A Phase 1, Randomized Pharmacokinetic and Safety Study of a 90 Day Intravaginal Ring Containing Tenofovir
Phase: PHASE1
Conditions: HIV Infections
Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

 
 
MTN-038 
 
 
A Phase 1, Randomized Pharmacokinetic and Safety Study of a 90 Day 
Intravaginal Ring Containing Tenofovir  
 
 
 
 
 
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: 
UM1 AI068633 
 
DAIDS Protocol ID: 38460 
 
IND Sponsor: 
DAIDS 
 
IND #: TBD 
 
 
Protocol Chair: 
Albert Liu, MD, MPH 
 
 
 
 
Version 1.0 
 
July 11, 2018

 
MTN-038, Version 1.0                               2                              
July 11, 2018 
 
MTN-038 
 
A Phase 1, Randomized Pharmacokinetic and Safety Study of a 90 Day 
Intravaginal Ring Containing Tenofovir  
 
TABLE OF CONTENTS 
TABLE OF CONTENTS .................................................................................................. 2 
LIST OF ABBREVIATIONS AND ACRONYMS ............................................................... 6 
PROTOCOL TEAM ROSTER ......................................................................................... 9 
INVESTIGATOR SIGNATURE FORM .......................................................................... 18 
PROTOCOL SUMMARY ............................................................................................... 19 
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 
Microbicides in HIV/AIDS Prevention .............................................................. 25 
2.2 
Tenofovir ......................................................................................................... 26 
2.3 
Nonclinical Studies of Tenofovir ...................................................................... 27 
2.4 
Clinical Studies of Tenofovir............................................................................ 35 
2.5 
Study Hypotheses and Rationale for Study Design ........................................ 41 
3 
OBJECTIVES .................................................................................................. 42 
3.1 
Primary Objectives .......................................................................................... 42 
3.2 
Secondary Objectives ..................................................................................... 42 
3.3 
Exploratory Objectives .................................................................................... 42 
4 
STUDY DESIGN ............................................................................................. 43 
4.1 
Identification of Study Design .......................................................................... 43 
4.2 
Primary Endpoints ........................................................................................... 43 
4.3 
Secondary Endpoints ...................................................................................... 43 
4.4 
Exploratory Endpoints ..................................................................................... 44 
4.5 
Description of Study Population ...................................................................... 44 
4.6 
Time to Complete Accrual ............................................................................... 44 
4.7 
Study Groups .................................................................................................. 45 
4.8 
Expected Duration of Participation .................................................................. 45 
4.9 
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 ............................................................................... 49 
6 
STUDY PRODUCT ......................................................................................... 50 
6.1 
Regimen.......................................................................................................... 50 
6.2 
Administration ................................................................................................. 50 

 
MTN-038, Version 1.0                               3                                      July 11, 2018 
6.3 
Study Product Formulation and Storage ......................................................... 50 
6.4 
Supply and Accountability ............................................................................... 51 
6.5 
Concomitant Medications ................................................................................ 52 
6.6 
Prohibited Medications .................................................................................... 52 
6.7 
Intravaginal and Rectal Medications, Products and Practices ........................ 53 
7 
STUDY PROCEDURES ................................................................................. 53 
7.1 
Pre-screening .................................................................................................. 54 
7.2 
Screening Visit - Visit 1 ................................................................................... 54 
7.3 
Enrollment Visit - Visit 2 (Day 0) ..................................................................... 55 
7.4 
Follow-up Visits ............................................................................................... 57 
7.5 
Follow-up Procedures for Participants Who Permanently Discontinue Study 
Product ........................................................................................................... 63 
7.6 
Interim Visits ................................................................................................... 65 
7.7 
Protocol Counseling: Adherence and Contraception Counseling.................... 65 
7.8 
Pharmacokinetics ............................................................................................ 65 
7.9 
Behavioral Measures ...................................................................................... 66 
7.10 
Clinical Evaluations and Procedures ............................................................... 68 
7.11 
Laboratory Evaluations ................................................................................... 69 
7.12 
Specimen Management .................................................................................. 70 
7.13 
DAIDS Laboratory Oversight........................................................................... 71 
7.14 
Biohazard Containment .................................................................................. 71 
8 
ASSESSMENT OF SAFETY ........................................................................... 71 
8.1 
Safety Monitoring ............................................................................................ 71 
8.2 
Clinical Data and Safety Review ..................................................................... 71 
8.3 
Adverse Events Definitions and Reporting Requirements .............................. 72 
8.4 
Adverse Event Reporting Requirements ......................................................... 74 
8.5 
Pregnancy and Pregnancy Outcomes ............................................................ 75 
8.6 
Regulatory Requirements ............................................................................... 76 
8.7 
Social Harms Reporting .................................................................................. 76 
9 
CLINICAL MANAGEMENT ............................................................................. 76 
9.1 
Grading System .............................................................................................. 76 
9.2 
Dose Modification Instructions ........................................................................ 76 
9.3 
General Criteria for Temporary Hold and Permanent Discontinuation of Study 
Product ........................................................................................................... 77 
9.4 
Temporary Product Hold/Permanent Discontinuation in Response to Adverse 
Events ............................................................................................................. 77 
9.5 
Sexually Transmitted Infection/Reproductive Tract Infection .......................... 78 
9.6 
Management of Specific Genital Events ......................................................... 78 
9.7 
HIV Infection ................................................................................................... 79 
9.8 
Pregnancy ....................................................................................................... 79 
9.9 
Criteria for Early Termination of Study Participation ....................................... 80 
10 
STATISTICAL CONSIDERATIONS ................................................................ 81 
10.1 
Overview and Summary of Design .................................................................. 81 
10.2 
Study Endpoints .............................................................................................. 81 
10.3 
Primary Study Hypotheses.............................................................................. 82 
10.4 
Sample Size and Power Calculations ............................................................. 82 

 
MTN-038, Version 1.0                               4                                      July 11, 2018 
10.5 
Participant Accrual, Follow-up, and Retention ................................................ 84 
10.6 
Randomization ................................................................................................ 84 
10.7 
Data and Safety Monitoring and Analysis ....................................................... 85 
11 
DATA HANDLING AND RECORDKEEPING .................................................. 87 
11.1 
Data Management Responsibilities ................................................................. 87 
11.2 
Source Documents and Access to Source Data/Documents .......................... 87 
11.3 
Quality Control and Quality Assurance ........................................................... 88 
12 
CLINICAL SITE MONITORING ....................................................................... 88 
13 
HUMAN SUBJECTS PROTECTIONS ............................................................ 88 
13.1 
Institutional Review Boards/Ethics Committees .............................................. 89 
13.2 
Protocol Registration ....................................................................................... 89 
13.3 
Study Coordination ......................................................................................... 90 
13.4 
Risk Benefit Statement ................................................................................... 90 
13.5 
Informed Consent Process.............................................................................. 93 
13.6 
Participant Confidentiality................................................................................ 94 
13.7 
Special Populations ........................................................................................ 95 
13.8 
Compensation ................................................................................................. 95 
13.9 
Communicable Disease Reporting .................................................................. 95 
13.10 Access to HIV-related Care............................................................................. 95 
13.11 Study Discontinuation ..................................................................................... 96 
14 
PUBLICATION POLICY .................................................................................. 96 
15 
APPENDICES ................................................................................................. 97 
APPENDIX I:  SCHEDULE OF STUDY VISITS AND EVALUATIONS .......................... 98 
APPENDIX II:  ALGORITHM FOR HIV TESTING FOR SCREENING AND ENROLLED 
PARTICIPANTS .......................................................................................................... 101 
APPENDIX III:  SAMPLE INFORMED CONSENT FORM (SCREENING, 
ENROLLMENT, LONG-TERM STORAGE AND FUTURE TESTING) ........................ 102 
REFERENCE LIST...................................................................................................... 121 
 
Table of Figures 
Figure 1: Study Visit Schedule ...................................................................................... 20 
Figure 2: Mean (+SD) Plasma TFV Concentrations following Intravaginal Treatment with 
TFV IVRs (Left, n = 8) and TFV 1% Gel (Right, n = 6-7) in Female Sheep for 90 
Days plus 3 Days following IVR Removal or 28 Days plus 3 Days following daily gel 
administration ......................................................................................................... 32 
Figure 3: Mean (+SD) TFV Vaginal Fluid Concentrations following Intravaginal 
Treatment with TFV IVRs (n = 8) in Female Sheep for 90 days plus 3 days following 
IVR Removal .......................................................................................................... 32 
Figure 4: Mean (+SD) TFV Vaginal Fluid Concentrations following Intravaginal 
Treatment with TFV 1% Gel (n = 6-7) in Female Sheep for 28 days plus 3 days ... 33 
Figure 5: Mean (+SD) TFV Vaginal Tissue Concentrations following Intravaginal 
Treatment with TFV IVRs (n = 8) in Female Sheep for 90 days plus 3 days following 
IVR Removal .......................................................................................................... 33 
Figure 6: Mean (+SD) TFV Vaginal Tissue Concentrations following Intravaginal 
Treatment with TFV 1% Gel (n = 6-7) in Female Sheep for 28 days plus 3 days ... 34 
Figure 7: Study Visit Schedule ...................................................................................... 54 

 
MTN-038, Version 1.0                               5                                      July 11, 2018 
Table of Tables 
 
Table 1: Mean (SD) TFV PK Parameters Determined following 90-day Intravaginal 
Treatment with TFV IVR and once-daily Intravaginal Administration of TFV 1% Gel 
for 28 Days in Sheep .............................................................................................. 31 
Table 2: Study Regimen ................................................................................................ 50 
Table 3:  Retrieval of IVR .............................................................................................. 52 
Table 4: Screening Visit - Visit 1 ................................................................................... 55 
Table 5: Enrollment Visit - Visit 2 (Day 0) ...................................................................... 56 
Table 6: Days 1 and 7- Visits 3 and 4............................................................................ 57 
Table 7: Day 14 - Visit 5 ................................................................................................ 58 
Table 8: Day 28 - Visit 6 ................................................................................................ 59 
Table 9: Day 42 - Visit 7 ................................................................................................ 60 
Table 10: Day 56 - Visit 8 .............................................................................................. 61 
Table 11: PUEV/Early Termination Visit - Visit 9 - Day 91 ............................................ 62 
Table 12: Final Contact - Visit 10 - Day 92 .................................................................... 63 
Table 13: PK, PD, and Biomarkers Specimen Collection Schedule .............................. 66 
Table 14: Analysis of PK Event Frequency ................................................................... 82 
Table 15: Analysis of Safety Event Frequency .............................................................. 83 
Table 16: Precision of Exact 2-sided 95% CIs for Observed Event Rates .................... 83 
Table 17: Safety Event Rates that Provide 90% Power for Testing Equality of Safety 
Event Rates ........................................................................................................... 84 
 

 
MTN-038, Version 1.0                               6                                      July 11, 2018 
MTN-038 
 
A Phase 1, Randomized Pharmacokinetic and Safety Study of a 90 Day 
Intravaginal Ring Containing Tenofovir  
 
 
LIST OF ABBREVIATIONS AND ACRONYMS 
 
AE 
 
adverse event  
AIDS 
 
Acquired Immunodeficiency Syndrome 
ALT 
 
alanine transaminase 
ART 
 
antiretroviral therapy 
ARV 
 
antiretroviral 
ASPIRE 
A Study to Prevent Infection with a Ring for Extended Use 
AST 
 
aspartate aminotransferase 
AUC 
 
area under the curve 
b.i.d. 
 
bis in die (twice daily) 
BMI 
 
body mass index 
BRWG  
Behavioral Research Working Group 
BSWG  
Biomedical Science Working Group 
BV 
 
bacterial vaginosis 
CASI 
 
computer assisted self-interview 
CBC 
 
complete blood count 
CCR5  
C-C chemokine receptor type 5   
CDC 
 
Centers for Disease Control and Prevention 
CFR 
 
Code of Federal Regulations 
Cmax  
maximum concentration 
CMRB  
Clinical Microbicide Research Branch 
CORE  
Coordinating and Operations Center 
CRF  
 
case report form 
CRMS  
Clinical Research Management System 
CROI 
 
Conference on Retroviruses and Opportunistic Infections 
CRS 
 
clinical research site 
Css 
 
steady state concentration 
CT  
 
Chlamydia trachomatis, chlamydia 
CTA 
 
Clinical Trial Agreement 
CVF 
 
cervicovaginal fluid 
CVL 
 
cervicovaginal lavage  
CWG 
 
Community Working Group 
CYP 
 
cytochrome P450 
DAERS  
DAIDS Adverse Event Reporting System 
DAIDS  
Division of AIDS  
DAPY  
di-amino-pyrimidine 
DLV 
 
delavirdine 
DMPA  
depot medroxyprogesterone acetate 
DNA 
 
deoxyribonucleic acid 
DPV 
 
dapivirine 
EAE 
 
expedited adverse event 
EC50 
 
median effective concentration 
EDC 
 
electronic data capture 
EFV 
 
efavirenz 
 
EMBRACE 
Evaluation of Maternal and Baby Outcome Registry After Chemoprophylactic Exposure 
ENR 
 
Enrollment 

 
MTN-038, Version 1.0                               7                                      July 11, 2018 
FAME  
Film Antiretroviral Microbicide Evaluation 
FDA 
 
(US) Food and Drug Administration 
FHCRC 
Fred Hutchinson Cancer Research Center 
FSH 
 
follicle-stimulating hormone 
FTC 
 
emtricitabine 
 
g 
 
grams 
GC  
 
Neisseria gonorrhoeae, gonorrhea 
GCP 
 
Good Clinical Practices 
GMP 
 
Good Manufacturing Practices 
hCG 
 
human chorionic gonadotropin 
HEC 
 
hydroxyethylcellulose 
HEENT  
Head, Eye, Ear, Nose and Throat Examination 
HHS 
 
US Department of Health and Human Services 
HIV 
 
Human Immunodeficiency Virus 
HPV 
 
human papillomavirus 
hu-PBL  
human peripheral blood lymphocytes 
IATA 
 
International Air Transport Association 
IB 
 
Investigator’s Brochure 
ICF 
 
informed consent forms 
ICH 
 
International Council for Harmonisation 
IDI 
 
in-depth interview 
IND 
 
Investigational New Drug 
IoR 
 
Investigator of Record 
IP 
 
Investigational Product 
IPM 
 
International Partnership for Microbicides  
IRB 
 
Institutional Review Board 
IUD 
 
intrauterine device 
IVR 
 
intravaginal ring 
kg 
 
kilogram 
KOH 
 
potassium hydroxide  
LC 
 
MTN Laboratory Center 
LDMS  
Laboratory Data Management System 
LLOQ  
lower limit of quantification 
LNG 
 
levonorgestrel 
LOC 
 
MTN Leadership and Operations Center 
μg 
 
microgram 
 
μM 
 
micromole 
m 
 
meter 
mg 
 
milligram 
MIV-160 
(-)-cis-1-(5-Cyanopyridin-2-yl)-3-(4,7-diflouro-1,1a,2,7b-tetrahydrocyclopropa[c]chromen- 
 
 
1-yl)-urea, MSR-216; an NNRTI 
mL 
 
milliliter 
mm 
 
millimeter 
MO 
 
Medical Officer 
MPID 
 
Maternal and Pediatric Infectious Diseases 
MTD 
 
maximum tolerated dose 
MTN 
 
Microbicide Trials Network 
NAAT  
nucleic acid amplification test 
ng 
 
nanogram 
NIAID  
National Institute of Allergy and Infectious Diseases 
NICHD  
Eunice Kennedy Shriver National Institute of Child Health and Human Development 
NIH 
 
National Institutes of Health  
NIMH  
National Institute of Mental Health  
NL 
 
network laboratory 
nM 
 
nanomole 
NNRTI  
non-nucleoside reverse transcriptase inhibitor 

 
MTN-038, Version 1.0                               8                                      July 11, 2018 
NOAEL  
no-observed-adverse-effect-level 
NVP 
 
nevirapine 
OHRP  
Office for Human Research Protections 
PD 
 
pharmacodynamics 
PEP 
 
post-exposure prophylaxis 
pg 
 
picogram 
PK  
 
pharmacokinetics 
PoR 
 
Pharmacist of Record 
PrEP 
 
pre-exposure prophylaxis 
PRO 
 
Protocol Registration Office 
PSP 
 
Prevention Sciences Program 
PSRT  
Protocol Safety Review Team 
PTID 
 
participant identification 
PUEV  
product use end visit 
PVI 
 
penile-vaginal intercourse 
RE 
 
Regulatory Entity 
RNA 
 
ribonucleic acid 
RSC 
 
Regulatory Support Center 
RT 
 
reverse transcriptase 
RTI 
 
reproductive tract infection 
SAE 
 
serious adverse event 
SCHARP 
Statistical Center for HIV/AIDS Research & Prevention 
SCID 
 
severe combined immunodeficiency 
SCR 
 
Screening 
SDMC  
Statistical Data Management Center 
SHBG  
sex hormone-binding globulin 
SMC 
 
Study Monitoring Committee 
SMS  
 
short message service 
SOC  
 
System Organ Class 
SOP 
 
standard operating procedure 
SSP 
 
study specific procedures 
STI 
 
sexually transmitted infection 
SUSARs 
suspected, unexpected serious adverse reactions 
TDF 
 
tenofovir diproxil fumarate 
TEAE  
treatment-emergent adverse events 
TFV 
 
tenofovir 
Tmax 
 
time to reach the maximum concentration 
UA 
 
urinalysis  
UNAIDS 
United Nations Programme on HIV/AIDS 
UPMC  
University of Pittsburgh Medical Center 
USA 
 
United States of America 
USP 
 
U.S. Pharmacopeial Convention 
UTI 
 
urinary tract infection 
VIDD 
 
Vaccine and Infectious Disease Division 
VR 
 
vaginal ring 
WHO 
 
World Health Organization 
w/w 
 
weight/weight 

 
MTN-038, Version 1.0                               9                                      July 11, 2018 
MTN-038 
 
A Phase 1, Randomized Pharmacokinetic and Safety Study of a 90 Day 
Intravaginal Ring Containing Tenofovir  
 
PROTOCOL TEAM ROSTER 
 
 
Protocol Chair 
 
Albert Liu, MD, MPH 
Protocol Chair 
Clinical Research Director 
Bridge HIV CRS 
San Francisco Department of Public Health 
25 Van Ness Avenue, Suite 100 
San Francisco, CA 94102 USA 
Phone: 415-437-7408 
Fax: 415-431-7029 
Email: albert.liu@sfdph.org 
 

 
MTN-038, Version 1.0                               10                                      July 11, 2018 
Site Investigators  
 
Albert Liu, MD, MPH 
Site Investigator 
Clinical Research Director 
Bridge HIV CRS 
San Francisco Department of Public Health 
25 Van Ness Avenue, Suite 100 
San Francisco, CA 94102 USA 
Phone: 415-437-7408 
Fax: 415-431-7029 
Email: albert.liu@sfdph.org 
 
Beatrice A. Chen, MD, MPH 
Site Investigator  
Magee-Womens Hospital of UPMC  
300 Halket Street  
Pittsburgh, PA 15213 USA  
Phone: 412-641-1403  
Fax: 412-641-1133  
Email: chenba@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   
 
 
 

 
MTN-038, Version 1.0                               11                                      July 11, 2018 
US National Institutes of Health (NIH) 
 
Roberta Black, PhD 
Microbicide Research Branch Chief 
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 
Fax: 301-402-3684 
Email: rblack@niaid.nih.gov 
 
Nahida Chakhtoura, MD, MsGH 
Maternal and Pediatric Infectious Disease Branch 
Eunice Kennedy Shriver National Institute of Child Health and Human Development 
(NICHD)  
National Institutes of Health (NIH) 
6710B Rockledge Drive 2155D, MSC 7002,  
Bethesda, MD 20817 
Phone: 301-435-6872 
Fax: 301-480-3882 
Email: nahida.chakhtoura@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, MSC 9831 
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 
 

 
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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 
 
Cindy Jacobson, PharmD 
Director of Pharmacy Affairs 
Microbicide Trials Network 
204 Craft Avenue 
Pittsburgh, PA  15213 USA 
Phone: 412-641-8913 
Fax: 412-641-6170 
Email: cjacobson@mail.magee.edu 
 
Katherine Bunge, MD 
Protocol Safety Physician 
Magee-Womens Hospital of UPMC 
300 Halket Street 
Pittsburgh, PA 15213 USA 
Phone: 412-641-3464 
Fax: 412-641-1133 
Email: kbunge@mail.magee.edu 
 
Sharon A. Riddler, MD, MPH 
Protocol Physician 
UPMC, 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 
 
Luis Duran, DrPH, MPIA 
Project Manager  
Microbicide Trials Network 
204 Craft Avenue 
Pittsburgh, PA 15213 USA 
Phone: 412-641-8539 
Fax: 412-641-6170 
Email: duranl2@mwri.magee.edu 
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 
 
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 
 
 
 
 

 
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MTN Laboratory Center (LC) 
 
May Beamer, BS 
Laboratory Manager/Supervisor 
Microbicide Trials Network 
204 Craft Avenue 
Pittsburgh, PA 15213 USA 
Phone: 412-641-6026 
Fax: 412-641-6170 
Email: mbeamer@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 
 
Jennifer Robinson, MD, MPH, FACOG 
Pharmacology LC Representative 
Johns Hopkins University 
600 North Wolfe Street, Harvey 502 
Baltimore, MD 21287 USA 
Phone: 410-550-7202 
Fax: 410-550-0196 
Email: jrobin87@jhmi.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 
 

 
MTN-038, Version 1.0                               14                                      July 11, 2018 
 MTN LOC – FHI 360 
Tara McClure, MPH 
Clinical Research Manager 
FHI 360 
359 Blackwell St, Suite 200 
Durham, NC 27701 USA 
Phone: 919-544-7040, Ext. 11012 
Fax: 919-544-7261 
Email: tmcclure@FHI360.org  
Rachel Scheckter, MPH 
Sr. Clinical Research Manager 
FHI 360 
359 Blackwell St, Suite 200 
Durham, NC 27701 USA 
Phone: 919-544-7040, Ext. 11392 
Fax: 919-544-7261 
Email: rscheckter@FHI360.org 
Rhonda White, RH Ed 
Community Program Manager 
FHI 360 
359 Blackwell St., Suite 200 
Durham, NC  27701 USA  
Phone: 919-544-7040, Ext. 11515 
Fax: 919-544-0207 
Email: rwhite@fhi360.org 
 
 
 
 

 
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MTN Statistical Data Management Center (SDMC) 
 
Amanda Brown 
Clinical Data Manager 
FHCRC – SCHARP  
1100 Fairview Ave. North, E3- 433D 
PO Box 19024 
Seattle, WA 98109-1024 USA 
Phone: 206-667-7052 
Fax: 206-667-2317 
Email: abrown@scharp.org 
 
Holly Gundacker, MS 
Statistical Research Associate  
FHCRC-SCHARP 
1100 Fairview Ave North, M2-C200 
PO Box 19024 
Seattle, WA 98109-1024 USA  
Phone: 206-667-6480 
Email: hgundack@scharp.org  
 
Karen Patterson, MPH 
Program & Portfolio Manager 
FHCRC – SCHARP  
1100 Fairview Ave. North, E3- 315 
PO Box 19024 
Seattle, WA 98109-1024 USA 
Phone: 206-667-7052 
Fax: 206-667-4812 
Email: karen@scharp.org 
 
Barbra Richardson, PhD 
Faculty Statistician 
FHCRC-SCHARP 
1100 Fairview Ave. North, M2-C200 
PO Box 19024 
Seattle, WA 98109-1024 USA 
Phone: 206-667-7788  
Fax: 206-667-4812 
Email: barbrar@uw.edu 
 
 
 

 
MTN-038, Version 1.0                               16                                      July 11, 2018 
MTN Qualitative Data Management Center (QDMC) 
 
Ariane van der Straten, PhD, MPH  
Center Director 
Women’s Global Health Imperative program 
Research Triangle Institute International  
114 Sansome Street, Suite 500  
San Francisco, CA 94104 USA  
Phone: 415-848-1324  
Fax: 415-848-1330  
Email: ariane@rti.org   
 
Kim Woodhouse 
Program and Portfolio Manager 
Women’s Global Health Imperative program 
Research Triangle Institute International  
114 Sansome Street, Suite 500  
San Francisco, CA 94104 USA  
Phone: 415-848-1344  
Fax: 415-848-1330  
Email: kwoodhouse@rti.org   
 
Sarah T. Roberts, PhD 
Project Director 
Women’s Global Health Imperative program 
Research Triangle Institute International  
351 California Street, Suite 500 
San Francisco, CA 94104 USA 
Phone: 415-848-1335 
Email: sroberts@rti.org  
 
Imogen Hawley, MA 
Project Coordinator and data manager 
Women’s Global Health Imperative program 
Research Triangle Institute International  
351 California Street, Suite 500 
San Francisco, CA 94104 USA 
Phone: 415-848-1339 
Email: ihawley@rti.org  
 
 
  
 
 
 
 
 
 
 
 

 
MTN-038, Version 1.0                               17                                      July 11, 2018 
Working Group Representatives 
 
Betsy C. Herold, MD 
Biomedical Science Working Group (BSWG) Representative  
Albert Einstein College of Medicine 
1300 Morris Park Avenue, Forcheimer 702 
Bronx, NY 10461 USA 
Phone: 718-430-2974  
Fax: 718-430-8893  
Email: betsy.herold@einstein.yu.edu   
 
Ariane van der Straten, PhD, MPH  
Behavioral Research Working Group (BRWG) Representative 
Women’s Global Health Imperative program 
Research Triangle Institute International  
114 Sansome Street, Suite 500  
San Francisco, CA 94104 USA  
Phone: 415-848-1324  
Fax: 415-848-1330  
Email: ariane@rti.org   
 
Sarah T. Roberts, PhD 
Research Analyst 
Women’s Global Health Imperative program 
Research Triangle Institute International  
351 California Street, Suite 500 
San Francisco, CA 94104 USA 
Phone: 415-848-1335 
Email: sroberts@rti.org  
 
Renee Weinman, BS, CCRP 
Community Working Group (CWG) Representative 
University of Pittsburgh  
Falk Medical Bldg. 7th floor 
3601 Fifth Avenue 
Pittsburgh, PA 15213 
Phone: 412-647-0322 
Email: weinmandr@upmc.edu 
 
 

 
MTN-038, Version 1.0                               18                                      July 11, 2018 
 
MTN-038 
 
A Phase 1, Randomized Pharmacokinetic and Safety Study of a 90 Day 
Intravaginal Ring Containing Tenofovir 
INVESTIGATOR SIGNATURE FORM 
Version 1.0; July 11, 2018 
 
A Study of the Microbicide Trials Network 
 
Funded by: 
Division of AIDS (DAIDS), US National Institute of Allergy and Infectious Diseases 
US Eunice Kennedy Shriver National Institute of Child Health and Human Development 
US National Institute of Mental Health 
US National Institutes of Health (NIH) 
 
IND Holder: 
DAIDS (DAIDS Protocol ID: 38460) 
 
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-038, Version 1.0                               19                                      July 11, 2018 
MTN-038 
A Phase 1, Randomized Pharmacokinetic and Safety Study of a 90 Day 
Intravaginal Ring Containing Tenofovir 
PROTOCOL SUMMARY 
 
Short Title: 
PK and Safety Study of a 90 Day Vaginal Ring Containing 
Tenofovir 
 
Clinical Phase: 
Phase 1 
 
IND Sponsor: 
DAIDS 
 
Protocol Chair: 
Albert Liu, MD, MPH 
 
Sample Size: 
Approximately 48 participants  
 
Study Population: 
Healthy, HIV-uninfected individuals assigned female sex at birth, 
18-45 (inclusive) years old 
 
Study Sites: 
US site(s) selected by the MTN Executive Committee 
 
Study Design: 
Phase 1, two-arm, multi-site, randomized (2:1), placebo-
controlled trial 
 
Study Duration: 
Approximately 92 days per participant, with approximately 6-9 
months planned for accrual 
 
Study Products: 
Tenofovir (TFV) intravaginal ring (IVR) 
 
Placebo IVR 
 
Study Regimen: 
Participants will be randomized to the study products in a 2:1 
TFV: placebo ratio and will not be told their group assignment. 
Participants will insert one IVR to be used for a period of 
approximately 91 days, followed by approximately 1 day of no 
product use  
 

 
MTN-038, Version 1.0                               20                                      July 11, 2018 
Figure 1: Study Visit Schedule 
  
 
 
Primary Objectives: 
 
Pharmacokinetics 
• To characterize the local and systemic pharmacokinetics of one TFV IVR used 
continuously for 91 days  
 
Safety 
• To evaluate the safety of one TFV IVR used continuously for 91 days 
 
Primary Endpoints: 
 
Pharmacokinetics 
• TFV levels in: 
o Plasma 
o Cervicovaginal fluid (CVF) 
o Rectal fluid 
o Cervical tissue 
•  Tenofovir diphosphate (TFV-DP) levels in: 
o Cervical tissue 
 
Safety 
• The proportion of participants with Grade 2 or higher genitourinary adverse event 
as defined by the Division of AIDS (DAIDS) Table for Grading the Severity of Adult 
and Pediatric Adverse Events, Corrected Version 2.1, July 2017, and/or 
Addendum 1 (Female Genital [Dated November 2007] Grading Table for Use in 
Microbicide Studies)  
• The proportion of participants with Grade 3 or higher adverse event as defined by 
the Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric 
Adverse Events, Corrected Version 2.1, July 2017 
 

 
MTN-038, Version 1.0                               21                                      July 11, 2018 
Secondary Objectives: 
 
Adherence 
• To evaluate participant adherence to one TFV IVR used continuously for 91 days 
 
Acceptability  
• To evaluate the overall acceptability of one TFV IVR used continuously for 91 days 
 
Secondary Endpoints: 
 
Adherence 
• Frequency of study IVR removal/expulsions (voluntary and involuntary) and 
duration without IVR in vagina (by self-report) 
• IVR use initiation and persistence (whether the IVR is in place when participants 
come to the clinic for their study visits) 
 
Acceptability 
• Degree to which study participants liked or disliked using the IVR (by self-report)  
 
Exploratory Objectives: 
 
Adherence 
• To evaluate markers of ring use for the TFV IVR 
 
Acceptability 
• To evaluate components of acceptability of ring use for the TFV IVR 
 
Vaginal Microenvironment 
• To describe the genital microenvironment in HIV-uninfected participants during 91 
days of continuous IVR use  
 
Pharmacodynamics 
• To determine the anti-HIV activity in CVF and cervical tissue 
• To determine the anti-HSV-2 activity in CVF 
 
Exploratory Endpoints: 
 
Adherence 
• Plasma and CVF TFV levels 
• Residual drug levels in returned IVRs 
• Biomarkers of ring use  
 

 
MTN-038, Version 1.0                               22                                      July 11, 2018 
Acceptability 
• Self-reported attitudes about ring attributes, including dosing regimen and 
willingness to use IVR in the future  
• Interest/preference in a single vs. dual-purpose indication 
• The proportion of participants who find the study IVR to be at least as acceptable 
as other HIV prevention methods 
 
Vaginal Microenvironment 
• Changes in microbiota and biomarkers 
• Impact of microbiota on TFV levels in tissue and plasma 
 
Pharmacodynamics 
• Measures of HIV inhibition in CVF and cervical tissue 
• Measures of HSV-2 inhibition in CVF

 
 
 
MTN-038, Version 1.0                             23                                      July 11, 2018 
 
 
 
1 
KEY ROLES 
 
1.1 
Protocol Identification 
 
Protocol Title:   
A Phase 1, Randomized Pharmacokinetic and Safety Study 
of a 90 Day Intravaginal Ring Containing Tenofovir  
 
Protocol Number: 
 
MTN-038 
 
Short Title: 
PK and Safety Study of a 90 Day Vaginal Ring Containing 
Tenofovir  
 
Date:  
 
July 11, 2018 
 
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) 
6700 B Rockledge Drive 
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 
Bethesda, MD 20892 USA 
 
IND Sponsor:   
US Division of AIDS (DAIDS)/National Institute of Allergy and 
Infectious Diseases (NIAID) 
National Institutes of Health (NIH) 
6700 B Rockledge Drive 
Rockville, MD 20852 USA 
 
Monitor: 
Pharmaceutical Product Development, Inc. (PPD) 
929 North Front Street 
Wilmington, NC  28401-3331 USA 
 
 

 
 
 
MTN-038, Version 1.0                             24                                      July 11, 2018 
 
 
 
1.3 
Medical Officer 
 
Medical Officer: 
Jeanna Piper, MD  
5601 Fishers Lane, Room 8B68, MSC 9831 
Rockville, MD 20852 USA 
 
1.4 
Laboratory Centers 
 
 
 
 
MTN Laboratory Center (LC) 
 
 
 
204 Craft Avenue 
 
 
 
Pittsburgh, PA 15213 USA 
 
 
 
 
 
MTN Pharmacology LC 
 
 
 
 
600 N. Wolfe Street, Osler 527 
 
 
 
 
Johns Hopkins University 
 
 
 
 
Baltimore, MD 21287 USA 
 
1.5 
Data Center 
 
Data Center: 
 
MTN Statistical Data and Management Center (SDMC) 
 
 
 
Statistical Center for HIV/AIDS Research & Prevention 
 
 
 
(SCHARP)/Fred Hutchinson Cancer Research Center 
 
 
 
(FHCRC) 
 
 
 
1100 Fairview Avenue N., LE-400  
 
 
 
PO Box 19024 
 
 
 
Seattle, WA 98109-1024 USA 
 
Qualitative Data Center: 
MTN Qualitative Data and Management Center (QDMC) 
 
 
 
Women’s Global Health Imperative program (WGHI)/ 
Research Triangle Institute International 
351 California Street, Suite 500 
San Francisco, CA 94104 USA 
 
1.6 
Study Implementation 
 
Study Implementation: 
MTN LOC - FHI 360 
 
 
 
359 Blackwell Street, Suite 200 
 
 
 
Durham, NC 27701 USA 
 
 

 
 
 
MTN-038, Version 1.0                             25                                      July 11, 2018 
 
 
 
2 
INTRODUCTION 
 
2.1 
Microbicides in HIV/AIDS Prevention 
 
In 2016, one million people lost their lives to human immunodeficiency virus (HIV)-related 
causes, and 1.8 million people around the world were newly infected.1  Every 60 seconds, 
a young woman is infected with HIV.2 Women and girls continue to be affected 
disproportionately by HIV in sub-Saharan Africa, where women account for approximately 
60% of people living with HIV.3 The ongoing development of safe and effective HIV 
prevention technologies that can be made easily accessible to women in under-resourced 
countries remains a public health priority. 
 
Unprotected heterosexual intercourse is the leading mode of HIV acquisition among 
women. Correct and consistent use of latex condoms is one proven method of preventing 
HIV acquisition; however, since many women may be unable to negotiate condom use 
with their partners, condom use is regarded as an inadequate prevention option for 
women. Thus, developing HIV prevention options that women can use independent of 
male partner consent remains a global concern. Vaginal microbicides, which are self-
initiated and controlled, offer women a critically needed biomedical prevention tool that 
will complement existing HIV prevention strategies as well as future products being 
developed.  
 
With successful proof-of-concept that antiretroviral (ARV)-based microbicides reduce the 
risk of HIV-1 acquisition,4,5 confirmatory work and further trials involving different ARV 
compounds, various formulations, and different dosing strategies are required to provide 
options to end-users and to improve upon the level of product effectiveness.  
 
For a microbicide to be effective, it is essential that it is used correctly and consistently, 
and is also acceptable to the user.  In addition, a product used independently of sex could 
be more convenient for women and provide long-term protection during anticipated and 
unanticipated sexual intercourse. Higher adherence to a product may translate into higher 
effectiveness of the product to help prevent HIV acquisition. It is likely that products that 
can be applied less frequently or products that can remain in situ for an extended duration 
will be more acceptable and will achieve better adherence. Vaginal rings (VRs) that need 
to be replaced monthly or less frequently may have benefits over dosage forms that need 
to be used more frequently.  
 
Multiple clinical trials have evaluated the safety and effectiveness of tenofovir (TFV) for 
the prevention of HIV acquisition in vaginal gel6-9 and in oral tablet formulations.10-13 
These clinical trials support the favorable safety profile and tolerability of TFV in general 
and specifically in vaginal and oral delivery formulations. Although the TFV vaginal gel 
formulation was not consistently shown to be effective for HIV prevention7-9, likely due to 
low rates of adherence, the efficacy of oral tablet formulations containing TFV is well-

 
 
 
MTN-038, Version 1.0                             26                                      July 11, 2018 
 
 
 
established.10-13 However, high levels of adherence to daily oral tenofovir disoproxil 
fumarate/emtricitabine (TDF/FTC) for pre-exposure prophylaxis (PrEP) are needed to 
protect against vaginal HIV acquisition. TFV delivered intravaginally may also help 
prevent herpes simplex virus type 2 (HSV-2) acquisition, as demonstrated in the 
CAPRISA 004 study of pericoitally applied TFV gel.14 
 
The development of an extended duration intravaginal ring (IVR) may allow less frequent 
IVR replacements (e.g., quarterly basis instead of monthly basis) that may further reduce 
patient and provider burden, streamline follow-up, and improve adherence. Such a 
delivery mechanism could overcome the adherence and efficacy issues observed with 
the vaginal gel formulation of TFV and challenges with daily dosing of oral TDF/FTC, thus 
providing a viable vaginal delivery complement to the oral tablet. 
 
MTN-038 is a collaboration between the Microbicide Trials Network (MTN) and CONRAD 
to evaluate the pharmacokinetics (PK) and safety of an extended duration (90 day) TFV 
IVR (loaded with 1.4 g TFV), as compared to a placebo ring.  
 
2.2 
Tenofovir  
 
2.2.1 Description 
 
TFV, 9-[(R)-2-(phosphonomethoxy) propyl]adenine or PMPA, is an adenosine nucleoside 
monophosphate analog of a nucleotide reverse transcriptase inhibitor (NtRTI) with potent 
activity against retroviruses. The orally bioavailable form of TFV, tenofovir disoproxil 
fumarate (TDF) (Viread®), has been approved for the treatment of HIV-1 infection since 
2001 in the U.S. and since 2002 in Europe. TDF is indicated in combination with other 
antiretroviral agents for the treatment of HIV-1 infection and for the treatment of chronic 
hepatitis in adults. TDF is also a component of 3 marketed fixed-dose, orally administered 
combination products for treatment of HIV-1 infection: Truvada® (emtricitabine 200 
mg/TDF 300 mg), Atripla (efavirenz 600 mg/emtricitabine 200 mg/TDF 300 mg), and 
Complera (emtricitabine 200 mg/TDF 300 mg/rilpivirine 25 mg). Gilead has approval from 
the U.S. Food and Drug Administration (FDA) for the use of Truvada for HIV prevention 
in both men and women. 
 
PK studies of vaginally applied TFV have demonstrated lower blood levels and higher 
vaginal tissue levels of drug compared to oral administration, suggesting that topical 
administration may provide protection against vaginal acquisition of HIV with less 
systemic exposure to drug. Gilead has granted co-exclusive rights to CONRAD and the 
International Partnership for Microbicides (IPM) to develop and manufacture TFV as a 
microbicide gel and other dosage forms. 
 
Evaluation of TFV formulated in a vaginal gel for prevention of HIV-1 has been conducted 
in multiple Phase I and II/IIb clinical studies. In a Phase IIb study of vaginally administered 
TFV 1% gel (CAPRISA 004), TFV was shown to significantly reduce HIV acquisition rates 

 
 
 
MTN-038, Version 1.0                             27                                      July 11, 2018 
 
 
 
by approximately 39% (CI 0.06 – 0.60, p = 0.017). In that study, the participants were 
instructed to insert one dose of gel up to 12 hours before sex and a second dose as soon 
as possible up to 12 hours after sex but no more than 2 doses in 24 hours, known as the 
BAT24 regimen.7 To confirm the CAPRISA 004 efficacy findings, an additional Phase III, 
multi-center, double-blind, randomized, placebo-controlled trial, the FACTS 001 study, 
was conducted to evaluate the safety and effectiveness of pericoital TFV 1% gel when 
using the BAT24 regimen. Unlike in the CAPRISA study, pericoital vaginal TFV 1% gel 
was not effective in preventing HIV acquisition in the FACTS 001 study; among 2029 
sexually active, healthy women that were enrolled and included in the primary study 
analysis, 61 HIV infections occurred in the TFV arm and 62 in the placebo group 
(incidence rate ratio [IRR], 1.0; 95% CI: 0.7-1.4).9 
 
Vaginal TFV 1% gel applied daily, as opposed to pericoitally, was also studied for HIV 
prevention in the VOICE study, a Phase IIb study designed and conducted by the MTN. 
The VOICE study (daily administration) did not confirm the protective benefit of TFV gel 
reported from the CAPRISA 004 study (pericoital dosing) due to low adherence: plasma 
levels of TFV were measurable in only 28% of participants in the oral TDF arm, 29% of 
women in the Truvada group, and 23% among those in the TFV gel group.8 
 
TFV has been formulated as IVRs having a diameter of 55 mm and delivering 10 mg of 
TFV/day. This product is being evaluated in safety, PK, and pharmacodynamics (PD) 
studies to establish its usefulness as a vaginal microbicide product. 
 
2.2.2 Mechanism of Action 
 
TFV is an acyclic nucleotide analogue of adenosine monophosphate.  TFV is an NtRTI. 
TFV requires subsequent phosphorylations by cellular enzymes to form tenofovir 
diphosphate (TFV-DP). TFV-DP inhibits the activity of HIV-1 reverse transcriptase by 
competing with the natural substrate deoxyadenosine 5’-triphosphate and, after 
incorporation into DNA, by DNA chain termination. TFV-DP is a weak inhibitor of 
mammalian DNA polymerases α, β, and mitochondrial DNA polymerase γ.   
  
2.3 
Nonclinical Studies of Tenofovir 
 
A full battery of nonclinical studies has been carried out on oral TDF.15 In addition, 
nonclinical testing has been performed using TFV 1% gels.14,16 The toxicity of TFV has 
been studied in rats, rabbits, dogs, and monkeys. It has been administered intravenously, 
orally, subcutaneously, vaginally, and rectally. Except at very high systemic doses (i.e., 
≥75 mg/kg), TFV is well tolerated. It is excreted primarily via the kidneys in unchanged 
form.  
 

 
 
 
MTN-038, Version 1.0                             28                                      July 11, 2018 
 
 
 
2.3.1 In vitro Studies of Tenofovir 
 
In Vitro Pharmacology 
 
Radiolabeled (3H) TFV is rapidly taken up by resting (3-4 μM) and activated (1-2 μM) 
peripheral blood mononuclear cells (PBMCs), suggesting cellular uptake is via 
endocytosis. Once target cells have taken up TFV, subsequent metabolism appears to 
proceed quickly. The mono- and diphosphate metabolites of TFV accumulate rapidly, 
reaching approximately 1 μM and approximately 0.3 μM, respectively, at 6 hours post-
exposure, whereas the adenine mono-phosphate (TFV) is not detectable to facilitate the 
formation of a barrier to HIV infection. This suggests that TFV is rapidly processed upon 
entry to the cell to TFV mono- and diphosphate, with a sufficiently long half-life to facilitate 
the formation and maintenance of a barrier to virus replication that could promote its 
deployment from both coitally associated and coitally disassociated microbicide 
applications. 
 
Anti-HIV-1 Activity 
 
The antiviral activity of TFV against laboratory and clinical isolates of HIV-1 has been 
assessed in lymphoblastoid cell lines, primary monocyte/macrophage cells and 
peripheral blood cells.17-19 The EC50 (50% effective concentration) values for TFV are in 
the range of 0.04 μM to 8.5 μM. TFV displays antiviral activity in cell cultures against HIV-
1 clades A, B, C, D, E, F, G, and O (EC50 values range from 0.5 μM to 2.2 μM) and strain-
specific activity against HIV-2 (EC50 values range from 1.6 μM to 5.5 μM).15   
 
Resistance 
 
Information regarding resistance studies can be found in the package inserts for 
Truvada10 and Viread.15  
 
Condom Compatibility Studies of Tenofovir 
  
The compatibility of TFV 1% vaginal gel (as well as matched placebo gel, and 
hydroxyethyl cellulose (HEC) placebo gel) with various types of male condoms were 
conducted.6 Studies included various male condoms: lubricated condoms, the Alatech 
Healthcare latex condoms, and other commercially available condoms such as Latex 
w/Silicone Lubricant by Rough Rider, Latex w/Aqueous Lubricant by Durex and Latex 
w/Aqueous Lubricant by Trojan, and many additional condom types.6 
 
The airburst test was used to evaluate changes in film integrity (strength) and test 
specimens were measured before and after treatment with the gels to assess changes in 
dimensional profiles (shrinkage).  
 

 
 
 
MTN-038, Version 1.0                             29                                      July 11, 2018 
 
 
 
In general, the results show that there were no statistically significant changes in the 
strength properties following the application of the 3 gel preparations, or only slight 
changes but within the normal range. It was concluded that the TFV 1% gel, the matched 
placebo gel, and HEC placebo gel were all compatible with the condom types in this study. 
More details are provided in the TFV IVR investigator brochure (IB).6 
 
2.3.2 In vivo (Animal Studies) of Tenofovir 
 
Anti-HIV-1 Activity 
 
Six studies conducted by the National Institute of Allergy and Infectious Diseases (NIAID) 
Division of AIDS (DAIDS) and two studies at the Centers for Disease Control and 
Prevention (CDC) were performed to test the hypothesis that vaginal dosing of TFV 
prevents vaginal transmission of virus. These studies provided proof-of-concept that TFV 
applied topically could prevent the transmission of simian immunodeficiency virus 
(SIV)/SHIV) when vaginal dosing mimics coital usage and that extended protection may 
be possible. Although the total data are limited and a powered statistical determination as 
to the efficacy of TFV 1% gel versus 10% cannot be made, empirical examination of the 
efficacy data identifies TFV 1% gel as the lowest efficacious concentration tested when 
given within 2 hours of exposure. Thus, these data provided a scientific rationale for 
clinical study of vaginally applied TFV 1% gel as a method to prevent transmission of HIV. 
Two additional studies performed at the CDC using a repeat-challenge macaque model 
with a low-dose SHIV inoculum containing an R5-tropic HIV-1 envelope similar to 
naturally transmitted human viruses (10-50% tissue culture infective dose [TCID50]) 
showed that application of TFV consistently protected from vaginal SHIV infection.6 
 
Pharmacokinetics 
 
Nonclinical PK testing has been carried out on oral TDF.15 In addition, nonclinical PK 
testing has been performed on TFV 1% vaginal gel.14 All nonclinical PK testing performed 
on the TFV IVR that is described in this section can be found in the TFV IVR IB.6 
 
Rabbits: PK study of IVR segments 
A PK and local tissue effects study of surgically implanted IVR segments containing TFV 
for 1, 2, and 3 months compared to once daily intravaginal administration of TFV 1% for 
1 month was conducted in female rabbits (CONRAD Study 1645-066). TFV and placebo 
IVR segments loaded with approximately 0.23 g of the TFV/glycerin/water (equivalent to 
0.15 g TFV per IVR segment, or approximately one-tenth the TFV loading of a full-sized 
IVR) or placebo were implanted in the abdominal (i.e., cranial) vagina.6  
 
The mean TFV plasma PK parameters following dosing with TFV IVR segments or TFV 
gel in female rabbits for 28 days were the following: TFV IVR segment:  Tmax= 504 hours; 
Cmax = 31.9 ng/mL; AUC 0-t = 14600 ng*hr/mL; AUC/Day (normalized per day for 
comparison) = 421 [ng*hr/mL]/Day. For the TFV 1% gel: Tmax= 4 hours; Cmax = 96.5 

 
 
 
MTN-038, Version 1.0                             30                                      July 11, 2018 
 
 
 
ng/mL; AUC 0-t = 877 (Day 1), 109 (day 15), 62.7 (Day 28) ng*hr/mL; AUC/Day 
(normalized per day for comparison) = 493 [ng*hr/mL]/Day. Mean (and standard 
deviation) TFV and TFV-DP concentrations in urinary vaginal tissues at 28 days post-TFV 
IVR segment implantation were 12,500 (9,260) ng/g and 404 (485) ng/g, respectively. 
Mean (and standard deviation) TFV and TFV-DP concentrations in urinary vaginal tissues 
after 28 days of daily intravaginal administration of TFV gel were 1870 (2610) ng/g and 
below limit of quantification, respectively. TFV and TFV-DP concentrations in urinary 
vaginal tissues were undetectable at 60 and 90 days post IVR implantation. 
 
Measurable TFV concentrations were found in plasma of most animals treated with TFV 
IVR through day 45 and in vaginal tissue and fluids through day 29. Based upon 
evaluation of mean AUC/Day in animals with serial sample collections, systemic exposure 
to TFV was generally similar after intravaginal implantation of TFV ring segment (28 Days) 
and once-daily intravaginal administration of 10 mg/day TFV vaginal gel (28 Days).  
 
Mean TFV concentrations in vaginal fluids were highest on Day 8 for animals implanted 
with a TFV IVR segment. By Day 45, levels dropped to BLQ and remained BLQ on days 
61, 75, and 91. When comparing the first month of IVR segment implantation to daily 
intravaginal gel doses, the highest concentration evident with intravaginal gel doses was 
3.2-fold higher than that of the ring segment group. In vaginal tissue, mean TFV and TFV-
DP concentrations were higher for those animals implanted with a ring segment 
compared to those administered gel intravaginally. Mean TFV levels in tissue were 6.7- 
to 7.0-fold higher for animals implanted with a IVR segment. Measurable levels of mean 
TFV-DP were no longer detectable at 60 days post-implantation and, for mean free TFV, 
at 90 days post-implantation.6 
 
Residual drug content analysis of TFV IVR segments retrieved from rabbits confirmed 
that 68.2 ± 12.7% of the total TFV load was released by day 29, giving time-averaged 
daily release rate of 3.7 ± 0.7 mg/d TFV. By day 61, >99.9% of the total TFV load had 
been released. It is unclear why the release rate in rabbits was observed to be higher 
than expected based on both in vitro drug release from IVRs (full-size IVRs or rabbit-size 
IVR segments) and sheep study results (below); however, differences in the geometry of 
the IVR segment compared to that of the full IVR may have played a contributing part. 
 
Sheep 
A GLP study, Pharmacokinetic Study of Vaginal Ring or Gel Administration in Female 
Sheep (CONRAD 1645-071), evaluated the PK of TFV when administered as an IVR for 
up to 3 months or once daily vaginal gel administration for up to 28 days in female Dorset 
crossbred sheep. The IVR was administered once (on day 1) via vaginal insertion and 
remained in place for 90 days. The IVR contained approximately 1.6 g TFV for an 
intended daily dose of 10 mg/day, the same dose intended for use clinically. The vaginal 
gel was administered intravaginally once daily for 28 consecutive days. The vaginal gel 
contained 1% TFV in a 4 mL dose volume, giving a daily dose of approximately 40 
mg/day. Blood and vaginal fluid samples were collected at various intervals to determine 

 
 
 
MTN-038, Version 1.0                             31                                      July 11, 2018 
 
 
 
TFV levels. In addition, vaginal tissue biopsy samples were collected (from the cranial 
and caudal vaginal sites) at various intervals and analyzed for TFV and TFV-DP. For the 
TFV gel group, PK samples were only collected after dosing on Days 1, 15 and 28. TFV 
IVRs were retrieved from the animals after 90 days of treatment and were analyzed for 
residual drug content. The residual drug content results were then used to estimate the 
in vivo daily release rate of TFV over the 90-day treatment period. At the termination of 
the study (day 31 for TFV gel group and day 94 for TFV IVR group), samples of vaginal 
tissue were taken and analyzed for free TFV and TFV-DP.  
 
The mean TFV PK parameters following dosing with the TFV IVR and TFV 1% gel in 
female sheep are shown in Table 1. Mean TFV concentrations in plasma as functions of 
time post-TFV IVR insertion or time post-TFV 1% gel administration are shown in Figure 
2. Mean TFV concentrations in caudal and cranial vaginal fluids are shown in Figure 3 for 
TFV IVRs and in Figure 4 for TFV 1% gel. Mean TFV concentrations in caudal and cranial 
vaginal tissues are shown in Figure 5 for TFV IVRs and in Figure 6 for TFV 1% gel. 
 
Table 1: Mean (SD) TFV PK Parameters Determined following 90-day Intravaginal Treatment with 
TFV IVR and once-daily Intravaginal Administration of TFV 1% Gel for 28 Days in Sheep 
 
 
Tmax (h)a 
Cmax (ng/mL or ng/g) 
AUCt (ng h/mL 
or ng h/g)b 
AUC/d ([ng 
h/mL/d] or [ng 
h/g]/d])c 
 
IVR 
(90 
d) 
Gel  
(28 
d) 
IVR 
(90 d) 
Gel  
(28 d) 
IVR  
(90 d) 
Gel  
(28 d) 
IVR 
 (90 d) 
Gel  
(28 d) 
Plasma 
336 
2 
31.3 (8.3) 
46.8 
(20.8) 
32,052 (6,433) 
n.a. 
354 (71) 
107 (66) 
Vaginal 
Fluid 
(caudal) 
72 
8 
5,092,569 
(2,542,586) 
898,257 
(615,089) 
2,427,074,548 
(2,228,774,298) 
n.a. 
NDd 
NDd 
Vaginal 
Fluid 
(cranial) 
504 
336 
23,646,483 
(38,702,589) 
1,119,417 
(818,849) 
13,434,760,463 
(22,185,098,647) 
n.a. 
ND 
ND 
Vaginal 
Tissue 
(caudal) 
2,160 
8 
88,088 
(97,231) 
8,134 
(11,151) 
49,837,599 
(39,625,202) 
n.a. 
ND 
ND 
Vaginal 
Tissue 
(cranial) 
1,056 
8 
45,288 
(26,540) 
27,491 
(28,218) 
51,625,202 
(19,772,858) 
n.a. 
ND 
ND 
a Median tmax reported 
b AUCt: Area under the curve from the time of dosing to the time of the last observation 
c Average AUC per Day for TFV IVR = AUC0-2160/90 
d ND = Not determined 
 

 
 
 
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Figure 2: Mean (+SD) Plasma TFV Concentrations following Intravaginal Treatment with TFV IVRs 
(Left, n = 8) and TFV 1% Gel (Right, n = 6-7) in Female Sheep for 90 Days plus 3 Days following IVR 
Removal or 28 Days plus 3 Days following daily gel administration 
 
 
 
 
Figure 3: Mean (+SD) TFV Vaginal Fluid Concentrations following Intravaginal Treatment with TFV 
IVRs (n = 8) in Female Sheep for 90 days plus 3 days following IVR Removal 
 
 

 
 
 
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Figure 4: Mean (+SD) TFV Vaginal Fluid Concentrations following Intravaginal Treatment with TFV 
1% Gel (n = 6-7) in Female Sheep for 28 days plus 3 days 
 
 
 
Figure 5: Mean (+SD) TFV Vaginal Tissue Concentrations following Intravaginal Treatment with 
TFV IVRs (n = 8) in Female Sheep for 90 days plus 3 days following IVR Removal 
 
 
  

 
 
 
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Figure 6: Mean (+SD) TFV Vaginal Tissue Concentrations following Intravaginal Treatment with 
TFV 1% Gel (n = 6-7) in Female Sheep for 28 days plus 3 days 
 
 
 
Based upon comparison of mean Cmax values, exposure to TFV in plasma was 
approximately 0.67-fold less following intravaginal implantation of TFV IVR than following 
once daily intravaginal administration of TFV 1% Gel. Based upon comparison of mean 
AUC/day, exposure to TFV in plasma was approximately 3.32-fold greater following 
intravaginal implantation of TFV IVR than following once daily intravaginal administration 
of TFV 1% Gel. In caudal and cranial vaginal fluids, mean Cmax values were approximately 
5.7- and 21.1-fold greater, respectively, following intravaginal implantation of TFV IVR 
than following once daily intravaginal administration of TFV 1% Gel. In caudal and cranial 
vaginal tissues, mean Cmax values were approximately 10.8- and 1.7-fold greater following 
intravaginal implantation of TFV IVR than following once daily intravaginal administration 
of TFV 1% Gel. For vaginal fluids and vaginal tissue TFV AUC values, comparisons 
between the TFV IVR and TFV 1% Gel could not be made because the time points for 
PK evaluation were different. Therefore, comparisons between the two dosage forms 
were restricted to Cmax.   
 
Residual drug content analysis of TFV IVRs retrieved from sheep after 90 days of 
treatment revealed a time-averaged daily TFV release rate of 17.0 ± 1.1 mg/d. 
 
TFV Reservoir Intravaginal Rings PK study in Macaques 
This non-GLP study involved vaginal administration of miniature TFV IVRs to pigtail 
macaques (n=6) for 1 month for the assessment of PK and safety (Study TPN1137-CON-
2). TFV plasma, and vaginal fluid were evaluated. Overall, TFV was detected at low 
(mean < 20 ng/mL) plasma levels and were sustained for the duration of treatment with 
the TFV IVR. Vaginal fluid levels were also sustained at mean levels of nearly 1x107 ng/g 

 
 
 
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(Weck-Cel spears collected proximal and distal to the IVR location) and 1x106 ng/mL 
(vaginal lavage). TFV levels in proximal and distal vaginal tissues were sustained at or 
above 1x105 ng/g, and TFV was detected in rectal tissues on the order of 1x101 to 1x103 
ng/g. TFV-DP levels were BLQ in rectal tissues but were sustained at 170-1265 ng/g 
(~380-2830 fmol/mg) in vaginal tissues.  
 
Residual drug content analysis was performed on retrieved TFV IVRs to estimate the 
time-averaged in vivo daily release rate.  The time-averaged in vivo TFV release rate was 
13.6 ± 7.6 mg/d. The in vitro release rate for these macaque-sized TFV IVRs was 
approximately 6.5 mg/d TFV. It is unclear why the mean in vivo release rate was higher 
in macaques; possible explanations may be IVR geometry or increased vaginal pH. 
 
Toxicology (vaginal irritation studies) 
Rabbit study (CONRAD Study 1645-066) involved assessment of the effect of TFV IVR 
segments surgically implanted into the vagina of rabbits for 1, 2, or 3 months as compared 
to intravaginal gel administration for one month (details provided in earlier section on PK).   
Both IVR and gel administration were well tolerated. No test article related effects were 
evident in the following parameters for either IVRs or gel: mortality, clinical observations, 
body weights, and macroscopic and microscopic pathology examinations.6    
 
Macaque study (CONRAD Study PN1137-CON-2): Macaque-sized reservoir IVRs 
containing approximately 600 mg TFV or placebo were administered to female pigtailed 
macaques. The IVRs were kept in place for 28 days. Regular examination of the 
macaques throughout the study revealed no abnormal behavioral changes. Similarly, 
routine visual inspections of the vaginal compartment indicated that the TFV IVRs and 
placebo IVRs did not have any obvious detrimental effects on vaginal tissue. Menstrual 
cycle monitoring in the macaques by the analysis of plasma progesterone levels showed 
normal cycling during the study period. A comparative analysis of the levels of mucosal 
pro-inflammatory cytokines or chemokines between the two groups, as well as analysis 
of temporal-based cytokine/chemokine changes in individual macaques, showed minimal 
changes, if any, after IVR insertion. 
 
2.4 
Clinical Studies of Tenofovir 
 
Oral preparations of TFV (as TDF, Viread) are currently marketed and the investigational 
TFV 1% vaginal gel has been studied in multiple clinical trials. In addition, two early phase 
clinical studies of the TFV IVR, CONRAD A13-128 and CONRAD A15-140, were recently 
conducted.   
 
2.4.1 Safety and Pharmacokinetics of Orally Administered Tenofovir 
 
Information regarding the safety and pharmacokinetics of orally administered tenofovir is 
available in the package inserts for Truvada10 and Viread.15  
 

 
 
 
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2.4.2   Safety and Pharmacokinetics of Vaginally Administered Tenofovir Gel 
 
Safety of vaginally administered tenofovir gel  
 
TFV 1% vaginal gel is generally very well tolerated with mostly mild, transient symptoms. 
Among women, most product-related AEs are genitourinary and most commonly include 
genital pruritus, genital burning, and vaginal discharge. Vaginal candidiasis was the most 
common infection, although its incidence varied between studies, occurring in between 
2.1% of women (CONRAD A04-095) and 16% of women in HPTN 059, which is not 
surprising as the duration of use was 2 weeks compared to 24 weeks, respectively. The 
gel was also well tolerated in CONRAD A04-099, a male tolerance study of tenofovir gel 
following multiple topical exposures.14  
 
In placebo-controlled trials [TFV-010, HPTN 059, CAPRISA 004, MTN-003 (VOICE), 
FACTS 001], there were generally no significant differences in adverse event (AE) rates 
between placebo and TFV gel arms.14  In the CAPRISA 004 study no increase in overall 
AE rates (including renal, hepatic, pregnancy-related, or genital AEs) was observed in the 
TFV 1% gel arm when compared to a placebo gel arm.7 In CAPRISA 004, the incidence 
of diarrhea was not statistically different between the arms, but when diarrhea was 
grouped with enteritis, diarrhea hemorrhagic, diarrhea infectious, dysentery, and 
gastroenteritis, the difference was significant (16.9% in TFV group vs. 11% in placebo 
group, p=0.015).6 VOICE was a large Phase 2B, randomized, placebo-controlled study 
that assessed the safety and effectiveness of daily oral TDF, oral TDF-FTC, or TFV 1% 
vaginal gel for the prevention of HIV infection in 5029 African women.8  In VOICE, no 
significant differences were observed in the frequencies of AEs between active and 
placebo arms, except for more frequent elevated serum creatinine levels among 
participants receiving oral TDF-FTC (1.3% vs. 0.2%, p = 0.004). FACTS 001 was a Phase 
3, multi-center, double-blind, randomized, placebo-controlled trial conducted in South 
Africa to confirm the CAPRISA 004 findings.9 FACTS 001 evaluated the safety and 
effectiveness of pericoital TFV 1% gel when using the BAT-24 regimen, and also found 
no adverse safety signals for the TFV 1% gel when compared to placebo gel. 
 
The incidence of colposcopic findings in one study (HPTN 050) was higher than that seen 
in the 14-day trial of the HEC universal placebo,20 while the incidence in HPTN 059 was 
about the same. The clinical relevance of colposcopic findings has not been established. 
 
Safety labs: Very few changes have been seen in tests evaluating renal function, liver 
function, and phosphate. Hypophosphatemia, which was mild and possibly product-
related, was seen in 1 subject in HPTN 050.6  
 
Microflora and vaginal immunity: In HPTN 059, the presence of E. coli and Enterococcus 
species increased significantly across all study arms from enrollment to week 24, and 
Staphylococcus aureus decreased (p<0.05). There were no significant differences 
between treatment vs. placebo arms or among regimens. No changes were seen in 

 
 
 
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inflammatory markers in 2 studies (HPTN 050 and HPTN 059). In TFV-010, several 
inflammatory markers (SLPI, IL-1α, IL-1RA, and IL-8) were significant at a p-value of 0.05, 
but none were significant at a p-value of 0.01.6    
 
Pharmacokinetics of vaginally administered tenofovir gel 
 
Studies of vaginal administration of TFV gel uniformly show Cmax values for TFV in the 
blood plasma of around 4 ng/ml, equal to approximately 1/100 the systemic concentration 
after oral dosing. Concentrations of TFV-DP in PBMCs were undetectable or very low.6 
While the exact level of genital tract exposure needed to prevent HIV is not known, TFV 
concentrations in undiluted aspirated cervicovaginal fluid (CVF) of >1000 ng/ml were 
associated with protection from HIV in the CAPRISA 004 study.21 Median values for TFV 
Cmax in CVF aspirate in the CONRAD A04-095 and MTN-001 studies were well above the 
protective level from the CAPRISA 004 study and were also well above the concentration 
seen after oral dosing.  
 
The CONRAD A04-095 study indicated that both single and multiple dose exposures of 
TFV gel led to high genital tract levels up to 24 hours post-dose.  Concentrations of TFV-
DP, the active metabolite, were detectable in about 40% of the vaginal tissue biopsy 
samples at concentrations similar to or higher than what is seen in PBMCs after oral 
exposure.6 MTN-001 showed that TFV-DP levels in tissue after vaginal dosing are 100 
times higher than after oral dosing. High concentrations of TFV-DP were also seen in 
endocervical cells.22   
 
Additional studies that reported vaginal TFV PK data in non-pregnant women include 
MTN-011 and MTN-014. MTN-011 was a Phase 1 study that evaluated the effect of sex 
on PK of vaginally administered TFV 1% gel. Compared with dosing without sex, median 
TFV concentrations after sex decreased 72% and 78% (p < .001) in CVF, 75% and 71% 
(p < .001) in vaginal tissue, and 75% (p = .06) and 55% (p < .001) in cervical tissue with 
−1 hour and −24 hour dosing, respectively. Median concentration of TFV–DP also 
decreased significantly in cervical tissue with −1 hour dosing. BAT dosing resulted in drug 
levels at least as great as those in the absence of sex.23  MTN-014 was a Phase 1 cross-
over study that evaluated the cross–compartment PK of TFV 1% gel (a reduced glycerin 
[RG] formulation) between the vagina and the rectum. After two weeks of daily 
administration of TFV 1% RG gel, TFV and TFV-DP levels were low or undetectable in 
cross-compartment tissue samples collected at 24 hours after administration of the last 
gel dose.24  
 
2.4.3   Safety and Pharmacokinetics of Tenofovir IVRs  
 
To date, there have been two completed clinical studies to assess safety, PK, and PD of 
TFV in an IVR formulation:  CONRAD A13-128 and CONRAD A15-140. 
CONRAD A13-128 was a Phase 1, randomized, placebo-controlled, multi-site study to 

 
 
 
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assess the safety, PK, PD, and acceptability of the tenofovir and levonorgestrel 
intravaginal ring (TFV/LNG IVR) and the TFV-only IVR. Specifically, the study aimed to 
evaluate the safety of the TFV/LNG IVR, TFV-only IVR, and placebo IVR, PK of TFV and 
LNG, PD surrogates of contraceptive efficacy of LNG, and acceptability of all IVRs. The 
study enrolled healthy, non-pregnant, ovulatory, HIV-uninfected women aged 18 to 45 
with a body mass index (BMI) less than 30 kg/m2. Participants were assigned to use 
either the TFV-only IVR (release of 8-10 mg of TFV only per day), the TFV/LNG IVR 
(release of 8-10 mg of TFV and 20 μg of LNG per day), or the placebo IVR (no active 
experimental ingredients) for 16-18 days. Eighty-six participants were enrolled and 50 
were randomized and completed the study across two sites, one in the United States and 
one in the Dominican Republic. The study was completed in February 2016.6   
In the study, each participant had up to 9 study visits, depending on randomization. 
Following consent at Visit 1 and confirmation of eligibility, including confirmation of 
ovulation at Visits 1 and 2, participants underwent baseline sampling at Visit 3. 
Randomization and initiation of IVRs occurred at Visit 4. Fifty participants were 
randomized to type of IVR in a 2:2:1 ratio (20 TFV/LNG:20 TFV-only:10 placebo), as well 
as sampling time point at Visit 4 (1, 2, 4, or 8 hours post IVR insertion) and TFV PK biopsy 
collection time point post IVR removal (24 or 72 hours). Sample collection occurred 24 
hours post IVR insertion (Visit 5), on the day of ovulation (Visit 6) based on an ovulation 
predictor kit, 8-10 days after ovulation (Visit 7), 24 hours post IVR removal (Visit 8), and 
72 hours post IVR removal (Visit 9) based on randomization. Colposcopy was performed 
at Visit 4 (pre IVR insertion), 5, 6, and 7. In addition to sample collection, an acceptability 
questionnaire was completed at Visit 7. All participants received a follow up safety phone 
call 1-2 weeks following their last study visit. 
 
The second study was CONRAD A15-140, a phase 1, prospective, parallel-group study 
designed to compare the anti-HIV efficacy of Truvada oral tablet and TFV intravaginal 
ring (IVR) at the cervicovaginal (CV) mucosal and fluid level using ex-vivo HIV infection 
models. The study enrolled healthy, non-pregnant, HIV-negative, premenopausal women 
(aged 18-50 years, with regular menstrual cycles) who were not at risk of pregnancy. 
Participants were assigned to use Truvada (combined FTC [200 mg] and TDF [300 mg] 
oral doses taken for 14 consecutive days) or TFV IVR (release of 8-10 mg TFV per day 
inserted vaginally and worn for 14 consecutive days). A total of 22 participants (12 in the 
Truvada group and 10 in the TFV IVR group) were enrolled and all of them finished the 
study. The study was completed in August 2016.6     
 
During this study, participants completed 4 visits over a period of two to three months. At 
Visit 1 volunteers were consented and underwent procedures to confirm their eligibility 
for the study. Baseline blood for HIV, CBC, serum chemistries and Hepatitis B surface 
antigen (HBsAg) were collected, as well as genital swabs to test for Trichomonas, 
Gonorrhea and Chlamydia. At Visit 2 CVF, cervical and vaginal biopsies were collected. 
At Visit 3 a pelvic exam was conducted to ensure the site of biopsies had healed. 

 
 
 
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Participants were assigned the study product and instructed to use it for 14 days. When 
participants returned for Visit 4, product use data and follow-up blood, CVF and biopsy 
samples were collected. Final follow-up telephone calls were conducted approximately 1 
to 2 weeks after Visit 4 to collect AEs experienced since the last visit. Participants then 
exited the study unless any symptoms required further follow up. 
 
MTN-038 will be the first study to evaluate safety and PK of TFV IVR in humans for the 
full intended 90 days of use. 
 
Safety of Tenofovir IVR 
 
In CONRAD A13-128, there were no serious adverse events (SAEs). One participant in 
the TFV IVR group had two events considered possibly related to study product: a 
moderate headache lasting 2 days and mild vulvovaginal pruritus lasting 3 days, both of 
which resolved without sequelae. There were no product-related events nor AEs leading 
to discontinuation of IVR use. The only IVR discontinuation during the study was due to 
personal reasons and not related to study product or procedures. Only one event met the 
definition for moderate or severe urogenital AE in a woman in the TFV IVR group: an 
episode of severe vulvovaginal pain considered related to a study procedure but not study 
product, which resolved without sequelae after 10 hours. There were 6 unrelated TEAEs 
in 4 women in the placebo arm: 3 nasopharyngitis, 1 abdominal pain, 1 procedural pain, 
and 1 triglyceride change. No significant colposcopic findings or abnormalities in vital 
signs or physical exam were noted in participants.6  
 
In CONRAD A15-140, ten participants were enrolled in the TFV IVR group. Overall, the 
TFV IVR inserted vaginally and worn for 14 consecutive days appeared to be generally 
safe and well-tolerated in this population. Overall, 2 participants out of 10 reported 2 
TEAEs, bladder discomfort and a procedural complication. There were no clinically 
important changes noted in clinical laboratory evaluations, vital signs, physical 
examinations, or pelvic examinations with respect to safety.  
 
A Phase 1, randomized, single-blind, placebo-controlled trial was conducted to evaluate 
the safety and pharmacokinetics of 3 months use of a tenofovir disoproxil fumarate (TDF) 
IVR (360 mg + 60 mg NaCI) in sexually active women on contraception (at least 4 sex 
acts per month). Participants were assigned in a 3:1 ratio to TDF IVR or placebo. In total, 
17 of 40 planned women were enrolled before study termination (12 TDF, 5 placebo). The 
study was terminated early because 8 participants in the TDF arm developed Grade 1 
vaginal and cervical ulceration, which occurred on average 32 days after ring use (range 
23-56 days). Two women in the TDF arm completed the study without any complications 
and the study team elected to remove the ring early in 2 others. Four of 8 women with 
ulceration were symptomatic and 3 had bilateral ulcers. All ulceration resolved after ring 
removal. No ulcers developed with the placebo IVR. A total of 70 AEs was reported for 
the study, 66 of them were Grade 1 and 4 were Grade 2. No Grade 3 or 4 AEs or SAEs 
were reported.25     

 
 
 
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Pharmacokinetics of Tenofovir IVR 
 
In CONRAD A13-128, all participants had plasma TFV levels below the limit of 
quantification (BLQ) at baseline. The plasma TFV levels rose to a median (IQR) of 2.3 
(1.7-3.3) ng/mL prior to IVR removal, which is well within the low range expected from 
topical dosing of TFV vaginal gel as compared to oral dosing of TFV, and fell to BLQ 
values within 24 hours of IVR removal. These data support that after 16-18 days of IVR 
use, plasma TFV levels remain in the low range expected for topical dosing. TFV 
concentrations in CV aspirate exceeded 1,000,000 ng/mL (n=38) during IVR use and 
1,000 ng/mL at 24 hours post removal, suggesting that the IVR delivers consistent TFV 
concentrations similar to or exceeding peak concentrations achieved with TFV 1% gel. 
TFV and TFV-DP concentrations in vaginal tissues during IVR use and post IVR 
removal were also consistent with ranges found after dosing of TFV vaginal gel in 
women.6 
 
In CONRAD A15-140, concentrations of TFV in plasma were greater following oral 
treatment with Truvada than following TFV IVR, while concentrations of TFV and TFV-
DP in cervical and vaginal tissue were greater following TFV IVR use than following 
Truvada. TFV and TFV-DP concentrations met established concentrations in tissue after 
14 days of IVR use. TFV concentrations in the plasma was low as expected with topical 
administration. Median TFV concentrations in tissue were >104 ng/g and median TFV-DP 
concentrations in tissue were >106 fmol/g.  
 
Pharmacodynamics of Tenofovir IVR 
 
In CONRAD A13-128, once participants were exposed to TFV-containing IVRs, the HIV 
inhibitory activity of the CV secretions increased to the range of 99% inhibition, similar to 
levels seen with use of TFV vaginal gel. The mean production of HIV p24 antigen in tissue 
was lower in the presence of TFV, and the lack of increased production of p24 throughout 
the culture period (21 days) in tissues exposed to TFV suggests inhibition of HIV 
replication.6  
 
In CONRAD A15-140, anti-HIV activity of CVF was measured in TZM-bl cells infected 
with HIV-1BaL. There were statistically significant decreases from baseline in cervical 
fluid mean infection percentage after TFV IVR use for 14 days.   
 
2.4.4   Efficacy of Tenofovir (for HIV prevention in women) 
 
Orally administered tenofovir 
Information regarding the efficacy of orally administered TFV for HIV prevention in women 
(and in men having sex with men) is available in the package inserts for Truvada10 and 
Viread.15  
 

 
 
 
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Vaginally administered tenofovir (Gel Studies) 
CAPRISA 004 was a large Phase 2B, randomized, double-blind, placebo-controlled study 
that assessed the safety and effectiveness of vaginal TFV 1% gel for the prevention of 
HIV infection in South African women. CAPRISA 004 results indicated that coitally related 
TFV gel use (using the BAT-24 regimen) reduced HIV infection in women by an estimated 
39%. This protective effect was evident irrespective of sexual behavior, condom use, 
HSV-2 infection, or urban/rural differences.  A trend of higher effectiveness was observed 
as gel adherence improved: high adherers in the tenofovir gel arm had a 54% lower HIV 
incidence rate.7   
 
MTN-003 (VOICE) was a large Phase 2B, randomized, placebo-controlled study that 
assessed the safety and effectiveness of daily treatment with oral TDF, oral TDF-FTC, or 
TFV 1% vaginal gel for the prevention of HIV infection in 5029 African women.8  Results 
of VOICE showed that neither oral TDF, oral TDF-FTC nor TFV gel were effective in 
reducing HIV acquisition.  The main reason was low adherence across all groups, with 
only 25-30% of women having used the study product.8 
 
FACTS 001 was a Phase 3, multi-center, double-blind, randomized, placebo-controlled 
trial conducted in South Africa to confirm the CAPRISA 004 findings. FACTS 001 
evaluated the safety and effectiveness of pericoital TFV 1% gel when using the BAT-24 
regimen. However, pericoital vaginal TFV 1% gel failed to confirm the results of CAPRISA 
004. The gel was not effective in preventing HIV acquisition. Among the 2029 sexually 
active, healthy women that were enrolled and included in the primary analysis, 61 HIV 
infections occurred in the TFV arm and 62 in the placebo group (incidence rate ratio [IRR], 
1.0; 95% CI: 0.7-1.4). However, TFV gel was effective only in women who reported 
consistent product use.9  
  
2.5 
Study Hypotheses and Rationale for Study Design 
 
2.5.1 Study Design 
 
The design of MTN-038, a clinical study of the TFV IVR, will provide data to compare the 
PK and safety profile of an extended duration TFV IVR (1.4 g) to a placebo IVR. A single 
IVR will be used continuously for approximately 91 days (13 weeks); this period of time 
was selected to optimize scheduling feasibility at study sites. (Note that the 92-day study 
duration takes the final visit into account.) In vitro release testing performed by CONRAD 
during IVR formulation development demonstrated that IVRs like the one being evaluated 
in this study provided high sustained release and high levels of TFV over a 90-day period.6 
It is important to note that the drug exposure due to the release from 90-day TFV IVR is 
anticipated to fall within pre-established preclinical and clinical safety margins for which 
vaginally administered data exist.6  
 
MTN-038 will evaluate TFV and TFV-DP levels in plasma, CVF, rectal fluid, and cervical 
tissue during approximately 91 days of continuous use of a single ring containing 1.4 g 

 
 
 
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TFV. PK data will help determine the concentration-time profile using pooled data across 
all participants. The study design includes frequent collection of corresponding blood, 
rectal and CVF samples following the insertion of a TFV IVR to allow for the detection of 
drug release from the ring. PK parameters of TFV will be calculated for blood plasma, 
CVF, rectal fluid, and cervical tissue. 
  
2.5.2 Study Hypotheses  
 
• Plasma, CVF, and rectal fluid TFV levels and cervical tissue TFV and TFV-DP 
levels will be measurable in all participants  
• Continuous exposure to TFV due to sustained release from the 1.4 g TFV IVR for 
91 days will be safe 
 
 
3 
OBJECTIVES 
 
3.1 
Primary Objectives 
 
Pharmacokinetics 
• To characterize the local and systemic pharmacokinetics of one TFV IVR used 
continuously for 91 days  
 
Safety 
• To evaluate the safety of one TFV IVR used continuously for 91 days 
 
3.2 
Secondary Objectives 
 
Adherence 
• To evaluate participant adherence to one TFV IVR used continuously for 91 days 
 
Acceptability  
• To evaluate the overall acceptability of one TFV IVR used continuously for 91 days 
 
3.3 
Exploratory Objectives 
 
Adherence 
• To evaluate markers of ring use for the TFV IVR 
 
Acceptability 
• To evaluate components of acceptability of ring use for the TFV IVR 
 
Vaginal Microenvironment 

 
 
 
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• To describe the genital microenvironment in HIV-uninfected participants during 91 
days of continuous IVR use  
 
Pharmacodynamics 
• To determine the anti-HIV activity in CVF and cervical tissue 
• To determine the anti-HSV-2 activity in CVF 
 
 
4 
STUDY DESIGN 
 
4.1 
Identification of Study Design 
 
MTN-038 is a Phase 1, two-arm, multi-site, randomized (2:1), placebo-controlled trial of 
a polyurethane reservoir IVR containing the active ingredient TFV. Participants will not be 
told their group assignment to minimize potential bias in self-reports. The 1.4 g study IVR 
is inserted once and used continuously for a total of approximately 91 days by healthy, 
HIV-uninfected participants age 18-45 (inclusive). 
  
4.2 
Primary Endpoints 
 
Pharmacokinetics 
• TFV levels in: 
o Plasma 
o Cervicovaginal fluid (CVF) 
o Rectal fluid 
o Cervical tissue 
 
• Tenofovir diphosphate (TFV-DP) levels in: 
o Cervical tissue 
 
Safety 
• The proportion of participants with Grade 2 or higher genitourinary adverse event 
as defined by the Division of AIDS (DAIDS) Table for Grading the Severity of Adult 
and Pediatric Adverse Events, Corrected Version 2.1, July 2017, and/or 
Addendum 1 (Female Genital [Dated November 2007] Grading Table for Use in 
Microbicide Studies)  
• The proportion of participants with Grade 3 or higher adverse event as defined by 
the Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric 
Adverse Events, Corrected Version 2.1, July 2017 
 
4.3 
Secondary Endpoints 
 

 
 
 
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Adherence 
• Frequency of study IVR removal/expulsions (voluntary and involuntary) and 
duration without IVR in vagina (by self-report) 
• IVR use initiation and persistence (whether the IVR is in place when participants 
come to the clinic for their study visits) 
 
Acceptability 
• Degree to which study participants liked or disliked using the IVR (by self-report)  
 
4.4 
Exploratory Endpoints 
 
Adherence 
• Plasma and CVF TFV levels 
• Residual drug levels in returned IVRs 
• Biomarkers of ring use 
 
Acceptability 
• Self-reported attitudes about ring attributes, including dosing regimen and 
willingness to use IVR in the future  
• Interest/preference in a single vs. dual-purpose indication 
• The proportion of participants who find the study IVR to be at least as acceptable 
as other HIV prevention methods 
 
Vaginal Microenvironment 
• Changes in microbiota and biomarkers 
• Impact of microbiota on TFV levels in tissue and plasma 
 
Pharmacodynamics 
• Measures of HIV inhibition in CVF and cervical tissue 
• Measures of HSV-2 inhibition in CVF 
 
4.5 
Description of Study Population 
 
The study population will be healthy, HIV-uninfected participants, 18-45 (inclusive) who 
meet the criteria outlined in Section 5.2 and Section 5.3. 
 
4.6 
Time to Complete Accrual 
 
Accrual is expected to be complete in approximately 6-9 months. 
 

 
 
 
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4.7 
Study Groups 
 
Approximately 48 participants will be randomized in a 2:1 ratio to either 1.4 g TFV IVR or 
to a placebo IVR. 
  
4.8 
Expected Duration of Participation 
 
The expected trial duration for each enrolled participant is approximately 92 days.  
 
4.9 
Sites 
 
Sites selected by the MTN Executive Committee. 
 
 
 
5 
STUDY POPULATION 
 
5.1 
Selection of the Study Population 
 
The inclusion and exclusion criteria in Section 5.2 and Section 5.3 will be utilized to ensure 
the appropriate selection of study participants. 
 
5.1.1 Recruitment 
 
Participants will be recruited from a variety of sources across sites; these may include 
family planning and gynecological offices, colleges and universities, online websites, faith 
communities, as well as community-based organizations and street-based outreach. In 
addition, participants may be referred to the study from other local research projects and 
other health and social service providers.  Recruitment materials and the site recruitment 
plan will be approved by site Institutional Review Boards (IRBs) prior to use. Advice 
regarding these materials will be sought from site community representatives before they 
are submitted to the IRB for review. 
 
5.1.2 Retention 
 
Once a participant is enrolled/randomized in MTN-038, the study site will make every 
effort to retain the participants in follow-up to minimize possible bias associated with loss-
to-follow-up. An average retention rate of 95% will be targeted at each site.  All study sites 
will be responsible for developing and implementing local standard operating procedure 
(SOPs) to achieve this.  Engaging peer educators/advocates or organizations in retention 
messaging, etc. may be used to facilitate MTN-038 retention.  
 

 
 
 
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5.2 
Inclusion Criteria 
 
Participants must meet all the following criteria to be eligible for inclusion in the study: 
 
1) 
Assigned female sex at birth 
 
Note:  Participants who are female at birth, who now identify as male, will not be excluded 
so long as they are not on female-to-male transition therapy. 
 
2) 
Age 18 through 45 years (inclusive) at Screening, verified per site SOPs 
 
3) 
Able and willing to provide written informed consent to be screened for and enrolled 
in MTN-038 
 
4) 
Able and willing to provide adequate locator information, as defined in site SOPs 
 
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) 
Willing to abstain from receptive vaginal or anal sexual activities for 72 hours prior to 
each clinical visit and for 72 hours after biopsy collection 
 
8) 
Willing to use male condoms for penile-vaginal and penile-rectal sexual intercourse 
for the duration of study participation  
 
9) 
Per participant report, using an effective method of contraception for at least 30 days 
(inclusive) prior to Enrollment, and intending to continue use of an effective method 
for the duration of study participation; effective methods include: 
• hormonal methods (except contraceptive vaginal ring) 
• intrauterine device (IUD) 
• sterilization (of participant or partner, as defined in site SOPs) 
• having sex exclusively with individuals assigned female sex at birth 
• 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  
 
10) In general good health as determined by the Investigator of Record (IoR)/designee 
at Screening and Enrollment 
 
11) HIV-uninfected based on testing performed at Screening and Enrollment (per 
protocol algorithm in Appendix II) 
 

 
 
 
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12) Per participant report at Screening, regular menstrual cycles with at least 21 days 
between menses 
 
Note:  This criterion is not applicable to participants who report using a progestin-only 
method of contraception at Screening (e.g., Depo-Provera or levonorgestrel-releasing IUD) 
nor to participants using continuous combination oral contraceptive pills, as the absence of 
regular menstrual cycles is an expected, normal consequence in this context. 
  
13) Per participant report at Screening and Enrollment, states a willingness to refrain from 
inserting any non-study vaginal products or objects into the vagina or rectum 
including, but not limited to spermicides, female condoms, diaphragms, intravaginal 
rings, vaginal or rectal medications, menstrual cups, cervical caps, douches, 
lubricants, and sex toys (vibrators, dildos, etc.) for the 24 hours preceding the 
Enrollment Visit and for the duration of study participation.  
 
Note:  Use of tampons is permitted except for 24 hours prior to clinic visits in which CVF 
samples are scheduled to be collected. 
 
14) Participants over the age of 21 (inclusive) must have documentation of a satisfactory 
Pap within the past 3 years prior to Enrollment consistent with Grade 0 according to 
the Female Genital Grading Table for Use in Microbicide Studies Addendum 1 (Dated 
November 2007) to the DAIDS Table for Grading Adult and Pediatric Adverse Events, 
Corrected Version 2.1, July 2017, or satisfactory evaluation with no treatment 
required of Grade 1 or higher Pap result  
 
15) At Screening and Enrollment, agrees not to participate in other research studies 
involving drugs, medical devices, vaginal or rectal products, or vaccines after the 
Screening Visit and for the duration of study participation 
 
5.3 
Exclusion Criteria 
 
Participants who meet any of the following criteria will be excluded from the study: 
 
1) Pregnant at Screening or Enrollment or plans to become pregnant during the study 
period 
 
Note:  A documented negative pregnancy test performed by study staff is required for 
inclusion; however, a self-reported pregnancy is adequate for exclusion from the study.   
 
2) Diagnosed with symptomatic urinary tract infection (UTI) or reproductive tract infection 
(RTI) at Screening or Enrollment 
 
Otherwise eligible participants diagnosed with UTI/RTI during screening will be offered 
treatment. If treatment is complete and symptoms have resolved within the 45 day screening 
window, eligible participants may be enrolled.  

 
 
 
MTN-038, Version 1.0                             48                                      July 11, 2018 
 
 
 
 
Note: Asymptomatic BV and candidiasis are not exclusionary. 
 
3) Diagnosed with an acute sexually transmitted infection (STI) requiring treatment per 
current 
Centers 
for 
Disease 
Control 
and 
Prevention 
(CDC) 
guidelines 
(http://www.cdc.gov/std/treatment/) at Screening or Enrollment such as gonorrhea, 
chlamydia, trichomonas, pelvic inflammatory disease, and/or syphilis  
 
Note: Genital warts requiring treatment and frequent recurrence of HSV are considered 
exclusionary; however, infrequent HSV outbreaks are not. Genital warts requiring treatment 
are defined as those that cause undue burden or discomfort to the participant, including bulky 
size, unacceptable appearance, or physical discomfort. See MTN-038 Study-Specific 
Procedures (SSP) Manual for additional information. 
 
4) Has a clinically apparent Grade 2 or higher pelvic exam finding (observed by study 
staff) at Screening or Enrollment. *  
 
Note:  Cervical bleeding associated with speculum insertion and/or specimen collection 
judged to be within the range of normal according to the clinical judgment of the IoR/designee 
is considered expected non-menstrual bleeding and is not exclusionary.   
 
Note:  Otherwise eligible participants with exclusionary pelvic exam findings may be 
enrolled/randomized after the findings have improved to a non-exclusionary severity grading 
or resolved within 45 days of providing informed consent for screening.  
 
5) Participant report and/or clinical evidence of any of the following: 
 
a) Known adverse reaction to any of the study products (ever), including polyurethane 
b) Chronic and/or recurrent vaginal candidiasis 
c) Non-therapeutic injection drug use in the 12 months prior to Enrollment 
d) Last pregnancy outcome less than 90 days prior to Enrollment 
e) Gynecologic or genital procedure (e.g., tubal ligation, dilation and curettage, 
piercing) 45 days or less prior to Enrollment 
 
Note:  Colposcopy and cervical biopsies for evaluation of an abnormal Pap test as well as 
IUD insertion/removal are not exclusionary.   
 
f) Currently breastfeeding or planning to breastfeed during the study 
g) Participation in any other research study involving drugs, medical devices, vaginal 
or rectal products, or vaccines, in the 60 days prior to Enrollment  
 
6) Use of pre-exposure prophylaxis (PrEP) for HIV prevention and/or post-exposure 
prophylaxis (PEP) for potential HIV exposure within the 3 months prior to Enrollment, 
and/or anticipated use and/or unwillingness to abstain from PrEP during trial 
participation 

 
 
 
MTN-038, Version 1.0                             49                                      July 11, 2018 
 
 
 
 
7) Has any of the following laboratory abnormalities at Screening Visit: 
a) Grade 1 or higher Aspartate aminotransferase (AST) or alanine transaminase 
(ALT)*  
b) Grade 1 or higher Hemoglobin*  
c) Calculated creatinine clearance less than 60 mL/min by the Cockcroft-Gault 
formula 
d) Positive Hepatitis B surface antigen result 
 
Note:  Otherwise eligible participants with an exclusionary laboratory result may 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. 
  
8) 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. 
 
*Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events 
Corrected Version 2.1, July 2017 and/or Addendum 1 (Female Genital Grading Table for Use in 
Microbicide Studies [Dated November 2007]) 
 
5.4 
Co-enrollment Guidelines 
 
As indicated in Section 5.2 and Section 5.3, participants must not take part in other 
research studies involving drugs, medical devices, vaginal or rectal products, or vaccines 
after the Screening Visit and while taking part in MTN-038 unless approved by the 
Protocol Safety Review Team (PSRT) and Protocol Chair. Participation in the following 
types of studies may be allowed at the discretion of the IoR/designee after consultation 
with the Protocol Chair and PSRT: 
 
• Participants may take part in MTN ancillary studies 
• Participants who become infected with HIV may take part in observational and/or 
interventional studies for HIV-positive persons 
• Participants who become pregnant while on study product will be offered 
enrollment in MTN-016 (provided their study site is taking part in MTN-016) 
 
Should any participant report concurrent participation in contraindicated studies after 
enrolling in MTN-038, 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 
 
Each participant will be randomized to one of two IVRs: 
 
Table 2: Study Regimen 
Group 
N 
Ring Description 
A 
32 
TFV IVR containing 1.4 g TFV  
B 
16 
Matching Placebo IVR  
 
Each participant will receive either an TFV IVR containing 1.4 g TFV or a matching 
placebo IVR. Participants will be randomized in a 2:1 ratio. Participants will not be told 
their group assignment. The IVR is inserted once and used continuously for 
approximately 91 days. The IVR will be removed by the participant (or clinician/designee, 
if necessary) at the product use end visit (PUEV/Early Termination Visit). Participants will 
be followed for approximately 1 day following final IVR removal.  
 
6.2 
Administration 
 
At the Enrollment Visit the IVR will be inserted by the participant (or clinician/designee, if 
necessary). Participants will be given detailed instructions in the clinic on proper IVR 
insertion and removal procedures. Details on administration (ring insertion, removal, 
procedures in the event of expulsion) will be provided in the MTN-038 Study-Specific 
Procedures (SSP) Manual.   
 
6.3 
Study Product Formulation and Storage  
 
The 1.4 g TFV IVRs are designed to provide sustained release of drug for a 90-day period. 
 
6.3.1 1.4 g TFV IVR 
 
The 1.4 g TFV IVR is comprised of a drug-loaded hydrophilic polyether urethane (HPU) 
tube (white segment) that is sealed and joined together (transparent joint) to form the 
shape of a ring. This is a reservoir IVR using a water-absorbable polyurethane as a rate 
controlling membrane capable of delivering approximately 10 mg/day TFV for 90 days.  
The TFV IVR has a 0.7 mm wall thickness, 5.5 mm outer cross-sectional diameter and 
55 mm outer diameter.   
 
The TFV IVRs should be stored in the site pharmacy at 20°C to 25°C (68°F to 77°F), with 
allowable excursions between 15°C to 30°C (59F° to 86°F).  
 

 
 
 
MTN-038, Version 1.0                             51                                      July 11, 2018 
 
 
 
6.3.2 Matching Placebo IVR  
 
The matching Placebo IVR has a similar appearance and dimensions to the TFV IVR. 
The composition of the matching Placebo IVR is also similar to the TFV IVR except that 
modified starch, which is non-eluting from the reservoir, is used to replace the TFV to 
provide a similar white filled tube appearance.  
 
The matching Placebo IVRs should be stored in the site pharmacy at 20°C to 25°C (68°F 
to 77°F), with allowable excursions between 15°C to 30°C (59F° to 86°F). 
 
6.4 
Supply and Accountability 
 
6.4.1 Supply 
 
CONRAD (Arlington, VA) will oversee the manufacture of all the study IVRs and 
analysis/release of the rings under Good Manufacturing Practices (GMP). The API TFV 
is supplied by Gilead Sciences, Inc. 
 
6.4.2 IVR Dispensing 
 
Study IVRs will be dispensed from the pharmacy to clinic staff on behalf of the participant, 
upon receipt of a written prescription from an authorized prescriber. Participants will 
receive one TFV or placebo IVR at the enrollment visit (Visit 2) and will use the IVR for 
approximately 91 days. Provisions for the dispensation of additional IVRs will be at the 
discretion of the IoR and in consultation with the PSRT as needed. 
 
6.4.3 Accountability 
 
Each Clinical Research Site (CRS) Pharmacist of Record (PoR) is required to maintain a 
complete record of all IVRs received and subsequently dispensed. All unused study 
products 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-038 Pharmacy Study Product Management Procedures 
Manual.   
 
All IVRs provided to a participant must be documented by the clinic staff when they are 
returned. This includes IVR(s) brought back to the clinic by the participant and any ring 
removed at the clinic visit. Any IVRs not returned must also be documented by the clinic.   
 
6.4.4 Retrieval of Used Study Product 
 
Study participants will be instructed to return for IVR removal at the PUEV/Early 
Termination Visit. If the participant has removed the IVR and it is not returned at the 
PUEV/Early Termination Visit, site staff members will make every effort to encourage 

 
 
 
MTN-038, Version 1.0                             52                                      July 11, 2018 
 
 
 
participants to return the IVR as soon as possible (optimally within 5 working days). 
Attempts by study staff to retrieve the IVR from the participant must be documented.  
 
When product use is permanently discontinued for HIV infection or pregnancy, the IVR 
must be retrieved (optimally within 24 hours of site awareness) and returned to the clinic 
(see Table 3 below). Additional IVR retrieval specifications in response to 
discontinuations for other reasons, or IoR discretion, can be found in Table 3. Study 
product retrieval may occur either by the participant returning the IVR to study staff within 
the specified timeframe or attempts should be made by study staff to contact the 
participant and retrieve the IVR as soon as possible. If the IVR is not returned within the 
time frames outlined below, the MTN-038 PSRT must be notified. 
 
Table 3:  Retrieval of IVR 
Reason for Ring Removal 
Timeframe for Study Product Retrieval 
Permanent discontinuation or temporary hold 
due to potential HIV infection or pregnancy 
Within 24 hours 
Permanent discontinuation for any other reason 
or IoR discretion 
Within 5 working days 
Temporary hold for any other reason with 
expected duration of greater than 7 days  
Within 7 working days  
 
 
If there is a product hold, expulsion (i.e., ring removed and cannot be reinserted) or an 
extended period of time that the ring is removed, the MTN-038 PSRT should be notified.  
The PSRT will evaluate each reported event to determine if the ring should be reinserted, 
if a new ring should be dispensed, or if the participant should discontinue product use. 
See Section 9 for additional information related to product holds. Additional guidance 
regarding ring expulsions and/or removals will be provided in the SSP. 
 
6.5 
Concomitant Medications  
 
Enrolled study participants may use concomitant medications during study participation 
with the exception of medications and products noted as prohibited in Sections 6.6 and 
6.7. All concomitant medication use reported throughout the course of the study, including 
all prescription medications, over-the-counter preparations, vitamins, nutritional 
supplements, and herbal preparations, will be entered on case report forms (CRFs) 
designated for that purpose.  
 
6.6 
Prohibited Medications 
 
The use of PEP and PrEP are prohibited during study participation.  Use of anticoagulants 
or blood-thinners (such as heparin, Lovenox®, warfarin, and Plavix® [clopidogrel 
bisulfate]) is prohibited during study participation. See Section 9.3 for additional 
information. 
 

 
 
 
MTN-038, Version 1.0                             53                                      July 11, 2018 
 
 
 
Participants are asked to abstain from using aspirin (greater than 81 mg) within 72 hours 
prior to and following a cervical biopsy collection visit (Visits 5 and 8 or Visits 6 and 9). 
Should a participant report taking any of the medications noted above which may increase 
risk of bleeding or engaging in receptive vaginal or anal sexual activities 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 
Intravaginal and Rectal Medications, Products and Practices 
 
All participants will be counseled to avoid the use of non-study intravaginal or rectal 
products and other devices. These include, but are not limited to, spermicides, female 
condoms, diaphragms, IVRs, vaginal or rectal medications, menstrual cups, cervical 
caps, douches, lubricants, and sex toys (e.g., vibrators, dildos, etc.) for the 24 hours 
preceding the Enrollment Visit and for the duration of study participation. Use of these 
products will be captured as study data. Participants who report use of these products 
during the study product use period will be counseled regarding the use of alternative 
methods and study staff should reference Section 9.3 for permanent discontinuation 
guidelines. 
 
Participants are to abstain from receptive vaginal or anal sexual activities for 72 hours 
prior to each clinic visit and for 72 hours after biopsy collection.  
 
While tampon use is not prohibited, participants will be instructed to restrict use for 24 
hours prior to any clinic visit in which CVF samples are collected. 
 
Participants will be offered male condoms if indicated and/or per local standard of care. 
The condoms will be made available in the clinic and will be dispensed by the clinic staff. 
 
7 
STUDY PROCEDURES 
 
An overview of the study visit and evaluation schedule is provided in Appendix I.  
Presented in this section is additional information on visit-specific study procedures.  
Detailed instructions to guide and standardize procedures across sites as well as to 
specify the visit windows are provided in the MTN-038 SSP Manual available at 
www.mtnstopshiv.org. 
 

 
 
 
MTN-038, Version 1.0                             54                                      July 11, 2018 
 
 
 
Figure 7: Study Visit Schedule 
  
 
7.1 
Pre-screening 
 
As part of participant outreach and recruitment strategies, study staff may 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 the study site in the absence of written informed consent from 
potential participants, provided the information is collected in such a manner that it cannot 
be linked to participant identifiers, unless a waiver is granted from the local IRB. At each 
site, procedures and documentation will comply with local IRB requirements.  
 
7.2 
Screening Visit - Visit 1 
 
A Screening Visit may 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 participant consent for Screening/Enrollment will be obtained 
at the Screening Visit 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. 
 

 
 
 
MTN-038, Version 1.0                             55                                      July 11, 2018 
 
 
 
Table 4: Screening Visit - Visit 1 
Screening Visit - Visit 1  
Component 
Procedure/Analysis 
Administrative and 
Regulatory 
 
• 
Obtain written informed consent 
• 
Assign a unique Participant Identification (PTID) number 
• 
Assess eligibility 
• 
Collect demographic and background information 
• 
Collect locator information 
• 
Provide reimbursement 
• 
Schedule next visit/contact* 
Behavioral/Counseling 
• 
HIV pre- and post-test counseling  
• 
HIV/STI risk reduction counseling 
• 
Protocol counseling 
Clinical 
• 
Collect medical eligibility information (including exclusionary 
medical conditions and medications) 
• 
Collect medical and menstrual history  
• 
Collect concomitant medications 
• 
Perform physical examination  
• 
Perform pelvic examination 
• 
Treat or prescribe treatment for RTI/UTI/STIs* 
• 
Provide available test results 
Laboratory 
 
Urine 
• 
Pregnancy test π 
• 
Urine dipstick/culture* 
Blood 
• 
HIV-1/2 testing 
• 
Complete blood count (CBC) with differential and platelets  
• 
Serum creatinine 
• 
AST/ALT 
• 
Hepatitis B surface antigen  
• 
Syphilis serology 
Pelvic 
Samples 
• 
Nucleic acid amplification test (NAAT) for GC/CT and 
trichomonas 
• 
Pap test^ 
• 
Saline/potassium hydroxide (KOH) wet mount with pH for 
candidiasis and/or bacterial vaginosis (BV)* 
Study Product Supply 
• 
Offer male condoms* 
* If indicated and/or per local standard of care 
^ If indicated (if participant [over age 21] is unable to provide documentation of a satisfactory Pap test within 3 years  
   prior to enrollment) 
π Not required for participants who have undergone supracervical hysterectomy or bilateral oophorectomy verified by   
   medical records 
 
7.3 
Enrollment Visit - Visit 2 (Day 0) 
 
All enrollment procedures must occur on the same day. The participant’s menstrual cycle 
must be considered when scheduling Visit 2-Enrollment (Day 0). Ideally, no bleeding 
should occur within the first 7 days of product use, e.g., Study Visits 2-4 (Days 0, 1, and 

 
 
 
MTN-038, Version 1.0                             56                                      July 11, 2018 
 
 
 
7). Participants will be randomized to provide cervical tissue samples at either Visits 5 
and 8 (Days 14 and 56) or at Visits 6 and 9 (Days 28 and 91).  
 
Table 5: Enrollment Visit - Visit 2 (Day 0) 
Enrollment Visit - Visit 2 (Day 0) 
Component 
Procedure/Analysis 
Administrative and 
Regulatory 
 
• 
Assess and confirm eligibility  
• 
Review/update locator information 
• 
Randomization to product and biopsy schedule 
• 
Provide reimbursement 
• 
Schedule next visit/contact* 
Behavioral/Counseling 
• 
HIV pre- and post-test counseling 
• 
HIV/STI risk reduction counseling 
• 
Protocol counseling 
• 
Collect product preference/acceptability information 
• 
Behavioral assessment 
Clinical 
• 
Collect medical eligibility information (including exclusionary 
medical conditions and medications) 
• 
Review/update medical and menstrual history  
• 
Review/update concomitant medications 
• 
Perform targeted physical examination 
• 
Perform pelvic examination 
• 
Treat or prescribe treatment for RTI/UTI/STIs* 
• 
Digital examination by clinician to check IVR placement 
• 
Provide available test results  
Laboratory 
Urine 
• 
Pregnancy test π 
• 
Urine dipstick/culture* 
Blood 
• 
HIV-1/2 testing 
• 
CBC with differential and platelets* 
• 
Serum creatinine* 
• 
Plasma for archive 
• 
HSV 1/2 serology 
Pelvic 
Samples 
• 
NAAT for GC/CT and trichomonas* 
• 
Saline/KOH wet mount with pH for candidiasis and/or BV* 
• 
Vaginal swabs for microbiota 
• 
Vaginal Gram stain 
• 
Cervicovaginal fluid (CVF) TFV levels▲  
• 
CVF for anti-HSV-2 activity ¤ 
• 
CVF for biomarkers ¤  
• 
Cervicovaginal lavage (CVL) for PD and biomarkers ¤  
Study Product Supply 
• 
Provision of study IVR  
• 
Insertion of the provided study IVR 
• 
Provision of study IVR use instructions 
• 
Offer male condoms* 
* If indicated and/or per local standard of care 
▲ Samples to be taken approximately 1 and 4 hours following ring insertion 

 
 
 
MTN-038, Version 1.0                             57                                      July 11, 2018 
 
 
 
 ¤ Samples to be taken prior to ring insertion 
 π Not required for participants who have undergone supracervical hysterectomy or bilateral oophorectomy verified by  
    medical records 
 
7.4 
Follow-up Visits  
 
7.4.1 Days 1 and 7 - Visits 3 and 4 
 
Table 6: Days 1 and 7- Visits 3 and 4 
Days 1 and 7 - Visits 3 and 4  
Component 
Procedure/Analysis 
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 and menstrual history  
• 
Review/update concomitant medications 
• 
Perform targeted physical examination*  
• 
Perform pelvic examination 
• 
Treat or prescribe treatment for RTI/UTI/STIs* 
• 
Provide available test results 
• 
Collect AEs 
Laboratory 
Urine 
• 
Pregnancy test* 
• 
Urine dipstick/culture* 
Blood 
• 
HIV-1/2 testing* 
• 
CBC with differential and platelets* 
• 
Serum creatinine* 
• 
Syphilis serology* 
• 
TFV levels   
Pelvic 
Samples 
 
• 
NAAT for GC/CT and trichomonas* 
• 
Saline/KOH wet mount with pH for candidiasis and/or BV* 
• 
CVF TFV levels  
• 
CVF for biomarkers 
Rectal 
Samples 
• 
Rectal fluid TFV levels (Day 1 only) 
Study Product Supply 
• 
Offer male condoms* 
* If indicated and/or per local standard of care 
 
 
 

 
 
 
MTN-038, Version 1.0                             58                                      July 11, 2018 
 
 
 
7.4.2 Day 14 - Visit 5 
 
The MTN-038 cohort will be randomized to provide cervical tissue for assessment of PK 
at alternate study visits starting with Visit 5 on Day 14. One half of the cohort will be 
randomized to provide tissue at Visits 5 and 8, and the other half will be randomized to 
provide tissue at Visits 6 and 9. 
 
Table 7: Day 14 - Visit 5 
Day 14 - Visit 5 
Component 
Procedure/Analysis 
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 and menstrual history  
• 
Review/update concomitant medications 
• 
Perform targeted physical examination* 
• 
Perform pelvic examination 
• 
Treat or prescribe treatment for RTI/UTI/STIs* 
• 
Provide available test results 
• 
Collect AEs 
Laboratory 
Urine 
• 
Pregnancy test* 
• 
Urine dipstick/culture* 
Blood 
• 
HIV-1/2 testing* 
• 
CBC with differential and platelets* 
• 
Serum creatinine* 
• 
Syphilis serology* 
• 
TFV levels   
Pelvic  
Samples  
• 
NAAT for GC/CT and trichomonas* 
• 
Saline/KOH wet mount with pH for candidiasis and/or BV* 
• 
CVF TFV levels 
• 
CVF for biomarkers 
• 
Cervical biopsies for PKǂ 
Rectal 
Samples 
• 
Rectal fluid TFV levels 
Study Product Supply 
• 
Offer male condoms* 
* If indicated and/or per local standard of care 
ǂ Participants will be randomized to biopsy collection either at Visits 5 and 8 or Visits 6 and 9  
 
 
 

 
 
 
MTN-038, Version 1.0                             59                                      July 11, 2018 
 
 
 
7.4.3 Day 28 - Visit 6  
 
Table 8: Day 28 - Visit 6  
Day 28 - Visit 6  
Component 
Procedure/Analysis 
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  
• 
Collect product use information 
• 
Collect product preference/acceptability information 
• 
Behavioral assessment 
Clinical 
• 
Review/update medical and menstrual history  
• 
Review/update concomitant medications 
• 
Perform targeted physical examination* 
• 
Perform pelvic examination 
• 
Treat or prescribe treatment for RTI/UTI/STIs* 
• 
Provide available test results 
• 
Collect AEs 
Laboratory 
Urine 
• 
Pregnancy test π 
• 
Urine dipstick/culture* 
Blood 
• 
HIV-1/2 testing* 
• 
AST/ALT*  
• 
CBC with differential and platelets*  
• 
Serum creatinine* 
• 
Syphilis serology* 
• 
TFV levels  
Pelvic  
Samples  
• 
NAAT for GC/CT and trichomonas* 
• 
Saline/KOH wet mount with pH for candidiasis and/or BV* 
• 
Vaginal swabs for microbiota 
• 
Vaginal Gram stain 
• 
CVF TFV levels 
• 
CVF for anti-HSV-2 activity 
• 
CVF for biomarkers 
• 
Cervical biopsies for PKǂ 
• 
CVL for PK, PD, and biomarkers  
Rectal 
Samples 
• 
Rectal fluid TFV levels 
Study Product Supply 
• 
Offer male condoms* 
* If indicated and/or per local standard of care 
π Not required for participants who have undergone supracervical hysterectomy or bilateral oophorectomy verified by  
   medical records 
ǂ Participants will be randomized to biopsy collection either at Visits 5 and 8 or Visits 6 and 9  
 
 

 
 
 
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7.4.4 Day 42 - Visit 7  
 
Table 9: Day 42 - Visit 7  
Day 42 - Visit 7  
Component 
Procedure/Analysis 
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 and menstrual history  
• 
Review/update concomitant medications 
• 
Perform targeted physical examination* 
• 
Perform pelvic examination 
• 
Treat or prescribe treatment for RTI/UTI/STIs* 
• 
Provide available test results 
• 
Collect AEs 
Laboratory 
Urine 
• 
Pregnancy test* 
• 
Urine dipstick/culture* 
Blood 
• 
HIV-1/2 testing* 
• 
AST/ALT*  
• 
CBC with differential and platelets*  
• 
Serum creatinine* 
• 
Syphilis serology* 
Pelvic  
Samples  
• 
NAAT for GC/CT and trichomonas* 
• 
Saline/KOH wet mount with pH for candidiasis and/or BV* 
• 
CVF for biomarkers 
Study Product Supply 
• 
Offer male condoms* 
* If indicated and/or per local standard of care 
 
 

 
 
 
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7.4.5 Day 56 - Visit 8 
 
Table 10: Day 56 - Visit 8 
Day 56 - Visit 8 
Component 
Procedure/Analysis 
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  
• 
Collect product use information 
• 
Behavioral assessment 
Clinical 
• 
Review/update medical and menstrual history  
• 
Review/update concomitant medications 
• 
Perform targeted physical examination* 
• 
Perform pelvic examination 
• 
Treat or prescribe treatment for RTI/UTI/STIs* 
• 
Provide available test results 
• 
Collect AEs 
Laboratory 
Urine 
• 
Pregnancy test π 
• 
Urine dipstick/culture* 
Blood 
• 
HIV-1/2 testing* 
• 
AST/ALT*  
• 
CBC with differential and platelets*  
• 
Serum creatinine* 
• 
Syphilis serology* 
• 
TFV levels  
Pelvic  
Samples  
• 
NAAT for GC/CT and trichomonas* 
• 
Saline/KOH wet mount with pH for candidiasis and/or BV* 
• 
Vaginal swabs for microbiota 
• 
Vaginal Gram stain 
• 
CVF TFV levels 
• 
CVF for anti-HSV-2 activity 
• 
CVF for biomarkers 
• 
Cervical biopsies for PK and PDǂ 
• 
CVL for PK, PD, and biomarkers 
 
Rectal 
Samples 
• 
Rectal fluid TFV levels 
Study Product Supply 
• 
Offer male condoms* 
* If indicated and/or per local standard of care 
π Not required for participants who have undergone supracervical hysterectomy or bilateral oophorectomy verified by  
   medical records 
ǂ Participants will be randomized to biopsy collection either at Visits 5 and 8 or Visits 6 and 9  
 

 
 
 
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7.4.6 PUEV/Early Termination Visit Ring Removal - Visit 9 - Day 91 
 
Table 11: PUEV/Early Termination Visit - Visit 9 - Day 91 
PUEV/Early Termination Visit - Visit 9 – Day 91 
Component 
Procedure/Analysis 
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  
• 
Collect product use information 
• 
Collect product preference/acceptability information 
• 
Behavioral assessment 
• 
In-depth interview (IDI) (Subset)♦ 
Clinical 
• 
Review/update medical and menstrual history  
• 
Review/update concomitant medications 
• 
Perform targeted physical examination* 
• 
Perform pelvic examination  
• 
Treat or prescribe treatment for RTI/UTI/STIs* 
• 
Provide available test results 
• 
Collect AEs 
Laboratory 
Urine 
• 
Pregnancy test π 
• 
Urine dipstick/culture* 
Blood 
• 
HIV-1/2 testing 
• 
CBC with differential and platelets 
• 
Serum creatinine 
• 
AST/ALT 
• 
Syphilis serology* 
• 
TFV levels∞  
Pelvic  
Samples  
• 
NAAT for GC/CT and trichomonas* 
• 
Saline/KOH wet mount with pH for candidiasis and/or BV* 
• 
Vaginal swabs for microbiota 
• 
Vaginal Gram stain 
• 
CVF TFV levels∞ 
• 
CVF for biomarkers 
• 
Cervical biopsies for PK and PDǂ 
 
Rectal 
Samples 
• 
Rectal fluid TFV levels∞ 
Study Product Supply 
• 
Removal and collection of study IVR 
• 
Offer male condoms* 
* If indicated and/or per local standard of care 
∞ Samples to be taken immediately prior to ring removal and approximately 4 hours following ring removal 
ǂ Participants will be randomized to biopsy collection either at Visits 5 and 8 or Visits 6 and 9  
♦ May be scheduled for later date due to visit length and/or to accommodate participant availability 
π Not required for participants who have undergone supracervical hysterectomy or bilateral oophorectomy verified by  
   medical records 
 

 
 
 
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7.4.7 Final Contact - Visit 10 - Day 92 
 
Participants will be encouraged to contact the study clinic if they experience any untoward 
medical occurrences after the Final Contact visit. 
 
Table 12: Final Contact - Visit 10 - Day 92 
Final Contact - Visit 10 - Day 92 
Component 
Procedure/Analysis 
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 and menstrual history  
• 
Review/update concomitant medications 
• 
Perform targeted physical examination* 
• 
Perform pelvic examination* 
• 
Treat or prescribe treatment for RTI/UTI/STIs* 
• 
Provide available test results 
• 
Collect AEs 
Laboratory 
Urine 
• 
Pregnancy test* 
• 
Urine dipstick/culture* 
Blood 
• 
CBC with differential and platelets* 
• 
Serum creatinine* 
• 
TFV levels  
Pelvic  
Samples  
• 
Saline/KOH wet mount with pH for candidiasis and/or BV* 
• 
CVF TFV levels 
Study Product Supply 
• 
Offer male condoms* 
* If indicated and/or per local standard of care  
 
7.5 
Follow-up Procedures for Participants Who Permanently Discontinue Study 
Product 
 
7.5.1 Participants Who Become Infected with HIV 
 
If a participant tests positive for HIV 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 and thus follow-up visits will be discontinued, 
study product use will cease, and the participant will be considered terminated from the 
study. Participants who become infected after randomization may be offered additional 
laboratory testing (such as HIV RNA and HIV drug resistance testing), as clinically 
indicated per discussions between IoR and LC. Please reference the MTN-038 SSP 
Manual for additional details (www.mtnstopshiv.org). 
 

 
 
 
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7.5.2 Participants Who Become Pregnant 
 
If a participant becomes pregnant, she will be referred to local health care services and 
may return to the research clinic for additional counseling, as needed. Continued study 
participation would be of no added benefit to the participant, thus follow-up visits and 
procedures will be discontinued and the participant will be considered terminated from 
the study. A participant who is pregnant at study termination will continue to be followed 
until the pregnancy outcome is ascertained; see Section 9.8 for additional details.  
Participants who become pregnant while on study product will be offered enrollment in 
MTN-016 (www.mtnstopshiv.org), provided their study site is taking part in MTN-016, 
which includes follow-up throughout the pregnancy and for the first year of the infant’s 
life. For participants who do not enroll in MTN-016, 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. For additional details 
regarding obtaining pregnancy outcome, please reference the MTN-038 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 clinician-initiated 
reason other than HIV infection or pregnancy, site investigators may, after consultation 
with the PSRT and MTN-038 Management Team, decide to discontinue study follow-up 
visits and procedures. Participants will, however, be asked to complete all the procedures 
scheduled to occur at the PUEV/Early Termination Visit (Visit 9), if willing.  
 
Participants who permanently discontinue study product use due to an AE must continue 
to be followed in the study, if they are willing, until resolution (return to baseline) or 
stabilization of the AE is documented. 
 
If study follow-up is continued, participants will have their remaining protocol-specified 
visits through Final Contact. Protocol-specified procedures will continue except the 
following:  
• Pelvic exams* 
• Sample collection for TFV levels 
• Sample collection for anti-HSV-2 activity 
• Sample collection for PK, PD, and biomarkers 
• Swabs for microbiota  
• Collection of blood for safety assessments* 
• Behavioral assessments 
• Protocol counseling will be modified 
 
 
 
*Unless required for AE follow-up  
 

 
 
 
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The above procedures should be conducted at the visit in which study product is 
discontinued and omitted thereafter, unless the participant was already on a temporary 
hold.   
 
Note: The MTN-038 Management Team, in consultation with the MTN Pharmacology Core, may 
provide guidance to the site regarding a modified study visit schedule to ensure PK samples are 
collected at the appropriate time points and/or omitted if the collection of samples would not be 
anticipated to yield analyzable data.  Participants’ duration of use and timing of study product 
permanent discontinuation will be factored into a modified schedule.   Refer to the MTN-038 SSP 
Manual for additional details. 
 
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), she can return for an interim visit to make up certain missed 
visit procedures and specimen collections. Refer to the MTN-038 SSP Manual for 
additional details. 
 
7.7 
Protocol Counseling: Adherence and Contraception Counseling 
 
Study product and protocol adherence counseling will be provided to all participants in 
the study. Contraception counseling will be provided to all participants beginning at the 
Screening Visit. Persons who have undergone supracervical hysterectomy or bilateral 
oophorectomy verified by medical records are not required to receive contraceptive 
counseling. Counseling will be provided in accordance with standard methods, and will 
include reminders regarding concomitant medication and behavioral restrictions prior to 
and following collection of biopsies and CVF.  
 
7.8 
Pharmacokinetics  
 
The entire MTN-038 cohort will provide plasma for assessment of TFV levels at Visits 3, 
4, 5, 6, 8, 9 and 10, CVF for assessment of TFV levels at Visits 2, 3, 4, 5, 6, 8, 9 and 10, 
and rectal fluid for assessment of TFV levels at Visits 3, 5, 6, 8, and 9. Half of all 
participants will be randomized to provide cervical tissue for assessment of PK at Visits 
5 and 8, and the other half will be randomized to provide cervical tissue for PK at Visits 6 
and 9.  
 
Detailed instructions are provided in the MTN-038 SSP Manual available at 
http://www.mtnstopshiv.org.  
 

 
 
 
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Table 13: PK, PD, and Biomarkers Specimen Collection Schedule 
Visit 
Specimens Collected for PK 
Specimens Collected for PD 
and/or  
to Assess Biomarkers of 
Mucosal Safety 
Visit 2 – Enrollment 
(Day 0) 
• Cervicovaginal fluid (CVF) ▲ 
• Cervicovaginal lavage (CVL) ¤ 
• CVF ¤   
Visit 3 - Day 1 
Visit 4 - Day 7 
Visit 5 - Day 14 
• Plasma 
• CVF 
• Rectal fluid (Visits 3 and 5 only) 
• Cervical tissue ǂ (Visit 5 only) 
• CVF  
Visit 6 - Day 28 
• Plasma 
• CVF 
• Rectal fluid 
• Cervical tissue ǂ  
• CVL 
• CVL 
• CVF 
Visit 7 – Day 42 
 
• CVF 
Visit 8 - Day 56 
• Plasma 
• CVF 
• Rectal fluid 
• Cervical tissue ǂ  
• CVL 
• CVL 
• CVF 
• Cervical tissue ǂ  
Visit 9 - PUEV/Early 
Termination Visit 
(Day 91) 
• Plasma ∞ 
• CVF ∞ 
• Rectal fluid ∞ 
• Cervical tissue ǂ  
• Cervical tissue ǂ  
• CVF 
Visit 10 - Final 
contact (Day 92) 
• Plasma 
• CVF 
 
 ¤ Collected prior to ring insertion 
▲To be collected at approximately 1 hour and 4 hours following ring insertion 
ǂ Participants will be randomized to biopsy collection either at Visits 5 and 8 or Visits 6 and 9  
∞ To be collected immediately prior to ring removal and approximately 4 hours following ring removal 
 
7.9 
Behavioral Measures 
 
Behavioral Assessment  
All participants will complete a Computer-Assisted Self Interview (CASI) baseline 
questionnaire at the Enrollment Visit. In addition to collecting demographic information, 
this baseline questionnaire assesses participants’ motivation to join the trial, recent sexual 
behavior, alcohol and drug use, vaginal and sexual practices, partner types, condom use, 
and other HIV prevention methods used. The assessment includes questions on use of 
vaginal products, douching practices and other behavioral practices that may affect the 

 
 
 
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vaginal compartment. A subset of these behaviors will be assessed in follow-up 
questionnaires at Visit 6 (Day 28), Visit 8 (Day 56), and Visit 9 (PUEV/Early Termination 
Visit).  Measures used previously in other microbicide trials will be employed.  
 
Product Adherence Assessment 
Key adherence measures will be captured by CASI and by CRFs to ensure maximum 
confidentiality of responses. Product use information will be collected at Visit 6 (day 28), 
Visit 8 (Day 56), and Visit 9 (PUEV/Early Termination Visit). The questions will assess 
study IVR use, report of frequency of study IVR removal/expulsions (voluntary and 
involuntary) and duration without IVR inserted in the vagina. Clinician-initiated VR 
removals for the purpose of clinical examination are to be excluded from consideration 
during product adherence assessment. A series of questions will ask if the study IVR was 
out, whether it was removed or expelled, under what circumstances or conditions it was 
removed or expelled, and whether it was re-inserted. A combination of self-administered 
and interviewer-administered questionnaires will be employed to capture the above 
information. Study staff will provide participants with guidance on strategies to optimize 
recall of relevant behavioral and adherence data. This quantitative assessment will be 
modeled on the adherence assessment for protocols MTN-036 (www.mtnstopshiv.org) 
and other previous trials of the DPV ring (MTN-013, MTN-020 and IPM 027 
[http://www.ipmglobal.org/]). Additionally, at all visits in which a pelvic exam is performed, 
clinicians will assess whether the IVR is in place through visualization on speculum exam 
(or bimanual exam if needed) and record this assessment on a CRF. 
 
Product Preference/Acceptability Assessment  
A product preference/acceptability questionnaire will be administered by CASI to 
participants at the Enrollment Visit and Visit 6 (Day 28), with a more thorough 
questionnaire administered at Visit 9 (PUEV/Early Termination Visit). HIV prevention 
product preference will also be assessed at the PUEV/Early Termination Visit. This 
questionnaire includes structured questions about the participant’s attitude related to the 
IVR (product characteristics; likes and dislikes concerning the IVR), her experiences 
using the IVR (e.g., genitourinary discomfort, ease of use/removal, displacement, 
willingness to use during menstruation, willingness to use in the future), effect on sex, 
and partner’s reactions. Measures used previously in MTN-036 and other microbicide 
trials will be employed.26,27  
 
In-Depth Interview 
A subset of approximately 24 participants will be randomly selected to complete an in-
depth interview (IDI) before exiting from the study. Depending on participant availability 
and visit length, it may be necessary to conduct this assessment as a separate visit after 
the PUEV. The interview will address study IVR use and acceptability during the trial. 
These IDIs will be conducted by a trained qualitative interviewer and will follow a semi-
structured questionnaire guide and are anticipated to last approximately 45-60 minutes. 
Participants will be compensated for the completion of the IDI. These interviews may be 
conducted over the computer. The audio from the interview will be recorded and 

 
 
 
MTN-038, Version 1.0                             68                                      July 11, 2018 
 
 
 
transcribed for analysis. The interview notes, recording and transcript will be considered 
as source documentation. 
 
Data on acceptability and factors affecting adherence will be collected during the IDI. The 
interviews will include topics such as: 
  
• Challenges to use of study products, specifically in relation to hygiene, menses 
and sex 
• Effect of IVR use on sex 
• Perceived benefits and barriers to IVR use 
• Perceived method(s) preferences for HIV prevention and multipurpose prevention 
technologies 
 
7.10 Clinical Evaluations and Procedures 
 
Physical exams will include the following assessments:  
 
• General appearance 
• Weight* 
• Vital signs 
o Temperature 
o Pulse  
o Blood pressure 
o Respirations* 
• Height* 
• Lymph nodes* 
• Neck* 
• Head, Eye, Ear, Nose and Throat (HEENT)*  
• Heart* 
• Lungs*  
• Abdomen* 
• Extremities* 
• Skin*  
• Neurological* 
 
*may be omitted during targeted physical examinations 
 
Pelvic Examination and Specimen Collection 
Pelvic examinations will be conducted per guidelines for naked eye inspection described 
in the WHO/CONRAD Manual for Standardization of Colposcopy for the Evaluation of 
Vaginal Products, Update 2004, available at http://www.conrad.org/publications-13.html.   
 

 
 
 
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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. 
 
The required sequence of procedures and specimen collection performed during pelvic 
exams will be specified in the MTN-038 SSP Manual. 
 
7.11 Laboratory Evaluations 
 
Local Laboratory 
• Urine 
o Pregnancy test 
o Dipstick/culture 
 
• Blood 
o AST/ALT  
o CBC with differential and platelets  
o Serum creatinine 
o HIV-1/2 testing (including HIV-1/2 confirmation testing) 
o Syphilis serology 
o Hepatitis B surface antigen 
 
• Pelvic 
o Pap test 
o Saline/KOH wet mount with pH for candidiasis and/or BV 
o NAAT for GC/CT and trichomonas 
 
Network Laboratory Center (LC)  
• Blood 
o Plasma for TFV levels  
o Confirmation HIV-1/2 testing for seroconversion 
o HIV-1 resistance tests for confirmed seroconverters 
o HSV 1/2 serology 
o Plasma for archive  
 
• Pelvic 
o CVF for TFV levels  
o CVF for biomarkers 
o CVL for PK, anti-HIV PD, biomarkers 
o Cervical tissue for PK and anti-HIV PD 
o Vaginal swabs for microbiota 
o Gram stain of vaginal smear 
 
• Rectal 
o Rectal fluid for TFV levels  

 
 
 
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Designated Laboratory 
• Study Product 
o Used study IVR residual drug level assessment (TFV) 
o Used study IVR biomarker assessment (residual glycerin content and other 
bioassays) 
 
• Anti-HSV-2 activity 
o CVF for anti-HSV-2 activity 
 
Once all required study analyses of collected specimens are complete, any remaining 
samples 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 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. 
 
7.12 Specimen Management 
 
Each study site will adhere to the standards of good clinical laboratory practice 
(https://www.niaid.nih.gov/sites/default/files/gclp.pdf) in accordance with current US 
Division of AIDS (DAIDS) Laboratory Requirements, MTN-038 Study Specific Procedures 
Manual (http://www.mtnstopshiv.org) 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, sites are 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, and 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. 
 

 
 
 
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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 U.S. CDC and NIH. All 
biological specimens will be transported using packaging mandated by US Code of 
Federal Regulations (CFR) 42 Part 72. All dangerous goods materials, including 
diagnostic specimens and infectious substances, must be transported according to 
instructions detailed in the International Air Transport Association (IATA) Dangerous 
Goods Regulations. Biohazardous waste will be contained according to institutional, 
transportation/carrier, and all other applicable regulations.     
 
 
8 
ASSESSMENT OF SAFETY 
 
8.1 
Safety Monitoring 
 
Site IoRs/designees 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, Protocol 
Safety Physician(s), and CONRAD Safety Physician(s) will serve as the Protocol Safety 
Review Team (PSRT). The MTN 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 site 
IoRs 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.  
 

 
 
 
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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 and SDMC staff, and the CONRAD safety physician for review. 
 
The PSRT will meet approximately every month, or as needed, 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 10.7.1), since no Data and Safety Monitoring Board 
oversight is planned for MTN-038. 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 and the Site IoRs will notify the 
responsible IRBs expeditiously. 
 
The MTN SMC will also 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 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 all study products. 

 
 
 
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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.  AEs 
will be graded per the Division of AIDS (DAIDS) Table for Grading the Severity of Adult 
and Pediatric Adverse Events, Corrected Version 2.1, July 2017, and Addendum 1 
(Female Genital Grading Table for Use in Microbicide Studies [Dated November 2007]).   
 
In cases where a genital AE is covered in multiple tables, the Female Genital Grading 
Table for Use in Microbicide Studies will be the grading scale utilized. 
 
Please note: 
• Asymptomatic BV and asymptomatic candidiasis will not be reportable AEs; 
• Fetal losses (e.g., spontaneous abortions, spontaneous fetal deaths, stillbirths) will 
not be reported as AEs (however, fetal loss data will be collected); 
• Untoward maternal conditions that either result in or result from fetal losses are 
reported as reproductive system AEs; 
• Genital bleeding clinically assessed to be expected is not to be reported as an AE.   
 
8.3.2 Serious Adverse Events  
 
Serious adverse events (SAEs) will be defined by the Manual for Expedited Reporting of 
Adverse Events to DAIDS (Version 2.0, January 2010), as AEs occurring at any dose 
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: 

 
 
 
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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: 
 
• 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 reporting of expedited adverse events (EAEs) 
are outlined in Version 2.0 of the DAIDS EAE Manual, which is available on the RSC 
website at http://rsc.tech-res.com/clinical-research-sites/safety-reporting/manual. 
 
The DAIDS Adverse Experience Reporting System (DAERS), an internet-based reporting 
system, must be used for EAE reporting to DAIDS. In the event of system outages or 
technical difficulties, EAEs may be submitted via the DAIDS EAE Form. This form is 
available on the DAIDS RSC website at http://rsc.tech-res.com/clinical-research-
sites/safety-reporting/daids/paper-eae-reporting. 
 
For 
questions 
about 
DAERS, please 
contact 
NIAID 
CRMS 
Support 
at 

 
 
 
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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 the TFV IVR  
 
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 the Female Genital 
Grading Table for Use in Microbicide Studies (Addendum 1 to the DAIDS Table for 
Grading the Severity of Adult and Pediatric Adverse Events, Version 1.0, November 
2007), will be used and are available on the RSC website at http://rsc.tech-
res.com/clinical-research-sites/safety-reporting/daids-grading-tables.  
 
8.4.4 Expedited AE Reporting Period 
 
The EAE reporting period for this study begins at enrollment 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 Pregnancy Outcomes 
 
Pregnant women are excluded from this study. 
 
A participant who is pregnant after enrollment will continue to be followed until the 
pregnancy outcome is ascertained. A participant who becomes pregnant during the study 
will have study product discontinued and will be terminated from the study. Please see 
Section 9.8 for additional details.  
 

 
 
 
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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 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 
temporary 
product 
hold/permanent 
discontinuation of study product are outlined in this section. In general, the IoR/designee 
has the discretion to hold study product use at any time if s/he feels that continued product 
use would be harmful to the participant or interfere with treatment deemed clinically 
necessary. Unless otherwise specified below, the IoR/designee must immediately consult 
the PSRT for further guidance on resuming study product, continuing the hold temporarily, 
or progressing to permanent discontinuation of study product. The IoR/designee will 
document all temporary product holds and permanent discontinuations on applicable 
CRFs.  
 
Participants reporting any unresolved AEs at the time of study termination will be followed 
clinically until the occurrence resolves (returns to baseline) or stabilizes. 
 
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. 
 

 
 
 
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9.3 
General Criteria for Temporary Hold and Permanent Discontinuation of 
Study Product 
 
A participant will be permanently discontinued from IVR product use by the IoR/designee 
for any of the following reasons: 
 
• Acquisition of HIV-1/2 infection; such participants will not resume product use at 
any time. The study IVR must be held beginning immediately upon recognition of 
the first reactive rapid HIV test.  
• Allergic reaction to the IVR 
• Pregnancy 
• Breastfeeding 
• Non-therapeutic injection drug use 
 
A participant will be temporarily discontinued from IVR product use (a product hold will be 
implemented) by the IoR/designee and a PSRT query submitted for any of the following 
reasons: 
 
• Reported use of PEP for HIV exposure 
• Reported use of PrEP for HIV prevention 
• Use of heparin, Lovenox®, warfarin, Plavix® (clopidogrel bisulfate), or other 
anticoagulant 
• Any clinical study product hold lasting more than 7 days 
• 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. (May result in 
temporary hold or permanent discontinuation) 
 
The IoR/designee must consult the PSRT once the temporary hold is initiated. Together, 
the IoR/designee and the PSRT will discuss resuming product use, continuing the 
temporary hold, or progressing to permanent discontinuation. 
 
9.4 
Temporary Product Hold/Permanent Discontinuation in Response to 
Adverse Events 
 
Grade 1 or 2 
In general, a participant who develops a Grade 1 or 2 AE not specifically addressed 
below, regardless of relationship to study product, may continue product use.   
 
Grade 3 
Participants who develop a Grade 3 AE not specifically addressed below, judged by the 
IoR/designee to be not related to study product, may continue product use.   
 

 
 
 
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If a participant develops a Grade 3 AE not specifically addressed below and the AE is 
judged by the IoR/designee to be related to study product, the IoR/designee must 
temporarily hold study product and consult the PSRT. The hold must continue until a 
recommendation is obtained from the PSRT.   
 
Grade 4 
Participants who develop a Grade 4 AE (regardless of relationship to study product), that 
is not specifically addressed below, must have the study product held. The IoR/designee 
must consult the PSRT and continue the temporary product hold until a recommendation 
is obtained from the PSRT.   
 
9.5 
Sexually Transmitted Infection/Reproductive Tract Infection 
 
The IoR/designee must manage STI/RTI per current CDC guidelines, available at 
http://www.cdc.gov/std/treatment/.   
 
IVR use need not be held in the event of an STI/RTI requiring treatment, unless other 
temporary product hold/permanent discontinuation guidelines described below apply.  
Should the IoR/designee determine that a temporary product hold is warranted due to an 
STI or RTI, consultation with the PSRT is required. 
 
9.6 
Management of Specific Genital Events 
 
If a suspected finding is reported by the participant between scheduled visits, an interim 
visit may be scheduled at the discretion of the site investigator. Management of genital 
events observed at scheduled or interim visits will be in accordance with the following: 
 
Superficial epithelial disruption or localized erythema or edema: area of less than 
50% of vulvar surface or combined vaginal and cervical surface 
• Continue study IVR use (at study clinician’s discretion) 
 
• Perform naked eye evaluation 
 
• Re-evaluate by speculum examination in approximately 3-5 days 
• If condition worsens or does not resolve at that time, temporarily hold study 
IVR use and consult the PSRT. 
 

 
 
 
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Deep epithelial disruption (ulceration) or generalized erythema or severe edema: 
area of more than 50% of vulvar surface or combined vaginal and cervical surface 
affected by erythema or severe edema  
• Temporarily hold study IVR 
• Perform naked eye evaluation 
• Re-evaluate in approximately 3-5 days and resume study IVR use if 
resolved 
• If unresolved at re-evaluation, continue temporary product hold, and re-
evaluate within approximately 2-3 days. If resolved at that time may resume 
use. If unresolved at this second re-evaluation, continue temporary product 
hold, consult with PSRT regarding permanent discontinuation, and provide 
care per local standard 
• If there is reoccurrence with no identified etiology, continue temporary 
product hold and consult PSRT regarding permanent discontinuation. 
 
Unexpected genital bleeding  
• Continue study IVR use (at study clinician’s discretion) 
 
• Perform naked eye evaluation 
 
• If determined to be due to deep epithelial disruption, refer to guidelines 
above; otherwise continue study IVR use. 
 
Genital petechia(e) and genital ecchymosis  
• Continue study IVR use (at study clinician’s discretion) 
 
 
• Perform naked eye evaluation  
• No further evaluation or treatment is required. 
 
9.7 
HIV Infection 
 
Participants who test positive for HIV must have study product permanently discontinued 
by the IoR/designee. A participant who is confirmed to be HIV positive during the study 
will have study product discontinued, all follow-up visits will be discontinued and the 
participant will be considered terminated from the study, as per Section 7.5.1. Guidance 
regarding management and referral for participants confirmed to be HIV-positive is 
located in Section 13.10.1. 
 
9.8 
Pregnancy 
 
Pregnancy testing will be performed at designated study visits and participants will be 
encouraged to report all signs or symptoms of pregnancy to study staff. Pregnancy testing 
is not required for participants who have undergone supracervical hysterectomy or 
bilateral oophorectomy verified by medical records. The IoR/designee will counsel any 
participant who becomes pregnant regarding possible risks to the fetus according to site 

 
 
 
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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 the study will have study product 
discontinued and will be terminated from the study, as per Section 7.5.2. 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). Pregnancy outcomes will be reported on 
relevant CRFs. Pregnancy outcomes will not be expeditiously reported to CONRAD and 
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 DAIDS EAE Manual (Version 2.0, January 2010) guidelines for 
expedited reporting.  
 
A participant who becomes pregnant during study participation may be offered 
participation in MTN-016, HIV Prevention Agent Pregnancy Exposure Registry: 
EMBRACE Study, at sites participating in MTN-016. This registry study captures 
pregnancy outcomes as well as infant health information (including growth) to evaluate 
the safety and teratogenic risks of microbicide and oral PrEP exposure in pregnancy. For 
participants who do not enroll in MTN-016, 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. 
  
9.9 
Criteria for Early Termination of Study Participation 
 
Participants may voluntarily withdraw from the study for any reason at any time. The 
IoR/designee also may withdraw participants from the study to protect their safety and/or 
if they are unwilling or unable to comply with required study procedures, after consultation 
with the PSRT. Participants also may be withdrawn if 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. Study staff members will record the reason(s) 
for all withdrawals in participants’ study records.   
 
 

 
 
 
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10 
STATISTICAL CONSIDERATIONS 
 
10.1 Overview and Summary of Design 
 
This is a Phase 1, two-arm, multi-site, randomized (2:1), placebo-controlled trial of a 
polyurethane reservoir IVR containing the active ingredient TFV. A total of approximately 
48 healthy, HIV-uninfected participants will be enrolled and randomized 2:1 (32 in the 
active arm and 16 in the placebo arm) to use a study IVR. Participants will use the study 
IVR continuously for approximately 91 days. 
 
 
10.2 Study Endpoints 
 
Consistent with the primary study objective to assess the PK of the 1.4 g TFV IVR when 
used continuously for 91 days, the following endpoints will be assessed: 
 
• TFV concentrations in plasma 
• TFV concentrations in CVF 
• TFV concentrations in rectal fluid 
• TFV and TFV-DP concentrations in cervical tissue  
 
Consistent with the primary study objective to assess safety of the 1.4 g TFV IVR when 
used continuously for 91 days, the primary safety endpoints are the proportion of 
participants with the following: 
 
• Grade 2 or higher genitourinary adverse events as defined by the Division of AIDS 
(DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events, 
Corrected Version 2.1, July 2017, and/or Addendum 1 (Female Genital Grading 
Table for Use in Microbicide Studies [Dated November 2007]) 
• Grade 3 or higher adverse events as defined by the Division of AIDS (DAIDS) 
Table for Grading the Severity of Adult and Pediatric Adverse Events, Corrected 
Version 2.1, July 2017 
 
Consistent with the secondary study objective to assess adherence to the study products 
during study participation, the following endpoints will be assessed:  
 
• Frequency of study IVR removal/expulsions (voluntary and involuntary) and 
duration without IVR in vagina (by self-report) 
• IVR use initiation and persistence (whether the IVR is in place when participants 
come to the clinic for their study visits) 
 

 
 
 
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Consistent with the secondary study objective to assess the overall acceptability to the 
study products during study participation, the following endpoint will be assessed:  
 
• Degree to which study participants liked or disliked using the IVR (by self-report)  
 
10.3 Primary Study Hypotheses 
 
• Plasma, CVF, and rectal fluid TFV levels and cervical tissue TFV and TFV-DP 
levels will be measurable in all participants  
• Continuous exposure to TFV due to sustained release from the 1.4 g TFV IVR for 
91 days will be safe 
 
10.4 Sample Size and Power Calculations 
 
10.4.1 Primary Endpoints 
 
The proposed total sample size is approximately N=48 adult participants. The sample 
size is based upon the size of similar Phase 1 studies of vaginal microbicide products. 
  
As a means to characterize the statistical properties of this study, Table 14 below presents 
the probability of observing thirty or more, thirty-one or more, or thirty-two participants 
with detectable PK levels (or a level above a specified threshold value) among the 32 
participants in the active arm given a true event rate. For example, if the true rate of 
detection (or rate above a specified threshold) among participants using a ring is 99% 
then the probability we will see 31 or more participants with detectable PK levels is 96%. 
 
Table 14: Analysis of PK Event Frequency 
“True” Event Rate 
(PK Detectable or 
above a specified 
threshold value) 
P (>30 events | n=32) 
P (>31 events | n=32) 
P (32 events | n=32) 
90% 
0.37 
0.16 
0.03 
95% 
0.79 
0.52 
0.19 
99% 
>0.99 
0.96 
0.72 
 
Table 15 below presents the probability of observing zero, one or more and two or more 
safety events among the 32 participants in the active arm given a true event rate. For 
example, if the true rate of a safety event among participants using a ring is 10% then the 
probability we will see 1 or more participants with this event is 97%. 
 

 
 
 
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Table 15: Analysis of Safety Event Frequency 
“True” Event Rate 
(Safety Event) 
P (0 events | n=32) 
P (>1 events | n=32) 
P (>2 events | n=32) 
1% 
0.72 
0.28 
0.04 
5% 
0.19 
0.81 
0.48 
10% 
0.03 
0.97 
0.84 
 
An alternative way of describing the statistical properties of the study design is in terms 
of the 95% confidence interval (95% CI) for the true rate based on the observed data.  
Table below shows the exact 2-sided 95% CIs for the probability of an event based on a 
particular observed rate. If none of the 32 participants in the active arm experience a 
safety event, the 95% exact 2-sided upper confidence bound for the true rate of such 
events in that study arm is 11%. Similarly, if all 32 participants in the active arm have 
detectable PK, the 95% exact 2-sided lower confidence bound for the true rate of PK 
detection is 89%. 
 
Table 16: Precision of Exact 2-sided 95% CIs for Observed Event Rates 
Observed Event Rate 
Exact 2-sided 95% CI (n=12) 
32/32 (100%) 
89%, 100% 
30/32 (94%) 
79%, 99% 
25/32 (78%) 
60%, 91% 
16/32 (50%) 
32%, 68% 
10/32 (31%) 
16%, 50% 
3/32 (9%) 
2%, 25% 
0/12 (0%) 
0%, 11% 
 
An additional aim of the study is to compare the safety between the active and placebo 
IVR arms. Assuming a one-sided test with α=0.05 and Fisher’s Exact Test, Table   below 
provides the difference in the rates of safety events (proportion of participants 
experiencing the safety event of interest) between the active IVR arm and the placebo 
IVR arm that is detectable with 90% power for a given rate in the placebo IVR arm.  For 
example, if the true rate of a given safety endpoint in the placebo IVR arm is 12.5% (2 of 
16 participants experience a safety event), the proposed sample size provides 90% power 
to exclude safety endpoint rates greater than 57.5% (51.9% with 80% power). Hence, 
while comparisons will be made between the active IVR arm and the placebo IVR arm, 
the study will only have power to detect large differences in safety event rates.  
 

 
 
 
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Table 17: Safety Event Rates that Provide 90% Power for Testing Equality of Safety Event Rates 
Rate in Placebo IVR Arm 
Rate in Active IVR Arm 
6.3% 
48.7% 
12.5% 
57.5% 
18.8% 
65.2% 
25.0% 
71.9% 
31.3% 
78.0% 
* Note: the figures in this table represent examples and are not actual rates of adverse events. 
 
10.4.2 Secondary Endpoints 
 
Adherence will be measured by the percentage of participants who keep the IVR inserted 
at all times in the vagina over the course of 91 days. (Clinician-initiated VR removals for 
the purpose of clinical examination will be excluded from consideration.) A sample size 
of 48 participants will provide a precision of 13.0% (i.e., half the width of the 95% 
confidence interval) assuming an observed adherence of 75%. 
 
Overall acceptability will be measured by the degree (on a scale of 1 to 10) to which 
participants like or dislike using the IVR over the course of 91 days. Previous studies 
using such a scale indicate that the standard deviation of this score is approximately 2.4.  
Assuming a similar standard deviation and 32 participants in the active IVR arm and 16 
in the placebo arm, the study will have 90% power to detect a difference in the 
acceptability score of 2.65.28  
 
10.5 Participant Accrual, Follow-up, and Retention 
 
Based on previous studies of vaginal products with similar eligibility requirements, the 
accrual of 48 eligible participants will take approximately 6-9 months. Participants lost to 
follow-up and/or on temporary hold or permanent product discontinuation will not be 
replaced. However, every effort will be made to complete their regularly scheduled safety 
evaluations. Additionally, participants who are found to be HIV-infected and/or pregnant 
after enrollment will be terminated from the study and will not be replaced. Each site will 
target retention of 95% of enrolled participants over the 92-day follow-up period. 
 
10.6 Randomization 
 
Participants will be randomized in a 2:1 ratio to the active and placebo arms of the study.  
The 2:1 ratio of active to placebo arms is to allow for the collection of additional safety 
and PK endpoints in the TFV IVR arm. Study arm randomization will be stratified by site 
to ensure balanced assignment of products at each site. In addition, approximately 24 
participants will be randomly selected for IDIs. Finally, the timing of biopsies will also be 
randomly assigned. Biopsy schedule randomization will be ideally balanced between 
active and placebo groups and in a 1:1 ratio of Day 14 and Day 56 to Day 28 and Day 
91. 

 
 
 
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The randomization schemes will be generated and maintained by the MTN SDMC and 
will be specified in the MTN-038 SSP manual. 
 
10.7 Data and Safety Monitoring and Analysis 
 
10.7.1 Study Monitoring Committee  
 
Data and Safety Monitoring Board oversight is not planned for this study. The MTN SMC 
will conduct interim reviews of study progress, including rates of participant accrual, 
retention, completion of primary and main secondary endpoint assessments, study or lab 
issues, and a closed safety data report to voting SMC members. The review 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. For further information regarding the SMC, 
please reference the MTN Manual of Operational Procedures (www.mtnstopshiv.org).   
 
10.7.2 Primary Analyses 
 
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).  
 
To assess the adequacy of the randomization, participants in each of the two arms will 
be compared for baseline characteristics including demographics and laboratory 
measurements using descriptive statistics. Due to the small sample size, formal 
comparisons will not be done. 
 
Pharmacokinetic Analysis 
The proportion of participants with detectable drug levels in the active arm and the 
measured drug concentration levels will be summarized using descriptive statistics and 
graphics.  Routine PK parameters will also be used to describe drug concentrations where 
appropriate. 
 
Safety Analysis 
All visits in which a woman 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. 
To assess genitourinary safety, the number and the percentages of participants 
experiencing each safety endpoint (see Section 10.2) will be tabulated by study arm. Each 
participant will contribute once in each category (i.e., only for highest severity AE for each 

 
 
 
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participant) for the calculation of event rates. Exact binomial confidence intervals will be 
calculated for each safety endpoint for each arm and Fisher’s Exact test used to test for 
differences in event rates between the drug containing IVR arm and the placebo IVR arm. 
 
10.7.3   Secondary Analyses 
 
Adherence Analysis 
To assess participant adherence to the IVR, the proportion of participants who reported 
keeping the study IVR inserted at all times during the 91 days will be calculated along 
with a 95% confidence interval. (Clinician-initiated VR removals for the purpose of clinical 
examination will be excluded from consideration during product adherence analysis.) For 
participants who were not fully adherent, the number of self-reported removal/expulsion 
events and average duration of these events will be reported. Additionally, the average 
cumulative period of time during the study period when the study IVR was outside the 
vagina will be calculated. Number, type and circumstances of expulsions (voluntary and 
involuntary) will be described. 
 
Acceptability Analysis 
To assess acceptability of the study IVR, the 10-point acceptability scale will be 
summarized by calculating the mean, standard deviation, and 95% CI overall, and by 
study arm. In addition, acceptability between the active and placebo arms will be 
compared using the t-test or Mann-Whitney U test depending on the distribution of the 
data. 
  
The acceptability analysis will be supplemented by presenting the above proportion by 
randomization arm along with its corresponding 95% confidence interval. 
 
10.7.4   Missing Data 
 
In any situation with missing data, appropriate secondary analyses will be performed to 
adjust for variables that may be related to the missingness mechanism. If missing data 
rates are higher than 10%, covariates that are related to missingness in likelihood-based 
regression models will be included. A sensitivity analyses to assess the potential impact 
of the missing data will also be performed. These analyses will include imputing the data 
under the most extreme scenarios of information missingness, such as assuming 
everyone missing has an extreme value of the missing variable, and less informative 
imputation approaches. 
 
 

 
 
 
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11 
DATA HANDLING AND RECORDKEEPING 
 
11.1 Data Management Responsibilities 
 
Data collection tools will be developed by the MTN SDMC in conjunction with the protocol 
team. Quality control and data integrity are managed manually and systematically with 
reports and queries 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 will 
identify all CRFs to be used as source documents, and will submit test CASI data to 
confirm proper data transfer to the SDMC. Study CRF data will be entered and cleaned 
using the Medidata Rave EDC tool, a data management system compliant with the 
International Council for Harmonization (ICH), Good Clinical Practices (GCP) and US 
CFR guidelines for electronic data capture.   
 
Research Triangle Institute will manage all qualitative data for the study. Qualitative data 
will be collected, stored and analyzed by Research Triangle Institute. Audio files from 
interviews conducted by qualitative analysts will be stored securely on HIPAA compliant 
servers. The audio files will be transcribed by an external transcription service and sent 
only over a secure file transfer protocol site. The transcriptionist will follow all procedures 
outlined in the Data Use Agreement with Research Triangle Institute. Transcripts will be 
stored securely on HIPAA compliant servers. The paper notes taken by the qualitative 
analyst during the interviews will be saved in a locked files cabinet in the Research 
Triangle Institute office. 
 
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 regarding testing 
investigational products, the IoR/designee will maintain all study documentation for at 
least two years following the date of marketing approval for the study product being tested 
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.  
 

 
 
 
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11.3 Quality Control and Quality Assurance 
 
All 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 may visit the 
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 US 
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 
• Verify proper storage, dispensing, and accountability of investigational study 
products 
• Assess implementation and documentation of internal site quality management 
procedures 
 
The IoR/designee 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. The IoR/designee also 
will allow inspection of all study-related documentation by authorized representatives of 
the MTN Leadership and Operations Center (LOC), SDMC, LC, NIAID, FDA, OHRP, 
CONRAD, IRBs and other local, US or international regulatory authorities. A site visit log 
will be maintained at the study site to document all visits. 
 
 
13 
HUMAN SUBJECTS PROTECTIONS 
 
Site investigators will make every effort to minimize risks to participants.  Participants and 
study staff members will take part in a thorough informed consent process. Before 
beginning the study, the IoR/designee will have obtained IRB approval and the protocol 
will have been submitted to the FDA. The IoR/designee 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. 

 
 
 
MTN-038, Version 1.0                             89                                      July 11, 2018 
 
 
 
 
13.1 Institutional Review Boards/Ethics Committees 
 
Each participating institution is responsible for assuring that this protocol, the associated 
site-specific informed consent forms, and study-related documents (such as participant 
education and recruitment materials) are reviewed by an IRB responsible for oversight of 
research conducted at the study sites. Any amendments to the protocol must be approved 
by the responsible IRBs prior to implementation. 
 
Subsequent to 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 (DAIDS 
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, 
each site must have the protocol and the protocol informed consent form(s) approved, as 
appropriate, by their local institutional review board (IRB)/ethics committee (EC) and any 
other applicable regulatory entity (RE). Upon receiving final approval, sites will submit all 
required protocol registration documents to the DAIDS PRO at the Regulatory Support 
Center (RSC). The DAIDS PRO will review the submitted protocol registration packet to 
ensure that all the required documents have been received.   
 
Site-specific informed consent forms (ICFs) WILL be reviewed and 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. A copy of the Initial 
Registration Notification should be retained in the site's regulatory files. 
 
Upon receiving final IRB/EC and any other applicable RE 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 the site's regulatory files. 
 

 
 
 
MTN-038, Version 1.0                             90                                      July 11, 2018 
 
 
 
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 
sponsor responsibilities for this study will be specified in a Clinical Trial Agreement (CTA) 
executed by NIAID and CONRAD. 
 
Study implementation will be directed by this protocol, which may not be amended without 
proper regulatory approvals. Study implementation will also be guided by a common 
study-specific procedures manual (SSP) 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 all 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, 
documentation, and information-sharing across sites. Rates of accrual, adherence, 
follow-up, and AE incidence will be monitored closely by the team as well as the SMC. 
 
13.4 Risk Benefit Statement 
 
13.4.1 Risks 
 
It is not expected that this trial will expose human subjects to unreasonable risk.   
 
Vaginal Fluid Collection 
Collection of vaginal fluid may cause discomfort or pressure in the vagina or genital area. 
 
Rectal Fluid Collection 
Insertion of a lubricated anoscope to collect rectal fluid will likely cause some discomfort 
or pressure in the rectum or anorectal area. There is the risk of mild discomfort in addition 
to a slight risk of bleeding with the insertion of rectal swabs or sponges. 
 
Pelvic Examination and Procedures 
Pelvic examination and procedures may cause mild discomfort, pressure and/or vaginal 
bleeding or spotting. 
 

 
 
 
MTN-038, Version 1.0                             91                                      July 11, 2018 
 
 
 
Cervical Biopsy Collection 
Cervical biopsies carry the risk of discomfort or pain during the procedure and for a few 
hours afterwards. Participants may have mild vaginal spotting (bleeding) for one or two 
days. Participants will be instructed not to use aspirin (over 81 mg per day) or any other 
drugs that are associated with the increased likelihood of bleeding for 72 hours before 
and after the collection of the cervical biopsies. Participants are to abstain from receptive 
vaginal or anal sexual activities for 72 hours prior to each clinical visit and for 72 hours 
following cervical biopsy collection. 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 (soaking through 
a pad or tampon in an hour or less) or if the participant develops any abnormal odor or 
discharge from the vagina.  
 
Phlebotomy 
Phlebotomy may lead to discomfort, feelings of dizziness or faintness, and/or bruising, 
swelling, having a blood clot and/or infection.  
 
Other Risks 
Being tested for HIV, HSV and STIs and waiting for test results may cause worry, sadness 
or depression. Provision of positive test results 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.  
 
Participants at sites where local regulatory authorities require partner notification in 
response to diagnosed STI or HIV infection could have problems in participants’ 
relationships. Participants also could have problems in their partner relationships 
associated with use of study product and abstinence requirements. 
 
Participants who take part in an IDI may be asked questions about their study product 
use, vaginal and menstrual hygiene, and sexual practices. These questions may make 
some participants uncomfortable. 
 
Although study sites 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, 
communities, and/or employer(s). 
 

 
 
 
MTN-038, Version 1.0                             92                                      July 11, 2018 
 
 
 
Risks Associated with Vaginal Rings 
Use of the study IVR may lead to vaginal symptoms, including irritation, increased 
discharge, and discomfort (including with vaginal intercourse if it were to occur). It is 
possible that a participant may have an allergic reaction to the study IVR. Symptoms of 
an allergic reaction include rash or other skin irritation, itching, joint pain, or difficulty in 
breathing. 
 
Toxic shock syndrome has been reported with currently marketed contraceptive VRs, 
though a causal relationship between the two has not been established.29 As with any 
vaginally retained product, the possibility of toxic shock syndrome, although rare, exists. 
Detailed information regarding the plan for diagnosis and management of this condition 
should it arise is provided in the MTN-038 SSP Manual. 
 
Risks Associated with Tenofovir 
The following side effects have been associated with the use of TFV in oral tablet form: 
• Upset stomach, vomiting, gas, loose or watery stools   
• Generalized weakness 
• Dizziness  
• Depression 
• Headache 
• Abdominal pain  
• Worsening or new kidney damage or failure 
• Inflammation or swelling and possible damage to the pancreas and liver. 
Symptoms for liver problems may include jaundice, dark urine, stomach pain, loss 
of appetite, upset stomach or vomiting, pale colored stools, and itchy skin 
• Shortness of breath  
• Rash  
• Allergic reaction: symptoms may include fever, rash, upset stomach, vomiting, 
loose or watery stools, abdominal pain, achiness, shortness of breath, a general 
feeling of illness or a potentially serious swelling of the face, lips, and/or tongue 
• Bone pain and bone changes such as thinning and softening which may increase 
the risk of breakage  
• Muscle pain and muscle weakness 
• Nucleotide Analogue: Lactic acidosis and severe hepatomegaly with steatosis that 
may result in liver failure, other complications or death have been reported with the 
use of antiretroviral nucleoside analogues alone or in combination.  
• Sleeping problems  
 
The following possible side effects have been associated with the use of vaginal rings 
containing TFV in previous studies: 
• Headache  
• Vulvovaginal pruritus 
• Vulvovaginal pain 

 
 
 
MTN-038, Version 1.0                             93                                      July 11, 2018 
 
 
 
• Bladder discomfort 
• Vaginal discharge 
• Vaginal erythema 
• Vaginal and cervical ulceration 
 
13.4.2 Benefits 
 
Participants will receive HIV/STI risk reduction counseling, HIV, HSV and STI testing, 
physical examination, pelvic examination, and routine laboratory testing. Participants will 
be provided with STI treatment in accordance with CDC guidelines. 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 
participants may have the opportunity to access expedient treatment and as a result may 
have decreased morbidity due to early diagnosis and treatment of abnormalities identified 
during tests, examinations and referrals.  
 
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 transmission. Information learned in this study may 
also help to understand issues important for broader implementation of the TFV ring. 
Participants may also appreciate the opportunity to contribute to the field of HIV 
prevention research. 
 
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. Consent for long-term specimen storage is not required for study 
participation. In obtaining and documenting informed consent, the IoR and their 
designees will comply with applicable local and US regulatory requirements and will 
adhere to GCP and to the ethical principles that have their origin in the Declaration of 
Helsinki.  Study staff must document the informed consent process in accordance with 
the Requirements for Source Documentation in DAIDS Funded and/or Sponsored Clinical 
Trials 
(https://www.niaid.nih.gov/sites/default/files/daids-sourcedocpolicy.pdf).  
Participants will be provided with copies of the informed consent forms if they are willing 
to receive them.   
 
In addition to informed consent forms, 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 all study 
sites, which will be detailed in the SSP manual.   
 

 
 
 
MTN-038, Version 1.0                             94                                      July 11, 2018 
 
 
 
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 1.4 g TFV IVR 
• Randomization and the importance of participants in both of the 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. Each study site will 
implement confidentiality protections that reflect the local study implementation plan and 
the input of study staff and community representatives to identify potential confidentiality 
issues and strategies to address them. In addition to local considerations, the protections 
described below will be implemented at all sites. 
 
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 collection, and administrative forms will be identified by coded number only to 
maintain participant confidentiality. All local databases will be secured with password 
protected access systems. Forms, lists, logbooks, appointment books, and any other 
listings that link participants’ ID numbers to identifying information will be stored in a 
separate, locked file in an area with limited access. After receiving appropriate approval, 
all study documents/data will be properly disposed of, including the proper destruction 
and/or deletion of paper files, electronic study data, and electronic documents. 
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, OHRP, 
NIH, and/or contractors of the NIH, and other local, US or international regulatory 
authorities 
• Representatives of CONRAD and PPD 
• Representatives of the MTN LOC, SDMC, and/or LC 
• Study staff  

 
 
 
MTN-038, Version 1.0                             95                                      July 11, 2018 
 
 
 
• Site IRBs 
 
MTN has obtained a Certificate of Confidentiality from the US Department of Health and 
Human Services that is applicable for this study. This Certificate protects study staff from 
being compelled to disclose study-related information by any US Federal, State or local 
civil, criminal, administrative, legislative or other proceedings. It thus serves to protect the 
identity and privacy of study participants.  
 
13.7 Special Populations 
 
13.7.1 Pregnant Women 
 
Women who test positive for pregnancy at the Screening or Enrollment Visit will not be 
eligible to participate in this study.  Should a participant test positive for pregnancy after 
Enrollment, a product discontinuation will be implemented. Follow-up will be completed 
and data collected per Section 7.5.2. Please refer to Section 9.8 for further details. During 
the informed consent process, participants will be informed that the study IVR is not 
proven to be an effective method of contraception and the effects of the study IVR on a 
developing human fetus are unknown. 
 
13.7.2 Children 
 
The NIH has mandated that children be included in research trials when appropriate. This 
study meets “Justifications for Exclusion” criteria for younger children as set forth by the 
NIH. Specifically, “insufficient data are available in adults to judge potential risk in 
children” and “children should not be the initial group to be involved in research studies.”  
This study does not plan to enroll children under 18 years old. 
 
13.8 Compensation 
 
Pending IRB approval, participants will be compensated for time and effort in this study, 
and/or be reimbursed for travel to study visits. Site specific compensation amounts will 
be specified in the study informed consent forms of each individual site. 
 
13.9 Communicable Disease Reporting 
 
Study staff will comply with local requirements to report communicable diseases including 
HIV-1/2 identified among study participants to health authorities. Participants will be made 
aware of reporting requirements during the informed consent process. 
 
13.10 Access to HIV-related Care 
 
HIV test-related counseling will be provided to all potential study participants who consent 
to undergo HIV screening to determine their eligibility for this study, and to all enrolled 

 
 
 
MTN-038, Version 1.0                             96                                      July 11, 2018 
 
 
 
participants at each follow-up HIV 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 each site and additionally will 
emphasize the unknown efficacy of the study products in preventing HIV infection. In 
accordance with the policies of the NIH, participants must receive their HIV test results to 
take part in this study.   
 
13.10.1 
Care for Participants Identified as HIV-Positive 
 
An individual who has been identified as infected with HIV will be managed or referred for 
management according to the local standard of care. Should a participant test positive for 
HIV after the Enrollment Visit, follow-up procedures will be performed as per Section 
7.5.1.   
 
13.11 Study Discontinuation 
 
This study may be discontinued at any time by NIAID, the MTN, CONRAD, the US FDA, 
OHRP, other government or international regulatory authorities, or site IRBs. 
 
 
14 
PUBLICATION POLICY 
 
DAIDS/NIAID and MTN policies and a CTA between NIAID and CONRAD will govern 
publication of the results of this study.   
 

 
 
 
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15 
APPENDICES 
 
 

 
 
 
MTN-038, Version 1.0                             98                                      July 11, 2018 
 
 
 
APPENDIX I:  SCHEDULE OF STUDY VISITS AND EVALUATIONS 
 
Visit 
1     
SCR 
Visit 2       
ENR        
(Day 0) 
Visit 3, 
4      
(Days 
1, 7) 
Visit 5 
(Day 
14) 
Visit 6 
(Day 28) 
Visit 7 
(Day 
42) 
Visit 8 
(Day 
56) 
Visit 9 
PUEV/Early 
Termination 
(Day 91) 
Visit 10  
Final 
Contact  
(Day 92) 
ADMINISTRATIVE AND REGULATORY 
Obtain written informed 
consent(s) 
X 
 
 
 
 
 
 
 
 
Assign a unique Participant 
Identification (PTID) number 
X 
 
 
 
 
 
 
 
 
Assess and/or confirm 
eligibility 
X 
X 
 
 
 
 
 
 
 
Collect demographic and 
background information 
X 
 
 
 
 
 
 
 
 
Collect/review/update locator 
information 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Randomization to product and 
biopsy schedule 
 
X 
 
 
 
 
 
 
 
Provide reimbursement 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Schedule next visit/contact  
* 
* 
X 
X 
X 
X 
X 
X 
* 
BEHAVIORAL/COUNSELING 
HIV pre- and post-test 
counseling 
X 
X 
* 
* 
* 
* 
* 
X 
* 
HIV/STI risk reduction 
counseling 
X 
X 
* 
* 
* 
* 
* 
X 
* 
Protocol counseling 
X 
X 
X 
X 
X 
X 
X 
X 
 
Collect product use 
information 
 
 
 
 
X 
 
X 
X 
 
Collect product preference/ 
acceptability information 
 
X 
 
 
X 
 
 
X 
 
Behavioral assessment 
 
X 
 
 
X 
 
X 
X 
 
In-depth interview (IDI) 
 
 
 
 
 
 
 
X♦ 
(subset) 
 
CLINICAL 
Collect medical eligibility 
information (including 
exclusionary conditions and 
medications) 
X 
X 
 
 
 
 
 
 
 
Collect/review/update 
medical/menstrual history 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Collect/review/update 
concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Perform physical exam 
(Targeted at Visits 2-10) 
X 
X 
* 
* 
* 
* 
* 
* 
* 
Perform pelvic exam 
X 
X 
X 
X 
X 
X 
X 
X 
* 
Treat or prescribe treatment 
for RTI/UTI/STIs 
* 
* 
* 
* 
* 
* 
* 
* 
* 
Digital exam by clinician to 
check IVR placement 
 
X 
 
 
 
 
 
 
 
Provide available test results  
X 
X 
X 
X 
X 
X 
X 
X 
X 
Collect AEs 
 
 
X 
X 
X 
X 
X 
X 
X 

 
 
 
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Visit 
1     
SCR 
Visit 2       
ENR        
(Day 0) 
Visit 3, 
4      
(Days 
1, 7) 
Visit 5 
(Day 
14) 
Visit 6 
(Day 28) 
Visit 7 
(Day 
42) 
Visit 8 
(Day 
56) 
Visit 9 
PUEV/Early 
Termination 
(Day 91) 
Visit 10  
Final 
Contact  
(Day 92) 
LABORATORY 
URINE 
Pregnancy test 
X π 
X π 
* 
* 
X π 
* 
X π 
X π 
* 
Urine dipstick/culture 
* 
* 
* 
* 
* 
* 
* 
* 
* 
BLOOD 
HIV-1/2 testing 
X 
X 
* 
* 
* 
* 
* 
X 
 
Plasma for archive 
 
X 
 
 
 
 
 
 
 
AST/ALT 
X 
 
 
 
* 
* 
* 
X 
 
CBC with differential and 
platelets 
X 
* 
* 
* 
* 
* 
* 
X 
* 
Serum creatinine 
X 
* 
* 
* 
* 
* 
* 
X 
* 
Hep B surface antigen 
X 
 
 
 
 
 
 
 
 
Syphilis serology 
X 
 
* 
* 
* 
* 
* 
* 
 
HSV 1/2 serology 
 
X 
 
 
 
 
 
 
 
TFV levels 
 
 
X 
X 
X 
 
X 
X∞ 
X 
PELVIC 
NAAT for GC/CT and 
trichomonas 
X 
* 
* 
* 
* 
* 
* 
* 
 
Saline/KOH wet mount 
with pH for candidiasis 
and/or BV 
* 
* 
* 
* 
* 
* 
* 
* 
* 
Pap test 
X^ 
 
 
 
 
 
 
 
 
Vaginal swabs for 
microbiota 
 
X 
 
 
X 
 
X 
X 
 
Vaginal Gram stain 
 
X 
 
 
X 
 
X 
X 
 
CVF anti-HSV-2 activity 
 
X¤ 
 
 
X 
 
X 
 
 
CVF TFV levels 
 
X▲ 
X 
X 
X 
 
X 
X∞ 
X 
CVF for biomarkers 
 
X¤ 
X 
X 
X 
X 
X 
X 
 
CVL for PK, PD, and 
biomarkers 
 
X¤ 
(PD and 
biomarkers 
only) 
 
 
X 
 
X 
 
 
Cervical biopsies for PK 
 
 
 
Xǂ 
Xǂ 
 
 
 
 
Cervical biopsies for PK 
and PD 
 
 
 
 
 
 
Xǂ 
Xǂ 
 
RECTAL 
Rectal fluid TFV levels 
 
 
X  
(Day 
1 
only) 
X 
X 
 
X 
X∞ 
 
STUDY PRODUCT SUPPLY 
Provision of study IVR 
 
X 
 
 
 
 
 
 
 
Insertion of the provided study 
IVR 
 
X 
 
 
 
 
 
 
 
Provision of study IVR use 
instructions 
 
X 
 
 
 
 
 
 
 
Removal and collection of 
study IVR 
 
 
 
 
 
 
 
X 
 
Offer male condoms 
X* 
X* 
X* 
X* 
X* 
X* 
X* 
X* 
X* 

 
 
 
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Visit 
1     
SCR 
Visit 2       
ENR        
(Day 0) 
Visit 3, 
4      
(Days 
1, 7) 
Visit 5 
(Day 
14) 
Visit 6 
(Day 28) 
Visit 7 
(Day 
42) 
Visit 8 
(Day 
56) 
Visit 9 
PUEV/Early 
Termination 
(Day 91) 
Visit 10  
Final 
Contact  
(Day 92) 
X required 
* If indicated and/or per local standard of care 
^ If participant [over age 21] is unable to provide documentation of a satisfactory Pap test within 3 years prior to enrollment 
▲Samples to be taken approximately 1 and 4 hours following ring insertion 
∞ Samples to be taken immediately prior to ring removal and approximately 4 hours following ring removal 
¤ Samples to be taken prior to ring insertion 
ǂ Participants will be randomized to biopsy collection either at Visits 5 and 8 or Visits 6 and 9 
♦ May be scheduled for later date due to visit length and/or to accommodate participant availability 
π Not required for participants who have undergone supracervical hysterectomy or bilateral oophorectomy verified by  
   medical records 
 
 
 
 

 
 
 
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APPENDIX II:  ALGORITHM FOR HIV TESTING FOR SCREENING AND ENROLLED 
PARTICIPANTS 
 
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
 
 
 

 
 
 
MTN-038, Version 1.0                             102                                      July 11, 2018 
 
 
 
APPENDIX III:  SAMPLE INFORMED CONSENT FORM (SCREENING, 
ENROLLMENT, LONG-TERM STORAGE AND FUTURE TESTING) 
 
SAMPLE INFORMED CONSENT FORM 
DIVISION OF AIDS, NIAID, NIH 
 
MTN-038 
Version 1.0 
July 11, 2018 
 
A Phase 1, Randomized Pharmacokinetic and Safety Study of a 90 Day 
Intravaginal Ring Containing Tenofovir 
 
PRINCIPAL INVESTIGATOR: [Sites to insert] 
PHONE: [Sites to insert] 
SHORT TITLE: PK and Safety Study of a 90 Day Vaginal Ring Containing Tenofovir 
 
INFORMED CONSENT 
 
IMPORTANT INFORMATION ABOUT THE RESEARCH STUDY 
 
You are being asked to take part in this research study because you: 
• were assigned female sex at birth   
• are HIV-negative  
• are healthy  
• are between the ages of 18 and 45 years old  
 
Approximately 48 people will participate at three study sites in the United States. This 
study is sponsored by the US National Institutes of Health (NIH) and conducted by the 
Microbicide Trials Network (MTN). At this site, the person in charge of this study is 
[INSERT NAME OF PRINCIPAL INVESTIGATOR].   
 
Important things you should know: 
• The study products in this clinical trial are two intravaginal rings (IVR). One 
contains 1.4 g tenofovir (TFV), an anti-HIV medication, and the other is a placebo. 
The placebo ring has a similar appearance, size and make-up to the TFV IVR but 
does not contain study drug or active ingredients.  
• The purposes of this study are: 
o To find out if the TFV IVR is safe and well-tolerated when worn continuously 
for 91 days 
o To find out how the study drug TFV enters and exits the body when the IVR 
is inserted into the vagina and left in place for approximately 91 days.  

 
 
 
MTN-038, Version 1.0                             103                                      July 11, 2018 
 
 
 
• If you qualify and choose to participate, you will be asked to insert one of the two 
IVRs in your vagina and wear it continuously for approximately 91 days. You will 
be randomly assigned to one of two study groups (among 3 participants, 2 will be 
assigned to the TFV IVR group and 1 assigned to the placebo IVR group): 
o An IVR containing 1.4 g of TFV 
o A placebo IVR 
• You will be asked to attend 10 clinic visits at this study clinic and will be followed 
for approximately 92 days. The total length of your participation in this study will 
be about four and a half 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 pelvic exam will be performed;  
o Blood will be obtained to test for HIV and/or other sexually transmitted 
infections (STI); 
o Urine will be collected to test for infections and (if applicable) pregnancy; 
 If your medical records confirm that you have had your uterus 
removed above the cervix or have had both ovaries removed, you 
will not have to have pregnancy testing performed.   
o Vaginal and rectal fluids will be collected for research purposes and to test 
for STIs (if applicable). At 4 visits, cervical tissue will also be collected;  
o You will be asked to complete several short interviews. You may also be 
selected to complete a longer interview at Visit 9. 
• Some common risks or discomforts from the IVR and the use of TFV in other forms 
include: upset stomach, fatigue, dizziness, depression, headache, vaginal irritation 
and/or discharge, allergic reaction, and vaginal or cervical ulcers. One serious but 
rare adverse reaction reported with the use of VR is toxic shock syndrome caused 
by poisons (toxins) released by some types of Staphylococcus aureus, a common 
bacteria, though a causal relationship has not been established. 
• You may not experience any direct benefit from participation 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, HSV and STI testing, physical and pelvic examinations, and routine laboratory 
testing.  
• Taking part in this research project is voluntary. You don’t have to participate and 
you can stop at any time. 
• 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 the trial, you will sign your name on 
this form. A copy of this form will be offered to you. Signing this consent form does not 

 
 
 
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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 (see Your 
Rights as a Research Participant/Volunteer for more information).  
 
STUDY PRODUCT 
 
The drug TFV is used in the treatment and prevention of HIV. TFV works by preventing 
HIV from making copies of itself, which stops the spread of HIV in the body. HIV is the 
virus that causes AIDS.     
 
TFV, in combination with other drugs, has been studied as an oral tablet (e.g., Truvada®) 
and shown to be safe and effective in the treatment and prevention of HIV infection. TFV 
has also been studied as a vaginal gel and shown to be safe but not consistently effective 
in prevention of HIV infection, due in part to inconsistent use of the gel in these studies. 
Very little clinical data exists on the safety or effectiveness of TFV when it is delivered via 
IVR. However, early results suggest that the TFV IVR would be safe and may deliver 
enough drug to prevent the spread of HIV in people. 
 
The study IVRs are made of flexible plastic and are supplied by CONRAD, a not-for-profit 
research organization.  
 
STUDY GROUPS 
 
Approximately 48 eligible participants will be randomly assigned to one of two IVR study 
groups:   
• A ring containing 1.4 g TFV, to be worn continuously for a total of 91 days 
• A placebo ring that contains no drug or active ingredients, to be worn 
continuously for a total of 91 days 
 
Approximately 32 participants will be assigned to use the TFV IVR, and approximately 16 
participants will be assigned to the placebo IVR. Participants will be assigned to a group 
by random chance (like rolling dice). Neither you nor the study staff can control which 
group you will be assigned to.   
 
WHAT WILL HAPPEN DURING THE STUDY VISITS? 
 
The study includes a total of ten (10) clinic visits, including the Screening Visit today. All 
visits will take place at this clinic.  

 
 
 
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Screening Visit Procedures: 
 
The procedures done today will take about [SITES TO INSERT TIME]. Study staff will: 
• Ask you questions to confirm that you are able to join the study.  
• Ask you to provide study staff with your contact information (i.e., where you live 
and how we can get in touch with you). 
• Ask you questions about your medical health (including what medications you are 
taking), menstrual history, and your understanding of the study requirements.  
They may also ask to view your medical records with your permission. 
• Talk with you about the requirements of the study, including the importance of 
completing clinic visits and study activities and procedures according to the study 
schedule.   
• Test your urine for pregnancy and, if needed, for infections. 
o If you are pregnant you cannot join this study.  
o Study staff will talk with you about ways to avoid becoming pregnant.   
o You will answer questions about whether you are using an effective method of 
contraception and intend to use this method for the entire time that you are in 
this study. Effective methods include:  
 Sterilization by you or your partner (tubal ligation, vasectomy, etc.). 
 Hormonal methods except contraceptive vaginal rings. 
 Intrauterine devices (IUDs) inserted at least 30 days before enrollment. 
 Having sex exclusively with individuals assigned female sex at birth.  
 Abstinence from penile-vaginal intercourse for 90 days before 
enrollment and planning to remain abstinent for the duration of study 
participation. 
• Perform a physical examination. 
• Perform a pelvic examination: 
o The study clinician will use a speculum (a plastic or metal instrument inserted 
in the vagina). Study staff will ask if you are experiencing symptoms of an 
infection. They will check your vagina and cervix for signs of infection and other 
problems.   

 
 
 
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o Collect a small amount of vaginal fluid via swab(s), like a Q-tip. These swabs 
will be used to test for sexually transmitted infections and diseases (commonly 
known as STIs or STDs) and other problems. 
o If you are 21 years or older, the study staff may also collect samples from your 
cervix for a “Pap test” or “Pap smear”.  Study staff will inform you of the results 
of your Pap test.  It takes about [SITES TO INSERT AMOUNT OF TIME] before 
Pap test results are ready.  If you are 21 years of age or older and have a 
written report confirming a normal Pap test in the past 3 years, or if you had an 
abnormal Pap test but had follow-up indicating no treatment was required, you 
will not need to have a Pap test taken at this screening visit. The results of your 
Pap test may affect whether you can join the study.  
• Take a blood sample [SITES TO INSERT AMOUNT]: 
o To test the health of your blood, liver and kidneys. 
o To test for infections typically passed through sex, including HIV and Hepatitis 
B. 
 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 STIs. 
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. The study staff will tell you about other studies you may be 
eligible for, if any.  
• If needed, give you treatment or refer you for treatment of STIs or other urinary or 
reproductive tract infections. 
• Inform you about other services, if needed.  
• Provide you with the results of your tests, when available. It is expected that all 
your results will be available by [SITES TO SPECIFY TIMEFRAME].     
• Offer you male condoms, if you need them. 
• Reimburse you for your visit. 
• Schedule your next visit to enroll in the study, if you are willing and eligible. 
o Your menstrual cycle will be considered when scheduling your next visit 
because, ideally, no bleeding should occur on the first 7 days of product use. 
 
It may be necessary to conduct more than one clinic visit to complete all required 
screening procedures. 
 
If you do not join the study, blood and other samples collected at the Screening visit(s) 
will not be kept or used for any tests other than those listed above.  
 

 
 
 
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If you enroll in the study, you will be asked to abstain from sexual practices, tampon use 
and other non-study products for specified periods of time prior to your clinic visits. See 
stated length of time highlighted below: 
 
Activity: 
For How Long? 
• 
Receptive sexual practices, including: 
o 
Penile-vaginal intercourse 
o 
Penile-anal intercourse 
o 
Receptive oral intercourse 
o 
Finger stimulation 
• 
For 72 hours before each clinic visit and for
72 hours after biopsy collection 
• 
Tampon use 
• 
For 24 hours before each clinic visit 
• 
Inserting any objects into your vagina or
rectum, including: 
o 
Sex toys 
o 
Female condoms  
o 
Diaphragms 
o 
Menstrual cups  
o 
Cervical caps or any other
vaginal barrier method 
• 
For the duration of study participation,
beginning 24 hours before the enrollment visit
• 
Use of vaginal products, including: 
o 
Spermicides 
o 
Lubricants 
o 
Contraceptive VRs 
o 
Douches  
o 
Vaginal medications 
o 
Vaginal moisturizers 
• 
For the duration of study participation,
beginning 24 hours before the enrollment visit
• 
Use of oral post-exposure or pre-
exposure prophylaxis (PEP or PrEP) 
• 
For the duration of study participation,
beginning 3 months before the enrollment 
visit 
• 
Use of anticoagulants (e.g., heparin, 
Lovenox®, warfarin, Plavix® [clopidogrel
bisulfate]) 
• 
For the duration of study participation 
• 
Use of aspirin (greater than 81 mg)  
• 
For 72 hours before and after a cervical 
biopsy collection visit 
 
Enrollment and Follow-up Visit Procedures: 
 
If you are found to be eligible, your next visit will be within 45 days of your Screening Visit 
today, and is called the Enrollment Visit. The procedures done during the Enrollment Visit 
will take about [SITES TO INSERT TIME]. This visit will take longer than most because 
we will collect a small amount of vaginal fluid over a period of 4 hours. At your Enrollment 
Visit, study staff will: 
• Ask you questions to confirm you are able to join the study. 
• Randomly assign you to one of two study groups. Participants in both study groups 
will have the same study visit schedule. 
• Take blood samples [SITES TO INSERT AMOUNT]. 
 The blood samples will be collected: 

 
 
 
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o For HIV testing. 
o For research purposes, to test for herpes simplex virus (HSV). 
 The HSV test results will not be available until the end of the study, 
and neither you nor study staff will know your HSV status until then. 
If you would like to receive your HSV test results after the end of the 
study, please let study staff know.     
o In case there is a question about your lab results in the future. 
o The same tests may be done when these samples are collected at future 
visits. 
• Give you the study IVR to insert at the clinic. Study staff may help you insert the 
IVR if you cannot do it on your own. All participants will have an examination to 
ensure the ring is inserted correctly.   
 You will be asked to keep the IVR in place until the Day 91 study visit (Visit 9) 
and not remove it between visits. You will be given further instructions about 
what to do in the rare occasion the ring comes out or you need to remove it.   
 Study staff will show you how to take the ring out in case you need to.  
 Study staff will talk with you about what to do if you have any problems or 
symptoms while using the ring. 
• Collect a small amount of vaginal fluid via swabs at two time points including at 
one and four hours after you insert the study IVR.   
 Collect swabs: 
o To measure the amount of TFV present in the vagina when using the study 
IVR and for other research purposes. 
o The same tests may be done when these samples are collected at future 
visits. 
 
Follow-up study visits will take about [SITES TO INSERT TIME]. At most of these visits, 
including the Enrollment Visit, study staff will: 
• Ask you to update your contact information. 
• Talk with you about the requirements of the study and how to follow them, including 
keeping the IVR in place and not removing it between visits as well as restrictions 
on vaginal and sexual practices. 
• Talk with you about STIs, HIV, HIV/STI testing, and ways to avoid HIV and other 
infections passed through sex. 
• Ask you about any health or medical problems you may be currently experiencing 
or that have occurred since your last visit (including what medications you are 
taking). 
• Ask you about any menstrual periods or spotting you may have had since your last 
visit. 
• Ask you questions about vaginal practices that may affect how your body absorbs 
the study drugs. 
• Ask you questions about your study product use and about your thoughts on the 
study product.  

 
 
 
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 You may use a computer to answer these questions.  It is important that you 
know that you will answer these questions in private and your responses will 
be kept confidential. 
• Talk with you about any problems or symptoms that you encounter as a result of 
wearing the IVR or undergoing any of the study procedures. 
• Test your urine for pregnancy and, if needed, for infections. 
• Take blood samples [SITES TO INSERT AMOUNT] to test your health and for 
research purposes, including to measure the amount of TFV present in your body 
when using the study IVR. 
• Perform a targeted physical examination (including general appearance, 
temperature, heart rate and blood pressure) if needed. 
• Perform a pelvic examination. 
 The study clinician will use a speculum to check your vagina and cervix for 
signs of problems due to the ring or infection. They may also collect vaginal 
fluid to test for infections and for research purposes. 
 At the Enrollment, Day 28 and Day 56 clinic visits (Visits 2, 6 and 8), the study 
clinician will perform a cervicovaginal lavage (CVL). For the CVL, a clinician 
rinses your vagina and cervix with a small amount of sterile fluid and collects 
that fluid in a tube for testing. The CVL fluid collected will be used for research 
purposes only. 
 At both the Day 14 and Day 56 clinic visits (Visits 5 and 8), or at both the Day 
28 and Day 91 clinic visits (Visits 6 and 9), the study clinician will perform a 
cervical biopsy to collect tissue samples from your cervix. Which two visits you 
will be assigned to have the cervical biopsy will be selected randomly. At Visits 
5 and 6, study clinicians will take approximately 2 small tissue samples from 
your cervix, each about the size of a grain of rice; at Visits 8 and 9, they will 
take approximately 4 small tissue samples from your cervix. These samples 
will be used to see how much of the study drug is in your tissue. It is important 
that you do not put anything in your vagina for 3 days before the biopsy tissue 
collections and 3 days after, which includes avoiding sexual intercourse, 
because you may be at higher risk for getting or spreading an infection until the 
biopsy sites have healed. It is also important that you do not take any aspirin 
doses higher than 81 mg per day for 3 days before and after the cervical biopsy 
tissue collections, because you may be at higher risk of bleeding. 
• Take rectal fluid samples.  
o At the Day 1, Day 14, Day 28, Day 56 and Day 91 clinic visits (Visits 3, 5, 6, 8 
and 9), the study clinician will use an anoscope (a short hollow tube inserted in 
your rectum) and insert swabs and sponges through the tube to collect rectal 
fluid for research purposes.    
• Give you treatment or refer you for treatment for any issues they may find. 
• Give you your test results, if available. 
• Offer you condoms, if you need them. 
• Reimburse you for your visit. 

 
 
 
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• Schedule your next visit, if applicable. 
 
As with the Enrollment visit, your Day 91 study visit (Visit 9, when the study IVR is 
removed) will take longer than most because we will collect your blood and vaginal and 
rectal fluids over a period of 4 hours. This visit will take about [SITES TO INSERT TIME]. 
During this visit, study staff will: 
• Take blood samples [SITES TO INSERT AMOUNT] right before you remove the 
study IVR and at four hours after you remove the study IVR.  The blood samples 
will be collected: 
o For HIV testing. 
o To test the health of your blood, liver and kidneys, and for research 
purposes. 
• Collect a small amount of vaginal fluid via swab and rectal fluid via anoscope at 
two time points including right before you remove the study IVR and at four hours 
after you remove the study IVR. 
• Collect the study IVR from all participants. 
 
In addition to the procedures listed above, it is possible that study staff may need to 
perform additional tests if medically necessary (for example, you report having symptoms 
of a urinary, genital, or other infection and/or other issues).   
 
It is important that you remember that at any time during the study, study staff can answer 
any questions you may have about any study visit procedures. 
 
Additional Visits and Procedures 
It may be necessary for you to have additional visit(s) and/or provide additional samples 
if any of the above procedures need to be repeated due to one or more of the following: 
• Issues with sample processing, testing or shipping. 
• If you are experiencing any symptoms or changes in your physical condition. 
• If tests or procedures were missed or not conducted.   
 
Additional testing may be performed as part of quality control to ensure that the tests work 
correctly and supply accurate data. 
 
In-depth Interview Subset: 
You may be asked to participate in an interview with a trained staff member at your Day 
91 clinic visit (Visit 9) to discuss your experiences during study participation. A total of 
approximately 24 participants across 3 sites will be interviewed. If you are asked to 
participate in this interview, you will be asked questions about your use of the ring, your 
preferences and opinions, your experiences with using the ring during sex, any problems 
you may have had using the ring, and whether you used the vaginal ring or not.  This 
interview may take approximately 45-60 minutes and may occur over video chat. The 
interviews will be audio-recorded to make sure to record your words exactly how you said 
them. The audio recording, notes, and analyses from these materials will be kept 

 
 
 
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confidential and will only use study numbers or fake names, and the hardware will be 
physically protected in a locked area. This means that no one other than the MTN-038 
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-038 study team for the purposes of this research. [Sites to modify with their 
site-specific source documentation storage duration requirements if required by 
their IRBs: The audio recordings, notes, and transcripts from these materials will be kept 
for at least two years after the intravaginal ring is approved for marketing or two years 
after all developmental research on the intravaginal ring is stopped.] 
 
RISKS AND/OR DISCOMFORTS 
 
Risks of Blood Draws 
Whenever your blood is drawn, you may have: 
• Discomfort. 
• Feelings of dizziness or faintness. 
• Bruising, swelling, small clot and/or infection. 
 
Risks of Pelvic Exams 
During pelvic exams and cervical and vaginal fluid collection, you may feel discomfort or 
pressure in your vagina, genital area and/or pelvis. You may also have vaginal bleeding 
or spotting, which should stop shortly after the examination.  
 
Cervical biopsies carry the risk of discomfort or pain during the procedure and for a few 
hours afterwards. Participants may have spotting (bleeding) for one or two days. With 
cervical biopsies, there is also a small risk of infection and heavier bleeding. You may 
also be at increased risk for STIs and HIV acquisition, if exposed, while the biopsy sites 
are healing. You will be encouraged to call the clinic to report any problems after the 
collection, especially if heavy bleeding is noted (soaking through a pad or tampon in an 
hour or less) or if you develop any abnormal vaginal odor or discharge. 
 
Risks of Vaginal Rings 
Based on side effects reported among participants in previous IVR studies, vaginal rings 
may be associated with side effects listed below: 
• Vaginal discharge 
• Vaginal irritation or discomfort (including with vaginal intercourse) 
• Itching of the vagina (vulvovaginal pruritus)  
• Allergic reaction (including rash or other skin irritation, itching, joint pain, or 
difficulty breathing) 
 
With any product inserted vaginally, it is possible you could experience toxic shock 
syndrome. Toxic shock syndrome is a rare but serious illness caused by poisons (toxins) 
released by some types of Staphylococcus aureus, a common bacterium. The likelihood 
of this occurring is rare. 

 
 
 
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Risks of Tenofovir 
The following side effects have been associated with the use of TFV in oral tablet form: 
• Upset stomach, vomiting, gas, loose or watery stools   
• Generalized weakness 
• Dizziness  
• Depression 
• Headache 
• Abdominal pain  
• Worsening or new kidney damage or failure 
• Inflammation or swelling and possible damage to the pancreas and liver. If you 
are developing liver problems, you may have one or more of the following 
symptoms: 
o Yellowing of the skin or whites of your eyes 
o Dark urine 
o Pain on the right side of your stomach 
o Loss of appetite, upset stomach or vomiting 
o Pale colored stools 
o Itchy skin 
• Shortness of breath  
• Rash  
• Allergic reaction: symptoms may include fever, rash, upset stomach, vomiting, 
loose or watery stools, abdominal pain, achiness, shortness of breath, a general 
feeling of illness or a potentially serious swelling of the face, lips, and/or tongue 
• Bone pain and bone changes such as thinning and softening which may increase 
the risk of breakage  
• Muscle pain and muscle weakness 
• Elevated lactic acid levels in the blood and enlarged liver with fatty liver that may 
result in liver failure, other complications or death have been reported with the use 
of TFV and similar anti-HIV medications alone or in combination. The liver 
complications have been seen more often in women on these drug regimens. 
Some nonspecific symptoms that might indicate elevated lactic acid levels in the 
blood include: unexplained weight loss, stomach discomfort, nausea, vomiting, 
fatigue, cramps, muscle pain, weakness, dizziness and shortness of breath. 
• Sleeping problems  
 
The following possible side effects have been associated with the use of TFV IVR: 
• Headache  
• Vulvovaginal pruritus 
• Vulvovaginal pain 
• Bladder discomfort 
• Vaginal discharge 
• Vaginal erythema 

 
 
 
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• Vaginal and cervical ulceration 
 
Risks of Anoscope Rectal Exams 
During collection of rectal fluid samples, insertion of a lubricated anoscope may cause 
mild discomfort or pressure in the rectum or anorectal area. There is a risk of mild 
discomfort in addition to a slight risk of bleeding with the insertion of rectal swabs or 
sponges.  
 
Other Possible Risks 
You may become embarrassed and/or worried when discussing your sexual practices, 
ways to protect against HIV and other STIs, and your test results. You may be worried 
while waiting for your test results. If you have HIV or other infections, learning this could 
make you worried. Trained study counselors will help you deal with any feelings or 
questions you have.  
 
We will make every effort to protect your privacy and confidentiality during the study visits. 
Your visits will take place in private. Reports via computer will be stored in computers that 
are password-protected and will not include personal information that could identify or link 
information to you; only your study ID number will be recorded. 
 
If you are selected for an in-depth interview, the interview will be audio recorded and 
questions of a personal nature may be asked. Responding to these questions may make 
you uncomfortable. The audio files will be put into writing by the person interviewing you 
or by another person who does not know you and does not have your personal 
information. You should NOT identify anyone in the interviews and any names that might 
be mentioned on the recording will only be noted in the transcript using a generic 
description. The audio files will be stored in computers that are password-protected.   
 
It is possible that your 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, 
communities, and/or employer(s). Finding out your HIV, HSV or STI status could cause 
depression, suicidal thoughts and/or problems between you and your partner. If you have 
any problems, study counselors will talk with you and/or your partner to try to help resolve 
them.   
 
Pregnancy and Breastfeeding  
The TFV IVR is not birth control. We do not know what effect TFV has on pregnancy, 
including the effect of TFV on the fetuses of women who use the IVR when pregnant, or 
the babies of women who use the IVR when breastfeeding. Because of this, anyone who 
is pregnant or breastfeeding may not join this study. Participants who join the study must 
agree to use an acceptable method of contraception (see Screening Visit for details). 
Participants who join this study will have pregnancy tests while in the study.  

 
 
 
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If you become pregnant at any time during the study, study staff will refer you to available 
medical care and other services you may need. The study does not pay for this care. You 
will not receive (or you will stop using) the study IVR and you will exit the study. The 
outcome of your pregnancy is important to study staff; therefore, your pregnancy will be 
followed until the results of your pregnancy are known. We may contact you to find out 
about the health of your pregnancy. 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. [SITE TO INCLUDE/AMEND THE 
FOLLOWING]: We will also contact you about a study that collects information about 
pregnancy and babies up to one year old. 
 
If You Become Infected with HIV 
Your participation in this study will not cause HIV infection. The study drug does not cause 
HIV. However, there is always a chance that through sexual activity or other activities that 
you may become HIV-positive. In the unlikely event that you become HIV-positive, study 
staff will give you counseling and refer you for medical care and other available services. 
Tests may be performed to see if you have HIV drug resistance. This will allow doctors to 
know what HIV drugs would be best for the treatment of your type of HIV. If the HIV tests 
indicate you may be infected with HIV, you will stop using the IVR. If HIV infection is 
confirmed, you will stop your participation in this study.   
 
BENEFITS 
As mentioned previously, TFV has been shown to be safe and effective in preventing HIV 
when taken orally, but we do not yet know if it will prevent HIV when delivered via IVR. 
Though you may not experience any direct benefit from participation in this study, 
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, HSV 
and STI testing, physical examinations, pelvic examinations, and routine laboratory 
testing, including tests to check the overall health of your liver and kidneys. 
 
This study cannot provide you with general medical care, but study staff will refer you to 
other available sources of care.  
 
If you are infected with HIV, you will be referred for medical care, counseling, and other 
services available to you. Medical care for HIV infection will not be part of this study. If 
you are diagnosed with a STI, you will receive medicine or a referral, if needed. You can 
bring your partner here for counseling and referral for testing and treatment for STIs, if 
needed. 
 
NEW INFORMATION 
You will be told of any new information learned during this study that might affect your 
willingness to stay in the study. For example, if information becomes available that shows 
that the IVR may be causing bad effects, you will be told about this. You will also be told 

 
 
 
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when the study results are available, and how to learn about them. Additionally, you will 
be told of any new information about other effective HIV-prevention products as they 
become available. 
 
WHY YOU MAY BE WITHDRAWN FROM THE STUDY WITHOUT YOUR CONSENT 
You may be removed from the study early without your permission if: 
• The study is cancelled by the US FDA, US NIH, CONRAD (the nonprofit 
organization that supplies the IVRs), the US Office for Human Research 
Protections (OHRP), the MTN, the local government or international 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. The 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. 
• You become pregnant. 
• Study staff decide that using the IVR would be harmful to you, for example, if you 
have a bad reaction to the study ring. 
• Other reasons that may prevent you from completing the study successfully, such 
as inability to consistently keep appointments or to stop using prohibited 
medications or engaging in prohibited practices. 
 
If study staff ask you to stop using the IVR, you will be asked to complete an interim visit 
during which time the procedures highlighted to occur at Visit 9 will be completed.  
Thereafter, you may continue your regular clinic visit schedule with modified procedures, 
unless otherwise informed by study staff.  
 
If you are removed from or choose to leave this study, it will have no effect on the regular 
medical care that is available to you at this clinic or elsewhere. You will be asked to return 
your IVR and complete a final evaluation. If you do not have the IVR with you at the time 
of your contact with staff, staff members will make every effort to assist you in returning 
the ring as soon as possible. [SITE TO SPECIFY ALLOWANCES FOR SPECIAL 
CIRCUMSTANCES]  
 
ALTERNATIVES TO PARTICIPATION 
You may choose not to participate in this study. Researchers are continuing to study TFV 
to learn more about how it works in humans to protect against HIV infection. There are 
currently available methods to prevent sexually transmitted HIV: consistent condom use 
during sex and/or the use of daily oral Truvada® for pre-exposure prophylaxis (PrEP) or 
post-exposure prophylaxis (PEP). PrEP is a HIV prevention method where 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 or PEP if you are interested in 
learning more. 
 

 
 
 
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[SITES TO INCLUDE/AMEND THE FOLLOWING, IF APPLICABLE]: There may be 
other studies going on here or in the community that you may be eligible for. If you wish, 
we will tell you about other studies that we know about. There also may be other places 
where you can go for HIV counseling and testing and birth control. We will tell you about 
those places if you wish. 
 
COSTS TO YOU 
[SITE TO COMPLETE ACCORDING TO SITE CAPACITY]: There is no cost to you for 
study related visits, the IVR, physical/pelvic examinations, laboratory tests or other 
procedures. Treatments available to you from the study site for HIV/STIs may be given to 
you free of charge or you will be referred for available treatment for the duration of the 
study. 
 
REIMBURSEMENT 
[SITE TO INSERT INFORMATION ABOUT LOCAL REIMBURSEMENT]: You will 
receive [SITE TO INSERT AMOUNT $XX] for your time, effort, and travel to and from the 
clinic at each scheduled visit. If chosen to take part in the in-depth interview, you will 
receive [SITE TO INSERT AMOUNT $XX]. You may receive [SITE TO INSERT 
AMOUNT $XX] for any visits which occur in between your normally scheduled visits.  
  
CONFIDENTIALITY 
Any information about you obtained from this research will be kept as private as possible.  
All records related to your involvement in this research study will be kept in a [SITES TO 
INSERT]. Your identity on these records will be indicated by a number rather than by your 
name, and the information linking these numbers with your name will be kept separate 
from the research records. 
 
Efforts will be made to keep your information confidential. However, it is not possible to 
guarantee confidentiality. Your personal information may be disclosed if required by law. 
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 
may know about. Any publication of this study will not use your name or identify you 
personally. 
 
Your records may be reviewed by: 
• Representatives of the US Federal Government, including the US FDA, US OHRP, 
NIH and/or contractors of NIH, and other local, US or international regulatory 
authorities. 
• Representatives of CONRAD, including study monitors. 
• Site IRBs or Ethics Committees. 
• Study staff. 
 

 
 
 
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[SITE 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 STIs 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]. 
 
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. 
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. This Certificate does 
not prevent you from releasing information about yourself and your participation in the 
study.  
 
RESEARCH-RELATED INJURY 
[SITE 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. 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. 
 
CLINICALTRIALS.GOV 
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. 
 
YOUR RIGHTS AS A RESEARCH PARTICIPANT/VOLUNTEER 
[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.  
 
PROBLEMS OR QUESTIONS 
If you ever have any questions about the study, or if you have a research-related injury, 
you should contact [INSERT NAME OF THE INVESTIGATOR OR OTHER STUDY 
STAFF] at [INSERT TELEPHONE NUMBER AND/OR PHYSICAL ADDRESS]. 
 

 
 
 
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If you have questions about your rights as a research participant, you should contact 
[INSERT NAME OR TITLE OF PERSON ON THE IRB/EC OR OTHER ORGANIZATION 
APPROPRIATE FOR THE SITE] at [INSERT PHYSICAL ADDRESS AND TELEPHONE 
NUMBER]. 
 

 
 
 
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CONSENT FOR LONG-TERM STORAGE AND FUTURE TESTING OF 
SPECIMENS  
There might be a small amount of blood, tissue, rectal or vaginal fluid left over after 
we have done all 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.   
 
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.  
 
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 is planned for 
leftover specimens 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 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. 
 
 

 
 
 
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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 
 
 
 
 
 

 
 
 
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