Clinical trial NCT04047420
Conditions: HIV Infections
Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Start date: 2019-12-11; Completion date: 2021-04-07
Enrollment: 23 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to evaluate the safety and pharmacokinetics of rectal administration of a tenofovir alafenamide (TAF)/elvitegravir (EVG) insert at two dose levels in HIV-uninfected individuals.

Detailed description:
This study will evaluate the safety and pharmacokinetics of rectal administration of a tenofovir alafenamide (TAF)/elvitegravir (EVG) insert at two dose levels in HIV-uninfected individuals.

All participants will receive a single TAF/EVG Insert at Study Visit 3. After a washout period of at least 7 days, participants will receive two TAF/EVG Inserts at Study Visit 7. The inserts will be administered rectally by study staff. After each dosing visit, samples will be collected over a 3-day period.

Participants will attend 10 study visits and will be followed for approximately 6 to 13 weeks. Study visits may include physical and rectal examinations; collection of blood, urine, rectal and vaginal fluid; and interviews. The total duration of the study will be approximately 11 months.

Arms: arm 1: On the first dosing visit (Visit 3), participants will receive a single TAF/EVG Insert for rectal administration. On the second dosing visit (Visit 7), after a washout period of at least 7 days, participants will receive two TAF/EVG Inserts for rectal administration. Each participant will be on study for approximately 6-13 weeks.
Interventions: intervention 1: TAF/EVG Insert
Intervention descriptions: intervention 1: TAF/EVG Insert (20/16 mg) administered rectally by study staff

Protocol documents:
Prot_ICF_000.pdf: 
1 
 
MTN-039 
 
 
 
A Phase 1 Open Label Safety and Pharmacokinetic Study of Rectal 
Administration of a Tenofovir Alafenamide/Elvitegravir Insert at Two Dose Levels 
 
 
 
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 Number: 
5UM1 AI068633 
 
DAIDS Protocol ID: 
38470 
 
IND Sponsor: 
DAIDS 
 
 
IND # TBD 
 
 
Protocol Chair: Sharon Riddler, MD, MPH 
 
 
 
Version 1.0 
 
March 6, 2019 
 
 
 
 
 


 
 
MTN-039, Version 1.0 
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March 6, 2019 
 
MTN-039 
 
A Phase 1 Open Label Safety and Pharmacokinetic Study of Rectal Administration of 
a Tenofovir Alafenamide/Elvitegravir Insert at Two Dose Levels 
 
TABLE OF CONTENTS 
 
LIST OF ABBREVIATIONS AND ACRONYMS ..................................................................... 6 
PROTOCOL TEAM ROSTER ............................................................................................. 11 
INVESTIGATOR SIGNATURE FORM ................................................................................ 19 
PROTOCOL SUMMARY ..................................................................................................... 20 
1 KEY ROLES .................................................................................................................. 23 
1.1 
Protocol Identification ............................................................................................ 23 
1.2 
Funding Agencies, Sponsor and Monitor Identification ......................................... 23 
1.3 
Medical Officer ...................................................................................................... 24 
1.4 
Laboratory Centers ............................................................................................... 24 
1.5 
Data Center ........................................................................................................... 24 
1.6 
Study Implementation ........................................................................................... 24 
2 INTRODUCTION ........................................................................................................... 25 
2.1 
Background of Rectal Microbicide Research and Study Rationale ....................... 25 
2.2 
Elvitegravir (EVG) – Description and Mechanism of Action .................................. 25 
2.3 
Non-Clinical Studies of Elvitegravir ....................................................................... 26 
2.4 
Tenofovir Alafenamide (TAF) – Description and Mechanism of Action ................. 30 
2.5 
Non-Clinical Studies of Tenofovir Alafenamide ..................................................... 31 
2.6 
Non-Clinical Studies of Elvitegravir and Tenofovir Alafenamide ........................... 33 
2.7 
Clinical Studies of Elvitegravir and Tenofovir Alafenamide ................................... 36 
2.8 
Study Hypotheses and Rationale for Study Design .............................................. 42 
3 OBJECTIVES................................................................................................................. 43 
3.1 
Primary Objectives ................................................................................................ 43 
3.2 
Secondary Objective ............................................................................................. 43 
3.3 
Exploratory Objectives .......................................................................................... 43 
4 STUDY DESIGN ............................................................................................................ 44 
4.1 
Identification of Study Design ................................................................................ 44 
4.2 
Summary of Major Endpoints ................................................................................ 44 
4.3 
Description of Study Population ............................................................................ 45 
4.4 
Time to Complete Accrual ..................................................................................... 45 
4.5 
Study Groups ........................................................................................................ 45 
4.6 
Expected Duration of Participation ........................................................................ 45 
4.7 
Sites ...................................................................................................................... 45 
5 STUDY POPULATION ................................................................................................... 45 
5.1 
Selection of the Study Population ......................................................................... 45 
5.2 
Inclusion Criteria ................................................................................................... 46 
5.3 
Exclusion Criteria .................................................................................................. 47 
5.4 
Co-enrollment Guidelines ..................................................................................... 48 
6 STUDY PRODUCT ........................................................................................................ 49 


 
 
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6.1 
Regimen................................................................................................................ 49 
6.2 
Administration ....................................................................................................... 49 
6.3 
Study Product Formulation and Storage ............................................................... 49 
6.4 
Study Product Supply and Accountability ............................................................. 50 
6.5 
Ancillary Study Supplies ....................................................................................... 51 
6.6 
Concomitant Medications ...................................................................................... 51 
6.7 
Prohibited Medications, Products and Practices ................................................... 51 
7 STUDY PROCEDURES ................................................................................................ 53 
7.1 
Pre-screening ........................................................................................................ 54 
7.2 
Screening .............................................................................................................. 54 
7.3 
Enrollment (Day 0) ................................................................................................ 55 
7.4 
Follow-up Visits ..................................................................................................... 56 
7.5 
Follow-up Procedures for Participants Who Permanently Discontinue Study 
Product ................................................................................................................. 61 
7.6 
Interim Visits ......................................................................................................... 62 
7.7 
Protocol Counseling: Adherence and Contraception Counseling.......................... 62 
7.8 
Clinical Evaluations and Procedures ..................................................................... 62 
7.9 
Behavioral Assessments ....................................................................................... 63 
7.10 
Pharmacokinetics (PK) and Pharmacodynamics (PD) .......................................... 64 
7.11 
Laboratory Evaluations ......................................................................................... 64 
7.12 
Specimen Management ........................................................................................ 66 
7.13 
DAIDS Laboratory Oversight................................................................................. 66 
7.14 
Biohazard Containment ........................................................................................ 66 
8 ASSESSMENT OF SAFETY ......................................................................................... 67 
8.1 
Safety Monitoring .................................................................................................. 67 
8.2 
Clinical Data and Safety Review ........................................................................... 67 
8.3 
Adverse Events Definitions and Reporting Requirements .................................... 68 
8.4 
Adverse Event Reporting Requirements ............................................................... 70 
8.5 
Pregnancy and Infant Outcomes ........................................................................... 71 
8.6 
Regulatory Requirements ..................................................................................... 71 
8.7 
Social Harms Reporting ........................................................................................ 71 
9 CLINICAL MANAGEMENT ............................................................................................ 71 
9.1 
Grading System .................................................................................................... 72 
9.2 
Dose Modification Instructions .............................................................................. 72 
9.3 
General Criteria for Permanent Discontinuation of Study Product ........................ 72 
9.4 
Follow-up in Response to Observed Adverse Events ........................................... 72 
9.5 
Pregnancy ............................................................................................................. 73 
9.6 
Criteria for Early Termination of Study Participation ............................................. 73 
10 STATISTICAL CONSIDERATIONS ............................................................................... 73 
10.1 
Overview and General Design .............................................................................. 73 
10.2 
Study Endpoints .................................................................................................... 74 
10.3 
Primary Study Hypotheses.................................................................................... 74 
10.4 
Sample Size and Power Calculations ................................................................... 74 
10.5 
Randomization Procedures ................................................................................... 75 
10.6 
Participant Accrual, Follow-up and Retention ....................................................... 76 
10.7 
Data and Safety Monitoring and Analysis ............................................................. 76 


 
 
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11 DATA HANDLING AND RECORDKEEPING ................................................................. 77 
11.1 
Data Management Responsibilities ....................................................................... 77 
11.2 
Source Documents and Access to Source Data/Documents ................................ 78 
11.3 
Quality Control and Quality Assurance ................................................................. 78 
12 CLINICAL SITE MONITORING...................................................................................... 78 
13 HUMAN SUBJECTS PROTECTIONS ........................................................................... 79 
13.1 
Institutional Review Boards/Ethics Committees .................................................... 79 
13.2 
Protocol Registration ............................................................................................. 79 
13.3 
Study Coordination ............................................................................................... 80 
13.4 
Risk Benefit Statement ......................................................................................... 81 
13.5 
Informed Consent Process.................................................................................... 84 
13.6 
Participant Confidentiality...................................................................................... 85 
13.7 
Special Populations .............................................................................................. 86 
13.8 
Compensation ....................................................................................................... 86 
13.9 
Communicable Disease Reporting ........................................................................ 86 
13.10 Access to HIV-related Care................................................................................... 86 
13.11 Study Discontinuation ........................................................................................... 86 
14 PUBLICATION POLICY ................................................................................................. 87 
15 APPENDICES ................................................................................................................ 87 
APPENDIX I:  SCHEDULE OF STUDY VISITS AND EVALUATIONS ................................ 88 
APPENDIX II:  ALGORITHM FOR HIV TESTING FOR SCREENING AND FOLLOW-UP . 91 
APPENDIX III: SAMPLE INFORMED CONSENT FORM (SCREENING, ENROLLMENT, 
LONG-TERM STORAGE AND FUTURE TESTING) ........................................................... 92 
REFERENCE LIST............................................................................................................ 115 
 
TABLE OF TABLES AND FIGURES 
 
Table 1:  In vitro Dissolution of 8 mg Elvitegravir Insert ....................................................... 27 
Table 2:  Study design of the pharmacokinetic study of EVG/TDF vaginal inserts in 
pigtailed macaques ............................................................................................................. 28 
Table 3:  Group Assignments in EVG Vaginal and Rectal Irritation Studies ........................ 29 
Table 4:  In vitro Dissolution of 20/16 mg TAF/EVG Insert .................................................. 34 
Table 5:  Adverse Reactionsa (All Grades) Reported in ≥5% of Subjects with Chronic 
HBV Infection and Compensated Liver Disease in Studies Gilead Studies 108 and 110 
(Week 96 Analysisb) ............................................................................................................ 41 
Table 6:  Adverse Reactions (All Grades) Reported in ≥5% of HIV-1 Infected 
Treatment-Naïve Adults Receiving Genvoya or Stribild in Gilead Studies 104 and 111 
(Week 144 Analysis) ........................................................................................................... 42 
Table 7: Study Product Regimen ........................................................................................ 49 
Table 8: Prohibited CYP Inhibitors ...................................................................................... 52 
Table 9: Prohibited CYP Inducers ....................................................................................... 52 
Table 10:  Screening Visit ................................................................................................... 54 
Table 11:  Enrollment Visit .................................................................................................. 55 
Table 12: Dosing Procedures .............................................................................................. 56 
Table 13:  24-hour Post-Dosing Visits ................................................................................. 58 
Table 14:  Other Post-Dosing Visits .................................................................................... 59 
Table 15:  Final Contact/Early Termination Visit ................................................................. 60 


 
 
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Table 16: Specimens to be Collected to Assess Safety, PK and Ex Vivo Antiviral 
Activity ................................................................................................................................. 64 
Table 17: Analysis of Safety Event Frequency .................................................................... 74 
Table 18: Exact 2-sided 95% Confidence Intervals Based on Observing a Particular 
Rate of Safety Endpoints among 20 Participants ................................................................ 75 
 
Figure 1: MTN-039 Study Visit Schedule ............................................................................ 21 
Figure 2: Study Product ....................................................................................................... 50 
Figure 3: MTN-039 Study Visit Schedule ............................................................................ 54 
 
 
 


 
 
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MTN-039 
 
A Phase 1 Open Label Safety and Pharmacokinetic Study of Rectal Administration of 
a Tenofovir Alafenamide/Elvitegravir Insert at Two Dose Levels 
LIST OF ABBREVIATIONS AND ACRONYMS 
 
AE 
adverse event 
AIDS 
Acquired Immunodeficiency Syndrome 
ALT 
alanine transaminase 
API 
active pharmaceutical ingredient 
ARV 
antiretroviral drugs 
AST 
aspartate aminotransferase 
AUC 
area under the curve 
AUCinf 
area under the curve extrapolated to infinity 
AUClast 
area under the curve up to the last measurable concentration 
BID 
bis in die, or twice per day 
BPA 
bisphenol A 
BRWG 
Behavioral Research Working Group 
BSWG 
Biomedical Science Working Group 
BV 
bacterial vaginosis 
CASI 
computer assisted self-interview 
CBC 
complete blood count 
CD4 
cluster of differentiation 4 
CDC 
Centers for Disease Control and Prevention 
cDNA 
complementary DNA 
CFR 
Code of Federal Regulations 
CI 
Confidence Interval 
Cmax 
maximum concentration 
CMRB 
Clinical Microbicide Research Branch 
CNS 
central nervous system 
COBI 
cobicistat  
CRF 
case report form 
CRMS 
Clinical Research Management System 
CRS 
Clinical Research Site 
CT 
Chlamydia trachomatis, Chlamydia 
CTA 
Clinical Trial Agreement 
CVF 
cervicovaginal fluid 
CWG 
Community Working Group 
CYP1A2 
cytochrome P450 family 1, subfamily A2 genetic locus  
CYP2C8 
cytochrome P450 family 2, subfamily C8 genetic locus  
CYP2C9 
cytochrome P450 family 2, subfamily C9 genetic locus  
CYP2C19 
cytochrome P450 family 2, subfamily C19 genetic locus  
CYP2D6 
cytochrome P450 family 2, subfamily D6 genetic locus  
CYP2E1 
cytochrome P450 family 2, subfamily E1 genetic locus  
CYP3A 
cytochrome P450, family 3, subfamily A genetic locus 
CYP3A4 
cytochrome P450 family 3, subfamily A4 genetic locus  
CYP450 
cytochrome P450 


 
 
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DAERS 
DAIDS Adverse Experience Reporting System 
DAIDS 
Division of AIDS 
DAIDS PRO 
DAIDS Protocol Registration Office 
DAPY 
di-amino-pyrimidine 
DLV 
delavirdine 
DNA 
deoxyribonucleic acid 
DOD 
directly observed dosing 
EAE 
expedited adverse event 
EC 
ethics committees 
EC50 
50% effective concentration 
EFV 
efavirenz 
ENR 
enrollment 
EU 
European Union 
EVG 
elvitegravir 
FDA 
(US) Food and Drug Administration 
FHCRC 
Fred Hutchinson Cancer Research Center 
FMO 
flavin-containing monooxygenase 
FTC 
emtricitabine  
g 
grams 
GC 
Neisseria gonorrhoeae, gonorrhea 
GCP 
Good Clinical Practices 
GEE 
generalized estimating equations 
GMP 
Good Manufacturing Practices 
HBsAg 
hepatitis B surface antigen 
HBV 
hepatitis B virus 
HCG 
human chorionic gonadotropin 
HCV 
hepatitis C virus 
HEC 
hydroxyethylcellulose 
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 
HIV-1 IIIB 
Human Immunodeficiency Virus type 1, IIIB strain 
HPTN 
HIV Prevention Trials Network 
HPV 
human papillomavirus 
HSV 
herpes simplex virus 
HSV-1/2 
herpes simplex virus type 1/2 
hu-PBL 
human peripheral blood lymphocytes 
hu-SCID 
humanized severe combined immunodeficient 
IATA 
International Air Transport Association 
IB 
Investigator’s Brochure 
IC50 
half maximal inhibitory concentration 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IDI 
In-Depth Interview 
IL 
Interleukin 
IND 
Investigational New Drug 
INR 
International normalized ratio 
INSTI 
Integrase strand transfer inhibitor 


 
 
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IoR 
Investigator of Record 
IRB 
Institutional Review Board 
IUD 
intrauterine device 
kg 
kilogram 
LC 
Laboratory Center 
LDMS 
Laboratory Data Management System 
LLOQ 
lower limit of quantification 
LOC 
Leadership and Operations Center 
μg 
microgram 
MDP 
Microbicides Development Programme 
mg 
milligram 
mL 
milliliter 
mM 
millimolar 
MO 
Medical Officer 
mOsm 
milliosmole 
MPA 
medroxyprogesterone acetate 
mRNA 
mitochondrial ribonucleic acid 
MT-2 
human melatonin receptor 2 
MTN 
Microbicide Trials Network 
MTT 
3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, a tetrazole 
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 
NNRTI 
non-nucleoside reverse transcriptase inhibitor 
NRTI 
nucleotide analogue reverse transcriptase inhibitor 
NOAEL 
no observed adverse effect level 
NOEL 
no observed effect level 
NS 
normal saline 
NSAIDS 
non-steroidal anti-inflammatory drugs 
NVP 
nevirapine 
OHRP 
Office for Human Research Protections 
P24 
protein 24 
PBL 
peripheral blood lymphocytes 
PBS 
phosphate-buffered saline 
PCR 
polymerase chain reaction 
PD 
pharmacodynamics 
PEP 
post-exposure prophylaxis 
pH 
potential of hydrogen 
PI 
protease inhibitors 
PID 
pelvic inflammatory disease 
PK 
pharmacokinetics 


 
 
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PMPA 
9-[(R)-2-(phosphonomethoxy)propyl]adenine monohydrate 
PoR 
Pharmacist of Record 
PPD 
Pharmaceutical Product Development, Inc. 
PrEP 
pre-exposure prophylaxis 
PRO 
Protocol Registration Office 
PSP 
Prevention Sciences Program 
PSRT 
Protocol Safety Review Team 
PSS 
polystyrene sulfonate 
PT 
prothrombin time 
PTID 
participant identification 
PVC 
polyvinyl chloride 
QD 
quaque die, or once per day 
RAI 
receptive anal intercourse 
RE 
Regulatory Entity 
RF 
rectal fluid 
RG 
reduced-glycerin 
RNA 
ribonucleic acid 
RSC 
Regulatory Support Center 
RT 
reverse transcriptase 
RTI 
reproductive tract infection 
RT-PCR 
real-time polymerase chain reaction 
Rx 
treatment 
SAE 
serious adverse event 
SCHARP 
Statistical Center for HIV/AIDS Research & Prevention 
SCID 
severe combined immunodeficient 
SCR 
screening 
SDMC 
Statistical Data Management Center 
SHIV 
simian human immunodeficiency virus 
SMC 
Study Monitoring Committee 
SOP 
standard operating procedure 
SMS 
short message service 
SSP 
study specific procedures 
STI 
sexually transmitted infection 
SubQ 
subcutaneous 
SUSAR 
suspected, unexpected serious adverse reaction 
TAF 
tenofovir alafenamide  
TCID 
tissue culture infective dose 
TDF 
tenofovir disoproxil fumarate 
TFV 
tenofovir 
TFV-DP 
tenofovir diphosphate 
TEAE 
treatment emergent adverse event  
T1/2 
half-life 
Tmax 
time at which Cmax is observed 
TPGS 
tocopheryl polyethylene glycol succinate 
TV 
trichomonas vaginalis 
UA 
urinalysis 
ULN 
upper limit of normal 
UPMC 
University of Pittsburgh Medical Center 
USA 
United States of America 


 
 
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USP 
United States Pharmacopoeia 
UTI 
urinary tract infection 
WHO 
World Health Organization 
w/w 
weight/weight 


 
 
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MTN-039 
 
A Phase 1 Open Label Safety and Pharmacokinetic Study of Rectal Administration of 
a Tenofovir Alafenamide/Elvitegravir Insert at Two Dose Levels 
PROTOCOL TEAM ROSTER 
 
 
 
Protocol Chair  
 
Sharon A. Riddler, MD, MPH 
Keystone Building, Suite 510 
3520 Fifth Avenue 
Pittsburgh, PA 15213 USA 
Phone: 412-383-1741 or 412-383-1675 
Fax: 412-383-2900 
Email: riddler@pitt.edu 
 


 
 
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Site Investigators  
 
Ken Ho, MD 
Site Investigator   
UPMC, Keystone Building, Suite 533 
3520 Fifth Avenue 
Pittsburgh, PA 15213 USA 
Phone: 412-383-7178 
Fax: 412-383-2900 
Email: hok2@upmc.edu  
 
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 
 
 


 
 
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US National Institutes of Health (NIH) 
 
Roberta Black, PhD 
Chief, Clinical Microbicide Research Branch 
National Institute of Allergy and Infectious Diseases (NIAID), Division of AIDS 
(DAIDS)  
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  
National Institutes of Health (NIH) - U.S. Department of Health and Human 
Services (HHS) 
5601 Fishers Lane, Room 8B27 
Rockville, MD 20852 USA 
Phone: 240-292-4779 
Email: clelandn@niaid.nih.gov   
 
Jeanna Piper, MD 
DAIDS Senior Medical Officer 
NIAID, DAIDS 
5601 Fishers Lane, Room 8B68, MSC 9831 
Rockville, MD 20852 USA 
Phone: 240-292-4798 
Fax: 301-402-3684 
Email: piperj@niaid.nih.gov 
 
Dianne M. Rausch, PhD 
Director 
DAIDS Research, 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 
Chief, HIV Care Engagement and Secondary Prevention Program 
National Institute of Mental Health (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 
MTN 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 
 
Devika Singh MD, MPH 
Protocol Safety Physician 
Box 359927, Dept. of Global Health, ICRC 
325 Ninth Ave. 
Seattle WA 98104 USA 
Phone: 206-744-8311 
Fax: 206-520-3831 
Email: devika@mtnstopshiv.org 
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 
 
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 
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 
 
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 
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 
 
 


 
 
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MTN Laboratory Center (LC) 
 
Craig Hendrix, MD 
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 
 
Ratiya Pamela Kunjara Na Ayudhya, MT, ASCP 
Laboratory Manager 
Microbicide Trials Network 
204 Craft Avenue, Room A541 
Pittsburgh, PA  15213 USA 
Phone: 412-641-6393 
Fax: 412-641-6170 
Email: pkunjara@mwri.magee.edu 
 
Mark Marzinke, PhD, DABCC 
Johns Hopkins at Bayview 
Clinical Pharmacology Analytical Laboratory 
(CPAL)/Marzinke Lab 
4940 Eastern Avenue 
Mason F. Lord (MFL) Center Tower Suite 6000, Room 
621 
Baltimore, Maryland 21224 
Office: 443-287-7516 
CPAL Office: 410-550-9703 
Fax: 410-955-0767 
Email: mmarzin1@jhmi.edu 
 
John Mellors, MD 
MTN LC Co-Principal Investigator 
University of Pittsburgh 
3550 Terrace Street, Suite 818 
Pittsburgh, PA 15261 USA 
Phone: 412-624-8512 
Fax: 412-383-7982 
Email: jwm1@pitt.edu 
 
Lisa C. Rohan, PhD 
MTN LC Co-Principal Investigator 
University of Pittsburgh 
Magee-Womens Research Institute & Foundation 
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 
 
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 
 
Marcus Bolton, M.Ed. 
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: mbolton@fhi360.org 
 
Nicole Macagna, MA  
Clinical Research Manager 
FHI 360 
359 Blackwell Street 
Suite 200  
Durham, NC  27701 USA 
Phone: 919.544.7040 Ext.11717  
Fax: 919-544-0207 
Email: nmacagna@fhi360.org  
 
 
 
 


 
 
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MTN Statistical Data Management Center (SDMC) 
 
Elizabeth Brown, ScD 
SDMC Principal Investigator  
FHCRC-SCHARP 
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 
 
Cliff Kelly, MS 
Senior Statistical Analyst 
FHCRC-SCHARP 
1100 Fairview Avenue North, M2-C200 
PO Box 19024 
Seattle, WA 98109-1024 USA 
Phone: 206-667-2502 
Fax: 206-667-4378 
Email: cwkelly@scharp.org 
 
Julie Ngo, MPH 
Clinical Data Manager 
FHCRC – SCHARP  
1100 Fairview Avenue North, E3-129  
PO Box 19024  
Seattle, WA 98109-1024 USA  
Phone: 206-667-2094  
Fax: 206-667-4812 
Email: jhngo@scharp.org 
 
 
 


 
 
MTN-039, Version 1.0 
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Working Group Representatives 
 
Jose A. Bauermeister, MPH, PhD  
Behavioral Research Working Group (BRWG) Representative 
University of Pennsylvania  
418 Curie Blvd., Suite 222L  
Philadelphia, PA 19104  
Phone: 215-898-9993 
Email: bjose@upenn.edu 
 
Craig Hendrix, MD 
Biomedical Science Working Group (BSWG) Representative 
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 
 
Sherri J. Karas, MEd 
Community Working Group (CWG) Representative 
University of Pittsburgh 
Presbyterian University Hospital 
3520 Fifth Ave. 
Pittsburgh, PA 15213  
Phone: 412-383-1313 
Email: sjk91@pitt.edu   
 


 
 
MTN-039, Version 1.0 
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MTN-039 
 
A Phase 1 Open Label Safety and Pharmacokinetic Study of Rectal Administration of 
a Tenofovir Alafenamide/Elvitegravir Insert at Two Dose Levels  
INVESTIGATOR SIGNATURE FORM 
Version 1.0; March 6, 2019 
 
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 Holder: 
DAIDS (DAIDS Protocol ID: 38470) 
 
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); 
applicable U.S. Food and Drug Administration regulations; standards of the International 
Conference for Harmonization Guideline for Good Clinical Practice (E6); Institutional Review 
Board/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 all study documentation for at least two years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated 
marketing applications in an ICH region or at least two years have elapsed since the formal 
discontinuation of clinical development of the investigational product. These documents 
should be retained for a longer period, however, if required by the applicable regulatory 
requirements or by an agreement with the sponsor. DAIDS will inform the 
investigator/institution as to when these documents no longer need to be retained 
 
I have read and understand the information in the Investigator's Brochure(s), including the 
potential risks and side effects of the products under investigation, 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 (print) 
 
____________________________ 
______________________________ 
Signature of Investigator of Record  
Date 


 
 
MTN-039, Version 1.0 
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MTN-039 
 
A Phase 1 Open Label Safety and Pharmacokinetic Study of Rectal Administration of 
a Tenofovir Alafenamide/Elvitegravir Insert at Two Dose Levels  
 
PROTOCOL SUMMARY 
 
Short Title:  
Safety and PK Study of TAF/EVG Administered Rectally 
 
Clinical Phase: 
Phase 1 
 
IND Sponsor: 
DAIDS 
 
Protocol Chair:  
Sharon Riddler, MD, MPH 
 
Sample Size: 
MTN-039 will enroll approximately 20 participants.   
 
Study Population:  
HIV-uninfected individuals 18 years of age or older 
 
Study Sites: 
Sites selected by MTN Executive Committee 
 
Study Design: 
Phase 1, multi-site, open-label, single arm, two-period study of 
rectal administration of one Tenofovir Alafenamide/Elvitegravir 
Insert, 20/16 mg and then two TAF/EVG Inserts 
 
Study Duration: 
Approximately 6-13 weeks of follow-up per participant is planned 
with a projected accrual period of 6-8 months. The total duration of 
the study will be approximately 11 months.  
 
Study Products: 
TAF/EVG Insert, 20/16 mg  
 
Study Regimen:  
Participants will apply a single TAF/EVG Insert rectally and samples 
will be collected over a 3-day period. After a washout period of at 
least 7 days, participants will apply two TAF/EVG Inserts rectally 
and samples will be taken over a 3-day period. 
  


 
 
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Figure 1: MTN-039 Study Visit Schedule 
  
 
 
Primary Objectives:  
 
Safety 
• 
To evaluate the safety of the TAF/EVG Insert, 20/16 mg administered rectally at two dose 
levels: 1 insert and 2 inserts 
 
Pharmacokinetics 
• 
To characterize the systemic and rectal pharmacokinetics of the TAF/EVG Insert, 20/16 
mg applied rectally at two dose levels: 1 insert and 2 inserts 
 
Primary Endpoints: 
 
Safety 
• 
All Grade 2 and higher AEs  
 
Pharmacokinetics 
• 
EVG concentrations in: 
o Blood  
o Rectal fluid 
o Rectal mucosal tissue homogenates 
 
• 
TAF and TFV concentrations in  
o Blood  
o Rectal fluid 
 
• 
TFV-DP concentration in: 
o Rectal mucosal tissue homogenates 
o Rectal mucosal tissue cell isolates 
 
 


 
 
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Secondary Objective:  
 
Acceptability 
• To identify product attributes considered likely to challenge and/or facilitate future 
sustained use of the TAF/EVG Insert applied rectally 
 
Secondary Endpoints:  
 
Acceptability 
• 
Participant report of overall acceptability of the TAF/EVG Insert applied rectally  
 
Exploratory Objectives:  
 
Ex Vivo Efficacy 
• 
To assess the preliminary (ex vivo) efficacy of TAF/EVG after product is inserted rectally 
 
Pharmacokinetics 
• 
To characterize the cervicovaginal pharmacokinetics of the TAF/EVG Insert, 20/16 mg 
applied rectally at two dose levels: 1 insert and 2 inserts 
 
Mucosal Safety  
• 
To evaluate mucosal safety of the TAF/EVG Insert, 20/16 mg applied rectally at two dose 
levels: 1 insert and 2 inserts  
 
Exploratory Endpoints:  
 
Ex Vivo Efficacy 
• 
Changes in HIV-1 replication in colorectal explant culture supernatant  
• 
Anti-HIV activity in rectal fluid 
• 
Anti-HIV activity in cervicovaginal fluid 
 
Pharmacokinetics 
• 
EVG, TAF and TFV concentrations in cervicovaginal fluid 
 
Mucosal Safety  
• 
Rectal histology  
• 
Rectal proteomics  
• 
Rectal metabolomics  
• 
Rectal immunophenotype 
• 
Rectal microbiome 
• 
Cervicovaginal microflora  


 
 
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1 
KEY ROLES 
 
1.1 
Protocol Identification 
 
Protocol Title:   
A Phase 1 Open Label Safety and Pharmacokinetic Study of 
Rectal Administration of a Tenofovir Alafenamide/Elvitegravir 
Insert at Two Dose Levels  
 
Protocol Number: 
MTN-039 
 
Short Title: 
Safety and PK Study of TAF/EVG Administered Rectally 
 
Date:  
March 6, 2019 
 
1.2 
Funding Agencies, Sponsor and Monitor 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 
 
IND Sponsor:  
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 
 
Monitor: 
Pharmaceutical Product Development (PPD), Inc.  
929 North Front St.  
Wilmington, NC  28401-3331 USA 
 


 
 
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1.3 
Medical Officer 
 
Medical Officer: 
 
Jeanna Piper, MD 
5601 Fishers Lane, Room 8B68, MSC 9831 
Rockville, MD 20852 USA 
 
1.4 
Laboratory Centers 
 
Network: 
 
MTN Laboratory Center (LC) 
 
 
 
204 Craft Ave. 
 
 
 
Pittsburgh, PA 15213 USA 
 
Pharmacology: 
 
Johns Hopkins at Bayview 
 
 
 
Clinical Pharmacology Analytical Laboratory/Marzinke Lab 
 
 
 
4940 Eastern Avenue 
 
 
 
Mason F. Lord (MFL) Center Tower Suite 6000 
 
 
 
Room 621 
 
 
 
Baltimore, MD 21224 USA 
 
1.5 
Data Center 
MTN Statistical and Data 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 
 
1.6 
Study Implementation 
 
 
 
 
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 While the original impetus for vaginal 
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, 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.2,3 Globally, transgender females 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 
 
Elvitegravir (EVG) is a human immunodeficiency virus-1 (HIV-1) integrase inhibitor that 
has shown potent activity against laboratory viral strains and clinical isolates of HIV-1 and 
against virus with resistance to nucleoside reverse transcriptase inhibitors (NRTIs), non-
nucleoside reverse transcriptase inhibitors (NNRTIs), and protease inhibitors (PIs). 
Elvitegravir is FDA approved and currently available in single tablet combination 
formulations for the treatment of HIV-1 infection.  
 
Tenofovir alafenamide (TAF: formally known as GS-7340) is a prodrug of the antiviral 
acyclic nucleoside phosphonate tenofovir (TFV) with improved properties relative to 
tenofovir disoproxil fumarate (TDF). By enhancing stability in biological matrices while 
being rapidly activated in cells, TAF produces higher levels of intracellular TFV 
diphosphate, the pharmacologically active metabolite, in HIV-target cells at substantially 
reduced oral dose of TFV equivalents. It has been shown to have improved renal function 
and possibly reduced bone impairment compared to TDF.6 TAF is US Food and Drug 
Administration (FDA) approved and currently available as a single tablet formulation for 
the treatment of chronic hepatitis B (Vemlidy®) and also co-formulated with other drugs 
for the treatment of HIV infection (Genvoya®, Odefsey® and Descovy®).  
 
MTN-039 will evaluate the safety and pharmacokinetics (PK) of the TAF/EVG Insert 
administered rectally at two dose levels. Fast-dissolve topical inserts are an on-demand 
dosage form that is economical, discreet, user-friendly and user-initiated, factors that may 
encourage use in populations at risk for HIV acquisition. 
2.2 Elvitegravir (EVG) – Description and Mechanism of Action 
2.2.1 
Description 
Elvitegravir (EVG) drug substance is a 2nd generation human immunodeficiency virus 
(HIV) integrase inhibitor. EVG is a white crystalline irregularly shaped material and has 
an acidic pKa of 6.6 and Log D of 4.5 at pH 6.8. EVG is a poorly water soluble and highly 


 
 
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permeable drug. It is considered a BCS class-2 compound. EVG (anhydrous crystalline 
form γ) is chemically stable in the solid state when exposed to heat, humidity and light. 
 
The 
chemical 
name 
of 
EVG 
is 
(S)-6-(3-chloro-2-fluorobenzyl)-1-(1-hydroxy-3-
methylbutan-2-yl)-7methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid. It has a 
molecular formula of C23H23ClFNO5 and a molecular weight of 447.9 (free acid). It has 
the following structural formula: 
 
EVG is a white to off-white crystalline powder with a solubility of > 35μg/mL in aqueous 
buffers at pH 9.0. EVG is stable for at least three years at 30°C. 
2.2.2 
Mechanism of action 
EVG is an HIV-1 integrase strand transfer inhibitor (INSTI). Integrase is an HIV-1 encoded 
enzyme that is required for viral replication. Inhibition of integrase prevents the integration 
of HIV-1 DNA into host genomic DNA, blocking the formation of the HIV-1 provirus and 
propagation of the viral infection. EVG does not inhibit human topoisomerases I or II.7 
2.2.3 
Strength of Study Product 
The doses of EVG proposed for use in MTN-039 are 16 mg in one insert and 32 mg in 
two inserts. 
2.3 Non-Clinical Studies of Elvitegravir 
2.3.1 
In Vitro Studies 
2.3.1.1  Anti-HIV-1 Activity 
The antiviral activity of EVG against laboratory and clinical isolates of HIV-1 was 
assessed in T lymphoblastoid cells, monocyte/macrophage cells, and primary peripheral 
blood lymphocytes. The 50% effective concentration (EC50) values ranged from 0.02 to 
1.7 nM. EVG displayed antiviral activity in cell culture against HIV-1 clades A, B, C, D, E, 
F, G, and O (EC50 values ranged from 0.1 to 1.3 nM) and activity against HIV-2 (EC50 
value of 0.53 nM). The antiviral activity of EVG with antiretroviral drugs in two-drug 
combination studies was not antagonistic when combined with the INSTI raltegravir, 
NNRTIs (efavirenz, etravirine, or nevirapine), NRTIs (abacavir, didanosine, emtricitabine, 
lamivudine, stavudine, tenofovir, or zidovudine), PIs (amprenavir, atazanavir, darunavir, 
indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, or tipranavir), the fusion inhibitor 


 
 
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enfuvirtide, or the CCR5 co-receptor antagonist maraviroc. EVG did not show inhibition 
of replication of HBV or HCV in cell culture.7 
 
The antiviral activity of EVG drug substance prepared at varying doses in suspension with 
insert formulation components was tested in a cervicovaginal tissue explant model. 
Complete protection against HIV-1BAL infection was observed when EVG tissue 
concentrations were in the range of ~103-104 ng/g, whereas only partial protection was 
observed at ~102 ng/g. These data suggest that EVG tissue concentration of at least 1000 
ng/g will be efficacious prophylactically against HIV infection of cervicovaginal tissue and 
therefore were set as the target benchmark for drug development.8   
2.3.1.2 Resistance (HIV) 
HIV-1 isolates with reduced susceptibility to EVG were selected in cell culture. Reduced 
susceptibility to EVG was associated with the primary integrase substitutions T66A/I, 
E92G/Q, S147G, and Q148R. Additional integrase substitutions observed in cell culture 
selection included D10E, S17N, H51Y, F121Y, S153F/Y, E157Q, D232N, R263K, and 
V281M.7 
2.3.1.3  Cross-resistance (HIV) 
EVG-resistant viruses showed varying degrees of cross-resistance in cell culture to 
raltegravir in the INSTI class depending on the type and number of substitutions in HIV-
1 integrase.7 
2.3.1.4  Mutagenicity and Carcinogenesis 
EVG was not genotoxic in the reverse mutation bacterial test (Ames test) and the rat 
micronucleus assay. In an in vitro chromosomal aberration test, EVG was negative with 
metabolic activation; however, an equivocal response was observed without activation.7 
2.3.1.5 In Vitro Metabolism 
The metabolism of EVG is mediated primarily via intestinal and hepatic cytochrome P450 
(CYP) 3A enzymes.7 
2.3.1.6 In Vitro Dissolution (EVG insert)  
An EVG insert offers rapid dissolution: an in vitro 96% dissolution is achieved within 15 
minutes (see Table 1).9  
Table 1:  In vitro Dissolution of 8 mg Elvitegravir Insert  
Time (min) 
Average (% release) 
N=3 
%RSD 
N=3 
5 
44.9 
4.5 
10 
76.1 
3.9 
15 
95.7 
2.0 
30 
99.9 
1.1 
45 
100.1 
1.0 
60 
100.1 
0.9 


 
 
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RSD – relative standard deviation 
2.3.2 
Animal Studies 
2.3.2.1 Pharmacokinetics 
Oral EVG 
 
EVG displays modest bioavailability following oral administration in rats and dogs of 
34.1% and 29.6%, respectively, and systemic clearance values of 0.5 L/h/kg and 1.0 
L/h/kg, respectively, representing low to intermediate values relative to hepatic blood flow 
in these species (3.5 and 2.6 L/h/kg, respectively). Maximum plasma concentrations 
(Cmax) were achieved in 0.5–1.0 hour post-dose and terminal t½ (t½b) values were 2.3 
and 5.2 hours, respectively.10 
EVG/TDF Insert – Macaque Study 
 
A dose-ranging PK study of EVG-containing inserts administered vaginally to female 
pigtail macaques was conducted by CONRAD (see Table 2 for study design). Vaginal 
inserts containing a combination of 2.7 mg or 8 mg elvitegravir/tenofovir disoproxil 
fumarate (EVG/TDF) were administered to female pigtailed macaques to assess systemic 
and local pharmacokinetics (PK). Blood, vaginal and rectal fluid, and/or vaginal tissue 
biopsy samples were collected at baseline, 0.5, 2, 6, and 24 hours, and 7 and 8 days 
following once weekly dosing for 4 weeks. Following a single dose of 8mg EVG/TDF, 
samples were also collected at 3 and 7 days post-dose to assess the PK tail. The samples 
were analyzed for concentrations of EVG. Study results can be found in the IB of the EVG 
insert.8   
Table 2:  Study design of the pharmacokinetic study of EVG/TDF vaginal inserts in 
pigtailed macaques 
Group 
Treatment 
Week(s) Dosed 
Number of 
Animals 
PK (2-24 hours) 
1A 
2.7mg EVG/TDF 
1-4 
3 
2A 
2.7mg EVG/TDF 
1-4 
3 
1B 
8mg EVG/TDF 
1-4 
3 
2B 
8mg EVG/TDF 
1-4 
3 
PK Tail 
1A, 1B, 2A, and 2B 
8mg EVG/TDF 
1 
12 
Note: The same animals used for the PK assessment were also used in the PK Tail assessment, following 
a 2 week rest period. 
 
EVG Insert – Vaginal Irritation Study of EVG in Rabbits 
 
Twenty-four rabbits were involved in CONRAD Study 1645-113, a vaginal irritation study 
of EVG to evaluate potential local irritation and determine the pharmacokinetics following 
once daily intravaginal administration of EVG in New Zealand White Hra:(NZW) SPF 
rabbits for 14 consecutive days – group assignments are shown in Table 3.11The samples 


 
 
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were analyzed for concentrations of EVG. Study results can be found in the IB of the EVG 
insert.8 
 
Table 3:  Group Assignments in EVG Vaginal and Rectal Irritation Studies  
Group 
Number 
Treatment 
Dose 
Level 
Number of 
Animals in 
Vaginal Irritation 
study 
Number of Animals in 
Rectal Irritation study 
Male 
Female 
1  
Reference Control 
(N-9)  
4%  
4  
4  
4  
2  
Vehicle 
Control 
(PBS+5% glycerin)  
0 mg  
4  
4  
4  
3  
Placebo Control  
0 mg  
4  
4  
4  
4  
1X EVG * 
2 mg  
4  
4  
4  
5  
3X EVG ** 
6 mg  
4  
4  
4  
6  
10X EVG ** 
20 mg  
4  
4  
4  
N-9 = 4% nonoxynol-9; PBS= phosphate buffered saline 
* 1X EVG (8 mg active drug/4 mL vehicle) was prepared from ground elvitegravir insert powder formulated 
in PBS and glycerin 
** 3X EVG (24 mg active drug/4 mL vehicle) and 10X EVG (80 mg active drug/4 mL vehicle) was prepared 
from ground placebo insert powder and elvitegravir drug substance formulated in PBS and glycerin 
For vaginal irritation study: Dose route was intravaginal for all animals; volume = 1 mL 
For rectal irritation study: Dose route was rectal for all animals; volume = 1 mL 
 
EVG Insert – Rectal Irritation Study of EVG in Rabbits 
 
Forty-eight rabbits were involved in CONRAD Study 1645-114, a rectal irritation study of 
EVG to evaluate potential local irritation and determine the pharmacokinetics following 
once daily intrarectal administration of EVG in New Zealand White Hra:(NZW) SPF 
rabbits for 14 consecutive days. Group assignments are shown in Table 3. 
Pharmacokinetic study findings can be found in the IB of the EVG insert.8  
 
2.3.2.2 Toxicology 
EVG Insert – Vaginal Irritation Study of EVG in Rabbits 
CONRAD Study 1645-113 assessed PK and potential for local irritation following once 
daily intravaginal administration of EVG in New Zealand White Hra:(NZW) SPF rabbits 
for 14 consecutive days. The assessment of toxicity in this study was made based on 
mortality, clinical observations, body weights, vaginal irritation scoring examinations, and 
anatomic pathology. There were no test article-related effects or definitive control article-
related effects observed for these parameters.8  
EVG Insert – Rectal Irritation Study of EVG in Rabbits 
CONRAD Study 1645-114 assessed PK and potential for local irritation following once 
daily intrarectal administration of EVG in New Zealand White Hra:(NZW) SPF rabbits for 
14 consecutive days. The assessment of toxicity in this study was made based on 
mortality, clinical observations, body weights, and macroscopic and microscopic 


 
 
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pathology of the rectum and surrounding tissues. There were no test article-related effects 
or definitive control article-related effects observed for these parameters.8  
2.3.2.3 Mutagenicity and Carcinogenesis 
EVG was not genotoxic in the rat micronucleus assay. Long-term carcinogenicity studies 
of oral EVG were carried out in mice (104 weeks) and in rats (up to 88 weeks in males 
and 90 weeks in females). No drug-related increases in tumor incidence were found in 
mice at doses up to 2000 mg per kg per day alone or in combination with 25 mg per kg 
per day ritonavir at exposures 3- and 14-fold, respectively, the human systemic exposure 
at the recommended daily dose of 150 mg. No drug-related increases in tumor incidence 
were found in rats at doses up to 2000 mg per kg per day at exposures 12- to 27-fold, 
respectively, in male and female, the human systemic exposure.7 
2.3.2.4 Pregnancy, Teratogenic Effects, and Lactation 
Oral EVG studies in animals have shown no evidence of teratogenicity or an effect on 
reproductive function. In offspring from rat and rabbit dams treated with EVG during 
pregnancy, there were no toxicologically significant effects on developmental endpoints. 
The exposures (AUC) at the embryo-fetal No Observed Adverse Effects Levels (NOAELs) 
in rats and rabbits were respectively 23 and 0.2 times higher than the exposure in humans 
at the recommended daily dose of 150 mg.7 
Studies in rats have demonstrated that EVG is secreted in milk.7 
2.3.2.5  Reproductive Toxicity 
Oral EVG did not affect fertility in male and female rats at approximately 16- and 30-fold 
higher exposures (AUC), respectively, than in humans at the therapeutic 150 mg daily 
dose. Fertility was normal in the offspring of rats exposed daily from before birth (in utero) 
through sexual maturity at daily exposures (AUC) of approximately 18-fold higher than 
human exposures at the recommended 150 mg daily dose.7 
2.4 Tenofovir Alafenamide (TAF) – Description and Mechanism of Action 
2.4.1 
Description 
Tenofovir alafenamide (TAF) is a nucleotide reverse transcriptase inhibitor and a prodrug 
of tenofovir. TAF is converted in vivo to tenofovir, an acyclic nucleoside phosphonate 
(nucleotide) analog of adenosine 5′-monophosphate.12 
 
The chemical name of tenofovir alafenamide fumarate drug substance is L-alanine, N- 
[(S)-[[(1R)-2-(6-amino-9H-purin-9-yl)-1-methylethoxy]methyl]phenoxyphosphinyl]-, 
1- 
methylethyl ester, (2E)-2-butenedioate (2:1). It has an empirical formula of 
C21H29O5N6P•½(C4H4O4) and a formula weight of 534.50. It has the following 
structural formula:  


 
 
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Tenofovir alafenamide fumarate is a white to off-white or tan powder with a solubility of 
4.7 mg per mL in water at 20 °C.12 
2.4.2 
Mechanism of action 
TAF is a phosphonamidate prodrug of tenofovir (2’-deoxyadenosine monophosphate 
analog). Plasma exposure to TAF allows for permeation into cells and then TAF is 
intracellularly converted to tenofovir through hydrolysis by cathepsin A. Tenofovir is 
subsequently phosphorylated by cellular kinases to the active metabolite tenofovir 
diphosphate (TFV-DP). TFV-DP inhibits HIV-1 replication through incorporation into viral 
DNA by the HIV reverse transcriptase, which results in DNA chain-termination.  
 
TFV has activity that is specific to human immunodeficiency virus and hepatitis B virus. 
Cell culture studies have shown that both emtricitabine and tenofovir can be fully 
phosphorylated when combined in cells. TFV-DP is a weak inhibitor of mammalian DNA 
polymerases that include mitochondrial DNA polymerase γ and there is no evidence of 
mitochondrial toxicity in cell culture based on several assays including mitochondrial DNA 
analyses.13 
2.4.3 
Strength of Study Product 
The doses of TAF proposed for use in MTN-039 are 20 mg in 1 insert and 40 mg in 2 
inserts. 
2.5 Non-Clinical Studies of Tenofovir Alafenamide 
2.5.1 
In Vitro Studies 
2.5.1.1 Anti-HIV-1 Activity 
 
The antiviral activity of TAF against laboratory and clinical isolates of HIV-1 subtype B 
was assessed in lymphoblastoid cell lines, peripheral blood mononuclear cells (PBMCs), 
primary monocyte/macrophage cells and CD4-T lymphocytes. The EC50 values for TAF 
ranged from 2.0 to 14.7 nM. TAF displayed antiviral activity in cell culture against all HIV-
1 groups (M, N, O), including sub-types A, B, C, D, E, F, and G (EC50 values ranged from 
0.10 to 12.0 nM) and strain specific activity against HIV-2 (EC50 values ranged from 0.91 
to 2.63 nM).13 


 
 
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2.5.1.2 Resistance (HIV) 
 
HIV-1 isolates with reduced susceptibility to TAF have been selected in cell culture. HIV-
1 isolates selected by TAF expressed a K65R substitution in HIV-1 RT, sometimes in the 
presence of S68N or L429I substitutions; in addition, a K70E substitution in HIV-1 RT was 
observed.13 
 
2.5.1.3 Cross-resistance (HIV) 
 
TFV resistance substitutions, K65R and K70E, result in reduced susceptibility to abacavir, 
didanosine, emtricitabine, lamivudine, and tenofovir. HIV-1 with multiple TAMs (M41L, 
D67N, K70R, L210W, T215F/Y, K219Q/E/N/R), or multinucleoside resistant HIV-1 with a 
T69S double insertion mutation or with a Q151M mutation complex including K65R, 
showed reduced susceptibility to TAF in cell culture.13 
 
2.5.1.4 In Vitro Metabolism 
 
TAF is reportedly hydrolyzed within cells to form TFV, which is phosphorylated to the 
active metabolite, TFV-DP. In vitro, TAF is reportedly metabolized to TFV by 
carboxylestrase 1 in hepatocytes, by cathepsin A in PBMCs and macrophages, with 
minimal metabolism via CYP3A.14  
 
2.5.2 
Animal Studies 
 
2.5.2.1 Pharmacokinetics 
 
Oral TAF – Dog Studies 
 
The hepatic delivery and metabolism of TAF in primary human hepatocytes in vitro and 
in dogs in vivo were evaluated in one study. Incubation of primary human hepatocytes 
with TAF resulted in high levels of the pharmacologically active metabolite TFV-DP, which 
persisted in the cell with a half-life of >24 h. Following oral administration of TAF to dogs 
for 7 days, TAF was rapidly absorbed. The appearance of the major metabolite TFV in 
plasma was accompanied by a rapid decline in circulating TAF. Consistent with the in 
vitro data, high and persistent levels of TFV-DP were observed in dog livers. Notably, 
higher liver TFV-DP levels were observed after administration of TAF than those given 
TDF.15  
 
To understand how TAF reduces first-pass clearance to be an effective oral prodrug, its 
permeability and stability were characterized in vitro and detailed pharmacokinetic studies 
were completed in dogs. TAF showed concentration-dependent permeability through 
monolayers of caco-2 cells and dose-dependent oral bioavailability in dogs, increasing 
from 1.7% at 2 mg/kg to 24.7% at 20 mg/kg, suggesting saturable intestinal efflux 
transport. Consistent with the proposed role of intestinal efflux transport, coadministration 
of low dose GS-7340 with a transport inhibitor substantially increased GS-7340 exposure. 
The result of effective oral absorption and efficient lymphoid cell loading was reflected in 
the high and persistent levels of the pharmacologically active metabolite, TFV 


 
 
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diphosphate, in peripheral blood mononuclear cells following oral administration to 
dogs.16  
2.5.2.2 Mutagenicity, Carcinogenesis and Impairment of Fertility 
 
Since TAF is rapidly converted to tenofovir and a lower tenofovir exposure in rats and 
mice is observed after TAF administration compared to TDF administration, 
carcinogenicity studies were conducted only with TDF. Long-term oral carcinogenicity 
studies of TDF in mice and rats were carried out at exposures up to approximately 10 
times (mice) and 4 times (rats) those observed in humans at the 300 mg therapeutic dose 
of TDF for HIV-1 infection. The TFV exposure in these studies was approximately 167 
times (mice) and 55 times (rat) those observed in humans after administration of Genvoya 
treatment. At the high dose in female mice, liver adenomas were increased at tenofovir 
exposures 10 times (300 mg TDF) and 167 times (10 mg TAF in Genvoya) that in humans. 
In rats, the study was negative for carcinogenic findings.13  
 
TAF was not genotoxic in the reverse mutation bacterial test (Ames test), mouse 
lymphoma or rat micronucleus assays.  
 
There were no effects on fertility, mating performance or early embryonic development 
when TAF was administered to male rats at a dose equivalent to 155 times the human 
dose based on body surface area comparisons for 28 days prior to mating and to female 
rats for 14 days prior to mating through Day 7 of gestation.13 
 
2.5.2.3  Toxicology  
 
Minimal to slight infiltration of mononuclear cells in the posterior uvea was observed in 
dogs with similar severity after three and nine month administration of TAF; reversibility 
was seen after a three month recovery period. At the NOAEL for eye toxicity, the systemic 
exposure in dogs was 5 (TAF) and 15 (TFV) times the exposure seen in humans at the 
recommended daily Genvoya dosage.13 
 
2.6 
Non-Clinical Studies of Elvitegravir and Tenofovir Alafenamide 
2.6.1 
In Vitro Studies 
 
2.6.1.1 In Vitro Dissolution (TAF/EVG Insert)  
 
A test of the in vitro dissolution of the TAF/EVG Insert was completed and the dissolution 
rate is listed in Table 4. 
 
 
 
 
 
 
 


 
 
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Table 4:  In vitro Dissolution of 20/16 mg TAF/EVG Insert  
 
Time (min) 
TAF 
EVG 
 
Average (% release) 
N=6 
%RSD 
N=6 
Average (% release) 
N=6 
%RSD 
N=6 
5 
20 
9.5 
18 
11.3 
10 
41 
10.3 
38 
11.2 
15 
59 
9.9 
57 
10.4 
30 
90 
5.3 
87 
5.3 
45 
97 
1.7 
95 
1.5 
60 
97 
1.6 
95 
1.5 
75 
97 
1.6 
96 
1.4 
RSD – relative standard deviation 
2.6.2 
Animal Studies 
2.6.2.1 Pharmacokinetics 
 
TAF + EVG Solution – Mice Study 
 
A pharmacokinetic and tissue distribution study of drug-loaded nanoparticle (NP) was 
performed in female humanized CD34+-NSG mice to explore if a long-acting parenteral 
formulation of AVR may be an effective alternative to daily oral dosing. Mice received 
200 mg/kg each of TAF and EVG as free drugs (TAF + EVG solution) or as drug loaded 
NP (TAF + EVG NP) formulation by subcutaneous (SubQ) administration. Plasma and 
tissue were collected to determine tenofovir (TFV) and EVG concentrations using LC-
MS/MS. SubQ administration of TAF + EVG NP formulation resulted in long residence 
time and exposure for both drugs. The AUC(0-72h) of TFV and EVG was 14.1 ± 2.0, 
7.2 ± 1.8 μg × hr./mL from free drugs in solution and the AUC(0-14day) for the same drugs 
was 23.1 ± 4.4, 39.7 ± 6.7 μg × hr./mL from NPs. The observed elimination half-life (t1/2) 
for TFV of free and NPs were 14.2 h, 5.1 days and for EVG 10.8 h, 3.3 days, 
respectively.17 
 
TAF/EVG Insert – Macaque Study  
 
CONRAD study 2708 evaluated the PK of TAF and EVG following administration of 
vaginal inserts containing a combination of TAF/EVG in female pigtailed macaques. 
Vaginal inserts containing 10/8 mg, 10/16 mg or 40/24 mg of TAF/EVG were administered 
to groups of 4 female macaques. One insert was administered vaginally to each macaque 
5 times over an 8-week period with at least 1 week between doses. Animals were dosed 
on a single occasion at the 24h PK interval and on two separate occasions for both 2 and 
4h PK intervals. Plasma, vaginal fluid and vaginal tissue biopsy samples were collected 
at 0.5 (blood only), 2, 4 and 24 hours post-dose. These samples were analyzed for 
concentrations of TAF, TFV and EVG. Vaginal biopsies were also evaluated for TFV-DP 
concentrations. The TAF/EVG insert did not result in adverse behavioral changes, 
physical changes in the vaginal vault or measurable systemic exposure to TAF, TFV or 
EVG in the macaques.14 There was minimal dose proportionality between inserts for 
vaginal fluid or tissue concentrations. TFV and EVG in vaginal fluid after administration 


 
 
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of TAF/EVG (20/16 mg) showed the most favorable PK and resulted in TFV-DP and EVG 
tissue levels in range with those shown to provide in vivo protection against vaginal SHIV 
infection in macaques.18  
     
TAF/EVG Insert – Vaginal Irritation Study of EVG/TAF in Rabbits 
 
CONRAD Study 1645-116 evaluated the PK of TAF/EVG following once daily intravaginal 
administration of TAF/EVG formulated drug substance in female NZW SPF rabbits for 14 
consecutive days. 5/4, 15/12 or 25/20 mg TAF/EVG formulated drug substance were 
administered to 5 groups of 4 female rabbits. The bioanalytical and PK assessments are 
summarized below.    
 
Median peak EVG plasma concentrations were observed by 0.5 to 1 hour postdose on 
Days 1 and 13. Mean Cmax values, ranging from 17.5 to 49.4 ng/mL, for EVG appeared 
to increase with increasing dose across the dose range on Days 1 and 13. Mean AUC0-
24hr values appeared to increase with increasing dose across the dose range on Day 1 
and did not appear to increase with increasing dose on Day 13. Systemic exposure 
(AUC0-24hr) to EVG did not appear to consistently change following repeated 
administration. Following the highest dose administered vaginally (25/20 mg TAF/EVG), 
mean EVG AUC0-24hr was 441 hr*ng/ml on Day 1 and 366 hr*ng/ml on Day 13.    
 
Median peak TFV plasma concentrations were observed by 0.5 and 1 hour postdose on 
Days 1 and 13. Mean Cmax values, ranging from 41.0 to 354 ng/mL, for TFV appeared to 
increase with increasing dose across the dose range on Days 1 and 13. Mean AUC0-24hr 
values for TFV also appeared to increase with increasing dose across the dose range on 
Days 1 and 13. Systemic exposure (AUC0-24hr) to TFV did not appear to consistently 
change following repeated administration. Following the highest dose administered 
vaginally (25/20 mg TAF/EVG), mean TFV AUC0-24hr was 861 hr*ng/ml on Day 1 and 1400 
hr*ng/ml on Day 13.19    
 
TAF/EVG Insert – Rectal Irritation Study of EVG/TAF in Rabbits 
 
CONRAD Study 1645-117 evaluated potential local irritation and determined the PK 
following once daily intrarectal administration of EVG and TAF to male and female rabbits 
for 14 consecutive days. PK assessments and analysis are summarized below.  
 
Median peak EVG plasma concentrations were observed by 0.5 hours postdose on Days 
1 and 13. Mean Cmax values, ranging from 2.42 to 8.31 ng/mL, for EVG appeared to 
increase with increasing dose across the dose range on Days 1 and 13. Mean AUC0-24hr 
values did not appear to increase with increasing dose on Day 1 and appeared to increase 
with increasing dose across the dose range on Day 13. Systemic exposure (AUC0-24hr) to 
EVG did not appear to consistently change following repeated administration of 4 mg 
EVG in combination with 5 mg TAF, however, appeared to increase following repeated 
administration of 12 and 20 mg EVG in combination with 15 and 25 mg TAF, respectively. 
Following the highest dose administered rectally (25/20 mg TAF/EVG), mean EVG AUC0-
24hr was 22.1 hr*ng/ml on Day 1 and 58.2 hr*ng/ml on Day 13.20  
   


 
 
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Median peak TFV plasma concentrations were observed by 0.5 hours postdose on Days 
1 and 13. Mean Cmax values, ranging from 13.6 to 128, for TFV appeared to increase with 
increasing dose across the dose range on Days 1 and 13. Mean AUC0-24hr values for TFV 
also appeared to increase with increasing dose across the dose range on Days 1 and 13. 
Systemic exposure (AUC0-24hr) to TFV generally appeared to increase following repeated 
administration of EVG in combination with TAF. Following the highest dose administered 
rectally (25/20 mg TAF/EVG), mean TFV AUC0-24hr was 11.6 hr*ng/ml on Day 1 and 33.9 
hr*ng/ml on Day 13.    
 
2.6.2.2 Toxicity 
 
TAF/EVG Insert – Vaginal Irritation Study of EVG/TAF in Rabbits 
 
CONRAD Study 1645-116 evaluated potential local irritation and determined the PK 
following once daily intravaginal administration of EVG and TAF to female rabbits for 14 
consecutive days. 24 female rabbits were randomized to 6 groups: vehicle control, 
placebo control, reference control (N-9), or 4/5, 12/15, or 20/25 mg EVG/TAF. The 
assessment of toxicity in this study was made based on mortality, clinical observations, 
body weights, vaginal irritation scoring, micro and macroscopic pathology of reproductive 
tissues. Results can be found in the TAF/EVG insert IB.14 
 
TAF/EVG Insert – Rectal Irritation Study of EVG/TAF in Rabbits 
 
CONRAD Study 1645-117 evaluated potential local irritation and determined the PK 
following once daily intrarectal administration of EVG and TAF to male and female rabbits 
for 14 consecutive days. 24 male and 24 female rabbits were randomized to 6 groups for 
drug administration at a dose level of 4/5, 12/15, or 20/25 mg (EVG/TAF). The 
assessment of toxicity in this study was made based on mortality, clinical observations, 
body weights and body weight change. All animals survived to study termination on Day 
14. There were no test article-related or definitive control article-related effects observed 
on study for the following parameters evaluated: bodyweights, clinical observations, 
macroscopic or microscopic pathology of tissues. TAF/EVG insert was generally safe and 
well tolerated by the rabbits in the study.21  
All macroscopic findings were considered incidental changes as they lacked microscopic 
correlates, had no dose relationship in incidence or severity, occurred at a low incidence 
or as a single occurrence, or are known background incidental findings for the species. 
Both edema and mucosal hyperplasia were noted in males and females in the vehicle 
control, placebo control, and all test article-treated groups. These findings are considered 
most likely to be related to the procedure of intrarectal administration. There was a slight 
increase in severity in edema within the 12/15 and 20/25 mg EVG/TAF groups, but this 
was not considered test article related given the low incidence and variation in 
appearance of edema within the tissues.21  
2.7 
Clinical Studies of Elvitegravir and Tenofovir Alafenamide  
 
2.7.1 
Resistance (HIV) 
 


 
 
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2.7.1.1 EVG 
 
Pooled resistance analysis was performed on virus samples from subjects receiving EVG-
containing regimens in 6 clinical trials of EVG (as single drug in combination with a 
regimen containing a protease inhibitor/ritonavir or as the fixed dose combination 
STRIBILD). Development of substitutions T66A/I/K, E92G/Q, T97A, S147G, Q148H/K/R, 
and N155H in the HIV-1 integrase protein was primarily associated with resistance to 
EVG. In addition to these primary EVG resistance-associated substitutions, E92A, 
F121C/Y, P145S, Q146I/L/R, and N155S were also occasionally observed and were 
shown to confer reduced susceptibility to EVG. Substitutions at positions E92 and N155 
were the most frequently observed (39% and 27% of those evaluated subjects, 
respectively). In virus isolates harboring the observed primary EVG resistance-associated 
substitutions, additional substitutions in integrase were detected including H51Y, L68I/V, 
G70R, V72A/N, I73V, Q95K/R, S119R, E138A/K, G140A/C/S, E157Q, K160N, 
E170A,S230R, and D232N.7 
2.7.1.2 TAF 
 
In Treatment-Naïve Subjects:  
 
In a pooled analysis of antiretroviral-naïve subjects receiving GENVOYA in Studies 104 
and 111, genotyping was performed on plasma HIV-1 isolates from all subjects with HIV-
1 RNA greater than 400 copies per mL at confirmed virologic failure, at Week 144, or at 
time of early study drug discontinuation. As of Week 144, the development of genotypic 
resistance to elvitegravir, emtricitabine, or TAF was observed in 12 of 22 subjects with 
evaluable resistance data from paired baseline and GENVOYA treatment-failure isolates 
(12 of 866 subjects [1.4%]) compared with 13 of 20 treatment-failure isolates from 
subjects with evaluable resistance data in the STRIBILD treatment group (13 of 867 
subjects [1.5%]). Of the 12 subjects with resistance development in the GENVOYA group, 
the resistance-associated substitutions that emerged were M184V/I (N=11) and K65R/N 
(N=2) in reverse transcriptase and T66T/A/I/V (N=2), E92Q (N=4), E138K (N=1), 
Q148Q/R (N=1) and N155H (N=2) in integrase. Of the 13 subjects with resistance 
development in the STRIBILD group, the resistance-associated substitutions that 
emerged were M184V/I (N=9), K65R/N (N=4), and L210W (N=1) in reverse transcriptase 
and E92Q/V (N=4), E138K (N=3), Q148R (N=2), and N155H/S (N=3) in integrase. In both 
treatment groups, most subjects who developed substitutions associated with resistance 
to elvitegravir also developed emtricitabine resistance-associated substitutions. These 
genotypic resistance results were confirmed by phenotypic analyses.13  
 
In Virologically Suppressed Subjects:  
 
Three virologic failure subjects were identified with emergent genotypic and phenotypic 
resistance to GENVOYA (all three with M184I or V and one with K219Q in reverse 
transcriptase; two with E92Q or G in integrase) out of 8 virologic failure subjects with 
resistance data in a clinical study of virologically-suppressed subjects who switched from 
a regimen containing emtricitabine/TDF and a third agent to GENVOYA (Study 109, 
N=959).13 
 


 
 
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2.7.2 
Pharmacokinetics of EVG and TAF 
Oral EVG 
 
Oral EVG must be co-administered with a pharmacokinetic booster to ensure adequate 
serum concentrations and facilitate once-daily dosing. Following oral administration of 
EVG and ritonavir with food, in HIV-1 infected subjects, peak EVG plasma concentrations 
were observed approximately 4 hours post-dose. EVG plasma exposures increased in a 
less than dose proportional manner, likely due to solubility-limited absorption.22 
 
As EVG is metabolized by CYP3A, drugs that induce CYP3A activity are expected to 
increase the clearance of EVG. EVG undergoes primarily oxidative metabolism via 
CYP3A, and is secondarily glucuronidated via UGT1A1/3 enzymes. The median terminal 
plasma half-life of EVG following administration of EVG and ritonavir was approximately 
8.7 hours.22 
 
Oral TAF 
 
A single-center, open-label, dose-ranging PK study investigated a single TAF dose in 24 
healthy, premenopausal HIV seronegative female volunteers 18-49 years old. They were 
given 5, 10 or 25mg of TAF and each participant provided plasma, PBMC and cervical, 
vaginal and rectal tissue samples over 14 days. For each group, median (IQR) tenofovir 
plasma AUC0–14 days was 52.8 (49.5–59.6), 78.1 (68.2–86.9) and 169.7 (131.2-211.4) 
ng-h/mL and tenofovir-dp PBMC AUC0–14 days was 2268 (1519-4090), 4584 (3113-5734) 
and 9306 (6891-10785) fmol-h/106 cells, respectively. Tenofovir was quantifiable in 52% 
and 92% of FGT and GI tissues, whereas tenofovir-dp was quantifiable in only 5% and 
19% of female genital tract and lower gastrointestinal tissues, respectively. Plasma 
tenofovir and PBMC tenofovir-dp were dose proportional (90% CI 0.87-1.15 and 0.62-
1.02, respectively).23  
 
In a study of safety, antiviral activity, and pharmacokinetics of TAF, non-cirrhotic, 
treatment-naïve subjects with chronic hepatitis B were randomized (1:1:1:1:1) to receive 
TAF 8, 25, 40, or 120 mg, or TDF 300 mg for 28 days and assessed for safety, antiviral 
response, and pharmacokinetics, followed-up by off-treatment for 4 weeks. Following 
single dose administration on day 1, concentrations of TAF in plasma increased in 
proportion to dose, reaching maximum concentrations within 30-40 minutes. Consistent 
with the short elimination half-life of TAF (<45 min), plasma concentrations of the drug 
were below the limit of quantification 6-8 hours following dosing. TAF was completely 
undetectable in trough (pre-dose) plasma samples, collected over the 28 day dosing 
period. At each of the dose levels evaluated, mean plasma TFV concentrations following 
administration of TAF were substantially lower than those following TDF dosing. Relative 
to the mean TFV exposure (AUCinf) with TDF 300 mg (2267 ng-h/ml), percentage 
reductions in mean TFV exposures for TAF of 97%, 92%, 81%, and 33%, were seen 
following TAF doses of 8, 25, 40, and 120 mg, respectively.24 
 
In another study of pharmacokinetics, safety and antiviral activity of 40 or 120 mg of TAF 
compared with 300 mg of TDF, TAF and TDF were administered as monotherapy once 
daily for 14 days in 30 HIV-1-infected, treatment-naive subjects. Administration of 40 mg 


 
 
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TAF resulted in lower tenofovir Cmax (13 versus 207 ng/mL) and lower systemic 
exposures (AUC0–t, 383 versus 1810 ng-h/mL) compared with subjects who received 
TDF. There were higher intracellular tenofovir concentrations within peripheral blood 
mononuclear cells with both 40 mg (8.2 uM) and 120 mg (16.9 uM) of TAF compared with 
300 mg of TDF (0.9 uM).25  
 
A phase 1b, randomized, partially blinded, active- and placebo-controlled, dose-ranging 
study was also conducted with 38 treatment-naive and experienced HIV-1–positive adults 
currently off antiretroviral therapy. Participants were randomized to receive 8, 25, or 40 
mg TAF, 300 mg TDF, or placebo, each once daily for 10 days. After administration of 8, 
25, or 40 mg TAF, TAF was rapidly absorbed (median Tmax ~0.50 hours), displayed a 
short plasma half-life (t½ ;0.40 hours), and was below the limit of quantitation in plasma 
by ~5 hours post-dose. After administration of 8, 25, or 40 mg TAF or 300 mg TDF, the 
highest TFV plasma concentrations were observed with TDF. At steady state, 8, 25, and 
40 mg TAF yielded mean TFV plasma exposures AUCtau of 97%, 86%, and 79% lower, 
respectively, as compared with the TFV exposures observed with 300 mg TDF. For 25 
and 40 mg TAF, the mean intracellular peripheral blood mononuclear cell tenofovir-dp 
AUCtau was ~7-fold and ~25-fold higher relative to 300 mg TDF.26 
 
Oral EVG and TAF in combination therapy 
 
A single-arm, open-label study was conducted in 50 treatment-naïve adolescents with 
HIV aged 12-18 years from ten hospital clinics in South Africa, Thailand, Uganda, and the 
USA. The study aimed to assess safety, pharmacokinetics, and efficacy of the single-
tablet, fixed-dose combination of elvitegravir, cobicistat, emtricitabine, and tenofovir 
alafenamide (Genvoya®). The mean AUCtau for EVG was 23840 ng-h per mL (CV 25.5%), 
and the mean AUClast for TAF was 189 ng-h per mL (CV 55.8%). Both the AUClas and 
Cmax of TAF in adolescents were similar to those noted in adults after administration of 
Genvoya. Notably, tenofovir exposure in adolescents following this administration was 
more than 90% lower than tenofovir exposure following this administration in adults.27 
 
In a single-arm, multicenter, open-label Phase 3 study, Genvoya was administered once 
daily to 242 virologically suppressed HIV-1-infected participants with renal impairment to 
assess it safety and efficacy. Plasma PK parameters was measured in a subset of 
patients who participated in the intensive PK substudy (n = 30). The EVG and cobicistat 
(COBI) PK parameters were in the range of historical data after administration of Genvoya 
in HIV infected patients without renal impairment. TAF PK parameters were consistent 
with historical data in nonrenally impaired patients. Additionally, the TAF metabolite TFV 
was higher in patients in this study vs historical TAF data in nonrenally impaired patients 
but was well below the TFV exposures from TDF-containing regimens.28  
 
Two controlled, double-blind, Phase 3 studies were conducted to compare the safety and 
efficacy of E/C/F/TAF versus E/C/F/TDF in 1733 treatment-naive HIV-infected patients 
from 178 outpatient centers in 16 countries. Participants were randomly assigned (1:1) to 
receive once-daily oral tablets containing 150 mg elvitegravir, 150 mg cobicistat, 200 mg 
emtricitabine, and 10 mg tenofovir alafenamide (E/C/F/TAF) or 300 mg tenofovir 
disoproxil fumarate (E/C/F/TDF) with matching placebo. 65 participants participated in the 
intensive pharmacokinetic Substudy. Of those, 35 patients participated in the PBMC 


 
 
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substudy. Plasma tenofovir exposure AUCtau after administration of E/C/F/TAF was 91% 
lower than tenofovir exposure achieved with E/C/F/TDF. The PBMC tenofovir-dp AUCtau 
was 4.1 times higher in participants receiving E/C/F/TAF than in those receiving 
E/C/F/TDF.29 
 
Insert: Placebo and Drug-containing (TFV/FTC) 
CONRAD 117 was a randomized, double blind, placebo-controlled, Phase 1 trial 
designed to evaluate safety, PK/PD, and disintegration time after a single use of a vaginal 
insert containing TFV and/or FTC and during and after 14 days of once-daily use. 49 
women were randomized 1:1:1:1 to use inserts containing 40 mg TFV, 40 mg FTC, 40 
mg TFV + 40 mg FTC, or placebo. Participants self-administered one insert per day for 
14 days. The TFV levels in vaginal aspirate were similar to those after TFV 1% vaginal 
gel administration associated with protection in a previous clinical study, and levels of 
TFV-DP in vaginal tissue associated with protection in a nonhuman primate study. Levels 
of FTC in aspirate and FTC-TP in genital tissue appeared to be at least as high as those 
seen after oral dosing in women and macaques. Systemic levels of both TFV and FTC 
were low.14    
 
TAF/EVG Vaginal Insert 
 
CONRAD will conduct A18-146, a Phase 1 clinical trial of the TAF/EVG vaginal insert. 
This will be the first-in-human study for the vaginally administered TAF/EVG insert and 
will evaluate the safety, tolerability, PK, and PD after a single dose. The study will recruit 
healthy, non-pregnant women aged 18-50 years who are not at risk for pregnancy and at 
low risk for sexually transmitted infections. Participants will use a single TAF/EVG insert 
in the clinic and will be randomized to 1 of 2 sample collection groups (2 and 48 hours 
after dosing or 24 and 72 hours after dosing). Plasma, cervicovaginal fluid and cervical 
tissue for PK will collected. It is expected that much lower plasma concentrations will be 
obtained for all drugs and aid in demonstrating systemic safety and refuting the need for 
further or extensive systemic PK characterization.14 CONRAD will keep MTN apprised of 
any serious AEs that occur in this study. 
      
2.7.3 
Safety of EVG and TAF  
Oral EVG is currently approved for use as part of combination therapy. For the treatment 
of HIV infection, oral TAF is also approved for use as part of combination therapies. 
Therefore, large scale studies examining the safety and tolerability of EVG and TAF are 
limited to clinical trials where EVG or TAF were administered in combination with other 
ARVs. 
 
Oral EVG 
Gilead Study GS-US-183-0101 demonstrated minimal AEs with the use of oral EVG. The 
study was a randomized, double-blind, placebo controlled, monotherapy phase 1/2 trial 
with 40 HIV-1 infected participants – a mix of both treatment naïve and treatment 
experienced (but not currently receiving ARV therapy) individuals. Participants received 
EVG or placebo for 10 days at 5 dosage levels: 200 mg BID, 400 mg BID, 800 mg QD, 
800 mg BID, or 50 mg + 100 mg ritonavir QD.  TEAEs of grade 2 or 3 were reported in 


 
 
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27% of participants receiving EVG and 40% of those receiving placebo; no participants 
reported serious AEs, dosage interruptions, or discontinued from the study.8 
Oral TAF 
The safety of TAF(Vemlidy®) was assessed based on pooled data through the Week 96 
data analysis from 1298 subjects in two randomized, double-blind, active-controlled trials 
(Gilead Study 108 and Study 110), in adult subjects with chronic hepatitis B and 
compensated liver disease. The most common adverse reaction (all Grades) reported in 
at least 10% of subjects in the TAF group was headache. The proportion of subjects who 
discontinued treatment with TAF or TDF due to adverse reactions of any severity was 
1.5% and 0.9%, respectively. Table 5 displays the frequency of the adverse reactions (all 
Grades) greater than or equal to 5% in the TAF group.12  
 
Table 5:  Adverse Reactionsa (All Grades) Reported in ≥5% of Subjects with Chronic HBV 
Infection and Compensated Liver Disease in Studies Gilead Studies 108 and 110 (Week 96 
Analysisb) 
Adverse reaction 
Tenofovir 
alafenamide (TAF) 
N=866 
Tenofovir Disoproxil 
Fumarate (TDF) 
N=432 
Headache 
12% 
10% 
Abdominal painc 
9% 
6% 
Cough  
8% 
8% 
Back pain 
6% 
6% 
Fatigue  
6% 
5% 
Nausea  
6% 
6% 
Arthralgia  
5% 
6% 
Diarrhea 
5% 
5% 
Dyspepsia  
5% 
5% 
a. Frequencies of adverse reactions are based on all treatment-emergent adverse events,  
regardless of relationship to study product. 
b. Double-bind phase 
c. Grouped term including abdominal pain upper, abdominal pain, abdominal pain lower,  
and abdominal tenderness.  
 
EVG and TAF in Combination Therapy 
Additional clinical trials of EVG or TAF in HIV-infected individuals were conducted with 
EVG and TAF as part of combination therapy, administered in combination with other 
antiretrovirals; thus it is not possible to attribute individual AEs to EVG or TAF.8  Genvoya 
is a four drug combination that includes EVG, cobicistat, emtricitabine and TAF.   
 
In clinical trials in antiretroviral treatment-naïve HIV-infected adults, the primary safety 
assessment of Genvoya was based on Week 144 pooled data from 1733 subjects from 
two randomized, double-blind, active-controlled trials – Gilead Studies 104 and 111. A 
total of 866 subjects received one tablet of Genvoya once daily. 


 
 
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The most common adverse event (all grades) reported in at least 10% of subjects in the 
Genvoya group was nausea. The proportion of subjects who discontinued treatment with 
Genvoya or Stribild due to AEs (regardless of severity) was 1% and 2%, respectively. The 
majority of AEs were grade 1. See Table 6 for the frequency of AEs (all grades) ≥5% in 
the Genvoya group.  
Table 6:  Adverse Reactions (All Grades) Reported in ≥5% of HIV-1 Infected Treatment-
Naïve Adults Receiving Genvoya or Stribild in Gilead Studies 104 and 111 (Week 144 
Analysis) 
Adverse reaction 
Genvoya 
N=866 
Stribild 
N=867 
Nausea 
11% 
13% 
Diarrhea 
7% 
9% 
Headache 
6% 
5% 
Fatigue 
5% 
4% 
 
Insert: Placebo and Drug-containing (TFV/FTC) 
In CONRAD 134, an open-label study that assessed in-vivo disintegration time, safety, 
and product acceptability of 4 placebo vaginal inserts in 32 women aged 18-50 who were 
not at risk of pregnancy – placebo inserts were found to be safe, with one mild AE reported 
that was subsequently assessed as being unrelated to study drug. The optimized insert 
prototypes were found to disintegrate faster and have higher acceptability over first 
generation inserts.8,30  
In CONRAD 117, the first-in-human study of vaginal microbicide inserts using TFV and/or 
FTC containing vaginal inserts - treatment-emergent adverse events (TEAEs) were 
minimal; only one TEAE met the pre-specified criterion for the safety endpoint, but this 
event was in the placebo group. Colposcopy and physical exam findings were minimal, 
as were changes in microflora and systemic laboratory values.8 
2.7.4 
Efficacy 
Efficacy data for EVG or TAF containing antiretroviral regimens is summarized in the IB, 
and in the package inserts for EVG/COBI/FTC/TDF (Stribild, Gilead Sciences, Inc.) and 
EVG/COBI/FTC/TAF (Genvoya, Gilead Sciences, Inc.).13 
2.8 Study Hypotheses and Rationale for Study Design 
 
2.8.1 
Study Primary Hypotheses 
It is hypothesized that the two dose levels of the TAF/EVG Insert in this study will be safe 
when applied to the rectum and well-tolerated among healthy individuals who have a 
history of receptive anal intercourse (RAI). 


 
 
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2.8.2 
Rationale for Study Design 
Rectal microbicides are needed for individuals at risk of acquiring HIV infection through 
unprotected RAI. It is important to expand the rectal microbicide pipeline with the addition 
of products from different classes such as EVG, an integrase inhibitor, and TAF, a 
nucleotide reverse transcriptase inhibitor. 
Rationale for the Dosing and PK Sampling Schedule 
 
MTN-039 is the first study to assess the safety and PK of the TAF/EVG Insert applied 
rectally. Antiviral activity studies of EVG in tissue explant models have shown that an 
EVG tissue concentration of at least 1000 ng/g will be efficacious prophylactically against 
HIV infection. Previous vaginal PK/PD studies suggested that a concentration of 1000 
fmol/mg TFV-DP in tissue could be a good predictor of high efficacy against HIV 
infection.31 Based on the preclinical and animal data collected to date, the TAF/EVG insert 
with 20 mg TAF and 16 mg EVG doses will achieve the target tissue concentration of 
1000 ng/g EVG and 1000 fmol/mg TFV-DP in humans.  
 
The PK sampling schedule in this study will provide valuable information regarding the 
rectal TAF/EVG PK profile in humans. This will provide guidance for ongoing product 
development efforts to develop a combination topical insert containing TAF and EVG. 
  
 
 
3 
OBJECTIVES  
 
3.1 Primary Objectives 
 
Safety 
• 
To evaluate the safety of the TAF/EVG Insert, 20/16 mg administered rectally at two 
dose levels: 1 insert and 2 inserts 
 
Pharmacokinetics 
• 
To characterize the systemic and rectal pharmacokinetics of the TAF/EVG Insert, 
20/16 mg applied rectally at two dose levels: 1 insert and 2 inserts 
 
3.2 Secondary Objective 
 
Acceptability 
• To identify product attributes considered likely to challenge and/or facilitate future 
sustained use of a TAF/EVG insert applied rectally 
 
3.3 Exploratory Objectives 
 
Ex Vivo Efficacy 
• 
To assess the preliminary (ex vivo) efficacy of TAF/EVG after product is inserted 
rectally 
 


 
 
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Pharmacokinetics 
• 
To characterize the cervicovaginal pharmacokinetics of the TAF/EVG Insert, 20/16 mg 
applied rectally at two dose levels: 1 insert and 2 inserts 
 
 Mucosal Safety  
• 
To evaluate mucosal safety of the TAF/EVG Insert, 20/16 mg applied rectally at two 
dose levels: 1 insert and 2 inserts   
 
 
4 
 STUDY DESIGN 
4.1 Identification of Study Design 
 
MTN-039 is a phase 1, multi-site, open-label, single arm, two-period study of rectal 
administration of one TAF/EVG Insert, 20/16 mg and then two TAF/EVG Inserts.  
 
4.2 Summary of Major Endpoints 
 
Primary Endpoints: 
 
Safety 
• 
All Grade 2 and higher AEs  
 
Pharmacokinetics 
• 
EVG concentrations in: 
o Blood  
o Rectal fluid 
o Rectal mucosal tissue homogenates 
 
• 
TAF and TFV concentrations in: 
o Blood 
o Rectal fluid  
 
• 
TFV-DP concentration in: 
o Rectal mucosal tissue homogenates 
o Rectal mucosal tissue cell isolates 
 
Secondary Endpoint:  
 
Acceptability 
• 
Participant report of overall acceptability of the TAF/EVG Insert applied rectally  
Exploratory Endpoints:  
 
Ex Vivo Efficacy 
• 
Changes in HIV-1 replication in colorectal explant culture supernatant  
• 
Anti-HIV activity in rectal fluid 
• 
Anti-HIV activity in cervicovaginal fluid 


 
 
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Pharmacokinetics 
• 
EVG, TAF and TFV concentrations in cervicovaginal fluid 
 
Mucosal Safety  
• 
Rectal histology  
• 
Rectal proteomics  
• 
Rectal metabolomics  
• 
Rectal immunophenotype 
• 
Rectal microbiome 
• 
Cervicovaginal microflora 
 
4.3 Description of Study Population 
 
The study population will consist of HIV-uninfected individuals 18 years of age or older 
who 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 6-8 months.   
 
4.5 Study Groups  
 
MTN-039 will enroll approximately 20 evaluable participants.  
 
4.6 Expected Duration of Participation 
 
Each participant will be on study for approximately 6-13 weeks. The total duration of the 
study will be approximately 11 months. 
 
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 and community-based locations.  Recruitment materials will be approved by 


 
 
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site Institutional Review Boards (IRBs) prior to use.   
 
5.1.2 
Retention 
 
Once a participant is enrolled in MTN-039, study sites will make every effort to retain the 
participant in follow-up to minimize possible bias associated with loss-to-follow-up. Sites 
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) Individuals who are 18 years of age or older at Screening, verified per site SOP 
 
2) Able and willing to provide written informed consent to be screened for and enrolled 
in MTN-039 
 
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) Able to communicate in spoken and written English 
 
6) Available for all visits and able and willing to comply with all study procedural 
requirements  
 
7) In general good health at Screening and Enrollment, as determined by the site IoR or 
designee 
 
8) At Screening, history of consensual RAI at least once in lifetime per participant report 
 
9) Willing not to 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) 
 
10) Willing to comply with abstinence and other protocol requirements as outlined in 
Section 6.7 
 
11) For participants of childbearing potential: a negative pregnancy test at Screening and 
Enrollment 
 
12) For participants of childbearing potential: 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:   
• Hormonal methods 
• Intrauterine device (IUD) inserted at least 30 days prior to Enrollment (but not 
past the maximum length of recommended usage according to package 
instructions)  
• Sterilization (of participant or partner, as defined in site SOPs)  


 
 
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• Sexually abstinent as defined by abstaining from penile-vaginal intercourse for 
90 days prior to Enrollment and intending to remain abstinent for the duration 
of study participation; this includes having sex exclusively with individuals 
assigned female sex at birth  
 
5.3 Exclusion Criteria 
 
Individuals who meet any of the following criteria will be excluded from the study:   
 
1) At Screening: 
a) Hemoglobin Grade 1 or higher* 
b) Platelet count Grade 1 or higher*  
c) Aspartate aminotransferase (AST) or alanine transaminase (ALT) Grade 1 or 
higher* 
d) Serum creatinine >1.3× the site laboratory upper limit of normal (ULN) 
e) International normalized ratio (INR) >1.5× the site laboratory ULN 
f) History of inflammatory bowel disease by participant report 
 
*As per the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events 
Corrected Version 2.1, July 2017. 
 
Note: Otherwise eligible participants with an exclusionary test result (other than HIV) can 
be re-tested during the screening process. If a participant is re-tested and a non-
exclusionary result is documented within 45 days of providing informed consent for 
screening, the participant may be enrolled.  
 
2) Anticipated use of and/or unwillingness to abstain from the following medications 
during study participation: 
a) Anticoagulant medications  
b) Non-study rectally-administered medications and any products containing N-9 
 
3) Known adverse reaction to any of the components of the study product    
 
4) Use of pre-exposure prophylaxis (PrEP) for HIV prevention within 3 months prior to 
Enrollment, and/or anticipated use and/or unwillingness to abstain from PrEP during 
trial participation 
 
5) Use of post-exposure prophylaxis (PEP) for potential HIV exposure within 6 months 
prior to Enrollment 
 
6) Condomless RAI and/or penile-vaginal intercourse with a partner who is known to be 
HIV-positive or whose status is unknown in the 6 months prior to Enrollment 
 
7) History of transactional sex in the 12 months prior to Enrollment 
 
8) Non-therapeutic injection drug use or use of non-therapeutic, non-injection stimulant 
drugs in the 12 months prior to Enrollment 
 
9) Participation in research studies involving drugs, medical devices, genital or rectal 
products, or vaccines within 30 days of the Enrollment Visit 
 


 
 
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10) Per participant report, medical records, clinical diagnosis and/or diagnostic testing at 
either Screening or Enrollment: 
 
a. Diagnosis or treatment of an anogenital STI in the 3 months prior to enrollment  
(including window between Screening and Enrollment). 
 
b. Symptoms, clinical or laboratory diagnosis of active pharyngeal, anorectal, or  
reproductive tract infection (RTI) requiring treatment per current CDC guidelines 
(http://www.cdc.gov/std/treatment). 
  
c. Current symptomatic urinary tract infection (UTI). 
 
Infections requiring treatment include Neisseria gonorrhea (GC), Chlamydia 
trachomatis (CT) infection, syphilis, active herpes simplex virus (HSV) lesions, or 
symptomatic genital warts, chancroid, pelvic inflammatory disease (PID), bacterial 
vaginosis (BV), symptomatic vaginal candidiasis, and trichomoniasis. 
Note:  Otherwise eligible participants with an exclusionary UTI, BV and/or candida finding 
may be re-tested during the screening process. 
 
11) For participants of childbearing potential: Pregnant or breastfeeding at either 
Screening or Enrollment or planning to become pregnant during study participation 
Note:  A documented negative pregnancy test performed by study staff is required for 
inclusion; however, a self-reported pregnancy is adequate for exclusion from 
screening/enrollment into the study. 
 
12) For participants of childbearing potential: 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 the interpretation of 
study outcome data, or otherwise interfere with achieving the study objectives 
including any significant uncontrolled active or chronic medical condition. 
 
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, rectal and genital products, or vaccines after 
the Screening Visit and while taking part in MTN-039 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: 
 
• Participants may take part in ancillary studies if approved by MTN-039 PSRT 
 
Should any participant report concurrent participation in contraindicated studies after 
enrolling in MTN-039, the IoR/designee will consult the PSRT regarding ongoing product 
use and other potential safety considerations associated with co-enrollment. 
 
 


 
 
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6 
STUDY PRODUCT 
6.1 Regimen 
 
The product being used in this study is Tenofovir Alafenamide (TAF)/Elvitegravir (EVG) 
Vaginal Insert 20/16 mg. This product was initially developed for a study (A18-146) 
involving vaginal administration, however rectal administration of the product is now being 
studied in this trial. Therefore, the product can simply be referred to as “TAF/EVG Insert” 
for this study. Each insert for rectal administration contains 20 mg tenofovir alafenamide 
(TAF) and 16 mg elvitegravir (EVG).  
 
Participants will self-administer a saline enema at home the evening prior to a clinic 
dosing visit. Each participant will receive a single TAF/EVG Insert for rectal 
administration. After a washout period of at least 7 days, participants will each receive 
two TAF/EVG Inserts for rectal administration. After each dose is administered in the 
clinic, PK and PD sampling will be conducted over a three-day period.  
 
Table 7: Study Product Regimen 
 
 
 
 
 
 
 
 
6.2 Administration 
 
Participants will be instructed to present to the clinic for each of the 2 doses of rectally 
administered TAF/EVG Inserts. Administration of the TAF/EVG Insert(s) will be performed 
by study staff. 
 
6.3 
Study Product Formulation and Storage  
 
Normal Saline Home Enemas 
 
Participants will be provided with two 120 mL sealed cups of sterile USP normal saline 
(NS) solution for home enema administration. The participant will use a 60 mL oral syringe 
(provided) to transfer the entire content of the NS cup to the enema bottle. Although all of 
the solution should be transferred to the enema bottle, the participant will be instructed to 
discard any unused solution remaining in the original container. The NS solution should 
be stored at room temperature 25ºC (77°F). Additionally, participants will be instructed to 
dispose the prepared saline enema if not used within 24 hours of filling. 
 
Each participant will receive a sheet of instructions which will outline the process for 
preparing the enema, disposing unused solution and enema administration. A review of 
these instructions will be conducted with the participant at the clinic prior to providing the 
enema kit to be administered at home.    
Visit 3 
 
Visit 7 
1 TAF/EVG Insert 
 
 
 
 
7-49 days following 
tissue sampling 
2 TAF/EVG Inserts 
 


 
 
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TAF/EVG Inserts 
 
TAF/EVG Inserts have been formulated into white to off-white uncoated bullet shaped 
inserts containing 22.40 mg of TAF Fumarate (equivalent to 20 mg TAF free base) and 
16 mg of EVG. TAF is a nucleotide reverse transcriptase inhibitor (NRTI) and a prodrug 
of Tenofovir (TFV) and EVG is an integrase inhibitor. Both the active pharmaceutical 
ingredients (APIs) are supplied by Gilead Sciences, Inc.  
 
Figure 2: Study Product  
 
 
 
In addition to TAF and EVG this insert contains the following inactive excipients: 
povidone, magnesium stearate, polaxomer (also known as Kolliphor P188), polyethylene 
glycol, mannitol, and lactose anhydrous. The insert dimensions are: length: 1.5 cm (0.6 
inches), width: 0.7 cm (0.28 inches), height: 0.6 cm (0.23 inches). Each insert is 
approximately 500 mg in weight. The TAF/EVG Insert should be stored as supplied in a 
white induction-sealed HDPE bottle of 20 inserts along with polyester coil and a desiccant 
at room temperature (20° - 25°C) (68° - 77°F) until dispensed for use. Excursions between 
15 ° - 30°C (59° - 86°F) are allowed. 
 
6.4 
Study Product Supply and Accountability 
6.4.1 
Study Product Supply 
 
CONRAD (the organization that supplies the rectal insert) will oversee the manufacture 
and analysis/release (Patheon, Whitby, ON, Canada) of the study product under current 
Good Manufacturing Practices (cGMP). 
 
Sealed cups containing 120 mL USP normal saline and USP are supplied by Nurse 
Assist, Inc, Fort Worth. 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. 
6.4.2 
Study Product Dispensing 
 


 
 
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TAF/EVG Inserts will be dispensed to clinic staff on behalf of the participant, 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 Form FDA 
1572. 
6.4.3 
Study Product Accountability 
 
Each Clinical Research Site (CRS) Pharmacist of Record (PoR) is required to maintain a 
complete record of all TAF/EVG Inserts received and subsequently dispensed. All unused 
TAF/EVG Inserts must be returned to the MTN Pharmacist after the study is completed 
or terminated unless otherwise instructed by the MTN Pharmacist. The procedures to be 
followed are provided in the MTN-039 Pharmacy Study Product Management Procedures 
Manual. 
 
6.5 Ancillary Study Supplies 
 
Clinic staff will provide male condoms to all participants. Lubricant will be provided at each 
dosing for ease of administration (if needed).  
 
6.6 
Concomitant Medications  
 
Enrolled study participants may use concomitant medications during study participation 
except for medications and products not permitted per the inclusion and exclusion criteria 
and listed in Section 6.7 below. 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.  
 
6.7 
Prohibited Medications, Products and Practices 
6.7.1 
Prohibited Medications and Products  
 
Several concomitant medications/practices will not be permitted. Participants are 
prohibited from using strong and moderate CYP3A inhibitors and inducers. These 
medications are not permitted because EVG is a CYP3A substrate. A listing of these 
specific prohibited agents is provided below (see Table 8 and Table 9) and in the MTN-
039 SSP Manual available at www.mtnstopshiv.org. Mild inducers/inhibitors are permitted 
as long as stable dose is anticipated throughout the study. 
 
 
 
 
 
 
 
 
 


 
 
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Table 8: Prohibited CYP Inhibitors 
Strong Inhibitors 
≥ 5-fold increase in AUC 
or > 80% decrease in CL 
Moderate Inhibitors 
≥2 but < 5-fold increase in 
AUC or 50-80% decrease in CL 
Antibiotics: 
clarithromycin, telithromycin 
Antidepressants: 
nefazodone 
Azole Antifungals:  
ketoconazole, itraconazole, 
posaconazole, voriconazole 
Pharmacokinetic Enhancers:  
cobicistat 
Protease Inhibitors:  
ritonavir, indinavir, lopinavir/ritonavir, 
nelfinavir, saquinavir, boceprevir, 
telaprevir 
Reverse Transcriptase Inhibitors: 
delavirdine 
Vasopression Receptor Antagonists: 
conivaptan 
Antiarrhythmics: 
dronedarone 
Antibiotics:  
erythromycin, 
ciprofloxacin 
Antiemetics: 
aprepitant 
Antineoplastics: 
imatinib 
Azole Antifungals: 
fluconazole, miconazole 
Calcium Channel Blockers: 
verapamil, diltiazem 
Protease Inhibitors:  
atazanavir, darunavir/ritonavir, 
fosamprenavir 
 
Table 9: Prohibited CYP Inducers 
Strong Inducers 
≥ 80% decrease in AUC 
Moderate Inducers 
50-80% decrease in AUC 
Anticonvulsants/Mood Stabilizers: 
phenytoin, carbamazepine 
Anticonvulsants/Barbiturates: 
primidone 
Antituberculars: 
rifampin 
Barbiturates: 
phenobarbital, butalbital 
Glucocorticoids: 
dexamethasone 
Herbal Supplements: 
St. John’s wort^ 
Protease Inhibitors: 
tipranavir (alone) 
Antibiotics: 
nafcillin 
Antihypertensives: 
bosentan 
Antituberculars: 
rifabutin 
CNS Stimulants: 
modafinil 
Reverse Transcriptase Inhibitors: 
efavirenz, etravirine, nevirapine 
^The effect of St. John’s wort and echinacea varies widely and is preparation-dependent. 
 
 


 
 
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The use of study product concurrently with PEP and PrEP is prohibited during study 
participation. Individuals who need PEP or PrEP due to known or potential HIV exposure 
will permanently discontinue study product use. See Section 9.3 for additional 
information. Use of rectally-administered medications and products, including N-9 
products, is also prohibited.  
 
Use of anticoagulants or blood-thinners (such as heparin, Lovenox®, warfarin, Plavix® 
[clopidogrel bisulfate]) is also prohibited during study participation. See Section 9.3 for 
additional information. 
 
Participants will be counseled to abstain from using aspirin (greater than 81 mg) and non-
steroidal anti-inflammatory drugs (NSAIDS) within 72 hours prior to and following a tissue 
sample collection visit. Should a participant report taking any of the medications noted 
above, which may increase risk of bleeding, or report the use of rectal medications or 
products within 72 hours prior to tissue collection, the visit should be rescheduled within 
the visit window, if possible. If it is determined that rescheduling the visit within the window 
is not possible, the visit may proceed at IoR discretion after proper participant counseling 
has occurred.  
6.7.2 
Prohibited Practices  
 
All participants are to abstain from inserting any non-study products (including rectal 
medications, enemas, lubricant and sex toys) into the rectum, rectal stimulation with 
fingers, receptive oral anogenital stimulation and receptive anal intercourse for 72 hours 
prior to and following clinic visits. Participants should abstain from inserting anything into 
the vagina for 72 hours prior to each clinic visit, including fingers, spermicides, vaginal 
medications (including hormones), vaginal douches, lubricants and moisturizers, sex toys 
(vibrators, dildos, etc.) and vaginal intercourse. 
 
If desired, the IoR may request rapid PSRT consultation to assist in making the 
determination as to whether or not to proceed with the visit at that time or to reschedule 
an interim visit. If the decision is made to reschedule an interim visit, any missed 
procedures (including biopsy collection) should be performed during the interim visit. 
 
 
 
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-039 SSP Manual available at 
http://www.mtnstopshiv.org. 
 


 
 
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Figure 3: MTN-039 Study Visit Schedule 
 
 
  
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 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 study sites 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. At each 
site, procedures and documentation will comply with local IRB 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: Participants who fail their first screening attempt may be re-screened one time. 
 
Table 10:  Screening Visit 
Screening Visit - Visit 1 
Component 
Procedures 
Administrative and 
Regulatory 
 
• 
Obtain written informed consent 
• 
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


 
 
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Clinical 
• 
Collect concomitant medications 
• 
Collect medical history 
• 
Perform physical examination 
• 
Perform genital examination* 
• 
Perform pelvic examination*▲ 
• 
Perform rectal examination 
• 
Treat or prescribe treatment for RTI/UTI, or STIs* 
• 
Provide available test results 
Laboratory 
 
Pharyngeal 
• 
NAAT for GC/CT 
Urine 
• 
NAAT for GC/CT▼ 
• 
Urine dipstick/culture* 
• 
Pregnancy test ■ 
Blood 
• 
CBC with differential and platelets 
• 
Chemistries (AST/ALT/creatinine) 
• 
Syphilis serology  
• 
HIV-1/2 test 
• 
Coagulation (PT/INR) 
Pelvic▲ 
• 
NAAT for GC/CT/TV 
Anorectal 
• 
NAAT for GC/CT 
Study Product/Supplies 
• 
Offer condoms 
* If indicated  ▲Participants assigned female sex at birth and if anatomy allows ▼If pelvic GC/CT cannot 
be performed  ■ Participants of childbearing potential  
 
7.3 Enrollment (Day 0) 
 
The Enrollment Visit can occur up to 45 days after the Screening Visit. All Enrollment 
procedures must occur on the same day. 
 
Participants will be assigned to one of two groups to obtain samples: Group 1 will have 
biopsies, rectal fluid and cervicovaginal fluid (if applicable) collected at 2 hours (Visits 3 
and 7) and 48 hours (Visits 5 and 9) following each administration of product; participants 
in this group will also have rectal and cervicovaginal fluid collected at 6 hour post-dose at 
Visits 3 and 7. Group 2 will have biopsies, rectal fluid and cervicovaginal fluid (if 
applicable) collected at 24 hours (Visits 4 and 8) and 72 hours (Visits 6 and 10) following 
each administration of product; participants in this group will also have rectal and 
cervicovaginal fluid collected at 4 hours post-dose at Visits 3 and 7. Both groups will have 
blood collected at each visit from Visit 3 through Visit 10. At least three participants 
assigned female sex at birth should be enrolled and assigned to each group.  
 
Table 11:  Enrollment Visit 
Enrollment Visit – Visit 2 
Component 
Procedures 
Administrative and Regulatory 
 
• 
Assess and confirm eligibility 
• 
Review/update locator information 
• 
Random assignment to sampling schedule 
• 
Provide reimbursement 
• 
Schedule next visit/contact* 
Behavioral/Counseling 
• 
HIV pre- and post-test counseling 


 
 
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March 6, 2019 
• 
HIV/STI risk reduction counseling 
• 
Protocol counseling 
• 
Behavioral assessment (CASI) 
Clinical 
• 
Review/update concomitant medications 
• 
Review/update medical history 
• 
Perform physical examination 
• 
Perform genital examination* 
• 
Perform pelvic examination*▲ 
• 
Perform rectal examination 
• 
Treat or prescribe treatment for RTI/UTI, or STIs* 
• 
Provide available test results 
Laboratory 
 
Pharyngeal 
• 
NAAT for GC/CT* 
Urine 
• 
NAAT for GC/CT*▼ 
• 
Urine dipstick/culture* 
• 
Pregnancy test ■ 
Blood 
• 
CBC with differential and platelets* 
• 
Chemistries (AST/ALT/creatinine)* 
• 
Syphilis serology* 
• 
Plasma for archive 
• 
HIV-1/2 test 
• 
Blood for PK 
Pelvic▲ 
• 
NAAT for GC/CT/TV* 
• 
CVF for PD 
• 
CVF for microflora 
Anorectal 
• 
Rectal fluid for PD 
• 
Rectal fluid for microbiome 
• 
Rectal enema prior to biopsy collection 
• 
Rectal tissue for PD  
• 
Rectal tissue for biomarkers 
• 
NAAT for GC/CT* 
Study Product/Supplies 
• 
Offer condoms 
• 
Provide home enema kit 
* If indicated  ▲ Participants assigned female sex at birth and if anatomy allows  ▼If pelvic GC/CT cannot 
be performed  ■ Participants of childbearing potential 
 
7.4 Follow-up Visits 
 
7.4.1 Dosing – Visits 3 and 7 
 
The first dosing visit (Visit 3) should occur at least 7 days after the Enrollment Visit. The 
second and final dosing visit (Visit 7) should occur at least 7 days after the last tissue 
sampling visit following Dose 1 (following Visit 5 or 6 with a 1- to 7-week washout period). 
 
Table 12: Dosing Procedures 
Dosing Procedures – Visits 3 and 7  
Component 
Procedures 


 
 
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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 genital examination* 
• 
Perform pelvic examination*▲ 
• 
Perform rectal examination 
• 
Treat or prescribe treatment for RTI/UTI, or STIs* 
• 
Provide available test results 
• 
Collect/update AEs 
Laboratory 
Pharyngeal 
• 
NAAT for GC/CT* 
Urine 
• 
NAAT for GC/CT*▼ 
• 
Urine dipstick/culture* 
• 
Pregnancy test*■ 
Blood 
• 
CBC with differential and platelets* 
• 
Chemistries (AST/ALT/creatinine)* 
• 
Syphilis serology* 
• 
HIV-1/2 test* 
• 
Blood for PK  
Pelvic▲ 
• 
CVF for PK ** 
• 
CVF for PD ♣  
• 
CVF for microflora ♣   
• 
NAAT for GC/CT/TV* 
Anorectal 
• 
Rectal fluid for PK ** 
• 
Rectal fluid for PD ♣  
• 
Rectal fluid microbiome ♣  
• 
Rectal tissue for PK ♣ 
• 
Rectal tissue for PD ♣ 
• 
Rectal tissue for biomarkers ♣ 
• 
NAAT for GC/CT* 
Study Product/Supplies 
• 
Administration of study product  
• 
Offer condoms 
• 
Offer lubricant 
* If indicated ▲ Participants assigned female sex at birth and if anatomy allows ▼If pelvic GC/CT cannot 
be performed  ■ Participants of childbearing potential   
 All participants will have blood collected at 1, 2, 4, and 6 hours following product administration.  
♣ Group 1 only at 2 hours post-dose  
** Group 1: 2 and 6 hours post-dose; Group 2: 4 hours post-dose 
 
 


 
 
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7.4.2 
Post-Dosing Visits – Visits 4 and 8 
 
The 24-hour Post-Dosing Visits (Visits 4 and 8) should occur between 22 and 26 hours 
(+/- 2 hours) after each dosing visit.  
 
Table 13:  24-hour Post-Dosing Visits  
24-Hour Post-Dosing Visits - Visits 4 and 8 
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 
• 
Behavioral assessment (Brief CASI) 
Clinical 
• 
Review/update medical history 
• 
Review/update concomitant medications 
• 
Perform targeted physical examination* 
• 
Perform genital examination* 
• 
Perform pelvic examination*▲ 
• 
Perform rectal examination 
• 
Treat or prescribe treatment for RTI/UTI, or STIs* 
• 
Provide available test results 
• 
Collect/update AEs 
Laboratory 
Pharyngeal 
• 
NAAT for GC/CT* 
Urine 
• 
NAAT for GC/CT*▼ 
• 
Urine dipstick/culture* 
• 
Pregnancy test*■ 
Blood 
• 
CBC with differential and platelets* 
• 
Chemistries (AST/ALT/creatinine)*  
• 
Syphilis serology* 
• 
HIV-1/2 test* 
• 
Blood for PK   
Pelvic▲ 
• 
CVF for PK ☼ 
• 
CVF for PD ☼ 
• 
CVF for microflora ☼ 
• 
NAAT for GC/CT/TV* 
Anorectal 
 
• 
Rectal fluid for PK ☼ 
• 
Rectal fluid for PD ☼ 
• 
Rectal fluid for microbiome ☼ 
• 
Rectal tissue for PK ☼ 
• 
Rectal tissue for PD ☼ 
• 
Rectal tissue for biomarkers ☼  
• 
NAAT for GC/CT* 
Study Product/Supplies 
• 
Offer condoms 


 
 
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* If indicated ▲ Participants assigned female sex at birth and if anatomy allows ▼If pelvic GC/CT cannot 
be performed  ■ Participants of childbearing potential ☼ Group 2 only 
7.4.3 
Other Post-Dosing Visits – Visits 5, 6, 9, and 10 
 
The 48-hour Post-Dosing Visits (Visits 5 and 9) should occur between 44 and 52 hours 
(+/- 4 hours) after each dosing visit. The 72-hour Post-Dosing Visits (Visits 6 and 10) 
should occur between 66 and 78 hours (+/- 6 hours) after each dosing visit.    
 
Table 14:  Other Post-Dosing Visits  
Other Post-Dosing Visits -  Visits 5, 6, 9, and 10  
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 
• 
Behavioral In-Depth Interview (IDI) (Visit 10 only) 
Clinical 
• 
Review/update medical history 
• 
Review/update concomitant medications 
• 
Perform targeted physical examination* 
• 
Perform genital examination* 
• 
Perform pelvic examination*▲ 
• 
Perform rectal examination 
• 
Treat or prescribe treatment for RTI/UTI, or STIs* 
• 
Provide available test results 
• 
Collect/update AEs 
Laboratory 
Pharyngeal 
• 
NAAT for GC/CT* 
Urine 
• 
NAAT for GC/CT*▼ 
• 
Urine dipstick/culture* 
• 
Pregnancy test*■  
Blood 
• 
CBC with differential and platelets* (required at Visit 
10) 
• 
Chemistries (AST/ALT/creatinine)* (required at Visit 
10) 
• 
Syphilis serology* 
• 
HIV-1/2 test* (required at Visit 10) 
• 
Blood for PK   
Pelvic▲ 
• 
CVF for PK ⌂  
• 
CVF for PD ⌂  
• 
NAAT for GC/CT/TV* 


 
 
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Anorectal 
 
• 
Rectal fluid for PK ⌂   
• 
Rectal fluid for PD ⌂  
• 
Rectal enema prior to biopsy collection ⌂  
• 
Rectal tissue for PK ⌂  
• 
Rectal tissue for PD ⌂  
• 
NAAT for GC/CT* 
Study Product/Supplies 
• 
Offer condoms 
• 
Provide home enema kit (Visit 6 only) 
* If indicated ▲ Participants assigned female sex at birth and if anatomy allows ▼If pelvic GC/CT cannot 
be performed  ■ Participants of childbearing potential   
⌂ Group 1 will have biopsies, rectal fluid and cervicovaginal fluid (if applicable) collected at 48 hours (Visits 
5 and 9) following each administration of product;  
Group 2 will have biopsies, rectal fluid and cervicovaginal fluid (if applicable) collected at 72 hours (Visits 
6 and 10) following each administration of product.  
 
 
7.4.4 Final Contact/Early Termination Visit 
 
The Final Contact (Visit 11) should occur approximately 3-7 days following Visit 10 and 
may be conducted over the phone. This contact will also serve as the participant’s study 
termination. Participants who permanently discontinue study product and follow-up visits 
prior to study completion will be asked to complete an Early Termination Visit, if willing.   
 
Table 15:  Final Contact/Early Termination Visit    
Final Contact/Early Termination Visit - Visit 11 
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* 
Clinical 
• 
Review/update medical history 
• 
Review/update concomitant medications 
• 
Perform targeted physical examination* 
• 
Perform genital examination* 
• 
Perform pelvic examination*▲ 
• 
Perform rectal examination* 
• 
Treat or prescribe treatment for RTI/UTI, or STIs* 
• 
Provide available test results 
• 
Collect/update AEs 
Laboratory 
Pharyngeal 
• 
NAAT for GC/CT* 
Urine 
• 
NAAT for GC/CT*▼ 
• 
Urine dipstick/culture* 
• 
Pregnancy test*■ 


 
 
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Blood 
• 
CBC with differential and platelets* 
• 
Chemistries (AST/ALT/creatinine)* 
• 
Syphilis serology* 
• 
HIV-1/2 test* 
Pelvic▲  
• 
NAAT for GC/CT/TV* 
Anorectal 
• 
NAAT for GC/CT* 
Study Product/Supplies 
• 
Offer condoms* 
* If indicated ▲ Participants assigned female sex at birth and if anatomy allows ▼If pelvic GC/CT cannot 
be performed ■Participants of childbearing potential 
 
7.5 Follow-up Procedures for Participants Who Permanently Discontinue Study 
Product 
 
7.5.1 
Participants Who Become Infected with HIV-1 
 
If a participant tests positive for HIV-1 after the Enrollment Visit, the participant 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 to the participant, thus follow-up visits will be 
discontinued, study product use will cease, and the participant will be considered 
terminated from the study.  An Early Termination Visit will occur and additional laboratory 
testing (including HIV RNA and HIV drug resistance testing) will be conducted for 
participants who have received one or more doses of study product. Please reference the 
MTN-039 SSP Manual for additional details (www.mtnstopshiv.org). 
 
7.5.2 
Participants Who Become Pregnant 
 
If a participant becomes pregnant, the participant 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 product 
use, 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. A participant who is pregnant at study termination will continue to be 
followed until the pregnancy outcome is ascertained, see Section 9.5 for additional 
details. 
 
For participants who become pregnant while on study product, the study site will make 
every reasonable effort to contact participants and collect infant outcome information at 
approximately one year after delivery for those pregnancies that result in live birth. For 
additional details regarding obtaining pregnancy and infant outcomes, please reference 
the MTN-039 SSP Manual (www.mtnstopshiv.org). 
 
7.5.3 
Participants Who Permanently Discontinue Study Product for Other 
Reasons 
 
For participants who permanently discontinue study product use for any reason other than 
HIV seroconversion or pregnancy, site investigators may, after consultation with the 


 
 
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PSRT and MTN-039 Management Team, decide to discontinue study follow-up visits and 
procedures. Participants will, however, be asked to complete the procedures scheduled 
to occur at the Early Termination Visit (Visit 11), if willing. In the event study follow-up is 
continued, participants will have the protocol-specified visits through Final Contact. Sites 
should contact the PSRT and management team to determine whether the participant 
should be followed on study and what study procedures should be completed. 
 
Participants who permanently discontinue study product use due to an AE must continue 
to be followed in the study, if willing, until resolution (return to baseline) or stabilization of 
the AE is documented. 
  
7.6 Interim Visits 
 
Interim visits may be performed at any time during the study, and any visit procedures 
may be conducted as indicated. All interim contacts and visits will be documented in 
participants' study records. If a participant misses a visit (e.g., presents to the clinic 
outside of the visit window), the participant can return for an interim visit to make up 
certain missed visit procedures and specimen collections. Refer to the MTN-039 SSP 
Manual for additional details. 
 
All interim contacts and visits will be documented in participants' study records.   
 
7.7 Protocol Counseling: Adherence and Contraception Counseling 
 
At the Dosing Visit, participants will receive study product counseling appropriate to the 
visit. Study staff will document administration of study product and that the counseling 
was provided. Study product counseling will be provided to study participants upon 
enrollment into the study. Contraception counseling will be provided to participants of 
childbearing potential beginning at the Screening Visit. Protocol adherence counseling 
will be provided beginning at the Screening Visit. Counseling will be provided in 
accordance with standard study methods. Counseling also will include reminders 
regarding concomitant medication and behavioral restrictions prior to and following 
collection of biopsies.   
 
7.8 Clinical Evaluations and Procedures 
 
Physical Examination 
The physical examination will include the following assessments:  
• General appearance 
• Weight*  
• Vital signs 
− Temperature 
− Pulse  
− Blood pressure 
− Respirations 
• Height* 
• Abdomen*  


 
 
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• Head, Eye, Ear, Nose and Throat (HEENT) Examination* 
• Oral mucosa* 
• Lymph nodes*  
• Neck*  
• Heart* 
• Lungs*  
• Extremities* 
• Skin*  
• Neurological* 
• Other components as indicated by participant symptoms 
 
 
* = May be omitted after Enrollment Visit 
 
Anorectal Examination 
The anorectal examination may include the following:  
• Visual exam 
• Digital exam 
• Anoscopy  
• Flexible sigmoidoscopy 
 
Note:  Detailed information regarding the rectal and genital examination, as well as the 
associated procedures required for collecting specimens at each visit, can be found in the 
MTN-039 SSP Manual. 
 
Additional clinical assessments may be performed at the discretion of the examining 
clinician in response to symptoms or illnesses present at the time of the exam.  
 
7.9 Behavioral Assessments 
 
Participants will respond to brief computer administered self-interviews (CASI) at the 
Enrollment visit (Visit 2), and at the post-dose visits (Visits 4 and 8). The baseline 
assessment, done at Enrollment, will include, among other topics, questions on 
participants’ prior experience and comfort using rectal products as well as douching or 
other rectal hygiene practices. The follow-up assessments will explore reactions to 
product and administration method. These assessments will allow us to identify product 
attributes likely to challenge and/or facilitate future sustained use when applied rectally 
by participants (secondary objective: acceptability). Suggestions for product improvement 
will also be collected. 
 
An in-depth interview is planned at Visit 10. The in-depth interviews will include, among 
other topics, questions on user acceptability of the product, user-centered suggestions 
for product design and delivery, and experiences with the direct application method. The 
interview notes, recording and transcript from the in-depth interview will be considered as 
source documentation. Major components of these assessments to be used have been 
validated in prior rectal microbicide trials (e.g., MTN-006, MTN-007, MTN-017) and on-
going trials (MTN-026, MTN-033, and MTN-037). 
 


 
 
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7.10 Pharmacokinetics (PK) and Pharmacodynamics (PD) 
 
The MTN-039 cohort will provide samples for PK and PD throughout the study from Visits 
2 through 10. At study randomization, participants will be assigned to one of two 
schedules for collection of rectal tissue (collected with flexible sigmoidoscopy), rectal fluid, 
and cervicovaginal fluid (if applicable): 
Group 1: Visits 3, 5, 7, and 9 
Group 2: Visits 4, 6, 8, and 10 
Note: Both groups 1 and 2 will provide blood at Visits 3-10. At Visits 3 and 7, both groups 
will provide rectal fluid and cervicovaginal fluid (if applicable) – Group 1 at 2 and 6 
hours post-dose, and Group 2 at 4 hours post-dose. All sampling times are 
approximate; allowable windows and detailed instructions are provided in the MTN-
039 SSP Manual. 
 
Table 16: Specimens to be Collected to Assess Safety, PK and Ex Vivo Antiviral Activity 
Study Visit 
Specimens collected for PK, PD and mucosal safety 
 
Blood 
Rectal Fluid 
Rectal Tissue 
CVF  
Visit 2 - 
Enrollment 
 
• Blood for PK 
 
• RF for microbiome  
• RF for PD  
 
• 7 samples for biomarkers 
o 1 histology 
o 1 proteomics 
o 1 metabolomics 
o 4 flow cytometry  
• 4 samples for PD 
• 
CVF for microflora 
• 
CVF for PD 
Visit 3 & Visit 7 -  
Samples 
collected at 1, 2, 
4 and 6 hours  
 
• Blood for PK 
 
  
Group 1 at 2-hour  
• RF for microbiome  
• RF for PK 
• RF for PD 
 
Group 1 at 6-hour 
• RF for PK 
Group 2 at 4-hour  
• RF for PK 
 
Group 1 only at 2-hour 
• 7 samples for biomarkers 
• 4 samples for PD 
• 11 samples for PK  
o 1 for EVG 
o 1 for TFV/TFV-DP 
o 1 for backup 
o 8 for MMC isolation 
Group 1 at 2-hour  
• CVF for microflora  
• CVF for PK 
• CVF for PD 
 
Group 1 at 6-hour 
• CVF for PK 
Group 2 at 4-hour  
• CVF for PK 
 
Visits 4 & 8 -  
24 hour  
• Blood for PK 
 
Group 2 only  
• RF for microbiome 
• RF for PK 
• RF for PD 
 
Group 2 only 
• 7 samples for biomarkers 
• 4 samples for PD 
• 11 samples for PK  
 
Group 2 only   
• CVF for microflora  
• CVF for PK 
• CVF for PD 
 
Visits 5 & 9 -  
48 hour 
• Blood for PK 
 
Group 1 only  
• RF for PK 
• RF for PD 
 
Group 1 only 
• 4 samples for PD 
• 11 samples for PK  
 
Group 1 only   
• CVF for PK 
• CVF for PD 
 
Visits 6 & 10 -  
72 hour 
• Blood for PK 
 
Group 2 only  
• RF for PK 
• RF for PD 
 
Group 2 only 
• 4 samples for PD 
• 11 samples for PK  
 
Group 2 only   
• CVF for PK 
• CVF for PD 
 
 
7.11 Laboratory Evaluations 


 
 
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Local Laboratory 
The local laboratory will run the following, as indicated: 
 
• Pharyngeal specimens 
o NAAT for GC/CT 
• Vaginal specimens 
o NAAT for GC/CT/TV 
• Urine specimens 
o hCG 
o NAAT for GC/CT 
o Dipstick/culture 
• Rectal specimens 
o Rectal fluids for:  
 NAAT for GC/CT  
o Rectal tissue for: 
 PD (MTN LC approved) 
• Blood specimens 
o HIV-1/2 testing, with confirmatory testing as needed 
o CBC with differential and platelets  
o Chemistries (AST/ALT/creatinine) 
o Syphilis serology 
o Coagulation (PT/INR) 
 
Network Laboratory Center (LC) 
• Cervicovaginal specimens  
o Fluid for PK (Pharmacology Core) 
o Fluid for PD (Pharmacodynamics Core) 
o Fluid for microflora  
• Blood specimens 
o PK (Pharmacology Core) 
o Plasma archive 
• Rectal specimens  
o Rectal fluids for:  
 PK (Pharmacology Core) 
 PD (Pharmacodynamics Core) 
 Microbiome   
o Rectal tissue for: 
 PK (Pharmacology Core) 
 Biomarkers 
 
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. Specimens obtained from participants who do not consent to long 
term storage will not be used for assay validation or proficiency testing purposes. 
 


 
 
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7.12 Specimen Management 
 
Study sites will adhere to the standards of good clinical laboratory practice 
(https://www.niaid.nih.gov/sites/default/files/gclp.pdf), in accordance with current US 
Division of AIDS (DAIDS) Laboratory Requirements, MTN-039 Study Specific Procedures 
Manual (http://www.mtnstopshiv.org/studies) and site standard operating procedures 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 on leftover samples that are stored for the purposes 
of future research. 
 
7.13 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) 
 
7.14 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. 
 
 


 
 
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8 
ASSESSMENT OF SAFETY 
 
8.1 Safety Monitoring 
 
Site IoRs are responsible for continuous close safety monitoring of all study participants 
and for alerting the Protocol Team if unexpected concerns arise. A sub-group of the 
Protocol Team, including the Protocol Chair, DAIDS Medical Officer, a CONRAD 
representative, and MTN Protocol Safety Physicians will serve as the PSRT. The MTN 
Statistical Data and 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, the PSRT and study sponsors. 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. AE reports 
submitted in an expedited manner to the DAIDS Safety Office will be forwarded to the 
DAIDS Medical Officer, SDMC Clinical Safety & Coding Group staff, and CONRAD 
representative for review. 
 
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 
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 their 
regular reviews (see Section 10), since no Data and Safety Monitoring Board oversight is 
planned for MTN-039. 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, DAIDS will notify the FDA as necessary and Site IoRs will notify 
the responsible IRB expeditiously. 


 
 
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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 study groups, and is 
applied to all groups beginning at the time of enrollment (i.e., once a participant is 
randomized) through the termination visit. The term “investigational product” for this study 
refers to the TAF/EVG Insert, 20/16 mg.   
 
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. With appropriate permission of the participant, whenever possible, 
records from all non-study medical providers related to untoward medical occurrences 
will be obtained and required data elements will be captured in the study database. All 
participants reporting an untoward medical occurrence will be followed clinically until the 
occurrence resolves (returns to baseline) or stabilizes. 
 
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).  
 
Please note: 
• Asymptomatic BV and asymptomatic candidiasis will not be reportable AEs; 
Note: Asymptomatic BV and asymptomatic candidiasis will be captured on the 
CRF that captures STI results. 
• Fetal losses (e.g., spontaneous abortions, spontaneous fetal deaths, stillbirths) will 
not be reported as AEs; 
Note: Fetal loss data will be captured on the Pregnancy Outcome CRF. 


 
 
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• Untoward maternal conditions that either result in or result from fetal losses are 
reported as reproductive system AEs. 
 
Bleeding at the time of anoscope, flexible sigmoidoscope insertion/removal, and/or biopsy 
collection that is judged by the clinician to be within the range of what is normally 
anticipated will not be reportable as an AE. Bleeding of greater quantity or longer duration 
than what is typical, per clinician assessment, will be reportable as an AE. Fecal urgency, 
bloating and flatulence associated with rectal procedures deemed to be within the range 
of what is normally expected will not be reportable as AEs. 
 
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), 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 and is not subject to expedited reporting. 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) 
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 a serious adverse drug experience 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: 
 


 
 
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• 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 Adverse Event Reporting Requirements 
 
8.4.1 
Expedited Adverse Event Reporting to DAIDS 
 
Requirements, definitions and methods for expedited reporting of AEs are outlined in 
Version 2.0 of the DAIDS EAE Manual, which is available on the DAIDS RSC website at 
https://rsc.niaid.nih.gov/clinical-research-sites/manual-expedited-reporting-adverse-
events-daids.  
 
The DAIDS Adverse Experience Reporting System (DAERS), an internet-based reporting 
system, must be used for expedited adverse event (EAE) reporting to DAIDS. In the event 
of system outages or technical difficulties, EAEs may be submitted using the DAIDS EAE 
Form. 
This 
form 
is 
available 
on 
the 
DAIDS 
RSC 
website 
at 
https://rsc.niaid.nih.gov/clinical-research-sites/paper-eae-reporting.  
 
DAIDS will be responsible for all FDA correspondence and for all site and DAIDS 
reporting. DAIDS will inform CONRAD of any reportable events and send a copy of all 
FDA correspondence to CONRAD. For questions about DAERS, please contact NIAID 
CRMS Support at CRMSSupport@niaid.nih.gov. Please note that site queries may also 
be sent from within the DAERS application itself. 
 
For questions about expedited reporting, please contact the DAIDS RSC Safety Office at 
DAIDSRSCSafetyOffice@tech-res.com. 
 
8.4.2 
Reporting Requirements for this Study        
 
The SAE Reporting Category, as defined in Version 2.0 of the DAIDS EAE Manual, will 
be used for this study. The study agent for which expedited reporting is required is: 
Tenofovir Alafenamide (TAF)/Elvitegravir (EVG) Insert, 20/16 mg.            
                     
8.4.3 
Grading Severity of Events 
 
The grading of severity of events and the reporting period will be the same as for all AEs, 
as described in Section 8.3.1. The most current Division of AIDS Table for Grading Adult 
and Pediatric Adverse Events, Corrected Version 2.1, July 2017 and 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) will 
be used and are available on the RSC website at https://rsc.niaid.nih.gov/clinical-
research-sites/daids-adverse-event-grading-tables.   
 


 
 
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8.4.4 
Expedited AE Reporting Period 
 
The EAE reporting period for this study begins at enrollment (i.e., randomization) and 
continues through the participant’s termination from the study. 
 
After the protocol-defined AE reporting period, unless otherwise noted, only Suspected, 
Unexpected Serious Adverse Reactions (SUSARs) as defined in Version 2.0 of the EAE 
Manual will be reported to DAIDS if the study staff become aware of the events on a 
passive basis (from publicly available information). 
 
8.5 Pregnancy and Infant Outcomes 
 
Pregnant women are excluded from this study. 
 
A participant who becomes pregnant after enrollment will continue to be followed until the 
end of pregnancy and, if applicable, infant outcome is ascertained, see Section 9.5 for 
additional details. Pregnancy and infant outcomes will be reported on relevant CRFs. 
Pregnancy outcomes will not be expeditiously reported to CONRAD or the DAIDS Medical 
Officer (MO) unless there is an associated AE in the pregnant participant that meets 
expedited reporting criteria or the pregnancy results in a congenital anomaly meeting the 
Manual for Expedited Reporting of EAEs to DAIDS (Version 2.0, January 2010) guidelines 
for expedited reporting.  
 
8.6 Regulatory Requirements 
 
Information on all reported AEs will be included in reports to the FDA and other applicable 
government and regulatory authorities. Site IoRs/designees will submit AE and any 
relevant safety information in accordance with local regulatory requirements. 
 
8.7 Social Harms Reporting 
 
Although study sites 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 according to their individual requirements. 
 
 
9 
CLINICAL MANAGEMENT 
Guidelines for clinical management and permanent discontinuation of study product are 
outlined in this section. In general, the IoR/designee has the discretion to permanently 
discontinue study product use at any time if he/she feels that continued product use would 
be harmful to the participant or interfere with treatment deemed clinically necessary. 
IoRs/designees will document all permanent discontinuations on applicable CRFs. 
 


 
 
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9.1 Grading System 
 
AE severity grading is described in Section 8.4.3. 
 
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 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 or breastfeeding 
• Anogenital STIs 
• 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. 
• Reported use of or need for PrEP or PEP. Participants who experience a known 
or potential HIV exposure during study participation or have a recognized risk of 
exposure and thus need PEP or PrEP will have study product permanently 
discontinued and will be referred for PEP or PrEP initiation. Those who need PEP 
will be encouraged to start it as quickly as possible and within 72 hours of potential 
exposure. Since continued study follow-up would be of no benefit following 
permanent discontinuation of study product use, these participants will be exited 
from the study.      
• Anticoagulant use (e.g., heparin, Lovenox, warfarin and Plavix) 
• Use of certain CYP3A inhibitors and inducers (as specified in Table 8 and Table 
9) 
• Participant develops a Grade 4 adverse event.  
 
9.4 Follow-up in Response to Observed Adverse Events 
 
Grade 1 and Grade 2 Unrelated  
In general, a participant who develops a Grade 1 AE, regardless of relationship to study 
product, may continue product use. Participants who develop a Grade 2 AE that is judged 
by the IoR/designee to be unrelated to study product may also continue product use. If 
the IoR/designee opts to temporarily hold study product, the PSRT must be notified. 
 
 
Grade 2 Related and Grade 3 
For participants who develop a Grade 2 AE that is judged by the IoR/designee to be 
related to product or any Grade 3 AE, study product must be held and the IoR must 
consult with PSRT regarding provision of the second dose. 
 
Grade 4 
For participants who develop a Grade 4 AE study product must be permanently 
discontinued and the PSRT notified. 


 
 
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9.5 Pregnancy 
 
Female participants 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 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 study participation will have study product 
discontinued and will be terminated from the study, as per Section 7.5.2. The study site 
will make every reasonable effort to contact participants and collect infant outcome at 
approximately one year after delivery for those pregnancies that result in live birth. A 
participant who is pregnant at study termination will continue to be followed until the 
pregnancy outcome is ascertained (or, in consultation with the PSRT, it is determined that 
the pregnancy outcome cannot be ascertained).  
 
9.6 Criteria for Early Termination of Study Participation 
 
Participants may voluntarily withdraw from the study for any reason at any time. 
IoRs/designees 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 CONRAD, NIAID, 
MTN, government or regulatory authorities, including the FDA and Office for Human 
Research Protections (OHRP), or site IRBs 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). Study staff members will record the 
reason(s) for all withdrawals in participants’ study records. 
 
  
10 
STATISTICAL CONSIDERATIONS 
 
10.1 Overview and General Design 
 
MTN-039 is a phase 1, open label, single-arm, two-period trial designed to characterize 
the safety and PK profiles of the TAF/EVG Insert, 20/16 mg administered rectally at two 
dose levels (one insert in the first period and two inserts in the second period). Twenty 
HIV-uninfected individuals 18 years of age or older will receive a single dose (one insert), 
then allow time for adequate washout before application of the two-insert dose. Samples 
will be taken over a 3-day period after each dose application. 
 


 
 
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10.2 Study Endpoints 
 
Primary Endpoints 
 
Consistent with the primary study objectives to (1) evaluate the safety of the TAF/EVG 
Insert when applied rectally at two dose levels and (2) characterize the systemic and 
rectal pharmacokinetics of the TAF/EVG Insert(s) following rectal application, the 
following endpoints will be assessed: 
 
• Safety 
All Grade 2 and higher AEs  
 
• Pharmacokinetics 
EVG concentrations in: 
o Blood 
o Rectal fluid 
o Rectal mucosal tissue homogenates  
 
TAF and TFV concentrations in: 
o Blood 
o Rectal fluid  
 
TFV-DP concentrations in: 
o Rectal mucosal tissue homogenates 
o Rectal mucosal tissue cell isolates 
 
10.3 Primary Study Hypotheses 
 
MTN-039 hypothesizes that TAF and EVG will be safe when applied to the rectum and 
well-tolerated among healthy men and women who have a history of receptive anal 
intercourse (RAI). 
 
10.4 Sample Size and Power Calculations 
 
Safety Endpoints 
 
The proposed total sample size for assessing safety is approximately N=20 participants.  
This sample size is based upon the size of similar Phase 1 studies of microbicides for 
HIV prevention. 
 
As a means to characterize the statistical properties of this study, Table 17 below presents 
the probability of observing zero, at least one, and two or more safety endpoints among 
the 20 participants for various “true” event rates: 
 
Table 17: Analysis of Safety Event Frequency 
Event Rate 
P (0 events | n=20) 
P (>1 event | n=20) 
P (>2 events | n=20) 
1% 
81.8 
18.2 
1.7 


 
 
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If the true rate of a safety endpoint is 5%, the probability of observing that endpoint in at 
least one out of 20 participants is 0.64.  
 
An alternative way of describing the statistical properties of the study design is in terms 
of the 95% confidence interval for the true rate based on the observed data. Table 18 
below shows the exact 2-sided 95% confidence intervals for the probability of an event 
based on a particular observed rate. If none of the 20 participants receiving a particular 
dose (one insert or two inserts) experience a safety event, then the 95% exact 2-sided 
upper confidence bound for the true rate of such events for that dose is 16.8%. 
 
Table 18: Exact 2-sided 95% Confidence Intervals Based on Observing a Particular Rate of 
Safety Endpoints among 20 Participants 
Observed event rate 
Confidence interval (%) 
0/20 (0%) 
0.0, 16.8 
1/20 (5%) 
0.1, 24.9 
2/20 (10%) 
1.2, 31.7 
3/20 (15%) 
3.2, 37.9 
  
Additional participants may enroll in the study, at the discretion of the protocol team, to 
replace currently enrolled participants lost to follow-up or to permanent product 
discontinuation. Thus, if additional participants are recruited for this purpose, the total 
sample size at the end of the study may slightly exceed 20 participants who received 
either dose of TAF and EVG. 
 
10.5 Randomization Procedures 
 
There will be no randomization to dose of TAF and EVG (one insert or two inserts) in this 
open-label, single-arm, and two-period trial. However, upon enrollment, participants will 
be randomly assigned to one of two sample collection schedules for the collection of rectal 
tissue (collected with flexible sigmoidoscopy), rectal fluid, and cervicovaginal fluid (if 
applicable): 
Group 1: Visits 3, 5, 7, and 9 
Group 2: Visits 4, 6, 8, and 10 
Note: Both groups 1 and 2 will provide blood at Visits 3-10. At Visits 3 and 7, both 
groups will provide rectal fluid and cervicovaginal fluid (if applicable) – Group 1 at 
2 and 6 hours post-dose, and Group 2 at 4 hours post-dose. 
 
Randomization will be stratified by sex at birth to incorporate at least three participants 
assigned female sex at birth in each group. 
 
The randomization scheme will be generated and maintained by the MTN SDMC. 
 
5% 
35.8 
64.2 
26.5 
10% 
12.2 
87.8 
60.8 
15% 
3.9 
96.1 
82.4 
20% 
1.2 
98.8 
93.0 
25% 
0.3 
99.7 
97.6 


 
 
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10.6 Participant Accrual, Follow-up and Retention 
 
Based on previous studies of rectal products with similar eligibility requirements, the 
accrual of approximately 20 eligible participants will take approximately 6-8 months. 
Individuals lost to follow-up or to permanent product discontinuation may be replaced after 
statistical and team input have been received. However, every effort will be made to 
complete the regularly scheduled safety evaluations and retain all enrolled participants in 
follow-up to minimize possible bias associated with loss-to-follow-up. 
 
10.7 Data and Safety Monitoring and Analysis 
 
10.7.1  Study Monitoring Committee 
 
No Data and Safety Monitoring Board oversight is planned for this study. The MTN SMC 
will conduct interim reviews of participant safety data and 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 this review, or at any other time, the SMC may 
recommend that the study proceed as designed, proceed with design modifications, or 
be discontinued. 
 
10.7.2  Primary Analysis 
 
When the use of descriptive statistics to assess group characteristics or differences is 
required, the following methods will be used: for categorical variables, the number and 
percent in each category; for continuous variables, the mean, median, standard deviation, 
quartiles and range (minimum, maximum). Within-treatment group assessment of the 
change from the baseline measurement to a follow-up measurement will be analyzed 
using McNemar’s test (for categorical response variables) or the paired t-test or Wilcoxon 
signed-ranks test (for continuous variables). 
 
Safety Endpoints 
All visits in which a participant has been exposed to the study product will be included in 
the primary analyses of safety. Secondary intent to treat analyses may also be performed. 
The number and the percentages of participants experiencing each safety endpoint (see 
Section 10.2) will be tabulated by dose (one insert or two inserts). Each participant will 
contribute once in each category (i.e., only for highest severity AE for each participant) 
for the calculation of event rates for each dose. 
 
To assess the overall tolerability of the two doses (one insert or two inserts), participants 
in each dose may be compared for characteristics including safety events and laboratory 
measurements using descriptive statistics. Due to the small sample size, formal 
comparisons will not be done.  
 
Pharmacokinetic Analysis  
We will use descriptive statistics for continuous variables as defined above to describe 
the EVG and tenofovir-related analyte (TAF, TFV) concentrations in blood, rectal fluid, 
and rectal tissue assessed at all scheduled time points.  For each dose (one insert or two 


 
 
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inserts), the 1 to 72-hour time points will be used to describe the concentrations beginning 
soon after a dose exposure through time to peak concentrations through initial elimination 
among different matrices. EVG developmental PK studies are planned to be conducted 
in parallel with this study to inform interpretation of EVG tissue PK and explant results. 
 
10.7.3  Secondary and Exploratory Analyses 
 
Acceptability Analysis 
We will use descriptive statistics to summarize overall acceptability of the two dose 
regimens and to identify product attributes considered likely to challenge and/or facilitate 
future sustained use of the TAF/EVG Insert when applied rectally.  
 
Pharmacokinetic/Pharmacodynamic Analysis  
We will use descriptive statistics for continuous variables as defined above to describe 
the EVG and tenofovir-related analyte (TAF, TFV) concentrations in cervicovaginal fluid 
at all scheduled time points.  For each dose (one insert or two inserts), the 1 to 72-hour 
time points will be used to describe the concentrations beginning soon after a dose 
exposure through time to peak concentrations through initial elimination in cervicovaginal 
fluid. 
 
Ex vivo HIV explant data will use virus levels to compare baseline levels with virus levels 
on study product. Concentration-response relationships may also be explored using 
appropriate linear and non-linear models. Rectal fluid and cervicovaginal fluid will be 
assessed for anti-HIV activity, and the percent inhibition will be correlated to EVG and 
tenofovir-related analyte (TAF, TFV) concentrations. 
10.7.4 Missing Data 
 
Every effort will be made to complete the regularly scheduled safety and PK evaluations 
and retain all enrolled participants in follow-up over the two dose evaluations lasting 
approximately 21 to 77 days total, including washout. Based on previous MTN trials, we 
expect to have minimal missing data. If participants are lost to follow-up or to permanent 
product discontinuation, they may be replaced, as mentioned above. If missing data rates 
are higher than anticipated (over 15%) for a particular dose safety evaluation or for 
individual pharmacokinetic measure time points, then additional participants may enroll 
in the study at the discretion of the protocol team.  
 
 
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 reports and queries will be routinely generated and provided by the 
SDMC to the study sites for verification and resolution. As part of the study activation 
process, each study site must identify all CRFs to be used as source documents. Study 
CRF data will be entered into the MTN-039 database, transferred in compliance with the 


 
 
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US-EU Safe Harbor Requirements and the EU Data Protection Directive 95/46/EC to the 
MTN SDMC, entered, and cleaned using Medidata Rave, a data management system 
compliant with the International Council on Harmonization (ICH) Good Clinical Practices 
(GCP) and US CFR guidelines for electronic data capture.  
 
Transcriptions of interviews will be generated using the audio files recorded at University 
of Pennsylvania. Both the audio files and the transcripts will be uploaded and managed 
using a qualitative software package. Interview notes will be kept at the University of 
Pennsylvania in the participant files. 
 
11.2 Source Documents and Access to Source Data/Documents 
 
All study sites will maintain source data/documents in accordance with current DAIDS 
policies. (https://www.niaid.nih.gov/sites/default/files/daids-sourcedocpolicy.pdf)   
 
Each IoR/designee will maintain, and store securely, complete, accurate and current 
study records throughout the study. In accordance with U.S. regulations, for the 
investigational products tested, IoRs/designees will maintain all study documentation for 
at least two years following the date of marketing approval for the indication in which they 
were studied.  If no marketing application is filed, or if the application is not approved, the 
records will be retained for two years after the investigation is discontinued and the US 
FDA is notified.   
 
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.   
 
11.3 Quality Control and Quality Assurance 
 
Study sites 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 MONITORING 
 
Study monitoring will be carried out by Pharmaceutical Product Development, Inc. (PPD) 
(Wilmington, NC) in accordance with current DAIDS policies. Study monitors will visit 
study sites to do the following: 
 
• Review informed consent forms, procedures, and documentation 
• Assess compliance with the study protocol, Good Clinical Practices (GCP) 
guidelines, and applicable regulatory requirements (US and non-US), including 
CFR Title 45 Part 46 and Title 21 Parts 50, 56, and 312  
• Perform source document verification to ensure the accuracy and completeness 
of study data 
• Verify proper collection and storage of biological specimens 


 
 
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• Verify proper storage, dispensing, and accountability of investigational study 
products 
• Assess implementation and documentation of internal site quality management 
procedures 
 
IoRs/designees will allow study monitors to inspect study facilities and documentation 
(e.g., informed consent forms, clinic and laboratory records, other source documents, 
CRFs), as well as observe the performance of study procedures. IoRs/designees also will 
allow inspection of all study-related documentation by authorized representatives of the 
MTN LOC, SDMC, LC, CONRAD, NIAID, FDA, OHRP, IRBs, and other local, US or 
international regulatory authorities. A site visit log will be maintained at study sites 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, IoRs/designees will have obtained IRB approval and the protocol will have been 
submitted to the FDA. IoRs/designees will permit audits by the NIH, CONRAD, the FDA, 
OHRP, MTN LOC, IRBs, 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 
participant education and recruitment materials) are reviewed by an IRB responsible for 
oversight of research conducted at each study site. Any amendments to the protocol must 
be approved by the responsible IRBs prior to implementation. 
 
After the initial review and approval, the responsible IRBs must review the study at least 
annually. Each IoR/designee will make safety and progress reports to the IRBs 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. Study sites 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, 
sites must have the protocol and the protocol consent forms approved, as appropriate, by 
its local IRB and any other applicable regulatory entity (RE). Upon receiving final 
approval, sites will submit all required protocol registration documents to the DAIDS PRO 


 
 
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at the RSC. The DAIDS PRO will review the submitted protocol registration packet to 
ensure that all of the required documents have been received.  
 
Site-specific ICFs will be reviewed or approved by the DAIDS PRO, and sites will receive 
an Initial Registration Notification when the DAIDS PRO receives a complete registration 
packet. Receipt of an Initial Registration Notification indicates successful completion of 
the protocol registration process. Sites will not receive any additional notifications from 
the DAIDS PRO for the initial protocol registration. A copy of the Initial Registration 
Notification should be retained in each site's regulatory files. 
 
Upon receiving final IRB and any other applicable RE approval(s) for an amendment, 
sites should implement the amendment immediately. Sites are 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 sites will receive an Amendment Registration Notification when 
the DAIDS PRO receives a complete registration packet. A copy of the Amendment 
Registration Notification should be retained in site 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. 
 
13.3 Study Coordination 
 
DAIDS holds the Investigational New Drug (IND) application for this study. Assignment of 
all sponsor responsibilities for this study will be specified in a Clinical Trials Agreement 
(CTA) executed by NIAID and CONRAD. 
 
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 sites 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 team as well as the SMC. 
 


 
 
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13.4 Risk Benefit Statement 
 
13.4.1 
Risks 
 
It is not expected that this trial will expose human subjects to unreasonable risk. 
 
Vaginal Fluid Collection 
Collection of vaginal fluid may cause discomfort or pressure in the vagina or genital area. 
 
Phlebotomy and IV Cannula Placement 
Phlebotomy may lead to discomfort, feelings of dizziness or faintness, and/or bruising, 
swelling, having a blood clot, excessive bleeding, and/or infection.  
 
Pharyngeal Swab 
Pharyngeal (throat) swab collection often causes a momentary gagging reflex. 
 
Rectal Enema 
An enema is a standard procedure that may be used prior to insertion of a flexible 
sigmoidoscope since fecal matter can obscure the test. The main risk from having an 
enema is temporary discomfort.  A hollow tube about the thickness of a pencil will be used 
to put approximately 120 mL of normal saline 0.9% into the rectum and flush it out again 
(a larger volume may be required if the initial volume does not produce results), along 
with any stool that is there. There is a risk of a bloated/cramping feeling. The tube is small, 
but it might cause some anal or rectal discomfort if the participant has any hemorrhoids 
or other painful conditions. There is also a remote possibility of rectal perforation 
associated with the use of an enema. 
    
Finger and Anoscope Rectal Exams 
During rectal exams and collection of rectal fluid and tissue samples, insertion of a finger 
or lubricated anoscope will likely cause some discomfort. 
 
Flexible Sigmoidoscopy and Rectal Biopsy Collection 
Flexible sigmoidoscopy is a commonly practiced endoscopic medical procedure and will 
not involve any increased risk over usual sigmoidoscopy performed for clinical indications.  
There is a low risk of infection, mild rectal irritation, low blood pressure, and feeling a 
sudden urge to defecate during or after the flexible sigmoidoscopy procedure. There is a 
very low risk of an intestinal tear during the flexible sigmoidoscopy procedure. 
 
There is a risk of limited rectal bleeding 1-2 days after flexible sigmoidoscopy, associated 
with collection of biopsy samples. The rate of perforation of a hollow viscus following 
endoscopic biopsy occurs less than 88 out of every 100,000 times.32 A recent 
retrospective analysis of approximately 1,000 research flexible sigmoidoscopies 
(including collection of rectal biopsies) conducted at the University of Pittsburgh 
demonstrated an overall adverse event rate of 1.6%. The majority of AEs were 
gastrointestinal in nature and of mild/moderate severity.33  
 
Participants will be instructed to refrain from sexual intercourse and counseled not to use 
aspirin (over 81 mg per day) and non-steroidal anti-inflammatory drugs (NSAIDS) within 


 
 
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72 hours prior to and following a tissue sample collection visit.  If participants engage in 
sexual intercourse before the biopsy has healed they may experience some temporary 
discomfort. If participants are sexually active they may also be at increased risk for STIs 
and HIV acquisition, if exposed. There is a small risk of infection and heavier bleeding. 
Participants will be instructed to contact the clinic if symptoms are bothersome, if heavy 
bleeding is noted or if the participant develops any abnormal odor or discharge from the 
rectum. 
 
Rectal Fluid Collection 
There is the risk of mild discomfort in addition to a slight risk of bleeding with the insertion 
of rectal swabs and sponges for collection of rectal fluid.  
 
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. 
 
Sexual partner notification in response to diagnosed STI or HIV infection could cause 
problems in participants’ relationships. Participants also could have problems in their 
partner relationships associated with study-required abstinence.   
 
Site staff will make every effort to protect participant privacy while in the study.  Although 
study sites 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.   
 
Risks Associated With EVG Insert8 
If administered rectally, an insert containing EVG may cause the following: 
• Rectal urgency 
• Rectal irritation 
• Rash 
• Exacerbation of hemorrhoid symptoms 
 
Risks Associated With Oral EVG7 
These risks are based on the safety assessment of EVG oral tablets when co-
administered with other ARVs: 
 
Most Common Adverse Reactions (All grades, incidence ≥10%) in subjects receiving 
EVG were:  
• Headache 
• Diarrhea 


 
 
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• Nausea 
• Fatigue 
 
Other Common Adverse Reactions (All grades, incidence ≥1% and <10%) were: 
• Depression 
• Insomnia 
• Abdominal pain 
• Vomiting 
• Dyspepsia 
• Rash  
 
Uncommon Adverse Reactions (All grades, incidence ≥0.1% and <1%) in patients with 
a pre-existing history of depression or psychiatric illness were: 
• Depression 
• Insomnia 
• Suicidal ideation and suicide attempt 
 
Risks Associated With TAF12 
These risks are based on the safety assessment of TAF oral tablets from previous 
randomized, double-blind, active-controlled trials: 
 
Most Common Adverse Reactions (All grades, incidence ≥5%) were:   
• Headache 
• Abdominal pain 
• Cough 
• Back pain 
• Fatigue 
• Nausea 
• Arthralgia  
• Diarrhea 
• Dyspepsia  
 
Other Common Adverse Reactions (All grades, incidence ≥1% and <5%) were: 
• Vomiting 
• Rash  
• Flatulence  
 
There is a theoretical risk of the development of HIV drug resistance to tenofovir or 
elvitegravir if the participant acquires HIV infection around the time of study drug 
administration. 
 
Risks Associated With Rectally-Applied Drugs     
In previously completed studies involving repeated use of rectally-applied gel products, 
the following AEs were observed. These side effects may or may not be associated with 
the use of TAF/EVG Insert administered rectally:  
 
More Common Adverse Reactions (incidence ≥5%) were:  


 
 
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• Flatulence  
• Defecation urgency  
• Diarrhea  
 
Less Common Adverse Reactions (incidence <5%) were:  
• Abdominal distension  
• Abdominal bloating 
• Abdominal pain/cramps 
• Tenesmus 
• Irritation in the rectum 
• Rash  
• Worsening of existing problems due to hemorrhoids 
 
13.4.2 
Benefits 
 
Participants in this study may 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, physical 
and rectal examination, and routine laboratory testing related to blood, liver, and kidney 
function. Participants may be provided or referred for STI treatment free of charge, and 
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 sources of care available in 
their community. Some volunteers may have the opportunity to access expedient 
treatment and 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. 
Written informed consent also will be obtained for long-term specimen storage and 
possible future testing, although consent for long-term specimen storage is not required 
for study participation. In obtaining and documenting informed consent, IoRs 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 provided with copies of the ICF if they are willing to receive them.  
 
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 study sites, which will be 


 
 
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detailed in the SSP Manual.  
 
The informed consent process will cover all elements of informed consent required by 
research regulations. In addition, the process specifically will address the following topics 
of importance to this study: 
 
• The unknown safety and unproven efficacy of the study product 
• The need to abstain from sexual intercourse for protocol defined periods 
• The importance of participants in all study groups 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.  Study sites 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.  
 
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 FDA, the US 
OHRP, NIH and/or contractors of the NIH, and other local, US or international 
regulatory authorities 
• PPD 
• Representatives of CONRAD, including study monitors 
• Representatives of the MTN LOC, SDMC, and/or LC Study staff  
• Site IRBs 
 
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 


 
 
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civil, criminal, administrative, legislative or other proceedings. It thus serves to protect  
the identity and privacy of study participants. 
 
13.7 Special Populations 
 
13.7.1 
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 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 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 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 sites and additionally will 
emphasize the unknown efficacy of the study products in preventing HIV-1 infection. In 
accordance with the policies of the NIH, participants must receive their HIV-1/2 test 
results to take part in this study.   
 
13.11 Study Discontinuation 
 
This study may be discontinued at any time by NIAID, the MTN, CONRAD, the US FDA, 
the OHRP, other government or regulatory authorities, or site IRBs. 
 
 
 


 
 
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14 
 PUBLICATION POLICY 
 
DAIDS/NIAID and MTN policies and a CTA between NIAID and CONRAD 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, 
and NIMH for review prior to submission. 
 
 
15 
APPENDICES 
 
 


 
 
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APPENDIX I:  SCHEDULE OF STUDY VISITS AND EVALUATIONS 
  
Screening  
Visit 1         
Enrollment   
Visit 2            
(Day 0) 
Dosing         
Visits 3, 7  
24 hours 
Post-
Dosing 
Visits 4 and 
8 
Other Post-
Dosing  
Visits 5, 6, 9, 
and 10 
Final 
Contact/Early 
Termination 
Visit 11 
ADMINISTRATIVE AND REGULATORY 
Obtain written informed 
consent 
X 
 
 
 
 
 
Assign a unique Participant 
Identification (PTID) number 
X 
 
 
 
 
 
Assess and/or confirm 
eligibility 
X 
X 
 
 
 
 
Collect demographic 
information 
X 
 
 
 
 
 
Collect/review/update locator 
information 
X 
X 
X 
X 
X 
X 
Random assignment of 
sampling schedule 
 
X 
 
 
 
 
Provide reimbursement 
X 
X 
X 
X 
X 
X 
Schedule next visit/contact  
* 
* 
X 
X 
X 
* 
BEHAVIORAL/COUNSELING 
HIV pre- and post-test 
counseling 
X 
X 
* 
* 
* 
* 
HIV/STI risk reduction 
counseling 
X 
X 
* 
* 
* 
* 
Protocol counseling 
X 
X 
X 
X 
X 
 
Behavioral assessment 
(CASI) 
 
X 
 
 
 
 
Behavioral assessment (Brief 
CASIs) 
 
 
 
X  
 
 
Behavioral IDI 
 
 
 
 
X (Visit 10) 
 
CLINICAL 
Collect/review/update 
concomitant medications 
X 
X 
X 
X 
X 
X 
Collect/review/update medical 
history 
X 
X 
X 
X 
X 
X 
Perform physical exam  
(Targeted at Visits 3-10) 
X 
X 
* 
* 
* 
* 
Perform genital exam 
* 
* 
* 
* 
* 
* 
Perform pelvic exam ▲ 
* 
* 
* 
* 
* 
* 
Perform rectal exam 
X 
X 
X 
X 
X 
* 
Treat or prescribe treatment 
for RTI/UTI/STIs 
* 
* 
* 
* 
* 
* 
Provide available test results  
X 
X 
X 
X 
X 
X 
Collect/update AEs 
 
 
X 
X 
X 
X 
LABORATORY 
PHARYGEAL 
NAAT for GC/CT 
X 
* 
* 
* 
* 
* 
URINE 
NAAT for GC/CT▼ 
X 
* 
* 
* 
* 
* 
Pregnancy test ■ 
X 
X 
* 
* 
* 
* 
Urine dipstick/culture 
* 
* 
* 
* 
* 
* 


 
 
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Screening  
Visit 1         
Enrollment   
Visit 2            
(Day 0) 
Dosing         
Visits 3, 7  
24 hours 
Post-
Dosing 
Visits 4 and 
8 
Other Post-
Dosing  
Visits 5, 6, 9, 
and 10 
Final 
Contact/Early 
Termination 
Visit 11 
BLOOD 
CBC with differential and 
platelets 
X 
* 
* 
* 
* 
(required at 
visit 10) 
* 
Chemistries 
(AST/ALT/creatinine) 
X 
* 
* 
* 
* 
(required at 
Visit 10) 
* 
Syphilis serology 
X 
* 
* 
* 
* 
* 
Coagulation (PT/INR) 
X 
 
 
 
 
 
Plasma for archive 
 
X 
 
 
 
 
HIV-1/2 test 
X 
X 
* 
* 
* 
(required at 
Visit 10) 
* 
Blood for PK 
 
X 
X  
X 
X  
 
PELVIC ▲ 
NAAT for GC/CT/TV 
X 
* 
* 
* 
* 
* 
CVF for PK 
 
 
X ** 
☼ 
X ⌂ 
 
CVF for PD 
 
X 
♣ (2 hrs 
post-
dose) 
☼ 
X ⌂ 
 
CVF for microflora 
 
X 
♣ (2 hrs 
post-
dose) 
☼ 
 
 
ANORECTAL 
NAAT for GC/CT 
X 
* 
* 
* 
* 
* 
Rectal fluid for PK  
 
 
X ** 
☼ 
X ⌂ 
 
Rectal fluid for PD 
 
X 
♣ (2 hrs 
post-
dose) 
☼ 
X ⌂ 
 
Rectal fluid for 
microbiome 
 
X 
♣ (2 hrs 
post-
dose) 
☼ 
 
 
Rectal enema prior to 
biopsy collection 
 
X 
 
 
X ⌂ 
 
Rectal tissue for PK  
 
 
♣ (2 hrs 
post-
dose) 
☼ 
X ⌂ 
 
Rectal tissue for PD  
 
X 
♣ (2 hrs 
post-
dose) 
☼ 
X ⌂ 
 
Rectal tissue for 
biomarkers 
 
X 
♣ (2 hrs 
post-
dose) 
☼ 
 
 
STUDY PRODUCT SUPPLY 
Administration of study 
product 
 
 
X 
 
 
 
Offer condoms 
X 
X 
X 
X 
X 
* 
Offer lubricant 
 
 
X 
 
 
 
Provide home enema kit 
 
X 
 
 
X  
(Visit 6 only) 
 
*  If indicated 
▲Participants assigned female sex at birth and if anatomy allows 
▼If pelvic GC/CT cannot be performed 
■ Participants of childbearing potential 
 All participants will have blood collected at 1, 2, 4, and 6 hours following product administration 


 
 
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Screening  
Visit 1         
Enrollment   
Visit 2            
(Day 0) 
Dosing         
Visits 3, 7  
24 hours 
Post-
Dosing 
Visits 4 and 
8 
Other Post-
Dosing  
Visits 5, 6, 9, 
and 10 
Final 
Contact/Early 
Termination 
Visit 11 
⌂ Group 1 will have biopsies, rectal fluid and cervicovaginal fluid (if applicable) at 48 hours (Visits 5 and 9) following 
each administration of product; Group 2 will have biopsies, rectal fluid and cervicovaginal fluid (if applicable) 
collected at 72 hours (Visits 6 and 10) following each administration of product. 
♣ Group 1 only 
☼ Group 2 only 
** Group 1: 2 and 6 hours post-dose; Group 2: 4 hours post-dose 
Note: All sampling times are approximate; allowable windows are provided in the MTN-039 SSP manual. 
 


 
 
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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
Ind: Indeterminate test results 
LC: Laboratory Center
 
 
 


 
 
 
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APPENDIX III: SAMPLE INFORMED CONSENT FORM (SCREENING, 
ENROLLMENT, LONG-TERM STORAGE AND FUTURE TESTING) 
 
DIVISION OF AIDS, NIAID, NIH 
 
MTN-039 
Version 1.0 
March 6, 2019 
 
A Phase 1 Open Label Safety and Pharmacokinetic Study of Rectal 
Administration of a Tenofovir Alafenamide/Elvitegravir Insert at Two Dose Levels  
 
PRINCIPAL INVESTIGATOR: [Site to insert] 
PHONE: [Site to insert] 
Short Title for the Study: Safety and PK Study of TAF/EVG Administered Rectally 
 
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-
negative adult, 18 years of age or older and reported at least one experience of 
consensual receptive anal sex in your lifetime. Approximately 20 people will participate in 
this study at two sites in the United States. National Institute of Health’s Division of AIDS 
(DAIDS) is the sponsor of 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 study product in this clinical trial is an insert that contains tenofovir 
alafenamide (TAF) and elvitegravir (EVG). The insert resembles a tablet and 
dissolves quickly once inside the body. It contains 20 mg TAF and 16 mg EVG. 
Both drugs are used to treat HIV and are now being tested to see if they also 
prevent HIV. 
• The purposes of this study are: 
o To find out if it is safe to apply the TAF/EVG Insert in the rectum.  
o To better understand the way the body absorbs, distributes, and gets rid of 
TAF and EVG when the insert is used in the rectum. 
o To understand whether you find it acceptable to use the insert when applied 
to the rectum.  
• If you qualify and choose to participate, you will receive two doses of the TAF/EVG 
Insert, 20/16 mg. The first dose will be one insert and the second dose will be two 
inserts. After each dose, you will have laboratory tests and clinical evaluations or 
exams for research purposes and to make sure you do not have any side effects. 
The second dose will be administered 7-49 days (1-7 weeks) after the first one. 
You will be randomly assigned to one of two sampling schedules for the lab tests. 


 
 
 
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• You will be asked to attend 10 clinic visits at this study clinic and will be followed 
for approximately 6-13 weeks. The total length of your participation in this study 
will be about 4 months.  
• At some of the clinic visits, the following will occur (other things may happen that 
are not listed here but are in the detailed descriptions of the study procedures): 
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) and for research purposes; 
o Urine will be collected to test for infections and (if applicable) pregnancy; 
o Rectal and vaginal fluids will be collected for research purposes and to test 
for STIs (if applicable). At 5 of the 10 visits, rectal tissue will also be 
collected;  
o You will be asked to complete 3 short interviews and a longer interview at 
Visit 10. 
• Some common side effects from the use of TAF and/or EVG in oral forms include: 
headache, diarrhea, nausea, fatigue, abdominal pain, cough, back pain, vomiting 
and rash. Uncommon adverse reactions include depression, insomnia and suicidal 
thoughts and attempts in patients with a history of depression or psychiatric illness. 
• There are no direct benefits for taking part in this study, but information learned 
from this study may help in the development of ways to prevent the spread of HIV 
in the future. You will receive HIV/STI risk reduction counseling, HIV and STI 
testing, physical and rectal examinations, and routine laboratory testing.  
• If you decide not to join this study: there are methods available to prevent sexually 
transmitted HIV, including 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.  
 
Please take time to read this entire form and ask questions before deciding whether to 
take part in this study. If you do decide to take part in this study, you will sign your name 
on this form. A copy of this form 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 your participation in this 
research is your decision and taking part in this study is completely voluntary. You may 
decide to stop being in the study at any time.   
 
What is the study product?   
Elvitegravir (EVG) is an anti-HIV medication that is FDA approved for oral use in 
combination with other medications for the treatment of HIV. EVG works in a specific way 
to potentially prevent HIV from making copies of itself, thereby stopping the spread of HIV 
in the human body.  
 
Oral EVG has been tested in combination with other medications in large clinical studies 
for treatment of HIV infection. These studies have shown that EVG in combination with 
other drugs is generally safe, with the most frequently reported adverse events being 


 
 
 
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related to the stomach and intestines. EVG in the form of an insert has been tested in 
animals in the vagina and in the rectum for drug absorption and safety with no findings of 
concern.  
 
Tenofovir alafenamide (TAF) is a medication that is FDA approved for the treatment of 
chronic hepatitis B or in combination with other medications for the treatment of HIV. TAF 
also inhibits the replication of HIV virus, therefore stopping the spread of HIV in the human 
body.  
 
TAF has been tested in clinical studies for safety and efficacy alone and as part of 
combination therapy that includes EVG. Similarly, study results indicated that TAF taken 
alone or in combination with other anti-HIV medications is generally safe.  
  
Researchers now would like to learn about the safety of the TAF/EVG Insert applied 
rectally and how the body absorbs, distributes, and gets rid of TAF and EVG. In this study, 
TAF and EVG are being tested for the first time in humans as a rectally-applied insert.    
 
Who will be in this research study and what will I be asked to do if I join? 
The study includes a total of 10 clinic visits and one final contact, including the Screening 
Visit which is taking place today. All clinical visits will take place at this study clinic.  
 
Study Visit Schedule   
 
 
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, your medical history, including what 
medications you are taking    
• Provide study staff your contact information (i.e. where you live and how we can 
contact you) 


 
 
 
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• Be asked to abstain from some medications during your participation in the study: 
 Blood thinners 
 Non-study related rectally-administered medications and any products
containing N-9 
 Certain medications that might interact with TAF or EVG  
 Medications used for PrEP (oral Truvada® or other PrEP) or PEP (post-
exposure prophylaxis). However, if you need medication due to a
known or potential exposure to HIV, you should take it but let the study
staff know as soon as possible 
• Talk with study staff about sexually transmitted infections (STIs), HIV, HIV/STI 
testing, and ways to avoid HIV and other infections passed through sex   
• Have a physical exam 
• If applicable, have your urine or vaginal fluid collected (via a swab) to test for 
sexually-transmitted diseases and other infections 
• Provide a blood sample [SITES TO INSERT AMOUNT]: 
o To test the health of your blood, liver and kidneys 
o To test for infections that typically are passed through sex, including HIV 
and syphilis 
 You will be told your test results as soon as they are available. You 
will talk with the study staff about the meaning of your results, how 
you feel about them, and learn about ways to prevent HIV and other 
sexually transmitted infections. Sometimes HIV tests are not clearly 
positive, but also not clearly negative. In that case, we will do more 
tests until we are sure of your status. To participate in the study, you 
must receive the results of your HIV test. 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.  
• Have a throat swab (like a Q-tip) collected, to test for infections passed through 
sex 
• Have a rectal examination. Rectal fluid will be collected with a swab; these will be 
used to test for sexually transmitted infections (STIs). To examine the rectum, 
study staff will insert a short hollow tube called an anoscope. The clinician will 
insert the swab through the hollow tube to collect the sample. 
• If applicable: 
o Your urine will be tested for pregnancy 
 If you are pregnant you cannot join this study 
 Staff will discuss with you ways to avoid getting pregnant 
• Be treated or referred for treatment of sexually transmitted infections, and/or be 
referred for any other care if needed 
• Receive your test results, when available. It is expected that all of your results will 
be available by [SITES TO SPECIFY TIMEFRAME].     
• Be offered male condoms 
• Be compensated for your visit 
• Schedule your next visit to enroll in the study, if you are willing and eligible. 


 
 
 
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You will be asked to abstain from the following activities at timepoints specified during 
the study: 
 
Activity: 
Abstain For How Long? 
• 
Receptive intercourse 
o 
Anal 
o 
Oral 
• 
Receptive anal or genital 
stimulation (e.g., fingers, partner 
placing their mouth on your anal or 
genital area) 
• 
Inserting any non-study products 
or objects into your rectum, 
including: 
o 
Fingers 
o 
Rectal medications 
o 
Enemas 
o 
Lubricants 
o Sex toys (dildos, anal 
plugs, etc.) 
• 
72 hours (3 days) prior to each clinic 
visit 
• 
72 hours (3 days) following each clinic 
visit 
 
• 
Receptive vaginal intercourse 
• 
Inserting non-study products or 
objects into your vagina, including: 
o 
Fingers 
o 
Spermicides 
o 
Vaginal medications 
(including hormones) 
o 
Vaginal douches 
o 
Lubricants 
o 
Vaginal moisturizers 
o 
Sex toys (vibrators, dildos, 
etc.) 
• 
72 hours (3 days) prior to each clinic 
visit 
 
• 
Using aspirin (greater than 81 mg) 
and non-steroidal anti-
inflammatory drugs (NSAIDS) 
• 
72 hours (3 days) prior to tissue 
sample collection visit 
• 
72 hours (3 days) following tissue 
sample collection visit 
 
If you do not think you can be sexually abstinent for the required length of time 
before and after study visits, you should not join this study.  
 
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 about [SITES TO 
INSERT TIME.]  


 
 
 
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The following procedures are specific to the Enrollment Visit, which will take place up to 
45 days after your Screening Visit.  
 
You will: 
• Answer questions to confirm you are able and willing to join the study 
• Update your contact information  
• Be assigned to a study sample collection sequence  
o You will be assigned to one of two groups for timing of sample collection 
(rectal fluid and vaginal fluid [if applicable] and rectal tissue) by random 
chance (like a roll of the dice). Neither you nor the study staff can control 
which group you will be assigned to.  
o At some of your study visits after the Enrollment Visit, these samples may 
be collected at approximately 2, 4, and/or 6 hours after receiving the 
TAF/EVG Insert(s), and approximately 24, 48, or 72 hours later, depending 
on the timing of sample collection you have been assigned to. This table 
shows the different times when each group has samples collected: 
 
Visit 
Post-
Dose 
Hours 
Rectal Tissue 
Rectal Fluid 
Vaginal fluid 
 Group 
1 
Group 
2 
 Group 
1 
Group 
2 
 Group 
1 
Group 
2 
Dosing Visits 
(Visits 3 and 7) 
 
2 
X 
 
X 
 
X 
 
4 
 
 
 
X 
 
X 
6 
 
 
X 
 
X 
 
24-hour Post-
Dosing Visits 
(Visits 4 and 8) 
 
24 
 
X 
 
X 
 
X 
48-hour Post-
Dosing Visits 
(Visits 5 and 9) 
 
48 
X 
 
X 
 
X 
 
72-hour Post-
Dosing Visits 
(Visits 6 and 10) 
 
72 
 
X 
 
X 
 
X 
 
o You will be able to find out today at which visit(s) you will have these 
samples collected and how long each study visit will last.  
o These samples will help researchers learn how the body absorbs, 
distributes, and gets rid of TAF and EVG. 


 
 
 
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• Talk with study staff about the following: 
o The instructions and procedures of the study and how to follow the study 
guidelines, including the sexual abstinence requirement and use of non-
study products/objects.  
o Sexually transmitted infections (STIs), HIV, HIV/STI testing, and ways to 
avoid HIV and other infections passed through sex   
• Discuss any health problems you may have had in the past or since your last visit 
(including what medications you are taking) 
• Discuss with study staff the initiation of any new medication, over the counter drug 
or food supplement product (vitamins, nutritional supplements and herbal 
preparations).  
• Complete a brief computer-administered self-interview (CASI). This will take 
approximately 20-30 minutes. You will be asked some questions about your 
experience and comfort in using rectal products, as well as douching or other rectal 
hygiene practices, among other things.   
• Provide a blood sample [SITES TO INSERT AMOUNT]: 
o In case there’s a question about your test results at a later time  
o To test your blood for HIV, the virus that causes AIDS 
o To see if there is study drug in your body prior to the use of study product  
• Have a physical exam 
• In preparation for the rectal sample collection, you will have an enema.  
o During an enema, a hollow tube about the thickness of a pencil will be used 
to put some saline solution (salt water) through your anus and squeeze it 
into your rectum to flush it out and cleanse the bowel of fecal matter (stool). 
An enema is standard procedure prior to insertion of a flexible 
sigmoidoscope, since fecal matter can obscure the test. This may need to 
be repeated so that any stool that is there is removed 
• Have a rectal exam where rectal fluid and tissue samples will be collected.  
o To collect rectal fluid samples: Study staff or the clinician will insert a short 
hollow tube called an anoscope inside your rectum and insert swabs and/or 
sponges through the hollow tube to collect the sample. 
o To collect rectal tissue samples: A flexible sigmoidoscopy will be performed.  
  A flexible sigmoidoscope is a flexible, hollow tube that is placed 
inside your rectum so that the study clinician can take samples of 
tissue.   
 The study clinician will collect approximately 11 tissue samples, each 
about the size of a grain of rice 
• If applicable: 
o Have a urine test for pregnancy and discuss with study staff ways to avoid 
getting pregnant 
o Have a swab inserted in the vagina to collect fluid for research purposes    
• Be given test results, if available 
• Be given male condoms, if you need them 


 
 
 
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• Be given a home enema kit. Study staff will tell you how to use the kit at home 
the evening prior to Dosing Visit 3. 
• Be reimbursed for your visit 
• Schedule your next visit, if applicable. 
 
Dosing Visits (Visits 3 and 7): 
 
All participants will receive a single TAF/EVG Insert at Visit 3, and two TAF/EVG Inserts 
at Visit 7, administered by study staff. Visits 3 and 7 will take approximately [SITES TO 
INSERT AMOUNT OF TIME]. 
You will: 
• Update your contact information 
• Review the instructions and procedures of the study and how to follow the 
guidelines, including about sexual abstinence and insertion of non-study products 
or objects 
• Discuss any health problems you may have had since your last visit (including 
what medications you are taking) 
• Have study insert(s) administered by study staff 
• Have blood samples collected [SITES TO INSERT AMOUNT]  
o At approximately 1 hour, 2 hours, 4 hours, and 6 hours after each dose  
o An intravenous cannula (IV tube) may be placed for up to 6 hours after 
administration of the insert(s) for the blood draws. These samples will be 
collected to help researchers better understand how the study drug is 
processed by the body. 
• Have a rectal examination and have rectal fluid and tissue collected using the 
anoscope and flexible sigmoidoscope  
o For Group 1 participants, both rectal fluid and tissue samples will be 
collected at 2 hours after each dose of study insert(s) and only rectal fluid 
will be collected at 6 hours after each dose of study insert(s). At 2 hours, 
the study clinician will also collect approximately 22 tissue samples, each 
about the size of a grain of rice 
o For Group 2 participants, only rectal fluid sample will be collected at 4 hours 
after each dose of study insert(s).   
•  If applicable: 
o Have vaginal fluid collected with a swab 
o For Group 1 participants, vaginal fluid sample will be collected at 2 hours 
and 6 hours after each dose of study insert(s).   
o For Group 2 participants, vaginal fluid sample will be collected at 4 hours 
after each dose of study insert(s).   
• Discuss with study staff about any problems that you may be experiencing as a 
result of administration of the study insert(s), or as a result of procedures 
performed during your visit 
• Be provided with any available test results and with treatment or a referral for 
treatment if your test results indicate that you require it 


 
 
 
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• Be given male condoms, if you need them  
• Be reimbursed for your visit 
• Schedule your next visit or contact. 
 
24-Hour Post-Dosing Visits (Visits 4 and 8): 
 
You will be asked to attend a 24-Hour Post-Dosing Visit (Visits 4 and 8) approximately 24 
hours (1 day) after each dosing visit. Each visit will take between [SITES TO SPECIFY 
TIMEFRAME] to complete.  
At these visits, you will: 
• Update your contact information 
• Review the instructions and procedures of the study and how to follow the 
guidelines, including about sexual abstinence and insertion of non-study products 
or objects 
• Discuss any health problems you may have had since your last visit (including 
what medications you are taking) 
• Complete a brief computer-administered self-interview. This interview may take 
approximately 10 -15 minutes. You will be asked questions about your thoughts 
on the study product, what might make the product more appealing to use and 
your experience with the insert administration in the clinic. 
• Have a rectal examination and have rectal fluid and tissue collected using the 
anoscope and flexible sigmoidoscope (Group 2 participants only). The study 
clinician will collect approximately 22 tissue samples, each about the size of a grain 
of rice.  
• If applicable (Group 2 participants only) 
o Provide a small amount of vaginal fluid via swab for research purposes 
• Provide a blood sample [SITES TO INSERT AMOUNT]: 
o To help researchers to better understand how the body absorbs, distributes, 
and gets rid of the study drug  
• Speak with study staff about any problems that you may be experiencing as a 
result of administration of the study insert(s), or as a result of procedures 
performed during your visit 
• Be given any available test results 
• Be given condoms, if you need them 
• Be reimbursed for your visit 
• Schedule your next visit or contact. 
 
48-Hour Post-Dosing Visits (Visits 5 and 9): 
 
You will be asked to attend a 48-Hour Post-Dosing Visit (Visits 5 and 9) approximately 48 
hours (2 days) after each dosing visit. Each visit will take between [SITES TO SPECIFY 
TIMEFRAME] to complete.  
 
At these visits, you will: 


 
 
 
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• Update your contact information 
• Talk with study staff about the instructions and procedures of the study and how 
to follow the guidelines, including about sexual abstinence and insertion of non-
study products or objects 
• Discuss any health problems you may have had since your last visit (including 
what medications you are taking) 
• Have a rectal examination and have rectal fluid and tissue collected using the 
anoscope and flexible sigmoidoscope (Group 1 participants only) 
o In preparation for the tissue collection you will have an enema (rectal 
lavage).    
o The study clinician will collect approximately 15 tissue samples, each about 
the size of a grain of rice.  
• If applicable (Group 1 participants only) 
o Provide a small amount of vaginal fluid via swab for research purposes  
• Provide a blood sample [SITES TO INSERT AMOUNT]:  
o To help researchers to better understand how the study drug is processed 
by the body 
• Discuss with study staff about any problems that you may be experiencing as a 
result of administration of the study insert(s), or as a result of procedures 
performed during your visit 
• Be given any available test results 
• Be given condoms, if you need them 
• Be reimbursed for your visit 
• Schedule your next visit or contact. 
 
72-Hour Post-Dosing Visits (Visits 6 and 10) 
 
You will be asked to attend a 72-Hour Post-Dosing Visit (Visits 6 and 10) approximately 
72 hours (3 days) after each dosing visit. Each visit will take between [SITES TO 
SPECIFY TIMEFRAME] to complete.  
 
At these visits, you will: 
• Update your contact information 
• Talk with study staff about the instructions and procedures of the study and how 
to follow the guidelines, including about sexual abstinence and insertion of non-
study products or objects 
• Discuss any health problems you may have had since your last visit (including 
what medications you are taking) 
• Have an in-depth interview (at Visit 10 only). This interview may take approximately 
30 - 45 minutes. You will be asked questions about your thoughts on the study 
product, if the product is acceptable to you, what might make the product more 
appealing to use and your experience with the insert administration in the clinic, 
among other topics. This conversation will be audio-recorded to make sure to 
record your words exactly how you said them. The audio recording, notes, and 


 
 
 
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analyses from these materials will be kept confidential and will only use study 
numbers or made up names, and the hardware will be physically protected in a 
locked area. This means that no one other than the study team will have access 
to your responses. The 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-039 
study team for the purposes of this research. 
• Have a rectal examination and have rectal fluid and tissue collected using the 
anoscope and flexible sigmoidoscope (Group 2 participants only) 
o In preparation for the tissue collection you will have an enema (rectal 
lavage).    
o The study clinician will collect approximately 15 tissue samples, each about 
the size of a grain of rice.  
• If applicable (Group 2 participants only) 
o Provide a small amount of vaginal fluid via swab for research purposes 
• Provide a blood sample [SITES TO INSERT AMOUNT]:  
o To test the health of your blood, liver and kidneys (Visit 10 only) 
o To test your blood for HIV, the virus that causes AIDS (Visit 10 only) 
o To help researchers to better understand how the body absorbs, 
distributes, and gets rid of the study drug 
• Discuss with study staff about any problems that you may be experiencing as a 
result of administration of the study insert(s), or as a result of procedures 
performed during your visit 
• Be given any available test results 
• Be given condoms, if you need them 
• Be given a home enema kit at Visit 6. Study staff will tell you how to use the kit at 
home the evening prior to Dosing Visit 7.  
• Be reimbursed for your visit 
• Schedule your next visit or contact.  
 
Final Contact (Visit 11) 
 
Your Final Contact will take place approximately 3-7 days following Visit 10. This 
visit/contact will take approximately [SITES TO SPECIFY TIMEFRAME] to complete and 
can be conducted over the phone.  
 
At this visit, you will: 
• Update your contact information 
• Discuss any health 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 
insert(s) or as a result of procedures performed during the study 
• Be reimbursed for your visit, if required  
• Schedule your next visit or contact (if necessary) 
• Be given any available test results 


 
 
 
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• Be given male condoms, if you need them. 
 
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, 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 
• Pelvic exam 
• Genital exam 
• Rectal exam 
• Test rectal or throat samples for STIs 
• Test cervix/vaginal samples for STIs 
• Test your urine for STIs or other infections 
• Test your blood for STIs 
• Test your blood to check the health of your blood, liver and kidneys 
• Give you treatment or refer you for treatment of STIs or other issues, if needed. 
 
Further you may need to provide additional samples if any of the above procedures need 
to be repeated due to issues with sample processing, and/or testing or shipping.  
Additional testing may be performed as part of quality control. 
 
What are the possible risks, side effects, and discomforts of this research study? 
It is not expected that participation into this study will expose you to unreasonable risks.  
 
Risks from study drug 
The following side effects have been associated with the use of EVG in participants in 
other studies in which the drug was taken by mouth. These side effects may or may not 
be associated with the use of EVG when the drug is taken rectally:  
 
Most Common Adverse Reactions occurring in 10% or more of participants receiving EVG 
by mouth:  
• Headache 
• Diarrhea 
• Nausea 
• Tiredness 
 


 
 
 
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Other Common Adverse Reactions occurring in between 1% and 10% of participants 
receiving EVG by mouth: 
• Depression 
• Inability to sleep 
• Pain in abdomen 
• Vomiting 
• Indigestion 
• Rash  
 
Uncommon Adverse Reactions occurring in between 0.1% and <1% of participants 
receiving EVG by mouth: 
• Depression 
• Inability to sleep 
• Suicidal thoughts and suicide attempt in patients with a history of depression 
or psychiatric illness 
 
The following side effects have been associated with the use of TAF in participants in 
other studies in which the drug was taken by mouth. These side effects may or may not 
be associated with the use of TAF when the drug is taken rectally:  
 
Most Common Adverse Reactions occurring in 5% or more of participants receiving TAF:   
• Headache 
• Abdominal pain 
• Cough 
• Back pain 
• Fatigue 
• Nausea 
• Joint pain 
• Diarrhea 
• Dyspepsia  
 
Other Common Adverse Reactions occurring in between 1% and 5% of participants 
receiving TAF: 
• Vomiting 
• Rash  
• Flatulence  
 
There is a theoretical risk of the development of HIV drug resistance to tenofovir or 
elvitegravir if the participant acquires HIV infection around the time of study drug 
administration. 
 
It is also possible that you may have an allergic reaction to the study product. Signs of 
allergic reaction may include: rash, dizziness, itching, muscle aches, nausea, fainting, 
facial flushing, chest tightness, cough, hives, fever, and shortness of breath. 


 
 
 
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Risks from rectally-applied drugs 
The following side effects have been associated with the repeated use of rectally-applied 
gel in other studies. These side effects may or may not be associated with the use of 
TAF/EVG Insert administered rectally:  
 
More Common Adverse Reactions occurring in 5% or more of participants:  
• Passing gas from the intestinal tract  
• A sudden, almost uncontrollable, need to relieve the bowels 
• Diarrhea (loose, frequent stools) 
 
Less Common Adverse Reactions occurring in less than 5% of participants:  
• Abdominal bloating, feeling full, or a sense of abdominal pressure and/or pain 
• Feeling a constant need to pass stools, despite an empty bowel 
• Irritation in the rectum 
• Rash  
• Worsening of existing problems due to hemorrhoids 
 
Risks from phlebotomy and IV cannula placement (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 throat swab often causes a momentary gagging reflex. 
 
Risks of enemas 
• The main risk from having an enema is temporary discomfort. A hollow plastic tube 
about the thickness of a pencil will be used to administer about 120-125 mL of 
enema fluid 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. 
• There is also a remote possibility of rectal perforation associated with the use of 
an enema. 
 
Risks of finger and anoscope rectal exams 
• During rectal exams and collection of rectal fluid and tissue samples, insertion of 
a finger or lubricated anoscope will likely cause mild discomfort. 
 
Risks of rectal swab/sponge insertion 


 
 
 
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• Insertion of rectal swabs and sponges may cause mild discomfort, in addition to a 
slight risk of bleeding. 
 
Risks of flexible sigmoidoscopy 
• A flexible sigmoidoscopy is a commonly practiced medical procedure where a 
flexible tube with a small camera attached is used to look inside the rectum and 
lower colon. The procedures done in this study will not involve any increased risk 
over usual flexible sigmoidoscopy performed for clinical indications (for routine 
medical diagnosis or treatment).  
• The risks associated with these procedures include mild discomfort, a sudden urge 
to relieve the bowels, the feeling of having a “bloated stomach”, low blood 
pressure, light bleeding following a bowel movement, abnormal odor or discharge 
from the rectum, as well as flatulence (gas passed through the anus/rectum) 
following the procedure. 
 
Risks of endoscopic biopsy 
• Endoscopic biopsies (biopsies done using a slender, lighted optical tube) to collect 
rectal tissue samples are painless and heal quickly within 3 days.  
• On extremely rare occasions, the endoscopic procedure or biopsies may lead to 
pain, infection (sepsis), bleeding or perforation (small hole or tear) of the stomach 
or intestines. Perforation occurs less than once out of every 1,000 procedures 
(88/100,000 procedures). If this extremely rare complication occurs, antibiotics and 
surgery to repair the tear may be necessary. 
• If you engage in sexual intercourse before the biopsy has healed, there exists the 
risk of temporary discomfort, and increased risk of STIs and HIV infection. 
 
(If applicable) Risks of vaginal swab 
• During vaginal fluid collection, you may feel discomfort or pressure in your vagina 
or genital area. 
 
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 cause depression and/or suicidal thoughts. It 
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.  
• It is possible that you and/or your partner(s) may experience problems in your 
relationship(s) associated with maintenance of the study-required abstinence. 


 
 
 
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• 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. 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). 
 
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 infection.   
• It is important that you know that you will not be paid any additional money (beyond 
the reimbursement described below for study participation) if the study product 
being studied is eventually licensed for use.  
• You will have physical and rectal exams. You will also have tests to check the 
overall health of your liver, kidneys, and blood cells. If these tests 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.  
• You will get counseling and testing for HIV and STIs. If you have infections passed 
through sex, other than HIV infection, you will be offered medicine to treat them or 
provided information for where you may receive treatment, and study staff will 
discuss options available for counseling and treatment of your partner. This 
treatment or referral for treatment is available to you even if you do not enroll in 
this study.   
• If you become infected with 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. 
 
Will this study product prevent HIV infection? 
We do not know if the drugs contained within the insert work to protect men and women 
from getting HIV. This study is not testing to see if TAF/EVG Insert prevents HIV infection. 
Researchers are continuing to study TAF and EVG to learn more about how they work in 
humans to protect against HIV infection. There are two known effective ways to reduce 
your risk of contracting HIV: the use of condoms and/or the use of oral pre-exposure 
prophylaxis (PrEP) medication, Truvada®, or post-exposure prophylaxis (PEP).  PrEP is 


 
 
 
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an HIV prevention method in which people who do not have HIV take an oral tablet to 
reduce their risk of becoming infected. 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. If you are currently taking PrEP or PEP or plan to take PrEP in the near future, 
you will not be eligible for this study.   
 
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. 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 FDA, US NIH, CONRAD (the organization that 
supplies the rectal insert), the US Office for Human Research Protections (OHRP), 
MTN, the local or other government or regulatory agency, or the Institutional 
Review Board (IRB). An IRB 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 are found to be infected with HIV (see “If You Become Infected With HIV” 
section below) or an STI in your anal or genital area. 
• (Females) You become pregnant or are breastfeeding (see “If You Become 
Pregnant” section below).  
• If you start on medication for PEP or PrEP 
• You report the use of the following prohibited medications: 
o Anticoagulants (e.g., heparin, Lovenox, warfarin and Plavix) 
o Certain CYP3A inhibitors or inducers (e.g., grapefruit, Prozac, Zoloft, 
Prednisone, Prilosec) 
• A study clinician decides that using the study would be harmful to you, for example 
you have a bad reaction to the study insert(s). 
• Other reasons that may prevent you from completing the study successfully, such 
as you are not able to reliably keep appointments. 
 
If You Become Infected With HIV 
Your participation in this study will not cause HIV infection. However, there is 
always a chance that through sexual activity or other activities (e.g., needle sharing 
for recreational drug use) you may become infected with HIV. In the unlikely event 


 
 
 
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that you become infected with 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 will be performed to see if you have HIV drug 
resistance. This 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 been infected 
with HIV, you will stop using the study insert. 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. 
 
(If applicable) If You Become Pregnant  
The study insert is not a birth control method. 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), 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). You should use an 
effective method of contraception at least 30 days prior to enrollment or abstain 
from penile-vaginal intercourse 90 days prior to enrollment.    
 
We do not know what effect TAF/EVG Insert has on pregnancy, including its effect 
on the fetuses of women who use the rectal insert when pregnant, or the babies of 
women who use the insert when breastfeeding. Because of this, pregnant women 
and women who are breastfeeding may not join this study. Women 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 insert and you will exit the study. We will 
contact you to find out about your pregnancy and the outcome of your pregnancy. 
The outcome of your pregnancy is important to study staff; therefore, your 
pregnancy will be followed until the results of your pregnancy are known. If you 
become pregnant and you deliver a baby from that pregnancy, we will contact you 
approximately one year after your delivery to collect information about the health 
of your baby.  
 
If you are removed from or choose to leave this study, you will be asked to complete the 
procedures described for Visit 11, if you are willing to do so. The study clinician will ask 
you to stop using the study insert but continue to come in for follow-up visits and 
procedures if you have a bad reaction to the insert. 
 
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 $] for your time, effort, and travel to and from the 
clinic at each scheduled visit. You may receive [SITES TO INSERT AMOUNT $] for any 
visits which occur in between your normally scheduled visits. 
 


 
 
 
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What are the costs? 
[SITES TO COMPLETE ACCORDING TO SITE CAPACITY] There is no cost to you for 
study related visits, physical/rectal examinations, 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 I 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 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. We will keep the audio recordings and materials from all 
interviews and discussions confidential and will only use study numbers or fake names. 
[Sites to modify with their site-specific source documentation storage duration 
requirements if required by their IRBs/IECs: All original study documents that provide 
information about you for this study will be kept for at least two years after either the study 
insert is approved for use or research on the insert is stopped.] 
 
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 Institutional Review Boards 
• PPD (a contract research organization that monitors clinical trials for safety and data 
quality) 
• Representatives of CONRAD, the nonprofit organization that supplies the study rectal 
insert 
• Representatives of the US Federal Government, including the US Food and Drug 
Administration (FDA), US Office for Human Research Protections (OHRP), NIH, 
and/or contractors of NIH 
• Other local, US and international regulatory authorities. 


 
 
 
MTN-039, Version 1.0 
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[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 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. 
With limited exceptions, researchers may not disclose names, information or documents 
containing information you give for study purposes. This Certificate does not expire.  
 
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 required to tell the proper authorities. Also, we may have to 
release your information if the organization that is funding this study, [Funding Agency], 
requests the information, or if the FDA, EMA or other regulatory body tells us to release 
this information. 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? 


 
 
 
MTN-039, Version 1.0 
112 
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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]. 
 


 
 
 
MTN-039, Version 1.0 
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CONSENT FOR LONG-TERM STORAGE AND FUTURE TESTING OF 
SPECIMENS  
There might be a small amount of blood, rectal tissue, rectal fluid, or vaginal fluid 
left over after we have done all of the study-related testing. We would like to ask 
your permission to store these leftover samples and related health information for 
use in future studies, such as future research to fight HIV and other related 
diseases. This health information may include personal facts about you such as 
your race, ethnicity, sex, medical conditions and your age range.   
 
If you agree, your samples and related health data will be stored safely and securely 
at facilities that are designed so that only approved researchers will have access to 
the samples. Some employees of the facilities will need to have access to your 
samples to store them and keep track of where they are, but these people will not 
have information that directly identifies you. The de-identified data and specimens 
could then be used for future research by our research team or other researchers 
without notifying you or asking your permission for this use. Your biospecimens will 
never be used for commercial profit.    
 
The type of testing planned for your leftover specimens is not yet known. However, 
samples may be used by the MTN Laboratory Center to complete additional quality 
assurance testing, ensuring that the tests work correctly and supply accurate data.  
No genetic testing on either a limited set or the full set of genes or sequencing (for 
example, the mapping of all of your genes, also known as whole genome 
sequencing) is planned for leftover samples that are stored for the purposes of 
future research. It is important that you know that any future testing or studies 
planned for these specimens must be approved by an Institutional Review Board 
before they can be done.   
 
You can still enroll in this study if you decide not to have leftover samples stored for 
future studies.  If you do not want the leftover samples stored, we will destroy them. 
You can withdraw your consent for the storage and future testing of specimens at 
any time by providing your request in writing to the person in charge of this study. 
However, researchers will not be able to destroy samples or information from 
research that is already underway. 
 
_______________  
 
Initials and Date 
I DO agree to allow my biological specimens and health 
data to be stored and used in future research studies. 
 
_______________  
 
Initials and Date 
I DO NOT agree to allow my biological specimens and 
health data to be stored and used in future research 
studies. 
 
 
 


 
 
 
MTN-039, Version 1.0 
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SIGNATURES- VOLUNTARY CONSENT 
 
[INSERT SIGNATURE BLOCKS AS REQUIRED BY THE LOCAL IRB/EC]: 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 
 
 
 
 
 
 
 
 
 
 


 
 
 
MTN-039, Version 1.0 
115 
 March 6, 2019 
 
 
REFERENCE LIST 
 
1. 
McGowan I. Microbicides for HIV prevention: Reality or hope? Current Opinion in 
Infectious Diseases 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, S.P. Per-
contact risk of human immunodeficiency virus transmission between male sexual partners. 
American Journal of Epidemiology 1999;150:306-11. 
4. 
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 Education and Prevention 2010;22:430-
44. 
5. 
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. Sexually Transmitted Diseases 2009;36:193-8. 
6. 
Ray AS, Fordyce MW, Hitchcock MJ. Tenofovir alafenamide: A novel prodrug of tenofovir 
for the treatment of Human Immunodeficiency Virus. Antiviral Res 2016;125:63-70. 
7. 
Gilead Sciences I. Gilead Sciences. VITEKTA- elvitegravir tablet, film coated: Package 
insert (2012). 2012. 
8. 
CONRAD. Investigator's Brochure: Elvitegravir Vaginal Insert 8mg. 2017. 
9. 
CONRAD. In vitro Dissolution of Elvitegravir Insert. 2017. 
10. 
Ramanathan S, Mathias AA, German P, Kearney BP. Clinical pharmacokinetic and 
pharmacodynamic profile of the HIV integrase inhibitor elvitegravir. Clin Pharmacokinet 
2011;50:229-44. 
11. 
CONRAD. A 14-Day Rectal Irritation and Pharmakinetic Study of Elvitegravir in Rabbits - 
Draft Pathology Report (MPI Study Number: 1645-114). 2017. 
12. 
Gilead Sciences I. VEMLIDY Packet Insert. 2018. 
13. 
Gilead Sciences I. GENVOYA Packet Insert. 2017. 
14. 
CONRAD. Investigator's Brochure: Tenofovir Alafenamide/Elvitergravir (TAF/EVG) 
Combo Vaginal Insert. 2018. 
15. 
Murakami E, Wang T, Park Y, et al. Implications of efficient hepatic delivery by tenofovir 
alafenamide (GS-7340) for hepatitis B virus therapy. Antimicrob Agents Chemother 
2015;59:3563-9. 
16. 
Babusis D, Phan TK, Lee WA, Watkins WJ, Ray AS. Mechanism for effective lymphoid 
cell and tissue loading following oral administration of nucleotide prodrug GS-7340. 
Molecular pharmaceutics 2013;10:459-66. 
17. 
Prathipati PK, Mandal S, Pon G, Vivekanandan R, Destache CJ. Pharmacokinetic and 
Tissue Distribution Profile of Long Acting Tenofovir Alafenamide and Elvitegravir Loaded 
Nanoparticles in Humanized Mice Model. Pharm Res 2017;34:2749-55. 
18. 
Dobard C, Peet MM, Nishiura K, al. e. Dose-Ranging Pharmacokinetic Assessment of 
Vaginally Administered EVG/TAF Inserts in Macaques for PrEP.  HIVR4P; 2018 October 
21-25; Madrid, Spain. 
19. 
CONRAD. A 14-Day Vaginal Irritation and Pharmakinetic Study of Elvitegravir and 
Tenofovir Alafenamide Fumarate in Rabbits (Study No. 1645-116) Draft Report. 2018. 
20. 
CONRAD. A 14-Day Rectal Irritation and Pharmakinetic Study of Elvitegravir and 
Tenofovir Alafenamide Fumarate in Rabbits (Study No. 1645-117) Draft Report. 2018. 
21. 
CONRAD. A 14-day rectal irritation and pharmacokinetic study of Elvitegravir and 
Tenofovir Alafenamide fumarate in rabbits (Study No. 1645-117)2018. 


 
 
 
MTN-039, Version 1.0 
116 
 March 6, 2019 
 
 
22. 
Unger NR, Worley MV, Kisgen JJ, Sherman EM, Childs-Kean LM. Elvitegravir for the 
treatment of HIV. Expert Opin Pharmacother 2016;17:2359-70. 
23. 
Cottrell ML, Garrett KL, Prince HMA, et al. Single-dose pharmacokinetics of tenofovir 
alafenamide and its active metabolite in the mucosal tissues. J Antimicrob Chemother 
2017;72:1731-40. 
24. 
Agarwal K, Fung SK, Nguyen TT, et al. Twenty-eight day safety, antiviral activity, and 
pharmacokinetics of tenofovir alafenamide for treatment of chronic hepatitis B infection. 
Journal of hepatology 2015;62:533-40. 
25. 
Markowitz M, Zolopa A, Squires K, et al. Phase I/II study of the pharmacokinetics, safety 
and antiretroviral activity of tenofovir alafenamide, a new prodrug of the HIV reverse 
transcriptase inhibitor tenofovir, in HIV-infected adults. J Antimicrob Chemother 
2014;69:1362-9. 
26. 
Ruane PJ, DeJesus E, Berger D, et al. Antiviral activity, safety, and 
pharmacokinetics/pharmacodynamics of tenofovir alafenamide as 10-day monotherapy 
in HIV-1-positive adults. J Acquir Immune Defic Syndr 2013;63:449-55. 
27. 
Gaur AH, Kizito H, Prasitsueubsai W, et al. Safety, efficacy, and pharmacokinetics of a 
single-tablet regimen containing elvitegravir, cobicistat, emtricitabine, and tenofovir 
alafenamide in treatment-naive, HIV-infected adolescents: a single-arm, open-label trial. 
Lancet HIV 2016;3:e561-e8. 
28. 
Pozniak A, Arribas JR, Gathe J, et al. Switching to Tenofovir Alafenamide, Coformulated 
With Elvitegravir, Cobicistat, and Emtricitabine, in HIV-Infected Patients With Renal 
Impairment: 48-Week Results From a Single-Arm, Multicenter, Open-Label Phase 3 
Study. J Acquir Immune Defic Syndr 2016;71:530-7. 
29. 
Sax PE, Wohl D, Yin MT, et al. Tenofovir alafenamide versus tenofovir disoproxil 
fumarate, coformulated with elvitegravir, cobicistat, and emtricitabine, for initial treatment 
of HIV-1 infection: two randomised, double-blind, phase 3, non-inferiority trials. Lancet 
2015;385:2606-15. 
30. 
Zhang W, Littlefield S, McCormick T, et al. Development and Proof-of-Concept Clinical 
Evaluation of a Freeze-dried Topical Microbicide Insert for On-demand HIV Prevention.  
HIV R4P; 2016. 
31. 
Dobard C, Sharma S, Martin A, et al. Durable protection from vaginal simian-human 
immunodeficiency virus infection in macaques by tenofovir gel and its relationship to 
drug levels in tissue. J Virol 2012;86:718-25. 
32. 
Gatto NM, Frucht H, Sundararajan V, Jacobson JS, Grann VR, Neugut AI. Risk of 
perforation after colonoscopy and sigmoidoscopy: a population-based study. J Natl 
Cancer Inst 2003;95:230-6. 
33. 
Chiu WK, Brand R, Camp D, et al. The safety of multiple flexible sigmoidoscopies in 
clinical trial participants (Poster).  HIV Research for Prevention (HIV R4P) 2016; 2016 
10/11/2016; Chicago, IL, USA; 2016. 
 


MTN-039, Version 1.0, LoA #04 
30 September 2021 
Page 1 of 4 
 
LETTER OF AMENDMENT #04 TO: 
 
MTN-039 
 
A Phase 1 Open Label Safety and Pharmacokinetic Study of Rectal 
Administration of a Tenofovir Alafenamide/Elvitegravir Insert at Two Dose Levels 
 
Version 1.0, dated March 6, 2019 
 
DAIDS Protocol #38470 
IND #145334 
 
Date of Letter of Amendment: 30 September 2021 
______________________________________________________________________ 
 
Site Instruction 
The following information impacts the MTN-039 study and must be forwarded to your Institutional Review 
Board (IRB)/Ethics Committee (EC) as soon as possible for their information and review. The following 
information does not impact the sample informed consent. Upon receiving final IRB/EC and any other 
applicable Regulatory Entity (RE) approval(s) for this LoA, sites should submit a LoA registration packet 
to the DAIDS Protocol Registration Office (PRO) at the Regulatory Support Center (RSC). Sites will 
receive a registration notification for the LoA once the DAIDS PRO verifies that all the required LoA 
registration documents have been received and are complete. A copy of the LoA registration notification 
along with this letter and any IRB/EC correspondence should be retained in the site’s regulatory files.  
 
Summary of Revisions 
This LoA does not impact the overall design or the study visit schedule for MTN-039. The primary 
purpose of this LoA is to clarify sample testing for tenofovir alafenamide (TAF) and tenofovir diphosphate 
(TFV-DP) concentrations as primary endpoints in the protocol. This LoA will add rectal mucosal tissue 
homogenates to sample testing to measure TAF concentrations and remove rectal mucosal tissue 
homogenates from testing to measure TFV-DP concentrations.   
 
Unless otherwise noted below, text to be deleted is noted by strikethrough, text to be added is noted in 
bold, and text in bold italics is not to be added, but to serve as a clarification of the implementation item 
in question. 
______________________________________________________________________ 
 
Detailed Listing of Revisions 
 
The following revisions (1-4) were made to add rectal mucosal tissue homogenates to sample 
testing to measure TAF concentration and remove rectal mucosal tissue homogenates from 
testing to measure TFV-DP concentration.   
 
1. In the second to fourth bullet lists of pharmacokinetics in the “Primary Endpoints” sub-
section of Protocol Summary:  
 
Pharmacokinetics 
• 
EVG concentrations in: 
o 
Blood  
o 
Rectal fluid 
o 
Rectal mucosal tissue homogenates 


MTN-039, Version 1.0, LoA #04 
30 September 2021 
Page 2 of 4 
 
 
• 
TAF and TFV concentrations in  
o 
Blood  
o 
Rectal fluid 
o 
Rectal mucosal tissue homogenates 
 
• 
TFV-DP concentration in: 
o 
Rectal mucosal tissue homogenates 
o 
Rectal mucosal tissue cell isolates 
 
• 
TFV concentrations in  
o 
Rectal mucosal tissue homogenates  
 
2. In the second to fourth bullets of pharmacokinetics in the “Primary Endpoints” sub-
section of Section 4.2, Summary of Major Endpoints:  
 
Pharmacokinetics 
• 
EVG concentrations in: 
o 
Blood  
o 
Rectal fluid 
o 
Rectal mucosal tissue homogenates 
 
• 
TAF and TFV concentrations in  
o 
Blood  
o 
Rectal fluid 
o 
Rectal mucosal tissue homogenates 
 
• 
TFV-DP concentration in: 
o 
Rectal mucosal tissue homogenates 
o 
Rectal mucosal tissue cell isolates 
 
• 
TFV concentrations in  
o 
Rectal mucosal tissue homogenates  
 
3. In the second to fourth bullets of pharmacokinetics in the “Primary Endpoints” sub-
section of Section 10.2, Study Endpoints:  
 
Pharmacokinetics 
• 
EVG concentrations in: 
o 
Blood  
o 
Rectal fluid 
o 
Rectal mucosal tissue homogenates 
 
• 
TAF and TFV concentrations in  
o 
Blood  
o 
Rectal fluid 
o 
Rectal mucosal tissue homogenates 
 
• 
TFV-DP concentration in: 
o 
Rectal mucosal tissue homogenates 
o 
Rectal mucosal tissue cell isolates 


MTN-039, Version 1.0, LoA #04 
30 September 2021 
Page 3 of 4 
 
 
• 
TFV concentrations in  
o 
Rectal mucosal tissue homogenates  
 
4. In the “Rectal Tissue” column in Table 16: Specimens to be Collected to Assess Safety, 
PK and Ex Vivo Antiviral Activity, of Section 7.10, Pharmacokinetics (PK) and 
Pharmacodynamics (PD):  
 
Study Visit 
Specimens collected for PK, PD and mucosal safety 
 
Blood 
Rectal Fluid 
Rectal Tissue 
CVF  
Visit 3 & Visit 7 -  
Samples 
collected at 1, 2, 
4 and 6 hours  
 
• Blood for PK 
 
  
Group 1 at 2-hour  
• RF for microbiome  
• RF for PK 
• RF for PD 
 
Group 1 at 6-hour 
• RF for PK 
Group 2 at 4-hour  
• RF for PK 
 
Group 1 only at 2-hour 
• 7 samples for biomarkers 
• 4 samples for PD 
• 11 samples for PK  
o 1 for EVG 
o 1 for TAF and TFV and TFV-
DP 
o 1 for backup 
o 8 for MMC isolation 
Group 1 at 2-hour  
• CVF for microflora  
• CVF for PK 
• CVF for PD 
 
Group 1 at 6-hour 
• CVF for PK 
Group 2 at 4-hour  
• CVF for PK 
 
 
5. Protocol Signature Page was updated to include Letter of Amendment #04; it is 
appended to the end of this document. 
 
 
The above information, as well as the changes from LoA#01, LoA#02 and LoA#03, will be 
incorporated into the next version of the protocol at a later time if it is amended. 
 
 


MTN-039, Version 1.0, LoA #04 
30 September 2021 
Page 4 of 4 
 
MTN-039 
 
A Phase 1 Open Label Safety and Pharmacokinetic Study of Rectal Administration of 
a Tenofovir Alafenamide/Elvitegravir Insert at Two Dose Levels 
 
INVESTIGATOR SIGNATURE FORM 
Version 1.0; March 6, 2019 
Letter of Amendment #01; 20 September 2019 
Letter of Amendment #02; 23 March 2020 
Letter of Amendment #03; 24 July 2020 
Letter of Amendment #04; 30 September 2021 
 
 
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 Holder: 
DAIDS (DAIDS Protocol ID: 38470) 
 
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); 
applicable U.S. Food and Drug Administration regulations; standards of the International 
Conference for Harmonization Guideline for Good Clinical Practice (E6); Institutional Review 
Board/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 all study documentation for at least two years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated 
marketing applications in an ICH region or at least two years have elapsed since the formal 
discontinuation of clinical development of the investigational product. These documents 
should be retained for a longer period, however, if required by the applicable regulatory 
requirements or by an agreement with the sponsor. DAIDS will inform the 
investigator/institution as to when these documents no longer need to be retained 
 
I have read and understand the information in the Investigator's Brochure(s), including the 
potential risks and side effects of the products under investigation, 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 (print) 
 
 
____________________________   
 
______________________________ 
Signature of Investigator of Record   
 
Date 

SAP_001.pdf: 
 
 
 
 
Confidential 
MTN-039 Statistical Analysis Plan rev. 2.0 eff: 10/8/2021 
All proprietary rights reserved 
Page 1 of 16 
 
 
 
 
 
STATISTICAL ANALYSIS PLAN  
 
 
A Phase 1 Open Label Safety and Pharmacokinetic 
Study of Rectal Administration of a Tenofovir 
Alafenamide/Elvitegravir Insert at Two Dose Levels 
 
MTN-039 
 
 Effective Date: October 8, 2021 
Version: 2.0 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
  
 
 
 
Confidential 
MTN-039 Statistical Analysis Plan rev. 2.0 eff: 10/8/2021 
All proprietary rights reserved 
Page 2 of 16 
STATISTICAL ANALYSIS PLAN 
 
Protocol Name:  
A Phase 1 Open Label Safety and Pharmacokinetic Study of 
Rectal Administration of a Tenofovir Alafenamide/Elvitegravir 
Insert at Two Dose Levels 
Protocol Number:  
 
MTN-039 
Author(s):  
Elizabeth Brown, ScD, Faculty Statistician 
Cliff Kelly, MS, Senior Statistical Analyst 
Version:  
2.0 
 
Author(s): 
 
 
Elizabeth Brown, ScD 
 
 
 
 
See appended email signature 
 
 
Faculty Statistician 
 
Cliff Kelly, MS 
 
 
Signature  
 
See appended email signature 
 
Date:  
Senior Statistical Analyst 
 
 
 
 
Signature 
 
Date:  


 
  
 
 
 
Confidential 
MTN-039 Statistical Analysis Plan rev. 2.0 eff: 10/8/2021 
All proprietary rights reserved 
Page 3 of 16 
TABLE OF CONTENTS 
1. 
LIST OF ABBREVIATIONS AND ACRONYMS .................................................................... 4 
2. 
INTRODUCTION ............................................................................................................ 5 
2.1 
GENERAL DESIGN CONSIDERATIONS ........................................................................................... 5 
2.2 
STUDY OBJECTIVES AND ENDPOINTS ........................................................................................... 6 
2.3 
RANDOMIZATION .................................................................................................................... 7 
2.4 
BLINDING .............................................................................................................................. 8 
2.5 
SAMPLE SIZE AND POWER ........................................................................................................ 8 
3. 
GENERAL DATA ANALYSIS CONSIDERATIONS ................................................................ 8 
3.1 
ANALYSIS SET(S) ..................................................................................................................... 8 
3.2 
STATISTICAL ANALYSIS ISSUES .................................................................................................... 8 
4. 
INTERIM ANALYSIS AND DATA MONITORING COMMITTEE ........................................... 9 
5. 
GENERAL ANALYSIS METHODS ..................................................................................... 9 
6. 
TRIAL PARTICIPANT DISPOSITION ................................................................................. 9 
6.1 
DISPOSITION OF PARTICIPANTS .................................................................................................. 9 
6.2 
TREATMENT EXPOSURE .......................................................................................................... 10 
6.3 
PROTOCOL DEVIATIONS ......................................................................................................... 10 
7. 
BASELINE DATA .......................................................................................................... 10 
8. 
SAFETY ANALYSES ...................................................................................................... 10 
8.1 
PRIMARY SAFETY ANALYSES .................................................................................................... 10 
8.2 
ADVERSE EVENTS .................................................................................................................. 11 
8.3 
LABORATORY EVALUATIONS .................................................................................................... 11 
8.4 
OTHER SAFETY MEASURES ...................................................................................................... 11 
9. 
PHARMACOKINETIC ANALYSES ................................................................................... 11 
9.1 METHODS FOR HANDLING MISSING AND BLOQ DATA ..................................................................... 12 
9.2 PRIMARY PK ANALYSES .............................................................................................................. 13 
10. 
SECONDARY ENDPOINTS ............................................................................................ 15 
10.1 ACCEPTABILITY ANALYSES ......................................................................................................... 15 
11. 
REFERENCES ............................................................................................................... 15 
12. 
CHANGE HISTORY ....................................................................................................... 16 


 
  
 
 
 
Confidential 
MTN-039 Statistical Analysis Plan rev. 2.0 eff: 10/8/2021 
All proprietary rights reserved 
Page 4 of 16 
 
1. LIST OF ABBREVIATIONS AND ACRONYMS  
A list of abbreviations used in the SAP. 
Term/Abbreviation 
Definition 
AE 
adverse event 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
%AUCex 
Percentage of AUC0-∞ obtained by extrapolation, calculated as [(Clast / ke) / AUC0-
∞ *100] 
AUC 
area under the concentration-time curve 
AUC0-t  
AUC from time zero to the time of the last measurable concentration 
AUC0-∞  
AUC from time zero extrapolated to infinity, equal to AUC0-t plus AUCt-∞ = (Clast / 
ke) 
BMI 
body mass index 
BLOQ 
below the limit of quantitation 
CASI 
computer assisted self-interviews 
Clast 
last observed concentration 
Cmax 
peak concentration 
CRS 
Clinical Research Site 
EVG 
elvitegravir 
h 
hour 
ke 
terminal elimination rate constant 
LLOQ 
lower limit of quantification 
MedDRA 
Medical Dictionary for Regulatory Activities 
PK 
pharmacokinetics 
RF 
rectal fluid 
RT 
rectal mucosal tissue 
SAP 
statistical analysis plan 
SSP 
study specific procedures 
t1/2 
terminal concentration half-life 
TAF 
tenofovir alafenamide 
Tmax 
time to peak concentration 


 
  
 
 
 
Confidential 
MTN-039 Statistical Analysis Plan rev. 2.0 eff: 10/8/2021 
All proprietary rights reserved 
Page 5 of 16 
2. INTRODUCTION 
This Statistical Analysis Plan (SAP) describes the plan for the final analysis of data regarding the safety, 
pharmacokinetics, and acceptability among HIV-uninfected individuals 18 years of age or older in a 
Phase I, multi-site, open-label, single arm, two-period study of rectal administration of one Tenofovir 
Alafenamide/Elvitegravir Insert, 20/16 mg, and then two TAF/EVG Inserts. 
2.1 General Design Considerations 
PROTOCOL SUMMARY 
 
Short Title:  
Safety and PK Study of TAF/EVG Administered Rectally 
 
Clinical Phase:  
Phase 1 
 
IND Sponsor:  
DAIDS 
 
Protocol Chair:  
Sharon Riddler, MD, MPH 
 
Sample Size:  
MTN-039 will enroll approximately 20 participants.  
Study Population:  
HIV-uninfected individuals 18 years of age or older  
Study Sites:  
Alabama CRS and University of Pittsburgh CRS 
Study Design:  
Phase 1, multi-site, open-label, single arm, two-period study of rectal 
administration of one Tenofovir Alafenamide/Elvitegravir Insert, 20/16 mg 
and then two TAF/EVG Inserts 
 
Study Duration:  
Approximately 6-13 weeks of follow-up per participant is planned with a projected 
accrual period of 6-8 months. The total duration of the study will be 
approximately 11 months. 
 
Study Products:  
TAF/EVG Insert, 20/16 mg 
 
Study Regimen:  
Participants will apply a single TAF/EVG Insert rectally and samples will be 
collected over a 3-day period. After a washout period of at least 7 days, 
participants will apply two TAF/EVG Inserts rectally and samples will be taken 
over a 3-day period. 


 
  
 
 
 
Confidential 
MTN-039 Statistical Analysis Plan rev. 2.0 eff: 10/8/2021 
All proprietary rights reserved 
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Figure 1: MTN-039 Study Visit Schedule 
  
 
 
As displayed in Figure 1, participants will receive a rectally administered dose of one TAF/EVG insert at 
Visit 3 and have safety laboratory tests, PK and PD assessments performed over the next three days 
(Visits 4, 5, and 6). Participants will self-administer a saline enema at home the evening prior to a clinic 
dosing visit (Visits 3 and 7). After a washout period of one to seven weeks following the last tissue 
sampling associated with one TAF/EVG insert dosing, participants will receive dosing of two TAF/EVG 
inserts at Visit 7 and have safety laboratory tests, PK and PD assessments performed over the next three 
days (Visits 8, 9, and 10). A final study contact will occur approximately 3-7 days after Visit 10 and may 
be conducted over the phone. 
2.2 Study Objectives and Endpoints 
The primary, secondary and exploratory objectives and endpoints of this study are described below.  This 
SAP will describe the plan for the statistical analyses of the primary and secondary endpoints only.  
 
Primary Objectives: 
 
Safety 
• 
To evaluate the safety of the TAF/EVG Insert, 20/16 mg administered rectally at two dose levels: 
1 insert and 2 inserts 
 
Pharmacokinetics 
• 
To characterize the systemic and rectal pharmacokinetics of the TAF/EVG Insert, 20/16 mg 
applied rectally at two dose levels: 1 insert and 2 inserts 
 
Primary Endpoints: 
 
Safety 
• 
All Grade 2 and higher AEs 
 
Pharmacokinetics 
• 
EVG concentrations in: 
o 
Blood 
o 
Rectal fluid 
o 
Rectal mucosal tissue homogenates 
 
• 
TAF and TFV concentrations in 
o 
Blood 


 
  
 
 
 
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o 
Rectal fluid 
o 
Rectal mucosal tissue homogenates 
 
• 
TFV-DP concentration in: 
o 
Rectal mucosal tissue cell isolates 
 
Secondary Objective: 
 
Acceptability 
• 
To identify product attributes considered likely to challenge and/or facilitate future sustained use 
of the TAF/EVG Insert applied rectally 
 
Secondary Endpoints: 
 
Acceptability 
• 
Participant report of overall acceptability of the TAF/EVG Insert applied rectally 
 
Exploratory Objectives: 
 
Ex Vivo Efficacy 
• 
To assess the preliminary (ex vivo) efficacy of TAF/EVG after product is inserted rectally 
 
Pharmacokinetics 
• 
To characterize the cervicovaginal pharmacokinetics of the TAF/EVG Insert, 20/16 mg applied 
rectally at two dose levels: 1 insert and 2 inserts 
 
Mucosal Safety 
• 
To evaluate mucosal safety of the TAF/EVG Insert, 20/16 mg applied rectally at two dose levels: 
1 insert and 2 inserts 
 
Exploratory Endpoints: 
 
Ex Vivo Efficacy 
• 
Changes in HIV-1 replication in colorectal explant culture supernatant 
• 
Anti-HIV activity in rectal fluid 
• 
Anti-HIV activity in cervicovaginal fluid 
 
Pharmacokinetics 
• 
EVG, TAF and TFV concentrations in cervicovaginal fluid 
 
Mucosal Safety 
• 
Rectal histology 
• 
Rectal proteomics 
• 
Rectal metabolomics 
• 
Rectal immunophenotype 
• 
Rectal microbiome 
• 
Cervicovaginal microflora 
2.3 Randomization 
There will be no randomization to dose of TAF and EVG (one or two inserts) in this open-label, single 
arm, and two-period trial. 


 
  
 
 
 
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At study randomization upon enrollment, participants will be assigned to one of two sampling group 
schedules for collection of rectal tissue (collected with flexible sigmoidoscopy), rectal fluid, and 
cervicovaginal fluid (if applicable): 
Group 1:  
Visits 3, 5, 7, and 9 
Group 2:  
Visits 4, 6, 8, and 10 
Notes:  
Both sampling groups 1 and 2 will provide blood at Visits 3-10. At Visits 3 and 7, both 
sampling groups will provide rectal fluid and cervicovaginal fluid (if applicable) – Group 1 
at 2- and 6-hours post-dose, and Group 2 at 4-hours post-dose. At Visits 3 and 7, rectal 
tissue sampling will be conducted in Group 1 participants at 2-hours post-dose.  All 
sampling times are approximate; allowable windows and detailed instructions are 
provided in the MTN-039 SSP Manual. 
 
Each participant will have a total of 5 flexible sigmoidoscopies for rectal tissue sampling: 
 
at baseline (both sampling groups, 1 set of biopsies) 
 
at 2- and 48-hours post-dose for each dose (Group 1 only, 4 sets of biopsies) 
 
at 24- and 72-hours post-dose for each dose (Group 2 only, 4 sets of biopsies). 
 
Randomization will be stratified by sex at birth to incorporate at least three participants assigned female 
sex at birth in each sampling group. 
 
2.4 Blinding 
There is no blinding in this open-label study. 
 
2.5 Sample Size and Power 
The study is designed for a total accrual of twenty (20) participants, which gives sufficient power for the 
detection of adverse events as described in the protocol. Descriptive safety analyses and 
pharmacokinetic analyses are planned with no formal statistical testing. 
 
3. GENERAL DATA ANALYSIS CONSIDERATIONS 
3.1 Analysis Set(s) 
The analysis set consists of all participants enrolled in the study who are administered a TAF/EVG insert 
at any dosing visit (Visit 3 or 7).  All available safety, PK, and acceptability data will be analyzed on this 
set of participants, as described below. 
3.2 Statistical Analysis Issues 
For the primary safety analyses, safety endpoints will be classified into groups by dose regimen (one or 
two inserts) based on the doses administered at a dosing visit (Visit 3 and 7).  If a participant was not 
administered a particular dose, then the participant will be excluded from analyses describing that 
particular dose regimen.   
 
For the primary pharmacokinetics analyses, timing of drug concentration results will be based on the time 
the specimen was actually collected, and not based on time points as planned for each sampling group 


 
  
 
 
 
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per randomization.  Time points may still be grouped into categories based the average or targeted time 
point for specimen collection.  The handling of missing data and concentration data below the limit of 
quantitation (BLOQ) are described in the section on pharmacokinetic analyses below. 
4. INTERIM ANALYSIS AND DATA MONITORING COMMITTEE 
No interim statistical analysis was planned or performed for the MTN-039 study. 
 
One study monitoring committee (SMC) review was conducted for MTN-039, on December 7, 2020, for 
which a closed report was produced. Evaluation of safety was based on descriptive tables of adverse 
events, with no formal statistical testing. 
5. GENERAL ANALYSIS METHODS 
When the use of descriptive statistics to assess dosing regimen characteristics or differences is required, 
the following methods will be used: for categorical variables, the number and percent in each category; 
for continuous variables, the mean, median, standard deviation, quartiles, and range (minimum, 
maximum). Within-treatment group assessment of the change from the baseline measurement to a follow-
up measurement will be analyzed using McNemar’s test (for categorical response variables) or the paired 
t-test or Wilcoxon signed-ranks test (for continuous variables). 
 
The following descriptions may be used to distinguish the dosing regimens: “One Insert” and “Two 
Inserts”.  
6. TRIAL PARTICIPANT DISPOSITION 
Enrollment will take place at two sites:  Birmingham and Pittsburgh, USA. 
6.1 Disposition of Participants 
6.1.1 Screening and Enrollment 
 
Dates of site activation, first enrollment, and last enrollment, as well as the number or participants 
screened, number and percentage of participants enrolled, and the screening-to-enrollment ratio will be 
displayed in a table overall and by site.   
 
6.1.2 Retention 
 
A table will display for each visit the number and percentage of participants who are expected, retained, 
missing, and lost-to-follow-up or terminated with respect to that visit, overall and by site.  
 
6.1.3 Treatment Discontinuation 
 
The number and percentage of participants who ended product use early, as well as the reasons for 
terminating product use early, will be presented in a table overall and by site.  
 
6.1.4 Study Discontinuation 
 
The number and percentage of participants who completed the study, as well as the reasons for non-
completion, will be displayed in a table overall and by site. 


 
  
 
 
 
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6.1.5 Completion of Procedures 
 
The completion of required and expected procedures will be displayed in a table overall and by site. The 
table will display the number and percentages of participant-visits for each procedure.  
6.2 Treatment Exposure 
The number and percentage of enrolled participants administered the one insert dosing regimen at Visit 3 
and then number of participants administered the two inserts dosing regimen at visit 7 will be displayed 
overall and by site.  Participants will be classified into groups by dosing regimen based on the time from 
dosing up until just before the next higher dosing regimen is administered (e.g., for the one insert dosing 
regimen, any safety endpoints which occur between the time of one insert administration at Visit 3 up 
until, but not including, the time of the two insert administration at Visit 7.) 
 
If applicable, the number and percentage of participants who had study product held during follow-up will 
be displayed overall and by site (along with the reasons why product was held). 
6.3 Protocol Deviations 
Protocol deviations occurring in MTN-039 will be summarized in a table of each type of deviation by site 
and overall, and in a listing of deviation events.  
 
These data will be reviewed prior to the analysis of the primary and secondary endpoints to determine if 
any protocol deviations in this study impact participant eligibility or treatment administration and 
subsequently necessitate adjustments to the analysis set. 
7. BASELINE DATA  
Baseline participant demographic characteristics such as age, sex at birth, ethnicity, race, gender, sexual 
orientation, height, weight, and body mass index (BMI) will be summarized and displayed in tables overall 
and by site, and in tables overall and by sex at birth.  Descriptive statistics will be presented for age, 
height, weight, and BMI.  Frequency counts and percentages will be presented for sex at birth, ethnicity, 
race, gender, and sexual orientation.  No formal comparisons are planned. 
 
Individual participant baseline characteristics (medical history and results from baseline anorectal exam 
findings, pelvic exam findings, physical exam findings, STI test findings, hematology, and local laboratory 
results) will be presented in listings. 
8. SAFETY ANALYSES  
All participants enrolled and administered any TAF/EVG insert will be assessed for safety. 
8.1 Primary Safety Analyses  
The primary safety endpoint is defined as follows: 
All Grade 2 and higher AEs 
The number and the percentage of participants experiencing each safety endpoint will be tabulated by 
dosing regimen (one insert or two inserts). This table will display a summary for any primary safety 
endpoint and for each individual safety endpoint. Each participant will contribute once in each category 


 
  
 
 
 
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(i.e., only for highest severity AE for each participant) for the calculation of event rates for each dosing 
regimen. Exact binomial confidence intervals (Clopper-Pearson) will be calculated for each safety 
endpoint, even if no events occur for an endpoint for a particular dosing regimen. 
8.2 Adverse Events 
Summaries of adverse events will include a cumulative listing of adverse events, a table displaying the 
total number of adverse events by severity grade and relationship to study product, a table of the 
incidence of adverse events by MedDRA organ system class/preferred term and severity, and a table of 
incidence of adverse events by MedDRA organ system class/preferred term and relationship to study 
product.  Tables will be displayed by dosing regimen, and listings will include the dosing regimen when 
the AE occurred. 
8.3 Laboratory Evaluations  
The number and percentage of participants with a positive result for the following laboratory tests will be 
displayed in a table overall and by site:  hCG for pregnancy and HIV. A listing of participants with positive 
results of STI testing (syphilis, trichomonas, gonorrhea, chlamydia) after dose administration will be 
presented. 
 
Hematology results after dosing with each regimen, including hemogram (hemoglobin, hematocrit, MCV, 
platelets, WBC) and differential (neutrophils, lymphocytes, monocytes, eosinophils, and basophils) results 
will be tabulated by dosing regimen using descriptive statistics. 
 
Serum chemistries (AST, ALT, and creatinine) after dosing with each dosing regimen will be tabulated by 
dosing regimen using descriptive statistics. 
8.4 Other Safety Measures  
Additional safety summaries include: 
 
A listing of participants with abnormal findings on pelvic examination or rectal examination after dose 
administration (with dosing regimen when finding occurred) will be presented. 
 
Concomitant medications are defined as any medication taken during the study. A participant listing of all 
concomitant medications will be presented. 
9. PHARMACOKINETIC ANALYSES 
Descriptive statistics will be used to summarize actual PK sample collection times (from dose 
administration) for blood, rectal fluid, rectal tissue, and cervicovaginal fluid samples, and these summaries 
will be provided by site and overall.  
 
For each dosing regimen, blood samples are expected to be collected from all participants at baseline 
and at 1h, 2h, 4h, 6h, 24h, 48h, and 72h after dose administration.  Samples of rectal fluid and 
cervicovaginal fluid (if applicable) are expected to be collected at the following study time points after 
dose administration: 2h, 4h, 6h, 24h, 48h, and 72h with samples collected for each participant only at 
specific time points based upon their group status (see table below).  Similarly, samples of rectal tissue 
are expected to be collected at the following study time points after dose administration: 2h, 24h, 48h, 
and 72h with samples collected for each participant only at specific time points based upon their group 
status (see Table 1 below). 
 
Table 1: Expected PK Sample Collection by Study Time Point 


 
  
 
 
 
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PK Specimen Type 
Baseline 
Visit 2 
1h, 
Visits 
3 & 7 
2h, 
Visits 
3 & 7 
4h, 
Visits 
3 & 7 
6h, 
Visits 
3 & 7 
24h, 
Visits 
4 & 8 
48h, 
Visits 
5 & 9 
72h, 
Visits 
6 & 10 
Blood 
G12 
G12 
G12 
G12 
G12 
G12 
G12 
G12 
Rectal fluid 
 
 
G1 
G2 
G1 
G2 
G1 
G2 
Rectal tissue 
 
 
G1 
 
 
G2 
G1 
G2 
Cervicovaginal fluid 
 
 
G1 
G2 
G1 
G2 
G1 
G2 
NOTE:  G1=Group 1, G2=Group 2, G12=Groups 1 and 2. 
 
A table summarizing the number and percentage of blood, rectal fluid, rectal tissue, and cervicovaginal 
fluid samples collected outside of the windows of the expected time points will be provided overall and by 
site.  For samples collected outside of the window, a listing of sample collection times along with the 
amount of time before (-) the window or after (+) the window will be provided.   
 
Allowable windows for the collection of blood, rectal fluid, rectal tissue, and cervicovaginal fluid are 
detailed in the MTN-039 SSP Manual in section 5.4.2 and Table 5-1 Sample Collection Time-Points Post-
Insert Administration (and provided below). 
 
 
9.1 Methods for Handling Missing and BLOQ Data  
Each bioanalytical assay for blood, rectal fluid, rectal tissue, and cervicovaginal fluid has an assay 
sensitivity described by a lower limit of quantitation (LLOQ).  These LLOQs will be reported for each 
matrix.  Concentration values assayed below the LLOQ, as well as those classified as “Not Detected”, are 
identified as below the limit of quantitation (BLOQ).  
 
In individual participant data listings, actual concentration values below the LLOQ will be displayed, if 
provided from the lab, along with the LLOQ for the assay.  For values identified as BLOQ in the data, a 
listing will be provided displaying the assay and time point(s) of the BLOQ values. 


 
  
 
 
 
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Baseline samples that are BLOQ or missing will be assigned a numerical value of zero for the calculation 
of area under the concentration-time curve (AUC).  Baseline samples that are missing will be excluded 
from the concentration summary calculations at baseline.  Any anomalous quantifiable concentration 
values (at or above the LLOQ) observed at baseline will be identified in the study report and used for the 
computation of AUC.   
 
Any other BLOQ concentrations that precede quantifiable samples in the initial portion of the profile or a 
BLOQ value that occurs between quantifiable data points, especially prior to Cmax, will be evaluated to 
determine if an assigned concentration of zero makes sense, or if reanalysis or exclusion of the data is 
warranted.  Following Cmax, BLOQ values embedded between two quantifiable data points will be treated 
as missing when calculating AUC.  If BLOQ values occur at the end of the collection interval (after the last 
quantifiable concentration), these will be treated as missing data.  If consecutive BLOQ concentrations 
are followed by quantifiable concentrations in the terminal portion of the concentration curve, these 
quantified values will be excluded from the PK analysis by assigning them a value of missing, unless 
otherwise warranted by the concentration-time profile. 
 
Drug concentration-time data will be listed for each participant and summarized by descriptive statistics at 
each nominal collection time.  BLOQ concentrations will be treated as zero for computation of descriptive 
statistics. Concentrations assigned a value of missing will be omitted from the calculation of descriptive 
statistics.  If the calculated mean concentration is BLOQ, the mean value will be reported as BLOQ, and 
SD will be reported as ND (not determined). Median, quartiles, minimum and maximum may be reported, 
and if any of these values are BLOQ, they will be reported as BLOQ. 
 
When a concentration of zero cannot be plotted, the concentration may be assigned the value of LLOQ 
divided by 2 so that it may be displayed. 
9.2 Primary PK Analyses  
The primary PK analyses describe the concentrations of EVG, TAF, TFV, and TFV-DP in some or all of 
the following matrices: 1) blood, 2) rectal fluid (RF), 3) rectal mucosal tissue (RT) homogenates, and 4) 
rectal mucosal tissue cell isolates during each dosing regimen, one insert or two inserts.  For each dosing 
regimen (one insert and two inserts), Table 2 below displays the drug concentrations to be analyzed for 
each PK specimen type.   
 
Table 2: Expected PK Drug Concentrations per PK Specimen Type 
PK Specimen Type 
EVG 
TAF 
TFV 
TFV-DP 
Blood 
X 
X 
X 
 
Rectal fluid 
X 
X 
X 
 
Rectal tissue homogenates 
X 
X 
X 
 
Rectal tissue cell isolates 
 
 
 
X 
NOTE:  X=Drug concentrations expected. 
 
As blood samples are collected among all participants at the enrollment visit and at seven post-dose time 
points per dose, RF samples are collected at three time points per dose for Group 1 participants and 
three separate time points per dose for Group 2 participants, and RT samples are collected at two time 
points per dose for Group 1 and two time points per dose for Group 2 participants, there are differences 
between how the concentration data for these matrices will be analyzed and summarized. 
 
In general, due to the small number of concentrations available at sampling time points, a log 
transformation of the concentrations will be considered if the data suggest strong skewness.  In this case, 
figures and tables will report medians with 95% C.I. at each sampling time point and figures will be 
presented on a semi-logarithmic scale (y-axis: logarithmic concentration; x-axis: linear time (h)).  If no log 


 
  
 
 
 
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transformation of concentration is needed, then figures and tables will report the mean (with 95% 
confidence interval based on a Student’s t-distribution approximation) at each sampling time point and 
figures will be presented on a linear scale. 
 
Blood Concentrations 
 
For blood, EVG, TAF, and TFV concentrations can be plotted over time for each individual participant, 
and PK parameters (defined below) may be calculated for each participant and then summarized across 
all participants. 
 
Displays of blood concentration data include: 
• 
Tables summarizing the distribution of concentrations at each sampling time point for each dose 
administration (3 tables, one for each drug, with a column for each dose administration). 
• 
Plots of individual participant concentration-time data presented in a panel for each dose 
administration (6 panels of plots (1 panel for each dose administration and drug)).   
• 
Individual participant concentration-time data will also be overlaid on a single plot for each dose 
administration and drug (6 plots). 
• 
Plots of mean/median concentration at each time point (with 95% C.I.) for each dose 
administration and drug (3 panels, one for each drug, with 2 plots (1 for each dose 
administration)). 
• 
Listings of individual participant PK parameters for each dose administration and drug (6 listings). 
• 
Tables summarizing the distributions of PK parameters across all participants for each dose 
administration and drug (6 tables). 
 
Rectal Fluid and Rectal Tissue Concentrations 
 
For rectal fluid and rectal tissue, the concentration-time profile will consist of data from different 
participants at different sampling time points.  Individual participant PK parameters will not be calculated 
for concentration data from rectal fluid and rectal tissue since data were not collected at each time point 
for each participant.  
 
Displays of rectal fluid and rectal tissue concentration data include: 
• 
For each matrix (RF, RT), tables summarizing the distribution of concentrations at each sampling 
time point for each dose administration and drug (7 tables (3 for RF, 4 for RT) with a column for 
each dose administration). 
• 
For each matrix (RF, RT), scatter plots of drug concentration-time data for each dose 
administration (7 panels (3 for RF, 4 for RT) with 2 plots (1 for each dose administration)).   
• 
For each matrix (RF, RT), plots of mean/median concentration at each time point (with IQR or 
95% C.I., as appropriate) for each dose administration (7 panels (3 for RF, 4 for RT) with 2 plots 
(1 for each dose administration)). 
 
The PK parameters are: 
 
Cmax  
 
Maximum observed drug concentration. 
Clast  
 
Last observed drug concentration. 
tmax  
 
Time of occurrence for Cmax 
AUC0-t 
Area under the drug concentration-time curve to the time of the last measurable 
concentration. 
AUC0-∞ 
Area under the drug concentration-time curve to infinite time.  Equal to AUC0-t plus AUCt-∞ 
= (Clast / ke). 
ke  
 
Terminal elimination rate constant. 


 
  
 
 
 
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t1/2 
 
Half-life of drug elimination in the terminal phase. 
%AUCex  
Percentage of AUC0-∞ obtained by extrapolation, calculated as [(Clast / ke) / AUC0-∞ *100] 
The time, in hours, to each sample collection time is calculated from the time of dose administration.  The 
area under the curve (AUC) is calculated for each participant using the trapezoidal method from the time 
of dose administration to the time of the last sample collection (AUC0-t), typically at 72h.   
Concentrations after Cmax are used to determine the terminal elimination rate constant (ke) and associated 
half-life of drug elimination in the terminal phase (t1/2), when at least three such concentration values are 
available, according to the following formulas: 
 
ke = ln (C1/C2) / (t2 – t1) 
t1/2 = ln(2) / ke 
where ln is the natural logarithm, C1 is the first drug concentration value in the elimination phase 
after Cmax, C2 is the last drug concentration in the elimination phase after Cmax, and t1 and t2 are 
the time (hours) of the first and last drug concentration values in the elimination phase after Cmax, 
respectively, as measured from the time of dose administration. 
The area under the blood drug concentration-time curve to infinite time (AUC0-∞) is calculated by 
extrapolating the area of the curve after the last observed blood drug concentration (Clast) by dividing Clast 
by the terminal elimination rate constant (ke) and adding the result to AUC0-t.  The percentage of AUC0-∞ 
obtained by extrapolation (%AUCex) is calculated as [(AUCt-∞ / AUC0-∞ )*100]. 
10. SECONDARY ENDPOINTS 
10.1 Acceptability Analyses 
Enrolled participants are administered computer assisted self-interviews (CASI) questionnaires at 
Enrollment (Visit 2) and at 24 hours after the one-insert and two-insert dosing visits (Visits 4 and 8, 
respectively).  The CASI questionnaires after dosing visits explore such topics as experiences with trial 
participation, rectal insert acceptability, experiences using the product, recommendations, etc. 
 
To address the secondary endpoint of participant report of overall acceptability of the TAF/EVG insert 
applied rectally, responses to CASI questions in section B (Rectal Insert Acceptability) of the dosing visits 
(Visits 4 and 8) will be summarized in a table by insert dose (one inserts or two inserts).   
11. REFERENCES  
A Phase 1 Open Label Safety and Pharmacokinetic Study of Rectal Administration of a Tenofovir 
Alafenamide/Elvitegravir Insert at Two Dose Levels (MTN-039).  Microbicide Trials Network (MTN) clinical 
study protocol, Version 1.0, March 6, 2019.  
 
LETTER OF AMENDMENT #03 TO MTN-039 A Phase 1 Open Label Safety and Pharmacokinetic Study 
of Rectal Administration of a Tenofovir Alafenamide/Elvitegravir Insert at Two Dose Levels, Version 1.0, 
dated March 6, 2019; Date of Letter of Amendment: 24 July 2020. 
 
LETTER OF AMENDMENT #04 TO MTN-039 A Phase 1 Open Label Safety and Pharmacokinetic Study 
of Rectal Administration of a Tenofovir Alafenamide/Elvitegravir Insert at Two Dose Levels, Version 1.0, 
dated March 6, 2019; Date of Letter of Amendment: 29 September 2021. 
 


 
  
 
 
 
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MTN-039 SSP Manual, Version 1.2, 17 August 2020, Section 5, Page 5-5 and 5-6 of 5-10, Section 5.4.2 
Pharmacokinetics, Pharmacodynamics, and Biomarker Sample Collection. Table 5-1 Sample Collection 
Time-Points Post-Insert Administration. 
12. CHANGE HISTORY  
Version 
Affected 
Section(s) 
Activity Description 
Number 
Effective 
Date 
2.0 
08OCT2021 
2.2, 9.2, 11 
Clarify sample testing for TAF and TFV-DP concentrations 
as primary endpoints in the protocol. This change adds 
rectal mucosal tissue homogenates to sample testing to 
measure TAF concentration and removes rectal mucosal 
tissue homogenates from sample testing to measure TFV-
DP concentrations. Changes are documented in Letter of 
Amendment #04, which is added as a reference.