A Follow-On, Open-Label Trial To Assess Continued Safety Of And Adherence To The Dapivirine (25 Mg) Vaginal Ring-004 In Healthy, HIV-Negative Women
Phase: PHASE3
Conditions: HIV Prevention
Sponsor: International Partnership for Microbicides, Inc.

 
IPM 032 
Protocol 
 
CONFIDENTIAL 
CLIN-TEM-GEN-0001.00, 13Jan2016 
 
Page 1 of 1 
 
NCT02862171 
 
IPM 032 
 
A FOLLOW-ON, OPEN-LABEL TRIAL TO ASSESS CONTINUED SAFETY OF AND 
ADHERENCE TO THE DAPIVIRINE (25 mg) VAGINAL RING-004 IN HEALTHY, HIV-NEGATIVE 
WOMEN  
 
• 
Protocol Version 2.0 Amendment 1.0 dated 22 October 2015 
 

IPM 032 
 
   22 October 2015 
Version 2.0 Amendment 1.0 
 
Page 1 of 69 
Restricted * Confidential – Limited Access* 
IPM 032 
 
Version 2.0 Amendment 1.0 
 
22 October 2015 
 
 
 
A FOLLOW-ON, OPEN-LABEL TRIAL TO ASSESS CONTINUED SAFETY OF AND 
ADHERENCE TO THE DAPIVIRINE (25 mg) VAGINAL RING-004 IN HEALTHY, 
HIV-NEGATIVE WOMEN 
 
 
 
 
Phase IIIb 
 
 
 
 
SPONSOR: 
International Partnership for Microbicides 
8401 Colesville Road, Suite 200 
Silver Spring, MD 20910 U.S.A. 
Phone: 1-301-608-2221 
Fax: 1-301-608-2241 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

IPM 032 
 
   22 October 2015 
Version 2.0 Amendment 1.0 
 
Page 2 of 69 
Restricted * Confidential – Limited Access* 
SIGNATURE PAGE 
 
 
IPM 032 
 
A FOLLOW-ON, OPEN-LABEL TRIAL TO ASSESS CONTINUED SAFETY OF AND 
ADHERENCE TO THE DAPIVIRINE (25 mg) VAGINAL RING-004 IN HEALTHY, 
HIV-NEGATIVE WOMEN 
 
I have read this protocol and appendices and agree to conduct the trial as stipulated and 
in compliance with the principles of the World Medical Association Declaration of 
Helsinki, the International Conference on Harmonisation (ICH) Good Clinical Practice 
(GCP) guidelines, and all applicable regulations and guidelines. 
 
 
 
__________________________________   
__________________________ 
Investigator Signature 
 
 
 
Date 
 
 
__________________________________  
___________________________ 
Investigator Name (Printed)  
 
 
Research Centre Name 
 
 
 
On behalf of the International Partnership for Microbicides, I confirm that the sponsor will 
comply with all obligations as detailed in all applicable regulations and guidelines. I will 
ensure that the investigator is informed of all relevant information that becomes available 
during the conduct of this trial. 
 
 
____________________________________ 
_____________________________ 
Chief Medical Officer Signature 
 
 
Date 
 
 
Annaléne Nel, MBChB, PhD  
 
 
 
Chief Medical Officer Name (Printed) 
 
 
 
 

IPM 032 
 
   22 October 2015 
Version 2.0 Amendment 1.0 
 
Page 3 of 69 
Restricted * Confidential – Limited Access* 
TABLE OF CONTENTS 
 
ACRONYMS AND ABBREVIATIONS.............................................................................. 6 
1. 
Introduction ............................................................................................................ 18 
1.1. Background ..................................................................................................... 18 
1.2. Dapivirine Vaginal Ring ................................................................................... 18 
1.3. Nonclinical Studies .......................................................................................... 19 
1.4. Clinical Trials ................................................................................................... 20 
1.5. Rationale for Protocol IPM 032 ........................................................................ 23 
2. 
Trial Objectives ...................................................................................................... 23 
2.1. Trial Objectives ............................................................................................... 23 
2.2. Trial Endpoints and Assessments ................................................................... 24 
3. 
Overall Trial Design................................................................................................ 25 
3.1. Trial Design ..................................................................................................... 25 
3.2. Trial Duration .................................................................................................. 26 
3.3. Trial Population ............................................................................................... 26 
4. 
Trial Visits and Procedures .................................................................................... 27 
4.1. Screening Visit ................................................................................................ 27 
4.2. Enrolment Visit ................................................................................................ 28 
4.3. Trial Visits (monthly research centre visits for the first one to three months, and 
3-monthly research centre visits thereafter) .......................................................... 29 
4.4. Last Product Use Visit (LPUV) or Early Discontinuation Visit........................... 30 
4.5. Exit Visit .......................................................................................................... 32 
4.6. Unscheduled Visits .......................................................................................... 32 
4.7. Missed and Late Visits .................................................................................... 33 
4.8. Protocol Deviations ......................................................................................... 33 
4.9. Early Discontinuation Visits ............................................................................. 33 
4.10. Premature Discontinuation of the Trial ........................................................ 34 
5. 
Trial Procedure Details ........................................................................................... 34 
5.1. Informed Consent ............................................................................................ 34 
5.2. Comprehension Assessment Checklist ........................................................... 36 
5.3. HIV Counselling .............................................................................................. 36 
5.4. HIV Testing and Management ......................................................................... 36 
5.5. Contraceptive Counselling and Management of Contraception ....................... 40 
5.6. Pregnancy Testing and Management .............................................................. 41 

IPM 032 
 
   22 October 2015 
Version 2.0 Amendment 1.0 
 
Page 4 of 69 
Restricted * Confidential – Limited Access* 
5.7. Demographics and Medical History ................................................................. 42 
5.8. Physical Examination ...................................................................................... 42 
5.9. Pelvic Examination .......................................................................................... 42 
5.10. Laboratory testing for safety assessments and urine dipstick analysis ........ 42 
5.11. STI Testing and Management ..................................................................... 43 
5.12. Cervical Cytology ........................................................................................ 43 
5.13. Vaginal Ring Dispensing ............................................................................. 44 
5.14. Vaginal Ring Insertion and Ring Removal ................................................... 44 
5.15. Vaginal Ring Adherence Counselling .......................................................... 45 
5.16. Participant Questionnaire ............................................................................ 45 
5.17. Sample Storage and Analysis ..................................................................... 45 
5.18. Screening Identification (SCR-ID) and Participant Identification (PID) 
Numbers ............................................................................................................... 46 
5.19. Diary cards .................................................................................................. 46 
5.20. Reimbursement ........................................................................................... 46 
5.21. Participant Compensation ........................................................................... 46 
5.22. Participant Responsibility ............................................................................ 46 
5.23. Study Operations Manual (SOM) ................................................................ 47 
6. 
Investigational Product ........................................................................................... 47 
6.1. Investigational Product Composition ............................................................... 47 
6.2. Packaging and Labelling ................................................................................. 47 
6.3. Investigational Product Storage ....................................................................... 47 
6.4. Investigational Product Administration ............................................................. 48 
6.5. Investigational Product Expulsion or Loss ....................................................... 48 
6.6. Retrieval of Investigational Product ................................................................. 48 
6.7. Investigational Product (IP) Accountability....................................................... 49 
6.8. Concomitant Medications and Products .......................................................... 49 
7. 
Adverse Events ...................................................................................................... 49 
7.1. Definition ......................................................................................................... 49 
7.2. Assessment of Adverse Event Severity ........................................................... 50 
7.3. Relationship to Investigational Product ............................................................ 50 
7.4. Serious Adverse Event .................................................................................... 51 
7.5. Immediately Reportable Events ....................................................................... 53 
7.6. Safety Monitoring ............................................................................................ 53 
7.7. Data Handling at Research Centres ................................................................ 53 
7.8. Source Data Verification .................................................................................. 53 
8. 
Statistical Methods ................................................................................................. 54 
8.1. Trial Endpoints ................................................................................................ 54 
8.2. Primary Trial Hypotheses ................................................................................ 54 
8.3. Sample Size and Power Calculations .............................................................. 54 
8.4. Statistical Analyses ......................................................................................... 54 

IPM 032 
 
   22 October 2015 
Version 2.0 Amendment 1.0 
 
Page 5 of 69 
Restricted * Confidential – Limited Access* 
8.5. Data and Safety Monitoring Board .................................................................. 56 
8.6. Handling of Missing Data and Dropouts .......................................................... 56 
9. 
Investigator Requirements ..................................................................................... 56 
9.1. Trial Initiation ................................................................................................... 56 
9.2. Institutional Review Boards or Independent Ethics Committee Approval ......... 56 
9.3. Trial Monitoring and Audits .............................................................................. 57 
9.4. Case Report Forms (CRFs)............................................................................. 57 
9.5. Disclosure of Data ........................................................................................... 57 
9.6. Record Retention ............................................................................................ 57 
10. Ethical Considerations ........................................................................................... 58 
10.1. Ethical Review ............................................................................................ 58 
10.2. Reporting and Management of Social Harms related to trial participation .... 58 
10.3. Community Engagement ............................................................................. 58 
11. Publications ........................................................................................................... 59 
12. References ............................................................................................................ 60 
APPENDIX A: SCHEDULE OF PROCEDURES ............................................................ 61 
APPENDIX B: HIV TESTING ALGORITHM................................................................... 63 
APPENDIX C: VISIT SCHEDULE AND APPROXIMATE BLOOD VOLUMES ............... 68 
APPENDIX D: TRIAL DESIGN ...................................................................................... 69 
 
 
 

IPM 032 
 
   22 October 2015 
Version 2.0 Amendment 1.0 
 
Page 6 of 69 
Restricted * Confidential – Limited Access* 
ACRONYMS AND ABBREVIATIONS 
AE  
Adverse Event  
AIDS  
Acquired Immunodeficiency Syndrome  
ALT  
Alanine aminotransferase  
ARV  
Antiretroviral  
AST  
Aspartate aminotransferase  
AUC  
Area Under Plasma Concentration-time Curve  
BV 
Bacterial Vaginosis  
b.i.d. 
“bis in die”/twice a day 
ºC 
Degree Celsius 
CI 
Confidence Interval 
CNS 
Central Nervous System 
CRF  
Case Report Form  
CT 
Chlamydia Trachomatis 
DAIDS  
Division of Acquired Immunodeficiency Syndrome  
DAPY  
Di-aminopyrimidine  
DSMB  
Data and Safety Monitoring Board  
EC50  
50% Effective Inhibition Concentration 
FBC  
Full Blood Count  
FDA  
Food & Drug Administration (U.S.)  
GCP  
Good Clinical Practice  
HIV  
Human Immunodeficiency Virus  
Hu-SCID 
Humanized Severe Combined Immunodeficient  
ICF 
Informed Consent Form 
ICH  
International Conference on Harmonisation  
IEC  
Independent Ethics Committee  
IB 
Investigator’s Brochure 
IP 
Investigational Product 
IPM  
International Partnership for Microbicides  
IRB  
Institutional Review Board  
IRE  
Immediately Reportable Event  
ITT  
Intent-To-Treat 
LPUV 
Last Product Use Visit 
MedDRA 
Medical Dictionary for Regulatory Activities  
MTD  
Maximum Tolerated Dose  
MTN  
Microbicide Trials Network  
NAAT 
Nucleic Acid-Amplification Testing 
NG 
Neisseria Gonorrhoeae 
NNRTI  
Non-nucleoside Reverse Transcriptase Inhibitor  
NOAEL 
No Adverse Effect Level 
PCR  
Polymerase Chain Reaction  
PID  
Participant Identification  
PMTCT  
Prevention of Mother-to-Child Transmission of HIV  
PEP  
Post-Exposure Prophylaxis 
PT 
Preferred Term 
RNA  
Ribonucleic Acid  
RPR  
Rapid Plasma Reagin  
RT 
Reverse transcriptase 
SAE  
Serious Adverse Event  
SAP  
Statistical Analysis Plan  

IPM 032 
 
   22 October 2015 
Version 2.0 Amendment 1.0 
 
Page 7 of 69 
Restricted * Confidential – Limited Access* 
SCR-ID 
Screening Identification  
SOC 
System Organ Class 
SOM 
Study Operations Manual 
SOP 
Standard Operating Procedure 
STI  
Sexually Transmitted Infection 
TEAE  
Treatment Emergent Adverse Event  
TPHA  
Treponema Pallidum Haemagglutination Test  
TPPA  
Treponema Pallidum Particle Agglutination Assay  
TV 
Trichomonas Vaginalis 
UNAIDS  
Joint United Nations Programme on HIV/AIDS  
WHO  
World Health Organization 
 
 
 
 
 
 

IPM 032 
 
   22 October 2015 
Version 2.0 Amendment 1.0 
 
Page 8 of 69 
Restricted * Confidential – Limited Access* 
 
PROTOCOL SYNOPSIS 
IPM 032 
 
A FOLLOW-ON, OPEN-LABEL TRIAL TO ASSESS CONTINUED SAFETY OF AND 
ADHERENCE TO THE DAPIVIRINE (25 mg) VAGINAL RING-004 IN HEALTHY, 
HIV-NEGATIVE WOMEN 
 
BACKGROUND:  
The Phase III clinical program of Dapivirine Vaginal Ring-004, 
containing 25 mg of dapivirine, consists of the MTN-020 and 
IPM 027 clinical trials. These trials are conducted in South Africa, 
Uganda, Zimbabwe and Malawi, to assess the safety and efficacy 
of the Dapivirine Vaginal Ring-004 in preventing the acquisition of 
HIV-1 infection through male to female transmission in healthy, 
HIV-negative women. 
 
IPM 032, a Phase IIIb follow-on trial to IPM 027, has been 
designed as an open-label clinical trial to collect additional safety 
data and establish adherence to ring use of the Dapivirine (25 mg) 
Vaginal Ring-004 in healthy, HIV-negative women with monthly (at 
least one to a maximum of three months) followed by 3-monthly 
research centre follow-up visits over 12 months.  The safety results 
and the level of efficacy observed in IPM 027 and MTN-020 will be 
communicated to the relevant local and international regulatory 
authorities, IRBs/IECs, community representatives, participants 
and key stakeholders, as appropriate, before activation of IPM 
032. 
 
IPM 032 will be an open-label clinical trial to assess the continued 
safety of and adherence to the Dapivirine Vaginal Ring-004, 
inserted monthly in healthy, HIV-negative women. 
 
OBJECTIVES: 
The Primary Trial Objectives are: 
 
1. To assess the safety profile of the 25 mg Dapivirine Vaginal 
Ring-004, when inserted at monthly intervals, in an open-label 
trial  
2. To assess adherence to the use of the 25 mg Dapivirine 
Vaginal Ring-004 inserted at monthly intervals, in an open-
label trial  
 
The Secondary Trial Objectives are: 
 
1. To assess the incidence of HIV-1 seroconversion 
2. To assess the frequency of HIV-1 drug resistance in women 
who acquire HIV-1 infection 
 
 
 
 
 
 
 

IPM 032 
 
   22 October 2015 
Version 2.0 Amendment 1.0 
 
Page 9 of 69 
Restricted * Confidential – Limited Access* 
 
The Exploratory Trial Objectives are: 
 
1. 
To assess the feasibility of 3-monthly follow-up visits, as a 
possible schedule for post-licensure vaginal ring clinical 
follow-up 
2. 
To explore the correlation between drug concentrations and 
results from the visual inspection of the returned vaginal rings 
by research staff between the monthly and 3-monthly research 
centre follow-up schedules 
3. 
To determine the proportion of participants electing to undergo 
HIV rapid tests at the research centres between scheduled 3-
monthly visits 
 
 
ENDPOINTS AND ASSESSMENTS:  
 
 
The primary endpoints are: 
 
1. 
Safety  
• 
All Adverse Events (AEs) assessed by the investigator to 
be related to the Dapivirine Vaginal Ring-004 
• 
All Grade 3 and 4 AEs 
• 
All Serious Adverse Events (SAEs) 
 
2. 
Adherence 
• 
Residual amounts of dapivirine in returned rings; and/or 
dapivirine concentrations in plasma and/or dapivirine 
concentrations in vaginal fluid  
 
 
The primary endpoints will be assessed through: 
 
1. 
Safety  
• 
All product-related AEs, Grade 3 or 4 AEs, SAEs, physical 
examination, 
gynaecological 
assessments, 
including 
pelvic/speculum examination, laboratory tests and other 
indicated investigations 
 
2. 
Adherence 
• 
Determined dapivirine residual amounts in returned used 
vaginal rings and/or 
• 
Measured concentrations of dapivirine in plasma and/or 
• 
Measured concentrations of dapivirine in vaginal fluids  
 
 
 
 

IPM 032 
 
   22 October 2015 
Version 2.0 Amendment 1.0 
 
Page 10 of 69 
Restricted * Confidential – Limited Access* 
 
The secondary endpoints are: 
 
• 
The HIV-1 seroconversion rate per 100 woman-years of 
product use at the end of the vaginal ring use period 
• 
HIV-1 drug resistance mutations among participants who 
acquire HIV-1 infection 
 
 
The secondary endpoints will be assessed through: 
 
• 
Rapid and specialised laboratory testing according to a 
pre-specified HIV testing algorithm 
• 
Viral genotype resistance testing methods 
 
  
 
The exploratory endpoints are: 
 
• 
Feasibility of 3-monthly clinical follow-up schedule 
• 
Dapivirine residual amounts in returned used vaginal rings 
and/or dapivirine concentrations in blood and/or vaginal 
fluid in correlation with results from the visual inspection 
of the returned used vaginal rings by research staff 
• 
Proportion of participants opting for HIV rapid tests at the 
research centre between scheduled 3-monthly research 
centre follow-up visits 
 
 
The exploratory endpoints will be assessed through: 
 
• 
Participant report of feasibility regarding a 3-monthly 
clinical follow-up schedule (Participant Questionnaire)    
• 
Number of women opting not to receive two additional 
rings at the 3-monthly visits  
• 
Proportion of returned rings (used and unused) during the 
3-monthly clinical follow-up schedule 
• 
Dapivirine residual amounts in returned used vaginal rings 
and/or dapivirine concentrations in blood and/or vaginal 
fluid 
• 
Visual inspection of the returned used vaginal rings by 
research centre staff 
• 
Number of participants undergoing HIV rapid tests at the 
research centre between scheduled 3-monthly research 
centre follow-up visits 
 
TRIAL DESIGN:  
IPM 032 is a Phase IIIb, multi-centre follow-on open-label trial to 
evaluate the continued adherence to and safety of the Dapivirine 
Vaginal Ring-004 inserted at monthly intervals in healthy, HIV-

IPM 032 
 
   22 October 2015 
Version 2.0 Amendment 1.0 
 
Page 11 of 69 
Restricted * Confidential – Limited Access* 
negative women who have participated in the IPM 027 Phase III 
Dapivirine Vaginal Ring-004 trial. All women who have participated 
in IPM 027 and are HIV-negative at screening for IPM 032 will be 
eligible. An estimate of approximately 1400 participants will be 
enrolled.    
 
All participants will attend a research centre follow-up visit one 
month after enrolment.  Following this visit, at investigator’s 
discretion, a participant can continue on a 3-monthly visit 
schedule.   Monthly visits may however be extended up to the first 
three months of participation. Once the 3-monthly trial visit 
schedule commences, three rings will be dispensed to the 
participant.  One ring will be self-inserted at the research centre 
and two additional rings will be dispensed for the participant to 
take home, or dispensing will take place as arranged with the 
participant.  
 
 
  
TRIAL DURATION:  Each participant will engage in the screening process for up to 45 
days prior to enrolment and will use the Dapivirine Vaginal Ring-
004 for a period of up to 12 months. IPM will have the option to 
extend this trial period. Accrual will take place over approximately 
6 months and those participants who are enrolled more than 6 
months after the onset of the study site’s accrual period may have 
a shortened follow-up period. 
 
Each participant will have an exit visit 1-2 months after ring 
discontinuation, to assess safety and identify HIV seroconversions 
after product discontinuation.  
 
POPULATION AND SAMPLE SIZE: 
 
Approximately 1400 HIV-negative women who have participated in 
the IPM 027 Phase III Dapivirine Vaginal Ring-004 trial, who 
understand the trial, and can provide informed consent, are 
expected to enrol in this open-label trial.   
 
INCLUSION CRITERIA: 
Women must meet all of the following criteria to be eligible for trial 
enrolment: 
 
1. 
Previously enrolled in the IPM 027 trial  
2. 
Available for all visits and consent to follow all procedures 
scheduled for the trial 
3. 
Using an effective method of contraception at the 
Enrolment Visit, and intending to use an effective 
contraceptive method for the duration of trial participation, 
unless post-menopausal with no history of menses for 
one year prior to screening  
4. 
HIV-negative as determined by the HIV algorithm applied 
at Screening/Pre-Enrolment 

IPM 032 
 
   22 October 2015 
Version 2.0 Amendment 1.0 
 
Page 12 of 69 
Restricted * Confidential – Limited Access* 
5. 
Willing to refrain from participation in another research 
trial using drugs, vaccines, medical devices and 
microbicides for the duration of the IPM 032 trial 
6. 
Willing to provide adequate locator information for trial 
retention purposes and be reachable per local standard 
procedures (e.g. by home visit or telephone; or via family 
or close neighbour contacts); confidentiality to be 
maintained 
 
EXCLUSION CRITERIA: 
Women who meet any of the following criteria are NOT eligible to 
enroll in the trial: 
 
1. 
Investigational product use permanently discontinued in 
response to an AE (where the AE was considered related 
to investigational product) or safety-related concern while 
taking part in the IPM 027 trial  
2. 
Participant self-report of taking post-exposure prophylaxis 
(PEP) within ≤ 2 months at Screening Visit 
Note: Participants may be enrolled after completing the 
PEP regimen and a negative HIV test was documented at 
least 2 months prior to screening for IPM 032 
3. 
Currently pregnant, intends to become pregnant, or 
currently breast-feeding 
4. 
Known drug abuse or alcohol dependence in the 12 
months prior to screening 
5. 
Participated in another research trial (other than IPM 027) 
using drugs, medical devices, microbicides or oral pre-
exposure prophylaxis agents within 30 days prior to 
screening 
6. 
Any new illness or condition(s), chronic condition(s) or 
abnormal laboratory finding(s) that, in the opinion of the 
investigator, might put the participant at risk, or interfere 
with the trial objectives or the participant’s adherence to 
trial requirements 
 
METHODS: 
Screening Visit:  
 
Potential participants who are HIV-negative, who participated in 
IPM 027 and who provide informed consent will be invited to 
screen for the trial and to enrol in the open-label follow-on study. 
After informed consent is obtained, a SCR-ID number will be 
assigned to each potential participant for identification purposes 
and the potential participant will be screened to assess eligibility 
for the study. A comprehension checklist will be used to support 
the informed consent process.   
 
 At screening, potential participants will provide information on 
inclusion and exclusion criteria, including locator and basic 

IPM 032 
 
   22 October 2015 
Version 2.0 Amendment 1.0 
 
Page 13 of 69 
Restricted * Confidential – Limited Access* 
menses information, demographic information, and medical and 
concomitant medication history.  Each potential participant will 
receive a general physical examination and pelvic examination.  
 
All potential participants will be provided with HIV/STI risk-
reduction counselling (including provision of male condoms, 
should 
participants 
wish 
to 
receive 
them), 
contraceptive 
counselling 
and 
HIV 
pre- 
and 
post-test 
counselling. 
Contraceptives will be provided if necessary, as well as treatment 
and/or referral for sexually transmitted infections (STIs) and other 
findings as necessary. Safety laboratory assessments, urine 
dipstick analysis (microscopy only if clinically indicated), cervical 
sample collection for cytology and testing for pregnancy, HIV, 
STIs, and syphilis will be performed. Blood samples for HIV-1 
RNA PCR and HIV viral genotype resistance testing will be 
collected and stored for retrospective testing subsequent to a 
confirmed HIV-1 seroconversion. 
 
 
Enrolment Visit: 
 
At the Enrolment Visit, potential participants will provide 
information on inclusion and exclusion criteria, including locator 
and basic menses information, and medical and concomitant 
medication history.  AEs (post-enrolment) and the occurrence of 
possible social harms will be assessed. 
 
All potential participants will be provided with HIV/STI risk-
reduction counselling (including provision of male condoms, 
should 
participants 
wish 
to 
receive 
them), 
contraceptive 
counselling and provision of contraceptives (if necessary), HIV 
pre- and post-test counselling and vaginal ring adherence 
counselling. Participants will be provided with feedback on the 
IPM 027 and MTN-020 trial results. Diary cards will be issued with 
instructions for completion. Testing for pregnancy and HIV will be 
performed. Blood samples will be collected for storage, and HIV-1 
RNA PCR and HIV viral genotype resistance testing will be 
performed 
retrospectively 
subsequent 
to 
confirmed 
HIV-1 
seroconversion.  
 
Eligible women will be assigned a unique PID number. Each  
participant will be provided with vaginal ring use and storage  
instructions and instructed to self-insert a newly dispensed vaginal  
ring.  
 
Trial Visits:  
All participants will provide information on concomitant medication, 
locator details and menses. Participants will receive pre- and post-
test HIV counselling; HIV/STI risk reduction counselling; vaginal 
ring adherence counselling; HIV rapid testing and pregnancy 
testing. Male condoms will be provided at all visits, should 
participants wish to receive them, as part of HIV/STI risk reduction 

IPM 032 
 
   22 October 2015 
Version 2.0 Amendment 1.0 
 
Page 14 of 69 
Restricted * Confidential – Limited Access* 
counselling. Contraceptive counselling and contraceptives (if 
needed) will be provided at all visits. Possible occurrence of social 
harms will be assessed during research centre visits.   
 
Blood samples will be collected for storage at each trial visit and 
will be tested retrospectively by HIV-1 RNA PCR and HIV viral 
genotype resistance testing subsequent to confirmed HIV 
seroconversion.  At the point of HIV seroconversion, vaginal ring 
use will be discontinued, and in addition, blood samples for viral 
genotype resistance testing will be collected at the scheduled exit 
visit, 1-2 months following seroconversion.  
 
Blood and vaginal fluid samples will be collected for possible 
measurement of dapivirine concentrations. Returned rings will be 
visually inspected by research centre staff and may also be 
analysed for residual amounts of dapivirine. 
 
Returned diary cards will be reviewed and new diary cards issued 
to participants as applicable. Each participant will be asked to 
complete a Participant Questionnaire at every trial visit.  AEs will 
be assessed at all visits post-enrolment. In addition, if clinically 
indicated, safety laboratory assessments, urine dipstick analysis 
(microscopy only if clinically indicated), pelvic examinations, 
cervical sample collection for cytology, physical examinations and 
STI tests will be performed. Treatment and/or referral for STIs and 
other findings may be performed, if required.    
 
At each trial visit, participants will return used vaginal rings and 
each participant will be instructed to self-insert a newly-dispensed 
vaginal ring and be provided with vaginal ring use and storage 
instructions. Two additional rings will be dispensed once 
participants commence with the 3-monthly trial visit schedule,  
which the participants should self-insert at monthly intervals, at 
home, until the next Trial Visit. Participants who prefer not to have 
additional vaginal rings in their possession may also choose to 
return and to collect the vaginal rings from the research centre at 
time intervals suitable to them, providing a new ring is inserted 
monthly. HIV rapid tests will be offered to participants during these 
interim visits. 
 
If a participant is unable to attend the next scheduled visit, the 
investigator or designee could dispense additional ring(s) on a 
case-by-case basis. All such circumstances must be documented 
fully by the investigator or designee as described in the IPM 032 
Study Operations Manual (SOM). If a participant requires an 
additional ring at a time other than when they are scheduled to 
receive one, they will be required to attend the clinic for an interim 
visit. 
 
 
 

IPM 032 
 
   22 October 2015 
Version 2.0 Amendment 1.0 
 
Page 15 of 69 
Restricted * Confidential – Limited Access* 
Last product use visit (LPUV):   
At the last product use visit, participants will return any 
used/unused rings; report any medical problems, social harms and 
concomitant medications since the last visit; provide locator and 
basic menses information; receive pre- and post-test HIV 
counselling, contraceptive counselling and HIV/STI risk-reduction 
counselling (including provision of male condoms, should 
participants wish to receive them); undergo a physical examination 
as well as a pelvic examination; be tested for STIs, pregnancy and 
HIV; and may undergo safety laboratory assessments,  urine 
dipstick analysis (microscopy only if clinically indicated) and 
cervical sample collection for cytology (if no result is evident within 
the previous year, or abnormal at last cervical cytology).  
Contraception and STI treatment will be provided or participants 
will be referred, if needed.   Blood samples will be collected for 
storage, and will be tested retrospectively by HIV-1 RNA PCR and 
HIV viral genotype resistance testing subsequent to confirmed HIV 
seroconversion. Blood and vaginal fluid samples may be collected 
for measurement of dapivirine concentrations. Returned rings will 
be visually inspected by research centre staff and may also be 
analysed for residual amounts of dapivirine. Returned diary cards 
will be reviewed. Participants will be asked to complete a 
Participant Questionnaire. 
 
Exit visit - 1-2 months after ring discontinuation:  
On the day of the scheduled exit visit, participants will return to the 
research centre to receive results from their STI testing and safety 
laboratory assessments performed at the last product use visit, if 
applicable, and receive treatment or referral as needed. AEs, 
concomitant medications and possible social harms will be 
recorded at this visit. 
 
Participants will receive pre- and post-test counselling for HIV and 
undergo HIV testing. HIV/STI risk reduction counselling (including 
provision of male condoms, should they wish to receive them) and 
contraceptive counselling will also be provided at the exit visit. 
Contraception and STI treatment will be provided or the participant 
will be referred, if needed. The following procedures are not 
required, but may be conducted if clinically indicated: physical and 
pelvic examination, cervicovaginal sample collection for STI 
testing, provision of treatment and/or referral for STIs and other 
findings, laboratory testing for safety assessments, urine dipstick 
analysis (microscopy only if clinically indicated) and cervical 
sample collection for cytology (if no result is evident within the 
previous year, or abnormal at last cervical cytology). 
Blood samples will be collected for storage, and will be tested 
retrospectively by HIV-1 RNA PCR and HIV viral genotype 
resistance testing subsequent to confirmed HIV seroconversion. 
 
Participants will then be considered to have completed trial 
participation. 

IPM 032 
 
   22 October 2015 
Version 2.0 Amendment 1.0 
 
Page 16 of 69 
Restricted * Confidential – Limited Access* 
STATISTICAL CONSIDERATIONS: 
Sample Size:  
This is an open-label, follow-on trial to IPM 027 to evaluate the 
safety of and adherence to Dapivirine Vaginal Ring-004, inserted 
at monthly intervals in healthy, HIV-negative women who have 
participated in the IPM 027 trial. No formal sample size or power 
calculations have thus been performed. 
 
It is expected that approximately 70% of the participants enrolled 
in IPM 027 will participate in this trial. Therefore, a total sample 
size of approximately 1400 HIV-negative women is anticipated.  
 
Statistical Analyses:  
The primary analysis will focus on safety as well as adherence 
assessments, performed under the intent-to-treat (ITT) principle. 
As it is possible that the inclusion of non-adherent participants or 
participants who discontinued from ring use may artificially lower 
the rates of safety outcomes, additional analyses will be 
conducted on the per-protocol population, which will include only 
participants who were adherent to the protocol. 
 
A descriptive analysis of all AEs will be presented in tables and 
listings. AEs will be summarised by MedDRA System Organ Class 
(SOC) and Preferred Term (PT). The proportion of participants 
experiencing adverse events, including the proportion of 
participants experiencing product-related adverse events, Grade 3 
or 4 AEs, or SAEs, will be determined, and presented with 
corresponding 95% confidence intervals (CIs).  
 
Residual levels of dapivirine in returned rings, and/or plasma 
and/or vaginal fluid concentrations of dapivirine will be used as 
measures of adherence to ring use. The data will be listed, 
summarised and presented graphically. Participants will be 
categorized as either adherent or non-adherent, based on these 
measures. The ring residual levels and/or plasma and/or vaginal 
fluid concentrations of dapivirine associated with non-adherence 
will be informed by the results from IPM 027, and will be described 
in detail in the SAP, which will be finalised prior to final database 
lock.  The correlation between the amount of residual dapivirine in 
the used rings and the corresponding plasma and/or vaginal fluid 
levels of dapivirine will be explored graphically and summarised 
descriptively.  
 
For the secondary analysis, the number of HIV-1 seroconversions, 
the incidence density rate of HIV-1 seroconversion, i.e. HIV-1 
seroconversion rate per 100 woman-years of product use at the 
end of the ring use period, as well as a 95% confidence interval for 
the HIV-1 seroconversion rate per 100 woman-years based on the 
normal approximation of the Poisson distribution will be presented 
for each research centre and overall. Kaplan-Meier curves will 
also be presented, stratified by research centre. The analysis of 

IPM 032 
 
   22 October 2015 
Version 2.0 Amendment 1.0 
 
Page 17 of 69 
Restricted * Confidential – Limited Access* 
HIV-1 drug resistance will be primarily descriptive in nature, and 
will depend on the pattern of resistance mutations observed in the 
HIV-1 seroconverters.  A frequency tabulation of individual 
resistance mutations associated with the various classes of 
antiretrovirals, e.g. Protease Inhibitors, Nucleoside Reverse 
Transcriptase 
Inhibitors 
and 
Non-nucleoside 
Reverse 
Transcriptase Inhibitors, will be produced. The proportion of HIV-1 
seroconverters with at least one HIV-1 drug resistant mutation will 
be presented, with the corresponding 95% CI.  
 
Appropriate statistical analyses of the exploratory endpoints will be 
performed. 
 
 
 
 
Full details of the planned statistical analyses will be provided in a  
 
 
 
Statistical Analysis Plan (SAP) that will be finalised before final  
 
 
 
database lock. 
 
 
 
 
 
 

IPM 032 
 
   22 October 2015 
Version 2.0 Amendment 1.0 
 
Page 18 of 69 
Restricted * Confidential – Limited Access* 
1. Introduction 
1.1. Background 
Women continue to be affected disproportionately by HIV in sub-Saharan Africa, where 
they account for 58% of people living with HIV1. It is estimated that every hour, 50 young 
women are newly infected with HIV2. 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, many women 
are unable to negotiate condom use with their partners. Most current HIV prevention 
methods require the consent (as well as some action or behaviour change) of the male 
partner3. Therefore, the ongoing development of safe and effective HIV prevention 
technologies that can be made easily accessible to developing countries remains a 
public health priority.  
 
Developing HIV prevention options that women can use therefore remains a global 
challenge. Antiretroviral (ARV) approaches to prevention have the potential to transform 
the response to the HIV/AIDS pandemic. For women, further research is needed on 
microbicides that contain different ARV compounds in different formulations and dosing 
strategies, in order to provide various options for HIV prevention. Vaginal microbicides, 
which are self-initiated, could offer women a critically needed new tool to prevent HIV, 
especially for those women who are not able to negotiate mutual monogamy or condom 
use4. ARV-based microbicides can be formulated in a number of dosage forms that 
allow them to be used in a variety of ways, such as around the time of sex, or daily or 
monthly, independent of sexual activity.  
 
In order for a microbicide to be most effective, it is essential that it is used correctly and 
consistently, and is acceptable to women and their male partners. A product used 
independently of sexual intercourse could be more convenient for women and provide 
long-term protection during anticipated and unanticipated sexual intercourse. Vaginal 
rings that need monthly replacement may therefore have benefits. The Dapivirine 
Vaginal Ring-004 is currently in Phase III clinical development.   
 
1.2. Dapivirine Vaginal Ring 
1.2.1. Dapivirine 
Dapivirine, a non-nucleoside reverse transcriptase inhibitor (NNRTI), is a di-amino-
pyrimidine 
(DAPY) 
derivative 
with 
the 
chemical 
name 
4-[[4-[(2,4,6-
trimethylphenyl)amino]-2-pyrimidinyl]amino] benzonitrile. NNRTIs bind directly to the HIV 
reverse transcriptase (RT) enzyme, preventing viral replication. Dapivirine was originally 
developed by Janssen Research and Development (formerly Tibotec Pharmaceuticals) 
as an oral antiretroviral compound and was tested in Phase I and II clinical trials in more 
than 200 participants. Although first conceived as an oral therapeutic, dapivirine is a 
promising candidate for development as a topical microbicide due to its proven in vitro 
and in vivo efficacy and favourable safety profile as well as its physical and chemical 
properties. Dapivirine has potent activity against wild-type HIV-1 strains and strains 
harbouring different resistance-inducing mutations. Dapivirine’s antiretroviral profile is 
superior to that of earlier NNRTI class compounds such as nevirapine, delavirdine, and 
efavirenz. In vitro tests have shown that dapivirine is inactive against HIV-2 and has no 
efficacy against common sexually transmitted infections. Dapivirine is therefore not 
intended to protect against HIV-2 or other sexually transmitted infections, nor does it 
have any contraceptive properties. 

IPM 032 
 
   22 October 2015 
Version 2.0 Amendment 1.0 
 
Page 19 of 69 
Restricted * Confidential – Limited Access* 
 
1.2.2. Formulation of a Silicone Elastomer Matrix ring containing 25 mg of  
 Dapivirine 
The dapivirine silicone elastomer vaginal matrix ring (Ring-004) is an off-white flexible 
ring containing 25 mg of dapivirine dispersed in a platinum-catalysed silicone matrix. The 
dimensions of the ring are 56 mm (outer diameter) and 7.7 mm (cross-sectional 
diameter). Details regarding the formulation and dimensions are provided in the 
Dapivirine Vaginal Ring-004 Investigator’s Brochure (IB)5. The dapivirine vaginal ring is 
designed to provide sustained release of dapivirine for a minimum of one month. 
 
1.3. Nonclinical Studies 
The potential of dapivirine as a microbicide for prevention of sexual transmission of HIV 
has been assessed in a variety of in vitro, ex vivo and in vivo models.  Furthermore, a 
comprehensive program of preclinical studies was used to evaluate the toxicity of 
dapivirine. The studies are described in the IB5. 
 
Virology: 
The activity of dapivirine against wild-type 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 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. The anti-HIV activity was also confirmed in an ex vivo 
model of human cervical explant cultures and in an in vivo humanized severe combined 
immunodeficient (hu-SCID) mouse model. 
 
Nonclinical safety pharmacology: 
In a series of preclinical safety pharmacology studies, dapivirine was generally devoid of 
adverse effects on overt behaviour, reflexes and other body functions. Although safety 
pharmacology studies revealed no cardiovascular effects, there was evidence of an 
increase in QT interval during the 4- and 6-month oral toxicity study in dogs. However, 
this was only seen at ≥ 30 mg/kg/day, at which Cmax and AUC values were respectively 
more than 3800 and 2500 times the values achieved in women following use of the 
Dapivirine Vaginal Ring-004. 
 
Nonclinical pharmacokinetics:  
Systemic exposure to dapivirine was low following vaginal administration of dapivirine 
gels to rabbits. Much higher systemic exposures were obtained in single dose oral and 
subcutaneous toxicity studies in mice and rats, and in repeat dose oral toxicity studies in 
rats, dogs and monkeys. The free fraction of dapivirine in plasma was 0.19-0.34% in the 
male rat, 0.18-0.39% in the female rat, 0.21–0.22% in the dog and 0.15% in man. In rats, 
tissue to plasma AUC0-24 ratios following a single oral dose were 11 in liver, 7-8 in lung, 
kidney and adrenals, about 4 in spleen and lymph nodes, and 2-3 in brain, heart and 
muscle. Plasma/tissue equilibrium was rapid, and there was no undue retention of 
dapivirine in tissues.  
 
For virtually all tissues, maximal concentrations after vaginal dosing were < 1% of those 
after oral dosing. Preliminary metabolism studies demonstrated the presence of free and 
conjugated metabolites in rats, dogs, monkeys and humans, but the molecular structures 
have not been elucidated. There was evidence of extensive cytochrome P450 

IPM 032 
 
   22 October 2015 
Version 2.0 Amendment 1.0 
 
Page 20 of 69 
Restricted * Confidential – Limited Access* 
(particularly CYP3A4) mediated metabolism. 
 
Nonclinical toxicology:  
Dapivirine has been investigated in single and repeat dose toxicity studies, in a range of 
reproductive toxicity and mutagenicity studies, and in a carcinogenicity study. In vaginal 
studies in rabbits there were no significant local or systemic findings following repeat 
administration at up to 20 mg/mL for 14 days, up to 5 mg/mL for 13 weeks or up to 2 
mg/mL for 39 weeks, or in reproductive toxicity studies in rats and rabbits performed at 
concentrations up to 2 mg/mL (0.2%). In a 13-week study in sheep using Ring-004, there 
was no evidence of local or systemic toxicity. 
 
The no adverse effect level (NOAEL) in rats and dogs following oral administration was 
20 mg/kg/day. At higher dose levels, hepatotoxicity was observed in dogs and slight 
hematological and clinical chemistry changes were observed in rats. The NOAEL in oral 
reproductive toxicity studies in the rat was also 20 mg/kg/day, whereas in the rabbit no 
effects were seen at dosages up to 90 mg/kg/day. Dapivirine was considered to be non-
genotoxic. In the guinea pig, dapivirine (2 mg/mL) did not demonstrate any potential to 
cause contact sensitization. No treatment-related neoplastic or non-neoplastic findings 
were seen in a vaginal carcinogenicity study in rats at concentrations up to 5 mg/mL. 
 
1.4. Clinical Trials 
Multiple clinical trials have evaluated the safety of dapivirine in different formulations. 
Below is a summary of the data collected through these studies. More detailed 
information is available in the Dapivirine Vaginal Ring-004 IB5.  
 
Across all clinical trials with multiple ring configurations in healthy participants, the 
dapivirine vaginal ring was generally safe and well tolerated. No drug-related serious 
adverse events (SAEs) have been reported to date and no trials were stopped for safety 
reasons. Three Grade 3 SAEs (polytrauma event of thoracic vertebral fractures in IPM 
034, fracture of the right acetabulum in IPM 028 and tonsillitis in IPM 015), were reported 
for three participants who used the Dapivirine Vaginal Ring-004); all three events were 
regarded by the Investigator as unrelated to ring use. Six non-ring related SAEs were 
experienced by five participants using placebo rings in two Ring-004 trials (IPM 015 and 
IPM 024). One participant was discontinued from the Dapivirine Vaginal Ring-004 due to 
an investigational product-related adverse event (generalized pruritus) in IPM 013. 
 
1.4.1. Phase I and II 
To date, 27 Phase I and Phase I/II clinical trials of dapivirine have been completed: 8 
trials of dapivirine vaginal rings in 469 participants (298 using dapivirine rings and 183 
using placebo rings); 8 trials of dapivirine vaginal gel in 774 participants (491 using 
dapivirine gel and 283 using placebo gel); and 11 trials of oral dapivirine in which a total 
of 211 participants used oral dapivirine. Two Phase I clinical trials that evaluated a 
vaginal film formulation of dapivirine in 71 women have been conducted.  In addition, 
one Phase I clinical trial in male participants to assess the safety and tolerability of a 
dapivirine vaginal gel, following multiple topical penile exposures, was conducted in 48 
healthy, HIV-negative, adult males, 24 of whom were circumcised and 24 uncircumcised 
(MTN-012/IPM 010). The dapivirine gel formulation was well tolerated by the 
participants. No SAEs or discontinuations due to TEAEs were reported during this trial. 
 

IPM 032 
 
   22 October 2015 
Version 2.0 Amendment 1.0 
 
Page 21 of 69 
Restricted * Confidential – Limited Access* 
Based on information in the current IB5, across all completed Dapivirine Ring-004 trials 
(IPM 024, IPM 013, IPM 015, IPM 028 and IPM 034), the most commonly occurring 
TEAEs that were documented in at least 5% of participants in dapivirine versus 
placebo treated participants (n=259 using dapivirine rings and n=160 using placebo 
rings, respectively) were metrorrhagia (29.7% vs 24.4%), headache (15.1% vs 11.9%), 
gynaecological chlamydia infection (8.5% vs 13.4%), vaginal candidiasis (8.1% vs 7.5%), 
urinary tract infection (6.9% vs 8.8%), vaginal discharge (6.6% vs 6.3%), upper 
respiratory tract infection (5.8% vs 10.0%) and lower abdominal pain (5.4% vs 5.0%). 
 
 
Oral Dapivirine 
There have been 11 oral administration trials in which a total of 211 participants have 
been dosed with dapivirine. The maximum tolerated dose (MTD) established was 350 
mg for a single dose, and for multiple doses, 300 mg b.i.d. for 14 days. There were no 
deaths during the clinical trials of oral dapivirine, and no trials were stopped for safety 
reasons. A total of 10 participants stopped dapivirine treatment prior to trial completion 
for safety reasons, 6 of whom stopped due to a clear dose-dependent increase in central 
nervous system (CNS) and gastrointestinal TEAEs, thereby establishing the MTD at 300 
mg b.i.d. These TEAEs resolved within 1-2 days after discontinuation of use of oral 
dapivirine.  
 
Adverse events documented in 5 or more participants (> 2%) after oral exposure to 
dapivirine were headache, dizziness, nausea, diarrhoea, fatigue, tremor, somnolence, 
flatulence, and vomiting. Most (≥ 80%) of these TEAEs were Grade 1 or 2 (mild or 
moderate) and most (≥ 80%) were considered to be related to dapivirine. Grade 3 
(severe) TEAEs included headache, dizziness, injury, nausea, tremor, paraesthesia, 
disturbance in attention, abrasion, AST increased, ALT increased, polyuria, fever, 
diarrhoea, and vomiting. The increases in AST and ALT were transient and the Grade 3 
increases in AST and ALT occurred in a single participant who received 50 mg oral 
dapivirine as a twice daily dose.  
 
1.4.2. Phase III  
The Phase III clinical program of the dapivirine vaginal ring, containing 25 mg of 
dapivirine (Ring-004), consists of the MTN-020 and IPM 027 clinical trials. These trials 
are conducted in South Africa, Uganda, Zimbabwe and Malawi, to assess the safety and 
efficacy of the Dapivirine Vaginal Ring-004 in preventing the acquisition of HIV-1 
infection through male to female transmission in healthy, HIV-negative women.  
 
IPM 027 is a double-blind, multicentre, placebo-controlled trial that has been designed to 
assess the safety and efficacy of the Dapivirine Vaginal Ring-004, inserted once every 4 
weeks over a period of 24 months, in healthy, sexually active HIV-negative women, 18 to 
45 years of age, when compared to a placebo vaginal ring. It is conducted at 7 research 
centres, six in South Africa and one in Uganda. A total of 1959 eligible women were 
randomized in a 2:1 ratio to receive either the dapivirine vaginal ring or placebo vaginal 
ring. This trial was initiated in March 2012 and is expected to complete in 2016/2017.  
 
MTN-020 has been designed to assess the safety and effectiveness of the Dapivirine 
Vaginal Ring-004, inserted once every 4 weeks, in healthy, sexually active, HIV-negative 
women, 18 to 45 years of age, when compared to a placebo vaginal ring. It is conducted 
in Malawi, South Africa, Uganda and Zimbabwe. A total of 2629 women were 

IPM 032 
 
   22 October 2015 
Version 2.0 Amendment 1.0 
 
Page 22 of 69 
Restricted * Confidential – Limited Access* 
randomized. Each participant will use the investigational product until 120 events (HIV-1 
seroconversions) are observed in the trial. All participants are anticipated to use the 
investigational product for a minimum of 12 months. The trial was initiated in August 
2012 and clinical conduct completed in June 2015.  
 
 
1.4.3. Adherence to and Acceptability of the Dapivirine Vaginal Ring 
IPM 011 was an open-label, crossover trial conducted in South Africa and Tanzania 
among sexually active women to assess the safety and acceptability of a silicone 
elastomer placebo vaginal ring (containing no active ingredient), intended as a 
microbicide delivery method for the prevention of HIV infection. Participants were 
randomly assigned in a 1:1 ratio to one of two trial groups. Both groups participated in 
two regimens: a placebo vaginal ring regimen and an observational safety regimen (with 
no placebo vaginal ring). Each regimen had 12-week duration. Eighty-two percent (82%) 
of women in this trial reported no ring removals at all for the entire duration of the trial, 
across trial groups and visits, and 99% of participants reported wearing the ring for at 
least 80% of the days they were meant to. Eighteen percent (18%) of women self-
reported at least one ring removal or expulsion during the course of trial participation. 
This proportion increased to 22% when pharmacy records were incorporated. Many of 
the reported expulsions and removals were related to menses, e.g. heavy blood flow or 
concern about the ring becoming dirty or retaining odour, leading to removal. Ninety-five 
percent (95%) of women found the ring to be very comfortable. All questionnaire 
responders were willing to use the vaginal ring if shown to be effective for HIV 
prevention6. 
 
IPM 015 was a Phase I/II randomized, double-blind, placebo-controlled trial conducted at 
10 research centres in Kenya, Malawi, Tanzania and South Africa. The trial was 
performed in 280 HIV-negative, sexually active women, 18 to 40 years of age, to assess 
and compare the safety of 28-day use of Dapivirine Vaginal Ring-004, and a placebo 
vaginal ring, containing no dapivirine. Eligible women were randomly assigned in a 1:1 
ratio to the dapivirine ring or placebo ring,  inserted once every 28 days over a 12-week 
period.  In IPM 015, “perfect adherence” was reported by 92% of the female participants.  
Perfect adherence was defined as never having the ring out for more than an entire day. 
The most frequent activity associated with ring expulsion was urination/defecation and 
the most common reason reported by participants for removing the ring themselves was 
cleaning.  At the end of the trial, 96% of participants reported that the ring was usually 
comfortable to wear, and 97% reported that they would be willing to use it in the future if 
it were proven effective and they thought they were at risk for HIV infection. Just over 
60% of the participants in both arms reported that their male partners did not feel the ring 
at Visit 5 (study week 12). A further 22% reported that their partner felt the ring during 
sex, but that it was not a problem. Only a small number (3%) at Visit 3 (study week 4) 
and (1%) at Visit 5 (study week 12) reported that her male partner felt the ring and it 
might be, or definitely was a problem for her to continue ring use7. 
 
 
1.4.4. Condom Compatibility 
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 

IPM 032 
 
   22 October 2015 
Version 2.0 Amendment 1.0 
 
Page 23 of 69 
Restricted * Confidential – Limited Access* 
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.  
 
Studies with dapivirine-containing vaginal gel formulations (0.05%, 2.5 g) were 
conducted on the following types of male and female condoms: 
• 
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) 
• 
Nitrile condoms with silicone lubricant (female condom) 
 
All types of condoms met the acceptance criteria established in the protocol for the mean 
values of the treated samples after treatment with dapivirine gels. The results of condom 
compatibility testing indicate that dapivirine-containing vaginal gel formulations (0.05%, 
2.5 g) have no deleterious effects on the integrity of male or female condoms5. 
 
1.5. Rationale for Protocol IPM 032 
The potential of dapivirine as a safe and efficacious microbicide for prevention of sexual 
transmission of HIV has been evaluated in nonclinical studies (virology studies, 
secondary/safety pharmacology, pharmacokinetics, toxicology) using different in vitro, ex 
vivo and in vivo models, as well as Phase I-II clinical trials. Once results from the two 
pivotal Phase III clinical trials demonstrate that the dapivirine vaginal ring is safe and 
efficacious, these results will be communicated to the relevant local and international 
regulatory authorities, IRBs/IECs, community representatives, participants and key 
stakeholders, as appropriate, before activation of IPM 032. 
 
IPM 032, a Phase IIIb follow-on trial to IPM 027, has been designed as an open-label 
clinical trial to collect additional safety data and establish adherence to ring use of the 
Dapivirine (25 mg) Vaginal Ring-004 in healthy, HIV-negative women with monthly (at 
least one to a maximum of three months) followed by 3-monthly research centre follow-
up visits over 12 months. Further, IPM 032 will examine incidence of HIV-1 
seroconversion and monitor HIV-1 resistance in women who acquire HIV-1 infection. 
The assessment of the monthly visits (first one to three months) followed by 3-monthly 
research centre follow-up visits will provide insight into the feasibility of a 3-monthly 
scheduling strategy that would be less costly and time-consuming in a resource-limited 
environment such as sub-Saharan Africa.  
2. Trial Objectives 
2.1. Trial Objectives 
The primary trial objectives are: 
1. 
To assess the safety profile of the 25 mg Dapivirine Vaginal Ring-004, when 
inserted at monthly intervals, in an open-label trial  
2. To assess adherence to the use of the 25 mg Dapivirine Vaginal Ring-004 
inserted at monthly intervals, in an open-label trial  

IPM 032 
 
   22 October 2015 
Version 2.0 Amendment 1.0 
 
Page 24 of 69 
Restricted * Confidential – Limited Access* 
The secondary trial objectives are: 
1. To assess the incidence of HIV-1 seroconversion 
2. To assess the frequency of HIV-1 drug resistance in women who acquire HIV-1 
infection 
 
The exploratory trial objectives are: 
1. To assess the feasibility of  3-monthly follow-up visits, as a possible schedule for 
post-licensure vaginal ring clinical follow-up 
2. To explore the correlation between drug concentrations and results from the 
visual inspection of the returned vaginal rings by research staff between the 
monthly and 3-monthly research centre follow-up schedules 
3. To determine the proportion of participants  electing to undergo HIV rapid tests at 
the research centres between scheduled 3-monthly visits 
 
2.2. Trial Endpoints and Assessments 
The primary endpoints are: 
1. Safety  
• 
All Adverse Events (AEs) assessed by the investigator to be related to the 
Dapivirine Vaginal Ring-004 
• 
All Grade 3 and 4 AEs 
• 
All Serious Adverse Events (SAEs) 
 
2. Adherence 
• 
Residual amounts of dapivirine in returned rings; and/or dapivirine 
concentrations in plasma and/or dapivirine concentrations in vaginal fluid  
 
The primary endpoints will be assessed through: 
1. Safety  
• 
All product-related AEs, Grade 3 or 4 AEs, SAEs, physical examination, 
gynaecological 
assessments, 
including 
pelvic/speculum 
examination, 
laboratory tests and other indicated investigations 
2. Adherence 
• 
Determined dapivirine residual amounts in returned used vaginal rings and/or 
• 
Measured concentrations of dapivirine in plasma and/or 
• 
Measured concentrations of dapivirine in vaginal fluids 
 
The secondary endpoints are: 
• 
The HIV-1 seroconversion rate per 100 woman-years of product use at the 
end of the vaginal ring use period 
• 
HIV-1 drug resistance mutations among participants who acquire HIV-1 
infection 

IPM 032 
 
   22 October 2015 
Version 2.0 Amendment 1.0 
 
Page 25 of 69 
Restricted * Confidential – Limited Access* 
The secondary endpoints will be assessed through: 
• 
Rapid and specialised laboratory testing according to a pre-specified HIV 
testing algorithm 
• 
Viral genotype resistance testing methods 
 
 
The exploratory endpoints are: 
• 
Feasibility of 3-monthly clinical follow-up schedule 
• 
Dapivirine residual amounts in returned used vaginal rings and/or dapivirine 
concentrations in blood and/or vaginal fluid in correlation with results from the 
visual inspection of the returned used vaginal rings by research staff 
• 
Proportion of participants opting for HIV rapid tests at the research centre 
between scheduled 3-monthly research centre follow-up visits 
 
The exploratory endpoints will be assessed through: 
• 
Participant report of feasibility regarding a 3-monthly clinical follow-up 
schedule (Participant Questionnaire) 
• 
Number of women opting not to receive two additional rings at the 3-monthly 
visits 
• 
Proportion of returned rings (used and unused) during the 3-monthly clinical 
follow-up schedule 
• 
Dapivirine residual amounts in returned used vaginal rings and/or dapivirine 
concentrations in blood and/or vaginal fluid 
• 
Visual inspection of the returned used vaginal rings by research centre staff 
• 
Number of participants undergoing HIV rapid tests at the research centres 
between scheduled 3-monthly research centre follow-up visits 
3. Overall Trial Design 
3.1. Trial Design 
IPM 032 is a Phase IIIb, multi-centre follow-on open-label trial to evaluate the continued 
adherence to and safety of the Dapivirine Vaginal Ring-004, inserted at monthly intervals 
in healthy, HIV-negative women who have participated in the IPM 027 Phase III 
Dapivirine Vaginal Ring-004 trial. All women who have participated in IPM 027 and are 
HIV-negative at screening for IPM 032 will be eligible. An estimate of approximately 
1400 participants will be enrolled.  All participants will receive the dapivirine vaginal ring 
containing 25 mg dapivirine (Ring-004) at enrolment and will attend a research centre 
follow-up visit one month after enrolment.  Following this visit, at investigator’s discretion, 
a participant can continue on a 3-monthly visit schedule.   Monthly visits may however be 
extended up to the first three months of participation. Once the 3-monthly trial visit 
schedule commences, three rings will be dispensed.  One ring will be self-inserted at the 
research centre and two additional rings will be dispensed for the participant to take 
home, or dispensing will take place as arranged with the participant.  
 

IPM 032 
 
   22 October 2015 
Version 2.0 Amendment 1.0 
 
Page 26 of 69 
Restricted * Confidential – Limited Access* 
3.2. Trial Duration 
Each participant will engage in the screening process for up to 45 days prior to 
enrolment and will use the Dapivirine Vaginal Ring-004 for a period of up to 12 months. 
IPM will have the option to extend this trial period. Accrual will take place over 
approximately 6 months and those participants who are enrolled more than 6 months 
after the onset of the study site’s accrual period may have a shortened follow-up period. 
 
Each participant will have an exit visit 1-2 months after ring discontinuation, to assess 
safety and identify HIV seroconversions after product discontinuation.   
 
3.3. Trial Population 
Approximately 1400 HIV-negative women who have participated in the IPM 027 Phase 
III Dapivirine Vaginal Ring-004 trial, who understand the trial, and can provide informed 
consent are expected to enrol in this open-label trial.   
 
3.3.1. Inclusion Criteria 
Women must meet all the following criteria to be eligible to enrol in the trial: 
 
1. Previously enrolled in the IPM 027 trial 
2. Available for all visits and consent to follow all procedures scheduled for the trial 
3. Using an effective method of contraception at the Enrolment Visit, and intending 
to use an effective contraceptive method for the duration of trial participation, 
unless post-menopausal with no history of menses for one year prior to screening   
4. HIV-negative as determined by the HIV algorithm applied at Screening/Pre-
Enrolment 
5. Willing to refrain from participation in another research trial using drugs, vaccines, 
medical devices and microbicides for the duration of the IPM 032 trial 
6. Willing to provide adequate locator information for trial retention purposes and be 
reachable per local standard procedures (e.g., by home visit or telephone; or via 
family or close neighbour contacts); confidentiality to be maintained 
 
3.3.2. Exclusion Criteria 
Women who meet any of the following criteria are NOT eligible to enrol in the trial: 
 
1. Investigational product use permanently discontinued in response to an AE 
(where the AE was considered related to investigational product) or safety-related 
concern while taking part in the IPM 027 trial  
2. Participant self-report of taking post-exposure prophylaxis (PEP) within ≤ 2 
months at Screening Visit 
Note: Participants may be enrolled after completing the PEP regimen and a 
negative HIV test was documented at least 2 months prior to screening for IPM 
032 
3. Currently pregnant, intends to become pregnant or currently breast-feeding 
4. Known drug abuse or alcohol dependence in the 12 months prior to screening 

IPM 032 
 
   22 October 2015 
Version 2.0 Amendment 1.0 
 
Page 27 of 69 
Restricted * Confidential – Limited Access* 
5. Participated in another research trial (other than IPM 027) using drugs, medical 
devices, microbicides or oral pre-exposure prophylaxis agents within 30 days prior 
to screening 
6. Any new illness or condition(s), chronic condition(s) or abnormal laboratory 
finding(s) that, in the opinion of the investigator, might put the participant at risk, or 
interfere with the trial objectives or the participant’s adherence to trial 
requirements 
4. Trial Visits and Procedures 
4.1. Screening Visit  
NOTE: For potential participants who do not meet the eligibility criteria, screening 
procedures will be discontinued once ineligibility has been determined. Women who fail 
screening may be re-screened once and may be enrolled if they are found to meet ALL 
inclusion and NO exclusion criteria at the second screening visit.  
 
In the event that the IPM 027 trial is stopped prematurely and IPM 032 is activated at the 
research centre, the IPM 027 LPUV and the IPM 032 Screening and Enrolment Visits 
may be combined for participants who are eligible to enrol in the IPM 032. In these 
situations, a separate Screening visit will not be required, and only the procedures 
indicated in italics are required. 
 
a. Explain the screening, enrolment and trial procedures to the potential participant.  
b. If the potential participant agrees, obtain written informed consent. Illiterate 
participants may provide a thumbprint or mark witnessed and signed by a person 
independent from trial staff (refer to Section 5.1). A comprehension assessment 
checklist will be used to support the consent process (refer to Section 5.2).  
c. Assign a unique SCR-ID number to the potential participant.  
d. Conduct a review of inclusion/exclusion criteria with the potential participant.  
e. Collect demographic information from the potential participant.  
f. Obtain and record locator information.  
g. Record basic menses information, relevant medical history, and concomitant 
medication taken within the last 30 days (refer to Section 5.7 for more details 
about relevant medical history).  
h. Perform urine pregnancy testing. Refer pregnant women to local prenatal clinic 
for support services (refer to Section 5.6).  
i. 
Provide HIV/STI risk-reduction counselling (including provision of male condoms, 
should participants wish to receive them), contraceptive counselling and the 
provision of contraceptives, if necessary (refer to Sections 5.3.2 and 5.5).  
j. 
Provide HIV pre- and post-test counselling (refer to Section 5.3.1).  
k. Perform HIV rapid testing as detailed in Section 5.4.1.  
l. 
Collect a blood specimen by venepuncture for storage for possible HIV viral 
genotype resistance and HIV-RNA PCR testing (Blood volume specified in 
Appendix C). 
m. Perform general physical examination (refer to Section 5.8 for a description of the 
elements required in the general physical examination).  

IPM 032 
 
   22 October 2015 
Version 2.0 Amendment 1.0 
 
Page 28 of 69 
Restricted * Confidential – Limited Access* 
n. Perform a pelvic examination (refer to Section 5.9). If the pelvic examination 
indicates abnormal findings, e.g., any symptoms or evidence of genital infections, 
abrasions, ulcerations, etc., provide or refer for appropriate treatment.  
NOTE: If the participant is menstruating at this visit, the pelvic examination may 
be conducted as per investigator and participant discretion. If this is not possible, 
the participant will be asked to return 2 days after completion of menstruation.  
o. Collect cervicovaginal swabs for STI testing and a specimen for cervical cytology, 
if no result is evident within the previous year, or abnormal at last cervical 
cytology (refer to Sections 5.11.1 and 5.12).  
p. Provide treatment and/or referral for STIs and other findings, as necessary (refer 
to Section 5.11.2). 
q. Perform a urine dipstick analysis (microscopy only if clinically indicated). Collect 
blood samples by venepuncture for syphilis testing (RPR) and confirmatory test 
(if required), and the following safety laboratory tests (Blood volumes specified in 
Appendix C): haematology (FBC with differential and platelet count), and 
chemistry (creatinine, ALT, AST) (refer to Section 5.10).  
r. Other procedures, as clinically indicated and with prior approval from IPM. 
s. Schedule the Enrolment Visit within 45 days 
  
4.2. Enrolment Visit 
Note: The Enrolment Visit will occur within 45 days after the Screening Visit.  
 
In the event that the IPM 027 trial is stopped prematurely and the IPM 032 is activated at 
the research centre, the IPM 027 LPUV and the IPM 032 Screening and Enrolment Visits 
may be combined for participants who are eligible to enrol in IPM 032. Trial procedures 
conducted as part of the IPM 027 LPUV will not be repeated for the IPM 032 trial. Only 
the procedures indicated in italics are required. 
 
Pre-enrolment: 
a. Update locator, menses and pre-enrolment medical history information as 
necessary (refer to Section 5.7).  
b. Provide contraceptive counselling and contraceptives, if necessary (refer to 
Section 5.5).  
c. Provide HIV/STI risk reduction counselling, including provision of male condoms 
if the participant wishes to receive them (refer to Section 5.3.2).  
d. Record possible social harms (refer to Section 10.2)  
e. Obtain and record any concomitant medication information since the last visit.  
f. Perform urine pregnancy testing. Refer pregnant women to local prenatal clinic 
for support services (refer to Section 5.6).  
g. Provide HIV pre- and post-test counselling (refer to Section 5.3.1).  
h. Perform HIV rapid testing as detailed in Section 5.4.2.  
NOTE: Additional procedures for participants who test HIV-positive are also 
described in Section 5.4.2 of the protocol.  
i. 
Reassess and confirm eligibility. 

IPM 032 
 
   22 October 2015 
Version 2.0 Amendment 1.0 
 
Page 29 of 69 
Restricted * Confidential – Limited Access* 
 
Post-enrolment: 
j. 
Assign a unique PID number to the participant.   
k. Collect a blood specimen by venepuncture for storage for possible HIV viral 
genotype resistance and HIV-RNA PCR testing (Blood volume specified in 
Appendix C). 
l. 
Obtain and record any AE information.  
m. Provide adherence counselling, including adherence to trial visit schedule and 
requirements and vaginal ring adherence (refer to Section 5.15). At the 
Enrolment Visit, participants will be provided with feedback on the IPM 027 and 
MTN-020 trial results during the vaginal ring adherence counselling. Participants 
will be instructed to keep the ring inserted for a period of one month. Adherence 
counselling will include information on actions that should be taken in the event of 
expulsion or removal of the ring. If the ring comes out or is removed during this 
period, the participant should wash her hands, rinse the ring thoroughly in clean 
water and re-insert it.  
n. Provide and explain the use of the diary card to the participant (refer to Section 
5.19). 
o. Dispense one vaginal ring to each participant and provide vaginal ring use and 
storage instructions (refer to Sections 5.13 and 6.4). 
p. Instruct the participant to insert the vaginal ring (refer to Section 5.14). 
q. The following procedures are not required, but may be conducted if clinically 
indicated: physical and pelvic examination, cervicovaginal sample collection for 
STI testing, provision of treatment and/or referral for STIs and other findings, 
laboratory testing for safety assessments, urine dipstick analysis (microscopy 
only if clinically indicated) and cervical sample collection for cytology (if no result 
is evident within the previous year, or abnormal at last cervical cytology). 
r. Schedule the next visit. 
 
4.3. Trial Visits (Monthly research centre visits for the first one to three 
months, and 3-monthly research centre visits thereafter) 
Note: All visit dates will be calculated from the enrolment visit as baseline date. Each 
scheduled visit while the participant is on the IP has a window period of ± 7 days. 
 
a. Update locator and menses information as necessary.  
b. Obtain and record any AE and concomitant medication information since the last 
visit.  
c. Record possible social harms (refer to Section 10.2). 
d. Perform urine pregnancy test. Refer pregnant women to local prenatal clinic for 
support services (refer to Section 5.6).  
e. Provide HIV pre- and post-test counselling (refer to Section 5.3.1).  
f. Perform HIV rapid testing as detailed in Section 5.4.3.  
NOTE: Additional procedures for participants who test HIV-positive are also 
described in Section 5.4.3 of the protocol. 

IPM 032 
 
   22 October 2015 
Version 2.0 Amendment 1.0 
 
Page 30 of 69 
Restricted * Confidential – Limited Access* 
g. Collect a blood specimen by venepuncture for storage for possible HIV viral 
genotype resistance and HIV-RNA PCR testing (Blood volume specified in 
Appendix C). 
h. Collect blood (Blood volume specified in Appendix C) and vaginal fluid samples 
(refer to Section 5.17) for possible measurement of dapivirine concentrations. 
NOTE: For dapivirine concentration measurements, blood and vaginal fluid 
samples should preferably be collected prior to removal of the vaginal ring.   
i. 
Instruct the participant to remove the vaginal ring. Perform IP accountability and 
visual inspection of the returned ring(s). Returned rings may be analysed for 
residual amounts of dapivirine and will be stored until shipment to the analytical 
laboratory. 
Dispense one vaginal ring to participants during monthly visits and three vaginal 
rings during 3-monthly visits (or dispense as arranged with the participant) and 
provide vaginal ring use and storage instructions (refer to Sections 5.13 and 6.4).  
j. 
Instruct the participant to insert the vaginal ring during monthly visits.   Once the 
3-monthly trial visit schedule commences, one ring will be inserted at the 
research centre and two additional rings will be dispensed for the participant to 
take home (or dispense as arranged with the participant (refer to Section 5.14).  
k. Collect and review the diary card(s) and provide a new diary card(s) if applicable 
(refer to Section 5.19).  
l. 
Administer the Participant Questionnaire at every trial visit (refer to Section 5.16). 
m. Provide adherence counselling, including adherence to trial visit schedule and 
requirements, and vaginal ring adherence (refer to Section 5.15). Participants will 
be instructed to keep the ring inserted for a period of one month. Adherence 
counselling will include information on actions that should be taken in the event of 
expulsion or removal. If the ring comes out or is removed during this period, the 
participant should wash her hands, rinse the ring thoroughly in clean water and 
re-insert it.  
n. Provide contraceptive counselling and contraceptives, if necessary (refer to 
Section 5.5).  
o. Provide HIV/STI risk reduction counselling; including provision of male condoms 
if the participant wishes to receive them (refer to Section 5.3.2).  
p. The following procedures are not required, but may be conducted if clinically 
indicated: physical and pelvic examination, cervicovaginal sample collection for 
STI testing, provision of treatment and/or referral for STIs and other findings, 
laboratory testing for safety assessments, urine dipstick analysis (microscopy 
only if clinically indicated) and cervical sample collection for cytology (if no result 
is evident within the previous year, or abnormal at last cervical cytology). 
q. Schedule the next visit.  
 
4.4. Last Product Use Visit (LPUV) or Early Discontinuation Visit  
Note: LPUVs will be calculated from the enrolment visit as baseline date. This scheduled 
visit has a window period of ± 7 days. 
 
a. Update locator and menses information as necessary.  

IPM 032 
 
   22 October 2015 
Version 2.0 Amendment 1.0 
 
Page 31 of 69 
Restricted * Confidential – Limited Access* 
b. Obtain and record any AE and concomitant medication information since the last 
visit.  
c. Perform a pelvic examination (refer to Section 5.9). If the pelvic examination 
indicates abnormal findings, e.g., any symptoms or evidence of genital infections, 
abrasions, ulcerations, etc., provide the participant with or refer the participant for 
appropriate treatment.  
NOTE: If the participant is menstruating at this visit, the pelvic examination may 
be conducted as per investigator and participant discretion. If this is not possible, 
the participant will be asked to return 2 days after completion of menstruation.  
d. Record possible social harms (refer to Section 10.2)  
e. Perform a general physical examination (refer to Section 5.8 for a description of 
the elements required in the general physical examination).  
f. Instruct the participant to remove the vaginal ring. Perform IP accountability and 
visual inspection of the returned ring(s). Returned rings may be analysed for 
residual amounts of dapivirine and will be stored until shipment to the analytical 
laboratory. 
g. Collect and review the diary card(s).  
h. Administer the Participant Questionnaire (refer to Section 5.16). 
i. 
Provide HIV/STI risk reduction counselling; including provision of male condoms 
if the participant wishes to receive them (refer to Section 5.3.2).  
j. 
Perform contraceptive counselling and provide contraceptives, if necessary (refer 
to Section 5.5).  
k. Perform urine pregnancy test. Refer pregnant women to local prenatal clinic for 
support services (refer to Section 5.6).  
l. 
Collect cervicovaginal swabs for STI testing (refer to Sections 5.11.1).  
m. Provide STI treatment if needed (refer to Section 5.11.2). 
n. Provide HIV pre- and post-test counselling (refer to Section 5.3.1).  
o. Perform HIV rapid testing as detailed in Section 5.4.3.  
p. Collect a blood specimen by venepuncture for storage for possible HIV viral 
genotype resistance and HIV-RNA PCR testing (Blood volume specified in 
Appendix C). 
q. Collect blood (Blood volume specified in Appendix C) and vaginal fluid samples 
(refer to Section 5.17) for possible measurement of dapivirine concentrations. 
NOTE: For dapivirine concentration measurements, blood and vaginal fluid 
samples should preferably be collected prior to removal of the vaginal ring.   
r. The following procedures are not required, but may be conducted if clinically 
indicated: laboratory testing for safety assessments, urine dipstick analysis 
(microscopy only if clinically indicated) and cervical sample collection for cytology 
(if no result is evident within the previous year, or abnormal at last cervical 
cytology).  
s. Schedule the exit visit. 
 
 

IPM 032 
 
   22 October 2015 
Version 2.0 Amendment 1.0 
 
Page 32 of 69 
Restricted * Confidential – Limited Access* 
4.5. Exit Visit 
Note: Exit Visits will occur 1-2 months after ring discontinuation. If the outcome of 
confirmatory tests is pending, the exit visit may be conducted more than 2 months after 
the last product use visit, but should be performed as soon as possible after the results 
are available. Participants will be notified of any abnormal laboratory findings, and return 
to the research centre prior to the exit visit as needed for treatment and/or referral. 
Additional trial procedures for exit visits scheduled following HIV seroconversion are 
described in Section 5.4.4. 
 
a. Obtain and record any AE and concomitant medication information since the last 
visit.  
b. Record possible social harms (refer to Section 10.2). 
c. Perform contraceptive counselling and provide contraceptives, if necessary (refer 
to Section 5.5).  
d. Provide HIV/STI risk reduction counselling; including provision of male condoms 
if the participant wishes to receive them (refer to Section 5.3.2).  
e. Provide HIV pre- and post-test counselling (refer to Section 5.3.1).  
f. Perform HIV rapid testing as detailed in Section 5.4.4 (additional procedures for 
participants who test HIV-positive are also described in Section 5.4.4 of the 
protocol).  
g. Collect a blood specimen by venepuncture for storage for possible HIV viral 
genotype resistance and HIV-RNA PCR testing (Blood volume specified in 
Appendix C). 
h. Provide final safety and STI laboratory test results to participant.  
i. 
The following procedures are not required, but may be conducted if clinically 
indicated: physical and pelvic examination, cervicovaginal sample collection for 
STI testing, provision of treatment and/or referral for STIs and other findings, 
laboratory testing for safety assessments, urine dipstick analysis (microscopy 
only if clinically indicated) and cervical sample collection for cytology (if no result 
is evident within the previous year, or abnormal at last cervical cytology). 
j. 
Exit the participant from the trial.  
 
4.6. Unscheduled Visits 
Unscheduled visits may be performed at any time during the trial for HIV, STI or 
pregnancy testing, collection of an additional ring , or if the participant is experiencing 
any problems, e.g., vaginal complaints, difficulties with re-inserting the ring in cases of 
accidental expulsion or ring removal, or accidental loss of the ring. Participants will also 
be notified of any abnormal laboratory findings, and return to the research centre prior to 
the next scheduled visit as needed for treatment and/or referral to an outside medical 
facility. Additional laboratory testing to evaluate AEs that are suspected to be associated 
with use of the IP may be performed where indicated, in consultation with the IPM 
Clinical Physician. 
 
All unscheduled visits will be documented in the source documents and applicable case 
report forms (CRFs). 
 

IPM 032 
 
   22 October 2015 
Version 2.0 Amendment 1.0 
 
Page 33 of 69 
Restricted * Confidential – Limited Access* 
4.7. Missed and Late Visits 
Trial staff will make every effort to contact participants to return to the research centre for 
scheduled visits. If a participant does not return to the research centre for a scheduled 
visit during the trial window, e.g., within ± 7 days of a scheduled visit, continued attempts 
to contact the participant will be made as per local standard operating procedure (SOP) 
and documented in the source documents. 
 
If the participant does not return to the research centre for a scheduled visit prior to the 
start of the trial window of the next visit, the visit will be considered missed. For example, 
if a participant does not return for Visit 2 by the time the trial window has begun for Visit 
3, i.e., within 7 days from Visit 3, Visit 2 will be considered missed. Trial procedures will 
be performed as scheduled for the current visit (e.g. Visit 3 in this instance) or as 
deemed necessary by the investigator or IPM Clinical Physician (or designee). Missed 
visits will be documented as protocol deviations. Trial staff should ensure that all used or 
unused vaginal rings that were to be returned at the missed visit are retrieved as soon as 
possible. 
 
In the event that a participant will be away and unable to attend one of the Trial Visits 
where new vaginal rings would be dispensed, the investigator or designee could 
dispense additional ring(s) on a case-by-case basis. Research centre staff will enquire 
about adverse events and concomitant medication over the telephone; and other 
information will be collected as applicable.  
 
If a participant presents for a visit outside the window for a scheduled trial visit but prior 
to the start of the window for the next visit, it will be treated as a late visit and 
documented as a protocol deviation. All trial procedures scheduled for the late 
scheduled visit will still be performed. The participant will then resume her original visit 
schedule. 
 
If a LPUV is missed, STI testing should be performed at the Exit Visit. 
 
4.8. Protocol Deviations 
A protocol deviation is defined as any change, non-compliance or divergence from the 
approved protocol. The non-compliance may be either on the part of the participant, the 
investigator, the research centre staff or laboratory staff. It is the responsibility of the 
research centre to identify and report protocol deviations according to the guidelines of 
the sponsor and the local IRB/IEC. The research centre must report protocol deviations 
to IPM using designated forms. The principal investigator and research centre staff are 
responsible for being familiar with and adhering to their IRB/IEC requirements. In 
response to noted protocol deviations, research centre personnel are to promptly 
implement corrective actions. 
 
4.9. Early Discontinuation Visits 
Participants may be discontinued early from the trial prior to completion of the last trial 
visit for any of the following reasons: 
• 
Participant withdraws her consent. 
• 
Participant fails to follow protocol requirements which are deemed to be 
serious enough by the investigator to warrant a discontinuation, e.g., in the 

IPM 032 
 
   22 October 2015 
Version 2.0 Amendment 1.0 
 
Page 34 of 69 
Restricted * Confidential – Limited Access* 
absence of an AE or discomfort, participant refuses to keep vaginal ring 
inserted for duration of the trial. 
• 
Participant is lost to follow-up, i.e., research centre is unsuccessful (following 
reasonable attempts as defined in the research centre SOP) in contacting 
participant or bringing the participant back to the research centre. 
• 
Participant tests HIV-positive according to the HIV-testing algorithm in 
Appendix B.  
• 
If, for safety reasons, the investigator considers it in the best interest of the 
participant to discontinue her from the trial.  
• 
At the discretion of the investigator, Sponsor, IRB/IEC or the government 
health authority. 
The date and reason for permanent trial discontinuation will be noted in the source 
documents and applicable CRFs. All participants who are prematurely discontinued from 
the trial will be encouraged to return to the research centre for a final evaluation, at 
which time all trial procedures scheduled for the last product use visit will be performed. 
An optional exit visit 1-2 months after product discontinuation can be completed. 
 
Participants who are considered lost to follow-up will be temporarily discontinued from 
the trial. Reasonable contact attempts will be made according to the locator information 
provided by the participant and local SOPs, and temporarily early trial termination will be 
documented in the source documents and applicable CRFs. If a participant already 
considered lost to follow-up returns to the research centre prior to the centre’s trial 
completion, the participant’s file (including CRFs) may be re-opened to perform trial 
discontinuation procedures. The participant may be considered for continuation on the 
trial at the discretion of the principal investigator in consultation with the IPM Clinical 
Project Manager, depending on the reason for the missed visits. A final trial termination 
will be documented in the source documents and applicable CRFs during the trial 
closure for all temporarily early trial terminations. 
 
4.10. Premature Discontinuation of the Trial 
IPM has the right to terminate this trial at any time for any reason. If the trial is 
prematurely terminated, the investigator must promptly inform the participants and the 
IRBs/IECs, and ensure proper medical follow-up of participants in consultation with IPM. 
If the trial is prematurely terminated, all procedures and requirements pertaining to the 
archiving of the trial documents will be observed. IPM will provide the research centres 
with instructions on the proper disposition of any clinical supplies at the centre.  
5. Trial Procedure Details  
5.1. Informed Consent 
The informed consent documents will include all the information about the trial required 
by GCP and will make provision for the dated signatures of the participant, the principal 
investigator or designated trial staff conducting the informed consent process, and when 
required, also for a dated signature by an impartial witness. The informed consent 
process will be administered at the Screening Visit. 
 
The informed consent process will include adequate time for each potential participant to 

IPM 032 
 
   22 October 2015 
Version 2.0 Amendment 1.0 
 
Page 35 of 69 
Restricted * Confidential – Limited Access* 
have any trial related questions answered by appropriately qualified and trained trial staff 
as designated by the investigator, and the entire process will be documented in the 
source documents. 
 
At screening, potential participants who agree to participate in the trial will sign and date 
the ICF. The ICF will also be signed and dated by the trial staff administering the consent 
process as delegated by the principal investigator according to the research centre SOP. 
If a potential participant is functionally illiterate, the informed consent document(s) and 
any written study-related materials must be read to her in the language best understood 
by the potential participant in the presence of an impartial literate witness. After the 
illiterate participant has orally consented to participate in the trial, and, if capable of 
doing so, has signed the ICF or provided a thumbprint or mark that was witnessed by the 
impartial witness, this impartial witness must sign and personally date the ICF. By 
signing the ICF the impartial witness attests that the information in the participant 
information sheet and any other written information was explained to, and apparently 
understood by, the participant or the participant’s legally acceptable representative and 
that informed consent was freely given by the participant or the participant’s legally 
acceptable representative. 
 
The signed and dated ICFs will be retained at the research centre. A copy of the signed 
and dated ICFs will be offered to the participant. If the participant is not willing to receive 
the documents, the second copy will be retained at the research centre. Likewise, during 
the trial, signed and dated ICF updates and any amendments to written trial-related 
materials to be given to participants will be offered to the participant but retained at the 
research centre if the participant is unwilling to receive the documents. Documentation of 
the participant’s refusal to accept a copy of the ICF(s) or other trial-related materials will 
be noted in the source documents.  
 
The consent documents and any trial-related materials given to the participant will be 
translated and back-translated in the local languages according to local IRB/IEC 
requirements and regulatory authority guidelines. Information in the informed consent 
documents and trial-related material will be verbally communicated by trial staff, in the 
language preferred by the participant, and copies of the documents and trial-related 
materials will be offered to her in her preferred language. Documentation will be required 
to verify who performed translation/back-translation of the materials as well as a written 
statement by the translator indicating that the consent form(s) is an accurate translation 
of the accompanying English version. This is the principal investigator’s responsibility. 
 
All research centre-specific informed consent documents will first be reviewed and 
approved by IPM and then approved by the responsible IRB and/or local IEC prior to 
administration to the participants. 
 
If new information becomes available which may be relevant to the participant’s 
willingness to continue trial participation, the information will be provided via IRB and/or 
IEC-approved revised informed consent documents or addenda to the original informed 
consent documents in a timely manner and will be signed and dated by the participant in 
the same manner described above. 
 
 

IPM 032 
 
   22 October 2015 
Version 2.0 Amendment 1.0 
 
Page 36 of 69 
Restricted * Confidential – Limited Access* 
5.2. Comprehension Assessment Checklist  
Trial staff will assess the potential participant’s understanding of informed consent 
information prior to obtaining a signature on the ICF at the Screening Visit. This 
assessment will be done using a standardised comprehension assessment checklist. All 
comprehension problems that are discovered during the assessment will be discussed 
until staff member(s) are satisfied that the participant can verbalise her understanding of 
the issue. This process will be documented on the comprehension assessment checklist. 
This checklist will be recorded in source documentation at the research centre. A 
participant who cannot demonstrate comprehension of the informed consent information 
will not be enrolled in the trial. 
 
5.3. HIV Counselling 
5.3.1. HIV Pre-and post-Test Counselling 
At all visits where HIV testing is performed, pre- and post-test counselling will be 
provided according to the National Guidelines for HIV Counselling and Testing. 
Adaptations of these guidelines in accordance with locally accepted standards of 
practice are allowed. Each research centre will document the counselling policies and 
procedures prior to trial implementation for purposes of staff training, quality assurance, 
and trial monitoring. 
 
A comprehensive package of post-test counselling and psychosocial support will be 
provided to women who test HIV reactive at any point during trial participation. Initial 
counselling services will be provided at the research centre and women will be referred 
for additional counselling, support services and treatment. These services will be 
identified by the research centres prior to trial initiation and referral procedures will be 
documented in writing by the centre. 
 
5.3.2. HIV/STI Risk Reduction Counselling 
HIV/STI risk reduction counselling will be in accordance with local guidelines. 
Counselling will be provided at all research centre visits. Efforts will be made to ensure 
standardisation of risk reduction counselling at the trial research centres. 
 
NOTE: Risk reduction counselling will include recommendation of male condom use. 
Participants will be provided with a supply of male non-spermicidal condoms during each 
trial visit, if they are willing to accept them. The use of female condoms is permitted in 
this trial. 
 
5.4. HIV Testing and Management 
The research centres will inform IPM Medical Safety of any new HIV seroconversions 
within 48 hours of diagnosis. The applicable regulatory authorities and independent 
ethics committees who require expedited notification of HIV seroconversion will be 
notified by either IPM or the research centre in accordance with standard operating 
procedures and policies of the regulatory authorities or independent ethics committees. 
The details of the HIV rapid test kits will be specified in the Laboratory Manual, as part of 
the SOM. Participants will be tested for HIV using two highly sensitive antibody rapid 
tests (Test 1 and Test 2). 
 

IPM 032 
 
   22 October 2015 
Version 2.0 Amendment 1.0 
 
Page 37 of 69 
Restricted * Confidential – Limited Access* 
5.4.1. Screening Visit 
If both test results are non-reactive, the participant could potentially be enrolled in the 
trial if she is otherwise eligible.  
 
If both Test 1 and Test 2 are reactive at screening, the potential participant is considered 
to be HIV seropositive and not eligible for enrolment. Initial counselling services will be 
provided at the research centre and the participant will be referred for additional 
counselling, support services and treatment. These referral systems will be implemented 
by research centres prior to trial start. It is the participant’s responsibility to follow up with 
relevant medical services once referral has been initiated by the research centre. 
 
If Test 1 and Test 2 yield discordant results, a highly specific HIV antibody Test 3 will be 
performed. If Test 3 is reactive then the potential participant is considered to be HIV-
seropositive and is not eligible for enrolment. If Test 3 is non-reactive, the person is 
considered to be potentially HIV-seronegative and can be given a date for enrolment into 
the trial. Refer to Appendix B: HIV Testing Algorithms. 
 
A blood sample will be obtained by venepuncture to be sent for sample storage locally or 
at a central laboratory, for potential HIV-1 RNA PCR and viral genotype resistance 
testing if the participant seroconverts (blood volume specified in Appendix C). Storage 
samples for participants who do not enrol will be destroyed according to research centre 
SOPs. 
 
NOTE: For the purposes of HIV rapid testing at screening, blood may be obtained by 
finger prick or venous sampling. If the national regulatory authority of the country in 
which the research centre is situated requires that a national testing algorithm be used 
during the screening process, this will be performed, in addition to the IPM 032 HIV 
testing algorithm, as part of the screening process and documented as such. 
 
5.4.2. Enrolment Visit 
On the scheduled day of possible enrolment, the participant will be tested for HIV and 
will only be enrolled if the results are considered to be HIV-seronegative and the 
participant is otherwise eligible.  
 
Test 1 and Test 2 will be performed. If both test results are non-reactive and there is no 
history to suggest recent exposure that could be masked during the window period, the 
potential participant will be considered HIV-seronegative and eligible for enrolment. A 
blood sample will be obtained by venepuncture to be sent for sample storage locally or 
at a central laboratory, for potential HIV-1 RNA PCR and viral genotype resistance 
testing if the participant seroconverts (blood volume specified in Appendix C). Storage 
samples for participants who do not enrol will be destroyed according to local SOPs. 
 
If both Test 1 and Test 2 are reactive, the participant is considered to be HIV 
seropositive and not eligible for enrolment. Initial counselling services will be provided at 
the research centre and the woman will be referred for additional counselling, support 
services and treatment. 
 
A rapid Test 3 will be performed for all discordant rapid test results. If Test 3 is reactive 
then the potential participant is considered to be HIV-seropositive and not eligible for 

IPM 032 
 
   22 October 2015 
Version 2.0 Amendment 1.0 
 
Page 38 of 69 
Restricted * Confidential – Limited Access* 
enrolment. If Test 3 is non-reactive, the participant is considered to most likely be HIV-
seronegative, and a sample will be collected for HIV-1 RNA PCR testing and the 
Enrolment Visit should be re-scheduled within the screening window period (split visit). If 
the HIV-1 RNA PCR does not detect HIV RNA copies, the participant can be enrolled. 
Storage samples should be collected on the second day of the split visit. If the HIV-1 
RNA PCR does detect HIV RNA copies then she is not eligible for enrolment. She will be 
counselled and referred to the local health facilities for appropriate follow-up. Refer to 
Appendix B: HIV Testing Algorithms. 
 
5.4.3. Trial Visits and LPUV 
The rapid and confirmatory laboratory tests used in the HIV-testing algorithm will detect 
both subtypes, HIV-1 and HIV-2. The testing algorithm (refer to Appendix B) will be 
applied for all Trial Visits and LPUV. HIV testing while the participant is enrolled in the 
trial will be performed on blood samples obtained by venepuncture (blood volumes 
specified in Appendix C). 
 
If both the HIV rapid tests (Test 1 and Test 2) are non-reactive, the participant will be 
considered HIV-seronegative and continue using the IP. If both HIV rapid tests are 
reactive, IP will be withheld until HIV infection has been confirmed. Trial procedures 
relevant to the LPUV will be performed. Additional confirmatory testing will be performed 
by Western Blot and other confirmatory tests, where appropriate. IP may be re-
introduced after consultation with IPM, if confirmatory test(s) indicate(s) that the 
participant is not HIV infected. The participant must have a negative pregnancy test prior 
to re-introduction of IP. A pelvic examination should be performed according 
investigator’s discretion prior to re-introduction of IP if clinical indicated. If confirmatory 
test(s) indicate(s) that the participant is HIV infected, the participant will be permanently 
discontinued from IP and the trial. 
 
If the Test 1 and Test 2 results are discordant, a HIV rapid Test 3 will be performed on 
the same blood sample as used for Test 1 and Test 2. If Test 3 is reactive, IP will be 
withheld until HIV infection has been confirmed. Trial procedures relevant to the LPUV 
will be performed. Additional confirmatory testing will be performed by Western Blot and 
other confirmatory tests, where appropriate. IP may be re-introduced after consultation 
with IPM, if confirmatory test(s) indicate(s) that the participant is not HIV infected. The 
participant must have a negative pregnancy test result prior to re-introduction of IP. A 
pelvic examination should be performed according investigator’s discretion prior to re-
introduction of IP, if clinical indicated.  Nucleic acid-amplification testing (NAAT) by a 
HIV-1 RNA PCR test will be performed on stored samples in reverse sequential order to 
estimate the time point of HIV infection. The participant will be counselled and referred 
for appropriate counselling and care. 
 
If Test 3 is non-reactive, the participant is considered to be HIV-seronegative. The 
participants who have discordant HIV test results at Trial Visits will continue on IP and be 
requested to return for repeat HIV rapid testing after two weeks. In such cases the 
research centre will notify the IPM Clinical Project Manager or designee. Additional 
confirmatory tests may be indicated at any stage in consultation with the IPM Clinical 
Project Manager or designee. If a similar result is obtained on testing after two weeks, a 
sample should be collected for a quantitative HIV-1 PCR test and the research centre 
will notify the IPM Clinical Project Manager and Laboratory Specialist. 
 

IPM 032 
 
   22 October 2015 
Version 2.0 Amendment 1.0 
 
Page 39 of 69 
Restricted * Confidential – Limited Access* 
If the HIV-1 RNA PCR result is undetectable: 
• 
The participant is considered to not be HIV-infected. 
• 
The participant should continue in the trial with HIV rapid testing only 
performed at scheduled visits, even if the same pattern of discordant results 
continues. It will not be necessary to recall the participant for 2-weekly 
testing. 
• 
The research centre will notify the IPM Clinical Project Manager or designee 
of the outcome. 
 
If the HIV-1 RNA PCR result is detectable: 
• 
The participant should be considered HIV-infected and IP should be 
discontinued immediately. The research centre will notify the IPM Clinical 
Project Manager or designee immediately. 
 
All enrolled participants will in addition, have blood samples collected at each trial visit to 
be stored locally or at a central laboratory, for possible viral genotype resistance testing 
and HIV-1 RNA PCR testing. If a participant subsequently seroconverts (i.e. is confirmed 
HIV-positive) while on the IP, the stored samples will be tested in reverse sequential 
order until an undetectable PCR test result is obtained. This will be conducted to 
approximate the period of HIV infection. If the enrolment HIV-1 RNA PCR test result is 
positive, the participant is not considered to have been infected while using the IP. 
Blood (blood volume as specified in Appendix C) and vaginal fluid samples will also be 
obtained for dapivirine measurement at the point of HIV seroconversion according to the 
HIV testing algorithm described above. Stored samples (blood and vaginal fluids) will be 
analysed retrospectively as described in Section 5.17. 
 
Any participant who is confirmed HIV-infected while on the trial will be permanently 
discontinued from IP and the trial. An exit visit will be scheduled approximately 1-2 
months following IP discontinuation. Initial counselling services will be provided at the 
research centre and women will be referred for additional counselling, support services 
and treatment. In addition, these women will be offered the option of enrolling for IPM’s 
seroconverter protocol. 
 
In an instance where a participant is determined to be HIV-seropositive (as determined 
by HIV rapid tests, Western Blot; and any other confirmatory tests, if applicable), but 
cannot be confirmed as HIV-infected (HIV RNA PCR) the participant will be discontinued 
from IP and the protocol-required procedures as per original  trial visit schedule will be 
conducted at the investigator’s discretion. Samples for measurement of dapivirine levels 
will no longer be collected. Additional testing to demonstrate HIV infection may be 
performed. Participants will be followed up until the exit visit according to the original 
enrolment date. 
 
5.4.4. Exit Visit  
For participants confirmed as HIV-negative prior to the exit visit 
If both HIV rapid tests (Test 1 and Test 2) are non-reactive, the participant will be 
considered HIV-seronegative. If both Test 1 and Test 2 are reactive, additional 
confirmatory testing will be performed by Western Blot and other confirmatory tests, 
where appropriate. Samples for possible viral genotype resistance testing and HIV-1 

IPM 032 
 
   22 October 2015 
Version 2.0 Amendment 1.0 
 
Page 40 of 69 
Restricted * Confidential – Limited Access* 
RNA PCR testing will be collected. Once HIV infection has been confirmed, this will be 
considered an HIV seroconversion after product discontinuation and may be a 
combination of both women infected during IP use who seroconverted after IP 
discontinuation, as well as women infected after IP use. Nucleic acid-amplification 
testing (NAAT) by a HIV-1 RNA PCR test will be performed on stored samples in reverse 
sequential order to estimate the time point of HIV infection. 
 
Initial counselling services will be provided at the research centre and women will be 
referred for additional counselling, support services and treatment. 
 
A HIV rapid Test 3 will be performed for discordant rapid Test 1 and Test 2 results. If 
Test 3 is reactive then the participant will be considered to be HIV-seropositive. 
Additional confirmatory testing will be performed by Western Blot and other confirmatory 
tests, where appropriate. Samples for possible viral genotype resistance testing and 
HIV-1 RNA PCR testing will be collected. The participant will be counselled and referred 
to local health facilities for social support or other medical services as clinically indicated. 
If Test 3 is non-reactive, the participant is considered to be HIV-seronegative and will be 
counselled appropriately. Refer to Appendix B: HIV Testing Algorithms, and Appendix C: 
Visit Schedule and Blood Volumes. 
 
For participants confirmed as HIV-infected prior to the exit visit 
As stated in Section 5.4.3 above, an exit visit will be scheduled approximately 1-2 
months following confirmed HIV-seroconversion and IP discontinuation. Blood samples 
for viral genotype resistance testing and HIV-1 RNA PCR will be collected from these 
participants, but no further HIV counselling and testing will be done unless indicated for 
additional confirmatory testing. 
 
Participants who become infected with HIV during the course of an IPM trial will be 
referred for appropriate HIV-related care and ARV therapy as above. The threshold for 
initiation of ARV treatment will be determined with reference to the WHO treatment 
guidelines if no country specific guidelines are available. Women who become pregnant 
and HIV positive during the trial will be referred for appropriate Prevention of Mother-to-
Child Transmission (PMTCT) services. 
 
The research centres will inform IPM Medical Safety of any new HIV infections within 48 
hours of diagnosis. The applicable regulatory authorities and ethics committees who 
require expedited notification of HIV seroconversion will be notified by either IPM or the 
research centre in accordance with standard operating procedures and policies of the 
regulatory authorities or ethics committees. 
 
5.5. Contraceptive Counselling and Management of Contraception  
Contraceptive counselling will be provided at all research centre visits. Counselling will 
be tailored per research centre, depending on local community and regional guidelines 
and will be detailed in research centre procedures. Counselling will include information 
about medication side effects and interactions, the importance of contraceptive 
adherence for the duration of the trial; what to do in the event of accidental non-
adherence and advice on how to remain adherent. 
 
Participants will also be counselled that if they become pregnant during the trial, they will 
immediately discontinue the IP and be referred to the local prenatal services for support 

IPM 032 
 
   22 October 2015 
Version 2.0 Amendment 1.0 
 
Page 41 of 69 
Restricted * Confidential – Limited Access* 
and further management of the pregnancy. Refer to Pregnancy Testing and 
Management below in Section 5.6. 
 
To meet eligibility criteria, unless postmenopausal with no history of menses for one year 
prior to screening, participants must be on an effective method of contraception prior to 
enrolment, have demonstrated adherence to her chosen method of contraception and 
have no significant resultant problems.  
 
In order to address challenges that participants may experience in consistently obtaining 
an effective method of contraception, research centres will provide participants with 
contraceptives from screening for the duration of the trial, if required. The contraceptives 
provided will be consistent with what is available locally. Alternatively, participants will be 
referred to the local family planning clinic or continue accessing contraception from local 
family planning clinics. Under supervision of the investigator or designated qualified 
personnel, enrolled participants may switch from one contraceptive method to another, if 
effective contraception is maintained. 
 
5.6. Pregnancy Testing and Management 
A urine pregnancy test will be performed at all scheduled trial visits, except for the Exit 
Visit, and can be performed additionally at unscheduled visits if any reason exists to 
suspect pregnancy or, in the event of a participant defaulting on her contraception, prior 
to recommencing contraception. 
 
If a potential participant tests positive for pregnancy during screening, she is not eligible 
to enrol in the trial, but will receive referrals to prenatal clinics or other appropriate 
facilities. 
 
A product hold will be implemented if a woman tests positive for pregnancy while on IP. 
Vaginal ring(s) will be retrieved from the participant, but the participant will not be 
withdrawn from the study. Protocol-specified visit schedule and procedures will continue 
except for IP-related procedures and other examinations if contra-indicated by 
pregnancy. The participant will be referred to a local prenatal clinic for medical services. 
The research centres will be asked to report all pregnancies to IPM within 48 hours of a 
positive pregnancy test or a confirmatory serum pregnancy test, if indicated. A 
confirmatory serum pregnancy test may be requested at the discretion of the investigator 
or a designated qualified member of the trial staff if reason exists to suspect a false 
positive urine pregnancy test. If the serum pregnancy test is negative, the investigator 
can consider recommencing use of the ring. If the participant indicates a change in 
pregnancy status or the participant’s clinical history indicates a change in her pregnancy 
status after the product hold (birth or termination), a urine pregnancy test may be 
performed. A confirmatory serum pregnancy test may be requested at the discretion of 
the investigator or a designated qualified member of the trial staff if reason exists to 
suspect a false positive urine pregnancy test. If the urine pregnancy test is negative, the 
investigator can consider recommencing IP. The participant must have a negative urine 
pregnancy test prior to re-introduction of IP, and should not be breast-feeding. A pelvic 
examination should be performed prior to re-introduction of IP. 
Women who become pregnant and HIV-positive during the trial will be referred for 
appropriate PMTCT services. 
 
 

IPM 032 
 
   22 October 2015 
Version 2.0 Amendment 1.0 
 
Page 42 of 69 
Restricted * Confidential – Limited Access* 
Should a participant have a positive pregnancy test in an instance where she was 
determined to be HIV-seropositive but could not be confirmed as HIV-infected, was 
discontinued from IP use and consented to continued participation in the trial without IP, 
she will be allowed to continue in the trial to allow for continued follow-up and evaluation 
of her HIV status until the Exit Visit according to the original enrolment date. 
 
The research centres will be required to provide quarterly updates on the progress and 
outcome of the pregnancy as well as the first year of life of the child for inclusion in the 
Sponsor maintained pregnancy registry. This requirement may vary, depending on 
country-specific regulations. 
 
5.7. Demographics and Medical History 
At the Screening Visit basic demographic information will be collected. A confidential 
master log of participants, with demographic and locator information will be maintained.  
 
At both the Screening and Enrolment Visits (pre-enrolment) relevant medical history will 
be obtained, including but not limited to history of STIs, gynaecological conditions, 
hospitalisations, surgery, allergies, any conditions requiring prescription or chronic 
medication, i.e. > 2 weeks in duration, and acute conditions occurring prior to enrolment. 
 
5.8. Physical Examination 
A general physical examination will be conducted at screening and the LPUV, and will 
include weight, vital signs (body temperature, pulse rate, respiration rate, blood 
pressure), and examination of skin, respiratory, cardiovascular, central nervous and 
abdominal systems, as well as an assessment of cervical and axillary lymph nodes. 
Height will be measured only at the Screening Visit. A symptom-directed physical 
examination will be conducted at any visit if clinically indicated. 
 
5.9. Pelvic Examination 
A pelvic examination will be performed at screening and LPUV, or at any visit if clinically 
indicated. On-trial examinations will be performed to assess safety, i.e., any local vaginal 
reactions. 
 
If the participant is menstruating on the day of a visit where pelvic examination is due, all 
procedures, including the pelvic examination can be conducted as per investigator and 
participant discretion. If this is not possible, the participant will be asked to return 2 days 
after completion of menstruation, within the window period of the visit. 
 
Any unexpected or abnormal vaginal bleeding should be investigated to identify the 
possible source. A follow-up pelvic examination should be performed to ensure 
resolution of the condition as indicated. 
 
5.10. Laboratory testing for safety assessments and urine dipstick analysis 
Safety laboratory assessments and urine dipstick analysis (microscopy only if clinically 
indicated) will be conducted at the screening visit, or any other trial visit if clinically 
indicated.  Blood specimens for laboratory testing (haematology and chemistry testing) 
will be obtained by venepuncture. Haematology will include a full blood count, 

IPM 032 
 
   22 October 2015 
Version 2.0 Amendment 1.0 
 
Page 43 of 69 
Restricted * Confidential – Limited Access* 
differential, and platelet count. Chemistry tests will include creatinine, AST and ALT. 
Details of blood volumes are specified in Appendix C. At the discretion of the investigator 
or designee, each potential participant may be retested once for safety laboratory tests 
during the screening period. 
 
Additional tests may be performed at the investigator’s discretion after discussion with 
the IPM Clinical Physician (or designee) based on symptomatology and clinical 
assessment of participants. Additional descriptive information regarding specimen 
collection and processing for all tests will be detailed in the SOM. 
 
All laboratory results will be reviewed by the investigator or appropriately qualified and 
trained trial staff as designated by the investigator, and documented on the original 
laboratory report itself. 
 
5.11. STI Testing and Management 
5.11.1. STI Testing 
Cervicovaginal samples will be collected for STI testing at screening and the LPUV, or 
any other trial visit if clinical indicated. All participants will be evaluated for Trichomonas 
vaginalis (TV), Neisseria gonorrhoeae (NG) and Chlamydia trachomatis (CT). At 
screening, blood will be collected by venepuncture for Syphilis (RPR) testing (Blood 
volume specified in Appendix C). TPHA/TPPA testing will be performed if the RPR is 
reactive. 
 
Additional descriptive information regarding specimen collection to test for STIs and 
processing of all tests will be detailed in the Laboratory Manual, as part of the SOM. 
 
NOTE: Documentation will be made in applicable CRFs for all cervicovaginal samples 
obtained in the presence of cervicovaginal blood. 
 
The investigator or appropriately qualified and trained trial staff as designated by the 
investigator will review all results, including rapid and laboratory tests, and the review will 
be documented by the reviewer on the original laboratory report itself. 
 
5.11.2. STI Management 
All participants who present with STIs will be managed appropriately as clinically 
indicated at the research centre or referred to a local health facility, according to local 
STI Treatment Guidelines.  Cervicovaginal swabs may be collected from these 
participants, at the investigator’s discretion or when required by local standard of care. 
Aetiological management may be applicable following STI testing, according to the 
aetiological diagnosis. 
 
The Clinical Management of Genital Diagnoses will be detailed in the SOM for guidelines 
to determine whether the vaginal ring requires temporary or permanent removal and to 
provide guidance regarding follow up recommendations.  
 
5.12. Cervical Cytology 
A cervical cytology sample will be collected at the Screening Visit if not done within the 
previous year, or if the result was abnormal at the last point of testing. Further details will 

IPM 032 
 
   22 October 2015 
Version 2.0 Amendment 1.0 
 
Page 44 of 69 
Restricted * Confidential – Limited Access* 
be provided in the Laboratory Manual, as part of the SOM. 
 
Women with abnormal cytology findings will be referred for appropriate medical services 
based on local standard of care for management of abnormal cervical cytology. 
Research centres will implement these referral systems prior to trial start.  
 
5.13. Vaginal Ring Dispensing 
Vaginal rings will be dispensed at the Enrolment Visit and subsequent Trial Visits. In the 
event that a participant will be away and unable to attend one of the Trial Visits where 
new vaginal ring(s) would be dispensed, the investigator or designee could dispense 
additional ring(s) on a case-by-case basis. All such circumstances must be documented 
fully by the investigator as described in the IPM 032 SOM. If a participant requires an 
additional ring at a time other than when they are scheduled to receive one, they will be 
required to attend the clinic for an interim visit.  During the monthly trial visit period, the 
participants will be instructed to self-insert the newly-dispensed vaginal ring at the 
research centre and to remove the ring at the next scheduled visit. During the 3-monthly 
trial visit period, the participants should self-insert one ring during the trial visit and each 
of the two additional rings at monthly intervals until their next scheduled research centre 
visit. Vaginal ring bags will be provided to participants during the 3-monthly trial visit 
period for the storage of the used rings, together with instructions on the storage of the 
unused and used rings. 
 
During the 3-monthly trial visit period, optional vaginal ring dispensing and return 
arrangement will be made with participants who prefer not to have additional vaginal 
rings in their possession. These participants will be provided with the option to return 
used vaginal rings and to collect new rings at the research centres at time intervals 
suitable to them, provided that the intervals allow for new vaginal rings to be inserted 
monthly. Optional HIV rapid tests will be offered to participants during these interim visits 
and will be conducted according to the Trial Visits HIV algorithm (refer to Appendix B). 
Participants’ preference regarding the intervals for product dispensing and return will be 
documented in the source document and applicable CRFs. 
 
5.14. Vaginal Ring Insertion and Ring Removal 
At the Enrolment and Trial Visits, participants will insert the vaginal rings under research 
centre supervision. The participant will be instructed to thoroughly wash her hands, 
relax, and get into a comfortable position either standing with one foot on a chair, lying 
on her back with her knees up, or squatting. After opening the folds of skin around the 
vagina, she will gently squeeze the ring into an oval shape and push it upwards and 
backwards towards the back as far as it will go, thereby depositing the ring in the vagina. 
She will then be instructed to thoroughly wash her hands again. At all research centre 
visits during which a pelvic examination is performed, the participant will remove the ring 
prior to the examination. 
 
If the participant requests help with either removal or insertion of the vaginal ring, or after 
she has made several attempts to remove/insert the ring without success, trained trial 
staff may give assistance. Re-education of the participant on ring removal/re-insertion 
will be given. This will be noted in the source documents and applicable CRFs. 
Additional instructions about ring use will be provided in the SOM. 
 

IPM 032 
 
   22 October 2015 
Version 2.0 Amendment 1.0 
 
Page 45 of 69 
Restricted * Confidential – Limited Access* 
All rings that are removed will be inspected visually, and an assessment will be made by 
the principal investigator or designee as to whether the ring appears to have been used 
or not, together with a reason for the assessment. The rings should then be rinsed in 
running water, patted dry, placed in a ring return bag, and stored between 15°C and 
30°C until shipment to the analytical laboratory for testing of residual dapivirine amounts. 
 
5.15. Vaginal Ring Adherence Counselling 
At the Enrolment and Trial Visits, participants will receive vaginal ring adherence 
counselling, including adherence to trial visit schedule and requirements. At the 
Enrolment Visit, participants will be provided with feedback on the IPM 027 and MTN-
020 trials, which will include information on trial adherence trends, as part of the vaginal 
ring adherence counselling. Research centre staff will counsel participants to refrain from 
removing the ring (except as directed during research centre visits) and will provide 
instructions to all participants in case of accidental ring expulsion (e.g., during sex or 
exercise), or removal, and guidance will be provided on how the ring should be handled 
when it is out of the vagina. Research centre staff will also provide instructions to the 
participants during the 3-monthly trial visit period for insertion of a new ring after a month 
and the participants will be counselled on how to store the used and unused rings at 
home, if applicable.  
 
If, for any reason, the participant is non-adherent to the use of the vaginal ring (i.e. she 
removes the ring for any purpose other than as instructed at a trial visit), this should be 
documented according to the guidelines specified in the SOM.  
 
5.16. Participant Questionnaire 
The Participant Questionnaire will be administered at every trial visit and the LPUV. This 
questionnaire includes acceptability questions about the monthly and 3-monthly 
research centre follow-up during the trial. 
 
5.17. Sample Storage and Analysis 
Blood (blood volume as specified in Appendix C) and vaginal fluid samples will be 
collected for storage locally or at a central laboratory at all research centre visits. Blood 
samples for HIV viral genotype resistance testing and HIV-1 RNA PCR will be stored at 
the Screening Visit, the Enrolment Visit, every Trial Visit, LPUV and Exit Visit and will be 
tested subsequent to confirmed HIV-1 seroconversion, according to the HIV testing 
algorithm described in Section 5.4. Testing will also be conducted on a random sample 
of HIV-negative participants. For possible dapivirine concentration measurements, 
plasma and vaginal fluid samples should preferably be collected prior to removal of the 
vaginal ring. Further details regarding these procedures will be provided in the 
Laboratory Manual, as part of the SOM. 
 
All specimens will be collected and analysed according to methods described in the 
Laboratory Manual and research centre SOPs for proper collection, processing, 
labelling, and transport of specimens to the laboratories conducting the analysis. Where 
possible and appropriate, stored specimens will be re-tested to assess validity of 
unusual or unexpected assay results. 
 
 

IPM 032 
 
   22 October 2015 
Version 2.0 Amendment 1.0 
 
Page 46 of 69 
Restricted * Confidential – Limited Access* 
Any residual specimens will be destroyed at the end of the trial after all protocol-required 
and quality control testing has been completed. 
 
5.18. Screening Identification (SCR-ID) and Participant Identification (PID) 
Numbers 
After informed consent is obtained, a SCR-ID number will be assigned to each 
participant for identification purposes and the participant will be screened to assess 
eligibility for the trial. As each new participant enters the trial, a unique PID number will 
be assigned in consecutive order, starting with the lowest number available at the 
research centre at the time. 
 
5.19. Diary cards 
Participants will be provided with diary cards at enrolment and at trial visits, as 
applicable, except the LPUVs and Exit Visits. The diary cards are meant to be completed 
by the participants, and returned to the research centre at each Trial Visit and the LPUV 
to serve as a memory aid for participants to review during their scheduled visits and 
adherence counselling. The diary card will be used to document the removal and 
insertion date of the additional rings and for documenting AEs experienced and 
concomitant medications taken between trial visits. Participants will be requested to 
document the details of all cases of accidental ring expulsion or removal. Additional 
instructions on diary cards will be provided in the SOM. 
 
5.20. Reimbursement 
Participants will be reimbursed for any travel costs incurred in compliance with local 
regulations. Reimbursements will be made after the completion of each trial visit. 
Research centre specific reimbursement amounts will be documented in the trial ICF 
approved by the applicable IRB/IEC. Upfront reimbursement for travel expenses may be 
made if this has been approved by the relevant ethics committee. 
Note: During the 3-monthly trial visit period, participants who choose to not receive the 
two additional vaginal rings during trial visits, will be responsible for the travel costs 
incurred during the optional vaginal ring collection/return visits to the research centre. 
 
5.21. Participant Compensation 
If a participant in an IPM clinical trial becomes ill or injured as a result of participation in 
the trial, medical treatment for the adverse reaction or injury will be provided 
appropriately. The research centre staff will refer the participant for ongoing treatment for 
the injury, if needed. The Sponsor will be responsible for compensation for appropriate 
medical expenses for treatment of any such illness or injury. An HIV infection that occurs 
during the course of the trial will not be considered an injury or illness caused by trial 
participation. 
 
5.22. Participant Responsibility 
Referral systems to local medical services will be implemented by research centres prior 
to trial start. It remains the participant’s responsibility to follow up with relevant medical 
services once referral has been initiated by the research centre. 

IPM 032 
 
   22 October 2015 
Version 2.0 Amendment 1.0 
 
Page 47 of 69 
Restricted * Confidential – Limited Access* 
5.23. Study Operations Manual (SOM) 
A SOM will be supplied to all research centres to provide general guidance on the 
conduct of trial procedures. The Laboratory Manual is contained within the SOM. 
6. Investigational Product  
6.1. Investigational Product Composition 
The dapivirine silicone elastomer vaginal matrix ring is an off-white flexible ring 
containing 25 mg of dapivirine dispersed in a platinum-catalysed silicone matrix. The 
dimensions of the ring are 56 mm (outer diameter) and 7.7 mm (cross sectional 
diameter). The dapivirine silicone elastomer vaginal matrix ring is designed to provide 
sustained release of dapivirine over a minimum of one month. 
 
The Dapivirine Vaginal Ring-004 is comprised of dapivirine, the polydimethylsiloxane 
liquid MED-360 and the silicone MED-4870. The safety of dapivirine has been 
established in a comprehensive nonclinical and clinical development programme 
described in the IB5. Both the silicone elastomers and the liquid silicone dispersant have 
been evaluated in in vitro cytotoxicity, haemolysis tests, cytogenic damage and 
genotoxicity assays, and in in vivo systemic toxicity studies, intracutaneous toxicity 
studies, pyrogen studies and delayed contact sensitisation studies. The silicone 
elastomer was also evaluated in muscle implantation studies of up to 12 weeks duration. 
In addition, a number of preclinical tests were performed on the finished Dapivirine 
Vaginal Ring-004, including a panel of biocompatibility tests (in vitro cytotoxicity and 
genotoxicity assays, and in vivo vaginal irritation and sensitisation studies) using extracts 
of the ring, and a study in sheep, in which Dapivirine Vaginal Ring-004 containing 25 mg 
dapivirine was inserted into the vagina (up to 3 consecutive rings; each ring for a period 
of 30 days). None of these tests identified any significant safety concerns. 
 
6.2. Packaging and Labelling 
IPM will bear the responsibility for primary and secondary packaging and labelling. The 
packaged rings will be labelled according to local regulatory requirements. 
 
6.3. Investigational Product Storage 
The recommended storage condition for the dapivirine ring is 15°C to 30°C, excursions 
permitted. The proposed shelf life is 48 months when stored in the original packaging 
under the recommended storage conditions. In the event that the IP has been subjected 
to different storage conditions than specified above, the affected IP will not be used 
(unless IPM or its designee provides written authorisation for use). IPM should be 
notified immediately in the event that IP storage conditions have been breached. 
 
The investigator (or pharmacist) will maintain an inventory and acknowledge receipt of all 
shipments of IP. More information on IP storage will be provided in the SOM. 
 
Participants will be provided with instructions on storage of used and unused rings 
during the 3-monthly trial visit schedule. 
 

IPM 032 
 
   22 October 2015 
Version 2.0 Amendment 1.0 
 
Page 48 of 69 
Restricted * Confidential – Limited Access* 
6.4. Investigational Product Administration  
The participants will be instructed to self-insert the Dapivirine Vaginal Ring-004 at the 
Enrolment Visit, and monthly thereafter. The participants will be reminded of proper 
vaginal ring insertion and removal procedures.  
 
During the 3-monthly trial visit schedule, participants will be instructed to remove the 
vaginal rings and self-insert each of the two additional rings at monthly intervals until 
their next scheduled research centre visit. The self-insertion and removal of the rings 
should take place at the research centres during the months that the participants attend 
their scheduled trial visits.  Participants should be advised to continue ring use through 
menses. 
 
6.5. Investigational Product Expulsion or Loss 
If a participant accidentally expels the ring, e.g., during sex or exercise, she will be 
instructed to rinse the vaginal ring thoroughly in clean water and re-insert the ring as 
soon as possible. If the vaginal ring is expelled and cannot be successfully reinserted, 
the ring should be appropriately rinsed, patted dry and stored in the bag provided for this 
purpose, until the earliest possible opportunity the participant can return for help with the 
reinsertion of a ring at the research centre.  
 
During monthly visits, if the ring is expelled in such a manner that the participant is 
unwilling to re-insert it, e.g., during urination or a bowel movement, or if the ring is lost, 
the participant should return to the research centre at the earliest possible opportunity to 
receive a replacement ring.  
 
During the 3-monthly trial visit schedule, participants will be instructed that if the ring is 
expelled in such a manner that the participant is unwilling to re-insert it, e.g., during 
urination or a bowel movement, or if the ring is lost, the participant should use one of the 
unused, additional rings dispensed. If the expelled ring was the last of the additional 
vaginal rings dispensed, the participant should return to the research centre at the 
earliest possible opportunity to receive a replacement ring.  
 
Also, in cases where a ring is removed due to a genital infection, a new ring will be 
inserted or dispensed. Visits associated with expulsion or loss of rings will be regarded 
as unscheduled visits unless the visit is within the 7-day window period of the next 
scheduled visit. 
 
6.6. Retrieval of Investigational Product 
All participants who are prematurely discontinued from the trial will be encouraged to 
return to the research centre for a final evaluation, at which time all vaginal rings in the 
participant’s possession should be retrieved. If the participant does not return her used 
or unused vaginal ring at this visit, it should be retrieved as soon as possible after this 
visit, either by the participant returning it to the trial staff, or by trial staff conducting a 
home visit. 
 
For participants who are considered lost to follow-up and permanently discontinued from 
the trial, reasonable contact attempts will be made according to the locator information 
provided by the participant and local SOPs. Any used or unused vaginal rings that could 
not be retrieved will be documented in the source documents and applicable CRFs. 

IPM 032 
 
   22 October 2015 
Version 2.0 Amendment 1.0 
 
Page 49 of 69 
Restricted * Confidential – Limited Access* 
6.7. Investigational Product (IP) Accountability 
The principal investigator or designee will be responsible for adequate and accurate 
accounting, handling, storage and dispensing of the IP. The IP will be stored safely and 
properly in a secure location with access available only to the principal investigator and 
designated trial personnel. IP and clinical supplies are to be dispensed only in 
accordance with the protocol. Accurate records of IP received from IPM, the amount 
dispensed to the participants, the amount returned by the participants, the quantity 
remaining at the conclusion of the trial and any wasted or expired IP will be maintained. 
 
Unused and used rings not analysed for residual amounts of dapivirine will be destroyed 
according to IPM instruction and local regulatory requirements. 
 
6.8. Concomitant Medications and Products 
Prescription and non-prescription medications will be recorded on the source documents 
and applicable CRFs. Vaginal products and practices including the use of spermicides, 
intravaginal medication, douches, lubricants, tampons and female condoms may be 
used during the trial and will be captured. Further details will be provided in the SOM. 
7. Adverse Events 
7.1. Definition 
An AE is any untoward medical occurrence during the course of a trial in a participant 
who received an IP at any dose, which does not necessarily have a causal relationship 
with the IP. An AE can therefore be any unfavourable and unintended sign (including an 
abnormal laboratory finding), symptom or disease temporally associated with the use of 
an IP, whether or not considered related to the IP. This definition includes inter-current 
illnesses or injuries and exacerbation of pre-existing conditions. 
 
An unexpected adverse event is an adverse event, the nature or severity (intensity) of 
which is not consistent with the applicable product information (i.e. IB, package insert, or 
summary of product characteristics). Final determination of whether an event is 
considered unexpected will be made by the Sponsor, however, the investigator should 
be knowledgeable of the contents of the IB. 
 
Whenever possible, the laboratory abnormalities should be considered in the context of 
the primary clinical diagnosis and should be reported as such (e.g. acute hepatitis with 
increased bilirubin). Clinically significant laboratory abnormalities will be considered AEs 
and graded for severity based on the Division of AIDS (DAIDS Table for Grading 
Severity of Adult and Pediatric Adverse Events) as appropriate. 
 
Any condition occurring prior to enrolment will be reported as a pre-existing condition 
under Medical or Gynaecological History. All AEs occurring during the trial will be 
recorded in the source documents and applicable CRFs.  All AEs will be reported and 
graded according to the latest version of the DAIDS Table for Grading Severity of Adult 
and Pediatric Adverse Events and Female Genital Grading Table for Use in Microbicide 
Studies (which will be provided to research centres in the SOM). A vaginal bleeding 
abnormality thought to be due to contraception, asymptomatic BV and asymptomatic 
candidiasis will not be reported as an AE for this trial. 
 

IPM 032 
 
   22 October 2015 
Version 2.0 Amendment 1.0 
 
Page 50 of 69 
Restricted * Confidential – Limited Access* 
If a unifying diagnosis is possible, the investigator should record a specific disease or 
syndrome rather than individual associated signs and symptoms. However, if an 
observed or reported sign, symptom, or clinically significant laboratory abnormality is not 
considered a component of a specific disease or syndrome by the investigator, it should 
be recorded as a separate AE. 
 
All AEs will be monitored until resolution and/or the cause are identified, or until the 
investigator does not expect any improvement or worsening of condition/symptoms. If a 
SAE, urogenital AE or related AE remains unresolved at the participant’s Exit Visit, the 
research centre investigator will make a clinical assessment with the IPM Clinical 
Physician to determine whether continued follow-up of the AE is warranted. All other AEs 
that are not serious, not urogenital and assessed to be unrelated to IP will be noted as 
ongoing at trial end if the outcome is not yet determined at the time of the exit visit. 
 
7.2. Assessment of Adverse Event Severity 
The investigator is responsible for assessing the severity of AEs occurring on trial. All 
AEs except genital complaints will be graded according to the latest version of the 
DAIDS Table for Grading Severity of Adult and Pediatric Adverse Events. All genital 
complaints will be graded according to the latest version of the Female Genital Grading 
Table for Use in Microbicide Studies, which will be provided to research centres in the 
SOM. 
 
For AEs not listed on either of these tables, the following criteria will be used to estimate 
the grade of severity: 
• 
Mild 
Symptoms causing no or minimal interference with usual social and functional 
activities 
• 
Moderate 
Symptoms causing greater than minimal interference with usual social and 
functional activities 
• 
Severe 
Symptoms causing inability to perform usual social and functional activities 
• 
Potentially Life-threatening 
Symptoms causing inability to perform basic self-care functions OR medical 
or operative intervention indicated to prevent permanent impairment, 
persistent inability, or death 
 
7.3. Relationship to Investigational Product 
The investigator is responsible for determining the relationship of all AEs occurring 
during the trial and will assess AEs based on the following criteria: 
• 
Not Related 
There is not a temporal relationship or a reasonable possibility of a causal 
relationship (i.e. some level of evidence is lacking) to administration of the 
investigational product. The AE is clearly explained by another cause 
(concurrent disease, concomitant medication, environmental or toxic factors, 

IPM 032 
 
   22 October 2015 
Version 2.0 Amendment 1.0 
 
Page 51 of 69 
Restricted * Confidential – Limited Access* 
etc.). 
• 
Related 
There is a reasonable possibility of a causal relationship between the 
investigational product and the AE, (i.e. there is some level of evidence as to 
the causal association). The event may respond to withdrawal of the 
investigational product (dechallenge), and recurs with rechallenge by 
administration of the investigational product. In other cases the AE is clearly 
related and most likely explained by the administration of the investigational 
product. 
 
7.4. Serious Adverse Event 
7.4.1. Serious Adverse Event Definition 
A serious adverse event (SAE) or reaction is any untoward medical occurrence that at 
any dose: 
• 
Results in death. 
• 
Is life-threatening. 
This criterion applies if the participant is at immediate risk of death from the 
event as it occurred, in the opinion of the investigator; it does not refer to an 
event which hypothetically might have caused death if it were more severe. 
• 
Requires in patient hospitalisation or prolongation of existing 
hospitalisation. 
This criterion applies if the event requires inpatient hospitalisation and results 
in an overnight stay in hospital or, if in the opinion of the investigator, 
prolongs 
an 
existing 
hospitalisation. 
A 
hospitalisation 
(including 
hospitalisation for an elective procedure or routinely scheduled treatment not 
associated with an adverse event) for a pre-existing condition which has not 
worsened does not constitute an SAE. 
• 
Results in persistent or significant disability/incapacity. 
This criterion applies if the event causes a substantial disruption of a person’s 
ability to conduct normal life functions. 
• 
Is a congenital anomaly/birth defect. 
This criterion applies if a participant gives birth to a child with a congenital 
anomaly or birth defect or if the anomaly/birth defect is diagnosed by any 
prenatal tests. 
• 
Important medical events (medically significant) that may not be 
immediately life-threatening or result in death or hospitalisation but may 
jeopardize the participant or may require intervention in order to prevent one 
of the outcomes listed above should also be considered serious; e.g., 
bronchospasm requiring intensive treatment in an emergency room or at 
home. 
NOTE: A SAE does not have to be severe in nature to meet any of the above criteria. 
 
 
 
 

IPM 032 
 
   22 October 2015 
Version 2.0 Amendment 1.0 
 
Page 52 of 69 
Restricted * Confidential – Limited Access* 
All SAEs that occur from the time the participant is enrolled through the duration of the 
trial, whether considered associated with the IP or not, must be reported to the IPM 
Medical Safety Physician and/or designee within 24 hours of the centre becoming aware 
of the event. All SAEs should be recorded in the source documents and the relevant 
CRFs and reported using the Immediately Reportable Events (IRE) Form provided. 
 
The IRE Report Form should be completed with all the available information at the time 
of reporting. The investigator is required to write a detailed report and complete SAE 
follow up in a timely manner until the SAE has resolved, the participant returns to normal 
health, or until the investigator does not expect any further improvement or worsening of 
the condition. Medical Records may be requested by IPM to assist in assessing 
relatedness and severity of the SAE, and for possible submission to the Regulatory or 
Health Authorities as appropriate. To maintain confidentiality, the participant’s name 
must be blacked out on any medical records submitted and replaced with the PID 
number and the initials. 
 
More details on SAE reporting requirements and processes are described in the Safety 
Reporting Plan (provided in the SOM) provided to the research centres. 
 
7.4.2. Serious Adverse Event Contact Information 
 
SAEs will be reported to IPM or designee within 24 hours of any research centre staff 
member becoming aware of the event. If the SAE is related, and life-threatening or fatal, 
IPM Medical Safety should additionally be notified immediately by email or telephone. 
 
The following email will be used for communication with the IPM Medical Safety team 
regarding any IREs: safetyreports@ipmglobal.org. Contact details of relevant safety 
personnel will be provided in the Safety Reporting Plan. 
 
IPM will process all safety events. The IPM Medical Safety Physician will review all SAEs 
and generate the necessary queries. Further SAE reporting guidelines will be specified 
in the Safety Reporting Plan. 
 
7.4.3. Sponsor Notification of SAEs to the Regulatory Agencies 
Any unexpected serious adverse events which are deemed related to investigational 
product, will be considered “associated with the use of investigational product” and, as 
such, IPM will notify the appropriate regulatory authorities of the event in an expedited 
manner unless policies of the local regulatory authorities mandate such reporting by the 
research centre.  
 
Any unexpected SAE deemed to be unrelated to the IP will not be reported to the 
regulatory authorities in an expedited manner, unless policies of the local regulatory 
authorities mandate such reporting. 
 
7.4.4. Research Centre Notification of SAEs to Local Independent Ethics 
 Committee or Local Health and Regulatory Authorities 
The investigator will report all SAEs to the local IEC and/or regulatory or health 
authorities in accordance with standard operating procedures and policies of the IEC 
and/or regulatory or health authorities. 

IPM 032 
 
   22 October 2015 
Version 2.0 Amendment 1.0 
 
Page 53 of 69 
Restricted * Confidential – Limited Access* 
7.5. Immediately Reportable Events 
These are events which, while not necessarily meeting criteria for seriousness, are 
considered important by IPM and as such warrant immediate reporting to IPM. The 
following events should be reported to the Sponsor within 48 hours of any research 
centre staff member becoming aware of the event: 
• 
Pregnancy: Although not considered an AE, pregnancy must be reported if it 
occurs at any time while on IP during the trial;  
• 
HIV infection any time during the trial;  
• 
Any non-serious AE (including laboratory abnormalities) leading to permanent 
discontinuation of the investigational product.  
 
All IREs that occur from the time the participant is enrolled should be reported to IPM 
within the time periods specified above. All IREs should be recorded in the source 
documents and the relevant CRFs and should be reported to the IPM Medical Safety 
Physician using the IRE Form provided. 
 
As with SAEs, the IRE form should be completed with all available information at the 
time of reporting. The investigator is required to follow up the IRE in a timely manner 
until such time as it is deemed appropriate by IPM that all relevant information has been 
collected, or until such time as the participant is lost to follow up. 
 
7.6. Safety Monitoring 
The IPM 032 trial team will monitor safety and participant recruitment throughout the trial 
for all participants.  
 
7.7. Data Handling at Research Centres 
All trial data will first be collected on designated source documents and then recorded on 
CRFs with the exception of the Participant Questionnaire, for which the CRFs will serve 
as the source document, unless otherwise specified by IPM. Research centre staff 
responsible for completing the CRFs will receive appropriate training prior to the start of 
the trial, and will follow standardised procedures. Data must be legibly entered onto the 
CRFs. Data corrections will be made in accordance with standard procedures provided 
by IPM or its designee. Instructions for CRF completion will be provided on the back of 
the CRF pages, as well as in the SOM.  
 
The investigator will maintain, and store in a secure manner, complete, accurate and 
current trial records throughout the trial. Standard GCP practices will be followed to 
ensure accurate, reliable and consistent data collection. 
 
7.8. Source Data Verification 
All trial data must be verifiable to the source documentation (which includes original 
recordings, laboratory requisitions and reports, medical records, etc.). Source 
documentation will be made available to the IPM or representative(s) for review to 
ensure that the collected data is consistent with CRFs and has been completely and 
accurately reported as required by the trial protocol. 

IPM 032 
 
   22 October 2015 
Version 2.0 Amendment 1.0 
 
Page 54 of 69 
Restricted * Confidential – Limited Access* 
8. Statistical Methods  
IPM 032 is a Phase IIIb, multi-centre, open-label follow-on trial to IPM 027 to evaluate 
the safety of and adherence to Dapivirine Vaginal Ring-004, inserted at monthly intervals 
in healthy, HIV-negative women who have participated in the IPM 027 trial.  
 
Individuals meeting all inclusion criteria and no exclusion criteria will be eligible to 
receive the Dapivirine Vaginal Ring-004 with monthly research centre follow-up for one 
month (which may be extended to three months  at the investigator’s discretion) followed 
by  3-monthly research centre follow-up visits.  
 
Approximately 1400 participants are expected to be enrolled in the trial. 
 
Participants will self-insert the vaginal rings. Once participants commence the period of 
3-monthly follow up visits, two additional rings will be dispensed at each trial visit, the 
first of which the participants should self-insert one month later, and the second ring one 
month after that, before returning to the research centre for their next scheduled visit.  
 
An exit visit will be conducted 1-2 months after removal of the last ring (last product use 
visit).  
  
8.1. Trial Endpoints  
The primary and secondary trial endpoints are described in detail in Section 2.2 of the 
protocol. 
 
8.2. Primary Trial Hypotheses 
From previous clinical and safety trials of dapivirine, there is reason to believe that the 
Dapivirine Vaginal Ring-004 is safe and well tolerated. Thus, it is hypothesised that the 
Dapivirine Vaginal Ring-004 will be safe and well tolerated in healthy HIV-negative 
women over a 12-month period of exposure.  
 
8.3. Sample Size and Power Calculations 
This trial will be conducted in healthy, HIV-negative women who have participated in the 
IPM 027 trial. No formal sample size or power calculations have thus been performed. 
 
It is expected that approximately 70% of the participants enrolled in IPM 027 will 
participate in this trial. Therefore, a total sample size of approximately 1400 HIV-negative 
women is anticipated.  
 
8.4. Statistical Analyses 
The primary analysis will focus on safety as well as adherence assessments.  
 
The primary analysis will be performed under the intent-to-treat (ITT) principle, which will 
include all participants enrolled in the trial.  As it is possible that the inclusion of non-
adherent participants or participants who discontinued from the IP may artificially lower 
the rates of safety outcomes, additional analyses will be conducted on the per-protocol 
population, which will include only participants who were adherent to the protocol. 
Details on the definition of the per-protocol population, in addition to models that will be 

IPM 032 
 
   22 October 2015 
Version 2.0 Amendment 1.0 
 
Page 55 of 69 
Restricted * Confidential – Limited Access* 
used to examine the exploratory objectives and other technical aspects of these 
analyses will be provided in a SAP, which will be finalised prior to final database lock. 
 
The analysis of the secondary safety assessments will be mainly descriptive in nature. 
The incidence density rate of HIV-1 seroconversion and the frequency of HIV-1 drug 
resistance in women who seroconvert will be summarised descriptively.   
 
The data will be presented using appropriate statistical measures including, but not 
limited to: mean, standard deviation, median, and interquartile range for continuous data; 
frequency and relative frequency for categorical data. When appropriate, 95% 
confidence intervals will be presented.       
 
8.4.1. Primary Safety Analysis 
A descriptive analysis of all AEs will be presented in tables and listings. AEs will be 
summarised by MedDRA System Organ Class (SOC) and Preferred term (PT). The 
proportion of participants experiencing adverse events, including the proportion of 
participants experiencing product-related adverse events, Grade 3 or 4 AEs, or SAEs, 
will be determined, and presented with corresponding 95% CIs.  
All data will be presented by research centre, and overall across research centres.  
 
8.4.2. Primary Adherence Analysis 
Residual levels of dapivirine in returned rings and/or plasma and/or vaginal fluid 
concentrations of dapivirine will be used as measures of adherence to ring use. The data 
will be listed, summarised and presented graphically. Participants will be categorized as 
either adherent or non-adherent, based on these measures. The ring residual levels 
and/or plasma and/or vaginal fluid concentrations of dapivirine associated with non-
adherence will be informed by the results from IPM 027, and will be described in detail in 
the SAP, which will be finalised prior to final database lock.  The correlation between the 
amount of residual dapivirine in the used rings and the corresponding plasma and/or 
vaginal fluid levels of dapivirine will be explored graphically and summarised 
descriptively.  
 
8.4.3. Secondary Analyses 
 
Incidence of HIV-1 seroconversion 
The incidence of HIV-1 seroconversions, the incidence density rate of HIV-1 
seroconversion, i.e. HIV-1 seroconversion rate per 100 woman-years of product use at 
the end of the ring use period, as well as a 95% CI for the HIV-1 seroconversion rate per 
100 woman-years based on the normal approximation of the Poisson distribution will be 
presented for each research centre, and overall. Kaplan-Meier curves will be presented, 
stratified by research centre.  
 
 
HIV-1 drug resistance 
The analysis of HIV-1 drug resistance will be primarily descriptive in nature, and will 
depend on the pattern of resistance mutations observed in the HIV-1 seroconverters.  
The resistance associated mutations observed will be listed by participant, and a 
frequency tabulation of individual resistance mutations associated with the various 

IPM 032 
 
   22 October 2015 
Version 2.0 Amendment 1.0 
 
Page 56 of 69 
Restricted * Confidential – Limited Access* 
classes of antiretrovirals, e.g. Protease Inhibitors, Nucleoside Reverse Transcriptase 
Inhibitors and Non-nucleoside Reverse Transcriptase Inhibitors, will be produced. The 
proportion of HIV-1 seroconverters with at least one HIV-1 drug resistant mutation will be 
presented, with the corresponding 95% CI. 
 
8.4.4. Interim Analysis 
No interim analysis is planned for this trial. However, the Sponsor will review the 
treatment emergent safety data at regular intervals during the conduct of the trial.  
 
8.5. Data and Safety Monitoring Board 
This clinical trial will not be subject to DSMB overview. 
 
8.6. Handling of Missing Data and Dropouts 
Some degree of missing data, primarily associated with missed visits, is expected. The 
amount of missing data will be explored and incorporated into the analyses, where 
appropriate. For the analysis of adherence to monthly ring use, patterns of missing data 
may be informative. Depending on the proportion of participants who discontinue early, 
an analysis of time to discontinuation may be conducted. Such an analysis would allow 
investigation of the covariates associated with early discontinuation and could provide 
information that would be useful in designing future trials of other microbicide rings. 
Patterns of missing data may also provide further insight into participants’ preference for 
monthly or 3-monthly follow-up visits to research centres. 
9.  Investigator Requirements 
9.1. Trial Initiation 
The trial can be initiated at the research centre once all relevant IRB/IEC and regulatory 
approvals have been obtained in compliance with country specific requirements, and the 
relevant essential documents are available on file. Following IPM approval, IPM will 
notify the research centre in writing via letter correspondence to begin trial operations 
according to the protocol. 
 
9.2. Institutional Review Boards or Independent Ethics Committee Approval 
This protocol, the informed consent document, and relevant supporting information will 
be submitted to the IRBs/IECs for review and must be approved before the trial is 
initiated. 
 
The principal investigator is responsible for communicating with IRBs/IECs regarding the 
progress of the trial and changes made to the protocol as deemed appropriate, at least 
once a year. The principal investigator will also keep the IRBs/IECs informed of any 
significant AEs and SAEs, in accordance with standard operating procedures and 
policies of the IRB/IEC. 
 
 

IPM 032 
 
   22 October 2015 
Version 2.0 Amendment 1.0 
 
Page 57 of 69 
Restricted * Confidential – Limited Access* 
9.3. Trial Monitoring and Audits 
Trial monitors will regularly visit participating research centres to review trial documents 
including, but not limited to individual participant records, consent forms, source 
documents, CRFs, supporting data, laboratory specimen records and medical records 
(physicians’ progress notes, nurses’ notes, individuals’ hospital charts) to ensure 
protection of trial participants, compliance with the protocol, and accuracy and 
completeness of records. The trial monitors will also inspect the research centre’s 
regulatory files to ensure that regulatory requirements are being followed; the research 
centre’s pharmacies to review product storage, management, and drug accountability; 
and the research centre’s laboratory and other clinical supplies to ensure proper storage 
and continued viability of supplies. All applicable trial documents should be readily 
available for review during the visits. The trial monitors will also check that clinical trial 
procedures are observed and will discuss any problems with investigator or designee as 
applicable. 
 
During or after the clinical trial, the governmental regulatory authorities, local IRB/IEC 
and/or representatives of the IPM may request access to all trial documents for on-
research centre audit or inspection. 
 
9.4. Case Report Forms (CRFs) 
CRFs will be supplied by IPM or its designee and will be handled in accordance with 
instructions from IPM. 
 
All CRFs will be completed by the designated trial staff in accordance with the 
instructions provided by IPM. Upon trial completion, the CRF is reviewed, signed, and 
dated by an investigator listed on the Statement of Investigator, Form FDA 1572. 
 
All CRFs will be completed in a neat, legible manner to ensure accurate interpretation of 
data. Black ink is required to ensure clarity. When making changes or corrections, the 
original entry will be crossed out with a single line, and the change initialled and dated. 
Erasures, overwriting, and correction fluid are NOT allowed on the CRFs. 
 
9.5. Disclosure of Data 
Participant medical information is confidential and disclosure to third parties other than 
those described in Section 9.3 is strictly prohibited. All trial data will be stored securely at 
the research centre. All participant information including laboratory reports, forms, lists, 
logbooks, appointment books and administrative forms will be stored in locked file 
cabinets or rooms in areas with access limited to trial staff. 
 
Participants’ trial information will not be released without written permission of the 
participant, except as necessary for monitoring by the Sponsor, Sponsor’s designated 
monitors, regulatory authorities, or local IRBs/IECs. 
 
9.6. Record Retention 
The principal investigator will retain in a secure manner, complete, accurate and current 
trial records for a minimum of two years after marketing approval or termination of 
product development. Trial records include administrative documentation, including 
research centre registration documents and all reports and correspondence relating to 

IPM 032 
 
   22 October 2015 
Version 2.0 Amendment 1.0 
 
Page 58 of 69 
Restricted * Confidential – Limited Access* 
the trial, as well as documentation related to each participant screened and/or enrolled in 
the trial, including ICFs, CRFs, notations of all contacts with the participant, and all other 
source documents. All records must be retained on-site throughout the trial’s period of 
performance. IPM will provide the research centre with written instructions for long-term 
record storage at the completion of the trial. 
 
No records should be destroyed without prior written permission from IPM. 
10. Ethical Considerations 
10.1. Ethical Review 
This protocol, research centre-specific informed consent documents, participant 
education, outreach, recruitment materials and any other requested documents or 
subsequent modifications will be reviewed and approved by the ethical review bodies 
responsible for oversight of research conducted at the research centre. 
 
Subsequent to initial review and approval, the local IRB and/or IEC will be notified about 
trial completion within three months following trial termination or completion. This trial will 
be conducted in accordance with: 
• 
World Medical Association Declaration of Helsinki8 
• 
ICH GCP guidelines9 
• 
Applicable national ethics and regulatory requirements in countries where the 
trial is being conducted, e.g. Guidelines for Good Practice in the Conduct of 
Clinical Trials in Human Participants in South Africa10. 
 
10.2. Reporting and Management of Social Harms related to trial participation 
Social harms, e.g., disruption of family or personal relationships may result due to 
participation in this trial becoming known to others. In addition, IP use could potentially 
be unacceptable to the participant’s sex partner and result in difficulties with her sex 
partner. If a participant is or becomes HIV-infected, she may also experience social 
harms. 
 
During each HIV counselling session, enrolled participants will be asked questions to 
assess the occurrence of social harms related to trial participation. Participants who 
experience social harms considered to be related to trial participation will be counselled 
accordingly and provided with assistance to mitigate the circumstances if possible. This 
will be recorded in the source documents and applicable CRFs. 
 
10.3. Community Engagement 
Community Liaison Officers have been appointed at each research centre to oversee the 
information provided to local stakeholders, target population and general community. 
They have been tasked with capturing, monitoring and evaluating feedback from the 
community. Comments will be captured in various ways at each research centre using 
methods such as suggestion boxes, door-to-door campaigns, group level discussions, 
pre/post-tests, distributed feedback forms, etc. Each research centre has a process for 
consulting with the community. The primary vehicle for this consultation is through formal 
structures such as the Community Advisory Boards/Groups/Committees. These systems 

IPM 032 
 
   22 October 2015 
Version 2.0 Amendment 1.0 
 
Page 59 of 69 
Restricted * Confidential – Limited Access* 
allow investigators and communities to identify and respond rapidly to concerns raised. 
11.  Publications 
Any presentation, abstract, or manuscript shall be reviewed and approved by the 
Sponsor prior to submission. Publication of the results of this trial will be governed by the 
IPM’s clinical trial agreement with the investigator.  Authorship criteria will be based on 
contributions to the design, work, and analysis of the trial. 
 
 
 

IPM 032 
 
   22 October 2015 
Version 2.0 Amendment 1.0 
 
Page 60 of 69 
Restricted * Confidential – Limited Access* 
12. References 
 
 
1 Regional Fact Sheet 2012. Sub-Saharan Africa. 
http://www.unaids.org/en/media/unaids/contentassets/documents/epidemiology/2012/gr2
012/2012_FS_regional_ssa_en.pdf 
 
2 AIDS by the numbers; UNAIDS 2013. 
http://www.unaids.org/en/media/unaids/contentassets/documents/unaidspublication/201
3/20131120_AIDSbynumbers_A5brochure_en.pdf 
 
3 Elias CJ, Coggins C. Female-controlled methods to prevent sexual transmission of 
HIV. AIDS 1996;10:S43-S51. 
 
4 Karim SSA, Richardson BA, et al. Safety and effectiveness of BufferGel and 0.5% 
PRO2000 gel for the prevention of HIV infection in women. AIDS 2011; 25(7):957. 
 
5 Dapivirine Vaginal Ring Investigator’s Brochure, Version 9.0, 3 December 2014  
 
6 IPM 011; Clinical Study Report;  Version 1.0, 15 March 2011 
 
7 IPM 015; Clinical Study Report;  Version 1.0, 06 July 2012 
 
8 World Medical Association Declaration of Helsinki. Ethical Principles for Medical 
Research Involving Human Subjects; WMA General Assembly, Fortaleza, Brazil, October 
2013. Available at:  http://www.wma.net/en/30publications/10policies/b3/index.html 
 
9 Guidance for Industry: E6 Good Clinical Practice: Consolidated Guidance. 
 (http://www.fda.gov/downloads/Drugs/Guidances/ucm073122.pdf) 
 
10 Guidelines for Good Practice in the Conduct of Clinical Trials in Human Participants in 
South Africa. 
(http://www.kznhealth.gov.za/research/guideline2.pdf) 
 
 

IPM 032 
 
    
 
 
22 October 2015  
Version 2.0 Amendment 1.0 
 
 
 
 
 Page 61 of 69 
 
 
 
 
 
 
Restricted * Confidential – Limited Access* 
APPENDIX A: SCHEDULE OF PROCEDURES 
Visits 
Screening 
Enrolment 
Trial Visits 
LPUV 
Exit Visit 
As needed 
Trial Months 
Screening 
must occur 
within 45 
days of 
enrolmentk 
0 
 Months 1-11h,i 
Month 12i 
Months 13-
14i 
Informed Consent 
X 
 
 
 
 
 
Comprehension Assessment 
X 
 
 
 
 
 
Assign Screening Identification Number 
X 
 
 
 
 
 
Assign Participant Identification Number  
 
X 
 
 
 
 
Demographics 
X 
 
 
 
 
 
Medical History 
X 
X 
 
 
 
 
Concomitant Medication Evaluation 
X 
X 
X 
X 
X 
X 
Inclusion/Exclusion Criteria  
X 
X 
 
 
 
 
Locator Information 
X 
X 
X 
X 
 
 
Basic Menses Information 
X 
X 
X 
X 
 
 
Physical Examination 
X 
 
 
X 
 
X 
Adverse Event Evaluation 
 
X 
X 
X 
X 
X 
Social Harms Assessment 
 
X 
X 
X 
X 
X 
Pelvic Exam 
X 
 
 
X 
 
X 
Vaginal Ring Dispensing and Insertion 
 
X 
X 
 
 
 
Vaginal Ring Return / Collection 
 
 
X 
X 
 
 
Visual  Inspection of Returned Ring(s) 
 
 
X 
X 
 
 
Provision of Vaginal Ring Use and Storage Instructions 
 
X 
X 
 
 
 
Vaginal Ring Adherence Counselling 
 
X 
X 
 
 
 
Provision of Diary Card(s) 
 
X 
Xj 
 
 
 
Collection of Diary Card(s) 
 
 
X 
X 
 
 
Participant Questionnaire 
 
 
Xa 
X 
 
 
HIV/STI Risk Reduction Counselling 
X 
X 
X 
X 
X 
 
Contraceptive Counselling 
X 
X 
X 
X 
X 
X 
Provision of and/or referral for Contraceptives 
X 
X 
X 
X 
X 
X 
Provision of Male Condoms (if participant wishes to 
receive them) 
X 
X 
X 
X 
X 
 
Urine Pregnancy Test (hCG)  
X 
X 
X 
X 
 
X 
Cervicovaginal 
Sample 
Collection 
for 
STI 
Tests 
Trichomonas vaginalis (TV), Neisseria gonorrhoeae (NG) 
and Chlamydia trachomatis (CT) 
X 
 
 
 
X 
 
X 
Provision of treatment and/or referral for STIs and Other 
Findings 
 
 
 
 
 
X 
HIV Pre- & Post-Test Counselling 
X 
X 
X 
X 
X 
 

IPM 032 
 
    
 
 
22 October 2015  
Version 2.0 Amendment 1.0 
 
 
 
 
 Page 62 of 69 
 
 
 
 
 
 
Restricted * Confidential – Limited Access* 
Visits 
Screening 
Enrolment 
Trial Visits 
LPUV 
Exit Visit 
As needed 
Trial Months 
Screening 
must occur 
within 45 
days of 
enrolmentk 
0 
 Months 1-11h,i 
Month 12i 
Months 13-
14i 
HIV Rapid Tests b 
X 
X 
X 
X 
X 
X 
HIV-1 RNA PCR Test c, d 
X 
X 
X 
X 
X 
 
Plasma Viral Genotype Sample c, d 
X 
X 
X 
X 
X 
 
Plasma Dapivirine Concentrations 
 
 
X 
X 
 
 
Vaginal Fluid Dapivirine Concentrations 
 
 
X 
X 
 
 
Laboratory Testing for Safety Assessments e 
X 
 
 
 
 
X 
Urine Dipstick Analysis (Urine Microscopy If Clinically 
Indicated Only) 
X 
 
 
 
 
X 
RPR f 
X 
 
 
 
 
 
Cervical Sample Collection for Cytology g 
X 
 
 
 
 
X 
Final Laboratory results provided 
 
 
 
 
X 
 
 
a) 
Participant Questionnaire will be administered at all Trial Visits. 
b) 
Performed in accordance with HIV testing algorithm 
c) 
Sample will be stored and will only undergo testing subsequently or after confirmation of seroconversion and at every visit for seroconverters. 
d) 
Sample will be obtained at the point of two reactive HIV rapid tests and analysed subsequently or after confirmation of seroconversion. 
e) 
Blood draw by venepuncture for laboratory testing (haematology and chemistry). Haematology will include full blood counts, differential, and platelet count. Chemistry tests 
will include creatinine, AST and ALT. 
f) 
TPHA/TPPA should be performed if RPR positive. 
g) 
Cervical sample collection for cytology may be conducted at any study visit if no result is evident within the previous year, or abnormal at last cervical cytology. 
h) 
All women will attend a research centre follow-up visit one month after enrolment.  Following this visit, at investigator’s discretion, a participant can continue on a 3-monthly 
visit schedule.   Monthly visits may however be extended up to the first three months of participation. 
i) 
IPM will have the option to extend the trial period. 
j) 
Participants will receive a diary card at enrolment and at trial visits, as applicable.  Returned diary cards will be reviewed at all scheduled trial visits.  
k) 
Only procedures in italics required for participants rolling over directly from LPUV at IPM 027 to IPM 032. 
   

IPM 032 
 
    
 
 
22 October 2015  
Version 2.0 Amendment 1.0 
 
 
 
 
 Page 63 of 69 
 
 
 
 
 
 
Restricted * Confidential – Limited Access* 
APPENDIX B: HIV TESTING ALGORITHM 
 
Figure 1: Screening Algorithm 
 
 
 
 
Not eligible for 
enrolment; 
Refer for appropriate 
counselling and care 
TEST 1 
Non-reactive 
HIV-seronegative 
Discordant 
TEST 3 
Reactive 
HIV-seropositive 
 
Non-reactive 
HIV-seronegative 
 
Potentially eligible 
for enrolment 
Potentially eligible  
for enrolment 
TEST 2 
Reactive 
HIV-seropositive 

IPM 032 
 
    
 
 
22 October 2015  
Version 2.0 Amendment 1.0 
 
 
 
 
 Page 64 of 69 
 
 
 
 
 
 
Restricted * Confidential – Limited Access* 
Figure 2: Pre-Enrolment Algorithm 
 
 
Not eligible for 
enrolment; 
Refer for appropriate 
counselling and care 
TEST 1 
Non-reactive 
HIV-seronegative 
Discordant 
TEST 3 
Reactive 
HIV-seropositive 
 
Non-reactive 
HIV-seronegative 
Perform PCR Test 
If undetectable: 
Enrol; 
Sample for storage 
taken 
Enrol 
Sample for storage 
taken 
TEST 2 
Reactive 
HIV-seropositive 
If detectable: 
Not eligible for 
enrolment; 
Counsel as 
appropriate 

IPM 032 
 
    
 
 
22 October 2015  
Version 2.0 Amendment 1.0 
 
 
 
 
 Page 65 of 69 
 
 
 
 
 
 
Restricted * Confidential – Limited Access* 
Figure 3: Trial Visits Algorithm 
 
 
TEST 1 
Non-reactive 
HIV-seronegative 
Discordant 
TEST 3 
Reactive 
HIV-seropositive 
 
Non-reactive 
HIV-seronegative 
 
Undetectable HIV-1 RNA PCR result: 
Not infected; Continue IP  
 
HIV testing performed only at scheduled visits even 
if same pattern of discordant results continues 
Continue IP 
Sample for storage 
taken 
TEST 2 
Discontinue IP;  
Draw sample for 
endpoint confirmation 
by WB and other 
confirmatory tests; 
Analysis of stored 
samples 
Reactive 
HIV-seropositive 
Detectable HIV-1 RNA PCR result: 
 
HIV-infected; Discontinue IP 
Refer for appropriate counselling and care; 
Option to enrol in seroconverter protocol 
 
Continue IP and 
repeat testing in 2 
weeks 
At 2-week follow up visit: 
If same pattern of HIV rapid test results (discordant), 
collect a sample for quantitative HIV-1 RNA PCR 

IPM 032 
 
    
 
 
22 October 2015  
Version 2.0 Amendment 1.0 
 
 
 
 
 Page 66 of 69 
 
 
 
 
 
 
Restricted * Confidential – Limited Access* 
Figure 4: LPUV Algorithm 
 
 
 
 
TEST 1 
Non-reactive 
HIV-seronegative 
Discordant 
TEST 3 
Reactive 
HIV-seropositive 
 
Non-reactive 
HIV-seronegative 
 
HIV-negative 
Sample for storage 
taken 
TEST 2 
Reactive 
HIV-seropositive 
Draw sample for 
endpoint confirmation 
WB;  
Analysis of stored 
samples 
 
Refer for appropriate 
counselling and care; 
Option to enrol in 
seroconverter protocol 

IPM 032 
 
    
 
 
22 October 2015  
Version 2.0 Amendment 1.0 
 
 
 
 
 Page 67 of 69 
 
 
 
 
 
 
Restricted * Confidential – Limited Access* 
TEST 1 
Non-reactive 
HIV-seronegative 
Discordant 
TEST 3 
Reactive 
HIV-seropositive 
 
Non-reactive 
HIV-seronegative 
 
HIV-negative 
TEST 2 
Figure 5: Exit Visit Algorithm 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Reactive 
HIV-seropositive 
Draw sample for 
endpoint confirmation 
WB; 
Analysis of stored 
samples 
 
Refer for appropriate 
counselling and care 

IPM 032 
 
22 October 2015  
Version 2.0 Amendment 1.0 
 
Page 68 of 69 
 
 
 
 
 
 
Restricted * Confidential – Limited Access* 
APPENDIX C: VISIT SCHEDULE AND APPROXIMATE BLOOD VOLUMES 
 
Visit 
Test and 
volume 
(mL) 
Test and 
volume 
(mL) 
Test and 
volume 
(mL) 
Test and 
volume 
(mL) 
Test and 
volume 
(mL) 
Total 
Blood 
Volume 
Screening 
HIV rapid* 
5 mL 
 
Chemistry 
5 mL 
Haematology 
5 mL 
RPR 
5 mL 
HIV viral 
genotype 
resistance#  
10 mL 
HIV PCR# 
5 mL 
35mL 
 
 
 
 
 
 
 
Enrolment 
HIV rapid 
5 mL 
 
 
HIV viral 
genotype 
resistance#  
10 mL 
HIV PCR# 
5 mL 
20 mL 
 
 
 
 
 
 
 
Trial Visits 
HIV rapid 
5 mL 
Dapivirine 
levels# 
6 mL 
 
HIV viral 
genotype 
resistance#  
10 mL 
HIV PCR# 
5 mL 
26 mL 
 
 
 
 
 
 
 
LPUV 
HIV rapid 
5 mL 
Dapivirine 
levels# 
6 mL 
 
HIV viral 
genotype 
resistance#  
10 mL 
HIV PCR# 
5 mL 
26 mL 
 
 
 
 
 
 
 
Exit Visit 
HIV rapid^ 
5 mL 
 
 
HIV viral 
genotype 
resistance## 
10 mL 
HIV PCR# / 
## 
5 mL 
5 mL or 
15 mL## 
 
 
 
 
 
 
 
Seroconverter 
tests+ 
Western 
blot 
5mL 
Dapivirine 
levels++ 
6 mL 
 
HIV viral 
genotype 
resistance#  
10 mL 
HIV PCR# 
5 mL 
20 mL++ or 
26 mL 
 
• * Depending on the research centre SOP on HIV testing, sampling may be performed 
by finger prick or venepuncture.  
• # Stored plasma samples; tested retrospectively to evaluate different parameters at 
the time of seroconversion.  
• ## Blood samples for viral genotype resistance and HIV-1 RNA PCR testing will be 
collected at the scheduled exit visit following seroconversion.  
• ^ HIV rapid testing will not be conducted at the scheduled exit visit following 
seroconversion.  
• 
+ At the point of seroconversion, these samples will be collected and tested in addition 
to relevant visit-specific tests, but no samples should be duplicated during the same 
visit. No additional storage samples will be collected.  
NOTE: Additional tests may be also performed, as required.  
• 
++ Test sample for possible dapivirine measurements will not be required if the 
seroconversion occurs at the Exit Visit. 

IPM 032 
 
    
 
 
22 October 2015 
Version 2.0 Amendment 1.0 
 
 
 
 
 Page 69 of 69 
 
 
 
 
Restricted * Confidential – Limited Access* 
APPENDIX D: TRIAL DESIGN 
 
 
 
 
 
 
 
   
 
 
 
 
 
MONTH 12 
RING USE DISCONTINUED 
 
DAY 0 
RING INSERTION 
LPUV 
EXIT VISIT 
1-2 months 
≤ 45 days 
Monthly trial visit schedule 
 
First month after enrolment  
(or up to 3 months after enrolment at 
investigator’s discretion) 
3-monthly trial visit schedule 
2 additional rings dispensed at each trial visit, or 
dispensed as arranged 
ENROLMENT 
Approximately 
1400 women 
SCREENING