Conditions: HIV Infections Contraception Drug-drug Interaction
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 110
Healthy volunteers: no

Brief summary:
The study investigators are conducting an observational, parallel group pharmacokinetic (PK) study among women living with HIV (WLHIV) already on 1st line antiretroviral therapy (ART) and virally suppressed, 18-45 years old (inclusive), to evaluate any bidirectional drug-drug interactions (DDIs) between doravirine (DOR)-containing ART and hormonal contraceptive methods. This PK study will enroll women in five distinct groups, each with 21 participants (total of 105 participants), and follow them for approximately 18-30 weeks.

Detailed description:
While DOR-containing ART has been evaluated in two large clinical trials, only 16-17% of the study participants were women and only 6-10% of them were African. In an epidemic, where the gendered majority affected by the disease are women of reproductive age living in Africa, it is imperative to conduct a study evaluating reproductive health outcomes among and specific to African women. Further underscoring the issue is a notable data gap for DOR regarding DDIs with the most common leading hormonal contraceptives.

Our intention is to study potential DDIs between DOR and the most common contraceptive methods used by WLHIV in an African context, which generally include short- (e.g., OCPs/COCs), intermediate (e.g., injectable) or long-acting (e.g., implants or IUDs) methods. Since the drug maker of DOR has already conducted the industry standard PK study with DOR and a COC product, containing ethinyl estradiol and levonorgestrel, which did not demonstrate any bidirectional DDI, the investigators have chosen to exclude this method from the current study. Thus, the current EPIC study focuses on intermediate- and long-acting contraceptive methods, which have different PK profiles than daily administrated oral drugs and may be more susceptible to potential DDIs with DOR.

Participants who are interested in self-selecting and initiating one of the study contraceptive methods listed will be recruited for screening and eligibility assessments. If eligible and enrolled, there will be a 6-week lead-in period with daily use of oral DOR-containing ART followed by contraceptive method initiation of their choice. Study follow-up will take place every 2-4 weeks, at a minimum, for an additional 12 or 24 weeks for a total of 18 or 30 weeks of follow-up depending on the contraceptive method chosen.

The investigators will also enroll a dolutegravir (DTG) + IM DMPA group, who will be followed for 12 weeks, as the comparator group for the DOR + IM DMPA group.

The comparator group for the DOR + etonogestrel (ETG) implant group will be a historical control group from a similar PK study called PARVI (PK study of ARVs and Implants in Kenya) that is currently being conducted by Dr. Patel and colleagues in Kenya.

The five study groups are summarized below in Table 1.

Table 1: Study groups by ART regimen and contraceptive method choice

Group number N ART regimen and contraceptive method Group 1 21 DOR-containing ART + initiating ETG implant Group 2 21 DOR-containing ART + initiating IM DMPA Group 3 21 DOR-containing ART + initiating SC MPA Group 4 21 DOR-containing ART + initiating non-hormonal IUD Group 5 21 DTG-containing ART + initiating IM DMPA

The co-primary objectives are to evaluate any associations between doravirine (DOR), a newer antiretroviral agent for the treatment of HIV, exposure and hormonal contraceptive use in the four groups of DOR + 1) etonogestrel implant (ETG), 2) intramuscular depomedroxyprogesterone acetate (IM DMPA), 3) subcutaneous medroxyprogesterone acetate (SC MPA), or 4) non-hormonal IUD users by generating mean hormone concentrations at 12 weeks for IM and SC DMPA or 24 weeks for ETG implants and IUD groups; also to evaluate any bi-directional associations between hormonal contraceptive exposure and DOR use by generating mean DOR concentration at 24 hours.

The first hypotheses are: the mean implant hormone concentrations for DOR + ETG implant at 24 weeks after implant placement will be similar (i.e. geometric mean ratio \[GMR\] within 0.80 and 1.25) to the mean implant hormone concentrations for DTG + ETG implant (historical controls from Dr. Patel's current PARVI study in a similar population in Kenya). The mean MPA concentrations for DOR + IM DMPA or SC MPA at 12 weeks after DMPA/MPA administration will be similar (i.e. GMR within 0.8 and 1.25) to the mean DMPA concentrations for DTG + DMPA (contemporaneous study group). Also, the mean C24 hours of DOR in the ETG implant and MPA groups will be similar to the non-hormonal contraceptive method (i.e. the non-hormonal IUD) group.

The secondary objectives are to measure DOR-containing ART's efficacy, via HIV viral load \<40 copies/mL, at 12-24 weeks after contraceptive initiation among women of reproductive age using hormonal and non-hormonal contraceptives.

The second hypothesis is that proportion of women suppressed (defined as HIV viral load \<40 copies/mL) at 16-30 weeks after DOR-containing ART initiation will be similar to a contemporaneous or historical comparison of the proportion of women suppressed with non-DOR containing ART from the same study population/sample.

The exploratory objectives are to qualitatively explore decision-making around ART and contraceptive options, study experiences of ART switch, and use of the contraceptive method, including self-administration of SC MPA, and to describe self-reported experiences of social harms and social benefits related to study participation. Also, safety including side effects, satisfaction, and continuation rates of both the hormonal contraceptive method and ART will be assessed.

The third hypothesis is that the safety, satisfaction, and continuation rates of the various contraceptive methods will be similar to each other at 12-24 weeks after contraceptive initiation. The investigators will gain interesting insights into women's decision-making around ART and contraceptive method options and are uniquely positioned to describe experiences of self-administration of SC MPA.

Arms:
arm 1: 100mg DOR-containing ART \[oral tablet taken daily\] + 68mg ETG implant (follow up for 30 weeks) arm 2: 100mg DOR-containing ART \[oral tablet taken daily\] + 150mg IM DMPA (follow up for 18 weeks) arm 3: 100mg DOR-containing ART \[oral tablet taken daily\] + 104mg SC MPA (follow up for 18 weeks) arm 4: 100mg DOR-containing ART \[oral tablet taken daily\] + 1 non-hormonal IUD device (follow up for 30 weeks) arm 5: 50mg DTG-containing ART \[oral tablet taken daily\] + 150mg IM DMPA DMPA administered at enrolment (follow up for 18 weeks)

Interventions: intervention 1: Etonogestrel (ETG) implant intervention 2: Intramuscular depo-medroxyprogesterone acetate (IM DMPA) intervention 3: Sub-cutaneous medroxyprogesterone acetate (SC MPA) intervention 4: Non-hormonal intrauterine device (IUD)
Intervention descriptions: intervention 1: Contraceptive progestin implants are thin rods inserted under the skin of a woman's arm. The most widely available implant in South Africa is currently Implanon®/Nexplanon®/Implanon NXT®, containing etonogestrel (ETG, 3-keto desogestrel). Implanon® consists of a single rod of ethylene vinyl acetate and contains 68 mg of ETG; it is manufactured by Merck and is approved for 3 years. intervention 2: DMPA (150 mg of depo-medroxyprogesterone acetate (MPA)/ml IMI) is the most commonly used injectable contraceptive worldwide, and the most commonly used method of reversible injectable contraception in sub-Saharan Africa. intervention 3: SC MPA or Sayana® Press is a single-dose container with 104 mg medroxyprogesterone acetate (MPA) in 0.65 mL suspension for injection. Sayana® Press is indicated for medium-long term female contraception. intervention 4: The NOVA T-380 non-hormonal IUD consists of a T-shaped polyethylene frame wound with copper wire, along with two monofilament threads to aid in removal of the IUD. IUDs may be left in place for up to 5 years.

Protocol document:
Prot_SAP_ICF_000.pdf: 
 
 
 
Title: Evaluation of Pharmacokinetic drug-drug Interactions between hormonal  
contraceptives and doravirine-containing ART among women living with HIV in South Africa 
(EPIC) 
 
NCT number: NCT04669678 
 
Document Date: 
August 1, 2023 


EPIC Study Protocol                                                          Page 1 of 49                                                           Version 1.3 14 July2022 
Short Title: EPIC  
 
Long Title: Evaluation of Pharmacokinetic drug-drug Interactions between hormonal 
Contraceptives and doravirine-containing ART among women living with HIV in South Africa 
 
Funding: Merck & Co., Inc. 
 
Grant Number: pending  
 
IND Sponsor and Number: Merck & Co., Inc.  
 
Co-Principal Investigators: 
Rena Patel, MD, MPH, MPhil 
Thesla Palanee-Phillips, M Med Sci, PhD, M Sc 
Nkosiphile Ndlovu, MBChB, Dip HIV Man (SA) 
Anna Wald, MD, MPH 
Version 1.4 
01 August 2023 
 
 


EPIC Study Protocol                                                          Page 2 of 49                                                           Version 1.3 14 July2022 
EPIC 
Evaluation of Pharmacokinetic drug-drug Interactions between hormonal Contraceptives and 
doravirine-containing ART among women living with HIV in South Africa 
 
TABLE OF CONTENTS 
CONTENT 
PAGE 
LIST OF ABBREVIATIONS AND ACRONYMS                                  
3 
PROTOCOL TEAM ROSTER 
5 
PROTOCOL SIGNATURE PAGE 
7 
PROTOCOL SUMMARY 
8 
INTRODUCTION 
10 
OBJECTIVES 
14 
STUDY DESIGN 
15 
STUDY POPULATION, ACCRUAL AND FOLLOW UP 
17 
STUDY PRODUCT 
21 
STUDY PROCEDURES 
26 
CLINICAL DATA SAFETY REVIEW 
36 
CLINICAL MANAGEMENT 
39 
STATISTICAL CONSIDERATIONS 
41 
GOOD PARTICIPATORY PRACTICE 
43 
DATA MANAGEMENT 
44 
HUMAN SUBJECTS PROTECTIONS 
45 
PUBLICATION POLICY 
47 
REFERENCES 
49 
APPENDICES 
52 
 
 
 
                                                                                                                           
 
 
 


EPIC Study Protocol                                                          Page 3 of 49                                                           Version 1.3 14 July2022 
EPIC 
 
Evaluation of Pharmacokinetic drug-drug Interactions between hormonal Contraceptives and 
doravirine-containing ART among women living with HIV in South Africa 
 
LIST OF ABBREVIATIONS AND ACRONYMS 
 
3TC 
 
Lamivudine 
CASI  
Audio computer-assisted self-interviewing 
AE 
 
Adverse Events  
AGYW  
Adolescent girls and young women 
AIDS  
Acquired Immunodeficiency Syndrome 
ART 
 
Antiretroviral therapy 
AUC 
 
Area under the curve 
BARC  
Bioanalytical Research Corporation 
BCEPS 
Biometric Co-enrolment Prevention System 
CAB 
 
Community Advisory Board 
CBC 
 
Complete blood count 
CDC 
 
Centre of Disease Control 
CHW  
Community Health Workers 
CLO 
 
Community Liaison Officer 
CLS 
 
Clinical Laboratory Services 
CMP  
Comprehensive metabolic panel 
CRF 
 
Case report form 
CRS 
 
Clinical Research site 
CYP450 
Cytochrome P450 
DAIDS  
Division of AIDS 
DDI 
 
Drug-drug interactions 
DOR  
Doravirine 
DMPA  
Depomedroxyprogesterone acetate 
DNA 
 
Deoxyribonucleic Acid 
DTG 
 
Dolutegravir 
EFV 
 
Efavirenz 
ENG 
 
Etonogestrel 
FDA 
 
U.S. Food and Drug Administration 
FTC 
 
Emtricitabine 
GCP 
 
Good Clinical Practices 
GMP  
Good Manufacturing Practices 
GMR  
Geometric mean ratio 
GPP 
 
Good Pharmacy Practice 
HBsAG 
Hepatitis B surface Antigen 
HBsAB 
Hepatitis B surface Antibody 
HB core AB 
Hepatitis B core Antibody 
 
HCP 
 
Healthcare Professional 
HHP 
 
Hillbrow Health Precinct 
HIV  
 
Human Immunodeficiency Virus 
IATA  
International Air Transport Association 
IM  
 
Intramuscular 
IND 
 
Investigational drug 
IRB 
 
Institutional Review Board 
IUD 
 
Intra-uterine device 
LDMS  
Laboratory Data Management System 
LNG 
 
Levonorgestrel 
MG 
 
Milligrams 


EPIC Study Protocol                                                          Page 4 of 49                                                           Version 1.3 14 July2022 
ML 
 
Milliliters 
MPA   
Medroxyprogesterone acetate 
MRC  
Medical Research Council 
NDoH  
National Department of Health 
NGO  
Non-Governmental Organization 
NIH 
 
National Institute of Health 
NNRTI  
Non-nucleoside reverse transcriptase inhibitors 
PARVI  
PK study of ARVs and implants in Kenya 
PEPFAR 
President’s Emergency Plan for AIDS Relief 
PI 
 
Principal Investigator 
PID 
 
Pelvic Inflammatory Disease  
PK 
 
Pharmacokinetic 
PPE 
 
Personal Protective Equipment 
PrEP  
Pre-exposure prophylaxis 
RNA 
 
Ribonucleic Acid 
RC 
 
Research Centre 
RT 
 
Reverse transcriptase 
SAHPRA 
South African Health Product Regulatory Agency 
SAE 
 
Serious adverse events 
SAPC  
South African Pharmacy Council 
SC 
 
Subcutaneous 
SH 
 
Social harms 
SMC  
Study Monitoring Committee 
SOP 
 
Standard Operating Procedures 
SRH 
 
Sexual and reproductive health 
SUSAR 
Suspected unexpected serious adverse event 
TDF 
 
Tenofovir 
UNAIDS 
United Nations Programme on HIV and AIDS 
USAID  
United States Agency for International Development  
UW 
 
University of Washington 
VPD 
 
Vaccine preventable diseases 
WHO  
World Health Organization 
Wits RHI 
Wits Reproductive Health and HIV Institute 
WLHIV  
Women living with HIV 
 
 
 
 


EPIC Study Protocol                                                          Page 5 of 49                                                           Version 1.3 14 July2022 
EPIC  
Evaluation of Pharmacokinetic drug-drug Interactions between hormonal Contraceptives and 
doravirine-containing ART among women living with HIV in South Africa 
 
PROTOCOL TEAM ROOSTER 
 
Protocol Co-Principal Investigators (PIs) 
 
Rena Patel, MD, MPH, MPhil (Scientific Lead & Senior Clinical Advisor) 
Department of Medicine  
University of Alabama at Birmingham 
1808 7th Avenue South 
Birmingham, AL 35233 
Office Phone: +1-205-934-8145 
Mobile Phone: +1-650-353-0718 
Email: renapatel@uabmc.edu   
 
Thesla Palanee-Phillips, M Med Sci, PhD, M Sc  
Wits Reproductive Health and HIV Institute, Research Centre Clinical Research Site  
7 Esselen Street, Hillbrow  
Johannesburg, 2001 South Africa  
Phone: +2711 358-5471  
Email: tpalanee@wrhi.ac.za  
 
Nkosiphile Ndlovu, MBChB, Dip HIV Man 
Wits Reproductive Health and HIV Institute, Research Centre Clinical Research Site  
7 Esselen Street, Hillbrow  
Johannesburg, 2001 South Africa  
Phone: +2711 358-5471  
Email: nkndlovu@wrhi.ac.za  
 
Anna Wald, MD, MPH (Administrative PI) 
Head of Allergy and Infectious Diseases Division, Professor of Medicine, Laboratory Medicine & 
Pathology, & Epidemiology 
University of Washington 
325 9th Ave. 
Seattle, WA 98104 
Phone: +1-206-520-4340 
Email: annawald@uw.edu 
 
Protocol Team Roster  
 
Technical Head and Sub-Investigator  
Krishnaveni Reddy, M. Med. Sci 
Wits Reproductive Health and HIV Institute, Research Centre Clinical Research Site  
7 Esselen Street, Hillbrow  
Johannesburg, South Africa 
Phone: +2711 358-5470 
Email: kreddy@wrhi.ac.za  
 
Medical Officer and Sub-Investigator 
Ché Moshesh, MBBCh  
Wits Reproductive Health and HIV Institute, Research Centre Clinical Research Site  
7 Esselen Street, Hillbrow,  
Johannesburg, South Africa 


EPIC Study Protocol                                                          Page 6 of 49                                                           Version 1.3 14 July2022 
Phone: +2711 358-5424 
Email: cmoshesh@wrhi.ac.za  
 
 
 
 
Pharmacist  
Nazneen Cassim , B. Pharm (Hons) 
Wits Reproductive Health and HIV Institute, Research Centre Clinical Research Site  
7 Esselen Street, Hillbrow,  
Johannesburg, South Africa 
Phone: +2711 358-5424 
Email: ncassim@wrhi.ac.za  
 
Regulatory Compliance Officer  
Lerato Shale, BPH 
Wits Reproductive Health and HIV Institute, Research Centre Clinical Research Site  
7 Esselen Street, Hillbrow,  
Johannesburg, South Africa 
Phone: +2711 358-5424 
Email: lshale@wrhi.ac.za 
 
Laboratory Coordinator  
Nompumelelo Sigcu, B Tech Biomedical Technology 
Wits Reproductive Health and HIV Institute, Research Centre Clinical Research Site  
7 Esselen Street, Hillbrow,  
Johannesburg, South Africa 
Phone: +2711 358-5424 
Email: sismail@wrhi.ac.za 
 
Community Liaison officer  
Hlalifi Rampyapedi, BA 
Wits Reproductive Health and HIV Institute, Research Centre Clinical Research Site  
7 Esselen Street, Hillbrow,  
Johannesburg, South Africa 
Phone: +2711 358-5424 
Email: hrampyapedi@wrhi.ac.za  
 
Qualitative Research Associate  
Siyanda Tenza, B.Soc Sci (Hons) 
Wits Reproductive Health and HIV Institute, Research Centre Clinical Research Site  
7 Esselen Street, Hillbrow,  
Johannesburg, South Africa 
Phone: +2711 358-5424 
Email: stenza@wrhi.ac.za  
   
Pharmacology Advisor 
Kimberly Scarsi, PharmD, MS, FCCP 
University of Nebraska Medical Center 
986145, Nebraska Medical Center 
Omaha, NE 68198-6145 
Phone: 402-559-9916   
Email: kim.scarsi@unmc.edu  
 
 


EPIC Study Protocol                                                          Page 7 of 49                                                           Version 1.3 14 July2022 
INVESTIGATORS SIGNATURE PAGE 
 
Version 1.3, 12 July 2022  
Institution: Wits Reproductive Health and HIV Institute 
The signature below constitutes the approval of this protocol and the attachments, and provides 
the necessary assurances that this study will be conducted according to all stipulations of the 
protocol, including all statements regarding confidentiality, and according to all applicable legal 
and regulatory requirements and regulations as well as ICH and SA GCP guidelines. 
We, as the Co-Principal Investigators, agree to conduct this study in full accordance with the 
provisions of this protocol. Publication of the results of this study will be governed by Wits RHI 
policies.  
We have read and understand the information in this protocol and will ensure that all associates, 
colleagues, and employees assisting in the conduct of the study are informed about the 
obligations incurred by their contribution to the study. 
 
Principal Investigator: 
Signature 
Name:  
Title:    
Date:  
 
 
 
Principal Investigator: 
Signature 
Name:  
Title:    
Date:  
 
 
 
 
 


EPIC Study Protocol                                                          Page 8 of 49                                                           Version 1.3 14 July2022 
EPIC  
 
Evaluation of Pharmacokinetic drug-drug Interactions between hormonal Contraceptives and 
doravirine-containing ART among women living with HIV in South Africa 
 
PROTOCOL SUMMARY 
 
Short Title:   
EPIC 
 
IND Sponsor:  
Merck & Co., Inc. 
 
Funder: 
 
Merck & Co., Inc. 
 
Protocol Co-PIs:  
Rena Patel, Thesla Palanee-Phillips, Nkosiphile Ndlovu 
 
Study Site: 
Wits Reproductive Health and HIV Institute, Research Centre Clinical 
Research Site  
 
Study Design:  
Observational, parallel group pharmacokinetic (PK) study 
 
Study Population:  Women living with HIV (WLHIV) already on 1st line antiretroviral therapy 
(ART) and virally suppressed, 18-45 years old (inclusive) 
 
Sample size:   
Minimum of 105 participants 
 
Study Duration:  
Approximately 18-30 weeks of follow-up per participant 
 
Study Products:  
Doravirine (DOR)-containing ART tablets taken orally daily and one of the 
following contraceptive methods    
• Etonogestrel (ETG) implant 
• Intramuscular depo-medroxyprogesterone acetate (IM DMPA) 
• Subcutaneous medroxyprogesterone acetate (SC MPA)  
• Non-hormonal intrauterine device (IUD) 
 
Study Regimen: 
Participants who are interested in self-selecting and initiating one of the 
study contraceptive methods listed will be recruited for screening and 
eligibility assessments. If eligible and enrolled, there will be a 6-week lead-
in period with daily use of oral DOR-containing ART followed by 
contraceptive method initiation of their choice. Study follow-up will take 
place every 2-4 weeks, at a minimum, for an additional 12 or 24 weeks for 
a total of 18 or 30 weeks of follow-up depending on the contraceptive 
method chosen. 
 
We will also enroll a dolutegravir (DTG) + IM DMPA group, who will be 
followed for 12 weeks, as the comparator group for the DOR + IM DMPA 
group.  
 
The comparator group for the DOR + ETG implant group will be a historical 
control group from a  similar PK study called PARVI (PK study of ARVs 
and Implants in Kenya) that is currently being conducted by Dr. Patel and 
colleagues in Kenya.1 
 
 
 
 


EPIC Study Protocol                                                          Page 9 of 49                                                           Version 1.3 14 July2022 
Table 1:  Study groups by ART regimen and contraceptive method choice 
  
Group number  
N 
ART regimen and contraceptive method 
Group 1  
21 
DOR-containing ART + initiating ETG implant 
Group 2 
21 
DOR-containing ART + initiating IM DMPA 
Group 3 
21 
DOR-containing ART + initiating SC MPA 
Group 4 
21 
DOR-containing ART + initiating non-hormonal IUD  
Group 5 
21 
DTG-containing ART + initiating IM DMPA 
NDoH First line regimens: TDF + 3TC or FTC + EFV or DTG 
Study ART product is Delstrigo® tablet: DOR + 3TC +TDF 
 
Co-Primary Objectives: Pharmacokinetics 
• To evaluate any associations between DOR exposure and hormonal contraceptive use in the 
four groups of DOR + 1) ETG implant, 2) IM DMPA, 3) SC MPA, or 4) non-hormonal IUD 
users by generating mean hormone concentrations at 12 weeks for IM and SC DMPA or 24  
weeks for ETG implants and IUD groups; and  
• To evaluate any bi-directional associations between hormonal contraceptive exposure and 
DOR use by generating mean DOR concentration at 24 hours (C24 hours) per Table 2 (see 
below) 
 
Primary Endpoints 
• Mean hormone concentrations at 12 or 24 weeks after contraceptive method initiation and 
use (for MPA and implants/IUD respectively)  
• DOR concentration at 24 hours (C24 hours) 
 
Table 2: DOR study and comparator groups for contraceptive hormone and antiretroviral 
(ARV) concentrations  
 
DOR study group 
Comparator group 
Contraceptive Hormone concentrations 
ARV concentrations 
Group 1  
DOR + ETG implant 
DTG + ETG implant [primary] (historical 
group from PARVI) 
HIV-uninfected + ETG implant [secondary] 
(historical group from PARVI) 
Group 4 DOR + non-
hormonal IUD) 
Group 2  
DOR + IM DMPA 
Group 5 DTG + IM DMPA 
Group 4 DOR + non-
hormonal IUD 
Group 3  
DOR + SC MPA 
Group 2 DOR + IM DMPA 
Group 4 DOR + non-
hormonal IUD 
DTG=dolutegravir; PARVI=PK study of ARVs and Implants in Kenya 
 
Secondary Objectives 
• To measure DOR-containing ART’s efficacy, via HIV viral load <40 copies/mL, at 12-24 
weeks after contraceptive initiation among women of reproductive age using hormonal and 
non-hormonal contraceptives. 
 
Secondary Endpoints: 
• HIV-1 viral load 12-24 weeks after contraceptive method initiation 
 
 
 
Exploratory Objectives 
• To assess safety, including side effects, satisfaction, and continuation rates of both the 
hormonal contraceptive method and ART; 


EPIC Study Protocol                                                          Page 10 of 49                                                           Version 1.3 14 
July2022 
• To qualitatively explore decision-making around ART and contraceptive method options, 
study experiences of ART switch, use of contraceptive method and self-administration of SC 
MPA; and  
• To describe self-reported experiences of social harms and social benefits related to study 
participation.  
 
Exploratory Endpoints 
• Safety, satisfaction, and continuation rates at 12-24 weeks after contraceptive initiation; 
• Participant report of acceptability, preferences and adherence; and 
• Participants experiences around decision-making around ART and contraceptive options, 
and perceived self-reports of social harms and social benefits associated with study 
participation.  
 
1.0 
INTRODUCTION 
 
1.1 
Doravirine-containing antiretroviral therapy and drug-drug interactions 
Doravirine (DOR)-containing antiretroviral therapy (ART) has demonstrated efficacy for those with 
HIV drug resistance mutations to efavirenz (EFV)2, currently the leading ART for millions of 
persons living with HIV worldwide.  Integrase-inhibitor containing ART, such as dolutegravir 
(DTG), is now the recommended 1st line ART by the World Health Organization (WHO) for use 
worldwide.3  However,  enthusiasm for its use among women of reproductive age was dampened 
by its possible association with neural tube defects, despite this signal declining over the last two 
years since it was first reported in 2018.4,5  With growing drug resistance to EFV6,7 and possible 
limitation to use of DTG  in women of reproductive age, DOR may be the leading alternative ART 
recommendation for the largest group of HIV-infected individuals—women of reproductive age 
living in resource-limited settings, including in sub-Saharan Africa. Thus, eliciting any drug-drug 
interactions (DDIs) with a fuller range of hormonal contraceptives early is critical as the vast 
majority of women, including women living with HIV (WLHIV), use hormonal contraceptives at 
some point in their lives and these data may increase awareness of impact on contraceptive 
efficacy. 
 
1.2 
Efavirenz-containing ART and DDIs, and need for early studies on possible DDIs 
Unintended pregnancies among WLHIV have significant consequences for HIV and maternal 
morbidity and vertical transmission of HIV.  An estimated 40% of all pregnancies worldwide and 
35% of pregnancies in Africa are unplanned.8  Among WLHIV across sub-Saharan Africa, 35%–
65% of pregnancies are considered unplanned, with up to 62% of WLHIV reporting unplanned 
pregnancies in South Africa.8  However, the current evidence for the association between HIV 
status, ART use and unplanned pregnancy remains inconsistent.8  Contraception reduces 
maternal morbidity and may be the most cost-effective tool for preventing vertical transmission of 
HIV by reducing rates of unintended pregnancies in the first place.9,10  Therefore, optimizing 
contraceptive efficacy in combination with ART concurrently to avoid unintended pregnancies is 
imperative. Critical gaps exist, however, in current international and national HIV treatment 
guidelines regarding the concomitant use of ART and hormonal contraception.  Due to concerns 
regarding DDIs, current HIV treatment and family planning guidelines advise using alternative or 
additional contraceptive methods when using certain combinations of antiretrovirals (ARVs) and 
hormonal contraceptives, including the combination of EFV and contraceptive implants. These 
guidelines are largely based on data extrapolated from various pharmacokinetic (PK) studies,11-
13 and now studies that investigate DDIs with the concomitant use of hormonal contraceptives 
and EFV exist.14-17  
 
Some clinical data supporting the PK findings between implants and EFV is emerging.  Four case 
reports have described WLHIV already on implants who then initiated EFV-containing ART and 
subsequently became pregnant.18-21 Three out of 20 women initiating implants while on EFV-
containing ART in a PK study became pregnant within the first year of implant use.16  A 
retrospective review of 332 concomitant implant and ART users in eSwatini (formerly Swaziland) 
found 12.4% contraceptive failures among those using EFV-containing ART and none among 


EPIC Study Protocol                                                          Page 11 of 49                                                           Version 1.3 14 
July2022 
those using nevirapine-containing ART.22  Finally, a three-year retrospective cohort study in 
Kenya conducted by Dr. Patel and colleagues examined pregnancy rates among nearly 25,000 
WLHIV aged 15-45 years enrolled in PEPFAR-supported HIV facilities using various 
combinations of contraceptive methods and ART regimens.23  Among implant users, the adjusted 
pregnancy rate was 3.3 per 100 women-years with EFV-containing ART, compared with 1.1 with 
nevirapine-containing ART and 1.3 with no current ART use. These data indicate that among 
women using implants, those using EFV-containing ART had three times higher pregnancy rates 
than women using nevirapine-containing ART (95% CI 1.3-4.6). These findings indicate that the 
potential DDI between EFV-containing ART and implants may lead to the clinical outcome of 
contraceptive failure and incident pregnancies, although implants still retain relatively high 
effectiveness compared to leading alternative contraceptive methods such as oral pills or 
injectables.   
 
Despite the prior cohort data demonstrating that concomitant implant and EFV use retain 
relatively high effectiveness, there has been a significant gap regarding communication about 
these findings with patients, providers, and policy makers regarding its concomitant use in various 
resource-limited settings, including  in South Africa.24-26  Thus, it is imperative that a fuller profiling 
of potential DDIs between ARVs and hormonal contraceptive methods occur prior to full-scale 
programmatic roll out of new ARVs and contraceptive methods. 
 
 
 
1.3 
Clinical studies with DOR, regulatory approval status outside of South Africa 
Doravirine is  a registered drug in South Africa since August 2021. At the time of the initial 
submission of the protocol, it was unregistered for local use hence institutional review board, drug 
regulatory and import approval was required prior to shipment into South Africa. The South 
African Health Product Regulatory Agency (SAHPRA) was requested to approve the importation 
of the study product once the protocol was approved by the local IRB. On receipt of both local 
IRB and SAHPRA approval, the import of DOR commenced. 
 
1.4 
Clinical pharmacokinetics of DOR, mechanism of action 
Doravirine is a pyridinone non-nucleoside reverse transcriptase inhibitor (NNRTI) of HIV-1 and 
inhibits HIV-1 replication by non-competitive inhibition of HIV-1 reverse transcriptase (RT). 
Doravirine does not inhibit the human cellular DNA polymerases α, ß, and mitochondrial DNA 
polymerase γ. The chemical name for DOR is 3-chloro-5-[[1-[(4,5-dihydro-4-methyl-5-oxo-1H-
1,2,4-triazol-3-yl)methyl]-1,2-dihydro-2-oxo-4-(trifluoromethyl)-3-pyridinyl]oxy]benzonitrile. It has 
a molecular formula of C17H11ClF3N5O3 and a molecular weight of 425.75 g/mol.  It has the 
following structural formula: 
 
 
 
 
Figure 1: Structural formula of Doravirine 
 
1.5  
DOR metabolism and potential mechanisms for DDIs between hormonal 
contraceptives and ARVs 
Concurrent use of hormonal contraceptives and ART can lead to DDIs, predominantly due to 
effects on liver metabolism of the therapeutics.11,12,27  In the liver, cytochrome P450 (CYP) 
enzymes catalyze many important reactions, with the most significant enzyme for contraceptive 
metabolism being CYP3A4.  Many antiretrovirals, especially NNRTIs and PIs are substrates, 
inhibitors, and/or inducers of CYP 450 enzymes, including CYP3A4, resulting in increases or 
decreases in the concentration of concomitantly administered drugs, including hormonal 
contraceptives.27  Such interactions could lead to decreased contraceptive effectiveness 
(increasing risk of unintended pregnancy), decreased concentrations of ART effectiveness 
(associated with resistance and/or HIV disease progression), or increased ART or contraceptive 


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toxicity.  Etonogestrel (ETG) and medroxyprogesterone acetate (MPA) hormones are known 
substrates of and metabolized by CYP3A.  However, due to the limited data available on the effect 
of various hormonal contraceptive methods on DOR metabolism, the study will provide valuable 
insight regarding these DDIs.   
 
1.6 
Rationale for study design 
While DOR-containing ART has been evaluated in two large clinical trials, only 16-17% of the 
study participants were women and only 6-10% of them were African.2,28  In an epidemic, where 
the gendered majority affected by the disease are women of reproductive age living in Africa, it 
is imperative to conduct a trial evaluating outcomes among and specific to African women.  
Further underscoring the relevance of this issue is a notable data gap for DOR regarding DDIs 
with the most common leading hormonal contraceptive methods offered in public family planning 
clinics in Africa. 
 
Dr. Patel (Co-PI) is currently conducting a study evaluating the DDIs between contraceptive 
implants and EFV- and DTG-containing ART in Kenya.1  Therefore, the proposed study is well-
poised to leverage this ongoing study in Kenya and efficiently address the current knowledge 
gaps regarding the use of DOR in women of reproductive age in South Africa. The Kenyan study, 
PARVI, is parallel to the proposed study with some key differences, namely:  
1. A change in ART regimen did not occur in PARVI; women were continuing their current 
ART regimen and simply starting a contraceptive method.   
2. the PARVI study team did not offer women a contraceptive method; instead, as women 
chose a method of interest to the study, the study staff approached the women to enrol in 
this study.   
Otherwise, the study procedures, including the timing of study visits and sample collections are 
parallel in both studies. 
Our intention is to study potential DDIs between DOR and the most common contraceptive 
methods used by WLHIV in an African context, which generally include short- (e.g., oral 
contraceptive pills (OCPs)/combined oral contraceptives (COCs)), intermediate (e.g., injectable) 
or long-acting (e.g., implants or intra-uterine device (IUD)) methods.  Since the manufacturer of 
DOR has already conducted the industry standard PK study with DOR and a COC product, 
containing ethinyl estradiol and levonorgestrel,29 which did not demonstrate any bidirectional DDI, 
we have chosen to exclude this method from the current study.  Thus, the current EPIC study 
focuses on intermediate- and long-acting contraceptive methods, which have different PK profiles 
than daily administrated oral drugs and may be more susceptible to potential DDIs with DOR. 
 
Participants enrolling in the study will not be randomized to groups, including contraceptive 
methods, of the trial, and instead participants will be given the choice to select a contraceptive 
method group where applicable.  Those already on EFV- or DTG-containing ART and wishing to 
switch to DOR-containing ART will be included in the DOR groups (Groups 1-4, Table 1) and 
those already on DTG and wishing to remain on DTG will be included in the DTG group (Group 
5, Table 1). 
 
1.7  
Justification for not randomizing women to a contraceptive method 
Randomization is not essential for and rarely done in the context of PK studies. In this PK study, 
contraceptive method related persistence and high continuation rates are crucial for the duration 
of the study for the PK sampling while on ART to effectively assess DDI. The study team believes 
that prioritizing contraceptive method informed choice through counselling and education and 
making allowance for  women to select a method that best suits their lifestyles and pregnancy 
intentions for the future will likely increase women’s adherence and persistence on that self-
selected method. The study investigators acknowledge the possibility that the group of women 
choosing one contraceptive method over another may have some fundamental differences.30  To 
address this, we plan to utilize multivariate models which will help account for confounding by 
potential covariates, such as body mass index (BMI) or age.  We do not have reasons to believe 
that selection of the contraceptive method by the women would bias the study in ways other than 


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via potential confounders.  Additionally, PK studies, including this one, are powered on the 
variance detected in hormone concentrations within groups, which already account for variation 
within the group of factors such as BMI or age.  Thus, this study is appropriately powered for the 
primary outcome to detect differences in hormone concentrations that may exist across the 
groups. 
 
1.8  
Justification of choice of contraceptive methods for the EPIC study  
The study investigators have elected to include intramuscular depo-medroxyprogesterone 
acetate (IM DMPA), sub-cutaneous medroxyprogesterone acetate (SC MPA), the etonogestrel 
(ETG) implants and non-hormonal IUD for the reasons summarised below.  As noted earlier, the  
pharmaceutical manufacturer of DOR has already conducted the industry standard PK study with 
DOR and a COC product, containing ethinyl estradiol and levonorgestrel,29 therefore, the 
investigators have prioritized greater profiling of DOR with different, commonly used contraceptive 
methods over repeating a PK study with the same therapeutics, even if conducted in a different 
population.  
1.8.1  DMPA  
DMPA (150 mg of depo-medroxyprogesterone acetate (MPA)/ml IMI) is the most commonly used 
injectable contraceptive worldwide, and the most commonly used method of reversible injectable 
contraception in sub-Saharan Africa.  In perfect use, DMPA is highly effective and with consistent 
and correct use has a 0.2% failure rate; typical use failure rates are higher (~6%).31 Since SC 
MPA (104 mg of medroxyprogesterone acetate (MPA)/ml SC) was recently registered in South 
Africa, and can be self-administered, it may be a method suitable for community-based 
distribution and teaching women how to safely perform self-administration of the injectable is 
paramount,  potentially increasing ease of  contraceptive access and continuation without carrying 
any additional risks above what DMPA may already carry.32 
Advantages of DMPA include its ease of administration, its ability to be used covertly, and the 
fact that one injection lasts for 3 months plus a ‘grace period’ of 4 weeks if a woman is late for her 
next injection. The short follow-up period for this method on the EPIC study will assure adherence 
to the contraceptive method as only one dose of the injectables will be required. On exit, additional 
doses will be offered to the participant.  
Although side effects or adverse events (AEs) may be experienced by women using this method 
(e.g., headache, dizziness, mood changes, acne), major problems are rare.  Menstrual irregularity 
and spotting, along with amenorrhea, are the most common side effects.33  While frequently cited 
as the main reason for early discontinuation, menstrual irregularity is considered a nuisance, and 
is common for all progestin-only methods, and does not present a health risk for the user.  
1.8.2  Contraceptive implants  
Contraceptive progestin implants are thin rods inserted under the skin of a woman's arm.  The 
most widely available implant in South Africa is currently Implanon®/Nexplanon®/Implanon 
NXT®, containing etonogestrel (ETG, 3-keto desogestrel).  Implanon® consists of a single rod of 
ethylene vinyl acetate and contains 68 mg of ETG; it is manufactured by Merck and is approved 
for 3 years.  
Implants are highly effective and user independent, with failure rates of <1% for both perfect and 
typical use since no user action is required after placement.  Continuation rates for implants 
average ~90% at the end of the first year and 70% by the end of the third year.34  
During the first year of implant use many women experience prolonged or irregular bleeding or 
both; in subsequent years, bleeding patterns tend to improve. As with other hormonal 
contraceptives, headache, minor weight increase, skin problems (such as acne), dizziness, and 
mood changes have been associated with use of progestin implants.35  


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1.8.3  Non-hormonal copper IUD  
The NOVA T-380 non-hormonal IUD consists of a T-shaped polyethylene frame wound with 
copper wire, along with two monofilament threads to aid in removal of the IUD.  IUDs may be left 
in place for up to 5 years. IUD continuation rates vary significantly and may range from 78% in a 
two year randomised trial in South Africa to 92% in the randomised, multicentre, open-label ECHO 
trial.36-38  
Non-hormonal IUDs are extremely safe, effective, reversible, and are available worldwide, 
including in sub-Saharan Africa, but issues with demand, provider bias, and supplies have limited 
their use in most of sub-Saharan Africa.39,40  Provider concerns about IUD use, especially in young 
nulliparous women, include beliefs that IUDs may increase the risk of pelvic inflammatory disease 
(PID) and thus tubal infertility or ectopic pregnancy.  IUD use in young women and those at high 
risk of sexually transmitted infections (STIs) has been limited in the past by such concerns.  Data 
suggest that IUDs do not increase the risk of PID in nulliparous women beyond a small increased 
risk for all women post-insertion.  In a pooled analysis of the WHO clinical trials, the overall rate 
of PID among 22,908 IUD insertions and with 51,399 years of follow-up was 1.6/1000 woman-
years (w-y) of use.41 Additionally, IUDs do not cause tubal infertility42 or ectopic pregnancy.43  
Even among WLHIV, PID rates with IUD insertion are low and do not vary by level of HIV disease 
severity.44-46  IUDs are becoming more widely used in some African settings.47 
Non-hormonal IUD users may experience heavier periods than they did before IUD insertion and 
may have more dysmenorrhea.  However, data do not support a drop in haemoglobin as a result 
of IUD use.36 Moreover, no other non-hormonal, highly effective, long-acting, reversible 
contraceptive method is available. 
2.0 
OBJECTIVES AND HYPOTHESES 
2.1 
Co-Primary Objectives: Pharmacokinetics 
• To evaluate any associations between DOR exposure and hormonal contraceptive use in the 
four groups of DOR + 1) ETG implant, 2) IM DMPA, 3) SC MPA, or 4) non-hormonal IUD 
users by generating mean hormone concentrations at 12 weeks for IM and SC DMPA or 24  
weeks for ETG implants and IUD groups; and  
• To evaluate any bi-directional associations between hormonal contraceptive exposure and 
DOR use by generating mean DOR concentration at 24 hours (C24 hours) per Table 2.  
 
Hypotheses 1:  
• The mean implant hormone concentrations for DOR + ETG implant at 24 weeks after implant 
placement will be similar (i.e. geometric mean ratio [GMR] within 0.80 and 1.25) to the mean 
implant hormone concentrations for DTG + ETG implant (historical controls from Dr. Patel’s 
current PARVI study in a similar population in Kenya).  The mean MPA concentrations for DOR 
+ IM DMPA or SC MPA at 12 weeks after DMPA/MPA administration will be similar (i.e. GMR 
within 0.8 and 1.25) to the mean DMPA concentrations for DTG + DMPA (contemporaneous 
study group). 
• The mean C24 hours of DOR in the ETG implant and MPA groups will be similar to the non-
hormonal contraceptive method (i.e. the non-hormonal IUD) group. 
 
 
 
2.2 
Secondary Objectives 
To measure DOR-containing ART’s efficacy, via HIV viral load <40 copies/mL, at 12-24 weeks 
after contraceptive initiation among women of reproductive age using hormonal and non-
hormonal contraceptives. 
 
Hypothesis 2: The proportion of women suppressed (defined as HIV viral load <40 copies/mL) 
at 16-30 weeks after DOR-containing ART initiation will be similar to a contemporaneous or 


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historical comparison of proportion of women suppressed with non-DOR containing ART from the 
same study population/sample. 
 
2.3 
Exploratory Objectives 
• Safety, including side effects, satisfaction, and continuation rates of both the hormonal 
contraceptive method and ART will be assessed; and  
• To qualitatively explore decision-making around ART and contraceptive options, study 
experiences of ART switch and use of contraceptive method, including self-administration of 
SC MPA, and to describe self-reported experiences of social harms and social benefits 
related to study participation.  
 
Hypotheses 3: Safety, satisfaction, and continuation rates of the various contraceptive methods 
will be similar to each other at 12-24 weeks after contraceptive initiation.  We will gain interesting 
insights into women’s decision-making around ART and contraceptive method options and be 
uniquely positioned to describe experiences of self-administration of SC MPA. 
 
3.0 
STUDY DESIGN OVERVIEW 
3.1 
Description of study design 
This is an observational, parallel group PK study, investigating a cohort of women of reproductive 
age (18-45 years) living with HIV. This cohort of women will be enrolled in the study if they are 
already on South African standard-of-care 1st line ART, which is currently largely either EFV- or 
DTG-containing ART and have demonstrated viral suppression within the last three months. In 
addition, this group of women should not currently be on any hormonal contraceptives or received 
IM DMPA or SC MPA in the last two months prior to study screening but interested in initiating 
one of the study contraceptive method in the next 6 weeks.  A total of 5 groups of women will be 
recruited for this study (minimum participants n=21 per group or total n=105; Table 1).  Groups 
1-4 will comprise  of women switching from their current ART to DOR-containing ART, and 6 
weeks after DOR initiation (for a lead-in period with DOR), the woman will be offered a choice of 
ETG  implant, IM DMPA, SC MPA, or non-hormonal IUD. The 5th Group will comprise of women 
remaining on DTG containing ART and willing to initiate IM DMPA.  Group 5 participants will 
already be on DTG-containing ART, and because they will not be switching their ART, they can 
initiate the IM DMPA without any lead-in periods (Figure 2). 
 
 


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Figure: 2 EPIC study design schematics 
 
3.2 
Summary of major endpoints 
The major study endpoints are PK parameters at 12 or 24 weeks after contraceptive initiation, 
depending on the contraceptive method. 
 
3.3 
Site 
This is a single-site study conducted at the Wits-RHI Research Centre Clinical Research Site (RC 
CRS),  part of a leading African institute focusing on research within the areas of HIV, sexual and 
reproductive health (SRH) and vaccine preventable diseases (VPD) and more recently COVID-
19 prevention and treatment research. Wits RHI RC CRS is an NIH and Division of AIDS (DAIDS) 
clinical research site and are part of a NIH-supported Clinical Trials Unit. Additionally, Wits RHI 
is a UNAIDS, USAID, WHO and South African Medical Research Council (MRC) collaborating 
partner. The organization’s focus ranges from investigating HIV prevention technologies and 
improving approaches on HIV diagnoses, care and treatment to optimizing ART and developing 
models of care for men and women as well as key populations and marginalized groups such as 
adolescent girls and young women (AGYW), sex workers, migrants and mobile populations while 
adhering to the principles of good participatory practice (GPP) and community engagement.  
 
Wits RHI has a regional, national and international footprint running research projects and 
providing direct service delivery in various districts across the nine provinces of South Africa (SA). 
Their footprint across the African continent also includes research and technical assistance 
projects with active collaborations in Uganda, Rwanda, Kenya, Tanzania, Malawi, Mozambique, 
Zambia, Zimbabwe, Namibia and eSwatini. Wits RHI develops and delivers innovative, locally 
relevant, evidence-based solutions to improve the health and well-being of the people of South 
Africa, the African region and globally. Within SA, Wits RHI has a close working relationship with 
both the provincial and national Departments of Health (DoH) and supports the DoH as the 
stewards of the country’s health system to strengthen the response to the HIV/AIDS and 
reproductive health related epidemics.  
 
Wits RHI is especially suited to support the proposed project because of the well-established 
research infrastructure; well-equipped network of clinical, pharmacy, and laboratory facilities that 
conform to the highest local and international standards and the highly experienced clinicians, 
nurse counsellors with specialized adherence and motivational interviewing skills, medical 
laboratory scientists, pharmacists, community, behavioral and social science staff. Wits RHI has 
established three Community Advisory Boards (CAB) – namely the Youth, HIV Prevention and 
HIV Treatment CABs, to support the broad spectrum research agenda, strong collaborative 
relationships with local hospitals, public health clinics, and other local community resources and 
a proven track record of working effectively with local community leaders and residents. Key 
resources of the Wits RHI Research Centre RC CRS are described below. All resources and 
facilities are immediately available and are adequate to support the scope of work in the proposed 
timeframe  
 
The Wits RHI RC CRS is a large (1.840m2) purpose-built research clinic housed in the basement 
of the former University of the Witwatersrand student residence in the vulnerable inner-city urban 
regeneration zone known as the Hillbrow Health Precinct (HHP) in Region F, Johannesburg. The 
Wits RHI RC CRS provides a range of clinical, counselling and laboratory services that are fully 
compliant with local and international regulatory standards.  
 
3.4 
COVID-19 containment measures  
The Wits RHI RC CRS will ensure that infection identification and control procedures are in place 
and that an adequate supply of personal protective equipment (PPE) is available as per 
institutional standard operating procedures (SOPs), and national and international guidelines.  
 
4.0 
STUDY POPULATION, ACCRUAL AND FOLLOW-UP 


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4.1 
Description of study population 
The study population consists of 18-45-year-old (inclusive) WLHIV currently virally suppressed 
on 1st line ART 
 
4.2 
Time to complete accrual 
We anticipate accrual will take ~ 9-12 months from study initiation to complete, and the last 
participant will complete study follow-up 15-18 months after study initiation. 
 
4.3 
Expected duration of participation 
Participants will be followed for the 6 weeks of oral lead-in period to ensure they tolerate the DOR 
-containing ART where applicable, then followed for an additional 12-24 weeks while using the 
contraceptive method.  We anticipate following each participant for 18-30 weeks in total 
depending on contraceptive method. 
 
4.4 
Recruitment 
Recruitment for this study will be led by the Wits RHI RC CRS community team consisting of a 
Community Liaison Officer (CLO) and Community Health Workers (CHWs) who have more than 
10 years of experience recruiting in Hillbrow and surrounding areas and have successfully met 
and exceeded site accrual targets in all studies conducted since 2010. The team is well-suited to 
developing innovative recruitment methods and collaborating with local stakeholders to ensure 
that they achieve the accrual rate needed and enroll WLHIV between the ages of 18-45 years on 
ART  who clearly comprehend the study objectives and the level of commitment required of them 
for the duration of the study.  The team will leverage long-established recruitment strategies 
refined over years of clinical research implementation to initiate a multi-faceted approach to 
identify and timeously enroll a cohort of eligible women. Wits RHI staff will recruit participants in 
the City of Johannesburg (COJ) district from a variety of sources across Region F. Strategies will 
include, but are not limited to:  
 
1) Identifying women who are either on EFV- or DTG-containing 1st line ART regimens through 
peer referrals. 
2) Active recruitment by Wits RHI community health workers and community liaison officer in 
identifying women on ART who are interested in initiating intermediate- or long-acting 
contraceptive methods.   
3) Recruiting eligible WLHIV from collaborating family planning or ART clinics, targeting those 
enrolled in HIV care and virally suppressed  
a. Recruiting from within interested WLHIV, those willing to switch to the study 
specified ART regimens and willing to consider initiation of one of the study 
contraceptive methods. 
b. Preliminary discussions with local clinics have indicated access to large numbers 
of WLHIV on HIV treatment but not on reliable contraception (pers comm). The 
study team will work with these clinics to recruit participants if interested.   
4) Local research projects within Wits RHI and other health and social service providers serving 
the target study population.  
 
Local IRB approved recruitment and educational materials will be used during these recruitment 
sessions to educate women about the study as well about the side effects and benefits associated 
with ART and contraceptive uptake.  Interested individuals will be followed-up with a phone 
interview to assess their interest in participating in this study.  As the study team proceeds with 
recruitment, they will identify strategies that are highest yielding in terms of accrual and shift focus 
to primarily rely on maximizing the screen:enrol ratio of participants.  
 
Safe recruitment practices will be implemented in line with COVID-19 risk reduction practices 
including use of PPE and social distancing as well as informed by routine updates to guidelines 
in the Wits RHI COVID-19 pandemic site specific SOPs.   
 
4.5 
Inclusion criteria 


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For the EPIC study, participants must meet all of the following inclusion criteria to be eligible to 
participate in this research study: 
1. 
Female,  
2. 
HIV-positive, 
3. 
Aged 18-45 years, 
4. 
Currently on 1st line ART (namely EFV- or DTG-containing ART), 
5. 
Have documented or confirmed viral suppression for HIV (defined as <40 copies/mL) within 
3 months prior to study screening and after the start of the current ART regimen, 
6. 
Contraception use: 
a) Not currently on reliable contraception and intending to or willing to initiate use of study 
hormonal/non-hormonal contraceptive methods 6 weeks after DOR lead in period (and 
willing to continue use for subsequent 12 to 24 weeks), 
7. 
Able and willing to comply with all study procedural requirements, 
8. 
Able and willing to provide informed consent for study participation in either English or Zulu, 
9. 
Able and willing to provide adequate locator information, as defined in site SOPs, 
10. Negative pregnancy test at Screening and Enrollment, and 
11. At Screening and Enrollment, agrees not to participate in other research studies involving 
drugs, medical devices, vaginal products, or vaccines for the duration of study participation. 
 
4.6 
Exclusion criteria 
Participants who present with any of the following will not be included in the study: 
1. 
Currently on 2nd line, 3rd line, or salvage ART regimens, 
2. 
Currently pregnant or intending to become pregnant within the next 6 months, 
3. 
Currently breastfeeding or intending to breastfeed within the next 6 months, 
4. 
Use or anticipated use of drugs for the duration of the study period known to interact with 
hormonal implants, DMPA/MPA, or the respective ART regimen (Table 3), 
5. 
Current or planned concomitant use of other hormonal contraceptives, 
6. 
Currently obese (BMI≥30), 
7. 
Has any of the following laboratory abnormalities at Screening Visit:  
a) Haemoglobin abnormality Grade 2 or higher 
b) Calculated creatinine clearance less than 50 mL/min by the Schwartz Equation, 
c) Evidence of chronic Hepatitis B infection, 
8. 
Per participant report at Screening and Enrollment, intends to do any of the following during 
her study participation period: 
a) relocate away from the study site 
b) travel away from the study site for a time period that would interfere with product resupply 
and study participation, 
9. Per participant report and/or clinical evidence of any of the following: 
a) Known adverse reaction to any of the study products (ever), 
b) Participation in any other research study involving drugs, medical devices or vaccines 
within 60 days of enrolment, 
c) At Enrollment, as determined by the PI/designee, has any significant uncontrolled active 
or chronic cardiovascular, renal, liver, hematologic, neurologic, gastrointestinal, 
psychiatric, endocrine, respiratory, immunologic disorder, metabolic bone disease or 
infectious disease,  
10. Has any other condition that, in the opinion of the PI/designee, would preclude informed 
consent, make study participation unsafe, complicate interpretation of study outcome data, 
or otherwise interfere with achieving the study objectives.  
 
Table 3: Prohibited concomitant medications with doravirine-containing ART  
Drug name 
Drug class/type 
Carbamazepine 
Anticonvulsants 
Oxcarbazepine 
Anticonvulsants 
Phenobarbital 
Anticonvulsants 
Phenytoin 
Anticonvulsants 
Rifampicin 
Antimycobacterials 


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Rifapentine 
Antimycobacterials 
St. John’s wort (Hypericum perforatum) 
Herbal remedy for depression and anxiety 
Mitotane 
Cytotoxic agent 
Enzalutamide 
Androgen receptor inhibitor 
Lumacaftor 
Cystic fibrosis transmembrane conductance 
regulator 
 
4.7 
Screening and enrollment 
WLHIV of reproductive age will be recruited from HIV care programs in Johannesburg, South 
Africa and invited to screen for enrollment in this study. If a woman is interested, she will be pre-
screened either in person or telephonically to determine presumptive eligibility and scheduled for 
an in-person screening visit at the study site.  At the screening visit, she will be taken to a separate 
room at the facility to undergo informed, written consent and a unique study ID will be assigned 
to her.  Following informed consent, relevant study procedures will be conducted, and specimens 
will be collected to assess eligibility. Once the results have been returned to the study team, which 
is anticipated to take between 1-48 hours, the study staff will inform the participant in-person or 
by phone, and if eligible or ineligible. If eligible, she will be scheduled for a return study visit for 
enrollment.  At the time of enrollment, the participant will be provided sufficient study product 
(DOR-containing ART) for the lead in period if choosing to enroll in Groups 1-4.  For participants 
in Group 5, they will proceed with receiving IM DMPA and continuing their DTG-containing ART. 
Participant will be considered fully enrolled when contraceptive method is chosen. 
 
4.8 
Co-enrollment guidelines 
Participants may not take part in other research studies involving drugs, medical devices, 
products or vaccines after the Screening Visit and while taking part in the EPIC study. Exceptions 
to this guideline may be made for participants to co-enrol in the following types of studies at the 
discretion of the PI/designee:  
• Participants may take part in ancillary studies approved by the PIs.  
• Participants who become pregnant may take part in observational studies, including pregnancy 
registries through referrals to appropriate partners.  
Should any participant report or should study staff discover concurrent participation in any other 
study after enrolling in the study, the PI/designee will consult the Senior Clinical Advisor regarding 
ongoing study product use and other potential safety considerations associated with co-
enrolment. 
 
4.9 
Follow-up 
After enrollment, the participant will return for scheduled visits up until approximately 12-24 weeks 
(+/- 2 weeks) after contraceptive method initiation.  For participants in Groups 1-4, they will first 
have a lead-in period of 6 weeks to ensure they tolerate DOR-containing ART and to allow their 
prior ART regimen to wash out, especially if on EFV -containing ART.  We are anticipating that 
the majority of women enrolling in this study will be on EFV-containing ART, and because EFV is 
a known potent inducer of CYP450 enzymes and known to influence PK parameters of both DOR 
and hormonal contraceptives, it is necessary to have a “washout” period for the EFV induction to 
decrease markedly over the next 6 weeks.48  The participants will have these visits scheduled 
ahead of time, and the study staff will make a reminder text message or phone call the week and 
day before the appointment.  Standard questionnaires, assessing safety and satisfaction, will be 
administered and blood and urine samples collected for various laboratory assessments at these 
visits. 
 
4.10 
Retention 
The experience and commonly used effective strategies of the Wits RHI community team will be 
leveraged to ensure high retention rates among participants in the proposed study. These 
strategies include:  


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• 
Exclusion of participants who lack understanding of the research objectives or commitment to 
the research process, or who may experience personal challenges with compliance with study 
visits such as travel outside of the study area,  
• 
Collection and verification of adequate participant locator information (including residential 
address, contact numbers and multiple alternate contacts if we are unable to make direct 
contact with the participant,  
• 
Regular update and verification of locator information at every study visit along with reminders 
to contact the study team should details change between visits,  
• 
Visit reminders for all enrolled participants (text message or phone call) a week before and a 
day prior to each scheduled study visit (Participants who do not attend a scheduled visit will 
receive a phone call the day after the scheduled visit and as needed until the visit is attended),   
• 
Provision of long-distance transport (e.g. bus tickets) or additional reimbursement (with ethics 
approval) for participants who relocate,   
• 
Conduct of off-site visits (with participants permission) for those who may miss a visit at a 
venue of their choice. 
 
 
 
5.0 
STUDY PRODUCTS 
5.1 
DOR-containing ART 
5.1.1 Regimen 
Each participant will be initiated in one of five groups, four of which contain the use of DOR 100mg 
oral tablet taken daily 18 or 30 weeks total (6 weeks lead in and 12-24 weeks (depending on the 
self-selected method of contraception) following contraceptive initiation): 
 
Table 4: ART regimen, contraceptive method and total follow-up period per group 
 
Group 
ART regimen, contraceptive method and total follow-up period per group 
Group 1  100mg DOR-containing ART + 68mg ETG implant (30 weeks) 
Group 2 
100mg DOR-containing ART + 150mg IM DMPA (18 weeks) 
Group 3 
100mg DOR -containing ART + 104mg SC MPA (18 weeks) 
Group 4 
100mg DOR -containing ART + 1 non-hormonal IUD device (30 weeks) 
Group 5 
50mg DTG -containing ART + 150mg IM DMPA (18 weeks) 
 
5.1.2 Administration 
Delstrigo® tablet (100 mg of DOR, 300 mg of lamivudine, and 300 mg of tenofovir 
disoproxil fumarate) 
Study participants will be instructed to take one Delstrigo® oral tablet daily for the 18-30-week 
study period. Delstrigo® can be taken with or without food and should be taken close to the same 
time each day. If a participant misses a dose, the missed dose should be taken as soon as 
possible, unless the next dose is estimated to be due within 12 hours. If the next dose is estimated 
to be due within 12 hours, the missed dose must be skipped. The next dose must be taken as 
originally scheduled. 
 
5.1.3 Study product formulation 
Delstrigo® is a film-coated yellow, oval-shaped, tablet of dimensions 21.59 mm x 11.30 mm, 
debossed with the corporate logo and 776 on one side and plain on the other side.  Each pill 
contains 100 mg of DOR, 300 mg of lamivudine, and 300 mg of tenofovir disoproxil fumarate. The 
tablets include the following inactive ingredients: croscarmellose sodium E468; hypromellose 
acetate succinate; magnesium stearate E470b; microcrystalline cellulose E460; silica, colloidal 
anhydrous E551; sodium stearyl fumarate. The tablets are film coated with a coating material 
containing the following inactive ingredients: carnauba wax E903, hypromellose E464; iron oxide 
yellow E172; lactose monohydrate; titanium dioxide E171; and triacetin E1518. 


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Delstrigo® should be optimally stored in the site pharmacy between 20°C to 25°C and kept in the 
original bottle. Excursions are permitted between 15°C and 30°C (59°F and 86°F). Study 
participants will be counselled on storage prior to receiving study drugs.  
 
5.1.4 Supply, accountability and dispensing 
5.1.4.1 Supply 
Delstrigo® Merck Sharp & Dohme B.V. will oversee the manufacture of the tablet and release the 
tablets under Good Manufacturing Practices (GMP). Delstrigo® tablets are supplied by Merck & 
Co, Inc. (White House Station, New Jersey, USA).  
 
5.1.4.2 Accountability  
The Wits RHI CRS Pharmacist is required to maintain a complete record of all study products 
received and subsequently dispensed. All study products not dispensed must be returned to the 
drug donor after the study is completed or terminated unless otherwise instructed by the supplying 
pharmacist/study donor. All study product dispensed to a participant must be documented by the 
clinic staff when dispensed. Any unused study products not returned must also be documented 
by the clinic staff. 
 
5.1.4.3 Study product dispensing  
Study tablets are dispensed only to enrolled study participants or clinic staff on behalf of the 
participant, upon receipt of a written prescription from an authorized prescriber. Authorized 
prescribers include the PI or licensed clinicians.  Dispensing takes place on the day of enrolment 
and at each scheduled follow-up visit. The pharmacist will dispense one bottle of 30 tablets per 
month. Two bottles will be provided at enrolment for the lead in period to ensure adequate supply. 
Any unused tablets to be returned at next scheduled visit.  
 
During study product use, participants will receive a new supply of tablets monthly. Product will 
be dispensed in quantities sufficient to last until the next scheduled study visit. In the event that 
additional study products between visits are needed, participants will be instructed to contact the 
study site. If the participant is unable to attend their next scheduled visit, it is up to the discretion 
of the PI/designee to allow the provision of additional study product. The PI/designee will 
document approval of this additional dispensation 
 
5.1.5 Discontinuation of study product 
General criteria for discontinuation of study product  
Participants will be temporarily/permanently discontinued from study products by the PI/designee 
for any of the following reasons:  
• Allergic reaction to the study product (Grade 3 or above, as per DAIDS Table for Grading the 
Severity of Adult and Pediatric Adverse Events, Version 2.1, July 2017 and Addendum 1, 
(Female Genital Grading Table for Use in Microbicide Studies; dated November 2007) 
• Positive pregnancy test 
• Non-therapeutic injection drug use  
• Serious Adverse Event (SAE) (senior clinical advisor to be notified, and guidance to be 
provided)  
 
5.2 
Subcutaneous medroxyprogesterone acetate (SC MPA) or (Sayana® Press) 
 
SC MPA was registered (registration number: 45/21.8.2/1139) in South Africa in June 2019 per 
the SAHPRA website.  Implementation plans as part of its inclusion in the revised draft 
contraceptive policy related to expansion of method mix have been delayed due to COVID-19. 
We include available information about it below, for ease of reference.  Sayana® Press is a single-
dose container with 104 mg medroxyprogesterone acetate (MPA) in 0.65 mL suspension for 
injection. Sayana® Press is indicated for medium-long term female contraception. 
 


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5.2.1 Administration 
Sayana® Press 104 mg/0.65 ml suspension for injection 
Sayana® Press may be administered by a healthcare professional (HCP) or when considered 
appropriate by the HCP, self-injected by the patient, with medical follow-up as necessary in 
accordance with local clinical guidance. 
 
Administration of Sayana® Press will be initiated under the supervision of a nurse or study 
clinician at the site. After comprehensive counselling and training in injection technique and 
schedule of administration, patients may self-inject with Sayana® Press if their HCP determines 
that it is appropriate and with medical follow-up as necessary. 
 
The Sayana® Press single-dose container should be at room temperature. It must be vigorously 
shaken just before use to ensure that the dose being given represents a uniform suspension. The 
contents are completely sealed inside the reservoir of the injector. The injector must be activated 
before use. The activation process pierces an internal seal so that the medicine can come out 
through the needle when the reservoir is squeezed. The liquid does not completely fill the 
reservoir. There is a small bubble of air above the liquid. A dose of 104 mg of MPA is given 
subcutaneously (into the fatty layer just under the skin), into the front upper thigh or abdomen 
every 3 months (12 to 13 weeks) for the 16-28-week study period. When the injection is being 
given, the injector must be used with the needle downwards. This ensures that the full dose of 
liquid is delivered out through the needle. The medication should be injected slowly for 5-7 
seconds.  
 
5.2.2 Study product formulation 
The active substance is medroxyprogesterone acetate (MPA). The pre-filled injector contains 104 
mg medroxyprogesterone acetate (MPA) in 0.65 ml. The other ingredients are macrogol, methyl 
parahydroxybenzoate (E218), propyl parahydroxybenzoate (E216), sodium chloride, polysorbate 
80, monobasic sodium phosphate monohydrate, disodium phosphate dodecahydrate, 
methionine, povidone, sodium hydroxide and/or hydrochloric acid for pH adjustment and water 
for injection. 
 
Sayana® Press is a white to off-white suspension for subcutaneous injection (an injection given 
under the skin). It is supplied in a single-dose container in the form of a pre-filled injector. Sayana® 
Press is available with a pack size of one single-dose container. 
 
5.2.3 Supply and accountability 
5.2.3.1 Supply  
Pfizer Manufacturing (Belgium) will oversee the manufacture of the injection and release the 
subcutaneous injection under Good Manufacturing Practices (GMP). Sayana® Press is supplied 
by Pfizer Limited (Ramsgate Road, Sandwich, Kent, CT13 9NJ, United Kingdom). 
 
5.2.3.2 Accountability 
The Wits RHI RC CRS Pharmacist is required to maintain a complete record of all study products 
received and subsequently dispensed. All study product dispensed to a participant must be 
documented by the clinic staff when dispensed. Any unused study products not returned must 
also be documented by the clinic. 
 
5.2.3.3 Study product dispensing  
Study injection is dispensed only to enrolled study participants or clinic staff on behalf of the 
participant, upon receipt of a written prescription from an authorized prescriber. An authorized 
prescriber includes the PI or a licensed clinician directly responsible to the PI as noted on the 
FDA Form 1572.  Dispensing takes place on the day of Visit 3 and at each scheduled follow-up 
visit. The pharmacist will dispense a single dose container every 12 weeks.  
 
During study product use, participants will receive a new injection every 12 weeks. Product will 
be dispensed in quantities sufficient to last until the next scheduled study visit. In the event that 


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additional study products between visits are needed, participants will be instructed to contact the 
study site. If the participant is unable to attend their next scheduled visit, it is up to the discretion 
of the PI/designee to allow the provision of additional study product for administration remotely 
off-site. The PI/designee will document approval of this additional dispensation 
 
5.3 
Intramuscular depomedroxyprogesterone acetate (IM DMPA) 
5.3.1 Administration 
For women choosing IM DMPA, site staff will inject the initial IM DMPA injection at Visit 3.  
Subsequent injections will be given every 12 weeks at the study site. Sites will assess participants 
who are more than 4 weeks late for their DMPA injections for pregnancy prior to administering a 
subsequent injection.  
 
 
5.3.2 Study product formulation 
Medroxyprogesterone acetate sterile aqueous suspension 150 mg per 1 ml. 
 
5.3.3 Supply and accountability 
5.3.3.1 Supply  
Pfizer Manufacturing (South Africa) will oversee the manufacture of the injection and release the 
intramuscular injection under Good Manufacturing Practices (GMP).  
 
5.3.3.2 Accountability 
The Wits RHI RC CRS Pharmacist is required to maintain a complete record of all study products 
received and subsequently dispensed. All study product dispensed to a participant must be 
documented by the clinic staff when dispensed. Any unused study products not returned must 
also be documented by the clinic. 
 
5.3.3.3 Study product dispensing  
Study injection is dispensed only to enrolled study participants or clinic staff on behalf of the 
participant, upon receipt of a written prescription from an authorized prescriber. An authorized 
prescriber includes the PI or a licensed clinician directly responsible to the PI as noted on the 
FDA Form 1572.  Dispensing takes place on the day of Visit 3. The pharmacist will dispense a 
single dose container.  
 
During study product use, participants will receive a new injection every 12 weeks. Product will 
be dispensed in quantities sufficient to last until the next scheduled study visit. In the event that 
additional study products between visits are needed, participants will be instructed to contact the 
study site. If the participant is unable to attend their next scheduled visit, it is at the discretion of 
the PI/designee to allow the provision of additional study product for administration remotely off-
site. The PI/designee will document approval of this additional dispensation.  
 
5.4 
ETG implant  
5.4.1 Administration 
For women choosing ETG implant, trained and proficient clinicians and nurses will insert the 
implant under the skin of her inner upper arm using standard manufacturer recommended 
techniques. Sites will observe women for 10 minutes after implant insertion and she will be shown 
how to palpate for the rod.  This will occur at Visit 3.  Subsequent insertion is not required as the 
implant is active for up to 3 years. She will be given a letter to note when it will need to be removed 
after the active date.  
 
5.4.2 Study product formulation 
68mg of ETG in a single ethylene vinyl acetate co-polymer rod. 
 
5.4.3 Supply and accountability 
5.4.3.1 Supply  


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Merck Sharp Dohme (South Africa) will oversee the manufacture of the implant and release the 
implant under Good Manufacturing Practices (GMP).  
 
5.4.3.2 Accountability 
The Wits RHI RC CRS Pharmacist is required to maintain a complete record of study products 
received and subsequently dispensed. Study product dispensed to a participant must be 
documented by the clinic staff when dispensed.  
 
 
 
5.4.3.3 Study product dispensing  
ETG implant will be dispensed only to enrolled study participants or clinic staff on behalf of the 
participant, upon receipt of a written prescription from an authorized prescriber. An authorized 
prescriber includes the PI or a licensed clinician directly responsible to the PI as noted on the 
FDA Form 1572.  Dispensing takes place on the day of Visit 3 defined in the EPIC study schedule.  
 
5.5 
Non-hormonal IUD 
5.5.1 Administration 
For women choosing a non-hormonal IUD, trained clinicians and nurses will insert the IUD using 
standard insertion techniques.  Study staff will observe women for 10 minutes after IUD insertion.  
This will occur at Visit 3.  Women will be provided a letter notifying the participant when it will need 
to be replaced for her records. The IUD will be active for up to 5 years. 
 
5.5.2 Study product formulation 
Non-hormonal intrauterine device (NOVA T 380) 
 
5.5.3 Supply and accountability 
5.5.3.1 Supply  
Bayer (Pty) Ltd will oversee the manufacture of the IUD and release the IUD under Good 
Manufacturing Practices (GMP). 
 
5.5.3.2 Accountability 
The Wits RHI RC CRS Pharmacist is required to maintain a complete record of study products 
received and subsequently dispensed. Study product dispensed to a participant must be 
documented by the clinic staff when dispensed.  
 
5.5.3.3 Study product dispensing  
The non-hormonal IUD will be dispensed only to enrolled study participants or clinic staff on behalf 
of the participant, upon receipt of a written prescription from an authorized prescriber. An 
authorized prescriber includes the PI or a licensed clinician on the study delegation log and as 
noted on the FDA Form 1572.  Dispensing takes place on the day of Visit 3.  
 
5.6  
Concomitant medications and practices 
Study staff will be provided with a comprehensive list of drugs known to have drug-drug 
interactions with the study-related medications. With the exception of those listed as prohibited in 
Table 3, enrolled participants may use concomitant medications during study participation. 
Throughout the course of the study, prescription medications, over-the-counter preparations, 
medications used to manage or treat AEs, vitamins and nutritional supplements, and herbal 
preparations will be recorded as concomitant medications on a case report form (CRF) 
designated for that purpose.  
Interactions with other medical treatments (including oral anticoagulants) have rarely been 
reported, but causality has not been determined. The possibility of interactions should be borne 
in mind in patients receiving concurrent treatment with other drugs. 
5.7 
Prohibited medications 


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The use of additional antiretrovirals are undesired for enrollment in this study.  However, 
ultimately, if the participant deems necessary to initiate other antiretrovirals, we may choose to 
terminate study participation in such cases. 
 
5.8 
Condoms 
All participants will be offered male and female condoms, which will be made available in the 
clinic and dispensed by clinic staff with the required levels of counselling and education related 
to correct use.  
6.0 
STUDY PROCEDURES 
6.1 
Overview of study procedures and evaluations 
Once participants are enrolled in the study, 6 weeks after the start of DOR-containing ART (to 
account for a “washout/lead-in”  period from the prior ART regimen), they will be ready to initiate 
their chosen contraceptive method, and study staff will call the participant in advance to remind 
them of this visit. The study team anticipates, based on national guidelines, that the majority of 
women screening and enrolling in this study will be on EFV-containing ART. Since EFV is a known 
potent inducer of CYP450 enzymes and known to influence PK parameters of both DOR and 
hormonal contraceptives, it would be necessary to have a “washout” period for the EFV induction 
to decrease markedly over the next 6 weeks.48 The 6-week washout period has been used 
previously for similar PK studies when transitioning persons off of EFV- to non-EFV containing 
ART.49,50  A second reason for the 6-week period without hormonal contraceptive use is to allow 
for a “lead-in” period so that those switching onto DOR-containing ART have some time to 
demonstrate tolerating the switch prior to starting the contraceptive method and regular PK 
sampling.  After the 6-week “washout/lead-in” period, options for contraceptive methods will be 
offered for administration by the study staff, including ETG implants, IM DMPA, SC MPA, or non-
hormonal IUD.  All participants will be offered male or female condoms.  For those participants 
wishing to have a non-hormonal IUD placed, this service will also be provided on-site.  Women 
will have a choice of which contraceptive method they want and will not be randomized or 
assigned to a contraceptive method by the study team. Once a group’s sample size of n=21 
women enroll in the study, that group will be closed for any future enrollment; if a participant 
withdraws or terminates earlier than the planned terminal study visit, then enrollment in that group 
may be re-opened to achieve the target sample size. 
 
Once enrolled, additional questionnaires and blood and urine samples will be taken at various 
time intervals for the various assessments (Table 5).   
 
Table 5: Schedule of evaluations (week numbers are post contraceptive method start) 
 
Protocol Activity 
Visit 1: 
Screen
ing 
Visit 2: 
Enrollment 
(start of lead-
in period) 
Visit 
3: 
Visit 
4: 
Visit 
5: 
Visit 
6: 
Visit 
7: 
Visit 
8: 
(impla
nt 
/IUD) 
Visit 
9: 
(impla
nt/ 
IUD) 
Weeks (w) since DOR 
initiation  
 
 
6w 
min.  
8w 
10w 
14w 
18w 
26w 
30w 
Weeks (w) since 
contraception initiation  
0w 
2w 
4w 
8w 
12w 
20w 
24w 
Informed Consent 
X 
 
 
 
 
 
 
 
 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study Registration 
 
X 
X 
 
 
 
 
 
 
Drug provision, when 
applicable  
 
X 
X 
 
X 
X 
X 
X 
 
Contraceptive 
Counselling 
X 
X 
X 
X 
X 
X 
X 
X 
X 


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Syndromic STI 
assessment and 
management 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Offering and provision of 
Hepatitis B vaccination if 
eligible 
 
X* 
 
 
 
 
 
 
 
Laboratory 
 
 
 
 
 
 
 
 
 
Complete Blood Count 
(CBC) 
X 
 
 
 
 
 
X 
 
X 
Comprehensive 
Metabolic Panel (CMP) 
X 
 
 
 
 
 
X 
 
X 
HBsAg 
X 
 
 
 
 
 
 
 
 
HBsAb 
X 
 
 
 
 
 
 
 
 
HB core Ab 
X 
 
 
 
 
 
 
 
 
Urine pregnancy test 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HIV-1 RNA quantification 
(if no confirmation in 
medical records within 
the preceding 3 months) 
X 
 
 
 
 
 
 
 
 
Assessment 
 
 
 
 
 
 
 
 
 
Review of concomitant 
medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HIV-1 RNA quantification 
 
 
 
 
 
 
X 
 
X 
Contraceptive hormonal 
PK assessment, via 
serum 
 
 
X 
X 
X 
X 
X 
X 
X 
ARV PK assessment, via 
plasma  
 
 
X 
X 
X 
X 
X 
X 
X 
Contraceptive & ART 
questionnaires (side 
effects and tolerability) 
X 
 
X** 
X 
X 
X 
X 
X 
X 
Qualitative interviews, 
including social 
harms/benefits 
 
 
X 
 
 
 
X 
 
X 
*Offering and provision of Hepatitis B vaccination, if eligible, can be offered and provided at any 
subsequent study visit if participant declines for any reason at enrollment visit 
**Visit 3 for Groups 1-4 only ART Questionnaire is completed, and for Group 5, both Contraceptive 
& ART questionnaires must be completed. 
 
Women in the D/MPA groups will be followed for 12 weeks total after D/MPA administration.  
Women in the implant or IUD group will be followed for 24 weeks total after implant or IUD 
placement.  Implant or IUD removals will be conducted by study staff upon request by the women, 
during the study.  After the study ends, participants will be referred to local facilities for the implant 
or IUD removal and provided with detailed letters projecting out dates of viability of the methods 
concerned.   
 
The study team will also enroll a DTG + DMPA group who will be followed for 12 weeks, as the 
comparator group for the DOR + DMPA group.  The comparator groups for the DOR + implant 
group will be to the historical control group from PARVI study currently being conducted by Dr. 
Patel and colleagues in Kenya (Figure 3). 
 


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July2022 
 
 
Figure 3: Schematics of PARVI study design, groups, and sample collection 
 
 
6.2 
Assays 
Blood hormone concentrations: At each visit after study enrollment, 15-20 mL of whole blood 
will be collected in vacutainers containing ethylenediaminetetraacetic acid (EDTA) anticoagulant 
and/or in serum-separating tubes (SST) and processed within 30 minutes of collection, 
centrifuged at 3000 revolutions per minute for 10 minutes to separate plasma when needed, 
stored at -800C.  Selected  samples will be shipped frozen to University of Washington’s (UW) 
International Clinical Research Center’s (ICRC) repository for storage until ready for subsequent 
analysis, for the types of analyses where the assays or analytics are currently unavailable in-
country and, therefore, cannot be conducted in South Africa, while other samples will be shipped 
frozen to local research laboratories for future analyses including for pharmacogenomics 
analysis, where the assays are currently available in South Africa.  Specifically, serum samples 
for contraceptive hormone concentrations will be analyzed by Dr. David Erikson’s laboratory at 
the Oregon Health and Sciences University in the USA which specializes in detection of 
exogenous and endogenous hormones, including implant hormones, which is currently only 
available in a handful of laboratories around the world.  Dr. Erikson’s laboratory has validated the 
use of liquid chromatography-heated electrospray ionization-tandem triple quadrupole mass 
spectrometry (LC-MS/MS) with the lower limit of quantification to 10 pg/mL for ETG. 
 
Plasma ARV concentrations: At every visit with blood collection, we will also measure plasma 
trough ARV concentrations to detect any negative effects of the hormonal contraceptives on the 
concentrations of these ARVs. Dr. Scarsi’s laboratory, the Antiviral Pharmacology Laboratory 
(APL) in the Center for Drug Discovery at the University of Nebraska Medical Center, will conduct 
this analysis. The APL is a CLIA-certified lab affiliated with the AIDS Clinical Trials Group.  The 
195 women recruited 
• Ages 18-45 years
• ENG/LNG initiation 0-2 weeks prior to study enrollment
• Plans to use implant for next 6 months
• On current ART regimen for ≥ 30 days (HIV-positive)
• Viral suppression (HIV-positive)
47 efavirenz 
600mg
50 efavirenz 
400mg
49 dolutegravir
50mg
49 HIV-negative
24 ENG 
implant
23 LNG 
implant
25 ENG 
implant
25 LNG 
implant
23 ENG 
implant
26 LNG 
implant
25 ENG 
implant
24 LNG 
implant
Study Visit 
Week
0
2
4
8
12
16
20
24
21 22 23
Whole blood: Pharmacogenetics
Plasma: Antiretroviral and contraceptive 
hormone concentrations
Serum: Contraceptive concentrations
Hair: Antiretroviral concentrations
Implant 
insertion
Blood
Hair


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plasma samples will be analyzed using validated LC-MS/MS techniques.  The LLQ in plasma for 
DOR is 5 ng/mL. The study investigators remain open to considering alternative, including local 
commercial, laboratories for analysis of ARV concentrations.   
 
6.3  
Contraceptive method related counselling  
General contraceptive, and specifically method related adherence counselling is complex, 
however the site’s study team has gained invaluable expertise on contraceptive counselling and 
contraceptive method delivery due to the teams participation in the ECHO trial38.  This study 
included use of short, intermediate- and long-acting reversible contraceptive methods, including 
IM DMPA, the non-hormonal IUD and an LNG implant. The team is proficient in insertion and 
management of the ETG study through other prior and ongoing studies as well. The skills and 
lessons learned from the ECHO trial will be leveraged for use in the EPIC Study to guide 
participants to make informed choices related to their contraceptive method and to continue with 
contraceptive use beyond the life of the trial if they so choose. This counselling will support each 
method choice without bias.  
 
Contraceptive counselling in the research clinic setting will include participants receiving 
comprehensive counselling on all contraceptive methods available in the study to enable them to 
make their own choice.  As a research-focused clinic, the team encounters fewer limitations, such 
as high client volumes, as compared to public sector clinics, resulting in extra time and effort 
invested in the counselling process to ensure participants are well informed of the options 
available.  The study team will adhere to, and when possible bolster, the content outlined in the 
National Family Planning guidelines in this research focused clinic.  The site meets all the logistic, 
training and operational requirements related to being able to offer and manage insertion and 
support for use of the range of contraceptive methods.  The nurses and PIs at the site have had 
extensive experience with contraceptive counselling and provision from former and ongoing 
studies.   
 
At Screening and Enrolment visits, clinical staff will provide contraception counselling to potential 
study participants in the context of the study eligibility criteria related to pregnancy intentions and 
willingness to use an effective contraceptive method. All contraception counseling will be provided 
by the contraception staff in a client-centered manner and will guide and support each participant 
in making the best contraceptive method choice for her and in maintaining adherence to an 
effective method for the duration of the study at a minimum. When providing information on 
various contraceptive methods to study participants, the following will be provided for each 
method:  
• Standard information in terms of: 
o administration 
o mechanism of action  
o level of effectiveness  
• Information on the potential advantages and disadvantages  
  
Contraception staff may use images from the World Health Organizations Family Planning: 
Guidance Global Handbook for Healthcare Providers to guide the discussions on the different 
contraceptive methods.51 
 
At follow-up visits, participants will be provided with contraceptive method adherence counselling 
and side effects/AE management to maximize continuation on the chosen contraceptive method. 
This will be conducted in a client-centered manner by study staff. Issues discussed at the previous 
counselling session will be reviewed and discussed with the participant as needed. The clinic staff 
will assess whether the participant has any current concerns, questions, problems, or concerns 
with her current contraceptive method that would lead to non-adherence or intention to 
discontinue the method while on the study.  
 


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For participants with no concerns or problems, counselling sessions during follow-up may be brief 
and supportive. These sessions will also provide clear method use instructions and always 
reinforce key adherence messages. 
 
For participants with concerns or problems with their current method, counselling sessions during 
follow-up may require more time. In some cases, only counselling and reassurance may be 
required to address the issues or problems. These sessions will also include discussion of the 
specific problems encountered and identification of potential strategies to address these issues. 
Some participants may experience side effects associated with use of contraception for e.g., 
prolonged bleeding, for which participants will be managed and treatment issued by the study 
clinical team. For care or issues related to contraception that falls outside the scope of the study 
clinic, referrals will be provided to the local health tertiary care providers within the study 
catchment area. 
 
6.4  
General study visits  
Generally, at all study visits, components and procedures pertinent to: 1) administrative and 
regulatory; 
2) 
behavioral/counseling; 
3) 
clinical, 
4) 
laboratory, 
and 
5) 
study 
products/administration will be performed (more below per visit schedule). Follow-up visits will 
occur as per schedule with approximately 7 days before target date and approximately 7 days 
after target date. 
A Screening Visit may take place up to 30 days prior to the Enrolment Visit. Multiple visits may 
be conducted to complete all required screening procedures, if necessary. Written informed 
consent will be obtained for all participants legally able to provide consent. For participants who 
do not meet the eligibility criteria, screening will be discontinued once ineligibility is determined 
and referrals provided to appropriate care.  
NOTE: Participants who fail their first screening attempt may be re-screened at the discretion of 
the PI/Designee. 
Visit 1 – Screening visit 
Component 
Procedures 
Administrative and Regulatory 
• Obtain informed consent for screening and enrolment 
• Assign a unique Participant Identification (PTID) 
Number 
• Assess eligibility 
• Demographic information 
• Collect locator information 
• Provide reimbursement 
• Schedule next visit/contact 
Behavioural/Counselling  
• HIV ART counselling 
• Contraceptive counselling 
• Contraceptive & ART questionnaires (side effects and 
tolerability) 
Clinical 
• Medical/menstrual history 
• Concomitant medications 
• Physical exam 
• Vital signs 
• Disclosure of available test results 
Laboratory – Urine  
• Human chorionic gonadotropin (hCG) 
Laboratory – Blood 
• HIV-1 RNA quantification 


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• Complete Blood Count (CBC) 
• Hepatitis B surface Antigen (HBsAg) 
• Hepatitis B surface Antibody (HBsAb) 
• Hepatitis B core Antibody (HBcAb) 
• Comprehensive 
Metabolic 
Panel 
(CMP), 
which 
includes creatinine clearance and hepatic function 
Study Product/Supplies 
• Offer male condoms 
• Offer Hepatitis B vaccination, if applicable 
 
Visit 2 – Enrolment visit/ Visit 3* 
Component 
Procedures 
Administrative and Regulatory 
• Re-assess and confirm eligibility 
• Review and update locator information 
• Provide reimbursement 
• Schedule next visit/contact 
Behavioural/Counselling  
• ART/Contraceptive counselling 
Clinical 
• Review/update medical/menstrual history 
• Review/update concomitant medications 
• Physical exam** 
• Vital signs 
• Disclosure of available test results 
• Collect AEs 
Laboratory – Urine  
• Human chorionic gonadotropin (hCG) 
Study Product/Supplies 
• Provision of contraception, if applicable 
• Provision of ART, if applicable 
• Provision of product use instructions 
• Offer male condoms 
* Enrolment and Visit 3 will occur as 1 visit for participants in Group 5 
**If applicable 
 
Visit 3-6: Week 0/2/4/8 
Component 
Procedures 
Administrative and Regulatory 
• Review and update locator information 
• Provide reimbursement 
• Schedule next visit/contact 
Behavioural/Counselling  
• ART/Contraceptive counselling 
• Adherence Assessment 
• Contraceptive & ART questionnaires (side effects and 
tolerability) 
Clinical 
• Review/update medical/menstrual history 
• Review/update concomitant medications 
• Initiation of chosen contraceptive method (Week 0 only) 
• Physical exam** 
• Vital signs 
• Disclosure of available test results 
• Collect AEs 
Laboratory – Urine  
• Human chorionic gonadotropin (hCG) 
Laboratory – Blood 
• Contraceptive hormonal PK assessment, via serum 


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• ARV PK assessment, via plasma 
Study Product/Supplies 
• Provision of study products* 
• Provision of product use instructions* 
• Offer male condoms 
**If applicable 
 
Visit 7: Week 12 
Component 
Procedures 
Administrative and Regulatory 
• Review and update locator information 
• Provide reimbursement 
• Schedule next visit/contact 
Behavioural/Counselling  
• ART/Contraceptive counselling 
• Adherence Assessment 
• Contraceptive & ART questionnaires (side effects and 
tolerability) 
• Qualitative interviews, including social harms/social 
benefit assessment^ 
Clinical 
• Review/update medical/menstrual history 
• Review/update concomitant medications 
• Physical exam** 
• Vital signs 
• Disclosure of available test results 
• Collect AEs 
Laboratory – Urine  
• Human chorionic gonadotropin (hCG) 
Laboratory – Blood 
• Contraceptive hormonal PK assessment, via serum 
• ARV PK assessment, via plasma 
• Complete Blood Count (CBC)^ 
• Comprehensive Metabolic Panel (CMP)^ 
• HIV-1 RNA quantification^ 
Study Product/Supplies 
• Provision of study products* 
• Provision of product use instructions* 
• Offer male condoms 
• Re-initiation of ART regimen as per NDoH guidelines^ 
• Linkage to care referral to local clinic for ART and 
contraceptive continuation^ 
^ DMPA groups only 
** if applicable 
 
Visit 7/8: Weeks 20 (Implant/IUD users only) 
Component 
Procedures 
Administrative and Regulatory 
• Review and update locator information 
• Provide reimbursement 
• Schedule next visit/contact 
Behavioural/Counselling  
• ART/Contraceptive counselling 
• Adherence Assessment 
• Contraceptive & ART questionnaires (side effects and 
tolerability) 
Clinical 
• Review/update medical/menstrual history 
• Review/update concomitant medications 
• Physical exam** 
• Vital signs 


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• Disclosure of available test results 
• Collect AEs 
Laboratory – Urine  
• Human chorionic gonadotropin (hCG) 
Laboratory – Blood 
• Contraceptive hormonal PK assessment, via serum 
• ARV PK assessment, via plasma 
Study Product/Supplies 
• Provision of study products* 
• Provision of product use instructions* 
• Offer male condoms 
** if applicable 
 
Visit 9: Week 24 (Implant/IUD users only) 
Component 
Procedures 
Administrative and Regulatory 
• Review and update locator information 
• Provide reimbursement 
• Schedule next visit/contact 
Behavioural/Counselling  
• ART/Contraceptive counselling 
• Adherence Assessment 
• Contraceptive & ART questionnaires (side effects and 
tolerability) 
• Qualitative interviews, including social harms/benefit 
assessment 
Clinical 
• Review/update medical/menstrual history 
• Review/update concomitant medications 
• Physical exam** 
• Vital signs 
• Disclosure of available test results 
• Collect AEs 
Laboratory – Urine  
• Human chorionic gonadotropin (hCG) 
Laboratory – Blood 
• Contraceptive hormonal PK assessment, via serum 
• ARV PK assessment, via plasma 
• Complete Blood Count (CBC) 
• Comprehensive Metabolic Panel (CMP) 
• HIV-1 RNA quantification 
Study Product/Supplies 
• Offer male condoms 
• Re-initiation of ART regimen as per SA National 
Department of Health (NDoH) guidelines. 
• Linkage to care referral to local clinic for ART and 
contraceptive continuation 
** if applicable 
 
6.5  
Interim/unscheduled visits 
Interim visits may be conducted at any time during the study, for reasons such as administrative 
reasons (e.g., participant may have to re-schedule missed procedures), for product-related 
reasons, including to provide participants with a replacement tablets, or contraceptive,  
at participant request, or follow-up and management of any SAEs.  Such interim visits will be 
documented accordingly in the study records for the participant. 
 
6.6  
Product use end visit or early termination visit 
Participants will undergo the Week 12 or Week 24 procedures at the Product Use End/Early 
Termination Visit.   
 


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6.7  
Follow-up procedures for participants who temporarily hold or permanently 
discontinue study product  
Due to the fundamental nature of the PK study, if a participant temporarily holds or permanently 
discontinues the study products, including the contraceptive method, then she will undergo study 
termination.  For all early terminations or withdrawals, the study team aim to replace the enrolment 
slot for the participant to enable reaching the desired sample size numbers through to the end of 
the follow-up period. 
 
6.7.1  Participants who become pregnant  
During the 6-week lead in period on DOR, it is essential that the participant reduce risk of 
pregnancy as DOR safety during pregnancy is unestablished. Participant will be counselled to 
present to the study site immediately for pregnancy testing if they have concerned related to an 
unplanned incident pregnancy.  
 
If any participants become pregnant during the study follow-up, she will be counselled on her 
options and provided appropriate referrals for antenatal and other care. Pregnant participants will 
immediately be discontinued from DOR and terminated from the study.  Any unused study 
products not returned at that visit will be retrieved. She will be referred to relevant healthcare 
providers to be switched to her prior ART regimen or another updated regimen which is the current 
standard of care for pregnant WLHIV per SA NDoH guidelines.  Study staff will follow up with 
exited pregnant participants regarding ART re-initiation and pregnancy outcomes.  Where 
possible, the site will contact participants and collect infant outcomes 1 month postpartum, based 
on the estimated delivery date.  
 
Upon documentation of a positive pregnancy test, the following procedures must be performed 
regardless of whether or not they are scheduled to be completed:  
• CBC with platelets  
• Blood creatinine for creatinine clearance  
• Collection of PK and biomarker specimens  
• Behavioral, adherence, and product preference/acceptability assessments  
 
Given the overall short period of follow-up for this PK study, the study investigators do not plan to 
re-enroll a women post-partum into the study again if she wishes to, for example, initiate a 
contraceptive method of interest in the study.  
 
6.7.2  Withdrawal 
Participants may voluntarily withdraw from the study at their discretion for any reason at any time 
during follow-up. The PI also may withdraw participants from the study to protect their safety 
and/or if they are unwilling or unable to comply with required study procedures. The Senior Clinical 
Advisor must be notified of all terminations conducted per PI discretion. Participants also may be 
withdrawn if the sponsors, government or regulatory authorities, or site IRBs/ECs terminate the 
study prior to its planned end date. Every reasonable effort will be made to complete a final 
evaluation of participants who withdraw or are withdrawn from the study prior to completing follow-
up. Study staff members will record the reason(s) for all withdrawals in participants’ study records. 
In the event that participants who voluntarily withdraw from the study wish to re-join the study, 
they may resume product use (if applicable) and follow-up through their originally scheduled study 
exit date, pending consultation with the Senior Clinical Advisor. 
 
6.7.3  Study end 
At the end of study follow-up or termination, participants will be switched from DOR-containing 
ART to either their prior ART regimen or another regimen if a more updated recommendation 
exists as delineated by the SA NDOH standard-of-care.  Such transitions will be coordinated with 
the existing HIV providers and clinics. 
 
6.8  
Specimen management 


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Blood and urine samples will be collected from the participants per the schedule outlined in Table 
5. The study team anticipate collecting up to 15-20 mL or approximately 2 tablespoons of whole 
blood, in order to process the samples for real-time laboratory testing, such as HIV-1 RNA 
quantification, and for storage for the required PK studies.  Samples will be centrifuged at 3000 
revolutions per minute (RPM) for 10 minutes to separate plasma.  Plasma or serum aliquots will 
be stored at -800 C on-site at Wits RHI RC CRS  All samples for hormone and ARV concentration 
analyses will later be shipped frozen in batches to UW ICRC’s repository for storage, from which 
it will then be sent to appropriate laboratories for subsequent analysis.  Such shipment of samples 
from South Africa to the USA are necessary, as detailed above, due to currently unavailable 
laboratory assays or analytics in-country for certain analyses.   
 
6.9  
Biohazards containment 
As the transmission of HIV and other blood-borne pathogens can occur through contact with 
contaminated needles, blood, and blood products, appropriate infectious disease, blood and 
physiological samples management procedures will be implemented. Safety precautions will be 
employed by all personnel in the drawing of blood and shipping and handling of all specimens for 
this study as recommended by the U.S. CDC, International Air Transport Association (IATA) and 
NIH guidelines.  All biological specimens will be transported using packaging mandated by US 
Code of Federal Regulations (CFR) 42 Part 72.  All dangerous goods materials, including 
diagnostic specimens and infectious substances, must be transported according to instructions 
detailed in the IATA Dangerous Goods Regulations.  Biohazard waste will be contained according 
to institutional, transportation/carrier, and all other applicable regulations and destroyed 
appropriately. 
 
6.10  Qualitative interviews 
The study team will apply qualitative research methodology to conduct in-depth interviews (IDIs) 
with a subset of participants enrolled in the EPIC study at Visit 3 and study exit.  The study team 
plans to enroll ~ 4-5 women from Groups 1-4 (total n=16-20 women) to better understand: 1) their 
experiences in switching from their current ART regimen to one containing DOR  2) their 
experiences with their contraceptive method of choice, and understand user experiences 
between IM DMPA vs. SC MPA, including potential use of self-injectable Sayana Press®.   
 
Figure 4: Domains of the socio-ecological model 
 
 
 
Table 6. Domains and example preliminary questions to query in IDIs with WLHIV 
enrolled 
Domains 
Sample questions 
Individual  
 
How do you feel about your experiences with ART /contraceptive method to 
date? 
Interpersonal  
 
How has your partner, family, your circle of friends, or others influenced 
your use of ART/contraceptive method and your adherence to it? 
Community 
What do you think would be helpful to have in your community to support 
your and other young women’s use of ART/contraceptive methods? Who 
do you think could be most helpful for this? 


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Organizational  
 
What influence does your school, work, or clinic have on your use of your 
use of ART/contraceptive method?  If it’s a positive influence, how could 
this be amplified? If the influence is negative, how could this be reduced? 
Public policy 
How do you think the SA government could incorporate ways to support 
young women with their assessment of DOR for HIV treatment? 
 
Using the socioecological model (Figure 4),52  the team aims to explore influences, from 
individual, interpersonal, clinic, to structural/societal level, on both ART and contraceptive  method 
use.  Specifically, the interview guide covers the following domains: 1) knowledge and health 
literacy around ARVs, 2) priorities for and experiences in switches of ARVs, and 3) contraceptive 
use, decision-making, and experiences within study, including for SC MPA.  An initial interview 
guide is included in Appendix 1, which will be iteratively modified as needed once the team 
begins piloting and conducting interviews.  The IDIs will be conducted by trained, local 
interviewers in English or Zulu, digitally audio-recorded, and transcribed and translated into 
English.  Another bilingual member of the study staff will verify accuracy of the translations against 
the audio files.  The interviews will last for 30-60 minutes, and will be conducted serially, twice 
with the first time being at study enrollment and a second time at study exit (either visit Week 12 
or Week 24 depending on contraceptive method type/group).  Ultimately, the total number of 
interviews will be guided by saturation of themes. 
 
 
 
7.0  
CLINICAL DATA SAFETY REVIEW 
 
7.1  
Internal advisory committee 
The study investigators have established an internal advisory committee to periodically review 
data on study implementation, including metrics on participant safety. The committee includes 
experts working in the fields of ART implementation and contraceptive use, including the lead 
investigators and 2 independent individuals/researchers from South Africa and the United States. 
The committee will meet quarterly via Skype/Zoom with the study investigators and will be 
governed by a charter that is agreed on by all members. Advisory committee members will be 
required to provide suggestions about the conduct of research and its implications for health 
policy in South Africa.  Reports from all reviews and advisory committee recommendations will 
be provided for submission to overseeing IRBs/ECs. 
 
A multi-tiered safety review process will be followed for the duration of this study.  The study site 
investigators are the first category of this tiered system and are responsible for the initial 
evaluation and reporting of safety information at the participant level, and for alerting the Senior 
Clinical Advisor/Lead Investigator if unexpected concerns arise.   
 
During the trial, the Senior Clinical Advisor/Lead Investigator will review safety reports and 
conduct calls with the local study team to review the data as appropriate.  
 
The internal advisory committee has study oversight and is required to review participant safety 
data as no DSMB is planned for this study.   
 
7.2  
Adverse events definitions and reporting requirements 
7.2.1    Adverse events (AE) 
An AE is defined as any untoward medical occurrence in a clinical research participant 
administered an investigational product and which does not necessarily have a causal 
relationship with the investigational product.  As such, an AE may be an unfavorable or 
unintended sign (including an abnormal laboratory finding, for example), symptom or disease 
temporally associated with the use of an investigational product, whether or not considered 
related to the product.  This definition is applied to all study groups and is applied beginning at 


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the time of enrollment. The term “investigational products” for this study refers to use of DOR and 
DDIs with hormone contraception use. 
 
Study participants will be provided instructions for contacting the study site to report any untoward 
medical occurrences they may experience.  In cases of potentially life-threatening events, 
participants will be instructed to seek immediate emergency care.  Where feasible and deemed 
medically appropriate, participants will be encouraged to seek evaluation at their local hospital. 
With appropriate permission of the participant, whenever possible, records from all non-study 
medical providers related to untoward medical occurrences will be obtained and required data 
elements will be recorded on study CRFs.  All participants reporting an untoward medical 
occurrence will be followed clinically until the occurrence resolves (returns to baseline) or 
stabilizes while enrolled in the study. Post-exit, appropriate referrals will be provided at the 
discretion of the study clinician for ongoing care.  
 
Study site staff will document all AEs reported by or observed in enrolled study participants in 
source documents regardless of severity and presumed relationship to study product.   
 
Study staff will also report on CRFs the following subset of AEs reported by or observed in enrolled 
participants: 
• All genital, genitourinary, and reproductive system AEs, including STIs 
• All AEs of severity Grade 2 or higher  
• All Serious AEs  
• All AEs that result in permanent discontinuation of study product use 
• All lab test abnormalities specified in the DAIDS Table for Grading the Severity of Adult and 
Pediatric Adverse Events, corrected Version 2.1, July 2017 and Addendum 1, (Female Genital 
Grading Table for Use in Microbicide Studies, dated November 2007), that are not otherwise 
associated with a reported clinical AE 
• AEs that do not meet the above-listed criteria but do meet expedited reporting requirements 
per Section 7.4 below; this includes all congenital anomalies identified in the fetuses and/or 
infants of study participants 
 
AE severity and laboratory tests will be graded per the DAIDS Table for Grading the Severity of 
Adult and Pediatric Adverse Events, Version 2.0, July 2017 and Addendum 1, (Female Genital 
Grading Table for Use in Microbicide Studies; dated November 2007), except that asymptomatic 
BV and asymptomatic candidiasis will not be reportable AEs.  In cases where a genital AE is 
covered in both tables, the Female Genital Grading Table will be the grading scale utilized.  In 
addition, changes in genital bleeding or irregular bleeding judged to be related to contraceptive 
use (hormonal or non-hormonal) will considered an AE unless it is known at baseline as a pre-
existing condition. For those AEs requiring re-assessment, if the AE has not resolved or stabilized 
at the time of re-assessment, study staff will continue to re-assess the participant at least once 
per month while the study is ongoing or at the discretion of the PI/designee.   
 
For any serious AEs (SAEs) or SUSAR (Suspected unexpected serious adverse event) that are 
continuing at a participant’s study exit visit, the PI/designee must establish a clinically appropriate 
follow-up plan for the AE.  At a minimum, the SAE/SUSAR must be re-assessed by study staff 30 
days after the participant’s study exit visit; additional evaluations also may take place at the 
discretion of the PI/designee.  The same approach must be taken for any AEs that are found to 
have increased in severity at the study exit visit.  After the study has ended, all AEs requiring re-
assessment will be re-assessed at the discretion of the PI/designee.  The Senior Clinical Advisor 
may advise study staff as to whether any additional follow-up may be indicated on a case by case 
basis.  For AEs that are re-assessed after study exit for any reason, information on the status of 
the AE at the time of re-assessment will be recorded in source documents only — no updates 
should be made to AE Log CRFs based on the re-assessments.  
 
7.2.2  Serious adverse events  
SAEs will be recorded on the RedCap database and defined as AEs occurring at any dose/group 
that:  


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• Results in death 
• Grade 3 or higher AEs 
• AEs resulting in DOR discontinuation 
• Is life-threatening  
• Requires inpatient hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability/incapacity  
• Is a congenital anomaly/birth defect 
• Is an important medical event that may not result in death, be immediately life-threatening, or 
require hospitalization but may jeopardize the participant or require intervention to prevent one 
of the outcomes listed in the definition above. 
 
7.2.3  Adverse event relationship to study product 
Relatedness is an assessment made by a study clinician of whether or not the event is related to 
the study agent.  Degrees of relatedness will be categorized according to current DAIDS-
approved guidelines.  The relationship categories that will be used for this study are: 
• Related: There is a reasonable possibility that the AE may be related to the study agent 
• Not Related: There is not a reasonable possibility that the AE is related to the study agent 
 
7.3  
Adverse event reporting  
For each study participant, AE reporting will be conducted throughout the scheduled duration of 
follow-up, i.e., from the time of Enrollment through study exit or termination.  All AEs must be 
reported on the Study AE Tracking Log.   
 
The following AEs must be reported on the Study AE CRF form within REDCap:   
• All potentially DOR related AEs  
• All AEs of severity grade 3 or higher  
• All SAEs  
• All AEs that result in permanent discontinuation of DOR use 
 
All SAEs must be reported on the Study SAE CRF form within REDCap. 
 
 
7.3.1  Grading severity of events 
The grading of severity of events and the reporting period will be the same as for all AEs.  The 
most current DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, 
Version 2.1, July 2017 and the Female Genital Grading Table for Use in Microbicide Studies 
(Addendum 1, dated November 2007), will be used.  
 
7.4  
SUSAR reporting period 
The SUSAR reporting period for this study begins once the participant is enrolled and continues 
up through the participant’s final study visit (Visit 7 or 9, depending on the Group).  After the 
protocol-defined AE reporting period, unless otherwise noted, only suspected, unexpected 
serious adverse reactions (SUSARs) will be reported  if the study staff become aware of the 
events on a passive basis (from publicly available information). 
 
7.5  Social harms reporting 
Although study sites will make every effort to protect participant privacy and confidentiality, it is 
possible that participants’ involvement in the study could become known to others and that social 
harms may result.  For example, participants could be treated unfairly, or could have problems 
being accepted by their families, partners and/or communities.  Social harms that are judged by 
the PI/designee to be serious or unexpected will be reported to the Senior Clinical Advisor and 
responsible site IRBs/ECs according to their individual requirements.  In the event that a 
participant reports social harm, every effort will be made by study staff to provide appropriate care 
and counseling to the participant, and/or referral to appropriate resources for the safety of the 
participant as needed.  While maintaining participant confidentiality, study sites may engage their 
community advisory boards (CABs) in exploring the social context surrounding instances of social 
harm. All SHs must be reported on the Study SH CRF. 


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7.6  
Regulatory requirements 
Information on all reported CRFs will be included in reports to SAHPRA and other applicable 
government and regulatory authorities.  Site Co-PI designees will submit AE information in 
accordance with local regulatory agencies’ or other local authorities’ requirements.  Site PIs 
designees also will submit AE information and any other relevant safety information to their 
IRBs/ECs in accordance with IRB/ECs requirements. 
 
8.0  
CLINICAL MANAGEMENT 
Guidelines for clinical management and temporary product hold/permanent discontinuation of 
study product are outlined in this section.  In general, the PI/designee has the discretion to hold 
study product temporarily at any time if s/he feels that continued product use would be harmful to 
the participant or interfere with treatment deemed clinically necessary.  Unless otherwise 
specified below, the PI/designee should immediately consult the Senior Clinical Advisor for further 
guidance on resuming study product, continuing the hold temporarily, or progressing to 
permanent discontinuation of study product.  The PI/designee will document all temporary product 
holds and permanent discontinuations on applicable CRFs.  
 
8.1  Grading system 
The DAIDS AE severity grading is described in the Adverse Events Section. 
 
8.2  Dose modification instructions 
No dose modifications will be undertaken in this study. 
 
8.3  General criteria for temporary/permanent discontinuation of study product 
Participants will be permanently discontinued from study product (containing 100mg DOR) use 
by the PI/designee for any of the following reasons: 
• Allergic reaction to the study product* 
• Non-therapeutic injection drug use 
*In the event of an allergic reaction (Grade 3 or above), participants will be permanently 
discontinued from study product use. 
 
A participant will be permanently discontinued from study product for any of the following reasons: 
• Pregnancy  
• Breastfeeding.   
• Participant is unable or unwilling to comply with required study procedures, or otherwise might 
be put at undue risk to their safety and well-being by continuing product use, according to the 
judgment of the PI/designee.  The PI/designee must consult the Senior Clinical Advisor on all 
temporary product holds instituted for this reason for further guidance on resuming product 
use, continuing the temporary hold, or progressing to permanent discontinuation.  If product 
use is temporarily held/permanently discontinued for this reason, but the underlying reason for 
the temporary hold later resolves, the PI/designee should consult the Senior Clinical Advisor 
to resume product use at that time.   
 
8.3.1  Temporary product hold/permanent discontinuation in response to observed 
adverse events 
 
Grade 1 or 2 
In general, a participant who develops a Grade 1 or 2 AE not specifically addressed below, 
regardless of relatedness to study product, may continue product use.   
 
Grade 3 
Participants who develop a Grade 3 AE that is not specifically addressed below and is judged by 
the PI/designee to be not related to study product may continue product use.   
In general, for participants who develop a Grade 3 AE not specifically addressed below, judged by 
the PI/designee to be related to study product, and unless otherwise decided in consultation with 
the Senior Clinical Advisor, the PI/designee should: 


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• Temporarily hold the study product. 
• Re-evaluate the participant at least weekly for up to 2 weeks. 
• Resume study product if improvement to ≤ Grade 2 is documented within 2 weeks. 
• Consult the Senior Clinical Advisor regarding further study product management if 
improvement to severity ≤ Grade 2 cannot be documented within 2 weeks.   
 
If product use is resumed and the same Grade 3 AE deemed related to study product recurs at 
any time, the PI/designee must temporarily hold study product and consult the Senior Clinical 
Advisor within 24 hours of awareness for further guidance on continuing the temporary hold or 
progressing to permanent discontinuation of the study product. 
 
Grade 4 
Participants who develop a Grade 4 AE (regardless of relationship to study product) should have 
the study product held.  The PI/designee must consult the Senior Clinical Advisor and continue the 
temporary product hold until a recommendation is obtained from the Senior Clinical Advisor.   
 
8.3.2  Other clinical findings 
If the creatinine clearance is <50mL/min, study product should be held, the Senior Clinical Advisor 
notified, and the test repeated within one week.  If a level of <50mL/min is confirmed, study 
product will be permanently discontinued.  If either retesting cannot occur within one week or if 
retesting yields a result of ≥50 mL/min, the PI/designee must consult the Senior Clinical Advisor 
for further guidance on resuming product use. 
 
8.4  
Pregnancy 
Pregnancy testing will be performed at designated study visits and participants will be encouraged 
to report all signs or symptoms of pregnancy to study staff. The PI/designee will counsel any 
participant who tests positive for pregnancy regarding possible risks to the fetus according to site 
SOPs. The PI/designee also will refer the participant to all applicable services; however, sites will 
not be responsible for paying for pregnancy-related care.  
 
A participant who tests positive for pregnancy during the course of the study will have study 
product(s) discontinued and will be withdrawn from the study due to the unestablished safety of 
DOR during pregnancy. A participant who is pregnant at study termination will continue to be 
followed until the pregnancy outcome is ascertained (or if in consultation with the Senior Clinical 
Advisor it is determined that the pregnancy outcome cannot be ascertained). Pregnancy and 
infant outcomes will be reported on relevant CRFs, and outcomes meeting criteria for SUSAR 
reporting also will be reported on SUSAR forms. The study site will make every reasonable effort 
to contact participants and collect infant outcomes up to one year after delivery for those 
pregnancies that result in live birth. 
 
8.5  
Criteria for early termination of study participation 
Participants may voluntarily withdraw from the study for any reason at any time. The PI also may 
withdraw participants from the study to protect their safety and/or if they are unwilling or unable 
to comply with required study procedures. The Senior Clinical Advisor will be notified of all 
terminations conducted per PI discretion. Participants also may be withdrawn if the sponsors, 
government or regulatory authorities, or site IRBs/ECs terminate the study prior to its planned 
end date. Every reasonable effort will be made to complete a final evaluation of participants who 
withdraw or are withdrawn from the study prior to completing follow-up. Study staff members will 
record the reason(s) for all withdrawals in participants’ study records.  
 
9.0  
STATISTICAL CONSIDERATIONS 
 
9.1  
Analytic groups 
For primary PK objectives, mean implant hormone concentrations will be analyzed at 24 or 12 
weeks (+/- 2 weeks) after implant insertion or IM DMPA/SC MPA administration, respectively.  
The comparisons will be between DOR + ETG implant (Group 1) and DTG + ETG implant groups 
(the latter is from a historical control from one of Dr. Patel’s currently ongoing study in a similar 


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population in Kenya; Table 2).  A secondary analysis will make comparisons between DOR + 
ETG implant and no ART + ETG implant/HIV-negative groups (again, the latter is from a historical 
control group from one of Dr. Patel’s currently ongoing study in Kenya). The mean MPA 
concentrations for DOR + D/MPA at 12 weeks (+/- 2 weeks) after D/MPA injection (Groups 2 and 
3) will be compared to the mean MPA concentrations for DTG + DMPA group (contemporaneous 
study Group 5). 
 
For primary PK objectives, the mean C24 hours of DOR in the ETG implant and D/MPA groups will 
be compared to no hormonal contraceptive method group (Group 4). 
 
For the secondary objective, the proportion of women suppressed (defined as HIV viral load 
<40 copies/mL) at 24 weeks (+/- 2 weeks) after DOR-containing ART initiation will be compared 
to the proportion of women suppressed with non-DOR containing ART from aggregated data 
shared with the study team from the respective HIV treatment clinics that our study sample is 
recruited from.   
 
All exploratory analyses, including safety (including side effects), satisfaction, and continuation 
rates of both the hormonal contraceptive method and ART will be assessed in the cohort at 12 or 
24 weeks for DMPA or implant use, respectively. 
 
9.2  
Power/sample size 
For the PK sub-study, a sample size of 20 women per study arm will provide us with the ability to 
detect a GMR ≥20% (i.e. the FDA standard of bioequivalence bounds of 0.8-1.25) in hormonal 
concentrations 24 weeks after implant insertion or 12 weeks after D/MPA injection between the 
DOR and DTG ART groups with ≥80% power (Table 4).  This sample size assumes a 40% 
coefficient of variability in hormonal levels (which is what is detected in our historical comparison 
group of implant users for GMR at 24 weeks; it ranges from 22-43% in DMPA users on various 
ART for AUC at 12 weeks in the published literature17,53) and one-sided type I error of 10%, which 
is the standard error percentage used and reported in PK studies (e.g. geometric mean with 90% 
confidence intervals).  We have chosen to power on one-sided type I errors as only reductions in 
implant hormone concentrations are concerning for reduction in efficacy, and not elevations in 
concentrations.  Another assumption is that the concentrations in the DOR groups will not vary 
significantly from those of the implant without DOR (which is expected given the lack of drug-drug 
interactions with DOR and oral contraceptives with ethinyl estradiol and levonorgestrel, per 
product package insert).  A recent study found 53% mean difference in levonorgestrel implant 
concentrations at 24 weeks after implant placement between women receiving EFV 600mg 
versus no ART54 so aiming to detect a difference of at least 20% is extremely conservative.  
Generally, we would consider reductions in mean differences that are <20-30% as not being 
clinically significant.  Therefore, we are able to power this PK study to also show any clinically 
insignificant decreases with the groups.  At our site in South Africa, we have extremely high 
retention rate (in part, due to the outreach by our community health workers and liaison), so we 
will sample one additional woman in each group (n=21 in each ART group) to ensure we have 
sufficient samples for our primary outcome at the end of the observation period. 
 
Therefore, we anticipate enrolling and retaining a minimum of n=105 women, with n=21 
participants in each of the 5 groups.  We are anticipating a very conservative screening to 
enrollment ratio of 2:1, so may screen approximately 210 women. 
 
Table 4. Sample size required per group to compare hormone 
concentrations with 80% power 
  
Estimated mean difference in progestin 
concentrations 
Inter-individual 
variation 
10% 
20% 
30% 
40% 
50% 


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40% 
89 
20 
8 
4 
3 
50% 
189 
31 
12 
6 
4 
All sample size calculations assume an alpha level of 0.10 (one-sided) 
and 80% power 
  
Given the exploratory nature of study Secondary Objective, power calculations are not conducted 
a priori. 
 
9.3  
Statistical methods and analyses 
For study co-primary objectives, the hormonal contraceptive blood samples will be analyzed 
using LCMS techniques55,56. The lower limit of quantification (LLOQ) for ETG and MPA is 20 
pg/mL of plasma.  To compare mean concentrations at 24 weeks after implant insertion in the 
DOR vs. DTG groups (primary objective), we will analyze the geometric mean ratios using 
Wilcoxon rank sum test.  Similarly, to compare mean MPA concentrations at 12 weeks after 
D/MPA injection in the DOR vs. DTG groups (primary objective), we will analyze the geometric 
mean ratios using Wilcoxon rank sum test.  Of note, for Objective 1a, for a secondary analysis, 
will compare mean concentrations 24 weeks after implant insertion between the DOR vs. HIV-
uninfected groups.  The mean C24 hours of DOR in the ETG implant and D/MPA will be compared 
to no hormonal contraceptive method arm, and analyzed via geometric mean ratios using 
Wilcoxon rank sum test (primary objective).  Potential confounders we will consider in the above 
analyses may include age, disease/immune status (measured via CD4 cell counts or pre-
treatment HIV RNA levels, for example), co-morbidities, and weight or body mass index. 
 
For study secondary objective, the proportion of women achieving viral suppression at 12-24 
weeks between the DOR groups will be compared against summary data provided by the HIV 
treatment clinics from which the study sample will be recruited, and a two-sample t-test will be 
conducted if feasible.  If comparator data is not feasibly obtained from the treatment clinics, we 
will compare the viral suppression rates in the DOR groups in our PK study against proportions 
with DOR- and non-DOR-containing ART reported in the published literature (e.g. from the DRIVE 
studies), and a two-sample t-test will be conducted if feasible.  Related analyses, including the 
exploratory objective of evaluating the proportion of side effects, satisfaction, etc. will be 
compared similarly.  Pending future funding support, we may consider future analyses, such as 
pharmacodynamic or pharmacogenetic analyses on existing study data.  Such future analyses 
will be considered on a case by case basis.  Of note, separate consent will be obtained from 
participants to consent to such future analyses. 
 
For the exploratory objective utilizing qualitative study methods for the IDIs, we anticipate the 
following.  The English transcripts will be imported into Nvivo 12 for coding.  We will use a 
combination of inductive (allowing the data to speak for itself) and deductive coding (to draw upon 
the respective frameworks we are relying on to build the guides).  We will develop a codebook to 
iteratively document the codes, their definitions, and guidelines on when to use the code with 
example quotes. The initial, primary codes will be developed from the domains and themes 
queried in the interview/discussion guides. We will have 2-3 study staff independently code the 
transcripts, including double coding of the first few transcripts until we have confidence in the 
relative standard application of the codebook.  After the initial round of coding, the researchers 
will meet to discuss their coding process, assess intercoder agreement, and resolve 
discrepancies through consensus.  With iterative review of the transcripts, we will expand the 
initial codes into more detailed, secondary codes.  Once the coding is complete, we will use 
content analysis to organize the data for further analysis.57,58  Finally, analytic memos will be 
written to lift the primary and secondary codes into thematic analyses that represent a full range 
of perspectives, both convergent and divergent.  Several measures will be taken to ensure high 
quality data and rigorous analysis.59 Principles of reflexivity, such as acknowledging bias and 
power dynamics among the study staff, will be used when collecting and analyzing data.60  
Principles of rigor, such as exploring for discrepant data and remaining faithful to participants’ 


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experiences, will guide our analysis.59,61  We will describe the setting and context transparently 
so that readers can easily judge the transferability and trustworthiness of the findings.58,61  We 
will also pursue participant validation of our interpretation of the findings by sharing the results 
with them through meetings held at Wits RHI, taking field notes to be included in analyses. 
 
10.0  GOOD PARTICIPATORY PRACTICE (GPP) 
 
The EPIC study will use the most recent edition of the GPP guidelines (2011) to guide the 
study’s engagement with site communities and local, national, regional and global stakeholders. 
According to the GPP guidelines, “community stakeholders” include both individuals and groups 
that are ultimately representing the interests of people who would be recruited to or participate 
in a trial, and others locally affected by the trial. These may include trial participants, people 
living in the area where the research is being conducted, people in the area who are infected 
and affected by family planning needs, reproductive health issues and HIV, local non-
governmental organizations, community groups and community-based organizations.  
 
Good participatory practice in HIV research goes beyond having a Treatment Community 
Advisory Board (CAB). It involves utilizing a range of stakeholder advisory mechanisms to 
promote transparent, meaningful, collaborative, and mutually beneficial relationships with all 
levels of stakeholders (See Figure 5). The EPIC study will strive to embrace the GPP guiding 
principles throughout the implementation of the study. These include: respect, mutual 
understanding, integrity, transparency, accountability and community stakeholder autonomy. 
 


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Figure 5: Examples of stakeholder advisory mechanisms from GPP guidelines, 2011 
 
The EPIC team is committed to conducting meaningful community consultation, from protocol 
development and implementation to results dissemination and policy development where 
appropriate. To facilitate effective implementation of the GPP Guidelines, all members of the 
study team will be trained on the GPP Guidelines. 
 
11.0  DATA MANAGEMENT 
 
11.1  Data management responsibilities 
The investigators have ultimate responsibility for the collection and reporting of all clinical, safety 
and laboratory data entered on the case reporting forms (CRFs) and any other data collection 
forms (source documents) and ensuring that they are accurate, authentic/original, attributable, 
complete, consistent, legible, timely (contemporaneous), enduring and available when required.  
The CRFs must be signed by the investigator or by an authorized staff member to attest that the 
data contained on the CRFs is true.  Any corrections to entries made in the CRFs, source 
documents must be dated, initialed and explained (if necessary) and should not obscure the 
original entry. 


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11.2  Source documents and access to source data/documents 
To enable evaluations and/or audits, the investigator agrees to keep records, including the identity 
of all participating patients (sufficient information to link records, e.g., CRFs and hospital records), 
all original signed informed consent documents, copies of all CRFs, safety reporting forms, source 
documents, and detailed records of treatment disposition, and adequate documentation of 
relevant correspondence (e.g., letters, meeting minutes, telephone calls reports) securely stored 
under access controlled conditions. 
11.3  Quality control and assurance 
During the study period, periodic monitoring may be conducted to ensure that the protocol and 
Good Clinical Practices (GCPs) are being followed.  The monitors may review source documents 
to confirm that the data recorded on CRFs is accurate.  Additionally, the study site may be subject 
to review by the Institutional Review Board (IRB) and/or to inspection by appropriate regulatory 
authorities. 
 
12.0  HUMAN SUBJECTS PROTECTIONS 
 
12.1  Institutional review board/ethics committees 
In South Africa, the protocol will be reviewed by South African Health Products Regulatory 
Authority (SAHPRA) and by University of the Witwatersrand, Human Research Ethics Committee 
(Wits HREC). In the US, the University of Washington’s Institutional Review Board’s Committee 
on Human Research will review this protocol.  We will ensure that all procedures conform to South 
African, US, and international ethical standards regarding research involving human subjects.  
 
12.2  Human subjects’ involvement 
The proposed study aims to enroll a minimum of 105 WLHIV in South Africa aged 18-45 years. 
Women will be followed for up to 30 weeks. No prisoners or institutionalized individuals will be 
included in this cohort. Eligibility criteria will include the ability to provide written informed consent. 
 
The Wits Reproductive Health and HIV Institute (RHI) Research Centre Clinical Research Site 
(CRS), South Africa will be responsible for implementation of the study protocol and related 
activities with this cohort of young women. This responsibility includes the protection of human 
subjects, under the direction of the site Co-Principal Investigators (Dr. Palanee-Philips and Dr. 
Ndlovu+). The investigators at Wits RHI will prepare and submit the study protocol to the Wits 
HREC and SAHPRA for approval to ensure the rights, safety and welfare of the study participants 
are assured prior to implementation. The protocol will outline the plans for the implementation of 
the study, including recruitment, study visit procedures, and retention. Written informed consent 
will be obtained for prospective follow-up. Wits RHI will serve as the data center for the study and 
coordinate data management and the specimen repository in collaboration with University of 
Washington. Data obtained at the research site will be managed by a local data team, routinely 
entered into data management software, and transferred to the University of Washington via a 
secure internet connection.  
Original data collection forms, including consent forms, locator forms, case report forms, notations 
of all contacts with the participants, and all other source documents will be stored in a secure 
manner at the Wits RHI RC CRS. The Wits RHI RC CRS has a secure, restricted-access space 
dedicated to data management and data storage and has capacity for both paper based and 
electronic data management. Paper case report forms (CRFs) and other support documents are 
stored in lockable, fire and water-resistant steel cabinets for optimal data storage. The data centre 
has a file sign in and sign out process to ensure aware of staff who remove and return files daily. 
No participants confidential identifiers will be stored within participants main file routinely. A 
separate file will be kept with the participants informed consent forms, locator information and 
copies of personal identification documents so that there is no inadvertent breach of participants 
personal details such as her name and personal contact information. Study staff are all Good 
clinical practice trained and compliant and trained on adherence to confidentiality principles.   
 
12.3  Informed consent 


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Written informed consent will be obtained from each study participant prior to the conduct of 
screening procedures. In obtaining and documenting informed consent, the investigator and their 
designees will comply with applicable local regulatory requirements and will adhere to Good 
Clinical Practice and to the ethical principles that have their origin in the Declaration of Helsinki. 
These consents will include consent for screening and enrollment as well as storage of specimens 
for future studies related to HIV transmission and prevention as well as contraception. Research 
staff at the Wits RHI CRS will administer informed consent to each participant in their preferred 
language (choice between English and Zulu) as per site SOPs and participants will sign the 
consent form indicating whether they have understood the nature of the study and the potential 
risks and benefits from participation. Copies of signed ICFs will be offered to the participant for 
her reference.  
 
12.4  Protections against risk 
We anticipate participants may face potential risks, including pregnancy and phlebotomy-related 
issues. 
 
Since concomitant use of DOR is not anticipated to reduce hormonal contraceptive 
concentrations, the risk of contraceptive failure or pregnancy is anticipated to be low.  In order to 
minimize the risks of pregnancy, we will counsel the women extensively on the use of dual 
contraceptive methods with condoms.  Male or female condoms will be provided to the women 
on site by the study staff at no additional costs.  We will also counsel the women extensively on 
the use of non-hormonal contraceptive methods such as IUDs.  Women wishing to have these 
placed, will be provided to them at no additional cost. 
 
Phlebotomy-related risks may include pain, bruising, hematoma, or phlebitis.  In order to minimize 
any physical risks associated with phlebotomy, experienced clinical nurses will conduct the 
phlebotomy. Furthermore, this person will undergo additional training in phlebotomy if required.  
We anticipate these steps will significantly help minimize any potential physical risks associated 
with phlebotomy. 
 
DOR-specific risks: Risks associated with DOR use include nausea, headaches, fatigue, diarrhea, 
abdominal pain, dizziness, rash, abnormal dreams, insomnia and possible somnolence. 
Participants will be closely monitored and managed for all potential side effects. 
 
Risk of Adverse Reactions or Loss of Virologic Response Due to Drug Interactions: The 
concomitant use of DOR and certain other drugs may result in known or potentially significant 
drug interactions, some of which may lead to loss of therapeutic effect of DOR  and possible 
development of resistance. 
 
Contraceptive-specific risks: Risks associated with implant insertion or D/MPA injection include 
scarring, pain, bleeding and infection. Implant insertion or D/MPA injection will be performed by 
highly trained study staff under aseptic techniques in order to reduce these risks. Risks associated 
with the insertion of a non-hormonal IUD include infection, expulsion or perforation, however the 
risks are low. Similar common adverse reactions (>10%) have been reported for the 
contraceptives, and include headache, change in menstrual bleeding, weight gain, acne, breast 
pain and abdominal pain.  Participants will be counseled to follow up with their primary care 
clinicians should these symptoms persist.  
 
No psychological, financial, or legal risks are anticipated with study participation.  The participants 
will have the alternative to not participate in the studies, which carries no risks.  They will be 
reassured that their HIV care is not in any way influenced by their participation in these studies.   
 
12.5  Benefits  
Though there are no direct anticipated benefits to the participants in these studies, findings from 
the studies will be shared with the participants directly, through venues determined most 


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appropriate by the study staff and facility leadership (e.g. through group meetings at the facilities, 
letters to participants, or phone calls). We also anticipate that findings from the proposed study 
will impact international and national HIV treatment guidelines’ recommendations for concomitant 
ART and implant use, and study participants will be interested in participating to help determine 
findings for this type of impact.  Optimizing concomitant ART and contraception for WLHIV is 
important in avoiding unintended pregnancies, which have implications for HIV-related and 
maternal morbidity and vertical transmission of HIV.  We believe that given the large potential for 
impact, the potential risks of the proposed studies are minimal and, therefore, find them 
reasonable despite the lack of any anticipated direct benefits to the participants. 
 
12.6  Participant privacy and confidentiality  
All study procedures will be conducted in private, and every effort will be made to protect 
participant privacy and confidentiality to the extent possible. All study-related information will be 
stored securely at the Wits RHI Data Centre.  All participant information will be stored in locked 
areas with access limited to designated study staff. All laboratory specimens, study data, and 
administrative forms will be identified by coded number only to maintain participant confidentiality. 
All records that contain names or other personal identifiers, such as locator forms and informed 
consent forms, will be stored securely.  All electronic files of the collected data will be saved de-
identified on password protected and encrypted computers. Only de-identified information will be 
shared and used amongst the research staff.  With participant permission, remaining plasma 
samples after completion of our analysis may be stored at the UW ICRC repository for future 
studies.  Use of the specimens, with de-identified information only, for future studies will be 
conditional on written request by investigators to the PI of the study (Dr. Rena Patel) and approval 
of respective IRBs to conduct the study. 
 
12.7  Protocol registration 
The protocol will be registered with the U.S. clinicaltrials.gov and the South African National 
Clinical Trials Register. 
 
12.8  Compensation 
Pending IRB/EC approval, participants will be compensated for time, inconvenience and 
expenses incurred as a consequence of their attendance to a study visit.  The value of 
compensation is in line with standard national guidelines from  Wits HREC and SAHPRA  related 
to attendance to study visits and procedures conducted. Site specific reimbursement amounts 
will be specified in the site specific ICF  
 
12.9  Study suspension or discontinuation 
This study may be discontinued at any time by study sponsors, other government or regulatory 
authorities, or site IRBs/ECs. 
 
13.0  PUBLICATION POLICY AND PLAN 
Study findings will be disseminated to researchers through oral or written presentations at 
scientific conferences and through peer-reviewed journals.  Full anonymity of subject’s details will 
be maintained throughout.  We will also disseminate the findings directly with the study 
participants, through venues determined by the study staff and facility leadership. Participants 
wanting to see the results of the trial can request a copy of the article from the investigators once 
it has been published.  In South Africa, study results will be communicated to the National 
Department of Health (NDoH) program managers through meetings and reports and 
disseminated amongst Wits RHI staff.  The study will be registered on Clinicaltrials.gov. 
 
 
 


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55. Blue SW, Winchell AJ, Kaucher AV, et al. Simultaneous quantitation of multiple contraceptive 
hormones in human serum by LC-MS/MS. Contraception 2018;97:363-9. 
56. Pyra M, Lingappa JR, Heffron R, et al. Concordance of self-reported hormonal contraceptive 
use and presence of exogenous hormones in serum among African women. Contraception 
2018;97:357-62. 
57. Calman L, Brunton L, Molassiotis A. Developing longitudinal qualitative designs: lessons 
learned and recommendations for health services research. BMC Med Res Methodol 
2013;13:14. 
58. Graneheim UH, Lundman B. Qualitative content analysis in nursing research: concepts, 
procedures and measures to achieve trustworthiness. Nurs Educ Today 2004;24:105-12. 
59. Patton MQ. Enhancing the quality and credibility of qualitative analysis. Health Serv Res 
1999;34:1189-208. 
60. Shaw JA. Reflexivity and the "Acting Subject": Conceptualizing the Unit of Analysis in 
Qualitative Health Research. Qual Health Res 2016. 
61. Hammersley M. What's wrong with ethnography? : methodological explorations. London ; 
New York: Routledge; 1992. 
 
 


 
 
EPIC Protocol Version 1.3 dated 14 July 2022                                                    
Screening and Enrolment IS and Informed consent (English; Version 1.7 dated 02 February 2023)                        Page 1 of 13 
Investigator’s name: Prof Thesla Palanee-Phillips and Dr Nkosiphile Ndlovu
 
 
 
Approved by Wits IEC (HREC) 
 
 
Date approved: 04 April 2023 
 
               Participant Initials: ____   ____   ____       
 
 
INFORMATION SHEET (IS) AND INFORMED CONSENT  
Each participant must receive, read and understand this document before any study-related 
procedure. 
 
SHEET 1:                    
 Screening and Enrolment 
 
 
 
 
TITLE FOR THE STUDY: 
EPIC- Evaluation of Pharmacokinetic drug-drug Interactions   
                                                           between hormonal Contraceptives and doravirine-  
                                                           containing ART among women living with HIV in South  
                                                           Africa 
 
SPONSOR:   
 
           Merck, Inc 
 
PRINCIPAL INVESTIGATORS: 
Prof Thesla Palanee-Phillips and Dr Nkosiphile Ndlovu 
 
INSTITUTION: 
Wits Reproductive Health and HIV Institute (Wits RHI), 
University of the Witwatersrand 
 
DAY TIME AND AFTER-HOURS TELEPHONE NUMBERS:       Day Tel: 011 358 5424 
                                                                                               A/H Tel: 084 722 5877 
 
 
 
 
 
 
 
DATE AND START TIME OF INFORMED CONSENT DISCUSSION:  
 
 
 
 
 
: 
DD 
MMM 
YYYY 
 
Time (24hr clock) 
 
KEY INFORMATION:  
Consent is being sought for this research study and your participation is voluntary. If you decide not 
to take part in this study, you can still join another research study later if one is available and you 
qualify.  
 
The purpose of this study is to assess any interactions between HIV treatment medications and family 
planning methods. You are being asked to join this study because you are already on antiretroviral 
therapy for HIV treatment, and study drug doravirine works like how your current antiretroviral therapy 
by stopping HIV from making copies of itself. But not a lot is known about interactions between 
doravirine and family planning methods, and that is why we are doing this study. If you decide to join 
the study, the duration of your participation is this study will be approximately 18-30 weeks.  
 
Each participant will choose to be in one of five groups with 21 participants in each group. If you join 
one of the four doravirine groups, you will be asked to switch from your current ART to doravirine-
containing ART called Delstrigo®, which is a tablet taken by mouth once a day. Six weeks after 
doravirine initiation, you will be offered a choice to start a family planning method contraceptive 
To the potential Participant: This consent form may contain words that you do not 
understand.   Please ask the study doctor or the study staff to explain any words or 
information that you do not clearly understand.   You may take home an unsigned copy 
of this consent form to think about or discuss with family or friends before making your 
decision


 
 
EPIC Protocol Version 1.3 dated 14 July 2022                                                    
Screening and Enrolment IS and Informed consent (English; Version 1.7 dated 02 February 2023)                        Page 2 of 13 
Investigator’s name: Prof Thesla Palanee-Phillips and Dr Nkosiphile Ndlovu
 
 
 
Approved by Wits IEC (HREC) 
 
 
Date approved: 04 April 2023 
 
               Participant Initials: ____   ____   ____       
 
 
containing hormones [implant, or injection under skin (SC MPA) or in the muscle (DMPA), and IUD].  
If you are already on dolutegravir-containing ART and choose to continue using it, you will be asked 
to join the fifth group and remain on your dolutegravir-containing ART and start the DMPA, you will 
not get to pick your contraceptive for this study. For the six-week window after starting DOR, you 
must be on an effective form of contraception to avoid pregnancy. You will receive comprehensive 
counselling on all contraceptive methods available in the study as described below to enable you to 
make your own choice.  
 
There are no direct benefits to participating in this study.  
 
Risks associated with doravirine-containing ART include common side effects such as headaches, 
fatigue, diarrhoea, abdominal pain, dizziness, rash, abnormal dreams, insomnia (trouble sleeping) 
and possible somnolence (drowsiness). Rare, but more severe side effects include bone or renal 
toxicities. Risks associated with implant insertion or DMPA or SC MPA injection include scarring, 
pain, bleeding, and infection. Risks associated with implant use include prolonged or irregular 
bleeding or both; in subsequent years, bleeding patterns tend to improve. Risks associated with the 
insertion of a non-hormonal IUD include infection, expulsion (IUD being pushed out the womb) or 
perforation (tearing of the womb), however the risks are low. Common adverse reactions have been 
reported for the contraceptives, and include headache, change in menstrual bleeding, weight gain, 
acne, breast pain, dizziness, mood changes and abdominal pain. Some of the risks related to drawing 
blood include pain, bruising, hematoma, or phlebitis. 
 
INTRODUCTION 
Hello my name is _________________________________________________ and I work at 
the 
Wits 
Reproductive 
Health 
and 
HIV 
Institute 
(Wits 
RHI) 
as 
a 
_____________________________________________________. The Wits RHI does 
research in reproductive health, including HIV. We have projects in many areas including 
Esselen Street in Hillbrow (Esselen Street Clinic and Research Centre) and Yeoville.  The 
Wits RHI is a part of the University of Witwatersrand, Johannesburg. 
 
The Wits RHI would like to invite you to participate in the research study called EPIC 
“Evaluation of Pharmacokinetic drug-drug Interactions between hormonal Contraceptives and 
doravirine-containing ART among women living with HIV in South Africa” which is funded by 
Merck, Inc. The persons in charge of this study at this clinic is Prof. Thesla Palanee-Phillips 
and Dr. Nkosiphile Ndlovu.   
 
Before you decide if you want to join this study, we want you to know about it.  This form gives 
you information about this study.  The study staff will talk with you about it and answer your 
questions. If you would like to speak with a medical doctor or if you have medical questions, 
please let me know so that this can be arranged. You may choose to stop being in the study 
at any time. Once you read (or have read to you) this form, discuss and understand the study, 
and if you agree to participate, we will ask you to sign or mark this form.  We will offer you a 
copy of this form to keep. 
 
If you have a personal doctor, you are welcome to discuss with or inform him/her of your 
possible participation in this study. If you wish, I can also notify your personal doctor in this 
regard. 
 
YOUR PARTICIPATION IS VOLUNTARY 


 
 
EPIC Protocol Version 1.3 dated 14 July 2022                                                    
Screening and Enrolment IS and Informed consent (English; Version 1.7 dated 02 February 2023)                        Page 3 of 13 
Investigator’s name: Prof Thesla Palanee-Phillips and Dr Nkosiphile Ndlovu
 
 
 
Approved by Wits IEC (HREC) 
 
 
Date approved: 04 April 2023 
 
               Participant Initials: ____   ____   ____       
 
 
If you decide not to take part in the study, you can still join another research study later, if one 
is available and you qualify. However, you cannot join this study if you are taking part in 
another study of medicines, medical devices, or vaccines. You are asked to tell the study staff 
about any other studies you are taking part in or thinking of taking part in.  
 
We check for your co-enrolment in other studies by capturing your fingerprints on an electronic 
system called the Biometric Co-Enrolment Prevention System (BCEPS). You will need to 
place your fingers onto a mini screen which will enter your fingerprints onto BCEPS. This 
system will then check if your fingerprints are stored on the system for any other studies.  Only 
a few members of the study team can see the information in BCEPS using a secure password. 
This is done at the beginning of your visit and is covered on a separate informed consent form.  
 
PURPOSE OF THE STUDY 
This research study is known as EPIC. The purpose of this study is to assess any drug 
interactions between Doravirine exposure and hormonal contraceptive use. The possible risks 
of taking the combination of contraceptives and doravirine are unknown, and that is why this 
study is taking place. You are being asked to join this study because you are already on 
antiretroviral therapy. Doravirine is not a registered medicine in South Africa however it works 
like how your current antiretroviral therapy works. Doravirine works by stopping HIV from 
making copies of itself. 
 
WHO WILL BE IN THIS RESEARCH STUDY? 
A minimum of 105 women in Johannesburg and surrounding areas, aged 18-45 years old, living 
with HIV, already on antiretroviral therapy (ART) and virally suppressed.  
 
WHAT DO I HAVE TO DO IF I DECIDE TO TAKE PART IN THIS STUDY?  
If you decide to join you will be in the study for approximately 18-30 weeks. Each participant 
will be put in one of five groups as described in the table below. We will have 21 participants 
in each group. 
 
Group 
Number of 
participants 
ART regimen and contraceptive method 
Group 1  
21 
doravirine-containing ART + initiating etonogestrel implant 
Group 2 
21 
doravirine-containing ART + initiating Intramuscular 
depomedroxyprogesterone acetate (IM DMPA) 
Group 3 
21 
doravirine-containing ART + initiating subcutaneous 
Medroxyprogesterone acetate (SC MPA) 
Group 4 
21 
doravirine-containing ART + initiating non-hormonal intrauterine device 
Group 5 
21 
dolutegravir-containing ART + initiating IM DMPA 
 
If you join one of the four doravirine groups, you will be asked to switch from the standard of 
care ART to doravirine-containing ART and take the Delstrigo® tablet which contains 100 mg 
of Doravirine, 300 mg of Lamivudine, and 300 mg of Tenofovir Disoproxil Fumarate. Delstrigo® 
is a film-coated yellow, oval-shaped, tablet taken orally once a day.  
 
Six weeks after doravirine initiation, you will be offered a choice of either etonogestrel implant, 
depomedroxyprogesterone acetate (DMPA), subcutaneous medroxyprogesterone acetate 
(SC MPA) or non-hormonal intrauterine device (IUD; which can be placed on site).   
 


 
 
EPIC Protocol Version 1.3 dated 14 July 2022                                                    
Screening and Enrolment IS and Informed consent (English; Version 1.7 dated 02 February 2023)                        Page 4 of 13 
Investigator’s name: Prof Thesla Palanee-Phillips and Dr Nkosiphile Ndlovu
 
 
 
Approved by Wits IEC (HREC) 
 
 
Date approved: 04 April 2023 
 
               Participant Initials: ____   ____   ____       
 
 
If you are already on dolutegravir-containing ART and wish to start DMPA, you will be asked 
to join the fifth group and remain on Dolutegravir-containing ART and start the DMPA. 
 
You will receive comprehensive counselling on all contraceptive methods available in the 
study as described below to enable you to make your own choice. 
• Contraceptive implants- Contraceptive progestin implants are thin rods inserted under the 
skin of a woman's arm. The most widely available implant in South Africa is currently 
Implanon/Nexplanon/Implanon NXT. 
• Depot Medroxyprogesterone Acetate (DMPA), also known as Depo Provera. The DMPA 
injection is a hormone injection that is given in the buttocks every 3 months. 
• Subcutaneous Medroxyprogesterone acetate (SC MPA) or Sayana® Press is given 
subcutaneously (into the fatty layer just under the skin), into the front upper thigh or 
abdomen every 3 months. 
• Non-hormonal intrauterine device (IUD) is the T-380A copper IUD, a small T-shaped device 
made of plastic and copper, which a doctor or nurse places in the uterus (womb). IUDs may 
be left in place for up to 10 years and can be removed if needed. 
 
DO YOU HAVE TO BE IN THIS STUDY? 
You do not have to be in this study.  You can still get the care you need from your local/public 
clinic even if you do not join the study.  If you join today, you can change your mind at any 
time. 
 
WHAT PROCEDURES WILL BE DONE FOR THIS STUDY? 
Your first visit will happen today after you read (or have read to you), discuss, understand, and 
sign this form.  The procedures done at this visit will let us know if you can join this study and 
will take about 4 hours. At today’s visit you will complete questionnaires related to your 
contraceptive and ART use and we will ask you to provide a blood sample (approximately 15-
20 ml or two tablespoons) to test your blood counts, kidney and liver function, HIV viral load, 
and a urine sample to test for pregnancy. We will test for hepatitis B and if you have the 
infection, you will be excluded from the study. We also will test for hepatitis B immunity and if 
you are not immune, we will offer you vaccination against hepatitis B infection. 
 
If it seems like you can join, you will be asked to come back for an Enrolment visit no later 
than 30 days from today. After enrolment, we will ask to you to return for scheduled visits up 
until approximately 12-24 weeks (+/- 2 weeks) after starting your contraceptive method. 
 
The following things may happen during your study visits: 
 
• 
We will ask questions about your health and any medications you may be taking. We will 
also ask questions about your living situation to see if it affects your use of the study 
product, and about your reasons for wanting to join this study. We will collect a blood 
sample (approximately 15-20 ml or two tablespoons ml) to test your blood counts, ARV 
and hormone contraceptive levels, kidney, and liver function 
• 
We will collect a urine sample to test for pregnancy 
• 
At some visits, you may be asked to complete a questionnaire. You will be asked to 
answer some questions in private, using a computer. The study staff will show you how 
to use the computer to answer the questions. You will answer questions about using the 


 
 
EPIC Protocol Version 1.3 dated 14 July 2022                                                    
Screening and Enrolment IS and Informed consent (English; Version 1.7 dated 02 February 2023)                        Page 5 of 13 
Investigator’s name: Prof Thesla Palanee-Phillips and Dr Nkosiphile Ndlovu
 
 
 
Approved by Wits IEC (HREC) 
 
 
Date approved: 04 April 2023 
 
               Participant Initials: ____   ____   ____       
 
 
study product and other behaviours, including sexual activity, if you are sexually active, 
contraceptive needs and other questions that can help researchers better understand 
participants’ experiences while in the study. Some of the questions may be sensitive. If 
you ever feel uncomfortable, you can choose not to answer questions at any time. You 
will also answer questions about what you liked and did not like about this study and about 
the study product. 
• 
At some visits, we will give you a physical exam to make sure you are healthy.  
• 
We will give you treatment for sexually transmitted and other kinds of infections if you 
need them. 
• 
We will give you referrals for other services if you need them 
• 
You may be asked to take part in a one-on-one in-depth interview that will last 30-60 
minutes and be conducted twice, at the start of the study and after you complete the study. 
You may choose not to be interviewed. During the interviews, we may ask participants 
about their experiences in switching from their current ART regimen to one containing 
Doravirine, and about their experiences with their contraceptive method of choice, as well 
as experiences between the DMPA versus the subcutaneous medroxyprogesterone 
acetate, including self-injections. We will record the interviews (audio record). We will 
keep the recordings and other related things confidential and no one else other than those 
in the study team will have access to your answers. 
 
It is important for you to come to every study visit. If you cannot come to the visit, please tell 
the study staff as soon as possible so that the visit can be rescheduled.  
 
INTERIM/UNSCHEDULED VISITS 
Study staff will discuss with you the importance of contacting the clinic as soon as you notice 
changes in your physical condition or when you experience health related issues.   Also, it is 
possible that you may be asked to come to the clinic for an unscheduled visit in the event of 
an abnormal test result; difficulties in sample shipping, processing, or testing or to have study 
procedures repeated; or for other reasons. We will do this if there are abnormal test results or 
a mistake during the collection or the processing of your samples. We will also do this if you 
experience any changes in your physical condition, including symptoms of urine or sexually 
transmitted infections (STIs). 
 
PREGNANCY AND BREASTFEEDING  
Pregnant and breastfeeding women may not join this study.  You may be able to start using 
the study products after your pregnancy, provided that you are not breastfeeding.  The study 
staff will talk more with you about this after your pregnancy.   
 
If you become pregnant during the study, you will stop using the study products and you will 
stop   participating in the study. We will collect blood form you for testing and ask you to do an 
assessment with questions about your participation in this study. We will also refer you to 
available medical care and other services for ongoing care including any needed changes to 
your ART according to the local Department of Health Guidelines. The study does not pay for 
this care. We will contact you for information about your baby’s health one month after delivery. 
Additionally, upon documentation of a positive pregnancy test, the following procedures will 
be performed regardless of whether or not the participant scheduled to be completed:  
• 
Full blood count  


 
 
EPIC Protocol Version 1.3 dated 14 July 2022                                                    
Screening and Enrolment IS and Informed consent (English; Version 1.7 dated 02 February 2023)                        Page 6 of 13 
Investigator’s name: Prof Thesla Palanee-Phillips and Dr Nkosiphile Ndlovu
 
 
 
Approved by Wits IEC (HREC) 
 
 
Date approved: 04 April 2023 
 
               Participant Initials: ____   ____   ____       
 
 
• 
Kidney function  
• 
Collection of blood samples for further analysis  
• 
Behavioural adherence, and product preference/acceptability questionnaires.  
 
RISKS AND/OR DISCOMFORTS 
Risks of Blood Draws  
You may feel discomfort or pain when your blood is drawn.  You may feel dizzy or faint.  You 
may have a bruise, swelling, small clot, or infection where the needle goes into your hand or 
arm. 
 
Risks of study products 
Side effects of doravirine-containing ART: 
Common side effects include headaches, fatigue, diarrhea, abdominal pain, dizziness, rash, 
abnormal dreams, insomnia (trouble sleeping) and possible somnolence (drowsiness). Rare, 
but more severe side effects include bone or renal toxicities. 
 
Risk of bad reactions or loss of virologic response due to drug interactions:  
 
Using doravirine and other drugs at the same time may cause drugs to interact in powerful 
ways that we do not yet know about. Some of these reactions might mean that doravirine will 
not work for you the way it’s supposed to and your body might become resistant to the drug. 
 
Contraceptive-specific risks:  
Risks associated with implant insertion or DMPA or SC MPA injection include scarring, pain, 
bleeding and infection. Risks associated with implant use include prolonged or irregular 
bleeding or both; in subsequent years, bleeding patterns tend to improve. Risks associated 
with the insertion of a non-hormonal IUD include infection, expulsion (IUD being pushed out 
the womb) or perforation (tearing of the womb), however the risks are low. Common adverse 
reactions have been reported for the contraceptives, and include headache, change in 
menstrual bleeding, weight gain, acne, breast pain, dizziness, mood changes and abdominal 
pain.  You will receive contraception counselling.  
 
Other Possible Risks 
You may feel embarrassed and/or worried when talking about sexual activities (if you are 
currently sexually active) and your living situation. 
 
We will make every effort to protect your privacy and confidentiality during the study visits. 
Your visits will take place in private. However, it is possible that others may learn of your 
participation here and, because of this, may treat you unfairly or discriminate against you. For 
example, you could have problems getting or keeping a job, or being accepted by your family 
or community. If you have any problems, study staff will talk with you and if you choose, your 
partner, to try to help resolve them. 
 
BENEFITS 
There are no direct benefits to participating in this study. This study cannot provide you with 
general medical care, but study staff will refer you to other available sources of care if needed.  
You will be offered free condoms, if you need them.   


 
 
EPIC Protocol Version 1.3 dated 14 July 2022                                                    
Screening and Enrolment IS and Informed consent (English; Version 1.7 dated 02 February 2023)                        Page 7 of 13 
Investigator’s name: Prof Thesla Palanee-Phillips and Dr Nkosiphile Ndlovu
 
 
 
Approved by Wits IEC (HREC) 
 
 
Date approved: 04 April 2023 
 
               Participant Initials: ____   ____   ____       
 
 
 
NEW INFORMATION 
You will be told any new information learned during this study that may affect your willingness 
to stay in the study.  For example, we will let you know if we learn that the study products may 
be causing bad side effects.  We will also tell you when study results may be available, and 
how to learn about them. 
 
WHY YOU MAY STOP TAKING THE STUDY DRUG EARLY OR BE ASKED TO LEAVE 
THE STUDY 
You may need to leave the study early without your permission if: 
• 
The study is cancelled by the study sponsors, the local government or regulatory agency, 
or the Institutional Review Board (IRB)/Ethics Committee (EC).  An IRB/EC is a committee 
that watches over the safety and rights of study participants. 
• 
You are not able to keep appointments. 
• 
Other reasons that may prevent you from completing the study successfully such as 
pregnancy. 
 
The study doctor will ask you to stop using the study products if you: 
• 
Become pregnant 
• 
Use drugs for HIV treatment beyond what the study gives you.  
• 
Use injectable drugs for fun. 
• 
Have a bad reaction to study product, or a study doctor decides that using study product 
would be bad for you. 
• 
Are unable or unwilling to follow the study rules. 
 
If a study doctor asks you to stop using study product, we will ask you to come in for all 
remaining study visits to have some of the procedures we talked about earlier. 
 
If you are removed from the study or choose to leave, we will ask you to return the study 
product and to come back for one final clinic visit.  If you do not have the study product with 
you when you come to the clinic, staff members will make every effort where possible to assist 
you in returning it.  
 
ALTERNATIVES TO BEING IN THE STUDY 
You may be able to join other studies here or in the community.  There may be other places 
where you can go for family planning.  We will tell you about those studies and those places 
if you wish. 
 
EMERGENCY CARE AND HOSPITALISATION  
If you have a medical emergency during the time you are enrolled in the study, please seek 
emergency care at the nearest hospital and inform the doctor treating you that you are 
participating in the study. That doctor is welcome to call the study staff for information. This 
includes the time of up to 1 month after you have completed your time in the study. Please 
inform the study staff of your time in the hospital as soon as possible. 


 
 
EPIC Protocol Version 1.3 dated 14 July 2022                                                    
Screening and Enrolment IS and Informed consent (English; Version 1.7 dated 02 February 2023)                        Page 8 of 13 
Investigator’s name: Prof Thesla Palanee-Phillips and Dr Nkosiphile Ndlovu
 
 
 
Approved by Wits IEC (HREC) 
 
 
Date approved: 04 April 2023 
 
               Participant Initials: ____   ____   ____       
 
 
COSTS TO YOU 
There is no cost to you for study visits, study products, physical exams, laboratory tests or 
other procedures.  We can give you treatments for STIs free of charge while you are in the 
study, or we can refer you for available treatment. 
 
REIMBURSEMENT 
You will receive R 400 for your time, inconvenience and expense to and from the clinic at each 
scheduled visit according to South African Health Products Regulatory Authority requirements.  
You may receive R 200 for any study related visits which occur in between your normally 
scheduled visits depending on your travel and procedures to be completed.  
 
CONFIDENTIALITY 
We will make every effort to keep your information private and confidential.  
 
Study visits will take place in private.  We will keep the information about your study visits in a 
secure place that only certain people can access for the purposes of this study. We will only 
enter your information into computers protected by passwords and will not include information 
that could identify you. If you are selected to participate in an in-depth interview, you can 
choose not to answer questions at any time. We will keep the audio recordings and materials 
from all interviews confidential and will only use study numbers or fake names. We store the 
recordings for 2 years after publication of the study results or 6 years if there is no publication. 
 
Your personal information may be disclosed if required by law.  For example, if we learn 
something that would immediately put you or others in danger, the study staff must take steps 
to keep you and others safe.  This means that we have to share any information with the 
authorities (hospital, police, or social services) that tells us you may be in danger. For example, 
if you tell us that you plan to hurt or kill yourself, hurt or kill someone else, or if you tell us that 
someone is abusing or neglecting you. 
 
The study staff will only use your fingerprints and personal information to verify that you are 
not taking part in any other research studies on BCEPS. This study will not use your name or 
identify you personally in any publication. 
 
Your records may be reviewed by: 
• Study sponsors and funders 
• United States (US), local and international regulatory entities 
• Members of the study protocol team and external advisors 
• South African Health Products Regulatory Authority  
• Human Research Ethics Committee, University of the Witwatersrand, an Ethics Committee 
is a committee that watches over the safety and rights of research participants  
• National Health Research Ethics Committee (NHREC)  
• Members of an Independent Data Safety Monitoring Board who review this clinical trial  
• Study monitors 
• Study staff 
 
A description of this clinical trial will also be available on http://www.clinicaltrials.gov as 
required by U.S. Law.  This Web site will not include information that can identify you. At most, 
the Web site will include a summary of the results. You can search this Web site at any time. 


 
 
EPIC Protocol Version 1.3 dated 14 July 2022                                                    
Screening and Enrolment IS and Informed consent (English; Version 1.7 dated 02 February 2023)                        Page 9 of 13 
Investigator’s name: Prof Thesla Palanee-Phillips and Dr Nkosiphile Ndlovu
 
 
 
Approved by Wits IEC (HREC) 
 
 
Date approved: 04 April 2023 
 
               Participant Initials: ____   ____   ____       
 
 
 
The study staff will do everything they can to protect your privacy.  
  
SPECIMEN COLLECTION 
The information and/or specimens that we obtain from you for this study might be used for 
future studies. We may remove anything that might identify you from the information and 
specimens. If we do so, that information and specimens may then be used for future research 
studies or given to another investigator without getting additional permission from you. It is 
also possible that in the future we may want to use or share study information that might 
identify you. If we do, a review board will decide whether or not we need to get additional 
permission from you. 
 
RESEARCH-RELATED INJURY 
Wits RHI has obtained insurance for you in the event of study related injury or illness. A study-
related injury or illness is one that occurs as a direct result of the administration of the study 
medicine or of study specific procedures. It is unlikely that you will be injured as a result of 
participating in this study. If you are injured as a result of study procedures, the Wits RHI will 
give you immediate necessary treatment for your injuries. You will not have to pay for this 
treatment. You will be told where you can get additional treatment for your injuries.  
 
The research site or sponsor is not responsible for any loss, injuries and/or damages that are 
caused by any of the following things: 
• 
Any injury that happens because you used other medicine during the study that you did 
not tell us about. 
• 
Any injury that happens because you did not follow instructions given by the study doctor 
or nurse. 
• 
Any injury that happens because of negligence on your part. 
 
Merck will not cover any injuries or harms arising from study involvement, unless it is 
determined that the injuries or harms occurred in direct connection to manufacturing defects 
in study drug. 
 
If a research related injury occurs, you have not waived any of the legal rights by signing this 
form. 
 
INSURANCE AND ABPI STATEMENT 
The Wits RHI through trial insurance will provide compensation for reasonable medical 
expenses incurred as a result of study-related injury or illness, determined according to the 
guidelines laid down by the Association of the British Pharmaceutical Industry (ABPI 
Guidelines, Version 2014), and Guidelines for Good Practice in the Conduct of Clinical 
Trials in Human Participants in South Africa (version 2006). 
 
Please notify the study staff immediately of any complications, side effects and/or injuries 
during the study and the nature of the expenses to be covered. Further detailed information 
on the payment of medical treatment and compensation due to injury can be obtained from 
me or other study staff. We have a copy of the ABPI Guidelines (version 2014) and the 
Insurance Certificate, should you wish to review them. 


 
 
EPIC Protocol Version 1.3 dated 14 July 2022                                                    
Screening and Enrolment IS and Informed consent (English; Version 1.7 dated 02 February 2023)                        Page 10 of 13 
Investigator’s name: Prof Thesla Palanee-Phillips and Dr Nkosiphile Ndlovu
 
 
 
Approved by Wits IEC (HREC) 
 
 
Date approved: 04 April 2023 
 
               Participant Initials: ____   ____   ____       
 
 
 
The insurance does not cover and the sponsors will not pay for:  
• 
Medical treatment of other injuries or illnesses 
• 
Injury caused by non-observance of the protocol 
 
The staff working on this study is covered by the insurance as long as they: 
• 
Comply with the applicable requirements of the study protocol 
• 
Comply with the regulations of the South African Health Products Regulatory Authority and 
the University of the Witwatersrand, Human Research Ethics Committee (HREC)  
• 
Ensure that the handling and administration of the study medication is in accordance with 
instructions and guidelines provided in the protocol, subsequent amendments and related 
documents. 
This insurance is not intended to be and is not a substitute for the study staff’s personal 
malpractice insurance. 
 
Please note that if you have a life insurance policy you should enquire whether your insurance 
company requires notification of your intention to participate in a clinical study.  Information to 
date is that it should not affect any life insurance policy taken out.  Nevertheless, you are 
strongly advised to clarify it with the company concerned. 
 
YOUR RIGHTS AS A RESEARCH PARTICIPANT 
• Voluntary: Your participation in this study is entirely voluntary and you can refuse to 
participate or stop at any time without stating any reason.  If you choose not to join or to 
leave the study, you can still join other studies you are eligible for at this clinic.  If you decide 
to withdraw from the study, the study staff will encourage you to come to the clinic for one 
final visit to check on your health. Your withdrawal will not affect your access to other 
medical care at your local clinic. If you want the results of the study after the study is over, 
let the study staff members know. 
• Discontinuation of study products: You must inform the study team if you wish to stop the 
study products as soon as possible.  
• New findings: The study clinic staff will provide you with any additional information that 
becomes available during the study, which may affect your willingness to continue in the 
study.  
 
PROBLEMS OR QUESTIONS 
If you have any questions about the study, who to contact at the study site, or if you have a 
research related injury or any other problems related to the study, please feel free to contact 
the clinic staff by visiting the clinic between 08:00 to 16:30 or phoning on 011 358 5424 or 
after hours on 084 722 5877/ 083 797 0144. If you feel that you require more information than 
the clinic staff are able to give you please contact one of the people listed below: 
 
 
 
 
 
 


 
 
EPIC Protocol Version 1.3 dated 14 July 2022                                                    
Screening and Enrolment IS and Informed consent (English; Version 1.7 dated 02 February 2023)                        Page 11 of 13 
Investigator’s name: Prof Thesla Palanee-Phillips and Dr Nkosiphile Ndlovu
 
 
 
Approved by Wits IEC (HREC) 
 
 
Date approved: 04 April 2023 
 
               Participant Initials: ____   ____   ____       
 
 
Prof Thesla Palanee - Phillips 
Co-Principal Investigator 
Wits RHI, Research Centre 
No. 7 Esselen Street, Hillbrow 
Tel: 011 358 5471 
 
Dr Nkosiphile Ndlovu 
Co-Principal Investigator 
Wits RHI, Research Centre 
No. 7 Esselen Street, Hillbrow 
Tel: 011 358 5424 
Emergency Number: 084 722 5877 
This study is conducted in accordance with the Department of Health Guidelines for the South 
African Good Clinical Practice: Clinical Trial Guidelines (2020) and has received ethical 
approval from the University of the Witwatersrand, Human Research Ethics Committee. If you 
want any information regarding your rights as a research participant, or complaints regarding 
this research study, you may contact Prof. Clement Penny, Chairperson of the University of 
Witwatersrand, Human Research Ethics Committee, which is an independent committee 
established to help protect the rights of research participants at 011 717 2301 
 
 
If you have questions about this trial you should first discuss them with your personal/study 
doctor or the ethics committee (contact details as provided on this form). After you have 
consulted your personal/study doctor or the ethics committee and if they have not provided 
you with the answers to your satisfaction, you should write to the South African Health 
Products Regulatory Authority (SAHPRA) at: 
 
The Chief Executive Officer 
South African Health Products Regulatory Authority  
Department of Health 
Private Bag X828 
Pretoria  
0001 
E-mail: Boitumelo.Semete@sahpra.org.za 
Tel: 012 501 0410                   
 
ETHICAL APPROVAL OF THIS STUDY: 
This study protocol has been submitted to the University of The Witwatersrand, Human 
Research Ethics Committee and written approval has been granted by the committee.  The 
study has been structured in accordance with the Declaration of Helsinki (last update October 
2013), which deals with the recommendations guiding doctors in biomedical research 
involving human subjects. A copy can be obtained from me if you wish to review it.  
 
DATE AND TIME OF COMPLETION OF INFORMED CONSENT DISCUSSION:  
 
 
 
 
: 
DD 
MMM 
YYYY 
 
Time  (24 hour clock) 
 
 
 
 
Prof. Clement Penny 
Chairperson for the Committee for Human Research Ethics Committee 
University of the Witwatersrand             Tel: 011 717 2301 


 
 
EPIC Protocol Version 1.3 dated 14 July 2022                                                    
Screening and Enrolment IS and Informed consent (English; Version 1.7 dated 02 February 2023)                        Page 12 of 13 
Investigator’s name: Prof Thesla Palanee-Phillips and Dr Nkosiphile Ndlovu
 
 
 
Approved by Wits IEC (HREC) 
 
 
Date approved: 04 April 2023 
 
               Participant Initials: ____   ____   ____       
 
 
NOTIFICATION OF PERSONAL DOCTOR: 
Please indicate whether you would like us to inform your personal doctor about your 
participation in this study 
Please sign or place your mark/thumbprint next to the option you choose 
 
 
________________________________ 
Participant’s signature/mark or  
thumbprint  
Yes, I want you to inform my personal doctor 
(Staff to obtain personal doctor contact details) 
 
 
____________________________ 
 Participant’s signature/mark or  
Thumbprint 
No, I do not want you to inform my personal 
doctor 
 
 
____________________________ 
 Participant’s signature/mark or  
Thumbprint 
I do not have a personal doctor. 
 
 
AUDIO RECORDING OF INTERVIEWS SESSIONS 
Please sign or place your mark/thumbprint next to the option you choose 
 
 
___________________________ 
Participant’s signature/mark or 
Thumbprint 
Yes, I agree to have my interview audio recorded. 
 
 
_________________________ 
Participant’s signature/mark or 
thumbprint 
 
No, I do not agree to have my interview audio 
recorded 
*  If a potential participant does not agree to audio recording for the interview, she will not be able to 
participate in the interview. 
 
INFORMED CONSENT: 
▪ 
I 
hereby 
confirm 
that 
I 
have 
been 
informed 
by 
the 
study 
staff 
member_________________________________________________(Print full name), 
about the nature, conduct, benefits and risks of the study  
▪ 
I have also received, read (or had read to me) and understood the above written 
information (Participant Information Sheet and Informed Consent for Screening and 
Enrolment) regarding the study. 
▪ 
I am aware that the results of the study, including personal details regarding my ethnicity, 
race, sex, age, medical conditions, date of birth, initials and diagnosis will be anonymously 
processed into a study report. 
▪ 
I may, at any stage, without prejudice, withdraw my consent and participation in the study. 
▪ 
I have had sufficient opportunity to ask questions and (of my own free will) declare myself 
prepared to participate in the study 
 
 


 
 
EPIC Protocol Version 1.3 dated 14 July 2022                                                    
Screening and Enrolment IS and Informed consent (English; Version 1.7 dated 02 February 2023)                        Page 13 of 13 
Investigator’s name: Prof Thesla Palanee-Phillips and Dr Nkosiphile Ndlovu
 
 
 
Approved by Wits IEC (HREC) 
 
 
Date approved: 04 April 2023 
 
               Participant Initials: ____   ____   ____       
 
 
Signature of participant: 
Signature/mark or 
thumbprint 
 
 
Date of 
signature 
 
 
 
DD 
MMM 
YYYY 
Print name 
 
 
 
Time of 
signature 
: 
(24 hour clock) 
 
 
 
Signature of witness (if applicable): 
Signature 
 
 
 
Date of 
signature 
 
 
 
DD 
MMM 
YYYY 
Print name 
 
 
 
Time of 
signature 
: 
(24 hour clock) 
 
 
Signature of study staff taking consent: 
Signature 
 
 
Date of 
signature 
 
 
 
DD 
MMM 
YYYY 
Print name 
 
 
 
Time of 
signature 
: 
(24 hour clock) 
 
 
 
 


 
 
EPIC Protocol Version 1.3 dated 14 July 2022 
Specimen Storage IS and Informed consent (English; Version 1.5 dated  14 July 2022)                                       Page 1 of 5 
Investigator’s name: Prof. Thesla Palanee-Phillips and Dr Nkosiphile Ndlovu
 
 
 
Approved by Wits IEC (HREC) 
 
 
Date approved:13 October 2022 
Approved by SAHPRA: 14 October 2022    
 
               Participant Initials: ____   ____   ____       
 
 INFORMATION SHEET (IS) AND INFORMED CONSENT  
Each participant must receive, read and understand this document before any study-related 
procedure 
 
SHEET 2: 
Storage and Future Testing of Specimens 
TITLE FOR THE STUDY: 
EPIC- Evaluation of Pharmacokinetic drug-drug            
Interactions between hormonal Contraceptives and 
doravirine- containing ART among women living with 
HIV in South Africa 
SPONSOR: 
Merck, Inc 
PRINCIPAL INVESTIGATORS:      
Prof. Thesla Palanee-Phillips and Dr Nkosiphile 
Ndlovu 
INSTITUTION: 
Wits Reproductive Health and HIV Institute (Wits 
RHI), University of the Witwatersrand 
DAY TIME AND AFTER HOURS 
TELEPHONE NUMBERS:        
Day Tel: 011 358 5424                                                     
A/H Tel: 084 722 5877 
 
 
 
 
 
 
 
 
DATE AND START TIME OF INFORMED CONSENT DISCUSSION:  
 
 
 
 
: 
DD 
MMM 
YYYY 
 
Time (24hr clock) 
 
INTRODUCTION 
While you are in the EPIC study, you agreed to have biological specimens collected and tested 
to check on your health or other infections. After the study is done, there may be some biological 
specimens left over that might be useful for future research. You are being asked to agree to the 
storage of these biological specimens. No additional specimens will be collected; only leftover 
biological specimens will be kept and used for future testing. 
 
This consent form gives you information about the collection, storage, and use of these 
biological specimens and related health information for use in future studies.  The study staff 
will talk with you about this information. Please ask study staff any questions you may have. If 
you would like to speak with a medical doctor or if you have medical questions, please let me 
know so that this can be arranged.  You will be asked to sign or make your mark on this form 
to indicate whether you agree to have your biological specimens stored and tested in the future. 
You will be offered a copy of this form to keep. 
 
HOW WILL WE USE YOUR BIOLOGICAL SPECIMENS? 
We would like permission to store your biological specimens. At the moment we cannot provide 
exact details of what will be looked at as this is not yet known, but we give assurance that no 
research will be done on the specimens without the approval of the Wits Human Research Ethics 
Committee as well as the applicable Research Ethics Committee (REC) at the places where 
further testing may be done. 
To the potential Participant: This consent form may contain words that you do not 
understand.   Please ask the study doctor or the study staff to explain any words or 
information that you do not clearly understand.   You may take home an unsigned copy 
of this consent form to think about or discuss with family or friends before making your 
decision. 


 
 
EPIC Protocol Version 1.3 dated 14 July 2022 
Specimen Storage IS and Informed consent (English; Version 1.5 dated  14 July 2022)                                       Page 2 of 5 
Investigator’s name: Prof. Thesla Palanee-Phillips and Dr Nkosiphile Ndlovu
 
 
 
Approved by Wits IEC (HREC) 
 
 
Date approved:13 October 2022 
Approved by SAHPRA: 14 October 2022    
 
               Participant Initials: ____   ____   ____       
 
 
The future research will be related to HIV transmission and prevention as well as contraception 
Your biological specimens will be used to look for damage caused by infection; or your body's 
response to infection and drug testing. For instance, researchers may look at your blood cells 
and substances in your biological specimens called proteins and chemicals. Additional testing 
may be performed as part of specimen quality control.  Some of these tests may be done outside 
of your country. 
 
Only approved researchers will be able to use these specimens and health information. The 
researchers do not plan to contact you or your regular doctor with any results from tests done on 
your stored biological specimens. This is because research tests are often done using ways 
that are experimental, so the results do not usually help doctors manage your health. If a rare 
situation comes up in which the researchers decide that a test result is important for your 
health, the researchers will notify your study doctor and your study doctor will try to contact 
you. If you wish to be contacted with this type of test result, you must give the study doctor or 
nurse any change to your contact information. If you want your regular doctor to be told about 
this type of test result, you must provide the study doctor or nurse with your regular doctor’s 
name and contact information. 
 
Your biological specimens will not be sold or used directly to produce commercial products. 
Research studies wishing to use your biological specimens will be reviewed by the University 
of Witwatersrand Human Research Ethics Committee.  The role of this committee is to protect 
you and other research volunteers from harm. 
 
HOW LONG WILL WE KEEP YOUR BIOLOGICAL SPECIMENS? 
Your specimens will be stored for a period of 15 years and may be shipped and/or stored outside 
of the country.  We do not yet know the specific type of testing that will be done with these 
specimens. But, they may be used to check that certain laboratory tests perform correctly.  Any 
other testing beyond that will have to be approved by the Wits Human Research Ethics Committee 
 
HOW WILL YOUR BIOLOGICAL SPECIMENS BE STORED? 
Your biological specimens will be stored at special facilities that are designed to store 
specimens safely and securely. Specimens will be stored by the Wits RHI laboratory or 
laboratories who have been contracted by Wits RHI and will be shipped at intervals to other 
facilities outside the country for use.  The storage facilities are designed so that only approved 
researchers will have access to the specimens. Some employees of the storage facilities will 
need to have access to your specimens to store them and keep track of where they are, but 
these people will not have information that directly identifies you. 
 
DOES STORAGE OF YOUR BIOLOGICAL SPECIMENS HAVE BENEFIT TO YOU? 
There are no direct benefits to you. The benefit of doing research on stored biological specimens 
includes learning more about HIV infection. 
 
GENETIC TESTING 
Genetic testing is not currently a requirement of the protocol and your stored specimens will not 
be used for any genetic testing at this stage. Should the protocol team decide at a later stage to 
conduct a study that involves genetic testing a formal application process will be made to the 
Wits Human Research Ethics Committee and a separate consent will be requested from you. 
 
WHAT ARE THE RISKS? 
There are no direct risks related to storing your biological specimens.  
 
WHAT ABOUT CONFIDENTIALITY? 
To keep your information private, your biological specimens will be labeled with a code that can 


 
 
EPIC Protocol Version 1.3 dated 14 July 2022 
Specimen Storage IS and Informed consent (English; Version 1.5 dated  14 July 2022)                                       Page 3 of 5 
Investigator’s name: Prof. Thesla Palanee-Phillips and Dr Nkosiphile Ndlovu
 
 
 
Approved by Wits IEC (HREC) 
 
 
Date approved:13 October 2022 
Approved by SAHPRA: 14 October 2022    
 
               Participant Initials: ____   ____   ____       
 
only be traced back to your research clinic. Your name and other personal information will be 
protected by the research clinic. When researchers are given your stored biological specimens 
to study, they will not be given your personal information. 
 
The results of future tests will not be included in your health records. Any publication about the 
results of future tests will not use your name or identify you personally. The researchers will do 
everything they can to protect your privacy. Every effort will be made to keep your personal 
information confidential. Your personal information may be disclosed if required by law. Your 
records may be reviewed by: 
• Study sponsors and funders 
• United States (US), local and international regulatory entities 
• Members of the study protocol team and external advisors 
• South African Health Products Regulatory Authority  
• Human Research Ethics Committee, University of the Witwatersrand, an Ethics Committee is 
a committee that watches over the safety and rights of research participants  
• National Health Research Ethics Committee (NHREC)  
• Members of an Independent Data Safety Monitoring Board who review this clinical trial  
• Study monitors 
• Study staff 
 
WHAT ARE YOUR RIGHTS? 
Allowing your biological specimens to be stored is completely voluntary. If you decide not to have 
any biological specimens stored other than what is needed to complete the study, you can 
still remain in the study, and your leftover biological specimens will be destroyed after all of the 
study procedures are finished.  If you decide now that your biological specimens can be stored 
for future research, you may change your mind at any time. However, you must inform the study 
staff that you no longer want your specimens used for future research. Your biological specimens 
will then not be used and will be destroyed but researchers will not be able to destroy specimens 
or information from research that is already started. 
 
PROBLEMS OR QUESTIONS 
If you have any questions about the study, who to contact at the study site, or if you have a 
research related injury or any other problems related to the study, please feel free to contact the 
clinic staff by visiting the clinic between 08:00 to 16:30 or phoning on 011 358 5424 or after hours 
on 084 722 5877/ 083 797 0144. If you feel that you require more information than the clinic staff 
are able to give you please contact one of the people listed below: 
Prof. Thesla Palanee - Phillips 
Co-Principal Investigator 
Wits RHI, Research Centre 
No. 7 Esselen Street, Hillbrow 
Tel: 011 358 5471 
 
Dr Nkosiphile Ndlovu 
Co-Principal Investigator 
Wits RHI, Research Centre 
No. 7 Esselen Street, Hillbrow 
Tel: 011 358 5424 
Emergency Number: 084 722 5877 
This study is conducted in accordance with the Department of Health Guidelines for the South 
African Good Clinical Practice: Clinical Trial Guidelines (2020) and has received ethical approval 
from the University of the Witwatersrand, Human Research Ethics Committee. If you want any 
information regarding your rights as a research participant, or complaints regarding this research 
study, you may contact Prof. Clement Penny, Chairperson of the University of Witwatersrand, 
Human Research Ethics Committee, which is an independent committee established to help 
protect the rights of research participants at 011 717 2301 
Prof. Clement Penny 
Chairperson for the Committee for Human Research Ethics Committee 


 
 
EPIC Protocol Version 1.3 dated 14 July 2022 
Specimen Storage IS and Informed consent (English; Version 1.5 dated  14 July 2022)                                       Page 4 of 5 
Investigator’s name: Prof. Thesla Palanee-Phillips and Dr Nkosiphile Ndlovu
 
 
 
Approved by Wits IEC (HREC) 
 
 
Date approved:13 October 2022 
Approved by SAHPRA: 14 October 2022    
 
               Participant Initials: ____   ____   ____       
 
 
If you have questions about this trial you should first discuss them with your personal/study doctor 
or the ethics committee (contact details as provided on this form). After you have consulted your 
personal/study doctor or the ethics committee and if they have not provided you with the answers 
to your satisfaction, you should write to the South African Health Products Regulatory Authority 
(SAHPRA) at: 
The Chief Executive Officer 
South African Health Products Regulatory Authority  
Department of Health 
Private Bag X828 
Pretoria  
0001 
E-mail: Boitumelo.Semete@sahpra.org.za 
Tel: 012 501 0410                   
 
DATE AND TIME OF COMPLETION OF INFORMED CONSENT DISCUSSION:  
 
 
 
 
: 
DD 
MMM 
YYYY 
 
Time  (24 hour clock) 
 
INFORMED CONSENT: 
▪ 
I    hereby    confirm    that    I    have    been    informed    by    the    study    staff 
member                       ________________                                 (PRINT   FULL   NAME),   
about   the storage and future testing of specimens collected during my participation in the 
study. 
▪ 
I have also received, read (or had read to me) and understood the above written 
information (Participant Information Sheet and Informed Consent: Storage and Future 
Testing of Specimens). 
▪ 
I understand that my decision of whether to have my specimens stored and tested in the 
future will not affect my participation in the study or my medical care. 
▪ 
I am aware that, if I agree to have my specimens stored and tested in the future, the 
results of tests on my specimens and health data, which may include personal details 
regarding my race, ethnicity, sex, age, medical conditions, date of birth, initials and 
diagnosis, will be anonymously processed into a study report. 
▪ 
I may, at any stage, without prejudice, withdraw my consent for my specimens to be 
stored and tested in the future. 
▪ 
I have had sufficient opportunity to ask questions and (of my own free will) agree to the 
storage of specimens for future testing. 
 
Please sign or place your mark/thumbprint next to the option you choose 
University of the Witwatersrand             Tel: 011 717 2301 
 
 
________________________________ 
Participant’s signature/mark or 
thumbprint 
I DO agree to allow my biological specimens and 
health data to be stored and used in future 
research studies 


 
 
EPIC Protocol Version 1.3 dated 14 July 2022 
Specimen Storage IS and Informed consent (English; Version 1.5 dated  14 July 2022)                                       Page 5 of 5 
Investigator’s name: Prof. Thesla Palanee-Phillips and Dr Nkosiphile Ndlovu
 
 
 
Approved by Wits IEC (HREC) 
 
 
Date approved:13 October 2022 
Approved by SAHPRA: 14 October 2022    
 
               Participant Initials: ____   ____   ____       
 
 
 
Signature of participant: 
Signature/mark or 
thumbprint 
 
 
 
Date of 
signature 
 
 
 
DD 
MMM 
YYYY 
Print name 
 
 
 
Time of 
signature 
: 
(24 hour clock) 
 
Signature of witness (if applicable): 
Signature 
 
 
 
Date of 
signature 
 
 
 
DD 
MMM 
YYYY 
Print name 
 
 
 
Time of 
signature 
: 
(24 hour clock) 
 
 
Signature of study staff taking consent: 
Signature 
 
 
Date of 
signature 
 
 
 
DD 
MMM 
YYYY 
Print name 
 
 
 
Time of 
signature 
: 
(24 hour clock) 
 
 
 
_________________________________ 
Participant’s signature/mark or 
thumbprint 
I DO NOT agree to allow my biological specimens 
and health data to be stored and used in future 
research studies