A Phase 3B Open-Label Follow-on Trial to Assess the Continued Safety of and Adherence to a Vaginal Ring Containing Dapivirine in Women
Phase: PHASE3
Conditions: Human Immunodeficiency Virus
Sponsor: International Partnership for Microbicides, Inc.

 
MTN-025 
Protocol 
 
CONFIDENTIAL 
CLIN-TEM-GEN-0001.00, 13Jan2016 
 
Page 1 of 1 
 
NCT02858037 
 
MTN-025 
 
A Phase 3B Open-Label Follow-on Trial to Assess the Continued Safety of and 
Adherence to a Vaginal Ring Containing Dapivirine in Women 
 
TABLE OF CONTENTS 
• Protocol Version 1.0, dated 22 August 2014 
• Protocol Version 2.0, dated 16 December 2014 
• Summary of Changes Version 1.0 to Version 2.0, dated 16 December 2014 
• Letter of Amendment #01, dated 11 April 2016 
• Letter of Amendment #02, dated 28 March 2018 
• Clarification Memorandum #01, dated 05 August 2016 
• Clarification Memorandum #02, dated 11 November 2016 

 
 
MTN-025 
 
 
 
A Phase 3B Open-Label Follow-on Trial to Assess the Continued Safety of and 
Adherence to a Vaginal Ring Containing Dapivirine in Women  
 
 
 
Microbicide Trials Network 
 
 
 
 
 
 
Funding Agencies: 
Division of AIDS, US National Institute of Allergy and Infectious Diseases 
US Eunice Kennedy Shriver National Institute of  
Child Health and Human Development 
US National Institute of Mental Health 
US National Institutes of Health 
 
 
Grant Numbers: 
 
UM1AI068633, UM1AI068615, UM1AI106707 
 
DAIDS Protocol ID: 11985 
 
IND Sponsor: 
International Partnership for Microbicides 
 
IND #108,743 
 
 
Protocol Chair: 
Jared Baeten, MD, PhD 
 
Protocol Co-chairs: 
Nyaradzo M. Mgodi, MBChB, MMed 
Thesla Palanee-Phillips, PhD 
 
 
Version 1.0 
 
August 22, 2014

MTN-025, Version 1.0 
2 
August 22, 2014 
 
MTN-025 
 
A Phase 3B Open-Label Follow-on Trial to Assess the Continued Safety of and 
Adherence to a Vaginal Ring Containing Dapivirine in Women  
 
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS AND ACRONYMS ............................................................................................................. 5 
PROTOCOL TEAM ROSTER ...................................................................................................................................... 8 
INVESTIGATOR SIGNATURE FORM ....................................................................................................................... 22 
1 
KEY ROLES ......................................................................................................................................... 27 
1.1 
PROTOCOL IDENTIFICATION ............................................................................................................................. 27 
1.2 
SPONSOR AND MONITOR IDENTIFICATION ......................................................................................................... 27 
1.3 
MEDICAL OFFICER ......................................................................................................................................... 27 
1.4 
CLINICAL LABORATORIES................................................................................................................................. 28 
1.5 
DATA CENTERS ............................................................................................................................................. 28 
1.6 
STUDY OPERATIONS ...................................................................................................................................... 28 
2 
INTRODUCTION ................................................................................................................................. 29 
2.1 
MICROBICIDES AND HUMAN IMMUNODEFICIENCY VIRUS (HIV) PREVENTION ........................................................... 29 
2.2 
DAPIVIRINE VAGINAL RING (VR) ...................................................................................................................... 30 
2.3 
NONCLINICAL STUDIES OF DAPIVIRINE ............................................................................................................... 31 
2.4 
CLINICAL STUDIES ......................................................................................................................................... 33 
2.5 
PREVALENCE OF PRIMARY NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITOR (NNRTI) RESISTANCE MUTATIONS ..... 39 
2.6 
BEHAVIORAL STUDIES .................................................................................................................................... 39 
2.7 
RATIONALE FOR STUDY DESIGN ....................................................................................................................... 40 
3 
OBJECTIVES ....................................................................................................................................... 41 
3.1 
PRIMARY OBJECTIVES .................................................................................................................................... 41 
3.2 
SECONDARY OBJECTIVES................................................................................................................................. 41 
3.3 
EXPLORATORY OBJECTIVES .............................................................................................................................. 41 
4 
STUDY DESIGN .................................................................................................................................. 42 
4.1 
IDENTIFICATION OF STUDY DESIGN ................................................................................................................... 42 
4.2 
SUMMARY OF MAJOR ENDPOINTS .................................................................................................................... 42 
4.3 
DESCRIPTION OF STUDY POPULATION ............................................................................................................... 42 
4.4 
TIME TO COMPLETE ACCRUAL ......................................................................................................................... 43 
4.5 
STUDY GROUPS ............................................................................................................................................ 43 
4.6 
EXPECTED DURATION OF PARTICIPATION ........................................................................................................... 43 
4.7 
SITES .......................................................................................................................................................... 43 
5 
STUDY POPULATION ......................................................................................................................... 43 
5.1 
SELECTION OF THE STUDY POPULATION ............................................................................................................. 43 
5.2 
INCLUSION CRITERIA ...................................................................................................................................... 44 
5.3 
EXCLUSION CRITERIA ..................................................................................................................................... 44 
5.4 
INCLUSION CRITERIA- MTN-025 DECLINER GROUP ONLY .................................................................................... 46 
5.5 
EXCLUSION CRITERIA- MTN-025 DECLINER GROUP ONLY ................................................................................... 46 
5.6 
CO-ENROLLMENT GUIDELINES ......................................................................................................................... 47 
6 
STUDY PRODUCT ............................................................................................................................... 47 
6.1 
REGIMEN .................................................................................................................................................... 47 

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August 22, 2014 
 
6.2 
ADMINISTRATION .......................................................................................................................................... 47 
6.3 
STUDY PRODUCT FORMULATION ...................................................................................................................... 47 
6.4 
SUPPLY AND ACCOUNTABILITY ......................................................................................................................... 48 
6.5 
CONCOMITANT MEDICATIONS ......................................................................................................................... 50 
6.6 
USE OF INTRAVAGINAL MEDICATIONS AND PRACTICES ......................................................................................... 50 
6.7 
CONDOMS ................................................................................................................................................... 50 
7 
STUDY PROCEDURES ......................................................................................................................... 51 
7.1 
PRE-SCREENING............................................................................................................................................ 51 
7.2 
SCREENING VISIT .......................................................................................................................................... 51 
7.3 
ENROLLMENT VISIT (DAY 0) ............................................................................................................................ 53 
7.4 
FOLLOW-UP VISITS ........................................................................................................................................ 54 
7.5 
MTN-025 DECLINER GROUP .......................................................................................................................... 58 
7.6 
FOLLOW-UP PROCEDURES FOR PARTICIPANTS WHO TEMPORARILY HOLD OR PERMANENTLY DISCONTINUE STUDY PRODUCT
 ................................................................................................................................................................. 58 
7.7 
FINAL CONTACT ............................................................................................................................................ 60 
7.8 
BEHAVIORAL EVALUATIONS ............................................................................................................................. 61 
7.9 
ADHERENCE COUNSELING ............................................................................................................................... 61 
7.10 
CLINICAL EVALUATIONS AND PROCEDURES ......................................................................................................... 61 
7.11 
LABORATORY EVALUATIONS ............................................................................................................................ 62 
7.12 
HIV INFECTION (SECONDARY ENDPOINT) DETERMINATION ................................................................................... 63 
7.13 
SPECIMEN COLLECTION AND PROCESSING .......................................................................................................... 64 
7.14 
SPECIMEN HANDLING .................................................................................................................................... 64 
7.15 
BIOHAZARD CONTAINMENT ............................................................................................................................ 65 
8 
ASSESSMENT OF SAFETY ................................................................................................................... 65 
8.1 
SAFETY MONITORING .................................................................................................................................... 65 
8.2 
CLINICAL DATA SAFETY REVIEW ....................................................................................................................... 65 
8.3 
ADVERSE EVENTS DEFINITIONS AND REPORTING REQUIREMENTS ........................................................................... 66 
8.4 
EXPEDITED ADVERSE EVENT REPORTING REQUIREMENTS ...................................................................................... 68 
8.5 
SOCIAL HARMS REPORTING ............................................................................................................................ 69 
8.6 
REGULATORY REQUIREMENTS ......................................................................................................................... 70 
9 
CLINICAL MANAGEMENT .................................................................................................................. 70 
9.1 
GRADING SYSTEM ......................................................................................................................................... 70 
9.2 
DOSE MODIFICATION INSTRUCTIONS ................................................................................................................ 70 
9.3 
GENERAL CRITERIA FOR TEMPORARY HOLD AND PERMANENT DISCONTINUATION OF STUDY PRODUCT .......................... 70 
9.4 
TEMPORARY PRODUCT HOLD/PERMANENT DISCONTINUATION IN RESPONSE TO OBSERVED ADVERSE EVENTS ................ 71 
9.5 
OTHER CLINICAL FINDINGS.............................................................................................................................. 72 
9.6 
HIV INFECTION ............................................................................................................................................. 74 
9.7 
PREGNANCY ................................................................................................................................................. 75 
9.8 
CRITERIA FOR EARLY TERMINATION OF STUDY PARTICIPATION ............................................................................... 75 
10 
STATISTICAL CONSIDERATIONS ......................................................................................................... 76 
10.1 
OVERVIEW AND SUMMARY OF DESIGN .............................................................................................................. 76 
10.2 
STUDY ENDPOINTS ........................................................................................................................................ 76 
10.3 
SAMPLE SIZE ................................................................................................................................................ 77 
10.4 
PARTICIPANT ACCRUAL, FOLLOW-UP AND RETENTION .......................................................................................... 77 
10.5 
RANDOMIZATION .......................................................................................................................................... 77 
10.6 
BLINDING .................................................................................................................................................... 77 
10.7 
DATA AND SAFETY MONITORING PROCEDURES ................................................................................................... 77 
10.8 
PRIMARY ANALYSES ....................................................................................................................................... 78 
10.9 
ANALYSIS OF SECONDARY ENDPOINTS ............................................................................................................... 80 

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August 22, 2014 
 
10.10 
MISSING DATA ............................................................................................................................................. 81 
11 
DATA HANDLING AND RECORDKEEPING ........................................................................................... 81 
11.1 
DATA MANAGEMENT RESPONSIBILITIES ............................................................................................................ 81 
11.2 
SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/DOCUMENTS ....................................................................... 81 
11.3 
QUALITY CONTROL AND QUALITY ASSURANCE .................................................................................................... 82 
12 
CLINICAL SITE MONITORING ............................................................................................................. 82 
13 
HUMAN SUBJECTS PROTECTIONS ..................................................................................................... 83 
13.1 
INSTITUTIONAL REVIEW BOARDS/ETHICS COMMITTEES ........................................................................................ 83 
13.2 
PROTOCOL REGISTRATION .............................................................................................................................. 83 
13.3 
STUDY COORDINATION .................................................................................................................................. 84 
13.4 
RISK BENEFIT STATEMENT............................................................................................................................... 84 
13.5 
INFORMED CONSENT PROCESS ........................................................................................................................ 86 
13.6 
PARTICIPANT CONFIDENTIALITY ........................................................................................................................ 87 
13.7 
SPECIAL POPULATIONS ................................................................................................................................... 88 
13.8 
COMPENSATION ........................................................................................................................................... 88 
13.9 
COMMUNICABLE DISEASE REPORTING............................................................................................................... 88 
13.10 
ACCESS TO HIV-RELATED CARE ........................................................................................................................ 88 
13.11 
STUDY DISCONTINUATION .............................................................................................................................. 89 
14 
PUBLICATION POLICY ........................................................................................................................ 89 
15 
APPENDICES ...................................................................................................................................... 90 
APPENDIX I: SCHEDULE OF STUDY VISITS AND EVALUATIONS.............................................................................. 91 
APPENDIX II:  ALGORITHM FOR HIV ANTIBODY TESTING- SCREENING/ENROLLMENT .......................................... 92 
APPENDIX III:  ALGORITHM FOR HIV ANTIBODY TESTING FOR FOLLOW-UP ......................................................... 93 
APPENDIX IV: SAMPLE INFORMED CONSENT DOCUMENT (SCREENING) .............................................................. 94 
APPENDIX V: SAMPLE INFORMED CONSENT DOCUMENT (ENROLLMENT) ......................................................... 101 
APPENDIX VI: SAMPLE INFORMED CONSENT DOCUMENT (MTN-025 DECLINER GROUP) ................................... 114 
 
Table of Figures 
 
TABLE 1: CLINICAL PHASE I/II TRIALS OF DAPIVIRINE VAGINAL RINGS ......................................................................................... 35 
TABLE 2: FREQUENCY OF K103N ........................................................................................................................................ 39 
TABLE 3: FREQUENCY OF Y181C ......................................................................................................................................... 39 
TABLE 4: STUDY REGIMEN .................................................................................................................................................. 43 
TABLE 5:  RETRIEVAL OF STUDY PRODUCT ............................................................................................................................. 49 
TABLE 6: SCREENING VISIT ................................................................................................................................................. 52 
TABLE 7: ENROLLMENT VISIT .............................................................................................................................................. 53 
TABLE 8: FOLLOW-UP VISITS: MONTHS 1, 2, 4, 5, 7, 8, 10, 11................................................................................................ 54 
TABLE 9: FOLLOW-UP VISITS: MONTHS 3, 6, 9 ...................................................................................................................... 55 
TABLE 10: PUEV: MONTH 12 ............................................................................................................................................ 56 
TABLE 11: STUDY EXIT/TERMINATION VISIT .......................................................................................................................... 57 
TABLE 12: SCREENING AND ENROLLMENT PROCEDURES ........................................................................................................... 58 
 
FIGURE 1: STUDY SCHEDULE ............................................................................................................................................... 24 
FIGURE 2: COMPARISON OF RATES OF ADHERENCE (LOW GROUP VS. HIGH GROUP)..................................................................... 80 

MTN-025, Version 1.0 
5 
August 22, 2014 
 
MTN-025 
 
A Phase 3B Open-Label Follow-on Trial to Assess the Continued Safety of and 
Adherence to a Vaginal Ring Containing Dapivirine in Women  
 
LIST OF ABBREVIATIONS AND ACRONYMS 
 
AE   
adverse event  
AIDS  
acquired immunodeficiency syndrome  
ALT 
alanine aminotransferase 
ART 
antiretroviral therapy 
ARV 
Antiretroviral 
AST  
aspartate aminotransferase 
ASPIRE 
AUC  
A Study to Prevent Infection with a Ring for Extended Use 
area under plasma concentration-time curve 
AVAC 
Global Advocacy for HIV Prevention 
BRWG 
Behavioral Research Working Group 
BSWG 
Biomedical Science Working Group 
CAB 
community advisory board 
CAPRISA 
Centre for the AIDS Programme of Research in South Africa 
CBC 
complete blood count 
CDC  
U.S. Centers for Disease Control and Prevention 
CFR 
Code of Federal Regulations 
Cmax 
maximum concentrations 
Cmin 
minimum concentrations 
CMRB 
Clinical Microbicide Research Branch 
CRF  
Case Report Form 
CROI 
Conference on Retroviruses and Opportunistic Infections 
CT 
Chlamydia trachomatis 
CTA 
clinical trial agreement 
CTU 
Clinical trials unit 
CWG 
Community Working Group 
DAERS 
DAIDS Adverse Events Reporting System 
DAIDS  
Division of Acquired Immunodeficiency Syndrome 
DAPY 
di-aminopyrimidine 
DLV 
Delavirdine 
DNA 
deoxyribonucleic acid 
EAE 
expedited adverse event 
EC 
Ethics Committee 
EC50 
50% effective concentration 
EFV 
efavirenz 
FDA  
Food & Drug Administration (U.S.) 
FHCRC 
Fred Hutchinson Cancer Research Center 
FTP 
File Transfer Protocol 
g 
Grams 
GC 
Neisseria gonorrhoeae 

MTN-025, Version 1.0 
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August 22, 2014 
 
GCP 
Good Clinical Practice 
GMP 
good manufacturing practices 
hCG 
human chorionic gonadotropin 
HOPE 
hu-PBL 
HIV Open-label Prevention Extension 
human peripheral blood lymphocytes 
hu-SCID 
human severe combined immunodeficient 
HIV-1  
human immunodeficiency virus-1 
HPTN 
HIV Prevention Trials Network 
IATA 
International Association of Air Transport 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
IDI 
in-depth interview 
IND 
Investigational New Drug 
IoR 
IPM  
Investigator of Record 
International Partnership for Microbicides 
IRB  
Institutional Review Board 
ITT 
intent-to-treat 
IUCD 
intrauterine contraceptive device 
JHU 
Johns Hopkins University 
JKUAT 
Jomo Kenyatta University of Agriculture and Technology 
KOH 
potassium hydroxide 
LC 
LDMS 
Laboratory Center 
Laboratory Data Management System 
LLOQ 
lower limit of quantification 
LOC 
Leadership and Coordinating Center 
μg 
microgram 
μM 
micromolar (10−3 mol/m3) 
mg 
Milligram 
mL 
Milliliter 
MO 
Medical Officer 
MOP 
Manual of Operational Procedures 
MTN 
Microbicide Trials Network 
MU 
Makerere University 
MU-JHU 
Makerere University - Johns Hopkins University 
NAAT 
nucleic acid amplification test 
ng 
nanogram per milliliter  
NIAID 
National Institute of Allergy and Infectious Diseases 
NIH 
National Institutes of Health 
NIMH 
National Institute of Mental Health 
nM 
nanomolar (10−6 mol/m3) 
NNRTI  
non-nucleoside reverse transcriptase inhibitor 
NOAEL 
no-observed-adverse-effect-level 
NRTI  
Nucleoside reverse transcriptase inhibitor 
NVP 
Nevirapine 
OHRP 
Office for Human Research Protections 
PCR  
polymerase chain reaction 

MTN-025, Version 1.0 
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August 22, 2014 
 
 
 
PEP 
post-exposure prophylaxis 
pg/mL 
picogram/milliliter 
PID  
pelvic inflammatory disease 
PK  
Pharmacokinetic 
PPD 
Pharmaceutical Product Development, Inc. 
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 
QD 
RNA 
RPR  
quaque die (once daily) 
ribonucleic acid 
rapid plasma reagin 
RSC 
Regulatory Support Center 
RT 
reverse transcriptase 
RTI 
reproductive tract infection 
SAE  
serious adverse event 
SCHARP 
Statistical Center for HIV/AIDS Research & Prevention 
SDMC 
Statistical Data Management Center 
SMC 
Study Monitoring Committee 
SSP 
study specific procedure(s) 
STI  
sexually transmitted infection  
TEAE  
treatment emergent adverse event  
UCSF 
University of California- San Francisco 
UNAIDS 
UNC 
UPMC 
Joint United Nations Programme on HIV/AIDS 
University of North Carolina 
University of Pittsburgh Medical Center 
USA 
United States of America 
UTI 
urinary tract infection 
VR 
WHO  
vaginal ring 
World Health Organization 
wt 
wild-type 

MTN-025, Version 1.0 
8 
August 22, 2014 
 
MTN-025 
 
A Phase 3B Open-Label Follow-on Trial to Assess the Continued Safety of and 
Adherence to a Vaginal Ring Containing Dapivirine in Women  
 
PROTOCOL TEAM ROSTER 
Protocol Chair 
 
Jared Baeten, MD, PhD 
Protocol Chair 
International Clinical Research Center 
Department of Global Health, University of Washington 
Box 359927 
325 Ninth Avenue 
Seattle, WA  98104 
Phone: 206-520-3808 
Fax: 206-520-3831 
Email: jbaeten@uw.edu 
 
Protocol Co-chairs 
 
Nyaradzo M. Mgodi  MBChB,  MMed  
Protocol Co-chair 
UZ-UCSF 
15 Phillips Avenue, Belgravia 
Harare, Zimbabwe 
Phone: +263 4 704 920 
Fax: + 263 4 704 897 
Email: nmmgodi@uz-ucsf.co.zw 
 
Thesla Palanee-Phillips, PhD 
Protocol Co-chair 
Wits Reproductive Health and HIV Institute (Wits RHI)  
Research Centre  
 
7 Esselen Street, Hillbrow 
Johannesburg, 2038 South Africa 
Phone: 27-11-358-5471 
Fax: 27-86-554-1093 
Email: tpalanee@whri.ac.za

MTN-025, Version 1.0 
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August 22, 2014 
 
Site Investigators 
 
 
Blantyre CRS 
 
Taha E. Taha, PhD 
CTU PI 
Johns Hopkins University  
Bloomberg School of Public Health,  
615 N. Wolfe Street 
Baltimore, MD 21205 
Phone: 410-614-5255 
Fax: 410-502-0688 
Email: ttaha@jhsph.edu 
 
Bonus Makanani, MBBS, FCOG(SA)  
Site Investigator of Record 
Johns Hopkins University Research Project  
Chipatala Avenue 
P.O. Box 1131  
Blantyre, Malawi  
Phone: 265-1875-129  
Fax: 265-1870-132  
Email: bmakanani@jhu.medcol.mw 
 
Newton I. Kumwenda PhD  
Site- Investigator, CRS Leader 
Johns Hopkins University Research Project  
Chipatala Avenue 
P.O. Box 1131  
Blantyre, Malawi  
Phone: 265-1875-129  
Fax: 265-1870-132  
Email: nikumwenda@jhu.medcol.mw 
 
 
 

MTN-025, Version 1.0 
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August 22, 2014 
 
eThekwini CRS 
 
Quarraisha Abdool Karim, PhD 
CTU PI 
CAPRISA, 2nd Floor DDMRI,  
Nelson R. Mandela School of Medicine,  
719 Umbilo Road  
Durban, KwaZulu-Natal, 4001  
South Africa 
Phone: 27-31-2604208  
Fax: 27-31-2604566 
Email: abdoolq2@ukzn.ac.za  
 
Gonasagrie Nair, MBChB 
Site Investigator of Record 
eThekwini CRS 
3 Richards Road 
Durban 4001 South Africa 
Phone: 27-31-260-1972 
Fax: 27-31-307-7119 
Email: nairg1@ukzn.ac.za 
 
 
Emavundleni CRS 
 
Linda-Gail Bekker MB ChB, FCP, PhD 
CTU PI 
Desmond Tutu HIV Centre, IIDMM,  
Faculty of Health Sciences, UCT, 
Anzio Road, Observatory, 
Western Cape Province, 7705, 
Cape Town, South Africa 
Phone: 27-21-6506959 
Fax: 27-21-6330182 
Email: linda-gail.bekker@hiv-research.org.za  
 
Danielle Crida, MBChB 
Site Investigator of Record 
Emavundleni Research Centre 
14 Sonwabile Drive 
Crossroads7750 
Cape Town South Africa 
Phone: 27-21-3860053 
Fax: 27-21-3860054 
Email: danielle.crida@hiv-research.org.za 
 
 
 

MTN-025, Version 1.0 
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August 22, 2014 
 
Makerere University - Johns Hopkins University (MU-JHU) Research Collaboration CRS 
 
Mary Glenn Fowler 
CTU Co-PI 
Johns Hopkins University School of Medicine,  
600 N. Wolfe Street 
Baltimore, MD 21287 
Phone: 410 502 0683 
Fax: 410 502 0688 
Email: mgfowler@mujhu.org 
 
Brooks Jackson, MD 
CTU Co-PI 
Medical School Dean's Office 
C607 Mayo Memorial Bldg 
420 Delaware Street SE 
Minneapolis, MN 55455 
Phone 612-626-4949  
Fax: 612-626-4911 
 
Email: jacksonb@umn.edu  
 
Clemensia Nakabiito, MBChB, MMed  
Site Principal Investigator MTN MU-JHU Research Collaboration 
P.O. Box 23491  
Kampala, Uganda  
Phone: 256-41-541044/256-772-405332  
Fax: 256-41-541044/256-41-532091  
Email: cnakabiito@mujhu.org 
 
Flavia Matovu Kiweewa, MBChB, Msc. Epidemiology  
Site Investigator of Record 
MU-JHU Research Collaboration  
P.O. Box 23491, Kampala, Uganda  
Phone: 256-414-541044/256-702-544759  
Fax: 256-414-541044/256-414-532091  
Email: fmatovu@mujhu.org 
 
 
 
 

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August 22, 2014 
 
Malawi CRS 
 
Joseph Eron, MD 
CTU Co-PI 
Division of Infectious Diseases  
CB# 7030, Bioinformatics Building  
130 Mason Farm Road, 2nd Floor  
Chapel Hill, North Carolina 27599-7030 
Phone: 919-966-2536  
Fax: 919-966-6714 
Email: joseph_eron@med.unc.edu 
 
Mina Hosseinipour, MD, MPH 
CTU Co-PI 
UNC Project, Tidziwe Centre 
Private Bag A-104 
Lilongwe, Malawi  
Phone: 265-1-755-056 
Fax: 265-1-755-954 
Email: mina_hosseinipour@med.unc.edu 
 
Francis Martinson, MBChB, PhD 
Site Investigator of Record 
UNC Project, Tidziwe Centre, Kamuzu Central Hospital 
Private Bag A-104 
Lilongwe, Malawi 
Phone: 265-1-755-056 
Fax: 265-1-755-954 
Email: fmartinson@unclilongwe.org 
 
Jeffrey SA Stringer, MD 
CTU Co-PI 
130 Mason Farm Road, Suite 2131, CB 7577 
Bioinformatics Bldg., Second Floor 
University of North Carolina at Chapel Hill 
Chapel Hill, NC 27599-7577 
Phone: 919-962-0756 
Fax: 919-966-6714 
Email: Jeffrey_stringer@med.unc.edu 
 
 
 

MTN-025, Version 1.0 
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August 22, 2014 
 
South African Medical Research Council Clinical Trials Unit (CTU) 
 
Gita Ramjee, PhD 
CTU Principal Investigator (PI) 
Medical Research Council of South Africa 
HIV Prevention Research Unit 
123 Jan Hofmeyr Road 
Westville 3630 
Durban, South Africa 
Phone: +27 31 242 3600 
Fax: +27 31 242 3800 
Email: gita.ramjee@mrc.ac.za 
 
Faeeza Arbee, BPharm 
Site Investigator of Record 
Medical Research Council of South Africa 
HIV Prevention Research Unit 
123 Jan Hofmeyr Road 
Westville 3630 
Durban, South Africa 
Phone: +27 31 242 3600 
Fax: +27 31 242 3800 
Email: faeeza.arbee@mrc.ac.za 
 
 
The University of Zimbabwe-University of California San Francisco Collaborative 
Research Program (UZ-UCSF) Clinical Trials Unit 
 
Z. Mike Chirenje MD, FRCOG 
CTU PI 
UZ-UCSF 
15 Phillips Avenue, Belgravia 
Harare, Zimbabwe 
Phone: +263 4 704 966 
Fax: + 263 4 704 897 
Email: chirenje@uz-ucsf.co.zw 
 
Nyaradzo M. Mgodi  MBChB,  MMed  
Site Investigator of Record 
UZ-UCSF 
15 Phillips Avenue, Belgravia 
Harare, Zimbabwe 
Phone: +263 4 704 920 
Fax: + 263 4 704 897 
Email: nmmgodi@uz-ucsf.co.zw 
 
 
 

MTN-025, Version 1.0 
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August 22, 2014 
 
Felix G. Muhlanga  MBChB,  MMed  
Site Investigator of Record 
UZ-UCSF 
15 Phillips Avenue, Belgravia 
Harare, Zimbabwe 
Phone: +263 4 704 920 
Fax: + 263 4 704 897 
Email: fmhlanga@uz-ucsf.co.zw 
 
 
Wits Reproductive Health and HIV Institute (Wits RHI) CRS 
 
Ian Sanne, MD, FCP 
CTU Co- PI 
Helen Joseph Hospital, Perth Road, Westdene, Themba Lethu Clinic  
Johannesburg, 2092 South Africa 
Phone: 27-11-276-8800 
Fax: 27-11 482 2130 
Email: isanne@witshealth.co.za 
 
Helen Vera Rees, OBE, MBBChir, MA, DRCOG, DCH 
CTU Co-PI 
Wits Reproductive Health and HIV Institute (Wits RHI)  
22 Esselen Street, Hillbrow  
Johannesburg, 2001  
Phone: 27-11-358-5300  
Email: hrees@wrhi.ac.za 
 
Thesla Palanee-Phillips, PhD  
Site Principal Investigator and Investigator of Record 
Wits Reproductive Health and HIV Institute (Wits RHI)  
Research Centre  
7 Esselen Street, Hillbrow  
Johannesburg, 2038 South Africa  
Phone: 27-11-358-5471  
Fax: 27-86-554-1093  
Email: tpalanee@whri.ac.za 
 
 
 

MTN-025, Version 1.0 
15 
August 22, 2014 
 
 
US National Institutes of Health (NIH) 
 
Roberta Black, PhD 
Chief, Clinical Microbicide Research Branch 
National Institute of Allergy and Infectious Diseases (NIAID), Division of AIDS (DAIDS) 
5601 Fishers Lane, Room 8B62, MSC 9831 
Rockville, MD 20892-9831 
Phone: 301-496-8199 
Email: rblack@niaid.nih.gov 
 
Naana Cleland, MHCA 
Health Specialist, Clinical Microbicide Research Branch (CMRB) 
Prevention Sciences Program (PSP) DAIDS, NIAID  
National Institutes of Health (NIH) - U.S. Department of Health and Human Services (HHS) 
5601 Fishers Lane, Room 8B27 
Rockville, MD 20892-9830 
Phone: 240 292 4779 
Email: clelandn@niaid.nih.gov 
 
Cynthia Grossman, PhD 
Chief, HIV Care Engagement and Secondary Prevention Program,  
National Institute of Mental Health (NIMH) 
5601 Fishers Lane Room 9G19, MSC 9831 
Bethesda, MD 20892 
Phone: 240-627-3868 
Email: grossmanc@mail.nih.gov 
 
Dianne M. Rausch, PhD 
Director 
DAIDS Research, NIMH 
5601 Fishers Lane Room 8D20, MSC 9831 
Bethesda, MD 20892 
Phone: 240-627-3874 
Fax: 240-627-3467 
Email: drausch@mail.nih.gov 
 
Lydia E. Soto-Torres, MD, MPH 
DAIDS Medical Officer 
NIAID, DAIDS 
5601 Fishers Lane  
Rockville, MD 20892-9831 
Phone: 301-594-9705 
Cell: 301-213-1154 
Email: lsoto-torres@niaid.nih.gov 

MTN-025, Version 1.0 
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August 22, 2014 
 
MTN Leadership and Operations Center (LOC)- Pitt 
 
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 
 
Patrick Ndase, MBChB, MPH 
Regional Physician 
Microbicide Trials Network 
Center of Excellence for HIV prevention, IDI 
Next to Kasangati Health Center 
Kampala, Uganda 
Phone: 256-753-080-489 
Fax: 256-41-532091 
Email: pndase@u.washington.edu 
 
Beth Galaska Burzuk, MID 
Protocol Development Manager 
Microbicide Trials Network 
204 Craft Avenue 
Pittsburgh, PA 15213 USA 
Phone: 412-641-5579 
Fax: 412-641-6170 
Email: galaskaburzukb@upmc.edu 
Ian McGowan, MBChB, MD, DPhil, FRCP  
Co-Principal Investigator 
Microbicide Trials Network 
204 Craft Avenue 
Pittsburgh, PA 15213 USA 
Phone: 412-641-8999 
Fax: 412-641-6170 
Email: imcgowan@pitt.edu 
 
Sharon Hillier, PhD 
Co-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 
 
Sharon A. Riddler, MD, MPH 
Protocol Physician 
UPMC, Keystone Building, Suite 510 
3520 Fifth Avenue 
Pittsburgh, PA 15213 USA 
Phone:  412-383-1741or 412-383-1675 
Fax: 412-383-2900 
Email: riddler@dom.pitt.edu 
 
Ken Ho, MD 
Safety Physician 
UPMC, Keystone Building, Suite 533 
3520 Fifth Avenue 
Pittsburgh, PA 15213 USA 
Phone: 412-383-7178 
Fax: 412-383-2900 
Email: hok2@upmc.edu 
Devika Singh, MD, MPH 
Protocol Safety Physician 
Box 359927, Dpt. of Global Health 
ICRC, 325 Ninth Ave. 
Seattle, WA  98104 USA 
Phone: 206-744-8311 
Fax: 206-520-3831 
Email: dsingh@u.washington.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 
 
 

MTN-025, Version 1.0 
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August 22, 2014 
 
MTN Laboratory Center (LC) 
 
Wayne Hall, MT(ASCP) 
Clinical Laboratory Representative 
Microbicide Trials Network 
204 Craft Ave. Room A534 
Pittsburgh, PA 15213 USA 
Phone: 412-641-6956 
Fax:412-641-6170 
Email:hallwb@mwri.magee.edu 
 
Craig Hendrix, MD 
Pharmacology LC Principal Investigator 
Johns Hopkins University 
600 North Wolfe Street, Harvey 502 
Baltimore, MD 21287 USA 
Phone: 410-955-9707 
Fax: 410-955-9708 
Email: cwhendrix@jhmi.edu 
 
Edward Livant, BSMT (ASCP), MPH 
MTN LC Research Manager 
Microbicide Trials Network 
204 Craft Avenue 
Pittsburgh, PA 15213 USA 
Phone: 412-641-3772 
Fax: 412-641-5290 
Email: livantew@upmc.edu 
 
John Mellors, MD 
Virology LC Principal Investigator 
University of Pittsburgh Physicians 
3550 Terrace Street 
Scaife Hall, Suite 818 
Pittsburgh, PA 15261 USA 
Phone: 412-624-8512 
Fax: 412-383-7982 
Email: mellors@dom.pitt.edu 
 
Urvi Parikh, PhD 
Virology LC Associate Director 
University of Pittsburgh 
3550 Terrace Street 
Scaife Hall, Suite 817-A 
Pittsburgh, PA 15261 USA 
Phone: 412-648-3103 
Fax: 412-648-8521 
Email: ump3@pitt.edu 
 

MTN-025, Version 1.0 
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August 22, 2014 
 
MTN LOC – FHI 360 
 
Ashley Mayo, MPH  
Clinical Research Manager  
359 Blackwell St., Suite 200 
PO Box 21059 
Durham, NC  27701 USA  
Phone: 919-544-7040 Ext. 11164  
Fax: 919-544-0904 
Email: amayo@fhi360.org 
 
Rachel Scheckter, MPH, IBCLC  
Clinical Research Manager 
359 Blackwell St., Suite 200 
PO Box 21059 
Durham, NC  27701 USA  
Phone: 919-544-7040 Ext. 11392  
Fax: 919-544-0904 
Email: rscheckter@fhi360.org    
 
Katie Schwartz, MPH  
Sr. Clinical Research Manager  
359 Blackwell St., Suite 200 
PO Box 21059 
Durham, NC  27701 USA  
Phone: 919-544-7040 Ext. 11425  
Fax: 919-544-0904 
Email: kschwartz@fhi360.org 
 
Rhonda White, RH Ed 
Community Program Manager 
359 Blackwell St., Suite 200 
PO Box 21059 
Durham, NC  27701 USA  
Phone: 919-544-7040, Ext. 11515 
Fax: 919-544-0207 
Email: rwhite@fhi360.org 

MTN-025, Version 1.0 
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August 22, 2014 
 
MTN Statistical Data Management Center (SDMC) 
 
Jennifer M. Berthiaume, MPH, MSW 
Project Manager  
Fred Hutchinson Cancer Research Center 
(FHCRC)/Statistical Center for HIV/AIDS Research & 
Prevention (SCHARP) 
1100 Fairview Ave. North, LE-400 
P.O. Box 19024 
Seattle, WA  98109-1024 
Phone: 206-667-1230  
Fax: 206-667-4812 
Email: jberthia@scharp.org 
 
 
Elizabeth Brown, ScD 
SDMC Principal Investigator 
FHCRC – SCHARP 
1100 Fairview Avenue North, M2-C200 
PO Box 19024 
Seattle, WA 98109-1024 USA 
Phone: 206-667-1731 
Fax: 206-667-4812 
Email: erbrown@fhcrc.org 
 
 
Marla Husnik, MS 
SDMC Statistical Research Associate 
FHCRC – SCHARP  
1100 Fairview Avenue North, M2-C200 
PO Box 19024 
Seattle, WA 98109-1024 USA 
Phone: 206-667-5633 
Fax: 206-667-4812 
Email: marla@scharp.org 
 
Karen Patterson, MPH 
MTN Program 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 
 
 
 
 
 
 
 
 

MTN-025, Version 1.0 
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August 22, 2014 
 
MTN Behavioral Research Working Group (BRWG) 
 
Ariane van der Straten, PhD, MPH  
BRWG Representative 
RTI International  
351 California Street, Suite 500 
San Francisco, CA 94104 USA  
Phone: 415-848-1324  
Fax: 415-848-1330  
Email: ariane@rti.org 
 
Kenneth Ngure, PhD 
BRWG Representative 
JKUAT-College of Health Sciences 
P.O. Box 19704-00202 
Nairobi, Kenya 
Phone: 254-722-362219  
Email: kngure@uw.edu 

MTN-025, Version 1.0 
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August 22, 2014 
 
MTN Community Working Group (CWG) Representatives 
 
Fatima Glyn Zulu, MSc 
CWG Representative 
Johns Hopkins Research Project 
College of Med. JHU CRS  
PO Box 1131, Chipatala Avenue 
Blantyre, Malawi 
Phone: 265-1-875-129 
Mobile: 265-999-955-028 
Fax: 265-1-870-132 
Email: fatimazulu@jhu.medcol.mw  
 
Manju Chatani-Gada 
CWG Representative 
AVAC: Global Advocacy for HIV Prevention 
423 West 127th Street, 4th Floor  
New York, NY 10027 
Phone: 212-796-6423  
Fax: 646-365-3452 
Email: manju@avac.org 
 
 

MTN-025, Version 1.0 
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August 22, 2014 
 
MTN-025 
 
 
A Phase 3B Open-Label Follow-on Trial to Assess the Continued Safety of and 
Adherence to a Vaginal Ring Containing Dapivirine in Women  
 
INVESTIGATOR SIGNATURE FORM 
 
Version 1.0 
 
August 22, 2014 
 
A Study of the Microbicide Trials Network 
 
Funded by: 
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 
 
IND Holder: 
International Partnership for Microbicides (IPM) 
 
I, the Investigator of Record, agree to conduct this study in full accordance with the 
provisions of this protocol.  I will comply with all requirements regarding the obligations 
of investigators as outlined in the Statement of Investigator (Form FDA 1572), which I 
have also signed.  I agree to maintain all study documentation for at least two years 
following the date of marketing approval for the study product for the indication in which 
it was 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 Food and Drug Administration is notified.  Publication of the results of this study will 
be governed by MTN policies.  Any presentation, abstract, or manuscript will be 
submitted to the MTN Manuscript Review Committee, DAIDS, IPM and other entities for 
review prior to submission, as required by the MTN Publication Policy. 
 
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 
 
____________________________ 
______________________________ 
Signature of Investigator of Record  
Date 
 
 

MTN-025, Version 1.0 
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August 22, 2014 
 
MTN-025 
 
A Phase 3B Open-Label Follow-on Trial to Assess the Continued Safety of and 
Adherence to a Vaginal Ring Containing Dapivirine in Women  
 
PROTOCOL SUMMARY 
 
Short Title: 
HIV Open-label Prevention Extension (HOPE) 
 
IND Sponsor: 
International Partnership for Microbicides 
 
Funders:  
Division of AIDS, NIAID, NIMH, NICHD, US NIH 
 
Protocol Chair: 
Jared Baeten, MD, PhD 
 
Protocol Co-chairs: 
Nyaradzo M. Mgodi, MBChB, MMed  
 
 
Thesla Palanee-Phillips, PhD 
 
Sample Size: 
Eligible former MTN-020 participants 
 
Study Population: 
Former MTN-020 participants who are HIV-uninfected and not 
pregnant 
 
 
 
Decliner Group: Former MTN-020 participants who decline 
participation in the main MTN-025 study  
 
Study Sites: 
Approved former MTN-020 sites 
 
Study Design: 
Phase 3B, open-label, multi-site, randomized trial   
 
 
 
Following demonstration of safety and efficacy of the dapivirine 
vaginal ring in MTN-020, eligible MTN-020 participants will be 
offered enrollment into MTN-025, a trial designed to obtain 
additional safety and adherence data in women randomized to 
monthly vs. quarterly follow-up.  
 
Study Duration: 
Approximately 13 months of follow-up per participant with a 
projected accrual period of approximately 6 months at each 
site.   
 
 
 
Note:  In an effort to provide women with the maximum ability to enter 
the MTN-025 trial, following the formal ~6-month study accrual period 
participants will continue to be enrolled throughout the duration of the 
trial, provided that at least 4 months of time on study is supported by 
the timeline.  An adjusted (shortened) follow-up period will be 
employed for women who enroll after the formal accrual period.  
 

MTN-025, Version 1.0 
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August 22, 2014 
 
Study Product: 
Dapivirine VR 
 
Study Regimen: 
Participants will receive a silicone elastomer vaginal matrix ring 
containing 25 mg of dapivirine to be replaced each month for a 
total period of 12 months of use. 
 
 
 
MTN-025 participants are to be randomized to one of two types 
of follow-up: 
 Monthly  
 Quarterly  
 
Figure 1: Study Schedule 
SCREENING
ENROLLMENT
RANDOMIZATION
Month 
1
Month 
2
Month 
3
Month 
4
Month 
5
Month 
6
Month 
7
Month 
8
Month 
9
Month 
10
Month 
11
Month 
12
PUEV
STUDY EXIT/
TERMINATION
MONTHLY FOLLOW-UP
QUARTERLY FOLLOW-UP
 
 
Primary Objectives: 
 
1. Safety 
- 
To characterize the safety profile associated with the open label use of the 
dapivirine vaginal matrix ring (25 mg) in women, and to assess safety when 
randomized to a monthly vs. quarterly follow-up schedule 
 
2. Study Product Adherence   
- 
To characterize adherence the open label use of the dapivirine vaginal matrix 
ring (25 mg) in women and to compare adherence when randomized to a 
monthly vs. quarterly follow-up schedule 
 
Primary Endpoints: 
 
1. Safety 
- 
Grade 2 adverse events (AEs) judged to be related to the dapivirine vaginal 
ring 
- 
Grade 3 and higher AEs 
- 
All serious AEs 
 
-

MTN-025, Version 1.0 
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August 22, 2014 
 
2. Study Product Adherence 
- 
Residual levels of dapivirine in returned vaginal rings 
 
- 
Blood dapivirine levels  
 
Secondary Objectives: 
 
1. Incidence 
- 
To assess incidence of HIV-1 infection 
 
2. Drug Resistance 
- 
To assess the frequency of HIV-1 drug resistance in women who acquire HIV-
1 infection  
 
Secondary Endpoints: 
 
1. Incidence  
- 
HIV-1 infection as measured by the protocol algorithm 
 
2. Drug Resistance 
- 
HIV-1 drug resistance mutations among participants who acquire HIV-1, as 
measured by standard genotype analysis and more sensitive methods to 
detect low frequency drug-resistant variants 
 
Exploratory Objectives:  
 
1. To explore participant understanding of efficacy  
 
2. To explore ring acceptability in the context of known efficacy 
 
3. To assess the feasibility of a one-month vs. three-month follow-up schedule  
 
4. To describe the genital microenvironment in women exposed to the dapivirine 
vaginal ring 
 
5. To characterize the MTN-020 participants who choose not to enroll into MTN-025 
 
Exploratory Endpoints: 
 
1. Understanding of efficacy  
- 
Self-reported understanding of partial efficacy  
 
2. Understanding of ring acceptability in the context of known efficacy 
- 
Self-reported product acceptability and attitudes towards combination 
prevention  
 
 

MTN-025, Version 1.0 
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August 22, 2014 
 
3. Feasibility of one month vs. three month follow-up 
- 
Participant report of product storage issues and feasibility regarding the 
follow-up schedule 
- 
Visit retention by arms 
- 
Proportion of returned rings (used and unused) by arms 
 
4. Genital microenvironment 
- 
In genital swab samples, candidate biomarkers of safety, adherence and 
efficacy, HIV exposure and antiretroviral resistance, and genital microflora 
 
5. Characterization of MTN-020 participants who do not enroll in MTN-025 
- 
Participant report of the factors that led to her decision to decline enrollment 
into MTN-025 
 

MTN-025, Version 1.0 
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August 22, 2014 
 
1 
KEY ROLES 
 
1.1 Protocol Identification 
 
Protocol Title:   
A Phase 3B Open-Label Follow-on Trial to Assess the 
Continued Safety of and Adherence to a Vaginal Ring 
Containing Dapivirine in Women 
 
Protocol Number: 
 
MTN-025 
 
Short Title: 
HIV Open-label Prevention Extension (HOPE) 
 
Date:  
 
August 22, 2014 
 
1.2 Sponsor and Monitor Identification 
 
Funding Agencies:  
US Division of AIDS (DAIDS)/National Institute of Allergy 
and Infectious Diseases (NIAID) 
National Institutes of Health (NIH) 
5601 Fishers Lane 
Bethesda, MD 20892 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)  
6100 Executive Boulevard 
Bethesda, MD 20892 USA 
 
IND Sponsor:  
International Partnership for Microbicides (IPM) 
 
 
8401 Colesville Road, Suite 200 
Silver Spring, MD 20910 USA 
 
 
Monitor: 
Pharmaceutical Product Development (PPD), Inc.  
929 North Front Street 
Wilmington, NC  28401-3331 USA 
 
1.3 Medical Officer 
 
Medical Officer: 
Lydia E. Soto-Torres, MD, MPH 
 
 
5601 Fishers Lane  
 
 
Rockville, MD 20892-9831 
 

MTN-025, Version 1.0 
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August 22, 2014 
 
1.4 Clinical Laboratories 
 
Laboratory Center: 
MTN Laboratory Center (LC) 
 
 
 
204 Craft Avenue 
 
 
 
Pittsburgh, PA 15213 USA 
 
Pharmacology: 
MTN Pharmacology LC 
 
 
600 N. Wolfe Street, Osler 527 
 
 
Johns Hopkins University 
 
 
Baltimore, MD 21287 USA 
 
1.5 Data Centers 
 
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: 
RTI International 
 
 
 
351 California Street, Suite 500 
San Francisco, CA 94104 USA 
 
1.6 Study Operations 
 
Study Operations:  
MTN LOC - FHI 360 
 
 
 
359 Blackwell Street, Suite 200 
 
 
 
PO Box 21059 
 
 
 
Durham, NC 27701 USA 
 
 
 
 

MTN-025, Version 1.0 
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August 22, 2014 
 
2 
INTRODUCTION 
 
2.1 Microbicides and Human Immunodeficiency Virus (HIV) Prevention 
 
In 2012, 2.3 million people became newly infected with HIV and 1.6 million lost their 
lives to acquired immunodeficiency syndrome (AIDS).  Every 60 seconds, a young 
woman is infected with HIV.1  According to the Joint United Nations Programme on 
Human Immunodeficiency Virus-1(HIV)/AIDS (UNAIDS) Global Report, the estimated 
number of individuals living with HIV is 35.3 million globally.  Given the high rates of HIV 
infection among women, female controlled prevention options remain a global priority.  
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.  The 
ongoing development of safe and effective HIV prevention technologies that can be 
made easily accessible to developing countries remains a public health priority. 
 
Unprotected heterosexual intercourse is currently the leading mode of HIV acquisition 
among women.  Correct and consistent use of latex condoms is one proven method of 
preventing HIV acquisition; however, condoms are widely regarded as inadequate 
prevention options for women, because many women are unable to negotiate condom 
use with their partners.  The most widely available HIV prevention methods require the 
consent of the male partner.  Thus, developing HIV prevention options that women can 
use 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, 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 most effective, it is essential that it is used correctly and 
consistently, and is 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.  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 may have benefits over dosage forms that need to be used more 
frequently.  
 
Multiple clinical trials have evaluated the safety of dapivirine in VRs, gels and in an oral 
formulation.  These clinical trials support the favorable safety profile and tolerability of 
dapivirine in general and specifically in vaginal delivery formulations.  Initiation of the 
MTN-025 study of the dapivirine VR will be contingent upon demonstration of the safety 
and efficacy of the product in the ongoing MTN-020 (ASPIRE) study.  The specific level 

MTN-025, Version 1.0 
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August 22, 2014 
 
of effectiveness required to trigger activation of the MTN-025 study will be decided upon 
following discussions with key stakeholders including regulatory authorities, community 
representatives, and sponsoring agencies.  The MTN-025 protocol will be updated with 
MTN-020 safety and efficacy data, once available. 
 
2.2 Dapivirine Vaginal Ring (VR) 
 
2.2.1 Description 
 
Dapivirine, a non-nucleoside reverse-transcriptase inhibitor (NNRTI), is a substituted di-
amino-pyrimidine (DAPY) derivative with potent antiviral activity against HIV-1.  
Dapivirine 
is 
chemically 
described 
as 
4-[[4-[(2,4,6-trimethylphenyl)amino]-2-
pyrimidinyl]amino]benzonitrile.2The dapivirine matrix VR is a flexible ring containing 25 
mg of drug substance dispersed in a platinum-catalyzed cured silicone matrix.  When 
delivered via VR, dapivirine has demonstrated favorable safety and pharmacokinetic 
profiles as described below.   
 
Dapivirine was originally developed by Janssen Research and Development (formerly 
Tibotec Pharmaceuticals Ltd.), a subsidiary of Johnson & Johnson, as an oral ARV 
compound for treatment of HIV/AIDS and was tested in Phase 1 and 2 clinical trials in 
more than 200 participants.3 However, dapivirine is also a promising topical microbicide 
candidate due to its proven in vitro and in vivo efficacy and favorable safety profile as 
well as its physical and chemical properties.  Dapivirine has potent activity against wild-
type HIV-1 strains and strains harboring different resistance-inducing mutations.  
Dapivirine’s ARV profile is superior to that of several other NNRTI drugs, including 
nevirapine (NVP), delavirdine (DLV), and efavirenz (EFV).  Like other NNRTIs, in vitro 
tests have also shown that dapivirine is not active against HIV-2 and has little or no 
activity against common sexually transmitted infections (STI), therefore, it is not 
intended for use against HIV-2 or other STIs.  Dapivirine does not have any 
contraceptive properties.4 Detailed information on dapivirine is available in the 
Dapivirine VR Investigator’s Brochure (IB).5 
 
The International Partnership for Microbicides (IPM) has investigated a wide range of 
dosage forms for the development of topical microbicide products, including vaginal 
gels, rings, films, tablets and soft gel capsules.  The vaginal gel was the initial dosage 
form chosen for a dapivirine-based microbicide because the majority of previous 
microbicides to have entered clinical trials were also vaginal gels and therefore a wealth 
of information was available on that dosage form.  However, the dapivirine silicone 
elastomer VR has now been prioritized over all other dosage forms for the following 
reasons:  
 
 Clinical trials have demonstrated sustained delivery of high levels of dapivirine 
throughout the cervicovaginal vault for up to 1 month;  
 Since the ring is able to deliver drug for at least 1 month, the burden of user-
dependent adherence is lower than for once daily products;  

MTN-025, Version 1.0 
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August 22, 2014 
 
 Product acceptability studies and the experience gained from marketed VR 
products have established a high level of acceptance and adherence from 
women using VR with similar physical characteristics;  
 The overall cost for the VR is relatively low;  
 Minimal storage space is required for the VR when compared with once daily 
products. 
Summaries of the safety and tolerability of dapivirine orally and vaginally as evaluated in 
clinical studies by IPM and Tibotec Pharmaceuticals delivered can be found below.  
 
2.2.2 Mechanism of Action 
 
Dapivirine is an NNRTI; NNRTIs bind to the HIV reverse transcriptase (RT) enzyme 
preventing viral replication and therefore the production of infectious virus.   
 
2.2.3 Strength of Study Product 
 
The dapivirine VR (Ring-004) contains 25 mg of dapivirine.  Ring-004 is a matrix VR in 
which the drug substance is dispersed in a platinum-catalyzed cured silicone.   
 
2.3 Nonclinical Studies of Dapivirine 
 
2.3.1 In vitro Studies of Dapivirine 
 
Anti-HIV-1 Activity 
The activity of dapivirine against wild-type (wt) HIV-1, African isolates of HIV-1 
(including subtype C virus), and a panel of NNRTI-resistant viruses has been 
established using in vitro models, with 50% effective concentration (EC50) values 
ranging from 0.3 ng/mL (0.9 nM) against laboratory isolates to <33 ng/mL (<100 nM) for 
HIV-1 isolates encoding one or more known NNRTI resistance mutations.2, 4 
 
The anti-HIV activity was also confirmed in an ex vivo model of human cervical explant 
cultures and a humanized severe combined immunodeficient (hu-SCID) mouse model.2, 
4 Pre-treatment of tissue with dapivirine for 2 or 24 hours inhibited HIV-1 infection when 
challenged with virus on Days 0, 2, 4 and 6 post drug removal.  Dapivirine was also able 
to inhibit virus dissemination by migratory cells up to 6 days post drug removal at 
concentrations down to 10 μM (3.3 μg/mL) following treatment for 2 or 24 hours.  In 
addition, dapivirine (32.9 ng/mL) was able to block transfer of free virus by migratory 
dendritic cells to indicator T-cells (IC50= 0.1 nM [0.03 ng/mL]).   
 
Resistance 
HIV-1 breakthrough in the presence of dapivirine was initially evaluated in studies in 
which cells were infected with wild-type HIV-1 laboratory strains at a high multiplicity of 
infection and in the presence of increasing concentrations of dapivirine.  At 40 nM virus 

MTN-025, Version 1.0 
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August 22, 2014 
 
breakthrough occurred between 4 and 7 days, at 200 nM breakthrough occurred 
between 7 and 10 days and at 1 μM it took up to 30 days to observe virus breakthrough.  
In all cases, mutations were present.  Virus that selected Y181C mutation was resistant 
to dapivirine.  Subsequently, cells were infected with wild-type HIV-1 at low multiplicity 
of infection and were exposed to very low concentrations of dapivirine to mimic the 
extremely low systemic concentrations observed in the first clinical trial of one 
formulation of topical dapivirine (Gel-001). 
 
In the first experiment, population sequencing performed following prolonged exposure 
of HIV-1LAI-infected MT4 cells to low concentrations of dapivirine for a period of 
approximately 30 days identified several NNRTI resistance-associated mutations, 
including Y181C, at dapivirine concentrations of 10 nM and 100 nM, but not at 1 nM and 
0.1 nM concentrations.  However, both Y181C and V179I were detected when single 
viral genomes were analyzed by end-point dilution at 1 and 0.1 nM concentrations.  The 
frequency of Y181C was 10-12% both at 1 and 0.1 nM.  
 
In a second series of experiments using the same and lower dapivirine concentrations, 
population sequencing identified the Y181C mutation at 1 nM, but not at lower 
concentrations.  Analysis using a more sensitive end-point dilution technique in which 
the genotypic sequence of 25 to 30 individual viral genomes was determined indicated 
the presence of Y181C at 0.1 nM, and possibly 0.01 nM (approximately 10-fold lower 
than the EC50 for dapivirine).  
 
The significance of Y181C in a single clone at 0.01 nM in the 31-day culture is not clear.  
It is possible that the sensitive single genome sequencing technology detected some of 
the pre-existing natural variants present in a virus population in the absence of selective 
pressure.  It was concluded that prolonged exposure to low concentrations of dapivirine 
can result in selection of viruses carrying NNRTI resistance-associated mutations, but 
the clinical relevance of these in vitro data is not known. 
 
Experiments comparing the selection of resistant viruses following exposure to 
dapivirine with that following exposure to the NNRTIs UC781, MIV-160, nevirapine and 
efavirenz, showed that dapivirine demonstrated a high genetic barrier to resistance 
development in three viral isolates from subtypes B, C, and CRF02_AG.  Fully resistant 
viruses took 12 weeks to emerge, whereas reduced susceptibility to the NNRTIs 
UC781, efavirenz and nevirapine was detected within 5 weeks.  Unlike UC781 and MIV-
160, dapivirine did not select for mutations common to all three isolates, although the 
subtype C VI829 and CRF02_AG MP568 viruses contained the mutations L100I and 
E138K.  Other mutations selected under dapivirine pressure included E138Q, K101E, 
V108I, K103N, Y181C, V179M/E and F227Y. 
 
To evaluate whether the presence of resistance mutations impaired replication fitness, 
p2/p7/p1/p6/PR/RT/INT-recombinant NNRTI-resistant viruses were constructed and 
viral growth evaluated.  Only four out of 15 resistant viruses showed impairment in 
replicative fitness; however, one of them was a dapivirine-resistant form of VI829. 
 

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Cross-resistance 
In comparison with NVP, DLV, EFV and emivirine, dapivirine showed significantly better 
in vitro activity against laboratory and recombinant HIV strains resistant to one or more 
drugs of the same class.  The EC50 was below 32.9 ng/mL (100 nM) for 80% of the 
strains compared with only 56% of the strains for EFV.  
 
When tested against 433 clinical isolates with phenotypic resistance to at least one of 
the NNRTIs NVP, DLV, EFV or dapivirine, dapivirine was able to inhibit 46% (202/433) 
of the samples including 41% (142/350) of the strains resistant to EFV.  In contrast, only 
10% (24/231) of the dapivirine-resistant strains were inhibited by EFV. 
 
2.3.2 Condom Compatibility Studies of Dapivirine 
 
Results from male and female condom compatibility studies, IPM 029 and IPM 033, 
respectively, are anticipated in 2014.  
 
Chemical compatibility studies with different dapivirine-containing gel formulations have 
been conducted on the following types of condoms:5 
 
 Non-lubricated latex condoms (male condom); 
 Silicone lubricated latex condoms (male and female condoms); 
 Aqueous lubricated latex condoms (male condom);  
 Polyurethane condoms with silicone lubricant (male and female condoms); and  
 Nitrile condoms with silicone lubricant (female condom). 
 
The results of condom compatibility testing indicate that dapivirine-containing vaginal 
gel formulations (0.05%) have no deleterious effects on the integrity of male or female 
condoms, as indicated by tensile condom properties tested pre- and post-treatment.   
 
2.4 Clinical Studies 
 
2.4.1 Clinical Studies of Dapivirine Vaginal Rings 
 
To date, 26 Phase 1 and Phase 1/2 clinical trials of dapivirine have been conducted:  
 
 Seven trials of dapivirine VRs (25 mg and 200 mg loads) in which 234 
participants were assigned to dapivirine VRs,  
 Eight trials of dapivirine vaginal gel in which 491 participants used dapivirine 
vaginal gel,  
 And, eleven trials of oral dapivirine among 211 participants.2 
 
Efficacy and safety results from MTN-020 and IPM 027 and other ongoing (as of Q1 
2014) clinical trials, including the adolescent trial (MTN-023/IPM 030) and the post-
menopausal trial (MTN-024/IPM 031) will be made available to MTN-025 participants. 
 

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Pharmacokinetics 
 
Dapivirine VRs 
IPM conducted a 28-day safety and pharmacokinetics (PK) trial (IPM 018) in HIV-
uninfected women using tin-catalyzed silicone matrix and reservoir rings containing 25 
mg of dapivirine.  The rings were found to be generally safe and well-tolerated with a 
promising drug release profile.6 
 
IPM also conducted a 28-day trial (IPM 024) involving 16 healthy, HIV-uninfected, 
sexually abstinent women, between 18 and 40 years of age.  The women were 
randomly assigned (1:1) to a dapivirine (25 mg) matrix ring or a placebo ring for 28 
consecutive days.  Post-ring insertion (1.5 hour), quantifiable plasma dapivirine 
concentrations (lower limit of quantification (LLOQ) = 3.00 pg/mL) were observed.7, 8 
These concentrations showed a gradual increase over time, reaching a mean Cmax of 
355.0 pg/mL by day 7 (median Tmax).  
 
The individual plasma dapivirine concentrations did not exceed 1 ng/mL, and were well 
below plasma levels at the maximum tolerated dose for oral treatment.  
 
For dapivirine in vaginal fluids quantifiable concentrations (LLOQ = 0.40 ng) were also 
observed 1.5 hours after ring insertion.  Generally, maximum concentrations were 
reached earlier than in plasma.  The highest concentrations were observed in the area 
near where the ring was placed (mean Cmax: 79.9 μg/g; median Tmax: day 3), followed by 
the cervix (mean Cmax: 66.6 μg/g; median Tmax: day 4).  Dapivirine vaginal fluid 
concentrations were well above the reported in vitro IC50 (50% inhibitory concentration 
for virus replication) of 0.3 ng/mL in MT4 T cells and the concentration at which greater 
than 99% inhibition of integrated provirus was observed (3.3 ng/mL) in cervical tissue.  
On day 28, prior to ring removal, the mean concentrations (Cpre-ring removal) were 
38.6 μg/g, 35.8 μg/g and 13.3 μg/g in the area of the ring, in the cervix and near the 
introitus, respectively.7, 9 
 
By day 56 (final visit), the plasma dapivirine concentrations of all participants but one 
were below the LLOQ (3.00 pg/mL) and vaginal fluid concentrations in all participants 
were below the LLOQ. 
 
IPM 013 was a Phase 1, randomized, double-blind, placebo-controlled trial conducted 
over three months in 48 healthy, HIV-negative, sexually active women, 18 to 40 years of 
age in Belgium.  This trial evaluated the delivery of dapivirine from the same ring as 
used in IPM 024, but over different periods of use and assessed local and systemic 
safety.  Participants were randomized (3:1) to either active or placebo ring.  Two groups 
completed the trial with varying lengths of use.  In Group A, the VR was removed on 
Day 28, and a new ring was inserted on day 31 for 28 days in Group A.  In Group B, the 
initial ring was removed on day 35 and a new ring was inserted on day 38 for 21 days.  
Group B had a third ring inserted on day 59; this ring was worn for 24 hours.  
 

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Compared to vaginal fluids, systemic exposure to dapivirine in plasma was low.7 Plasma 
concentrations did not exceed 553 pg/mL, while the highest vaginal fluid concentration 
obtained was 171 μg/g.  Data suggest that dapivirine is readily released from the ring 
and absorbed into the surrounding tissue and bloodstream.  Concentrations of 
dapivirine collected within 4 hours of first ring insertion showed quantifiable plasma 
(LLOQ = 3.00 pg/mL) and cervicovaginal fluid (LLOQ = 0.4 ng) levels.  Interestingly, 
extending the period the ring was worn from 28 to 35 days resulted in some reductions 
in cervicovaginal fluid concentrations in the area of the ring (32.4 to 20.3 µg/g) and at 
the cervix (27.8 to 18.5 µg/g), but were similar at the introitus (10.3 to 9.9 µg/g).  These 
values remained at least 3000 times higher than the in vitro 99% inhibitory 
concentration (3.3 ng/mL) in cervical tissue following challenge with HIV-1BaL. 
 
Safety  
 
Table 1: Clinical Phase I/II Trials of Dapivirine Vaginal Rings 
Trial Details 
Number of Participants 
Trial 
Number 
Description 
Country 
Ring-001 
reservoir 
(200 mg) 
Ring-002 
reservoir 
(25 mg) 
Ring-003 
matrix* 
(25 mg) 
Ring-004 
matrix** 
(25 mg) 
Placebo 
Ring 
IPM 001 
Safety and PK 
in women; 7 
days 
Belgium 
 
12 
-- 
-- 
-- 
12 
(crossover) 
IPM 008 
Safety and PK 
in women; 7 
days 
Belgium 
-- 
10 
-- 
-- 
3 
IPM 013 
Safety and PK 
in women; 
56/57 days 
Belgium 
-- 
-- 
-- 
36 
12 
IPM 015 
Safety and PK 
in women; 84 
days 
Multiple 
Countries 
in Sub-
Saharan 
Africa 
-- 
-- 
-- 
140 
140 
IPM 018 
Safety and PK 
in women; 28 
days 
Belgium 
-- 
8 
8 
-- 
8 
IPM 024 
Safety and PK 
in women; 28 
days 
Belgium 
-- 
-- 
-- 
8 
8 
MTN-013/ 
IPM 026*** 
Safety and PK 
in women 
United 
States 
 
 
 
12 
12 
TOTAL 
12 
18 
8 
196 
195 
*Tin-catalyzed matrix ring. 
**Platinum-catalyzed matrix ring 
***MTN-013/ IPM 026 was the first in human clinical trial of a vaginal ring containing maraviroc alone, 
dapivirine alone or a combination of the two (dapivirine/maraviroc) compared to placebo.  The 
dapivirine VR arm included 12 participants. It should be noted, however, that the dapivirine VR was 
similar to Ring-004, but of slightly different composition. 
 

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Across all clinical trials with multiple ring configurations in healthy participants, the 
dapivirine VR was generally safe and well-tolerated.9 IPM has conducted a review of 
aggregate safety information which identifies vaginal candidiasis as a possible adverse 
drug reaction caused by dapivirine vaginal ring use.  The highest reported severity for 
vaginal candidiasis across studies was a Grade 2 in women using a Vaginal Ring-004. 
 
The first dapivirine VR tested in humans, Ring-001, consisted of two reservoir cores 
containing a total of 200 mg dapivirine surrounded by a controlled-release outer sheath 
of silicone elastomer.  Ring-001 was tested in a Phase 1, open-label, crossover trial in 
12 healthy, sexually abstinent, HIV-uninfected women at a single research center in 
Belgium (IPM 001).6 Women used the placebo ring for 7 days followed by the dapivirine 
ring for 7 days.  There were no serious adverse events (SAEs) during the trial and few 
treatment-emergent adverse events (TEAEs).  The dapivirine ring was considered to be 
safe based on the results of this trial in healthy participants.  
 
Ring-002, a similar formulation with a single dapivirine reservoir core containing 25 mg 
dapivirine, was tested in a Phase 1, randomized, placebo-controlled trial conducted at a 
single research center in Belgium (IPM 008).10 Ten women underwent 7-day exposure 
to dapivirine Ring-002, and three women used a placebo ring for 7 days.  There were no 
SAEs during the trial and few TEAEs.  The trial results showed that the dapivirine ring 
was safe in healthy participants.  
 
Ring-003, a dapivirine matrix VR containing 25 mg of drug substance dispersed in a tin-
catalyzed-cured silicone matrix, was compared with Ring-002 in a Phase 1, 
randomized, placebo-controlled trial conducted at a single research center in Belgium 
(IPM 018).  Twenty-four healthy, HIV-uninfected women, 18 to 35 years of age, were 
randomly assigned (1:1:1) to dapivirine matrix ring, dapivirine reservoir ring, or placebo 
ring for 28 consecutive days.  No SAEs were reported during the study.  No TEAEs 
were assessed by the investigator as definitely or probably related to the ring, and 
similar percentages of participants in the dapivirine and placebo ring groups had TEAEs 
considered to be possibly related to the ring.  
 
Ring-004, the current formulation, is a dapivirine matrix VR containing 25 mg of drug 
substance dispersed in a platinum-catalyzed-cured silicone matrix.   
 
IPM 015 was a double-blind, randomized, placebo-controlled Phase 1/2 trial conducted 
at 10 research centers in Kenya, Malawi, Tanzania and South Africa.  The trial was 
performed in 280 healthy, HIV-negative women who inserted a vaginal ring once every 
21-35 days over a 12-week period.  Five SAEs occurred during the trial, of which four 
occurred in placebo participants.11 None of the SAEs were judged to be related to 
product.  No TEAEs led to premature discontinuation of ring use. 
 
One participant in the dapivirine treatment group reported Grade 3 tonsillitis, which was 
unrelated to the investigational product.  Four participants in the placebo treatment 
group reported one instance each of bronchiectasis (Grade 3), peritonsillar abscess 
(Grade 3), suicide attempt (Grade 3), and hemopneumothorax (Grade 4).  The 

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hemopneumothorax was caused by a physical assault; this event was unrelated to the 
investigational product.  A chemical pregnancy was reported for one participant in the 
placebo ring group who discontinued product use, but continued to attend the research 
center for safety evaluations and completed the remainder of trial visits.  In IPM 015, 
two vaginal bleeding events were reported; both occurred in the placebo ring arm.  
Apart from the latter two events, chemical pregnancy and hemopneumothorax, none of 
the SAEs or TEAEs led to premature discontinuation of ring use. 
 
At least one TEAE was experienced by most participants (81% in the dapivirine ring 
group, and 86% in the placebo ring group).  Metrorrhagia was reported most frequently 
reported, with a similar incidence observed in the dapivirine ring and placebo ring 
groups.  
 
At least 10% of participants using dapivirine rings experienced the following TEAEs: 
gynecological chlamydia infection, urinary tract infection, vaginal candidiasis, and upper 
respiratory tract infection.  Participants in both the dapivirine and placebo ring treatment 
groups experienced gynecological chlamydia infection at a rate of 16% (22/140).  
Urinary tract infection was experienced by participants using dapivirine and placebo 
rings, 13% (18/140) and 10% (14/140), respectively.  
 
Approximately 38% (54/140) of participants in the dapivirine ring group and 42% 
(59/140) of participants in the placebo ring group reported Grade 1 (mild) TEAEs.  
Forty-one percent (57/140) of participants in the dapivirine ring group and 37% (52/140) 
of participants in the placebo ring group experienced Grade 2 (moderate) events.  
 
Grade 3 (severe) TEAEs were experienced by three participants in the dapivirine ring 
group: tonsillitis (also reported as an SAE), vulvovaginal pruritus (considered possibly 
related), and increased ALT level.  Nine participants in the placebo ring group 
experienced Grade 3 AEs: bronchiectasis (SAE), peritonsillar abscess (SAE), 
metrorrhagia, decreased blood phosphorus (two participants), decreased lymphocyte 
count, neutropenia (considered possibly related), stress, and a suicide attempt (SAE).  
 
One Grade 4 (potentially life-threatening) TEAE occurred in the placebo treatment 
group: one participant died due to hemopneumothorax, which occurred as a result of 
physical assault.  
 
No TEAEs were considered by the Investigator as definitely related to ring use during 
IPM 015.  The most commonly observed TEAE that was regarded as possibly or 
probably related to ring use was metrorrhagia, which was reported for 6% (9/140) of 
participants using dapivirine rings and 3% (4/140) of participants using placebo rings. 
 
IPM 024, conducted in Belgium, enrolled 16 healthy, HIV-uninfected, sexually abstinent 
women, between 18 to 40 years of age.  The women were randomly assigned to a 
dapivirine (25 mg) matrix ring or a placebo ring for 28 consecutive days.  No SAEs were 
reported in the dapivirine VR group.  No AEs were judged by the investigator to be 
related to the study agent.  Most dapivirine VR group participants, 87.5% (7/8), 
experienced at least one TEAE.  Of the women in the dapivirine VR group who 

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experienced a TEAE, 50% (4/8) reported headache.  Of the participants using dapivirine 
VRs, 50% experienced Grade 1 or Grade 2 metrorrhagia, 38% experienced 
vulvovaginal discomfort and 25% experienced nasopharyngitis.  One participant 
experienced a Grade 1 vaginal hemorrhage in the dapivirine VR group. 
 
MTN-013/IPM 026, a Phase 1 safety and pharmacokinetics study of dapivirine VR, 
maraviroc VR, dapivirine/maraviroc VR and placebo VR, enrolled approximately 48 
women between the ages of 18-40.  The participants were randomized in a 1:1:1:1 ratio 
to 28 days of continuous study vaginal ring use.  Over the course of 52 days, 14 follow-
up visits occurred.  There was no statistically significant difference in the number of 
participants with genitourinary AEs between placebo arm and any other treatment arms.  
Twenty-two women experienced 33 grade 1 and one grade 2 related genitourinary 
AEs.12 Two grade 2 AEs were determined to be related to study product.  At Day 28, 
dapivirine vaginal fluid levels were 14.9 µg/mL in women assigned to the dapivirine only 
ring.   
 
In March of 2012, IPM 027, also known as The Ring Study, was initiated.  IPM 027 is a 
randomized, double-blind, placebo-controlled efficacy and long-term safety study that 
will enroll 1,650 healthy, HIV-uninfected women, ages 18-45.  The study is being 
conducted in South Africa and Uganda.  Study participants will use either the dapivirine 
ring or the placebo ring every four weeks over approximately two years.  The main 
goals of The Ring Study are to evaluate the long-term safety and efficacy of the 
dapivirine ring for the prevention of HIV-1 as compared to a placebo ring, when used by 
healthy, HIV-negative women over a two-year period.  Additional goals include 
measuring the incidence of curable STIs, HIV-2 and pregnancy; monitoring ring 
acceptability (how well women like using the ring) and adherence (if women use the ring 
as intended) as reported by the study participants; and tracking the development of any 
HIV-1 drug resistance in participants who become HIV positive during the study.  The 
study is anticipated to conclude in 2015/16. 
 
MTN-020, A Study to Prevent Infection with a Ring for Extended Use (ASPIRE), is a 
Phase 3 clinical trial designed to assess the efficacy and safety of a ring containing 25 
mg of dapivirine for the prevention of HIV-1 acquisition in women.  The double-blind, 
randomized controlled trial is being conducted in HIV-uninfected women, between the 
ages 18 – 45.  A total of 2629 women from Malawi, South Africa, Uganda, and 
Zimbabwe have enrolled in the trial.  Participants replace the ring monthly for a 
minimum of one year.  MTN-020 aims to determine the safety and efficacy of the 
dapivirine ring in preventing HIV-1 infection among health sexually active HIV-
uninfected women when inserted vaginally once every 4 weeks.  Additional goals of 
MTN-020 include the assessment of participant acceptability and adherence to the 
investigational product, HIV-1 drug resistance mutations among participants who 
acquire HIV-1 infection and establishing steady state drug concentrations in the study 
population.  The study is anticipated to conclude in 2015. 
 
 

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2.5 Prevalence of Primary Non-nucleoside Reverse Transcriptase Inhibitor 
(NNRTI) Resistance Mutations 
 
Recent data on primary NNRTI resistance from a WHO threshold surveillance study  
conducted between 2005-2009 categorized Kwa-Zulu Natal as having 5-15% NNRTI 
resistance.13 MTN-009 found 6.5% NNRTI resistance amongst participants screening 
for VOICE who were already HIV positive, with 87% of those with NNRTI resistance 
having HIV-1 with Y181C and/or K103N.14  In the Stanford University HIV Drug 
Resistance Database, which compiled data from 12,014 HIV-1 subtype C sequences, 
and 5831 subtype A & D sequences from treatment-naïve and NNRTI-treated persons, 
the following was found:15 
 
Table 2: Frequency of K103N 
 
Treatment-Naïve 
NNRTI-experienced 
Subtype C 
1.2% 
42% 
Subtypes A and D 
no data 
14% 
 
Table 3: Frequency of Y181C 
 
Treatment-Naïve 
NNRTI-experienced 
Subtype C 
no data 
27% 
Subtypes A and D 
no data 
18-20% 
 
2.6 Behavioral Studies 
 
2.6.1 Acceptability of Dapivirine VR 
 
IPM 011 assessed the acceptability of the dapivirine VR and the placebo VR in 170 
women.  The trial was conducted across multiple sites in Tanzania and South Africa.  
The study participants found the ring to be very comfortable (95%), very easy to insert 
(94%) and remove (92%), and rarely were the rings felt during daily activities.  All 
questionnaire respondents, when asked if they would be willing to use the vaginal ring if 
shown to be effective for HIV prevention, replied that they would use the VR.16 
 
In IPM 015, at Week 12, 97% of African women reported that the dapivirine VR was 
comfortable and that they were willing to use the VR if it was found to be effective.  
Women preferred to wear the VR every day (97%) and reported that the ring did not 
interfere with their daily activities (89%).  In terms of the male partner acceptability, 63% 
of women reported that their partner did not feel the ring during sex.  Of those 
participants who reported that their partner felt the ring, only 1% reported that this might 
be or definitely was a problem.11 
 
2.6.2 Adherence of Dapivirine VR 
 
In IPM 011, 11% of the women experienced expulsions/removal, with the most common 
reason being ‘menses related’.  In the majority of cases (64%), the VR was washed and 
re-inserted.16 
 

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In IPM 015, perfect adherence was reported by 92% of the female participants.  Perfect 
adherence was defined as never having the VR out for more than an entire day.  Of the 
women who reported that the ring was out, the most common activity for expulsion was 
urination/defecation.  The most common reason reported by participants for VR removal 
was cleaning.  As the study progressed, more women reported removing the VR prior to 
sexual intercourse, 17% at week 2 and 36% by week 12.11 
 
2.7 Rationale for Study Design 
 
2.7.1 Study Design 
 
The dapivirine VR advanced to evaluation in Phase 3 safety and effectiveness trials 
based on data from preclinical and early clinical safety trials.  Upon demonstration of the 
safety and effectiveness of the dapivirine VR in the MTN-020, implementation of the 
follow-on trial, MTN-025, will commence. 
 
The primary focus of MTN-025 is the collection of additional adherence and safety data, 
including the examination of multiple approaches to follow-up and safety monitoring 
(monthly vs. quarterly).  Further, MTN-025 will examine incidence of HIV-1 infection and 
explore the way in which people adopt this biomedical prevention method and 
incorporate it into the context of their everyday lives.   
 
While there are many facets to the future roll-out of ARV-based prevention that are 
worthy of study, including potential impacts on behavior, optimizing drug adherence, 
and implementation strategies for the public sector, all future approaches must be 
grounded in an evidence base for safe management of these drugs in healthy 
populations.  MTN-025 will contribute to this evidence base by describing the safety 
outcomes associated with both monthly and quarterly monitoring schedules for women 
using an ARV for HIV prevention.  Safety data will be forwarded to regulatory entities.  
Roll-out of ARV-based prevention in the public sector in resource-limited environments 
will likely require a pharmacovigilance strategy that is less costly and time-consuming 
than the options described here.  MTN-025 will provide valuable information that will 
help guide the development of those strategies. 
 
MTN-025, the HIV Open-label Prevention Extension (HOPE) trial will provide additional 
safety and adherence data of dapivirine (25 mg) in a silicone elastomer vaginal matrix 
ring (Ring-004) when inserted monthly in healthy, HIV-uninfected, not pregnant, 
sexually active research-experienced women should efficacy be demonstrated in MTN-
020. 
 
2.7.2 Incorporating Emergent Effective HIV-1 Prevention Strategies 
 
As of June 2014, the United States was the only country where ARVs (the combination 
daily oral pill emtricitabine/tenofovir disoproxil fumarate [Truvada®]) are licensed for use 
as pre-exposure prophylaxis (PrEP).  However, as candidate microbicides continue to 
demonstrate evidence of efficacy, the potential for one or more licensed HIV-1 

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prevention strategies in sub-Saharan Africa may soon become a reality.  The HOPE 
Protocol Team will follow all relevant national policies regarding HIV-1 prevention and 
will actively consult with stakeholders in the event that an effective intervention is 
approved locally.  Consultation with target populations, policy makers, governments and 
other stakeholders will be ongoing throughout the duration of study implementation and 
participant follow-up by study leadership, Microbicide Trial Network (MTN) Leadership 
and the MTN Community Working Group (CWG). 
 
 
 
3 
OBJECTIVES 
 
3.1 Primary Objectives 
 
1. Safety 
- 
To characterize the safety profile associated with the open label use of the 
dapivirine vaginal matrix ring (25 mg) in women, and to assess safety when 
randomized to a monthly vs. quarterly follow-up schedule 
 
2. Study Product Adherence   
- 
To characterize adherence the open label use of the dapivirine vaginal matrix 
ring (25 mg) in women and to compare adherence when randomized to a 
monthly vs. quarterly follow-up schedule 
 
3.2 Secondary Objectives 
 
1. Incidence 
- 
To assess incidence of HIV-1 infection 
 
2. Drug Resistance 
- 
To assess the frequency of HIV-1 drug resistance in women who acquire HIV-
1 infection  
 
3.3 Exploratory Objectives 
 
 
1. To explore participant understanding of efficacy  
 
2. To explore ring acceptability in the context of known efficacy 
 
3. To assess the feasibility of a one-month vs three-month follow-up schedule  
 
4. To describe the genital microenvironment in women exposed to the dapivirine 
vaginal ring 
 
5. To characterize the MTN-020 participants who choose not to enroll into MTN-025 
 

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4 
STUDY DESIGN 
 
4.1 Identification of Study Design 
 
The MTN-025 trial, HOPE, is a multi-site, open-label, randomized, Phase 3B trial that 
will be implemented if the dapivirine VR is found to be a safe and an effective HIV 
prevention method in the MTN-020 trial.  Eligible MTN-020 HIV-uninfected participants 
will be randomized to either a monthly or a quarterly follow-up schedule.  The study will 
compare the safety of and adherence to dapivirine (25 mg) in a silicone elastomer 
vaginal matrix ring between the two follow-up schedules. 
 
4.2 Summary of Major Endpoints 
 
Primary Endpoints: 
 
1. Safety  
- 
Grade 2 AEs judged to be related to the dapivirine vaginal ring 
- 
Grade 3 and higher AEs 
- 
All serious AEs 
 
2. Study Product Adherence 
- 
Residual levels of dapivirine in returned vaginal rings  
- 
Blood dapivirine levels  
 
Secondary Endpoints: 
 
1. Incidence  
- 
HIV-1 infection as measured by the protocol algorithm 
 
2. Drug Resistance 
- 
HIV-1 drug resistance mutations among participants who acquire HIV-1, as 
measured by standard genotype analysis and more sensitive methods to 
detect low frequency drug-resistant variants 
 
4.3 Description of Study Population 
 
Former MTN-020 participants who are healthy, HIV-uninfected, not pregnant and meet 
eligibility criteria as described in Sections 5.2 and 5.3 
 
Decliner Group: Former MTN-020 participants who decline participation in the main 
MTN-025 study and meet eligibility criteria as described in Sections 5.4 and 5.5 
 

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4.4 Time to Complete Accrual 
 
The majority of former ASPIRE participants are anticipated to enroll approximately 3-6 
months following site activation, see Section 10.4 for additional details. 
 
4.5 Study Groups 
 
Study arms include monthly and quarterly follow-up arms as defined in Table 4.   
 
Table 4: Study Regimen 
Group 
Group Description 
Follow-Up 
A 
Dapivirine VR, containing 25 mg dapivirine 
Monthly 
B 
Dapivirine VR, containing 25 mg dapivirine 
Quarterly 
 
4.6 Expected Duration of Participation 
 
The majority of former ASPIRE participants will complete approximately 13 months of 
follow-up, see Section 10.4 for additional details.  
 
Visits may be completed within specified windows around target dates.  Detailed 
information regarding visit windows will be described in the MTN-025 SSP Manual. 
 
4.7 Sites 
 
Approved former MTN-020, ASPIRE, sites will participate in MTN-025, HOPE. 
 
 
 
5 
STUDY POPULATION 
 
5.1 Selection of the Study Population 
 
If safety and efficacy of the dapivirine vaginal ring are demonstrated in MTN-020 
(ASPIRE); MTN-025 (HOPE), will be implemented as a follow-on trial.  Inclusion and 
Exclusion Criteria, Sections 5.2 and 5.3, respectively, are used to ensure the 
appropriate selection of study participants for MTN-025.   
 
Decliner Group: Former MTN-020 participants who decline participation in the main 
MTN-025 study, and who meet inclusion and exclusion criteria in Sections 5.4 and 5.5, 
will be invited to complete behavioral assessment(s). 
 
5.1.1 Recruitment 
 
Participants will be recruited from study site cohorts of MTN-020 participants.  Efforts 
will be made by study sites to maintain contact with MTN-020, ASPIRE, participants 
between the end of follow-up in MTN-020 and the initiation of the MTN-025 trial, HOPE, 
I 
I 

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to provide MTN-020 study results and information regarding the HOPE study to 
participants.  Recruitment materials will be approved by site Institutional Review 
Boards/Ethics Committees (IRBs/ECs) prior to use.  Site community representatives 
should advise on these materials before they are submitted to the IRB/EC for review.  
Community education strategies, including group sessions, may be employed as part of 
participant/partner outreach. 
 
5.1.2 Retention 
 
Once a participant is enrolled/randomized into the HOPE trial, 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 across sites.  
Each study site will establish and follow standard operating procedures (SOPs) for 
participant retention.   
 
5.2 Inclusion Criteria 
 
Women must meet all of the following criteria to be eligible for inclusion in the study: 
 
1) Previously enrolled in MTN-020 (ASPIRE) 
 
2) Able and willing to provide written informed consent to be screened for and to take 
part in the study 
 
3) Able and willing to provide adequate locator information, as defined in site SOPs 
 
4) HIV-uninfected based on testing performed by study staff at Screening and 
Enrollment (per applicable algorithm in Appendix II) 
 
5) Using an effective method of contraception at Enrollment, and intending to use an 
effective method for the duration of study participation; effective methods include 
hormonal methods (except contraceptive ring); intrauterine contraceptive device 
(IUCD); and sterilization (of participant, as defined in site SOPs) 
 
6) At Screening and Enrollment, agrees not to participate in other research studies 
involving drugs, medical devices, vaginal products, or vaccines for the duration of 
study participation 
 
5.3 Exclusion Criteria 
 
Women who meet any of the following criteria will be excluded from the study: 
 
1) Study product use permanently discontinued in response to an AE or safety related 
concern while taking part in the MTN-020 (ASPIRE) trial  
 

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August 22, 2014 
 
2) Per participant report at Screening: 
a) Plans to relocate away from the study site during study participation 
b) Plans to travel away from the study site for more than three consecutive months 
during study participation 
 
3) Per participant report at Enrollment, currently taking Post-Exposure Prophylaxis 
(PEP) 
 
Note:  PEP use at Screening is not exclusionary.  Participants may be 
enrolled/randomized after the PEP regimen is complete and a negative HIV test is 
documented within 56 days of providing informed consent for Screening.  
 
4) With the exception of MTN-020 (ASPIRE), participation in any other research study 
involving drugs, medical devices, vaginal products, or vaccines, within 60 days of 
enrollment  
 
5) Is pregnant at Screening/Enrollment or planning to become pregnant in the 
participant’s anticipated study participation 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 
screening/enrollment into the study.   
 
6) Currently breastfeeding 
 
7) Diagnosed with urinary tract infection (UTI), pelvic inflammatory disease (PID), STI 
or reproductive tract infection (RTI) requiring treatment per WHO guidelines 
 
Note: Otherwise eligible participants diagnosed during screening with a UTI, PID or 
STI/RTI requiring treatment per WHO guidelines — other than asymptomatic BV and 
asymptomatic 
candidiasis 
— 
are 
offered 
treatment 
consistent 
with 
WHO 
recommendations and may be enrolled after completing treatment if all symptoms have 
resolved.  If treatment is completed and symptoms have resolved within 56 days of 
obtaining informed consent for screening, the participant may be enrolled.  Genital warts 
requiring treatment also must be treated prior to enrollment.  Genital warts requiring 
therapy are defined as those that cause undue burden or discomfort to the participant, 
including bulky size, unacceptable appearance, or physical discomfort. 
 
8) At Screening, has a clinically apparent Grade 3 pelvic exam finding (observed by 
study staff) as per the Division of AIDS Table for Grading the Severity of Adult and 
Pediatric Adverse Events Version 1.0, December, 2004 (Clarification dated August 
2009), Addendum 1-Female Genital Grading Table for Use in Microbicide Studies 
 
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.  If improvement to a non-exclusionary grade or resolution is 
documented within 56 days of providing informed consent for screening, the participant 
may be enrolled.  
 

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August 22, 2014 
 
9) Has any of the following laboratory abnormalities at Screening Visit: 
a) Aspartate aminotransferase (AST) or alanine transaminase (ALT) > Grade 3* 
b) Creatinine > Grade 3* 
c) Hemoglobin > Grade 3* 
d) Platelet count > Grade 3* 
e) Pap result > Grade 3 according to the Female Genital Grading Table for Use in 
Microbicide Studies Addendum 1 to the DAIDS Table for Grading Adult and 
Pediatric Adverse Events, Version 1.0, December 2004 (Clarification dated 
August 2009) 
 
Note:  Otherwise eligible participants with an exclusionary test may be re-tested during 
the screening process. 
 
Note: Women with a documented normal result within the 12 months prior to enrollment 
need not have Pap smear during the screening period.  Need for a repeat Pap within 6 
months does not preclude enrollment prior to that result becoming available. 
 
*Per the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse 
Events Version 1.0, December, 2004 (Clarification dated August 2009) 
 
10) Has any significant medical condition or other condition that, in the opinion of the 
IoR/designee, would preclude informed consent, make study participation unsafe, 
complicate interpretation of study outcome data, or otherwise interfere with 
achieving the study objectives 
 
5.4 Inclusion Criteria- MTN-025 Decliner Group Only 
 
MTN-025 Decliner Group participants must meet all of the following criteria to be 
eligible for inclusion in the study: 
 
1) Able and willing to provide informed consent  
2) Participated in MTN-020 (ASPIRE) 
3) Declines MTN-025 (main) study trial participation  
4) Able and willing to perform the Decliner Group study procedures 
 
5.5 Exclusion Criteria- MTN-025 Decliner Group Only 
 
MTN-025 Decliner Group participants who meet the following criteria will be 
excluded from the study: 
 
1) Has any condition that, in the opinion of the Investigator of Record 
(IoR)/designee, would preclude informed consent, make study participation 
unsafe, complicate interpretation of study outcome data, or otherwise interfere 
with achieving the study objectives. 
 
 

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5.6 Co-enrollment Guidelines 
 
As indicated in Section 5.2 and 5.3, participants should not take part in other research 
studies involving drugs, medical devices, vaginal products or vaccines after the 
Screening Visit and while taking part in this study.  Each site will be responsible for 
defining procedures for management and prevention of co-enrollment prior to initiation.  
 
Exceptions to this guideline may be made for participants to co-enroll in the following 
types of studies at the discretion of the IoR/designee: 
 
 Participants may take part in ancillary studies approved by the MTN-025 
Protocol Chair  
 Participants who become infected with HIV may take part in observational 
and/or interventional studies for HIV-positive persons 
 Participants who become pregnant may take part in observational studies, 
including pregnancy registries approved by the MTN-025 Protocol Chair  
 
Should any participant report or should study staff discover concurrent participation in 
any other study after enrolling in MTN-025, the IoR/designee will consult the Protocol 
Safety Review Team (PSRT) regarding ongoing product use and other potential safety 
considerations associated with co-enrollment.  
 
 
 
6 
STUDY PRODUCT 
 
6.1 Regimen 
 
All participants will receive a vaginal ring containing 25 mg of dapivirine to be worn 
monthly.  One new ring will be inserted each month.  Participants will be randomized to 
either monthly or quarterly follow-up visits. 
 
6.2 Administration 
 
The participant will self-insert the study VR monthly.  Study participants will be reminded 
of proper VR insertion and removal procedures at the Enrollment Visit and as needed at 
subsequent visits.  Details on administration (ring insertion, removal, procedures in the 
event of expulsion or loss) will be provided in the MTN-025 Study Specific Procedures 
(SSP) Manual.   
 
6.3 Study Product Formulation 
 
The study VR is an off-white, flexible ring containing 25 mg of dapivirine dispersed in a 
platinum-catalyzed-cured silicone matrix.  The ring dimensions are as follows: 56 mm 
and 7.7 mm, outer diameter and cross-sectional diameter, respectively.   
 

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The ring is designed to provide sustained release of drug over a minimum period of one 
month. 
 
6.3.1 Dapivirine VR 
 
Dapivirine 0.3125% (w/w) is dispersed in a flexible, opaque, cured silicone VR delivery 
device.  The VR will contain 25 mg of dapivirine.  The dapivirine VR optimally should be 
stored in the site pharmacy at 20°C to 25°C, with excursions between 15°C to 30°C.  
 
6.4 Supply and Accountability 
 
6.4.1 Supply 
 
IPM (Silver Spring, MD) will oversee the manufacture of the study VRs and 
analyze/release the rings under Good Manufacturing Practices (GMP).   
 
6.4.2 Study Product Dispensing 
 
Study VRs are dispensed only to enrolled study participants or clinic staff on behalf of 
the participant, upon receipt of a written prescription from an authorized prescriber.  
Dispensing takes place on the day of enrollment and at each scheduled follow-up visit, 
except at the Product Use End Visit and Study Exit/Termination Visit.  
 
Participants randomized to monthly follow-up visits will receive a new ring at each visit.  
If the participant is unable to attend her next scheduled visit it is up to the discretion of 
the IoR to provide an additional ring(s).  All such circumstances must be documented 
fully by the IoR/designee as described in the MTN-025 SSP Manual. 
 
Participants randomized to quarterly follow-up visits will be dispensed three rings at 
each study visit or the option of returning to the site pharmacy or the clinic (based on 
site dispensing capacity) to obtain a new vaginal ring each month.  Participant’s 
preference regarding product dispensation and their choice will be documented.  
 
The pharmacist will only dispense one ring per month or up to three rings per quarter 
depending on the participant’s regimen.  If a participant requires an additional ring for 
any reason, at a time other than when she is scheduled to receive one, she will be 
required to attend the clinic for an interim visit.  
 
6.4.3 Accountability 
 
Each CRS Pharmacist of Record (PoR) is required to maintain a complete record of all 
study product 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-025 Pharmacist Study Product Management Procedures Manual. 

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August 22, 2014 
 
 
All study product dispensed to a participant must be documented by the clinic staff 
when it is returned.  This includes ring(s) brought back to the clinic by the participant 
and any ring removed at the clinic visit.  Any study products not returned must also be 
documented by the clinic.   
 
6.4.4 Retrieval of Study Product 
 
As per Section 9, study product use for a participant may be temporarily held or 
permanently discontinued.  Study product must be retrieved within 24 hours and 
returned to the clinic when product use is permanently discontinued for HIV 
seroconversion or held temporarily due to potential HIV seroconversion (see Table 5 
below).  Additional study product retrieval specifications in response to product holds, 
discontinuations for other reasons, or IoR discretion, can be found in the table below.  
Study product retrieval may occur either by the participant returning the VR (used and 
unused) to study staff within the specified timeframe or by study staff conducting 
outreach to retrieve the product from the participant (e.g., at her home).   
 
Table 5:  Retrieval of Study Product 
Condition  
Timeframe for Retrieval 
 
Permanent discontinuation due to HIV 
seroconversion 
 
Temporary hold due to potential HIV seroconversion 
Within 24 hours 
 
Permanent discontinuation for any other reason or 
IoR discretion  
 
Temporary hold due to pregnancy 
Within 5 working days 
 
Temporary hold for reasons other than pregnancy 
with expected duration of more than 7 days  
Within 7 working days 
 
If product has not been retrieved within the timeframe specified in the table above, study 
staff members must make every effort to retrieve study product as soon as possible. 
 
It is not necessary to retrieve study products from participants for whom study product 
use is being temporarily held for less than 7 days.  However, to protect participant 
safety, study product(s) may be retrieved from participants if there is concern that the 
participant may not comply with clinic staff instructions to refrain from study product use 
for the duration of the temporary hold.   
 
For all study product holds due to seroconversion, pregnancy or other safety related 
concerns, if the study product(s) are not retrieved within timeframe noted, the MTN-025 
PSRT must be informed. 
 
For each participant, all VRs remaining in the participant’s possession should be 
retrieved at the Study Exit/Termination Visit.  If the participant does not bring her 
remaining VR(s) to this visit, study staff must arrange to retrieve the ring(s) within 5 
business days.   
 

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The PoR will document all unused product returns and store returned unused study 
products in designated areas within the study pharmacy. 
 
6.5 Concomitant Medications 
 
Enrolled study participants may use concomitant medications during study 
participation.  All concomitant medications as well as illicit substances reported 
throughout the course of the study will be recorded on case report forms designated for 
that purpose.  All prescription medications, over-the-counter preparations, vitamins, 
nutritional supplements, and herbal preparations will be recorded on forms for 
concomitant medications.  
 
6.6 Use of Intravaginal Medications and Practices 
 
Concomitant use of devices such as diaphragms, menstrual cups, and cervical caps, 
will be discouraged.  Use of contraceptive VRs is prohibited.  Products and practices 
including the use of spermicides, vaginally applied medication, douches, lubricants, 
tampons, etc., are permitted.  Use of intravaginal medications and practices will be 
captured.  
 
6.7 Condoms 
 
All participants will be offered male condoms.  Condoms are highly effective in 
preventing the sexual transmission of HIV and reducing the risk other STIs, including 
infections transmitted by genital secretions, and to a lesser degree, genital ulcer 
diseases.17-19Study staff may also offer guidance on the use of the female condoms 
upon participant request, see SSP for additional details. 
 
 
 
 

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7 
STUDY PROCEDURES 
 
An overview of the study visit and evaluations schedule is provided in Appendix I.  
Follow-up study visits may take place on-site, in a participant’s home, or at other 
community-based 
locations, 
depending 
on 
site 
capacity 
and 
site/participant 
preference.  If genital symptoms are reported during an off-site visit, the participant is 
instructed to report to the on-site clinic for a clinical evaluation.  Presented in this 
section is additional information on visit-specific study procedures.  Detailed instructions 
to guide and standardize procedures across sites (including the conduct of off-site study 
visits) are provided in the MTN-025 Study Specific Procedures (SSP) Manual available 
at http://www.mtnstopshiv.org/studies.  
 
7.1 Pre-Screening 
 
As part of participant outreach and recruitment strategies, study staff may pre-screen 
potential study participants either on-site or at 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 on-site screening visits.  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 potential participant identifiers.  At each site, 
procedures and documentation will comply with local IRB/EC requirements.  
 
7.2 Screening Visit 
 
The Screening Visit may take place up to 56 days prior to the Enrollment Visit.  Multiple 
visits may be conducted within this period to complete all required screening 
procedures, if necessary.  Written informed consent for screening will be obtained 
before any screening procedures are initiated.  For participants who do not meet the 
eligibility criteria, screening will be discontinued once ineligibility is determined.   
 
 
 

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Table 6: Screening Visit 
Screening Visit 
Component 
Procedures 
Administrative  and 
Regulatory 
 
 Obtain written informed consent for screening 
 Assign a Participant Identification (PTID) Number  
 Assess eligibility 
 Collect locator information 
 Provide reimbursement for study visit 
 Schedule next visit* 
Behavioral 
 Provide counseling 
 
Contraceptive 
 
HIV/STI risk reduction 
 
HIV pre- and post-test 
Clinical 
 Obtain medical and menstrual history 
 Obtain concomitant medications 
 Conduct a physical examination 
 Perform a pelvic exam 
 Offer contraceptives* ⁪ 
 Treat or prescribe treatment for UTIs/RTIs/STIs or refer for 
other findings* 
Laboratory 
Urine 
 Collect urine 
 
human chorionic gonadotropin (hCG)  
 
Nucleic Acid Amplification Test (NAAT) for GC/CT 
 
Urine culture*Ŧ⁪ 
Blood 
 Collect blood 
 
HIV-1 serology 
 
Complete blood count (CBC) with platelets 
 
Chemistries 
 
Syphilis serology 
Pelvic 
 
 Collect pelvic specimens 
 
Rapid test for Trichomonas 
 
Pap smear interpretation* 
Study Product/ Supplies 
 Offer condoms 
* if indicated; Ŧ⁪ per local standard of care 
 

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7.3 Enrollment Visit (Day 0) 
 
The Enrollment Visit must be completed within 56 days of the Screening Visit.   
 
Note: All enrolled participants will receive regular individual HIV counseling, condoms (if 
participant is willing to accept them), risk reduction counseling, and treatment for STIs as part of 
their clinic visits.  If other new prevention strategies are found to be efficacious and are 
incorporated into the national HIV prevention policies, study participants will be counseled about 
these interventions, and either be offered these interventions by the site or referred to local 
centers with appropriate expertise, in accordance with WHO/UNAIDS guidelines and local 
practice and stakeholder consultation. 
 
Table 7: Enrollment Visit 
Enrollment Visit 
Component 
Procedures 
Administrative  and 
Regulatory 
 
 
Obtain written informed consent for enrollment 
 
Reassess and confirm eligibility 
 
Review/update locator information 
 
Randomization 
 
Provide reimbursement for study visit 
 
Schedule next study visit* 
Behavioral 
 
Conduct behavioral assessment 
 
Provide counseling 
 
Contraceptive  
 
HIV/STI risk reduction 
 
HIV pre- and post-test  
 
Protocol adherence  
Clinical 
 
Update medical and menstrual history 
 
Update concomitant medications 
 
Disclose available test results 
 
Perform a physical examination* 
 
Perform a pelvic exam* 
 
Offer contraceptives* 
 
Treat or prescribe treatment for UTIs/RTIs/STIs or refer for 
other findings* 
Laboratory 
 
Urine 
 
Collect urine 
 
hCG  
 
Urine culture* Ŧ⁪ 
 
NAAT for GC/CT* ⁪ 
Blood 
 
Collect blood 
 
Plasma archive 
 
HIV-1 serology 
Pelvic 
 
 
Collect pelvic specimens 
 
Vaginal fluid (self-collected) 
 
Rapid test for Trichomonas*⁪ 
Study Product/Supplies 
 
Offer condoms 
 
Provision of study VR use instructions 
 
Provision of study VR(s) 
 
Insertion of one study VR  
 
Digital exam by clinician to check VR placement* 
* if indicated; Ŧ⁪ per local standard of care 
 

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7.4 Follow-up Visits 
 
7.4.1 Months 1, 2, 4, 5, 7, 8, 10, 11 
 
Procedures listed below will occur at study months 1, 2, 4, 5, 7, 8, 10, 11 for participants 
randomized to the monthly follow-up arm. 
 
Table 8: Follow-up Visits: Months 1, 2, 4, 5, 7, 8, 10, 11 
Follow-up Visits: Months 1, 2, 4, 5, 7, 8, 10, 11 
Component 
Procedures 
Administrative and 
Regulatory 
 
 
Review/update locator information 
 
Provide reimbursement for study visit 
 
Schedule next visit 
Behavioral 
 
Provide counseling (modified, if necessary)  
 
Contraceptive 
 
Protocol adherence  
 
HIV/STI risk reduction 
 
HIV pre- and post-test  
Clinical 
 
Review/update medical and menstrual history 
 
Disclosure of available test results 
 
Record/update AEs 
 
Review/update concomitant medications* 
 
Offer contraceptives*⁪ 
 
Perform a physical examination* 
 
Perform a pelvic examination* 
 
Treat or prescribe treatment for UTIs/RTIs/STIs or refer for 
other findings* 
Laboratory 
 
Urine 
 
Collect urine 
 
hCG 
 
NAAT for GC/CT* ⁪ 
 
Urine culture* ⁪ Ŧ⁪ 
Blood 
 
Collect blood 
 
HIV-1 serology 
 
Chemistries*  
 
Syphilis serology*  
Pelvic 
 
 
Collect pelvic specimens 
 
Vaginal fluid (self-collected) 
 
Rapid test for Trichomonas*  
Study 
Product 
 
Adherence assessment(s):  Returned study VR 
Study Product/Supplies 
 
Offer condoms 
 
Removal and collection of used/unused study VR  
 
Provision of VR use instructions* 
 
Provision of study VR  
 
Digital exam by clinician to check VR placement* 
* if indicated; Ŧ⁪ per local standard of care⁪ 
 

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August 22, 2014 
 
7.4.2 Months 3, 6, 9 
 
Participants in both study arms will undergo the following procedures quarterly. 
 
Table 9: Follow-Up Visits: Months 3, 6, 9 
Follow-up Visits:  Months 3, 6, 9 
Component 
Procedures 
Administrative and 
Regulatory 
 
 
Review/update locator information 
 
Provide reimbursement for study visit 
 
Schedule next visit 
Behavioral 
 
Conduct behavioral assessment  
 
Conduct social harms assessment 
 
Provide counseling (modified, if necessary)  
 
Contraceptive 
 
Protocol adherence 
 
HIV/STI risk reduction 
 
HIV pre- and post-test  
Clinical 
 
Review/update medical and menstrual history 
 
Review/update concomitant medications 
 
Perform physical examination ⁪(mandatory at Month 6, if 
indicated at other visits) 
 
Disclosure of available test results 
 
Record/update AEs 
 
Perform a pelvic examination* 
 
Offer contraceptives* 
 
Treat or prescribe treatment for UTIs/RTIs/STIs or refer for 
other findings* 
Laboratory 
 
Urine 
 
Collect urine 
 
hCG 
 
NAAT for GC/CT ⁪(mandatory at Month 6, if indicated at 
other visits) 
 
Urine culture*⁪ Ŧ⁪ 
Blood 
 
Collect blood 
 
HIV-1 serology 
 
Plasma  
 
Chemistries* 
 
Syphilis serology*  
Pelvic 
 
 
Collect pelvic specimens 
 
Vaginal fluid (self-collected) 
 
Rapid test for Trichomonas ⁪(mandatory at Months 6 only, if 
indicated at other visits)⁪ 
Study 
Product 
 
Adherence assessment(s):  Returned study VR 
Study Product/Supplies 
 
Offer condoms 
 
Removal and collection of used/unused study VR(s) 
 
Provision of VR use instructions* 
 
Provision of study VR(s)  
 
Digital exam by clinician to check VR placement* 
* if indicated; Ŧ⁪ per local standard of care 
 

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7.4.3 Product Use End Visit (PUEV) 
 
Participants in both study arms will undergo the following procedures at Month 12.  
 
Table 10: PUEV: Month 12 
PUEV: Month 12 
Component 
Procedures 
Administrative and Regulatory 
 
 Review/update locator information 
 Provide reimbursement for study visit 
 Schedule next visit 
Behavioral 
 Conduct behavioral assessment  
 Conduct social harms assessment 
 Provide counseling (modify, if necessary)  
 Contraceptive  
 HIV/STI risk reduction 
 HIV pre- and post-test 
Clinical 
 Review/update medical and menstrual history 
 Review/update concomitant medications 
 Perform a physical examination 
 Perform a pelvic examination  
 Disclosure of available test results 
 Record update AEs 
 Offer contraceptives* ⁪ 
 Treat or prescribe treatment for UTIs/RTIs/STIs or refer for other 
findings* 
Laboratory 
 
Urine 
 Collect urine 
 hCG 
 NAAT for GC/CT 
 Urine culture* ⁪ Ŧ⁪ 
Blood 
 Collect blood 
 HIV-1 serology 
 Syphilis serology 
 Chemistries 
 CBC with platelets 
 Plasma  
Pelvic 
 
 
 Collect pelvic specimens 
 Vaginal fluid (self-collected) 
 Rapid test for Trichomonas 
Study Product 
 Adherence assessment(s):  Returned study VR 
Study Product 
 Offer condoms  
 Removal and collection of used/unused study VR  
* if indicated; Ŧ⁪ per local standard of care 
 

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7.4.4 Study Exit/Termination Visit 
 
The Study Exit/Termination Visit is to be scheduled approximately 4 weeks after the 
PUEV. 
 
Table 11: Study Exit/Termination Visit 
Study Exit/ Termination Visit 
Component 
Procedures 
Administrative and 
Regulatory 
 
 
Review/update locator information 
 
Provide reimbursement for study visit 
 
Schedule next visit* 
Behavioral 
 
Conduct behavioral assessment 
 
Provide counseling  
 
Contraceptive*  
 
HIV/STI risk reduction 
 
HIV pre- and post-test  
Clinical 
 
Review/update medical and menstrual history 
 
Review/update concomitant medications 
 
Disclosure of available test results 
 
Record/update AEs 
 
Offer contraceptives* 
 
Perform a physical examination* 
 
Perform pelvic examination* 
 
Treat or prescribe treatment for UTIs/RTIs/STIs or refer for other 
findings* 
Laboratory 
 
Urine 
 
Collect urine 
 
hCG  
 
NAAT for GC/CT* ⁪ 
 
Urine culture* ⁪ Ŧ⁪ 
Blood 
 
Collect blood 
 
HIV-1 serology 
 
Plasma  
Pelvic 
 
Collect pelvic specimens 
 
Vaginal fluid (self-collected) 
 
Rapid test for Trichomonas* 
Study Product 
 
Offer condoms  
* if indicated; Ŧ⁪ per local standard of care 
 

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7.5 MTN-025 Decliner Group 
 
7.5.1 MTN-025 Decliner Group: Screening and Enrollment Procedures 
 
Former ASPIRE participants who decline or express no interest in joining the main 
MTN-025 trial, may opt to take part in the MTN-025 Decliner Subset.  Multiple visits may 
be conducted to complete all required procedures, as necessary.  See Section 7.8, 
Behavioral Evaluations for additional details.   
 
Table 12: Screening and Enrollment Procedures 
Screening and Enrollment 
Component 
Procedures 
Administrative and 
Regulatory 
 
 
Confirm eligibility  
 
Obtain written informed consent  
 
Collect demographic data  
 
Provide reimbursement for study visit 
Behavioral 
 
Administer behavioral assessment 
 
Conduct in-depth interview (IDI)* 
*=if indicated 
 
 
7.6 Follow-up Procedures for Participants Who Temporarily Hold or 
Permanently Discontinue Study Product 
 
7.6.1 Participants Who Become Infected with HIV 
 
Participants who become infected with HIV are offered the option to continue follow-up 
visits per their original study schedule until their originally scheduled study exit date.  All 
participants who become infected with HIV while on study product will be offered 
enrollment in MTN-015, the MTN Seroconverter Study.  Participants are offered 
enrollment in MTN-015 (http://www.mtnstopshiv.org/studies) at the visit when 
seroconversion confirmation test results are discussed with the participant.  
 
For those participants who choose to be maintained in MTN-025 follow-up, regardless 
of co-enrollment in MTN-015, protocol-specified procedures for MTN-025 will continue, 
except the following: 
 
 HIV serology, HIV pre- and post-test counseling 
 Provision of VR, instructions, product adherence counseling 
 Complete blood count  
 Chemistries 
 Scheduled HOPE Study Exit/Termination Visit 
 

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For participants who delay or decline enrollment in MTN-015, the following procedures 
are being completed as part of the MTN-025 study; these procedures are discontinued 
immediately if the participant enrolls in MTN-015: 
 
 Plasma collection 
 CD4+ T cell count 
 HIV-1 RNA PCR 
 HIV-1 Genotyping (standard resistance testing) 
 
The aforementioned procedures are performed at the following time points:  
 
 Plasma collection, CD4+ T cell count and HIV-1 RNA PCR will be 
performed upon each instance of a positive HIV rapid test(s) during follow-
up 
 Plasma collection, CD4+ T cell count and HIV-1 RNA PCR will be 
performed at the clinic visit immediately following confirmation of an HIV-
infection and every three months thereafter for the remaining follow-up 
period, or as indicated 
 HIV-1 Genotyping (standard resistance testing) will be performed on the 
stored plasma closest to the time of confirmed HIV-1 infection.  It may be 
performed at additional/alternate time points as requested by site IOR or 
at the discretion of the Laboratory Center.   
 
Please reference the SSP for additional details (http://www.mtnstopshiv.org/studies). 
 
7.6.2 Participants Who Become Pregnant 
 
All protocol-specified study procedures will continue except the following: 
 
 Provision of VR, product use instructions, and adherence counseling.  
Product use may be resumed after birth or other termination of the 
pregnancy, as evidenced by a negative pregnancy test performed by 
study staff, provided the participant is not breastfeeding.  VR use should 
not be resumed earlier than 2 weeks after a 1st trimester loss, or earlier 
than 4 weeks after 2nd trimester (or later) pregnancy loss or delivery.  A 
pelvic exam must be performed prior to resumption to confirm the absence 
of any findings that would contraindicate resumption, in the opinion of the 
IoR/designee. 
 Pelvic examination as well as associated procedures, and vaginal fluid 
collection, after 24 weeks of pregnancy, unless the participant indicates 
comfort with continuing vaginal procedures post 24 weeks.  See SSP 
Manual for additional guidance. 
 
A participant who becomes pregnant during the course of study participation may be 
offered participation in MTN-016, the Prevention Agent Pregnancy Exposure Registry. 
 

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7.6.3 Participants Who Temporarily Hold or Permanently Discontinue Study 
Product Use  
 
All protocol-specified study procedures will continue except the following: 
 
 Provision of VR, product use instructions, and adherence counseling 
 
In the event that a participant permanently discontinues study product early, the 
Adherence and Acceptability Assessments will be administered according to guidance 
provided from the protocol team.  See the MTN-025 SSP Manual for additional 
guidance. 
 
Guidance related to permanent discontinuation of study product, including consultation 
with the PSRT, is included in Section 9.   
 
7.6.4 Interim Visits 
 
Interim visits may be performed at any time during the study, for the following or other 
reasons: 
 
 For administrative reasons, e.g., a participant may have questions for study staff, 
or may need to re-schedule a follow-up visit. 
 For product-related reasons, including to provide participants with a replacement 
or additional vaginal ring. 
 In response to AEs and/or SAEs.  When interim contacts or visits are completed 
in response to participant reports of AEs and/or SAEs, study staff will assess the 
reported event clinically and provide or refer the participant to appropriate 
medical care (see also Section 9). 
 For interim STI counseling and testing in response to STI symptoms.  
 For interim HIV counseling and testing in response to participant report of 
symptoms consistent with acute seroconversion or presumed exposure to HIV 
 To provide participants with the results of confirmatory HIV test results, per the 
algorithm in Appendix III. 
 For other reasons at participant request, e.g., social harm. 
 
All interim contacts and visits will be documented in participants' study records and on 
CRFs, if applicable.  
 
7.7 Final Contact 
 
Since participants’ Study Exit/Termination Visit include laboratory testing for HIV, a final 
contact may be required to provide her additional study test results, and post-test 
counseling, if needed.  In addition, for participants who become pregnant during study 
participation, an additional contact may be required to ascertain the participant’s 
pregnancy outcome.  Study sites may complete these contacts at the study site or at 

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community-based locations, depending on site capacities and site and participant 
preferences.  All final contacts will be documented in participant study records.   
 
7.8 Behavioral Evaluations 
 
The following attitudes and behaviors, including the endpoints to assess exploratory 
objectives, will be assessed either via Audio Computer-Assisted Self Interviewing or 
CRFs.  Additionally, a subset of eligible participants at selected sites will be asked to 
participate in in-depth interviews and/or focus group discussions (IDI and/or FGDs) at a 
predetermined time point.  These will be conducted by trained interviewers/facilitators to 
gain further insight on the following behavioral and attitudinal issues: 
 
 Attitudes and understanding of VR efficacy 
 VR acceptability and attitudes towards combination prevention (i.e.,  use-related 
attributes and preferences, access, cost, health system delivery)    
 Motivations for joining or declining participation in research study  
 Reports of products storage and use 
 Perceived feasibility of study visit regimen 
 Sexual activity, including condom use 
 Vaginal practices 
 
MTN-025 Decliner Group 
 
Former ASPIRE participants who decline or express no interest in joining the MTN-025 
trial either prior to screening or prior to enrollment, will be invited to complete behavioral 
assessment(s), which may include IDI(s) to explore reasons for disinterest. 
 
 
7.9 Adherence Counseling 
 
Study product adherence counseling will be provided as a component of the Protocol 
Adherence Counseling to all study participants by site staff.  Counseling will be provided 
in accordance with standard methods based on participant-centered strategies with 
discussions focused on describing experiences and identifying factors facilitating the 
ease/comfort of product use.  Participants will also be counseled on the importance of 
using the product as prescribed.  
 
7.10 Clinical Evaluations and Procedures 
 
Physical exams will include the following assessments:  
 
 General appearance 
 Weight  
 Vital signs 
 Temperature 
 Pulse  

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 Blood pressure 
 Respirations 
 Abdomen  
 Height* 
 Lymph nodes*  
 Neck*  
 Heart* 
 Lungs*  
 Extremities* 
 Skin*  
 Neurological* 
 
*may be omitted after the Screening Visit 
 
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-025 SSP Manual. 
 
Participants for whom there is documentation of surgical sterilization may have 
contraceptive counseling omitted, in accordance with any relevant site SOPs.   
 
7.11 Laboratory Evaluations 
 
Local Laboratory 
 Urine 
 hCG 
 NAAT for GC/CT 
 Culture (per local standard of care) 
 Blood 
 Plasma archive (stored at site until notified by MTN Laboratory Center 
(LC)) 
 Plasma (stored at site until notified by MTN LC) 
 Syphilis serology 
 HIV serology 
 CBC with platelets 
 Chemistries 
o Creatinine, AST, ALT 
 Pelvic  
 Rapid test for Trichomonas 
 Vaginal fluid  
 

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Laboratory Center 
 Blood 
 HIV-1 confirmatory testing as needed (see Appendix III) 
 Drug concentration in blood 
 HIV drug resistance  
 
 Pelvic  
 Vaginal fluid for candidate biomarkers of safety, adherence and efficacy, 
HIV exposure and antiretroviral resistance, and/or genital microflora, as 
needed 
 
IPM or MTN Designated Laboratory: 
 Study Product- Vaginal Ring 
 Adherence assessment(s) 
 
7.12 HIV Infection (Secondary Endpoint) Determination 
 
All study sites will perform HIV testing per the algorithm in Appendix III for purposes of 
secondary endpoint determination.  Prior to study initiation, all sites will have validated 
this algorithm in accordance with the policies described in the MTN Manual of 
Operations (MOP) (http://www.mtnstopshiv.org/node/187).  All sites will participate in 
ongoing proficiency testing of their HIV testing procedures throughout the course of the 
study.  The HIV test kits used at each site are pre-approved by the MTN Laboratory 
Center (LC); at each testing time point when rapid tests are used at least one FDA-
approved rapid test kit is used.  All confirmatory testing is performed using FDA-
approved test kits.  
 
HIV DNA is not routinely used in MTN-025 for HIV diagnosis but may be used when 
requested by the MTN LC.  
 
The MTN LC will verify HIV testing performed at the study site laboratories for purposes 
of eligibility determination and secondary endpoint ascertainment as follows: 
 
 The MTN LC will test Study Entry, PUEV, and scheduled Termination Visit 
specimens from a 10% random sample of participants enrolled at each site for 
evidence of HIV infection using FDA-licensed tests.  Study Entry specimens are 
collected at participants’ Enrollment Visits.  If any false-negative local laboratory 
results are identified, the LC will test the respective Study Entry, PUEV and 
scheduled Termination Visit specimens from all enrolled participants from that 
Clinical Research Site. 
 
 The MTN LC will test the Study Entry and Seroconversion specimens from all 
study participants identified by the local laboratories as having become infected 
with HIV during the study follow-up period.  The LC will also test matched Study 
Entry and Follow-Up specimens from a random sample of uninfected participants 
(equal to the number of seroconversions).  Study Entry specimens are collected 

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at participants’ Enrollment Visit.  Seroconversion specimens are collected at the 
schedule specified in Section 7.6.1.  All specimens will be tested for evidence of 
HIV infection using FDA-licensed tests.  For all seroconverters, Study Entry 
specimens also will be confirmed.  
 
MTN LC staff will follow-up directly with site staff to resolve any quality control or quality 
assurance problems identified through proficiency testing, on-site assessments, and/or 
confirmatory HIV testing.  Further, as part of quality control, researchers may need to 
look at short pieces of non-coding repetitive DNA sequence (3-7 base pairs) from blood 
in the event of sample mix-up.  This test will only let researchers know the number of 
times this short segment is repeated and not specific genes or specific sequences of 
base pairs.  This sequence element does not contain any information about genes, 
therefore researchers will not be able to identify if participants are predisposed to 
specific diseases or any other genetic information based on this information.  This test 
will be an important tool for distinguishing whether two samples collected at the same or 
different time points are likely from the same person.  The test will only be used as part 
of a sample investigation with the knowledge of the site in situations where a known or 
suspected sample mix-up has occurred.  No genetic testing (limited or genome-wide) is 
planned on leftover samples that are stored for the purposes of future research. 
 
In addition to all of the above, an endpoint adjudication committee will provide guidance 
on endpoint determination to the Protocol Team on an as needed basis.  See the MTN 
MOP 
(http://www.mtnstopshiv.org/node/187) 
for 
detailed 
information 
on 
the 
composition, roles, and responsibilities of the endpoint adjudication committee.  
 
7.13 Specimen Collection and Processing 
 
Each study site will adhere to the standards of good clinical laboratory practice 
(http://apps.who.int/tdr/publications/tdr-research-publications/gclp-web/pdf/gclp-
web.pdf), in accordance with current US Division of AIDS (DAIDS) Laboratory 
Requirements, 
MTN-025 
Study 
Specific 
Procedures 
Manual 
(http://www.mtnstopshiv.org/studies) and site standard operating procedures for proper 
collection, processing, labeling, transport, and storage of specimens to standardize 
procedures.  Specimen collection, testing, and storage at the site laboratories will be 
documented when applicable using the Laboratory Data Management System.  In 
cases where laboratory results are not available due to administrative or laboratory 
error, sites are permitted to re-draw specimens. 
 
7.14 Specimen Handling 
 
Specimens will be handled in accordance with current requirements for DAIDS 
Sponsored 
and/or 
Funded 
Laboratories 
in 
Clinical 
Trials. 
(http://www.niaid.nih.gov/labsandresources/resources/daidsclinrsrch/documents/labpolic
y.pdf) 
 

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7.15 Biohazard Containment 
 
As the transmission of HIV and other blood-borne pathogens can occur through contact 
with contaminated needles, blood, and blood products, appropriate blood and secretion 
precautions will be employed by all personnel in the drawing of blood and shipping and 
handling of all specimens for this study as recommended by the U.S. Centers for 
Disease Control and Prevention (CDC) and National Institutes of Health (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.  Biohazard 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 Co-Chairs, DAIDS Medical Officer, 
Protocol Safety Physician(s), and SDMC Clinical Affairs Safety Associate 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 Safety Review 
 
A multi-tiered safety review process will be followed for the duration of this study.  The 
study site investigators are the first layer of this tiered system and 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 Clinical Affairs staff, the PSRT, and study sponsors.   
 
During the trial, the PSRT will review safety reports and conduct calls to review the data 
as appropriate.  The content, format and frequency of the safety reports will be agreed 
upon by the PSRT and the SDMC in advance of study implementation.  In addition to 
these 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, 

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experts external to the MTN with expertise in the fields of microbicides, biostatistics, or 
medical ethics may be invited to join the PSRT safety review.   
 
After the product use and the final safety visits are completed, less frequent reporting 
and safety reviews may be conducted at the discretion of the MTN-025 PSRT.   
 
A Study Monitoring Committee (SMC) has study oversight and is charged with 
reviewing participant safety data as no Data Safety Monitoring Board (DSMB) is 
planned for this study, see Section 10.7.1 for additional details.   
 
8.3 Adverse Events Definitions and Reporting Requirements 
 
8.3.1 Adverse Events  
 
An AE is defined as any untoward medical occurrence in a clinical research participant 
administered an investigational product and which does not necessarily have a causal 
relationship with the investigational product.  As such, an AE can be an unfavorable or 
unintended sign (including an abnormal laboratory finding, for example), symptom or 
disease temporally associated with the use of an investigational product, whether or not 
considered related to the product.  This definition is applied to all study groups, and is 
applied to both groups beginning at the time of enrollment (i.e., once a participant is 
randomized).  The term “investigational product” for this study refers to the vaginal ring. 
 
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 recorded on study 
CRFs.  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 all AEs reported by or observed in 
enrolled study participants regardless of severity and presumed relationship to study 
product.   
 
Study staff will also report on CRFs the following subset of AEs reported by or observed 
in enrolled participants: 
 
 All genital, genitourinary, and reproductive system AEs, including STIs 
 Fetal losses (e.g., spontaneous abortions, spontaneous fetal deaths, 
stillbirths) will not be reported as AEs.  However, untoward maternal 
conditions that either result in or result from fetal losses are reported as 
reproductive system AEs 

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 Genital bleeding clinically assessed to be expected is not an AE 
 All AEs of severity Grade 2 or higher  
 All serious AEs  
 All AEs that result in permanent discontinuation of study product use 
 All lab test abnormalities specified in the DAIDS Table for Grading Adult and 
Pediatric Adverse Events, Version 1.0, December 2004 (Clarification dated 
August 2009), that are not otherwise associated with a reported clinical AE 
 AEs that do not meet the above-listed criteria but do meet expedited reporting 
requirements per Section 8.3 below; this includes all congenital anomalies 
identified in the fetuses and/or infants of study participants 
 
AE severity and laboratory tests will be graded per the DAIDS Table for Grading Adult 
and Pediatric Adverse Events, Version 1.0, December 2004 (Clarification dated August 
2009) and the Female Genital Grading Table for Use in Microbicide Studies (Addendum 
1 to the DAIDS Table for Grading Adult and Pediatric Adverse Events, Version 1.0, 
December 2004 (Clarification dated August 2009), except that asymptomatic BV and 
asymptomatic candidiasis will not be reportable AEs.  In cases where a genital AE is 
covered in both tables, the Female Genital Grading Table for Use in Microbicide Studies 
will be the grading scale utilized.   
 
All AE Log forms completed for each participant should be reviewed at the study exit 
visit and updated as needed.  For AEs that are ongoing at the exit visit, the 
status/outcome of the AE should be updated to “continuing at end of study participation” 
and the AE Log form should be re-faxed to SCHARP DataFax.  For any serious or 
expedited AEs (SAEs/EAEs) that are continuing at a participant’s study exit visit, the 
IoR/designee must establish a clinically appropriate follow-up plan for the AE.  At a 
minimum, the SAE/EAE must be re-assessed by study staff 30 days after the 
participant’s study exit visit; additional evaluations also may take place at the discretion 
of the IoR/designee.  The same approach must be taken for any AEs that are found to 
have increased in severity at the study exit visit.  For those AEs requiring re-
assessment, if the AE has not resolved or stabilized at the time of re-assessment, study 
staff will continue to re-assess the participant at least once per month while the study is 
ongoing.  After the study has ended, all AEs requiring re-assessment will be re-
assessed at least once within the 30-60 days after the study end date.  The PSRT may 
advise study staff as to whether any additional follow-up may be indicated on a case by 
case basis.  For AEs that are re-assessed after study exit, information on the status of 
the AE at the time of re-assessment will be recorded in source documents only — no 
updates should be made to AE Log CRFs based on the re-assessments.  
 

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8.3.2 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  
 Requires inpatient hospitalization or prolongation of existing hospitalization 
 Results in persistent or significant disability/incapacity  
 Is a congenital anomaly/birth defect 
 Is an important medical event that may not result in death, be immediately life-
threatening, or require hospitalization but may jeopardize the participant or 
require intervention to prevent one of the outcomes listed in the definition 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 
 Not Related: There is not a reasonable possibility that the AE is related to the 
study agent 
 
8.4 Expedited Adverse Event Reporting Requirements 
 
8.4.1 Adverse Event Reporting to DAIDS 
 
Requirements, definitions and methods for expedited reporting of AEs are outlined in 
Version 2.0 of the DAIDS EAE Manual, which is available on the RSC website at 
http://rsc.tech-res.com/safetyandpharmacovigilance/.  For each study participant, 
expedited AE reporting will be undertaken throughout the scheduled duration of follow-
up, i.e., from the time of random assignment through study termination.   
 
The DAIDS Adverse Experience Reporting System (DAERS), an internet-based 
reporting system, must be used for expedited AE reporting to DAIDS.  In the event of 
system outages or technical difficulties, expedited AEs may be submitted via the DAIDS 
EAE Form.  For questions about DAERS, please contact DAIDS-ES at DAIDS-
ESSupport@niaid.nih.gov Site queries may also be sent from within the DAERS 
application itself. 
 
Where DAERS has not been implemented, sites will submit expedited AEs by 
documenting the information on the current DAIDS EAE Form.  This form is available on 

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the RSC website, http://rsc.tech-res.com/safetyandpharmacovigilance/.  For questions 
about EAE reporting, please contact the RSC (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 dapivirine VR  
 For all SAEs submitted, sites must file an initial report and an update to IPM and 
the DAIDS Medical Officer with the final or stable outcome unless the initial SAE 
submitted had a final or stable outcome noted already 
 
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, Version 1.0, December 2004 (Clarification, 
August 2009) and the Female Genital Grading Table for Use in Microbicide Studies 
(Addendum 1 to the DAIDS Table for Grading Adult and Pediatric Adverse Events, 
Version 1.0, December 2004 (Clarification, August 2009)), will be used and is available 
on the RSC website at http://rsc.tech-res.com/safetyandpharmacovigilance/. 
 
8.4.4 Expedited AE Reporting Period 
 
 The expedited AE reporting period for this study begins once the participant is 
randomized and continues up through the participant’s final study visit (Study 
Exit/Termination Visit). 
 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 Social Harms Reporting 
 
Although study sites will make every effort to protect participant privacy and 
confidentiality, it is possible that participants’ involvement in the study could become 
known to others and that social harms may result.  For example, participants could be 
treated unfairly, or could have problems being accepted by their families, partners 
and/or communities.  Social harms that are judged by the IoR/designee to be serious or 
unexpected will be reported to the PSRT and responsible site ECs/IRBs according to 
their individual requirements.  In the event that a participant reports social harm, every 
effort will be made by study staff to provide appropriate care and counseling to the 
participant, and/or referral to appropriate resources for the safety of the participant as 
needed.  Each site will provide such care and counseling in accordance with 
standardized guidance provided in the MTN-025 SSP Manual.  While maintaining 

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participant confidentiality, study sites may engage their community advisory boards 
(CABs) in exploring the social context surrounding instances of social harm. 
 
8.6 Regulatory Requirements 
 
Information on all reported CRFs will be included in reports to the FDA and other 
applicable government and regulatory authorities.  Site IoRs/designees will submit AE 
information in accordance with local regulatory agencies’ or other local authorities’ 
requirements.  Site IoRs/designees also will submit AE information and any other 
relevant safety information to their ECs/IRBs in accordance with ECs/IRB 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 temporarily 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 should 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.  
 
9.1 Grading System 
 
AE severity grading is described in Section 8.3.3. 
 
9.2 Dose Modification Instructions 
 
No dose modifications will be undertaken in this study. 
 
9.3 General Criteria for Temporary Hold and Permanent Discontinuation of 
Study Product 
 
A participant will be permanently discontinued from study VR use by the IoR/designee 
for any of the following reasons:   
 
 Acquisition of HIV infection; such participants will not resume product use at any 
time.  The study VR should be held beginning immediately upon recognition of 
the first reactive rapid HIV test.  If via the algorithm in Appendix III the participant 
is determined to be HIV-uninfected, she may resume product use.  The 
IoR/designee must permanently discontinue the study VR if HIV infection is 
confirmed.  
 Allergic reaction to the study VR. 

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A participant will be temporarily held from study VR for any of the following reasons: 
 
 A reactive rapid HIV test. 
 Pregnancy.  A participant who becomes pregnant may resume product use after 
giving birth or other pregnancy outcome, as evidenced by a negative pregnancy 
test performed by study staff, provided the participant is not breastfeeding.  A 
pelvic exam must be performed prior to resumption to confirm the absence of any 
findings that would contraindicate resumption, in the opinion of the IoR/designee. 
 Breastfeeding.  Product use may resume when the participant reports complete 
cessation of breastfeeding. 
 Report of use of PEP for HIV exposure.  The participant may resume product use 
when she reports completion of PEP and is confirmed HIV-uninfected based on 
testing performed at the study site per the algorithm in Appendix III. 
 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.  The IoR/designee 
must consult the PSRT on all temporary product holds instituted for this reason 
for further guidance on resuming product use, continuing the temporary hold, or 
progressing to permanent discontinuation.  If product use is temporarily 
held/permanently discontinued for this reason, but the underlying reason for the 
temporary hold later resolves, the IoR/designee should consult the PSRT to 
resume product use at that time.   
 
9.4 Temporary Product Hold/Permanent Discontinuation in Response to 
Observed Adverse Events 
 
Grade 1 or 2 
In general, a participant who develops a Grade 1 or 2 AE not specifically addressed 
below, regardless of relatedness to study product, may continue product use.   
 
Grade 3 
Participants who develop a Grade 3 AE that is not specifically addressed below and is 
judged by the IoR/designee to be not related to study product may continue product use.   
 
In general, for participants who develop a Grade 3 AE not specifically addressed below, 
judged by the IoR/designee to be related to study product, and unless otherwise decided 
in consultation with the PSRT, the IoR/designee should: 
 Temporarily hold the study product. 
 Re-evaluate the participant at least weekly for up to 2 weeks. 
 Resume study product if improvement to ≤ Grade 2 is documented within 2 
weeks. 
 Consult PSRT regarding further study product management if improvement to 
severity ≤ Grade 2 cannot be documented within 2 weeks.   
 

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August 22, 2014 
 
If product use is resumed and the same Grade 3 AE deemed related to study product, 
recurs at any time, the IoR/designee must temporarily hold study product and consult 
the PSRT for further guidance on continuing the temporary hold or progressing to 
permanent discontinuation of the study product. 
 
Grade 4 
Participants who develop a Grade 4 AE (regardless of relationship to study product) 
should 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 Other Clinical Findings 
 
The IoR/designee should manage STI/RTI per local guidelines or current WHO 
guidelines, available at http://www.who.int/en/.   
 
A thorough evaluation of genital complaints is expected in the context of this study; 
however, syndromic management of genital symptoms is acceptable while awaiting 
laboratory results if such practice is in line with the local standards of care.  Observed 
single dose treatment should be provided whenever possible, per clinician discretion.  
When clinically appropriate, investigators should use oral or parenteral (in the case of 
syphilis, for example) medications when at all possible.   
 
 Study VR need not be held in the event of an STI/RTI requiring treatment, unless 
other temporary product hold/permanent discontinuation guidelines apply. 
 Should the IoR/designee determine that a temporary hold is warranted, 
consultation with the PSRT is required. 
 
If a suspected finding is reported by a participant between scheduled visits, an interim 
visits 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 (abrasion/peeling)  
 Continue study VR use 
 Perform naked eye evaluation 
 
 Re-evaluate by speculum examination in 3-5 days 
 If condition worsens, temporarily hold study VR use and consult the PSRT; 
otherwise continue study VR use 
 
Deep epithelial disruption (ulceration) 
 Temporarily hold study VR for deep epithelial disruption confirmed by site 
investigator 
 Re-evaluate in 3-5 days and resume study VR use if resolved 
 If unresolved at 3-5 days, re-evaluate within 2-3 days.  If resolved at that time, 
may resume study VR use.  If unresolved at this second reevaluation, continue 

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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 the PSRT regarding permanent discontinuation 
 
Localized erythema or edema: area of less than 50% of vulvar surface or 
combined vaginal and cervical surface 
 
 Continue study VR use 
 
 Perform naked eye evaluation 
 
 If asymptomatic, re-evaluate at next regularly scheduled visit 
 If symptomatic, re-evaluate by speculum examination in 3-5 days 
 If worsened significantly, temporarily hold study VR use and consult the PSRT; 
otherwise continue study VR use 
 
Generalized erythema or severe edema: area of more than 50% of vulvar surface 
or combined vaginal and cervical surface affected by erythema  
 Temporarily hold study VR 
 Perform naked eye evaluation 
 
 Re-evaluate in 3-5 days and resume study VR use if resolved 
 If unresolved at 3-5 days, re-evaluate within 2-3 days.  If resolved at that time 
may resume use.  If unresolved at this second reevaluation, continue temporary 
product hold, consult with PSRT regarding permanent discontinuation, and 
provide care per local standard 
 
Unexpected genital bleeding 
 Continue study VR 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 VR use 
 
Cervicitis (including findings on exam such as inflammation and/or friability)  
 Temporarily hold study VR 
 Evaluate for GC/CT; consider syndromic management, pending results of testing 
and per clinician discretion 
 If GC/CT detected, provide or prescribe treatment 
 Reevaluate in 3-5 days.  If all symptoms and signs are resolved at that time 
resume study VR use  
 
Genital petechia(e)  
 Continue study VR use 
 
 Perform naked eye evaluation  
 Further evaluation or treatment per clinician discretion 
 
Genital ecchymosis  
 Continue study VR use 

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 Perform naked eye evaluation  
 Further evaluation or treatment per clinician discretion 
 
The study product need not be held in the event of an STI/RTI requiring treatment, 
unless other temporary product hold/permanent discontinuation guidelines apply.  
Should the IoR/designee determine that a temporary product hold is warranted, 
notification of the PSRT is required. 
 
9.6 HIV Infection 
 
A participant who has a positive test for HIV must have study product held, but will not 
be withdrawn from the study.  If the participant is subsequently determined to be HIV-
uninfected according to the algorithm in Appendix III, study product may be resumed.  If 
HIV infection is confirmed, study product will be permanently discontinued by the 
IoR/designee.  Participants identified as infected with HIV are managed or referred for 
management according to the local standard of care.  These participants are also 
offered participation in MTN-015, the MTN Seroconverter Study, which also includes 
provisions for the clinical management and/or referral of participants infected with HIV.   
 
The care provided at the referral sites is at a level that meets or exceeds the community 
standard for HIV care.  Written SOPs for referral for HIV care and treatment are in place 
at each study sites.  All study site investigators have identified facilities offering 
psychological and social services and medical care, including antiretroviral therapy 
(ART), to people infected with HIV-1 in the study countries.  Some of the research sites 
are part of health care institutions that provide HIV care and support, and can refer 
women to those services.  Other sites have established referral agreements with 
programs to expand access to ART.   
 
At every study visit, study staff will actively follow-up on prior referrals to HIV care and 
support services, to determine whether the participant sought the care to which she was 
referred, the outcome of the referral, and whether additional referrals are needed.  All 
follow-up actions, outcomes, counseling, and plans for next steps are documented in 
participant study records.  Results of study laboratory testing may be helpful in clinical 
management; these results are provided to the participant and her medical provider as 
soon as they are available. 
 

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9.7 Pregnancy 
 
A participant who becomes pregnant at any time during the study must have study 
product temporarily held, but will not be withdrawn from the study.  Every effort will be 
made to have the study participant continue in modified follow-up until her study 
termination visit or pregnancy outcome is ascertained.  The IoR/designee will counsel 
any participant who becomes pregnant regarding possible risks to the fetus according to 
site SOPs.  The IoR/designee also will refer the participant to all applicable services; 
however, sites will not be responsible for paying for pregnancy-related care.   
 
Participants who become both pregnant and HIV-infected will have expedited HIV-1 
resistance testing performed at the MTN LC to provide information about possible 
resistance that might impact the efficacy of ART regimens to reduce mother-to-child 
HIV-1 transmission.  The participant will be referred to local providers for antenatal care, 
and prevention of mother-to-child transmission services.  HIV testing for infants is 
provided by the study if not otherwise accessible by the participant.  
 
A participant who becomes pregnant during the course of study participation may be 
offered participation in MTN-016, the Prevention Agent Pregnancy Exposure Registry.  
This registry is anticipated to capture pregnancy outcomes as well as infant health 
information, (including growth and development), to evaluate the safety and teratogenic 
risks of microbicide and oral PrEP exposure in pregnancy.   
 
All pregnancies will be followed until a pregnancy outcome can be ascertained (or, in 
consultation with the PSRT, it is determined that the pregnancy outcome cannot be 
ascertained).  This includes participants who are pregnant at the Study Exit/Termination 
Visit.  Pregnancy outcomes are reported on relevant CRFs. 
 
9.8 Criteria for Early Termination of Study Participation 
 
Participants may voluntarily withdraw from the study for any reason at any time.  The 
IoR 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.  The PSRT must be 
notified of all terminations conducted per IoR discretion.  Participants also may be 
withdrawn if the study sponsors, government or regulatory authorities, including the 
FDA and Office for Human Research Protections (OHRP), or site IRBs/ECs terminate 
the study prior to its planned end date.  Every reasonable effort will be 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.  In the event that participants who voluntarily 
withdraw from the study wish to re-join the study, they may resume product use (if 
applicable) and follow-up through their originally scheduled study exit date, pending 
consultation with the PSRT.   
 
 
 

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10 
STATISTICAL CONSIDERATIONS 
 
10.1 Overview and Summary of Design 
 
This is a Phase 3B, open-label, multi-site, randomized trial.  A sample size of 
approximately 1000-2500 participants will be randomly assigned in a 1:1 ratio to either 
monthly or quarterly follow-up.  The two main goals of the trial are:  
1. To characterize the safety profile associated with the open label use of the 
dapivirine vaginal matrix ring (25 mg) in women, and to assess safety when 
randomized to a monthly vs. quarterly follow-up schedule 
 
2. To characterize adherence the open label use of the dapivirine vaginal matrix 
ring (25 mg) in women and to compare adherence when randomized to a 
monthly vs. quarterly follow-up schedule 
 
Secondary objectives of the study include assessing the incidence of HIV-1 infection 
and frequency of HIV-1 drug resistance in women who acquire HIV-1 infection.  
 
10.2 Study Endpoints 
 
10.2.1 Primary Endpoints 
 
1. Safety  
- 
Grade 2 AEs judged to be related to the dapivirine vaginal ring 
- 
Grade 3 and higher AEs 
- 
All serious AEs 
 
2. Study Product Adherence 
- 
Residual levels of dapivirine in returned vaginal rings  
- 
Blood dapivirine levels  
 
10.2.2 Secondary Endpoints 
 
1. Incidence  
- 
HIV-1 infection as measured by the protocol algorithm 
 
2. Drug Resistance 
- 
HIV-1 drug resistance mutations among participants who acquire HIV-1, as 
measured by standard genotype analysis and more sensitive methods to 
detect low frequency drug-resistant variants 

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10.3 Sample Size 
 
We expect between 1000 and 2500 participants to enroll in this study.  The final number 
is dependent upon both the final number enrolled in MTN-020, ASPIRE, and the 
proportion of ASPIRE participants who choose to enroll into MTN-025, HOPE.  Power is 
discussed with the primary analyses as appropriate. 
 
10.4 Participant Accrual, Follow-up and Retention 
 
The majority of former ASPIRE participants are anticipated to enroll within the first 3-6 
months after site activation, however this period could be shorter or longer depending 
upon accrual rates.  Because of the potential to randomize to a monthly or a quarterly 
follow-up schedule, it is anticipated that the study will close to accrual 4 months ahead 
of the anticipated closure of the study.  Based upon the timing of when a participant is 
enrolled, follow-up may last approximately 4-13 months.  
 
10.5 Randomization 
 
At the enrollment visit, participants will be randomly assigned to one of the two follow-up 
arms (monthly vs. quarterly) in a 1:1 ratio.  The randomization scheme will be stratified 
by site and will be generated and maintained by the MTN SDMC.  The randomized 
assignments will be in blocks to keep the balance of equal allocation.  The SDMC will 
provide each study site with a series of numbered, sealed envelopes containing the 
randomization assignment for each participant.  The envelopes will be assigned 
sequentially by site staff.  The MTN SDMC will coordinate the randomization 
procedures, which will be specified in the SSP Manual.  Assignment of the clinic 
randomization envelope is considered the effective act of participant randomization. 
 
10.6 Blinding 
 
This is an open-label and unblinded trial.  
 
10.7 Data and Safety Monitoring Procedures 
 
10.7.1 Study Monitoring Committee 
 
In addition to the safety monitoring done by the PSRT (described in Section 8), the MTN 
SMC will be responsible for study oversight by conducting interim reviews of study 
progress, including rates of participant accrual, participant retention, protocol and 
intervention adherence, data quality, laboratory quality and completion of primary and 
secondary endpoint assessments.  Since MTN-025 is not subject to DSMB review, the 
SMC also will review participant safety data, as specified in the MTN Manual of 
Procedures.  These reviews will take place approximately every 6 months and as 
needed.  
 

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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.  The 
SMC may consider recommending termination of this study if recruitment is lower than 
targeted, or if study data quality is poor.  If at any time, a decision is made to 
discontinue participants, IPM, after consultation with the protocol team, will inform the 
US Food and Drug Administration (FDA).  The Site PIs will notify the responsible ECs 
expeditiously. 
 
10.7.2 Monitoring Quality of Study Conduct Operational Characteristics and 
Implementation 
  
The 
study 
may 
be 
terminated 
or 
modified 
for 
poor 
accrual/recruitment, 
adherence/product use, and/or retention.  Regular reports will be provided to the SMC 
that outline the potential impact on the study’s ability to meet its objectives if there 
are deviations from the statistical design in terms of accrual/recruitment, 
adherence/product use, retention, and/or low HIV acquisition rate. 
 
10.8 Primary Analyses 
 
10.8.1 Primary Safety Analysis 
 
Consistent with the primary safety objective, this analysis will characterize the safety 
profile for the overall population and the two arms.  Because women in the monthly arm 
will be seen more frequently, we expect that more safety events will be recorded that 
would otherwise go unreported or unobserved with less frequent follow-up.  Therefore, 
under this design a comparison between the arms is most appropriate for AEs that 
would be captured regardless of frequency of follow-up.  These include the two key 
secondary outcomes of drug resistance and breakthrough infections.  Those analyses 
will be covered in Section 10.9.  As a supporting analysis, rates of AEs between the 
arms at quarterly visits will be compared, recognizing that this may be imperfect as well 
since monthly participants may have AEs resolved before a quarterly visit that may have 
remained unresolved were they on the quarterly schedule.  Therefore, the AE rate in the 
monthly arm may look lower at quarterly visits because the AEs have been resolved. 
 
Adverse events will be analyzed using MedDRA preferred terms.  The number and 
percentage of participants experiencing each specific AE will be tabulated by severity 
and by relationship to treatment regimen.  For the calculations in these tables, each 
participant’s AE will be counted once under the maximum severity or the strongest 
recorded causal relationship to study product. 
 
All AEs will be grouped by body system and a confidence interval for the incidence of 
each AE will be calculated overall and by arm.  Finally, a listing of EAEs reported to the 
DAIDS Safety Office will provide details of the event including severity, relationship to 
study product, onset, duration and outcome.  
 

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Note that all of the above summaries will be calculated under the intention-to-treat (ITT) 
principle.  However, participants off study product and/or those who are non-adherent 
that are included in these analyses could potentially lower the rate of safety and toxicity 
endpoints.  Therefore, a ‘per-protocol’ analysis, where time off product is excluded from 
the analysis, will be used to explore the sensitivity of the conclusions obtained with the 
safety analysis under the ITT principle. 
 
Assuming between 1000 and 2500 participants are enrolled with an average of 11 
months of follow-up per participant, we expect between 917 and 2300 person-years of 
follow-up during this study.  The assumed 11-month average follow-up reflects both loss 
to follow-up and staggered entry. 
 
10.8.2 Primary Adherence Analysis 
 
For the primary study aim related to adherence, participants will be categorized as 
adherent if drug is detected in all quarterly plasma samples when participants are not on 
a product hold.  The arms will be compared using a chi-square test for 2x2 tables. 
 
Based on this primary analysis plan, we calculated power under a variety of 
assumptions.  The figure below shows hypothetical adherence rates for the two arms on 
the x- and y-axes.  The curves connect the comparisons for which the comparison has 
90% power.  Each curve represents a hypothetical sample size across both arms 
ranging from 2500 (representing a potential full study analysis) to 100 (representing a 
potential within site or subgroup analysis).  For example, with a sample size of 1500, if 
the higher adhering arm has 80% adherence, the study has 90% power to detect a 
difference between the two arms if the lower adherence arm has adherence of 73% or 
less.  If the sample, size were instead 200, we could detect a difference between an 
80% adherent arm and a 59% adherent arm. 

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Figure 2: Comparison of Rates of Adherence (Low Group Vs. High Group) 
 
The analysis described above compares rates of perfect adherence as measured in 
plasma.  In an effort to understand more complicated adherence patterns, secondary 
analyses for adherence will be performed.  Similar analysis of residual drug levels in 
VRs will also be performed.  Many of these will be informed by findings from ASPIRE 
and will be fully explained in a Statistical Analysis Plan prior to the completion of follow-
up in MTN-025. 
 
10.9 Analysis of Secondary Endpoints 
 
Primary analysis of the two main secondary endpoints, HIV seroconversion and 
acquisition of ARV-resistant HIV infection will be conducted similarly.  We will calculate 
the incidence overall and by arm for each endpoint.  Use of new and additional HIV-1 
prevention technologies, such as oral PrEP and/or topical vaginal gels, will be captured 
on standardized data forms and will be taken into account in the analysis of HIV-1 
incidence.  We will calculate confidence intervals for the differences between arms in 
incidence rates using the Poisson distribution.  We anticipate this analysis to have low 
power since we will be comparing two arms in which participants are prescribed an 
active product that has been proven effective.  Although, statistical summaries will be 
provided, the results will likely have to be judged based on clinical and public health 
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MTN-025, Version 1.0 
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August 22, 2014 
 
acceptability.  Additional analyses will likely evolve based on results from ASPIRE.  
These will be outlined in the Statistical Analysis Plan prior to the end of study follow-up. 
 
10.10 Missing Data 
 
We are targeting a retention rate of 95% over the study period.  Based on previous HIV 
Prevention Trials Network (HPTN) and MTN trials, we expect to have minimal missing 
data.  In any situation with missing data, we will do appropriate secondary analyses that 
adjust for variables that may be related to the missingness mechanism.  If missing data 
rates are higher than anticipated (over 10%), we will include covariates that are related 
to missingness in likelihood-based regression models.  We will also perform sensitivity 
analyses to assess the potential impact of the missing data.  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. 
 
 
 
11 
DATA HANDLING AND RECORDKEEPING 
 
11.1 Data Management Responsibilities 
 
Study CRFs will be developed by the MTN SDMC in conjunction with the protocol team.  
Quality control reports and queries routinely will be generated and distributed by the 
SDMC to the study sites for verification and resolution.  As part of the study activation 
process, each study site must identify all CRFs to be used as source documents.  Study 
CRF data are transferred to the MTN SDMC, entered, and cleaned using the DataFax 
data management system.   
 
Transcriptions of interviews will be generated in the field and electronically transferred 
to RTI International using a secure File Transfer Protocol (FTP) site, where they will be 
uploaded and managed using a qualitative software package.  RTI International will act 
as a hub, and manage all data for the study.  A convention for file naming will be 
developed, and all data will be labeled according to this process.  Original language and 
translated transcripts will be transferred to RTI International as they are completed.  RTI 
International will save all versions of all files on a secure, password-protected server.  
 
11.2 Source Documents and Access to Source Data/Documents 
 
All study sites will maintain source data/documents in accordance with Requirements 
for Source Documentation in DAIDS Funded and/or Sponsored Clinical Trials 
(http://www.niaid.nih.gov/LabsAndResources/resources/DAIDSClinRsrch/Documents/so
urcedocpolicy.pdf) and the relevant appendix regarding source documentation 
(http://www.niaid.nih.gov/LabsAndResources/resources/DAIDSClinRsrch/Documents/so
urcedocappndx.pdf).   
 

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Each IoR/designee will maintain, and store securely, complete, accurate and current 
study records throughout the study.  In accordance with U.S. regulations, for the 
investigational product tested, the IoR/designee will maintain all study documentation 
for at least two years following the date of marketing approval for the indication in which 
they were studied.  If no marketing application is filed, or if the application is not 
approved, the records will be retained for two years after the investigation is 
discontinued and the US FDA is notified.   
 
Study records must be maintained on site for the entire period of study implementation.  
Thereafter, instructions for record storage will be provided by DAIDS.  No study records 
may be moved to an off-site location or destroyed prior to receiving approval from 
DAIDS.   
 
Audio files will be transcribed and immediately destroyed following a transcription 
quality assurance check.  The site IoR or designee will be responsible for ensuring that 
these files have been destroyed. 
 
11.3 Quality Control and Quality Assurance 
 
All study sites will conduct quality control and quality assurance procedures in 
accordance with Requirements for Clinical Quality Management Plans at DAIDS 
Funded 
and/or 
Supported 
Clinical 
Research 
Sites    
(http://www.niaid.nih.gov/LabsAndResources/resources/DAIDSClinRsrch/Documents/q
mppolicy.pdfhttp://www.niaid.nih.gov/LabsAndResources/resources/DAIDSClinRsrch/D
ocuments/qmppolicy.pdf). 
 
 
 
12 
CLINICAL SITE MONITORING 
 
Study monitoring will be carried out by Pharmaceutical Product Development, Inc. 
(PPD) (Wilmington, NC) in accordance with current DAIDS policies.  Study monitors will 
visit the site to do the following: 
 
 Review informed consent forms, procedures, and documentation 
 Assess compliance with the study protocol, Good Clinical Practices (GCP) 
guidelines, and applicable regulatory requirements (US and non-US), including 
CFR Title 45 Part 46 and Title 21 Parts 50, 56, and 312  
 Perform source document verification to ensure the accuracy and completeness 
of study data 
 Verify proper collection and storage of biological specimens 
 Verify proper storage, dispensing, and accountability of investigational study 
products 
 Assess implementation and documentation of internal site quality management 
procedures 

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 Verify that current license/certification is available on site for study staff listed on 
the current FDA Form 1572, DAIDS IoRs, and Delegation of Responsibilities 
Log/Form. 
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 certain study procedures.  The 
IoR/designee will also allow inspection of all study-related documentation by authorized 
representatives of the MTN LOC, SDMC, and LC; NIAID, FDA, IPM, OHRP and local 
and US regulatory authorities.  A site visit log will be maintained at the study site to 
document all visits. 
 
 
 
13 
HUMAN SUBJECTS PROTECTIONS 
 
13.1 Institutional Review Boards/Ethics Committees 
 
Site investigators will make efforts to minimize risks to participants.  Participants and 
study staff members will take part in a thorough informed consent process.  Before 
beginning the study, the IoR will have obtained IRB/EC approval and the protocol will 
have been submitted to the FDA.  The IoR will permit audits by the NIH, IPM, the FDA, 
OHRP, or any of their appointed agents. 
 
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 consent forms approved, as 
appropriate, by their local IRB/ EC and any other applicable regulatory entity (RE).  
Upon receiving final approval, sites will submit all required protocol registration 
documents to the DAIDS Protocol Registration Office (DAIDS PRO) at the RSC.  The 
DAIDS PRO will review the submitted protocol registration packet to ensure that all of 
the required documents have been received.   
 
Site-specific informed consent forms (ICFs) will not be reviewed or approved by the 
DAIDS PRO, and sites will receive an Initial Registration Notification when the DAIDS 
PRO receives a complete registration packet.  Receipt of an Initial Registration 
Notification indicates successful completion of the protocol registration process.  Sites 
will not receive any additional notifications from the DAIDS PRO for the initial protocol 
registration.  A copy of the Initial Registration Notification should be retained in 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 

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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. 
 
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 
 
IPM holds the Investigational New Drug (IND) application for this study.  Copies of all 
regulatory documents submitted to this IND by IPM will be forwarded to DAIDS for 
cross-referencing with other INDs for the study product.  Assignment of all sponsor 
responsibilities for this study will be specified in a Clinical Trial Agreement executed by 
NIAID and IPM. 
 
Study implementation will also be guided by a common study-specific procedures 
manual that provides further instructions and operational guidance on conducting study 
visits; data and forms processing; specimen collection, processing, and shipping; AE 
assessment, management and reporting; dispensing study product 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 
 
General 
It is not expected that this trial will expose human subjects to unreasonable risk.   
 
Pelvic examination and procedures may cause mild discomfort and/or vaginal bleeding 
or spotting.  Phlebotomy may lead to discomfort, feelings of dizziness or faintness, 
and/or bruising, swelling and/or infection.  Disclosure of HIV and STI status may cause 
worry, sadness or depression.  Disclosure of HIV-positive status has been associated 
with depression, suicidal ideation, and denial as well as social isolation.  Trained 
counselors will be available to help participants deal with these feelings.  Participation in 

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clinical research includes the risks of loss of confidentiality and discomfort with the 
personal nature of questions when discussing sexual behaviors. 
 
Participants at sites requiring partner notification in response to diagnosed STI or HIV 
infection could have problems in their relationships with their sexual partners.  It is 
possible that the participant and her partner may feel the ring during sexual activity.  
Participants also could experience problems associated with use of study product in 
their partner relationships. 
 
Use of the study VR may lead to vaginal symptoms, including irritation, increased 
discharge, and discomfort (including with vaginal intercourse).  It is possible that a 
participant may have an allergic reaction to the study product.  Symptoms of an allergic 
reaction include rash or other skin irritation, itching, joint pain, or difficulty in breathing. 
 
Based on AEs reported among female participants in previous studies, dapivirine VRs 
may be associated with:  
 Vaginal candidiasis 
 Vaginal bleeding 
 Headache 
 Fatigue 
 Vulvovaginal or genital itching 
 Abdominal discomfort 
 Abdominal pain 
 Urinary incontinence 
 Nausea 
 Vaginal or genital discharge 
 
Please note:  Study product risks will be updated when the safety and 
effectiveness data from ASPIRE are available. 
 
As with any vaginally retained product, the possibility of toxic shock syndrome, although 
rare, exists. 
 
Based on in vitro data, HIV-infected participants who have prolonged exposure to low 
concentrations of dapivirine by continuing to use the ring after infection may have a risk 
of selecting viruses carrying NNRTI resistance-associated mutations.  Clinical relevance 
has yet to be established. 
 
Site staff will make every effort to protect participant privacy while in the study.  
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 and/or communities.   
 

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13.4.2 Benefits 
 
MTN-025 (HOPE) will only be implemented if the dapivirine vaginal ring as tested in 
MTN-020 (ASPIRE) is found to be safe and effective, therefore, participants in the 
HOPE study will experience the direct benefit of using a product that has been found to 
be safe and effective in preventing HIV acquisition and will be considered for potential 
regulatory approval.  Participants and others may benefit in the future from information 
learned from this study.  Specifically, information learned in this study may help to 
understand issues important for broader implementation of the dapivirine ring and/or for 
the development of other safe and effective interventions to prevent HIV acquisition.  
Participants may also appreciate the opportunity to contribute to the field of HIV 
prevention research.  
 
Participants will receive HIV/STI risk reduction counseling, HIV and STI testing, physical 
examination, pelvic examination, and routine laboratory testing.  Participants will be 
provided STI treatment in accordance with WHO guidelines free of charge.  In addition, 
STI testing, counseling and treatment, as well as HIV testing and counseling will be 
available for participants’ partners.  For other medical conditions identified as part of the 
study screening and/or follow-up procedures, participants will be referred to other 
sources of care available in their community.  Some volunteers may have the 
opportunity to access expedient treatment and decreased morbidity due to early 
diagnosis and treatment of abnormalities identified during tests, examinations and 
referrals.  
 
13.5 Informed Consent Process 
 
Each study participant will provide written informed consent prior to both screening and 
enrollment.  Written informed consent will also be obtained for long-term specimen 
storage and possible future testing, for off-site clinic visits as needed, as well as for 
participation in the ‘Decliner Cohort’.  Neither consent for long-term specimen storage 
nor off-site study visits are required for study participation.  Further, participation in the 
‘Decliner Cohort’ does not preclude MTN-025 full 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 
(http://rsc.tech-res.com/policiesandregulations/).  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 study-specific procedures manual.   
 

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The informed consent process will cover all elements of informed consent required by 
research regulations.  In addition, the process will specifically address the following 
topics of importance to this study: 
 Randomization and the importance of participants in both 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 benefit of study participation  
 The distinction between research and clinical care 
 The right to withdraw from the study at any time 
 New information, including results of MTN-020 (ASPIRE)and IPM 027 (The Ring 
Study),and information about other effective HIV-prevention products will be 
provided to MTN-025 (HOPE) participants.   
 
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 at the study site.  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 records that contain 
names or other personal identifiers, such as locator forms and informed consent forms, 
will be stored securely.  All local databases will be secured with password protected 
access systems.  Forms, lists, logbooks, appointment books, and any other listings that 
link participants’ identification numbers to identifying information will be stored in a 
locked file in an area with limited access.  All digital audio files will be stored on 
password-protected computers.  Audio files will be transcribed.  Please see SSP for 
guidance regarding audio file destruction.  Participants’ study information will not be 
released without their written permission, except as necessary for review, monitoring, 
and/or auditing by the following: 
 Representatives of the US Federal Government, including the US FDA, the US 
OHRP, NIH, and/or contractors of the NIH, and other local and US regulatory 
authorities 
 Representatives of IPM, including study monitors 
 PPD 
 Study staff  
 Site IRBs/ ECs 

MTN-025, Version 1.0 
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13.7 Special Populations 
 
13.7.1 Pregnant Women 
 
Women who test positive for pregnancy at Screening or Enrollment Visits will not be 
eligible to participate in this study.  Should a woman test positive for pregnancy after 
Enrollment, a product hold will be implemented but all follow-up visits will be completed 
and data collected per Section 7.6.2.  A urine pregnancy test will be performed at 
scheduled study visits, and additionally at interim visits as indicated; the IoR/designee 
will temporarily discontinue study product for participants who test positive for 
pregnancy.  During the informed consent process, women will be informed that the VR 
is not a method of contraception and the effects of the VR on a developing human fetus 
are unknown. 
 
Animal studies have failed to demonstrate risk to the fetus, but there are no adequate 
and well-controlled studies in pregnant women completed to support their inclusion to 
date.  
 
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/EC approval, participants will be compensated for time and effort in this 
study, and/or be reimbursed for travel to study visits and time away from work.  Site-
specific reimbursement amounts will be specified in the study informed consent forms.  
Each study site will determine appropriate compensation with their overseeing IRB/EC. 
 
13.9 Communicable Disease Reporting 
 
Study staff will comply with local requirements to report communicable diseases 
including HIV-1 identified among study participants to health authorities.  Participants 
will be made aware of reporting requirements during the informed consent process. 
 
13.10 Access to HIV-related Care 
 
13.10.1 
HIV Counseling and Testing 
 
HIV test-related counseling will be provided to all potential study participants who 
consent to undergo HIV-1 screening to determine their eligibility for this study, and to all 

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enrolled participants at each follow-up HIV-1 testing time point.  Testing will be 
performed in accordance with the algorithm in Appendix III.  Counseling will be provided 
in accordance with standard HIV counseling policies and methods at each site and 
additionally will provide information regarding the known efficacy of the study product in 
preventing HIV-1 infection.  In accordance with the policies of the NIH, participants must 
receive their HIV-1 test results to take part in this study.  Condoms will be offered to 
participants throughout the duration of their participation. 
 
13.10.2 
Care for Participants Identified as HIV-Infected 
 
Care for participants identified as HIV-infected is described in Section 9.6. 
 
13.11 Study Discontinuation 
 
This study may be discontinued at any time by NIH, the MTN, IPM, the US FDA, the 
OHRP, other government or regulatory authorities, or site IRBs/ECs. 
 
 
 
14 
PUBLICATION POLICY 
 
DAIDS/NIAID and MTN policies and a CTA between NIAID and IPM will govern 
publication of the results of this study. 
 

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15 
APPENDICES 
 
 
 

MTN-025, Version 1.0 
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Appendix I: SCHEDULE OF STUDY VISITS AND EVALUATIONS 
 
 
 
Study Months 
 
 
SCR 
ENR 
1, 2, 4, 5, 
7, 8, 10, 
11 
3, 6, 9 
PUEV 
~12 
Study Exit/ 
Term. Visit 
(~Month 13) 
ADMINISTRATIVE AND REGULATORY 
 
 
 
 
 
 
Obtain informed consent 
X 
X 
 
 
 
 
Assign a unique Participant Identification (PTID) 
number  
X 
 
 
 
 
 
Assess and/or confirm eligibility 
X 
X 
 
 
 
 
Collect/review/update locator information 
X 
X 
X 
X 
X 
X 
Randomization 
 
X 
 
 
 
 
Provide reimbursement for study visit 
X 
X 
X 
X 
X 
X 
Schedule next visit 
* 
* 
X 
X 
X 
* 
BEHAVIORAL 
 
 
 
 
 
 
Contraceptive counseling 
X 
X 
X 
X 
X 
* 
HIV/STI risk reduction counseling 
X 
X 
X 
X 
X 
X 
HIV pre- and post-test counseling 
X 
X 
X 
X 
X 
X 
Protocol adherence 
 
X 
X 
X 
 
 
Conduct a behavioral assessment 
 
X 
 
X 
X 
X 
Conduct social harms assessment 
 
 
 
X 
X 
 
CLINICAL 
 
 
 
 
 
 
Obtain/update medical and menstrual history 
X 
X 
X 
X 
X 
X 
Obtain/update concomitant medications 
X 
X 
* 
X 
X 
X 
Conduct a physical examination 
X 
* 
* 
¥ 
X 
* 
Perform a pelvic examination 
X 
* 
* 
* 
X 
* 
Offer contraceptives 
* ⁪ 
*  
* ⁪ 
* 
* ⁪ 
* ⁪ 
Disclose available test results 
 
X 
X 
X 
X 
X 
Record/update AEs 
 
 
X 
X 
X 
X 
Treat or prescribe treatment for UTIs/RTIs/STIs or 
refer for other findings 
* 
* 
* 
* 
* 
* 
LABORATORY 
 
 
 
 
 
 
URINE 
hCG 
X 
X 
X 
X 
X 
X 
Urine culture 
* ⁪ Ŧ 
* ⁪ Ŧ 
* ⁪ Ŧ 
* ⁪ Ŧ 
* ⁪ Ŧ 
* ⁪ Ŧ 
NAAT for GC/CT 
X 
* ⁪ 
* ⁪ 
¥ 
X ⁪ 
* ⁪ 
BLOOD 
HIV-1 serology 
X 
X 
X              X 
X 
X 
CBC with platelets 
X 
 
 
 
X 
 
Chemistries 
X 
 
* 
* 
X 
 
Syphilis serology 
X 
 
* 
* 
X 
 
Plasma  
 
◊ 
 
X 
X 
X 
PELVIC 
Rapid test for Trichomonas 
X 
* ⁪ 
* 
¥ 
X 
* 
Vaginal fluid (self-collected) 
 
X 
X 
X 
X 
X 
Pap Smear interpretation 
* 
 
 
 
 
 
Adherence assessment(s):  Returned Study VR 
 
 
X 
X 
X 
 
STUDY PRODUCT/ SUPPLIES 
 
 
 
 
 
 
Offer condoms 
X 
X 
X 
X 
X 
X 
Provision of study VR use instructions  
 
X 
* 
* 
 
 
Provision of study VR  
 
X 
X 
X 
 
 
Removal and collection of used/unused study VR  
 
 
X 
X 
X 
 
Digital exam(s) by clinician to check VR placement 
 
* 
* 
* 
 
 
 
X mandatory, *If indicated, ŦPer local standard of care, ¥ mandatory at month 6, if indicated at all other visits, ⁪◊ for archive 

MTN-025, Version 1.0 
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APPENDIX II:  ALGORITHM FOR HIV ANTIBODY TESTING- 
SCREENING/ENROLLMENT 
 
 
Report as 
HIV uninfected 
Ineligible 
for the study
-/-
+/- 
+/+
START
2 different Rapid Tests
Notify the MTN Laboratory Center 
for follow-up.
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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APPENDIX III:  ALGORITHM FOR HIV ANTIBODY TESTING FOR FOLLOW-UP 
START
2 different Rapid Tests
Report as HIV 
Uninfected 
-/-
+/+
or
+/-
HIV RNA  
- or Ind 
Confirmation Test
Report as HIV 
Infected
+
+
- 
Notify  MTN LC  
Repeat Confirmation Test after 1 month
Ind: Indeterminate test results
LC: Laboratory Center 

 
  
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APPENDIX IV: SAMPLE INFORMED CONSENT DOCUMENT (SCREENING) 
 
SAMPLE INFORMED CONSENT FORM 
DIVISION OF AIDS, NIAID, NICHD, NIMH, NIH 
 
MTN-025 
 
A Phase 3B Open-Label Follow-on Trial to Assess the Continued Safety of and 
Adherence to a Vaginal Ring Containing Dapivirine in Women 
 
HIV Open-label Prevention Extension (HOPE) 
 
Version 1.0 
August 22, 2014 
 
 
PRINCIPAL INVESTIGATOR:  [Sites to insert] 
PHONE:  [Sites to insert] 
 
INFORMED CONSENT 
This is a screening consent form.  You are being asked to volunteer for screening tests to find 
out if you are eligible for a research study MTN-025, otherwise known as the HIV Open-label 
Prevention Extension (HOPE) trial.  The research study you participated in, MTN-020: 
ASPIRE, A Study to Prevent Infection with a Ring for Extended Use, showed that the dapivirine 
vaginal ring can reduce the chances of HIV-uninfected women from getting the HIV virus by 
[SITES TO INSERT: from X to X percent].  The study also learned that the dapivirine vaginal 
ring is [SITES TO INSERT: safe (meaning that they do not produce significant health problems 
in persons who take them)] when used by HIV-uninfected women.  Only through the 
participation of volunteers in clinical research can the safety and effectiveness of medicine be 
better understood.  More data is needed on the safety of the dapivirine vaginal ring.  Because 
you took part in the ASPIRE study, you are being offered the opportunity to use the safe and 
effective dapivirine vaginal ring as part of this new study.  A total of 2629 women enrolled into 
MTN-020 (ASPIRE) and all former ASPIRE participants who are eligible for MTN-025 (HOPE) 
may take part. It is anticipated that approximately 1000 to 2500 former ASPIRE participants will 
enroll in HOPE. 
 
This Microbicide Trials Network (MTN) study is funded by the US National Institutes of Health 
(NIH) and is being conducted across multiple countries across Africa.  The International 
Partnership for Microbicides (IPM) supplies the study product. 
 
[INSERT NAME OF PRINCIPAL INVESTIGATOR] is in charge of this study at this clinic.  
Before you decide if you want to screen for this study, we want you to learn more about the trial.  
Screening examinations and tests, which include interview questions, urine, and blood tests, a 
physical examination and an examinations of your vagina, will be performed to better 
understand your health.  The study staff will explain the exams and tests to you and what is 
expected of you.  Once you understand the screening tests, and if you agree to take part, you 
will be asked to sign your name or make your mark on this form.  You will be offered a copy of 
this form to keep.   
 

 
  
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YOUR PARTICIPATION IS VOLUNTARY 
It is important that you know the following: 
 
You are only being asked to have the screening tests at this time.  Even if you agree 
to have the screening tests, you do not have to join this study. 
 
Your participation is voluntary; you do not have to have the screening tests if you do 
not want to participate in this study. 
 
You may decide not to have the screening tests, or to withdraw from the screening 
tests at any time, without losing your regular medical care. 
 
You will receive the results of the screening tests even if you are not eligible to join 
this study. 
 
Some people may not be able to join this study because of information found during 
the screening tests.  You are asked to tell the study staff about any other studies you 
are taking part in, or thinking about taking part in.  This is very important for your 
safety. 
 
If new information is learned about the study, or the study product, you will be told 
about this as soon as possible. 
 
PURPOSE OF THE SCREENING TESTS AND THE STUDY 
The main purpose of these screening exams and tests is to find out if you can join this research 
study.  This research study will test if a vaginal ring containing the medicine dapivirine is used 
as directed and found to be safe in participants who attend clinic visits at different time points 
(monthly vs. every three months).  Women will be in this study for approximately 13 months 
depending upon when they enroll in the study; however this period could be shorter or longer 
than anticipated.   
 
STUDY PRODUCT 
There is one kind of vaginal ring that will be used in this study, a ring containing dapivirine.  
Unlike ASPIRE, there is no placebo vaginal ring (a ring without the study medicine) in HOPE, so 
all HOPE participants will receive a vaginal ring containing dapivirine.  This ring is the same 
dapivirine vaginal ring used in ASPIRE.  Dapivirine vaginal rings have been previously tested 
and found to be generally safe, well-tolerated and effective in HIV prevention in women.  HIV is 
the virus that causes AIDS.  The medicines that are being tested by researchers to prevent HIV 
infection work in different ways.  Dapivirine works by preventing HIV from making copies of 
itself, thereby stopping the spread of HIV in the body.   
 
STUDY GROUPS  
If you join MTN-025, you will be in one of two study groups.  Both groups will use the same ring 
containing dapivirine, but the timing of clinic visits will differ.  Half of the women will be in a study 
group that will be asked to come to the clinic for monthly visits.  The other half of the women will 
come to the clinic for visits every three months.  You will be assigned to a group by random 
chance, like flipping a coin.  Neither you nor the staff can decide which follow-up schedule you 
will be assigned.  Both of the study groups are important to this study.  
 
WHAT DO I HAVE TO DO IF I DECIDE TO TAKE PART IN THE SCREENING EXAMS AND 
TESTS? 
If you agree to have screening tests, they can be done today.  Ideally, all procedures will be 
completed today.  However if you have to come back to complete this visit, some procedures 
may need to be repeated.   
 

 
  
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Screening Visit: 
The procedures done at this visit today will take about [sites to insert time]. 
 
 
You will be asked questions about: 
 
Where you live  
 
Your medical health, what medications you are taking, and menstrual history 
 
Other questions to ensure you are eligible for this study, and to make sure that you 
understand the study requirements.   
 
 
Study staff will: 
 
Perform a physical examination 
 
Talk with you about the requirements of the study including using an effective 
method of contraception throughout your participation in this study  
 
Test your urine for: 
o Infections passed through sex 
o Pregnancy  
 
If you are pregnant you cannot join this study because the risks to your 
baby are unknown.  
 
If the study is still open after your pregnancy, you may come back here to 
find out if you are eligible.  
 
If you are not pregnant, you will be told about ways to avoid becoming 
pregnant, such as the use of contraception.  
 
 
Take a blood sample [Sites to insert amount]: 
o To test the health of your blood, liver and kidneys 
o To test for infections passed through sex, including HIV 
 
You will be told your HIV test result as soon as it is available.  You will 
talk with the study staff about the meaning of your results, how you feel 
about them, and ways to prevent HIV and other sexually transmitted 
infections.  Sometimes HIV tests are not clearly positive, but also not 
clearly negative.  In that case, we will do more tests until we know your 
results for sure.  You must receive your HIV test results to be in this 
study.  If the test shows you have HIV, you cannot join this study.  We will 
tell you where you can get care and other services you may need.  The 
study staff will tell you about other studies you may be eligible for, if any. 
 
 
Perform a pelvic examination: 
o The study doctor or nurse will use a speculum, a plastic or metal instrument used 
to separate the walls of the vagina.  The study doctor or nurse will look at your 
vagina and cervix for signs of infection, and other problems.  Your cervix is 
located at the top of the vagina and it forms the lower end of the womb (uterus).  
They may also take some fluids to test for other possible problems if they feel it is 
necessary. 
o The study staff may also collect samples from your cervix for testing, including a 
“Pap test”.  If the test shows a problem, it could mean you should have more 
tests.  If you have a written report confirming that you had a normal Pap test in 
the past 12 months or if you had an abnormal Pap test but had follow-up and a 
written report indicating no treatment was required, you will not need to have a 
Pap test during this visit.   
 

 
  
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 
Give you treatment or refer you for treatment for infections passed through sex, if 
needed. 
 
Tell you about other services if you need them  
 
Offer you condoms.  Condoms are highly effective in preventing the sexual 
transmission of HIV and reducing the risk for other sexually transmitted diseases 
(STDs).  Study staff can provide you with condoms along with additional information 
about other ways to avoid getting HIV infection. 
 
Schedule your next visit to enroll in MTN-025, if you are eligible and willing 
 
The study staff will review your test results with you when they are available.  If the results show 
you can join the MTN-025 study, the study staff will explain the study to you and answer any 
questions you have.  If you decide to be in this study, you will be asked to sign another consent 
form. 
 
RISKS AND/OR DISCOMFORTS 
Risks of Blood Draws: You may feel discomfort or pain when your blood is drawn.  You may 
feel dizzy or faint.  You may have a bruise, swelling, small clot, or infection where the needle 
goes into your hand or arm. 
 
Risks of Genital Exams: You may feel discomfort or pressure during the examination of your 
genital area and inside your vagina.  You may have a small amount of vaginal bleeding which 
usually stops shortly after the examination. 
 
Other Possible Risks: You may become embarrassed or worried when discussing your sexual 
practices, ways to protect against HIV and other infections passed through sex.  You may 
become worried while waiting for your test results.  If you have HIV or other infections, learning 
this could make you angry, depressed or worried.  Trained study counselors will help you deal 
with any feelings or questions you have.   
 
Risks to your Privacy: We will make every effort to protect your privacy and confidentiality 
while you are having the screening tests.  Your visits will take place in private.  However, it is 
possible others may learn of your participation here and, because of this, may treat you unfairly.  
For example, you could have problems getting or keeping a job, or being accepted by your 
family or community.  Finding out your HIV status could also cause 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. 
 
BENEFITS 
The primary benefit to joining this study is having access to a product that has been shown to 
be safe and effective in preventing HIV.  If this screening visit shows you are eligible to 
participate, an enrollment visit will be scheduled.  
 
You will have a physical examination, pelvic examination, and tests to check on the health of 
your blood, liver, and kidneys.  If these tests show that you might have health problems, you will 
be told where to get medical care and other services available to you.  
 
You will be counseled and tested for infections passed through sex.  If you have these 
infections, you may be offered treatment for them, if needed.  If you are infected with HIV, you 
will be told about medical care, counseling, and other available services that could be of help to 
you.  For other health problems that cannot be treated at this clinic, the study staff will refer you 

 
  
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to other places where you may receive medical care.  If your Pap test result shows anything that 
is not normal, you will be referred for advice and/or treatment.   
 
REASONS WHY YOU MAY BE WITHDRAWN FROM THE SCREENING TESTS WITHOUT 
YOUR CONSENT 
You may be withdrawn from the screening tests without your consent if: 
 
 
You are found not to be eligible for this study 
 
The study is stopped or canceled 
 
The study staff feel that having the screening tests would be harmful to you 
 
You are not willing to find out your HIV test result 
 
You are not able to attend clinic visits or complete the screening tests 
 
Other reasons identified by study staff  
 
 
COSTS TO YOU 
[Site to complete according to site capacity] There is no cost to you for screening tests.  
Treatments available to you from the study site for infections passed through sex (other than 
HIV) will either be given to you free of charge or you will be referred for treatment while you are 
screening for this study.  
 
REIMBURSEMENT 
[Sites to insert information about local reimbursement:] You will receive [Sites to insert amount 
$xx] for your time, effort, and travel to and from the clinic at each scheduled screening visit.  
 
CONFIDENTIALITY 
Efforts will be made to keep your personal information confidential.  However, it is not possible 
to guarantee confidentiality.  Your personal information may be disclosed if required by law.  
The study staff will use your personal information, if needed, to verify that you are not taking 
part in any other research studies.  [Sites to insert information about systems currently in place 
to ensure participants are not part of other conflicting studies, including biometric identification 
systems.] This includes studies conducted by other researchers that study staff knows 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 Office for 
Human Research Protections (OHRP), NIH, and/or contractors of NIH 
 
[Insert applicable local authorities, e.g., Ministry of Health, medicine control authority] 
 
IPM, the organization that supplies the study rings 
 
Study monitors 
 
Site Institutional Review Board (IRB)/ Ethics Committee (EC), an Ethics Committee is a 
committee that watches over the safety and rights of research participants  
 
Study staff 
 
[Sites to include/amend the following:] [LOCAL/STATE/NATIONAL] regulations require study 
staff to report the names of people who test positive for HIV and other infections passed during 
sex to the [LOCAL HEALTH AUTHORITY].  Outreach workers from the [HEALTH AUTHORITY] 
may then contact you about informing your partners, since they also should be tested.  If you do 

 
  
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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. 
 
RESEARCH-RELATED INJURY 
[Sites to modify with their site-specific research-related injury institutional policy:] It is unlikely 
that you will be injured as a result of having the screening tests.  This US federally funded study 
does not have the ability to provide compensation for research-related injury.  If you are injured 
or become ill from taking part in this study, it is important to tell your study doctor.  Emergency 
treatment may be available but you or your insurance company will be charged for this 
treatment.  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 website 
will not include information that can identify you.  At most, the website will include a summary of 
the results.  You can search this website at any time. 
 
PROBLEMS OR QUESTIONS 
If you ever have any questions about the screening tests, or if you have a research-related 
injury, you should contact [insert name of the investigator or other study staff] at [insert 
telephone number and/or physical address]. 
 
If you have questions about your rights as a research participant, you should contact [insert 
name or title of person on the IRB/EC or other organization appropriate for the site] at [insert 
physical address and telephone number]. 
 
If you have questions about who to contact at the research site, you should contact [insert name 
of the investigator or community educator or community advisory board (CAB) member] at 
[insert physical address and telephone number]. 
 

 
  
MTN-025, Version 1.0 
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SIGNATURES 
[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 have the screening tests, 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 
 
Witness Signature  
 
Date 
(print) 

 
  
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APPENDIX V: SAMPLE INFORMED CONSENT DOCUMENT (ENROLLMENT) 
 
SAMPLE INFORMED CONSENT FORM 
DIVISION OF AIDS, NIAID, NICHD, NIMH, NIH 
 
MTN-025 
 
A Phase 3B Open-Label Follow-on Trial to Assess the Continued Safety of and 
Adherence to a Vaginal Ring Containing Dapivirine in Women 
 
HIV Open-label Prevention Extension (HOPE) 
 
Version 1.0 
August 22, 2014 
 
 
PRINCIPAL INVESTIGATOR:  [Sites to insert] 
PHONE:  [Sites to insert] 
 
INFORMED CONSENT 
You are being asked to take part in the MTN-025 HIV Open-label Prevention Extension 
(HOPE) trial.  The research study you participated in, MTN-020: ASPIRE, A Study to Prevent 
Infection with a Ring for Extended Use, showed that the dapivirine vaginal ring can reduce HIV-
uninfected women’s chances of getting the HIV virus by [SITES TO INSERT: from X to X 
percent].  The study also learned that the dapivirine vaginal ring is [SITES TO INSERT: safe 
(meaning that it does not cause significant health problems)] when used by HIV-uninfected 
women.  More data is needed on the safety of the dapivirine vaginal ring.  Because you took 
part in the ASPIRE study, you are being offered the opportunity to use the safe and effective 
dapivirine vaginal ring as part of this new study.  A total of 2629 women enrolled into MTN-020 
(ASPIRE) and all former ASPIRE participants who are eligible for MTN-025 (HOPE) may take 
part. It is anticipated that approximately 1000 to 2500 former ASPIRE participants will enroll in 
HOPE. 
 
This Microbicide Trials Network (MTN) study is funded by the US National Institutes of Health 
(NIH) and is being conducted across multiple countries across Africa.  The International 
Partnership for Microbicides (IPM) supplies the study product. 
 
[INSERT NAME OF PRINCIPAL INVESTIGATOR] is in charge of this study at this clinic site.  
 
YOUR PARTICIPATION IS VOLUNTARY 
Before you decide if you want to join this study, we want you to learn about the study.  The 
study staff will talk with you about the study and answer your questions.  Once you read, 
discuss, and understand the study, and if you agree to take part, you will be asked to sign your 
name or make your mark on this form.  You will be offered a copy of this form to keep.  You may 
decide not to join or to withdraw from the study at any time. 
 
PURPOSE OF THE STUDY 
This research study will test if a vaginal ring containing the medicine dapivirine is used as 
directed and found to be safe in participants who attend clinic visits at different time points 

 
  
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(monthly vs. every three months).  Women will be in this study for approximately 13 months 
depending upon when they enroll in the study; however the duration of study participation could 
be shorter or longer than anticipated.   
 
STUDY PRODUCT 
There is one kind of vaginal ring that will be used in this study, a vaginal ring containing 
dapivirine.  Unlike ASPIRE, there is no placebo vaginal ring (a ring without the study medicine) 
in HOPE, so all HOPE participants will receive a vaginal ring containing dapivirine.  This ring is 
the same dapivirine vaginal ring used in ASPIRE.  Dapivirine vaginal rings have been previously 
tested and found to be generally safe, well-tolerated and effective in HIV prevention in 
women.  This study is testing whether a vaginal ring containing dapivirine can help to prevent 
the spread of HIV.  HIV is the virus that causes AIDS.  The medicine that is being tested to 
prevent HIV infection works in different ways.  Dapivirine works by preventing HIV from making 
copies of itself, thereby stopping the spread of HIV in the body.   
 
The staff can provide you additional information about other ways to avoid getting HIV infection.  
The most effective way to protect against getting HIV infection during sex is to use a condom 
every time you have sex. 
 
STUDY GROUPS   
If you join MTN-025, you will be randomly assigned (like flipping a coin) to one of two study 
groups.  Both groups will use the same ring containing dapivirine, but the timing of clinic visits 
will differ.  Half of the women will be in a study group that will be asked to come to the clinic for 
monthly visits.  The other half of the women will come to the clinic for visits every three months.  
You will be assigned to a group by random chance, like flipping a coin.  Neither you nor the staff 
can decide which follow-up schedule you will be assigned.  Both of the study groups are 
important to this study.   
 
WHAT DO I HAVE TO DO IF I DECIDE TO TAKE PART IN THE MTN-025 STUDY? 
If you decide to enroll in the study, you will have a clinic visit today and monthly or every three 
months thereafter, depending upon which group you are randomly assigned to.  You will insert a 
new vaginal ring monthly for approximately 12 months.  For some participants, this period of 
time may be less, study staff will provide you with an estimate of how long you will use the ring.  
You will have a final study visit to check on your health approximately 4 weeks after the final 
ring is removed.  Study visits may be required beyond the final study visit to monitor your health.  
Visits will take approximately [site to insert required length of time]. 
 
You will be asked to: 
 
Confirm you are able to join the study and that you understand the study requirements 
 
Answer questions about your vaginal practices, including sexual activity 
 
Provide updated information about where you live and how we can contact you   
 
Describe any changes in your health, what medicines you are taking, and your 
menstrual periods 
 
Describe any health problems you have had since your last visit, including problems with 
the study ring 
 
You will be asked to use a study vaginal ring.  As part of using this ring you will: 
 
Talk with study staff about how to properly wear and use the study ring 

 
  
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 
Receive new study rings (monthly or every three months) and insert a new study ring 
(monthly).  If you are inserting a new ring at a clinic visit, and you are having difficulty a 
study clinician may help you 
 
If needed, have an examination performed to ensure the ring is properly inserted. 
 
Return your vaginal ring(s) to study staff.  Study researchers will keep these rings and 
run additional tests on them.  These tests will help researchers better understand your 
ring use. 
 
Be able to return to the clinic to have the ring reinserted if the ring falls out and you are 
uncomfortable reinserting it yourself 
 
You will be asked to answer questions about: 
 
Your experience using the vaginal ring, including whether or not the ring was removed 
from or fell out of your vagina.   
 
Any problems you may have had during your participation in this study.   
 
Vaginal practices that may affect how the study drug is absorbed by your body. 
 
Things that may make you uncomfortable, such as questions about drug use.  You may 
use a computer to answer these questions or a staff member may ask you these 
questions.  It is important that you know that you will answer these questions in private 
and your responses will be kept confidential. 
 
You will have the following clinical procedures performed: 
 
A physical examination 
 
Provide a sample of blood [insert amount]  to:  
- 
Check the health of your blood, liver and kidneys  
- 
Test for HIV.  You will be told your HIV test results as soon as they are available.  
You will talk about the meaning of your results and how you feel about them, and 
ways to prevent HIV and other STIs.  Sometimes HIV test results are not clearly 
positive, but also not clearly negative.  In that case, we will do more tests until we 
know your results for sure.  You must receive your HIV test results to be in the 
study.  If the test shows you have HIV, you cannot join the study.  We will tell you 
where you can get care and other services you may need.  You will be told about 
other studies you may be eligible for, if any.  
- 
Additional testing may be performed as part of quality control. 
- 
See how much of the study product is being absorbed by your body and how it 
affects your body.  
 
Provide a urine sample to: 
- 
Check to see if you are pregnant  
- 
Test for infections passed through sex 
 
Provide vaginal fluid and cervical fluid samples: 
o To see how the dapivirine vaginal ring protects against HIV and to explore the 
health of the female genital tract.  The vaginal fluid and cervical fluid collected will 
be used for research purposes only.   
 
A pelvic examination when the vaginal ring is removed for the final time.  The study 
doctor or nurse will use a speculum.  A speculum is a plastic or metal instrument used to 

 
  
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separate the walls of the vagina.  It is used so the doctor or nurse can examine the 
vagina and the cervix during the examination.  Your cervix is located at the top of the 
vagina and it forms the lower end of the womb (uterus).  They will check for signs of 
infection, and other problems.  They may also take some fluids to test for STIs and other 
possible problems if they feel it is necessary 
 
As part of the clinical procedures you will: 
 
Receive the results of your tests when available 
 
Learn about other services available to you 
 
Receive treatment or be referred for treatment for problems that the study staff may find.  
 
Receive counseling.  You will discuss: 
- 
Sexually transmitted infections (STIs), HIV, HIV/STI testing, and ways to prevent 
HIV and other infections passed through sex   
- 
The rules of the study and how to follow the rules  
- 
Contraception and ways to prevent getting pregnant  
 
Be offered condoms.  Condoms are highly effective in preventing the sexual 
transmission of HIV and reducing the risk of other sexually transmitted diseases (STDs).  
Study staff can provide you with condoms along with additional information about other 
ways to avoid getting HIV infection. 
 
You will schedule your next visit  
 
If you leave the study early, you will be asked to complete a final clinic visit and evaluations.  
Various procedures will be completed at this visit, including a pregnancy and HIV test. 
 
It may be necessary for additional visit(s) and procedures in the event of unforeseen or 
unanticipated results; difficulties in sample shipping, processing, or testing; and/or if you are 
experiencing any symptoms or changes in your physical condition. For example, at any time 
during the study, vaginal and/or cervical swabs, blood samples and urine may need to be 
collected if you are having symptoms or if you are suspected to have an infection. 
 
Interim/Unscheduled Visits 
Study staff will discuss with you the importance of contacting the clinic as soon as you notice 
changes in your physical condition or when you experience health related issues.  It may be 
necessary to come to the clinic for an unscheduled visit.  Also, it is possible that you may be 
asked to come to the clinic for an unscheduled visit in the event of an abnormal test result; 
difficulties in sample shipping, processing, or testing; or for other reasons. 
 
In-depth Interview(s) and Group Discussions 
You may be asked to participate in interview(s) with a trained staff member or you may be 
asked to participate in a group discussion with other study participants about opinions that you 
or other participants have.  If you are asked to participate in these study activities, you will be 
compensated for your time and effort.   
 
If you are asked to participate in a group discussion, you will be asked to discuss your use of 
the study product, your feelings about the study product and trial participation, your vaginal 

 
  
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practices and other questions that can help researchers to better understand participants’ 
experiences while taking part in the study.  These discussions will last about one hour.   
 
If you are asked to participate in an interview, you will be asked questions about your use of the 
ring, your preferences and opinions, your experiences with using the ring during sex, and any 
problems you may have had using the ring.  The interviews will be audio-recorded to make sure 
to record your words exactly how you said them.  The voice recordings will be destroyed as 
soon as the audio recording has been typed and checked.  The audio recording, notes, and 
analyses from these materials will be kept confidential and will only use study numbers or fake 
names.  This means that no one other than the MTN-025 (HOPE) 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-025(HOPE) study team for 
the purposes of this research. 
 
If you become infected with HIV 
Your participation in this study will not cause HIV infection.  However, there is always a chance 
that through sexual activity or other activities you may become HIV-positive.  If the HIV tests 
confirm that you have been infected with HIV, you will stop using the ring, but we will ask you to 
continue to come into the clinic for regularly scheduled visits for some of the study procedures.  
You will have more blood tests at different time points after your HIV infection is discovered to 
find out which drugs would be inappropriate for your type of HIV-1 (HIV drug resistance), the 
amount of immune protection in your blood (CD4+ T-cell count), and the amount of HIV in your 
blood (viral load).  You may be referred to other research studies.  If you join another study it 
may not be necessary to collect additional blood for testing.  In the event you become HIV-
positive, study staff will counsel and refer you for medical care and other available services 
while you are in this study. 
 
It may be necessary, depending upon local and national health requirements, for study staff to 
report diseases, including HIV, identified among MTN-020 (ASPIRE) study participants.  The 
reportable diseases at this site are [Sites to insert]. 
 
RISKS AND/OR DISCOMFORTS 
 
Risks of Blood Draws: You may feel discomfort or pain when your blood is drawn.  You may 
feel dizzy or faint.  You may have a bruise, swelling, small clot, or infection where the needle 
goes into your hand or arm. 
 
Risks of Genital Exams: You may feel discomfort or pressure during the examination of your 
genital area and inside your vagina.  You may have a small amount of vaginal bleeding which 
will stop shortly after the examination. 
 
Risks of Study Rings 
The study rings can cause some side effects, such as an allergic reaction.  Signs of an allergic 
reaction include, but are not limited to: Rash or other skin irritation, itching, joint pain, or difficulty 
in breathing.  We do not yet know all the side effects of the rings.  Some, but not all women who 
used the rings in other studies have had: 
 
Discharge from the vagina 
 
Vaginal irritation and discomfort 
 

 
  
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As with any product that is placed into the vagina, the possibility of toxic shock syndrome exists.  
Toxic shock syndrome is a serious but uncommon infection caused by bacteria.  While it is 
unlikely that you should experience toxic shock syndrome as a result of using the vaginal ring, it 
is important that you alert the study staff if you experience any symptoms associated with toxic 
shock syndrome, i.e., sudden high fever, a faint feeling, diarrhea, headache, a rash, and muscle 
aches.   
 
Finally, it is also possible that you or your partner may feel the ring during sexual activity.  If you 
have any problems, study counselors will talk with you and/or your partner to try to help resolve 
them. 
 
Risks of Study Drugs 
Based on side effects reported among women in previous studies, dapivirine vaginal rings may 
be associated with:  
 
Vaginal bleeding 
 
Headache 
 
Fatigue 
 
Itching on the external parts of your genitals  
 
Abdominal discomfort 
 
Abdominal pain 
 
The loss of bladder control 
 
Nausea 
 
Vaginal or genital discharge 
 
Other Possible Risks 
If you become infected with HIV and continue to use the ring it is possible that you may develop 
HIV drug resistance.  This means that any virus that is drug resistant will survive and continue to 
reproduce (make copies of new HIV) in the presence of the drug that normally weakens or kills 
it.  HIV drug resistance could make it difficult to use dapivirine or drugs like it to treat the HIV.  
Drug resistance only occurs if you were to become infected with HIV and continue to use the 
study product. 
 
You may become embarrassed and/or worried when discussing your sexual practices, ways to 
protect against HIV and other infections passed through sex, and your test results.  You may be 
worried while waiting for your test results.  If you have HIV or other infections, learning this could 
make you worried.  Finding out your HIV status could also cause problems between you and 
your partner.  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.  However, it is possible that others may learn of your participation 
here and, because of this, may treat you unfairly or discriminate against you.  For example, you 
could have problems getting or keeping a job, or being accepted by your family or community.  If 
you have any problems, study counselors will talk with you and if you choose, your partner, to 
try to help resolve them. 
 
If you are chosen to participate in the group discussion, other participants will hear what you 
say.  We will not reveal your full name to other participants.  We will also ask every participant 

 
  
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not to tell anyone outside of the group what any person said during the discussion.  While it is 
not at all likely that your discussion will be made public, we cannot guarantee that everyone will 
keep the discussion private. 
 
BENEFITS 
 [SITES TO UPDATE: Participants in the MTN-025 (HOPE) trial will experience the direct 
benefit of using a vaginal ring that has been found to be safe and efficacious in preventing HIV 
transmission.] 
 
In addition, you will have physical examinations, pelvic examinations, and tests to check on the 
health of your blood, liver, and kidneys.  If these tests show that you might have health 
problems, you will be told where to get medical care and other services available to you.  
 
This study cannot provide you with general medical care, but study staff will refer you to other 
available sources of care.   
 
You will be counseled and tested for HIV and STIs.  You will be offered free condoms, if you 
need them.  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.  You 
will need to receive care for HIV infection from your own health care provider or we will provide 
you with a referral.  If you have an STI diagnosed, you will receive medicine or a referral, if 
needed.   
 
PREGNANCY AND BREASTFEEDING  
The dapivirine ring is not birth control.  You must agree to use an effective method of birth 
control such as an intrauterine contraceptive device (IUCD), birth control pills or other hormonal-
based method (except for vaginal rings), unless you underwent a medical procedure to 
permanently be unable to become pregnant, i.e., sterilization. 
 
We do not know if the dapivirine ring has any effect on pregnancy, on the fetuses of a women 
who use the vaginal ring while pregnant, or on the babies of women who use the ring while 
breastfeeding.  Because of this, pregnant and breastfeeding women may not join this study.  
You may be able to start using the vaginal ring after your pregnancy, provided that you are not 
breastfeeding.  The study staff will talk more with you about this after your pregnancy.  Women 
who join the study must agree to use effective contraception and have scheduled pregnancy 
tests while in the study.  
 
If you become pregnant during the study, study staff will refer you to available medical care and 
other services you or your baby may need.  The study does not pay for this care.  You will stop 
using the ring, but we may ask you to keep coming here for study visits as originally planned.  
We will change the study procedures as needed to protect your health while you are pregnant.  
[Sites to include/amend the following: We may also contact you to find out about the health of 
your pregnancy, and the health of your baby up to one year old, if you have a baby.  We may 
also contact you about a study that collects information about pregnancy and babies up to one 
year old.] The outcome of your pregnancy is important to study staff; therefore your pregnancy 
will be followed until the results of your pregnancy are known.  
 
NEW INFORMATION 
You will be told about new information from this or other studies that may affect your welfare or 
willingness to stay in this study.  It is important you know that the study product, the dapivirine 

 
  
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ring, is among the most advanced HIV prevention products that can be offered to you [SITES 
TO INSERT MTN-020 DATA HERE].  In addition to being tested as part of the ASPIRE trial, the 
ring was also tested in IPM 027 [INSERT IPM 027 DESCRIPTION AND RESULTS AND/OR 
UPDATE, IF AVAILABLE, HERE].  In the future, vaginal rings containing more than one type of 
medicine may become available.  If a new product like this were to become available, it could be 
more protective than the ring tested as part of MTN-020 (ASPIRE) and IPM 027 (The Ring 
Study), leading to fewer HIV infections, however, no other vaginal ring has been found to work 
at this time. 
 
It is also important for you to know that other drugs are being tested for HIV prevention.  The 
HIV prevention researchers working on this MTN-025 (HOPE) are committed to sharing any 
data with you that becomes available, regardless of the product, if it is found to be effective in 
preventing the transmission of HIV.  You will also be told when study results may be available, 
and how to learn about them. 
 
WHY YOU MAY STOP TAKING THE STUDY DRUG EARLY OR BE WITHDRAWN FROM 
THE STUDY WITHOUT YOUR CONSENT 
A study doctor may need to remove you from the study early without your permission if: 
 
The study is cancelled by the US FDA, US NIH, International Partnership for 
Microbicides, the US Office for Human Research Protections (OHRP), MTN, the local 
government or regulatory agency, or the Institutional Review Board (IRB)/ the Ethics 
Committee (EC).  An IRB/EC is a committee that watches over the safety and rights of 
research participants 
 
The Study Monitoring Committee (SMC) recommends that the study be stopped early. 
(A SMC reviews the progress of the study and the kinds of effects that people report 
while they are participating in the study) 
 
You are not able to keep appointments 
 
Other reasons that may prevent you from completing the study successfully 
 
The study doctor will ask you to stop using the study vaginal ring but continue to come in for 
your follow-up visits and procedures if: 
 
You become pregnant  
 
You become infected with HIV 
 
A study doctor decides that using the vaginal ring would be harmful to you 
 
You require a treatment that you may not take while using the study vaginal ring 
 
You have a bad reaction to the study vaginal ring 
 
If a study doctor asks you to stop using the ring, you will need to come in for all scheduled visits 
described above, including for a physical examination, vital signs, and blood tests.  You will stop 
using study ring until the study doctor decides it is safe for you to start using it again, if possible. 
 
In the event that you are removed from or choose to leave this study, you will be asked to return 
your vaginal ring.  If you do not have the vaginal ring 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. 
[Sites to specify allowances for special circumstances.] 
 

 
  
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August 22, 2014 
 
ALTERNATIVES TO PARTICIPATION 
[Sites to include/amend the following:] There are no gels, tablets or vaginal rings currently 
available in this country to protect against HIV during sex.  Consistent use of condoms is the 
only available known way to protect against HIV during sex.  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 contraception.  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 
vaginal ring, physical examinations, laboratory tests or other procedures.  Treatments available 
to you from the study site for infections passed through sex (other than HIV) will be given to you 
free of charge or you will be referred for available treatment for the duration of the study. 
 
REIMBURSEMENT 
[Sites to insert information about local reimbursement:] You will receive [Sites to insert amount 
$xx] for your time, effort, and travel to and from the clinic at each scheduled visit.  You may 
receive [Sites to insert amount $xx] for any visits which occur in between your normally 
scheduled visits.  
 
CONFIDENTIALITY 
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.  [Sites to insert information about systems currently in place to ensure participants are 
not part of other conflicting studies, including biometric identification systems.] 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 Office for 
Human Research Protections (OHRP), NIH, and/or contractors of NIH 
 
[Insert applicable local authorities, e.g., Ministry of Health, medicine control authority] 
 
IPM, the organization that supplies the study rings 
 
Study monitors 
 
Site Institutional Review Board (IRB)/ Ethics Committee (EC), an Ethics Committee is a 
committee that watches over the safety and rights of research participants  
 
Study staff 
 
[Sites to include/amend the following:][LOCAL/STATE/NATIONAL] regulations require study 
staff to report the names of people who test positive for HIV and other infections passed during 
sex to the [LOCAL HEALTH AUTHORITY].  Outreach workers from the [LOCAL HEALTH 
AUTHORITY] may then contact you about informing your partners, since they also should be 
tested.  If you do not want to inform your partners yourself, the outreach workers will contact 
them, according to the confidentiality guidelines of the [HEALTH AUTHORITY]. 
 
The researchers will do everything they can to protect your privacy.   
 

 
  
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August 22, 2014 
 
RESEARCH-RELATED INJURY 
[Sites to modify with their site-specific research-related injury institutional policy:] It is unlikely 
that you will be injured as a result of study participation.  This US federally funded study does 
not have the ability to provide compensation for research-related injury.  If you are injured or 
become ill from taking part in this study, it is important to tell your study doctor.  Emergency 
treatment may be available but you or your insurance company will be charged for this 
treatment.  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 website 
will not include information that can identify you.  At most, the website will include a summary of 
the results.  You can search this website at any time. 
 
YOUR RIGHTS AS A RESEARCH PARTICIPANT/VOLUNTEER 
[Sites 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.  If you want the results of the study after the study is over, let 
the study staff members know. 
 
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]. 
 
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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SIGNATURES 
[Sites to insert signature/initial blocks as required by the local IRB/EC:] 
 [Sites to omit the following if a separate consent for Storage and Future Testing of Specimens 
is required] 
 
CONSENT FOR STORAGE AND FUTURE TESTING OF SPECIMENS  
There might be a small amount of blood, vaginal fluid and cervical fluid samples left over after 
we have done all of the study related testing after your study visits.  We would like to ask your 
permission to store your leftover blood, vaginal fluid, and cervical fluid samples, and related 
health information for use in future studies.  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 of 
these research facilities may be outside of your country.  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 blood, vaginal fluid and cervical fluid samples stored for future 
studies.  If you do not want the left-over blood, vaginal fluid and cervical fluid samples stored, 
we will destroy these left over specimens.  Any future studies that may be done will also have to 
be approved by an Ethics Committee/ Institutional Review Board.  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. 
 
_______________ 
 
 
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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CONSENT FOR OFF-SITE VISITS 
 [Sites to modify as needed] 
Members of the research team at this clinic may be able to schedule off site visits with you at 
your home or at another location as part of the study.  If needed, and, if you agree, some of the 
scheduled study visits and some of the study procedures may take place at your home or other 
location outside of the research clinic, if you are unable to come into the clinic.  If, for example, 
you need to receive a new ring or to have a urine or blood sample collected, study staff could 
come to you your home or meet you at another location, if you give your permission and if the 
study staff determine that it is appropriate.  The study personnel will explain in greater detail the 
requirements of these visits (like the conditions of the place, the type of visit and the time it will 
take) and the procedures in-place to maintain your information in a confidential manner.  
However it is important that you know that off-site visits may eventually affect your 
confidentiality even if the study staff take precautions not to disclose the purpose of the visits. 
 
In order to conduct visits outside of the clinic, we will need you to give us permission to do so.  
Please read carefully the following statement and initial and date one option.  Choosing not to 
be visited outside of the study clinic will not affect your participation in this study.  Even if you 
agree today, you can withdraw your consent for off-site visits at any time by providing your 
request in writing to the person in charge of this study.  In addition, before each off-site visit, we 
will confirm with you that you still agree and remember today’s discussion.  
 
___________        
I DO agree to be visited at a location other than the study clinic by clinic 
staff, when necessary 
Initials and Date 
 
___________        
I DO NOT agree to be visited at a location other than the study clinic by 
clinic staff, when necessary 
Initials and Date 
 
 
 

 
  
MTN-025, Version 1.0 
113 
August 22, 2014 
 
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 participate in this 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 
 
Witness Signature 
 
Date 
(print) 
 
 
 

 
  
MTN-025, Version 1.0 
114 
August 22, 2014 
 
 
APPENDIX VI: SAMPLE INFORMED CONSENT DOCUMENT (MTN-025 DECLINER 
GROUP) 
MTN-025 
 
SAMPLE INFORMED CONSENT FORM-  
Screening and Enrollment MTN-025 Decliner Group 
 
DIVISION OF AIDS, NIAID, NIH, NIMH, NICHD 
 
A Phase 3B Open-Label Follow-on Trial to Assess the Continued Safety of and 
Adherence to a Vaginal Ring Containing Dapivirine in Women 
 
Version 1.0 
August 22, 2014 
 
PRINCIPAL INVESTIGATOR:  
PHONE:  
 
INFORMED CONSENT 
You are being asked to take part in this research study because you are a woman who took part 
in the MTN-020 (ASPIRE) trial and have decided to delay, decline to take part in the MTN-025 
(HOPE) trial.  Other women like you will participate in this study across multiple sites.  Before 
you decide if you want to join this study, we want you to know about the study.  This 
Screening/Enrollment consent form gives you information about this study.  MTN-025 (HOPE) 
staff will talk with you about the study and answer any questions you may have.   
 
This Microbicide Trials Network (MTN) study is funded by the US National Institutes of Health 
(NIH) and is being conducted across multiple countries across Africa.  A total of 2629 women 
enrolled into MTN-020: ASPIRE and all former participants who are eligible may take part in the 
MTN-025 or in the MTN-025: Decliner Group. 
 
YOUR PARTICIPATION IS VOLUNTARY 
Participation in this study is voluntary.  You will be asked to sign or make your mark on this form 
to indicate whether you agree to participate in this study.  Before you decide whether to be in 
MTN-025 Decliner Group, we would like to explain the purpose of the study.  If you decide to 
enroll in this study, you may decide to withdraw from the study at any time.  There will be no 
penalty for refusing to participate or choosing to withdraw from this study. 
 
It is important that you know that if you change your mind and wish to take part in the MTN-025 
trial, you can enroll, provided that the study is ongoing and that you are eligible. 
 
PURPOSE OF THE DECLINER GROUP 
The main goal of the Decliner Group is to better understand MTN-020 (ASPIRE) participants’ 
reasons for refusal to take part in the MTN-025 (HOPE) trial.  MTN-025, is a study that provides 
former ASPIRE participants with access to the dapivirine vaginal ring, a product that has been 
shown to reduce the chances of women from getting the HIV virus by [To be updated: X to X 
percent].  The study also learned that the dapivirine vaginal ring is [To be updated: safe 
(meaning that it does not produce significant health problems in persons who take it)]. 
I 
I 

 
  
MTN-025, Version 1.0 
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August 22, 2014 
 
 
STUDY PROCEDURES 
It is expected that the procedures involved with the MTN-025 Decliner Group will be completed 
in one visit.  If you agree to join this study, you will be asked to answer questions about your 
behavior(s) and you also may be asked to complete an in-depth interview (IDI) in the presence 
of one or two MTN-025 (HOPE) research staff members.  If you agree to take part in this study, 
the interviewer will ask you some brief questions and write your responses on a form. Multiple 
visits may be needed to complete the IDI and questionnaire(s).  During the IDI, the interviewer 
will also ask in-depth questions, during which time notes may be taken and the conversation will 
be audio-recorded.  
 
You will be asked some general questions, such as your age, education, living situation, 
relationship status and health.  You will also be asked about other clinical trials or HIV-related 
studies that you may be currently participating in.  The interviewer will also ask questions about 
your experiences while participating in the ASPIRE trial.  These will include questions about 
different ways women used their study product, their sexual practices, as well as your use of the 
study product and your sexual practices. 
 
We expect the interview will take approximately 2 hours.  The IDI it will be completed at a place 
agreed upon by you and the study staff, which may be your home, a designated neutral study 
interview location, the clinic you went to for your ASPIRE visits or another convenient place of 
your choice.  
 
The audio recording, notes, and analyses from these materials will be kept confidential and will 
only use study numbers or fake names.  The information that links you to the research data will 
be kept in a secure location that will be accessed only by members of the HOPE study team for 
the purposes of this research. 
 
To obtain information about your participation in ASPIRE, the HOPE study team may need to 
access your ASPIRE research records.  By signing this form, you are giving the HOPE study 
team permission to look up and record the needed information from your research record. 
 
RISKS AND/OR DISCOMFORTS 
During the interview we may ask you some questions that cause you to feel embarrassed or 
uncomfortable.  You can choose not to answer questions in the interview at any time.  It is also 
possible that people or family members may find out you are participating in this study.  As a 
result, they may ask questions about the study, treat you unfairly, or you may encounter 
problems in being accepted by your family and/or community.   
 
Another possible risk of this study is loss of confidentiality of the information you give.  Every 
effort will be made to protect your confidential information, but this cannot be guaranteed.  To 
reduce this risk, we will strictly protect the information recorded during your interview.  The 
audio recording, notes, and analyses from these materials will be kept confidential.  This means 
that no one other than the HOPE interview team will have access to your responses.  The 
information that links you to the research materials will be kept in a secure location.  Your audio 
recordings will also be kept in a secure location and only people involved with the study will 
have access to these recordings.  When the information on the audio recording is typed onto 
paper and fully checked, the recording will be destroyed.  Study leaders will make sure this 
happens. 
 

 
  
MTN-025, Version 1.0 
116 
August 22, 2014 
 
[Sites to modify based upon their institutional policy: In the unlikely event that you get injured as 
a result of your study participation, it is important that you know the US National Institutes of 
Health (NIH) does not have a mechanism to provide direct compensation for research-related 
injury.] 
 
NEW INFORMATION 
You will be told about new information from this or other studies that may affect your welfare or 
willingness to stay in this study. 
 
BENEFITS 
There are no direct benefits to participating in this study.  However, the information you provide 
may help researchers improve the design of future studies. 
 
REASONS WHY YOU MAY BE WITHDRAWN FROM THE SUBSTUDY WITHOUT YOUR 
CONSENT 
You may be removed from this study without your consent for the following reasons: 
 
The study is stopped or canceled 
 
The study staff feels that staying in the study would be harmful to you 
 
The study is stopped by NIH, the MTN, International Partnership for Microbicides (IPM), 
the Office for Human Research Protections (OHRP), other government or regulatory 
authorities, or site IRBs/ECs 
 
Other administrative reasons 
 
ALTERNATIVES TO PARTICIPATION 
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 we know about.  
 
COSTS TO YOU 
There is no cost to you for being in this study.  
 
REIMBURSEMENT 
[Sites to modify/insert text as necessary for planned local reimbursement:] 
You will receive [$xx] for your time, effort, and travel.  
 
CONFIDENTIALITY 
We will do our best to make sure that the personal information gathered for this study is kept 
private.  However, absolute confidentiality cannot be guaranteed.  Your personal information 
may be disclosed if required by law.  Any publication of this study will not use your name or 
identify you personally. 
 
This Microbicide Trials Network (MTN) study is funded by the US NIH. 
 
Your records may be reviewed by any or all of the following: 
 
 
The MTN-025 study staff 
 
[insert applicable local authorities, e.g., Ministry of Health, medicine control authority] 
 
Site IRBs/ECs 
 
IPM 

 
  
MTN-025, Version 1.0 
117 
August 22, 2014 
 
 
Representatives of the US Federal Government, including the US FDA, US Office for 
Human Research Protections (OHRP), NIH, and/or contractors of NIH 
 
PROBLEMS OR QUESTIONS 
If you ever have any questions about this study, you should contact [insert name of the 
investigator or other study staff] at [insert telephone number and/or physical address].  
 
If you have questions about your rights as a research participant, you should contact [insert 
name or title of person on the IRB/EC or other organization appropriate for the site] at [insert 
telephone number and/or physical address of above]. 
 
If you have questions about whom to contact at the research site, you should contact [insert 
name of the investigator or community educator or community advisory board (CAB) member 
[staff will decide which] at [insert telephone number and/or physical address]. 
 
[Sites to modify with their site-specific research-related injury based upon their 
institutional policy:  
RESEARCH-RELATED INJURY 
It is unlikely that you will be injured as a result of taking part in the MTN-025 Decliner Group.  
This US federally funded study does not have the ability to provide compensation for research-
related injury.  If you are injured or become ill from taking part in this study, it is important to tell 
your study doctor.  Emergency treatment may be available but you or your insurance company 
will be charged for this treatment.  You do not give up any legal rights by signing this consent 
form. ] 
 
SIGNATURES 
[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 voluntarily agree to 
participate in the study, please sign your name or make your mark below.  
 
____________________ ________________________ ______________ 
Participant Name  
 
Participant Signature  
Date 
(print)  
 
 
or Mark 
 
 
____________________ ________________________ ______________ 
Study Staff Conducting  
Study Staff Signature  
Date 
Consent Discussion (print) 
 
 
____________________ ________________________ ______________ 
Witness Name  
 
Witness Signature 
 
Date 
 
 
 
 

 
  
MTN-025, Version 1.0 
118 
August 22, 2014 
 
 
 
Reference List 
 
 1.  UNAIDS, Joint United Nations Programme on HIV/AIDS.  UNAIDS Report on the Global 
AIDS Epidemic 2013. 
http://www.unaids.org/en/media/unaids/contentassets/documents/epidemiology/2013/gr20
13/UNAIDS_Global_Report_2013_en.pdf accessed 30 May 2014.  
 2.  Fletcher P, Harman S, Azijn H, et al. Inhibition of human immunodeficiency virus type 1 
infection by the candidate microbicide dapivirine, a nonnucleoside reverse transcriptase 
inhibitor. Antimicrob Agents Chemother 2009;53:487-95.   
 3.  Nel A, Coplan P, Smythe S, McCord K, Mitchnick M, Kaptur P, Romano J. 
Pharmacokinetic Assessment of Dapivirine Vaginal Microbicide Gel in Healthy, HIV-
Negative Women. AIDS Research and Human Retroviruses 2010; 26(11).    
 4.  Anderson RM, Swinton J, Garnett GP. Potential impact of low efficacy HIV-1 vaccines in 
populations with high rates of infection. Proc Biol Sci 1995;261:147-51.   
 5.  IPM. Investigator's Brochure: Dapivirine Vaginal Ring. 30 October 2012.   
 6.  Nel A, Smythe S, Young K, Malcolm K, Rosenberg Z, Romano J. Safety and 
Pharmacokinetic Assessment of 28 Day Anti-HIV Dapivirine Intravaginal Microbicide Rings 
In: CROI. Boston; 2008.   
 7.  Nuttall J, Hettema W, van Niekerk N, Nel A.  Pharmacokinetics of Monthly Dapivirine 
Vaginal Microbicide Rings (Ring-004) for HIV Prevention.  In: Microbicides 2012. Sydney; 
2012.   
 8.  Nel A, Haazen W, Nuttall J, Romano J, Rosenberg Z, Van Niekerk N.  A safety and 
pharmacokinetic trial assessing delivery of dapivirine from a vaginal ring in healthy 
women. AIDS 2014, 28:1479-1487.   
 
 9.  Di Fabio S, Van Roey J, Giannini G, et al. Inhibition of vaginal transmission of HIV-1 in hu-
SCID mice by the non-nucleoside reverse transcriptase inhibitor TMC120 in a gel 
formulation. Aids 2003;17:1597-604.   
 10.  Romano J, Variano B, Coplan P, et al. Safety and availability of dapivirine (TMC120) 
delivered from an intravaginal ring. AIDS Res Hum Retroviruses 2009;25:483-8.   
 11.  Nel A, Kamupira M, Woodsong C, van der Straten A, Monthomery E, van Niekerk N, 
Nuttall J. Safety, Acceptability and Pharmacokinetic Assessment (Adherence) of Monthly 
Dapivirine Vaginal Microbicide Rings (Ring-004) for HIV preventionIn: Microbicides 2012. 
Syndey; 2012.   
 12.  van der Straten A, Montgomery ET, Cheng H, Wegner L, Masenga G, von Mollendorf C, 
Bekker L, Ganesh S, Young K, Romano J, Nel A, Woodsong C, High Acceptability of a 
Vaginal Ring Intended as a Microbicide Delivery Method for HIV Prevention in African 
Women, AIDS and Behavior, 16 (7), pp. 1775-1786, October 2012.   

 
  
MTN-025, Version 1.0 
119 
August 22, 2014 
 
 13.  Hunt GM, Ledwaba J, Basson AE et al. Surveillance of Transmitted HIV-1 Drug 
Resistance in Gauteng and KwaZulu-Natal Provinces, South Africa, 2005Çô2009. 
Clinical Infectious Diseases 2012;54(suppl 4):S334-S338. 
 14.  Parikh UM,Kiepiela P,Ganesh S,Gomez K,Horn S,Eskay K,Kelly C,Mensch B,Gorbach 
P,Soto-Torres L,Ramjee G,Prevalence of HIV-1 Drug Resistance among Women 
Screening for HIV Prevention Trials in KwaZulu-Natal,South Africa (MTN-009); PLoS 
One.2013 Apr 9;8(4):e59787.doi: 10.1371/journal.pone.0059787.Print 2013.   
 15.  Stanford University HIV Drug Resistance Database. http://hivdb.stanford.edu/ accessed 13 
June 2014.  
 16.  Nel A, Young K, Romano J, Woodsong C, Montgomery E, Masenga G, Rees H, Bekker 
LG, Ganesh S. Safety & acceptability of silicone elastomer vaginal rings as potential 
microbicide delivery method in african women. In: CROI 2011. Boston Feb 27-Mar 2, 
2011.   
 17.  Workowski KA, Berman SM, Centers for Disease Control and Prevention (CDC). Sexually 
transmitted diseases treatment guidelines, 2010. Department of Health and Human 
Services, Centers for Disease Control and Prevention; 2010. 
 18.  Weller S, Davis K. Condom effectiveness in reducing heterosexual HIV transmission. 
Cochrane Database Syst Rev 2002;1. 
 19.  Holmes KK, Levine R, Weaver M. Effectiveness of condoms in preventing sexually 
transmitted infections. Bulletin of the World Health Organization 2004;82(6):454-461. 
 
 

 
MTN-025 
 
 
 
A Phase 3B Open-Label Follow-on Trial to Assess the Continued Safety of and 
Adherence to a Vaginal Ring Containing Dapivirine in Women  
 
 
 
Microbicide Trials Network 
 
 
 
 
 
 
Funding Agencies: 
Division of AIDS, US National Institute of Allergy and Infectious Diseases 
US Eunice Kennedy Shriver National Institute of  
Child Health and Human Development 
US National Institute of Mental Health 
US National Institutes of Health 
 
 
Grant Numbers: 
 
UM1AI068633, UM1AI068615, UM1AI106707 
 
DAIDS Protocol ID: 11985 
 
IND Sponsor: 
International Partnership for Microbicides 
 
IND #108,743 
 
 
Protocol Chair: 
Jared Baeten, MD, PhD 
 
Protocol Co-chairs: 
Nyaradzo M. Mgodi, MBChB, MMed 
Thesla Palanee-Phillips, PhD 
 
 
Version 2.0 
 
December 16, 2014

MTN-025, Version 2.0 
2 
December 16, 2014 
 
MTN-025 
 
A Phase 3B Open-Label Follow-on Trial to Assess the Continued Safety of and 
Adherence to a Vaginal Ring Containing Dapivirine in Women  
 
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS AND ACRONYMS .......................................................................................................... 5 
PROTOCOL TEAM ROSTER .................................................................................................................................. 8 
INVESTIGATOR SIGNATURE FORM ..................................................................................................................... 23 
1 
KEY ROLES ...................................................................................................................................... 28 
1.1 
PROTOCOL IDENTIFICATION ............................................................................................................................. 28 
1.2 
SPONSOR AND MONITOR IDENTIFICATION.......................................................................................................... 28 
1.3 
MEDICAL OFFICER ......................................................................................................................................... 28 
1.4 
CLINICAL LABORATORIES ................................................................................................................................. 29 
1.5 
DATA CENTERS ............................................................................................................................................. 29 
1.6 
STUDY OPERATIONS ...................................................................................................................................... 29 
2 
INTRODUCTION .............................................................................................................................. 30 
2.1 
MICROBICIDES AND HUMAN IMMUNODEFICIENCY VIRUS (HIV) PREVENTION ........................................................... 30 
2.2 
DAPIVIRINE VAGINAL RING (VR) ...................................................................................................................... 31 
2.3 
NONCLINICAL STUDIES OF DAPIVIRINE ............................................................................................................... 32 
2.4 
CLINICAL STUDIES ......................................................................................................................................... 34 
2.5 
PREVALENCE OF PRIMARY NON‐NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITOR (NNRTI) RESISTANCE MUTATIONS ..... 40 
2.6 
BEHAVIORAL STUDIES .................................................................................................................................... 40 
2.7 
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 
SUMMARY OF MAJOR ENDPOINTS .................................................................................................................... 43 
4.3 
DESCRIPTION OF STUDY POPULATION ............................................................................................................... 44 
4.4 
TIME TO COMPLETE ACCRUAL ......................................................................................................................... 44 
4.5 
EXPECTED DURATION OF PARTICIPATION ........................................................................................................... 44 
4.6 
SITES .......................................................................................................................................................... 44 
5 
STUDY POPULATION ....................................................................................................................... 44 
5.1 
SELECTION OF THE STUDY POPULATION ............................................................................................................. 44 
5.2 
INCLUSION CRITERIA ...................................................................................................................................... 45 
5.3 
EXCLUSION CRITERIA ..................................................................................................................................... 45 
5.4 
INCLUSION CRITERIA‐ MTN‐025 DECLINER POPULATION ONLY ............................................................................. 48 
5.5 
EXCLUSION CRITERIA‐ MTN‐025 DECLINER POPULATION ONLY ............................................................................ 48 
5.6 
CO‐ENROLLMENT GUIDELINES ......................................................................................................................... 48 
6 
STUDY PRODUCT ............................................................................................................................ 49 
6.1 
REGIMEN .................................................................................................................................................... 49 

MTN-025, Version 2.0 
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December 16, 2014 
 
6.2 
ADMINISTRATION .......................................................................................................................................... 49 
6.3 
STUDY PRODUCT FORMULATION ...................................................................................................................... 49 
6.4 
SUPPLY AND ACCOUNTABILITY ......................................................................................................................... 49 
6.5 
CONCOMITANT MEDICATIONS ......................................................................................................................... 51 
6.6 
USE OF INTRAVAGINAL MEDICATIONS AND PRACTICES ......................................................................................... 51 
6.7 
CONDOMS ................................................................................................................................................... 52 
7 
STUDY PROCEDURES ....................................................................................................................... 53 
7.1 
PRE‐SCREENING............................................................................................................................................ 53 
7.2 
SCREENING VISIT .......................................................................................................................................... 53 
7.3 
ENROLLMENT VISIT (DAY 0) ............................................................................................................................ 55 
7.4 
FOLLOW‐UP VISITS ........................................................................................................................................ 56 
7.5 
MTN‐025 DECLINER POPULATION .................................................................................................................. 60 
7.6 
FOLLOW‐UP PROCEDURES FOR PARTICIPANTS WHO TEMPORARILY HOLD OR PERMANENTLY DISCONTINUE STUDY PRODUCT
 ................................................................................................................................................................. 60 
7.7 
FINAL CONTACT ............................................................................................................................................ 62 
7.8 
BEHAVIORAL EVALUATIONS ............................................................................................................................. 63 
7.9 
ADHERENCE COUNSELING ............................................................................................................................... 63 
7.10 
CLINICAL EVALUATIONS AND PROCEDURES ......................................................................................................... 64 
7.11 
LABORATORY EVALUATIONS ............................................................................................................................ 64 
7.12 
HIV INFECTION (SECONDARY ENDPOINT) DETERMINATION ................................................................................... 65 
7.13 
SPECIMEN COLLECTION AND PROCESSING .......................................................................................................... 66 
7.14 
SPECIMEN HANDLING .................................................................................................................................... 67 
7.15 
BIOHAZARD CONTAINMENT ............................................................................................................................ 67 
8 
ASSESSMENT OF SAFETY ................................................................................................................. 67 
8.1 
SAFETY MONITORING .................................................................................................................................... 67 
8.2 
CLINICAL DATA SAFETY REVIEW ....................................................................................................................... 68 
8.3 
ADVERSE EVENTS DEFINITIONS AND REPORTING REQUIREMENTS ........................................................................... 68 
8.4 
EXPEDITED ADVERSE EVENT REPORTING REQUIREMENTS ...................................................................................... 70 
8.5 
SOCIAL HARMS REPORTING............................................................................................................................. 72 
8.6 
REGULATORY REQUIREMENTS ......................................................................................................................... 72 
9 
CLINICAL MANAGEMENT ................................................................................................................ 72 
9.1 
GRADING SYSTEM ......................................................................................................................................... 72 
9.2 
DOSE MODIFICATION INSTRUCTIONS ................................................................................................................ 72 
9.3 
GENERAL CRITERIA FOR TEMPORARY HOLD AND PERMANENT DISCONTINUATION OF STUDY PRODUCT .......................... 73 
9.4 
TEMPORARY PRODUCT HOLD/PERMANENT DISCONTINUATION IN RESPONSE TO OBSERVED ADVERSE EVENTS ................ 74 
9.5 
OTHER CLINICAL FINDINGS .............................................................................................................................. 74 
9.6 
HIV INFECTION ............................................................................................................................................. 76 
9.7 
PREGNANCY ................................................................................................................................................. 77 
9.8 
CRITERIA FOR EARLY TERMINATION OF STUDY PARTICIPATION ............................................................................... 78 
10 
STATISTICAL CONSIDERATIONS ....................................................................................................... 78 
10.1 
OVERVIEW AND SUMMARY OF DESIGN .............................................................................................................. 78 
10.2 
STUDY ENDPOINTS ........................................................................................................................................ 78 
10.3 
SAMPLE SIZE ................................................................................................................................................ 79 
10.4 
PARTICIPANT ACCRUAL, FOLLOW‐UP AND RETENTION .......................................................................................... 79 
10.5 
BLINDING .................................................................................................................................................... 79 
10.6 
DATA AND SAFETY MONITORING PROCEDURES ................................................................................................... 79 
10.7 
PRIMARY ANALYSES ....................................................................................................................................... 80 
10.8 
ANALYSIS OF SECONDARY ENDPOINTS ............................................................................................................... 81 

MTN-025, Version 2.0 
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10.9 
MISSING DATA ............................................................................................................................................. 81 
11 
DATA HANDLING AND RECORDKEEPING ......................................................................................... 82 
11.1 
DATA MANAGEMENT RESPONSIBILITIES ............................................................................................................ 82 
11.2 
SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/DOCUMENTS ....................................................................... 82 
11.3 
QUALITY CONTROL AND QUALITY ASSURANCE .................................................................................................... 83 
12 
CLINICAL SITE MONITORING ........................................................................................................... 83 
13 
HUMAN SUBJECTS PROTECTIONS .................................................................................................... 84 
13.1 
INSTITUTIONAL REVIEW BOARDS/ETHICS COMMITTEES ........................................................................................ 84 
13.2 
PROTOCOL REGISTRATION .............................................................................................................................. 84 
13.3 
STUDY COORDINATION .................................................................................................................................. 85 
13.4 
RISK BENEFIT STATEMENT ............................................................................................................................... 85 
13.5 
INFORMED CONSENT PROCESS ........................................................................................................................ 87 
13.6 
PARTICIPANT CONFIDENTIALITY ........................................................................................................................ 88 
13.7 
SPECIAL POPULATIONS ................................................................................................................................... 88 
13.8 
COMPENSATION ........................................................................................................................................... 89 
13.9 
COMMUNICABLE DISEASE REPORTING ............................................................................................................... 89 
13.10 
ACCESS TO HIV‐RELATED CARE ........................................................................................................................ 89 
13.11 
STUDY DISCONTINUATION .............................................................................................................................. 90 
14 
PUBLICATION POLICY ...................................................................................................................... 90 
15 
APPENDICES ................................................................................................................................... 91 
 
Table of Figures 
 
TABLE 1: CLINICAL PHASE I/II TRIALS OF DAPIVIRINE VAGINAL RINGS ................................................................... 35 
TABLE 2: FREQUENCY OF K103N .............................................................................................................................. 40 
TABLE 3: FREQUENCY OF Y181C .............................................................................................................................. 40 
TABLE 4:  RETRIEVAL OF STUDY PRODUCT ............................................................................................................... 51 
TABLE 6: SCREENING VISIT ........................................................................................................................................ 54 
TABLE 7: ENROLLMENT VISIT ..................................................................................................................................... 55 
TABLE 8: FOLLOW-UP VISITS: MONTHS 1 AND 2 ....................................................................................................... 56 
TABLE 9: QUARTERLY VISITS ..................................................................................................................................... 57 
TABLE 10: PUEV ........................................................................................................................................................ 58 
TABLE 11: STUDY EXIT/TERMINATION VISIT .............................................................................................................. 59 
TABLE 12: SCREENING AND ENROLLMENT PROCEDURES ........................................................................................ 60 
 
FIGURE 1: SAMPLE STUDY VISIT SCHEDULE ............................................................................................................. 25 

MTN-025, Version 2.0 
5 
December 16, 2014 
 
MTN-025 
 
A Phase 3B Open-Label Follow-on Trial to Assess the Continued Safety of and 
Adherence to a Vaginal Ring Containing Dapivirine in Women  
 
LIST OF ABBREVIATIONS AND ACRONYMS 
 
AE   
adverse event  
AIDS  
acquired immunodeficiency syndrome  
ALT 
alanine aminotransferase 
ART 
antiretroviral therapy 
ARV 
Antiretroviral 
AST  
aspartate aminotransferase 
ASPIRE 
AUC  
A Study to Prevent Infection with a Ring for Extended Use 
area under plasma concentration-time curve 
AVAC 
Global Advocacy for HIV Prevention 
BRWG 
Behavioral Research Working Group 
BSWG 
Biomedical Science Working Group 
CAB 
community advisory board 
CAPRISA 
Centre for the AIDS Programme of Research in South Africa 
CBC 
complete blood count 
CDC  
U.S. Centers for Disease Control and Prevention 
CFR 
Code of Federal Regulations 
Cmax 
maximum concentrations 
Cmin 
minimum concentrations 
CMRB 
Clinical Microbicide Research Branch 
CRF  
Case Report Form 
CROI 
Conference on Retroviruses and Opportunistic Infections 
CT 
Chlamydia trachomatis 
CTA 
clinical trial agreement 
CTU 
Clinical trials unit 
CWG 
Community Working Group 
DAERS 
DAIDS Adverse Events Reporting System 
DAIDS  
Division of Acquired Immunodeficiency Syndrome 
DAPY 
di-aminopyrimidine 
DLV 
Delavirdine 
DNA 
deoxyribonucleic acid 
EAE 
expedited adverse event 
EC 
Ethics Committee 
EC50 
50% effective concentration 
EFV 
efavirenz 
FDA  
Food & Drug Administration (U.S.) 
FHCRC 
Fred Hutchinson Cancer Research Center 
FTP 
File Transfer Protocol 
g 
Grams 
GC 
Neisseria gonorrhoeae 

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December 16, 2014 
 
GCP 
Good Clinical Practice 
GMP 
good manufacturing practices 
hCG 
human chorionic gonadotropin 
HOPE 
hu-PBL 
HIV Open-label Prevention Extension 
human peripheral blood lymphocytes 
hu-SCID 
human severe combined immunodeficient 
HIV-1  
human immunodeficiency virus-1 
HPTN 
HIV Prevention Trials Network 
IATA 
International Association of Air Transport 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
IDI 
in-depth interview 
IND 
Investigational New Drug 
IoR 
IPM  
Investigator of Record 
International Partnership for Microbicides 
IRB  
Institutional Review Board 
ITT 
intent-to-treat 
IUCD 
intrauterine contraceptive device 
JHU 
Johns Hopkins University 
JKUAT 
Jomo Kenyatta University of Agriculture and Technology 
KOH 
potassium hydroxide 
LC 
LDMS 
Laboratory Center 
Laboratory Data Management System 
LLOQ 
lower limit of quantification 
LOC 
Leadership and Coordinating Center 
μg 
microgram 
μM 
micromolar (10−3 mol/m3) 
mg 
Milligram 
mL 
Milliliter 
MO 
Medical Officer 
MOP 
Manual of Operational Procedures 
MTN 
Microbicide Trials Network 
MU 
Makerere University 
MU-JHU 
Makerere University - Johns Hopkins University 
NAAT 
nucleic acid amplification test 
ng 
nanogram per milliliter  
NIAID 
National Institute of Allergy and Infectious Diseases 
NIH 
National Institutes of Health 
NIMH 
National Institute of Mental Health 
nM 
nanomolar (10−6 mol/m3) 
NNRTI  
non-nucleoside reverse transcriptase inhibitor 
NOAEL 
no-observed-adverse-effect-level 
NRTI  
Nucleoside reverse transcriptase inhibitor 
NVP 
Nevirapine 
OHRP 
Office for Human Research Protections 
PCR  
polymerase chain reaction 

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December 16, 2014 
 
 
 
PEP 
post-exposure prophylaxis 
pg/mL 
picogram/milliliter 
PID  
pelvic inflammatory disease 
PK  
Pharmacokinetic 
PPD 
Pharmaceutical Product Development, Inc. 
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 
QD 
RNA 
RPR  
quaque die (once daily) 
ribonucleic acid 
rapid plasma reagin 
RSC 
Regulatory Support Center 
RT 
reverse transcriptase 
RTI 
reproductive tract infection 
SAE  
serious adverse event 
SCHARP 
Statistical Center for HIV/AIDS Research & Prevention 
SDMC 
Statistical Data Management Center 
SMC 
Study Monitoring Committee 
SSP 
study specific procedure(s) 
STI  
sexually transmitted infection  
TEAE  
treatment emergent adverse event  
UCSF 
University of California- San Francisco 
UNAIDS 
UNC 
UPMC 
Joint United Nations Programme on HIV/AIDS 
University of North Carolina 
University of Pittsburgh Medical Center 
USA 
United States of America 
UTI 
urinary tract infection 
VR 
WHO  
vaginal ring 
World Health Organization 
wt 
wild-type 

MTN-025, Version 2.0 
8 
December 16, 2014 
 
MTN-025 
 
A Phase 3B Open-Label Follow-on Trial to Assess the Continued Safety of and 
Adherence to a Vaginal Ring Containing Dapivirine in Women  
PROTOCOL TEAM ROSTER 
Protocol Chair 
 
Jared Baeten, MD, PhD 
Protocol Chair 
International Clinical Research Center 
Department of Global Health, University of Washington 
Box 359927 
325 Ninth Avenue 
Seattle, WA  98104 
Phone: 206-520-3808 
Fax: 206-520-3831 
Email: jbaeten@uw.edu 
 
Protocol Co-chairs 
 
Nyaradzo M. Mgodi,  MBChB,  MMed  
Protocol Co-chair 
UZ-UCSF 
15 Phillips Avenue, Belgravia 
Harare, Zimbabwe 
Phone: +263 4 704 920 
Fax: + 263 4 704 897 
Email: nmmgodi@uz-ucsf.co.zw 
 
Thesla Palanee-Phillips, PhD 
Protocol Co-chair 
Wits Reproductive Health and HIV Institute (Wits RHI)  
Research Centre  
 
7 Esselen Street, Hillbrow 
Johannesburg, 2038 South Africa 
Phone: 27-11-358-5471 
Fax: 27-86-554-1093 
Email: tpalanee@whri.ac.za

MTN-025, Version 2.0 
9 
December 16, 2014 
 
Site Investigators 
 
 
Blantyre CRS 
 
Taha E. Taha, PhD 
CTU PI 
Johns Hopkins University  
Bloomberg School of Public Health,  
615 N. Wolfe Street 
Baltimore, MD 21205 
Phone: 410-614-5255 
Fax: 410-502-0688 
Email: ttaha@jhsph.edu 
 
Bonus Makanani, MBBS, FCOG(SA)  
Site Investigator of Record 
Johns Hopkins University Research Project  
Chipatala Avenue 
P.O. Box 1131  
Blantyre, Malawi  
Phone: 265-1875-129  
Fax: 265-1870-132  
Email: bmakanani@jhu.medcol.mw 
 
Newton I. Kumwenda PhD  
Site Investigator, CRS Leader 
Johns Hopkins University Research Project  
Chipatala Avenue 
P.O. Box 1131  
Blantyre, Malawi  
Phone: 265-1875-129  
Fax: 265-1870-132  
Email: nikumwenda@jhu.medcol.mw 
 
 
 

MTN-025, Version 2.0 
10 
December 16, 2014 
 
eThekwini CRS 
 
Quarraisha Abdool Karim, PhD 
CTU PI 
CAPRISA, 2nd Floor DDMRI,  
Nelson R. Mandela School of Medicine,  
719 Umbilo Road  
Durban, KwaZulu-Natal, 4001  
South Africa 
Phone: 27-31-2604208  
Fax: 27-31-2604566 
Email: abdoolq2@ukzn.ac.za  
 
Gonasagrie Nair, MBChB 
Site Investigator of Record 
eThekwini CRS 
3 Richards Road 
Durban 4001 South Africa 
Phone: 27-31-260-1972 
Fax: 27-31-307-7119 
Email: nairg1@ukzn.ac.za 
 
 
Emavundleni CRS 
 
Linda-Gail Bekker MB ChB, FCP, PhD 
CTU PI 
Desmond Tutu HIV Centre, IIDMM,  
Faculty of Health Sciences, UCT, 
Anzio Road, Observatory, 
Western Cape Province, 7705, 
Cape Town, South Africa 
Phone: 27-21-6506959 
Fax: 27-21-6330182 
Email: linda-gail.bekker@hiv-research.org.za  
 
Danielle Crida, MBChB 
Site Investigator of Record 
Emavundleni Research Centre 
14 Sonwabile Drive 
Crossroads7750 
Cape Town South Africa 
Phone: 27-21-3860053 
Fax: 27-21-3860054 
Email: danielle.crida@hiv-research.org.za 
 
 
 
 
 

MTN-025, Version 2.0 
11 
December 16, 2014 
 
Makerere University - Johns Hopkins University (MU-JHU) Research Collaboration CRS 
 
Mary Glenn Fowler 
CTU Co-PI 
Johns Hopkins University School of Medicine,  
600 N. Wolfe Street 
Baltimore, MD 21287 
Phone: 410 502 0683 
Fax: 410 502 0688 
Email: mgfowler@mujhu.org 
 
Clemensia Nakabiito, MBChB, MMed  
Site Principal Investigator MTN MU-JHU Research Collaboration 
P.O. Box 23491  
Kampala, Uganda  
Phone: 256-41-541044/256-772-405332  
Fax: 256-41-541044/256-41-532091  
Email: cnakabiito@mujhu.org 
 
Flavia Matovu Kiweewa, MBChB, Msc. Epidemiology  
Site Investigator of Record 
MU-JHU Research Collaboration  
P.O. Box 23491, Kampala, Uganda  
Phone: 256-414-541044/256-702-544759  
Fax: 256-414-541044/256-414-532091  
Email: fmatovu@mujhu.org 
 
 
 
 

MTN-025, Version 2.0 
12 
December 16, 2014 
 
Lilongwe CRS 
 
Joseph Eron, MD 
CTU Co-PI 
Division of Infectious Diseases  
CB# 7030, Bioinformatics Building  
130 Mason Farm Road, 2nd Floor  
Chapel Hill, North Carolina 27599-7030 
Phone: 919-966-2536  
Fax: 919-966-6714 
Email: joseph_eron@med.unc.edu 
 
Mina Hosseinipour, MD, MPH 
CTU Co-PI 
UNC Project, Tidziwe Centre 
Private Bag A-104 
Lilongwe, Malawi  
Phone: 265-1-755-056 
Fax: 265-1-755-954 
Email: mina_hosseinipour@med.unc.edu 
 
Francis Martinson, MBChB, PhD 
Site Investigator of Record 
UNC Project, Tidziwe Centre, Kamuzu Central Hospital 
Private Bag A-104 
Lilongwe, Malawi 
Phone: 265-1-755-056 
Fax: 265-1-755-954 
Email: fmartinson@unclilongwe.org 
 
Jeffrey SA Stringer, MD 
CTU Co-PI 
130 Mason Farm Road, Suite 2131, CB 7577 
Bioinformatics Bldg., Second Floor 
University of North Carolina at Chapel Hill 
Chapel Hill, NC 27599-7577 
Phone: 919-962-0756 
Fax: 919-966-6714 
Email: Jeffrey_stringer@med.unc.edu 
 
 
 

MTN-025, Version 2.0 
13 
December 16, 2014 
 
South African Medical Research Council Clinical Trials Unit (CTU) 
 
Gita Ramjee, PhD 
CTU Principal Investigator (PI) 
MRC- HIV Prevention Research Unit 
123 Jan Hofmeyr Road 
Westville 3630 
Durban, South Africa 
Phone: +27 31 242 3600 
Fax: +27 31 242 3800 
Email: gita.ramjee@mrc.ac.za 
 
Zakir Gaffoor, M Med Sci  
Site Investigator of Record (Chatsworth) 
MRC- HIV Prevention Research Unit 
P.O. Box 70380 
Overport 4067  
KwaZulu-Natal, South Africa 
Phone: +27 31 242 3600 
Fax: +27 31 242 3800 
Email: Zakir.gaffoor@mrc.ac.za  
 
Vaneshree Govender, MBBCh 
Site Investigator of Record (Isipingo) 
MRC- HIV Prevention Research Unit 
P.O. Box 70380 
Overport 4067  
KwaZulu-Natal, South Africa 
Phone: +27 31 242 3600 
Fax: +27 31 242 3800 
Email:vaneshree.govender@mrc.ac.za 
 
Nitesha Jeenarain, BPharm 
Site Investigator of Record (Verulam) 
MRC- HIV Prevention Research Unit 
P.O. Box 70380 
Overport 4067  
KwaZulu-Natal, South Africa 
Phone: +27 31 242 3600 
Fax: +27 31 242 3800 
Email: nitesha.jeenarain@mrc.ac.za 
 
Logashvari Naidoo, MBChB 
Site Investigator of Record (Tongaat) 
MRC- HIV Prevention Research Unit 
P.O. Box 70380 
Overport 4067  
KwaZulu-Natal, South Africa 
Phone: +27 31 242 3600 
Fax: +27 31 242 3800 
Email: Logashvari.Naidoo@mrc.ac.za 
 
Arendevi Pather, BPharm 
Site Investigator of Record (Umkomaas) 
MRC- HIV Prevention Research Unit 
P.O. Box 70380 
Overport 4067  
KwaZulu-Natal, South Africa 
Phone: +27 31 242 3600 
Fax: +27 31 242 3800 
Email: arendevi.pather@mrc.ac.za 
 
Samantha Siva, MMed Sci 
Site Investigator of Record (Botha’s Hill) 
MRC- HIV Prevention Research Unit 
P.O. Box 70380 
Overport 4067  
KwaZulu-Natal, South Africa 
Phone: +27 31 242 3600 
Fax: +27 31 242 3800 
Email: samantha.siva@mrc.ac.za 
 
 
 
 
 

MTN-025, Version 2.0 
14 
December 16, 2014 
 
The University of Zimbabwe-University of California San Francisco Collaborative 
Research Program (UZ-UCSF) Clinical Trials Unit 
 
Z. Mike Chirenje MD, FRCOG 
CTU PI 
UZ-UCSF 
15 Phillips Avenue, Belgravia 
Harare, Zimbabwe 
Phone: +263 4 704 966 
Fax: + 263 4 704 897 
Email: chirenje@uz-ucsf.co.zw 
 
Nyaradzo M. Mgodi  MBChB,  MMed  
Site Investigator of Record 
UZ-UCSF 
15 Phillips Avenue, Belgravia 
Harare, Zimbabwe 
Phone: +263 4 704 920 
Fax: + 263 4 704 897 
Email: nmmgodi@uz-ucsf.co.zw 
 
Felix G. Muhlanga MBChB,  MMed  
Site Investigator of Record 
UZ-UCSF 
15 Phillips Avenue, Belgravia 
Harare, Zimbabwe 
Phone: +263 4 704 920 
Fax: + 263 4 704 897 
Email: fmhlanga@uz-ucsf.co.zw 
 
 
 
 

MTN-025, Version 2.0 
15 
December 16, 2014 
 
Wits Reproductive Health and HIV Institute (Wits RHI) CRS 
 
Ian Sanne, MD, FCP 
CTU Co- PI 
Helen Joseph Hospital, Perth Road, Westdene, Themba Lethu Clinic 
Johannesburg, 2092 South Africa 
Phone: 27-11-276-8800 
Fax: 27-11 482 2130 
Email: isanne@witshealth.co.za 
 
Helen Vera Rees, OBE, MBBChir, MA, DRCOG, DCH 
CTU Co-PI 
Wits Reproductive Health and HIV Institute (Wits RHI)  
22 Esselen Street, Hillbrow  
Johannesburg, 2001  
Phone: 27-11-358-5300  
Email: hrees@wrhi.ac.za 
 
Thesla Palanee-Phillips, PhD  
Site Principal Investigator and Investigator of Record 
Wits Reproductive Health and HIV Institute (Wits RHI)  
Research Centre  
7 Esselen Street, Hillbrow  
Johannesburg, 2038 South Africa  
Phone: 27-11-358-5471  
Fax: 27-86-554-1093  
Email: tpalanee@whri.ac.za 
 
 
 

MTN-025, Version 2.0 
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December 16, 2014 
 
 
US National Institutes of Health (NIH) 
 
Roberta Black, PhD 
Chief, Clinical Microbicide Research Branch 
National Institute of Allergy and Infectious Diseases (NIAID), Division of AIDS (DAIDS) 
5601 Fishers Lane, Room 8B62, MSC 9831 
Rockville, MD 20892-9831 
Phone: 301-496-8199 
Email: rblack@niaid.nih.gov 
 
Naana Cleland, MHCA 
Health Specialist, Clinical Microbicide Research Branch (CMRB) 
Prevention Sciences Program (PSP) DAIDS, NIAID  
National Institutes of Health (NIH) - U.S. Department of Health and Human Services (HHS) 
5601 Fishers Lane, Room 8B27 
Rockville, MD 20892-9830 
Phone: 240 292 4779 
Email: clelandn@niaid.nih.gov 
 
Cynthia Grossman, PhD 
Chief, HIV Care Engagement and Secondary Prevention Program,  
National Institute of Mental Health (NIMH) 
5601 Fishers Lane Room 9G19, MSC 9831 
Bethesda, MD 20892 
Phone: 240-627-3868 
Email: grossmanc@mail.nih.gov 
 
Dianne M. Rausch, PhD 
Director 
DAIDS Research, NIMH 
5601 Fishers Lane Room 8D20, MSC 9831 
Bethesda, MD 20892 
Phone: 240-627-3874 
Fax: 240-627-3467 
Email: drausch@mail.nih.gov 
 
Lydia E. Soto-Torres, MD, MPH 
DAIDS Medical Officer 
NIAID, DAIDS 
5601 Fishers Lane  
Rockville, MD 20892-9831 
Phone: 301-594-9705 
Cell: 301-213-1154 
Email: lsoto-torres@niaid.nih.gov 

MTN-025, Version 2.0 
17 
December 16, 2014 
 
MTN Leadership and Operations Center (LOC)- Pitt 
 
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 
 
Patrick Ndase, MBChB, MPH 
Regional Physician 
Microbicide Trials Network 
Center of Excellence for HIV prevention, IDI 
Next to Kasangati Health Center 
Kampala, Uganda 
Phone: 256-753-080-489 
Fax: 256-41-532091 
Email: pndase@u.washington.edu 
 
Beth Galaska Burzuk, MID 
Protocol Development Manager 
Microbicide Trials Network 
204 Craft Avenue 
Pittsburgh, PA 15213 USA 
Phone: 412-641-5579 
Fax: 412-641-6170 
Email: galaskaburzukb@upmc.edu 
Ian McGowan, MBChB, MD, DPhil, FRCP  
Co-Principal Investigator 
Microbicide Trials Network 
204 Craft Avenue 
Pittsburgh, PA 15213 USA 
Phone: 412-641-8999 
Fax: 412-641-6170 
Email: imcgowan@pitt.edu 
 
Sharon Hillier, PhD 
Co-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 
 
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@dom.pitt.edu 
 
Ken Ho, MD 
Safety Physician 
UPMC, Keystone Building, Suite 533 
3520 Fifth Avenue 
Pittsburgh, PA 15213 USA 
Phone: 412-383-7178 
Fax: 412-383-2900 
Email: hok2@upmc.edu 
Devika Singh, MD, MPH
Protocol Safety Physician 
Box 359927, Dpt. of Global Health 
ICRC, 325 Ninth Ave. 
Seattle, WA  98104 USA 
Phone: 206-744-8311 
Fax: 206-520-3831 
Email: dsingh@u.washington.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 
 
 

MTN-025, Version 2.0 
18 
December 16, 2014 
 
MTN Laboratory Center (LC) 
 
Wayne Hall, MT(ASCP) 
Clinical Laboratory Representative 
Microbicide Trials Network 
204 Craft Ave. Room A534 
Pittsburgh, PA 15213 USA 
Phone: 412-641-6956 
Fax:412-641-6170 
Email:hallwb@mwri.magee.edu 
 
Craig Hendrix, MD 
Pharmacology LC Principal Investigator 
Johns Hopkins University 
600 North Wolfe Street, Harvey 502 
Baltimore, MD 21287 USA 
Phone: 410-955-9707 
Fax: 410-955-9708 
Email: cwhendrix@jhmi.edu 
 
Edward Livant, BSMT (ASCP), MPH
MTN LC Research Manager 
Microbicide Trials Network 
204 Craft Avenue 
Pittsburgh, PA 15213 USA 
Phone: 412-641-3772 
Fax: 412-641-5290 
Email: livantew@upmc.edu 
 
John Mellors, MD 
Virology LC Principal Investigator 
University of Pittsburgh Physicians 
3550 Terrace Street 
Scaife Hall, Suite 818 
Pittsburgh, PA 15261 USA 
Phone: 412-624-8512 
Fax: 412-383-7982 
Email: mellors@dom.pitt.edu 
 
Urvi Parikh, PhD 
Virology LC Associate Director 
University of Pittsburgh 
3550 Terrace Street 
Scaife Hall, Suite 817-A 
Pittsburgh, PA 15261 USA 
Phone: 412-648-3103 
Fax: 412-648-8521 
Email: ump3@pitt.edu 
 

MTN-025, Version 2.0 
19 
December 16, 2014 
 
MTN LOC – FHI 360 
 
Ashley Mayo, MPH  
Clinical Research Manager  
359 Blackwell St., Suite 200 
PO Box 21059 
Durham, NC  27701 USA  
Phone: 919-544-7040 Ext. 11164  
Fax: 919-544-0904 
Email: amayo@fhi360.org 
 
Rachel Scheckter, MPH, IBCLC  
Clinical Research Manager 
359 Blackwell St., Suite 200 
PO Box 21059 
Durham, NC  27701 USA  
Phone: 919-544-7040 Ext. 11392  
Fax: 919-544-0904 
Email: rscheckter@fhi360.org    
 
Katie Schwartz, MPH  
Sr. Clinical Research Manager  
359 Blackwell St., Suite 200 
PO Box 21059 
Durham, NC  27701 USA  
Phone: 919-544-7040 Ext. 11425  
Fax: 919-544-0904 
Email: kschwartz@fhi360.org 
 
Rhonda White, RH Ed 
Community Program Manager 
359 Blackwell St., Suite 200 
PO Box 21059 
Durham, NC  27701 USA  
Phone: 919-544-7040, Ext. 11515 
Fax: 919-544-0207 
Email: rwhite@fhi360.org 

MTN-025, Version 2.0 
20 
December 16, 2014 
 
MTN Statistical Data Management Center (SDMC) 
 
Jennifer M. Berthiaume, MPH, MSW 
Project Manager  
Fred Hutchinson Cancer Research Center 
(FHCRC)/Statistical Center for HIV/AIDS Research & 
Prevention (SCHARP) 
1100 Fairview Ave. North, LE-400 
P.O. Box 19024 
Seattle, WA  98109-1024 
Phone: 206-667-1230  
Fax: 206-667-4812 
Email: jberthia@scharp.org 
 
 
Elizabeth Brown, ScD 
SDMC Principal Investigator 
FHCRC – SCHARP 
1100 Fairview Avenue North, M2-C200 
PO Box 19024 
Seattle, WA 98109-1024 USA 
Phone: 206-667-1731 
Fax: 206-667-4812 
Email: erbrown@fhcrc.org 
 
 
Marla Husnik, MS 
SDMC Statistical Research Associate 
FHCRC – SCHARP  
1100 Fairview Avenue North, M2-C200 
PO Box 19024 
Seattle, WA 98109-1024 USA 
Phone: 206-667-5633 
Fax: 206-667-4812 
Email: marla@scharp.org 
 
Karen Patterson, MPH 
MTN Program 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 
 
 
 
 
 
 
 

MTN-025, Version 2.0 
21 
December 16, 2014 
 
MTN Behavioral Research Working Group (BRWG) 
 
Ariane van der Straten, PhD, MPH  
BRWG Representative 
RTI International  
351 California Street, Suite 500 
San Francisco, CA 94104 USA  
Phone: 415-848-1324  
Fax: 415-848-1330  
Email: ariane@rti.org 
 
Kenneth Ngure, PhD 
BRWG Representative 
JKUAT-College of Health Sciences 
P.O. Box 19704-00202 
Nairobi, Kenya 
Phone: 254-722-362219  
Email: kngure@uw.edu 

MTN-025, Version 2.0 
22 
December 16, 2014 
 
MTN Community Working Group (CWG) Representatives 
 
Fatima Glyn Zulu, MSc 
CWG Representative 
Johns Hopkins Research Project 
College of Med. JHU CRS  
PO Box 1131, Chipatala Avenue 
Blantyre, Malawi 
Phone: 265-1-875-129 
Mobile: 265-999-955-028 
Fax: 265-1-870-132 
Email: fatimazulu@jhu.medcol.mw  
 
Manju Chatani-Gada 
CWG Representative 
AVAC: Global Advocacy for HIV Prevention 
423 West 127th Street, 4th Floor  
New York, NY 10027 
Phone: 212-796-6423  
Fax: 646-365-3452 
Email: manju@avac.org 
 
 

MTN-025, Version 2.0 
23 
December 16, 2014 
 
MTN-025 
 
 
A Phase 3B Open-Label Follow-on Trial to Assess the Continued Safety of and 
Adherence to a Vaginal Ring Containing Dapivirine in Women  
 
INVESTIGATOR SIGNATURE FORM 
 
Version 2.0 
 
December 16, 2014 
 
A Study of the Microbicide Trials Network 
 
Funded by: 
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 
 
IND Holder: 
International Partnership for Microbicides (IPM) 
 
I, the Investigator of Record, agree to conduct this study in full accordance with the 
provisions of this protocol.  I will comply with all requirements regarding the obligations 
of investigators as outlined in the Statement of Investigator (Form FDA 1572), which I 
have also signed.  I agree to maintain all study documentation for at least two years 
following the date of marketing approval for the study product for the indication in which 
it was 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 Food and Drug Administration is notified.  Publication of the results of this study will 
be governed by MTN policies.  Any presentation, abstract, or manuscript will be 
submitted to the MTN Manuscript Review Committee, DAIDS, IPM and other entities for 
review prior to submission, as required by the MTN Publication Policy. 
 
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 
 
____________________________ 
______________________________ 
Signature of Investigator of Record  
Date 
 
 

MTN-025, Version 2.0 
24 
December 16, 2014 
 
MTN-025 
 
A Phase 3B Open-Label Follow-on Trial to Assess the Continued Safety of and 
Adherence to a Vaginal Ring Containing Dapivirine in Women  
 
PROTOCOL SUMMARY 
 
Short Title: 
HIV Open-label Prevention Extension (HOPE) 
 
IND Sponsor: 
International Partnership for Microbicides 
 
Funders:  
Division of AIDS, NIAID, NIMH, NICHD, US NIH 
 
Protocol Chair: 
Jared Baeten, MD, PhD 
 
Protocol Co-chairs: 
Nyaradzo M. Mgodi, MBChB, MMed  
 
 
Thesla Palanee-Phillips, PhD 
 
Sample Size: 
Eligible former MTN-020 participants 
 
Study Population: 
Former MTN-020 participants who are HIV-uninfected and not 
pregnant 
 
 
 
Decliner Population: Former MTN-020 participants who decline 
participation in the main MTN-025 study and meet eligibility 
criteria as described in Sections 5.4 and 5.5 
 
Study Sites: 
Approved former MTN-020 sites 
 
Study Design: 
Phase 3B, open-label, multi-site trial   
 
 
 
Following demonstration of safety and efficacy of the dapivirine 
vaginal ring in MTN-020, eligible MTN-020 participants will be 
offered enrollment into MTN-025, a trial designed to obtain 
additional safety and adherence data in women.   
 
Study Duration: 
Approximately 13 months of follow-up per participant with a 
projected accrual period of approximately 6 months at each 
site.   
 
 
 
Note:  In an effort to provide women with the maximum ability to enter 
the MTN-025 trial, following the formal ~6-month study accrual period 
participants will continue to be enrolled throughout the duration of the 
trial, provided that at least 4 months of time on study is supported by 
the timeline.  An adjusted (shortened) follow-up period will be 
employed for women who enroll after the formal accrual period.  
 

MTN-025, Version 2.0 
25 
December 16, 2014 
 
Follow-up may be extended beyond 13 months based on need and 
requirements and with the necessary approvals.  
 
Study Product: 
Dapivirine VR 
 
Study Regimen: 
Participants will receive a silicone elastomer vaginal matrix ring 
containing 25 mg of dapivirine to be replaced each month for a 
total period of 12 months of use. 
 
 
 
The study follow-up schedule will be monthly for the first three 
months, then quarterly thereafter (Figure 1), reflecting a 
transition to a more real-world type of follow-up (versus a clinical 
trial 
approach) 
that 
would 
be 
important 
for 
informing 
implementation.   
 
Figure 1: Sample Study Visit Schedule 
 
Primary Objectives: 
 
1. Safety 
- 
To characterize the safety profile associated with the open label use of the 
dapivirine vaginal matrix ring (25 mg) in women 
 
2. Study Product Adherence   
- 
To characterize adherence to the open label use of the dapivirine vaginal 
matrix ring (25 mg) in women  
Primary Endpoints: 
 
1. Safety 
- 
Grade 2 adverse events (AEs) judged to be related to the dapivirine vaginal 
ring 
- 
Grade 3 and higher AEs 
- 
All serious AEs 
 
Screening • 
Enrollment I 
Monthly 
Visit 
(Month 1) 
Monthly 
Visit 
(Month 2) 
Monthly 
Visit 
(Month 3) -
-

MTN-025, Version 2.0 
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December 16, 2014 
 
2. Study Product Adherence 
- 
Residual levels of dapivirine in returned vaginal rings 
 
- 
Blood dapivirine levels  
 
Secondary Objectives: 
 
1. Incidence 
- 
To assess incidence of HIV-1 infection 
 
2. Drug Resistance 
- 
To assess the frequency of HIV-1 drug resistance in women who acquire HIV-
1 infection  
 
Secondary Endpoints: 
 
1. Incidence  
- 
HIV-1 infection as measured by the protocol algorithm 
 
2. Drug Resistance 
- 
HIV-1 drug resistance mutations among participants who acquire HIV-1, as 
measured by standard genotype analysis and more sensitive methods to 
detect low frequency drug-resistant variants 
 
Exploratory Objectives:  
 
1. To explore participant understanding of efficacy  
 
2. To explore ring acceptability in the context of known efficacy 
 
3. To assess the feasibility of a quarterly follow-up visit schedule 
 
4. To describe the genital microenvironment in women exposed to the dapivirine 
vaginal ring 
 
5. To characterize the MTN-020 participants who choose not to enroll into MTN-025 
 
Exploratory Endpoints: 
 
1. Understanding of efficacy  
- 
Self-reported understanding of partial efficacy  
 
2. Understanding of ring acceptability in the context of known efficacy 
- 
Self-reported product acceptability and attitudes towards combination 
prevention  
 
3. Feasibility: 

MTN-025, Version 2.0 
27 
December 16, 2014 
 
- 
Participant report of product storage issues and feasibility regarding the 
follow-up schedule 
- 
Visit retention  
- 
Proportion of returned rings (used and unused)  
 
4. Genital microenvironment 
- 
In genital swab samples, candidate biomarkers of safety, adherence and 
efficacy, HIV exposure and antiretroviral resistance, and genital microflora 
 
5. Characterization of MTN-020 participants who do not enroll in MTN-025 
- 
Participant report of the factors that led to her decision to decline enrollment 
into MTN-025 
 

MTN-025, Version 2.0 
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December 16, 2014 
 
1 
KEY ROLES 
 
1.1 Protocol Identification 
 
Protocol Title:   
A Phase 3B Open-Label Follow-on Trial to Assess the 
Continued Safety of and Adherence to a Vaginal Ring 
Containing Dapivirine in Women 
 
Protocol Number: 
 
MTN-025 
 
Short Title: 
HIV Open-label Prevention Extension (HOPE) 
 
Date:  
 
December 16, 2014 
 
1.2 Sponsor and Monitor Identification 
 
Funding Agencies:  
US Division of AIDS (DAIDS)/National Institute of Allergy 
and Infectious Diseases (NIAID) 
National Institutes of Health (NIH) 
5601 Fishers Lane 
Bethesda, MD 20892 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)  
6100 Executive Boulevard 
Bethesda, MD 20892 USA 
 
IND Sponsor:  
International Partnership for Microbicides (IPM) 
 
 
8401 Colesville Road, Suite 200 
Silver Spring, MD 20910 USA 
 
 
Monitor: 
Pharmaceutical Product Development (PPD), Inc.  
929 North Front Street 
Wilmington, NC  28401-3331 USA 
 
1.3 Medical Officer 
 
Medical Officer: 
Lydia E. Soto-Torres, MD, MPH 
 
 
5601 Fishers Lane  
 
 
Rockville, MD 20892-9831 
 

MTN-025, Version 2.0 
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December 16, 2014 
 
1.4 Clinical Laboratories 
 
Laboratory Center: 
MTN Laboratory Center (LC) 
 
 
 
204 Craft Avenue 
 
 
 
Pittsburgh, PA 15213 USA 
 
Pharmacology: 
MTN Pharmacology LC 
 
 
600 N. Wolfe Street, Osler 527 
 
 
Johns Hopkins University 
 
 
Baltimore, MD 21287 USA 
 
1.5 Data Centers 
 
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: 
RTI International 
 
 
 
351 California Street, Suite 500 
San Francisco, CA 94104 USA 
 
1.6 Study Operations 
 
Study Operations:  
MTN LOC - FHI 360 
 
 
 
359 Blackwell Street, Suite 200 
 
 
 
PO Box 21059 
 
 
 
Durham, NC 27701 USA 
 
 
 
 

MTN-025, Version 2.0 
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December 16, 2014 
 
2 
INTRODUCTION 
 
2.1 Microbicides and Human Immunodeficiency Virus (HIV) Prevention 
 
In 2012, 2.3 million people became newly infected with HIV and 1.6 million lost their 
lives to acquired immunodeficiency syndrome (AIDS).  Every 60 seconds, a young 
woman is infected with HIV.1  According to the Joint United Nations Programme on 
Human Immunodeficiency Virus (HIV)/AIDS (UNAIDS) Global Report, the estimated 
number of individuals living with HIV is 35.3 million globally.  Given the high rates of HIV 
infection among women, female controlled prevention options remain a global priority.  
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.  The 
ongoing development of safe and effective HIV prevention technologies that can be 
made easily accessible to developing countries remains a public health priority. 
 
Unprotected heterosexual intercourse is currently the leading mode of HIV acquisition 
among women.  Correct and consistent use of latex condoms is one proven method of 
preventing HIV acquisition; however, condoms are widely regarded as inadequate 
prevention options for women, because many women are unable to negotiate condom 
use with their partners.  The most widely available HIV prevention methods require the 
consent of the male partner.  Thus, developing HIV prevention options that women can 
use 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, 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 importantly, is 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.  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 may have benefits over dosage forms that need to be used more 
frequently.  
 
Multiple clinical trials have evaluated the safety of dapivirine in VRs, gels and in an oral 
formulation.  These clinical trials support the favorable safety profile and tolerability of 
dapivirine in general and specifically in vaginal delivery formulations.  Initiation of the 
MTN-025 study of the dapivirine VR will be contingent upon demonstration of the safety 
and efficacy of the product in the ongoing MTN-020 (ASPIRE) study.  The specific level 

MTN-025, Version 2.0 
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December 16, 2014 
 
of effectiveness required to trigger activation of the MTN-025 study will be decided upon 
following discussions with key stakeholders including regulatory authorities, community 
representatives, and sponsoring agencies.   
 
2.2 Dapivirine Vaginal Ring (VR) 
 
2.2.1 Description 
 
Dapivirine, a non-nucleoside reverse-transcriptase inhibitor (NNRTI), is a substituted di-
amino-pyrimidine (DAPY) derivative with potent antiviral activity against HIV-1.  
Dapivirine 
is 
chemically 
described 
as 
4-[[4-[(2,4,6-trimethylphenyl)amino]-2-
pyrimidinyl]amino]benzonitrile.2 The dapivirine matrix VR is a flexible ring containing 25 
mg of drug substance dispersed in a platinum-catalyzed cured silicone matrix.  When 
delivered via VR, dapivirine has demonstrated favorable safety and pharmacokinetic 
profiles as described below.   
 
Dapivirine was originally developed by Janssen Research and Development (formerly 
Tibotec Pharmaceuticals Ltd.), a subsidiary of Johnson & Johnson, as an oral ARV 
compound for treatment of HIV/AIDS and was tested in Phase 1 and 2 clinical trials in 
more than 200 participants.3 However, dapivirine is also a promising topical microbicide 
candidate due to its proven in vitro and in vivo efficacy and favorable safety profile as 
well as its physical and chemical properties.  Dapivirine has potent activity against wild-
type HIV-1 strains and strains harboring different resistance-inducing mutations.  
Dapivirine’s ARV profile is superior to that of several other NNRTI drugs, including 
nevirapine (NVP), delavirdine (DLV), and efavirenz (EFV).  Like other NNRTIs, in vitro 
tests have also shown that dapivirine is not active against HIV-2 and has little or no 
activity against common sexually transmitted infections (STI), therefore, it is not 
intended for use against HIV-2 or other STIs.  Dapivirine does not have any 
contraceptive properties.4 Detailed information on dapivirine is available in the 
Dapivirine VR Investigator’s Brochure (IB).5 
 
The International Partnership for Microbicides (IPM) has investigated a wide range of 
dosage forms for the development of topical microbicide products, including vaginal 
gels, rings, films, tablets and soft gel capsules.  The vaginal gel was the initial dosage 
form chosen for a dapivirine-based microbicide because the majority of previous 
microbicides to have entered clinical trials were also vaginal gels and therefore a wealth 
of information was available on that dosage form.  However, the dapivirine silicone 
elastomer VR has now been prioritized over all other dosage forms for the following 
reasons:  
 
 Clinical trials have demonstrated sustained delivery of high levels of dapivirine 
throughout the cervicovaginal vault for up to 1 month;  
 Since the ring is able to deliver drug for at least 1 month, the burden of user-
dependent adherence is lower than for once daily products;  

MTN-025, Version 2.0 
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December 16, 2014 
 
 Product acceptability studies and the experience gained from marketed VR 
products have established a high level of acceptance and adherence from 
women using VR with similar physical characteristics;  
 The overall cost for the VR is relatively low;  
 Minimal storage space is required for the VR when compared with once daily 
products. 
 
Summaries of the safety and tolerability of dapivirine orally and vaginally as evaluated in 
clinical studies by IPM and Tibotec Pharmaceuticals delivered can be found below.  
 
2.2.2 Mechanism of Action 
 
Dapivirine is an NNRTI; NNRTIs bind to the HIV reverse transcriptase (RT) enzyme 
preventing viral replication and therefore the production of infectious virus.   
 
2.2.3 Strength of Study Product 
 
The dapivirine VR (Ring-004) contains 25 mg of dapivirine.  Ring-004 is a matrix VR in 
which the drug substance is dispersed in a platinum-catalyzed cured silicone.   
 
2.3 Nonclinical Studies of Dapivirine 
 
2.3.1 In vitro Studies of Dapivirine 
 
Anti-HIV-1 Activity 
The activity of dapivirine against wild-type (wt) HIV-1, African isolates of HIV-1 
(including subtype C virus), and a panel of NNRTI-resistant viruses has been 
established using in vitro models, with 50% effective concentration (EC50) values 
ranging from 0.3 ng/mL (0.9 nM) against laboratory isolates to <33 ng/mL (<100 nM) for 
HIV-1 isolates encoding one or more known NNRTI resistance mutations.2, 4 
 
The anti-HIV activity was also confirmed in an ex vivo model of human cervical explant 
cultures and a humanized severe combined immunodeficient (hu-SCID) mouse model.2, 
4 Pre-treatment of tissue with dapivirine for 2 or 24 hours inhibited HIV-1 infection when 
challenged with virus on Days 0, 2, 4 and 6 post drug removal.  Dapivirine was also able 
to inhibit virus dissemination by migratory cells up to 6 days post drug removal at 
concentrations down to 10 μM (3.3 μg/mL) following treatment for 2 or 24 hours.  In 
addition, dapivirine (32.9 ng/mL) was able to block transfer of free virus by migratory 
dendritic cells to indicator T-cells (IC50= 0.1 nM [0.03 ng/mL]).   
 
Resistance 
HIV-1 breakthrough in the presence of dapivirine was initially evaluated in studies in 
which cells were infected with wild-type HIV-1 laboratory strains at a high multiplicity of 
infection and in the presence of increasing concentrations of dapivirine.  At 40 nM virus 
breakthrough occurred between 4 and 7 days, at 200 nM breakthrough occurred 
between 7 and 10 days and at 1 μM it took up to 30 days to observe virus breakthrough.  

MTN-025, Version 2.0 
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December 16, 2014 
 
In all cases, mutations were present.  Virus that selected Y181C mutation was resistant 
to dapivirine.  Subsequently, cells were infected with wild-type HIV-1 at low multiplicity 
of infection and were exposed to very low concentrations of dapivirine to mimic the 
extremely low systemic concentrations observed in the first clinical trial of one 
formulation of topical dapivirine (Gel-001). 
 
In the first experiment, population sequencing performed following prolonged exposure 
of HIV-1LAI-infected MT4 cells to low concentrations of dapivirine for a period of 
approximately 30 days identified several NNRTI resistance-associated mutations, 
including Y181C, at dapivirine concentrations of 10 nM and 100 nM, but not at 1 nM and 
0.1 nM concentrations.  However, both Y181C and V179I were detected when single 
viral genomes were analyzed by end-point dilution at 1 and 0.1 nM concentrations.  The 
frequency of Y181C was 10-12% both at 1 and 0.1 nM.  
 
In a second series of experiments using the same and lower dapivirine concentrations, 
population sequencing identified the Y181C mutation at 1 nM, but not at lower 
concentrations.  Analysis using a more sensitive end-point dilution technique in which 
the genotypic sequence of 25 to 30 individual viral genomes was determined indicated 
the presence of Y181C at 0.1 nM, and possibly 0.01 nM (approximately 10-fold lower 
than the EC50 for dapivirine).  
 
The significance of Y181C in a single clone at 0.01 nM in the 31-day culture is not clear.  
It is possible that the sensitive single genome sequencing technology detected some of 
the pre-existing natural variants present in a virus population in the absence of selective 
pressure.  It was concluded that prolonged exposure to low concentrations of dapivirine 
can result in selection of viruses carrying NNRTI resistance-associated mutations, but 
the clinical relevance of these in vitro data is not known. 
 
Experiments comparing the selection of resistant viruses following exposure to 
dapivirine with that following exposure to the NNRTIs UC781, MIV-160, nevirapine and 
efavirenz, showed that dapivirine demonstrated a high genetic barrier to resistance 
development in three viral isolates from subtypes B, C, and CRF02_AG.  Fully resistant 
viruses took 12 weeks to emerge, whereas reduced susceptibility to the NNRTIs 
UC781, efavirenz and nevirapine was detected within 5 weeks.  Unlike UC781 and MIV-
160, dapivirine did not select for mutations common to all three isolates, although the 
subtype C VI829 and CRF02_AG MP568 viruses contained the mutations L100I and 
E138K.  Other mutations selected under dapivirine pressure included E138Q, K101E, 
V108I, K103N, Y181C, V179M/E and F227Y. 
 
To evaluate whether the presence of resistance mutations impaired replication fitness, 
p2/p7/p1/p6/PR/RT/INT-recombinant NNRTI-resistant viruses were constructed and 
viral growth evaluated.  Only four out of 15 resistant viruses showed impairment in 
replicative fitness; however, one of them was a dapivirine-resistant form of VI829. 
 

MTN-025, Version 2.0 
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December 16, 2014 
 
Cross-resistance 
In comparison with NVP, DLV, EFV and emivirine, dapivirine showed significantly better 
in vitro activity against laboratory and recombinant HIV strains resistant to one or more 
drugs of the same class.  The EC50 was below 32.9 ng/mL (100 nM) for 80% of the 
strains compared with only 56% of the strains for EFV.  
 
When tested against 433 clinical isolates with phenotypic resistance to at least one of 
the NNRTIs NVP, DLV, EFV or dapivirine, dapivirine was able to inhibit 46% (202/433) 
of the samples including 41% (142/350) of the strains resistant to EFV.  In contrast, only 
10% (24/231) of the dapivirine-resistant strains were inhibited by EFV. 
 
2.3.2 Condom Compatibility Studies of Dapivirine 
 
Results from male and female condom compatibility studies, IPM 029 and IPM 033, 
respectively, are anticipated in 2014.  
 
Chemical compatibility studies with different dapivirine-containing gel formulations have 
been conducted on the following types of condoms:5 
 
 Non-lubricated latex condoms (male condom); 
 Silicone lubricated latex condoms (male and female condoms); 
 Aqueous lubricated latex condoms (male condom);  
 Polyurethane condoms with silicone lubricant (male and female condoms); and  
 Nitrile condoms with silicone lubricant (female condom). 
 
The results of condom compatibility testing indicate that dapivirine-containing vaginal 
gel formulations (0.05%) have no deleterious effects on the integrity of male or female 
condoms, as indicated by tensile condom properties tested pre- and post-treatment.  
Two clinical condom functionality studies (one with male condoms [IPM 029] and one 
with female condoms [IPM 033]) were conducted with a placebo vaginal ring (silicone 
elastomer ring containing no active ingredient). Results from both studies showed that 
the difference between the total clinical failure rate between condom use with the 
vaginal ring and condom use without the vaginal ring was less than the pre-defined non-
inferiority margins (3% for the male condom study and 8% for the female condom 
study). Condom use was safe and well tolerated with vaginal ring use. 
 
2.4 Clinical Studies 
 
2.4.1 Clinical Studies of Dapivirine Vaginal Rings 
 
To date, 27 Phase 1 and Phase 1/2 clinical trials of dapivirine have been conducted: 5  
 
 Eight trials of dapivirine VRs (25 mg and 200 mg loads) in which 469 participants 
were assigned to dapivirine VRs,  
 Eight trials of dapivirine vaginal gel in which 491 participants used dapivirine 
vaginal gel,  

MTN-025, Version 2.0 
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December 16, 2014 
 
 And, eleven trials of oral dapivirine among 211 participants.2 
 
Efficacy and safety results from MTN-020 and IPM 027 will be made available to MTN-
025 participants.  
 
Clinical Pharmacokinetics  
In all clinical trials of dapivirine vaginal rings and gels to date, dapivirine concentrations 
in plasma have been very low (less than 2 ng/mL) or undetectable after up to 84 days 
exposure. Plasma levels of dapivirine after vaginal exposure in clinical trials are 1000-
fold lower than maximum plasma concentrations after oral administration of dapivirine 
(e.g. Cmax after 300 mg b.i.d. for 14 days was 2286 ng/mL). 5  
 
The clinical pharmacokinetic profile of Ring-004 in IPM 013 showed a rapid increase in 
plasma and vaginal fluid concentrations of dapivirine after ring insertion, resulting in 
maximum concentrations in plasma by Day 7 and in vaginal fluids between Day 1 and 
Day 14, after which concentrations decreased steadily over the remainder of a 28-day 
or 35-day ring use period. Plasma dapivirine concentrations did not exceed 1 ng/mL, 
and were therefore well below concentrations at the maximum tolerated dose (MTD) for 
multiple oral doses (300 mg b.i.d. for 14 days; plasma Cmax of 2286 ng/mL). For 
dapivirine in vaginal fluids, the highest concentration was observed in the area where 
the ring was placed, followed by the cervix, with the lowest concentrations near the 
introitus.  
 
Data from post-use analysis of residual levels of dapivirine in Ring-004 (IPM 015, in 
which a ring was inserted once every 28 days over a 12-week period) indicate that, on 
average, 4 mg of dapivirine were released over approximately one month of ring use. 
The mean amounts of dapivirine remaining in the used rings were similar for Weeks 4, 8 
and 12 (post-insertion), at 21.09 mg, 21.54 mg and 21.84 mg, respectively. No clear 
relationship (neither linear nor exponential) was observed between the residual amount 
of dapivirine and corresponding plasma concentrations (i.e. at scheduled ring removal). 
It would appear that plasma concentrations below approximately 200 pg/mL were 
generally associated with above-average ring residual amounts, while the residual 
amounts appeared relatively constant (at levels between approximately 20 and 22 mg) 
for plasma concentrations above this value (200 pg/mL).  
 
Safety  
 
Table 1: Clinical Phase I/II Trials of Dapivirine Vaginal Rings 
Trial Details 
Number of Participants 
Trial 
Number 
Description 
Country 
Ring-001 
reservoir 
(200 mg) 
Ring-002 
reservoir 
(25 mg) 
Ring-003 
matrix* 
(25 mg) 
Ring-004 
matrix** 
(25 mg) 
Placebo 
Ring 
IPM 001 
Safety and PK in 
women; 7 days 
Belgium 
 
12 
-- 
-- 
-- 
12 
(crossover) 
IPM 008 
Safety and PK in 
women; 7 days 
Belgium 
-- 
10 
-- 
-- 
3 

MTN-025, Version 2.0 
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December 16, 2014 
 
Trial Details 
Number of Participants 
Trial 
Number 
Description 
Country 
Ring-001 
reservoir 
(200 mg) 
Ring-002 
reservoir 
(25 mg) 
Ring-003 
matrix* 
(25 mg) 
Ring-004 
matrix** 
(25 mg) 
Placebo 
Ring 
IPM 013 
Safety and PK in 
women; 56/57 
days 
Belgium 
-- 
-- 
-- 
36 
12 
IPM 015 
Safety and PK in 
women; 84 days 
Multiple 
Countries 
in Sub-
Saharan 
Africa 
-- 
-- 
-- 
140 
140 
IPM 018 
Safety and PK in 
women; 28 days 
Belgium 
-- 
8 
8 
-- 
8 
IPM 024 
Safety and PK in 
women; 28 days 
Belgium 
-- 
-- 
-- 
8 
8 
MTN-
013/ 
IPM 
026*** 
Safety and PK in 
women 
United 
States 
-- 
-- 
-- 
12 
12 
IPM 028 
Drug-drug 
Interaction 
(miconazole 
nitrate); 28 days  
Belgium 
 
 
 
36 
0 
IPM 034 
Safety and PK in 
women; 7, 14, 
28, 56, or 84 
days  
Belgium 
 
 
 
40 
0 
TOTAL 
12
18
8
172 
195
*Tin-catalyzed matrix ring. 
**Platinum-catalyzed matrix ring 
***MTN-013/ IPM 026 was the first in human clinical trial of a vaginal ring containing maraviroc alone, 
dapivirine alone or a combination of the two (dapivirine/maraviroc) compared to placebo.  The 
dapivirine VR arm included 12 participants. It should be noted, however, that the dapivirine VR was 
similar to Ring-004, but of slightly different composition. 
 
Across all clinical trials with multiple ring configurations in healthy participants, the 
dapivirine VR was generally safe and well-tolerated.9 IPM has conducted a review of 
aggregate safety information which identifies vaginal candidiasis as a possible adverse 
drug reaction caused by dapivirine vaginal ring use.  The highest reported severity for 
vaginal candidiasis across studies was a Grade 2 in women using a Vaginal Ring-004. 
 
The first dapivirine VR tested in humans, Ring-001, consisted of two reservoir cores 
containing a total of 200 mg dapivirine surrounded by a controlled-release outer sheath 
of silicone elastomer.  Ring-001 was tested in a Phase 1, open-label, crossover trial in 
12 healthy, sexually abstinent, HIV-uninfected women at a single research center in 
Belgium (IPM 001).6 Women used the placebo ring for 7 days followed by the dapivirine 
ring for 7 days.  There were no serious adverse events (SAEs) during the trial and few 
treatment-emergent adverse events (TEAEs).  The dapivirine ring was considered to be 
safe based on the results of this trial in healthy participants.  
 
Ring-002, a similar formulation with a single dapivirine reservoir core containing 25 mg 
dapivirine, was tested in a Phase 1, randomized, placebo-controlled trial conducted at a 

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December 16, 2014 
 
single research center in Belgium (IPM 008).10 Ten women underwent 7-day exposure 
to dapivirine Ring-002, and three women used a placebo ring for 7 days.  There were no 
SAEs during the trial and few TEAEs.  The trial results showed that the dapivirine ring 
was safe in healthy participants.  
 
Ring-003, a dapivirine matrix VR containing 25 mg of drug substance dispersed in a tin-
catalyzed-cured silicone matrix, was compared with Ring-002 in a Phase 1, 
randomized, placebo-controlled trial conducted at a single research center in Belgium 
(IPM 018).  Twenty-four healthy, HIV-uninfected women, 18 to 35 years of age, were 
randomly assigned (1:1:1) to dapivirine matrix ring, dapivirine reservoir ring, or placebo 
ring for 28 consecutive days.  No SAEs were reported during the study.  No TEAEs 
were assessed by the investigator as definitely or probably related to the ring, and 
similar percentages of participants in the dapivirine and placebo ring groups had TEAEs 
considered to be possibly related to the ring.  
 
Ring-004, the current formulation, is a dapivirine matrix VR containing 25 mg of drug 
substance dispersed in a platinum -cured silicone matrix.  It has been evaluated in 5 
completed clinical trials.5 
 
The first clinical trial, IPM 024 was conducted in Belgium, enrolled 16 healthy, HIV-
uninfected, sexually abstinent women, between 18 to 40 years of age.  The women 
were randomly assigned to a dapivirine (25 mg) matrix ring or a placebo ring for 28 
consecutive days.  No SAEs were reported in the dapivirine VR group.  No AEs were 
judged by the investigator to be related to the study agent.  Most dapivirine VR group 
participants, 87.5% (7/8), experienced at least one TEAE.  Of the women in the 
dapivirine VR group who experienced a TEAE, 50% (4/8) reported headache.  Of the 
participants using dapivirine VRs, 50% experienced Grade 1 or Grade 2 metrorrhagia, 
38% experienced vulvovaginal discomfort and 25% experienced nasopharyngitis.  One 
participant experienced a Grade 1 vaginal hemorrhage in the dapivirine VR group. 
 
IPM 013 was a Phase I, randomized, double-blind, placebo-controlled trial conducted 
over 3 months at one research center in Belgium (IPM 013).5 Forty-eight healthy, HIV-
negative, sexually active women, 18 to 40 years of age, were assigned in groups of 
eight to one of two groups, Group A or Group B (unblinded assignment). Within each 
group, participants were randomized in a blinded manner, in a 3:1 ratio, to either the 
dapivirine ring or placebo ring, for a total of four treatment arms. In Group A, the first 
vaginal ring was removed on Day 28, and a second vaginal ring inserted after 3 days, 
on Day 31, for another 28 days. In Group B, the first vaginal ring was removed on Day 
35, and a second vaginal ring was inserted after 3 days, on Day 38, for another 21 
days. A third vaginal ring was inserted immediately following removal of the second ring 
on Day 59, and was worn for 24 hours. No SAEs were reported during the trial. One 
participant discontinued the trial due to a TEAE of generalized pruritus; the event was 
not considered serious, of Grade 2 (moderate) intensity, and regarded by the 
investigator as possibly related to use of the dapivirine ring. No TEAEs were assessed 
by the investigator as definitely or probably related to the dapivirine ring, and a similar 

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percentage of participants in the dapivirine and placebo ring groups had TEAEs 
considered to be possibly related to the vaginal ring. 
 
IPM 015 was a double-blind, randomized, placebo-controlled Phase 1/2 trial conducted 
at 10 research centers in Kenya, Malawi, Tanzania and South Africa.  The trial was 
performed in 280 healthy, HIV-negative women who inserted a vaginal ring once every 
21-35 days over a 12-week period.  Five SAEs occurred during the trial, of which four 
occurred in placebo participants.11 None of the SAEs were judged to be related to 
product.  No TEAEs led to premature discontinuation of ring use.  One participant in the 
dapivirine treatment group reported Grade 3 tonsillitis, which was unrelated to the 
investigational product.  Four participants in the placebo treatment group reported one 
instance each of bronchiectasis (Grade 3), peritonsillar abscess (Grade 3), suicide 
attempt (Grade 3), and hemopneumothorax (Grade 4).  The hemopneumothorax was 
caused by a physical assault; this event was unrelated to the investigational product.  A 
chemical pregnancy was reported for one participant in the placebo ring group who 
discontinued product use, but continued to attend the research center for safety 
evaluations and completed the remainder of trial visits.  In IPM 015, two vaginal 
bleeding events were reported; both occurred in the placebo ring arm.  Apart from the 
latter two events, chemical pregnancy and hemopneumothorax, none of the SAEs or 
TEAEs led to premature discontinuation of ring use. 
 
IPM 028, the fourth trial of Ring-004 was a Phase I open-label, randomized, 3-period, 2-
sequence, cross-over trial, to assess the drug-drug-interaction potential between Ring-
004 and miconazole nitrate, administered as a single dose (1200 mg) vaginal capsule 
(Gyno-Daktarin®) in HIV-negative women, 18 to 40 years of age.5 The trial was 
conducted at a Phase I unit in Belgium and enrolled 36 women, randomly assigned to 
one of two treatment sequences, ABC or BAC, during which they received three 
treatments, each separated by a washout period of 3 weeks: Treatment A = Dapivirine 
Vaginal Ring-004 inserted for 28 days; Treatment B = Dapivirine Vaginal Ring-004 
inserted for 28 days along with a single dose of miconazole nitrate on Day 0; Treatment 
C = a single dose of miconazole nitrate inserted on Day 0. One SAE (fracture of the 
right acetabulum) was reported in a participant during the washout period who had been 
assigned to initial treatment with the dapivirine ring and miconazole vaginal capsule 
(Treatment B). The event was assessed as severe (Grade 3) and regarded by the 
Investigator as unrelated to the IP. One TEAE was considered by the Investigator as 
related to IP use during the trial. The participant was enrolled in Treatment Sequence 
ABC and experienced moderate (Grade 2) vulvovaginal candidiasis during the ring use 
period of Treatment A, two days before the scheduled ring removal. Based on all safety 
evaluations performed, no overall clinically significant differences were observed 
between treatment with the dapivirine vaginal ring alone, in co-administration with 
miconazole, or miconazole alone. 
 
IPM 034, the fifth trial of Ring-004 was a Phase I open-label, parallel group trial, to 
assess the release profile of Ring-004 over extended periods of ring use in HIV-
negative women, 18 to 40 years of age. The trial was conducted at a Phase I unit in 
Belgium and enrolled 40 women in five groups (Groups A, B, C, D and E) of eight 

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women each. Each woman was administered with one dapivirine ring and instructed to 
wear the ring continuously for a period of 7, 14, 28, 56, or 84 days (1, 2, 4, 8, or 12 
weeks). One SAE (thoracic vertebral fractures following a motor vehicle accident) was 
reported in a participant using the dapivirine ring in Group C. The event was assessed 
as severe (Grade 3) and regarded by the Investigator as unrelated to the IP. Product-
related TEAEs were reported for four women during the trial of whom three experienced 
mild vaginal discharge (one woman with a 56-day ring use period and two women with 
an 84-day ring use period) and one experienced moderate bacterial vaginitis (84-day 
ring use period). Based on all safety evaluations performed during the trial, no overall 
clinically significant differences were observed between the different ring use periods. 
 
MTN-013/IPM 026, a Phase 1 safety and pharmacokinetics study of dapivirine VR, 
maraviroc VR, dapivirine/maraviroc VR and placebo VR, enrolled approximately 48 
women between the ages of 18-40.  The participants were randomized in a 1:1:1:1 ratio 
to 28 days of continuous study vaginal ring use.  Over the course of 52 days, 14 follow-
up visits occurred.  There was no statistically significant difference in the number of 
participants with genitourinary AEs between placebo arm and any other treatment arms.  
Twenty-two women experienced 33 grade 1 and one grade 2 related genitourinary 
AEs.12 Two grade 2 AEs were determined to be related to study product.  At Day 28, 
dapivirine vaginal fluid levels were 14.9 µg/mL in women assigned to the dapivirine only 
ring.   
 
In March of 2012, IPM 027, also known as The Ring Study, was initiated.  IPM 027 is a 
randomized, double-blind, placebo-controlled efficacy and long-term safety study that 
will enroll 1,650 healthy, HIV-uninfected women, ages 18-45.  The study is being 
conducted in South Africa and Uganda.  Study participants will use either the dapivirine 
ring or the placebo ring every four weeks over approximately two years.  The main 
goals of The Ring Study are to evaluate the long-term safety and efficacy of the 
dapivirine ring for the prevention of HIV-1 as compared to a placebo ring, when used by 
healthy, HIV-negative women over a two-year period.  Additional goals include 
measuring the incidence of curable STIs, HIV-2 and pregnancy; monitoring ring 
acceptability (how well women like using the ring) and adherence (if women use the ring 
as intended) as reported by the study participants; and tracking the development of any 
HIV-1 drug resistance in participants who become HIV positive during the study.  The 
study is anticipated to conclude in 2015/16. 
 
MTN-020, A Study to Prevent Infection with a Ring for Extended Use (ASPIRE), is a 
Phase 3 clinical trial designed to assess the efficacy and safety of a ring containing 25 
mg of dapivirine for the prevention of HIV-1 acquisition in women.  The double-blind, 
randomized controlled trial is being conducted in HIV-uninfected women, between the 
ages 18 – 45.  A total of 2629 women from Malawi, South Africa, Uganda, and 
Zimbabwe have enrolled in the trial.  Participants replace the ring monthly for a 
minimum of one year.  MTN-020 aims to determine the safety and efficacy of the 
dapivirine ring in preventing HIV-1 infection among health sexually active HIV-
uninfected women when inserted vaginally once every 4 weeks.  Additional goals of 
MTN-020 include the assessment of participant acceptability and adherence to the 

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investigational product, HIV-1 drug resistance mutations among participants who 
acquire HIV-1 infection and establishing steady state drug concentrations in the study 
population.  The study is anticipated to conclude in 2015. 
 
2.5 Prevalence of Primary Non-nucleoside Reverse Transcriptase Inhibitor 
(NNRTI) Resistance Mutations 
 
Recent data on primary NNRTI resistance from a WHO threshold surveillance study  
conducted between 2005-2009 categorized Kwa-Zulu Natal as having 5-15% NNRTI 
resistance.13 MTN-009 found 6.5% NNRTI resistance amongst participants screening 
for VOICE who were already HIV positive, with 87% of those with NNRTI resistance 
having HIV-1 with Y181C and/or K103N.14  In the Stanford University HIV Drug 
Resistance Database, which compiled data from 12,014 HIV-1 subtype C sequences, 
and 5831 subtype A & D sequences from treatment-naïve and NNRTI-treated persons, 
the following was found:15 
 
Table 2: Frequency of K103N 
 
Treatment-Naïve 
NNRTI-experienced 
Subtype C 
1.2% 
42% 
Subtypes A and D 
no data 
14% 
 
Table 3: Frequency of Y181C 
 
Treatment-Naïve 
NNRTI-experienced 
Subtype C 
no data 
27% 
Subtypes A and D 
no data 
18-20% 
 
2.6 Behavioral Studies 
 
2.6.1 Acceptability of Dapivirine VR 
 
IPM 011 assessed the acceptability of the dapivirine VR and the placebo VR in 170 
women.  The trial was conducted across multiple sites in Tanzania and South Africa.  
The study participants found the ring to be very comfortable (95%), very easy to insert 
(94%) and remove (92%), and rarely were the rings felt during daily activities.  All 
questionnaire respondents, when asked if they would be willing to use the vaginal ring if 
shown to be effective for HIV prevention, replied that they would use the VR.16 
 
In IPM 015, at Week 12, 97% of African women reported that the dapivirine VR was 
comfortable and that they were willing to use the VR if it was found to be effective.  
Women preferred to wear the VR every day (97%) and reported that the ring did not 
interfere with their daily activities (89%).  In terms of the male partner acceptability, 63% 
of women reported that their partner did not feel the ring during sex.  Of those 
participants who reported that their partner felt the ring, only 1% reported that this might 
be or definitely was a problem.11 
 
2.6.2 Adherence of Dapivirine VR 
 

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In IPM 011, 11% of the women experienced expulsions/removal, with the most common 
reason being ‘menses related’.  In the majority of cases (64%), the VR was washed and 
re-inserted.16 
 
In IPM 015, perfect adherence was reported by 92% of the female participants.  Perfect 
adherence was defined as never having the VR out for more than an entire day.  Of the 
women who reported that the ring was out, the most common activity for expulsion was 
urination/defecation.  The most common reason reported by participants for VR removal 
was cleaning.  As the study progressed, more women reported removing the VR prior to 
sexual intercourse, 17% at week 2 and 36% by week 12.11 
 
2.7 Rationale for Study Design 
 
2.7.1 Study Design 
 
The dapivirine VR advanced to evaluation in Phase 3 safety and effectiveness trials 
based on data from preclinical and early clinical safety trials.  Upon demonstration of the 
safety and effectiveness of the dapivirine VR in the MTN-020, implementation of the 
follow-on trial, MTN-025, will commence. 
 
The primary focus of MTN-025 is the collection of additional adherence and safety data 
further, MTN-025 will examine incidence of HIV-1 infection and explore the way in which 
participants adopt this biomedical prevention method and incorporate it into the context 
of their everyday lives.   
 
While there are many facets to the future roll-out of ARV-based prevention that are 
worthy of study, including potential impacts on behavior, optimizing drug adherence, 
and implementation strategies for the public sector, all future approaches must be 
grounded in an evidence base for safe management of these drugs in healthy 
populations.  MTN-025 will contribute to this evidence base by describing the safety 
outcomes with a quarterly monitoring schedule for women using an ARV-based  HIV 
prevention  intervention.  Safety data will be forwarded to regulatory entities.  Roll-out of 
ARV-based prevention in the public sector in resource-limited environments will likely 
require a pharmacovigilance strategy that is less costly and time-consuming than the 
options described here.  MTN-025 will provide valuable information that will help guide 
the development of those strategies. 
 
MTN-025, the HIV Open-label Prevention Extension (HOPE) trial will provide additional 
safety and adherence data of dapivirine (25 mg) in a silicone elastomer vaginal matrix 
ring (Ring-004) when inserted monthly in healthy, HIV-uninfected, not pregnant, 
sexually active research-experienced women should efficacy be demonstrated in MTN-
020. 
 

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2.7.2 Incorporating Emergent Effective HIV-1 Prevention Strategies 
 
As of June 2014, the United States was the only country where ARVs (the combination 
daily oral pill emtricitabine/tenofovir disoproxil fumarate [Truvada®]) are licensed for use 
as pre-exposure prophylaxis (PrEP).  However, as candidate microbicides continue to 
demonstrate evidence of efficacy, the potential for one or more licensed HIV-1 
prevention strategies in sub-Saharan Africa may soon become a reality.  The HOPE 
Protocol Team will follow all relevant national policies regarding HIV-1 prevention and 
will actively consult with stakeholders in the event that an effective intervention is 
approved locally.  Consultation with target populations, policy makers, governments and 
other stakeholders will be ongoing throughout the duration of study implementation and 
participant follow-up by study leadership, Microbicide Trial Network (MTN) Leadership 
and the MTN Community Working Group (CWG). 
 
 
 
3 
OBJECTIVES 
 
3.1 Primary Objectives 
 
1. Safety 
- 
To characterize the safety profile associated with the open label use of the 
dapivirine vaginal matrix ring (25 mg) in women 
 
2. Study Product Adherence   
- 
To characterize adherence to the open label use of the dapivirine vaginal 
matrix ring (25 mg) in women  
 
3.2 Secondary Objectives 
 
1. Incidence 
- 
To assess incidence of HIV-1 infection 
 
2. Drug Resistance 
- 
To assess the frequency of HIV-1 drug resistance in women who acquire HIV-
1 infection  
 
3.3 Exploratory Objectives 
 
 
1. To explore participant understanding of efficacy  
 
2. To explore ring acceptability in the context of known efficacy 
 
3. To assess the feasibility of a quarterly follow-up visit schedule 
 

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4. To describe the genital microenvironment in women exposed to the dapivirine 
vaginal ring 
 
5. To characterize the MTN-020 participants who choose not to enroll into MTN-025 
 
 
 
4 
STUDY DESIGN 
 
4.1 Identification of Study Design 
 
The MTN-025 trial, HOPE, is a multi-site, open-label, Phase 3B trial that will be 
implemented if the dapivirine VR is found to be a safe and an effective HIV prevention 
method in the MTN-020 trial.  Eligible former MTN-020 HIV-uninfected participants will 
attend monthly study visits until the third month of follow-up and then quarterly visits 
thereafter.  The study will assess the safety of and participant adherence to a silicone 
elastomer vaginal matrix ring containing 25 mg of dapivirine. 
 
4.2 Summary of Major Endpoints 
 
Primary Endpoints: 
 
1. Safety  
- 
Grade 2 AEs judged to be related to the dapivirine vaginal ring 
- 
Grade 3 and higher AEs 
- 
All serious AEs 
 
2. Study Product Adherence 
- 
Residual levels of dapivirine in returned vaginal rings  
- 
Blood dapivirine levels  
 
Secondary Endpoints: 
 
1. Incidence  
- 
HIV-1 infection as measured by the protocol algorithm 
 
2. Drug Resistance 
- 
HIV-1 drug resistance mutations among participants who acquire HIV-1, as 
measured by standard genotype analysis and more sensitive methods to 
detect low frequency drug-resistant variants 
 

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4.3 Description of Study Population 
 
Former MTN-020 participants who are healthy, HIV-uninfected, not pregnant and meet 
eligibility criteria as described in Sections 5.2 and 5.3 
 
Decliner Population: Former MTN-020 participants who decline participation in the main 
MTN-025 study and meet eligibility criteria as described in Sections 5.4 and 5.5 
 
4.4 Time to Complete Accrual 
 
The majority of former ASPIRE participants are anticipated to enroll approximately 3-6 
months following site activation, see Section 10.4 for additional details. 
 
4.5 Expected Duration of Participation 
 
The majority of former ASPIRE participants will complete approximately 13 months of 
follow-up, see Section 10.4 for additional details. Follow-up may be extended beyond 13 
months based on need and requirements and with the necessary approvals.   
 
Visits may be completed within specified windows around target dates. Detailed 
information regarding visit windows will be described in the MTN-025 Study Specific 
Procedures (SSP) Manual. 
 
4.6 Sites 
 
Approved former MTN-020, ASPIRE, sites will participate in MTN-025, HOPE. 
 
 
 
5 
STUDY POPULATION 
 
5.1 Selection of the Study Population 
 
If safety and efficacy of the dapivirine vaginal ring are demonstrated in MTN-020 
(ASPIRE); MTN-025 (HOPE), will be implemented as a follow-on trial.  Inclusion and 
Exclusion Criteria, Sections 5.2 and 5.3, respectively, are used to ensure the 
appropriate selection of study participants for MTN-025.   
 
Decliner Population: Former MTN-020 participants who decline participation in the main 
MTN-025 study, and who meet inclusion and exclusion criteria in Sections 5.4 and 5.5, 
will be invited to complete behavioral assessment(s). 
 
5.1.1 Recruitment 
 
Participants will be recruited from study site cohorts of MTN-020 participants.  Efforts 
will be made by study sites to maintain contact with MTN-020, ASPIRE, participants 

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between the end of follow-up in MTN-020 and the initiation of the MTN-025 trial, HOPE, 
to provide MTN-020 study results and information regarding the HOPE study to 
participants.  Recruitment materials will be approved by site Institutional Review 
Boards/Ethics Committees (IRBs/ECs) prior to use.  Site community representatives 
should advise on these materials before they are submitted to the IRB/EC for review.  
Community education strategies, including group sessions, may be employed as part of 
participant/partner outreach. 
 
5.1.2 Retention 
 
Once a participant is enrolled into the HOPE trial, 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 across sites.  Each study 
site will establish and follow standard operating procedures (SOPs) for participant 
retention.   
 
5.2 Inclusion Criteria 
 
Women must meet all of the following criteria to be eligible for inclusion in the study: 
 
1) Previously enrolled in MTN-020 (ASPIRE) 
 
2) Able and willing to provide written informed consent to be screened for and to take 
part in the study 
 
3) Able and willing to provide adequate locator information, as defined in site SOPs 
 
4) HIV-uninfected based on testing performed by study staff at Screening and 
Enrollment (per applicable algorithm in Appendix II) 
 
5) Using an effective method of contraception at Enrollment, and intending to use an 
effective method for the duration of study participation; effective methods include 
hormonal methods (except contraceptive ring); intrauterine contraceptive device 
(IUCD); and sterilization (of participant, as defined in site SOPs) 
 
6) At Screening and Enrollment, agrees not to participate in other research studies 
involving drugs, medical devices, vaginal products, or vaccines for the duration of 
study participation 
 
5.3 Exclusion Criteria 
 
Women who meet any of the following criteria will be excluded from the study: 
 
1) Study product use permanently discontinued in response to an AE or safety related 
concern while taking part in the MTN-020 (ASPIRE) trial  
 

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2) Per participant report at Screening: 
a) Plans to relocate away from the study site during study participation 
b) Plans to travel away from the study site for more than three consecutive months 
during study participation 
 
3) Per participant report at Enrollment, currently taking Post-Exposure Prophylaxis 
(PEP) 
 
Note:  PEP use at Screening is not exclusionary.  Participants may be enrolled after the 
PEP regimen is complete and a negative HIV test is documented within 56 days of 
providing informed consent for Screening.  
 
4) With the exception of MTN-020 (ASPIRE), participation in any other research study 
involving drugs, medical devices, vaginal products, or vaccines, within 60 days of 
enrollment  
 
Note: Participation in the ‘Decliner Population’ does not preclude MTN-025 full study 
participation in the future.    
 
5) Is pregnant at Screening/Enrollment or planning to become pregnant in the 
participant’s anticipated study participation 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 
screening/enrollment into the study.   
 
6) Currently breastfeeding 
 
7) Diagnosed with urinary tract infection (UTI), pelvic inflammatory disease (PID), STI 
or reproductive tract infection (RTI) requiring treatment per WHO guidelines 
 
Note: Otherwise eligible participants diagnosed during screening with a UTI, PID or 
STI/RTI requiring treatment per WHO guidelines — other than asymptomatic BV and 
asymptomatic 
candidiasis 
— 
are 
offered 
treatment 
consistent 
with 
WHO 
recommendations and may be enrolled after completing treatment if all symptoms have 
resolved.  If treatment is completed and symptoms have resolved within 56 days of 
obtaining informed consent for screening, the participant may be enrolled.  Genital warts 
requiring treatment also must be treated prior to enrollment.  Genital warts requiring 
therapy are defined as those that cause undue burden or discomfort to the participant, 
including bulky size, unacceptable appearance, or physical discomfort. 
 
8) At Screening, has a clinically apparent Grade 3 pelvic exam finding (observed by 
study staff) as per the Division of AIDS Table for Grading the Severity of Adult and 
Pediatric Adverse Events Version 1.0, December, 2004 (Clarification dated August 
2009), Addendum 1-Female Genital Grading Table for Use in Microbicide Studies 
 
Note:  Otherwise eligible participants with exclusionary pelvic exam findings may be 
enrolled after the findings have improved to a non-exclusionary severity grading or 

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resolved.  If improvement to a non-exclusionary grade or resolution is documented within 
56 days of providing informed consent for screening, the participant may be enrolled.  
 
9) Has any of the following laboratory abnormalities at Screening Visit: 
a) Aspartate aminotransferase (AST) or alanine transaminase (ALT) > Grade 3* 
b) Creatinine > Grade 3* 
c) Hemoglobin > Grade 3* 
d) Platelet count > Grade 3* 
e) Pap result ≥ Grade 3 according to the Female Genital Grading Table for Use in 
Microbicide Studies Addendum 1 to the DAIDS Table for Grading Adult and 
Pediatric Adverse Events, Version 1.0, December 2004 (Clarification dated 
August 2009) 
 
Note:  Otherwise eligible participants with an exclusionary test may be re-tested during 
the screening process. 
 
Note: Women with a documented normal result within the 12 months prior to enrollment 
need not have Pap smear during the screening period.  Need for a repeat Pap within 6 
months does not preclude enrollment prior to that result becoming available. 
 
*Per the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse 
Events Version 1.0, December, 2004 (Clarification dated August 2009) 
 
10) Has any significant medical condition or other condition that, in the opinion of the 
IoR/designee, would preclude informed consent, make study participation unsafe, 
complicate interpretation of study outcome data, or otherwise interfere with 
achieving the study objectives 
 

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5.4 Inclusion Criteria- MTN-025 Decliner Population Only 
 
MTN-025 Decliner Population participants must meet all of the following criteria to be 
eligible for inclusion in the study: 
 
1) Able and willing to provide informed consent  
2) Participated in MTN-020 (ASPIRE) 
3) Declines MTN-025 (main) study trial participation  
4) Able and willing to perform the Decliner Population study procedures 
 
5.5 Exclusion Criteria- MTN-025 Decliner Population Only 
 
MTN-025 Decliner Population participants who meet the following criteria will be 
excluded from the study: 
 
1) Has any condition that, in the opinion of the Investigator of Record 
(IoR)/designee, would preclude informed consent, make study participation 
unsafe, complicate interpretation of study outcome data, or otherwise interfere 
with achieving the study objectives. 
 
 
5.6 Co-enrollment Guidelines 
 
As indicated in Section 5.2 and 5.3, participants should not take part in other research 
studies involving drugs, medical devices, vaginal products or vaccines after the 
Screening Visit and while taking part in this study.  Each site will be responsible for 
defining procedures for management and prevention of co-enrollment prior to initiation.  
 
Exceptions to this guideline may be made for participants to co-enroll in the following 
types of studies at the discretion of the IoR/designee: 
 
 Participants may take part in ancillary studies approved by the MTN-025 
Protocol Chair  
 Participants who become infected with HIV may take part in observational 
and/or interventional studies for HIV-positive persons 
 Participants who become pregnant may take part in observational studies, 
including pregnancy registries approved by the MTN-025 Protocol Chair  
 
Should any participant report or should study staff discover concurrent participation in 
any other study after enrolling in MTN-025, the IoR/designee will consult the Protocol 
Safety Review Team (PSRT) regarding ongoing product use and other potential safety 
considerations associated with co-enrollment.  
 
 
 

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6 
STUDY PRODUCT 
 
6.1 Regimen 
 
All participants will receive a vaginal ring containing 25 mg of dapivirine to be worn 
monthly.  One new ring will be inserted each month.  Participants will attend monthly 
clinic visits until month three and then will present to the clinic at quarterly visits 
thereafter. Participants are able to visit the clinic for any reason in between the 
scheduled visits. 
 
6.2 Administration 
 
The participant will self-insert the study VR monthly.  Study participants will be reminded 
of proper VR insertion and removal procedures at the Enrollment Visit and as needed at 
subsequent visits.  Details on administration (ring insertion, removal, procedures in the 
event of expulsion or loss) will be provided in the MTN-025 SSP Manual.   
 
6.3 Study Product Formulation 
 
The study VR is an off-white, flexible ring containing 25 mg of dapivirine dispersed in a 
platinum-catalyzed-cured silicone matrix.  The ring dimensions are as follows: 56 mm 
and 7.7 mm, outer diameter and cross-sectional diameter, respectively.   
 
The ring is designed to provide sustained release of drug over a minimum period of one 
month. 
 
6.3.1 Dapivirine VR 
 
Dapivirine 0.3125% (w/w) is dispersed in a flexible, opaque, cured silicone VR delivery 
device.  The VR will contain 25 mg of dapivirine.  The dapivirine VR optimally should be 
stored in the site pharmacy at 20°C to 25°C, with allowable excursions between 15°C to 
30°C.  
 
6.4 Supply and Accountability 
 
6.4.1 Supply 
 
IPM (Silver Spring, MD) will oversee the manufacture of the study VRs and 
analyze/release the rings under Good Manufacturing Practices (GMP).   
 
6.4.2 Study Product Dispensing 
 
Study VRs are dispensed only to enrolled study participants or clinic staff on behalf of 
the participant, upon receipt of a written prescription from an authorized prescriber.  
Dispensing takes place on the day of enrollment and at each scheduled follow-up visit, 
except at the Product Use End Visit and Study Exit/Termination Visit.  
 

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During each of the monthly clinic visits participants will receive a new ring.  If the 
participant is unable to attend her next scheduled visit it is up to the discretion of the IoR 
to provide an additional ring(s).  All such circumstances must be documented fully by 
the IoR/designee as described in the MTN-025 SSP Manual. 
 
When participants enter the quarterly follow-up phase, they will be dispensed three 
rings at each study visit or be given the option of returning to the site pharmacy or the 
clinic (based on site dispensing capacity) each month to obtain a new vaginal ring each 
month (e.g., if they do not feel comfortable having a supply of two additional unused 
rings at home).  Participant’s preference regarding product dispensation and their 
choice will be documented.  
 
The pharmacist will only dispense one ring per month or up to three rings per quarter 
depending on the participant’s regimen.  If a participant requires an additional ring for 
any reason, at a time other than when she is scheduled to receive one, additional 
product may be dispensed at the discretion of the IoR.  
 
6.4.3 Accountability 
 
Each CRS Pharmacist of Record (PoR) is required to maintain a complete record of all 
study product 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-025 Pharmacist Study Product Management Procedures Manual. 
 
All study product dispensed to a participant must be documented by the clinic staff 
when it is returned.  This includes ring(s) brought back to the clinic by the participant 
and any ring removed at the clinic visit.  Any study products not returned must also be 
documented by the clinic.   
 
6.4.4 Retrieval of Study Product 
 
As per Section 9, study product use for a participant may be temporarily held or 
permanently discontinued.  Study product must be retrieved within 24 hours and 
returned to the clinic when product use is permanently discontinued for HIV 
seroconversion or held temporarily due to potential HIV seroconversion (see Table 5 
below).  Additional study product retrieval specifications in response to product holds, 
discontinuations for other reasons, or IoR discretion, can be found in the table below.  
Study product retrieval may occur either by the participant returning the VR (used and 
unused) to study staff within the specified timeframe or by study staff conducting 
outreach to retrieve the product from the participant (e.g., at her home).   

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Table 4:  Retrieval of Study Product 
Condition  
Timeframe for Retrieval 
 
Permanent discontinuation due to HIV 
seroconversion 
 
Temporary hold due to potential HIV seroconversion 
Within 24 hours 
 
Permanent discontinuation for any other reason or 
IoR discretion  
 
Temporary hold due to pregnancy 
Within 5 working days 
 
Temporary hold for reasons other than pregnancy 
with expected duration of more than 7 days  
Within 7 working days 
 
If product has not been retrieved within the timeframe specified in the table above, study 
staff members must make every effort to retrieve study product as soon as possible. 
 
It is not necessary to retrieve study products from participants for whom study product 
use is being temporarily held for less than 7 days.  However, to protect participant 
safety, study product(s) may be retrieved from participants if there is concern that the 
participant may not comply with clinic staff instructions to refrain from study product use 
for the duration of the temporary hold.   
 
For all study product holds due to seroconversion, pregnancy or other safety related 
concerns, if the study product(s) are not retrieved within timeframe noted, the MTN-025 
PSRT must be informed. 
 
For each participant, all VRs remaining in the participant’s possession should be 
retrieved at the Study Exit/Termination Visit.  If the participant does not bring her 
remaining VR(s) to this visit, study staff must arrange to retrieve the ring(s) within 5 
business days.   
 
The PoR will document all unused product returns and store returned unused study 
products in designated areas within the study pharmacy. 
 
6.5 Concomitant Medications 
 
Enrolled study participants may use concomitant medications during study 
participation.  All concomitant medications as well as illicit substances reported 
throughout the course of the study will be recorded on case report forms designated for 
that purpose.  All prescription medications, over-the-counter preparations, vitamins, 
nutritional supplements, and herbal preparations will be recorded on forms for 
concomitant medications.  
 
6.6 Use of Intravaginal Medications and Practices 
 
Concomitant use of devices such as diaphragms, menstrual cups, and cervical caps, 
will be discouraged.  Use of contraceptive VRs is prohibited.  Products and practices 
including the use of spermicides, vaginally applied medication, douches, lubricants, 

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tampons, etc., are permitted.  Use of intravaginal medications and practices will be 
captured.  
 
6.7 Condoms 
 
All participants will be offered condoms.  Condoms are highly effective in preventing the 
sexual transmission of HIV and reducing the risk other STIs, including infections 
transmitted by genital secretions, and to a lesser degree, genital ulcer diseases.17-
19Study staff may also offer guidance on the use of the female condoms upon 
participant request, see MTN-025 SSP for additional details. 
 
 
 
 
 

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7 
STUDY PROCEDURES 
 
An overview of the study visit and evaluations schedule is provided in Appendix I.  
Follow-up study visits may take place on-site, in a participant’s home, or at other 
community-based 
locations, 
depending 
on 
site 
capacity 
and 
site/participant 
preference.  If genital symptoms are reported during an off-site visit, the participant is 
instructed to report to the on-site clinic for a clinical evaluation.  Presented in this 
section is additional information on visit-specific study procedures.  Detailed instructions 
to guide and standardize procedures across sites, including the conduct of off-site study 
visits and the follow-up schedule for participants who enroll after the prime accrual 
period 
are 
provided 
in 
the 
MTN-025 
SSP 
Manual 
available 
at 
http://www.mtnstopshiv.org/studies.  
 
7.1 Pre-Screening 
 
As part of participant outreach and recruitment strategies, study staff may pre-screen 
potential study participants either on-site or at 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 on-site screening visits.  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 potential participant identifiers.  At each site, 
procedures and documentation will comply with local IRB/EC requirements.  
 
7.2 Screening Visit 
 
The Screening Visit may take place up to 56 days prior to the Enrollment Visit.  Multiple 
visits may be conducted within this period to complete all required screening 
procedures, if necessary.  Written informed consent for screening will be obtained 
before any screening procedures are initiated.  For participants who do not meet the 
eligibility criteria, screening will be discontinued once ineligibility is determined.   
 
 
 

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Table 5: Screening Visit 
Screening Visit 
Component 
Procedures 
Administrative  and 
Regulatory 
 
 Obtain written informed consent for screening 
 Assign a Participant Identification (PTID) Number  
 Assess eligibility 
 Collect locator information 
 Provide reimbursement for study visit 
 Schedule next visit* 
Behavioral 
 Provide counseling
 
Contraceptive 
 
HIV/STI risk reduction 
 
HIV pre- and post-test 
Clinical 
 Obtain medical and menstrual history
 Obtain concomitant medications 
 Conduct a physical examination 
 Perform a pelvic exam 
 Offer contraceptives*   
 Treat or prescribe treatment for UTIs/RTIs/STIs or refer for 
other findings* 
Laboratory 
Urine 
 Collect urine
 
human chorionic gonadotropin (hCG)  
 
Nucleic Acid Amplification Test (NAAT) for GC/CT 
 
Urine culture*Ŧ  
Blood 
 Collect blood
 
HIV-1 serology 
 
Complete blood count (CBC) with platelets 
 
Chemistries 
 
Syphilis serology 
Pelvic 
 
 Collect pelvic specimens
 
Rapid test for Trichomonas 
 
Pap smear interpretation* 
Study Product/ Supplies 
 Offer condoms
* if indicated; Ŧ per local standard of care 
 

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7.3 Enrollment Visit (Day 0) 
 
The Enrollment Visit must be completed within 56 days of the Screening Visit.   
 
Note: All enrolled participants will receive regular individual HIV counseling, condoms (if 
participant is willing to accept them), risk reduction counseling, and treatment for STIs as part of 
their clinic visits.  If other new prevention strategies are found to be efficacious and are 
incorporated into the national HIV prevention policies, study participants will be counseled about 
these interventions, and either be offered these interventions by the site or referred to local 
centers with appropriate expertise, in accordance with WHO/UNAIDS guidelines and local 
practice and stakeholder consultation. 
 
Table 6: Enrollment Visit 
Enrollment Visit 
Component 
Procedures 
Administrative  and 
Regulatory 
 
 
Obtain written informed consent for enrollment 
 
Reassess and confirm eligibility 
 
Review/update locator information 
 
Provide reimbursement for study visit 
 
Schedule next study visit* 
Behavioral 
 
Conduct behavioral assessment
 
Provide counseling 
 
Contraceptive  
 
HIV/STI risk reduction 
 
HIV pre- and post-test  
 
Protocol adherence  
Clinical 
 
Update medical and menstrual history
 
Update concomitant medications 
 
Disclose available test results 
 
Perform a physical examination* 
 
Perform a pelvic exam* 
 
Offer contraceptives* 
 
Treat or prescribe treatment for UTIs/RTIs/STIs or refer for 
other findings* 
Laboratory 
 
Urine 
 
Collect urine
 
hCG  
 
Urine culture*Ŧ  
 
NAAT for GC/CT*   
Blood 
 
Collect blood
 
Plasma archive 
 
HIV-1 serology 
Pelvic 
 
 
Collect pelvic specimens
 
Vaginal fluid (self-collected) 
 
Rapid test for Trichomonas*  
Study Product/Supplies 
 
Offer condoms
 
Provision of study VR use instructions 
 
Provision of study VR(s) 
 
Insertion of one study VR  
 
Digital exam by clinician to check VR placement* 
* if indicated; Ŧ per local standard of care 
 

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7.4 Follow-up Visits 
 
7.4.1 Months 1 and 2 
 
Procedures listed below will occur at study months 1 and 2. 
 
Table 7: Follow-up Visits: Months 1 and 2 
Follow-up Visits: Months 1 and 2 
Component 
Procedures 
Administrative and 
Regulatory 
 
 
Review/update locator information
 
Provide reimbursement for study visit 
 
Schedule next visit 
Behavioral 
 
Provide counseling (modified, if necessary)  
 
Contraceptive 
 
Protocol adherence  
 
HIV/STI risk reduction 
 
HIV pre- and post-test  
Clinical 
 
Review/update medical and menstrual history 
 
Disclosure of available test results 
 
Record/update AEs 
 
Review/update concomitant medications* 
 
Offer contraceptives*  
 
Perform a physical examination* 
 
Perform a pelvic examination* 
 
Treat or prescribe treatment for UTIs/RTIs/STIs or refer for 
other findings* 
Laboratory 
 
Urine 
 
Collect urine
 
hCG 
 
NAAT for GC/CT*   
 
Urine culture*Ŧ  
Blood 
 
Collect blood
 
HIV-1 serology 
 
Chemistries*  
 
Syphilis serology*  
Pelvic 
 
 
Collect pelvic specimens
 
Vaginal fluid (self-collected) 
 
Rapid test for Trichomonas*  
Study 
Product 
 
Adherence assessment(s):  Returned study VR 
Study Product/Supplies 
 
Offer condoms
 
Removal and collection of used/unused study VR  
 
Provision of VR use instructions* 
 
Provision of study VR  
 
Digital exam by clinician to check VR placement* 
* if indicated; Ŧ per local standard of care 
 

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7.4.2 Quarterly Visits  
 
Procedures listed below will occur at quarterly visits (i.e., Months 3, 6, 9),until the 
Product Use End Visit (PUEV). 
 
Table 8: Quarterly Visits 
Follow-up Quarterly Visits 
Component 
Procedures 
Administrative and 
Regulatory 
 
 
Review/update locator information
 
Provide reimbursement for study visit 
 
Schedule next visit 
Behavioral 
 
Conduct behavioral assessment 
 
Conduct social harms assessment 
 
Provide counseling (modified, if necessary)  
 
Contraceptive 
 
Protocol adherence 
 
HIV/STI risk reduction 
 
HIV pre- and post-test  
Clinical 
 
Review/update medical and menstrual history 
 
Review/update concomitant medications 
 
Perform physical examination* 
 
Disclosure of available test results 
 
Record/update AEs 
 
Perform a pelvic examination* 
 
Offer contraceptives* 
 
Treat or prescribe treatment for UTIs/RTIs/STIs or refer for 
other findings* 
Laboratory 
 
Urine 
 
Collect urine
 
hCG 
 
NAAT for GC/CT* 
 
Urine culture*Ŧ  
Blood 
 
Collect blood
 
HIV-1 serology 
 
Plasma sample for DPV testing and archive 
 
Chemistries* 
 
Syphilis serology*  
Pelvic 
 
 
Collect pelvic specimens
 
Vaginal fluid (self-collected) 
 
Rapid test for Trichomonas* 
Study 
Product 
 
Adherence assessment(s):  Returned study VR 
Study Product/Supplies 
 
Offer condoms
 
Removal and collection of used/unused study VR(s) 
 
Provision of VR use instructions* 
 
Provision of study VR(s)  
 
Digital exam by clinician to check VR placement* 
* if indicated; Ŧ per local standard of care 
 

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7.4.3 Product Use End Visit (PUEV) 
 
Participants will undergo the following procedures at the PUEV.  
 
Table 9: PUEV 
PUEV 
Component 
Procedures 
Administrative and Regulatory 
 
 Review/update locator information
 Provide reimbursement for study visit 
 Schedule next visit 
Behavioral 
 Conduct behavioral assessment 
 Conduct social harms assessment 
 Provide counseling (modify, if necessary)  
 Contraceptive  
 HIV/STI risk reduction 
 HIV pre- and post-test 
Clinical 
 Review/update medical and menstrual history 
 Review/update concomitant medications 
 Perform a physical examination 
 Perform a pelvic examination  
 Disclosure of available test results 
 Record update AEs 
 Offer contraceptives*   
 Treat or prescribe treatment for UTIs/RTIs/STIs or refer for other 
findings* 
Laboratory 
 
Urine 
 Collect urine
 hCG 
 NAAT for GC/CT 
 Urine culture*Ŧ  
Blood 
 Collect blood
 HIV-1 serology 
 Syphilis serology 
 Chemistries 
 CBC with platelets 
 Plasma sample for DPV testing and archive 
Pelvic 
 
 
 Collect pelvic specimens
 Vaginal fluid (self-collected) 
 Rapid test for Trichomonas 
Study Product 
 Adherence assessment(s):  Returned study VR 
Study Product 
 Offer condoms 
 Removal and collection of used/unused study VR  
* if indicated; Ŧ per local standard of care 
 

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7.4.4 Study Exit/Termination Visit 
 
The Study Exit/Termination Visit is to be scheduled approximately 4 weeks after the 
PUEV. 
 
Table 10: Study Exit/Termination Visit 
Study Exit/ Termination Visit 
Component 
Procedures 
Administrative and 
Regulatory 
 
 
Review/update locator information
 
Provide reimbursement for study visit 
 
Schedule next visit* 
Behavioral 
 
Conduct behavioral assessment
 
Provide counseling  
 
Contraceptive*  
 
HIV/STI risk reduction 
 
HIV pre- and post-test  
Clinical 
 
Review/update medical and menstrual history 
 
Review/update concomitant medications 
 
Disclosure of available test results 
 
Record/update AEs 
 
Offer contraceptives* 
 
Perform a physical examination* 
 
Perform pelvic examination* 
 
Treat or prescribe treatment for UTIs/RTIs/STIs or refer for other 
findings* 
Laboratory 
 
Urine 
 
Collect urine
 
hCG  
 
NAAT for GC/CT*   
 
Urine culture*Ŧ  
Blood 
 
Collect blood
 
HIV-1 serology 
 
Plasma sample for DPV testing and archive 
Pelvic 
 
Collect pelvic specimens
 
Vaginal fluid (self-collected) 
 
Rapid test for Trichomonas* 
Study Product 
 
Offer condoms 
* if indicated; Ŧ per local standard of care 
 

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7.5 MTN-025 Decliner Population 
 
7.5.1 MTN-025 Decliner Population: Screening and Enrollment Procedures 
 
Former ASPIRE participants who decline or express no interest in joining the main 
MTN-025 trial, may opt to take part in the MTN-025 Decliner Subset.  Multiple visits may 
be conducted to complete all required procedures, as necessary.  See Section 7.8, 
Behavioral Evaluations for additional details.  
 
Table 11: Screening and Enrollment Procedures 
Screening and Enrollment 
Component 
Procedures 
Administrative and 
Regulatory 
 
 
Confirm eligibility 
 
Obtain written informed consent  
 
Collect demographic data  
 
Provide reimbursement for study visit 
Behavioral 
 
Administer behavioral assessment
 
Conduct in-depth interview (IDI)* 
*=if indicated  
 
7.6 Follow-up Procedures for Participants Who Temporarily Hold or 
Permanently Discontinue Study Product 
 
7.6.1 Participants Who Become Infected with HIV 
 
Participants who become infected with HIV are offered the option to continue follow-up 
visits per their original study schedule until their originally scheduled study exit date.  All 
participants who become infected with HIV while on study product will be offered 
enrollment in MTN-015, the MTN Seroconverter Study.  Participants are offered 
enrollment in MTN-015 (http://www.mtnstopshiv.org/studies) at the visit when 
seroconversion confirmation test results are discussed with the participant.  
 
For those participants who choose to be maintained in MTN-025 follow-up, regardless 
of co-enrollment in MTN-015, protocol-specified procedures for MTN-025 will continue, 
except the following: 
 
 HIV serology, HIV pre- and post-test counseling 
 Provision of VR, instructions, product adherence counseling 
 Complete blood count  
 Chemistries 
 Scheduled HOPE Study Exit/Termination Visit 
 

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For participants who delay or decline enrollment in MTN-015, the following procedures 
are being completed as part of the MTN-025 study; these procedures are discontinued 
immediately if the participant enrolls in MTN-015: 
 
 Plasma collection 
 CD4+ T cell count 
 HIV-1 RNA PCR 
 HIV-1 Genotyping (standard resistance testing) 
 
The aforementioned procedures are performed at the following time points:  
 
 Plasma collection, CD4+ T cell count and HIV-1 RNA PCR will be 
performed upon each instance of a positive HIV rapid test(s) during follow-
up 
 Plasma collection, CD4+ T cell count and HIV-1 RNA PCR will be 
performed at the clinic visit immediately following confirmation of an HIV-
infection and every three months thereafter for the remaining follow-up 
period, or as indicated 
 HIV-1 Genotyping (standard resistance testing) will be performed on the 
stored plasma closest to the time of confirmed HIV-1 infection.  It may be 
performed at additional/alternate time points as requested by site IOR or 
at the discretion of the Laboratory Center.   
 
Please reference the MTN-025 SSP for additional details.  
 
7.6.2 Participants Who Become Pregnant 
 
All protocol-specified study procedures will continue except the following: 
 
 Provision of VR, product use instructions, and adherence counseling.  
Product use may be resumed after birth or other termination of the 
pregnancy, as evidenced by a negative pregnancy test performed by 
study staff, provided the participant is not breastfeeding.  VR use should 
not be resumed earlier than 2 weeks after a 1st trimester loss, or earlier 
than 4 weeks after 2nd trimester (or later) pregnancy loss or delivery.  A 
pelvic exam must be performed prior to resumption to confirm the absence 
of any findings that would contraindicate resumption, in the opinion of the 
IoR/designee. 
 Pelvic examination as well as associated procedures, and vaginal fluid 
collection, after 24 weeks of pregnancy, unless the participant indicates 
comfort with continuing vaginal procedures post 24 weeks.  See MTN-025 
SSP Manual for additional guidance. 
 
A participant who becomes pregnant during the course of study participation may be 
offered participation in MTN-016, the Prevention Agent Pregnancy Exposure Registry. 
 

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7.6.3 Participants Who Temporarily Hold or Permanently Discontinue Study 
Product Use  
 
All protocol-specified study procedures will continue except the following: 
 
 Provision of VR, product use instructions, and adherence counseling 
 
In the event that a participant permanently discontinues study product early, the 
Adherence and Acceptability Assessments will be administered according to guidance 
provided from the protocol team.  See the MTN-025 SSP Manual for additional 
guidance. 
 
Guidance related to permanent discontinuation of study product, including consultation 
with the PSRT, is included in Section 9.   
 
7.6.4 Interim Visits 
 
Interim visits may be performed at any time during the study, for the following or other 
reasons: 
 
 For administrative reasons, e.g., a participant may have questions for study staff, 
or may need to re-schedule a follow-up visit. 
 For product-related reasons, including to provide participants with a replacement 
or additional vaginal ring. 
 In response to AEs and/or SAEs.  When interim contacts or visits are completed 
in response to participant reports of AEs and/or SAEs, study staff will assess the 
reported event clinically and provide or refer the participant to appropriate 
medical care (see also Section 9). 
 For interim STI counseling and testing in response to STI symptoms.  
 For interim HIV counseling and testing in response to participant report of 
symptoms consistent with acute seroconversion or presumed exposure to HIV 
 To provide participants with the results of confirmatory HIV test results, per the 
algorithm in Appendix III. 
 For other reasons at participant request, e.g., social harm. 
 
All interim contacts and visits will be documented in participants' study records and on 
CRFs, if applicable.  
 
7.7 Final Contact 
 
Since participants’ Study Exit/Termination Visit include laboratory testing for HIV, a final 
contact may be required to provide her additional study test results, and post-test 
counseling, if needed.  In addition, for participants who become pregnant during study 
participation, an additional contact may be required to ascertain the participant’s 
pregnancy outcome.  Study sites may complete these contacts at the study site or at 

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community-based locations, depending on site capacities and site and participant 
preferences.  All final contacts will be documented in participant study records.   
 
7.8 Behavioral Evaluations 
 
The following attitudes and behaviors, including the endpoints to assess exploratory 
objectives, will be assessed either via Audio Computer-Assisted Self Interviewing or 
CRFs.  Additionally, a subset of eligible participants at selected sites will be asked to 
participate in in-depth interviews and/or focus group discussions (IDI and/or FGDs) at a 
predetermined time point.  These will be conducted by trained interviewers/facilitators to 
gain further insight on the following behavioral and attitudinal issues: 
 
 Attitudes and understanding of VR efficacy 
 VR acceptability and attitudes towards combination prevention (i.e.,  use-related 
attributes and preferences, access, cost, health system delivery)    
 Motivations for joining or declining participation in research study  
 Reports of products storage and use 
 Perceived feasibility of study visit regimen 
 Sexual activity, including condom use 
 Vaginal practices 
 
MTN-025 Decliner Population 
 
Former ASPIRE participants who decline or express no interest in joining the MTN-025 
trial either prior to screening or prior to enrollment, will be invited to complete behavioral 
assessment(s), which may include IDI(s) to explore reasons for disinterest, indviduals 
who are found eligible and who take part are referred to as the MTN-025 Decliner 
Population.   
 
7.9 Adherence Counseling 
 
Study product adherence counseling will be provided as a component of the Protocol 
Adherence Counseling to all study participants by site staff.  Counseling will be provided 
in accordance with standard methods based on participant-centered strategies with 
discussions focused on describing experiences and identifying factors facilitating the 
ease/comfort of product use.  Participants will also be counseled on the importance of 
using the product as prescribed.  

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7.10 Clinical Evaluations and Procedures 
 
Physical exams will include the following assessments:  
 
 General appearance 
 Weight  
 Vital signs 
 Temperature 
 Pulse  
 Blood pressure 
 Respirations 
 Abdomen  
 Height* 
 Lymph nodes*  
 Neck*  
 Heart* 
 Lungs*  
 Extremities* 
 Skin*  
 Neurological* 
 
*may be omitted after the Screening Visit 
 
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-025 SSP Manual. 
 
Participants for whom there is documentation of surgical sterilization may have 
contraceptive counseling omitted, in accordance with any relevant site SOPs.   
 
7.11 Laboratory Evaluations 
 
Local Laboratory 
 Urine 
 hCG 
 NAAT for GC/CT 
 Culture (per local standard of care) 

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 Blood 
 Plasma archive (stored at site until notified by MTN Laboratory Center 
(LC) 
 Plasma (stored at site until notified by MTN LC) 
 Syphilis serology 
 HIV serology 
 CBC with platelets 
 Chemistries 
o Creatinine, AST, ALT 
 Pelvic  
 Rapid test for Trichomonas 
 Vaginal fluid  
 
Laboratory Center 
 Blood 
 HIV-1 confirmatory testing as needed (see Appendix III) 
 Drug concentration in blood 
 HIV drug resistance  
 
 Pelvic  
 Vaginal fluid for candidate biomarkers of safety, adherence and efficacy, 
HIV exposure and antiretroviral resistance, and/or genital microflora, as 
needed 
 
IPM or MTN Designated Laboratory: 
 Study Product- Vaginal Ring 
 Adherence assessment(s) 
 
7.12 HIV Infection (Secondary Endpoint) Determination 
 
All study sites will perform HIV testing per the algorithm in Appendix III for purposes of 
secondary endpoint determination.  Prior to study initiation, all sites will have validated 
this algorithm in accordance with the policies described in the MTN Manual of 
Operational Procedures (MOP) (http://www.mtnstopshiv.org/node/187).  All sites will 
participate in ongoing proficiency testing of their HIV testing procedures throughout the 
course of the study.  The HIV test kits used at each site are pre-approved by the MTN 
LC; at each testing time point when rapid tests are used at least one FDA-approved 
rapid test kit is used.  All confirmatory testing is performed using FDA-approved test 
kits.  
 
HIV DNA is not routinely used in MTN-025 for HIV diagnosis but may be used when 
requested by the MTN LC.  
 
The MTN LC will verify HIV testing performed at the study site laboratories for purposes 
of eligibility determination and secondary endpoint ascertainment as follows: 

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December 16, 2014 
 
 
 The MTN LC will test Study Entry, PUEV, and scheduled Termination Visit 
specimens from a 10% random sample of participants enrolled at each site for 
evidence of HIV infection using FDA-licensed tests.  Study Entry specimens are 
collected at participants’ Enrollment Visits.  If any false-negative local laboratory 
results are identified, the LC will test the respective Study Entry, PUEV and 
scheduled Termination Visit specimens from all enrolled participants from that 
Clinical Research Site. 
 
 The MTN LC will test the Study Entry and Seroconversion specimens from all 
study participants identified by the local laboratories as having become infected 
with HIV during the study follow-up period.  The LC will also test matched Study 
Entry and Follow-Up specimens from a random sample of uninfected participants 
(equal to the number of seroconversions).  Study Entry specimens are collected 
at participants’ Enrollment Visit.  Seroconversion specimens are collected at the 
schedule specified in Section 7.6.1.  All specimens will be tested for evidence of 
HIV infection using FDA-licensed tests.  For all seroconverters, Study Entry 
specimens also will be confirmed.  
 
MTN LC staff will follow-up directly with site staff to resolve any quality control or quality 
assurance problems identified through proficiency testing, on-site assessments, and/or 
confirmatory HIV testing.  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 
if there is a question regarding sample integrity.  This test will only let researchers know 
the number of times this short segment is repeated and not specific genes or specific 
sequences of base pairs.  This sequence element does not contain any information 
about genes. Therefore researchers will not be able to identify if participants are 
predisposed to specific diseases or any other genetic information based on this 
information.  This test will be an important tool for distinguishing whether two samples 
collected at the same or different time points are likely from the same person.  The test 
will only be used as part of a sample investigation with the knowledge of the site in 
situations where a known or suspected sample mix-up has occurred.  No genetic testing 
(limited or genome-wide) is planned on leftover samples that are stored for the 
purposes of future research. 
 
In addition to all of the above, an endpoint adjudication committee will provide guidance 
on endpoint determination to the Protocol Team on an as needed basis.  See the MTN 
MOP 
(http://www.mtnstopshiv.org/node/187) 
for 
detailed 
information 
on 
the 
composition, roles, and responsibilities of the endpoint adjudication committee.  
 
7.13 Specimen Collection and Processing 
 
Each study site will adhere to the standards of good clinical laboratory practice 
(http://apps.who.int/tdr/publications/tdr-research-publications/gclp-web/pdf/gclp-
web.pdf), in accordance with current US Division of AIDS (DAIDS) Laboratory 
Requirements, 
MTN-025 
Study 
Specific 
Procedures 
Manual 

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December 16, 2014 
 
(http://www.mtnstopshiv.org/studies) and site standard operating procedures for proper 
collection, processing, labeling, transport, and storage of specimens to standardize 
procedures.  Specimen collection, testing, and storage at the site laboratories will be 
documented when applicable using the Laboratory Data Management System.  In 
cases where laboratory results are not available due to administrative or laboratory 
error, sites are permitted to re-draw specimens. 
 
7.14 Specimen Handling 
 
Specimens will be handled in accordance with current requirements for DAIDS 
Sponsored 
and/or 
Funded 
Laboratories 
in 
Clinical 
Trials. 
(http://www.niaid.nih.gov/labsandresources/resources/daidsclinrsrch/documents/labpolic
y.pdf) 
 
7.15 Biohazard Containment 
 
As the transmission of HIV and other blood-borne pathogens can occur through contact 
with contaminated needles, blood, and blood products, appropriate blood and secretion 
precautions will be employed by all personnel in the drawing of blood and shipping and 
handling of all specimens for this study as recommended by the U.S. Centers for 
Disease Control and Prevention (CDC) and National Institutes of Health (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.  Biohazard 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 Co-Chairs, DAIDS Medical Officer, 
Protocol Safety Physician(s), IPM Representative, and SDMC Clinical Affairs Safety 
Associate 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.  
 

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8.2 Clinical Data Safety Review 
 
A multi-tiered safety review process will be followed for the duration of this study.  The 
study site investigators are the first layer of this tiered system and 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 Clinical Affairs staff, the PSRT, and study sponsors.   
 
During the trial, the PSRT will review safety reports and conduct calls to review the data 
as appropriate.  The content, format and frequency of the safety reports will be agreed 
upon by the PSRT and the SDMC in advance of study implementation.  In addition to 
these 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 with expertise in the fields of microbicides, biostatistics, or 
medical ethics may be invited to join the PSRT safety review.   
 
After the product use and the final safety visits are completed, less frequent reporting 
and safety reviews may be conducted at the discretion of the MTN-025 PSRT.   
 
A Study Monitoring Committee (SMC) has study oversight and is charged with 
reviewing participant safety data as no Data Safety Monitoring Board (DSMB) is 
planned for this study, see Section 10.7.1 for additional details.   
 
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 participants at 
the time of enrollment.  Enrollment is defined as once a participant has provided written 
informed consent for enrollment and it has been determined she is eligible for the study 
(based on IoR or designee sign-off after all protocol-specified inclusion/exclusion criteria 
have been assessed).  The term “investigational product” for this study refers to the 
vaginal ring. 
 
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 

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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 recorded on study 
CRFs.  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 all AEs reported by or observed in 
enrolled study participants regardless of severity and presumed relationship to study 
product.   
 
Study staff will also report on CRFs the following subset of AEs reported by or observed 
in enrolled participants: 
 
 All genital, genitourinary, and reproductive system AEs, including STIs 
 Fetal losses (e.g., spontaneous abortions, spontaneous fetal deaths, 
stillbirths) will not be reported as AEs.  However, 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 an AE 
 All AEs of severity Grade 2 or higher  
 All serious AEs  
 All AEs that result in permanent discontinuation of study product use 
 All lab test abnormalities specified in the DAIDS Table for Grading Adult and 
Pediatric Adverse Events, Version 1.0, December 2004 (Clarification dated 
August 2009), that are not otherwise associated with a reported clinical AE 
 AEs that do not meet the above-listed criteria but do meet expedited reporting 
requirements per Section 8.3 below; this includes all congenital anomalies 
identified in the fetuses and/or infants of study participants 
 
AE severity and laboratory tests will be graded per the DAIDS Table for Grading Adult 
and Pediatric Adverse Events, Version 1.0, December 2004 (Clarification dated August 
2009) and the Female Genital Grading Table for Use in Microbicide Studies (Addendum 
1 to the DAIDS Table for Grading Adult and Pediatric Adverse Events, Version 1.0, 
December 2004 (Clarification dated August 2009), except that asymptomatic BV and 
asymptomatic candidiasis will not be reportable AEs.  In addition, changes in genital 
bleeding judged to be related to a woman's contraceptive use will not be considered an 
AE, nor will a pelvic exam be required for follow-up.  In cases where a genital AE is 
covered in both tables, the Female Genital Grading Table for Use in Microbicide Studies 
will be the grading scale utilized.   
 
All AE Log forms completed for each participant should be reviewed at the study exit 
visit and updated as needed.  For AEs that are ongoing at the exit visit, the 
status/outcome of the AE should be updated to “continuing at end of study participation” 
and the AE Log form should be re-faxed to SCHARP DataFax.  For any serious or 
expedited AEs (SAEs/EAEs) that are continuing at a participant’s study exit visit, the 
IoR/designee must establish a clinically appropriate follow-up plan for the AE.  At a 

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minimum, the SAE/EAE must be re-assessed by study staff 30 days after the 
participant’s study exit visit; additional evaluations also may take place at the discretion 
of the IoR/designee.  The same approach must be taken for any AEs that are found to 
have increased in severity at the study exit visit.  For those AEs requiring re-
assessment, if the AE has not resolved or stabilized at the time of re-assessment, study 
staff will continue to re-assess the participant at least once per month while the study is 
ongoing.  After the study has ended, all AEs requiring re-assessment will be re-
assessed at least once within the 30-60 days after the study end date.  The PSRT may 
advise study staff as to whether any additional follow-up may be indicated on a case by 
case basis.  For AEs that are re-assessed after study exit, information on the status of 
the AE at the time of re-assessment will be recorded in source documents only — no 
updates should be made to AE Log CRFs based on the re-assessments.  
 
8.3.2 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  
 Requires inpatient hospitalization or prolongation of existing hospitalization 
 Results in persistent or significant disability/incapacity  
 Is a congenital anomaly/birth defect 
 Is an important medical event that may not result in death, be immediately life-
threatening, or require hospitalization but may jeopardize the participant or 
require intervention to prevent one of the outcomes listed in the definition 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 
 Not Related: There is not a reasonable possibility that the AE is related to the 
study agent 
 
8.4 Expedited Adverse Event Reporting Requirements 
 
8.4.1 Adverse Event Reporting to DAIDS 
 
Requirements, definitions and methods for expedited reporting of AEs are outlined in 
Version 2.0 of the DAIDS EAE Manual, which is available on the RSC website at 

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http://rsc.tech-res.com/safetyandpharmacovigilance/.  For each study participant, 
expedited AE reporting will be undertaken throughout the scheduled duration of follow-
up, i.e., from the time of Enrollment through study termination.   
 
The DAIDS Adverse Experience Reporting System (DAERS), an internet-based 
reporting system, must be used for expedited AE reporting to DAIDS.  In the event of 
system outages or technical difficulties, expedited AEs may be submitted via the DAIDS 
EAE Form.  For questions about DAERS, please contact DAIDS-ES at DAIDS-
ESSupport@niaid.nih.gov Site queries may also be sent from within the DAERS 
application itself. 
 
Where DAERS has not been implemented, sites will submit expedited AEs by 
documenting the information on the current DAIDS EAE Form.  This form is available on 
the RSC website, http://rsc.tech-res.com/safetyandpharmacovigilance/.  For questions 
about EAE reporting, please contact the RSC (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 dapivirine VR  
 For all SAEs submitted, sites must file an initial report and an update to IPM and 
the DAIDS Medical Officer with the final or stable outcome unless the initial SAE 
submitted had a final or stable outcome noted already 
 
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, Version 1.0, December 2004 (Clarification, 
August 2009) and the Female Genital Grading Table for Use in Microbicide Studies 
(Addendum 1 to the DAIDS Table for Grading Adult and Pediatric Adverse Events, 
Version 1.0, December 2004 (Clarification, August 2009)), will be used and is available 
on the RSC website at http://rsc.tech-res.com/safetyandpharmacovigilance/. 
 
8.4.4 Expedited AE Reporting Period 
 
 The expedited AE reporting period for this study begins once the participant is 
enrolled and continues up through the participant’s final study visit (Study 
Exit/Termination Visit). 
 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). 
 

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8.5 Social Harms Reporting 
 
Although study sites will make every effort to protect participant privacy and 
confidentiality, it is possible that participants’ involvement in the study could become 
known to others and that social harms may result.  For example, participants could be 
treated unfairly, or could have problems being accepted by their families, partners 
and/or communities.  Social harms that are judged by the IoR/designee to be serious or 
unexpected will be reported to the PSRT and responsible site ECs/IRBs according to 
their individual requirements.  In the event that a participant reports social harm, every 
effort will be made by study staff to provide appropriate care and counseling to the 
participant, and/or referral to appropriate resources for the safety of the participant as 
needed.  Each site will provide such care and counseling in accordance with 
standardized guidance provided in the MTN-025 SSP Manual.  While maintaining 
participant confidentiality, study sites may engage their community advisory boards 
(CABs) in exploring the social context surrounding instances of social harm. 
 
8.6 Regulatory Requirements 
 
Information on all reported CRFs will be included in reports to the FDA and other 
applicable government and regulatory authorities.  Site IoRs/designees will submit AE 
information in accordance with local regulatory agencies’ or other local authorities’ 
requirements.  Site IoRs/designees also will submit AE information and any other 
relevant safety information to their ECs/IRBs in accordance with ECs/IRB 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 temporarily 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 should 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.  
 
9.1 Grading System 
 
AE severity grading is described in Section 8.3.3. 
 
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 study VR use by the IoR/designee 
for any of the following reasons:   
 
 Acquisition of HIV infection; such participants will not resume product use at any 
time.  The study VR should be held beginning immediately upon recognition of 
the first reactive rapid HIV test.  If via the algorithm in Appendix III the participant 
is determined to be HIV-uninfected, she may resume product use.  The 
IoR/designee must permanently discontinue the study VR if HIV infection is 
confirmed.  
 Allergic reaction to the study VR. 
 
A participant will be temporarily held from study VR for any of the following reasons: 
 
 A reactive rapid HIV test. 
 Pregnancy.  A participant who becomes pregnant may resume product use after 
giving birth or other pregnancy outcome, as evidenced by a negative pregnancy 
test performed by study staff, provided the participant is not breastfeeding.  A 
pelvic exam must be performed prior to resumption to confirm the absence of any 
findings that would contraindicate resumption, in the opinion of the IoR/designee. 
 Breastfeeding.  Product use may resume when the participant reports complete 
cessation of breastfeeding. 
 Report of use of PEP for HIV exposure.  The participant may resume product use 
when she reports completion of PEP and is confirmed HIV-uninfected based on 
testing performed at the study site per the algorithm in Appendix III. 
 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.  The IoR/designee 
must consult the PSRT on all temporary product holds instituted for this reason 
for further guidance on resuming product use, continuing the temporary hold, or 
progressing to permanent discontinuation.  If product use is temporarily 
held/permanently discontinued for this reason, but the underlying reason for the 
temporary hold later resolves, the IoR/designee should consult the PSRT to 
resume product use at that time.   
 

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9.4 Temporary Product Hold/Permanent Discontinuation in Response to 
Observed Adverse Events 
 
Grade 1 or 2 
In general, a participant who develops a Grade 1 or 2 AE not specifically addressed 
below, regardless of relatedness to study product, may continue product use.   
 
Grade 3 
Participants who develop a Grade 3 AE that is not specifically addressed below and is 
judged by the IoR/designee to be not related to study product may continue product use.   
 
In general, for participants who develop a Grade 3 AE not specifically addressed below, 
judged by the IoR/designee to be related to study product, and unless otherwise decided 
in consultation with the PSRT, the IoR/designee should: 
 Temporarily hold the study product. 
 Re-evaluate the participant at least weekly for up to 2 weeks. 
 Resume study product if improvement to ≤ Grade 2 is documented within 2 
weeks. 
 Consult PSRT regarding further study product management if improvement to 
severity ≤ Grade 2 cannot be documented within 2 weeks.   
 
If product use is resumed and the same Grade 3 AE deemed related to study product, 
recurs at any time, the IoR/designee must temporarily hold study product and consult 
the PSRT for further guidance on continuing the temporary hold or progressing to 
permanent discontinuation of the study product. 
 
Grade 4 
Participants who develop a Grade 4 AE (regardless of relationship to study product) 
should 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 Other Clinical Findings 
 
The IoR/designee should manage STI/RTI per local guidelines or current WHO 
guidelines, available at http://www.who.int/en/.   
 
A thorough evaluation of genital complaints is expected in the context of this study; 
however, syndromic management of genital symptoms is acceptable while awaiting 
laboratory results if such practice is in line with the local standards of care.  Observed 
single dose treatment should be provided whenever possible, per clinician discretion.  
When clinically appropriate, investigators should use oral or parenteral (in the case of 
syphilis, for example) medications when at all possible.   
 
 Study VR need not be held in the event of an STI/RTI requiring treatment, unless 
other temporary product hold/permanent discontinuation guidelines apply. 

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 Should the IoR/designee determine that a temporary hold is warranted, 
consultation with the PSRT is required. 
 
If a suspected finding is reported by a participant between scheduled visits, an interim 
visits may be scheduled at the discretion of the site investigator.  Note: Changes in 
genital bleeding does not necessitate a pelvic exam for follow-up. 
 
Management of genital events observed at scheduled or interim visits will be in 
accordance with the following: 
 
Superficial epithelial disruption (abrasion/peeling)  
 Continue study VR use 
 Perform naked eye evaluation 
 
 Re-evaluate by speculum examination in 3-5 days 
 If condition worsens, temporarily hold study VR use and consult the PSRT; 
otherwise continue study VR use 
 
Deep epithelial disruption (ulceration) 
 Temporarily hold study VR for deep epithelial disruption confirmed by site 
investigator 
 Re-evaluate in 3-5 days and resume study VR use if resolved 
 If unresolved at 3-5 days, re-evaluate within 2-3 days.  If resolved at that time, 
may resume study VR use.  If unresolved at this second reevaluation, 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 the PSRT regarding permanent discontinuation 
 
Localized erythema or edema: area of less than 50% of vulvar surface or 
combined vaginal and cervical surface 
 
 Continue study VR use 
 
 Perform naked eye evaluation 
 
 If asymptomatic, re-evaluate at next regularly scheduled visit 
 If symptomatic, re-evaluate by speculum examination in 3-5 days 
 If worsened significantly, temporarily hold study VR use and consult the PSRT; 
otherwise continue study VR use 
 
Generalized erythema or severe edema: area of more than 50% of vulvar surface 
or combined vaginal and cervical surface affected by erythema  
 Temporarily hold study VR 
 Perform naked eye evaluation 
 
 Re-evaluate in 3-5 days and resume study VR use if resolved 
 If unresolved at 3-5 days, re-evaluate within 2-3 days.  If resolved at that time 
may resume use.  If unresolved at this second reevaluation, continue temporary 

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product hold, consult with PSRT regarding permanent discontinuation, and 
provide care per local standard 
 
Unexpected genital bleeding 
 Continue study VR 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 VR use 
 
Cervicitis (including findings on exam such as inflammation and/or friability)  
 Temporarily hold study VR 
 Evaluate for GC/CT; consider syndromic management, pending results of testing 
and per clinician discretion 
 If GC/CT detected, provide or prescribe treatment 
 Reevaluate in 3-5 days.  If all symptoms and signs are resolved at that time 
resume study VR use  
 
Genital petechia(e)  
 Continue study VR use 
 
 Perform naked eye evaluation  
 Further evaluation or treatment per clinician discretion 
 
Genital ecchymosis  
 Continue study VR use 
 Perform naked eye evaluation  
 Further evaluation or treatment per clinician discretion 
 
The study product need not be held in the event of an STI/RTI requiring treatment, 
unless other temporary product hold/permanent discontinuation guidelines apply.  
Should the IoR/designee determine that a temporary product hold is warranted, 
notification of the PSRT is required. 
 
9.6 HIV Infection 
 
A participant who has a positive test for HIV must have study product held, but will not 
be withdrawn from the study.  If the participant is subsequently determined to be HIV-
uninfected according to the algorithm in Appendix III, study product may be resumed.  If 
HIV infection is confirmed, study product will be permanently discontinued by the 
IoR/designee.  Participants identified as infected with HIV are managed or referred for 
management according to the local standard of care.  These participants are also 
offered participation in MTN-015, the MTN Seroconverter Study, which also includes 
provisions for the clinical management and/or referral of participants infected with HIV.   
 
The care provided at the referral sites is at a level that meets or exceeds the community 
standard for HIV care.  Written SOPs for referral for HIV care and treatment are in place 

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at each study sites.  All study site investigators have identified facilities offering 
psychological and social services and medical care, including antiretroviral therapy 
(ART), to people infected with HIV-1 in the study countries.  Some of the research sites 
are part of health care institutions that provide HIV care and support, and can refer 
women to those services.  Other sites have established referral agreements with 
programs to expand access to ART.   
 
At every study visit, study staff will actively follow-up on prior referrals to HIV care and 
support services, to determine whether the participant sought the care to which she was 
referred, the outcome of the referral, and whether additional referrals are needed.  All 
follow-up actions, outcomes, counseling, and plans for next steps are documented in 
participant study records.  Results of study laboratory testing may be helpful in clinical 
management; these results are provided to the participant and her medical provider as 
soon as they are available. 
 
9.7 Pregnancy 
 
A participant who becomes pregnant at any time during the study must have study 
product temporarily held, but will not be withdrawn from the study.  Every effort will be 
made to have the study participant continue in modified follow-up until her study 
termination visit or pregnancy outcome is ascertained.  The IoR/designee will counsel 
any participant who becomes pregnant regarding possible risks to the fetus according to 
site SOPs.  The IoR/designee also will refer the participant to all applicable services; 
however, sites will not be responsible for paying for pregnancy-related care.   
 
Participants who become both pregnant and HIV-infected will have expedited HIV-1 
resistance testing performed at the MTN LC to provide information about possible 
resistance that might impact the efficacy of ART regimens to reduce mother-to-child 
HIV-1 transmission.  The participant will be referred to local providers for antenatal care, 
and prevention of mother-to-child transmission services.  HIV testing for infants is 
provided by the study if not otherwise accessible by the participant.  
 
A participant who becomes pregnant during the course of study participation may be 
offered participation in MTN-016, the Prevention Agent Pregnancy Exposure Registry.  
This registry is anticipated to capture pregnancy outcomes as well as infant health 
information, (including growth and development), to evaluate the safety and teratogenic 
risks of microbicide and oral PrEP exposure in pregnancy.   
 
All pregnancies will be followed until a pregnancy outcome can be ascertained (or, in 
consultation with the PSRT, it is determined that the pregnancy outcome cannot be 
ascertained).  This includes participants who are pregnant at the Study Exit/Termination 
Visit.  Pregnancy outcomes are reported on relevant CRFs. 
 

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9.8 Criteria for Early Termination of Study Participation 
 
Participants may voluntarily withdraw from the study for any reason at any time.  The 
IoR 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.  The PSRT must be 
notified of all terminations conducted per IoR discretion.  Participants also may be 
withdrawn if the study sponsors, government or regulatory authorities, including the 
FDA and Office for Human Research Protections (OHRP), or site IRBs/ECs terminate 
the study prior to its planned end date.  Every reasonable effort will be 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.  In the event that participants who voluntarily 
withdraw from the study wish to re-join the study, they may resume product use (if 
applicable) and follow-up through their originally scheduled study exit date, pending 
consultation with the PSRT.   
 
 
 
10 
STATISTICAL CONSIDERATIONS 
 
10.1 Overview and Summary of Design 
 
This is a Phase 3B, open-label, multi-site trial.  A sample size of approximately 1000-
2500 participants will be followed for approximately 13 months, with approximately 12 
months of study product use.  The two main goals of the trial are:  
 
1. To characterize the safety profile associated with the open label use of the 
dapivirine vaginal matrix ring (25 mg) in women 
 
2. To characterize adherence to the open label use of the dapivirine vaginal matrix 
ring (25 mg) in women  
 
Secondary objectives of the study include assessing the incidence of HIV-1 infection 
and frequency of HIV-1 drug resistance in women who acquire HIV-1 infection.  
 
10.2 Study Endpoints 
 
10.2.1 Primary Endpoints 
 
1. Safety  
- 
Grade 2 AEs judged to be related to the dapivirine vaginal ring 
- 
Grade 3 and higher AEs 
- 
All serious AEs 
 
2. Study Product Adherence 
- 
Residual levels of dapivirine in returned vaginal rings  

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- 
Blood dapivirine levels  
 
10.2.2 Secondary Endpoints 
 
1. Incidence  
- 
HIV-1 infection as measured by the protocol algorithm 
 
2. Drug Resistance 
- 
HIV-1 drug resistance mutations among participants who acquire HIV-1, as 
measured by standard genotype analysis and more sensitive methods to 
detect low frequency drug-resistant variants 
 
10.3 Sample Size 
 
We expect between 1000 and 2500 participants to enroll in this study.  The final number 
is dependent upon the proportion of ASPIRE participants who are eligible and choose to 
enroll into MTN-025, HOPE.  Power is discussed with the primary analyses as 
appropriate. 
 
10.4 Participant Accrual, Follow-up and Retention 
 
The majority of former ASPIRE participants are anticipated to enroll within the first 3-6 
months after site activation, however this period could be shorter or longer depending 
upon accrual rates.  It is anticipated that the study will close to accrual 4 months ahead 
of the anticipated closure of the study.  Based upon the timing of participant enrollment, 
follow-up may last approximately 4-13 months. Follow-up may be extended beyond 13 
months based on need and requirements and with the necessary approvals.    
  
10.5 Blinding 
 
This is an open-label and unblinded trial.  
 
10.6 Data and Safety Monitoring Procedures 
 
10.6.1 Study Monitoring Committee 
 
In addition to the safety monitoring done by the PSRT (described in Section 8), the MTN 
SMC will be responsible for study oversight by conducting interim reviews of study 
progress, including rates of participant accrual, participant retention, protocol and 
intervention adherence, data quality, laboratory quality and completion of primary and 
secondary endpoint assessments.  Since MTN-025 is not subject to DSMB review, the 
SMC also will review participant safety data, as specified in the MTN Manual of 
Procedures.  These reviews will take place approximately every 6 months and as 
needed.  
 

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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.  The 
SMC may consider recommending termination of this study if recruitment is lower than 
targeted, or if study data quality is poor.  If at any time, a decision is made to 
discontinue participants, IPM, after consultation with the protocol team, will inform the 
US Food and Drug Administration (FDA).  The Site PIs will notify the responsible ECs 
expeditiously. 
 
10.6.2 Monitoring Quality of Study Conduct Operational Characteristics and 
Implementation 
  
The 
study 
may 
be 
terminated 
or 
modified 
for 
poor 
accrual/recruitment, 
adherence/product use, and/or retention.  Regular reports will be provided to the SMC 
that outline the potential impact on the study’s ability to meet its objectives if there 
are deviations from the statistical design in terms of accrual/recruitment, 
adherence/product use, retention, and/or low HIV acquisition rate. 
 
10.7 Primary Analyses 
 
10.7.1 Primary Safety Analysis 
 
Consistent with the primary safety objective, this analysis will characterize the safety 
profile for the overall population.   
 
Adverse events will be analyzed using MedDRA preferred terms.  The number and 
percentage of participants experiencing each specific AE will be tabulated by severity 
and by relationship to treatment regimen.  For the calculations in these tables, each 
participant’s AE will be counted once under the maximum severity or the strongest 
recorded causal relationship to study product. 
 
All AEs will be grouped by body system and a confidence interval for the incidence of 
each AE will be calculated overall and by arm.  Finally, a listing of EAEs reported to the 
DAIDS Safety Office will provide details of the event including severity, relationship to 
study product, onset, duration and outcome.  
 
Note that all of the above summaries will be calculated under the intention-to-treat (ITT) 
principle.  However, participants off study product and/or those who are non-adherent 
that are included in these analyses could potentially lower the rate of safety and toxicity 
endpoints.  Therefore, a ‘per-protocol’ analysis, where time off product is excluded from 
the analysis, will be used to explore the sensitivity of the conclusions obtained with the 
safety analysis under the ITT principle. 
 
Assuming between 1000 and 2500 participants are enrolled with an average of 11 
months of follow-up per participant, we expect between 917 and 2300 person-years of 
follow-up during this study.  The assumed 11-month average follow-up reflects both loss 
to follow-up and staggered entry. 

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10.7.2 Primary Adherence Analysis 
 
For the primary study aim related to adherence, participants will be categorized as 
adherent if drug is detected in all quarterly plasma samples when participants are not on 
a product hold and the proportion of adherent participants with a 95% confidence 
interval will be reported.  
 
In an effort to understand more complicated adherence patterns, secondary analyses 
for adherence will be performed.  Similar analysis of residual drug levels in VRs will also 
be performed.  Many of these will be informed by findings from ASPIRE and will be fully 
explained in a Statistical Analysis Plan prior to the completion of follow-up in MTN-025. 
 
10.8 Analysis of Secondary Endpoints 
 
Primary analysis of the two main secondary endpoints, HIV seroconversion and 
acquisition of ARV-resistant HIV infection will be conducted similarly.  We will calculate 
the incidence overall for each endpoint.  Use of new and additional HIV-1 prevention 
technologies, such as oral PrEP and/or topical vaginal gels, will be captured on 
standardized data forms and will be taken into account in the analysis of HIV-1 
incidence.  We will calculate confidence intervals for incidence rates using the Poisson 
distribution. Although, statistical summaries will be provided, the results will likely have 
to be judged based on clinical and public health acceptability.  Additional analyses will 
likely evolve based on results from ASPIRE.  These will be outlined in the Statistical 
Analysis Plan prior to the end of study follow-up. 
 
10.9 Missing Data 
 
We are targeting a retention rate of 95% over the study period.  Based on previous HIV 
Prevention Trials Network (HPTN) and MTN trials, we expect to have minimal missing 
data.  In any situation with missing data, we will do appropriate secondary analyses that 
adjust for variables that may be related to the missingness mechanism.  If missing data 
rates are higher than anticipated (over 10%), we will include covariates that are related 
to missingness in likelihood-based regression models.  We will also perform sensitivity 
analyses to assess the potential impact of the missing data.  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 
 
Study CRFs will be developed by the MTN SDMC in conjunction with the protocol team.  
Quality control reports and queries routinely will be generated and distributed by the 
SDMC to the study sites for verification and resolution.  As part of the study activation 
process, each study site must identify all CRFs to be used as source documents.  Study 
CRF data are transferred to the MTN SDMC, entered, and cleaned using the DataFax 
data management system.   
 
Transcriptions of interviews will be generated in the field and electronically transferred 
to RTI International using a secure File Transfer Protocol (FTP) site, where they will be 
uploaded and managed using a qualitative software package.  RTI International will act 
as a hub, and manage all data for the study.  A convention for file naming will be 
developed, and all data will be labeled according to this process.  Original language and 
translated transcripts will be transferred to RTI International as they are completed.  RTI 
International will save all versions of all files on a secure, password-protected server.  
 
11.2 Source Documents and Access to Source Data/Documents 
 
All study sites will maintain source data/documents in accordance with Requirements 
for Source Documentation in DAIDS Funded and/or Sponsored Clinical Trials 
(http://www.niaid.nih.gov/LabsAndResources/resources/DAIDSClinRsrch/Documents/so
urcedocpolicy.pdf) and the relevant appendix regarding source documentation 
(http://www.niaid.nih.gov/LabsAndResources/resources/DAIDSClinRsrch/Documents/so
urcedocappndx.pdf).   
 
Each IoR/designee will maintain, and store securely, complete, accurate and current 
study records throughout the study.  In accordance with U.S. regulations, for the 
investigational product tested, the IoR/designee will maintain all study documentation 
for at least two years following the date of marketing approval for the indication in which 
they were studied.  If no marketing application is filed, or if the application is not 
approved, the records will be retained for two years after the investigation is 
discontinued and the US FDA is notified.   
 
Study records must be maintained on site for the entire period of study implementation.  
Thereafter, instructions for record storage will be provided by DAIDS.  No study records 
may be moved to an off-site location or destroyed prior to receiving approval from 
DAIDS.   
 
Audio files will be transcribed and immediately destroyed following a transcription 
quality assurance check.  The site IoR or designee will be responsible for ensuring that 
these files have been destroyed. 
 

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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 Requirements for Clinical Quality Management Plans at DAIDS 
Funded 
and/or 
Supported 
Clinical 
Research 
Sites    
(http://www.niaid.nih.gov/LabsAndResources/resources/DAIDSClinRsrch/Documents/q
mppolicy.pdfhttp://www.niaid.nih.gov/LabsAndResources/resources/DAIDSClinRsrch/D
ocuments/qmppolicy.pdf). 
 
 
 
12 
CLINICAL SITE MONITORING 
 
Study monitoring will be carried out by Pharmaceutical Product Development, Inc. 
(PPD) (Wilmington, NC) in accordance with current DAIDS policies.  Study monitors will 
visit the site to do the following: 
 
 Review informed consent forms, procedures, and documentation 
 Assess compliance with the study protocol, Good Clinical Practices (GCP) 
guidelines, and applicable regulatory requirements (US and non-US), including 
CFR Title 45 Part 46 and Title 21 Parts 50, 56, and 312  
 Perform source document verification to ensure the accuracy and completeness 
of study data 
 Verify proper collection and storage of biological specimens 
 Verify proper storage, dispensing, and accountability of investigational study 
products 
 Assess implementation and documentation of internal site quality management 
procedures 
 Verify that current license/certification is available on site for study staff listed on 
the current FDA Form 1572, DAIDS IoRs, and Delegation of Responsibilities 
Log/Form. 
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 certain study procedures.  The 
IoR/designee will also allow inspection of all study-related documentation by authorized 
representatives of the MTN LOC, SDMC, and LC; NIAID, FDA, IPM, OHRP and local 
and US regulatory authorities.  A site visit log will be maintained at the study site to 
document all visits. 
 
 
 

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13 
HUMAN SUBJECTS PROTECTIONS 
 
13.1 Institutional Review Boards/Ethics Committees 
 
Site investigators will make efforts to minimize risks to participants.  Participants and 
study staff members will take part in a thorough informed consent process.  Before 
beginning the study, the IoR will have obtained IRB/EC approval and the protocol will 
have been submitted to the FDA.  The IoR will permit audits by the NIH, IPM, the FDA, 
OHRP, or any of their appointed agents. 
 
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 consent forms approved, as 
appropriate, by their local IRB/ EC and any other applicable regulatory entity (RE).  
Upon receiving final approval, sites will submit all required protocol registration 
documents to the DAIDS Protocol Registration Office (DAIDS PRO) at the RSC.  The 
DAIDS PRO will review the submitted protocol registration packet to ensure that all of 
the required documents have been received.   
 
Site-specific informed consent forms (ICFs) will not be reviewed or approved by the 
DAIDS PRO, and sites will receive an Initial Registration Notification when the DAIDS 
PRO receives a complete registration packet.  Receipt of an Initial Registration 
Notification indicates successful completion of the protocol registration process.  Sites 
will not receive any additional notifications from the DAIDS PRO for the initial protocol 
registration.  A copy of the Initial Registration Notification should be retained in 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. 
 
For additional information on the protocol registration process and specific documents 
required for initial and amendment registrations, refer to the current version of the 
DAIDS Protocol Registration Manual. 
 

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13.3 Study Coordination 
 
IPM holds the Investigational New Drug (IND) application for this study.  Copies of all 
regulatory documents submitted to this IND by IPM will be forwarded to DAIDS for 
cross-referencing with other INDs for the study product.  Assignment of all sponsor 
responsibilities for this study will be specified in a Clinical Trial Agreement executed by 
NIAID and IPM. 
 
Study implementation will also be guided by a common study-specific procedures 
manual that provides further instructions and operational guidance on conducting study 
visits; data and forms processing; specimen collection, processing, and shipping; AE 
assessment, management and reporting; dispensing study product 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 
 
General 
It is not expected that this trial will expose human subjects to unreasonable risk.   
 
Pelvic examination and procedures may cause mild discomfort and/or vaginal bleeding 
or spotting.  Phlebotomy may lead to discomfort, feelings of dizziness or faintness, 
and/or bruising, swelling and/or infection.  Disclosure of HIV and STI status may cause 
worry, sadness or depression.  Disclosure of HIV-positive status has been associated 
with depression, suicidal ideation, and denial as well as social isolation.  Trained 
counselors will be available to help participants deal with these feelings.  Participation in 
clinical research includes the risks of loss of confidentiality and discomfort with the 
personal nature of questions when discussing sexual behaviors. 
 
Participants at sites requiring partner notification in response to diagnosed STI or HIV 
infection could have problems in their relationships with their sexual partners.  It is 
possible that the participant and her partner may feel the ring during sexual activity.  
Participants also could experience problems associated with use of study product in 
their partner relationships. 
 

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Use of the study VR may lead to vaginal symptoms, including irritation, increased 
discharge, and discomfort (including with vaginal intercourse).  It is possible that a 
participant may have an allergic reaction to the study product.  Symptoms of an allergic 
reaction include rash or other skin irritation, itching, joint pain, or difficulty in breathing. 
 
Based on AEs reported among female participants in previous studies, dapivirine VRs 
may be associated with:  
 Metrorrhagia 
 Vaginal discharge 
 Vaginal candidiasis 
 Vaginitis bacterial 
 Urinary tract infection 
 
Please note:  Study product risks will be updated when the safety and 
effectiveness data from ASPIRE are available. 
 
As with any vaginally retained product, the possibility of toxic shock syndrome, although 
rare, exists. 
 
Based on in vitro data, HIV-infected participants who have prolonged exposure to low 
concentrations of dapivirine by continuing to use the ring after infection may have a risk 
of selecting viruses carrying NNRTI resistance-associated mutations.  Clinical relevance 
has yet to be established. 
 
Site staff will make every effort to protect participant privacy while in the study.  
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 and/or communities.   
 
13.4.2 Benefits 
 
MTN-025 (HOPE) will only be implemented if the dapivirine vaginal ring as tested in 
MTN-020 (ASPIRE) is found to be safe and effective, therefore, participants in the 
HOPE study will experience the direct benefit of using a product that has been found to 
be safe and effective in preventing HIV acquisition and will be considered for potential 
regulatory approval.  Participants and others may benefit in the future from information 
learned from this study.  Specifically, information learned in this study may help to 
understand issues important for broader implementation of the dapivirine ring and/or for 
the development of other safe and effective interventions to prevent HIV acquisition.  
Participants may also appreciate the opportunity to contribute to the field of HIV 
prevention research.  
 

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Participants will receive HIV/STI risk reduction counseling, HIV and STI testing, physical 
examination, pelvic examination, and routine laboratory testing.  Participants will be 
provided STI treatment in accordance with WHO guidelines free of charge.  In addition, 
STI testing, counseling and treatment, as well as HIV testing and counseling will be 
available for participants’ partners.  For other medical conditions identified as part of the 
study screening and/or follow-up procedures, participants will be referred to other 
sources of care available in their community.  Some volunteers may have the 
opportunity to access expedient treatment and decreased morbidity due to early 
diagnosis and treatment of abnormalities identified during tests, examinations and 
referrals.  
 
13.5 Informed Consent Process 
 
Each study participant will provide written informed consent prior to both screening and 
enrollment.  Written informed consent will also be obtained for long-term specimen 
storage and possible future testing, for off-site clinic visits as needed, as well as for 
participation in the ‘Decliner Population’.  Neither consent for long-term specimen 
storage nor off-site study visits are required for study participation.  Further, participation 
in the ‘Decliner Population’ does not preclude MTN-025 full study participation in the 
future.  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 (http://rsc.tech-res.com/policiesandregulations/).  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 study-specific procedures manual.   
 
The informed consent process will cover all elements of informed consent required by 
research regulations.  In addition, the process will specifically address the following 
topics of importance to this study: 
 The 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 benefit of study participation  
 The distinction between research and clinical care 
 The right to withdraw from the study at any time 
 New information, including results of MTN-020 (ASPIRE) and IPM 027 (The Ring 
Study), and information about other effective HIV-prevention products will be 
provided to MTN-025 (HOPE) participants.   

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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 at the study site.  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 records that contain 
names or other personal identifiers, such as locator forms and informed consent forms, 
will be stored securely.  All local databases will be secured with password protected 
access systems.  Forms, lists, logbooks, appointment books, and any other listings that 
link participants’ identification numbers to identifying information will be stored in a 
locked file in an area with limited access.  All digital audio files will be stored on 
password-protected computers.  Audio files will be transcribed.  Please see SSP for 
guidance regarding audio file destruction.  Participants’ study information will not be 
released without their written permission, except as necessary for review, monitoring, 
and/or auditing by the following: 
 Representatives of the US Federal Government, including the US FDA, the US 
OHRP, NIH, and/or contractors of the NIH, and other local and US regulatory 
authorities 
 Representatives of IPM, including study monitors 
 PPD 
 Study staff  
 Site IRBs/ ECs 
 
13.7 Special Populations 
 
13.7.1 Pregnant Women 
 
Women who test positive for pregnancy at Screening or Enrollment Visits will not be 
eligible to participate in this study.  Should a woman test positive for pregnancy after 
Enrollment, a product hold will be implemented but all follow-up visits will be completed 
and data collected per Section 7.6.2.  A urine pregnancy test will be performed at 
scheduled study visits, and additionally at interim visits as indicated; the IoR/designee 
will temporarily discontinue study product for participants who test positive for 
pregnancy.  During the informed consent process, women will be informed that the VR 
is not a method of contraception and the effects of the VR on a developing human fetus 
are unknown. 
 

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Animal studies have failed to demonstrate risk to the fetus, but there are no adequate 
and well-controlled studies in pregnant women completed to support their inclusion to 
date.  
 
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/EC approval, participants will be compensated for time and effort in this 
study, and/or be reimbursed for travel to study visits and time away from work.  Site-
specific reimbursement amounts will be specified in the study informed consent forms.  
Each study site will determine appropriate compensation with their overseeing IRB/EC. 
 
13.9 Communicable Disease Reporting 
 
Study staff will comply with local requirements to report communicable diseases 
including HIV-1 identified among study participants to health authorities.  Participants 
will be made aware of reporting requirements during the informed consent process. 
 
13.10 Access to HIV-related Care 
 
13.10.1 
HIV Counseling and Testing 
 
HIV test-related counseling will be provided to all potential study participants who 
consent to undergo HIV-1 screening to determine their eligibility for this study, and to all 
enrolled participants at each follow-up HIV-1 testing time point.  Testing will be 
performed in accordance with the algorithm in Appendix III.  Counseling will be provided 
in accordance with standard HIV counseling policies and methods at each site and 
additionally will provide information regarding the known efficacy of the study product in 
preventing HIV-1 infection.  In accordance with the policies of the NIH, participants must 
receive their HIV-1 test results to take part in this study.  Condoms will be offered to 
participants throughout the duration of their participation. 
 
13.10.2 
Care for Participants Identified as HIV-Infected 
 
Care for participants identified as HIV-infected is described in Section 9.6. 
 

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13.11 Study Discontinuation 
 
This study may be discontinued at any time by NIH, the MTN, IPM, the US FDA, the 
OHRP, other government or regulatory authorities, or site IRBs/ECs. 
 
 
 
14 
PUBLICATION POLICY 
 
DAIDS/NIAID and MTN policies and a CTA between NIAID and IPM will govern 
publication of the results of this study. 
 

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15 
APPENDICES 
 
 
 

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Appendix I: SCHEDULE OF STUDY VISITS AND EVALUATIONS 
 
 
 
Study Months 
 
 
SCR 
ENR 
M.  
1 and 2,  
Quarterly 
Visits 
PUEV 
 
Study Exit/ 
Term. Visit 
(~ 1 Month 
after the 
PUEV) 
ADMINISTRATIVE AND REGULATORY 
 
 
 
 
 
 
Obtain informed consent 
X 
X 
 
 
 
 
Assign a unique Participant Identification (PTID) 
number  
X 
 
 
 
 
 
Assess and/or confirm eligibility 
X 
X 
 
 
 
 
Collect/review/update locator information 
X 
X 
X 
X 
X 
X 
Provide reimbursement for study visit 
X 
X 
X 
X 
X 
X 
Schedule next visit 
* 
* 
X 
X 
X 
* 
BEHAVIORAL 
 
 
 
 
 
 
Contraceptive counseling 
X 
X 
X 
X 
X 
* 
HIV/STI risk reduction counseling 
X 
X 
X 
X 
X 
X 
HIV pre- and post-test counseling 
X 
X 
X 
X 
X 
X 
Protocol adherence 
 
X 
X 
X 
 
 
Conduct a behavioral assessment 
 
X 
 
X 
X 
X 
Conduct social harms assessment 
 
 
 
X 
X 
 
CLINICAL 
 
 
 
 
 
 
Obtain/update medical and menstrual history 
X 
X 
X 
X 
X 
X 
Obtain/update concomitant medications 
X 
X 
* 
X 
X 
X 
Conduct a physical examination 
X 
* 
* 
* 
X 
* 
Perform a pelvic examination 
X 
* 
* 
* 
X 
* 
Offer contraceptives 
*  
*  
*  
* 
*  
*  
Disclose available test results 
 
X 
X 
X 
X 
X 
Record/update AEs 
 
 
X 
X 
X 
X 
Treat or prescribe treatment for UTIs/RTIs/STIs or 
refer for other findings 
* 
* 
* 
* 
* 
* 
LABORATORY 
 
 
 
 
 
 
URINE 
hCG 
X 
X 
X 
X 
X 
X 
Urine culture 
*
Ŧ 
* 
Ŧ 
* 
Ŧ 
* 
Ŧ 
* 
 Ŧ 
* 
 Ŧ 
NAAT for GC/CT 
X 
*  
*  
* 
X  
*  
BLOOD 
HIV-1 serology 
X 
X 
X              X 
X 
X 
CBC with platelets 
X 
 
 
 
X 
 
Chemistries 
X 
 
* 
* 
X 
 
Syphilis serology 
X 
 
* 
* 
X 
 
Plasma sample for DPV testing and archive 
 
◊ 
 
X 
X 
X 
PELVIC 
Rapid test for Trichomonas 
X 
*  
* 
* 
X 
* 
Vaginal fluid (self-collected) 
 
X 
X 
X 
X 
X 
Pap Smear interpretation 
* 
 
 
 
 
 
 
Adherence assessment(s):  Returned Study VR 
 
 
X 
X 
X 
 
STUDY PRODUCT/ SUPPLIES 
 
 
 
 
 
 
Offer condoms 
X 
X 
X 
X 
X 
X 
Provision of study VR use instructions  
 
X 
* 
* 
 
 
Provision of study VR  
 
X 
X 
X 
 
 
Removal and collection of used/unused study VR  
 
 
X 
X 
X 
 
Digital exam(s) by clinician to check VR placement 
 
* 
* 
* 
 
 
X mandatory, *If indicated, 
ŦPer local standard of care 

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APPENDIX II:  ALGORITHM FOR HIV ANTIBODY TESTING- 
SCREENING/ENROLLMENT 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ineligible 
for the study 
+/+ 
START 
2 different Rapid Tests 
+/-
Notify the MTN Laboratory Center 
for follow-up. 
_,_ 
Report as 
HIV uninfected 

 
 
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APPENDIX III:  ALGORITHM FOR HIV ANTIBODY TESTING FOR FOLLOW-UP 
Report as HIV 
Infected 
+ 
Ind: Indeterminate test results 
LC: Laboratory Center 
START 
2 different Rapid Tests 
+/+ 
or 
+/-
Confirmation Test 
_,_ 
- or Ind 
Notify MTN LC 
Repeat Confirmation Test after 1 month 
Report as HIV 
Uninfected 
HIV RNA 
+ 

 
  
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APPENDIX IV: SAMPLE INFORMED CONSENT DOCUMENT (SCREENING) 
 
SAMPLE INFORMED CONSENT FORM 
DIVISION OF AIDS, NIAID, NICHD, NIMH, NIH 
 
MTN-025 
 
A Phase 3B Open-Label Follow-on Trial to Assess the Continued Safety of and 
Adherence to a Vaginal Ring Containing Dapivirine in Women 
 
HIV Open-label Prevention Extension (HOPE) 
 
Version 2.0 
December 16, 2014 
 
 
PRINCIPAL INVESTIGATOR:  [Sites to insert] 
PHONE:  [Sites to insert] 
 
INFORMED CONSENT 
This is a screening consent form.  You are being asked to volunteer for screening tests to find 
out if you are eligible for a research study MTN-025, otherwise known as the HIV Open-label 
Prevention Extension (HOPE) trial.  The research study you participated in, MTN-020: 
ASPIRE, A Study to Prevent Infection with a Ring for Extended Use, showed that the dapivirine 
vaginal ring can reduce the chances of HIV-uninfected women from getting the HIV virus by 
[SITES TO INSERT: from X to X percent].  The study also learned that the dapivirine vaginal 
ring is [SITES TO INSERT: safe (meaning that they do not produce significant health problems 
in persons who take them)] when used by HIV-uninfected women.  Only through the 
participation of volunteers in clinical research can the safety and effectiveness of medicine be 
better understood.  More data is needed on the safety of the dapivirine vaginal ring.  Because 
you took part in the ASPIRE study, you are being offered the opportunity to use the safe and 
effective dapivirine vaginal ring as part of this new study.  A total of 2629 women enrolled into 
MTN-020 (ASPIRE) and all former ASPIRE participants who are eligible for MTN-025 (HOPE) 
may take part. It is anticipated that approximately 1000 to 2500 former ASPIRE participants will 
enroll in HOPE. 
 
This Microbicide Trials Network (MTN) study is funded by the US National Institutes of Health 
(NIH) and is being conducted across multiple countries across Africa.  The International 
Partnership for Microbicides (IPM) supplies the study product. 
 
[INSERT NAME OF PRINCIPAL INVESTIGATOR] is in charge of this study at this clinic.  
Before you decide if you want to screen for this study, we want you to learn more about the trial.  
Screening examinations and tests, which include interview questions, urine, and blood tests, a 
physical examination and an examinations of your vagina, will be performed to better 
understand your health.  The study staff will explain the exams and tests to you and what is 
expected of you.  Once you understand the screening tests, and if you agree to take part, you 
will be asked to sign your name or make your mark on this form.  You will be offered a copy of 
this form to keep.   

 
  
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YOUR PARTICIPATION IS VOLUNTARY 
It is important that you know the following: 
 
You are only being asked to have the screening tests at this time.  Even if you agree 
to have the screening tests, you do not have to join this study. 
 
Your participation is voluntary; you do not have to have the screening tests if you do 
not want to participate in this study. 
 
You may decide not to have the screening tests, or to withdraw from the screening 
tests at any time, without losing your regular medical care. 
 
You will receive the results of the screening tests even if you are not eligible to join 
this study. 
 
Some people may not be able to join this study because of information found during 
the screening tests.  You are asked to tell the study staff about any other studies you 
are taking part in, or thinking about taking part in.  This is very important for your 
safety. 
 
If new information is learned about the study, or the study product, you will be told 
about this as soon as possible. 
 
PURPOSE OF THE SCREENING TESTS AND THE STUDY 
The main purpose of these screening exams and tests is to find out if you can join this research 
study.  This research study will test if a vaginal ring containing the medicine dapivirine is used 
as directed and found to be safe in participants who attend clinic visits.  Women will be in this 
study for approximately 13 months depending upon when they enroll in the study; however this 
period could be shorter or longer than anticipated.  You will be notified if the study extends 
beyond 13 months. 
 
STUDY PRODUCT 
There is one kind of vaginal ring that will be used in this study, a ring containing dapivirine.  
Unlike ASPIRE, there is no placebo vaginal ring (a ring without the study medicine) in HOPE, so 
all HOPE participants will receive a vaginal ring containing dapivirine.  This ring is the same 
dapivirine vaginal ring used in ASPIRE.  Dapivirine vaginal rings have been previously tested 
and found to be generally safe, well-tolerated and effective in HIV prevention in women.  HIV is 
the virus that causes AIDS.  The medicines that are being tested by researchers to prevent HIV 
infection work in different ways.  Dapivirine works by preventing HIV from making copies of 
itself, thereby stopping the spread of HIV in the body.   
 
 
WHAT DO I HAVE TO DO IF I DECIDE TO TAKE PART IN THE SCREENING EXAMS AND 
TESTS? 
If you agree to have screening tests, they can be done today.  Ideally, all procedures will be 
completed today.  However if you have to come back to complete this visit, some procedures 
may need to be repeated.   
 
Screening Visit: 
The procedures done at this visit today will take about [sites to insert time]. 
 
 
You will be asked questions about: 
 
Where you live  
 
Your medical health, what medications you are taking, and menstrual history 

 
  
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 
Other questions to ensure you are eligible for this study, and to make sure that you 
understand the study requirements.   
 
 
Study staff will: 
 
Perform a physical examination 
 
Talk with you about the requirements of the study including using an effective 
method of contraception throughout your participation in this study  
 
Test your urine for: 
o Infections passed through sex 
o Pregnancy  
 
If you are pregnant you cannot join this study because the risks to your 
baby are unknown.  
 
If the study is still open after your pregnancy, you may come back here to 
find out if you are eligible.  
 
If you are not pregnant, you will be told about ways to avoid becoming 
pregnant, such as the use of contraception.  
 
 
Take a blood sample [Sites to insert amount]: 
o To test the health of your blood, liver and kidneys 
o To test for infections passed through sex, including HIV 
 
You will be told your HIV test result as soon as it is available.  You will 
talk with the study staff about the meaning of your results, how you feel 
about them, and ways to prevent HIV and other sexually transmitted 
infections.  Sometimes HIV tests are not clearly positive, but also not 
clearly negative.  In that case, we will do more tests until we know your 
results for sure.  You must receive your HIV test results to be in this 
study.  If the test shows you have HIV, you cannot join this study.  We will 
tell you where you can get care and other services you may need.  The 
study staff will tell you about other studies you may be eligible for, if any. 
 
 
Perform a pelvic examination: 
o The study doctor or nurse will use a speculum, a plastic or metal instrument used 
to separate the walls of the vagina.  The study doctor or nurse will look at your 
vagina and cervix for signs of infection, and other problems.  Your cervix is 
located at the top of the vagina and it forms the lower end of the womb (uterus).  
They may also take some fluids to test for other possible problems if they feel it is 
necessary. 
o The study staff may also collect samples from your cervix for testing, including a 
“Pap test”.  If the test shows a problem, it could mean you should have more 
tests.  If you have a written report confirming that you had a normal Pap test in 
the past 12 months or if you had an abnormal Pap test but had follow-up and a 
written report indicating no treatment was required, you will not need to have a 
Pap test during this visit.   
 
 
Give you treatment or refer you for treatment for infections passed through sex, if 
needed. 
 
Tell you about other services if you need them  
 
Offer you condoms.  Condoms are highly effective in preventing the sexual 
transmission of HIV and reducing the risk for other sexually transmitted diseases 

 
  
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(STDs).  Study staff can provide you with condoms along with additional information 
about other ways to avoid getting HIV infection. 
 
Schedule your next visit to enroll in MTN-025, if you are eligible and willing 
 
The study staff will review your test results with you when they are available.  If the results show 
you can join the MTN-025 study, the study staff will explain the study to you and answer any 
questions you have.  If you decide to be in this study, you will be asked to sign another consent 
form. 
 
RISKS AND/OR DISCOMFORTS 
Risks of Blood Draws: You may feel discomfort or pain when your blood is drawn.  You may 
feel dizzy or faint.  You may have a bruise, swelling, small clot, or infection where the needle 
goes into your hand or arm. 
 
Risks of Genital Exams: You may feel discomfort or pressure during the examination of your 
genital area and inside your vagina.  You may have a small amount of vaginal bleeding which 
usually stops shortly after the examination. 
 
Other Possible Risks: You may become embarrassed or worried when discussing your sexual 
practices, ways to protect against HIV and other infections passed through sex.  You may 
become worried while waiting for your test results.  If you have HIV or other infections, learning 
this could make you angry, depressed or worried.  Trained study counselors will help you deal 
with any feelings or questions you have.   
 
Risks to your Privacy: We will make every effort to protect your privacy and confidentiality 
while you are having the screening tests.  Your visits will take place in private.  However, it is 
possible others may learn of your participation here and, because of this, may treat you unfairly.  
For example, you could have problems getting or keeping a job, or being accepted by your 
family or community.  Finding out your HIV status could also cause 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. 
 
BENEFITS 
The primary benefit to joining this study is having access to a product that has been shown to 
be safe and effective in preventing HIV.  If this screening visit shows you are eligible to 
participate, an enrollment visit will be scheduled.  
 
You will have a physical examination, pelvic examination, and tests to check on the health of 
your blood, liver, and kidneys.  If these tests show that you might have health problems, you will 
be told where to get medical care and other services available to you.  
 
You will be counseled and tested for infections passed through sex.  If you have these 
infections, you may be offered treatment for them, if needed.  If you are infected with HIV, you 
will be told about medical care, counseling, and other available services that could be of help to 
you.  For other health problems that cannot be treated at this clinic, the study staff will refer you 
to other places where you may receive medical care.  If your Pap test result shows anything that 
is not normal, you will be referred for advice and/or treatment.   
 

 
  
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REASONS WHY YOU MAY BE WITHDRAWN FROM THE SCREENING TESTS WITHOUT 
YOUR CONSENT 
You may be withdrawn from the screening tests without your consent if: 
 
 
You are found not to be eligible for this study 
 
The study is stopped or canceled 
 
The study staff feel that having the screening tests would be harmful to you 
 
You are not willing to find out your HIV test result 
 
You are not able to attend clinic visits or complete the screening tests 
 
Other reasons identified by study staff  
 
 
COSTS TO YOU 
[Site to complete according to site capacity] There is no cost to you for screening tests.  
Treatments available to you from the study site for infections passed through sex (other than 
HIV) will either be given to you free of charge or you will be referred for treatment while you are 
screening for this study.  
 
REIMBURSEMENT 
[Sites to insert information about local reimbursement:] You will receive [Sites to insert amount 
$xx] for your time, effort, and travel to and from the clinic at each scheduled screening visit.  
 
CONFIDENTIALITY 
Efforts will be made to keep your personal information confidential.  However, it is not possible 
to guarantee confidentiality.  Your personal information may be disclosed if required by law.  
The study staff will use your personal information, if needed, to verify that you are not taking 
part in any other research studies.  [Sites to insert information about systems currently in place 
to ensure participants are not part of other conflicting studies, including biometric identification 
systems.] This includes studies conducted by other researchers that study staff knows 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 Office for 
Human Research Protections (OHRP), NIH, and/or contractors of NIH 
 
[Insert applicable local authorities, e.g., Ministry of Health, medicine control authority] 
 
IPM, the organization that supplies the study rings 
 
Study monitors 
 
Site Institutional Review Board (IRB)/ Ethics Committee (EC), an Ethics Committee is a 
committee that watches over the safety and rights of research participants  
 
Study staff 
 
[Sites to include/amend the following:] [LOCAL/STATE/NATIONAL] regulations require study 
staff to report the names of people who test positive for HIV and other infections passed during 
sex to the [LOCAL HEALTH AUTHORITY].  Outreach workers from the [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. 

 
  
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RESEARCH-RELATED INJURY 
[Sites to modify with their site-specific research-related injury institutional policy:] It is unlikely 
that you will be injured as a result of having the screening tests.  This US federally funded study 
does not have the ability to provide compensation for research-related injury.  If you are injured 
or become ill from taking part in this study, it is important to tell your study doctor.  Emergency 
treatment may be available but you or your insurance company will be charged for this 
treatment.  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 website 
will not include information that can identify you.  At most, the website will include a summary of 
the results.  You can search this website at any time. 
 
PROBLEMS OR QUESTIONS 
If you ever have any questions about the screening tests, or if you have a research-related 
injury, you should contact [insert name of the investigator or other study staff] at [insert 
telephone number and/or physical address]. 
 
If you have questions about your rights as a research participant, you should contact [insert 
name or title of person on the IRB/EC or other organization appropriate for the site] at [insert 
physical address and telephone number]. 
 
If you have questions about who to contact at the research site, you should contact [insert name 
of the investigator or community educator or community advisory board (CAB) member] at 
[insert physical address and telephone number]. 
 

 
  
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SIGNATURES 
[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 have the screening tests, 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 
 
Witness Signature  
 
Date 
(print) 

 
  
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APPENDIX V: SAMPLE INFORMED CONSENT DOCUMENT (ENROLLMENT) 
 
SAMPLE INFORMED CONSENT FORM 
DIVISION OF AIDS, NIAID, NICHD, NIMH, NIH 
 
MTN-025 
 
A Phase 3B Open-Label Follow-on Trial to Assess the Continued Safety of and 
Adherence to a Vaginal Ring Containing Dapivirine in Women 
 
HIV Open-label Prevention Extension (HOPE) 
 
Version 2.0 
 
December 16, 2014 
 
 
PRINCIPAL INVESTIGATOR:  [Sites to insert] 
PHONE:  [Sites to insert] 
 
INFORMED CONSENT 
You are being asked to take part in the MTN-025 HIV Open-label Prevention Extension 
(HOPE) trial.  The research study you participated in, MTN-020: ASPIRE, A Study to Prevent 
Infection with a Ring for Extended Use, showed that the dapivirine vaginal ring can reduce HIV-
uninfected women’s chances of getting the HIV virus by [SITES TO INSERT: from X to X 
percent].  The study also learned that the dapivirine vaginal ring is [SITES TO INSERT: safe 
(meaning that it does not cause significant health problems)] when used by HIV-uninfected 
women.  More data is needed on the safety of the dapivirine vaginal ring.  Because you took 
part in the ASPIRE study, you are being offered the opportunity to use the safe and effective 
dapivirine vaginal ring as part of this new study.  A total of 2629 women enrolled into MTN-020 
(ASPIRE) and all former ASPIRE participants who are eligible for MTN-025 (HOPE) may take 
part. It is anticipated that approximately 1000 to 2500 former ASPIRE participants will enroll in 
HOPE. 
 
This Microbicide Trials Network (MTN) study is funded by the US National Institutes of Health 
(NIH) and is being conducted across multiple countries across Africa.  The International 
Partnership for Microbicides (IPM) supplies the study product. 
 
[INSERT NAME OF PRINCIPAL INVESTIGATOR] is in charge of this study at this clinic site.  
 
YOUR PARTICIPATION IS VOLUNTARY 
Before you decide if you want to join this study, we want you to learn about the study.  The 
study staff will talk with you about the study and answer your questions.  Once you read, 
discuss, and understand the study, and if you agree to take part, you will be asked to sign your 
name or make your mark on this form.  You will be offered a copy of this form to keep.  You may 
decide not to join or to withdraw from the study at any time. 
 
PURPOSE OF THE STUDY 

 
  
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This research study will test if a vaginal ring containing the medicine dapivirine is used as 
directed and found to be safe in participants who attend clinic visits.  Women will be in this study 
for approximately 13 months depending upon when they enroll in the study; however the 
duration of study participation could be shorter or longer than anticipated.  You will be notified if 
the study extends beyond 13 months. 
 
STUDY PRODUCT 
There is one kind of vaginal ring that will be used in this study, a vaginal ring containing 
dapivirine.  Unlike ASPIRE, there is no placebo vaginal ring (a ring without the study medicine) 
in HOPE, so all HOPE participants will receive a vaginal ring containing dapivirine.  This ring is 
the same dapivirine vaginal ring used in ASPIRE.  Dapivirine vaginal rings have been previously 
tested and found to be generally safe, well-tolerated and effective in HIV prevention in 
women.  This study is testing whether a vaginal ring containing dapivirine can help to prevent 
the spread of HIV.  HIV is the virus that causes AIDS.  The medicine that is being tested to 
prevent HIV infection works in different ways.  Dapivirine works by preventing HIV from making 
copies of itself, thereby stopping the spread of HIV in the body.   
 
The staff can provide you additional information about other ways to avoid getting HIV infection.  
The most effective way to protect against getting HIV infection during sex is to use a condom 
every time you have sex. 
 
WHAT DO I HAVE TO DO IF I DECIDE TO TAKE PART IN THE MTN-025 STUDY? 
If you decide to enroll in the study, you will have a clinic visit today and monthly for the next 
three months, then quarterly thereafter.  You will insert a new vaginal ring monthly for 
approximately 12 months.  For some participants, this period of time may be less, study staff will 
provide you with an estimate of how long you will use the ring.  You will have a final study visit 
to check on your health approximately 4 weeks after the final ring is removed.  Study visits may 
be required beyond the final study visit to monitor your health.  Visits will take approximately 
[site to insert required length of time]. 
 
You will be asked to: 
 
Confirm you are able to join the study and that you understand the study requirements 
 
Answer questions about your vaginal practices, including sexual activity 
 
Provide updated information about where you live and how we can contact you   
 
Describe any changes in your health, what medicines you are taking, and your 
menstrual periods 
 
Describe any health problems you have had since your last visit, including problems with 
the study ring 
 
You will be asked to use a study vaginal ring.  As part of using this ring you will: 
 
Talk with study staff about how to properly wear and use the study ring 
 
Receive new study rings (monthly or every three months) and insert a new study ring 
(monthly).  If you are inserting a new ring at a clinic visit, and you are having difficulty a 
study clinician may help you 
 
If needed, have an examination performed to ensure the ring is properly inserted. 
 
Return your vaginal ring(s) to study staff.  Study researchers will keep these rings and 
run additional tests on them.  These tests will help researchers better understand your 
ring use. 

 
  
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 
Be able to return to the clinic to have the ring reinserted if the ring falls out and you are 
uncomfortable reinserting it yourself 
 
You will be asked to answer questions about: 
 
Your experience using the vaginal ring, including whether or not the ring was removed 
from or fell out of your vagina.   
 
Any problems you may have had during your participation in this study.   
 
Vaginal practices that may affect how the study drug is absorbed by your body. 
 
Things that may make you uncomfortable, such as questions about drug use.  You may 
use a computer to answer these questions or a staff member may ask you these 
questions.  It is important that you know that you will answer these questions in private 
and your responses will be kept confidential. 
 
You will have the following clinical procedures performed: 
 
A physical examination 
 
Provide a sample of blood [insert amount]  to:  
- 
Check the health of your blood, liver and kidneys  
- 
Test for HIV.  You will be told your HIV test results as soon as they are available.  
You will talk about the meaning of your results and how you feel about them, and 
ways to prevent HIV and other STIs.  Sometimes HIV test results are not clearly 
positive, but also not clearly negative.  In that case, we will do more tests until we 
know your results for sure.  You must receive your HIV test results to be in the 
study.  If the test shows you have HIV, you cannot join the study.  We will tell you 
where you can get care and other services you may need.  You will be told about 
other studies you may be eligible for, if any.  
- 
Additional testing may be performed as part of quality control. 
- 
See how much of the study product is being absorbed by your body and how it 
affects your body.  
 
Provide a urine sample to: 
- 
Check to see if you are pregnant  
- 
Test for infections passed through sex 
 
Provide vaginal fluid and cervical fluid samples: 
o To see how the dapivirine vaginal ring protects against HIV and to explore the 
health of the female genital tract.  The vaginal fluid and cervical fluid collected will 
be used for research purposes only.   
 
A pelvic examination when the vaginal ring is removed for the final time.  The study 
doctor or nurse will use a speculum.  A speculum is a plastic or metal instrument used to 
separate the walls of the vagina.  It is used so the doctor or nurse can examine the 
vagina and the cervix during the examination.  Your cervix is located at the top of the 
vagina and it forms the lower end of the womb (uterus).  They will check for signs of 
infection, and other problems.  They may also take some fluids to test for STIs and other 
possible problems if they feel it is necessary 
 

 
  
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As part of the clinical procedures you will: 
 
Receive the results of your tests when available 
 
Learn about other services available to you 
 
Receive treatment or be referred for treatment for problems that the study staff may find.  
 
Receive counseling.  You will discuss: 
- 
Sexually transmitted infections (STIs), HIV, HIV/STI testing, and ways to prevent 
HIV and other infections passed through sex   
- 
The rules of the study and how to follow the rules  
- 
Contraception and ways to prevent getting pregnant  
 
Be offered condoms.  Condoms are highly effective in preventing the sexual 
transmission of HIV and reducing the risk of other sexually transmitted diseases (STDs).  
Study staff can provide you with condoms along with additional information about other 
ways to avoid getting HIV infection. 
 
You will schedule your next visit  
 
If you leave the study early, you will be asked to complete a final clinic visit and evaluations.  
Various procedures will be completed at this visit, including a pregnancy and HIV test. 
 
It may be necessary for additional visit(s) and procedures in the event of unforeseen or 
unanticipated results; difficulties in sample shipping, processing, or testing; and/or if you are 
experiencing any symptoms or changes in your physical condition. For example, at any time 
during the study, vaginal and/or cervical swabs, blood samples and urine may need to be 
collected if you are having symptoms or if you are suspected to have an infection. 
 
Interim/Unscheduled Visits 
Study staff will discuss with you the importance of contacting the clinic as soon as you notice 
changes in your physical condition or when you experience health related issues.  It may be 
necessary to come to the clinic for an unscheduled visit.  Also, it is possible that you may be 
asked to come to the clinic for an unscheduled visit in the event of an abnormal test result; 
difficulties in sample shipping, processing, or testing; or for other reasons. 
 
In-depth Interview(s) and Group Discussions 
You may be asked to participate in interview(s) with a trained staff member or you may be 
asked to participate in a group discussion with other study participants about opinions that you 
or other participants have.  If you are asked to participate in these study activities, you will be 
compensated for your time and effort.   
 
If you are asked to participate in a group discussion, you will be asked to discuss your use of 
the study product, your feelings about the study product and trial participation, your vaginal 
practices and other questions that can help researchers to better understand participants’ 
experiences while taking part in the study.  These discussions will last about one hour.   
 
If you are asked to participate in an interview, you will be asked questions about your use of the 
ring, your preferences and opinions, your experiences with using the ring during sex, and any 
problems you may have had using the ring.  The interviews will be audio-recorded to make sure 
to record your words exactly how you said them.  The voice recordings will be destroyed as 
soon as the audio recording has been typed and checked.  The audio recording, notes, and 

 
  
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analyses from these materials will be kept confidential and will only use study numbers or fake 
names.  This means that no one other than the MTN-025 (HOPE) 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-025(HOPE) study team for 
the purposes of this research. 
 
If you become infected with HIV 
Your participation in this study will not cause HIV infection.  However, there is always a chance 
that through sexual activity or other activities you may become HIV-positive.  If the HIV tests 
confirm that you have been infected with HIV, you will stop using the ring, but we will ask you to 
continue to come into the clinic for regularly scheduled visits for some of the study procedures.  
You will have more blood tests at different time points after your HIV infection is discovered to 
find out which drugs would be inappropriate for your type of HIV-1 (HIV drug resistance), the 
amount of immune protection in your blood (CD4+ T-cell count), and the amount of HIV in your 
blood (viral load).  You may be referred to other research studies.  If you join another study it 
may not be necessary to collect additional blood for testing.  In the event you become HIV-
positive, study staff will counsel and refer you for medical care and other available services 
while you are in this study. 
 
It may be necessary, depending upon local and national health requirements, for study staff to 
report diseases, including HIV, identified among MTN-020 (ASPIRE) study participants.  The 
reportable diseases at this site are [Sites to insert]. 
 
RISKS AND/OR DISCOMFORTS 
 
Risks of Blood Draws: You may feel discomfort or pain when your blood is drawn.  You may 
feel dizzy or faint.  You may have a bruise, swelling, small clot, or infection where the needle 
goes into your hand or arm. 
 
Risks of Genital Exams: You may feel discomfort or pressure during the examination of your 
genital area and inside your vagina.  You may have a small amount of vaginal bleeding which 
will stop shortly after the examination. 
 
Risks of Study Rings 
The study rings can cause some side effects, such as an allergic reaction.  Signs of an allergic 
reaction include, but are not limited to: Rash or other skin irritation, itching, joint pain, or difficulty 
in breathing.  We do not yet know all the side effects of the rings.  Some, but not all women who 
used the rings in other studies have had: 
 
Discharge from the vagina 
 
Vaginal irritation and discomfort 
 
As with any product that is placed into the vagina, the possibility of toxic shock syndrome exists.  
Toxic shock syndrome is a serious but uncommon infection caused by bacteria.  While it is 
unlikely that you should experience toxic shock syndrome as a result of using the vaginal ring, it 
is important that you alert the study staff if you experience any symptoms associated with toxic 
shock syndrome, i.e., sudden high fever, a faint feeling, diarrhea, headache, a rash, and muscle 
aches.   
 

 
  
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Finally, it is also possible that you or your partner may feel the ring during sexual activity.  If you 
have any problems, study counselors will talk with you and/or your partner to try to help resolve 
them. 
 
Risks of Study Drugs 
Based on side effects reported among women in previous studies, dapivirine vaginal rings may 
be associated with:  
 
Vaginal bleeding at irregular intervals, particularly between your expected menstrual 
periods 
 
Vaginal or genital discharge 
 
Yeast infection  
 
Urinary tract infection 
 
Other Possible Risks 
If you become infected with HIV and continue to use the ring it is possible that you may develop 
HIV drug resistance.  This means that any virus that is drug resistant will survive and continue to 
reproduce (make copies of new HIV) in the presence of the drug that normally weakens or kills 
it.  HIV drug resistance could make it difficult to use dapivirine or drugs like it to treat the HIV.  
Drug resistance only occurs if you were to become infected with HIV and continue to use the 
study product. 
 
You may become embarrassed and/or worried when discussing your sexual practices, ways to 
protect against HIV and other infections passed through sex, and your test results.  You may be 
worried while waiting for your test results.  If you have HIV or other infections, learning this could 
make you worried.  Finding out your HIV status could also cause problems between you and 
your partner.  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.  However, it is possible that others may learn of your participation 
here and, because of this, may treat you unfairly or discriminate against you.  For example, you 
could have problems getting or keeping a job, or being accepted by your family or community.  If 
you have any problems, study counselors will talk with you and if you choose, your partner, to 
try to help resolve them. 
 
If you are chosen to participate in the group discussion, other participants will hear what you 
say.  We will not reveal your full name to other participants.  We will also ask every participant 
not to tell anyone outside of the group what any person said during the discussion.  While it is 
not at all likely that your discussion will be made public, we cannot guarantee that everyone will 
keep the discussion private. 

 
  
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BENEFITS 
 [SITES TO UPDATE: Participants in the MTN-025 (HOPE) trial will experience the direct 
benefit of using a vaginal ring that has been found to be safe and efficacious in preventing HIV 
transmission.] 
 
In addition, you will have physical examinations, pelvic examinations, and tests to check on the 
health of your blood, liver, and kidneys.  If these tests show that you might have health 
problems, you will be told where to get medical care and other services available to you.  
 
This study cannot provide you with general medical care, but study staff will refer you to other 
available sources of care.   
 
You will be counseled and tested for HIV and STIs.  You will be offered free condoms, if you 
need them.  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.  You 
will need to receive care for HIV infection from your own health care provider or we will provide 
you with a referral.  If you have an STI diagnosed, you will receive medicine or a referral, if 
needed.   
 
PREGNANCY AND BREASTFEEDING  
The dapivirine ring is not birth control.  You must agree to use an effective method of birth 
control such as an intrauterine contraceptive device (IUCD), birth control pills or other hormonal-
based method (except for vaginal rings), unless you underwent a medical procedure to 
permanently be unable to become pregnant, i.e., sterilization. 
 
We do not know if the dapivirine ring has any effect on pregnancy, on the fetuses of a women 
who use the vaginal ring while pregnant, or on the babies of women who use the ring while 
breastfeeding.  Because of this, pregnant and breastfeeding women may not join this study.  
You may be able to start using the vaginal ring after your pregnancy, provided that you are not 
breastfeeding.  The study staff will talk more with you about this after your pregnancy.  Women 
who join the study must agree to use effective contraception and have scheduled pregnancy 
tests while in the study.  
 
If you become pregnant during the study, study staff will refer you to available medical care and 
other services you or your baby may need.  The study does not pay for this care.  You will stop 
using the ring, but we may ask you to keep coming here for study visits as originally planned.  
We will change the study procedures as needed to protect your health while you are pregnant.  
[Sites to include/amend the following: We may also contact you to find out about the health of 
your pregnancy, and the health of your baby up to one year old, if you have a baby.  We may 
also contact you about a study that collects information about pregnancy and babies up to one 
year old.] The outcome of your pregnancy is important to study staff; therefore your pregnancy 
will be followed until the results of your pregnancy are known.  
 
NEW INFORMATION 
You will be told about new information from this or other studies that may affect your welfare or 
willingness to stay in this study.  It is important you know that the study product, the dapivirine 
ring, is among the most advanced HIV prevention products that can be offered to you [SITES 
TO INSERT MTN-020 DATA HERE].  In addition to being tested as part of the ASPIRE trial, the 

 
  
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ring was also tested in IPM 027. IPM 027 results will be provided to participants when they 
become available. In the future, vaginal rings containing more than one type of medicine may 
become available.  If a new product like this were to become available, it could be more 
protective than the ring tested as part of MTN-020 (ASPIRE) and IPM 027 (The Ring Study), 
leading to fewer HIV infections, however, no other vaginal ring has been found to work at this 
time. 
 
It is also important for you to know that other drugs are being tested for HIV prevention.  The 
HIV prevention researchers working on this MTN-025 (HOPE) are committed to sharing any 
data with you that becomes available, regardless of the product, if it is found to be effective in 
preventing the transmission of HIV.  You will also be told when study results may be available, 
and how to learn about them. 
 
WHY YOU MAY STOP TAKING THE STUDY DRUG EARLY OR BE WITHDRAWN FROM 
THE STUDY WITHOUT YOUR CONSENT 
A study doctor may need to remove you from the study early without your permission if: 
 
The study is cancelled by the US FDA, US NIH, International Partnership for 
Microbicides, the US Office for Human Research Protections (OHRP), MTN, the local 
government or regulatory agency, or the Institutional Review Board (IRB)/ the Ethics 
Committee (EC).  An IRB/EC is a committee that watches over the safety and rights of 
research participants 
 
The Study Monitoring Committee (SMC) recommends that the study be stopped early. 
(A SMC reviews the progress of the study and the kinds of effects that people report 
while they are participating in the study) 
 
You are not able to keep appointments 
 
Other reasons that may prevent you from completing the study successfully 
 
The study doctor will ask you to stop using the study vaginal ring but continue to come in for 
your follow-up visits and procedures if: 
 
You become pregnant  
 
You become infected with HIV 
 
A study doctor decides that using the vaginal ring would be harmful to you 
 
You require a treatment that you may not take while using the study vaginal ring 
 
You have a bad reaction to the study vaginal ring 
 
If a study doctor asks you to stop using the ring, you will need to come in for all scheduled visits 
described above, including for a physical examination, vital signs, and blood tests.  You will stop 
using study ring until the study doctor decides it is safe for you to start using it again, if possible. 
 
In the event that you are removed from or choose to leave this study, you will be asked to return 
your vaginal ring.  If you do not have the vaginal ring 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. 
[Sites to specify allowances for special circumstances.] 
 
ALTERNATIVES TO PARTICIPATION 
[Sites to include/amend the following:] There are no gels, tablets or vaginal rings currently 
available in this country to protect against HIV during sex.  Consistent use of condoms is the 
only available known way to protect against HIV during sex.  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 

 
  
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studies that we know about.  There also may be other places where you can go for HIV 
counseling and testing and contraception.  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 
vaginal ring, physical examinations, laboratory tests or other procedures.  Treatments available 
to you from the study site for infections passed through sex (other than HIV) will be given to you 
free of charge or you will be referred for available treatment for the duration of the study. 
 
REIMBURSEMENT 
[Sites to insert information about local reimbursement:] You will receive [Sites to insert amount 
$xx] for your time, effort, and travel to and from the clinic at each scheduled visit.  You may 
receive [Sites to insert amount $xx] for any visits which occur in between your normally 
scheduled visits.  
 
CONFIDENTIALITY 
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.  [Sites to insert information about systems currently in place to ensure participants are 
not part of other conflicting studies, including biometric identification systems.] 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 Office for 
Human Research Protections (OHRP), NIH, and/or contractors of NIH 
 
[Insert applicable local authorities, e.g., Ministry of Health, medicine control authority] 
 
IPM, the organization that supplies the study rings 
 
Study monitors 
 
Site Institutional Review Board (IRB)/ Ethics Committee (EC), an Ethics Committee is a 
committee that watches over the safety and rights of research participants  
 
Study staff 
 
[Sites to include/amend the following:][LOCAL/STATE/NATIONAL] regulations require study 
staff to report the names of people who test positive for HIV and other infections passed during 
sex to the [LOCAL HEALTH AUTHORITY].  Outreach workers from the [LOCAL HEALTH 
AUTHORITY] may then contact you about informing your partners, since they also should be 
tested.  If you do not want to inform your partners yourself, the outreach workers will contact 
them, according to the confidentiality guidelines of the [HEALTH AUTHORITY]. 
 
The researchers will do everything they can to protect your privacy.   
 

 
  
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RESEARCH-RELATED INJURY 
[Sites to modify with their site-specific research-related injury institutional policy:] It is unlikely 
that you will be injured as a result of study participation.  This US federally funded study does 
not have the ability to provide compensation for research-related injury.  If you are injured or 
become ill from taking part in this study, it is important to tell your study doctor.  Emergency 
treatment may be available but you or your insurance company will be charged for this 
treatment.  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 website 
will not include information that can identify you.  At most, the website will include a summary of 
the results.  You can search this website at any time. 
 
YOUR RIGHTS AS A RESEARCH PARTICIPANT/VOLUNTEER 
[Sites 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.  If you want the results of the study after the study is over, let 
the study staff members know. 
 
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]. 
 
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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SIGNATURES 
[Sites to insert signature/initial blocks as required by the local IRB/EC:] 
 [Sites to omit the following if a separate consent for Storage and Future Testing of Specimens 
is required] 
 
CONSENT FOR STORAGE AND FUTURE TESTING OF SPECIMENS  
There might be a small amount of blood, vaginal fluid and cervical fluid samples left over after 
we have done all of the study related testing after your study visits.  We would like to ask your 
permission to store your leftover blood, vaginal fluid, and cervical fluid samples, and related 
health information for use in future studies.  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 of 
these research facilities may be outside of your country.  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 blood, vaginal fluid and cervical fluid samples stored for future 
studies.  If you do not want the left-over blood, vaginal fluid and cervical fluid samples stored, 
we will destroy these left over specimens.  Any future studies that may be done will also have to 
be approved by an Ethics Committee/ Institutional Review Board.  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. 
 
_______________ 
 
 
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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CONSENT FOR OFF-SITE VISITS 
 [Sites to modify as needed] 
Members of the research team at this clinic may be able to schedule off site visits with you at 
your home or at another location as part of the study.  If needed, and, if you agree, some of the 
scheduled study visits and some of the study procedures may take place at your home or other 
location outside of the research clinic, if you are unable to come into the clinic.  If, for example, 
you need to receive a new ring or to have a urine or blood sample collected, study staff could 
come to you your home or meet you at another location, if you give your permission and if the 
study staff determine that it is appropriate.  The study personnel will explain in greater detail the 
requirements of these visits (like the conditions of the place, the type of visit and the time it will 
take) and the procedures in-place to maintain your information in a confidential manner.  
However it is important that you know that off-site visits may eventually affect your 
confidentiality even if the study staff take precautions not to disclose the purpose of the visits. 
 
In order to conduct visits outside of the clinic, we will need you to give us permission to do so.  
Please read carefully the following statement and initial and date one option.  Choosing not to 
be visited outside of the study clinic will not affect your participation in this study.  Even if you 
agree today, you can withdraw your consent for off-site visits at any time by providing your 
request in writing to the person in charge of this study.  In addition, before each off-site visit, we 
will confirm with you that you still agree and remember today’s discussion.  
 
___________        
I DO agree to be visited at a location other than the study clinic by clinic 
staff, when necessary 
Initials and Date 
 
___________        
I DO NOT agree to be visited at a location other than the study clinic by 
clinic staff, when necessary 
Initials and Date 
 
 
 

 
  
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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 participate in this 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 
 
Witness Signature 
 
Date 
(print) 
 
 
 

 
  
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APPENDIX VI: SAMPLE INFORMED CONSENT DOCUMENT  
(MTN-025 DECLINER POPULATION) 
MTN-025 
 
SAMPLE INFORMED CONSENT FORM-  
Screening and Enrollment MTN-025 Decliner Population 
 
DIVISION OF AIDS, NIAID, NIH, NIMH, NICHD 
 
A Phase 3B Open-Label Follow-on Trial to Assess the Continued Safety of and 
Adherence to a Vaginal Ring Containing Dapivirine in Women 
 
Version 2.0 
December 16, 2014 
 
PRINCIPAL INVESTIGATOR:  
PHONE:  
 
INFORMED CONSENT 
You are being asked to take part in this research study because you are a woman who took part 
in the MTN-020 (ASPIRE) trial and have decided to delay, decline to take part in the MTN-025 
(HOPE) trial.  Other women like you will participate in this study across multiple sites.  Before 
you decide if you want to join this study, we want you to know about the study.  This 
Screening/Enrollment consent form gives you information about this study.  MTN-025 (HOPE) 
staff will talk with you about the study and answer any questions you may have.   
 
This Microbicide Trials Network (MTN) study is funded by the US National Institutes of Health 
(NIH) and is being conducted across multiple countries across Africa.  A total of 2629 women 
enrolled into MTN-020: ASPIRE and all former participants who are eligible may take part in the 
MTN-025 or in the MTN-025: Decliner Population. 
 
YOUR PARTICIPATION IS VOLUNTARY 
Participation in this study is voluntary.  You will be asked to sign or make your mark on this form 
to indicate whether you agree to participate in this study.  Before you decide whether to be in 
MTN-025 Decliner Population, we would like to explain the purpose of the study.  If you decide 
to enroll in this study, you may decide to withdraw from the study at any time.  There will be no 
penalty for refusing to participate or choosing to withdraw from this study. 
 
It is important that you know that if you change your mind and wish to take part in the MTN-025 
trial, you can enroll, provided that the study is ongoing and that you are eligible. 
 
PURPOSE OF THE DECLINER POPULATION 
The main goal of the Decliner Population is to better understand MTN-020 (ASPIRE) 
participants’ reasons for refusal to take part in the MTN-025 (HOPE) trial.  MTN-025, is a study 
that provides former ASPIRE participants with access to the dapivirine vaginal ring, a product 
that has been shown to reduce the chances of women from getting the HIV virus by [To be 
updated: X to X percent].  The study also learned that the dapivirine vaginal ring is [To be 

 
  
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updated: safe (meaning that it does not produce significant health problems in persons who take 
it)]. 
 
STUDY PROCEDURES 
It is expected that the procedures involved with the MTN-025 Decliner Population will be 
completed in one visit.  If you agree to join this study, you will be asked to answer questions 
about your behavior(s) and you also may be asked to complete an in-depth interview (IDI) in the 
presence of one or two MTN-025 (HOPE) research staff members.  If you agree to take part in 
this study, the interviewer will ask you some brief questions and write your responses on a form. 
Multiple visits may be needed to complete the IDI and questionnaire(s).  During the IDI, the 
interviewer will also ask in-depth questions, during which time notes may be taken and the 
conversation will be audio-recorded.  
 
You will be asked some general questions, such as your age, education, living situation, 
relationship status and health.  You will also be asked about other clinical trials or HIV-related 
studies that you may be currently participating in.  The interviewer will also ask questions about 
your experiences while participating in the ASPIRE trial.  These will include questions about 
different ways women used their study product, their sexual practices, as well as your use of the 
study product and your sexual practices. 
 
We expect the interview will take approximately 2 hours.  The IDI it will be completed at a place 
agreed upon by you and the study staff, which may be your home, a designated neutral study 
interview location, the clinic you went to for your ASPIRE visits or another convenient place of 
your choice.  
 
The audio recording, notes, and analyses from these materials will be kept confidential and will 
only use study numbers or fake names.  The information that links you to the research data will 
be kept in a secure location that will be accessed only by members of the HOPE study team for 
the purposes of this research. 
 
To obtain information about your participation in ASPIRE, the HOPE study team may need to 
access your ASPIRE research records.  By signing this form, you are giving the HOPE study 
team permission to look up and record the needed information from your research record. 
 
RISKS AND/OR DISCOMFORTS 
During the interview we may ask you some questions that cause you to feel embarrassed or 
uncomfortable.  You can choose not to answer questions in the interview at any time.  It is also 
possible that people or family members may find out you are participating in this study.  As a 
result, they may ask questions about the study, treat you unfairly, or you may encounter 
problems in being accepted by your family and/or community.   
 
Another possible risk of this study is loss of confidentiality of the information you give.  Every 
effort will be made to protect your confidential information, but this cannot be guaranteed.  To 
reduce this risk, we will strictly protect the information recorded during your interview.  The 
audio recording, notes, and analyses from these materials will be kept confidential.  This means 
that no one other than the HOPE interview team will have access to your responses.  The 
information that links you to the research materials will be kept in a secure location.  Your audio 
recordings will also be kept in a secure location and only people involved with the study will 
have access to these recordings.  When the information on the audio recording is typed onto 

 
  
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paper and fully checked, the recording will be destroyed.  Study leaders will make sure this 
happens. 
 
NEW INFORMATION 
You will be told about new information from this or other studies that may affect your welfare or 
willingness to stay in this study. 
 
BENEFITS 
There are no direct benefits to participating in this study.  However, the information you provide 
may help researchers improve the design of future studies. 
 
REASONS WHY YOU MAY BE WITHDRAWN FROM THE SUBSTUDY WITHOUT YOUR 
CONSENT 
You may be removed from this study without your consent for the following reasons: 
 
The study is stopped or canceled 
 
The study staff feels that staying in the study would be harmful to you 
 
The study is stopped by NIH, the MTN, International Partnership for Microbicides (IPM), 
the Office for Human Research Protections (OHRP), other government or regulatory 
authorities, or site IRBs/ECs 
 
Other administrative reasons 
 
ALTERNATIVES TO PARTICIPATION 
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 we know about.  
 
COSTS TO YOU 
There is no cost to you for being in this study.  
 
REIMBURSEMENT 
[Sites to modify/insert text as necessary for planned local reimbursement:] 
You will receive [$xx] for your time, effort, and travel.  
 
CONFIDENTIALITY 
We will do our best to make sure that the personal information gathered for this study is kept 
private.  However, absolute confidentiality cannot be guaranteed.  Your personal information 
may be disclosed if required by law.  Any publication of this study will not use your name or 
identify you personally. 
 
This Microbicide Trials Network (MTN) study is funded by the US NIH. 
 
Your records may be reviewed by any or all of the following: 
 
 
The MTN-025 study staff 
 
[insert applicable local authorities, e.g., Ministry of Health, medicine control authority] 
 
Site IRBs/ECs 
 
IPM 
 
Representatives of the US Federal Government, including the US FDA, US Office for 
Human Research Protections (OHRP), NIH, and/or contractors of NIH 
 

 
  
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PROBLEMS OR QUESTIONS 
If you ever have any questions about this study, you should contact [insert name of the 
investigator or other study staff] at [insert telephone number and/or physical address].  
 
If you have questions about your rights as a research participant, you should contact [insert 
name or title of person on the IRB/EC or other organization appropriate for the site] at [insert 
telephone number and/or physical address of above]. 
 
If you have questions about whom to contact at the research site, you should contact [insert 
name of the investigator or community educator or community advisory board (CAB) member 
[staff will decide which] at [insert telephone number and/or physical address]. 
 
[Sites to modify with their site-specific research-related injury based upon their 
institutional policy:  
RESEARCH-RELATED INJURY 
It is unlikely that you will be injured as a result of taking part in the MTN-025 Decliner 
Population.  This US federally funded study does not have the ability to provide compensation 
for research-related injury.  If you are injured or become ill from taking part in this study, it is 
important to tell your study doctor.  Emergency treatment may be available but you or your 
insurance company will be charged for this treatment.  You do not give up any legal rights by 
signing this consent form. ] 
 
SIGNATURES 
[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 voluntarily agree to 
participate in the study, please sign your name or make your mark below.  
 
____________________ ________________________ ______________ 
Participant Name  
 
Participant Signature  
Date 
(print)  
 
 
or Mark 
 
 
____________________ ________________________ ______________ 
Study Staff Conducting  
Study Staff Signature  
Date 
Consent Discussion (print) 
 
 
____________________ ________________________ ______________ 
Witness Name  
 
Witness Signature 
 
Date 
 
 
 
 

 
  
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December 16, 2014 
 
 
 
Reference List 
 
 1.  UNAIDS, Joint United Nations Programme on HIV/AIDS.  UNAIDS Report on the Global 
AIDS Epidemic 2013. 
http://www.unaids.org/en/media/unaids/contentassets/documents/epidemiology/2013/gr20
13/UNAIDS_Global_Report_2013_en.pdf accessed 30 May 2014.  
 2.  Fletcher P, Harman S, Azijn H, et al. Inhibition of human immunodeficiency virus type 1 
infection by the candidate microbicide dapivirine, a nonnucleoside reverse transcriptase 
inhibitor. Antimicrob Agents Chemother 2009;53:487-95.   
 3.  Nel A, Coplan P, Smythe S, McCord K, Mitchnick M, Kaptur P, Romano J. 
Pharmacokinetic Assessment of Dapivirine Vaginal Microbicide Gel in Healthy, HIV-
Negative Women. AIDS Research and Human Retroviruses 2010; 26(11).    
 4.  Anderson RM, Swinton J, Garnett GP. Potential impact of low efficacy HIV-1 vaccines in 
populations with high rates of infection. Proc Biol Sci 1995;261:147-51.   
 5.  IPM. Investigator's Brochure: Dapivirine Vaginal Ring. 3 December 2014.   
 6.  Nel A, Smythe S, Young K, Malcolm K, Rosenberg Z, Romano J. Safety and 
Pharmacokinetic Assessment of 28 Day Anti-HIV Dapivirine Intravaginal Microbicide Rings 
In: CROI. Boston; 2008.   
 7.  Nuttall J, Hettema W, van Niekerk N, Nel A.  Pharmacokinetics of Monthly Dapivirine 
Vaginal Microbicide Rings (Ring-004) for HIV Prevention.  In: Microbicides 2012. Sydney; 
2012.   
 8.  Nel A, Haazen W, Nuttall J, Romano J, Rosenberg Z, Van Niekerk N.  A safety and 
pharmacokinetic trial assessing delivery of dapivirine from a vaginal ring in healthy 
women. AIDS 2014, 28:1479-1487.   
 
 9.  Di Fabio S, Van Roey J, Giannini G, et al. Inhibition of vaginal transmission of HIV-1 in hu-
SCID mice by the non-nucleoside reverse transcriptase inhibitor TMC120 in a gel 
formulation. Aids 2003;17:1597-604.   
 10.  Romano J, Variano B, Coplan P, et al. Safety and availability of dapivirine (TMC120) 
delivered from an intravaginal ring. AIDS Res Hum Retroviruses 2009;25:483-8.   
 11.  Nel A, Kamupira M, Woodsong C, van der Straten A, Monthomery E, van Niekerk N, 
Nuttall J. Safety, Acceptability and Pharmacokinetic Assessment (Adherence) of Monthly 
Dapivirine Vaginal Microbicide Rings (Ring-004) for HIV preventionIn: Microbicides 2012. 
Syndey; 2012.   
 12.  van der Straten A, Montgomery ET, Cheng H, Wegner L, Masenga G, von Mollendorf C, 
Bekker L, Ganesh S, Young K, Romano J, Nel A, Woodsong C, High Acceptability of a 
Vaginal Ring Intended as a Microbicide Delivery Method for HIV Prevention in African 
Women, AIDS and Behavior, 16 (7), pp. 1775-1786, October 2012.   

 
  
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December 16, 2014 
 
 13.  Hunt GM, Ledwaba J, Basson AE et al. Surveillance of Transmitted HIV-1 Drug 
Resistance in Gauteng and KwaZulu-Natal Provinces, South Africa, 2005Çô2009. 
Clinical Infectious Diseases 2012;54(suppl 4):S334-S338. 
 14.  Parikh UM,Kiepiela P,Ganesh S,Gomez K,Horn S,Eskay K,Kelly C,Mensch B,Gorbach 
P,Soto-Torres L,Ramjee G,Prevalence of HIV-1 Drug Resistance among Women 
Screening for HIV Prevention Trials in KwaZulu-Natal,South Africa (MTN-009); PLoS 
One.2013 Apr 9;8(4):e59787.doi: 10.1371/journal.pone.0059787.Print 2013.   
 15.  Stanford University HIV Drug Resistance Database. http://hivdb.stanford.edu/ accessed 13 
June 2014.  
 16.  Nel A, Young K, Romano J, Woodsong C, Montgomery E, Masenga G, Rees H, Bekker 
LG, Ganesh S. Safety & acceptability of silicone elastomer vaginal rings as potential 
microbicide delivery method in african women. In: CROI 2011. Boston Feb 27-Mar 2, 
2011.   
 17.  Workowski KA, Berman SM, Centers for Disease Control and Prevention (CDC). Sexually 
transmitted diseases treatment guidelines, 2010. Department of Health and Human 
Services, Centers for Disease Control and Prevention; 2010. 
 18.  Weller S, Davis K. Condom effectiveness in reducing heterosexual HIV transmission. 
Cochrane Database Syst Rev 2002;1. 
 19.  Holmes KK, Levine R, Weaver M. Effectiveness of condoms in preventing sexually 
transmitted infections. Bulletin of the World Health Organization 2004;82(6):454-461. 
 
 
 

MTN-025 Summary of Changes  
 
 
December 16, 2014 
From Version 1.0 to Version 2.0 
1 
SUMMARY OF CHANGES 
INCLUDED IN THE FULL PROTOCOL AMENDMENT OF: 
 
MTN-025 
 
DAIDS Protocol #: 11985 
 
A Phase 3B Open-Label Follow-on Trial to Assess the Continued Safety of and Adherence to 
a Vaginal Ring Containing Dapivirine in Women  
 
THE AMENDED PROTOCOL IS IDENTIFIED AS: 
Version 2.0/ 16 December 2014 
 
 
Information/Instructions to Study Sites 
 
The information contained in this protocol amendment impacts the MTN-025 study and must be 
forwarded to your Institutional Review Board (IRB)/Ethics Committee (EC) as soon as possible for 
their information and review. IRB approval is required before implementation of the modifications 
contained in this amendment. All IRB requirements must be followed. 
 
Please file this Summary of Changes, Version 1.1 of the protocol and all associated IRB 
correspondence in your essential documents files for MTN-025. 
 
 
Summary of Revisions 
 
To ease in the review process, all revisions are displayed below. A summary of revisions is 
provided below: 
 
1. 
The Protocol Team Roster has been updated. 
2. 
In the Protocol Summary, updates were made to remove the randomization from the 
Study Design, to allow for an extension to follow-up, and to modify the visit schedule 
accordingly.  
3. 
In Section 2, INTRODUCTION, background information is updated to incorporate 
updated information contained within the IB and to omit product-specific language or 
reference to ongoing MTN trials. Study Design is updated to remove the 
randomization. 
4. 
In Section 3, STUDY OBJECTIVES, edits are made: to study objectives to prevent 
redundancy in data collection and analysis across protocols, and to coincide with the 
removal of randomization and the modified visit schedule. 
5. 
In Section 4, STUDY DESIGN, minor edits are made: for clarity and consistency with 
the modified study objectives, removal of randomization and modified visit schedule. 
6. 
In Section 5, STUDY POPULATION, eligibility criteria are clarified and the 
randomization language is removed. 
7. 
In Section 6, STUDY PRODUCT, edits are made: for consistency with the removal of 
randomization and the modified visit schedule. 
8. 
In Section 7, STUDY PROCEDURES, edits are made: for consistency with the 
removal of randomization and the modified visit schedule.  

MTN-025 Summary of Changes  
 
 
December 16, 2014 
From Version 1.0 to Version 2.0 
2 
9. 
In Section 8, ASSESSMENT OF SAFETY, minor edits are made: for clarity and 
consistency with current policy and with the removal of randomization. 
10. 
Section 10, STATISTICAL CONSIDERATIONS, language is modified to reflect the 
revised study objectives and endpoints, power estimates, oversight of the Interim 
Study Review (ISR) Committee, and planned data analysis resulting from the 
removal of randomization and from the modified visit schedule. Figure 2 was deleted. 
11. 
Section 13, HUMAN SUBJECTS PROTECTION, is updated to reflect the current 
DAIDS Protocol Registration template language, the removal of randomization and 
the new risk language based upon the updated Dapivirine Vaginal Ring Investigator’s 
Brochure. 
12. 
Appendix I: Schedule of Study Visits is edited for clarity and consistency with the 
modified study procedures, removal of randomization and modified visit schedule. 
13. 
The sample informed consent documents have been updated to reflect modified 
study procedures, removal of randomization, and modified visit schedule, and to 
facilitate participant understanding of the study. NEW INFORMATION is edited to 
say IPM 027 results will be provided when available, and RISK AND/OR 
DISCOMFORTS has been updated. 
14. 
Other minor updates, corrections, and clarifications are incorporated  
 
 
Rationale  
MTN-025/IPM 030 will characterize the safety profile associated with the open label use of the 
dapivirine vaginal matrix ring (25 mg) as well as characterize adherence to the dapivirine vaginal 
matrix ring in women who replace the dapivirine vaginal ring monthly.  After attending monthly clinic 
visits until Month 3 of follow-up omen will maintain a quarterly visit schedule.  The primary purpose 
of this Full Version Modification is to streamline the study design by removing the randomization of 
participants to a monthly vs. quarterly follow-up.   
 
 
Implementation 
 
This amendment is now official MTN-025 protocol documentation. Prior to implementing the 
revisions listed below, MTN-025 study sites will submit this Summary of Changes and protocol 
Version 1.1 to all relevant regulatory entities and IRBs/ECs. Upon receipt of all regulatory and IRB 
approvals and completion of protocol registration procedures, the protocol modifications listed 
below will be implemented. With exceptions to modifications to the Protocol Team Roster and 
updates to the Background Section 2.4.1 and Appendix I, detailed modifications of the protocol text 
are indicated by strikethrough (for deletions) and bold (for additions). Unless otherwise stated, 
section numbers reflect the current version of the protocol. 
 
 
Detailed Listing of Revisions New to Version 2.0 
 
1. 
Protocol Team Roster, the following individual was removed: Jackson, Arbee. 
 
2. 
Protocol Team Roster, the following individuals were added: 

MTN-025 Summary of Changes  
 
 
December 16, 2014 
From Version 1.0 to Version 2.0 
3 
Zakir Gaffoor, M Med Sci  
Site Investigator of Record 
MRC- HIV Prevention Research Unit 
P.O. Box 70380 
Overport 4067  
KwaZulu-Natal, South Africa 
Phone: +27 31 242 3600 
Fax: +27 31 242 3800 
Email: Zakir.gaffoor@mrc.ac.za  
Nitesha Jeenarain, BPharm 
Site Investigator of Record 
MRC- HIV Prevention Research Unit 
P.O. Box 70380 
Overport 4067  
KwaZulu-Natal, South Africa 
Phone: +27 31 242 3600 
Fax: +27 31 242 3800 
Email: nitesha.jeenarain@mrc.ac.za  
 
Logashvari Naidoo, MBChB 
Site Investigator of Record 
MRC- HIV Prevention Research Unit 
P.O. Box 70380 
Overport 4067  
KwaZulu-Natal, South Africa 
Phone: +27 31 242 3600 
Fax: +27 31 242 3800 
Email: Logashvari.Naidoo@mrc.ac.za 
Vaneshree Govender, MBBCh 
Site Investigator of Record 
MRC- HIV Prevention Research Unit 
P.O. Box 70380 
Overport 4067  
KwaZulu-Natal, South Africa 
Phone: +27 31 242 3600 
Fax: +27 31 242 3800 
Email:vaneshree.govender@mrc.ac.za 
Arendevi Pather, BPharm 
Site Investigator of Record 
MRC- HIV Prevention Research Unit 
P.O. Box 70380 
Overport 4067  
KwaZulu-Natal, South Africa 
Phone: +27 31 242 3600 
Fax: +27 31 242 3800 
Email: arendevi.pather@mrc.ac.za 
 
Samantha Siva, MMed Sci 
Site Investigator of Record 
MRC- HIV Prevention Research Unit 
P.O. Box 70380 
Overport 4067  
KwaZulu-Natal, South Africa 
Phone: +27 31 242 3600 
Fax: +27 31 242 3800 
Email: samantha.siva@mrc.ac.za 
 
3. 
Protocol Team Roster, Malawi CRS was renamed Lilongwe CRS: 
 
MalawiLilongwe CRS 
 
4. 
In Section 1, PROTOCOL SUMMARY, edits are made: to clarify that the Decliner Population: 
Former MTN-020 participants who decline participation in the main MTN-025 study must 
meet eligibility criteria: 
 
Decliner GroupPopulation: Former MTN-020 participants who decline participation in the 
main MTN-025 study and meet eligibility criteria as described in Sections 5.4 and 5.5 
 
Section 1, PROTOCOL SUMMARY, Study Design: Randomization information was 
removed: 
Phase 
3B, 
open-label, 
multi-site, 
randomized 
trial 
Following demonstration of safety and efficacy of the dapivirine vaginal ring in MTN-020, 
eligible MTN-020 participants will be offered enrollment into MTN-025, a trial designed to 
obtain additional safety and adherence data in women randomized to monthly vs. quarterly 
follow-up.. 
 
5. 
Section 1, PROTOCOL SUMMARY, Study Design:  Text added about the potential extension 
of follow-up:  
 

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From Version 1.0 to Version 2.0 
4 
Follow-up may be extended beyond 13 months based on need and requirements and 
with the necessary approvals.  
 
6. 
Section 1, PROTOCOL SUMMARY, Study Regimen, randomization information was 
removed: 
 
MTN-025 participants are to be randomized to one of two types of follow-up: 
Monthly 
Quarterly 
 
7. 
Section 1, PROTOCOL SUMMARY, Study Regimen, text added about extension of follow-
up: 
 
The study follow-up schedule will be monthly for the first three months, then quarterly 
thereafter (Figure 1), reflecting a transition to a more real-world type of follow-up 
(versus a clinical trial approach) that would be important for informing 
implementation. 
 
8. 
Section 1, PROTOCOL SUMMARY, Figure 1: Study Schedule has been updated as follows:  
 
 
9. 
In Section 1, Primary Objectives, 1 and 2 were updated to reflect the lack of randomization:  
 
1. To characterize the safety profile associated with the open label use of the dapivirine 
vaginal matrix ring (25 mg) in women, and to assess safety when randomized to a monthly 
vs. quarterly follow-up schedule 
 
 
2. To characterize adherence to the open label use of the dapivirine vaginal matrix ring (25 
mg) in women and to compare adherence when randomized to a monthly vs. quarterly follow-
up schedule 
 
10. 
In Section 1, Exploratory Objectives, follow-up schedule is adjusted: 
 
To assess the feasibility of a one-month vs. three-monthquarterly follow-up visit schedule 
 
11. 
In Section 1, Exploratory Endpoints, edits are made for clarity and in fidelity with changes 
mentioned elsewhere: 
 
­ Feasibility of one month vs. three month follow-up: 
­ Visit retention by arms 
­ Proportion of returned rings (used and unused) by arms 
 
Screening 
Monthly 
Visit 
(Month 1) 
Monthly 
Visit 
(Month 2) 
Monthly 
Visit 
(Month 3) 
Quarterly 
Visit 
(Month 6) 
Quarterly 
Visit 
(Month 9) 
Study + 
-
Exit/Termin-
ation Visit 
(Month 13) 

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From Version 1.0 to Version 2.0 
5 
12. 
In Section 2.1, Microbicides and Human Immunodeficiency Virus (HIV) Prevention, reference 
to MTN-020 data was removed: 
 
The MTN-025 protocol will be updated with MTN-020 safety and efficacy data, once 
available. 
 
13. 
In Section 2.1, Microbicides and Human Immunodeficiency Virus (HIV) Prevention, edits are 
made for clarity: 
 
For a microbicide to be most effective, it is essential that it is used correctly and consistently, 
and importantly, is acceptable to the user. 
  
14. 
In Section 2.3.2, Condom Compatibility Studies of Dapivirine, information regarding the 
condom functionality studies was added. 
 
Two clinical condom functionality studies (one with male condoms [IPM 029] and one 
with female condoms [IPM 033]) were conducted with a placebo vaginal ring (silicone 
elastomer ring containing no active ingredient). Results from both studies showed that 
the difference between the total clinical failure rate between condom use with the 
vaginal ring and condom use without the vaginal ring was less than the pre-defined 
non-inferiority margins (3% for the male condom study and 8% for the female condom 
study). Condom use was safe and well tolerated with vaginal ring use. 
 
15. 
Section 2.4.1, Clinical Studies of Dapivirine Vaginal Rings, data has been updated 
throughout to reflect the new Investigator’s Brochure 
 
16. 
In Section 2.4.1, Clinical Studies of Dapivirine Vaginal Rings, reference to other ongoing 
MTN trials was removed:  
 
Efficacy and safety results from MTN-020 and IPM 027 and other ongoing (as of Q1 2014) 
clinical trials, including the adolescent trial (MTN-023/IPM 030) and the post-menopausal trial 
(MTN-024/IPM 031) will be made available to MTN-025 participants. 
 
17. 
In Section 2.7.1, Study Design, edits are made and comments are added.  
 
MTN-025 will contribute to this evidence base by describing the safety outcomes with a 
quarterly monitoring schedule for women using an ARV-based  HIV prevention  intervention.  
Safety data will be forwarded to regulatory entities 
 
The primary focus of MTN-025 is the collection of additional adherence and safety data, 
including the examination of multiple approaches to follow-up and safety monitoring 
(monthly vs. quarterly).  Further further, MTN-025 will examine incidence of HIV-1 infection 
and explore the way in which peopleparticipants adopt this biomedical prevention method 
and incorporate it into the context of their everyday lives. 
 
MTN-025 will contribute to this evidence base by describing the safety outcomes associated 
with both monthly anda quarterly monitoring schedules for women using an ARV for-based  
HIV prevention  intervention. 
 
18. 
In Section 3.1, Primary Objectives, updates to ensure consistency with Section 1.0:  
 

MTN-025 Summary of Changes  
 
 
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From Version 1.0 to Version 2.0 
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1.) To characterize the safety profile associated with the open label use of the dapivirine 
vaginal matrix ring (25 mg) in women, and to assess safety when randomized to a monthly 
vs. quarterly follow-up schedule 
 
2.) To characterize adherence to the open label use of the dapivirine vaginal matrix ring (25 
mg) in women and to compare adherence when randomized to a monthly vs. quarterly follow-
up schedule 
 
19. 
In Section 3.3, Exploratory Objectives, edits are made modifying follow-up schedule: 
 
To assess the feasibility of a one-month vs three-monthquarterly follow-up visit schedule 
 
20. 
In Section 4.1, Identification of Study Design, edits are made including: 
 
The study will assess the safety of and participant adherence to a silicone elastomer vaginal 
matrix ring containing 25 mg of dapivirine. 
 
The MTN-025 trial, HOPE, is a multi-site, open-label, randomized, Phase 3B trial that will be 
implemented if the dapivirine VR is found to be a safe and an effective HIV prevention 
method in the MTN-020 trial.  Eligible former MTN-020 HIV-uninfected participants will be 
randomized to either aattend monthly or astudy visits until the third month of follow-up 
and then quarterly follow-up schedule.visits thereafter.  The study will compareassess the 
safety of and participant adherence to dapivirine (25 mg) in a silicone elastomer vaginal 
matrix ring between the two follow-up schedulescontaining 25 mg of dapivirine. 
 
21. 
In Section 4.3, Description of Study Population, the Decliner Population name has been 
updated:  
 
Decliner GroupPopulation: Former MTN-020 participants who decline participation in the 
main MTN-025 study and meet eligibility criteria as described in Sections 5.4 and 5.5 
 
22. 
Version 1.0, Section 4.5, Study Groups, was removed: 
 
4.5 Study Groups 
Study arms include monthly and quarterly follow-up arms as defined in Table 4 
Table 4: Study Regimen 
 
 
23. 
In Section 4.6, Expected Duration of Participation, edits are made:: 
 
The majority of former ASPIRE participants will complete approximately 13 months of follow-
up, see Section 10.4 for additional details. Follow-up may be extended beyond 13 months 
based on need and requirements and with the necessary approvals. 
Visits may be completed within specified windows around target dates.  Detailed information 
regarding visit windows will be described in the MTN-025 Study Specific Procedures (SSP) 
Manual. 
 
A 
MeRU:lly 
6 

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From Version 1.0 to Version 2.0 
7 
24. 
In Section 5.1, Selection of the Study Population, one edit is made: 
 
Decliner GroupPopulation: Former MTN-020 participants who decline participation in the 
main MTN-025 study, and who meet inclusion and exclusion criteria in Sections 5.4 and 5.5, 
will be invited to complete behavioral assessment(s). 
 
25. 
In Section 5.1.2, Retention, edit is made removing randomization language: 
 
Once a participant is enrolled/randomized into the HOPE trial, the study site will make every 
effort to retain the participants in follow-up to minimize possible bias associated with loss-to-
follow-up. 
 
26. 
In Section 5.3, Exclusion Criteria, edit is made removing randomization language: 
 
Note:  PEP use at Screening is not exclusionary.  Participants may be enrolled/randomized 
after the PEP regimen is complete and a negative HIV test is documented within 56 days of 
providing informed consent for Screening. 
 
27. 
In Section 5.3, Exclusion Criteria, edit is made allowing for possibility of MTN-025 full 
participation for decliners: 
 
Note: Participation in the ‘Decliner Population’ does not preclude MTN-025 full study 
participation. 
 
28. 
In Section 5.3, Exclusion Criteria, an edit is made removing randomization language: 
 
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.  
 
29. 
In Section 5.4, Inclusion Criteria,  MTN-025 Decliner Population Only, edits are made: 
 
MTN-025 Decliner GroupPopulation participants must meet all of the following criteria to be 
eligible for inclusion in the study: 
 
4) Able and willing to perform the Decliner GroupPopulation study procedures 
 
30. 
In Section 5.5, Exclusion Criteria,  MTN-025 Decliner Population Only, edits are made: 
 
MTN-025 Decliner GroupPopulation participants who meet the following criteria will be 
excluded from the study: 
 
31. 
In Section 6.1, Regimen, comments are added 
 
All participants will receive a vaginal ring containing 25 mg of dapivirine to be worn monthly.  
One new ring will be inserted each month.  Participants will be randomized to eitherattend 
monthly orclinic visits until month three and then will present to the clinic at quarterly 
follow-upvisits thereafter. Participants are able to visit the clinic for any reason in 
between the scheduled visits. 
 

MTN-025 Summary of Changes  
 
 
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From Version 1.0 to Version 2.0 
8 
32. 
In Section 6.3.1, Dapivirine VR, comments are added: 
 
The dapivirine VR optimally should be stored in the site pharmacy at 20°C to 25°C, with 
allowable excursions between 15°C to 30°C. 
 
33. 
In Section 6.4.2, Study Product Dispensing, second, third and fourth paragraphs were edited:  
 
Participants randomized toDuring each of the monthly follow-upclinic visits participants 
will receive a new ring at each visit.  If the participant is unable to attend her next scheduled 
visit it is up to the discretion of the IoR to provide an additional ring(s).  All such 
circumstances must be documented fully by the IoR/designee as described in the MTN-025 
SSP Manual. 
 
Participants randomized to When participants enter the quarterly follow-up visitsphase, 
they will be dispensed three rings at each study visit or be given the option of returning to 
the site pharmacy or the clinic (based on site dispensing capacity) each month to obtain a 
new vaginal ring each month. (e.g., if they do not feel comfortable having a supply of two 
additional unused rings at home).  Participant’s preference regarding product dispensation 
and their choice will be documented. 
 
The pharmacist will only dispense one ring per month or up to three rings per quarter 
depending on the participant’s regimen.  If a participant requires an additional ring for any 
reason, at a time other than when she is scheduled to receive one, she willadditional 
product may be required to attenddispensed at the clinic for an interim visitdiscretion of 
the IoR. 
 
34. 
In Section 6.7, Condoms, edits are made to the first and last sentences:  
 
All participants will be offered male condoms.[…] Study staff may also offer guidance on the 
use of the female condoms upon participant request, see MTN-025 SSP for additional 
details. 
 
35. 
In Section 7, Study Procedures, edits are made and comment is added to the last sentence: 
 
Detailed instructions to guide and standardize procedures across sites (, including the 
conduct of off-site study visits) and the follow-up schedule for participants who enroll 
after the prime accrual period are provided in the MTN-025 Study Specific Procedures 
(SSP) Manual available at http://www.mtnstopshiv.org/studies. 
 
36. 
In Section 7.3, Table 7, Enrollment Visit, one procedure has been removed:  
 
Randomization 
 
37. 
In Section 7.4.1, Table 8, Follow-up Visits: Months 1 and 2 headings have been updated as 
follows: 
 
Months 1, and 2, 4, 5, 7, 8, 10, 11 
 
38. 
In Section 7.4.2, Quarterly Visits, edits are made:  
 

MTN-025 Summary of Changes  
 
 
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From Version 1.0 to Version 2.0 
9 
Procedures listed below will occur at quarterly visits (i.e., Months 3, 6, 9 Participants in 
both study arms will undergo), until the following procedures quarterlyProduct Use End 
Visit. 
 
39. 
In Section 7.4.2, Quarterly Visits, Table 9 has been updated with ‘Quarterly Visits’. 
 
40. 
In Section 7.4.2, Quarterly Visits, Table 9 has been updated to require that the following 
procedures only be performed if indicated: Physical examination, NAAT for GC/CT, and rapid 
test for Trichomonas 
 
41. 
In Section 7.4.3 Product Use End Visit (PUEV) edits are made:  
 
Participants in both study arms will undergo the following procedures at Month 12the 
Product Use End Visit. 
 
42. 
Throughout Section 7.0 the collection of plasma has now been specified to be collected for 
dapivirine drug level testing and for archive.  
 
43. 
In Section 7.5, MTN-025 Decliner Population, Screening and Enrollment Procedures edits 
are made to maintain consistency with the rest of the protocol. 
 
44. 
In Section 7.6.1, Participants Who Become Infected with HIV, the SSP has been specified: 
 
Please reference the MTN-025 SSP for additional details 
(http://www.mtnstopshiv.org/studies). 
 
45. 
In Section 7.6.2, Participants Who Become Pregnant, the SSP has been specified: 
 
See MTN-025 SSP Manual for additional guidance. 
 
46. 
In Section 7.8, MTN-025 Decliner Population, edits are made: 
 
MTN-025 Decliner GroupPopulation 
Former ASPIRE participants who decline or express no interest in joining the MTN-025 trial 
either prior to screening or prior to enrollment, will be invited to complete behavioral 
assessment(s), which may include IDI(s) to explore reasons for disinterest, individuals who 
are found eligible and who take part are referred to as the MTN-025 Decliner 
Population. 
 
47. 
In Section 7.12, HIV Infection (Secondary Endpoint) Determination, edits are made: 
 
First paragraph- 
 
Prior to study initiation, all sites will have validated this algorithm in accordance with the 
policies described in the MTN Manual of OperationsOperational Procedures (MOP) 
(http://www.mtnstopshiv.org/node/187).  All sites will participate in ongoing proficiency testing 
of their HIV testing procedures throughout the course of the study.  The HIV test kits used at 
each site are pre-approved by the MTN Laboratory Center (LC);LC; at each testing time point 
when rapid tests are used at least one FDA-approved rapid test kit is used. 
 
Fourth paragraph, second through the fifth sentence- 

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From Version 1.0 to Version 2.0 
10
 
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 ofif there is a question 
regarding sample mix-upintegrity.  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,. tTherefore 
researchers will not be able to identify if participants are predisposed to specific diseases or 
any other genetic information based on this information.  
 
48. 
In Section 8.1, Safety Monitoring, edits are made: 
 
A sub-group of the Protocol Team, including the Protocol Co-Chairs, DAIDS Medical Officer, 
Protocol Safety Physician(s), IPM Representative, and SDMC Clinical Affairs Safety 
Associate will serve as the Protocol Safety Review Team (PSRT). 
 
49. 
In Section 8.3.1, Adverse Events, first paragraph comments are added: 
 
This definition is applied to all study groups, and is applied to both groups 
beginningparticipants at the time of enrollment (i.e.,.  Enrollment is defined as once a 
participant has provided written informed consent for enrollment and it has been 
determined she is randomizedeligible for the study (based on IoR or designee sign-off 
after all protocol-specified inclusion/exclusion criteria have been assessed). 
 
50. 
In Section 8.4.1, Adverse Event Reporting to DAIDS, edits are made: 
 
For each study participant, expedited AE reporting will be undertaken throughout the 
scheduled duration of follow-up, i.e., from the time of random assignmentEnrollment through 
study termination. 
 
51. 
In Section 8.4.4, Expedited AE Reporting Period, comments are added: 
 
The expedited AE reporting period for this study begins once the participant is 
randomizedenrolled and continues up through the participant’s final study visit (Study 
Exit/Termination Visit). 
 
52. 
In Section 10.1, Overview and Summary of Design, edits are made: 
 
This is a Phase 3B, open-label, multi-site, randomized trial.  A sample size of approximately 
1000-2500 participants will be randomly assigned in a 1:1 ratio to either monthly or quarterly 
follow-upfollowed for approximately 13 months, with approximately 12 months of study 
product use.  The two main goals of the trial are: 
 
1. To characterize the safety profile associated with the open label use of the dapivirine 
vaginal matrix ring (25 mg) in women, and to assess safety when randomized to a monthly 
vs. quarterly follow-up schedule 
 
2. To characterize adherence to the open label use of the dapivirine vaginal matrix ring (25 
mg) in women and to compare adherence when randomized to a monthly vs. quarterly 
follow-up schedule 
 

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December 16, 2014 
From Version 1.0 to Version 2.0 
11
53. 
In Section 10.3, Sample Size, comments are added 
 
The final number is dependent upon both the final number enrolled in MTN-020, ASPIRE, 
and the proportion of ASPIRE participants who are eligible and choose to enroll into MTN-
025, HOPE. 
 
54. 
In Section 10.4, Participant Accrual, Follow-up and Retention comment is added 
 
Because of the potential to randomize to a monthly or a quarterly follow-up schedule, itIt is 
anticipated that the study will close to accrual 4 months ahead of the anticipated closure of 
the study.  Based upon the timing of when a participant is enrolledenrollment, follow-up may 
last approximately 4-13 months. Follow-up may be extended beyond 13 months based 
on need and requirements and with the necessary approvals.  
 
55. 
Section 10.5 Randomization has been deleted: 
 
At the enrollment visit, participants will be randomly assigned to one of the two follow-up 
arms (monthly vs. quarterly) in a 1:1 ratio.  The randomization scheme will be stratified by 
site and will be generated and maintained by the MTN SDMC.  The randomized assignments 
will be in blocks to keep the balance of equal allocation.  The SDMC will provide each study 
site with a series of numbered, sealed envelopes containing the randomization assignment 
for each participant.  The envelopes will be assigned sequentially by site staff.  The MTN 
SDMC will coordinate the randomization procedures, which will be specified in the SSP 
Manual.  Assignment of the clinic randomization envelope is considered the effective act of 
participant randomization. 
 
56. 
In Section 10.8.1 Primary Safety Analysis text is removed: 
 
Consistent with the primary safety objective, this analysis will characterize the safety profile 
for the overall population and the two arms.  Because women in the monthly arm will be seen 
more frequently, we expect that more safety events will be recorded that would otherwise go 
unreported or unobserved with less frequent follow-up.  Therefore, under this design a 
comparison between the arms is most appropriate for AEs that would be captured regardless 
of frequency of follow-up.  These include the two key secondary outcomes of drug resistance 
and breakthrough infections.  Those analyses will be covered in Section 10.9.  As a 
supporting analysis, rates of AEs between the arms at quarterly visits will be compared, 
recognizing that this may be imperfect as well since monthly participants may have AEs 
resolved before a quarterly visit that may have remained unresolved were they on the 
quarterly schedule.  Therefore, the AE rate in the monthly arm may look lower at quarterly 
visits because the AEs have been resolved.. 
 
57. 
In Section 10.7.2 Primary Adherence Analysis comment is made and Figure 2 was deleted 
 
For the primary study aim related to adherence, participants will be categorized as adherent if 
drug is detected in all quarterly plasma samples when participants are not on a product hold.  
The arms will be compared using a chi-square test for 2x2 tables. and the proportion of 
adherent participants with a 95% confidence interval will be reported. 
 
Based on this primary analysis plan, we calculated power under a variety of assumptions.  
The figure below shows hypothetical adherence rates for the two arms on the x- and y-axes.  
The curves connect the comparisons for which the comparison has 90% power.  Each curve 

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From Version 1.0 to Version 2.0 
12
represents a hypothetical sample size across both arms ranging from 2500 (representing a 
potential full study analysis) to 100 (representing a potential within site or subgroup analysis).  
For example, with a sample size of 1500, if the higher adhering arm has 80% adherence, the 
study has 90% power to detect a difference between the two arms if the lower adherence 
arm has adherence of 73% or less.  If the sample, size were instead 200, we could detect a 
difference between an 80% adherent arm and a 59% adherent arm. 
Figure 2: Comparison of Rates of Adherence (Low Group Vs. High Group) 
The analysis described above compares rates of perfect adherence as measured in plasma. 
 
58. 
In Section 10.9 Analysis of Secondary Endpoints edits are made:: 
 
59. 
We will calculate the incidence overall and by arm for each endpoint.  Use of new 
and additional HIV-1 prevention technologies, such as oral PrEP and/or topical vaginal gels, 
will be captured on standardized data forms and will be taken into account in the analysis of 
HIV-1 incidence.  We will calculate confidence intervals for the differences between arms in 
incidence rates using the Poisson distribution.  We anticipate this analysis to have low power 
since we will be comparing two arms in which participants are prescribed an active product 
that has been proven effective. 
 
60. 
In Section 13.4.1, Risks, edits are made based upon the Treatment-Emergent Adverse 
Events with Causal Relationship to Dapivirine Ring-004 as Assessed by the Investigator 
within the Investigator’s Brochure: 
 Metrorrhagia 
 Vaginal or genital discharge 
 Vaginal candidiasis 
 Vaginal bleeding 
 Headache 
 Fatigue 
 Vulvovaginal or genital itching 
 Abdominal discomfort 
 Abdominal pain 
 Urinary incontinencetract infection 
 Nausea 
 Vaginal or genital discharge 
 
61. 
In Section 13.5, Informed Consent Process, edits are made:: 
 
Written informed consent will also be obtained for long-term specimen storage and possible 
future testing, for off-site clinic visits as needed, as well as for participation in the ‘Decliner 
Cohort’ Population’.  […] Further, participation in the ‘Decliner Cohort’Population’ does not 
preclude MTN-025 full study participation in the future. 
 
First Bullet removed- 
 
 
Randomization and the importance of participants in both study groups to the success 
of the study 
 

MTN-025 Summary of Changes  
 
 
December 16, 2014 
From Version 1.0 to Version 2.0 
13
62. 
Appendix I: Schedule of Study Visits and Evaluations has been edited to maintain 
consistency with Section 7.0, Study procedures. 
 
 
63. 
Appendix IV: Sample Informed Consent Document (Screening) edits are made: 
 
PURPOSE OF THE SCREENING TESTS AND THE STUDY- 
The main purpose of these screening exams and tests is to find out if you can join this 
research study.  This research study will test if a vaginal ring containing the medicine 
dapivirine is used as directed and found to be safe in participants who attend clinic visits at 
different time points (monthly vs. every three months)..  Women will be in this study for 
approximately 13 months depending upon when they enroll in the study; however this period 
could be shorter or longer than anticipated.  You will be notified if the study extends 
beyond 13 months. 
 
STUDY GROUPS 
If you join MTN-025, you will be in one of two study groups.  Both groups will use the same 
ring containing dapivirine, but the timing of clinic visits will differ.  Half of the women will be in 
a study group that will be asked to come to the clinic for monthly visits.  The other half of the 
women will come to the clinic for visits every three months.  You will be assigned to a group 
by random chance, like flipping a coin.  Neither you nor the staff can decide which follow-up 
schedule you will be assigned.  Both of the study groups are important to this study. 
 
64. 
Appendix V: Sample Informed Consent (Enrollment) edits are made: 
 
PURPOSE OF THE STUDY- 
 
This research study will test if a vaginal ring containing the medicine dapivirine is used as 
directed and found to be safe in participants who attend clinic visits at different time points 
(monthly vs. every three months)..  Women will be in this study for approximately 13 months 
depending upon when they enroll in the study; however the duration of study participation 
could be shorter or longer than anticipated.  You will be notified if the study extends 
beyond 13 months. 
 
STUDY GROUPS- 
 
STUDY GROUPS 
If you join MTN-025, you will be randomly assigned (like flipping a coin) to one of two study 
groups.  Both groups will use the same ring containing dapivirine, but the timing of clinic visits 
will differ.  Half of the women will be in a study group that will be asked to come to the clinic 
for monthly visits.  The other half of the women will come to the clinic for visits every three 
months.  You will be assigned to a group by random chance, like flipping a coin.  Neither you 
nor the staff can decide which follow-up schedule you will be assigned.  Both of the study 
groups are important to this study. 
 
WHAT DO I HAVE TO DO IF I DECIDE TO TAKE PART IN THE MTN-025 STUDY-  
 
If you decide to enroll in the study, you will have a clinic visit today and monthly or everyfor 
the next three months thereafter, depending upon which group you are randomly assigned 
to.  , then quarterly thereafter. 
 
Risks of Study Drugs 

MTN-025 Summary of Changes  
 
 
December 16, 2014 
From Version 1.0 to Version 2.0 
14
 
 Vaginal bleeding 
 Headache 
 Fatigue 
 Itching on the external parts of at irregular intervals, particularly between your 
genitals expected menstrual periods 
 Abdominal discomfort 
 Abdominal pain 
 The loss of bladder control 
 Nausea 
 Vaginal or genital discharge 
 Yeast infection  
 Urinary tract infection 
 
NEW INFORMATION- 
 
In addition to being tested as part of the ASPIRE trial, the ring was also tested in IPM 027 
[INSERT IPM 027 DESCRIPTION AND RESULTS AND/OR UPDATE, IF AVAILABLE, 
HERE]. . IPM 027 results will be provided to participants when they become available. 
 
65. Appendix VI: Sample Informed Consent Document (MTN-025 Decliner Population) to 
highlight that the ‘Decliner Group’ will now be referred to as the ‘Decliner Population’ and 
redundant text in the RISK AND/OR DISCOMFORTS  section  has been removed:  
 
[Sites to modify based upon their institutional policy: In the unlikely event that you get injured 
as a result of your study participation, it is important that you know the US National Institutes 
of Health (NIH) does not have a mechanism to provide direct compensation for research-
related injury.] 
 
 

MTN-025, LoA #01 
11 April 2016 
1 
 
LETTER OF AMENDMENT #01 TO: 
 
MTN-025 
 
A Phase 3B Open-Label Follow-on Trial to Assess the Continued Safety of and Adherence to a Vaginal Ring 
Containing Dapivirine in Women 
 
Version 2.0, dated 16 December 2014 
 
DAIDS Protocol #11985 
IND #108,743 
 
Date of Letter of Amendment: 11 April 2016 
 
 
Site Instruction 
The following information impacts the MTN-025 study and must be forwarded to your Institutional Review Board 
(IRB)/Ethics Committee (EC) as soon as possible for their information and review. This must be approved by your IRB/EC 
before implementation.  The following information impacts the sample informed consent. Your IRB/EC will be responsible 
for determining the process of informing participants of the contents of this Letter of Amendment (LoA). 
 
Implementation 
Upon receiving final IRB/EC and any other applicable Regulatory Entity (RE) approval(s) for this LoA, sites should 
implement the LoA immediately. DAIDS sites are still required to submit a LoA registration packet to the DAIDS Protocol 
Registration Office (PRO) at the Regulatory Support Center (RSC).  DAIDS sites will receive a registration notification for 
the LoA once the DAIDS PRO verifies that all the required LoA registration documents have been received and are 
complete. A LoA registration notification from the DAIDS PRO is not required prior to implementing the LoA. A copy of the 
LoA registration notification along with this letter and any IRB/EC correspondence should be retained in the site’s 
regulatory files. 
Summary of Revisions 
This LoA does not impact the overall design or the study visit schedule for MTN-025.  
 
The primary purpose of this LoA is to incorporate the primary results from IPM 027 (The Ring Study) and MTN-020 
(ASPIRE), two trials that evaluated the safety and efficacy of the dapivirine vaginal ring (Ring-004). This LoA also adds 
two new exploratory objectives for characterizing ASPIRE participants who do not accept study product in MTN-025 and 
to explore alternative markers of product adherence, including participant self-report and analysis of hair samples.  This 
LoA removes the protocol requirement to use FDA-approved HIV testing kit for HIV infection confirmation, allows for post-
infection/pre-seroconversion testing of plasma samples, modifies the list of procedures that should stop after an HIV 
seroconversion, allows the use of audio files as source documents for in-depth interview data, explicitly allows for the 
concomitant use of oral tenofovir-based PrEP, updates the DAIDS Adverse Event (AE) Grading Table from Version 1.0 to 
2.0, updates the risks associated with the dapivirine vaginal ring, updates DAERS contact information, updates the 
Protocol Team Roster, and makes other minor revisions to the protocol. 
 
Unless otherwise noted, text to be deleted is noted by strikethrough and text to be added is noted below in bold. 
 
 
Detailed Listing of Revisions 
 
The following revisions (#1-13) incorporate primary results from IPM 027 (The Ring Study) and MTN-020 (ASPIRE), 
including edits related to the start of MTN-025 implementation being contingent upon those two studies’ findings. 
 
1. In Section 2.1, Microbicides and Human Immunodeficiency (HIV) Prevention, after the second sentence in the fifth 
paragraph: 
 
The results from two recently completed Phase 3 safety and efficacy trials of the dapivirine VR, MTN-020 
(ASPIRE) and IPM 027 (the Ring Study), both of which found the VRs to be safe and effective in reducing HIV-
1 infection in healthy female adults in sub-Saharan Africa when used for one month and replaced monthly, 
would indicate the advisability of initiating Initiation of the MTN-025 study of the dapivirine VR as an open-label 
extension of MTN-020 (ASPIRE). will be contingent upon demonstration of the safety and efficacy of the product in 
the ongoing MTN-020 (ASPIRE) study.  The specific level of effectiveness required to trigger activation of the MTN-

MTN-025, LoA #01 
11 April 2016 
2 
 
025 study will be decided upon following discussions with key stakeholders including regulatory authorities, 
community representatives, and sponsoring agencies. 
 
2. A new, Extended Safety and Efficacy, sub-section was created in Section 2.4.1, Clinical Studies of Dapivirine 
Vaginal Rings, above the twelfth paragraph in the Safety subsection that starts “In March of 2012, IPM 027,”:    
 
Extended Safety and Efficacy 
 
In March of 2012, IPM 027, also known as The Ring Study, was initiated. IPM 027 iswas a randomized, double-blind, 
placebo-controlled efficacy and long-term safety study that will enroll 1,650 enrolled 1959 healthy, HIV-uninfected 
women, ages 18-45. Approximately 1762 women in South Africa and 197 in Uganda were randomized in a 2:1 
ratio to receive either a dapivirine ring or a placebo ring. The study is being conducted in South Africa and 
Uganda. Study participants will useused either the dapivirine ring or the placebo ring every four weeks over 
approximately two years. The main goals of The Ring Study arewere to evaluate the long-term safety and efficacy of 
the dapivirine ring for the prevention of HIV-1 as compared to a placebo ring, when used by healthy, HIV-negative 
women over a two-year period. Additional goals included measuring the incidence of curable STIs, HIV-2 and 
pregnancy; monitoring ring acceptability (how well women liked using the ring) and adherence (if women used the 
ring as intended) as reported by the study participants; and tracking the development of any HIV-1 drug resistance in 
participants who becomebecame HIV positive during the study. The study is anticipated to conclude in 2015/2016.  
 
The median age at enrollment was 25 years, and 91% were unmarried. At the data cut-off point, the total 
number of person years of follow-up was 2805, and 761 women had completed the two year follow-up period. 
A total of 133 post-randomization HIV-1 infections occurred: 77 among women assigned to dapivirine ring 
(incidence 4.08 per 100 person-years) and 56 among women assigned to placebo (incidence 6.10 per 100 
person-years). Dapivirine vaginal ring reduced the risk of HIV-1 infection by 30.7% (95% CI: 0.90-51.5%; 
p=0.0401) relative to placebo. A 37.5% (95% CI: 3.5-59.5%) reduction in HIV-1 infection was observed in a 
subgroup analysis of women older than 21 years. Product-related AEs included metrorrhagia, 
menometrorrhagia, pelvic discomfort/pain, suprapubic pain and application site pain. There were no 
statistically significant differences in the frequency of the primary safety endpoints between the study arms. 
Further, there was no overall difference between NNRTI resistance profiles.  
 
MTN-020, A Study to Prevent Infection with a Ring for Extended Use (ASPIRE), is was a Phase 3 clinical trial 
designed to assess the efficacy and safety of a ring containing 25 mg of dapivirine for the prevention of HIV-1 
acquisition in women. The double-blind, randomized controlled trial is being was conducted in HIV-uninfected women, 
between the ages of 18 and- 45. A total of 2629 women from Malawi, South Africa, Uganda, and Zimbabwe have 
enrolled in the trial. Participants replaced the ring monthly for a minimum of one year. MTN-020 aims aimed to 
determine the safety and efficacy of the dapivirine ring in preventing HIV-1 infection among healthy, sexually active, 
HIV-uninfected women when inserted vaginally once every 4 weeks. Additional goals of MTN-020 included the 
assessment of participant acceptability and adherence to the investigational product, HIV-1 drug resistance mutations 
among participants who acquired HIV-1 infection, and establishing steady state drug concentrations in the study 
population. The study is anticipated to conclude in 2015.  Results were presented at the Conference on 
Retroviruses and Opportunistic Infections (CROI) February 2016 (Abstract #109LB) and published in the New 
England Journal of Medicine (N Engl J Med. Epub 22 Feb 2016. DOI: 10.1056/NEJMoa1506110). 
 
A total of 168 HIV-1 infections occurred: 71 among those assigned the dapivirine vaginal ring and 97 among 
those assigned the placebo ring (incidence 3.3 and 4.5 per 100 person-years, respectively). Dapivirine ring 
resulted in a 27% (95% CI: 1-46%, p=0.046) relative reduction in HIV-1 incidence overall and a 37% (95% CI: 
12-56%, p=0.007) reduction in an analysis defined early in the study excluding data from two study sites with 
lower retention and adherence. In pre-defined as-randomized subgroup analyses, HIV protection differed 
significantly by age, with a 61% reduced risk of HIV for women ≥ 25 years [CI: 32%, 77%)] p<0.001, and 10% 
reduced risk for women < 25 years (CI: -41%, 43%) p=0.64. A post-hoc analysis was conducted to further 
explore this result, which indicated that a 56% (95% CI: 31-71%, p<0.001) reduction among women older than 
21 years of age, and no HIV-1 protection for women aged 18-21, with objective markers of adherence lower in 
this subgroup compared to women older than 21. The rate of adverse events was similar between study arms 
as was the frequency of antiretroviral resistance in those who acquired HIV-1. 
 
There were no statistically significant differences in the frequency of the primary safety endpoints between 
the study arms or in other adverse events commonly detected in the study population. Incident sexually 
transmitted infections occurred at a similar rate in the two study arms. Finally, among those acquiring HIV-1, 
detection of non-nucleoside reverse transcriptase inhibitor mutations did not differ by study arm (8/68 
assigned dapivirine and 10/96 assigned placebo, p=0.80).   

MTN-025, LoA #01 
11 April 2016 
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The dapivirine ring was safe and effective in preventing HIV infection in both ASPIRE and The Ring Study. 
Results suggest the dapivirine ring could be an important HIV prevention option for women at risk of HIV 
infection. 
 
3. The following revisions have been made to Section 2.7.1, Study Design, after the first sentence in the first paragraph: 
 
Upon demonstration of the safety and effectiveness of Given that the dapivirine VR was found to be safe and 
effective in the MTN-020 study, implementation of the follow-on trial, MTN-025, will commence  
 
4. The following revisions have been made to Protocol Summary, Study Design: 
 
Following demonstration of safety and efficacy of Given that the dapivirine vaginal ring was found to be safe and 
effective in the MTN-020, eligible MTN-020 participants will be offered enrollment into MTN-025, a trial designed to 
obtain additional safety and adherence data in women.   
 
5. The following revision has been made to Section 2.7.1, Study Design, fourth paragraph: 
 
[…] (Ring-004) when inserted monthly in healthy, HIV-uninfected, not pregnant, sexually active research-experienced 
women should efficacy be demonstrated in MTN-020. 
 
6. The following revisions have been made to Section 4.1, Identification of Study Design, first sentence:  
 
The MTN-025 trial, HOPE, is a multi-site, open-label, Phase 3B trial that will be implemented if the dapivirine VR is 
found to be a safe and an effective HIV prevention method in the MTN-020 trial.   
 
7. The following revisions have been made to Section 5.1, Selection of the Study Population, first sentence:  
 
If safety and efficacy of the dapivirine vaginal ring are demonstrated in MTN-020 (ASPIRE); MTN-025 (HOPE), will be 
is being implemented as a follow-on trial to MTN-020 (ASPIRE), which demonstrated safety and efficacy of the 
dapivirine VR. 
 
8. The following revisions have been made to Section 13.4.2, Benefits, first sentence of first paragraph: 
 
MTN-025 (HOPE) will only be implemented ifGiven that the dapivirine vaginal ring as tested in MTN-020 (ASPIRE) 
wasis found to be safe and effective, therefore, participants in the HOPE study will experience the direct benefit of 
using a product that has been found to be safe and effective in preventing HIV acquisition and will be considered for 
potential regulatory approval. 
 
9. The following revisions have been made to Appendix IV, Sample Informed Consent Document (Screening), Informed 
Consent sub-section, after the second sentence of the first paragraph: 
 
The research study you participated in, MTN-020: (ASPIRE), A Study to Prevent Infection with a Ring for Extended 
Use, showed that the dapivirine vaginal ring can reduce the chances of HIV-uninfected women from getting the HIV 
virus by [SITES TO INSERT: from X to X percent]prevented approximately one third of HIV infections.  Among 
women older than 21, who used the ring more consistently than younger women, more than half of HIV 
infections were prevented.  The study also learned that the dapivirine vaginal ring is [SITES TO INSERT: safe 
(meaning that VR use they do not produce significant did not cause health problems in persons who take them)] 
when used by HIV-uninfected women. In addition to being tested as part of the ASPIRE trial, the ring was also 
tested in IPM 027.  IPM 027 results were similar to those in ASPIRE, demonstrating the dapivirine ring is safe, 
well-tolerated and effective, reducing HIV-uninfected women’s chances of getting the HIV virus by 
approximately one third. Only through the participation of volunteers in clinical research can the safety and 
effectiveness of medicine be better understood.  More data is needed on the safety of the dapivirine vaginal ring.  
Because you took part in the ASPIRE study, yYou are being offered the opportunity to use the safe and effective 
dapivirine vaginal ring as part of this new study. 
 
10. The following revisions have been made to Appendix V, Sample Informed Consent Document (Enrollment), Informed 
Consent sub-section, after the first sentence of the first paragraph: 
 
The research study you participated in, MTN-020: (ASPIRE), A Study to Prevent Infection with a Ring for Extended 
Use, showed that the dapivirine vaginal ring can reduce HIV-uninfected women’s chances of getting the HIV virus by 

MTN-025, LoA #01 
11 April 2016 
4 
 
[SITES TO INSERT: from X to X percent]prevented approximately one third of HIV infections.  Among women 
older than 21, who used the ring more consistently than younger women, more than half of HIV infections 
were prevented.  The study also learned that the dapivirine vaginal ring is [SITES TO INSERT: safe (meaning that 
VR use it does not cause significant health problems)] when used by HIV-uninfected women. More data is needed on 
the safety of the dapivirine vaginal ring.  Because you took part in the ASPIRE study, y In addition to being tested 
as part of the ASPIRE trial, the ring was also tested in IPM 027.  IPM 027 results were similar to those in 
ASPIRE, demonstrating the dapivirine ring is safe, well-tolerated and effective, reducing HIV-uninfected 
women’s chances of getting the HIV virus by approximately one third. You are being offered the opportunity to 
use the safe and effective dapivirine vaginal ring as part of this new study. 
 
11. The following revision has been made to Appendix V, Sample Informed Consent Document (Enrollment), What do I 
have to do if I decide to take part in the MTN-025 study? sub-section titled “If you become infected with HIV”, first 
sentence of second paragraph:  
 
It may be necessary, depending upon local and national health requirements, for study staff to report diseases, 
including HIV, identified among MTN-020 (ASPIRE)5 (HOPE) study participants. 
 
12. The following revisions have been made to Appendix V, Sample Informed Consent Document (Enrollment), New 
Information sub-section, third and fourth sentence of the first paragraph, and second sentence of the second 
paragraph:  
 
[SITES TO INSERT MTN-020 DATA HERE]. In addition to being tested as part of the ASPIRE trial, the ring was also 
tested in IPM 027.  IPM 027 results will be provided to participants when they become available. 
 
The HIV prevention researchers working on this MTN-025 (HOPE) are committed to sharing any data with you that 
becomes available, regardless of the product, if it is found to be effective in preventing the transmission of HIV. 
 
13. The following revisions have been made to Appendix VI, Sample Informed Consent Document (MTN-025 Decliner 
Population), Purpose of the Decliner Population sub-section, after the first sentence: 
 
MTN-025, is a study that provides former ASPIRE participants with eligible women access to the dapivirine vaginal 
ring, a product that has been shown to reduce the chances of women from getting the HIV virus by. [To be updated: X 
to X percent]. MTN-020: (ASPIRE), A Study to Prevent Infection with a Ring for Extended Use, showed that the 
dapivirine vaginal ring prevented approximately one third of HIV infections were prevented.  Among women 
older than 21, who used the ring more consistently than younger women, more than half of HIV infections 
were prevented. The study also learned that the dapivirine vaginal ring is [To be updated: safe (meaning that it VR 
use does not produce significant cause health problems). in persons who take it]. 
 
The following revisions (#14-37) have been made to add a new exploratory objective: characterization of participants who 
do not accept study product and to make the necessary changes in the protocol to satisfy the objective/endpoint: 
 
14. The following bullet point items have been added to Protocol Summary, Exploratory Objectives, and to Section 3.3, 
Exploratory Objectives, to add the one new exploratory objective: 
 
6. To characterize the MTN-020 participants who do not accept study product in MTN-025 
 
15. The following bullet point items have been added to Protocol Summary, Exploratory Endpoints, to add the one new 
exploratory objectives’ endpoints: 
 
6. Characterization of MTN-020 participants who do not accept study product in MTN-025 
- 
Participant report of the factors that led to her decision to not accept study product  
 
16. The following revision has been made to Protocol Summary, Study Regimen, to clarify that HOPE participants have a 
choice regarding whether to accept study product: 
 
Participants will receivebe offered a silicone elastomer vaginal matrix ring containing 25 mg of dapivirine to be 
replaced each month for a total period ofapproximately 12 months of use. 
 
17. The following revision has been made to Section 6.1, Regimen, first two sentences, to clarify that HOPE participants 
have a choice regarding whether to accept study product: 
 

MTN-025, LoA #01 
11 April 2016 
5 
 
All participants will receivebe offered a vaginal ring containing 25 mg of dapivirine to be worn monthly. Participants 
will be able to choose whether to insert Oone new ring will be inserted each month.     
 
18. The following revision has been made to Section 6.2, Administration, first sentence, to clarify that HOPE participants 
have a choice regarding whether to accept study product: 
 
If they choose, The participants will self-insert the study VR monthly. 
 
19. The following revisions have been made to the second and third paragraph within Section 6.4.2, Study Product 
Dispensing, to clarify that HOPE participants have a choice regarding whether to accept study product: 
 
During each of the monthly clinic visits participants will receive a new ring.  If the participant is unable to attend her 
next scheduled visit it is up to the discretion of the IoR to provide provision of an additional ring(s) may be provided 
at the discretion of the IoR as permitted in the SSP.  All such circumstances must be documented fully by the 
IoR/designee as described in the MTN-025 SSP Manual. 
 
When participants enter the quarterly follow-up phase, they those who choose to use study product will be 
dispensed three rings at each study visit or be given the option of returning to the site pharmacy or the clinic (based 
on site dispensing capacity) each month to obtain a new vaginal ring each month (e.g., if they do not feel comfortable 
having a supply of two additional unused rings at home). Participant’s preference regarding product dispensation and 
their choice will be documented and updated as needed. 
 
20. The following revisions have been made to Section 7.3, Enrollment Visit (Day 0), Table 6, Enrollment Visit (Day 0), 
rows under “Study Product/Supplies” component to ensure that it is clear that study VR use instructions will only be 
offered to participants if the product is accepted and to allow ASPIRE participants to choose to use study product in 
MTN-025: 
 
Study Product/Supplies 
 
Provision of study VR use instructions* 
 
Provision ofOffer and, if accepted, provide study VR(s) 
 
21. The following revisions have been made to Section 7.4.1, Months 1 and 2, Table 7, Follow-up Visits, Months 1 and 2, 
rows under “Study Product/Supplies” component; and Section 7.4.2, Quarterly Visits (Months 3, 6, 9), Table 8, 
Quarterly Visits, rows under “Study Product/Supplies” component, to allow ASPIRE participants to choose to use 
study product in MTN-025: 
 
Study Product/Supplies 
 
Provision of study VR use instructions* 
 
Provision ofOffer and, if accepted, provide study VR(s) 
 
22. The following revisions have been made to Section 7.4.1, Months 1 and 2, Table 7, Follow-up Visits, Months 1 and 2, 
only row under “Laboratory-Study Product" and second row under “Study Product/Supplies”; Section 7.4.2, Quarterly 
Visits (Months 3, 6, 9), Table 8, Quarterly Visits, only row under “Laboratory-Study Product” and second row under 
“Study Product/Supplies”; and Section 7.4.3, Product Use End Visit (PUEV), Table 9, PUEV, Month 12, only row 
under “Laboratory-Study Product” and second row under “Study Product”, to complete procedures as indicated for 
those participants who choose to use study product in MTN-025: 
 
Study Product 
 
Adherence assessment(s):  Returned study VR(s)*
Study Product/Supplies 
 
Removal and collection of used/unused study VR(s)* 
 
 
23. The following revisions have been made to Section 7.6.1, Participants Who Become Infected with HIV, second bullet 
point after second paragraph, Section 7.6.2, Participants Who Become Pregnant, first bullet point; and Section 7.6.3, 
Participants Who Temporarily Hold or Permanently Discontinue Study Product Use, first bullet point, to clarify that 
HOPE participants have a choice regarding whether to accept study product:  
 
 
Provision of Offer and, if accepted, provide VR, product use instructions, and product adherence counseling 
 
24. The following bullet point has been added to Section 7.8, Behavioral Evaluations, after the first paragraph, to include 
assessment of the newly added exploratory endpoint of “participant report of the factors that led to her decision to not 
accept study product”: 
 
 
Motivations for using or declining to use study product while participating in this research study  

MTN-025, LoA #01 
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25. The following revisions have been made to Section 7.9, Adherence Counseling, first sentence, to clarify that HOPE 
participants have a choice regarding whether to accept study product: 
 
Study product adherence counseling will be provided as a component of the Protocol Adherence Counseling to all 
study participants by site staff. Messages will be tailored based on whether or not the participant chooses to 
accept study product. 
 
26. The following revisions have been made to Section 10.1, Overview and Summary of Design, second sentence of first 
paragraph, to clarify that HOPE participants have a choice regarding whether to accept study product: 
 
A sample size of approximately 1000-2500 participants will be followed for approximately 13 months, with 
approximately 12 months of study product use for participants who choose to use the VR. 
 
27. The following bullet points have been added to Section 13.5, Informed Consent Process, first bullet point after third 
paragraph, to accommodate MTN-025 participants who do not accept study product in MTN-025: 
 
 
The importance of study product adherence to its effectiveness 
 
That all participants may choose not to use study product at any time and still take part in the study  
 
28. The following revisions have been made to Appendix I, Schedule of Study Visits and Evaluations, last row in the 
“Laboratory” section and second to fourth rows under “Study Product/Supplies” section for consistency with changes 
made in Section 7.0: 
 
 
SCR 
ENR 
M.  
1 and 2  
Quarterly 
Visits 
PUEV 
 
Study Exit/ 
Term. Visit 
(~ 1 Month 
after the 
PUEV) 
Adherence assessment(s):  Returned Study VR(s) 
 
 
X* 
X* 
X* 
 
STUDY PRODUCT/ SUPPLIES 
 
 
 
 
 
 
Provision of study VR use instructions  
 
X* 
* 
* 
 
 
Provision ofOffer and, if accepted, provide study VR(s)  
 
X 
X 
X 
 
 
Removal and collection of used/unused study VR(s)  
 
 
X* 
X* 
X* 
 
 
29. The following revisions have been made to Appendix IV, Sample Informed Consent Document (Screening), Study 
Product section, second sentence of first paragraph; and to Appendix V, Sample Informed Consent Document 
(Enrollment), Study Product section, second sentence of first paragraph, to clarify that ASPIRE participants will be 
offered the vaginal ring MTN-025: 
 
Unlike ASPIRE, there is no placebo vaginal ring (a ring without the study medicine) in HOPE, so aAll HOPE 
participants will receive be offered the use of a vaginal ring containing dapivirine.   
 
30. The following revisions have been made to Appendix IV, Sample Informed Consent Document (Screening), Purpose 
of the Screening Tests and the Study, second sentence and to Appendix V, Sample Informed Consent Document 
(Enrollment), Purpose of the Study section, first sentence:  
 
This research study will test if a vaginal ring containing the medicine dapivirine is used as directed by participants 
and found to be is safe in participants who attend clinic visitswhen provided on a three-monthly schedule.   
 
31. The following revisions have been made to Appendix V, Sample Informed Consent Document (Enrollment), What Do I 
Have to Do if I Decide to Take Part in the MTN-025 Study? section, second and third sentence of first paragraph, to 
clarify that HOPE participants have a choice regarding whether to accept study product: 
 
You will insertbe offered a new vaginal ring to use, with a new ring to be inserted monthly for approximately 12 
months of use.  For some participants, this period of time may be less, for instance, if a participant enrolls in the 
study late or chooses not to insert the vaginal ring every month she is enrolled.  sStudy staff willcan provide 
you with an estimate of how long you will use the be offered access to the ring.  Study procedures will be similar 
regardless of whether or not you choose to use the ring. 
 
32. The following revision was made to Appendix V, Sample Informed Consent Document (Enrollment), What Do I Have 
to Do if I Decide to Take Part in the MTN-025 Study? section, fifth sentence edited: 
 

MTN-025, LoA #01 
11 April 2016 
7 
 
You will have a final study visit to check on your health approximately 4 weeks after the final ring is removed.   
 
33. The following revision was made to Appendix V, Sample Informed Consent Document (Enrollment), What Do I Have 
to Do if I Decide to Take Part in the MTN-025 Study? section, You will have the following clinical procedures 
performed, pelvic exam bullet: 
 
A pelvic examination when the vaginal ring is removed for the final time. 
 
34. The following revisions have been made to Appendix V, Sample Informed Consent Document (Enrollment), What Do I 
Have to Do if I Decide to Take Part in the MTN-025 Study? section, first sentence preceding second bullet point list, to 
clarify that HOPE participants have a choice regarding whether to accept study product: 
 
You will be offered asked to use a study vaginal ring to use. 
 
35. The following sentence has been added to Appendix V, Sample Informed Consent Document (Enrollment), What Do I 
Have to Do if I Decide to Take Part in the MTN-025 Study? section, at the end of the fourth bullet point in the second 
set of bullet points, and at the end of the second and fourth bullet points in the fourth set of bullet points, to inform 
participants that they may receive drug use results: 
 
You may receive these test results indicating your study product use if you choose to accept the vaginal ring. 
36. The following revision has been made to Appendix V, Sample Informed Consent Document (Enrollment), What Do I 
Have to Do if I Decide to Take Part in the MTN-025 Study? section, first bullet point of third bullet point list, to 
accommodate MTN-025 participants who do not accept study product in MTN-025: 
 
 
If you chose to accept a ring for use, Yyour experience using the vaginal ring, including whether or not the ring 
was removed from or fell out of your vagina. 
 
37. The following revisions have been made to Appendix V, Sample Informed Consent Document (Enrollment), What Do I 
Have to Do if I Decide to Take Part in the MTN-025 Study?, In-depth Interview(s) and Group Discussions sub-section, 
first sentence in the second and third paragraphs, to reiterate that MTN-025 participants who choose not to use study 
product may still be selected for in-depth interviews and group discussions: 
 
If you are asked to participate in a group discussion, you will be asked to discuss your use of the study product, your 
feelings about the study product and trial participation, your vaginal practices and other questions that can help 
researchers to better understand participants’ experiences while taking part in the study, whether you used the 
vaginal ring or not.  These discussions will last about one hour.   
[…] 
If you are asked to participate in an interview, you will be asked questions about your use of the ring, your preferences 
and opinions, your experiences with using the ring during sex, and any problems you may have had using the ring, 
and whether you used the vaginal ring or not. 
 
The following revisions (#38-43) have been made to add the new exploratory objective: To explore alternative markers of 
adherence and to make the necessary changes in the protocol to satisfy the objective/endpoint: 
 
38. The following bullet point items have been added to Protocol Summary, Exploratory Objectives, and to Section 3.3, 
Exploratory Objectives, to add one new exploratory objective: 
 
7. To explore alternative markers of adherence 
 
39. The following bullet point items have been added to Protocol Summary, Exploratory Endpoints, to add the new 
exploratory objective endpoints: 
 
7. Exploration of alternative markers of adherence 
- 
Hair dapivirine levels 
- 
Self-reported product use 
 

MTN-025, LoA #01 
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40. The following table sub-section has been added to; Section 7.4.1, Months 1 and 2, Table 7, Follow-up Visits, Months 
1 and 2; Section 7.4.2, Quarterly Visits (Months 3, 6, 9), Table 8, Quarterly Visits; Section 7.4.3, Product Use End 
Visit (PUEV), Table 9, PUEV, Month 12; and Section 7.4.4, Study Exit/Termination Visit, Table 10, Study 
Exit/Termination Visit, to include hair collection as a procedure at each visit: 
 
Hair 
 
Collect hair  
 
Hair sample for DPV testing and archive 
 
41. The following table sub-section has been added to Appendix I, Schedule of Study Visits and Evaluations to include 
hair collection as a procedure at each visit: 
 
 
SCR 
ENR 
M.  
1 and 2  
Quarterly 
Visits 
PUEV 
 
Study Exit/ 
Term. Visit 
(~ 1 Month 
after the 
PUEV) 
HAIR 
Hair sample(s) for DPV testing and archive 
 
 
X 
X 
X 
X 
 
42. The following bullet point has been added to Appendix V, Sample Informed Consent Document (Enrollment), What Do 
I Have to Do if I Decide to Take Part in the MTN-025 Study? section, at the end of the fourth bullet point list, to include 
hair collection as a procedure at each visit: 
 
 
You will also be asked to provide a hair sample to see how much dapivirine is being absorbed by your 
body. If you choose not to provide a hair sample, you can still participate in all other study activities. We 
will reconfirm the decision you make today at all study visits should you change your mind about hair 
collection.  
 
43. The following revisions have been made to Appendix V, Sample Informed Consent Document (Enrollment), Consent 
for Storage and Future Testing of Specimens, first, second, seventh and eighth sentences, to include hair samples in 
the list of specimen samples that may undergo further testing if any are left over after all MTN-025 related testing is 
completed: 
 
blood, hair, vaginal fluid and cervical fluid samples 
 
The following revisions (#44-45) have been made to update the risks associated with the vaginal ring  
 
44. The following revision has been made to Section 13.4.1, Risks,  General Subsection, fifth paragraph replaced to 
update the risks associated with DPV VR use: 
 
Based on AEs reported among female participants in previous studies, dapivirine VRs may be associated with:  
•             Metrorrhagia 
•             Vaginal discharge 
•             Vaginal candidiasis 
•             Vaginitis bacterial 
•             Urinary tract infection 
 
Please note:  Study product risks will be updated when the safety and effectiveness data from ASPIRE are 
available. 
Safety data were evaluated from two Phase 3 trials, MTN-020 (ASPIRE) and IPM 027 (The Ring Study), 
which enrolled a total of 4588 women, and results were reported in February 2016. No safety concerns 
were noted in DPV VR users as compared to placebo VR users.    
 
45. The following revision has been made to Appendix V, Sample Informed Consent Document (Enrollment), Risks of 
Study Drugs has been removed as the risks associated with the Study Rings is now sufficient: 
 
Risks of Study Drugs 
Based on side effects reported among women in previous studies, dapivirine vaginal rings may be associated 
with:  
 
Vaginal bleeding at irregular intervals, particularly between your expected menstrual periods 
 
Vaginal or genital discharge 
 
Yeast infection  
-
-
-
-
-
-
-
I 

MTN-025, LoA #01 
11 April 2016 
9 
 
 
Urinary tract infection 
 
The following revisions (#46-52) have been made to remove the protocol requirement to use FDA-approved HIV testing 
kits for HIV infection confirmation and to allow for post-infection/pre-seroconversion testing of plasma samples. 
 
46. Instances of “HIV seroconversion” have been changed to “HIV infection” in cases where it is associated with the new 
HIV testing methods.  This change impacts Section 6.4.4, Retrieval of Study Product, second sentence of first 
paragraph; Section 6.4.4, Retrieval of Study Product, Table 4, Retrieval of Study Product, first and second bullets; 
Section 6.4.4, Retrieval of Study Product, fourth paragraph; and Section 10.8, Analysis of Secondary Endpoints, first 
sentence in the first paragraph.  
 
47. The following revisions have been made to Section 7.2, Screening Visit, Table 5, Screening Visit; Section 7.3, 
Enrollment Visit (Day 0), Table 6, Enrollment Visit (Day 0); Section 7.4.1, Months 1 and 2, Table 7, Follow-up Visits, 
Months 1 and 2; Section 7.4.2, Quarterly Visits (Months 3, 6, 9), Table 8, Quarterly Visits; Section 7.4.3, Product Use 
End Visit (PUEV), Table 9, PUEV, Month 12; Section 7.4.4, Study Exit/Termination Visit, Table 10, Study 
Exit/Termination Visit; and Appendix I, Schedule of Study Visits and Evaluations:  
 
Blood 
 
HIV-1 testingserology 
 
48. The following revisions have been made to Section 7.6.1, Participants Who Become Infected with HIV, after the 
second sentence in the first paragraph:  
 
Participants are offered enrollment in MTN-015 (http://www.mtnstopshiv.org/studies) at the visit when HIV testing  
seroconversion confirmation test results are discussed with the participant.  
 
For those participants who choose to be maintained in MTN-025 follow-up, regardless of co-enrollment in MTN-015,  
protocol-specified procedures for MTN-025 will continue, except the following: 
 
 
HIV testingserology, HIV pre- and post-test counseling 
 
49. The following revisions have been made to Section 7.6.1, Participants Who Become Infected with HIV, second and 
third bullets in last bullet point list:  
 
 
Plasma collection, CD4+ T cell count and HIV-1 RNA PCR will be performed at the clinic visit immediately 
following confirmation of an HIV-infection and every three months scheduled visit thereafter for the remaining 
follow-up period, or as indicated 
 
HIV-1 Genotyping (standard resistance testing) will be performed on the stored plasma closest to the time of 
confirmed HIV-1 infection.   
 
ItHIV-1 RNA PCR or HIV-1 genotyping may be performed at additional/alternate time points as requested by site 
IOR or at the discretion of the Laboratory Center.   
 
50. The following revision has been made to Section 7.6.4, Interim Visits, fifth bullet in bullet point list:  
 
 
For interim HIV counseling and testing in response to participant report of symptoms consistent with acute HIV 
infectionseroconversion or presumed exposure to HIV 
 
51. The following revision has been made to Section 7.11, Laboratory Evaluations, Local Laboratory sub-section, fourth 
bullet point in second bullet point list (Blood):  
 
 
HIV testingserology 
 
52. The following revisions have been made to Section 7.12, HIV Infection (Secondary Endpoint) Determination, after the 
fourth sentence in the first paragraph:  
 
All confirmatory testing is performed using FDA-approved test kits.  
[…] 
 
The MTN LC will test Study Entry, PUEV, and scheduled Termination Visit specimens from a 10% random 
sample of participants enrolled at each site for evidence of HIV infection using FDA-licensed tests.  […] 
 

MTN-025, LoA #01 
11 April 2016 
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 
The MTN LC will test plasma specimens collected at the Study Entry visit and the visit at which HIV infection 
was detected Seroconversion specimens from all study participants identified by the local laboratories as having 
become infected with HIV during the study follow-up period.  The LC will also test matched Study Entry and 
Follow-Up specimens from a random sample of uninfected participants (equal to the number of infected 
participantsseroconversions).  Study Entry specimens are collected at participants’ Enrollment Visit.  
SeroconversionPost-infection specimens are collected at the schedule specified in Section 7.6.1.  All specimens 
will be tested for evidence of HIV infection using FDA-licensed tests.  For all HIV-infected 
participantsseroconverters, Study Entry specimens also will be confirmed.  
 
The following revisions (#53-54) have been made to accommodate for plasma sampling at follow-up Months 1 and 2 for 
DPV testing and archive. 
 
53. The following text has been added to Section 7.4.1, Months 1 and 2, Table 7, Follow-up Visits, Months 1 and 2, under 
“Laboratory-Blood” component, to include collection of plasma for archive at Months 1 and 2: 
 
Blood 
 
Plasma sample for DPV testing and archive 
 
54. The following revision has been made to Appendix I, Schedule of Study Visits and Evaluations, fifth row in the 
“Laboratory-Blood” section and superscript legend, to include collection of plasma for archive at Months 1 and 2: 
 
 
SCR 
ENR 
M.  
1 and 2  
Quarterly 
Visits 
PUEV 
 
Study Exit/ 
Term. Visit 
(~ 1 Month 
after the 
PUEV) 
Plasma sample for DPV testing and archive 
 
◊ 
X 
X 
X 
X 
 
X mandatory, *If indicated, ŦPer local standard of care, ◊ For archive 
 
The following revisions (#55-56) have been made to make clear that oral tenofovir-based PrEP concomitant use is 
permitted in countries where it is available: 
 
55. The following revisions have been made to Section 2.7.2, Incorporating Emergent Effective HIV-1 Prevention 
Strategies, to allow the use of oral Truvada for PrEP by participants in countries where it is licensed for that use: 
 
As of June 2014, the United States was the only country where ARVs (the combination daily oral pill 
emtricitabine/tenofovir disoproxil fumarate [Truvada®]) are licensed for use as pre-exposure prophylaxis (PrEP).  
However, as candidate microbicides continue to demonstrate evidence of efficacy, the potential for one or more 
licensed HIV-1 prevention strategies in sub-Saharan Africa may soon become a reality.  The HOPE Protocol Team 
will follow all relevant national policies regarding HIV-1 prevention and will actively consult with stakeholders in the 
event that an effective intervention is approved locally.  In study countries where oral tenofovir-based ARVs are 
provided to participants by a health care worker as PrEP, use will be documented as a concomitant 
medication.  Consultation with target populations, policy makers, governments and other stakeholders will be 
ongoing conducted as needed throughout the duration of study implementation and participant follow-up by study 
leadership, Microbicide Trial Network (MTN) Leadership and the MTN Community Working Group (CWG) as other 
products become available.  
 
56. The following sentence has been added to Section 6.5, Concomitant Medications, after the second sentence, to allow 
the use of oral Truvada for PrEP by participants in countries where it is licensed for that use: 
 
Oral tenofovir-based ARV use is permitted if approved, available, and provided to participants by a health 
care provider as PrEP.  Oral tenofovir-based ARV use will be documented as a concomitant medication. 
 
The following revisions (#57-61) have been made to accommodate the planned method of data management of the audio 
files and transcription of these files: 
 
57. Section 11.1, Data Management Responsibilities, second paragraph, has been revised to allow the use of audio files 
as source documents for in-depth interview data:  
 
Transcriptions of iInterviews and group discussion files (if applicable) will be generated in the field andwill be 
electronically transferred to RTI International using a secure File Transfer Protocol (FTP) site, where they will be 
1-1-1-=-l-=-I-I ==-1 

MTN-025, LoA #01 
11 April 2016 
11 
 
uploaded and managed using a qualitative software package.  RTI International will act as a hub, and manage all data 
for the study.  A convention for file naming will be developed, and all data will be labeled according to this process.  
Original language and translated tTranscripts will be transferred to RTI International as they are completed.  RTI 
International will save all versions of all files on a secure, password-protected server. 
 
58. Section 11.2, Source Documents and Access to Source Data/Documents, fourth paragraph, has been deleted to allow 
the use of audio files as source documents for in-depth interview data:  
 
Audio files will be transcribed and immediately destroyed following a transcription quality assurance check.  The site 
IoR or designee will be responsible for ensuring that these files have been destroyed. 
 
59. Section 13.6, Participant Confidentiality, eighth and ninth sentence in the second paragraph, has been revised to 
allow the use of audio files as source documents for in-depth interview data:  
 
Audio files will be translated and transcribed in English and securely stored. Please see SSP Manual for guidance 
regarding audio file destruction.   
 
60. Appendix V, Sample Informed Consent Document (Enrollment), What Do I Have to Do if I Decide to Take Part in the 
MTN-025 Study?, In-depth Interview(s) and Group Discussions, third sentence of the third paragraph, has been 
deleted to allow the use of audio files as source documents for in-depth interview data:  
 
The voice recordings will be destroyed as soon as the audio recording has been typed and checked. 
 
61. Appendix VI, Sample Informed Consent Document (MTN-025 Decliner Population), Risks and/or Discomforts, last two 
sentences of the second paragraph, have been deleted to allow the use of audio files as source documents for in-
depth interview data:  
 
When the information on the audio recording is typed onto paper and fully checked, the recording will be destroyed.  
Study leaders will make sure this happens. 
 
 
Additional minor modifications include:  
 
62. List of Abbreviations and Acronyms has been revised to include the acronym for NIAID’s Clinical Research 
Management System, CRMS: 
 
 
63. Throughout the protocol the DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events was 
updated from Version 1.0, December 2004 (Clarification dated August 2009) to Version 2.0, November 2014. 
 
64. Protocol Team Roster- Updates: MTN Leadership and Operations Center (LOC) Protocol Development Manager’s 
name has been updated to Beth Galaska.  Jennifer M. Berthiaume’s title has been updated to Clinical Data Manager. 
Danielle Crida’s telephone number has been updated to +27-21-6505873 
 
65. Protocol Team Roster- Removals:  Arendevi Pather, Patrick Ndase, Karen Patterson, Cynthia Grossman, Katie 
Schwartz, Flavia Matovu Kiweewa. 
 
66. Protocol Team Roster- Additions:  
 
Brenda Gati Mirembe, MBChB, MSc Epidemiology 
Site Investigator of Record 
MU-JHU Research Collaboration 
P.O. Box 23491, Kampala Uganda 
Phone: +256 414 541 044/+256 772 881 922 
Fax:+256 414 543 002 
Email: bgati@mujhu.org 
 
Portia Hunidzarira, MBChB  
Site Investigator of Record  
UZ-UCSF  
15 Phillips Avenue, Belgravia 
Harare, Zimbabwe 
Phone: +263 4 704920 
Fax:  +263 4 704897 
Email: phunidzarira@uz-ucsf.co.zw  
 
CRMS 
Clinical Research Management System 

MTN-025, LoA #01 
11 April 2016 
12 
 
Kailazarid Gomez, MPM  
Sr. Clinical Research Manager  
FHI 360  
PO Box 21059  
Durham, NC 27703 USA  
Phone: 919-544-7040, Ext. 11282  
Fax: 919-544-0207  
Email: kgomez@fhi360.org    
 
Melissa Peda, MPA 
Clinical Data Manager 
FHCRC – SCHARP  
1100 Fairview Ave. North, LE-400 
PO Box 19024 
Seattle, WA 98109-1024 USA 
Phone: 206-667-7672 
Email: mapeda@scharp.org  
 
Jason Pan  
Statistical Research Associate  
FHCRC-SCHARP  
1100 Fairview Ave. North, M2-C200  
PO Box 19024  
Seattle, WA 98109-1024 USA  
Phone: 206-667-7180  
Email: zpan@fhcrc.org 
 
 
67. Section 7.1, Pre-Screening a new fourth sentence has been added to include the planned collection of reasons former 
MTN-020 (ASPIRE) participants do not enroll in MTN-025 (HOPE). 
 
[…]  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 potential participant identifiers.  Reason(s) for 
not enrolling former MTN-020 (ASPIRE) participants (e.g., unable to contact, ineligible based upon pre-screen, 
associated reasons for ineligibility, refusal, etc.) will be recorded.  At each site, procedures and documentation 
will comply with local IRB/EC requirements. 
 
68. Section 7.6.1, Participants Who Become Infected with HIV, three bullets have been added after the fourth bullet 
following the second paragraph, to include plasma, hair and vaginal fluid collection in the list of procedures that would 
stop in the event of HIV seroconversion during the study:  
 
 
Plasma collection for DPV testing and storage 
 
Hair collection 
 
Vaginal fluid collection 
 
69. Section 8.1, Safety Monitoring, has been updated to clarify the composition of the PSRT:  
 
A sub-group of the Protocol Team, including the Protocol Co-Chairs, DAIDS Medical Officer, Protocol Safety 
Physician(s), and IPM Representative and SDMC Clinical Affairs Safety Associate will serve as the Protocol Safety 
Review Team (PSRT). 
  
70. Section 8.2, Clinical Data Safety Review, has been updated to remove the Clinical Affairs staff designation:  
 
Participant safety is also monitored at the Network level through a series of routine reviews conducted by the SDMC 
Clinical Affairs staff, the PSRT, and study sponsors. 
  
71. Section 8.3.1, Adverse Events, has been updated to remove the mention of the DataFax system:  
 
All AE Log forms completed for each participant should be reviewed at the study exit visit and updated as needed. For 
AEs that are ongoing at the exit visit, the status/outcome of the AE should be updated to “continuing at the end of 
study participation” and the AE log form should be re-faxed to SCHARP DataFax.  
 
72. Section 8.4.1, Adverse Event Reporting to DAIDS, has been revised to update the DAERS support contact 
information in case of DAERS-related queries, and to correct a number of acronym errors:  
 
Requirements, definitions and methods for expedited reporting of AEs are outlined in Version 2.0 of the DAIDS EAE  
Manual, which is available on the RSC website at http://rsc.tech-res.com/safetyandpharmacovigilance/.  For each  
study participant, expedited EAE reporting will be undertaken throughout the scheduled duration of follow-up, i.e.,  
from the time of Enrollment through study termination.   
 

MTN-025, LoA #01 
11 April 2016 
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The DAIDS Adverse Experience Reporting System (DAERS), an internet-based reporting system, must be used for  
expedited EAE reporting to DAIDS.  In the event of system outages or technical difficulties, expedited EAEs may be  
submitted via the DAIDS EAE Form.  This form is available on the RSC website,  
http://rsc.tech-res.com/safetyandpharmacovigilance/.   
 
For questions about DAERS, please contact NIAID Clinical Research Management System (CRMS)  
SupportDAIDS-ES at DAIDS-ESSupport@niaid.nih.gov CRMSSupport@niaid.nih.gov. Site queries may also be  
sent from within the DAERS application itself. 
 
Where DAERS has not been implemented, sites will submit expedited EAEs by documenting the information on the  
current DAIDS EAE Form,. This form is available on the RSC website,  
http://rsc.tech-res.com/safetyandpharmacovigilance/. For questions about EAE reporting, please contact the  
RSC (DAIDSRSCSafetyOffice@tech-res.com). 
 
73. Section 11.1, Data Management Responsibilities, has been updated to remove the mention of the DataFax system:  
 
Study CRFs will be developed by the MTN SDMC in conjunction with the protocol team.  Quality control reports and 
queries routinely will be generated and distributed by the SDMC to the study sites for verification and resolution.  As 
part of the study activation process, each study site must identify all CRFs to be used as source documents.  Study 
CRF data are transferred to the MTN SDMC, entered, and cleaned using the DataFax data management system.   
 
74. The following revisions have been made to Appendix IV, Sample Informed Consent Document (Screening), Informed 
Consent section, second to last sentence of first paragraph; and to Appendix V, Sample Informed Consent Document 
(Enrollment), Informed Consent section, second to last sentence of first paragraph: 
 
A total of 2629 women enrolled into MTN-020 (ASPIRE) and all former ASPIRE participants who are eligible for MTN-
025 (HOPE) may take part. It is anticipated that approximately 1000 to 2500 former ASPIRE eligible participants will 
enroll in HOPE. 
 
75. The following revisions have been made to Appendix VI, Sample Informed Consent Document (MTN-025 Decliner 
Population), Study Procedures sub-section, new third sentence was added to highlight that the in-depth Interviews are 
planned with a subset of participants only: 
 
STUDY PROCEDURES 
[…]  If you agree to take part in this study, the interviewer will ask you some brief questions and write your responses 
on a form. It is important you know that not all participants will take part in the IDI; most participants will 
complete a questionnaire only.  Multiple visits may be needed to complete the IDI and questionnaire(s).  During the 
IDI, the interviewer will also ask in-depth questions, during which time notes may be taken and the conversation will 
be audio-recorded.  
 
 
The above information will be incorporated into the next version of the protocol at a later time if it is amended. 

MTN-025, LoA #02 
28 March 2018 
1 
LETTER OF AMENDMENT #02 TO: 
 
MTN-025 
 
A Phase 3B Open-Label Follow-on Trial to Assess the Continued Safety of and Adherence to a Vaginal Ring 
Containing Dapivirine in Women 
 
Version 2.0, dated 16 December 2014 
 
DAIDS Protocol #11985 
IND #108,743 
 
Date of Letter of Amendment: 28 March 2018 
 
 
Site Instruction 
The following information impacts the MTN-025 study and must be forwarded to your Institutional Review Board 
(IRB)/Ethics Committee (EC) as soon as possible for their information and review. This must be approved by your IRB/EC 
before implementation.  The following information impacts the sample informed consent. Your IRB/EC will be responsible 
for determining the process of informing participants of the contents of this Letter of Amendment (LoA). 
 
Implementation 
Upon receiving final IRB/EC and any other applicable Regulatory Entity (RE) approval(s) for this LoA, sites should 
implement the LoA immediately. DAIDS sites are still required to submit a LoA registration packet to the DAIDS Protocol 
Registration Office (PRO) at the Regulatory Support Center (RSC).  DAIDS sites will receive a registration notification for 
the LoA once the DAIDS PRO verifies that all the required LoA registration documents have been received and are 
complete. A LoA registration notification from the DAIDS PRO is not required prior to implementing the LoA. A copy of the 
LoA registration notification along with this letter and any IRB/EC correspondence should be retained in the site’s 
regulatory files. 
Summary of Revisions 
This LoA does not impact the overall design or the study visit schedule for MTN-025. The primary purpose of this LoA is to 
include language allowing international regulatory authority review of study records in both the protocol and informed 
consent. This LoA also clarifies data management and documentation storage language for the in-depth interview (IDI) 
and focus group discussion (FGD) source data/documents, updates the Investigator Signature Page, corrects an 
inconsistency by copying the Exploratory Endpoints previously listed only in the Protocol Summary into Section 4 of the 
protocol, incorporates the protocol document changes made with Clarification Memos (CM) #1 and #2, updates the 
Protocol Team Roster, and makes other minor revisions to the protocol. 
 
Unless otherwise noted, text to be deleted is noted by strikethrough and text to be added is noted below in bold. 
 
 
Detailed Listing of Revisions 
 
The following revisions (#1-6) allow international regulatory authority review of study records: 
 
1. Section 12, Clinical Site Monitoring, last paragraph, second sentence:  
 
The IoR/designee will also allow inspection of all study-related documentation by authorized representatives of the 
MTN LOC, SDMC, and LC; NIAID, FDA, IPM, OHRP, IRBs/ECs, and other local, and US, or international regulatory 
authorities. 
 
2. Section 13.1, Institutional Review Boards/Ethics Committees, first paragraph, last sentence:  
 
The IoRs/designees will permit audits by the NIH, IPM, the FDA, OHRP, MTN LOC, IRBs/ECs, SDMC, and other 
local, US, or international regulatory authorities, or any of their appointed agents. 
 
3. Section 13.6, Participant Confidentiality, first bullet point:  
 
Representatives of the US Federal Government, including the US FDA, the US OHRP, NIH, and/or contractors of the 
NIH, and other local, and US, or international regulatory authorities 
 
 
 

MTN-025, LoA #02 
28 March 2018 
2 
4. Appendix IV, Sample Informed Consent Document (Screening), Confidentiality, second bullet point:  
 
Other local, US, or international regulatory authorities [Insert applicable local authorities, e.g., Ministry of Health, 
medicine control authority] 
 
5. Appendix V, Sample Informed Consent Document (Enrollment), Confidentiality, second bullet point:  
 
Other local, US, or international regulatory authorities [Insert applicable local authorities, e.g., Ministry of Health, 
medicine control authority] 
 
6. Appendix VI, Sample Informed Consent Document (MTN-025 Decliner Population), Confidentiality, second bullet 
point:  
 
Other local, US, or international regulatory authorities [Insert applicable local authorities, e.g., Ministry of Health, 
medicine control authority] 
 
 
The following revisions (#7-9) clarify/specify data management and documentation storage for the IDI and FGD source 
data, including audio recordings: 
 
7. Section 11.1, Data Management Responsibilities, second paragraph, first sentence, has been revised to describe the 
source data management process and to explicitly list which documents will be considered as source data for the 
qualitative behavioral evaluations (i.e., IDIs and FGDs):  
 
Transcriptions of interviews Interview and group discussions files (if applicable) will be generated using the audio 
recordings. Both the audio recordings and the transcripts in the field will be electronically transferred to RTI 
International using a secure File Transfer Protocol (FTP) site, where they will be uploaded and managed using a 
qualitative software package. Interview and group discussion notes (if applicable) will be kept at the site in the 
participant files. The qualitative data from MTN-025 will include three main data sources: original handwritten 
notes of IDIs and FGDs, audio-recorded IDIs and FGDs, and transcripts of IDIs and FGDs. 
 
8. Appendix V, Sample Informed Consent Document (Enrollment), What Do I Have to Do if I Decide to Take Part in the 
MTN-025 Study?, In-depth Interview(s) and Group Discussions, third paragraph, fifth sentence has been revised and 
last sentence has been added, to explicitly include audio recordings as one of the documents considered to be source 
data and to disclose to participants how long the audio recordings will be stored:  
 
Your audio recordings and any other 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-025(HOPE) study team for the purposes of this 
research. [Sites to modify with their site-specific source documentation storage duration requirements if 
required by their IRBs/IECs: The audio recordings, notes, and transcripts from these materials will be kept for 
at least two years after the vaginal ring is approved for marketing or two years after all developmental 
research on the vaginal ring is stopped.] 
 
9. Appendix VI, Sample Informed Consent Document (MTN-025 Decliner Population), Risks and/or Discomforts, second 
paragraph, last sentence, has been added to explicitly disclose to participants how long the audio recordings will be 
stored:  
 
[Sites to modify with their site-specific source documentation storage duration requirements if required by 
their IRBs/IECs: The audio recordings, notes, and transcripts from these materials will be kept for at least two 
years after the vaginal ring is approved for marketing or two years after all developmental research on the 
vaginal ring is stopped.] 
 
 
The following revision updates the Investigator Signature Form language describing the investigators’ responsibilities as 
per DAIDS requirements (see Appendix at the end of this LoA for the updated Investigator Signature Form): 
 
10. Investigator Signature Form, first paragraph:  
 
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 

MTN-025, LoA #02 
28 March 2018 
3 
(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 will 
comply with all requirements regarding the obligations of investigators as outlined in the Statement of Investigator 
(Form FDA 1572), which I have also signed. 
 
[new paragraph] 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. following the date of 
marketing approval for the study product for the indication in which it was 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 Food and Drug Administration is notified.  Publication of the results of this study will be governed by MTN 
policies.  Any presentation, abstract, or manuscript will be submitted to the MTN Manuscript Review Committee, 
DAIDS, IPM and other entities for review prior to submission, as required by the MTN Publication Policy. 
 
 
The following revision corrects an inconsistency by copying the Exploratory Endpoints previously listed only in the 
Protocol Summary into  Section 4, Study Design, as per our usual practice: 
 
11. Section 4.2, Summary of Major Endpoints, after Secondary Endpoints: 
 
Exploratory Endpoints: 
 
1. Understanding of efficacy  
 
Self-reported understanding of partial efficacy  
 
2. Understanding of ring acceptability in the context of known efficacy 
 
Self-reported product acceptability and attitudes towards combination prevention  
 
3. Feasibility: 
 
Participant report of product storage issues and feasibility regarding the follow-up schedule 
 
Visit retention  
 
Proportion of returned rings (used and unused)  
 
4. Genital microenvironment 
 
In genital swab samples, candidate biomarkers of safety, adherence and efficacy, HIV exposure and 
antiretroviral resistance, and genital microflora 
 
5. Characterization of MTN-020 participants who do not enroll in MTN-025 
 
Participant report of the factors that led to her decision to decline enrollment into MTN-025 
 
6. Characterization of MTN-020 participants who do not accept study product in MTN-025 
 
Participant report of the factors that led to her decision to not accept study product  
 
7.    Exploration of alternative markers of adherence 
 
Hair dapivirine levels 
 
Self-reported product use 
 
 
The following revisions (#12-17) update the URLs where current DAIDS guidance documents can be found:   
 
12. Section 7.13, Specimen Collection and Processing: 
 
Each 
study 
site 
will 
adhere 
to 
the 
standards 
of 
good 
clinical 
laboratory 
practice 
(https://www.niaid.nih.gov/sites/default/files/documents/gclp.pdf) 
 
13. Section 7.14, Specimen Handling: 
 

MTN-025, LoA #02 
28 March 2018 
4 
Specimens will be handled in accordance with current requirements for DAIDS Sponsored and/or Funded 
Laboratories 
in 
Clinical 
Trials. 
(https://www.niaid.nih.gov/sites/default/files/documents/laboratorypolicy1.pdf) 
(https://www.niaid.nih.gov/research/daids-clinical-research-policies-us-labs)  
 
14. Section 8.4.1, Adverse Event 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 RSC website, http://rsc.tech-res.com/clinical-research-sites/safety-reporting/daidsdaers/paper-eae-
reporting. 
 
15. Section 11.2, Source Documents and Access to Source Data/Documents: 
 
All study sites will maintain source data/documents in accordance with Requirements for Source Documentation in 
DAIDS Funded and/or Sponsored Clinical Trials (https://www.niaid.nih.gov/sites/default/files/documents/daids-
sourcedocpolicy.pdf) 
and 
the 
relevant 
appendix 
regarding 
source 
documentation 
(https://www.niaid.nih.gov/sites/default/files/documents/sourcedocappndx.pdf). 
 
16. Section 11.3, Quality Control and Quality Assurance: 
 
All study sites will conduct quality control and quality assurance procedures in accordance with Requirements for 
Clinical 
Quality 
Management 
Plans 
at 
DAIDS 
Funded 
and/or 
Supported 
Clinical 
Research 
Sites 
(https://www.niaid.nih.gov/sites/default/files/documents/qmppolicy.pdf). 
 
17. Section 13.5, Informed Consent Process: 
 
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/documents/daids-sourcedocpolicy.pdf). 
 
 
The following revisions (#18-21) incorporate the changes to protocol text made with CM #1: 
 
18. Section 7.3, Enrollment Visit (Day 0): Table 6, Enrollment Visit has been modified to correct the omission of an 
asterisk indicating that the insertion of one study vaginal ring at the Enrollment Visit is an “if indicated” procedure, see 
bolded text below: 
 
Table 6: Enrollment Visit 
Study Product/Supplies 
 
Offer condoms 
 
Provision of study VR use instructions* 
 
Offer and, if accepted, provide study VR(s) 
 
Insertion of one study VR* 
 
Digital exam by clinician to check VR placement*
 
19. Section 7.11, Laboratory Evaluations, has been modified to add language at the end of the section regarding hair 
collection for consistency with similar language elsewhere in the protocol and consent forms: 
 
IPM or MTN Designated Laboratoriesy: 
 
Study Product- Vaginal Ring 
o 
Adherence assessment(s) 
 
Hair for biomarkers and archive 
 
20. Section 7.13, Specimen Collection and Processing, has been modified to update the URL where the current DAIDS 
standards of good clinical laboratory practice can be found: 
 
Each study site will adhere to the standards of good clinical laboratory practice (http://apps.who.int/tdr/publications/tdr-
research-publications/gclp-web/pdf/gclp-web.pdf) 
(https://www.niaid.nih.gov/LabsAndResources/resources/DAIDSClinRsrch/Documents/gclp.pdf) 
 
21. Section 7.14, Specimen Handling, has been modified to update the URL where the current DAIDS Laboratory Policy 
can be found: 
 

MTN-025, LoA #02 
28 March 2018 
5 
Specimens will be handled in accordance with current requirements for DAIDS Sponsored and/or Funded 
Laboratories in Clinical Trials. 
(http://www.niaid.nih.gov/labsandresources/resources/daidsclinrsrch/documents/labpolicy.pdf)(https://www.niaid.nih.
gov/labsandresources/resources/daidsclinrsrch/Pages/Laboratories.aspx) 
 
 
The following revisions (#22-26) incorporate the changes to protocol text made with CM #2: 
 
22. The following modifications were made to delete language related to cervical fluid collection that remained in the 
protocol text due to an administrative error, as there are no cervical fluid samples being collected for research 
purposes in this study: 
 
a) Appendix V: Sample Informed Consent Document (Enrollment), What Do I Have to Do if I Decide to Take Part in 
the MTN-025 Study?: 
 
 
Provide vaginal fluid and cervical fluid samples: 
- 
To see how the dapivirine vaginal ring protects against HIV and to explore the health of the female genital 
tract.  The vaginal fluid and cervical fluid collected will be used for research purposes only.   
 
b) Appendix V: Sample Informed Consent Document (Enrollment), Consent for Storage and Future Testing of 
Specimens: 
 
There might be a small amount of blood, hair, and vaginal fluid and cervical fluid samples left over after we have 
done all of the study related testing after your study visits.  We would like to ask your permission to store your 
leftover blood, hair, and vaginal fluid, and cervical fluid samples, and related health information for use in future 
studies… You can still enroll in this study if you decide not to have leftover blood, hair, and vaginal fluid and 
cervical fluid samples stored for future studies.  If you do not want the left-over blood, hair, and vaginal fluid and 
cervical fluid samples stored, we will destroy these left over specimens. 
 
23. The following modifications were made to Section 6.4.2, Study Product Dispensing, to clarify that the IoR designee 
can also use their discretion to provide additional rings to participants unable to attend their next scheduled visit: 
 
If the participant is unable to attend her next scheduled visit an additional ring(s) may be provided at the discretion of 
the IoR/designee as permitted in the SSP… 
 
… If a participant requires an additional ring for any reason, at a time other than when she is scheduled to receive 
one, additional product may be dispensed at the discretion of the IoR/designee. 
 
24. The following modifications were made to clarify that hair sampling procedures are optional at each study visit, to be 
consistent with hair sampling language in the sample informed consent: 
 
a) Tables in Section 7.4.1 – Months 1 and 2, Section 7.4.2 –  Quarterly Visits (Months 3, 6, 9), Section 7.4.3 – 
Product Use End Visit (PUEV), and Section 7.4.4 – Study Exit/Termination Visit, only row under “Hair”: 
 
 
Collect hair (required unless participant declines) 
 
b) Appendix I, Schedule of Study Visits and Evaluations, only row under “Hair”: 
 
Hair sample(s) for DPV testing and archive (required unless participant declines) 
 
25. The following modifications were made to Section 11.1, Data Management Responsibilities, to explicitly state that the 
overall data management system used in this study adheres to the US-EU Safe Harbor requirements and the EU 
Data Protection Directive 95/46/EC and is both ICH GCP and CFR compliant, along with a note clarifying how 
paperless data collection is being rolled out in the HOPE study: 
 
Study CRF data are entered into the MTN-025 database, transferred in compliance with the US-EU Safe Harbor 
Requirements and the EU Data Protection Directive 95/46/EC to the MTN SDMC, entered, and cleaned using 
Medidata Rave, athe data management system compliant with the International Council on Harmonization (ICH) 
Good Clinical Practices (GCP) and US CFR guidelines for electronic data capture.   
 

MTN-025, LoA #02 
28 March 2018 
6 
26. The following modifications were made to update the URLs where current DAIDS guidance documents can be found: 
 
a) Section 7.13, Specimen Collection and Processing: 
 
Each 
study 
site 
will 
adhere 
to 
the 
standards 
of 
good 
clinical 
laboratory 
practice 
(https://www.niaid.nih.gov/LabsAndResources/resources/DAIDSClinRsrch/Documents/gclp.pdf) 
(https://www.niaid.nih.gov/sites/default/files/documents/gclp.pdf)  
 
b) Section 7.14, Specimen Handling: 
 
Specimens will be handled in accordance with current requirements for DAIDS Sponsored and/or Funded 
Laboratories 
in 
Clinical 
Trials. 
(https://www.niaid.nih.gov/labsandresources/resources/daidsclinrsrch/Pages/Laboratories.aspx) 
(https://www.niaid.nih.gov/sites/default/files/documents/laboratorypolicy1.pdf)  
 
c) Section 8.4.1, Adverse Event Reporting to DAIDS: 
 
Requirements, definitions and methods for expedited reporting of AEs are outlined in Version 2.0 of the DAIDS 
EAE 
Manual, 
which 
is 
available 
on 
the 
RSC 
website 
at 
http://rsc.tech-
res.com/safetyandpharmacovigilance/http://rsc.tech-res.com/clinical-research-sites/safety-reporting/manual. 
 
d) Section 8.4.1, Adverse Event 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 RSC website, http://rsc.tech-res.com/safetyandpharmacovigilance/http://rsc.tech-
res.com/clinical-research-sites/safety-reporting/daids/paper-eae-reporting. 
 
e) Section 8.4.3, Grading Severity of Events: 
 
The most current DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, Version 2.0, 
November 2014, 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 2.0, November 2014 [Dated 
November 
2007]), 
will 
be 
used 
and 
is 
available 
on 
the 
RSC 
website 
at 
http://rsc.tech-
res.com/safetyandpharmacovigilance/http://rsc.tech-res.com/clinical-research-sites/safety-reporting/daids-
grading-tables. 
 
f) 
Section 11.2, Source Documents and Access to Source Data/Documents: 
 
All study sites will maintain source data/documents in accordance with Requirements for Source Documentation 
in 
DAIDS 
Funded 
and/or 
Sponsored 
Clinical 
Trials 
(http://www.niaid.nih.gov/LabsAndResources/resources/DAIDSClinRsrch/Documents/sourcedocpolicy.pdf)(https:
//www.niaid.nih.gov/sites/default/files/documents/daids-sourcedocpolicy.pdf) and the relevant appendix 
regarding 
source 
documentation 
(http://www.niaid.nih.gov/LabsAndResources/resources/DAIDSClinRsrch/Documents/sourcedocappndx.pdf)(http
s://www.niaid.nih.gov/sites/default/files/documents/sourcedocappndx.pdf). 
 
g) Section 11.3, Quality Control and Quality Assurance: 
 
All study sites will conduct quality control and quality assurance procedures in accordance with Requirements for 
Clinical Quality Management Plans at DAIDS Funded and/or Supported Clinical Research Sites    
(http://www.niaid.nih.gov/LabsAndResources/resources/DAIDSClinRsrch/Documents/qmppolicy.pdfhttp://www.nia
id.nih.gov/LabsAndResources/resources/DAIDSClinRsrch/Documents/qmppolicy.pdf)(https://www.niaid.nih.gov
/sites/default/files/documents/qmppolicy.pdf). 
 
h) Section 13.5, Informed Consent Process: 
 
Study staff must document the informed consent process in accordance with the Requirements for Source 
Documentation 
in 
DAIDS 
Funded 
and/or 
Sponsored 
Clinical 
Trials 
(http://rsc.tech-
res.com/policiesandregulations/)(https://www.niaid.nih.gov/sites/default/files/documents/daids-
sourcedocpolicy.pdf). 
 

MTN-025, LoA #02 
28 March 2018 
7 
Additional minor modifications include:  
 
27. Protocol Team Roster- Updates, including those made with CM #1:  
 
a) From CM #1: 
 
Gonasagrie Nair will be Site Investigator of Record for the Cape Town Emavundleni CRS instead of the 
CAPRISA eThekwini CRS.  
 
 
Logashvari Naidoo will be Site Investigator of Record for the MRC-Chatsworth CRS instead of the MRC-
Tongaat CRS. 
 
 
Zip codes for all US NIH protocol team roster members changed from 20892 to 20852.  
 
 
Addresses for all MTN LOC – FHI 360 protocol team roster members edited to add FHI 360 and remove P.O. 
Box 21059. 
 
 
Ashley Mayo’s title changed to Sr. Clinical Research Manager. 
 
 
MRC CTU Site Investigator titles for Zakir Gaffoor, Nitesha Jeenarain and Samantha Siva changed to CRS 
Leader. 
 
b) Current updates: 
 
Vimla Naicker will be Site Investigator of Record for the MRC-Tongaat CRS and the MRC-Verulam CRS 
instead of the MRC-Botha’s Hill CRS.  
 
 
Zakir Gaffoor will be CRS Leader for the MRC-Verulam CRS instead of the MRC-Chatsworth CRS. 
 
 
Nitesha Jeenarain will be CRS Leader for the MRC-Chatsworth CRS instead of the MRC-Verulam CRS. 
 
 
The name of the University of Zimbabwe-University of California San Francisco Collaborative Research 
Program (UZ-UCSF) Clinical Trials Unit was changed to University of Zimbabwe College of Health Sciences 
Clinical Research Centre (UZCHS-CTRC). 
 
 
Email addresses for all UZCHS-CTRC protocol team roster members edited to change @uz-ucsf.co.zw to 
@uzchs-ctu.org. 
 
 
Luis Duran’s title changed to Project Manager. 
 
 
Devika Singh’s address was changed to 19 Randall Drive, Jericho, VT 05465 USA, her phone number was 
changed to 206-920-0975, and her fax number was removed. 
 
28. Protocol Team Roster- Removals, including those made with CMs #1 and #2:  
 
a) From CM #1: Danielle Crida, Newton Kumwenda, Jeffrey Stringer, Vaneshree Govender, Beth Galaska, 
Kailazarid Gomez, and Fatima Glyn Zulu. 
 
b) From CM #2: Ken Ho, Ian McGowan. 
 
c) Current removals: Arendevi Pather, Anamika Premrajh, Nishanta Singh, Francis Martinson, Ellen Conser, 
Jennifer Berthiaume. 
 
29. Protocol Team Roster- Additions, including those made with CM #1: 
 
a) From CM #1: 
 

MTN-025, LoA #02 
28 March 2018 
8 
Arendevi Pather, BPharm 
CRS Leader (Isipingo) 
MRC- HIV Prevention Research Unit 
P.O. Box 70380 
Overport 4067  
KwaZulu-Natal, South Africa 
Phone: +27 31 242 3600 
Fax: +27 31 242 3800 
Email: arendevi.pather@mrc.ac.za  
 
Bomkazi Tutshana, BA 
CRS Leader (Tongaat) 
MRC- HIV Prevention Research Unit  
P.O. Box 70380  
Overport 4067  
KwaZulu-Natal, South Africa  
Phone: +27 31 242 3600  
Fax: +27 31 242 3800 
Email: Bomkazi.Tutshana@mrc.ac.za 
Anamika Premrajh, MBChB 
Site Investigator of Record (Verulam, Tongaat) 
MRC- HIV Prevention Research Unit 
P.O. Box 70380 
Overport 4067  
KwaZulu-Natal, South Africa 
Phone: +27 31 242 3600 
Fax: +27 31 242 3800 
Email: anamika.premrajh@mrc.ac.za 
 
Vimla Naicker, MBChB 
Site Investigator of Record (Botha’s Hill) 
MRC- HIV Prevention Research Unit 
P.O. Box 70380 
Overport 4067 
KwaZulu-Natal, South Africa 
Phone: +27 31 242 3600 
Fax: +27 31 242 3800 
Email: vimla.naicker@mrc.ac.za 
Nishanta Singh, MBChB 
Site Investigator of Record (Isipingo) 
MRC- HIV Prevention Research Unit 
P.O. Box 70380 
Overport 4067  
KwaZulu-Natal, South Africa 
Phone: +27 31 242 3600 
Fax: +27 31 242 3800 
Email: nishanta.singh@mrc.ac.za 
 
Sufia Dadabhai, MHS, PhD 
Site Investigator, CRS Leader 
Johns Hopkins University Research Project  
Chipatala Avenue 
P.O. Box 1131  
Blantyre, Malawi  
Phone: 265-1875-129  
Fax: 265-1870-132  
Email: sufia@jhu.edu 
Leila Mansoor, B.Pharm, PhD 
Site Investigator of Record 
eThekwini CRS 
3 Richards Road 
Durban 4001 South Africa 
Phone: 27-31-260-4641 
Fax: 27-31-260-4549 
Email: leila.mansoor@caprisa.org 
 
Morgan Garcia, MPH 
Clinical Research Manager 
FHI 360 
359 Blackwell St., Suite 200 
Durham, NC 27703 USA 
Phone: 919-544-7040 x11367  
Fax: 919-544-0207 
Email: mgarcia@fhi360.org 
 
Luis Duran, DrPH, MPIA 
Protocol & Regulatory Specialist  
Microbicide Trials Network 
204 Craft Avenue 
Pittsburgh, PA 15213 USA 
Phone: 412-641-8539 
Fax: 412-641-6170 
Email: duranl2@mwri.magee.edu  
 
Ellen Conser, MA 
Protocol & Regulatory Specialist  
Microbicide Trials Network 
204 Craft Avenue 
Pittsburgh, PA 15213 USA 
Phone: 412-641-2282 
Fax: 412-641-6170 
Email: consere@mwri.magee.edu 
 
Ivan Balán, PhD 
BRWG Representative 
HIV Center for Clinical & Behavioral Studies 
New York State Psychiatric Institute 
1051 Riverside Drive, Unit 15 
New York, NY  10032 USA 
Phone: 646-774-6936 
Fax: 212-543-6003 
Email: balaniv@nyspi.columbia.edu 
 
 
b) Current additions: 
 

MTN-025, LoA #02 
28 March 2018 
9 
Vaneshree Govender, MBChB 
Site Investigator of Record (Isipingo) 
MRC- HIV Prevention Research Unit 
P.O. Box 70380 
Overport 4067  
KwaZulu-Natal, South Africa 
Phone: +27 31 242 3600 
Fax: +27 31 242 3800 
Email: vaneshree.govender@mrc.ac.za 
Kubashni Woeber, M Med Sci, MBA 
CRS Leader (Isipingo) 
MRC- HIV Prevention Research Unit 
P.O. Box 70380 
Overport 4067  
KwaZulu-Natal, South Africa 
Phone: +27 31 242 3600 
Fax: +27 31 242 3800 
Email: Kubashni.Woeber@mrc.ac.za 
Simone Hendricks, MBChB 
Site Investigator of Record (Botha’s Hill) 
MRC- HIV Prevention Research Unit 
P.O. Box 70380 
Overport 4067 
KwaZulu-Natal, South Africa 
Phone: +27 31 242 3600 
Fax: +27 31 242 3800 
Email: Simone.Hendricks@mrc.ac.za 
Lameck Chinula, MBBS, MMed, FCOG 
Site Investigator of Record 
UNC Project, Tidziwe Centre, Kamuzu 
Central Hospital 
Private Bag A-104 
Lilongwe, Malawi 
Phone: 265-99-88-248-3220 
Fax: 265-1-755-954 
Email: lchinula@unclilongwe.org 
 
Jared Baeten, MD, PhD  
Co-Principal Investigator  
University of Washington  
ICRC, Dept of Global Health 
325 Ninth Avenue, Box 359927 
Seattle, WA  98104 
Phone: 206-520-3808 
Fax: 206-520-3831 
Email: jbaeten@uw.edu 
 
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 
  
Teri Senn, PhD 
Program Chief, Psychosocial Co-morbidities of 
HIV Prevention and Treatment 
Division of AIDS Research, NIMH 
5601 Fishers Lane Room 9G29 
Rockville, MD 20852 USA 
Phone: 301-761-7852 
Email: teri.senn@nih.gov 
 
 
 
 
 
 
The above information will be incorporated into the next version of the protocol at a later time if it is amended. 
 
 
 
 
 
 
 
 
 

MTN-025, LoA #02 
28 March 2018 
10 
APPENDIX: MTN-025 INVESTIGATOR SIGNATURE FORM 
 
 
MTN-025 
 
A Phase 3B Open-Label Follow-on Trial to Assess the Continued Safety of and Adherence to a 
Vaginal Ring Containing Dapivirine in Women  
 
INVESTIGATOR SIGNATURE FORM 
Version 2.0; December 16, 2014 
Letter of Amendment #01; April 11, 2016 
Letter of Amendment #02; March 28, 2018 
 
A Study of the Microbicide Trials Network 
 
Funded by: 
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 
 
IND Holder: 
International Partnership for Microbicides (IPM) (DAIDS Protocol ID: 11985) 
 
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 
 
____________________________________ 
___________________________________ 
Signature of Investigator of Record                         Date 
 
 

 
MTN-025, CM #01 
5 August 2016 
1 
Microbicide Trials Network 
 
CLARIFICATION MEMO #01 TO: 
 
 
MTN-025 
 
A Phase 3B Open-Label Follow-on Trial to Assess the Continued Safety of and Adherence to a 
Vaginal Ring Containing Dapivirine in Women 
 
 
DAIDS Protocol #: 11985 
 
 
IND#: 108,743 
 
Version 2.0 / 16 December 2014 
Letter of Amendment #01 / 11 April 2016 
 
 
Clarification Memo Date: 5 August 2016 
Section 1:  Summary of Clarifications and Rationale  
 
The procedures clarified in this Clarification Memorandum (CM) have been approved by the NIAID 
Medical Officer and are to be implemented immediately upon issuance.  IRB approval of this CM is not 
required by the sponsor; however, investigators may submit the CM to the IRB overseeing the study at 
their site for information.  This CM is official MTN-025 documentation and is effective immediately.  A 
copy of this CM must be retained in each study site’s Essential Documents file for MTN-025.  No change 
in informed consent is necessitated by or included in this CM.   
 
This document clarifies language regarding the insertion of one study vaginal ring at the Enrollment Visit, 
and adds language to the laboratory section for consistency with other protocol and consent language 
regarding hair specimen collection. Additionally, this document updates the location of DAIDS laboratory 
policy and guidance documentation, and the Protocol Team Roster. 
 
Section 2:  Implementation  
 
With the exception of updates to the protocol team roster, text to be deleted is noted below with a 
strikethrough and text to be added is in bold. 
 
1.) Section 7.3, Enrollment Visit (Day 0): Table 6, Enrollment Visit has been modified to correct the 
omission of an asterisk indicating that the insertion of one study vaginal ring at the Enrollment 
Visit is an “if indicated” procedure, see bolded text below: 
 
Table 6: Enrollment Visit 
Study Product/Supplies 
 
Offer condoms 
 
Provision of study VR use instructions* 
 
Offer and, if accepted, provide study VR(s) 
 
Insertion of one study VR* 
 
Digital exam by clinician to check VR placement* 
 
 
2.) Section 7.11, Laboratory Evaluations, has been modified to add language at the end of the 
section regarding hair collection for consistency with similar language elsewhere in the protocol 
and consent forms. 
 
IPM or MTN Designated Laboratoriesy: 
 
Study Product- Vaginal Ring 
 
Adherence assessment(s) 

 
MTN-025, CM #01 
5 August 2016 
2 
 
Hair for biomarkers and archive 
 
3.) Section 7.13, Specimen Collection and Processing, has been modified to update the URL where 
the current DAIDS standards of good clinical laboratory practice can be found. 
 
Each study site will adhere to the standards of good clinical laboratory practice 
(http://apps.who.int/tdr/publications/tdr-research-publications/gclp-web/pdf/gclp-web.pdf) 
(https://www.niaid.nih.gov/LabsAndResources/resources/DAIDSClinRsrch/Documents/gcl
p.pdf) 
 
4.) Section 7.14, Specimen Handling, has been modified to update the URL where the current 
DAIDS Laboratory Policy can be found. 
 
Specimens will be handled in accordance with current requirements for DAIDS Sponsored and/or 
Funded Laboratories in Clinical Trials. 
(http://www.niaid.nih.gov/labsandresources/resources/daidsclinrsrch/documents/labpolicy.pdf) 
(https://www.niaid.nih.gov/labsandresources/resources/daidsclinrsrch/Pages/Laboratories
.aspx) 
 
5.) Protocol Team Roster-Updates:   
a) Gonasagrie Nair will be Site Investigator of Record for the Cape Town Emavundleni CRS 
instead of the CAPRISA eThekwini CRS.  
 
b) Logashvari Naidoo will be Site Investigator of Record for the MRC-Chatsworth CRS 
instead of the MRC-Tongaat CRS. 
 
c) Zip codes for all US NIH protocol team roster members changed from 20892 to 20852.  
 
d) Addresses for all MTN LOC – FHI 360 protocol team roster members edited to add FHI 
360 and remove P.O. Box 21059. 
 
e) Ashley Mayo’s title changed to Sr. Clinical Research Manager. 
 
f) 
MRC CTU Site Investigator titles for Zakir Gaffoor, Nitesha Jeenarain and Samantha Siva 
changed to CRS Leader. 
6.) Protocol Team Roster- Removals:  Danielle Crida, Newton Kumwenda, Jeffrey Stringer, 
Vaneshree Govender, Beth Galaska, Kailazarid Gomez, and Fatima Glyn Zulu. 
 
7.) Protocol Team Roster- Additions:  
 
Arendevi Pather, BPharm 
CRS Leader (Isipingo) 
MRC- HIV Prevention Research Unit 
P.O. Box 70380 
Overport 4067  
KwaZulu-Natal, South Africa 
Phone: +27 31 242 3600 
Fax: +27 31 242 3800 
Email: arendevi.pather@mrc.ac.za  
Bomkazi Tutshana, BA 
CRS Leader (Tongaat) 
MRC- HIV Prevention Research Unit  
P.O. Box 70380  
Overport 4067  
KwaZulu-Natal, South Africa  
Phone: +27 31 242 3600  
Fax: +27 31 242 3800 
Email: Bomkazi.Tutshana@mrc.ac.za  

 
MTN-025, CM #01 
5 August 2016 
3 
Anamika Premrajh, MBChB 
Site Investigator of Record (Verulam, Tongaat) 
MRC- HIV Prevention Research Unit 
P.O. Box 70380 
Overport 4067  
KwaZulu-Natal, South Africa 
Phone: +27 31 242 3600 
Fax: +27 31 242 3800 
Email: anamika.premrajh@mrc.ac.za 
 
Nishanta Singh, MBChB 
Site Investigator of Record (Isipingo) 
MRC- HIV Prevention Research Unit 
P.O. Box 70380 
Overport 4067  
KwaZulu-Natal, South Africa 
Phone: +27 31 242 3600 
Fax: +27 31 242 3800 
Email: nishanta.singh@mrc.ac.za 
 
Leila Mansoor, B.Pharm, PhD 
Site Investigator of Record 
eThekwini CRS 
3 Richards Road 
Durban 4001 South Africa 
Phone: 27-31-260-4641 
Fax: 27-31-260-4549 
Email: leila.mansoor@caprisa.org 
 
Luis Duran, DrPH, MPIA 
Protocol & Regulatory Specialist  
Microbicide Trials Network 
204 Craft Avenue 
Pittsburgh, PA 15213 USA 
Phone: 412-641-8539 
Fax: 412-641-6170 
Email: duranl2@mwri.magee.edu  
 
Ivan Balán, PhD 
BRWG Representative 
HIV Center for Clinical & Behavioral Studies 
New York State Psychiatric Institute 
1051 Riverside Drive, Unit 15 
New York, NY  10032 USA 
Phone: 646-774-6936 
Fax: 212-543-6003 
Email: balaniv@nyspi.columbia.edu  
Vimla Naicker, MBChB 
Site Investigator of Record (Botha’s Hill) 
MRC- HIV Prevention Research Unit 
P.O. Box 70380 
Overport 4067 
KwaZulu-Natal, South Africa 
Phone: +27 31 242 3600 
Fax: +27 31 242 3800 
Email: vimla.naicker@mrc.ac.za 
 
Sufia Dadabhai, MHS, PhD 
Site Investigator, CRS Leader 
Johns Hopkins University Research Project  
Chipatala Avenue 
P.O. Box 1131  
Blantyre, Malawi  
Phone: 265-1875-129  
Fax: 265-1870-132  
Email: sufia@jhu.edu 
 
Morgan Garcia, MPH 
Clinical Research Manager 
FHI 360 
359 Blackwell St., Suite 200 
Durham, NC 27703 USA 
Phone: 919-544-7040 x11367  
Fax: 919-544-0207 
Email: mgarcia@fhi360.org 
 
Ellen Conser, MA 
Protocol & Regulatory Specialist  
Microbicide Trials Network 
204 Craft Avenue 
Pittsburgh, PA 15213 USA 
Phone: 412-641-2282 
Fax: 412-641-6170 
Email: consere@mwri.magee.edu 
 
 
 
 
 
 
 
 
 
  
 
 
The above information will be incorporated into the next version of the protocol at a later time if it is 
amended.  

MTN-025, CM #02 
11 November 2016 
1 
Microbicide Trials Network 
 
CLARIFICATION MEMO #02 TO: 
 
 
MTN-025 
 
A Phase 3B Open-Label Follow-on Trial to Assess the Continued Safety of and Adherence to a Vaginal Ring 
Containing Dapivirine in Women 
 
 
DAIDS Protocol #: 11985 
 
 
IND#: 108,743 
 
Version 2.0 / 16 December 2014 
Letter of Amendment #01 / 11 April 2016 
 
 
Clarification Memo Date: 11 November 2016 
Section 1:  Summary of Clarifications and Rationale  
 
The procedures clarified in this Clarification Memorandum (CM) have been approved by the NIAID Medical Officer and 
are to be implemented immediately upon issuance.  IRB/IEC approval of this CM is not required by the sponsor; however, 
investigators may submit the CM to the IRB/IEC overseeing the study at their site for information.  This CM is official MTN-
025 documentation and is effective immediately.  A copy of this CM must be retained in each study site’s Essential 
Documents file for MTN-025.  No change in informed consent is necessitated by or included in this CM.   
 
This document clarifies the intent of one of the exclusion criteria in the context of an open-label follow-on trial to explicitly 
allow former MTN-020(ASPIRE) participants who have moved since ASPIRE and/or who plan to move or travel during 
MTN-025(HOPE) to enroll in HOPE. This document also deletes language related to cervical fluid collection from the 
sample informed consent, which was left in the informed consent text due to an administrative error, clarifies product 
dispensation and hair sampling language for consistency, and clarifies that the data management system utilized is 
compliant with US-EU Safe Harbor, the EU Data Protection Directive 95/46/EC, ICH GCP and CFR requirements. 
Additionally, this document updates the location of DAIDS policy and guidance documentation, and the Protocol Team 
Roster. 
 
Section 2:  Implementation  
 
With the exception of updates to the protocol team roster, text to be deleted is noted below with a strikethrough, text to be 
added is in bold, and text in bold italics is not to be added, but to serve as a clarification of the implementation item in 
question. This information will be included in the protocol the next time the protocol is updated. 
 
1.) The following refers to Section 5.3, Exclusion Criteria, and clarifies the intent of Exclusion Criteria 2a and 2b in the 
context of an open-label follow-on trial to explicitly allow enrollment of former ASPIRE participants who have 
relocated since ASPIRE and/or who plan to relocate or travel during HOPE, but who would otherwise be eligible 
and willing to participate in HOPE: 
 
The intent of Exclusion Criteria 2a and 2b is to ensure that only study participants who will be able to 
adhere to their Study Visit schedule are enrolled.   
 
A participant who plans to move away from the MTN-025 study site at which she will be enrolled (i.e., 
Exclusion Criteria 2a) may still be enrolled if, once she moves, she will have access to another MTN-025 
study site and can be transferred to that other site, or if she is willing and able to travel back to her study 
site to attend study visits. 
 
A participant who plans to travel for more than three months away from the MTN-025 study site at which 
she will be enrolled (i.e., Exclusion Criteria 2b) may still be enrolled if she is willing and able to travel 
back to the study site to attend study visits.   
 

MTN-025, CM #02 
11 November 2016 
2 
Therefore, participants should be excluded from enrollment as per Exclusion Criteria 2a and 2b only if 
they plan to move away from the study site or they plan to travel away from the study site for more than 
three months and they are unwilling or unable to travel back to their site to attend study visits and do not 
have access to any MTN-025 study sites to which they can be transferred for the study. 
 
2.) The following modifications have been made to delete language related to cervical fluid collection that remained in 
the protocol text due to an administrative error, as there are no cervical fluid samples being collected for research 
purposes in this study: 
 
a) Appendix V: Sample Informed Consent Document (Enrollment), What Do I Have to Do if I Decide to Take Part 
in the MTN-025 Study?: 
 
 
Provide vaginal fluid and cervical fluid samples: 
- 
To see how the dapivirine vaginal ring protects against HIV and to explore the health of the female 
genital tract.  The vaginal fluid and cervical fluid collected will be used for research purposes only.   
 
b) Appendix V: Sample Informed Consent Document (Enrollment), Consent for Storage and Future Testing of 
Specimens: 
 
There might be a small amount of blood, hair, and vaginal fluid and cervical fluid samples left over after we have 
done all of the study related testing after your study visits.  We would like to ask your permission to store your 
leftover blood, hair, and vaginal fluid, and cervical fluid samples, and related health information for use in future 
studies… You can still enroll in this study if you decide not to have leftover blood, hair, and vaginal fluid and 
cervical fluid samples stored for future studies.  If you do not want the left-over blood, hair, and vaginal fluid and 
cervical fluid samples stored, we will destroy these left over specimens. 
 
3.) The following modifications have been made to Section 6.4.2, Study Product Dispensing, to clarify that the IoR 
designee can also use their discretion to provide additional rings to participants unable to attend their next 
scheduled visit: 
 
If the participant is unable to attend her next scheduled visit an additional ring(s) may be provided at the discretion 
of the IoR/designee as permitted in the SSP… 
 
… If a participant requires an additional ring for any reason, at a time other than when she is scheduled to receive 
one, additional product may be dispensed at the discretion of the IoR/designee. 
 
4.) The following modifications have been made to clarify that hair sampling procedures are optional at each study 
visit, to be consistent with hair sampling language in the sample informed consent: 
 
a) Tables in Section 7.4.1 – Months 1 and 2, Section 7.4.2 –  Quarterly Visits (Months 3, 6, 9), Section 7.4.3 – 
Product Use End Visit (PUEV), and Section 7.4.4 – Study Exit/Termination Visit, only row under “Hair”: 
 
 
Collect hair (required unless participant declines) 
 
b) Appendix I, Schedule of Study Visits and Evaluations, only row under “Hair”: 
 
Hair sample(s) for DPV testing and archive (required unless participant declines) 
 
5.) The following modifications have been made to Section 11.1, Data Management Responsibilities, to explicitly 
state that the overall data management system used in this study adheres to the US-EU Safe Harbor 
requirements and the EU Data Protection Directive 95/46/EC and is both ICH GCP and CFR compliant, along 
with a note clarifying how paperless data collection is being rolled out in the HOPE study: 
 
Study CRF data are entered into the MTN-025 database, transferred in compliance with the US-EU Safe 
Harbor Requirements and the EU Data Protection Directive 95/46/EC to the MTN SDMC, entered, and 
cleaned using Medidata Rave, athe data management system compliant with the International Council on 
Harmonization (ICH) Good Clinical Practices (GCP) and US CFR guidelines for electronic data capture.   
 
Screening visit CRFs will first be completed in paper format, with data entered into the electronic format 
CRFs (eCRFs) in the Medidata Rave study database after an enrollment determination has been made for 
a given participant. The intent is for all other CRFs to be completed in electronic format (paperless) only. 

MTN-025, CM #02 
11 November 2016 
3 
Sites may continue to complete enrollment and follow-up visit CRFs in paper format first, prior to data 
entry into the study database, until they have completed their transition to paperless eCRF completion in 
the study database. 
 
6.) The following modifications have been made to update the URLs where current DAIDS guidance documents can 
be found: 
 
a) Section 7.13, Specimen Collection and Processing: 
 
Each 
study 
site 
will 
adhere 
to 
the 
standards 
of 
good 
clinical 
laboratory 
practice 
(https://www.niaid.nih.gov/LabsAndResources/resources/DAIDSClinRsrch/Documents/gclp.pdf) 
(https://www.niaid.nih.gov/sites/default/files/documents/gclp.pdf)  
 
b) Section 7.14, Specimen Handling, has been modified to update the URL where the current DAIDS Laboratory 
Policy can be found: 
 
Specimens will be handled in accordance with current requirements for DAIDS Sponsored and/or Funded 
Laboratories 
in 
Clinical 
Trials. 
(https://www.niaid.nih.gov/labsandresources/resources/daidsclinrsrch/Pages/Laboratories.aspx) 
(https://www.niaid.nih.gov/sites/default/files/documents/laboratorypolicy1.pdf)  
 
c) Section 8.4.1, Adverse Event Reporting to DAIDS, has been modified to update the URL where the current 
DAIDS EAE Manual can be found: 
 
Requirements, definitions and methods for expedited reporting of AEs are outlined in Version 2.0 of the DAIDS 
EAE 
Manual, 
which 
is 
available 
on 
the 
RSC 
website 
at 
http://rsc.tech-
res.com/safetyandpharmacovigilance/http://rsc.tech-res.com/clinical-research-sites/safety-reporting/manual. 
 
d) Section 8.4.1, Adverse Event Reporting to DAIDS, has been modified to update the URL where the current 
DAIDS EAE Form can be found: 
 
In the event of system outages or technical difficulties, EAEs may be submitted via the DAIDS EAE Form.  This 
form is available on the RSC website, http://rsc.tech-res.com/safetyandpharmacovigilance/http://rsc.tech-
res.com/clinical-research-sites/safety-reporting/daids/paper-eae-reporting. 
 
e) Section 8.4.3, Grading Severity of Events, has been modified to update the URL where the current DAIDS AE 
Grading Tables can be found: 
 
The most current DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, Version 2.0, 
November 2014, 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 2.0, November 2014 [Dated 
November 
2007]), 
will 
be 
used 
and 
is 
available 
on 
the 
RSC 
website 
at 
http://rsc.tech-
res.com/safetyandpharmacovigilance/http://rsc.tech-res.com/clinical-research-sites/safety-reporting/daids-
grading-tables. 
 
f) 
Section 11.2, Source Documents and Access to Source Data/Documents, has been modified to update the 
URL where the current Requirements for Source Documentation in DAIDS Funded and/or Sponsored Clinical 
Trials policy and appendices can be found: 
 
All study sites will maintain source data/documents in accordance with Requirements for Source Documentation 
in 
DAIDS 
Funded 
and/or 
Sponsored 
Clinical 
Trials 
(http://www.niaid.nih.gov/LabsAndResources/resources/DAIDSClinRsrch/Documents/sourcedocpolicy.pdf)(https:
//www.niaid.nih.gov/sites/default/files/documents/daids-sourcedocpolicy.pdf) and the relevant appendix 
regarding 
source 
documentation 
(http://www.niaid.nih.gov/LabsAndResources/resources/DAIDSClinRsrch/Documents/sourcedocappndx.pdf)(http
s://www.niaid.nih.gov/sites/default/files/documents/sourcedocappndx.pdf). 
 
g) Section 11.3, Quality Control and Quality Assurance, has been modified to update the URL where the current 
Requirements for Clinical Quality Management Plans at DAIDS Funded and/or Supported Clinical Research 
Sites policy can be found: 
 

MTN-025, CM #02 
11 November 2016 
4 
All study sites will conduct quality control and quality assurance procedures in accordance with Requirements for 
Clinical Quality Management Plans at DAIDS Funded and/or Supported Clinical Research Sites    
(http://www.niaid.nih.gov/LabsAndResources/resources/DAIDSClinRsrch/Documents/qmppolicy.pdfhttp://www.nia
id.nih.gov/LabsAndResources/resources/DAIDSClinRsrch/Documents/qmppolicy.pdf)(https://www.niaid.nih.gov
/sites/default/files/documents/qmppolicy.pdf). 
 
h) Section 13.5, Informed Consent Process, has been modified to update the URL where the current 
Requirements for Source Documentation in DAIDS Funded and/or Sponsored Clinical Trials policy can be 
found: 
 
Study staff must document the informed consent process in accordance with the Requirements for Source 
Documentation 
in 
DAIDS 
Funded 
and/or 
Sponsored 
Clinical 
Trials 
(http://rsc.tech-
res.com/policiesandregulations/)(https://www.niaid.nih.gov/sites/default/files/documents/daids-
sourcedocpolicy.pdf). 
 
7.) Protocol Team Roster- Removals:  Ken Ho, Ian McGowan. 
 
 
The above information will be incorporated into the next version of the protocol at a later time if it is amended.