor.   
 
Study records must be maintained on site for the entire period of study implementation.  
Thereafter, instructions for record storage will be provided by DAIDS.  No study records 
may be moved to an off-site location or destroyed prior to receiving approval from DAIDS.   
 

 
 
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11.3 Quality Control and Quality Assurance 
 
The study site will conduct quality control and quality assurance procedures in 
accordance 
with 
current 
DAIDS 
policies. 
(https://www.niaid.nih.gov/sites/default/files/qmppolicy.pdf) 
 
 
12 
 CLINICAL SITE OVERSIGHT 
 
Formal clinical site oversight is not planned for this study. However, representatives of 
the MTN, including but not limited to the LOC, SDMC, LC and the behavioral team, will 
review study-related documentation and procedures during the study to ensure 
compliance with the study protocol, Good Manufacturing Practice (cGMP), Good Clinical 
Practices (GCP), good clinical laboratory practice guidelines (GCLP) and other applicable 
US, local and international regulatory requirements. Responsible parties will do the 
following: 
 
• Assess study facilities, staffing and the quality of study conduct 
• Verify proper collection and storage of biological specimens 
• Verify proper storage, dispensing, and accountability of investigational study 
products 
 
The IoR/designee will also allow inspection of study facilities and study-related 
documentation by authorized representatives of NIAID, NIH and/or contractors of NIH, 
OHRP, CONRAD, IRBs/IECs, and other local, US or international regulatory authorities. 
These entities may also assess implementation and documentation of internal site quality 
management procedures. A site visit log will be maintained at the study site to document 
all visits. 
 
 
13 
 HUMAN SUBJECTS PROTECTIONS 
 
Site investigators will make efforts to minimize risks to participants. Participants and study 
staff members will take part in a thorough informed consent process. Before beginning 
the study, the IoR/designee will have obtained IRB/IEC approval(s). The IoR/designee 
will permit audits by the NIH, OHRP, CONRAD, MTN LOC, IRBs/IECs, SDMC, and other 
local, US, or international regulatory authorities, or any of their appointed agents. 
 
13.1 Institutional Review Boards/Ethics Committees 
 
The participating institution is responsible for assuring that this protocol, the associated 
site-specific informed consent forms (ICFs), and study-related documents (such as 

 
 
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participant education and recruitment materials) are reviewed by an IRB/IEC responsible 
for oversight of research conducted at the study site. Any amendments to the protocol 
must be approved by the responsible IRBs/IECs prior to implementation. 
 
After the initial review and approval, the responsible IRBs/IECs must review the study at 
least annually. Each IoR/designee will make safety and progress reports to the IRBs/IECs 
at least annually and within three months after study termination or completion. These 
reports will include the total number of participants enrolled in the study, the number of 
participants who completed the study, all changes in the research activity, and all 
unanticipated problems involving risks to human subjects or others. In addition, the results 
of all SMC reviews of the study will be provided to the IRBs/IECs. The study site will 
submit documentation of continuing review to the DAIDS Protocol Registration Office 
(PRO) in accordance with the DAIDS Protocol Registration Policy and Procedures 
Manual. 
 
13.2 Protocol Registration 
 
Prior to implementation of this protocol, and any subsequent full version amendments, 
the site must have the protocol and the protocol consent forms approved, as appropriate, 
by its local IRB/IEC and any other applicable regulatory entity (RE). Upon receiving final 
approval, the site will submit all required protocol registration documents 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.  
 
Site-specific ICFs will not be reviewed and approved by the DAIDS PRO, and 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. A copy of the Initial Registration 
Notification should be retained in the site’s regulatory files. 
 
Upon receiving final IRB/IEC and any other applicable RE approval(s) 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. Site-specific ICF(s) will not be reviewed and approved 
by the DAIDS PRO and the site 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. 
 
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. 
 

 
 
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13.3 Study Coordination 
 
Study implementation will be directed by this protocol, which may not be amended without 
prior written approval from the Protocol Chair and DAIDS Medical Officer. Study 
implementation will also be guided by a common Study-Specific Procedures (SSP) 
Manual that provides further instructions and operational guidance on conducting study 
visits; data and forms processing; specimen collection, processing, and shipping; AE 
assessment, management and reporting; dispensing study products and documenting 
product accountability; and other study operations. Standardized study-specific training 
will be provided to the site by the MTN LOC, SDMC, LC and other designated members 
of the Protocol Team.  
 
Close coordination between protocol team members is necessary to track study progress, 
respond to queries about proper study implementation, and address other issues in a 
timely manner. The PSRT will address issues related to study eligibility and AE 
management and reporting as needed to assure consistent case management and 
documentation. Rates of accrual, adherence, follow-up, and AE incidence will be 
monitored closely by the protocol team as well as the SMC. 
 
13.4 Risk Benefit Statement 
 
13.4.1 
Risks 
 
It is not expected that this trial will expose human subjects to unreasonable risk. 
 
Phlebotomy 
Phlebotomy may lead to excessive bleeding, discomfort, feelings of dizziness or 
faintness, bruising, swelling, venous thrombosis and/or infection.  
 
Pharyngeal Swab 
Pharyngeal (throat) swab collection often causes a momentary gagging reflex. 
 
Rectal Exam and Fluid Collection 
Insertion of a lubricated anoscope during the rectal examination will likely cause some 
discomfort or pressure in the rectum or anorectal area. Insertion of finger(s) in the rectum 
by a clinician during the rectal examination also will likely cause discomfort or pressure in 
the rectum or anorectal area. There is the risk of mild discomfort in addition to a slight risk 
of bleeding with the insertion of rectal swabs or sponges. 
 
Vaginal Fluid Collection 
Collection of vaginal fluid may cause discomfort or pressure in the vagina or genital area. 
 
Rectal Douche 
The main risk from administering a rectal douche is temporary discomfort.  A hollow tube 
about the thickness of a pencil will be used to put approximately 120 mL of water into the 
rectum and flush it out again, along with any stool that is there. There is a risk of a 

 
 
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bloated/cramping feeling. The tube is small and will be lubricated, but it might cause some 
anal or rectal discomfort if the subject has any hemorrhoids or other painful conditions. 
There is also a remote possibility of rectal perforation associated with the use of rectal 
douche products.    
 
Rectal products 
Side effects observed with application of rectal products in previous research studies 
include: mild rectal fullness; incontinence or diarrhea; flatulence; mild abdominal pain; 
anal discharge and proctalgia. 
 
Other Risks 
Disclosure of HIV and STI status may cause worry, sadness or depression. Disclosure of 
HIV-positive status has been associated with depression, suicidal ideation, and denial as 
well as social isolation. Trained counselors will be available to help participants deal with 
these feelings.  
 
Participation in clinical research includes the risks of loss of confidentiality and discomfort 
with the personal nature of questions when discussing sexual behaviors and other 
practices. 
 
Participants at sites where local regulatory authorities require partner notification in 
response to diagnosed STI or HIV infection could have problems in their relationships. 
Participants could also have problems in their partner relationships associated with use 
of study product.   
 
Site staff will make every effort to protect participant privacy while in the study.  Although 
the study site will make every effort to protect participant privacy and confidentiality, it is 
possible that participants' involvement in the study could become known to others, and 
that social harms may result (i.e., because participants could become known as HIV-
positive or at "high risk" for HIV infection).  For example, participants could be treated 
unfairly or discriminated against, or could have problems being accepted by their families 
and/or communities.   
 
13.4.2 
Benefits 
 
Participants in this study will experience no direct benefit. Participants and others may 
benefit in the future from information learned from this study. Specifically, information 
learned in this study may lead to the development of safe and effective interventions to 
prevent HIV acquisition and transmission. Participants also may appreciate the 
opportunity to contribute to the field of HIV prevention research.  
 
Participants will receive HIV/STI risk reduction counseling, HIV and STI testing, and 
physical and rectal examinations. Participants may be provided or referred for STI 
treatment free of charge. In addition, STI testing and treatment may be offered and/or 
referrals may be provided for their partners. For other medical conditions identified as part 
of the study screening and/or follow-up procedures, participants will be referred to other 

 
 
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sources of care available in their community. Some participants may have the opportunity 
to access expedited treatment and benefit from decreased morbidity due to early 
diagnosis and treatment of abnormalities identified during tests, examinations and 
referrals. 
 
13.5 Informed Consent Process 
 
Written informed consent will be obtained from each study participant prior to screening. 
In obtaining and documenting informed consent, the IoR and their designees will comply 
with applicable local and US regulatory requirements and will adhere to GCP and to the 
ethical principles that have their origin in the Declaration of Helsinki. Study staff must 
document the informed consent process in accordance with the Requirements for Source 
Documentation 
in 
DAIDS 
Funded 
and/or 
Sponsored 
Clinical 
Trials 
(https://www.niaid.nih.gov/sites/default/files/daids-sourcedocpolicy.pdf). Participants will 
be offered copies of the ICF.  
 
In addition to the ICF, the Protocol Team will work with study staff and community 
representatives to develop appropriate materials about the study and a standardized 
approach to the informed consent process to be implemented at the study site, which will 
be detailed in the SSP Manual.  
 
The informed consent process will cover all elements of informed consent required by 
research regulations. In addition, the process will specifically address the following topics 
of importance to this study: 
 
• The lack of efficacy of the placebo study products 
• Randomization and the importance of participation in all study sequences to the 
success of the study 
• The importance of adherence to the study visit and procedures schedule  
• The potential medical risks of study participation (and what to do if such risks are 
experienced) 
• The potential social harms associated with study participation (and what to do if 
such harms are experienced) 
• The real yet limited benefits of study participation  
• The distinction between research and clinical care 
• The right to withdraw from the study at any time 
 
13.6 Participant Confidentiality 
 
All study procedures will be conducted in private, and every effort will be made to protect 
participant privacy and confidentiality to the extent possible.  The study site will implement 
confidentiality protections that reflect the local study implementation plan and the input of 
study staff and community representatives to identify potential confidentiality issues and 
strategies to address them.  
 

 
 
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All study-related information will be stored securely. All participant information will be 
stored in locked areas with access limited to study staff. All laboratory specimens, study 
data, and administrative forms will be identified by coded number only to maintain 
participant confidentiality. All records that contain names or other personal identifiers, 
such as locator forms and informed consent forms, will be stored securely. All local 
databases will be secured with password-protected access systems. Forms, lists, 
logbooks, appointment books, and any other listings that link participants’ identification 
numbers to identifying information will be stored in a locked file in an area with limited 
access. Participants’ study information will not be released without their written 
permission, except as necessary for review, monitoring, and/or auditing by the following: 
 
• Representatives of the US Federal Government, including the US OHRP, NIH 
and/or contractors of the NIH, and other local, US or international regulatory 
authorities 
• Representatives of CONRAD, including study monitors 
• Study staff  
• Site IRBs/IECs 
 
The MTN has a Certificate of Confidentiality from the US Department of Health and 
Human Services that is applicable to this study. This Certificate protects study staff from 
being compelled to disclose study-related information by any US Federal, State or local 
civil, criminal, administrative, legislative or other proceedings. It thus serves to protect the 
identity 
and 
privacy 
of 
study 
participants 
at 
US-based 
study 
sites. 
 
13.7 Special Populations 
 
13.7.1 
Pregnant Women 
 
Anyone who tests positive for pregnancy at the Screening or Enrollment Visit will not be 
eligible to participate in this study.  Should a participant test positive for pregnancy after 
Enrollment, a product discontinuation will be implemented. Follow-up will be completed 
and data collected per Section 7.5.2. During the informed consent process, individuals 
who can get pregnant will be informed that the study products are not an effective method 
of contraception and the effects of the study products on a developing human fetus are 
unknown. 
 

 
 
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13.7.2 
Children 
 
The NIH has mandated that children be included in research trials when appropriate. This 
study meets “Justifications for Exclusion” criteria for younger children as set forth by the 
NIH. Specifically, “insufficient data are available in adults to judge potential risk in 
children” and “children should not be the initial group to be involved in research studies.” 
This study does not plan to enroll children under 18 years old. 
 
13.8 Compensation 
 
Pending IRB/IEC approval, participants will be compensated for time and effort in this 
study, and/or be reimbursed for travel to study visits and time away from work. Site 
specific reimbursement amounts will be specified in the site specific ICF. 
 
13.9 Communicable Disease Reporting 
 
Study staff will comply with local requirements to report communicable diseases, 
including HIV-1/2 identified among study participants to health authorities. Participants 
will be made aware of reporting requirements during the informed consent process. 
 
13.10 Access to HIV-related Care 
 
13.10.1 
HIV Counseling and Testing 
 
HIV test-related counseling will be provided to all potential study participants who consent 
to undergo HIV-1/2 screening to determine their eligibility for this study, and to all enrolled 
participants at each follow-up HIV-1/2 testing time point. Testing will be performed in 
accordance with the algorithm in Appendix II. Counseling will be provided in accordance 
with standard HIV counseling policies and methods at the site. In accordance with the 
policies of the NIH, participants must receive their HIV-1/2 test results to take part in this 
study.   
 
13.10.2 
Care for Participants Identified as HIV-Positive 
 
An individual who has been identified as infected with HIV-1/2 will be managed or referred 
for management according to the local standard of care.  Should a participant test positive 
for HIV after the Enrollment Visit, follow-up procedures will be performed as per Section 
7.5.1. Please refer to Section 9.6 for further details.   
 
13.11 Study Discontinuation 
 
This study may be discontinued at any time by NIAID, the MTN, the OHRP, other 
government or regulatory authorities, or site IRBs/IECs. 
 
 
 

 
 
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14 
 PUBLICATION POLICY 
 
DAIDS/NIAID and MTN policies will govern publication of the results of this study. Any 
presentation, abstract, or manuscript will be submitted by the investigator to the MTN 
Manuscript Review Committee, DAIDS, NIAID, NIMH, and CONRAD for review prior to 
submission. 
 
 
 

 
 
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15 
APPENDICES 
 
 
 

 
 
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APPENDIX I:  SCHEDULE OF STUDY VISITS AND EVALUATIONS 
 
 
Visit 1 
SCR 
Visit 2 
ENR 
Visits 3, 5 & 7 
PUEV 1-3 
Visits 4 & 6 
Product Switch 
Visits 
Visit 8 
Final / Early 
Term Visit 
ADMINISTRATIVE AND REGULATORY 
Informed consent (SCR/ENR) 
X 
 
 
 
 
Assess consent form comprehension 
X 
 
 
 
 
Review informed consent/Confirm 
participant willingness to be in study 
 
X 
 
 
 
Assign PTID  
X 
 
 
 
 
Collect demographic data 
X 
 
 
 
 
Assess/confirm eligibility 
X 
X 
 
 
 
Collect/update locator information 
X 
X 
X 
X 
X 
Provide reimbursement 
X 
X 
X 
X 
X 
Schedule next study visit/contact 
* 
* 
X 
X 
 
Randomization 
 
X 
 
 
 
BEHAVIORAL/COUNSELING 
 
 
HIV pre-/post-test and HIV/STI risk 
reduction counseling 
X 
X 
X 
(Required at 
Visit 7) 
* 
* 
Protocol counseling  
X 
X 
X 
X 
 
Training in SMS/IM Reporting System 
 
X 
 
 
 
Behavioral assessment 
 
X 
X 
 
X 
In-depth interview (IDI) 
 
 
X (brief IDI) 
 
X (subset) 
CLINICAL 
 
 
 
 
 
Collect/update medical history 
X 
X 
X 
X 
X 
Perform physical examination (Targeted 
after Screening Visit) 
X 
X 
* 
* 
* 
Perform rectal examination 
X 
X 
X 
* 
* 
Collect/update concomitant medications 
X 
X 
X 
X 
X 
Treat for UTI/RTI/STI or refer 
* 
* 
* 
* 
* 
Disclose available test results 
X 
X 
X 
X 
X 
Record/update AEs 
 
 
X 
X 
X 
LABORATORY  
PHARYNGEAL 
NAAT for GC/CT 
X 
* 
* 
(Required at 
Visit 7) 
* 
* 
URINE 
NAAT for GC/CT/Trichomonas 
X 
* 
* 
(Required at 
Visit 7) 
* 
* 
Urine dipstick/culture 
* 
* 
* 
* 
* 
Pregnancy test ϕ 
X 
X 
* 
* 
X 
BLOOD 
Plasma for archive 
 
X 
 
 
 
Syphilis serology 
X 
* 
* 
(Required at 
Visit 7) 
* 
* 

 
 
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Visit 1 
SCR 
Visit 2 
ENR 
Visits 3, 5 & 7 
PUEV 1-3 
Visits 4 & 6 
Product Switch 
Visits 
Visit 8 
Final / Early 
Term Visit 
HIV-1/2 test 
X 
X 
* 
(Required at 
Visit 7) 
* 
* 
PELVIC 
NAAT for GC/CT/Trichomonas ¤ 
X 
* 
* 
(Required at 
Visit 7) 
* 
* 
ANORECTAL 
HSV-1/2 detection (at sites with 
capacity) 
* 
* 
* 
* 
* 
NAAT for GC/CT 
X 
* 
* 
(Required at 
Visit 7) 
* 
* 
STUDY PRODUCT/SUPPLIES 
 
Provision of study product and study 
product use counseling 
 
X 
 
X 
 
Study product application at the clinic 
 
X 
 
X 
 
Offer condoms 
X 
X 
X 
X 
X 
Offer lubricant 
** 
** 
** 
** 
** 
X =Required, * = As Indicated and/or per local standard of care, ϕ = Individuals who can get pregnant, ¤ = Individuals 
with a vagina or neovagina, ** Lubricant will be provided at product administration visits and as per local standard of 
care at other visits  
 
 

 
 
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APPENDIX II:  ALGORITHM FOR HIV TESTING FOR 
SCREENING AND FOLLOW-UP  
 
 
START 
Immunoassay*
Sample 1 
HIV  Confirmation 
Test 
 
Is this a 
Screening 
Participant
?
-
+ or Ind
- or Ind
+
Yes
+
Sample 2
HIV Confirmation 
Test 
- or Ind
No
Report as 
HIV Uninfected 
Not eligible for 
enrollment
Report  as HIV
 Infected 
Consult LC
Consult LC
-/- or   -
 +/+ or  +/-
    + or Ind
*CLIA certified labs may perform 1 rapid test
Ind: Indeterminate test results
LC: Laboratory Center
 

 
 
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APPENDIX III: SAMPLE INFORMED CONSENT FORM (SCREENING AND 
ENROLLMENT) 
 
DIVISION OF AIDS, NIAID, NIH 
 
MTN-035 
 
Acceptability, Tolerability, and Adherence of Three Rectal Microbicide Placebo 
Formulations among HIV Seronegative Cisgender Men, Transgender Men and 
Transgender Women Who Engage in Receptive Anal Intercourse 
 
Version 1.0 
  
June 15, 2018 
 
PRINCIPAL INVESTIGATOR: [Site to insert] 
PHONE: [Site to insert] 
Short Title for the Study: Rectal Microbicide Acceptability, Tolerability, and Adherence 
 
INFORMED CONSENT 
 
IMPORTANT INFORMATION ABOUT THE RESEARCH STUDY 
 
You are being asked to take part in this research study because you are a healthy, HIV-uninfected 
[SITES TO INSERT PREFERRED DESCRIPTION OF STUDY POPULATION: cisgender man, 
transgender man (TGM), or transgender woman (TGW) / man who has sex with men (MSM) 
or transgender woman (TGW)] aged 18 to 35 years old who engages in receptive anal sex 
(penis into rectum). Approximately 210 people will participate in this study at multiple sites across 
the world. The US National Institutes of Health (NIH) sponsors this Microbicide Trials Network 
(MTN) study. At this site, the person in charge of this study is [INSERT NAME OF PRINCIPAL 
INVESTIGATOR].  
 
Important things you should know:  
• 
The three study products in this clinical trial are a rectal douche, a rectal suppository, and 
a rectal insert. All three are placebo study products.  
• 
The purposes of the study are:  
o To find out if [SITES TO INSERT PREFERRED DESCRIPTION OF STUDY 
POPULATION: cisgender men, TGM, and TGW / MSM and TGW] would accept 
and tolerate three different ways to potentially deliver [SITES TO INSERT 
PREFERRED DESCRIPTION: anti-HIV / antiretroviral] drugs into the rectum 
when used before receptive anal sex.  
o To understand whether [SITES TO INSERT PREFERRED DESCRIPTION OF 
STUDY POPULATION: cisgender men, TGM, and TGW / MSM and TGW] would 
actually use these three rectal products as part of their usual practices around 
receptive anal sex. 
o To evaluate if each study product is safe when applied rectally and used before 
receptive anal sex by [SITES TO INSERT PREFERRED DESCRIPTION OF 
STUDY POPULATION: cisgender men, TGM, and TGW / MSM and TGW].   
 

 
 
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• 
If you qualify and choose to participate, you will be asked to use the three rectal products 
before receptive anal sex, each for one month (4 weeks). The order in which you will use 
the three products will be decided by chance [SITES TO INSERT PREFERRED 
DESCRIPTION OF ‘RANDOMIZATION’]. Neither you nor the study staff can decide the 
order in which you use the products.  
• 
Once enrolled, you will be asked to attend 8 clinic visits here at this study clinic, including 
the Screening Visit which is taking place today. You will come to the clinic every four and 
five weeks. The total length of your participation in the study will be approximately three 
and a half months. 
• 
At some of the clinic visits, the following will occur: 
o A physical and/or rectal exam will be performed;  
o Blood will be obtained to test for HIV and/or other sexually transmitted infections 
(STI); 
o Urine will be collected to test for STIs and (if applicable) pregnancy;  
o Rectal, throat, and (if applicable) vaginal swabs will be collected to test for STIs;  
o You will be asked to complete a short interview. You may also be selected to 
complete a longer interview at the final visit. 
• 
Some risks or discomforts from previously tested rectal products include:  
o Abdominal bloating, feeling full, or a sense of abdominal pressure and/or pain; 
o Sudden, almost uncontrollable, need to relieve the bowels;  
o Diarrhea (loose, frequent stools); 
o Passing gas from the intestinal tract; 
o Feeling a constant need to pass stools, despite an empty bowel; 
o Anal discharge.  
• 
You may not experience any direct benefit from participation in this study, but you may 
learn more about HIV and other diseases and ways to protect yourself from acquiring HIV 
or other STIs. You will also have physical and rectal exams, receive HIV and STI 
counseling, and get referrals for other care if needed.     
• 
Taking part in this research project is voluntary. You do not have to participate and you 
can stop at any time. This will not affect the service you get at this clinic or clinics in 
surrounding areas. 
• 
If you decide not to join this study, there are other currently available methods to prevent 
sexually transmitted HIV: condom use during sex and/or the use of daily oral Truvada® 
for pre-exposure prophylaxis (PrEP) or post-exposure prophylaxis (PEP). Study staff can 
provide you with additional information about PrEP and PEP if you are interested. You 
may also join another study, if we have one and if you meet its requirements. 
 
Please take time to read this entire form and ask questions before you decide if you want to join 
this study. Once you read and understand the study and its requirements, you can decide if you 
want to join. If you do decide to take part in the study, you will sign your name on this form. A 
copy of this document will be offered to you. Signing this consent form does not mean you will be 
able to join the study. You must first complete the screening tests and exams to see if you are 
eligible.  
 
It is important to know that for this study these three rectal products will not contain any active 
drug. This means the products we will ask you to use will not protect you from acquiring HIV or 
any other STIs. Therefore, you should continue using HIV and STI prevention methods while in 
the study. 
 
Who will be in this research study and what will I be asked to do if I join? 

 
 
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Approximately 210 participants will be enrolled in the MTN-035 study across 7 sites, with 
approximately 30 participants enrolled at each site.  
 
If you enroll in the study, you will be asked to use the three rectal products before receptive anal 
sex, each for one month (4 weeks). The douche in this study will involve spraying water from the 
nozzle of a bottle into your rectum. The suppository is a small, cone-shaped object that you put 
in your rectum and dissolves quickly. An insert is a small, bullet-shaped object that you put in your 
rectum and dissolves quickly.  
 
If it seems like you can join this study based on the tests done today, you will be asked to come 
back for an Enrollment Visit no later than 45 days from today. At your Enrollment Visit, you will 
begin using the first of three rectal products – douche, suppository or insert – depending on which 
product use sequence you have been assigned to. 
 
Study Visit Schedule 
  
 
What will happen during study visits? 
 
Screening Visit:  
 
The procedures done today will take about [SITES TO INSERT TIME]. Multiple visits may be 
conducted to complete all required screening procedures. 
 
You will: 
• 
Answer questions to confirm you are able and willing to join the study. 
• 
Answer questions about where you live and other questions about you, your health 
(including what medications you are taking), and your sexual practices.   
• 
Provide study staff your contact information (i.e. about how we can locate you). 
• 
Talk with study staff about STIs, HIV, HIV/STI testing, and ways to avoid HIV and other 
infections passed through sex, including the use of oral Truvada® for PrEP.   
• 
Talk with study staff about the requirements of the study including, but not limited to: 
o Abstaining from using non-study rectally-administered medications or products 
during your participation in the study, except for personal lubricants and usual pre-
RAI douches that do not contain nonoxynol-9 (N-9). 
• 
Have a physical exam. 
• 
Have a rectal exam. Rectal fluid will be collected using a cotton swab (like a Q-tip or 
earbud) to test for STIs. 
o Study staff may insert a short (10 cm or 3-4 inches) hollow tube called an anoscope 
inside your rectum as part of the rectal exam and rectal fluid collection. Study staff 

 
 
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will insert their finger(s) inside your rectum as part of the rectal exam. You may 
feel some discomfort or pressure in your rectum or anus from the staff person’s 
finger(s) and/or anoscope. There is a slight risk of bleeding with the insertion of 
rectal swabs or sponges. 
• 
Have your urine tested for STIs and other infections. 
• 
[For individuals who can get pregnant] Have your urine tested for pregnancy. 
o If you are pregnant you cannot join this study. 
o Staff will discuss with you ways to avoid getting pregnant. 
• 
Have a pharyngeal (throat) swab collected to test for STIs. 
• 
[For individuals with a vagina or neovagina] Have some fluids collected from your 
vagina using a swab to test for STIs. 
• 
Provide a blood sample of about 10 ml [SITES TO MODIFY AMOUNT IF NEEDED]: 
o To test for STIs, including HIV and syphilis. 
▪ 
You will be told your test results as soon as they are available.  You will 
talk with study staff about the meaning of your results, how you feel about 
them, and learn about ways to prevent HIV and other STIs. Sometimes HIV 
tests are not clearly positive, but also not clearly negative. In that case, we 
will do more tests until we can confirm your status. To participate in the 
study, you must receive your HIV test results. 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. The study staff will tell you 
about other studies you may be eligible for, if any.  
• 
Be given treatment or a referral for treatment of STIs, if needed. 
• 
Be informed about other services, if needed.  
• 
Be given the results of your tests, when available. It is expected that all your results will 
be available by [SITES TO SPECIFY TIMEFRAME].     
• 
Be given male condoms, if you need them. 
• 
[SITES TO SPECIFY IF PARTICIPANTS MAY BE OFFERED LUBRICANT PER 
LOCAL STANDARD OF CARE] 
• 
Be reimbursed for your visit. 
• 
Schedule your next visit to enroll in the study, if you are willing and eligible. 
 
If you decide not to join this study, blood and other samples collected at this visit will not be kept 
or used for any tests other than those listed above. 
 
Enrollment Visit: 
 
Your Enrollment Visit (the visit where you enter the study) will take place up to 45 days after your 
Screening Visit. This visit will take about [SITES TO INSERT TIME].  
 
You will: 
• 
Answer questions to confirm you are able and willing to join the study. 
• 
Update study staff with your contact information (about where you live and how we can 
contact you). 
• 
Be assigned the order in which you will use the three study products. 
• 
Talk with study staff about the following: 
o The instructions and procedures of the study and how to follow the study rules, 
including use of non-study rectal medications or products. 
o STIs, HIV, HIV/STI testing, and ways to avoid HIV and other STIs.   

 
 
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• 
Discuss any health or medical problems you may have had in the past or since your last 
visit (including any medications you are taking). 
• 
Be asked some questions about your experience and comfort using rectal products and 
engaging in rectal hygiene practices such as douching, among other things. These 
questions will be asked privately via computer.  
• 
Be asked to respond to weekly electronic messages related to your use of the study 
products during each product use period. 
o You will receive instructions and training on how to receive and respond to these 
messages at the Enrollment Visit. 
• 
Provide a blood sample of about 15 ml [SITES TO MODIFY AMOUNT IF NEEDED]: 
o In case there’s a question about your test results at a later time (about 10 ml of 
blood may be left unused if there is no question about your test results).  
o To test your blood for HIV. 
• 
Have a physical exam. 
• 
Have a rectal exam. 
• 
[For individuals who can get pregnant] Have a urine test for pregnancy and discuss 
with study staff ways to avoid getting pregnant. 
• 
Receive the first of three rectal products (douche, suppository, or insert) that you will use 
during the study, along with instructions on how to use and store your assigned product. 
o You will use your assigned study product once at the clinic under the supervision 
of study staff to ensure you can tolerate using the product and will be able to use 
it as instructed during the study. 
• 
Be given test results, if available. 
• 
Be given male condoms, if you need them. 
• 
Be given lubricant to assist product insertion. 
• 
Be reimbursed for your visit. 
• 
Schedule your next visit, if applicable. 
 
Product Use End Visits (PUEV) – Visits 3, 5, and 7: 
 
Your PUEVs will take place approximately one month (4 weeks) after you begin using each of the 
three study products, with the first PUEV taking place approximately one month after the 
Enrollment Visit. These visits will take between [SITES TO SPECIFY TIMEFRAME] to complete.   
 
You will: 
• 
Update study staff with your contact information. 
• 
Review the instructions and procedures of the study and how to follow the study rules, 
including use of non-study rectal medications or products. 
• 
Discuss any health or medical problems you may have had since your last visit (including 
any medications you are taking). 
• 
Discuss any problems that you may be experiencing as a result of using the study product, 
or as a result of procedures performed during the study. 
• 
Be asked some questions about your experience using the study product. These 
questions will be asked privately via computer. 
• 
Be asked to take part in a brief interview (~15 minutes) about your responses to the 
electronic messages during the previous month of product use. This interview will be 
conducted by phone or via videoconference. This interview will be audio-recorded, but 
your responses will be kept private and confidential. 

 
 
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• 
Have a rectal exam. 
• 
Be given test results, if testing was done. 
• 
Be given male condoms, if you need them.  
• 
[SITES TO SPECIFY IF PARTICIPANTS MAY BE OFFERED LUBRICANT PER 
LOCAL STANDARD OF CARE] 
• 
Be reimbursed for your visit. 
• 
Schedule your next visit or contact. 
 
On your third PUEV (Visit 7), you will also: 
• 
Talk with study staff about STIs, HIV, HIV/STI testing, and ways to avoid HIV and other 
STIs. 
• 
Provide a blood sample of about 10 ml [SITES TO MODIFY AMOUNT IF NEEDED] to 
test your blood for STIs, including HIV and syphilis. 
• 
Have your urine tested for STIs and other infections. 
• 
Have a pharyngeal (throat) swab collected to test for STIs. 
• 
Provide a rectal fluid sample. This will be collected using a swab to test for STIs. 
• 
[For individuals with vagina or neovagina] Provide a vaginal fluid sample. This will be 
collected using a swab to test for STIs. 
 
Product Switch Visits – Visits 4 and 6: 
 
Your Product Switch Visits, Visits 4 and 6, will take place approximately one week after your first 
and second PUEVs, Visits 3 and 5, respectively. These visits will take between [SITES TO 
SPECIFY TIMEFRAME] to complete.  
 
You will: 
• 
Update study staff with your contact information. 
• 
Review the instructions and procedures of the study and how to follow the study rules, 
including use of non-study rectal medications or products. 
• 
Discuss any health or medical problems you may have had since your last visit (including 
any medications you are taking). 
• 
Discuss any problems that you may be experiencing as a result of using the study product, 
or as a result of procedures performed during the study. 
• 
Receive the rectal product assigned for your next product use period, along with 
instructions on how to use and store your assigned product. 
o You will use your assigned study product once at the clinic under the supervision 
of study staff to ensure you can tolerate using the product and will be able to use 
it as instructed during the study. 
• 
Be given test results, if testing was done. 
• 
Be given male condoms, if you need them. 
• 
Be given lubricant to assist product insertion. 
• 
Be reimbursed for your visit. 
• 
Schedule your next visit or contact. 
 
Final/Early Termination Visit – Visit 8: 
 
Your Final/Early Termination Visit will take place approximately one week after your third PUEV, 
Visit 7.  This visit will take approximately [SITES TO SPECIFY TIMEFRAME] to complete.  
 

 
 
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You will: 
• 
Update study staff with your contact information. 
• 
Discuss any health or medical problems you may have had since your last visit (including 
what medications you are taking). 
• 
Discuss any problems that you may be experiencing as a result of using the study product, 
or as a result of procedures performed during the study. 
• 
Be asked some questions to compare your experiences using the three study products. 
These questions will be asked privately via computer. 
o You may also be asked to take part in an in-depth interview (~45 minutes) about 
your experiences using the three study products, including questions about 
product design, application methods, product use influences, douching practices, 
and suggestions for product improvement. This interview will be conducted by 
phone or via videoconference. This interview will be audio-recorded, but your 
responses will be kept private and confidential. 
• 
[For individuals who can get pregnant] Have a urine test for pregnancy and discuss 
with study staff ways to avoid getting pregnant. 
• 
Be reimbursed for your visit. 
• 
Be given test results, if available. 
• 
Be given male condoms, if you need them. 
• 
[SITES TO SPECIFY IF PARTICIPANTS MAY BE OFFERED LUBRICANT PER 
LOCAL STANDARD OF CARE] 
 
It is important that you remember that at any time during the study, study staff can answer any 
questions you may have about the procedures mentioned above or any other aspect of this study. 
 
Other Procedures: 
In addition to the procedures listed above, it is possible that study clinicians may need to perform 
additional tests during any of the study visits, if necessary (e.g., if you report having symptoms of 
a urinary, genital, or other infection and/or other issues).  These tests might include the following: 
• 
Physical exam 
• 
Rectal exam 
• 
Test pharyngeal (throat), rectal and/or pelvic samples for STIs 
• 
Test your urine for STIs or other infections 
• 
[For individuals who can get pregnant] Test your urine for pregnancy 
• 
Test your blood for HIV and/or STIs 
• 
Give you treatment or refer you for treatment of STIs or other issues, if needed. 
 
You may need to provide additional samples if any of the study visit procedures need to be 
repeated due to issues with sample processing, testing and/or shipping. Additional testing may 
be performed as part of quality control. 
 
It may also be necessary for additional visits to be conducted for unforeseen events. For example, 
you may be asked to come to the clinic for repeat or additional testing to ensure that the study 
products continue to be safe for you to use. Or you may choose to come for an additional visit for 
any unforeseen issues, questions, or counseling. 
 
Some of your specimens collected in this study may be shipped and stored outside your country 
so that study-related testing can be performed. There might be a small amount of urine, blood, or 
vaginal and rectal fluid left over after we have done all of the study related testing, including testing 

 
 
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for quality assurance and control. These leftover samples will not be stored or used for any future 
testing, and they will be destroyed after all testing related to this study is completed.     
 
What are the possible risks, side effects, and discomforts of this research study? 
 
Risks from use of rectal products 
The use of any rectal product can cause some side effects. We do not yet know all the side effects 
of the three study products. Previously tested rectal products have been associated with: 
• 
Abdominal bloating, feeling full, or a sense of abdominal pressure and/or pain 
• 
A sudden, almost uncontrollable, need to relieve the bowels 
• 
Diarrhea (loose, frequent stools) 
• 
Passing gas from the intestinal tract 
• 
Feeling a constant need to pass stools, despite an empty bowel 
• 
Anal discharge 
• 
Proctalgia (anal pain) 
 
Risks from phlebotomy (blood tests)   
• 
You may feel discomfort 
• 
You may feel dizzy or faint 
• 
You may have a bruise, swelling, small clot, or infection where the needle goes in your 
arm  
• 
You may have excessive bleeding 
 
Risks of throat swab 
• 
A pharyngeal (throat) swab often causes a momentary gagging reflex (feeling like you 
want to vomit). 
 
Risks of rectal douching 
• 
The main risk from rectal douching is temporary discomfort. An enema bottle will be used 
to administer about 120-125 mL (i.e., 4 ounces or 8 tablespoons) of water into the rectum.  
• 
You may experience some mild discomfort and a bloated or “crampy” feeling.  
• 
If you have any hemorrhoids or other painful conditions, you might feel anal or rectal 
discomfort. 
• 
Some air may be pumped into the rectum as well, causing flatulence (feeling like you need 
to pass gas).   
• 
There is a remote possibility of rectal perforation.  
 
Risks of rectal exams 
• 
During rectal exams and collection of rectal fluid samples, insertion of the study staff’s 
finger(s) and/or insertion of a lubricated anoscope will likely cause mild discomfort. 
 
Risks of rectal swab/sponge insertion 
• 
Insertion of rectal swabs or sponges may cause mild discomfort, in addition to a slight risk 
of bleeding. 
 
(For individuals with a vagina or neovagina) Risks of vaginal swab 
• 
During vaginal fluid collection, you may feel discomfort or pressure in your vagina or 
genital area. 
 

 
 
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Other Possible Risks 
• 
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 feel anxious while waiting for your test results, and after receiving them. Trained 
study counselors 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(s). 
If you have any problems, study counselors will talk with you and/or your partner to try to 
help resolve them.  
• 
Disclosure of your HIV and STI status may cause worry, sadness or depression. 
Disclosure of HIV-positive status has been associated with depression, suicidal ideation, 
and denial as well as social isolation. 
• 
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.   
• 
The interviews that take place at some of your clinic visits will be computer-administered 
and questions of a personal nature may be asked. Responding to these questions may 
make you uncomfortable. You may choose not to answer any question that makes you 
uncomfortable. 
 
We will make every effort to protect your privacy and confidentiality during the study visits. Your 
visits will take place in private. Reports via computer or text messages will be stored in computers 
that are password-protected and will not include personal information that could identify or link 
information to you; only your study ID number will be recorded. You will be shown how to erase 
the text message sessions from your mobile phone by study staff. However, as with all text 
messages sent from and received on your phone, it is possible that others may see your personal 
messages. Precautions have been taken to ensure that questions asked via text message are 
vague and will not directly convey information about your participation in this research study. 
There is a possibility that you may exceed your cell phone plan limit and have to pay for that. 
 
When staff talk with you about how and when you used the study products they will audio record 
the discussion using a digital audio recorder. These audio files will be reviewed and analyzed by 
another person who is outside of the research site and does not know you or have your personal 
information. In addition, if you agree and are selected to participate in the in-depth interviews, 
these will be audio recorded.  The audio files will be put into writing by the person interviewing 
you or by another person who does not know you and does not have your personal information. 
Any names that might be mentioned during the interview will NOT be retained.  Instead a generic 
description will be used in the records (i.e., if you refer to a friend’s name, “FRIEND1” will be 
noted). 
 
Your audio recordings and any other information that links you to the research materials will be 
kept in a secure location that will be accessed only by members of the MTN-035 study team for 
the purposes of this research. [Sites to modify with their site-specific source documentation 
storage duration requirements if required by their IRBs/IECs: The audio recordings, notes, and 
transcripts from these materials will be kept for at least three years after the final study report is 
submitted to the study sponsors.] 
 

 
 
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What are possible benefits from taking part in this study? 
• 
There are no direct benefits for taking part in this study, but you or others may have future 
benefit from information learned in this study.  You may also learn more about HIV and 
other diseases and ways to protect yourself from acquiring HIV or other STIs.   
• 
You will have physical and rectal exams.  If these exams show that you might have any 
health problems, you will be told about medical care and other services available to you. 
This will be available to you even if you do not enroll in this study.  This study cannot 
provide you with general medical care, but study staff will refer you to other available 
sources of care, if needed.  
• 
You will get counseling and testing for HIV and STIs. If you have acquired an STI other 
than HIV, you will be offered medicine to treat it or provided information for where you may 
receive treatment, and study staff will discuss options available for counseling and 
treatment of your partner(s). This treatment or referral for treatment is available to you 
even if you do not enroll in this study.   
• 
If you acquire HIV, you will need to receive care from your own health care provider or we 
will provide you with a referral. This study does not provide medication for treatment of 
HIV/AIDS.    
• 
You will receive free male condoms, if you need them. 
• 
You may receive free lubricant per local standard of care. 
 
Will the study products prevent HIV infection? 
The study products used in this study are placebos and do not contain any active drugs, so they 
will not prevent HIV. There are other known effective ways to reduce your risk of contracting HIV: 
the use of condoms and/or the use of oral pre-exposure prophylaxis (PrEP) or post-exposure 
prophylaxis (PEP) medication. Truvada® as a PrEP is an HIV prevention method in which people 
who do not have HIV take an oral tablet to reduce their risk of acquiring the virus. Study staff can 
provide you with additional information about PrEP and PEP if you are interested in learning more. 
If you are interested in these alternative options you may also want to discuss them with your 
doctor.   
 
What if there is new information learned during this study? 
We will tell you about new information from this or other studies that may affect your willingness 
to stay in this study.  You will also be told when study results may be available, and how to learn 
about them. 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by 
the NIH Policy on Dissemination of NIH-Funded Clinical Trial Information. This web site will not 
include information that can identify you.  At most, the web site will include a summary of the 
results.  You can search this web site at any time. 
 
Is it possible that I may be taken out of the study without my consent? 
A study clinician may need to remove you from the study early without your permission if: 
• 
The study is cancelled by the US NIH, the US Office for Human Research Protections 
(OHRP), 
MTN, 
government 
or 
regulatory 
agencies, 
or 
Institutional 
Review 
Boards/Independent Ethics Committees (IRB/IEC). An IRB/IEC is a committee that 
watches over the safety and rights of research participants. 
• 
The Study Monitoring Committee (SMC) recommends that the study be stopped early. A 
SMC reviews the progress of the study and the kinds of effects that people report while 
they are participating in the study. 
• 
You acquire HIV (see “If You Acquire HIV” section below). 

 
 
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• 
(For individuals who can get pregnant) You become pregnant (see “If You Become 
Pregnant” section below).  
• 
You report the use of non-study rectal medications or products, except personal lubricants 
and usual pre-RAI douches that do not contain N-9. 
• 
A study clinician decides that using the study products would be harmful to you, for 
example, you have a bad reaction to the study product. 
• 
Other reasons that may prevent you from completing the study successfully, such as you 
are not able or willing to reliably keep appointments or follow study rules. 
 
In the event that you are removed from or choose to leave this study for any reason, you will be 
asked to complete some of the procedures described for the Final/Early Termination Visit, if you 
are willing to do so.  
 
The study clinician will ask you to stop using the study products but continue to come in for follow-
up visits and procedures if you have a bad reaction to the products. 
 
If You Acquire HIV 
Your participation in this study will not cause HIV infection. However, there is always a chance 
that through sexual activity or other activities you may acquire HIV. In the unlikely event that you 
acquire HIV, study staff will give you counseling and refer you to available medical care and other 
services you may need. The study does not pay for this care. Tests may be performed that will 
allow your doctor to know what HIV drugs would be best for the treatment of your type of HIV. If 
the HIV test shows that you have acquired HIV, you will stop using the study products. You may 
be referred to other research studies. Continued study participation would be of no added benefit 
to you, so your participation in the study will be discontinued. 
 
(For individuals who can get pregnant) If You Become Pregnant  
The study products are not birth control methods and will not prevent pregnancy. You must use 
an effective method of contraception for at least 30 days (inclusive) prior to Enrollment and for 
the duration of study participation. You must agree to use an effective method of birth control such 
as birth control pills or another hormonal-based method, or an intrauterine device (IUD) inserted 
at least 30 days prior to enrollment, or abstain from penile-vaginal intercourse for 90 days prior to 
enrollment and for the duration of study participation, unless you or your partner have been 
sterilized (i.e., no longer able to become pregnant), and/or you only have sex that cannot lead to 
pregnancy (no penile-vaginal intercourse).   
 
We do not know what effect the placebo study products may have on pregnancy, including the 
effect on the fetuses of individuals who use the products when pregnant. Because of this, 
individuals who are pregnant may not join this study. Individuals who can get pregnant and who 
join this study will have pregnancy tests while in the study. 
 
If you become pregnant during the study, study staff will refer you to available medical care and 
other services you or your baby may need. The study does not pay for this care. You will stop 
using the study products and you will exit the study. 
 
Will there be any payments if I take part in this research study? 
[SITES TO INSERT INFORMATION ABOUT LOCAL REIMBURSEMENT:] You will receive 
[SITES TO INSERT AMOUNT $xx] for your time, effort, and travel to and from the clinic at each 
scheduled visit. You may receive [SITES TO INSERT AMOUNT $xx] for any visits which occur 
in between your normally scheduled visits. For responding to text messages, you will receive up 

 
 
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to [SITES TO INSERT AMOUNT $xx]. If you are selected and agree to take part in the in-depth 
phone interview, you will receive [SITES TO INSERT AMOUNT $xx]. 
 
What are the costs? 
[SITES TO COMPLETE ACCORDING TO SITE CAPACITY] There is no cost to you for study 
related visits, physical/rectal exams, laboratory tests or other procedures. Treatments available 
to you from the study site for infections passed through sex will be given to you free of charge or 
you will be referred for available treatment for the duration of the study. 
 
Are there any other studies if you cannot join this one?  
There may be other studies going on at this study clinic or in the community for which you may 
be eligible.  If you wish, we will tell you about other studies that we know about.  There may also 
be other places where you can go for HIV counseling and testing.  We will tell you about those 
places if you wish.  If you choose not to take part in this study, it will have no effect on the regular 
medical care that is available to you at this clinic or elsewhere. 
 
Who will know about my participation in this research study? 
Any information about you obtained from this research will be kept as private as possible.  All 
records related to your involvement in this research study will be kept in a [SITES TO INSERT].  
Your identity on these records will be indicated by a number rather than by your name, and the 
information linking these numbers with your name will be kept separate from the research records. 
 
Efforts 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. Any publication of 
this study will not use your name or identify you personally. The study staff may use your personal 
information to verify that you are not in any other research studies. This includes studies 
conducted by other researchers that study staff know about.  
 
Your records may be reviewed by: 
• 
Study staff 
• 
Site IRBs/IECs 
• 
CONRAD, the organization that supplies the placebo insert 
• 
Representatives of the US Federal Government, including OHRP, NIH and/or contractors of 
NIH 
• 
Other local, US or international regulatory authorities 
 
[Sites to include/amend the following:] [LOCAL/STATE/NATIONAL] regulations require study 
staff to report the names of people who test positive for HIV and other infections passed during 
sex to the [LOCAL HEALTH AUTHORITY]. Outreach workers from the [LOCAL HEALTH 
AUTHORITY] may then contact you about informing your partners, since they also should be 
tested. If you do not want to inform your partners yourself, the outreach workers will contact them, 
according to the confidentiality guidelines of the [HEALTH AUTHORITY]. 
 
[Sites to include/amend the following:] 
The researchers will do everything they can to protect your privacy. In addition to the efforts of 
the study staff to help keep your personal information private, we have obtained a Certificate of 
Confidentiality from the US Federal Government. This Certificate protects study staff located in 
the US from being forced to tell people who are not connected with this study, such as the court 
system, about your participation or information you give for study purposes. However, if the study 
staff learns of possible child abuse and/or neglect or a risk of harm to you or others, they will be 

 
 
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required to tell the proper authorities. This Certificate does not prevent you from releasing 
information about yourself and your participation in the study. 
 
What if I am injured as a result of participating in this study? 
[SITES TO SPECIFY INSTITUTIONAL POLICY:] It is unlikely that you will be injured as a result 
of study participation. If you are injured, the [institution] will give you immediate necessary 
treatment for your injuries. You [will/will not] have to pay for this treatment. You will be told where 
you can receive additional treatment for your injuries. The U.S. National Institutes of Health (NIH) 
does not have a mechanism to pay money or give other forms of compensation for research 
related injuries. You do not give up any legal rights by signing this consent form. 
 
May I withdraw my consent for participation in this research study? 
[SITE TO SPECIFY INSTITUTIONAL POLICY:] 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, nor will the confidentiality of the care provided for you here be 
affected.  You should feel free coming back to this facility even if you decide not to participate in 
this study. If you want the results of the study after the study is over, let the study staff members 
know. 
 
What do I do if I have questions? 
If you ever have any questions about the study, or if you have a research-related injury, you 
should contact [insert name of the investigator or other study staff] at [insert telephone 
number and/or physical address]. 
 
If you have questions about your rights as a research participant, you should contact [insert name 
or title of person on the IRB or other organization appropriate for the site] at [insert 
physical address and telephone number]. 
 
 
 
 

 
 
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SIGNATURES- VOLUNTARY CONSENT 
 
[INSERT SIGNATURE BLOCKS AS REQUIRED BY THE LOCAL IRB/IEC]: If you have 
read this consent form, or had it read and explained to you, and you understand the 
information, and you voluntarily agree to the study, please sign your name or make your 
mark below. 
 
____________________ ________________________ ______________ 
Participant Name   
Participant Signature/Mark  
Date 
(print) 
 
____________________ ________________________ ______________ 
Study Staff Conducting  
Study Staff Signature 
 
Date 
Consent Discussion (print) 
 
 
____________________ ________________________ ______________ 
Witness Name (print) 
Witness Signature  
 
Date 
 
 
 
 

 
 
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REFERENCES 
 
1. 
McGowan I. Microbicides for HIV prevention: Reality or hope? Curr Opin Infect Dis 
2010;23:26-31. 
2. 
Leynaert B, Downs AM, de V, I. Heterosexual transmission of human immunodeficiency 
virus: variability of infectivity throughout the course of infection. European Study Group 
on Heterosexual Transmission of HIV. Am J Epidemiol 1998;148:88-96. 
3. 
Vittinghoff E, Douglas J, Judson F, McKirnan D, MacQueen K, Buchbinder SP. Per-
contact risk of human immunodeficiency virus transmission between male sexual 
partners. Am J Epidemiol 1999;150:306-11. 
4. 
Gorbach PM, Manhart LE, Hess KL, Stoner BP, Martin DH, Holmes KK. Anal 
intercourse among young heterosexuals in three sexually transmitted disease clinics in the 
United States. Sex Transm Dis 2009;36:193-8. 
5. 
Carlos JA, Bingham TA, Stueve A, et al. The role of peer support on condom use among 
Black and Latino MSM in three urban areas. AIDS Educ Prev 2010;22:430-44. 
6. 
Beyrer C, Baral SD, van Griensven F, et al. Global epidemiology of HIV infection in 
men who have sex with men. Lancet 2012;380:367-77. 
7. 
Sullivan PS, Hamouda O, Delpech V, et al. Reemergence of the HIV epidemic among 
men who have sex with men in North America, Western Europe, and Australia, 1996-
2005. Ann Epidemiol 2009;19:423-31. 
8. 
WHO. HIV/AIDS Surveillance in Europe 2017 - 2016 data. The European Centre for 
Disease Prevention and Control (ECDC) and the WHO Regional Office for Europe; 
2017. 
9. 
HIV among gay and bisexual men. CDC, 2018. (Accessed April 4, 2018, at 
https://www.cdc.gov/hiv/group/msm/index.html.) 
10. 
Stall R, Duran L, Wisniewski SR, et al. Running in Place: Implications of HIV Incidence 
Estimates among Urban Men Who Have Sex with Men in the United States and Other 
Industrialized Countries. AIDS Behav 2009;13:615-29. 
11. 
Millett GA, Jeffries WLt, Peterson JL, et al. Common roots: a contextual review of HIV 
epidemics in black men who have sex with men across the African diaspora. Lancet 
2012;380:411-23. 
12. 
HIV prevalence among South African MSM twice as high as general population. 2009. 
(Accessed October 26, 2017, at http://www.aidsmap.com/HIV-prevalence-among-South-
African-MSM-twice-as-high-as-general-population/page/1323795/.) 
13. 
Baral SD, Poteat T, Stromdahl S, Wirtz AL, Guadamuz TE, Beyrer C. Worldwide burden 
of HIV in transgender women: a systematic review and meta-analysis. Lancet Infect Dis 
2013;13:214-22. 
14. 
Clark H, Babu AS, Wiewel EW, Opoku J, Crepaz N. Diagnosed HIV Infection in 
Transgender Adults and Adolescents: Results from the National HIV Surveillance 
System, 2009–2014. AIDS Behav 2017;21:2774-83. 
15. 
Herbst JH, Jacobs ED, Finlayson TJ, McKleroy VS, Neumann MS, Crepaz N. Estimating 
HIV prevalence and risk behaviors of transgender persons in the United States: a 
systematic review. AIDS Behav 2008;12:1-17. 
16. 
Operario D, Soma T, Underhill K. Sex work and HIV status among transgender women: 
systematic review and meta-analysis. J Acquir Immune Defic Syndr 2008;48:97-103. 

 
 
MTN-035, Version 1.0 
93 
June 15, 2018 
 
17. 
Organization WH. Consolidated guidelines on HIV prevention, diagnosis, treatment and 
care for key populations. In: HIV/AIDS Do, ed. Geneva, Switzerland2014. 
18. 
Schmidt A, Benvenuti S, Breveglieri M, et al ftEc. The European MSM internet survey 
(EMIS) UNGASS indicators2011. 
19. 
Abell N, Rutledge SE, McCann TJ, Padmore J. Examining HIV/AIDS provider stigma: 
assessing regional concerns in the islands of the Eastern Caribbean. AIDS Care 
2007;19:242-7. 
20. 
Vu BN, Girault P, Do BV, Colby D, Tran LT. Male sexuality in Vietnam: the case of 
male-to-male sex. Sex Health 2008;5:83-8. 
21. 
Adam PC, de Wit JB, Toskin I, et al. Estimating levels of HIV testing, HIV prevention 
coverage, HIV knowledge, and condom use among men who have sex with men (MSM) 
in low-income and middle-income countries. J Acquir Immune Defic Syndr 2009;52 
Suppl 2:S143-51. 
22. 
Blair JM, Fleming PL, Karon JM. Trends in AIDS incidence and survival among 
racial/ethnic minority men who have sex with men, United States, 1990-1999. J Acquir 
Immune Defic Syndr 2002;31:339-47. 
23. 
Sandfort TGM, Nel J, Rich E, Reddy V, Yi H. HIV testing and self-reported HIV status 
in South African MSM: Results from a community-based survey. Sex Transm Infect 
2008;84:425-9. 
24. 
Hall HI, Byers RH, Ling Q, Espinoza L. Racial/ethnic and age disparities in HIV 
prevalence and disease progression among men who have sex with men in the United 
States. Am J Public Health 2007;97:1060-6. 
25. 
AIDS By the Numbers-2016. 2016. (Accessed 10/21/2016, 2016, at 
http://www.unaids.org/en/resources/documents/2016/AIDS-by-the-numbers.) 
26. 
Weissman A, Ngak S, Srean C, Sansothy N, Mills S, Ferradini L. HIV Prevalence and 
Risks Associated with HIV Infection among Transgender Individuals in Cambodia. PLoS 
One 2016;11:e0152906. 
27. 
Chemnasiri T, Netwong T, Visarutratana S, et al. Inconsistent condom use among young 
men who have sex with men, male sex workers, and transgenders in Thailand. AIDS 
Educ Prev 2010;22:100-9. 
28. 
CDC. HIV testing and risk behaviors among gay, bisexual, and other men who have sex 
with men – United States2013. 
29. 
Casalino E, Choquet C, Leleu A, et al. Trends in condom use and risk behaviours after 
sexual exposure to HIV: a seven-year observational study. PLoS One 2014;9:e104350. 
30. 
Elford J. Changing patterns of sexual behaviour in the era of highly active antiretroviral 
therapy. Curr Opin Infect Dis 2006;19:26-32. 
31. 
Elford J, Bolding G, Davis M, Sherr L, Hart G. Trends in sexual behaviour among 
London homosexual men 1998-2003: implications for HIV prevention and sexual health 
promotion. Sex Transm Infect 2004;80:451-4. 
32. 
Phillips AN, Cambiano V, Nakagawa F, et al. Increased HIV incidence in men who have 
sex with men despite high levels of ART-induced viral suppression: analysis of an 
extensively documented epidemic. PLoS One 2013;8:e55312. 
33. 
Pines HA, Gorbach PM, Weiss RE, et al. Acceptability of potential rectal microbicide 
delivery systems for HIV prevention: a randomized crossover trial. AIDS Behav 
2013;17:1002-15. 

 
 
MTN-035, Version 1.0 
94 
June 15, 2018 
 
34. 
Paz-Bailey G, Mendoza MC, Finlayson T, et al. Trends in condom use among MSM in 
the United States: the role of antiretroviral therapy and seroadaptive strategies. AIDS 
2016;30:1985-90. 
35. 
Grant RM, Anderson PL, McMahan V, et al. Uptake of pre-exposure prophylaxis, sexual 
practices, and HIV incidence in men and transgender women who have sex with men: A 
cohort study. Lancet Infect Dis 2014;14:820-9. 
36. 
Reece M, Herbenick D, Schick V, Sanders SA, Dodge B, Fortenberry JD. Condom Use 
Rates in a National Probability Sample of Males and Females Ages 14 to 94 in the United 
States. The Journal of Sexual Medicine 2010;7:266-76. 
37. 
Herbenick D, Reece M, Schick V, Sanders SA, Dodge B, Fortenberry JD. Sexual 
Behavior in the United States: Results from a National Probability Sample of Men and 
Women Ages 14–94. The Journal of Sexual Medicine 2010;7:255-65. 
38. 
Rosenberger JG, Reece M, Schick V, et al. Sexual Behaviors and Situational 
Characteristics of Most Recent Male-Partnered Sexual Event among Gay and Bisexually 
Identified Men in the United States. The Journal of Sexual Medicine 2011;8:3040-50. 
39. 
Fonner VA, Dalglish SL, Kennedy CE, et al. Effectiveness and safety of oral HIV 
preexposure prophylaxis for all populations. AIDS 2016;30:1973-83. 
40. 
Weber J, Tatoud R, Fidler S. Postexposure prophylaxis, preexposure prophylaxis or 
universal test and treat: the strategic use of antiretroviral drugs to prevent HIV acquisition 
and transmission. AIDS 2010;24 Suppl 4:S27-39. 
41. 
Liu AY, Vittinghoff E, Chillag K, et al. Sexual risk behavior among HIV-uninfected men 
who have sex with men participating in a tenofovir preexposure prophylaxis randomized 
trial in the United States. J Acquir Immune Defic Syndr 2013;64:87-94. 
42. 
Callahan R, Nanda K, Kapiga S, et al. Pregnancy and contraceptive use among women 
participating in the FEM-PrEP trial. J Acquir Immune Defic Syndr 2015;68:196-203. 
43. 
Murnane PM, Heffron R, Ronald A, et al. Pre-exposure prophylaxis for HIV-1 prevention 
does not diminish the pregnancy prevention effectiveness of hormonal contraception. 
AIDS 2014;28:1825-30. 
44. 
Sullivan PS, Carballo-Dieguez A, Coates T, et al. Successes and challenges of HIV 
prevention in men who have sex with men. Lancet 2012;380:388-99. 
45. 
Krakower D, Mayer KH. Engaging healthcare providers to implement HIV pre-exposure 
prophylaxis. Curr Opin HIV AIDS 2012;7:593-9. 
46. 
Zablotska IB, Prestage G, de Wit J, Grulich AE, Mao L, Holt M. The informal use of 
antiretrovirals for preexposure prophylaxis of HIV infection among gay men in Australia. 
J Acquir Immune Defic Syndr 2013;62:334-8. 
47. 
Mimiaga MJ, White JM, Krakower DS, Biello KB, Mayer KH. Suboptimal awareness 
and comprehension of published preexposure prophylaxis efficacy results among 
physicians in Massachusetts. AIDS Care 2014;26:684-93. 
48. 
Gilead Sciences. TRUVADA (emtricitabine and tenofovir disoproxil fumarate) tablets: 
Packge Insert (2016). 2016. 
49. 
Garg S, Goldman D, Krumme M, Rohan LC, Smoot S, Friend DR. Advances in 
development, scale-up and manufacturing of microbicide gels, films, and tablets. 
Antiviral Res 2010;88:S19-S29. 
50. 
Rosenberg ZF, Devlin B. Future strategies in microbicide development. Best Practice & 
Research Clinical Obstetrics & Gynaecology 2012;26:503-13. 

 
 
MTN-035, Version 1.0 
95 
June 15, 2018 
 
51. 
van der Straten A, Van DL, Haberer JE, Bangsberg DR. Unraveling the divergent results 
of pre-exposure prophylaxis trials for HIV prevention. AIDS 2012;26:F13-F9. 
52. 
Baeten JM, Haberer JE, Liu AY, Sista N. Pre-exposure prophylaxis for HIV prevention: 
where have we been and where are we going? Journal of acquired immune deficiency 
syndromes (1999) 2013;63:S122-S9. 
53. 
Brown E, Palanee-Philips T, Marzinke M, et al. Residual dapivirine ring levels indicate 
higher adherence to vaginal ring is associated with HIV-1 protection. AIDS 2016, July 
18-22, 2016, Durban, South Africa 2016:Abstract # TUAC0105LB. 
54. 
Ventuneac A, Carballo-Dieguez A, McGowan I, et al. Acceptability of UC781 gel as a 
rectal microbicide among HIV-uninfected women and men. AIDS Behav 2010;14:618-
28. 
55. 
Carballo-Dieguez A, Dolezal C, Bauermeister JA, O'Brien W, Ventuneac A, Mayer K. 
Preference for gel over suppository as delivery vehicle for a rectal microbicide: results of 
a randomised, crossover acceptability trial among men who have sex with men. Sex 
Transm Infect 2008;84:483-7. 
56. 
Carballo-Dieguez A, Giguere R, Dolezal C, et al. Rectal-specific microbicide applicator: 
evaluation and comparison with a vaginal applicator used rectally. AIDS Behav 
2014;18:1734-45. 
57. 
Javanbakht M, Stahlman S, Pickett J, LeBlanc MA, Gorbach PM. Prevalence and types 
of rectal douches used for anal intercourse: results from an international survey. BMC 
Infect Dis 2014;14:95. 
58. 
Carballo-Dieguez A, Bauermeister JA, Ventuneac A, Dolezal C, Balan I, Remien RH. 
The use of rectal douches among HIV-uninfected and infected men who have unprotected 
receptive anal intercourse: implications for rectal microbicides. AIDS Behav 
2008;12:860-6. 
59. 
CONRAD. A 14-Day Rectal Irritation and Pharmakinetic Study of Elvitegravir in 
Rabbits - Draft Pathology Report (MPI Study Number: 1645-114). 2017. 
60. 
Meisel JL, Bergman D, Graney D, Saunders DR, Rubin CE. Human rectal mucosa: 
proctoscopic and morphological changes caused by laxatives. Gastroenterology 1977;72. 
61. 
Leyva FJ, Bakshi RP, Fuchs EJ, et al. Isoosmolar Enemas Demonstrate Preferential 
Gastrointestinal Distribution, Safety, and Acceptability Compared with Hyperosmolar 
and Hypoosmolar Enemas as a Potential Delivery Vehicle for Rectal Microbicides. AIDS 
Res Hum Retroviruses 2013;29:1487-95. 
62. 
Yerkes EB, Rink RC, King S, Cain MP, Kaefer M, Casale AJ. Tap water and the Malone 
antegrade continence enema: a safe combination? The Journal of urology 2001;166:1476-
8. 
63. 
Chemical IO, Kuznik J. Witepsol® H5-based suppository products currently on the 
market. In: Rohan L, ed.2017. 
64. 
Stahlman S, Gorbach P. Rectal behaviors: a global overview.  Microbicides 2012. 
Sydney2012. 
65. 
Chakrapani V, Newman PA, Shunmugam M, et al. "Like Holding an Umbrella Before It 
Rains": Acceptability of Future Rectal Microbicides Among Men Who Have Sex With 
Men in India-A Modified Technology Acceptance Model. Qual Health Res 
2017;27:1236-48. 
66. 
Newman PA, Cameron MP, Roungprakhon S, Tepjan S, Scarpa R. Acceptability and 
Preferences for Hypothetical Rectal Microbicides among a Community Sample of Young 

 
 
MTN-035, Version 1.0 
96 
June 15, 2018 
 
Men Who Have Sex with Men and Transgender Women in Thailand: A Discrete Choice 
Experiment. AIDS Behav 2016;20:2588-601. 
67. 
Zhang G, Zhang H, Yu H, et al. Hypothetical Rectal Microbicide Acceptability and 
Factors Influencing It among Men Who Have Sex with Men in Tianjin, China. PLoS One 
2016;11:e0156561. 
68. 
Brown J, Haines S, Wilding IR. Colonic spread of three rectally administered mesalazine 
(Pentasa) dosage forms in healthy volunteers as assessed by gamma scintigraphy. 
Aliment Pharmacol Ther 1997;11:685-91. 
69. 
Galea JT, Kinsler JJ, Imrie J, Nurena CR, Sanchez J, Cunningham WE. Rectal douching 
and implications for rectal microbicides among populations vulnerable to HIV in South 
America: a qualitative study. Sex Transm Infect 2014;90:33-5. 
70. 
Noor SW, Rosser BR. Enema use among men who have sex with men: a behavioral 
epidemiologic study with implications for HIV/STI prevention. Arch Sex Behav 
2014;43:755-69. 
71. 
Galea JT, Kinsler JJ, McLean S, et al. Rectal Douching Prevalence and Practices Among 
Peruvian Men Who have Sex with Men and Transwomen: Implications for Rectal 
Microbicides. AIDS Behav 2016;20:2555-64. 
72. 
Lamblet LCR, da Silva RJC. Prevalence and types of rectal douches used for anal 
intercourse among men who have sex with men in Brazil. BMJ Open 2017;7:e011122. 
73. 
Mitchell JW, Sophus AI, Lee JY, Petroll AE. Anal Douche Practices and Willingness to 
Use a Rectal Microbicide Enema for HIV Prevention and Associated Factors Among an 
Internet Sample of HIV-Negative and HIV-Discordant Male Couples in the US. AIDS 
Behav 2016;20:2578-87. 
74. 
Hambrick HR, Park SH, Goedel WC, et al. Rectal Douching Among Men Who Have Sex 
with Men in Paris: Implications for HIV/STI Risk Behaviors and Rectal Microbicide 
Development. AIDS Behav 2017. 
75. 
Javanbakht M, Murphy R, Gorbach P, LeBlanc M-A, Pickett J. Preference and practices 
relating to lubricant use during anal intercourse: implications for rectal microbicides. 
Sexual Health 2010;7:193-8. 
76. 
Carballo-Dieguez A, Stein Z, Saez H, Dolezal C, Nieves-Rosa L, Diaz F. Frequent use of 
lubricants for anal sex among men who have sex with men: the HIV prevention potential 
of a microbicidal gel. Am J Public Health 2000;90:1117-21. 
77. 
Frasca T, Giguere R, Ibitoye M, et al. Lessons for Rectal Microbicide Development From 
an Acceptability Trial of a Placebo Gel Applied Prior to Receptive Anal Intercourse. 
Arch Sex Behav 2017;46:1101-9. 
78. 
Stone E, Heagerty P, Vittinghoff E, et al. Correlates of condom failure in a sexually 
active cohort of men who have sex with men. J Acquir Immune Defic Syndr Hum 
Retrovirol 1999;20:495-501. 
79. 
Baral S, Trapence G, Motimedi F, et al. HIV prevalence, risks for HIV infection, and 
human rights among men who have sex with men (MSM) in Malawi, Namibia, and 
Botswana. PLoS One 2009;4:e4997. 
80. 
Gorbach PM, Weiss RE, Fuchs E, et al. The slippery slope: lubricant use and rectal s
 
exually transmitted infections: a newly identified risk. Sex Transm Dis 2012;39:59-64. 
81. 
Carballo-Dieguez A, Bauermeister J, Ventuneac A, Dolezal C, Mayer K. Why rectal 
douches may be acceptable rectal-microbicide delivery vehicles for men who have sex 
with men. Sex Transm Dis 2010;37:228-33.