A Phase 3 Double Blind Safety and Efficacy Study of Long-Acting Injectable Cabotegravir Compared to Daily Oral TDF/FTC for Pre-Exposure Prophylaxis in HIV-Uninfected Women
Phase: PHASE3
Conditions: HIV Infections
Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

HPTN 084, FINAL, Version 3.0 
1 of 230 
Dated 12August2021 
HPTN 084: 
A Phase 3 Double Blind Safety and Efficacy Study of Long-Acting Injectable Cabotegravir 
Compared to Daily Oral TDF/FTC for Pre-Exposure Prophylaxis in HIV-Uninfected Women 
 
 
 
 
DAIDS Document ID: 38070 
A Study by the HIV Prevention Trials Network 
 
Sponsored by: 
Division of AIDS (DAIDS), United States (US) National Institute of Allergy and Infectious Diseases 
(NIAID),  
National Institutes of Health (NIH) 
 
Support Provided by: 
ViiV Healthcare 
Gilead Sciences, Inc. 
Bill & Melinda Gates Foundation (BMGF) 
      
 
 
IND Holder: 
DAIDS, US NIAID, NIH 
 
IND #: 122,744 
 
Protocol Chair: 
Sinead Delany-Moretlwe, MBBCh, PhD, DTM&H 
 
Protocol Co-Chair: 
Mina Hosseinipour, MD, MPH 
 
 
 
 
Protocol Version 3.0, dated 12Aug2021 
FINAL 
 
 
 
 
 
 

 
 
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HPTN 084: 
 
A Phase 3 Double Blind Safety and Efficacy Study of Long-Acting Injectable Cabotegravir 
Compared to Daily Oral TDF/FTC for Pre-Exposure Prophylaxis in HIV-Uninfected Women 
 
TABLE OF CONTENTS 
TABLE OF CONTENTS ........................................................................................................................................................... 2 
LIST OF ABBREVIATIONS AND ACRONYMS........................................................................................................................... 6 
PROTOCOL TEAM ROSTER ................................................................................................................................................. 10 
PROTOCOL SIGNATURE PAGE ............................................................................................................................................ 14 
TERMINOLOGY FOR CABOTEGRAVIR AND TDF/FTC FORMULATIONS ................................................................................ 15 
SCHEMA ............................................................................................................................................................................ 16 
OVERVIEW OF STUDY DESIGN AND RANDOMIZATION SCHEME ........................................................................................ 19 
 
INTRODUCTION ........................................................................................................................................................ 20 
1.1 
BACKGROUND AND RATIONALE ........................................................................................................................................... 20 
1.2 
OVERVIEW OF ORAL CAB AND CAB LA ................................................................................................................................ 22 
1.3 
METABOLISM .................................................................................................................................................................. 23 
1.4 
PRECLINICAL STUDIES ........................................................................................................................................................ 23 
1.5 
DOSE RATIONALE ............................................................................................................................................................. 24 
1.6 
CLINICAL EXPERIENCE TO DATE: ORAL CAB AND CAB LA ........................................................................................................ 31 
1.7 
PREGNANCY AND PREGNANCY PREVENTION WITH CAB USE ..................................................................................................... 35 
1.8 
HEPATIC AND CENTRAL NERVOUS SYSTEM ADVERSE EVENTS .................................................................................................... 37 
1.9 
WEIGHT GAIN .................................................................................................................................................................. 38 
1.10 RATIONALE FOR STUDY DESIGN ........................................................................................................................................... 38 
1.11 RATIONALE FOR USE OF ORAL RUN-IN PRIOR TO INJECTABLE DOSING ......................................................................................... 39 
 
STUDY OBJECTIVES AND DESIGN .............................................................................................................................. 40 
2.1 
PRIMARY OBJECTIVES ........................................................................................................................................................ 40 
2.2 
SECONDARY OBJECTIVES .................................................................................................................................................... 40 
2.3 
TERTIARY OBJECTIVES ........................................................................................................................................................ 40 
2.4 
EXPLORATORY OBJECTIVES ................................................................................................................................................. 41 
2.5 
STUDY DESIGN AND OVERVIEW ........................................................................................................................................... 41 
 
STUDY POPULATION ................................................................................................................................................. 44 
3.1 
INCLUSION CRITERIA ......................................................................................................................................................... 44 
3.2 
EXCLUSION CRITERIA ......................................................................................................................................................... 45 
3.3 
RECRUITMENT PROCESS ..................................................................................................................................................... 46 
3.4 
CO-ENROLLMENT GUIDELINES ............................................................................................................................................ 46 
3.5 
PARTICIPANT RETENTION ................................................................................................................................................... 47 
3.6 
PARTICIPANT WITHDRAWAL ............................................................................................................................................... 47 
 
STUDY PRODUCT CONSIDERATIONS ......................................................................................................................... 49 

 
 
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4.1 
STUDY PRODUCT REGIMENS/ADMINISTRATION/FORMULATION CONTENT................................................................................... 49 
4.2 
STUDY PRODUCT PREPARATION .......................................................................................................................................... 51 
4.3 
STUDY PRODUCT ACQUISITION AND ACCOUNTABILITY ............................................................................................................. 55 
4.4 
OTHER STUDY PRODUCT DISPENSING CONSIDERATIONS ........................................................................................................... 56 
4.5 
TOXICITY MANAGEMENT ................................................................................................................................................... 56 
4.6 
CONCOMITANT, PROHIBITED, AND PRECAUTIONARY MEDICATIONS ............................................................................................ 56 
 
STUDY PROCEDURES ................................................................................................................................................ 59 
5.1 
SCREENING ...................................................................................................................................................................... 59 
5.2 
STEP 1, ORAL RUN-IN PHASE: ENROLLMENT .......................................................................................................................... 59 
5.3 
STEP 1, ORAL RUN-IN PHASE: SAFETY VISITS ......................................................................................................................... 60 
5.4 
STEP 2, INJECTION PHASE: INJECTION VISITS .......................................................................................................................... 62 
5.5 
STEP 2, INJECTION PHASE: SAFETY VISITS .............................................................................................................................. 62 
5.6 
STEP 3, FOLLOW-UP PHASE ................................................................................................................................................ 63 
5.7 
STANDARD OF CARE (SOC) COUNSELING FOR ALL PARTICIPANTS ............................................................................................... 63 
5.8 
INJECTION VISIT WINDOWS ................................................................................................................................................ 64 
5.9 
PROCEDURES FOR CONTINUED ORAL AND INJECTABLE DOSING .................................................................................................. 64 
5.10 PROCEDURES FOR PARTICIPANTS IN STEP 2 WHO DO NOT COMPLETE THE FULL COURSE OF STUDY PRODUCT ................................... 64 
5.11 PARTICIPANTS WITH SUSPECTED OR CONFIRMED HIV INFECTION AT SCREENING, ENROLLMENT, OR FOLLOW-UP ................................ 65 
5.12 STIS ............................................................................................................................................................................... 66 
5.13 HBV AND HCV ................................................................................................................................................................ 66 
5.14 PREGNANCY .................................................................................................................................................................... 66 
5.15 PARTICIPANTS WHO DECLINE TO USE LONG ACTING CONTRACEPTION........................................................................................... 68 
5.16 ACCEPTABILITY ASSESSMENTS ............................................................................................................................................. 69 
5.17 INTERIM CONTACTS AND VISITS ........................................................................................................................................... 71 
5.18 PLANNED UNBLINDING OF STUDY PARTICIPANTS .................................................................................................................... 72 
5.19 CRITERIA FOR EARLY TERMINATION OF STUDY PARTICIPATION ................................................................................................... 72 
 
SAFETY MONITORING AND AE REPORTING .............................................................................................................. 73 
6.1 
AE DEFINITION AND REPORTING ......................................................................................................................................... 73 
6.2 
EAE REPORTING .............................................................................................................................................................. 73 
6.3 
SAFETY MONITORING ........................................................................................................................................................ 75 
6.4 
CLINICAL DATA REVIEW ..................................................................................................................................................... 75 
6.5 
SOCIAL HARMS REPORTING ................................................................................................................................................ 75 
6.6 
CRITICAL EVENTS REPORTING .............................................................................................................................................. 76 
 
STATISTICAL CONSIDERATIONS ................................................................................................................................ 77 
7.1 
REVIEW OF STUDY DESIGN ................................................................................................................................................. 77 
7.2 
ENDPOINTS ..................................................................................................................................................................... 77 
7.3 
SAMPLE SIZE AND INTERIM MONITORING .............................................................................................................................. 78 
7.4 
ACCRUAL AND RETENTION .................................................................................................................................................. 80 
7.5 
RANDOM ASSIGNMENT ..................................................................................................................................................... 80 
7.6 
BLINDING ........................................................................................................................................................................ 80 
7.7 
DATA AND SAFETY MONITORING BOARD OVERSIGHT AND STUDY MONITORING COMMITTEE OVERSIGHT ......................................... 81 
7.8 
STATISTICAL ANALYSIS ....................................................................................................................................................... 81 
 
HUMAN SUBJECTS CONSIDERATIONS ....................................................................................................................... 92 

 
 
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8.1 
ETHICAL REVIEW .............................................................................................................................................................. 92 
8.2 
INFORMED CONSENT ......................................................................................................................................................... 92 
8.3 
INCENTIVES ..................................................................................................................................................................... 92 
8.4 
CONFIDENTIALITY ............................................................................................................................................................. 92 
8.5 
COMMUNICABLE DISEASE REPORTING REQUIREMENTS ............................................................................................................ 93 
8.6 
STUDY DISCONTINUATION .................................................................................................................................................. 93 
 
LABORATORY SPECIMENS AND BIOHAZARD CONTAINMENT ................................................................................... 94 
9.1 
LOCAL LABORATORY SPECIMENS .......................................................................................................................................... 94 
9.2 
STORED SPECIMENS .......................................................................................................................................................... 95 
9.3 
QUALITY CONTROL AND QUALITY ASSURANCE PROCEDURES ..................................................................................................... 96 
9.4 
BIOHAZARD CONTAINMENT ................................................................................................................................................ 97 
 
ADMINISTRATIVE PROCEDURES ........................................................................................................................... 98 
10.1 PROTOCOL REGISTRATION .................................................................................................................................................. 98 
10.2 STUDY ACTIVATION ........................................................................................................................................................... 98 
10.3 STUDY COORDINATION ...................................................................................................................................................... 98 
10.4 STUDY MONITORING ......................................................................................................................................................... 99 
10.5 PROTOCOL COMPLIANCE .................................................................................................................................................. 100 
10.6 INVESTIGATOR'S RECORDS ................................................................................................................................................ 101 
10.7 USE OF INFORMATION AND PUBLICATIONS .......................................................................................................................... 101 
 
REFERENCES ....................................................................................................................................................... 102 
APPENDICES I - VIII .......................................................................................................................................................... 106 
APPENDIX IA: 
SCHEDULE OF EVALUATIONS – SCREENING AND STEP 1, ORAL RUN-IN PHASE .............................................................. 107 
APPENDIX IB: 
SCHEDULE OF EVALUATIONS - STEP 2, INJECTION PHASE .......................................................................................... 109 
APPENDIX IC: 
SCHEDULE OF EVALUATIONS - STEP 3, FOLLOW-UP PHASE # ..................................................................................... 111 
APPENDIX ID: 
SCHEDULE OF EVALUATIONS FOR PREGNANT PARTICIPANTS# .................................................................................... 113 
APPENDIX IE: 
SCHEDULE OF EVALUATIONS - CONTRACEPTIVE SUBSTUDY ONLY .............................................................................. 115 
APPENDIX II: 
SCHEDULE OF ADDITIONAL PROCEDURES FOR REACTIVE/ POSITIVE HIV TESTS ............................................................. 116 
APPENDIX III: 
TOXICITY MANAGEMENT ................................................................................................................................... 118 
APPENDIX IV: 
SAMPLE SCREENING AND ENROLLMENT INFORMED CONSENT FORM .......................................................................... 127 
APPENDIX V: 
SAMPLE QUALITATIVE INFORMED CONSENT FORM ................................................................................................. 146 
APPENDIX VI: GUIDANCE ON STUDY CONDUCT DURING THE COVID-19 PANDEMIC .............................................................................. 150 
APPENDIX VII: STUDY CONDUCT POST 5 NOVEMBER 2020 DSMB MEETING (LOA #4) ......................................................................... 154 
APPENDIX VIII: PROCEDURES FOR OFFERING OPEN LABEL (OL) CABOTEGRAVIR- THE NEXT PART OF HPTN 084 ...................................... 157 
1. 
BACKGROUND ................................................................................................................................................................ 157 
2. 
PURPOSE AND OVERVIEW ................................................................................................................................................ 158 
2.1 
DURATION .................................................................................................................................................................... 159 
2.2 
STUDY SITES AND POPULATION .......................................................................................................................................... 160 
2.3 
SPECIAL CONSIDERATIONS: ............................................................................................................................................... 160 
3. 
DESCRIPTION OF STEPS 4 AND 5 ........................................................................................................................................ 164 
3.1 
 OVERVIEW ................................................................................................................................................................... 164 
SECTION 3.0 (MODIFIED FROM THE MAIN PROTOCOL) .................................................................................................... 180 
3.4 
CO-ENROLLMENT: .......................................................................................................................................................... 180 
3.5 
PARTICIPANT RETENTION: ................................................................................................................................................ 181 
3.6 
PARTICIPANT WITHDRAWAL: ............................................................................................................................................ 181 
SECTION 4.0 (MODIFIED FROM THE MAIN PROTOCOL) .................................................................................................... 181 

 
 
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STUDY PRODUCT REGIMENS/ADMINISTRATION/FORMULATION CONTENT: ............................................................................... 181 
4.2 
STUDY PRODUCT PREPARATION: ....................................................................................................................................... 182 
4.3 
STUDY PRODUCT ACQUISITION AND ACCOUNTABILITY ........................................................................................................... 186 
4.4  OTHER STUDY PRODUCT DISPENSING CONSIDERATIONS ......................................................................................................... 186 
4.6 
CONCOMITANT, PROHIBITED, AND PRECAUTIONARY MEDICATIONS .......................................................................................... 187 
SECTION 5.0 (MODIFIED FROM THE MAIN PROTOCOL) .................................................................................................... 189 
5.8 
INJECTION VISIT WINDOWS .............................................................................................................................................. 189 
5.10  PROCEDURES FOR PARTICIPANTS IN STEP 4 WHO DO NOT COMPLETE THE FULL COURSE OF STUDY PRODUCT ................................. 189 
5.11 PARTICIPANTS WITH SUSPECTED OF CONFIRMED HIV INFECTION ............................................................................................. 189 
5.12 STIS ............................................................................................................................................................................. 190 
5.14 PREGNANCY .................................................................................................................................................................. 190 
5.17  INTERIM CONTACTS AND VISITS ........................................................................................................................................ 191 
5.19  CRITERIA FOR EARLY TERMINATION OF STUDY PRODUCT ....................................................................................................... 191 
SECTION 6.0 (NOT MODIFIED FROM THE MAIN PROTOCOL) ............................................................................................ 192 
6.1 
 AE DEFINITION AND REPORTING ....................................................................................................................................... 192 
6.2 
 EAE REPORTING ............................................................................................................................................................ 192 
6.2.1  REPORTING TO DAIDS ................................................................................................................................................... 193 
6.2.2  REPORTING REQUIREMENTS FOR THIS STUDY ...................................................................................................................... 193 
6.2.3  GRADING SEVERITY OF EVENTS ......................................................................................................................................... 193 
6.3 
 SAFETY MONITORING ..................................................................................................................................................... 194 
6.4 
 CLINICAL DATA REVIEW .................................................................................................................................................. 194 
6.5 
 SOCIAL HARMS REPORTING ............................................................................................................................................. 194 
SECTION 7.0 (MODIFIED FROM THE MAIN PROTOCOL) .................................................................................................... 195 
SECTION 8.0 (NOT MODIFIED FROM THE MAIN PROTOCOL) ............................................................................................ 197 
8.1 
 ETHICAL REVIEW ............................................................................................................................................................ 197 
8.2 
 INFORMED CONSENT ...................................................................................................................................................... 198 
8.3 
 INCENTIVES ................................................................................................................................................................... 198 
8.4 
 CONFIDENTIALITY ........................................................................................................................................................... 198 
8.5 
 COMMUNICABLE DISEASE REPORTING REQUIREMENTS ......................................................................................................... 199 
8.6 
 STUDY DISCONTINUATION ............................................................................................................................................... 199 
SECTION 10.0 (NOT MODIFIED FROM THE MAIN PROTOCOL) .......................................................................................... 199 
10.1  PROTOCOL REGISTRATION ............................................................................................................................................... 199 
10.3  STUDY COORDINATION ................................................................................................................................................... 199 
10.4  STUDY MONITORING ...................................................................................................................................................... 200 
10.5  PROTOCOL COMPLIANCE ................................................................................................................................................. 201 
10.6  INVESTIGATOR'S RECORDS ............................................................................................................................................... 201 
10.7  USE OF INFORMATION AND PUBLICATIONS ......................................................................................................................... 202 
TOXICITY MANAGEMENT (MODIFIED- APPENDIX III IN MAIN PROTOCOL) ....................................................................... 202 
ADDENDUM TO THE MAIN SAMPLE INFORMED CONSENT FORM .................................................................................... 211 
REFERENCES TO OLE APPENDIX ....................................................................................................................................... 228 

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LIST OF ABBREVIATIONS AND ACRONYMS 
ABC/3TC 
abacavir/lamivudine 
AE 
adverse event 
AIDS 
acquired immunodeficiency syndrome 
ALT 
alanine aminotransferase 
ART 
antiretroviral therapy 
ARV 
antiretroviral 
AST 
aspartate aminotransferase 
AUC 
area under the curve 
BCRP 
breast cancer resistance protein 
hCG 
beta human chorionic gonadotropin 
BMI 
body mass index 
BSC 
biological safety cabinet 
BUN 
blood urea nitrogen 
C 
Celsius 
C 
trough concentration 
CAB 
cabotegravir, oral and LA formulations 
CAB LA 
long-acting injectable formulation of cabotegravir 
CABG 
coronary artery bypass grafting 
CBC 
complete blood count 
CD4 
T-helper cells or T4 cells 
CDC 
(US) Centers for Disease Control and Prevention 
CFR 
(US) Code of Federal Regulations 
CI 
confidence interval 
CLIA 
Clinical Laboratory Improvement Amendments 
Cmax 
maximum or “peak” concentration of a drug observed after its 
administration 
CMC 
Clinical Management Committee 
Cmin 
minimum or “trough” concentration of a drug observed after its 
administration and just prior to the administration of a subsequent dose 
CPQA 
Clinical Pharmacology Quality Assurance  
CPK 
creatine phosphokinase 
CRF 
case report form 
CRM 
Clinical Research Manager 
CRPMC 
Clinical Research Products Management Center 
CT 
Chlamydia trachomatis 
CVb% 
geometric mean 
DAERS 
DAIDS Adverse Event Reporting System 
DAIDS 
Division of AIDS 
DAIDS PRO 
DAIDS Protocol Registration Office 
DAIDS RSC 
DAIDS Regulatory Support Contract 
DBS 
dried blood spot 
DMPA 
depot medroxyprogesterone acetate 
DSMB 
Data and Safety Monitoring Board 
EAE 
expedited adverse event 

 
 
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EC 
Ethics Committee 
ÉCLAIR 
Phase IIa Safety and PK Study of Cabotegravir LA in HIV-Uninfected 
Men 
EE 
ethinyl estradiol 
EFD 
early fetal development 
EFV 
efavirenz 
EQA 
external quality assurance 
FDA 
(US) Food and Drug Administration 
FEM-PrEP 
Pre-exposure Prophylaxis Trial for HIV Prevention among African 
Women 
FSH 
follicle stimulating hormone 
FTC 
emtricitabine 
FTC-TP 
emtricitabine triphosphate 
GC 
Neisseria gonorrheae 
GT 
genital tract 
HBcAb 
hepatitis B virus core antibody 
HBsAb 
hepatitis B virus surface antibody 
HBsAg 
hepatitis B surface antigen 
HBV 
hepatitis B virus 
HCAb 
HCV 
hepatitis C antibody 
hepatitis C virus 
HDL 
high-density lipoprotein 
HDPE 
high density polyethylene 
HIV 
human immunodeficiency virus 
HIV RNA 
HIV test using a ribonucleic acid 
HIV-1 
human immunodeficiency virus type 1 
HPTN 
HIV Prevention Trials Network 
HPTN LC 
(HPTN) Laboratory Center 
HPTN LDMS 
(HPTN) Laboratory Data Management System 
HPTN LOC 
(HPTN) Leadership and Operations Center 
HPTN SDMC 
(HPTN) Statistical and Data Management Center 
HR 
hazard ratio 
HSV-2 
herpes simplex virus type 2 
IATA 
International Air Transport Association 
IB 
Investigator Brochure 
ICF 
informed consent form 
ID 
identification 
IM 
intramuscular 
IND 
investigational new drug 
INSTI 
integrase strand transfer inhibitor  
IoR 
Investigator of Record  
IP 
intraperitoneal 
iPrEX OLE 
iPrEx Open Label Extension 
IRB 
Institutional Review Board 
ISR 
injection site reaction 
IUD 
intrauterine device 

 
 
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IUS 
Intrauterine system 
LA 
long-acting (injectable) 
LC 
(HPTN) laboratory center 
LATTE 
Cabotegravir plus Rilpivirine, once a day, after Induction with 
Cabotegravir plus Nucleoside Reverse Transcriptase Inhibitors in 
Antiretroviral-naïve Adults with HIV-1 Infection 
LATTE-2 
Cabotegravir plus Rilpivirine as Long-Acting Maintenance Therapy 
LDL 
low-density lipoprotein 
LDMS 
(HPTN) Laboratory Data and Management System 
LFTs 
liver function tests 
LH 
luteinizing hormone 
LOC 
(HPTN) Leadership and Operations Center 
MOP 
Manual of Operations 
MRC 
(HPTN) Manuscript Review Committee 
MSM 
men who have sex with men 
NAAT 
nucleic acid amplification test 
NET-EN 
Norethisterone enanthate 
NI 
non-inferiority 
NIAID 
(US) National Institute of Allergy and Infectious Diseases 
NNRTI 
non-nucleoside reverse transcriptase inhibitor 
NOAEL 
no observed adverse effect level 
NRTI 
nucleotide reverse transcriptase inhibitor 
OHRP 
Office for Human Research Protections 
Oral CAB 
oral formulation of cabotegravir 
PA-IC90 
protein-adjusted 90% inhibitory concentration 
PAL 
Protocol Analyte List 
PI 
package insert 
Pgp 
permeability glycoprotein 
PK 
pharmacokinetic 
PO 
by mouth/orally 
PPN 
pre- and postnatal development 
PrEP 
pre-exposure prophylaxis 
PRO 
(DAIDS) Protocol Registration Office 
PROUD 
Pre-exposure Prophylaxis to Prevent Acquisition of HIV-1 Infection 
PSRC 
(DAIDS) Prevention Science Review Committee 
PTCA 
percutaneous transluminal coronary angioplasty 
PY 
person-years 
QA 
quality assurance 
QC 
quality control 
QT 
time between the start of the Q wave and the end of the T wave 
RCT 
randomized clinical trial 
RE 
regulatory entity 
RNA 
ribonucleic acid 
RPV 
rilpivirine 
RPV LA 
rilpivirine long-acting (injectable) 
RSC 
(DAIDS) Regulatory Support Center 

 
 
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SAE 
serious adverse events 
SAHPRA 
South African Health Products Regulatory Authority 
SC 
subcutaneous 
SDMC 
(HPTN) Statistics and Data Management Center 
SHIV 
simian human immunodeficiency virus 
SMC 
Study Monitoring Committee 
SOE 
Schedule of Evaluations 
SOC 
standard of care 
SOP 
standard operating procedure 
SSA 
sub-Saharan Africa 
SSP 
Study Specific Procedures Manual 
SRC 
(HPTN) Scientific Review Committee 
STI 
sexually transmitted infection 
TBili 
total bilirubin 
TCID 
tissue culture infective dose 
TDF 
tenofovir disoproxil fumarate 
TDF/FTC 
tenofovir/emtricitabine (trade name: Truvada®) 
TFV 
tenofovir 
TFV-DP 
tenofovir diphosphate 
TGW 
transgender women 
TP 
triphosphate 
TV 
Trichomonis vaginalis 
ULN 
upper limit of normal 
US 
United States  
VOICE 
Vaginal and Oral Interventions to Control the Epidemic 
WHO 
World Health Organization 
 

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HPTN 084: 
A Phase 3 Double Blind Safety and Efficacy Study of Long-Acting Injectable Cabotegravir 
Compared to Daily Oral TDF/FTC for Pre-Exposure Prophylaxis in HIV-Uninfected Women  
 
PROTOCOL TEAM ROSTER 
PROTOCOL CHAIR: 
Sinead Delany-Moretlwe, MBBCh, 
PhD, DTM&H 
Research Professor and Director: 
Research 
Wits Reproductive Health and HIV Institute 
(Wits RHI)  
University of the Witwatersrand 
Hillbrow Health Precinct 
22 Esselen Street 
Johannesburg, SA 2001 
Phone:  +27 11 358 5414 
Fax:  +27 86 426 5575 
Email: sdelany@wrhi.ac.za 
 
 
Adeola Adeyeye, MD, MPA 
Medical Officer 
Prevention Science Program 
DAIDS, NIAID, NIH 
Room 8B36 MSC 9831 
5601 Fishers Lane  
Rockville, MD 20852-9832 
United States 
Phone:  240-669-5005  
Cell: 240-619-9365 
Email: adeyeyeao@niaid.nih.gov    
 
Yaw Agyei, MPH, BS (MT) 
HPTN Laboratory Center  
Johns Hopkins University  
Department of Pathology 
Pathology Building 306 
600 N. Wolfe Street 
Baltimore, MD 21287 
United States 
Phone: 410-614-6763 
Email: yagyei1@jhmi.edu 
 
 
 
 
 
 
PROTOCOL CO-CHAIR: 
Mina Hosseinipour, MD, MPH 
Professor of Medicine, University of North 
Carolina at Chapel Hill School of Medicine,  
Scientific Director, UNC Project-Malawi 
UNC Project, Tidziwe Centre 
Private Bag A-104 
Lilongwe, Malawi 
Phone:  265-1-755-056 
Fax:  265-1-755-954 
Email: mina_hosseinipour@med.unc.edu 
 
 
 
Priyanka Agarwal 
SDMC Clinical Data Manager 
1100 Fairview Avenue North 
E3-465 
Seattle, WA 98109 
Phone: 206.667.4384 
Fax: 206-667-4812 
Email: pagarwal@scharp.org 
 
Stephanie Beigel-Orme 
SDMC Clinical Data Manager 
1100 Fairview Avenue North 
E3-129 
Seattle, WA 98109 
United States 
Phone: 206-667-7109 
Fax: 206-667-4812 
Email: sbeigelo@scharp.org 
 

 
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Myron S. Cohen, MD  
Chief, Division of Infectious Diseases 
University of North Carolina at Chapel Hill 
130 Mason Farm Road  
Suite 2115, CB 7030   
Chapel Hill, NC 27599-7030 
United States 
 
Phone: 919-962-4646 
Email: Myron_cohen@med.unc.edu   
 
Lynda Emel, PhD 
HPTN SDMC Associate Director 
SCHARP-FHCRC  
1100 Fairview Avenue N, LE-400 
PO Box 19024 
Seattle, WA 98109 
United States 
Phone:  206-667-5803  
Fax:  206-667-4812 
Email: lemel@scharp.org    
 
Susan Eshleman, MD, PhD  
HPTN Laboratory Center Virologist 
Johns Hopkins University School of 
Medicine  
720 Rutland Avenue 
Ross Bldg., Room 646 
Baltimore, MD 21205 
United States 
Phone: 410-614-4734 
Fax: 410-502-9244 
Email: seshlem@jhmi.edu 
 
Jennifer Farrior, MS 
HPTN LOC CRM 
359 Blackwell Street, Suite 200 
Durham, NC 27701 
United States 
Phone : 919-544-7040, x11341 
Fax : 919-405-1402 
Email : jfarrior@fhi360.org 
 
Craig W. Hendrix, MD 
HPTN LC Protocol Pharmacologist 
Director, Clinical Pharmacology 
Johns Hopkins University 
Blalock 569 
600 N. Wolfe St. 
Baltimore, MD 21287 
United States 
Phone: 410-955-9707 
Fax: 410-955-9708 
Email: chendrix@jhmi.edu 
 
Sybil Hosek, PhD 
Clinical Psychologist/Director of Research 
Department of Psychiatry 
Stroger Hospital of Cook County 
1900 W Polk Street, #854 
Chicago, IL 60612 
United States 
Phone: 312-864-8030 
Fax: 312-864-9203 
Email: shosek@cookcountyhhs.org 
 
James Hughes, PhD 
HPTN SDMC  
SCHARP-FHCRC  
University of Washington 
Department of Biostatistics 
MS# 357232 
Seattle, WA 98195 
United States 
Phone:  206-616-2721  
Fax:  206-667-4812 
Email: hughes@scharp.org    
 
Mark Marzinke, PhD, DABCC 
HPTN Laboratory Center Analytical 
Pharmacologist 
Director, CPAL 
Johns Hopkins University 
Department of Pathology  
1800 Orleans Street 
Sheikh Zayed Tower, Room B1-1020F 
Baltimore, MD 21287  
United States 
Phone: (443) 287-7516 
CPAL Office: (410) 550-9702 
Email:  mmarzin1@jhmi.edu 
 
 

 
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Estelle M. Piwowar-Manning, BS, MT 
Johns Hopkins University  
Pathology Building, Room 313  
600 North Wolfe Street  
Baltimore, MD 21287, USA 
United States 
Phone: 410-614-6736  
Fax: 410-614-0430 
Email: epiwowa@jhmi.edu 
Alex Rinehart, PhD 
ViiV Healthcare 
5 Moore Drive 
Durham, NC 27709 
United States 
Phone:  919-483-2085 (office) 
Phone: 919-599-7551 (mobile) 
Email: alex.r.rinehart@viivhealthcare.com 
 
James Rooney, MD 
Gilead Sciences  
333 Lakeside Drive 
Foster City, CA 94404 
United States 
Phone: 650-522-5708  
Fax: 650-522-5854 
Email: jim.rooney@gilead.com    
Scott Rose, BS 
HPTN LOC CRM 
359 Blackwell Street, Suite 200 
Durham, NC 27701 
United States 
Phone : 919-405-1447 
Fax : 919-405-1402 
Email: srose@fhi360.org 
 
Katherine Shin, Pharm. D. 
Senior Pharmacist 
Pharmaceutical Affairs Branch 
Division of AIDS  
5601 Fishers Lane 
Room 9D30, MSC 9829 
Rockville, MD 20852-9829 
United States 
Phone: 240-627-3047 
Fax: 301-402-1506 
E-mail: KaShin@niaid.nih.gov 
 
Nirupama Sista, PhD 
HPTN LOC Director 
359 Blackwell Street, Suite 200 
Durham, NC 27701 
Phone: 919-405-1454 
United States 
Fax: 919-405-1402 
Email: nsista@fhi360.org 
 
Kimberly Smith, MD, MPH 
ViiV Healthcare  
5 Moore Drive 
Durham, NC 27709 
United States 
Phone: 919-315-9825 
Email: 
kimberly.y.smith@viivhealthcare.com    
 
Betsy Tolley, MA, PhD 
FHI 360 
359 Blackwell Street, Suite 200 
Durham, NC 27701, USA 
United States 
Phone: 919-544-7040, Ext. 11334 
Fax: 919-405-1402 
Email: btolley@fhi360.org 
 
Lut Van Damme, MD, PhD 
Senior Program Officer,  
Global Health Program-HIV Prevention 
Bill &Melinda Gates Foundation 
PO Box 23350 
Seattle, WA 98102 
United States 
Phone: 206-709-3407 
Email: 
Lut.VanDamme@gatesfoundation.org 
 

 
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CONTRACEPTIVE SUBSTUDY ADVISOR  
 
Kimberly Scarsi, PharmD, MS 
Associate Professor 
Department of Pharmacy Practice 
Nebraska Medical Center 
Omaha, NE 68198-6145 
Phone: 402-559-9916 
Email: kim.scarsi@unmc.edu  
 
 
PREGNANCY AND INFANT SUBSTUDY ADVISORS  
 
Lynda Stranix-Chibanda, MBChB MMed (Paeds)  
Child and Adolescent Health Unit 
Faculty of Medicine and Health Sciences 
University of Zimbabwe 
15 Phillips Avenue 
Belgravia 
Harare, Zimbabwe 
Phone: 263-242-704890 
Email: lstranix@uz-ctrc.org 
Friday Saidi, MMED 
University of North Carolina Project Malawi Kamuzu Central  
Hospital/Tidziwe Centre 
100 Mzimba Road 
P Bag A-104 
Lilongwe, Malawi 
Phone: 265-9-954-03113 
Email: fsaidi@unclilongwe.org 
 
 
 
 
 
 
 

 
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PROTOCOL SIGNATURE PAGE 
HPTN 084: 
A Phase 3 Double Blind Safety and Efficacy Study of Long-Acting Injectable Cabotegravir 
Compared to Daily Oral TDF/FTC for Pre-Exposure Prophylaxis in HIV-Uninfected Women  
 
 
FINAL Version 
Protocol Version 3.0, dated 12August2021 
DAIDS Document ID: 38070 
 
A Study of the HIV Prevention Trials Network (HPTN) 
 
Sponsored by: 
Division of AIDS, US National Institute of Allergy and Infectious Diseases 
National Institutes of Health 
Support Provided by: 
ViiV Healthcare 
Gilead Sciences, Inc. 
Bill & Melinda Gates Foundation (BMGF) 
 
 
I will conduct the study in accordance with the provisions of this protocol and all applicable protocol-
related documents. I agree to conduct this study in compliance with United States (US) Health and 
Human Service regulations (45 CFR 46); applicable U.S. Food and Drug Administration regulations; 
standards of the International Conference on Harmonization Guideline for Good Clinical Practice (E6); 
Institutional Review Board/Ethics Committee determinations; all applicable in-country, state, and local 
laws and regulations; and other applicable requirements (e.g., US National Institutes of Health, Division 
of AIDS) and institutional policies. 
 
I 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.  
 
 
__________________________________ 
Name of Investigator of Record (print name) 
       __________________________________ 
 
____________________ 
Signature of Investigator of Record 
 
 
  
Date  (MM/DD/YYYY) 
 
 
 
 
 

 
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HPTN 084 
A Phase 3 Double Blind Safety and Efficacy Study of Long-Acting Injectable Cabotegravir 
Compared to Daily Oral TDF/FTC for Pre-Exposure Prophylaxis in HIV-Uninfected Women  
 
TERMINOLOGY FOR CABOTEGRAVIR AND TDF/FTC FORMULATIONS 
 
Compound Name or 
Abbreviation 
Comments 
Cabotegravir or CAB 
When written as shown, this is the ViiV 
Healthcare compound under study and refers to 
the parent compound, irrespective of formulation, 
usually in the context of PK measurement.     
Oral CAB 
When written as shown, this refers to the oral 
tablet formulation of cabotegravir.    
 
NOTE: HPTN 084 will use the 30 mg tablets. 
CAB LA 
When written as shown, this refers to the long-
acting injectable formulation of cabotegravir. 
 
NOTE: HPTN 084 will use the 200 mg/mL 
intramuscular (IM) formulation. 
TDF/FTC (tenofovir disoproxil 
fumarate/emtricitabine) 
When written as shown, this refers to the 
antiretroviral drug tenofovir/emtricitabine (trade 
name: Truvada®), manufactured by Gilead 
Sciences, Inc.   
 
NOTE: HPTN 084 will use the 300 mg/200mg 
fixed-dose combination tablets. 
TFV (tenofovir) 
When written as shown, this is the inactive, de-
esterified form of TDF. This form of the drug is 
measured in plasma and other body fluids.   
TFV-DP (tenofovir diphosphate) 
When written as shown, this is the active, 
phosphorylated form of tenofovir that is 
generated in cells. This is the form of the drug 
that is measured in cells (including PBMCs and 
RBCs). It is rapidly dephosphorylated to the 
inactive form outside of cells, and has a very 
short half-life outside of cells in tissue 
FTC (emtricitabine) 
When written as shown, this is the inactive form 
of FTC. This form of the drug is measured in 
plasma and other body fluids.   
FTC-TP (emtricitabine 
triphosphate) 
When written as shown, this is the active form of 
FTC that is generated in cells. This is the form 
measured in cells (including PBMCs and RBCs).   

 
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HPTN 084: 
A Phase 3 Double Blind Safety and Efficacy Study of Long-Acting Injectable Cabotegravir 
Compared to Daily Oral TDF/FTC for Pre-Exposure Prophylaxis in HIV-Uninfected 
Women  
SCHEMA 
Purpose: 
To evaluate the safety and efficacy of the injectable agent, cabotegravir (CAB LA) compared to 
daily oral tenofovir disoproxil fumarate/emtricitabine (TDF/FTC), for pre-exposure prophylaxis 
(PrEP) in HIV-uninfected women. 
 
Design: 
Multi-site, double blind, two-arm, randomized (1:1), controlled superiority trial of the safety and 
efficacy of CAB LA compared to daily oral TDF/FTC for HIV prevention. 
Population: 
HIV-uninfected women at risk for acquiring HIV, 18 to 45 years old.   
 
Study Size: 
Approximately 3,350 women will be enrolled. 
 
Study 
Approximately 4.6 years total, with individual participants being followed on randomized 
Duration: 
study product between 1.6 years (for the last enrolling participants) to approximately 3.6  
 
years (for the earliest enrolling participants), and on oral TDF/ FTC for an additional 48 weeks.  
Accrual will require approximately 2 years.   
 
Study 
Study sites will be in sub-Saharan Africa (SSA).  
Sites:  
     
  
 
Study  
Once randomized to one of two arms, participants will move through the following steps (active 
Regimen:  
study products are shown in bold text):  
 
Step 1, Oral Run-in Phase:   
Arm A – Daily oral cabotegravir (CAB) and oral TDF/FTC placebo for five weeks plus an HIV 
prevention package including behavioral risk reduction and adherence counseling, and offer of 
condoms. 
 
Arm B – Daily TDF/FTC and oral CAB placebo for five weeks plus an HIV prevention package 
including behavioral risk reduction and adherence counseling, and offer of condoms.  
 
 
Step 2, Injection Phase:  
 
Arm A – CAB LA as a single intramuscular [IM] injection at two time points four  
 
weeks apart and every eight weeks thereafter and daily oral TDF/FTC placebo plus an HIV   
prevention package including behavioral risk reduction and adherence counseling, and offer of  
condoms. 
 
Arm B – Daily TDF/FTC and IM placebo (matching vehicle, identical volume as active 
injectable product in Arm A) at two time points four weeks apart and every eight weeks thereafter 
plus an HIV prevention package including behavioral risk reduction and adherence counseling, 
and offer of condoms.  
 

 
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HPTN 084: 
A Phase 3 Double Blind Safety and Efficacy Study of Long-Acting Injectable Cabotegravir 
Compared to Daily Oral TDF/FTC for Pre-Exposure Prophylaxis in HIV-Uninfected Women 
 
SCHEMA (continued) 
 
 
Study   
Step 2 will continue until the required number of endpoints (114) is reached, estimated to be 81 
Regimen  
weeks after enrolling the last participant. 
Continued: 
 
 
Step 3, Follow-up Phase:  
 
 
Arms A and B – Open-label daily TDF/FTC (in order to cover the pharmacokinetic [PK] tail  
 
 
for Arm A participants) will be provided no later than eight weeks after the last injection visit,  
for up to 48 weeks plus an HIV prevention package including behavioral risk reduction and 
adherence counseling, and offer of condoms.  Participants will then transition to locally available 
HIV prevention services, including services for PrEP, if available.  
 
 
Primary 
Objectives:
 
 
 
• 
Efficacy: To evaluate the relative efficacy of oral CAB/CAB LA (oral run-in and injections, 
Steps 1 and 2) vs. daily oral TDF/FTC for HIV prevention (Steps 1 and 2). 
 
• 
Safety: To evaluate the relative safety of oral CAB/CAB LA (oral run-in and injections, 
Steps 1 and 2) vs. daily oral TDF/FTC for HIV prevention (Steps 1 and 2). 
 
 
Secondary 
Objectives: 
• 
To compare HIV incidence among participants receiving oral CAB/CAB LA vs. daily oral 
TDF/FTC (Steps 1, 2 and 3). 
• 
To evaluate relative efficacy of oral CAB/CAB LA vs. oral TDF/FTC in subgroups defined 
by the baseline factors of: age, herpes simplex virus-2 (HSV-2) serostatus, contraceptive 
method, and body mass index (BMI). 
 
• 
To describe and model the relationship between HIV incidence and drug concentration, 
within each arm. 
 
• 
To describe the distribution and correlates of drug concentration, within each arm. 
 
• 
To compare the acceptability of and preferences for CAB LA vs. oral TDF/FTC. 
 
 
 
 
 
 
 

 
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HPTN 084: 
A Phase 3 Double Blind Safety and Efficacy Study of Long-Acting Injectable Cabotegravir 
Compared to Daily Oral TDF/FTC for Pre-Exposure Prophylaxis in HIV-Uninfected Women 
 
SCHEMA (continued) 
 
 
 
 
 
 
Tertiary 
Objectives: 
 
• 
To estimate sexual risk behaviors, as measured by self-report and rates of incident 
sexually transmitted infections (STIs).  
 
• 
To compare Grade >2 adverse event (AE) rates in women with baseline BMI </≥ 25 
kg/m2, within each study arm. 
 
• 
To compare differences in weight gain  and BMI, by arm. 
 
• 
To compare pregnancy incidence and outcomes between arms. 
 
• 
To evaluate rates of HIV drug resistance among participants who acquire HIV infection 
during the study among participants receiving oral CAB/CAB LA vs. oral TDF/FTC. 
 
• 
To determine plasma concentrations of depot medroxyprogesterone (DMPA) or 
norethisterone (NET-EN) or etonogestrel when co-administered for contraception with 
study products (TDF/FTC or CAB LA). 
 
 
Exploratory 
Objectives: 
 
 
• 
To compare the estimated programmatic cost, cost-effectiveness and disease impact 
indicators of CAB LA vs. daily oral TDF/FTC vs. no PrEP for HIV-uninfected women 
in the study sites locations. 
 
• 
To perform secondary laboratory assessments that may include evaluation of factors 
related to HIV infection, hepatitis infection, and other infections; antiretroviral (ARV) 
drug use; pharmacogenomics; characterization of HIV in infected participants; and 
evaluation of laboratory assays related to the study objectives. 
 

 
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HPTN 084: 
A Phase 3 Double Blind Safety and Efficacy Study of Long-Acting Injectable Cabotegravir 
Compared to Daily Oral TDF/FTC for Pre-Exposure Prophylaxis in HIV-Uninfected Women 
 
OVERVIEW OF STUDY DESIGN AND RANDOMIZATION SCHEME 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Screening 
Competitive Enrollment 
1:1 Randomization 
Step 3 
(Follow-
up Phase) 
48 weeks 
 
Step 1 
(Oral Run-
in Phase) 
5 weeks 
Daily oral CAB, Daily oral TDF/FTC placebo 
 
- behavioral risk reduction 
- adherence counseling 
- offer condoms  
Daily oral TDF/FTC 
 
- behavioral risk reduction 
- adherence counseling 
-  offer condoms  
Arm A 
Oral CAB, CAB LA, TDF/FTC placebo 
Daily oral TDF/FTC, Daily oral CAB 
placebo 
 
- behavioral risk reduction  
- adherence counseling 
- offer condoms  
Arm B 
Oral TDF/FTC, Oral CAB placebo,  
CAB LA placebo 
Daily oral TDF/FTC, CAB LA 
injectable placebo 
 
- behavioral risk reduction 
- adherence counseling 
- offer condoms  
Injectable CAB LA, daily oral TDF/FTC 
placebo 
 
- behavioral risk reduction 
- adherence counseling 
- offer condoms  
Step 2  
(Injection 
Phase) 
up to 185 
weeks 

 
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INTRODUCTION 
1.1 
Background and Rationale 
This study is a Phase 3 double-blind study designed to evaluate the efficacy of the long-acting 
injectable integrase inhibitor, cabotegravir (CAB LA), for HIV prevention when compared to 
oral tenofovir dispoproxil fumarate/emtricitabine (TDF/FTC) in a population of sexually-active 
HIV-uninfected women at risk for HIV and interested in using pre-exposure prophylaxis (PrEP) 
(oral or injectable).  This study has a similar design to an efficacy study in HIV-uninfected men 
who have sex with men (MSM) and transgender women (TGW) (HPTN 083) and will provide 
complementary information on uptake, usage and efficacy of CAB LA vs. daily oral TDF/FTC in 
HIV-uninfected women to be submitted as a single package for licensure of CAB LA for HIV 
prevention. Small single-dose and multiple-dose studies and Phase 2a safety/tolerability studies 
have been performed for CAB LA.  A parallel development program for use of cabotegravir 
(CAB) (oral and injectable) for treatment of HIV-infected individuals is currently in Phase 2b 
studies with a salutary safety and efficacy profile to date. 
The study of systemic antiretroviral (ARV) drug use for both HIV treatment and prevention has 
provided consistent and compelling evidence of efficacy.1-9 The United States (US) Food and 
Drug Administration (FDA) approved oral TDF/FTC for PrEP and the US Centers for Disease 
Control and Prevention (CDC) and the World Health Organization (WHO) have offered 
guidance for its use.10,11  Most recently, the WHO recommended that TFV-based PrEP be offered 
to individuals at substantial risk for HIV infection as part of a comprehensive package of HIV 
prevention. This recommendation was based on a systematic review of 15 randomized controlled 
trials of oral PrEP across a range of populations and settings and found that TFV-based oral PrEP 
was effective in reducing HIV risk across gender, PrEP regimen, dosing, and mode of acquisition 
subgroups.12  Several African countries have already licensed Truvada® (oral TDF/FTC) for 
PrEP, while others have started the guideline development process. 
A challenge in the use of current oral ARV formulations for HIV prevention is the requirement 
for adherence to daily or near-daily dosing strategies.13,14 In the same systematic review cited 
above, increased adherence was associated with a demonstrable increase in PrEP effectiveness. 
Among trials with adherence ≥80%, PrEP reduced risk of infection by 70% compared to placebo 
(relative risk [RR]=0.30, 95% confidence interval (CI): 0.21-0.45, p=0.001).12 In healthy HIV-
uninfected individuals, sustaining adherence becomes increasingly challenging over time.15  
 
In women, pharmacokinetic (PK) studies have indicated significantly lower concentrations of 
TFV-diphosphate (TFV-DP) in vaginal than rectal tissues,16,17 suggesting that adherence for 
women will need to be more consistent than for MSM. Low levels of adherence were observed 
in two blinded, placebo-controlled trials conducted in women from sub-Saharan Africa (SSA). 
Both the VOICE (Vaginal and Oral Interventions to Control the Epidemic) and FEM-PrEP (PrEP 
Trial for HIV Prevention among African Women) trials observed <30% had evidence of recent 
dose-taking based on plasma TFV concentrations. Subsequent analyses and qualitative research 
have revealed several reasons for low uptake and failure to sustain use of oral PrEP in these 
populations including concerns about randomization to placebo or a product of uncertain 
efficacy. Trial participants were reminded on a monthly basis that they may be in a placebo arm 

 
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and not receiving active product, and that the active product had not been determined to be 
effective—factors that may have influenced adherence behaviour.  
 
Oral PrEP uptake and adherence among participants in randomized clinical trials (RCTs) 
conducted prior to knowledge of product efficacy may not predict PrEP uptake and adherence 
after efficacy is known. In the PROUD (PrEP to Prevent Acquisition of HIV-1 Infection) trial 
conducted in MSM attending sexual health clinics in the United Kingdom (UK) randomised to 
immediate or deferred oral PrEP, HIV incidence was reduced by 86%, a much greater level of 
protection than observed in placebo-controlled trials in similar populations.18  There are fewer 
data on uptake and adherence to oral PrEP in women in SSA. In HPTN 067, a randomized trial 
of open-label oral TDF/FTC in 179 young women in South Africa, 79% of the 60 women 
randomized to the daily dosing arm had detectable drug in plasma at Week 30.19  
 
In addition to adherence challenges inherent to daily oral tablet regimens, concerns related to 
drug resistance and the safety of TFV-based PrEP have propelled the evaluation of additional 
agents (and delivery systems) for PrEP. TDF/FTC is used commonly in ARV regimens for 
treatment of HIV-infected individuals, and viral strains that are resistant to TDF and/or FTC 
exist and are transmitted in the community.  The most recent review of drug resistance following 
PrEP use across six randomized trials and one demonstration project found that the absolute risk 
of excess drug resistance during TDF/FTC PrEP was 0.05%.20  It is possible that an HIV variant 
resistant to one or more ARVs will be acquired in either arm of the study.  Acquired drug 
resistance is a risk if ARV(s) received in either arm of the study provides incomplete suppression 
of viral replication.  The primary objective of CAB LA PrEP is to prevent HIV transmission and 
subsequent chronic infection.  Preclinical NHP data indicates CAB monotherapy is capable of 
providing high-level protection from SIV/SHIV challenge (see protocol Section 1.2.1 and 1.2.2).  
In NHP studies where animals were repeatedly challenged intravaginally or intrarectally with 
virus under declining drug concentrations until infected, CAB drug resistance was not observed.   
The dosage schedule and dose of CAB selected are designed to mitigate against subtherapeutic 
concentration.  In an analogous manner to the appropriate use of TDF/FTC for HIV PrEP but not 
for stand-alone treatment of chronic HIV infection, we believe current data support evaluation of 
CAB LA monotherapy for HIV PrEP but not for treatment of established HIV infection. 
Concerns about the longer-term side effects of TDF/FTC include renal, hepatic and bone 
toxicity. Renal toxicity, including acute renal failure and Fanconi’s syndrome, can occur with 
prolonged TDF use.21,22  Across Phase 3 randomized studies, the rate of Grade 2-4 confirmed 
creatinine elevations was approximately 0.2%, with no documented cases of renal dysfunction 
requiring dialysis or permanent renal dysfunction.1,9,23-25  Several studies have reported small but 
significant decreases in renal function while taking TDF/FTC as PrEP, although renal function 
returns to normal following discontinuation of PrEP.25,26  There have also been reports of small 
decreases in liver function,24,27 and bone mineral density (0.5-1.5%) when taking TDF/FTC as 
PrEP.28,29,30    
 
PrEP may only reach its full potential for HIV prevention with agents that do not depend on 
daily or near-daily pill-taking. The development of alternative agents for PrEP, and/or more 
adherence-friendly schedules for currently available agents, could increase prevention choices 
and increase acceptability. Long-acting injectable agents have the potential to prevent HIV 
acquisition without relying on adherence to a daily oral regimen.31 Long-acting injectable 

 
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contraceptives provide a useful prevention parallel: injectable contraceptives are used widely by 
women in southern and eastern Africa, and are highly acceptable. The popularity of injectable 
contraception has raised total contraceptive use in many settings, although discontinuation and 
method-switching are frequent; most discontinue because of lack of access to renew the 
prescription, or fear of side effects.32  However, it is clear that increased choice in type and 
method of delivery of contraceptive methods has increased acceptability and reduced the unmet 
need for contraception.33 Our hypothesis is that expanded choices for HIV prevention will 
similarly increase utilization, satisfaction, and effectiveness.  
1.2 
Overview of Oral CAB and CAB LA  
The majority of information contained in this section of the protocol is a summary of information 
provided in the CAB Investigator’s Brochure (IB) V8.0, Effective Date 17 December 2018, 
unless otherwise noted. 
CAB is an investigational HIV integrase strand transfer inhibitor (INSTI) that has attributes 
favorable for both HIV treatment and prevention indications. Currently in Phase 2 and Phase 3 
clinical trials, it was initially selected for development based on its potential for a high genetic 
barrier to resistance and a PK profile that allows low-dose, once-daily oral dosing or monthly to 
quarterly parenteral dosing using a nanosuspension formulation. An oral tablet version of CAB 
has also been developed as lead-in therapy to establish acute safety and tolerability in individual 
subjects prior to switching to the long-acting formulation. CAB LA has a plasma half-life of 21 
to 50 days in healthy HIV-uninfected adults.  
 Non-human Primate Studies Relevant to Rectal Exposures 
CAB LA has demonstrated activity in preventing simian human immunodeficiency virus (SHIV) 
infection in non-human primate models.34 In a preclinical study evaluating the potential of CAB 
LA for PrEP, 2 weekly doses of CAB LA (50 mg/kg intramuscularly [IM]) were highly 
protective against weekly rectal challenges with SHIV162p3 (50% tissue culture infective dose 
[TCID]50) for up to eight exposures. In these protected animals, the plasma concentrations of 
CAB LA throughout the period of virus challenges were comparable to clinically-relevant 
concentrations in humans. In follow-up studies, a single dose of CAB 50 mg/kg IM one week 
prior to the serial weekly viral challenges with SHIV162p3 (50 TCID50) were evaluated. The 
percent of challenges resulting in infection was calculated relative to the plasma CAB protein-
adjusted 90% inhibitory concentration (PA-IC90) value. None of 59 challenges resulted in 
infection when plasma levels were greater than 3 times the PA-IC90, compared with 1 out of 22 
challenges resulting in infection when plasma levels were between one to three times the PA-
IC90, and 11 out of 43 challenges resulting in infection when plasma levels were less than 1 times 
the PA-IC90. Twelve out of 26 challenges resulted in infection in control animals; rectal tissue 
levels of CAB were approximately 20% of plasma levels.35   
 Non-human Primate Studies Relevant to Vaginal Exposure 
CAB prevented SHIV infection in two non- human primate models. In one study using depo 
provera to increase the risk of infection35 CAB LA 50 mg/kg offered 90% protection from high-
dose exposure to SHIV162P3. In a second study using the same SHIV with a low-dose challenge 

 
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model, animals were provided complete protection by CAB.34,35 To evaluate concentrations at 
the site of virus entry, CAB concentrations were measured in vaginal and rectal secretions. CAB 
was consistently detected in both vaginal and rectal secretions throughout the 4 weeks of the 
study.  At first dose, peak CAB concentrations in vaginal secretions (median, 911 ng/ml; range, 
427 to 1,877) were similar to those seen in rectal secretions (median, 2,215 ng/ml; range, 647 to 
2,680) (P = 0.240), albeit at concentrations significantly lower than in plasma (P = 0.002) Figure 
1.1. The area under the curve values over 28 days (AUC0–28d) in vaginal secretions were 
compared to the values with those seen in plasma or rectal secretions. The AUC0–28d values in 
vaginal secretions (median, 11,511 ng × day/ml; range, 3,956 to 14,011) were lower than those in 
rectal secretions (median, 26,717 ng × day/ml; range, 10,120 to 39,989), although the difference 
was not statistically significant. In contrast, AUC0–28d values in vaginal secretions were lower 
than those in plasma (median, 70,333 ng × day/ml; range, 40,265 to 169,341) (P = 0.002) (Figure 
1.1.). Despite the lower CAB concentrations in vaginal secretions, concentrations remained 
above the PA-IC90 throughout the entire 4-week period after each dose (Figure 1.1.). In 
summary, CAB partitioning in vaginal, cervical, and rectal tissues is within the range seen in 
humans. It should be noted that similar doses of CAB appeared to result in higher concentrations 
of drug in male animals than females.34,35  In addition, the concentration of SHIV in rectal tissues 
was greater than in cervical tissue.34,35  In summary, these preclinical non-human primate studies 
suggest that CAB can be expected to protect women from HIV.  However, because of 
differences in men and women and human and macaques, careful consideration of the most 
appropriate dose and frequency of dosing is essential (see below).  
 
1.3 
Metabolism 
CAB is highly protein bound in human plasma (>99%). It is a substrate for permeability 
glycoprotein (Pgp), but because of its high permeability, no alteration in absorption would be 
expected by co-administration of either Pgp or breast cancer resistance protein (BCRP) 
inhibitors. Elimination occurs predominantly in feces via biliary excretion. Renal excretion is 
minimal, with less than 1% of the dose eliminated in the urine. The primary route of 
biotransformation is conjugation with glucuronic acid (M1) via uridine diphosphate 
glucuronyltransferase type 1A1 (UGT 1A1).  
1.4 
Preclinical Studies 
The CAB toxicology package supports the careful conduct of clinical studies with CAB up to the 
no observed adverse effect level (NOAEL) exposure in the 39-week monkey toxicity study 
(Week 39 gender mean AUC0-24 and Cmax of 547 g·h/mL and 34.6 g x h/mL, respectively). 
The results of the multiple dose rat subcutaneous (SC) and IM toxicity study, along with data 
from the oral toxicity program, support the careful conduct of clinical studies with CAB LA up 
to the mean Cmax plasma concentration observed at the NOAEL in the 39-week monkey oral 
CAB toxicity study (34.6 g/mL) or the mean AUC1,440-2,160h following once monthly IM 
dosing at the NOAEL (75 mg/kg/dose) in the 3-month rat CAB LA toxicity study (92,566 g x   
h/mL). 
In a rat pre- and postnatal development (PPN) study, female pregnant rats were administered 0.5, 
5 or 1000 mg/kg of oral CAB daily from gestation day 6 to post-natal day 21 (without dosing to 
the offspring directly). In the high-dose (1000 mg/kg/day) group, there was an increased number 

 
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of rat offspring dead at birth (2.9% stillborn vs. 0.7% in control) and offspring that died during 
the early post-natal period (10.2% dead or missing on post-natal day 2-4 vs. 0.7% in control). 
This resulted in a decrease in rat offspring viability during post-natal day 1-4 (87.4% vs. 98.9%) 
and a corresponding decrease in live litter size on post-natal day four (10 offspring/litter vs. 11.5 
in control on post-natal day four). There were no treatment-related findings in the 0.5 or 5 
mg/kg/day groups. Clinical dosing in HPTN 077 (a safety, tolerability, and PK of CAB LA in 
HIV-uninfected, low-risk men and women) is approximately 7-fold below the NOAEL in 10-
day-old rat offspring. Importantly, an early fetal development (EFD) study in rats was negative. 
1.5 
Dose Rationale 
 Oral CAB  
CAB is readily absorbed following oral administration in healthy and HIV-infected participants 
with a median Tmax of approximately two hours. The apparent terminal phase half-life following 
oral administration is approximately 40 hours.   
In a short-term monotherapy study, seven HIV-infected participants received oral CAB 5 mg 
once daily for 10 days, which achieved a geometric mean Day 10 plasma trough concentration 
(C) of 0.57 g/mL, 3.4-fold above the PA-IC90 value, and was associated with a mean Day 11 
HIV ribonucleic acid (RNA) change from a baseline of -2.2 log10 c/mL.36,37 In LATTE, the Phase 
2b study in HIV-infected, ART-naïve adult participants,38 suppression of HIV replication was 
accomplished with oral CAB at doses of 10 mg to 60 mg once daily in combination with two 
nucleoside reverse transcriptase inhibitors (NRTIs), and HIV viral load was maintained below 
50c/mL at similar rates across oral CAB 10 mg to 60 mg doses through >72 weeks when 
combined with oral rilpivirine (RPV) 25 mg once daily. The geometric mean individual average 
plasma C following oral CAB 10 mg and 30 mg once daily were 1.35 g/mL, eight-fold above 
PA-IC90, and 4.2g/mL, 25-fold above PA-IC90, respectively.   
CAB 30 mg once daily has been used as the oral lead-in in both ÉCLAIR (Phase IIa Safety and 
PK Study of Cabotegravir LA in HIV-uninfected Men) and LATTE-2 (CAB + RPV as Long-
Acting Maintenance Therapy), where it achieved a similar pre-dose CAB concentration at 
baseline as observed in LATTE. The geometric mean (CVb%) Cmax following CAB 30mg once 
daily is 7.5g/mL (28%), which provides adequate safety coverage for the predicted median 
(90% IB [V8.0, Effective Date 17 December 2018] peak concentrations following CAB LA of 
4.0g/mL (1.8, 8.9g/mL). Therefore, CAB 30mg once daily has been selected for the oral run-
in regimen for this study. 
Relevant PK parameters following oral administration are listed in Table 1.1.  
 CAB LA  
CAB LA exhibits absorption-limited (flip-flop) kinetics, compressing plasma exposure to a 
narrow range of concentrations over extended periods of time. The CAB LA PrEP dose has been 
selected to deliver adequate drug concentrations to prevent sexual transmission of HIV. The 
proposed dosing schedule for evaluation in humans is based on maintaining CAB LA plasma 
concentrations well above the PA-IC90 value of 0.166 g/mL, a concentration range shown to 

 
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have significant antiviral activity.  
 
The ÉCLAIR study was undertaken to evaluate PK and safety following three injections of CAB 
LA 800mg IM Q12W in healthy male participants. This regimen was selected based in part on 
results of a small cohort (n=9) of healthy participants receiving two quarterly doses of CAB LA 
800 mg IM that achieved a geometric mean (CVb%) C of 1.11 g/mL (139%), approximately 
6.7-fold above the PA-IC90 and between the 5 mg and 10 mg oral doses (Table 1.1). These data 
were included in a population PK model with other PK data following CAB LA single or repeat 
doses ranging from 100mg to 800mg IM.  Simulations with this model showed that CAB LA 800 
mg IM given every 12 weeks (Q12W) was predicted to achieve a median concentration above 
the 1.35 g/mL target based on 10 mg daily oral dosing with the lower bound of the 90% CI at 
~four-fold PA-IC90. The overall range of predicted CAB C values following CAB LA 800 mg 
IM was similar to that following once daily dosing of oral CAB 10 mg.  
Results from ÉCLAIR, however, showed that only 30 to 37% of CAB LA C values were 4-
fold PA-IC90 following each of the three quarterly injections, while 15 to 31% were below the 
PA-IC90. Graphical evaluation of the CAB plasma concentration-time profiles suggests that 
absorption was more rapid among participants in the ÉCLAIR study than that observed in prior 
studies, resulting in higher peak and lower trough concentrations (Figure 1.1.). Of note, the CAB 
LA nanosuspension formulation has remained essentially unchanged throughout the clinical 
development program, indicating that other factors are contributing to the observed PK 
differences. Given this information, a regimen of CAB LA 800 mg Q12W may not maintain 
sufficient exposures in all participants, particularly in males.  
During the Follow-up Phase of ÉCLAIR, CAB was detectable in plasma at 52 weeks post last 
injection for some individuals (14 out of 83, 17%).39 The CAB concentrations in these study 
participants ranged from 0.029-0.105 g/ml, falling between the lower limit of quantitation 
(LOQ) of 0.025 g/ml and 1 x PA-IC90 (0.166 g/ml).  
Two regimens of CAB LA have been evaluated in HIV infected subjects – one 400mg IM Q4W 
and the other 600mg IM Q8W.  Both regimens were initiated with an 800mg IM loading dose, 
and 600mg IM was administered 4 weeks following the loading dose of the second regimen prior 
to commencing with dosing at Q8W intervals.  The Q8W regimen achieved a geometric mean 
CAB C of 1.49g/mL at Week 48 (Figure 1.2), above the geometric mean C value for the 10 
mg oral dose in LATTE. At Week 48, the proportion of participants maintaining suppression of 
HIV in the Q8W arm was 91%. 
HPTN 077 is Phase 2a study that was initiated to evaluate safety, tolerability, acceptability, and 
PK of the ÉCLAIR regimen (800mg IM Q12W) in low-risk HIV-uninfected men and women at 
eight sites globally. Based on the ÉCLAIR and LATTE-2 results, this study was amended to 
enroll a second cohort with dosing of CAB LA 600 mg IM at two time points 4 weeks apart and 
every eight weeks (Q8W) thereafter for five injection visits. Both cohorts were randomized 3:1 
active to placebo and included a 4-week lead in of daily oral CAB 30 mg orally (or matching 
placebo) to assess initial safety and tolerability. After completing the oral lead-in, Cohort 1 
participants (n=110, fully enrolled) received three IM injections of CAB LA 800mg at QW12 (or 
matching placebo injection), and were followed for 52 weeks after the final injection to observe 
PK washout.  Cohort 2 participants (n=90, fully enrolled) receive five IM injections of CAB LA 

 
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600mg at weeks 5, 9, and at 8 week intervals thereafter; these participants are also followed for 
52 weeks after the final injection.  The 800mg dose of CAB LA is administered as a split two x 
2cc injection administered as one injection to each buttock in sequence; the 600 mg dose is 
administered as a single 3cc injection to one buttock.  Given the persistent CAB concentrations 
detectable in 17% of ÉCLAIR participants at 52 weeks post Injection 3, HPTN077 was amended 
to extend the follow-up period from 52 to 76 weeks post final injection (24 weeks longer than the 
current follow-up of 52-weeks post last injection).  In HPTN 077, the median time to 
undetectable cabotegravir concentrations was 43.7 weeks for males and 67.3 weeks for females. 
At 76 weeks after the final injection, 13% of males and 42% of females had detectable 
cabotegravir; among women 11% still had cabotegravir levels >1x PA-IC90 which has been 
shown in NHP models with be consistent with 97% protection. T1/2app was significantly 
associated with female sex at birth and BMI.  HPTN 084 will help define further the clinical 
implications of these prolonged exposures, both in terms of ongoing HIV protection as well as 
the theoretical risk of seroconversion with resistant virus. 40 
The CAB population PK model has been updated with PK data from ÉCLAIR (an additional 94 
males) and LATTE-2 (an additional 230 participants; 216 males and 14 females), significantly 
increasing the data in the population PK dataset. The absorption rate constant following CAB LA 
was increased approximately 2-fold (4.54 x 10-4 hr-1 to 9.19 x 10-4 hr-1; i.e., more rapid 
absorption) and resulted in higher peak to trough ratios than previously observed. Preliminary 
data for males and females in each cohort of HPTN 077 have been compared to simulations 
based on the updated population PK model.  Good correspondence between model predictions 
and HPTN 077 data (currently not in the model) supports use of the simulations to select CAB 
LA doses for Phase 3 (Figure 1.3, female plot).  Both HPTN 083, the Phase 3 study of CAB LA 
in MSM and transgender women, and HPTN 084, the Phase 3 study of CAB LA in women, are 
employing the HPTN 077 Cohort 2 regimen supported by the updated population PK modeling 
and simulation results.  Therefore, the proposed regimen for this study is CAB LA 600 mg IM as 
a single injection at two time intervals four weeks apart and every eight weeks thereafter. This 
dosing regimen is predicted to yield a median steady-state C in females of approximately 2.5 
g/mL, which is approximately 15-fold above PA-IC90, with C above 4x PA-IC90 in > 95% of 
participants.  Simulated delays in dosing of Injection 2, 3, and 4 showed that little forgiveness 
occurs prior to Injection 2 (Table 1.2), and it is recommended that subjects receive their second 
injection 1 week early to on time.  However, more forgiveness is evident prior to subsequent 
injections, and a one-week delay is permitted per the protocol.  Percentage of participants 
predicted to achieve targets are shown in Figure 1.4.     
Relevant PK parameters following CAB LA in healthy and HIV-infected participants and 
following simulations based on the initial and updated population PK models are listed in Table 
1.1.   
 
 
 

 
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Table 1.1. Summary of CAB PK Parameters Following Oral and LA (IM) Administration 
and PK Simulations in Healthy and HIV-Infected Participants 
Route 
Study 
Population 
N 
CAB Regimen 
CAB PK Parameter  
C or C0 
(g/mL) 
Cmax 
(g/mL) 
AUC(0-) 
(g•h/mL) 
Geomean IQ 
C0 or C/PA- 
IC-90b 
Oral Data 
Ph2a - ITZ112929 
HIV-infected 
N=7 
Women = 2 
5 mg oral once daily 
x10 d monotherapy 
0.57 
[33%] 
1.02 
[25%] 
17.7 
[31%] 
3.4 
Ph2b - LATTE 
HIV-infected 
N=14 
Women= 0 
10 mg oral once 
daily with 2NRTIs 
1.35 
[45%] 
(n=57) 
2.77 
[33%] 
45.7 
[32%] 
8.1 
Ph2b -  
 LATTE 
HIV-infected 
N=12 
Women= 1 
30 mg oral once 
daily with 2 NRTIs 
4.20 
[40%] 
(n=53) 
7.49 
[28%] 
134 
[32%] 
25 
LA Data 
Ph1 - LAI115428 
Healthy Volunteers  
N=9 
Women = 4 
800 mg IM every 
12weeks x 2 
(2nd dose interval) 
1.11 
[139%] 
3.35 
[56%] 
4417 
[53%] 
6.7 
Ph2a - 201120 
(ÉCLAIR) 
Healthy Volunteers 
(N=85) 
Women = 0 
800 mg IM every 12 
weeks x 3 
(third dose)  
0.387 
[150%] 
(n=66) 
4.91 
[67%] 
4021 
[36%] 
2.3 
 
Ph2b – Q4WLATTE-2a 
HIV-infected 
(N=115) 
Women = 6 
800 mg IM Day 1, 
400 mg IM W4, 
then Q4W following 
30 mg PO QD with 
2 NRTIs lead-in 
2.30 
(0.85 – 5.0) 
(W32, n=85) 
3.40 
(1.64- 9.05) 
(W25, n=86) 
NDc 
13.9 
Ph2b – Q8W 
LATTE-2a 
HIV-infected(N=115) 
Women = 8 
800 mg IM LD, 600 
mg IM W4, W8, 
then Q8W 
following 30 mg PO 
QD with 2 NRTIs 
lead-in 
1.45 
(0.21 – 3. 9) 
(W32, n=84) 
3.36 
(0.75- 12.4) 
(W25, n=87) 
NDc 
8.7 
Modeling and Simulation 
PopPK simulation 
 (Initial PopPK model) 
(N=1000) 
800 mg IM every 12 
weeks x 5 
(last dose) 
1.57 
[56%] 
NDc 
NDc 
9.5 
PopPK simulationa 
(Current PopPK model) 
(N=10000) 
600 mg IM Day1, 
600 mg IM W4, 
then Q8W 
1.3 
(0.18, 2.84) 
4.0 
(1.8, 8.9) 
NDc 
8.0 
a. 
Data presented as geometric mean, [CVb%], LATTE-2 data presented as median (range), current population PK model 
predictions presented as median (90% prediction interval (PI)) 
b. 
PA-IC90=0.166 g/mL  
c. 
Not determined 

 
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Figure 1.1. Mean (SD) Plasma CAB Concentration-Time Profile following CAB LA 800 mg 
IM Q12W in ÉCLAIR and Original Simulated Phase 2 Dose Rationale Model Predictions 
(Sparse Time Points) 
 
Time (Weeks)
0
4
8
12
16
20
24
28
32
36
Plasma CAB ( g/mL)
0.01
0.1
1
10
Simulated CAB 800mg IM Q12W (males, n=663) 
Observed CAB 800mg IM Q12W (ECLAIR, n=94)
8x PA-IC90 (1.35 g/mL)
4x PA-IC90 (0.664 g/mL)
1x PA-IC90 (0.166 g/mL)

 
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Figure 1.2. Mean (SD) Plasma CAB Concentration-Time Profile following CAB LA Q8W 
Regimen (800 mg IM Loading Dose, 600 mg IM Week 4, Week 8, then Q8W) in LATTE-2  
 
 
 
 
 
Week
0 1
4
8
12
16
20
2425
28
32
32
36
4041
44
48
48
Plasma CAB ( g/mL)
0.1
1
10
100
800mg IM LD, 600mg IM W4, W8 and Q8W
10mg PO QD C  (LATTE, 1.35 g/mL)
4x PA-IC90 (0.664 g/mL)
PA-IC90 (0.166 g/mL)

 
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Figure 1.3. Simulated Plasma CAB Concentration-Time Profile for the Proposed Regimen  
(600 mg IM Day 1, Week 4 and Q8W) in Females based on Updated Population PK Model    
and Overlayed with Preliminary HPTN077 C2 Data in Females (semilog scale)  
 
 
 
 
Table 1.2. Predicted Percent Above Targets for Delayed Dosing in Females 
 
 
 
 
% >PA-IC90
% > 4x PA-IC90
% > 8x PA-IC90
Delayed Injection
0
+1 wk +2 wk +3 wk +4 wk
0
+1 wk +2 wk +3 wk +4 wk
0
+1 wk +2 wk +3 wk +4 wk
Injection 2 (W4)
99.6
99.6
99.5
99.5
99.2
80.4
79.4
75.7
71.5
65.4
39.6
32.6
23.2
15.1
8.7
Injection 3 (W12)
99.7
99.4
98.9
98.5
98.1
92.1
90.0
86.8
83.7
79.1
50.8
42.9
34.0
26.7
20.0
Injection 4 (W20)
99.6
99.2
98.8
98.2
97.7
94.9
92.6
89.6
86.4
83.1
60.6
53.1
45.4
39.3
32.5

 
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Figure 1.4. Percent Females Predicted to Achieve targets with Delayed Administration of 
Injection Four for the Proposed Regimen (600mg IM D1, W4, then Q8W) 
  
 
 
 
 
 
Updated models confirmed the selection of CAB LA 600 mg (3 mL unsplit) on day 1, week 4 and 
q8weekly thereafter for phase III PrEP studies in women to achieve steady state concentrations 
throughout the dosing interval above a threshold where CAB has demonstrated pre-clinical 
efficacy. 41 
 
 Genital Tract (GT) Tissue Concentrations after Oral and Injectable Administration 
Genital tissue concentrations have been measured after CAB LA 400 mg IM single dose 
administration in 24 healthy men and 15 healthy women. Median cervical and vaginal tissue 
concentrations ranged from 16-28% (overall range 0-70%) of plasma concentrations, roughly 1 
x PA-IC90 (0.166 µg/mL).  Median rectal tissue concentrations were ≤ 8% of plasma 
concentrations (range 0-20%).42 Further tissue studies using single and multiple doses of the 
800 mg IM dose are ongoing.   
1.6 
Clinical Experience to Date: Oral CAB and CAB LA 
Through  October, 2018, approximately 4,236 adult participants have been exposed to at least 
one dose of CAB (oral and/or LA) across 18 completed or ongoing Phase 1, 2 and 3 clinical 
trials (see Table 1.3).   
Two hundred and thirty (n=230) healthy participants from completed studies have received 
single or repeat doses of CAB LA in Phase 1 studies at doses ranging from 100-800 mg 
administered as single or split IM or SC injections. In the Phase 1 program, to date there have 
g
j
>1x
>4x
>8x
% of Subjects
0
10
20
30
40
50
60
70
80
90
100
No delay
+ 1 week
+ 2 weeks
+ 3 weeks
+ 4 weeks
>1x above PAIC90       >4x above PAIC90      >8x above PAIC90 
 

 
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been no drug-related Grade 3 or Grade 4 clinical AEs and only one participant has been 
withdrawn from dosing due to mild and transient rash.  
Injection site reactions (ISR) occurred in the majority of participants following IM (77% with 
any ISR) dosing, however, the reactions were mild and moderate (overall ISR Grade 2: 14% in 
IM without any Grade 3 or 4 ISRs).43  Thirty one ISRs related to CAB LA injection were 
common but generally mild (IM: 86%, SC: 99%) with no Grade 3 ISR AEs in Phase 1 studies. 
The most frequent ISRs for IM dosing were pain (71%), erythema (9%) and nodules (7%).  
Median IM ISR durations were approximately 5 days for pain and erythema, and approximately 
22 days for nodules.43  
AEs were reported at all studied doses. The most frequent (>5%) non-ISR AEs were headache 
(overall rate of 16%: 10% in oral and 27% in LA) which occurred more frequently than in 
placebo subjects (11%) and upper respiratory tract infection (overall rate of 6%: 2% in oral and 
12% in LA) versus none in placebo subjects. CAB was well tolerated across all studies with an 
overall incidence of 13% of any drug-related AEs and few drug related withdrawals. 
Table 1.3 Cumulative CAB Exposures from Phase 1 through Phase 3 Clinical Studies 
Through October 2018 
 
Treatment Population/ 
Dose 
Duration 
Completed 
Ongoing/ 
Concluded a 
Total 
Healthy Volunteers/HIV-Uninfected 
 
 
 
5 to 150 mg oral 
Single dose 
208 
0 
208 
10 to 30 mg once daily oral  
10 to 28 days 
293 
1694 
1987 
150 mg every 12 hours oral  
3 doses 
40 
0 
40 
100 – 800 mg IM/SC LA 
Max 763 days g 
230 b 
1377 c 
1607 
Any dose 
 
599 
1694 
2293 
HIV-infected patients 
 
 
 
5 to 30 mg once daily oral (Ph 2a) 
10 days 
15 
0 
15 
10 to 60 mg once daily oral (Ph 2b) 
Max 2247 days h 
0 
181 
181 
30 mg once daily oral (Ph 2b) 
 
0 
1739 
1739 
Up to 800 mg IM LA d 
Max 1477 days g 
0 
1745 e 
1745 
Any dose 
 
15 
1928 
1943 
All participants 
 
 
 
Single dose oral (5 to 150 mg) 
 
208 
0 
208 
Repeat dose once daily oral (5 to 60 mg) 
 
308 
3614 
3922 
150 mg oral every 12 hours x 3 
 
40 
0 
40 
Single or repeat dose LA injection (100 to 
800 mg) 
 
230 b 
3122 f 
3352 
Any dose 
 
614 
3622 
4236 
 
a. Concluded studies: study completed through follow-up; and/or clinical study report is in preparation 
b. 172 participants received both oral and LA dosing 
c. All participants received both oral and LA dosing 
d. Includes 400 mg Q4W and 600 mg Q8W dosing 
e. 1736 participants received both oral and LA dosing 
f. 3113 participants received both oral and LA dosing 
g. Detectable CAB concentrations can remain for up to 72 weeks following the last CAB injection 
h. As of 28 Dec 2014, all participants had transitioned to CAB 30 mg in the Open-Label phase of study LAI116482 
(LATTE-1), therefore, the longer durations apply to the 30 mg dose only 

 
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In the ÉCLAIR study, conducted in 10 US sites, 205 individuals were screened in order to enroll 
and randomize 127 HIV-uninfected low-risk men. Participants received daily oral CAB 30 mg or 
daily oral placebo in a randomized 5:1 ratio during the 4-week oral lead-in phase. One 
participant randomized to active study product (oral CAB and CAB LA) withdrew prior to the 
oral lead-in due to being incarcerated. During the oral lead-in, 11 participants withdrew prior to 
their first injection, all of whom were randomized to CAB LA, seven for AEs and four for other 
reasons. Ninety-four (94) participants received at least one injection of CAB LA 800 mg and 21 
participants received at least one injection of placebo. Of those that started injections 95% (20 of 
21) of those randomized to placebo and 93% (87 of 94) of those randomized to CAB LA 
completed all three injections. The participant in the placebo arm who did not complete all three 
injections reached a protocol-defined stopping criteria (he acquired HIV infection after his 
second injection). Four participants on the CAB LA arm withdrew after their second injection, 
citing injection tolerability as a primary reason. Three other participants discontinued study 
participation after receiving injections for non-AE and non-injection-related reasons. 
Fifteen participants experienced a Grade 1 or higher ALT and 14 experienced a Grade 1 or 
higher AST. There were no Grade 3 or 4 ALT elevations. AE events leading to withdrawal 
included transient neutropenia (three participants), transiently elevated CPK (three participants), 
and fatigue (one participant). Two SAEs were reported, one deep vein thrombosis on placebo 
that was considered possibly drug-related and one appendicitis on CAB LA that was not 
considered drug related. Eighteen participants reported Grade 3 ISR pain. Grade 4 treatment 
emergent CPK elevations with concomitant AST and/or ALT elevations were noted in four 
participants at the Week 4 visit, leading to early withdrawal in three participants.   One of the 
four participants described a new rigorous exercise regimen prior to the Week 4 study visit; a 
second of these events resolved despite ongoing exposure to study product. All four Grade 4 
abnormalities were resolving at one-week follow-up visits and have subsequently returned to 
normal off study product.  
In the LATTE study 181 HIV infected participants were randomized to receive oral CAB (10, 
30, or 60 mg once-daily, blinded doses) in combination with either TDF/FTC or abacavir-
lamivudine (ABC/3TC).47 An additional 62 participants were randomized to a control arm of 
open-label efavirenz (EFV) 600 mg once daily in combination with one of the two NRTIs. A 
Week 24 interim analysis demonstrated good initial efficacy and safety of CAB in combination 
with NRTIs. The overall response rate across the three dosing arms of oral CAB were 87% <50 
c/mL (FDA snapshot analysis) with minimal differences between oral CAB doses; the control 
arm response rate was 74% <50 c/mL. In the “maintenance” phase, participants randomized to 
any of the CAB doses who had viral loads < 50 copies/mL prior to Week 24 were transitioned to 
a regimen maintaining their CAB dosing but substituting oral RPV 25 mg daily for the NRTIs. 
EFV-treated participants were kept on their “induction” regimen of dual NRTIs with EFV. 96-
week data (representing 72 weeks of maintenance dosing)) showed virologic suppression (<50 
c/mL) rates via snapshot analysis to be 79%, 85% and 93% for oral CAB 10 mg, 30 mg, and 60 
mg daily, and 83% for the EFV control participants. One participant randomized to oral CAB 10 
mg who successfully transitioned to RPV plus oral CAB 10 mg daily experienced virologic 
failure at Week 48 in the context of subtherapeutic (<50% expected) CAB and RPV plasma 
levels (partially confounded by an extreme calorie-restricted diet during Weeks 40-48), and 
developed treatment-emergent high-level integrase (Q148R) and non-nucleoside reverse 
transcriptase inhibitor (NNRTI) (E138Q) resistance.36 

 
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Safety results through Week 96 support continuation of all three oral CAB dosing arms. There 
have been no deaths, oral CAB-related SAEs or clinically significant AE trends identified to date 
in LATTE. The most common clinical drug related AEs to date have been headache (15%), 
nausea (17%) and diarrhea (10%) with few oral CAB AEs leading to withdrawal from the study 
(744 - 4% vs EFV - 15%). Two HIV-infected participants receiving oral CAB 60 mg + 
ABC/3TC with pre-existing steatohepatitis developed an ALT >10x upper limit of normal 
(ULN) 4 weeks and 8 weeks after study initiation. Both participants remained asymptomatic with 
normal bilirubin levels and hepatic function, and ALT levels normalized after drug 
discontinuation. No other participants have required dose adjustment or discontinuation due to a 
change in transaminases through week 96. One participant receiving oral CAB and RPV 25 mg 
developed ALT values >10x ULN at Week 96 likely due to acute hepatitis C virus (HCV) 
infection. 
Plasma drug concentrations after administration of CAB LA are expected to remain between the 
oral CAB 10 mg and 30 mg exposures. At this stage of development, a lead-in of oral CAB is 
being employed to determine safety and tolerability in individual participants, prior to the 
transition to CAB LA. The accumulated efficacy and safety data with oral CAB and CAB LA in 
HIV-infected and HIV-uninfected participants supports continued clinical development for HIV 
treatment and PrEP. 
The LATTE-2 study evaluated a 20-week induction of HIV-1 RNA suppression with a three 
drug oral antiretroviral regimen consisting of CAB + ABC / 3TC Fixed Dose Combination 
(FDC) followed by randomization to a two-drug regimen consisting of intramuscular (IM) long-
acting (LA) CAB LA + RPV LA compared to continuation of oral CAB + ABC / 3TC for the 
maintenance of HIV-1 RNA suppression44.  A total of 309 participants were enrolled and treated. 
During the Induction Period there was a rapid and sustained decline in HIV-1 RNA, with 91% of 
participants (282/309) achieving HIV-1 RNA <50 c/mL through 20 weeks of therapy.  There was 
a single participant (with known compliance issues) with confirmed virologic failure during the 
Induction Period.  Virologic testing revealed no treatment emergent phenotypic or genotypic 
resistance in this participant. 
Through 32 weeks (primary endpoint) of two-drug maintenance therapy, 95% (Q8W) and 94% 
(Q4W) of participants on injectable dosing were virologic successes, compared to 91% of 
participants continuing three drug oral CAB + NRTIs, meeting pre-specified criteria for 
comparability between the dosing arms.  Week 48 data was a secondary endpoint for study 
200056, and permitted the evaluation of the two-drug long-acting combinations’ ability to 
maintain the virologic suppression demonstrated at Week 32.  At Week 48, 92% (Q8W) and 
91% (Q4W) of participants receiving injectable dosing had a sustained virologic response (HIV-
1 RNA <50 c/mL) compared to 89% of participants continuing oral CAB + 2 NRTIs.  Although 
the proportion of participants with virologic success was similar for Q8W and Q4W dosing, the 
reason for Snapshot failure was different between the arms.  There were more Snapshot failures 
for virologic reasons on the Q8W arm (n=8, 7%) than in the Q4W arm (n=1, <1%), and more 
participants with no virologic data (discontinued due to AE or other reasons) on the Q4W arm 
(n=9, 8%) compared to the Q8W arm (n=1, <1%).  Between Week 32 and Week 48, one 
additional participant (Q8W) had confirmed virologic failure, with treatment emergent NNRTI 
resistance (K103N, E138G, and E238T), and integrase resistance mutation Q148R. 

 
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Overall, AEs and clinical chemistries were similar to those observed in prior studies with CAB, 
without discernible trends between Q8W, Q4W, and oral.  Injections were well tolerated with 
two participants discontinuing due to injection tolerability through 48 weeks (both on Q8W 
dosing).  The vast majority of injection site reactions were due to pain/discomfort with nearly all 
injection site reactions classified as mild (82%) or moderate (17%), with <1% of reactions 
classified as severe.  There was no discernible tolerability difference between Q4W (2 mL) 
dosing and Q8W (3 mL dosing).  The most common non-ISR AEs during the Maintenance Phase 
were nasopharyngitis (24%), headache (16%), and diarrhea (13%) on IM arms and 
nasopharyngitis (30%), headache (11%), and diarrhea (5%) on oral CAB.  Through Week 48, 
SAEs during the Maintenance Period occurred in 7% of participants randomized to CAB LA + 
RPV LA and 5% of participants randomized to remain on oral treatment, none were drug related.  
Based on the data from the Week 48 endpoint, Q4W dosing was chosen to progress for further 
clinical development. 
Plasma drug concentrations after administration of CAB LA are expected to remain between the 
oral CAB 10 mg and 30 mg exposures. At this stage of development, a lead-in of oral CAB is 
being employed to determine safety and tolerability in individual participants, prior to the 
transition to CAB LA. The accumulated efficacy and safety data with oral CAB and CAB LA in 
HIV-infected and HIV-uninfected participants supports continued clinical development for HIV 
treatment and PrEP. 
In May 2020 at a pre-planned interim review the DSMB recommended that the blinded portion 
of HPTN 083, a companion phase III trial of CAB LA for HIV prevention in MSM and 
transgender women (TGW), be stopped for evidence of efficacy. Subsequent analysis confirmed 
that CAB was superior to TDF/FTC (HR 0.35; 95% CI 0.18-0.62) in preventing HIV infection. 
Overall incidence was 0.81% (95% CI 0.61- 1.07). CAB and TDF/FTC were both well tolerated; 
most adverse events were mild/moderate and balanced between arms. Injection site reactions 
were more common in the cabotegravir arm but were generally grade 1-2 and decreased with 
time on study. Injection intolerance led to discontinuation in 46 (2.2%) active CAB-LA 
recipients and was associated with the severity of the reaction. Grade 2+ events observed with 
significant higher frequency in the CAB LA arm included nasopharyngitis, increased blood 
glucose and pyrexia. These differences were not observed when compared grade 3+ events. 
There were no significant differences in serious adverse events between the two groups.45  
1.7 
Pregnancy and Pregnancy Prevention with CAB Use 
There is no requirement to exclude women of reproductive potential from clinical trials of CAB 
based on reprotoxicity findings available to date. Given the limitations of the data and because 
animal studies are not always predictive of the human situation women of reproductive potential 
are required to adopt highly reliable means of contraception during participation and throughout 
long term follow up phases of studies following exposure to CAB LA. 
 
In vitro and clinical data suggest that CAB is unlikely to cause or be subject to clinically 
significant drug interactions with the components of hormonal contraceptives. In a clinical drug-
drug interaction study in healthy female volunteers, oral CAB had no significant impact on the 
pharmacokinetics of either levonorgesterol (LNG) or ethinyl estradiol (EE) containing 
combination oral contraceptive.46 There were no apparent differences in pharmacodynamic 

 
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assessments of follicle stimulating hormone (FSH), lutenizing hormone (LH) or progesterone 
and concomitant administration of CAB and LNG/EE was well-tolerated in the study. Because 
the pathways of metabolism and excretion are comparable between the oral and injectable 
formulation of CAB, it is expected that the results of this drug interaction study can be 
extrapolated to long-acting CAB. In clinical studies, combination estrogen and progestin or 
progestin-only hormonal contraceptives available in oral, injectable or implant formulations may 
be used concurrently with CAB. However, clinical data are limited evaluating the use of 
injectable or implantable forms of hormonal contraceptives and CAB to date. Progestin-only 
products such as injectable NET-EN,DMPA and etonogestrel are commonly prescribed, 
specifically in SSA. Although the metabolic pathways for such products are complex and vary 
somewhat from ethinyl estradiol and levonorgesterol, no pharmacokinetic drug-drug interaction 
between CAB and progestin-only contraceptives is anticipated. HPTN 077 initially did not find 
any evidence that use of hormonal contraceptives altered the CAB LA concentration profile 
during or after injections in either univariate or multivariate analysis, using contraceptive status 
at baseline 40. However, a recent updated analysis using time-varying contraceptive status 
showed a statistically significant decrease in Cmax in women on hormonal contraception. The 
magnitude of the change is small and the clinical significance of this remains unclear (Landovitz, 
personal communication).  Data from HPTN 084 will provide further insight into the clinical 
implications of this finding 
 Dolutegravir and Pregnancy 
Dolutegravir (DTG) is an integrase inhibitor in the same class of pharmaceuticals as CAB.  Thus 
far, limited safety or efficacy data for DTG in pregnancy in humans have been published or 
presented.  
 
In May 2018, WHO and several other regulatory agencies released advisories regarding the 
safety of dolutegravir in early pregnancy based on an interim review of data from the Botswana 
NICHD-funded Tsepamo Birth Outcomes Surveillance Study, in Botswana. 47  This study was 
designed to evaluate adverse birth outcomes by maternal HIV status and ART regimen, and to 
determine whether there is an increased risk of neural tube defects (NTDs) among infants 
exposed to efavirenz (EFV) from conception. Botswana’s HIV program moved to universal ART 
with DTG/TDF/FTC in first line for patients starting ART (including pregnant women) in May 
of 2016 (women already on other regimens were not switched to DTG). The previous first-line 
regimen was EFV/TDF/FTC. Almost all women on DTG-based and EFV-based ART took these 
drugs in combination with TDF/FTC. 
Since August 2014, the Tsepamo study collected information on 153,899 deliveries. An updated 
analysis including births since March 2019 reported seven neural tube defects among 3,591 
women exposed to dolutegravir at conception (0.19, 95% CI 0.09%, 0.40%). In comparison, 
neural tube defects occurred in 21/19,361 (0.11%; 95%CI 0.07%, 0.17%) women on any non-
dolutegravir regimen at conception. The prevalence of neural tube defects did not differ 
significantly between dolutegravir and any non-dolutegravir antiretrovirals from conception 
(0.09% difference; 95%CI -0.03%, 0.30%). After a period of decline since the original safety 
signal, the prevalence of neural tube defects in infants born to women on dolutegravir around the 
time of conception appears to have stabilized at 2 per 1000.48 
 

 
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Cabotegravir is not dolutegravir. While these medications share a common molecular backbone, 
and have a similar mechanism of activity, they are separate chemical compounds and have 
differences in antiviral activity, pharmacokinetics, metabolism and drug-drug interactions. It is 
not known if the safety signal identified with dolutegravir will be observed with cabotegravir. 
Cabotegravir was evaluated in a complete package of reproductive toxicology studies, including 
embryofetal development studies, and no safety findings suggestive of teratogenesis or neural 
tube defects were identified in the December 2017 version of the Investigator’s Brochure (IB).  
Nevertheless, given limited experience with use of cabotegravir in pregnancy women of 
reproductive potential are required to adopt highly reliable means of contraception during 
participation and throughout long term follow up phases of studies following exposure to CAB 
LA. 
1.8 
Hepatic and Central Nervous System Adverse Events 
As part of the early phase development of CAB (HPTN 077, LATTE and LATTE-2), some 
participants developed transaminase elevations, which were clinically asymptomatic and 
resolved rapidly with cessation of study product.   
In a single-dose study, a healthy male volunteer with a history of prior seizure activity (one 
episode 14 years prior), on no anti-epileptic medication, experienced an unwitnessed seizure 
event 270 days after a single injection of CAB LA 400 mg IM.  Plasma levels of CAB were 
undetectable for 4 months prior to the seizure event. The event occurred in the context of 
consumption of approximately 10 cans of beer, and a magnetic resonance imaging (MRI) study 
was unrevealing for pathology. An electroencephalogram was consistent with benign juvenile 
epilepsy; the participant recovered without additional events.   
A participant in the ongoing Phase 2b LATTE-2 trial of HIV-infected individuals received oral 
ABC/3TC with CAB 30 mg daily for 20 weeks, and received ABC/3TC, CAB and oral RPV for 
4 weeks, all without incident or clinically significant AEs or laboratory abnormalities. He was 
randomized to continue CAB LA 400 mg IM + RPV LA 600 mg IM Q4W. On day 349 of 
overall CAB treatment (139 days of oral CAB + 210 days of CAB LA exposure), the participant 
was found in his apartment by emergency personnel unresponsive, unconscious, and having 
generalized tonic-clonic seizures. The participant was hospitalized in the intensive care unit, had 
recurrent seizures, and was found to have anoxic brain injury resulting in death. The participant 
had no prior history of seizures, and clinical history and toxicity screens suggested possible 
recreational substance use.   
A participant in the healthy volunteer HPTN 077 study, with a prior history of seizures treated 
with Dilantin had been taken off Dilantin 2 years prior to study participation, and had been 
seizure-free. A “spell” 1 month prior to study enrollment did not prompt re-initiation of anti-
epileptics. Oral CAB 30 mg (or placebo) was administered for four weeks without incident, and 
Day 62 after administration of CAB LA 800 mg IM x 1 (or placebo), the participant had an 
unwitnessed seizure event; he was subsequently hospitalized for transient dizziness and 
hemiparesis, for which work-up was unrevealing, and resolved with meclizine treatment. The 
participant recovered without additional events and is not planned for additional intraperitoneal 
(IP) dosing.  

 
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A participant in HPTN 077 without known pre-existing liver disease, and without HIV-infection 
developed Grade 3 ALT elevation after 12 weeks of injectable CAB LA or placebo treatment; 
the participant was asymptomatic, and ALT returned to normal 15 weeks after withdrawal of 
study product.  A serologic and ultrasonographic evaluation did not reveal alternative etiology 
for the ALT elevation; no biopsy was performed.   
1.9 
Weight gain 
There is emerging evidence from randomized trials that the use of INSTIs may lead to significant 
increases in body weight 49.  Two trials of raltegravir and three involving dolutegravir all 
observed greater weight gain increases in INSTI-containing regimens.  These effects appear to 
vary by gender and race, with highest increases observed in women and those of black race. The 
recently published ADVANCE trial conducted in South Africa in a predominantly black and 
female population found that there was significantly more weight gain (both lean and fat mass) 
with dolutegravir-containing regimens, especially in combination with TAF, compared to the 
standard of care regimen (TDF/FTC/Efavirenz) 50. The mechanism for this needs to be fully 
elucidated. These data are from populations receiving treatment and more data are needed in 
healthy HIV uninfected populations using PrEP. HPTN 077 evaluated changes in weight and 
fasting metabolic parameters in 177 HIV-uninfected individuals randomized to cabotegravir or a 
placebo who had received at least one injection. No differences between study groups were 
found for change in weight or fasting metabolic parameters overall, or for subgroups. Among the 
146 participants with paired weights, between W0 and W41 the median increase in weight for 
CAB treated participants was 1.1 (IQR -0.9, +3.0) kg compared to median 1.0 (IQR -1.2, +3.2) 
kg gained by PBO treated participants ( =+0.1 kg, p=0.66). The distribution of weight changes 
across the 41 week treatment period did not differ between CAB and PBO-treated participants, 
nor when divided into the oral phase ( =+0.3 kg, p=0.6) and the injection phase ( =+0.2 kg, 
p=0.65). A 5% or greater increase in weight from W0 to W41 was seen in 24 (22%) CAB 
participants and 7 (18%) of PBO participants (p=0.62). HPTN 084 provides an opportunity to 
collect additional data to address this question51.  
 
1.10 Rationale for Study Design  
Based on its antiviral activity and biological plausibility of the dosage schedule provided above, 
it is anticipated that CAB LA will be effective in preventing acquisition of HIV. Based on 
studies in MSM and heterosexual couples, TDF/FTC was approved as an agent for PrEP.  
Therefore, it is considered to be the ethically appropriate active comparator for CAB LA, an 
experimental PrEP agent. While provision of oral TDF/FTC to all participants could offer a 
further possibility of HIV prevention, concomitant use of TDF/FTC is not a development 
pathway for a new agent and the development of a combination of CAB LA/TDF/FTC (requiring 
both oral and injectable PrEP) would not be a desirable outcome for prevention of HIV in 
women.   
A non-inferiority design is often used to compare a new drug to an active control that has proven 
efficacy. However, as discussed in Section 7.8.4.1, multiple placebo-controlled trials of TDF/FTC 
in women in SSA have yielded mixed results, with some trials (primarily those done in young, 
unmarried women) showing no efficacy and some (primarily those done in HIV discordant 

 
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couples) showing high efficacy.  This finding has largely been ascribed to low adherence resulting 
in suboptimal levels of TFV in vaginal tissues. 
In the setting of HIV PrEP trials in women, the ability to construct a non-inferiority margin is not 
possible given the variable efficacy results from these trials (e.g., VOICE, FEM-PrEP vs TDF2 
and Partners PrEP). Therefore, the proposed HPTN 084 trial can only be designed as a superiority 
trial. Thus, our primary analysis is designed to show superiority of CAB/LA to TDF/FTC. If, 
contrary to expectations, adherence to TDF/FTC is substantially higher than expected, we will 
provide a supportive non-inferiority analysis with an adherence-dependent margin (Section 7.8.4).  
The increase in protection likely to occur with CAB LA results from the anticipated higher 
adherence to the long-acting injectable compared to daily oral TDF/FTC. Use of an injectable 
product should address the suboptimal adherence to an oral pill. This study is therefore primarily 
designed to answer the question whether CAB LA is superior to oral TDF/FTC in preventing new 
HIV infections in women in SSA. Thus, our primary analysis is designed to show superiority of 
CAB/LA to TDF/FTC. If, contrary to expectations, adherence to TDF/FTC is substantially higher 
than expected, we will provide a supportive non-inferiority analysis with an adherence-dependent 
margin (Section 7.8.4). 
1.11 Rationale for use of Oral Run-in Prior to Injectable Dosing 
The CAB LA formulation has a PK decay rate that exposes the injected individual to detectable 
levels of CAB for a year or more after an injection (see Section 1.5.2 of the protocol). In order to 
maximally identify any acute toxicity prior to administration of a non-dialyzable, non-removable 
depot injection, a five-week lead-in period of daily oral (short acting) CAB will be employed. This 
lead-in period will be evaluated with serial safety assessments prior to injectable administration. 
The current plans for product labeling should FDA approval be granted include an oral lead-in 
strategy when adequate safety is established after four weeks of oral drug exposure. The 5-week 
exposure in this study is designed to provide un-interrupted study product coverage while awaiting 
return of the Week 4 safety laboratory assessments.   
 

 
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STUDY OBJECTIVES AND DESIGN 
2.1 
Primary Objectives  
• Efficacy: To evaluate the relative efficacy of oral CAB/CAB LA (oral run-in and 
injections, Steps 1 and 2) vs. daily oral TDF/FTC for HIV prevention (Steps 1 and 2). 
 
• 
Safety: To evaluate the relative safety of oral CAB/CAB LA (oral run-in and injections, 
Steps 1 and 2) vs. daily oral TDF/FTC for HIV prevention (Steps 1 and 2).  
2.2 
Secondary Objectives 
• To compare HIV incidence among participants receiving oral CAB/CAB LA vs. daily 
oral TDF/FTC (Steps 1, 2 and 3). 
• To evaluate relative efficacy of oral CAB/CAB LA vs. oral TDF/FTC in subgroups 
defined by the baseline factors of: age, herpes simplex virus-2 (HSV-2) serostatus, 
contraceptive method, and body mass index (BMI). 
 
• To describe and model the relationship between HIV incidence and drug concentration, 
within each arm. 
 
• To describe the distribution and correlates of drug concentration, within each arm. 
 
• To compare the acceptability of and preferences for CAB LA vs. oral TDF/FTC. 
 
2.3 
Tertiary Objectives 
• To estimate sexual risk behaviors, as measured by self-report and rates of incident 
sexually transmitted infections (STIs).  
 
• To compare Grade >2 AE rates in women with baseline BMI </≥ 25 kg/m2, within each 
study arm. 
 
• To compare differences in weight gain and BMI, by arm. 
 
• To compare pregnancy incidence and outcomes between arms.  
 
• To evaluate rates of HIV drug resistance among participants who acquire HIV infection 
during the study among participants receiving oral CAB/CAB LA vs. oral TDF/FTC. 
• 
To determine plasma concentrations of DMPA, NET-EN or etonogestrel when co-administered 
for contraception with study products (TDF/FTC or CAB LA). 

 
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2.4 
Exploratory Objectives 
 
• To compare the estimated programmatic cost, cost-effectiveness and disease impact 
indicators of CAB LA vs. daily oral TDF/FTC vs. no PrEP for HIV-uninfected women in 
the study sites locations.  
• To perform secondary laboratory assessments that may include evaluation of factors 
related to HIV infection, hepatitis infection, and other infections; ARV drug use; 
pharmacogenomics; characterization of HIV in infected participants; and evaluation of 
laboratory assays related to the study objectives. 
2.5 
Study Design and Overview 
This is a Phase 3, randomized, multi-site, two-arm, double-blind study of CAB LA compared to 
daily oral TDF/FTC for HIV prevention.  Approximately 3,350 participants will be enrolled and 
randomized 1:1 to Arm A (CAB LA and placebo TDF/FTC) and Arm B (TDF/FTC and CAB 
LA placebo) through the three Steps listed below.  When the study reaches the required number 
of incident HIV endpoints (114), all participants will begin open-label daily oral TDF/FTC for 
approximately 48 weeks (to “cover the tail”), starting no later than 8 weeks after the last 
injection.   
Step 1, Oral Run-in Phase: 
Arm A – Daily oral CAB and oral TDF/FTC placebo for five weeks plus an HIV 
prevention package including behavioral risk reduction and adherence counseling, and 
offer of condoms. 
 
Arm B – Daily TDF/FTC and oral CAB placebo for five weeks plus an HIV prevention 
package including behavioral risk reduction and adherence counseling, and offer of  
condoms. 
 
Any participant who becomes HIV-infected during Step 1 will permanently discontinue 
study product, will be terminated from the study, and referred for HIV-related care.   
Step 2, Injection Phase: 
Arm A – Injections of CAB LA at two time points four weeks apart and every eight 
weeks thereafter and daily oral TDF/FTC placebo beginning at Week 5 plus an HIV 
prevention package including behavioral risk reduction and adherence counseling, and 
offer of condoms.  Injections will consist of 600 mg of CAB LA administered as one 3 
mL IM injection.   
 
Arm B – Daily TDF/FTC and IM placebo (matching vehicle, identical volume as active 
injectable product in Arm A) beginning at Week 5 plus an HIV prevention package 
including behavioral risk reduction and adherence counseling, and offer of condoms.  
This Step will continue until the required number of incident HIV endpoints (114) is reached, 
estimated to be when the last enrolled participant reaches approximately 76 weeks on Step 2 
(Week 81 for the last enrolled participant).  

 
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Participants who prematurely discontinue study product during Step 2 for any reason other 
than HIV infection or AE occurrence will be transitioned to open label TDF/FTC for 48 
weeks during Step 2 follow-up and then retained in annual testing for the duration of Steps 2 
and 3.  
Any participant who becomes HIV-infected during Step 2 will permanently discontinue 
study product, be referred for care, and will be followed at quarterly intervals for 
approximately 48 weeks.       
Step 3, Follow-up Phase:   
Arms A and B – Open-label daily TDF/FTC up to 48 weeks (to “cover the tail”), starting no 
later than 8 weeks after the last injection plus an HIV prevention package including 
behavioral risk reduction and adherence counseling, and offer of condoms.   
All participants will be transitioned to locally-available HIV prevention services including 
services for PrEP, if available when participation in Step 3 ends.   
Any participant who becomes HIV-infected during Step 3 will permanently discontinue 
product, continue to be followed for the duration of Step 3 visits (with possible additional 
assessments and follow-up determined by the Clinical Management Committee [CMC]), and 
referred for HIV-related care.   
All participants will receive HIV testing with pre- and post-test counseling, risk-reduction 
counseling, and be offered condoms.  All participants will be followed according to the 
Schedule of Evaluations (SOE) provided in Appendices I a-c, and in the event of possible 
HIV infection, according to Appendix II.   
Injectable Contraceptive Sub-study: 
Up to 180 evaluable participants will be invited to enroll in a sub-study after screening to evaluate 
the effect of CAB LA on the concentration and effectiveness of long acting contraceptive drugs: 
DMPA, NET-EN, and etonogestrel implant as compared to oral TDF/FTC.   This sub-study will 
be implemented at selected sites where all these methods are used.    Participants who are using 
injectable contraceptives (DMPA, NET-EN) or implants (etonogestrel) at enrollment will qualify 
for enrollment at these sites and will be asked their consent for this sub-study.  
 
Participants will be selected so that approximately equal numbers of women using DMPA, NET-
EN and etonogestrel implant are enrolled. These participants will go through the same study 
procedures as all other participants.  In addition, blood samples will be collected at enrollment 
(time 0) and at the regularly scheduled study visits at week 25, 49 and 73 for the determination of 
CAB, TFV/FTC (and/or intracellular metabolites), DMPA, NET-EN and etonogestrel plasma 
concentrations. These visits are chosen because they should be at an approximately similar point 
in the injection cycle for DMPA and NET-EN as the enrollment visit, assuming an 8 or 12 week 
cycle.  
 
Qualitative Sub-study: 
A prospective, qualitative sub-study will be conducted at four sites to collect more in-depth 
information on women’s preferences for and experiences with CAB LA versus other potential 

 
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HIV prevention methods, and to better understand circumstances related to special cases such as 
pregnancy, product disruption due to COVID- 19, early product termination or HIV 
seroconversion. The sub-study will include two sets of data collection activities: 1) a series of in-
depth interviews with a total of approximately 104 participants (approximately 26 participants per 
site) who are each interviewed at a maximum of 3 timepoints; and 2) quarterly semi-structured 
observations conducted in waiting rooms or other public clinic venues where participants are 
gathered.  
 
1) Repeated in-depth interviews:  At each of the four sites, a subset of approximately 10-16 
women will be invited to participate in a maximum of three in-depth interviews. Women will 
be sampled to reflect early (2018), middle (2019) and more recent enrollment (2020) into the 
trial, facilitating exploration of major events such as the dolutegravir and COVID-19 issues 
that affected trial implementation.   In addition, up to 10 women per site who, over the course 
of the trial, become pregnant, experience product or visit disruptions due to COVID-19 
measures, request to discontinue the study or terminate product use, or who seroconvert will 
be invited to participate in up two interviews to explore women’s reproductive choices or other 
circumstances affecting continued trial participation. 
2) Waiting room observations: Approximately once a quarter, as feasible, a qualitative team 
member will conduct a 45-minute semi-structured observation in the waiting room(s) of the 
study clinic.  The team will use a qualitative data extraction sheet to make notes about the 
overall demeanor of participants, topics of discussion and any information participants wish to 
share about their overall experiences, concerns, or recommendation related to the trial. 
 Participating Sites/Institutions 
Participating sites are listed in the SSP Manual and are located in SSA. 
Sub-studies for HPTN 084 will not necessarily be conducted at all sites. Sites selected for sub-
studies will be notified in writing by the study Chairs. 
2.5.1.1 Study Duration 
Study duration is approximately 4.6 years total, with individual participants being followed on 
randomized product between 1.6 years (for the last enrolling participants) to approximately 3.6 
years (for the earliest enrolling participants), and on open-label oral TDF/TDF for an additional 
48 weeks (starting no later than 8 weeks after the last injection for participants randomized to 
CAB LA).  Accrual will be competitive and require approximately 2 years.   
 
 

 
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STUDY POPULATION 
Approximately 3,350 HIV-uninfected women from SSA will be included in this study. Each site 
will be asked to work with its Community Advisory Board and outreach, education and 
recruitment teams to develop a recruitment plan appropriate for the local population. Participants 
will be selected for the study according to the criteria in Sections 3.1 and 3.2. Study participants 
will be recruited as described in Section 3.3. Requirements related to participant retention and 
withdrawal from the study are described in Sections 3.5 and 3.6, respectively. Individual sites 
will be given enrollment targets such that overall cross-site enrollment meets overall protocol 
goals.    
3.1 
Inclusion Criteria 
Participants who meet all of the following criteria are eligible for inclusion in this study: 
• Born female  
• 18-45 years at the time of screening 
• Willing and able to provide informed consent 
• Willing and able to undergo all required study procedures  
• Non-reactive HIV test results at Screening and Enrollment* 
• Sexually active (i.e., vaginal intercourse on a minimum of two separate days in the 30 days 
prior to Screening)  
• Score of >5 using a modified VOICE risk score52 
• No plans to re-locate or travel away from the site for >8 consecutive weeks during study 
participation 
• Creatinine clearance ≥60 mL/min (using Cockcroft-Gault equation) (use sex at birth for 
calculation) 
o Although not protocol exclusionary, sites should carefully consider the advisability 
of enrolling participants with calculated creatinine clearance between 60-70 
mL/min, as limited changes in creatinine clearance during study conduct will lead 
to protocol-mandated product holds and may alter the risk-benefit considerations of 
study participation 
• Hepatitis B virus (HBV) surface antigen (HBsAg) negative and accepts vaccination 
• Alanine aminotransferase (ALT) < 2x upper limit of normal (ULN) and total bilirubin 
(Tbili) ≤ 2.5 x ULN  
• HCV antibody negative  
• If of reproductive potential (defined as pre-menopausal women who have not had a 
sterilization procedure per self-report, such as hysterectomy, bilateral oophorectomy, tubal 
ligation or salpingectomy), must have a negative beta human chorionic gonadotropin 
(βHCG) pregnancy test (sensitivity of ≤ 25 mIU/mL) performed (and results known) on the 
same day as and before initiating the protocol-specified study product(s) at Enrollment.   

 
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• Have documented evidence of surgical sterilization, OR documented evidence of no uterus 
(e.g. hysterectomy), OR  must agree to use a reliable form of long acting contraception, 
during the trial and for 52 weeks after stopping the long acting injectable, or 30 days after 
stopping oral study product, from the list below: 
o Intrauterine device (IUD) or intrauterine system (IUS) that meets <1% failure rate 
as stated in the product label 
o Hormone-based contraceptive that meets <1% failure rate when used consistently 
and correctly as stated in the product label (implants or injectables only; this 
excludes combined oral contraception) 
• No medical condition that, in the opinion of the study investigator, would interfere with the 
conduct of the study (e.g., provided by self-report, or found upon medical history and 
examination or in available medical records)  
• No alcohol or substance use that, in the opinion of the study investigator, would interfere 
with the conduct of the study (e.g., provided by self-report, or found upon medical history 
and examination or in available medical records) 
 
*HIV-uninfected, based on HIV test results obtained at Screening and just prior to randomization 
at the Enrollment visit. All HIV test results from the Screening visit must be obtained and must 
all be negative/non-reactive. This includes testing for acute HIV infection, which must be 
performed within 14 days of Enrollment. In addition, at least one HIV test result using blood 
drawn at the Enrollment visit must be obtained prior to randomization into the study and must be 
negative/non-reactive. Individuals who have one or more reactive or positive HIV test result(s) 
will not be enrolled, even if subsequent confirmatory testing indicates that they are not HIV-
infected (see SSP Manual).  Those with any enrollment HIV test result positive will proceed 
through the HIV algorithm per the SSP but will not be able to receive study product regardless of 
subsequent test results.  
  
3.2 
Exclusion Criteria 
Participants who meet any of the following criteria will be excluded from this study: 
• One or more reactive HIV test results at Screening or Enrollment, even if HIV infection 
is not confirmed 
• Pregnant or currently breastfeeding, or intends to become pregnant and/or breastfeed 
during the study 
• Co-enrollment in any other HIV interventional research study (provided by self-report or 
other available documentation), with one exception: IMPAACT 2026  (co-enrollment in 
IMPAACT 2026 is permitted for participants who become pregnant)  
• Current or past enrollment in an HIV vaccine or broadly neutralizing antibody trial  
• Current or chronic history of liver disease (e.g., non-alcoholic or alcoholic 
steatohepatitis) or known hepatic or biliary abnormalities (with the exception of Gilbert's 
syndrome, asymptomatic gallstones, or cholecystectomy) 

 
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• History of seizure disorder, per self-report 
• Clinically significant cardiovascular disease, as defined by history/evidence of 
symptomatic arrhythmia, angina/ischemia, coronary artery bypass grafting (CABG) 
surgery or percutaneous transluminal coronary angioplasty (PTCA) or any clinically 
significant cardiac disease 
• Inflammatory skin conditions that compromise the safety of IM injections, per the 
discretion of the Investigator of Record (IoR). Mild skin conditions may not be 
exclusionary at the discretion of the IoR or designee  
• Has a tattoo or other dermatological condition overlying the buttock region which in the 
opinion of the IoR or designee may interfere with interpretation of ISRs 
• Coagulopathy (primary or iatrogenic) which would contraindicate IM injection  
• Active or planned use of prohibited medications as described in the IB or listed in the 
SSP Manual (provided by self-report, or obtained from medical history or medical 
records)  
• Known or suspected allergy to study product components (active or placebo), including 
egg or soy products (egg and soy products are contained in Intralipid) 
• If potentially able to conceive, unwilling to adhere to long acting contraception 
(IUD/IUS, injection, or implant) with a <1% failure rate when used consistently and 
correctly as stated in the product package insert/ manufacturer’s guidelines 
 
3.3 
Recruitment Process 
The study will be targeted towards most at-risk populations of women in each geographic setting 
(i.e., those with highest HIV incidence) in SSA. Enrollment will be competitive over 
approximately a two-year period, meaning that sites with a lengthy start-up period may end up 
with fewer enrolled participants versus those sites starting earlier. 
Sites will be responsible for developing appropriate recruitment processes that are geared toward 
their respective local communities.  All advertising materials must undergo approval by each 
participating site’s Institutional Review Board (IRB)/Ethics Committee (EC).  
Sites will implement wide-reaching educational efforts, community engagement, and multimedia 
advertising including rapidly changing and adaptive social media strategies to reach most at-risk 
populations. Participant retention during prolonged follow-up will be accomplished using study-
visit incentives as permitted by local IRBs at the maximum permissible level. 
3.4 
Co-Enrollment Guidelines 
In general, participants in this study will not be allowed to take part in other concurrent 
interventional research studies during their participation in the study. This is due in part to 
concerns about: 1) participant study burden, 2) American Red Cross-mandated limitations on 
per-unit-time phlebotomized blood volumes, 3) to avoid potential unblinding of studies, and 4) to 
avoid confounding in the interpretation of the study data. The CMC should be consulted for any 
possible exceptions, including for observational studies.   

 
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The one exception for co-enrollment is IMPAACT 2026.  An HPTN 084 participant who 
becomes pregnant following randomization and is enrolled at a site also participating in 
IMPAACT 2026 may co-enroll in that study. 
3.5 
Participant Retention 
Once a participant enrolls in this study, the study site will make every effort to retain her for the 
entire follow-up period. Optimally, participant retention procedures will be established such that 
loss rates do not exceed the range that would allow the incidence rate of the primary study 
outcome to be reliably estimated (i.e., a maximum of 5% per year as assumed in the sample size 
calculation). Study site staff are responsible for developing and implementing local standard 
operating procedures to target this goal. Components of such procedures may include: 
• Thorough explanation of the study visit schedule and procedural requirements during the 
informed consent process and re-emphasis at each study visit. 
• Thorough explanation of the importance of both arms and adherence to the overall 
success of the study. 
• Collection of detailed locator information at the study Screening Visit, and active review 
and updating of this information at each subsequent visit, including where the participant 
lives and other locator venues.  
• Use of appropriate and timely visit-reminder mechanisms, including SMS text 
messaging. 
• Immediate and multifaceted follow-up on missed visits, including SMS text messaging. 
• Mobilization of trained staff to complete in-person contact with participants at their 
homes and/or other community locations. 
• Regular communication with the study community at large to increase awareness about 
HIV/AIDS and explain the purpose of HIV prevention research and the importance of 
completing research study visits. 
• Incentives or reimbursements as permitted by local IRB/ECs.  
3.6 
Participant Withdrawal 
Regardless of the participant retention methods described in Section 3.5, participants may 
voluntarily withdraw from the study for any reason at any time.  
The IoR also may withdraw participants from study product dosing in order to protect their 
safety and/or if they are unwilling or unable to comply with required study procedures after 
consultation with the Protocol Chair, DAIDS Medical Officer, Statistical and Data Management 
Center (SDMC) Protocol Statistician, representatives from the Laboratory Center (LC), the 
Leadership and Operations Center (LOC) Clinical Research Manager (CRM), and others. 
Participants may be withdrawn from the study if the study sponsor, government or regulatory 
authorities (including Office for Human Research Protections [OHRP] and the FDA) or site 

 
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IRBs/ECs or if appropriate, the South African Health Products Regulatory Authority (SAHPRA), 
ViiV/Gilead terminate the study prior to its planned end date. 
Participants who decline to continue study product in Steps 1 or 3 should be offered the option of 
continued follow-up and at least annual HIV testing until study end. Participants who decline to 
continue study product in Step 2 and who have received study injections should be counselled 
about the long pharmacokinetic tail and offered transition to 48 weeks of open-label TDF/FTC   
followed by annual testing. Participants who decline follow up should be counselled regarding 
methods to reduce their HIV risk. (see section 5.10) 
Every reasonable effort will be made to complete a final evaluation of participants who terminate 
study product prior to the final protocol-dictated study week, and study staff will record the 
reason(s) for all withdrawals from the randomized study product in participants’ study records. 
In such cases, the IoR or designee must contact the CMC for guidance regarding final evaluation 
procedures.     

 
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STUDY PRODUCT CONSIDERATIONS 
4.1 
Study Product Regimens/Administration/Formulation Content 
Study Product Regimens 
Step 1 – Oral Run-in Phase (Blinded daily oral tablet) 
Participants will be randomized 1:1 to one of two study arms: 
• Arm A:  Oral CAB  tablets, 30 mg, one tablet orally daily for five weeks, with or without 
food AND placebo for TDF/FTC tablets, one tablet orally daily for five weeks, with or 
without food 
• Arm B:  TDF/FTC 300 mg/200 mg fixed dose combination tablet, one tablet orally daily 
for five weeks, with or without food AND placebo for oral CAB tablet, one tablet orally 
daily for five weeks, with or without food 
Step 2 – Injection Phase (Blinded injections and blinded daily oral tablet) 
 
• Arm A:  CAB LA 600 mg administered as one 3 mL (600 mg) IM injection in the gluteal 
muscle at two time points four weeks apart and every eight weeks thereafter, AND 
placebo for TDF/FTC tablet, one tablet orally daily, with or without food     
• Arm B:  TDF/FTC 300 mg/200 mg fixed dose combination tablet, one tablet orally daily, 
with or without food AND placebo for CAB LA (Intralipid 20% fat emulsion infusion) 
administered as one 3mL IM injection in the gluteal muscle at two time points four weeks 
apart and every eight weeks thereafter 
Step 3 – Follow-up Phase 
All participants, including those who permanently discontinue receiving injections before their 
Step 2 participation in the study ends, will receive open-label TDF/FTC 300 mg/200 mg fixed 
dose combination tablets, one tablet orally daily for up to 48 weeks.   
 Oral Product 
Oral CAB and placebo for oral CAB 
CAB 30 mg tablets (blinded) are formulated as white to almost white oval-shaped coated tablets 
for oral administration. The tablets are packaged in high density polyethylene (HDPE) bottles 
with child-resistant closure that include an induction seal. The bottles contain 30 tablets and a 
desiccant. The tablets must be stored in the original container.  The bottles are to be stored up to 
30 degrees Celsius (30o C, 86 o Fahrenheit [F]) and protected from moisture.     
Placebo for CAB 30 mg tablets (blinded) are formulated as white to almost white oval-shaped 
coated tablets to visually match the CAB tablets. The tablets are packaged in HDPE bottles with 
child-resistant closure that include an induction seal. The bottles contain 30 tablets and a 
desiccant. The tablets must be stored in the original container.  The bottles are to be stored up to 
30°C (86 o F) and protected from moisture.   

 
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Oral TDF/FTC and placebo for oral TDF/FTC 
TDF 300 mg/FTC 200mg tablets (blinded) are capsule-shaped, film-coated blue tablets that must 
be stored in the original container. Each bottle contains a silica gel desiccant canister to protect 
the product from humidity.  The bottles are to be stored up to 25°C (77°F). Excursions are 
permitted between 15° to 30°C (59°F to 86°F).  
 
Placebo for TDF 300 mg/FTC 200 mg tablets (blinded) are capsule-shaped, film-coated blue 
tablets that visually match the TDF/FTC tablets.  The tablets must be stored in the original 
container. Each bottle contains a silica gel desiccant to protect the product from humidity. The 
bottles are to be stored up to 25o C (77°F). Excursions are permitted between 15°C to 30°C (59°F 
to 86°F). 
 
TDF 300 mg/FTC 200 mg tablets (open-label) are capsule-shaped, film-coated blue tablets that 
must be stored in the original container. Each bottle contains a silica gel desiccant canister to 
protect the product from humidity. The bottles are to be stored at 25°C (77°F). Excursions are 
permitted between 15° to 30°C (59°F to 86°F).  The TDF/FTC fixed dose combination tablet 
containing 300 mg of TDF and 200 mg of FTC is available as Truvada®, and is approved by the 
U.S. FDA for treatment and prevention of HIV-1 infection. Further information on Truvada® is 
available in the current package insert (PI).53   
 Injectable Suspension 
The CAB study product (oral and LA injectable) being tested in this study is investigational and 
not yet approved by the US FDA for the treatment or prevention of HIV-1 infection. Further 
information on the study product is available in the IB, which will be provided by the DAIDS 
Regulatory Support Center (RSC). 
CAB LA formulation 
CAB LA is formulated as a sterile white to slightly pink colored suspension containing 200 
mg/mL of CAB LA for administration by IM. The product is packaged in a 2mL or 3 mL glass 
vial.  Each vial is for single use containing 2mL (400 mg), or 3mL (600mg), and does not require 
dilution prior to administration. CAB LA injectable suspension is to be stored up to 30o C (86oF), 
do not freeze.  
Placebo for CAB LA formulation 
Placebo for CAB LA injectable suspension will be Intralipid 20% fat emulsion infusion which is 
packaged in 100 mL IV bags.  Intralipid 20% fat emulsion infusion IV bags are to be stored 
below 25° C (77°F), do not freeze. 
 
 
 

 
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4.2 
Study Product Preparation 
 Preparation of the Oral Study Product 
The oral products for this study will be provided with customary two-part structure which 
includes a tear-off portion containing the un-blinded-product identification (i.e., active or 
placebo). 
 
Prior to dispensing, the un-blinded portion of the tear-off label must be removed and attached 
to the participant specific pharmacy record such as participant prescription or participant 
specific study product accountability record. The permanently affixed section of the label will 
remain on the original container. 
 
The site pharmacist will label the bottle with a participant specific label prior to dispensing. 
The participant specific label must be in accordance with the local regulations and the DAIDS 
Pharmacy Guidelines manual. 
 
The pharmacist will prepare the participant-specific study product and dispense sufficient 
quantity to last until the next follow-up visit plus approximately one-month buffer supply. 
Pharmacists will record dispensations on the Pharmacy Accountability Logs. 
 
 Preparation of Injectable Study Product 
The site pharmacist(s) must be proficient in the preparation of injectable study products using 
aseptic technique under a pharmacy biological safety cabinet (BSC) Class II or better. Local 
regulations and site institutional policies and procedures for use of personal protective 
equipment, such as gloves, gowns, masks, and safety glasses, must be followed. 
 
Preparation of Active Injectable Study Product (CAB LA 600 mg/3 mL) 
The designated pharmacy personnel will follow the steps below for preparation of active 
injectable study product, CAB LA injectable suspension. In Step 2 of the study, for the 
participants in Arm A, one syringe containing 3 mL (600 mg) of CAB-LA must be prepared 
using aseptic technique under a pharmacy BSC/Isolator. 
 
Materials required for preparation and administration of CAB LA 600mg; 3 mL dose: 
1. One CAB LA 600 mg/3 mL vial or two CAB LA 400 mg/2 mL vials 
2. Becton Dickenson (BD) 3-mL syringe, Luer-Lok Tip, Product No.: 309657 or equivalent 
3. Becton Dickinson (BD) 5-mL Syringe, Luer-Lok Tip, Product No.: 309646 or equivalent 
4. Needle for aspiration: BD general use sterile hypodermic needle, 21G x 1½ inch (e.g. 
Precision Glide Needle, Product No.: 305165 or equivalent) 
5. Needle for intramuscular injection: BD IM sterile hypodermic needle, 23G x 1½ inch 
(e.g. Precision Glide Needle, Product No.: 305194 or equivalent).  Refer to the HPTN 
084 SSP for further details on appropriate needle gauge size and length to use for IM 
administration. 
 
Preparation Steps: 
 

 
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1. Remove two vials of CAB LA (400 mg/2 mL per vial) or one vial of CAB LA (600 mg/3 
mL per vial) from storage.  If the vials are stored in the refrigerator (2°C to 8°C), remove 
vial(s) from the refrigerator and wait at least 15 minutes to equilibrate to room 
temperature. 
 
2. Vigorously shake the vial(s) for a full 10 seconds by shaking the vial(s) with long arm 
movements. 
 
3. Invert the vial(s) and inspect to ensure uniform suspension.  If solid remains undispersed, 
repeat Steps 2-3 until all material is uniformly suspended. 
 
NOTE: It is normal to see small air bubbles at the end of shaking the vial for re-
suspension. 
 
4. Using aseptic technique under a pharmacy BSC/isolator, flip off the plastic cap from the 
vial. Wipe the top of the vial with an alcohol pad (isopropyl alcohol 70% or similar) and 
allow to dry. Do not touch the rubber stopper at any time. 
 
5. Remove a 3 mL or 5 mL size syringe and 21G x 1½ inch (or equivalent) needle for 
aspiration.  Attach the needle to the Luer connection of the syringe. 
 
6. With the needle sheath on, pull the syringe plunger rod to allow approximately 1 mL of 
air into the syringe.  Remove the needle sheath.  
 
7. With the vial in the inverted position and the syringe with the needle in the upright 
position, push the needle through the vial stopper and inject approximately 1 mL of air 
into the vial.  
 
8. While keeping the syringe with the needle in the upright position, withdraw needed 
volume of CAB LA suspension from the vial(s) into the syringe  
• Withdraw total of 3 mL (600 mg) of CAB LA suspension from the vial(s) into a 
syringe. 
o If using two CAB LA 400 mg/2 mL vials to prepare the dose, a second new 
aspiration needle should be used to withdraw suspension from the second vial. 
Remove the first needle that was used to withdraw the suspension out of the 
first vial and discard properly. Attached the new 21G x 1½ inch needle to the 
syringe already containing suspension per instructions in Step 5 and repeat 
Steps 6 and 7 to withdraw the remaining needed volume from the second vial. 
 
Since the suspension can contain some air after having shaken the vial, withdraw enough 
suspension from the vial in order to be able to de-aerate the syringe properly. 
 
9. Remove the needle that was used to withdraw the suspension out of the vial and discard the 
needle properly. 
 
10. Place an overlay around the prepared syringe to maintain the blind. 

 
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11. Attach a 23G x 1½ inch (or equivalent) needle to the Luer connection of the prepared CAB 
LA syringe for IM injection for the participant.  Alternatively, the site pharmacist can 
attach a syringe cap to the prepared syringe.  The study staff can then attach the appropriate 
needle for administration to the prepared syringe in the clinic before administration. 
 
NOTE: The participant-specific prepared CAB LA in a syringe is to be de-aerated by 
administrator prior to injection so that the correct volume can be administered. 
 
De-aerate the syringe by first tapping with a finger against the syringe and then by moving 
the plunger rod carefully forward with the needle in an upright position until the first drop 
of suspension appears.  Remove the excess suspension in order to administer the correct 
volume (3 mL).  If needed, collect the excess suspension in a beaker to avoid spilling. 
 
12. Record the time that the suspension was withdrawn from the vial and into the syringe in the 
participant’s pharmacy log.  This is the time of preparation. 
 
13. Label the prepared syringe containing 3 mL (600 mg) of CAB-LA in a blinded fashion as 
“CAB LA 600 mg or Placebo for CAB LA”, including the volume (3 mL), route (IM), 
participant’s PTID, date and time of preparation, and date and time of expiration. Follow the 
DAIDS Pharmacy guidelines and local regulations for preparing the participant specific label. 
 
After withdrawal of the CAB-LA suspension from the vial into a syringe, it is 
recommended to inject the suspension immediately.  Do not exceed 2 hours between 
withdrawing the contents of the vial(s) into a syringe (Step 8) and administration to the 
study participant.  
 
The prepared CAB LA study product in a syringe must be stored at controlled room 
temperature between 20°C to 25°C (68°F-77°F) from the time it is withdrawn into a syringe 
to the time it is administered. 
 
Any entered vials or expired filled syringes should be disposed of in accordance with 
institutional or pharmacy policy. 
 
Preparation of Placebo Injectable Study Product (Intralipid 20%/ 3 mL syringe) 
The designated pharmacy personnel will follow the steps below for preparation of 
placebo injectable study product.  Placebo for CAB LA injectable suspension is Intralipid 
20% fat emulsion infusion. In Step 2 of the study, for the participants in Arm B, one 
syringe containing 3mL of intralipid 20% fat emulsion infusion will be prepared using 
aseptic technique under a pharmacy BSC/Isolator. 
 
Materials required for preparation and administration Placebo for CAB LA (Intralipid 
20%) 3 mL dose: 
1. One 100 mL IV bag of intralipid 20% fat emulsion  
2. Becton Dickenson (BD) 3-mL syringe, Leur-Lok Tip, Product No.: 309657 or equivalent 
3. Becton Dickinson (BD) 5-mL Syringe, Luer-Lok Tip, Product No.: 309646 or equivalent 

 
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4. Needle for aspiration: BD general use sterile hypodermic needle, 21G x 1½ inch (e.g. 
Precision Glide Needle, Product No.: 305165 or equivalent) 
6. Needle for intramuscular injection: BD IM sterile hypodermic needle, 23G x 1½ inch 
(e.g. Precision Glide Needle, Product No.: 305194 or equivalent).  Refer to the HPTN 
084 SSP for further details on appropriate needle gauge size and length to use for IM 
administration. 
 
Preparation Steps: 
 
1. Remove one 100 mL IV bag of Intralipid 20% from storage.  If the bags are stored in the 
refrigerator (2°C to 8°C), remove bag from the refrigerator and wait at least 15 minutes to 
equilibrate to room temperature. 
 
2. Using aseptic technique under a pharmacy BSC/ Isolator, wipe the additive port of the 
infusion bag with an alcohol pad (isopropyl alcohol 70% or similar) and allow to dry. 
 
3. Remove a 3 mL or 5 mL size syringe and 21G x 1½ inch (or equivalent) needle for 
aspiration.  Attach the needle to the Luer connection of the syringe.  
 
4. Remove the needle sheath.   
 
5. Push the needle through the additive port of the infusion bag and withdraw 3mL of 
Intralipid 20% into the syringe. 
   
6. Since the suspension can still contain some air, withdraw enough suspension from the 
Intralipid 20% IV bag in order to be able to de-aerate the syringe properly. 
 
7. Remove the needle that was used to withdraw the suspension out of the Intralipid IV bag 
and discard the needle properly. 
 
8. Place an overlay around the dosing syringe to maintain the blind. 
 
9. Attach a 23G x 1½ inch (or equivalent) needle to the Luer connection of the prepared 
Intralipid 20% (placebo) syringe for IM injection for the participant.  Alternatively, the 
site pharmacist can attach a syringe cap to the prepared syringe.  The study staff can then 
attach the appropriate needle for administration to the prepared syringe in the clinic 
before administration. 
 
NOTE: The participant-specific prepared Intralipid 20% syringe is to be de-
aerated by administrator prior to injection so that the correct volume can be 
administered. 
 
De-aerate the syringe by first tapping with a finger against the syringe and then by 
moving the plunger rod carefully forward with the needle in an upright position 
until the first drop of suspension appears.  Remove the excess suspension in order 

 
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to administer the correct volume (3 mL).  If needed, collect the excess suspension 
in a beaker to avoid spilling. 
 
10. Record the time the suspension was withdrawn from the Intralipid 20% IV bag into the 
syringe in the participant’s pharmacy log.  This is the time of preparation. 
 
11. Label the prepared syringe containing 3 mL of Intralipid 20% suspension in a blinded 
fashion as “CAB LA 600 mg or Placebo for CAB LA”, including the volume (3 mL), 
route (IM), participant’s PTID, date and time of preparation, and date and time of 
expiration. Follow the DAIDS Pharmacy guidelines and local regulations for preparing 
the participant specific label. 
 
12. Any entered IV bag or expired filled syringes should be disposed of in accordance with 
institutional or pharmacy policy. 
 
After withdrawal of the Intralipid 20% suspension from the IV bag into a syringe, 
it is recommended to inject the suspension immediately.  Do not exceed 2 hours 
between withdrawing from the IV bag into a syringe (Step 5) and administration 
to the study participant.  
 
The prepared Placebo for CAB LA study product in a syringe must be stored at 
controlled room temperature between 20° C to 25° C (68° F-77° F) from the time 
it is withdrawn into a syringe to the time it is administered. 
 
4.3 
Study Product Acquisition and Accountability 
CAB 30 mg tablets, Placebo for CAB tablets, and CAB LA injectables are manufactured and 
provided by ViiV Healthcare.  Intralipid 20% IV bags are manufactured by Fresenius Kabi and 
provided by ViiV Healthcare.  TDF 300 mg/FTC 200 mg tablets and Placebo for TDF/FTC 
tablets are manufactured and provided by Gilead Sciences, Inc. 
 
 Study Product Acquisition 
All study products (active and placebo) will be supplied through the National Institute of Allergy 
and Infectious Diseases (NIAID) Clinical Research Products Management Center (CRPMC). 
The study site pharmacist can obtain all the study products through the CRPMC by following the 
instructions in the Pharmacy Guidelines and Instructions for DAIDS Clinical Trial Networks, 
and instructions in the SSP Manual.    
DMPA,NET-EN and/or etonogestrel implants, which will be evaluated as part of the 
Contraceptive sub-study,  will not be provided by the Study Sponsor. 
 Study Product Accountability 
The site pharmacist is required to maintain complete records of all study products received from 
the CRPMC and subsequently dispensed to study participants. All study products must be stored 
in the pharmacy. All unused study products must be returned to the CRPMC after the study is 

 
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completed, terminated or otherwise instructed by the study sponsor. The procedures to be 
followed are provided in the Pharmacy Guidelines and Instructions for DAIDS Clinical Trials 
Networks. The site pharmacist at non-US clinical research sites must follow the instructions in 
the Pharmacy Guidelines and Instructions for DAIDS Clinical Trials Networks DAIDS 
Pharmaceutical Affairs for the destruction of unused study products. 
4.4 
Other Study Product Dispensing Considerations 
While it is not required, it is recommended that sites dispense two bottles of each study product 
(TDF/FTC or placebo and CAB or placebo) at Week 0, two bottles of oral TDF/FTC or placebo 
at Week 5, and three bottles at each dispensation visit throughout Step 2 to ensure an extra month 
supply between visits. Participants should be advised to bring open bottles to appointments, 
finish an open bottle before opening a new one, and should not combine or transfer pills between 
open bottles. A formal pill count is not required in Step 2 (or Step 3), but an open bottle can be 
used to assist with determining refill quantity (that is, whether there is sufficient remaining oral 
study product supply in the participant’s possession that only two bottles need be dispensed and 
still maintain a three-month supply in the participant’s possession). 
It is important to dispense all study products at each visit at which study product dispensation is 
scheduled per protocol. For example, if during Step 2 a participant reports for an injection visit 
but refuses the injection or does not receive the injection for any other reason, oral study product 
should not be dispensed. Participants should either receive all study products at each visit where 
study product is scheduled to be dispensed, or no study products. 
4.5 
Toxicity Management 
Toxicity management guidelines can be found in Appendix III.    
4.6 
Concomitant, Prohibited, and Precautionary Medications 
All concomitant medications/preparations (prescription and non-prescription) including 
alternative/complementary medications/preparations (e.g., herbs, vitamins, etc.) taken within 30 
days prior to enrollment and anytime thereafter during study participation will be collected in the 
study participant’s chart and on study case report forms (CRFs).  
In order to avoid AEs caused by drug interactions, whenever a concomitant medication is taken, 
site staff must review the concomitant medication's and study product’s most recent PI for 
TDF/FTC and the IB for cabotegravir to obtain the most current information on drug interactions 
and contraindications.  Concomitant medications (prescription and non-prescription) should be 
administered only as medically necessary during the study.  
 
After Enrollment, for any precautionary or prohibited drug listed in the TDF/FTC PI or 
cabotegravir IB, it is required that the HPTN 084 CMC be notified for recommendations for 
continuing or stopping (or holding) study product.     
 
Experimental agents not otherwise specified in the SSP Manual may not be administered. 
Precautionary and prohibited medications (as of the time this section was written) are listed 
below. 

 
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Cabotegravir: 
• Not to be administered concurrently: 
o Cytotoxic chemotherapy or radiation therapy 
o Systemically administered immunomodulators 
▪ NOTE: Stable physiologic glucocorticoid doses (defined as prednisone ≤15 mg/day 
or equivalent as a stable or tapering dose) are not prohibited. Use of corticosteroids 
for an acute condition such as asthma exacerbation or receiving a short course 
(defined as ≤2 weeks of pharmacologic glucocorticoid therapy) is also not 
prohibited. 
o immunomodulators 
o barbiturates 
o carbamazepine 
o oxcarbazepine 
o phenytoin 
o pheonobarbital 
o rifabutin 
o rifampin 
o rifapentine 
o St. John’s wort 
• Prohibited within 7 days before and 7 days after an injection 
o high dose aspirin (>325 mg per day) 
o anagrelide 
o apixaban 
o argatroban 
o bivalirudin 
o clopidogrel 
o dabigatran 
o dalteparin 
o enoxaparin 
o fondaparinux 
o heparin 
o lepirudin 
o prasugrel 
o rivaroxaban 
o ticagrelor 
o ticlopidine 
o warfarin 
• Oral formulation precautions 

 
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o Antacid products containing divalent cations (e.g., aluminum, calcium, and magnesium) 
must be taken at least 2 hours before or at least 4-6 hours after the oral CAB 
administration  
 
TDF/FTC: 
• Medications containing the following ingredients should not be administered concurrently: 
o emtricitabine or tenofovir disoproxil fumarate (e.g. ATRIPLA®, COMPLERA®, 
EMTRIVA, GENVOYA®, ODEFSEY®, STRIBILD®, or VIREAD, Descory). 
o lamivudine (e.g. Combivir, Dutrebis, Epivir, Epivir-HBV, Epivir A/F, Epzicom, 
Triumeq, or Trizivir) 
o adefovir (e.g. HEPSERA®) 
o tenofovir alafenamide (e.g. Vemlidy) 
o didanosine (e.g. Videx EC) 
o atazanavir (e.g. Reyataz, Evotaz (atazanari/cobicistat)) 
o ledipasvir/sofosbuvir (e.g. HARVONI®) 
o darunavir (e.g. Prezista) 
o lopinavir/ritonavir (e.g. Kaletra) 
o orlistat (e.g. Alli, Xenical) 
• Co-administration of the following drugs should be clinically monitored by site clinician, as 
per considerations below: 
• drugs that are eliminated by active tubular secretion (e.g. drug, cidofovir, ganciclovir, 
valacyclovir, valganciclovir, aminoglycosides (e.g., gentamicin), and high-dose (please refer 
to the table below) or multiple NSAIDS), as these may increase concentrations of 
emtricitabine, tenofovir, and/or the co-administered drug.   
• Drugs that decrease renal function (e.g., cause nephrotoxicity) as these may increase 
concentrations of emtricitabine and/or tenofovir. 
 
• NOTE:  Please report to the CMC if a participant takes a total daily dose of NSAIDS that meets 
or exceeds high dose, as designated in the table below, for MORE than 72 consecutive hours. 
• NOTE:  Acyclovir and valacyclovir may be used when indicated. If needed for treatment – sites 
do NOT need CMC permission for the use of these products, but sites should counsel the 
participant to increase hydration to avoid additive nephrotoxicity; no additional laboratory 
monitoring is required per protocol.  

 
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STUDY PROCEDURES 
Overviews of the study visit and procedures schedules are presented in Appendices I a-c, and 
Appendix II (for suspected and/or confirmed HIV infection). Presented below is additional 
information for visit-specific study procedures. Detailed instructions to guide and standardize all 
study procedures across sites are included in the SSP Manual. 
5.1 
Screening 
It is the responsibility of the local site to determine the best approach to screening.  For each 
participant, independent written informed consent will be obtained before any study procedures 
are initiated. Screening procedures may occur over one or more visits. The SSP Manual provides 
additional information regarding the procedures outlined below, including clinical and laboratory 
procedures and requirements. Enrollment must occur within 45 days of specimen collection at 
Screening for the clinical and laboratory evaluation and procedures (except for HIV RNA testing 
samples, which must be collected and results obtained within 14 days before enrollment).  
Sites will follow the HIV testing algorithm for Screening included in the SSP Manual. If a 
reactive/positive result is obtained for any HIV test, the person is not eligible for the study.  
Additional testing to confirm suspected HIV infection during Screening will be performed in 
accordance with local guidelines. If HIV infection is confirmed, participants will receive 
counseling and be referred for appropriate care, as necessary.   
Individuals deemed not eligible will be informed that they do not meet the elibility criteria for 
the study and will be referred for appropriate medical care, if necessary.   
Potential participants may be rescreened once at the discretion of the IoR or their designee.  
Further re-screening for administrative reasons may be permitted with the approval of the CMC. 
However, potential participants with clinically-significant cardiovascular disease as outlined in 
the exclusion criteria in Section 3.2, or any reactive HIV test, may not be re-screened. 
Participants with symptoms concerning for acute HIV infection (per IoR or designee) may be re-
screened in consultation with the CMC once appropriate testing has ruled out acute HIV 
infection.      
5.2 
Step 1, Oral Run-in Phase: Enrollment  
Enrollment/Week 0 Visit 
All HIV test results including testing for acute HIV from Screening, which must be performed 
within 14 days of Enrollment, and at least one HIV test result from Enrollment must be available 
and confirmed to be negative/non-reactive PRIOR to randomization and provision of study 
product.  Randomization is the point at which the participant is enrolled in the study. Results 
from the chemistry testing, liver function tests (LFTs), lipid profile, hematology testing, second 
instrumented HIV test, and urinalysis from this visit are NOT required prior to randomization.   
Up to 180 evaluable participants enrolling at sites selected for the contraceptive sub-study who 
consent to participate in the sub-study should have blood for pharmacological analysis, including 

 
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hormonal contraceptive agents, (DMPA, NET-EN and  etonogestrel) drawn prior to initiating 
study product.   
If of reproductive potential, a pregnancy test must be conducted on the same day that study 
product is dispensed and the pregnancy test result from the same day must be confirmed to be 
negative prior to randomization. Study product must be dispensed with instruction to 
participants.  Participants will take the first dose of the assigned study product in the presence of 
site staff.  
Eligible participants will be reminded that the use of anticoagulant and/or antiplatelet 
medications as outlined in the SSP Manual are prohibited within seven days before and seven 
days after injections. Reminders will be built in to the concomitant medication history.     
5.3 
 Step 1, Oral Run-in Phase: Safety Visits   
Oral Run-in Safety Visits at Weeks 2 and 4  
All HIV test results from previous visits and at least one HIV test result from the current visit 
must be available and reviewed. If any of these tests is reactive/positive, study drug must be 
discontinued and procedures in Section 5.11 will be followed.   
If of reproductive potential, study approved contraception should be confirmed and a pregnancy 
test must be conducted and the result from the current visit (same day) must be viewed.  If the 
participant is not pregnant, the site will follow the SOE for the visit.  If a participant tests 
positive for pregnancy, see Section 5.14.  
All participants must receive adequate product exposure during step 1, in order to assess 
tolerability prior to transition to step 2.  
Investigators should contact the CMC at 084cmc@hptn.org if a participant has missed her 
contraception, has a missed or delayed week 4 visit, or has not had sufficient oral drug exposure 
during the four-week oral run-in period to transition to step 2.  
 
 Management of Participants with AEs during Step 1 
The oral run-in (Step 1) is included to reduce risk to participants in Arm A.  Participants with 
significant, negative side effects to oral study product will not continue on to Step 2, the 
Injection Phase.  See  
 

 
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Table 5.1 for brief instruction and Appendix III, Toxicity Management for detailed instruction on 
participant management.  All AEs are to be followed until the return to < Grade 2. 
 
 
 

 
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Table 5.1. Management of Participants with AEs in Step 1 
Grade of AE 
Brief Instruction 
Grade 1 AE 
Proceed with SOE and to Step 2 
Grade 2 AE, excluding ALT 
Proceed with SOE and to Step 2 
Grade 2 ALT 
At Week 4→ continue oral product, repeat ALT labs in 1 week 
 
If < Grade 1 at Week 5, move participant to Step 2 
If > Grade 2 at Week 5, follow annually for HIV testing until 
study end of Step 3 
Grade 3 AE, excluding ALT & 
CPK 
Report to CMC and if determined to be: 
• 
Related AE→ permanently stop oral product, follow 
annually for HIV testing until study end of Step 3 
• 
NOT related AE→ see Toxicity Management Section 
and follow CMC guidance 
Grade 3 ALT 
Report to CMC  
 
Permanently stop oral product, repeat ALT labs weekly until < 
Grade 1, follow annually for HIV testing until study end of Step 
3 
Grade 3 CPK + < Grade 3 ALT 
Report to CMC for adjudication 
 
Grade 4 AE, excluding ALT & 
CPK 
Report to CMC 
 
Permanently stop oral product, follow annually for HIV testing 
until study end of Step 3 
Grade 4 ALT 
Report to CMC 
Regardless of CPK permanently stop oral product, repeat ALT 
labs weekly until < Grade 1, follow annually for HIV testing 
until study end of Step 3 
Grade 4 CPK + < Grade 3 ALT 
Report to CMC for adjudication 
 
 
 

 
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5.4 
Step 2, Injection Phase: Injection Visits  
Visits at Week 5, 9, and every 8 weeks thereafter (until end of Step 2) 
The first study product injection is given at the Week 5 visit.  All HIV test results from previous 
visits and at least one HIV test result from the current visit must be available and confirmed to be 
negative/non-reactive PRIOR to injection of study product. Neither the injection/placebo nor 
TDF/FTC/placebo may be given if any HIV test is reactive/positive. For management of 
participants with an HIV-positive test, see Section 5.11. 
 
If of reproductive potential, a pregnancy test must be conducted on the same day that study 
product is injected or dispensed and the pregnancy test result from the same visit day must be 
confirmed to be negative PRIOR to injection/dispensing of study product.  If the pregnancy test 
is positive, see Section 5.14. 
Results from the other clinical and laboratory evaluations (e.g., chemistry, LFTs, hematology) 
from previous visits must be available and be reviewed by the IoR or their designee prior to 
provision of study product.  For management of participants with AEs, see Appendix III, 
Toxicity Management. 
If participants miss injections, contact the CMC. 
In select circumstances e.g. “unconfirmed” pregnancy, use of prohibited concomitant drugs, or 
refusal to use long acting contraception it may be necessary to temporarily hold administration of 
blinded study product. If blinded study product cannot be administered for safety reasons, in 
consultation with the CMC, participants may be transitioned to open-label TDF/FTC 
temporarily.  Such participants remain in Step 2 follow-up and attend regularly scheduled Step 2 
visits. Should the reason(s) for temporary blinded study product later resolve and it becomes safe 
again for study product administration, participants may be transitioned back to blinded study 
product. The CMC must be contacted and its guidance must be followed in all cases of 
temporary blinded study product hold during Step 2. 
Contraceptive Sub-study 
Up to 180 evaluable participants enrolled at sites selected for the contraceptive sub-study who 
consented to participate in the sub-study should have blood for pharmacological analysis, 
including hormonal contraceptive agents, (DMPA, NET-EN and etonogestrel) drawn prior to 
study product administration.  Subjects participating in the contraceptive sub-study should have 
blood samples drawn at Weeks 25, 49 and 73.  These visits are chosen because they should be at 
an approximately similar point in the injection cycle for DMPA and NET-EN as the enrollment 
visit, assuming an 8 or 12 week cycle. Dosing date for all injectable contraceptives should be 
recorded throughout the study.   
5.5 
Step 2, Injection Phase: Safety Visits  
Injection Phase Safety Visits at Week 6, 13, 21 and 42 
All HIV test results from previous visits and at least one HIV test result from the current visit 
must be available and confirmed to be negative/non-reactive for the participant to continue with 
study product.  For management of participants with an HIV-positive test, see Section 5.11. 

 
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If of reproductive potential, a pregnancy test must be conducted on the same visit day and must 
be confirmed to be negative for the participant to continue with study product.  If the pregnancy 
test is positive, see Section 5.14. 
 
Results from the other clinical and laboratory evaluations (e.g., chemistry, LFTs, hematology) 
from previous visits must be available and be reviewed by the IoR or their designee prior to 
provision of study product.  For management of participants with AEs, see Appendix III, 
Toxicity Management.  
5.6 
Step 3, Follow-up Phase 
Follow-up Phase of Step 3 at Day 0 and Weeks 12, 24, 36, 48  
For each study participant, Day 0 of Step 3 must occur within 8 weeks following completion of 
Step 2.  All HIV test results from previous visits and at least one HIV test result from the current 
visit must be available and confirmed to be negative/non-reactive PRIOR to provision of study 
pills. For management of participants with an HIV-positive test, see Section 5.11. 
If of reproductive potential, a pregnancy test must be conducted on the same day that study 
product is dispensed and the pregnancy test result from the current visit must be confirmed to be 
negative. If the pregnancy test is positive, see Section 5.14. 
 
Results from the clinical and laboratory evaluations (e.g., chemistry, LFTs, hematology) must be 
available and be reviewed by the IoR or their designee prior to provision of study pills.   For 
management of participants with AEs, see Appendix III, Toxicity Management. 
5.7 
Standard of Care (SOC) Counseling for all Participants 
 HIV and Risk Reduction Counseling 
HIV testing and risk reduction counseling will be provided at each study visit, in accordance 
with local SOC, and will include messaging about consistent condom use. Condoms will be 
offered to all participants at each study visit consistent with local standards. In addition, 
counseling will emphasize the double-blind nature of the study. 
 Adherence Counseling and Monitoring  
It is clear that the effectiveness of daily oral TDF/FTC is tightly correlated with adherence.   
The study will provide adherence support/counseling at baseline and at all follow-up visits for all 
participants.  Counseling will be provided in accordance with recommendations from PrEP 
clinical guidance documents and in-country implementation strategies.54 55  Using a participant-
centered approach to frame discussions, standard adherence counseling will include education 
around the importance of daily pill adherence and supporting strategies that link pill taking to the 
participant’s daily routine.   Counseling will also focus on the importance of returning for 
injection visits on or as close to the scheduled date as practical. 

 
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Participants will receive oral adherence counseling during Steps 1, 2 and 3, and will also be 
regularly reminded during Step 2 of the importance of returning for injections.  Oral adherence 
counseling for which will include an emphasis on the known relationship between adherence and 
TDF/FTC efficacy. 
 
NOTE: While adherence to oral study product is important for the duration of the study; there are 
no minimal oral study product adherence requirements for Steps 2 or 3.  
5.8 
Injection Visit Windows 
The visit windows for all visits, including injection visits, are outlined in the SSP Manual.  
There are two types of visit windows: 1) narrower target visit windows, and 2) wider allowable 
visit windows.  Allowable visit windows are contiguous.  In general, the target visit window for 
injection visits is +/- 3 days.   Sites must attempt to schedule participants as close to a given visit 
target date as possible. 
Refer to SSP for instruction on managing participants who report to clinic outside of injection 
window. 
5.9 
Procedures for Continued Oral and Injectable Dosing 
Refer to Appendix III, Toxicity Management, for general toxicity management, as well as 
specific clinical and laboratory toxicity management guidelines, including directions regarding 
temporary and permanent study product holds.   Also consult Section 5.4 above for temporary 
study product hold instruction. 
5.10 Procedures for Participants in Step 2 Who Do Not Complete the Full Course of Study 
Product 
Participants who have received at least one injection and refuse further injections or discontinue 
due to an AE will be managed as follows: 
• Participants will be transitioned to open-label TDF/FTC no later than eight weeks 
after the last injection (if it is safe to do so) for up to 48 weeks  
• Participants will be followed on TDF/FTC according to the Step 3 SOE until the end 
of the participant’s Step 3 schedule  
Participants who refuse further TDF/FTC or discontinue due to an AE will be managed as 
follows: 
• Participants will be followed off study product according to the SOE until the end of 
each participant’s Step 3 schedule.  
 
All participants will be followed up thereafter at least annually for HIV testing until Step 2 and 3 
follow up is completed 
 

 
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5.11 Participants with Suspected or Confirmed HIV Infection at Screening, Enrollment, or 
Follow-Up 
 Screening and Enrollment 
HIV testing will be performed to identify participants with HIV infection.  Individuals who have 
one or more reactive or positive HIV tests at Screening or Enrollment are not eligible to 
participate in this study. Furthermore, at Screening and Enrollment (prior to randomization), 
individuals with any signs or symptoms consistent with acute (pre-seroconversion) HIV infection 
will not be enrolled, unless acute HIV infection is ruled out with appropriate laboratory testing, 
in consultation with the CMC. Signs and symptoms consistent with acute HIV infection are 
included in the SSP Manual.   
 After Study Enrollment/Randomization 
Frequent testing for HIV acquisition during the study period (at all scheduled study visits) will 
help prevent dosing with the study product in a participant who may have acquired HIV 
infection, minimizing the risk that resistant virus will emerge. In addition, if a participant has 
signs or symptoms consistent with acute HIV infection (see SSP Manual), or expresses a concern 
about recent HIV acquisition, HIV testing will be performed using an RNA test that, in the 
opinion of the IoR or designee, is able to detect early HIV infection. If possible, an assay that is 
US FDA-cleared for early HIV diagnosis such as the Aptima HIV-1 RNA Qualitative Assay 
should be used.   
Regardless of whether HIV RNA testing is used for diagnostic purposes, HIV acquisition after 
study enrollment must be confirmed in all cases using two independent samples collected on 
different days.   
Participants who have any reactive or positive HIV test result during follow-up visits will have 
further testing to confirm infection, as described in the SSP Manual and Appendix II. Study 
product will be withheld while this further testing is performed. 
Additional samples from participants with confirmed HIV infection may be sent to a local 
laboratory for resistance testing to assist with clinical management (results from resistance 
testing performed in local laboratories should not be reported to the HPTN SDMC or the HPTN 
LC). If a participant has a reactive or positive HIV test, the participant will not receive additional 
doses of study products pending further direction regarding testing and continued participation in 
the study from designated study team members (see SSP Manual for email alias regarding 
suspected HIV infection), including the HPTN LC. Refer to the SSP Manual for instructions 
regarding HIV testing. 
Step 1 
Participants with confirmed HIV infection prior to receipt of their first injection will have oral 
study product permanently discontinued and will be transitioned to local HIV-related care and 
terminated from the study. 
Step 2 
Participants with confirmed HIV infection during Step 2 will not receive additional injections or 

 
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oral study product, and will be followed per the SOE in Appendix II quarterly for approximately 
48 weeks. In addition, sites will have a standard operating procedure (SOP) that outlines a plan 
in the event that a participant becomes HIV-infected during any Step of the study, and in 
particular during Step 2 of the study, which must include the participant’s facilitation into 
locally-available ART to be started immediately, to prevent emergence of drug resistance; ART 
should be continued for a minimum of 52 weeks after the final injection. Participants who 
seroconvert will be referred for care; sites will not be responsible for the actual 
provision/payment of ART.  Neither ART nor funds for provision of ART will be provided by 
the study. 
Step 3 
Participants with confirmed HIV infection during Step 3 will have their TDF/FTC stopped and 
be followed quarterly at least for the duration of Step 3, with possible additional assessments and 
follow-up to be determined by guidance from  members of the HIV alias.  Study product will be 
discontinued and participants will be referred for care. 
5.12 STIs 
Testing for Neisseria gonorrhoeae (GC)/Chlamydia trachomatis (CT), Trichomonas vaginalis 
(TV) and syphilis will occur throughout the study. Testing will be performed at local 
laboratories.  
Participants will be referred for treatment of STIs as per local guidelines. Symptomatic screening 
for STIs beyond what is required by the protocol will be at a site’s discretion and cost.   
5.13 HBV and HCV 
Testing for HBV and HCV will be performed at Screening (HBsAg and HCAb). Persons positive 
for these tests will not be enrolled in the study and will be referred to their primary provider for 
management. Persons with a positive HCV Ab test at Screening will be excluded from the study. 
Participants will be tested for Hepatitis B surface antibody (HBsAb), and Hepatitis B core 
antibody (HBcAb, total). Participants who do not have evidence of immunity to HBV (e.g., 
negative HBsAb) will be provided HBV vaccination. Refer to the SSP Manual for persons who 
have a positive result for HBcAb (total) only.      
For enrolled individuals, HCV antibody testing will be performed at scheduled visits while on 
Step 2 (see Appendix Ib). Incident HCV infection during follow-up will not mandate 
discontinuation of study product absent other requirements per Appendix III - Toxicity 
Management.       
5.14 Pregnancy 
Because CAB and CAB LA are investigational agents, women may not enroll if they are 
pregnant or desire to become pregnant.  Receipt of study product by participants requires use of 
an effective method of contraception as outlined in Section 3.1. Participants should be 
encouraged to delay pregnancy for at least 52 weeks following discontinuation of IM dosing.  All 
participants must also use male or female condoms for prevention of HIV and other STIs. Study 
staff will provide contraceptive counseling to enrolled participants throughout the duration of 

 
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study participation and will facilitate access to contraceptive services through direct service 
delivery and/or active referrals to local service providers for methods that cannot be provided on-
site.   
Study staff should confirm adequate contraception with one of the study approved contraceptive 
methods (see section 3.1) at each visit.    In situations where adequate contraception cannot be 
confirmed, and in the opinion of the investigator early pregnancy cannot be excluded, then the 
investigator should contact the HPTN 084 CMC at 084cmc@hptn.org for further guidance 
regarding the administration of study injections. 
In the event of a first positive pregnancy test or where pregnancy cannot be excluded, a  four-
week supply of open label TDF/FTC should be given.  No study product injections should be 
given if there is a positive pregnancy test. Participants who have a first positive pregnancy test 
during Step 1 (Week 2 or Week 4) may transition to Step 2 if subsequent pregnancy testing done 
4 weeks after the initial positive pregnancy test determines that the participant is not pregnant 
and all other safety requirements for transition to Step 2 are met. 
All participants who are pregnant must be referred for an Ultrasound and evaluation by an 
obstetric specialist at about 12-14 weeks gestational age, for other testing, counseling, and 
management. Further biochemical blood test may be done as indicated.  All findings and 
outcomes will be collected and reported. 
Refer to procedures in Appendix Id. 
Study staff will also offer participants with male and/or female condoms and counseling on use 
of condoms.   
 
Participants of reproductive potential will have pregnancy testing as outlined in the SOE. 
Participants will be encouraged to report all signs or symptoms of pregnancy to study staff.   
Confirmed Pregnancies 
Participants with a positive pregnancy test will require confirmation of pregnancy at a 
subsequent visit at least four weeks later. All pregnancies that occur during the course of the 
study must be reported to the CMC within seven days of site awareness (either upon 
confirmation by urine or blood pregnancy testing during a study visit or as reported by the 
participant between study visits). Site staff will refer to their SOP for detailed management. 
All pregnant participants with a confirmed positive pregnancy test (four weeks after the initial 
pregnancy test) will be unblinded and followed by the study every 12 weeks. Regardless of the 
randomization assignment or point in the study, all pregnant participants will be placed on open-
label TDF/FTC for the duration of the pregnancy. No participant with a positive pregnancy test 
will be administered CAB, CAB LA, or CAB LA placebo.  The site IoR or designee will refer 
pregnant participants to all applicable pregnancy-related services and will be provided a letter to 
obstetric services detailing participation in the trial; however, sites will not be responsible for 
paying for pregnancy-related care.  The site IoR or designee will counsel any participants who 
become pregnant regarding possible risks to the fetus according to site-specific SOPs.   

 
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Once pregnancy outcome is reached, if the participant is not breastfeeding, she may resume 
study product and visits according to the SOE. Should a participant who delivers a child during 
the study elect to breastfeed, she will stay on open-label TDF/FTC and will be followed per the 
SOE. Once a participant has finished breastfeeding, she may resume study product and visits 
according to the SOE. To most closely reflect eventual real-world practice, unblinded 
participants will have the option to return to open-label study product in their original 
randomization arm (either CAB LA or oral TDF/FTC).  Participants who are pregnant at their 
last study visit will continue to be followed until the pregnancy outcome is ascertained or it is 
determined that the pregnancy outcome cannot be ascertained through all reasonable means.  All 
pregnancy outcomes will be reported on relevant CRFs.  Outcomes meeting criteria for expedited 
AE (EAE) reporting also will be reported. Infants will be followed up for one  year post-natally  
to ascertain final pregnancy outcomes in respect to congenital anomalies.   
5.15 Participants who decline to use long acting contraception 
All participants who are not currently pregnant and potentially able to conceive and decide to 
discontinue long acting contraception for any reason will be immediately placed onto open label 
TDF/FTC and follow procedures detailed in Appendix Ic.   
 
***Please note that if a participant transitioned to open-label TDF/FTC during Step 2, 
either because she wanted to become pregnant or declined to continue using long-acting 
contraception, and subsequently changes her mind she may continue in the study on 
blinded study product (per original randomization) once she has documentation of a 
negative pregnancy test and of resuming long-acting contraception; she must also meet 
all other standard visit criteria. 
 
 
Participants who continue to desire children and complete 48 weeks of TDF/FTC (initiated no 
later than eight weeks after her last injection) while study follow-up is ongoing will be required 
to be followed up at least annually for HIV testing. 
 
If the participant conceives, she should follow procedures for pregnant participants (see section 
5.14). 
 
Participants who complete pregnancy and cease breastfeeding may resume open-label study 
product in their original randomization arm (either CAB LA or oral TDF/FTC) 
and visits according to Appendix Ib, provided they agree to use an approved contraceptive 
method (either injection, implant or IUD/IUS).  If participants decline to use an approved 
contraceptive method, they will be given open-label TDF/FTC for 48 weeks starting no later than 
eight weeks after her last CAB LA/placebo injection. If study follow-up is ongoing she will be 
required to be followed up at least annually for HIV testing thereafter. 
 
In all cases contact the HPTN 084 CMC at 084cmc@hptn.org 
 

 
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5.16 Acceptability Assessments 
Acceptability of CAB LA and daily use of TDF/FTC will be assessed through administration of 
brief behavioral surveys conducted at Enrollment and every six months.  The surveys will include, 
but not be limited to, questions about participants’ attitudes/beliefs towards CAB LA and 
TDF/FTC; product and study-related motivations. In addition, four sites will participate in a 
qualitative sub-study.  
 
Qualitative Sub-study 
The qualitative sub-study includes two separate sets of activities: repeated in-depth interviews 
with a subsample of current trial participants and special cases; and semi-structured observations 
in waiting rooms. 
 
In-Depth Interviews (IDIs) 
The four sites participating in the qualitative sub-study will work with SCHARP to randomly 
select and short-list from 8-10 participants who are currently enrolled and on study product 
across several years of trial implementation (e.g., Jan-Dec 2018; Jan-Dec 2019; Jan 2020 to 
present). Sites will enroll from 4-6 participants in each of these time periods to participate in the 
sub-study. If a site is still enrolling, it may choose to enroll fewer (e.g., 4-5) participants each 
from 2018 or 2019, and more participants (6-8) from 2020.  
 
They IDIs may be conducted remotely (by cell phone or video chat) or be conducted in another 
private and mutually agreed upon location in sites that are limiting non-essential clinic visits. Sub-
study participants who participate in IDIs will be consented separately and must agree to being 
interviewed up to three times over the course of their trial participation.  If an interview takes 
place virtually, informed consent will be documented in a manner that is consistent with local ethics 
committee or IRB guidelines. Several options may be considered including administering and 
recording the informed consent document, as well as the participant’s verbal consent over the phone 
and documenting consent in a separate document. 
 
Topics for the recently enrolled participants (within 1st or second injection): 
 
• Household, relationship context, including any impact of COVID-19; 
• Current and future goals, including perspectives on delaying fertility during trial; 
• Perceived HIV risk;  
• Current/previous experience with prevention products – contraception, condoms, other 
HIV prevention methods, including how local response to COVID-19 affected product 
use;  
• Motivation for trial participation, including knowledge of and decisions related to joining 
HPTN 084 versus other HIV prevention trials;  
• Disclosure to partner(s), family, friends about trial;  
• Understanding of trial context – randomization, blood draws and other criteria; 
• Beliefs about trial products;  
• Understanding of and concerns about pregnancy restrictions;  
• Experience with oral pill use and with first injection.  
 

 
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Topics experienced participants (in Step 2, but have received five or more injections): 
 
• Household/relationship context, or any changes if previously interviewed;  
• Any significant life events, including how local response to COVID-19 affected 
household/daily routine and trial participation;  
• Partner/other support or lack for trial participation;  
• Attitudes towards aspects of trial participation, including interactions with trial staff; 
• Adherence to oral pills – focused on reasons for missing pills;  
• Adherence to injections – focused on getting to clinic, acceptability of injection; 
• Any impact of service disruption due to COVID-19 on product adherence; 
• Acceptability of oral pills versus injectable prevention;  
• Perceived HIV risk;  
• Reproductive desires, contraceptive experiences and thoughts about pregnancy 
restrictions;  
• Early preferences for prevention modalities and any other suggestions or concerns about 
the trial. 
 
The final in-depth interview will be conducted while participants are still in active follow-up but 
have been unblinded to the product they are using (e.g., if an individual or the trial moves to an 
open-label TDF/FTC). Topics for this interview include:  
 
• Any significant life events, including how local response to COVID-19 affected 
household/ daily routine and trial participation;  
• Participant thoughts about which arm she was in, Participant thoughts about level of 
adherence;  
• Perceptions about pregnancy restrictions for CAB LA;  
• Perceptions of, questions about the open-label arm;  
• Presentation of results (if available) and any discussion about discordance – explore 
barriers and facilitators of adherence, including any impact of COVID-19 on product 
adherence;  
• Recommendations about how to better support access and adherence to prevention 
methods beyond trial;  
• and Preferences for prevention beyond trial setting. 
 
Additional topics for participants recruited as “special cases” include:  
 
• Feelings toward and circumstances related to pregnancy, product discontinuation or 
seroconversion;  
• Partner and family member attitudes towards pregnancy and/or product use;  
• Impact of COVID-19 related clinic, community or household disruptions on trial 
participation, product use or general well-being 
• Attitudes towards product unblinding as related to pregnancy or seroconversion;  
• Attitudes towards using CAB LA and/or TDF/FTC during pregnancy;  
• Prevention preferences beyond trial and any recommendations;  
• treatment or care plans, if related to seroconversion. 

 
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Waiting room observations 
Approximately once a quarter, a qualitative team member will conduct a 45-minute semi-
structured observation in the waiting room(s) of the study clinic until data saturation. (This 
activity may take place less frequently if COVID-related policies suspend use of waiting rooms for 
study participants.) Because information about potential waiting room observations was included in 
the main study consent, no additional consent procedures are required for this activity. The 
qualitative team will use a data extraction sheet to note:  
 
• Date/time; Approximate # of participants in waiting room, including gender and any 
babies, children;  
• Materials, videos or other activities organized by site;  
• Overall activity within waiting room;  
• Focus on a nearby cluster of participants – overall demeanor of individuals (animated, 
calm, happy, bored, irritated) and topics of discussion if overheard;  
• If any brief intercepts with participant, information about wait time in clinic, overall 
experience in trial, concerns, recommendations or other thoughts shared with observer. 
 
 
Several measures will be taken to protect the confidentiality of trial participants who take part in 
semi-structured interviews. Single or repeated in-depth interviews aimed at understanding 
acceptability of an injectable PrEP product will be conducted in a private space. During 
interviews, the moderator will address participants by a unique number or pseudonym chosen by 
the participant after consenting to participation. This will ensure that no names are recorded on 
audio-recordings or appear in transcripts.  When data collectors conduct observations or engage in 
brief conversations in clinic waiting rooms or more public spaces, they will not record any names 
or identifying information related to the trial participants they observe or talk with. Field notes 
will be labeled by the date, time and location of the observation/informal discussion only.  Prior to 
engaging in a discussion with individuals or groups within waiting rooms, participants will be 
reminded that their identities will not be recorded in any notes and that they can choose whether or 
not to participate in these discussions.    
 
5.17 Interim Contacts and Visits 
Interim contacts and visits (those between regularly scheduled follow up visits) may be 
performed at participant request or as deemed necessary by the investigator or designee at any 
time during the study.  
Some interim visits may occur for administrative reasons. For example, the participant may have 
questions for study staff. Interim visits at which no data are collected are not documented on 
CRFs. Other interim contacts and visits may occur in response to AEs experienced by study 
participants. When interim contacts or visits are completed in response to participant reports of 
AEs, study staff will assess the reported event clinically, record the event on the CRF, and 
provide or refer the participant to appropriate medical care.   
Note: HIV testing is only required at interim visits if study product is administered, if HIV 
infection is suspected or is required as part of an AE investigation. 

 
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5.18 Planned Unblinding of Study Participants  
When the required number of incident HIV endpoints has been reached, or when the last 
participant completes scheduled Step 2 follow-up (meaning all participants will move to Step 3), 
and when all corresponding procedures at the HPTN SDMC, LC, and LOC have been completed, 
including final confirmation from the HPTN SDMC, the study will be unblinded.   
 
Participants with a confirmed pregnancy (see section 5.14) will be unblinded. Procedures for 
unblinding pregnant participants will be detailed in the SSP. 
 
5.19 Criteria for Early Termination of Study Participation 
Participants may voluntarily withdraw from the study for any reason at any time. Site IoRs may, 
with the agreement of the CMC, Protocol Chairs, DAIDS MO, and study statistician withdraw 
participants before their scheduled termination visit to protect their safety, the safety of the staff, 
and/or if participants are unable or unwilling to comply with study procedures. Participants also 
may be withdrawn if the study sponsors, government or regulatory authorities (including the 
OHRP and US FDA), or site IRBs/ECs or if appropriate, the SAHPRA, ViiV/Gilead terminate 
the study prior to its planned end date. Study staff will record the reason(s) for all withdrawals in 
participants’ study records. 

 
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SAFETY MONITORING AND AE REPORTING 
6.1 
AE Definition and Reporting 
An AE is defined as any untoward medical occurrence in a clinical research participant 
administered an investigational product and which does not necessarily have a causal 
relationship with the investigational product. As such, an AE can be an unfavorable or 
unintended sign (including an abnormal laboratory finding, for example), symptom or disease 
temporally associated with the use of an investigational product, whether or not considered 
related to the product. 
Study participants will be provided a 24-hour telephone number and contact information and 
instructed to contact the study clinician to report any AEs they may experience. For life-
threatening events, they will also be instructed to seek immediate emergency care. Where 
feasible and medically appropriate, participants will be encouraged to seek evaluation where the 
study clinician is based, and to request that the clinician be contacted upon their arrival. With 
appropriate permission of the participant, whenever possible, records from all non-study medical 
providers related to AEs will be obtained and required data elements will be recorded on study 
CRFs. All participants reporting an AE will be followed clinically, until the AE resolves (returns 
to baseline) or stabilizes. 
Study site staff will document in source documents and the appropriate CRF AEs  reported by or 
observed in enrolled study participants regardless of severity and presumed relationship to study 
product. AE severity will be graded per the DAIDS Table for Grading Adult and Pediatric 
Adverse Events, Corrected Version 2.1, July 2017. This version will be used for the entire 
duration of the study. 
The expedited AE reporting period for this study is from Enrollment (Week 0) until follow-up in 
the study ends. 
 
After the protocol-defined AE reporting period, unless otherwise noted, only SUSARs as defined 
in Version 2.0 of the EAE Manual will be reported to DAIDS if the study staff become aware of 
the events on a passive basis (from publicly available information). 
 
Relatedness is an assessment made by a study clinician of whether or not the event is related to 
the study agent. The relationship of all AEs to study product will be assessed as specified in 
Version 2.0, January 2010 of the DAIDS EAE Reporting Manual.   
6.2 
EAE Reporting 
Requirements, definitions, and methods for expedited reporting of AEs are outlined in Version 
2.0 of the DAIDS EAE Manual, which is available at https://rsc.niaid.nih.gov/clinical-research-
sites/manual-expedited-reporting-adverse-events-daids.   
 Reporting to DAIDS 
The DAIDS Adverse Event Reporting System (DAERS), an internet-based reporting system, 
must be used for EAE reporting to DAIDS. In the event of system outages or technical 

 
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difficulties, EAEs may be submitted via the DAIDS EAE form. For questions about DAERS, 
please contact CRMSSupport@niaid.nih.gov. Site queries may also be sent with the DAERS 
application itself. 
If the DAERS website or site internet is non-functional, sites will submit expedited AEs by 
documenting the information on the current DAIDS EAE form. This form is available on the 
RSC website:  https://rsc.niaid.nih.gov/clinical-research-sites/paper-eae-reporting. For questions 
about EAE reporting, please contact the RSC at DAIDSRSCSafetyOffice@tech-res.com. 
 Reporting Requirements for This Study 
The SAE Reporting Category, as defined in Version 2.0 of the DAIDS EAE manual, will be used 
for this study (the definition of an SAE is also included in the manual).   
In addition to SAEs, sites will report in an expedited manner the following:   
• ALT ≥ 3xULN AND total bilirubin ≥ 2xULN (must be both in order to require expedited 
reporting) 
• Any seizure event 
These reporting requirements are for each study participant from Enrollment (Week 0) until 
follow-up in the study ends. After this time, sites must report serious, unexpected, clinical 
suspected adverse drug reactions if the study site becomes aware of the event on a passive basis, 
i.e., from publicly available information. 
The study agents for the purposes of EAE reporting are: Oral CAB 30 mg oral tablet; CAB LA 
injectable suspension (200 mg/mL); TDF/FTC fixed dose combination tablet containing 200 mg 
of FTC and 300 mg of TDF (also outlined in Section 4.0). 
In addition to submitting EAE information to the DAIDS Safety Office via DAERS, the site 
investigator may be required to submit AE and EAE information to local regulatory agencies or 
other local authorities. 
Information on Grade 1 and higher AEs will be included in reports to the US FDA, and other 
government and regulatory authorities as applicable. Site staff will report information regarding 
AEs to their IRB in accordance with all applicable regulations and local IRB requirements. 
 Grading Severity of Events 
The Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, 
Corrected Version 2.1, July 2017, will be used for the entire duration of the study for 
determining and reporting the severity of AEs. The DAIDS grading table is available on the 
DAIDS RSC website at https://rsc.niaid.nih.gov/clinical-research-sites/daids-adverse-event-
grading-tables. 

 
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6.3 
Safety Monitoring 
Close cooperation between the Protocol Chair, study site Investigator(s), DAIDS Medical 
Officer, LOC Clinical Research Manager, SDMC Biostatistician, SDMC Clinical Affairs Staff, 
HPTN LC, and other study team members will be necessary in order to monitor participant 
safety and to respond to occurrences of toxicity in a timely manner.  
The study site Investigators are responsible for continuous close monitoring and management of 
AEs. Sites are required to have detailed SOPs describing methods for AE reporting and toxicity 
management to ensure that AEs are reported and managed in accordance with the protocol and 
for alerting the CMC (outlined below) if unexpected concerns arise. 
A sub-group of the Protocol Team, including the Protocol Chair, DAIDS Medical Officer, and 
other site investigators will serve as members of the CMC. The CMC provides support to sites 
regarding individual participant clinical management (e.g., questions related to eligibility, 
toxicity management, clinical holds of study drug, etc.). Sites will be instructed to not solicit 
guidance from the CMC regarding HIV seroconversions in order to ensure to the extent possible 
that the team is blinded to the number of infections occurring in the study. The HPTN LC will be 
available for questions regarding HIV confirmation testing. 
6.4 
Clinical Data Review 
A multi-tiered safety review process will be followed for the duration of this study. The study 
site investigators are responsible for the initial evaluation and reporting of safety information at 
the participant level, and for alerting the CMC if unexpected concerns arise.   
Participant safety data is also monitored by the SDMC Clinical Affairs staff who review 
incoming safety data for completeness and consistency on an ongoing basis. Events identified as 
questionable, inconsistent, or unexplained will be queried for verification.  
AE reports submitted in an expedited manner to the DAIDS Safety Office will be forwarded to 
the DAIDS Medical Officer for review and possible reporting to the FDA as a Safety Report. 
The SDMC will prepare routine reports of study conduct for the Study Monitoring Committee 
(SMC), which will meet by conference call approximately every 6 months. More frequent or ad 
hoc reviews may be conducted by the SMC as needed. 
This study also will be monitored by a NIAID Data and Safety Monitoring Board (DSMB), 
which will meet at least annually to review safety and efficacy data.  More frequent or ad hoc 
reviews of safety data may be conducted by the DSMB as needed.  
6.5 
Social Harms Reporting 
It is possible that participants' involvement in the study could become known to others, and that a 
social harm may result (i.e., because participants could be perceived as being HIV-infected or at 
"high risk" for HIV infection).  For example, participants could be treated unfairly, or could have 
problems being accepted by their families and/or communities.  These are social harm 
events.  Social harms events are those negative events that a participant reports as affecting them 

 
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as a result of being involved in a research study, not the researcher’s opinion of how they 
perceive an event has affected a participant.  A social harm that is reported by the participant and 
judged by the IoR/designee to be serious or unexpected will be reported to the responsible site’s 
IRBs at least annually, or according to their individual requirements.  Social harms will be 
collected and reported on CRFs during regular visits.  In the event that a participant reports a 
social harm, every effort will be made by study staff to provide appropriate care and counseling 
to the participant as necessary, and/or referral to appropriate resources for the safety of the 
participant.  Each site will provide such care and counseling in accordance with standardized 
guidance in the SSP Manual.  While maintaining participant confidentiality, study sites may 
engage their Community Advisory Board in exploring the social context surrounding instances 
of social harms, to minimize the potential occurrence of such an impact. In addition to social 
harms, any benefits of study participation will also be collected and reported into the database. 
6.6 
Critical Events Reporting 
Per the DAIDS policy on Identification and Classification of Critical Events, a critical event is 
defined as an unanticipated study-related incident that is likely to cause harm or increase the risk 
of harm to participants or others or has a significant adverse impact on study outcomes or 
integrity.  All such events must be reported following procedures specified in the DAIDS Critical 
Events Manual, available at: 
https://www.niaid.nih.gov/sites/default/files/documents/criticaleventsmanual.pdf

 
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STATISTICAL CONSIDERATIONS 
7.1 
Review of Study Design 
This is a Phase 3 randomized, multi-site, two-arm, double-blind study of the safety and efficacy 
of CAB LA vs. TDF/FTC for prevention of HIV-acquisition in HIV-uninfected women. All 
participants will receive a placebo product. Eligible participants will be randomized 1:1 to 
receive either oral CAB/CAB LA + placebo TDF/FTC (Arm A) or daily oral TDF/FTC + 
placebo CAB/CAB LA (Arm B), and move through 3 Steps. In Step 1, study participants will 
receive both active and placebo oral tablets (appropriate for their arm) for five weeks. In Step 2, 
participants will receive either i) an injection of CAB LA (at two time points four weeks apart 
and every eight weeks thereafter) and placebo TDF/FTC pills (Arm A) or ii) daily oral TDF/FTC 
and placebo injections (at two time points four weeks apart and every eight weeks thereafter) 
(Arm B) until the required number of incident HIV endpoints (114) is accrued, estimated to be 
when the final participant reaches 76 weeks on Step 2 (Week 81 in study).  In Step 3, all 
participants will receive open-label daily oral TDF/FTC for up to 48 weeks (starting 8 weeks 
after their last injection).  Participants will therefore be followed between approximately 137 
weeks to 241 weeks (between 81 and 185 weeks on study product during Steps 1 and 2 and up to 
48 weeks on open-label daily oral TDF/FTC). All participants will transition to local HIV 
prevention services after completion of Step 3.   
7.2 
Endpoints 
 Primary Efficacy Endpoint 
• Number of documented incident HIV infections in Steps 1 and 2 
 Primary Safety Endpoint 
• Grade 2 or higher clinical and laboratory AEs  
 Secondary Endpoints 
• Number of documented incident HIV infections in Steps 1, 2 and 3 
• Number of documented incident HIV infections in participants in subgroups broken down by 
baseline age, HSV-2 status, contraceptive use method and BMI </≥ 25 kg/m2 
• Plasma concentrations   of CAB in participants randomized to CAB/CAB LA  
• Plasma and DBS  concentrations of TFV/TFV-DP in a subset of participants randomized to 
TDF/FTC  
• Survey of attitudes and willingness to use CAB LA and TDF/FTC 
 
 Tertiary Endpoints  
• Sexual risk (number of partners, number of unprotected sex acts) 
• Incident STIs (GC/CT, trichomonas, syphilis) 

 
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• Grade 2 or higher clinical and laboratory AEs broken down by BMI </> 25kg/m2 
• Weight  
• Number of incident pregnancies 
• Pregnancy outcomes 
• Resistance mutations to study products (including but not limited to K65R, M184V/I, Q148R) 
among seroconverters 
• Plasma concentrations of DMPA,  or NET-EN, and etonogestrel when co-administered with 
study product (TDF/FTC or CAB LA) 
7.3 
Sample Size and Interim Monitoring 
The primary analysis will be based on HIV incidence during Steps 1 and 2. As described 
previously, we assume that participants will be followed between 81 (latest enrollees) and 185 
(earliest enrollees) weeks in Steps 1 and 2 (1.6 – 3.6 years), with a uniform distribution of 
enrollments over a two-year period. Thus, average time in Steps 1 and 2 will be 133 weeks (2.6 
years). Sample size calculations are based on the following assumptions: 
• Background HIV incidence, in the absence of any PrEP, is 3.5% per year 
• Both CAB LA and TDF/FTC are 85% effective when used with 100% adherence 
• 2.5% one-sided type I error rate and 90% power at the indicated alternative 
• Average follow-up duration of 2.6 years (range: 1.6 – 3.6 years) 
• Maximum 5% lost-to-follow-up per year  
Table 7.1 presents five scenarios and associated total sample sizes. All are superiority designs. 
The first scenario assumes that adherence to TDF/FTC and CAB/CAB LA will be 50% and 85%, 
respectively, averaged over the entire Step 1 and 2 follow-up period. The second and third 
scenarios assume a higher adherence to TDF/FTC (second line) and lower adherence to CAB LA 
(80%) (third line) (these scenarios are considered unlikely).   
The last two scenarios retain the conservative assumption of 80% adherence to CAB LA and 
assume lower adherence to TDF/FTC of 45% and 48%. The largest blinded trials of TDF/FTC 
among women in a similar setting have shown even lower adherence than assumed in Table 7.1 
(see section 7.8.4.1). Given this history we believe that a sample size of at least 3,128 (111 
events for a fixed sample size trial; we will target 114 events to allow for interim monitoring) 
provides an adequate degree of robustness against uncertainties in adherence rates to the two 
drug regimens.     
   
The trial will continue until we reach 114 events or a stopping boundary is crossed (see below). 
   
 

 
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Table 7.1. Five Case Scenarios 
Adherence 
HIV Incidence 
(%/year)1 
 
 
 
TDF/F
TC 
CAB 
LA 
TDF/F
TC 
CAB 
LA 
RR 
Number 
Events 
Sample 
Size 
.50 
.85 
2.01 
0.97 
.48 
78 
2352 
.55 
.85 
1.86 
0.97 
.52 
98 
3112 
.50 
.80 
2.01 
1.12 
.56 
125 
3590 
.48  
.80  
2.07  
1.12  
.54 
111 
3128  
.45  
.80  
2.16  
1.12 
.52  
98 
 
2686  
    
1Background incidence is reduced by a weighted average of fully adherent and non-adherent individuals 
 e.g. 2.01 = 3.5*((1-.85)*.5 + 1*(1-.5)) 
 
This study will be monitored by a NIAID DSMB, which will meet at least annually to review 
safety and efficacy data, as well as data quality. The DSMB will use an O’Brien-Fleming 
boundary to consider stopping the trial early for efficacy. Further details will be provided in a 
Statistical Analysis Plan prior to the first interim analysis.  
 
 
In a subset of women we will evaluate contraceptive drug levels for three groups of women 
defined by their contraceptive choice: i) DMPA, ii) NET-EN; iii) etonogestrel. Analyses will 1) 
estimate, for each contraceptive subgroup, the proportion of women in the CAB LA arm who 
have contraceptive drug concentrations (DMPA, NET-EN, and etonogestrel for the three 
contraceptive types, respectively) below the contraceptive threshold and 2) compare, for each 
contraceptive subgroup, mean contraceptive drug concentrations between the CAB LA and 
TDF/FTC arms. Table 7.2 shows the expected 95% CI for the estimated proportion of women 
below the contraceptive threshold, tabulated by the total sample size and the number of women 
Table 7.2.  95% CI for the estimated proportion of women below the contraceptive 
threshold in the CAB LA arm by contraceptive subgroup (assuming one observation per 
woman) 
 
 
Total number of women CAB LA arm for each contraceptive subgroup 
 
 
10 
15 
20 
30 
50 
 
Number 
below 
threshold 
0 
0 - .26 
0 - .18 
0 - .14 
0 - .095 
0 - .058 
1 
.002 - .44 
.002 - .32 
.001 - .25 
.001 - .17 
.000 - .11 
2 
.025 - .56 
.016 - .40 
.012 - .32 
.01 - .22 
.005 - .14 
3 
.07 - .65 
.04 - .48 
.03 - .38 
.02 - .26 
.012 - .16 

 
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below threshold. Table 7.3 shows the minimum detectable difference in mean DMPA levels 
between the CAB LA and TDF/FTC arms. Both Table 7.2 and Table 7.3 assume one observation 
per woman. In fact, we expect to have up to three observations per woman so the realized 
confidence intervals and minimum detectable differences will be smaller than shown in these 
tables. Based on these tables we will target approximately 30 women in each arm in each 
contraceptive subgroup. 
 
 
 
 
 
7.4 
Accrual and Retention 
Approximately 3,350 participants will be enrolled in approximately 24 months and followed 
through Steps 1 and 2 for 1.6 to 3.6 years and on oral TDF/ FTC for an additional 48 weeks. An 
average annual retention rate of at least 95% percent will be targeted (87 - 88% for the entire 
Step 1 and 2 follow-up period).  
7.5 
Random Assignment 
Participants will be randomized to one of two study arms in a 1:1 ratio. Randomization will be 
stratified by study site, and a permuted blocks design will be used to ensure balanced treatment 
assignments within study site. The randomization scheme will be generated, operationalized and 
maintained by the HPTN SDMC. Additional details regarding the process of randomization will 
be included in the SSP Manual. All endpoints will be analyzed according to a participant’s 
original blinded randomization assignment, regardless of timing of endpoint occurrence. 
7.6 
Blinding   
Study site staff, with the exception of the site Pharmacist of Record or their designee, and 
participants will be blinded to the random assignments. Blinding will be maintained until the trial 
is completed or stopped, i.e., the trial is stopped early, or the required number of endpoints (114)  
has been met. At a specified time directed by the HPTN SDMC, participants will be notified of 
their treatment assignment.  
In addition, as described in sections 5.14 and 5.18, participants with a confirmed pregnancy will 
be unblinded. Participants who are unblinded due to pregnancy may restart open-label study 
product in their original randomization arm (open label CAB LA or TDF/FTC) following 
delivery and cessation of breastfeeding. 
Table 7.3. Minimum detectable difference (ng/mL) in mean MPA levels 
(80% power) between  CAB LA and TDF/FTC arms, assuming  = .3 mg/mL 
and  = .05, two-tailed, assuming one observation per woman. 
Total number of women in each arm for each contraceptive subgroup 
10 
15 
20 
30 
50 
.37 
.31 
.26 
.22 
.17 

 
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7.7 
Data and Safety Monitoring Board Oversight and Study Monitoring Committee Oversight 
NIAID DSMB oversight is planned for this study. Monitoring guidance will be detailed in a 
separate Interim Monitoring Plan. In addition, approximately every six months the HPTN SMC 
will conduct interim reviews of study progress, including rates of participant accrual, visit 
retention, and completion of primary and main secondary endpoint collection. The frequency and 
content of SMC reviews will be determined prior to the start of the study as outlined in the 
HPTN Manual of Procedures (MOP). 
7.8 
Statistical Analysis 
This section briefly describes the final study analyses, unblinded as to treatment arm assignment. 
All analyses will be modified intent to treat (participants determined to be HIV-infected prior to 
randomization will be omitted from the analysis), unless otherwise specified. Detailed technical 
specifications of the statistical analyses will be described in a separate Statistical Analysis Plan.  
 Analyses of Primary Efficacy Objective 
• To evaluate the relative efficacy of oral CAB/CAB LA (oral run-in and injections, Steps 1 
and 2) vs. daily oral TDF/FTC for HIV prevention (Steps 1 and 2) 
To preserve the integrity of randomization, person-time and HIV events will be included in this 
analysis based on each individual’s scheduled duration of participation in steps 1 and 2, as 
determined at randomization. Specifically, individuals who refuse injections, pills or both, or 
who receive open-label study product (e.g. due to pregnancy) will be included in this analysis in 
their original randomization arm for the duration of their originally scheduled participation in 
Steps 1 and 2.. 
The Hazard Ratio (HR) comparing CAB LA vs TDF/FTC and a 95% confidence intervals will 
be estimated using a Cox proportional hazards model with treatment arm as the only covariate, 
stratified by site using data from steps 1 and 2 only. As outlined in greater detail in the Statistical 
Analysis Plan, version 2.0, dated June 9, 2020, and the HPTN 084 COVID Disruption document, 
prespecified intervals of COVID-19 disruption may be administratively censored from the 
analysis using the Anderson-Gill counting process formulation of the Cox model. We will test 
the hypothesis Ho: HR = 1.0 versus Ha: HR ≠ 1.0 using  = 0.05. If the number of events is 
small (<40) then the p-value will be confirmed using a permutation test based on 100,000 
random permutations of the treatment assignments; if there is a meaningful difference between 
the permutation and asymptotic procedures, the permutation p-value will be used. Treatment 
efficacy will be estimated as TE = 1 - HR.   
 Analyses of Primary Safety Objective 
• To evaluate the relative safety of oral CAB/CAB LA (oral run-in and injections, Steps 1 and 
2) vs. daily oral TDF/FTC for HIV prevention (Steps 1 and 2) 
Local reactions  
The number and percentage of participants experiencing local reactions to the injections will be 
tabulated by severity and treatment arm. For a given local reaction type, each participant’s 

 
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reaction will be counted once under the maximum severity for all injection visits. In addition to 
the individual reaction types, the maximum severity of local pain or tenderness, induration or 
erythema, and of systemic symptoms will be calculated. Wilcoxon rank sum tests will be used to 
test for differences in severity between arms. 
AEs and Serious Adverse Events (SAEs)  
AEs will be summarized using MedDRA System Organ Class and preferred terms. Tables will 
show by treatment arm the number and percentage of participants experiencing an AE within a 
System Organ Class or within preferred term category by severity. For the calculations in these 
tables, a participant with multiple AEs within a category will be counted once under the 
maximum severity.  
A listing of SAEs reported to the DAIDS Regulatory Support Center (RSC) Safety Office will 
provide details of the events including severity, time between onset and last dosing, and 
cumulative number of doses received. Formal statistical testing comparing arms is not planned 
since interpretation of differences must rely heavily upon clinical judgment. 
Local laboratory values  
Box plots of local laboratory values will be generated for baseline values and for values 
measured during the course of the study by treatment arm and visit. Each box plot will show the 
first quartile, the median, and the third quartile. Outliers will also be plotted. If appropriate, 
horizontal lines representing boundaries for abnormal values will be plotted.  
The number (percentage) of participants with local laboratory values recorded as meeting Grade 
2 AE criteria or above as specified in the DAIDS AE Grading Table will be tabulated by 
treatment arm for follow-up time points. Reportable clinical laboratory abnormalities without an 
associated clinical diagnosis will also be included in the tabulation of AEs described above. 
 Descriptive Analyses of Primary Efficacy Endpoint 
HIV incidence 
The HIV incidence rate will be calculated as the total number of participants with confirmed 
incident HIV infection during study follow-up of Step 1 and Step 2 divided by the person-years 
accumulated in each arm. 95% CIs will be calculated. 
Cumulative incidence over follow-up for each arm will be computed using product limit 
estimates and plotted with 95% CIs. 
 Considerations for a Supportive Analysis if Adherence to TDF/FTC is Higher than Expected 
The primary analysis for this protocol is the superiority analysis described in Section 7.8.1. 
However, there is substantial evidence that the efficacy of TDF/FTC (relative to placebo) is 
highly dependent on adherence to daily pill-taking and modestly dependent on sex. Specifically, 
if adherence to daily oral TDF/FTC is 50% or greater, there is credible evidence that TDF/FTC is 
superior to placebo (see section 7.8.4.1, below). The current HPTN 084 trial design has high 
power to show that CAB LA is superior to TDF/FTC for TDF/FTC adherence rates up to 48%, 
assuming adherence to CAB LA is 80% or higher.  This design is appropriate if adherence in 

 
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young, unmarried women in South Africa is consistent with the low rates seen in previous 
placebo controlled trials in that population. However, if adherence to TDF/FTC is high, as in 
some recent open-label trials, then the power to demonstrate CAB LA superiority declines and a 
non-inferiority (NI) comparison of injectable CAB LA to daily oral TDF/FTC would be more 
appropriate.  
 
In the following sections we outline the rationale and develop the methods for a supportive 
adherence-dependent NI comparison of injectable CAB LA to daily oral TDF/FTC. Specifically, 
we review the evidence showing that efficacy of TDF/FTC (relative to placebo) is adherence 
dependent, indicate how adherence to TDF/FTC could be measured in HPTN 084, describe how 
an NI margin could be chosen and provide results from analytic calculations and simulations 
showing that this procedure preserves the nominal type I error rate for the analysis. Since the 
primary superiority analysis is well-powered for TDF/FTC adherence up to 50%, the supportive 
NI analysis described here would only be triggered if TDF/FTC adherence is greater than 50%. 
Of course, if the primary analysis shows superiority, there is no need for an NI analysis. 
However, we note that Noninferiority and Superiority designs form a continuum where a 
superiority design can be thought of as a “Noninferiority” design with a margin equal to 1.0 (see 
section 7.8.4.2 for a discussion of margins). From that point of view, the adherence-dependent 
NI comparison described here encompasses the superiority analysis that has been designated as 
the primary analysis for the trial. 
 
7.8.4.1 Evidence Showing that Efficacy of TDF/FTC is Adherence Dependent 
 
Meta-analysis is a statistical technique for combining the results of studies to provide more 
information than any one study can on its own. We are fortunate to have comparable biomarker-
based measures of adherence in seven large, high-quality, randomized controlled trials (iPrEX, 
TDF2, Partners-PrEP, VOICE, FEM-PrEP, Bangkok, IPERGAY) (Table 7.4), that can be 
incorporated into a meta-analytic model to provide a robust model of the relationship between 
TDF/FTC efficacy and adherence. 
 
Table 7.4. Summary of Plasma-based Adherence Measurements from Previous RCTs of 
Daily Oral TDF or TDF/FTC.  
All trials used daily oral dosing except IPergay, which used event-driven dosing. 
Trial 
Year Gender 
How measured 
Detection 
limit 
(TFV) 
% TFV 
detectable  
RR – 
placebo 
vs active 
FEM-
PREP 
2012 Female 
Nested case-control 
 0.25 
ng/ml 
24 
1.05 
VOICE -
TDF/FTC 
2015 Female 
Quarterly sampling 
0.31 ng/ml 29 
0.97 
VOICE -  
TDF 
2015 Female 
Quarterly sampling 
0.31 ng/ml 30 
0.67 
iPrex 
2010 Male 
Nested case-control 
10 ng/ml 
51 
1.79 
Bangkok 
2013 Male/ 
Female 
Nested case-control 
0.3 ng/ml 
66 
1.59/4.56 

 
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Partners- 
TDF/FTC 
2012 Female 
Nested case-cohort 
0.3 ng/ml 
77 
2.84 
Partners- 
TDF 
2012 Female 
Nested case-cohort 
0.3 ng/ml 
80 
3.36 
Partners- 
TDF/FTC 
2012 Male 
Nested case-cohort 
0.3 ng/ml 
82 
6.32 
Partners- 
TDF 
2012 Male 
Nested case-cohort 
0.3 ng/ml 
85 
2.74 
TDF2 
2012 Male/ 
Female 
Nested case-control 
0.3 ng/ml 
80 
5.0/2.02 
IPERGAY 
2015 Male 
Every 2 months in 
first 113 
participants 
0.1 ng/ml 
86 
6.93 
Using the data from Table 7.4 we conducted a “random effects meta-analysis” (by fitting a 
mixed-effects regression model) with log (RR: placebo vs. active) as the outcome and adherence 
and gender as covariates. Each trial is weighted based on the inverse of the variance of the 
estimated log(RR) (primarily a function of the number of HIV infections). The random effects 
meta-analysis can account for heterogeneity between study populations (random effects 
component), and explicitly estimate the relationship between adherence and efficacy (fixed 
effects component). A broad range of adherence levels is represented in these trials, and this 
makes it possible to estimate efficacy at moderate (e.g., 55%) or moderately high (e.g., 75%) 
levels of adherence without extrapolating beyond the range of observed data1. A limitation, 
however, is that, for women, most data are available for very low (< 30%) and very high 
adherence levels (> 75%) with little in the middle range of interest to HPTN 084. 
The fitted regression model is 
 
log(𝑅𝑅) = −0.752 + 0.105 ∗𝑚𝑎𝑙𝑒+ 2.276 ∗𝑎𝑑ℎ 
 
(1) 
 
Figure 7.1 shows the meta-regression relating adherence to the RR (placebo vs PrEP) in women 
along with 95% confidence intervals. Note that in Figure 7.1 a RR greater than 1 implies efficacy 
because the RR compares placebo versus PrEP, not the reverse. Note also that the y-axis uses a 
log scale.  
 
This model indicates that, in women, TDF/FTC is superior to placebo (RR > 1.0) with high 
confidence for adherence rates greater than 44%. The ability to estimate efficacy of TDF/FTC 
relative to placebo (along with a 95% CI) as a function of adherence can be used to select an NI 
margin when TDF/FTC adherence is high (see section 7.8.4.3). 
 
1 Adherence measures for the published trials are based on proportion of samples with detectable drug concentrations 
measured in a randomly selected subset of HIV-infected controls randomized to Truvada. The lower limit of 0.31 ng/mL 
generally corresponds to evidence of TDF/FTC taken within 14 days of the visit. 

 
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Figure 7.1. Meta-regression Analysis of Previous Trials - RR (Placebo vs Active Drug) 
Versus Adherence to Daily Oral PrEP.  
 
Regression line (solid line) and 95% confidence intervals (dashed line) are specific to 
women. 
 
  
 
7.8.4.2 Measurement of Adherence 
 
As shown in Table 7.4 previous trials have generally measured adherence in longitudinal 
samples from randomly selected participants, or in randomly selected controls of a nested case-
control study. These assessments have used plasma TFV concentrations, which provide 
information on dosing in the last 1-2 weeks. For consistency with these previous studies, 
therefore, measurement of adherence to determine an NI margin using model (1) should be based 
on detectability of TFV in plasma.  
 
In HPTN 084, adherence will be measured at a subset of study visits in a random sample of 400 
participants enrolled into Arm B (active TDF/FTC). A participant will be defined as adherent at a 
given visit if her plasma TFV level is greater than 0.31 ng/ml. Given the average of 2.6 years of 
follow-up, this sampling plan should yield up to 1,600 samples for analysis, distributed 
proportionately across the follow-up period. Based on this sample size, the estimate of adherence 
for the study cohort should have a precision (width of a 95% confidence interval) of between 
+0.05 and +0.0167 (depending on the magnitude of the intra-class correlation between repeated 
samples on the same participant).  
 
0.2
0.4
0.6
0.8
1
2
5
Adherence
Relative Risk (RR) - Placebo vs. Active PrEP
Women
Men

 
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7.8.4.3 Selection of an NI Margin 
 
An NI margin is typically chosen to preserve (at least) p% of the proven benefit of the active 
control (TDF/FTC in this case). Such a margin may be defined as (1-p)*log(RRL) where RRL is 
the lower bound of the 95% confidence interval (CI) of the RR (Placebo vs PrEP). Typically, 
non-inferiority trials are designed to preserve at least 50% of the benefit of the active control 
giving a margin that is halfway (on a log scale) between RRL and 1.0.  
 
A critical issue in the design of NI trials is the assumption of constancy, namely, that the key 
conditions that lead to efficacy of the active control versus placebo in previous trials also hold in 
the current NI trial. In the context of a PrEP trial with TDF/FTC as the active control the most 
important constancy assumption is that adherence to TDF/FTC is comparable to previous trials 
where TDF/FTC has proven effective. This suggests that the NI margin of a PrEP trial with 
TDF/FTC as the active control should be based on the observed adherence in the current trial – if 
observed adherence is low then an NI margin of 1.0 (superiority) is required; if observed 
adherence is high than an appropriate NI margin may be chosen based on the meta-regression 
model (1) described above. 
 
An NI trial uses the following hypotheses: 
 
Ho: RR = margin 
Ha: RR < margin 
 
Table 7.5 gives, for CAB LA adherence of 85% and various levels of TDF/FTC adherence, the 
NI margin that preserves at least 50% of the active control benefit based on the meta- regression 
shown inFigure 7.1, as well as the expected RR under the alternative hypothesis, number of 
events needed for 90% power, and sample size. Other assumptions are as noted previously.  
 
 Based on this table an analysis with a variable, adherence-dependent margin that preserves at 
least 50% of the proven benefit of TDF/FTC is well-powered for TDF/FTC adherence from 55% 
up to 64%, assuming the original design sample size of 3200. Power will be greater for the 
increased sample size target of 3350. 
 
 
Table 7.5. Non-inferiority Designs for Various Levels of TDF/FTC Adherence Using a  
Margin Based onFigure 7.1. 
CAB adherence assumed to be 85%; other assumptions are the same as in Table 7.1. 
TDF/FTC 
Adherence 
RR (Cab 
vs TDF) 
Margin 
No. HIV events 
for 90% power 
N total 
Maximum 
observed RR1 
55% 
.52  
1.12 
71 
2254 
.70 
60% 
.56 
1.17 
77 
2572 
.75 
 
 
 
 
 
 
65% 
.62 
1.22 
92 
3256 
.81 
70% 
.68 
1.27 
108 
4062 
.87 
1  Maximum observed RR which would give a non-inferiority result for this margin and this number of events. 

 
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7.8.4.4 An Adaptive Margin Preserves Type I Error Rate 
 
In a typical NI trial a fixed margin is chosen and used to set the null and alternative hypotheses 
prior to trial initiation. Here we propose setting the margin and hypotheses based on the meta-
regression analysis of previous trials and the adherence rate observed in the current trial. To 
achieve interpretable results, it is critical that adherence in the current trial be assessed in a 
manner that is comparable to previous trials. In addition, the calculation of adherence in the 
current trial must be done in a completely pre-specified manner and prior to unblinding of the 
HIV results. Under these conditions, our calculations show that choosing the margin and setting 
the hypotheses based on the adherence measured on a random subset of the trial participants does 
not meaningfully increase the type 1 error rate for the trial.  
 
Specifically, we considered trials with the HPTN 084 design and true TDF/FTC adherence rates 
(a) of 60%, 65% and 70%. Define m(a) as the margin that preserves 50% of the proven benefit of 
TDF/FTC for adherence level a (see Section 7.8.4.3). Based on our meta-analysis, these levels of 
adherence would support NI margins (m(a)) of (1.17, 1.22, 1.27), respectively, (see ) and 
corresponding null hypotheses of Ho: RR = m(a). If the margin is fixed a priori based on the true 
adherence rate, then the type I error rate for testing Ho is 0.025, by definition.  If, instead, 
adherence is estimated by sampling and the margin is based on the estimated adherence (i.e. Ho: 
RR = (𝑎̂) ) then the type I error rate is given by the expression 
 
∫
Φ (log⁡(𝑚(𝑎̂)) −log⁡(𝑚(𝑎))
𝑠
−1.96) 𝑓(𝑎̂
1
𝑎̂=0
)𝑑𝑎̂ 
 
where s is the standard error of the estimated log(RR), () is the cumulative normal distribution, 
and 𝑓(𝑎̂) is the sampling distribution of the estimated adherence. Table 7.6 shows the results. As 
can be seen, there is a very slight inflation of the type I error rate – from 0.025 to 0.0254 across a 
range of adherence rates – associated with the adaptive margin procedure, conservatively 
assuming 400 independent samples are used to measure adherence. The degree of inflation 
declines as adherence is measured more precisely. These theoretical calculations were confirmed 
by simulation. 
 
Table 7.6. Results of Simulations (based on HPTN 084 design) with Nominal Type I Error 
Rate of 0.025. 
Number of HIV events for each scenario was chosen to provide 90% power as shown in 
Table 7.5. 
TDF/FTC 
adherence 
TDF/FTC arm 
incidence (%/yr) 
 
NI margin 
No. HIV 
events 
Type I rate – 
fixed margin 
Type I rate – 
adapt margin 
60% 
1.72 
1.17 
78 
.025 
.0254 
65% 
1.57 
1.22 
92 
.025 
.0254 
70% 
1.42 
1.27 
108 
.025 
.0254. 
 
Thus, the overall type I error rate inflation is minimal provided adherence is measured precisely. 
 
 

 
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7.8.4.5 Other Considerations 
 
In HPTN 084 women in the CAB/CAB LA arm may receive TDF/FTC during steps 1 and 2 
under certain circumstances, the most common of which is pregnancy. Such “cross-overs” bias 
the comparison between the arms towards non-inferiority. Thus, any non-inferiority analysis 
must be interpreted in light of the proportion of time that women in the CAB/CAB LA arm 
receive TDF/FTC. 
 
 Analyses of Secondary Objectives 
• To compare HIV incidence among participants receiving oral CAB/CAB LA vs. daily oral 
TDF/FTC (Steps 1, 2 and 3) 
The Hazard Ratio (HR) comparing CAB LA vs TDF/FTC and a 95% CIs will be estimated using 
a Cox proportional hazards model with treatment arm as the only covariate, stratified by site and 
using all HIV incidence data from steps 1 through 3. We will test the hypothesis Ho: HR = 1.0 
versus Ha: HR < 1.0 using  = 0.025.  
• To evaluate relative efficacy of oral CAB/CAB LA vs. oral TDF/FTC in subgroups defined 
by the baseline factors of: age, HSV-2 serostatus, contraceptive method, and BMI. 
For each of the specified baseline factors, a Cox proportional hazards model will be fit with 
treatment arm, baseline factor and their interaction as covariates, stratified by site. For baseline 
factor x, this model may be written as 
log⁡(𝜆(𝑡; 𝑎𝑟𝑚, 𝑥, 𝑠)) = log(𝜆𝑠(𝑡)) + 𝛽1𝑎𝑟𝑚+ 𝛽2𝑥+ 𝛽3𝑎𝑟𝑚∗𝑥 
The hazard ratio (HR) for the baseline factor equal to each level of x will be estimated as exp(1 
+ 3 x) and the corresponding treatment efficacy will be estimated as TE = 1 - HR. 95% 
confidence intervals for the HR for each level of x will be reported. The clinical significance of 
differences in the estimated efficacy between subgroups will be evaluated. If relevant, a test for 
effect modification may be conducted based on the hypotheses Ho: 3 = 0 versus Ha: 3 ≠ 0.  
• To describe and model the relationship between HIV incidence and drug concentration 
levels, within each arm. 
A Cox proportional hazards model with drug concentration as a continuous, time-dependent 
covariate will be fit separately for each arm, with stratification by site. Martingale residual plots 
will be used to guide selection of an appropriate functional form for drug concentration, starting with 
the assumption of a linear relationship between drug concentration and log hazard. Separate 
models will be fit for different measures of drug levels (i.e. DBS, plasma). The team will also 
investigate using a model to predict drug concentrations in continuous time based on observed 
plasma and DBS drug levels; the predicted values could then be used as a covariate in the 
analysis proposed here. Potential confounders (e.g. age, sexual risk behaviors) will be included 
in the model.  Once a final model is selected, the (possibly adjusted) relationship between log 
relative risk (y-axis) and drug concentration (x-axis), with 95% confidence intervals, will be 
plotted for each arm. We note that since this is an observational analysis (i.e. individuals are not 
randomized to drug levels), all inferences are associative, not causal. 
• To describe the distribution and correlates of drug concentration levels, within each arm. 

 
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We will plot boxplots of drug concentration over follow-up overall and by age groups (<= 24 vs 
> 24), separately for each arm. 
A mixed effects linear regression model with log of drug concentration as the outcome, a random 
effect for participant, and potential correlates of drug concentration as covariates will be fit to the 
longitudinal drug concentrations. Separate models will be fit for each arm. The association 
between drug concentration and each potential correlate will be evaluated by testing the 
corresponding regression coefficient using the hypotheses, Ho:  = 0 versus Ha:  ≠ 0 with  = 
0.05. 
• To compare the acceptability of and preferences for CAB LA vs. oral TDF/FTC. 
Descriptive statistics will be used to summarize acceptability measures as evaluated at the end of 
the study. The specific statistics chosen will depend on the form of the acceptability assessment.  
7.8.5.1 Qualitative Analysis  
All semi-structured interviews and observations will be conducted by trained, same-sex 
interviewers, audio-recorded, transcribed and translated into English, and then uploaded into a 
qualitative software analysis program (such as NVivo 12.) A team representing core and site 
behavioral investigators will follow a process of reading, coding, data display and data reduction 
56 in order to explore in greater depth participants’ attitudes towards and experiences with the 
product they were assigned. Detailed memos and/or matrices will be developed to examine how 
participants’ perceptions related to product use (i.e., ease of use, perceived efficacy, side effects) 
and to trial participation (i.e., motivations for participation, interactions with trial staff, impact on 
partner or other social relationships) influence acceptability and interest in future use of an 
injectable PrEP product.      
 Analyses of Tertiary Objectives 
• To estimate sexual risk behaviors, as measured by self-report and rates of incident STIs.   
Key sexual behaviors (numbers of partners, unprotected sex) will be dichotomized (i.e. >1 
partner, any unprotected sex). All post-randomization visits where the outcome information is 
collected will be included in the analysis. Mixed effects logistic regression will be used to 
estimate prevalence and 95% confidence intervals for each behavior. All analyses will use a 
robust variance. Results will be reported overall and by arm. 
Rates of incident STI’s will be computed for each arm as number of new STI’s divided by total 
person-years. Poisson regression with a robust variance will be used to model the number of 
incident STI for each woman. Person-time will be used as an offset. Incidence and a 95% CI will 
be reported overall and by arm. 
 
• To compare Grade >2 AE rates in women with baseline BMI </≥ 25 kg/m2, within each 
study arm. 
Local reactions, adverse events and local laboratory values will be summarized as described in 
section 7.8.2 separately for women with baseline body mass index (BMI) </≥ 25 kg/m2. 

 
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A multiplicative intensity model will be used to compare rates of Grade 2 or higher AE’s 
between women with BMI >25kg/m2 versus <25kg/m2, with separate models for each arm. The 
model will include time to Grade 2 or higher AE’s for each participant as the outcome and BMI 
category as a covariate. The coefficient of BMI category will be used to compare AE rates based 
on the hypotheses, Ho: bmi = 0 versus Ha: bmi ≠ 0 with  = 0.05. AE’s will be clustered by 
participant and a robust variance will be used. 
• To compare differences in weight gain and BMI, by arm 
 
Weight gain will be computed as change from baseline (enrollment) at each follow up visit. We 
will plot mean weight gain over follow-up by (time-varying) current treatment (i.e. as-treated 
analysis). A linear mixed model will be fit with categorical intervals for time in study, (time-
varying) treatment and time by treatment interaction to evaluate the effect of CAB LA on weight 
gain. 
• To compare pregnancy incidence and outcomes between arms. 
To compare pregnancy incidence between the arms, we will fit a Poisson regression with number 
of pregnancies for each participant as the outcome, follow-up time as an offset and arm as the 
covariate. Robust variances will be computed and the coefficient of arm will be evaluated using 
the hypotheses, Ho: arm = 0 versus Ha: arm ≠ 0 with  = 0.05. 
A table describing pregnancy outcomes for each arm will be provided.  
• To evaluate rates of HIV drug resistance among participants who acquire HIV infection 
during the study among participants receiving oral CAB/CAB LA vs. oral TDF/FTC. 
The number, proportion and types of resistance mutations will be reported by arm for all post-
randomization HIV seroconverters, separately for each step of the trial.  No formal statistical test 
will be performed. 
• To determine plasma concentrations of DMPA or NET-EN or etonogestrel when co-
administered for contraception with study products (TDF/FTC or CAB LA). 
 
For each contraceptive subgroup (DMPA,NET-EN, etonogestrel) we will estimate the proportion 
of women in the CAB LA arm with contraceptive drug levels (DMPA, NET-EN, etonogestrel for 
the three contraceptive subgroups, respectively) below the contraceptive threshold  (0.1 ng/mL 
for DMPA, TBD for NET-EN and 90 pg/mL for etonogestrel).  95% confidence interval for the 
proportion will be provided. . The confidence interval will be based on a robust variance if 
multiple observations are available for each woman. 
 
In addition, we will compare mean contraceptive drug concentrations (and/or other PK 
parameters) between the CAB LA and TDF/FTC arms for each contraceptive subgroup using a t-
test (or a t-test with robust variance if multiple observations on each woman are available).   
 
 
 
 

 
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 Analyses of Exploratory Objectives 
• To compare the estimated programmatic cost, cost-effectiveness and disease impact 
indicators of CAB LA vs. daily oral TDF/FTC vs. no PrEP for HIV-uninfected women in the 
study sites locations.  
• To perform secondary laboratory assessments that may include evaluation of factors related 
to HIV infection, hepatitis infection, and other infections; ARV drug use; 
pharmacogenomics; characterization of HIV in infected participants; and evaluation of 
laboratory assays related to the study objectives. 
 
Analysis plans for the assessments described in the laboratory Exploratory Objective will be 
determined at a later date based on the specific types of testing/assessments performed.  
Further details will be provided in the statistical analysis plan.  
 

 
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HUMAN SUBJECTS CONSIDERATIONS 
8.1 
Ethical Review 
This protocol and the template informed consent form contained in Appendix IV will be 
reviewed and approved by the HPTN Scientific Review Committee (SRC) and DAIDS 
Prevention Science Review Committee (PSRC) with respect to scientific content and compliance 
with applicable research and human subjects regulations.  
The protocol, site-specific informed consent forms, participant education and recruitment 
materials, and other requested documents — and any subsequent modifications — also will be 
reviewed and approved by the ethical review bodies responsible for oversight of research 
conducted at the study site.  
Subsequent to initial review and approval, the responsible IRBs/ECs will review the protocol at 
least annually. The Investigator will make safety and progress reports to the IRBs/ECs at least 
annually, and within three months of study termination or completion. These reports will include 
the total number of participants enrolled in the study, the number of participants who completed 
the study, all changes in the research activity, and all unanticipated problems involving risks to 
human subjects or others. Study sites are responsible for the submission of continuing review to 
the DAIDS Protocol Registration Office (PRO), in accordance with the current DAIDS Protocol 
Registration Policy and Procedure Manual. 
8.2 
Informed Consent 
Written informed consent will be obtained from each study participant. Each study site is 
responsible for developing study informed consent forms for local use, based on the template in 
Appendix IV that describes the purpose of the study, the procedures to be followed, and the risks 
and benefits of participation, in accordance with all applicable regulations. If applicable, the 
study site also is responsible for translating the template form into local languages, and verifying 
the accuracy of the translation by performing an independent back-translation. 
Participants will document their provision of informed consent by signing their informed consent 
forms. (Further details regarding DAIDS requirements for documenting the informed consent 
process can be found in the DAIDS Standard Operating Procedure for Source Documentation.)   
All participants will be offered a copy of their informed consent form. 
8.3 
Incentives 
Pending IRB approval, participants will be compensated for their time and effort in this study, 
and/or be reimbursed for travel to study visits and time away from work. Site-specific 
reimbursement amounts will be specified in the study informed consent forms. 
8.4 
Confidentiality 
All study-related information will be stored securely at the study site. All participant information 
will be stored in locked file cabinets in areas with access limited to study staff. All laboratory 

 
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specimens, reports, study data collection, process, and administrative forms will be identified by 
a 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 
separately from study records identified by code number. All local databases will be secured 
with password-protected access systems. Forms, lists, logbooks, appointment books, and any 
other listings that link participant ID numbers to other identifying information will be stored in a 
separate, locked file in an area with limited access. 
Participant’s study information will not be released without the written permission of the 
participant, except as necessary for monitoring by the NIAID and/or its contractors; 
pharmaceutical sponsors; representatives of the HPTN LOC, SDMC, and/or LC; the government 
or other local, US, or international regulatory authorities (including the OHRP and US FDA), 
site IRBs/ECs or if appropriate, the SAHPRA, ViiV/Gilead.  
8.5 
Communicable Disease Reporting Requirements 
Study staff will comply with all applicable local requirements to report communicable diseases 
identified among study participants to local health authorities. Participants will be made aware of 
all reporting requirements during the study informed consent process. 
8.6 
Study Discontinuation 
The study also may be discontinued at any time by NIAID, the HPTN, the study sponsors, 
government or regulatory authorities (including the OHRP and US FDA), site IRBs/ECs or if 
appropriate, the SAHPRA, ViiV/Gilead. This would be done primarily due to safety concerns for 
the patients or due to an earlier-than-expected indication of product efficacy or study futility. 

 
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LABORATORY SPECIMENS AND BIOHAZARD CONTAINMENT 
Laboratory procedures are described below and in Appendices I a-c. Refer to Appendix II for 
any participant who has a reactive or positive HIV test after Enrollment. 
9.1 
Local Laboratory Specimens 
The following types of tests will be performed at the local laboratory:  
• HIV testing (see SSP Manual) 
• Pregnancy testing (see below) 
• HBV and HCV testing to include HBsAg, HBsAb, HBcAb (total), HCV antibody tests   
• Complete blood count (CBC) with differential  
• Chemistry testing (blood-urea nitrogen (BUN) or urea, creatinine, CPK, glucose, calcium, 
phosphorous, amylase, lipase) 
• LFTs (AST, ALT, TBili, alkaline phosphatase) 
• Fasting lipid profile (total cholesterol, high-density lipoprotein (HDL), triglycerides, low-density 
lipoprotein (LDL)) – calculated or measured  
• Syphilis serologic testing 
• Urine (protein and glucose) 
• Vaginal swabs or urine for GC/CT nucleic acid amplification testing (NAAT) testing  
• Vaginal swab for Trichomonas vaginalis (TV) testing  
• Plasma storage 
• Dried blood spot (DBS) storage 
• HIV viral load (if HIV-infected) 
• CD4 cell count (if HIV-infected) 
• Real-time resistance testing for clinical management, if indicated and available (if HIV-infected) 
If the HIV testing algorithm includes HIV rapid testing, that testing may be performed in the 
clinic or laboratory.  
 
Pregnancy testing 
All women of reproductive potential will have a βHCG test for pregnancy (sensitivity of ≤ 25 
mIU/mL) at the majority of visits. Pregnancy testing may be performed in the clinic or the 
laboratory at all visits where this testing is indicated. Testing may be performed using a urine, 
plasma, or serum sample. Continued pregnancy testing is not required following a confirmed 
(done in 4 weeks after initial positive) positive test result.  It will be repeated after pregnancy 
completion and must have returned to normal prior to recommencement of study product. 
 

 
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Each study site will adhere to standards of clinical good laboratory practice (GCLP), the HPTN 
Manual of Operations (MOP), the SSP Manual and local SOPs for proper collection, processing, 
labeling, transport, and storage of specimens to the local laboratory. Specimen collection, testing, 
and storage at the local laboratory will be documented using the HPTN Laboratory Data 
Management System (LDMS) as described in the SSP Manual. 
All specimens will be shipped in accordance with International Air Transport Association 
(IATA) specimen shipping regulations. All shipments will be documented using the HPTN 
LDMS as described in the SSP Manual.  
9.2 
Stored Specimens 
Plasma, whole blood, and DBS will be stored at the local site throughout the study. A subset of 
the stored samples will be shipped to the HPTN LC (located in the US) for Quality Assurance 
(QA) and other assessments. As indicated below, testing on stored samples will be performed by 
the HPTN LC or another laboratory designated by the HPTN LC. 
NOTE: Samples may be unblinded at the HPTN Laboratory Center (Pharmacology Laboratory 
only), so the relevant assays are only performed on participants who received CAB LA. In any 
such case, no one outside the Pharmacology Laboratory will be unblinded prior to the end of the 
trial (see Section 5.18). 
 Virology 
The HPTN LC will perform QA testing, including testing to determine HIV infection status in 
selected cases. Additional assays may be performed at the HPTN LC or a laboratory designated 
by the HPTN LC. This testing may include the following tests for participants who acquire HIV 
infection: HIV viral load, HIV resistance testing, HIV subtyping, and other tests to characterize 
HIV viruses and/or the host response to HIV infection. Results will not be returned to the sites or 
study participants, with the exception of HIV testing (if results obtained at the HPTN LC do not 
agree with site results).  
Resistance testing will be performed at the HPTN LC or a laboratory designated by the HPTN 
LC. This testing will be performed retrospectively at the end of the study. Results of this testing 
will not be returned to study sites. Because real-time resistance testing may be needed for clinical 
management in the event of HIV infection, each site will have an SOP as to how they will 
accomplish real-time local or regional resistance testing to assist with clinical decision making; 
separate specimens should be collected for that testing.   
The HPTN LC will also perform testing for HSV-2 on stored plasma samples.   Testing for other 
infections may be performed. Results will not be returned to study sites or participants. 
 Pharmacology 
Plasma and DBS samples for drug concentrations will be collected throughout the study from all 
participants, although PK testing will be limited to a subset of the samples.  

 
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Plasma and DBS samples will be processed and frozen locally for subsequent shipment to the 
HPTN LC following procedures outlined in the SSP Manual. Pharmacology testing will be 
performed at the HPTN LC or at an outside laboratory designated by the HPTN LC. The primary 
pharmacologic assessments will be performed using assays that have been validated and 
approved by the Clinical Pharmacology Quality Assurance (CPQA) Committee. Results will not 
be returned to the study participants. 
NOTE: Samples may be unblinded at the HPTN Laboratory Center (Pharmacology Laboratory 
only) for the adherence subset testing so the relevant assays are only performed on participants 
who received CAB LA.  The HPTN LC (Pharmacology Laboratory) will not be unblinded for 
remaining analysis until the end of Step 2. 
 
Stored plasma may also be tested for the presence of other ARV drugs or other concomitant 
medications. 
 
Injectable Contraception Sub-Study 
Additional plasma and DBS will be stored for participants who enroll in the Injectable 
Contraception Sub-Study. Processing and storage procedures will be described in detail in the 
SSP. Assessments will be performed retrospectively; results will not be returned to study sites or 
participants. 
  Pharmacogenomics 
Samples collected for pharmacogenomics testing may be analyzed for genetic polymorphisms 
associated with study drug exposure. Sites and individual participants may choose to opt out of 
this testing. For sites that collect for this testing, results would not be returned to the sites or 
study participants. 
9.3 
Quality Control and Quality Assurance Procedures 
Study sites will document that their laboratories are certified under the Clinical Laboratory 
Improvement Amendments Act of 1988 (CLIA-certified) and/or participate in DAIDS-sponsored 
External Quality Assurance (EQA) programs. HPTN LC staff will conduct periodic visits to each 
site to assess the implementation of on-site laboratory quality control (QC) procedures, including 
proper maintenance of laboratory testing equipment and use of appropriate reagents. HPTN LC 
staff will follow up directly with site staff to resolve any QC or QA problems identified through 
proficiency testing and/or on-site assessments. 
 QC for HIV Diagnostic Testing 
HIV diagnostic tests will be listed on the site Protocol Analyte List (PAL) and will be subject to 
review and approval by DAIDS and the HPTN LC. Local laboratories will perform testing for 
HIV diagnosis at Screening, Enrollment, and follow-up visits. Algorithms for HIV diagnostic 
testing are provided in the SSP Manual. 
Throughout the course of the study, the sites will ship an aliquot per visit per participant 
quarterly. The HPTN LC with guidance from the SDMC will select a random sample of stored 

 
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specimens to test for QA purposes. The total number of specimens undergoing QA testing will 
follow the QA processes as described in the HPTN MOP and at the discretion of the HPTN LC. 
The HPTN LC will test the specimens for evidence of HIV infection and compare the results of 
their tests with the results obtained by the local labs. HPTN LC staff will follow-up directly with 
site staff to resolve any QA problems identified through this process. 
 Quality Assurance for General Laboratory Testing 
Local laboratories will perform hematology, chemistry, liver function, lipids, hepatitis, STI, and 
urinalysis testing as indicated in each relevant SOE. Non-US laboratories performing these tests 
will be monitored by by an External Quality Assurance Provider or specified quality assurance 
contractor and must demonstrate successful participation in the relevant EQA programs.  
 Quality Assurance for CD4 Cell Count Testing 
Local laboratories may also perform CD4 cell count testing as indicated in Appendix II. Non-US 
laboratories performing these tests will be monitored by an External Quality Assurance program 
and must demonstrate successful participation in these programs.       
 Quality Assurance for HIV RNA Testing 
Local laboratories may also perform HIV RNA/viral load testing (test kit approved by the HPTN 
LC) as indicated in Appendix II or for evaluation of possible acute HIV infection. Non-US sites 
may use local laboratories for this testing. Non-US laboratories performing these tests will be 
monitored by the DAIDS Virology Quality Assurance (VQA) program and must demonstrate 
successful participation in this program.  
 Specimen Storage and Possible Future Research Testing 
Study sites will store specimens collected in this study at least through the end of the study 
(completion of all study-related testing, including testing at the HPTN LC). In addition, at sites 
that allow this type of storage, study participants will be asked to provide written informed 
consent for these samples to be stored after the end of the study for possible future non-protocol 
listed testing. The specimens of participants who do not consent to long-term storage and 
additional testing will be destroyed after all of the protocol specified testing (including 
assessments at the HPTN LC) has been completed.  
Samples from participants who did not successfully enroll in the study may be discarded once 
sample lists are provided by the HPTN LC in consultation with the HPTN SDMC. 
9.4 
Biohazard Containment 
As the transmission of HIV and other blood-borne pathogens can occur through contact with 
contaminated needles, blood, and blood products, appropriate blood and secretion precautions 
will be employed by all personnel in the drawing of blood and shipping and handling of all 
specimens for this study, as currently recommended by the US CDC. All infectious specimens 
will be transported in accordance with United States regulations (42 CFR 72) and in accordance 
with IATA. 

 
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 ADMINISTRATIVE PROCEDURES 
10.1 Protocol Registration 
Initial Registration of the protocol by the DAIDS PRO is required prior to implementation of this 
protocol. As part of this process, each site must have the protocol and protocol informed consent 
form(s) (ICFs) approved, as appropriate, by their IRB/EC and any other applicable regulatory 
entity (RE). Upon receiving final approval, sites will submit all required protocol registration 
documents to the DAIDS PRO at the RSC. The DAIDS PRO will review the submitted protocol 
registration packet to ensure that all of the required documents have been received. In the case of 
Initial Registration, site-specific ICFs WILL be reviewed and approved by the DAIDS PRO. 
Sites will receive an Initial Registration Notification from the DAIDS PRO that indicates 
successful completion of the protocol registration process. A copy of the Initial Registration 
Notification should be retained in the site's regulatory files. 
Following Initial Registration, any full protocol amendments require submission of a protocol 
registration packet to the DAIDS PRO as described above; however, the DAIDS PRO WILL 
NOT review and approve site-specific ICFs. Upon receiving final IRB/EC and any other 
applicable RE approval(s) for an amendment, sites should implement the amendment 
immediately. Sites will receive a Registration Notification when the DAIDS PRO receives a 
complete registration packet.  A copy of the Amendment Registration Notification should be 
retained in the site’s regulatory files.   
There may be cases where a site submits as their Initial Registration a protocol amendment 
(Version 2.0 or higher of a protocol); in such cases, the instructions for Initial Registration will 
be followed. 
For additional information on the protocol registration process and specific documents required 
for initial and amendment registrations, refer to the current version of the DAIDS Protocol 
Registration Manual, which can be found at https://rsc.niaid.nih.gov/networks-protocol-
teams/protocol-templates. 
10.2 Study Activation 
Pending successful protocol registration and submission of all required documents, the HPTN 
LOC staff will “activate” a site. Study implementation may not be initiated until a study 
activation notice is provided to the site by the HPTN LOC. In addition, if study “activation” is 
determined to be necessary for any subsequent amendments, study implementation may not be 
initiated until a study activation notice is provided to the site by the HPTN LOC. 
10.3 Study Coordination 
DAIDS holds the Investigational New Drug (IND) application for this study. Copies of all 
regulatory documents submitted to this IND by DAIDS will be forwarded to ViiV Healthcare 
and Gilead Sciences, Inc. for cross-referencing with the company’s other INDs for the study 
product(s). Assignment of all sponsor responsibilities for this study will be specified in a Clinical 
Trials Agreement executed between DAIDS and each of the collaborating partners (ViiV 
Healthcare, and Gilead Sciences, Inc.). 

 
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Study implementation will be directed by this protocol as well as the SSP Manual. The SSP 
Manual, which will include links to the DAIDS SOPs for Source Documentation and Essential 
Documents, as well as links to the Manual for Expedited Reporting of AEs to DAIDS and the 
DAIDS Toxicity Tables, will outline procedures for conducting study visits; data and forms 
processing; AE assessment, management and reporting; dispensing study products and 
documenting product accountability; and other study operations. 
Study CRFs will be developed by the study team and HPTN SDMC.  Data will be transferred to 
the HPTN SDMC, entered, and cleaned using the HPTN SDMC.  Queries routinely will be 
generated and distributed to the study sites for verification and resolution. 
Close coordination between protocol team members will be necessary to track study progress, 
respond to queries about proper study implementation, and address other issues in a timely 
manner. Rates of accrual, adherence, follow-up, and AE incidence will be monitored closely by 
the team as well as the HPTN SMC. The protocol team’s CMC will address issues related to 
study eligibility and AE management and reporting as needed to assure consistent case 
management, documentation, and information-sharing across sites. 
10.4 Study Monitoring 
On-site study monitoring will be performed in accordance with DAIDS policies.  Study monitors 
will visit the site to: 
• verify compliance with human subjects and other research regulations and guidelines;  
• assess adherence to the study protocol, study-specific procedures manual, and local counseling 
practices; and 
• confirm the quality and accuracy of information collected at the study site and entered into the 
study database. 
Site investigators will allow study monitors to inspect study facilities and documentation (e.g., 
informed consent forms, clinic and laboratory records, other source documents, CRFs), as well 
as observe the performance of study procedures. Investigators also will allow inspection of all 
study-related documentation by authorized representatives of the HPTN LOC, HPTN SDMC, 
HPTN LC, NIAID, government or other local, US, or international regulatory authorities/entities 
(including the OHRP and US FDA). site IRBs/ECs or if appropriate, the SAHPRA, ViiV/Gilead. 
A site visit log will be maintained at each study site to document all visits. 
 Remote Study Monitoring 
Due to ongoing travel restrictions during the COVID-19 pandemic, some sites are unable to 
accommodate onsite monitoring visits. Remote monitoring visits to date consist of quality review 
of study data available in the Electronic Data Capture system without verification to 
corresponding source documents. Review of source documentation is a critical component of 
ensuring data integrity.  
Monitoring visits may be conducted on-site or remotely. Remote visits may include remote 
source document verification using methods specified for this purpose by NIAID. Remote 

 
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monitoring visits may be performed in place of, or in addition to onsite visits to ensure the 
safety of study participants and data integrity57. 
 
Other secure platforms that are 21 CFR Part 11 compliant may be utilized, as allowed by the 
DAIDS Office of Clinical Site Oversight (OCSO). 
 
Four options listed below will enable the facilitation of remote source document verification, 
which may vary site by site.  All offered are HIPAA and 21 CFR Part 11 compliant.  
 
Option #1 - Veeva SiteVault Platform- This platform is available for sites to self-subscribe at no 
cost from Veeva Systems. There is no software to download and the only requirement is internet 
access. Sites will upload source documents to this secure platform and assign permissions to 
monitors to access these data for a limited period of time. For sites that are already using this 
platform in some capacity, they can add specific DAIDS studies to their existing account. In the 
event that this platform is being used by another entity within the institution, the site can request 
access to the platform following their internal procedures. However, sites that are not currently 
using Veeva SiteVault, can obtain additional information by visiting 
https://www.veeva.com/products/sitevault/ or sign up to try at sites.veeva.com. Veeva SiteVault 
may require a signed agreement between the site and Veeva Systems. 
Option #2 - Site Controlled SharePoint or Cloud-Based Portal-Some sites may already have a 
platform which allows for sharing of participant source documents, which could be extended to 
allow monitor’s access. This option must be 21CRF 11 and HIPAA compliant as applicable. 
Option #3 – Direct Access to Electronic Medical Records by Monitors- This option may 
be feasible for sites that use Electronic Medical Records, and whose institutional policy allows 
for direct access of the site’s Electronic Medical Record to monitors for a limited period of time. 
Please contact your institution’s Security Officer for required approvals and any agreements to 
facilitate remote access to participant source documents. 
Option #4 - Medidata Rave Imaging Solution- This option does not require additional purchase 
of software and sign-on is through each site’s existing single iMedidata account. Sites will 
upload source documents to this secure platform and monitor permission and access is assigned 
by the SDMC. There is ongoing discussion regarding the implementation timeline for MediData 
Rave Imaging Solutions, and the SDMC will contact sites regarding demonstration of this 
solution. 
10.5 Protocol Compliance 
The study will be conducted in full compliance with the protocol. The protocol will not be 
amended without prior written approval by the Protocol Chair and DAIDS Medical Officer. All 
protocol amendments must be submitted to and approved by the relevant IRB(s) and the DAIDS 
RSC prior to implementing the amendment. 

 
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10.6 Investigator's Records 
The IoR will maintain, and store in a secure manner, complete, accurate, and current study 
records throughout the study. In accordance with Federal regulations, for each of the 
investigational products tested, the IoR will retain all study records for at least two years 
following the date of marketing approval for the study product for the indication in which it was 
studied, or if other applicable laws, regulations, policies, or other requirements (e.g., State, 
country-specific, and local laws, and sponsor or institutional policies) exist, the most stringent 
retention period will be followed. If no marketing application is filed, or if the application is not 
approved, the records must be retained for two years after the US FDA is notified that the IND is 
discontinued, or if other applicable laws, regulations, policies, or other requirements (e.g., State, 
country-specific, and local laws, and sponsor or institutional policies) exist, the most stringent 
retention period will be followed. Study records include administrative documentation — 
including protocol registration documents and all reports and correspondence relating to the 
study — as well as documentation related to each participant screened and/or enrolled in the 
study — including informed consent forms, locator forms, CRFs, notations of all contacts with 
the participant, and all other source documents. 
10.7 Use of Information and Publications 
Publication of the results of this study will be governed by HPTN policies.  Any presentation, 
abstract, or manuscript will be submitted by the Investigator to the HPTN Manuscript Review 
Committee (MRC), DAIDS, ViiV Healthcare, Gilead Sciences, Inc., and BMGF for review prior 
to submission.  
 

 
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APPENDICES I - VIII 

 
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Appendix Ia: Schedule of Evaluations – Screening and Step 1, Oral Run-in Phase 
 
Screening 
Step 1  
DAY 0/ 
Enrollment 
WEEK 2 
WEEK 4 
ADMINISTRATIVE, BEHAVIORAL, REGULATORY 
Informed consent  
X 
 
 
 
Locator information 
X 
X 
X 
X 
Demographic information 
 
X 
 
 
Randomization 
 
X 
 
 
HIV prevention counseling  
X 
X 
X 
X 
Offer condoms  
X 
X 
X 
X 
Baseline acceptability assessment  
 
X 
 
 
Baseline behavioral assessment 
 
X 
 
 
CLINICAL EVALUATIONS & PROCEDURES 
Dispense study product (enough for 5 weeks) 
 
X 
 
 
Observe participant take oral study product1 
 
X 
X1 
X1 
Adherence counseling/contraception 
counseling13/pill count (pill count Weeks 2 and 
4 only) 
 
X 
X 
X 
Medical history (including bleeding history at 
Screening), contraceptive use, con meds, 
physical exam (with pulse, BP, weight and BMI 
calculated at each visit)2 
X 
X 
X 
X 
Hep B vaccination (if needed)3 
 
 
X 
 
Blood collection 
X 
X 
X 
X 
Urine collection  
X6 
X 
X6 
X6 
Vaginal swab collection4  
 
X 
 
 
LOCAL LABORATORY EVALUATIONS & PROCEDURES 
HIV testing5 
X 
X 
X 
X 
Pregnancy testing6 
X 
X 
X 
X 
HBV and HCV testing7 
X 
X 
 
 
CBC with differential 
X 
X 
X 
X 
Chemistry testing8  
X 
X 
X 
X 
Liver function tests9 
X 
X 
 
X 
Fasting lipid profile10 
 
X 
 
 
Syphilis testing 
 
X 
 
 
GC/CT and TV testing4 
 
X 
 
 
Urinalysis (protein and glucose) 
 
X 
 
 

 
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Screening 
Step 1  
DAY 0/ 
Enrollment 
WEEK 2 
WEEK 4 
Plasma storage11  
X 
X 
X 
X 
DBS storage  
 
 
 
X 
Whole blood storage14 
 
X 
 
 
Additional sample storage for participants 
enrolled in the Injectable Contraception Sub-
Study12 
 
X 
 
 
 
 
 
FOOTNOTES FOR APPENDIX Ia 
1 Staff are required to observe participants take one pill at Enrollment.  If participants return with their pills at Weeks 2 & 4, staff will observe participant take one pill then as well 
unless the participant has already taken oral study product that day.  Participants must not be asked to take a second dose of oral study product for the sake of observation.  
2  Full physical exam is to be conducted during Enrollment.  A targeted physical exam will be done at all other visits. Participant pulse, blood pressure and weight must be recorded 
at every visit.  BMI must be calculated at all visits except Screening. 
3 The initial dose of the Hep B vaccination will ideally be given at Week 2, though there is flexibility around the timing of the vaccination.  Subsequent doses may be given at 
different visits than indicated in this SOE, as long as sites follow manufacturer guideline timing. 
4 GC/CT NAAT testing may be performed using urine or a vaginal swab; TV testing is performed using a vaginal swab.  If a woman is menstruating, the swab may be collected at 
a later visit and all testing using the swab may be performed at that later visit.  
5 The HIV testing algorithm is provided in the SSP Manual. Testing for acute HIV must be negative and must be performed within 14 days of enrolling the participant. If HIV 
rapid testing is indicated, this testing may be performed in the clinic or the laboratory.  At least one HIV test must be available the same day as sample collection and before 
product is administered.  
6 Pregnancy testing may be performed in the clinic or the laboratory. Results must be available the same day as sample collection and before product is administered.  
Testing may be performed using a urine, plasma, or serum sample. The assay used for pregnancy testing must have a limit of detection of 25 mIU/mL or lower. Pregnancy 
testing is not required at subsequent visits if a positive result is obtained and the participant is still pregnant. 
7 At Screening: HBsAg and HCV antibody testing. At Enrollment: HBsAb and HBcAb testing.  Note: These tests can all be done at Screening at the discretion of the IOR.        
8 At Screening: Creatinine. At and after enrollment: BUN/urea, creatinine, CPK, calcium, phosphorous, glucose, amylase, and lipase. 
9 At Screening: ALT and TBili. At and after Enrollment: AST, ALT, total bilirubin, and alkaline phosphatase.  
10 Total cholesterol, HDL, triglycerides, and LDL (either calculated or measured). Participants should have fasted for at least 8 hours, preferably 12 hours, prior to sample 
collection. If participants are not fasting, do not order the lipid testing. Participants may return for testing or it can be performed at next visit. 
11 Stored plasma will be used for Quality Assurance testing, HSV-2 and other assessments at the HPTN LC (see Section 9). Assessments will be performed retrospectively; 
results will not be returned to study sites or participants, except as noted in Section 9.0 
 12 Additional serum and/or plasma will be stored for participants who enroll in the Injectable Contraception Sub-Study. Processing and storage procedures will be described 
in detail in the SSP. Assessments will be performed retrospectively; results will not be returned to study sites or participants. 
13 Refer to the SSP Manual.  
14 Whole blood collection and storage is only required for participants who consent to genetic testing.    
 
  
 

 
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Appendix Ib: Schedule of Evaluations - Step 2, Injection Phase 
WEEKS in Study  
(shaded column = 
injection/ dispense pills 
visit) 
5
6
9
13
17
21
25
33
41
42
49
57
65
73
81
89
97
105
113
121
129
137
145
153
161
169
177
185*
ADMINISTRATIVE, BEHAVIORAL, REGULATORY 
Locator information 
X X X X X X X  X  X X X  X  X  X  X  X  X  X  X  X  X  X  X  X  X  X  X  X 
HIV prevention 
counseling 
X X X X X X X  X  X X X  X  X  X  X  X  X  X  X  X  X  X  X  X  X  X  X  X 
Offer condoms per local 
SOC 
X X X X X X X  X  X X X  X  X  X  X  X  X  X  X  X  X  X  X  X  X  X  X  X 
Acceptability 
assessment 
 
 
 
 X  
 
 
 
 X  
 
 
 
 X  
 
 
 
 X  
 
 
 
 
 
 
 
 
 
 X  
 
 
 
 
 
 
 
 
 
 X 
Behavioral assessment 
X  X  X  X  X  X  X  X  X  X  X  X  X  X  
 
 X  
 
 X  
 
 X  
 
 X  
 
 X 
CLINICAL EVALUATIONS & PROCEDURES 
Adherence counseling / 
contraception 
counseling10   
X X X X X X X  X  X X X  X  X  X  X  X  X  X  X  X  X  X  X  X  X  X  X  X 
Dispense oral products 
to all participants 
X  X  X  X  X  X  X  X  X  X  X  X  X  X  X  X  X  X  X  X  X  X  X  X 
Medical history, 
concomitant 
medications, 
contraceptive use, 
targeted physical exam 
(with pulse, BP, weight 
and BMI calculated at 
each visit) 
X X X X X X X  X  X X X  X  X  X  X  X  X  X  X  X  X  X  X  X  X  X  X  X 
Hep B vaccination (if 
needed) 1 
 X  
 
 
 
 
 X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood collection 
X X X X X X X  X  X X X  X  X  X  X  X  X  X  X  X  X  X  X  X  X  X  X  X 
Urine collection  
X
4 
X
4 
X
4 
X
4 
X
4 
X
4 
X
4 
 X
4 
 X
4 
X
4 
X
4 
 X  X
4 
 X
4 
 X
4 
 X
4 
 X
4 
 X  X
4 
 X
4 
 X
4 
 X
4 
 X
4 
 X  X
4 
 X
4 
 X
4 
 X
4 
Vaginal swab collection2 
 
 
 
 
 
 
 
 X  
 
 
 
 X  
 
 
 
 X  
 
 
 
 X  
 
 
 
 X  
 
 
 
 X  
 
 
 
 X  
 
Injections for all 
participants 
X  X  X  X  X  X  X  X  X  X  X  X  X  X  X  X  X  X  X  X  X  X  X  X 
ISR evaluation  
 X  X  X  
 
 
 
 X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
LOCAL LABORATORY EVALUATIONS & PROCEDURES 
HIV testing3 
X X X X X X X  X  X X X  X  X  X  X  X  X  X  X  X  X  X  X  X  X  X  X  X 
Pregnancy testing4  
X X X X X X X  X  X X X  X  X  X  X  X  X  X  X  X  X  X  X  X  X  X  X  X 
HCV testing5 
 
 
 
 
 
 
 
 
 
 
 
 
 
 X  
 
 
 
 
 
 
 
 
 
 X  
 
 
 
 
 
 
 
 
 
 X  
 
 
 
 
 
 
 
CBC with differential 
X X X X X X X  X  X X X  X  X  X  X  X  X  X  X  X  X  X  X  X  X  X  X  X 
Chemistry testing6 
X X X X X X X  X  X X X  X  X  X  X  X  X  X  X  X  X  X  X  X  X  X  X  X 
Liver function testing7 
X X X X X X X  X  X X X  X  X  X  X  X  X  X  X  X  X  X  X  X  X  X  X  X 

 
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WEEKS in Study  
(shaded column = 
injection/ dispense pills 
visit) 
5
6
9
13
17
21
25
33
41
42
49
57
65
73
81
89
97
105
113
121
129
137
145
153
161
169
177
185*
Fasting lipid profile8 
 
 
 
 
 
 
 
 
 
 
 
 
 
 X  
 
 
 
 
 
 
 
 
 
 X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Syphilis testing 
 
 
 
 
 
 
 
 X  
 
 
 
 X  
 
 
 
 X  
 
 
 
 X  
 
 
 
 X  
 
 
 
 X  
 
 
 
 X  
 
Vaginal GC/CT and TV 
testing2 
 
 
 
 
 
 
 
 X  
 
 
 
 X  
 
 
 
 X  
 
 
 
 X  
 
 
 
 X  
 
 
 
 X  
 
 
 
 X  
 
Urinalysis (protein, 
glucose) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 X  
 
 
 
 
 
 
 
 
 
 X  
 
 
 
 
 
 
 
 
 
 X  
 
 
 
 
 
 
 
Plasma storage9 
X X X X X X X  X  X X X  X  X  X  X  X  X  X  X  X  X  X  X  X  X  X  X  X 
DBS storage 
 
 
 
 
 
 
 
 X  
 
 
 
 X  
 
 
 
 X  
 
 
 
 X  
 
 
 
 X  
 
 
 
 X  
 
 
 
 X  
 
 
* Participants in Step 2 may be followed for longer than 185 weeks.  Any participant who reaches Week 185 prior to the implementation of the Open-Label Amendment, Protocol 
Version 3.0, should continue to be followed according to procedures at Week 185 every eight weeks.  Once the Open-Label amendment is implemented on site, the participant 
must be transitioned to that amendment. 
 
 
FOOTNOTES FOR APPENDIX Ib 
1 The initial dose of the Hep B vaccination is ideally given at Week 2, though there is flexibility around the timing of the vaccination.  Subsequent doses may be given at different 
visits than indicated in this SOE, as long as sites follow manufacturer guideline timing. 
2 GC/CT NAAT testing may be performed using urine or a vaginal swab; TV testing is performed using a vaginal swab.  If a woman is menstruating, the swab may be collected at 
a later visit and all testing using the swab may be performed at that later visit.  
3 The HIV testing algorithm is provided in the SSP Manual. If HIV rapid testing is indicated, this testing may be performed in the clinic or the laboratory.  At least one HIV test 
must be available the same day as sample collection and before product is administered. product is administered.   Additional HIV testing may be requested by the 084HIV alias 
committee. 
4 Pregnancy testing may be performed in the clinic or the laboratory. Results must be available the same day as sample collection and before product is administered. Testing may 
be performed using a urine, plasma, or serum sample. The assay used for pregnancy testing must have a limit of detection of 25 mIU/mL or lower. Pregnancy testing is not 
required at subsequent visits if a positive result is obtained and the participant is still pregnant. 
5 HCV antibody testing.  
6 BUN/urea, creatinine, CPK, calcium, phosphorous, glucose, amylase, and lipase. 
7 AST, ALT, TBili, and alkaline phosphatase.  
8 Total cholesterol, HDL, triglycerides, and LDL (either calculated or measured). Participants should have fasted for at least 8 hours, preferably 12 hours, prior to sample 
collection. If participants are not fasting, do not order the lipid testing. Participants may return for testing or it can be performed at next visit. 
9 Stored plasma will be used for Quality Assurance testing and other assessments at the HPTN LC (see Section 9). Assessments will be performed retrospectively; results will 
not be returned to study sites or participants, except as noted in Section 9.0.  
10 Refer to the SSP Manual.   
 
 

 
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Appendix Ic: Schedule of Evaluations - Step 3, Follow-up Phase # 
Time in Step 3 
Step 3, Day 0* 
Step 3, Week 12 
Step 3, Week 24 
Step 3, Week 36 
Step 3, Week 48 
ADMINISTRATIVE, BEHAVIORAL, REGULATORY 
 
Locator information 
X 
X 
X 
X 
X 
HIV prevention counseling 
X 
X 
X 
X 
X 
Offer condoms  
X 
X 
X 
X 
X 
Acceptability assessment 
X 
 
 
 
 
Behavioral assessment (if done in 
last 4 weeks, skip D0 and start at 
W12) 
X 
 
X 
 
 
X 
CLINICAL EVALUATIONS & PROCEDURES 
 
Dispense pills to all participants 
X 
X 
X 
X 
 
Adherence counseling/ 
contraception counseling8   for all 
participants 
X 
X 
X 
X 
 
Medical history, concomitant 
medications, contraceptive use, 
targeted physical exam (with 
pulse, BP, weight and BMI 
calculated at each visit)  
X 
X 
X 
X 
X 
Blood collection 
X 
X 
X 
X 
X 
Urine collection  
X6 
X3 
X 
X3 
X 
Vaginal swab collection1  
X6 
 
X 
 
X 
LOCAL LABORATORY EVALUATIONS & PROCEDURES 
HIV testing2 
X 
X 
X 
X 
X 
Pregnancy testing3  
X 
X 
X 
X 
X 
Chemistry testing4  
 
 
X 
 
X 
Liver function testing5 
 
 
X 
 
X 
Syphilis testing 
X6 
 
X 
 
X 
GC/CT and TV testing1 
X6 
 
X 
 
X 
Plasma storage7 
X 
X 
X 
X 
X 
DBS storage 
 
 
X 
 
X 
 
FOOTNOTES FOR APPENDIX Ic 
# Follow this SOE for participants on open label TDF/ FTC.  Also, please note that for applicable participants who complete this schedule and move to annual 
HIV testing visits, procedures for those visits are described in the SSP. 
 
* Day 0 of Step 3 should be scheduled no later than 8 weeks after the last injection.  Attempts should be made to bring the participant in earlier rather than later 
than the target date.  See SSP Manual for further details.       

 
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1 GC/CT NAAT testing may be performed using urine or a vaginal swab; TV testing is performed using a vaginal swab.  If a woman is menstruating, the swab 
may be collected at a later visit and all testing using the swab may be performed at that later visit.  
2 The HIV testing algorithm is provided in the SSP Manual. If HIV rapid testing is indicated, this testing may be performed in the clinic or the laboratory.  At 
least one HIV test must be available the same day as sample collection and before product is administered. 
3 Pregnancy testing may be performed in the clinic or the laboratory at all visits where this testing is indicated. Results must be available the same day as sample 
collection and before product is administered. Testing may be performed using a urine, plasma, or serum sample. The assay used for pregnancy testing must have 
a limit of detection of 25 mIU/mL or lower. Pregnancy testing is not required at subsequent visits if a positive result is obtained and the pregnancy is still 
ongoing. 
4 Chemistry testing includes: BUN/Urea, creatinine, CPK, calcium, phosphorous, glucose, amylase, and lipase.  
5 Liver function testing includes: AST, ALT, TBili, and alkaline phosphatase. 
6 Skip Day 0 if testing has occurred within the last 3 months of Day 0, and do only at Weeks 24 and 48.  
7 Stored plasma will be used for Quality Assurance testing, HSV-2  and other assessments at the HPTN LC (see Section 9). Assessments will be performed 
retrospectively; results will not be returned to study sites or participants, except as noted in Section 9.0. 
8  Refer to the SSP Manual. 
 
 
 
 

 
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Appendix Id: Schedule of Evaluations for Pregnant Participants# 
WEEKS in Study  
 
4 weeks after 
first positive 
pregnancy test 
Quarterly Visit 1 
(12 weeks since 
first positive 
pregnancy test) 
Quarterly Visit 2 
(24 weeks since 
first positive 
pregnancy test) 
Quarterly Visit 3 (36 
weeks since first 
positive pregnancy 
test) 
ADMINISTRATIVE, BEHAVIORAL, REGULATORY 
Locator information 
X 
X 
X 
X 
HIV prevention counseling 
X 
X 
X 
X 
Offer Condoms per local SOC 
X 
X 
X 
X 
Acceptability assessment 
 
X 
 
 
Behavioral assessment 
 
X 
 
X 
CLINICAL EVALUATIONS & PROCEDURES 
Adherence counseling 
X 
X 
X 
X 
Dispense TDF/FTC to all 
participants 
X 
X 
X 
X 
Medical history, concomitant 
medications, targeted physical 
exam (with pulse, BP, weight and 
BMI calculated at each visit) 
X 
X 
X 
X 
Blood collection 
X 
X 
X 
X 
Urine collection  
X 
 
X 
 
Vaginal swab collection1 
X 
 
X 
 
LOCAL LABORATORY EVALUATIONS & PROCEDURES 
HIV testing2 
X 
X 
X 
X 
Pregnancy testing3 
X 
 
 
 
Chemistry testing4 
 
 
X 
 
Liver function testing5 
 
 
X 
 
Syphilis testing 
X7 
 
X 
 
Vaginal GC/CT and TV testing 1 
X7 
 
X 
 
Plasma storage6 
X 
X 
X 
X 
DBS storage 
X 
X 
X 
X 
 
 
 
 
 
 
 
 

 
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FOOTNOTES FOR APPENDIX Id 
 
# All participants who continue to breastfeed beyond the initial “Quarterly Visit 3” will continue to be followed quarterly (approximately every 12 weeks).  Visit 
procedures will alternate between those done for “Quarterly Visit 2” and those done for “Quarterly Visit 3.” 
 
1 GC/CT NAAT testing may be performed using urine or a vaginal swab; TV testing is performed using a vaginal swab.  If a woman is menstruating, the swab 
may be collected at a later visit and all testing using the swab may be performed at that later visit.  
2 The HIV testing algorithm is provided in the SSP Manual. If HIV rapid testing is indicated, this testing may be performed in the clinic or the laboratory.  At 
least one HIV test must be available the same day as sample collection and before product is administered.  
3 Pregnancy testing may be performed in the clinic or the laboratory. Results must be available the same day as sample collection and before product is 
administered. Testing may be performed using a urine, plasma, or serum sample. The assay used for pregnancy testing must have a limit of detection of 25 
mIU/mL or lower. Pregnancy testing is not required at subsequent visits if a positive result is obtained and the participant is still pregnant.  If the confirmatory 
pregnancy test is positive, the participant is referred for an Ultrasound and evaluation by an obstetric specialist at about 12-14 weeks gestational age, for other 
testing, counseling, and management.  Further biochemical blood testing may be done as indicated.  All findings and outcomes will be collected and reported. 
4 BUN/urea, creatinine, CPK, calcium, phosphorous, glucose, amylase, and lipase. 
5 AST, ALT, TBili, and alkaline phosphatase.  
6  Stored plasma will be used for Quality Assurance testing and other assessments at the HPTN LC (see Section 9). Assessments will be performed 
retrospectively; results will not be returned to study sites or participants, except as noted in Section 9.0.  
7 If not done within 4 weeks of initial positive pregnancy test 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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Appendix Ie: Schedule of Evaluations - Contraceptive Substudy ONLY  
 
WEEKS in Study  
(shaded column = injection/ dispense 
pills visit) 
Enrollment 
5 
6 
9 
13 
17 
21 
25 
 
33 
 
41 
42 
49 
 
57 
 
65 
 
73 
CLINICAL EVALUATIONS & PROCEDURES 
Draw blood for PK samples2 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
LOCAL LABORATORY EVALUATIONS & PROCEDURES 
Plasma storage1 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
DBS 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
FOOTNOTES FOR APPENDIX Ie 
1  Additional stored plasma will be used for PK evaluations and DMPA, NET-EN, Etonogestrel 
2  Blood must be collected prior to study product administration during the visit. Also, record the date that the participant’s LARC was last injected/inserted. 
 
 
 
 
 
 
 
 
 
 

 
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Appendix II: Schedule of Additional Procedures for Reactive/ Positive HIV Tests 
(For enrolled participants) 
 
Note 1:  The procedures listed for the HIV Confirmation Visit apply to participants who acquire HIV infection at any time during the 
study.  The procedures listed for Weeks 12, 24, 36, and 48 apply to participants who acquire HIV infection in Step 2.  Participants 
who acquire HIV in Step 3 may undergo similar procedures as listed in Weeks 12, 24, 26, and 48, and will be determined by the 
members of 084HIV@hptn.org. Note that participants who acquire HIV-infection during Step 1 will permanently discontinue study 
product, will be terminated from the study, and be referred for HIV-related care.   
Participants who acquire HIV infection in Steps 2 and 3 only 
HIV Confirmation 
Visit 
Week 12 
Week 24 
Week 36 
Week 486 
ADMININISTRATIVE, BEHAVIORAL, REGULATORY 
Locator information  
X 
X 
X 
X 
X 
Offer condoms  
X 
X 
X 
X 
X 
HIV counseling  
X 
 
 
 
 
CLINICAL EVALUATIONS AND PROCEDURES 
History, con meds, physical exam (with 
pulse, BP, weight and BMI calculated at 
each visit) 
X 
X 
X 
X 
X 
Blood collection 
X 
X 
X 
X 
X 
LOCAL LABORATORY EVALUATIONS 
HIV testing1 
X 
 
 
 
 
CD4 cell count  
X 
 
X 
 
X 
HIV viral load testing 
X 
 
X 
 
X 
HIV resistance testing2 
X 
 
 
 
 
Chemistry testing3 
 
X 
X 
X 
X 
Liver function testing4 
 
X 
X 
X 
X 
Plasma storage5 
X 
X 
X 
X 
X 
DBS Storage 
X 
 
 
 
 

 
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FOOTNOTES FOR APPENDIX II 
1 The HIV confirmatory visit must be held on a different day from the visit where the participant had their initial reactive/positive HIV test.  The testing 
algorithm for the HIV Confirmation Visit is provided in the SSP Manual. If HIV rapid testing is included in the HIV testing algorithm, this testing may be 
performed in the clinic or the laboratory.    Additional HIV testing may be requested by the 084HIV alias committee. 
2 Sites may collect specimens for resistance testing at a local laboratory to assist with clinical management; results from resistance testing performed at local 
laboratories will not be reported to the SDMC.  Stored plasma may not be used real-time/local resistance testing; additional samples must be collected for this 
testing.     
3 Required chemistry testing: BUN/urea, creatinine, CPK, calcium, phosphorous, glucose, amylase, and lipase.  
4 Required LFTs: AST, ALT, total bilirubin, and alkaline phosphatase.  
5 Stored plasma will be used for Quality Assurance testing and other assessments at the HPTN LC (see Section 9). Assessments will be performed 
retrospectively; results will not be returned to study sites or participants, except as noted in Section 9.0.  Additional HIV testing may be requested by the 084HIV 
alias committee. 
6  For participants in Arm A who received injections, the Week 48 visit should be timed as closely as possible to 52 weeks after the participant received the last 
injection.      
 

 
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Appendix III: Toxicity Management 
Toxicity Management General Guidance 
In general, the IoR has the discretion to hold study product at any time if she/he feels that 
continued product use would be harmful to the participant, or interfere with treatment deemed 
clinically necessary according to the judgment of the IoR. In addition, a CMC has been 
established for this study. The CMC’s responsibilities will include consultation and decision-
making regarding management of toxicities and study product administration, including product 
resumption following the occurrence of certain types of toxicities and/or permanent 
discontinuation. Throughout this appendix are examples of AEs that require consultation with 
the CMC; in all such cases, the CMC should be notified as soon as possible and ideally within 72 
hours of site awareness of the AE in question. IoRs also should consult the CMC for further 
guidance in restarting study product or progressing to permanent discontinuation.  
The following general guidance refers to all AEs except for ALT, creatinine clearance (absolute 
and change from baseline), and CPK. Refer to the tables below for specific guidance about these 
laboratory abnormalities. 
Grade 1 or 2 
In general, participants who develop a Grade 1 or 2 AE regardless of relatedness to study 
product, and that is not specifically addressed elsewhere in the protocol or in the Tables below 
may continue use of the study product per protocol.             
Grade 3 
For participants who develop a Grade 3 AE or toxicity that is not specifically addressed 
elsewhere in the protocol or in the Tables below and is judged to be related to study product by 
the IoR, study product use should be temporarily discontinued in consultation with the CMC. In 
general, and unless otherwise decided in consultation with the CMC, the IoR should re-evaluate 
the participant until resolution of the toxicity.  
 
Related: 
For Grade 3 AEs deemed related to study product, the study product should be 
permanently discontinued if improvement to severity ≤ Grade 2 cannot be documented 
within 4 weeks of receipt of the initial result. If study product is resumed and the same 
Grade 3 AE recurs at any time, the IoR must consult the CMC for further guidance on 
holding of study product, frequency of reevaluation or progression to permanent 
discontinuation of the study product.   
 
Unrelated: 
For Grade 3 AEs deemed unrelated to study product, the CMC should be consulted for 
further management recommendations.  
Grade 4 
Participants who develop a Grade 4 AE or toxicity that is not specifically addressed elsewhere in 
the protocol or in the Tables below (regardless of relationship to study product) must have the 
study product temporarily discontinued. The IoR must consult the CMC and continue the 

 
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temporary study product hold until a recommendation is obtained from the CMC.  
 
In general, study product use will not be resumed if the Grade 4 AE is considered related to 
study product use. If, in consultation with the CMC, study product use is resumed and the same 
Grade 4 AE recurs at Grade 4 level at any time, study product must then be permanently 
discontinued. 
General Criteria for Discontinuation of Study Product 
Participants may voluntarily discontinue the study product for any reason at any time.   IoRs will 
permanently discontinue participants from study product per protocol for any of the specific 
criteria below, which may be further clarified in the SSP Manual. IoRs also may also temporarily 
or permanently discontinue participants for reasons not shown here or in the SSP Manual (e.g., to 
protect participants’ safety and/or if participants are unable or unwilling to comply with study 
product use procedures). In such cases, the IoR or designee must first query the CMC for review. 
The CMC will provide a written response to the site indicating whether the CMC has 
recommended temporary or permanent discontinuation of study product based on careful review 
of all relevant data. It should be noted that the safety of the participant should always take 
precedence, and therefore, an IoR may determine that study product be temporarily discontinued 
before the CMC has time to respond. This is acceptable, and in such cases, the CMC should be 
notified as soon as possible regarding the nature of the case and the course of action taken.   
The criteria for permanent discontinuation of study product use for an individual participant are: 
• Study product-related toxicity requiring permanent discontinuation of study product per the 
guidelines above and below 
• Completion of regimen as defined in the protocol 
• Request by participant to terminate study product 
• Clinical reasons determined by the IoR  
• Acquires HIV infection  
Study product will be temporarily withheld from a participant for any of the following reasons: 
• Report of use of prohibited concomitant medications as described in the SSP Manual.  Study 
product use may resume upon consultation with the CMC and when the participant reports that 
she is no longer taking the prohibited medication, provided other reasons for temporary study 
product hold/permanent discontinuation do not apply. The CMC should be consulted in all cases 
where a participant reports taking a prohibited product during the course of the study.   
• The participant is unable or unwilling to comply with required study procedures such as HIV 
testing and routine laboratory assessments, or otherwise might be put at undue risk to their safety 
and well-being by continuing study product use, according to the judgment of the IoR. The IoR 
must consult the CMC on all temporary study product holds instituted for this reason for further 
guidance on resuming study product use, continuing the temporary hold, or progressing to 
permanent discontinuation.   

 
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• The participant has one or more reactive HIV test results, or expresses a concern about having 
acute HIV infection. Criteria for resuming use of study product in these circumstances are 
defined in the protocol and SSP Manual. 
• During Step 2, if a participant becomes pregnant or declines to continue using long-acting 
contraception, and subsequently changes her mind she may continue in the study on blinded 
study product once she has documentation of a negative pregnancy test and of resuming long 
acting contraception; she must also meet all other standard visit criteria. 
Step 1 
Participants who temporarily or permanently discontinue study product during the Step 1, Oral 
Run-in Phase, will be instructed to return all study products as soon as possible.  Regardless of 
randomization, all of these participants will be followed until the study end of Step 3 for annual 
HIV testing. 
Step 2 
Participants who have received at least one injection and refuse further injections or discontinue 
due to an AE will be managed as follows: 
• Participants will be transitioned to open-label TDF/FTC no later than eight weeks 
after the last injection. 
• Participants will be followed on TDF/FTC according to the SOE for 48 weeks after 
beginning TDF/FTC, and then followed for annual HIV testing until the end of Step 
3.  
Step 3 
Participants in Step 3 who refuse further TDF/FTC or discontinue due to an AE will be managed 
on a per participant basis and in accordance with CMC guidance until the end of the participant’s 
Step 3 schedule.  Participants will be instructed to return all remaining study product as soon as 
possible. 
 
 
 

 
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Guidance on Toxicity Management for Specified Toxicities: 
 
Nausea, Vomiting, and Diarrhea 
CONDITION AND 
SEVERITY 
IMMEDIATE 
ACTION 
FOLLOW-UP AND MANAGEMENT 
Nausea, Vomiting, and Diarrhea 
Grade 1 and 2 
Continue study 
product (reminder to 
take oral study 
product with food) 
Treat symptomatically with hydration, oral 
antiemetic therapies or antiemetic suppositories at 
the discretion of the IoR. The IoR should order any 
clinically relevant laboratory analyses (per 
judgment of the IoR). 
Grade ≥ 3  
Discontinue study 
product temporarily 
Participants with Grade  3 nausea, vomiting, or 
diarrhea, for which an alternative etiology is not 
established, must discontinue the study product 
temporarily until Grade 2 or lower and be treated 
symptomatically. Should condition(s) not improve 
to Grade ≤ 2 within 7 days, the IoR should consult 
the CMC for guidance on continuing the temporary 
discontinuation or progressing to permanent 
discontinuation of study product. 
 

 
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Guidance on Toxicity Management for Specified Toxicities: 
ALT 
Note for all Grades:  
All study participants will be negative for HBsAg at study entry, and participants who enter the 
study without evidence of immunity to HBV will be provided HBV vaccination. Therefore, pre-
existing HBV infection is not likely to be a cause of AST/ALT elevations. 
Careful assessments should be done to rule out the use of alcohol, lactic acidosis syndrome, non-
study medication-related product toxicity, herbal medications/supplements, or infectious 
hepatitis as the cause of elevation in AST or ALT of any Grade. The participant must be 
carefully assessed for any symptoms or signs of hepatotoxicity, including fatigue, malaise, 
anorexia and nausea, jaundice, acholic stools, right upper quadrant pain, or hepatomegaly. If the 
AST/ALT elevation is considered most likely to be due to concomitant illness or medication, 
standard management, including discontinuation of the likely causative agent, if possible, should 
be undertaken. If symptoms or signs of clinical hepatitis are present, study product must be held 
or discontinued. In addition, all participants with elevated values should be considered for testing 
for hepatitis A, B, and C infection.  Contact the CMC for further guidance on investigation and 
study product administration. 
Note the following for cases of exercise-induced CPK abnormalities:   
Note the following for cases of exercise-induced CPK abnormalities: Cases of CPK abnormality 
> Grade 3 or higher, presumed to be exercise induced, accompanied by < Grade 3 ALT must be 
brought to the attention of the CMC for adjudication of further management and further 
administration of study product. Grades 3 and 4 elevations in ALT, regardless of CK elevation 
will prompt permanent discontinuation of study product and the participant will be followed 
annually for HIV testing only until the conclusion of Step 2 of the study. All such cases must be 
reported to the CMC.   
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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Guidance on Toxicity Management for Specified Toxicities: 
 
CONDITION AND 
SEVERITY 
FOLLOW-UP AND MANAGEMENT 
ELEVATIONS in ALT  
Grade 2 and higher 
Oral phase: A Grade 2 ALT abnormality reported at Week 2 or Week 4, 
regardless of relatedness to the study product, should be confirmed within one 
week. Oral study drug may continue until the confirmatory results are 
available; no injections should be administered until confirmatory results are 
available during consideration of the Week 4 ALT value. If the repeat value is 
< Grade 2 at Week 3, study drug may continue to Week 4. If the repeat value is 
< Grade 2 at Week 4, the participant may proceed to Step 2 injection phase. If 
the repeat value is Grade 2 or higher at Week 4, study product should be 
stopped, and the participant will be followed annually for HIV testing only. All 
such cases must be reported to the CMC. In addition, participants will be 
followed with weekly ALT assessments until they return to < Grade 1.   
A Grade 3 or higher ALT abnormality reported at Week 2 or Week 4, 
regardless of relatedness to the study product, will result in study product 
discontinuation and will prohibit a participant from entering the injection phase 
of the study, and the participant will be followed annually for HIV testing only 
until the conclusion of Step 2 of the study. All such cases must be reported to 
the CMC. In addition, participants will be followed with weekly ALT 
assessments until they return to < Grade 1.   
A Grade 3 ALT will lead to permanent study product discontinuation, and the 
participant will be followed annually for HIV testing only until the conclusion 
of Step 2 of the study. AEs will be followed until resolution (< Grade 1) in 
consultation with the CMC. 
Grade 2 and higher 
Injection phase: The CMC should be notified as soon as possible. For a 
Grade 2 ALT, the CMC will determine whether further injections may be given 
in cases where levels are ≤ Grade 2 prior to the next scheduled injection. 
Unless otherwise specified by the CMC, for Grade 2 ALT, repeat testing 
should be performed weekly until levels are ≤ Grade 1.  For Grade 3 and higher 
ALT, study product will be permanently discontinued.* For Grade 3 and 4 
ALT, repeat testing should be performed as soon as possible, and participants 
should be followed weekly until levels are ≤ Grade 1. Participants who are 
permanently discontinued from study product should continue to be followed 
on study/off study product, following the Step 3 Schedule of Evaluations. 

 
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Guidance on Toxicity Management for Specified Toxicities: 
 
Creatinine Clearance 
NOTE:  Adverse events related to creatinine clearance should be based on examination of BOTH 
the absolute creatinine clearance AND the change in creatinine clearance from baseline 
(Enrollment/ Visit 2.0). When gradable, only the higher grade of these two assessments should 
be entered on the Adverse Event e-CRF. Clinical Management of Grade 3 and Grade 4 changes 
in creatinine clearance should follow the “Toxicity Management General Guidance” ONLY 
when the absolute creatinine clearance is < 90 mL/min. That is, changes in creatinine clearance 
of >30% from baseline that DO NOT result in an absolute creatinine clearance < 90 mL/min do 
NOT need to be reported to the CMC or more frequent clinical monitoring. 
CONDITION AND 
SEVERITY 
IMMEDIATE 
ACTION 
FOLLOW-UP AND MANAGEMENT 
CREATININE CLEARANCE 
Estimated CrCl< 60 mL/min 
Discontinue study 
product temporarily 
If the calculated creatinine clearance is 
<60mL/min, it should be confirmed within 1 week 
of the receipt of the results, and the CMC should 
be consulted for adjudication and recommendation 
for further testing and follow-up.   
Confirmed CrCl< 60 mL/min  
Permanently 
discontinue study 
product  
If the calculated creatinine clearance is confirmed 
to be <60 mL/min, the CMC must be notified and 
the study product must be discontinued.  
Participants who fail to have a confirmed test 
within 2 weeks of receiving the initial result, 
should be discontinued from use of the study 
product until CMC adjudication and 
recommendation for further testing and follow-up. 
Re-testing result is             
≥60 mL/min 
Consult CMC for 
guidance 
If re-testing yields a result ≥ 60 mL/min, the IoR 
must consult the CMC for further guidance on 
resuming study product use, continuing the hold 
temporarily, or progressing to permanent 
discontinuation. 
If the IoR in consultation with the CMC has 
determined that the case has stabilized, it may be 
possible to decrease the frequency of follow-up 
laboratory testing in addition to resumption of 
study product.  
 

 
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Guidance on Toxicity Management for Specified Toxicities: 
 
Creatine Phosphokinase (CPK) 
Note the following for cases of exercise-induced CPK abnormalities:   
Note the following for cases of exercise-induced CPK abnormalities: Cases of CPK abnormality > 
Grade 3 or higher, presumed to be exercise induced, accompanied by < Grade 3 ALT must be brought to 
the attention of the CMC for adjudication of further management and further administration of study 
product. Grades 3 and 4 elevations in ALT, regardless of CK elevation will prompt permanent 
discontinuation of study product and the participant will be followed annually for HIV testing only until 
the conclusion of Step 2 of the study. All such cases must be reported to the CMC.   
CONDITION AND 
SEVERITY 
IMMEDIATE ACTION 
FOLLOW-UP AND MANAGEMENT 
Creatine Phosphokinase 
Grade 3  
Continue study product until 
repeat test results are 
available 
A Grade 3 or higher elevation in CPK should 
result in a repeat assessment within 2-4 
weeks to ensure the result is transient or due 
to exercise and will not require a change in 
study treatment. A history regarding use of 
products known to cause increase of CPK 
(such as statins) physical activity or exercise 
preceding the CPK evaluation should be 
obtained.  
Grade 4 
Continue study product until 
repeat test results are 
available if the elevation is 
thought to be possibly or 
probably related to study 
product. 
Grade 4 elevations in CPK should have a 
repeat assessment after the subject has 
abstained from exercise for >24 hours. For 
persistent Grade 4 CPK elevations that are 
considered possibly or probably related to the 
study product, study product should be 
discontinued and the participant should be 
followed on study/off study product.   

 
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Guidance on Toxicity Management for Specified Toxicities: 
Guidance for Injection Site Reactions (ISRs) 
The CMC must be informed of all Grade 3 or 4 ISRs to determine etiology and assess 
appropriate continued study participation. ISR discomfort can be managed symptomatically (e.g. 
cold/warm compress, acetaminophen, ibuprofen) if the reaction is interfering with the 
participant’s ability to perform activities of daily living.  
 
Guidance for Allergic Reactions 
Participants may continue to receive oral or injectable study product for Grade 1 or 2 allergic 
reactions at the discretion of the IoR or designee. The participant should be advised to contact 
the study site staff immediately if there is any worsening of symptoms or if further systemic 
signs or symptoms develop. Antihistamines, topical corticosteroids, or antipruritic agents may be 
prescribed.  
Participants with Grade ≥3 allergic reactions that are considered to be related to study product 
should permanently discontinue study product and continue to be followed on study/off study 
product. Participants should be treated as clinically appropriate and followed until resolution of 
the AE. 
 
 
 

 
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Appendix IV: Sample Screening and Enrollment Informed Consent Form 
HPTN 084: 
A Phase 3 Double Blind Safety and Efficacy Study of Long-Acting Injectable Cabotegravir 
Compared to Daily Oral TDF/FTC for Pre-Exposure Prophylaxis in HIV-Uninfected Women 
 
FINAL Version 
Protocol Version 3.0, dated 12August2021 
DAIDS Document ID: 38070 
 
 
Sponsored by: Division of AIDS, United States (US) National Institute of Allergy and Infectious 
Disease, US National Institutes of Health.   
 
Study products are provided by ViiV Healthcare and Gilead Sciences, Inc. Additional support is 
provided by the Bill & Melinda Gates Foundation (BMGF). 
 
PRINCIPAL INVESTIGATOR: [Insert Name] 
PHONE:  [Insert Number] 
GENERAL OVERVIEW 
You are being invited to take part in an investigational research study related to the Human 
Immunodeficiency Virus (HIV) because you live in a part of the world where women have a high risk of 
becoming infected with the virus.  The HIV virus causes Acquired Immunodeficiency Syndrome 
(AIDS).  As many as five to ten women out of 100 in SSA are newly infected with HIV each year. This 
study will be offered to about 3,350 other women who live in SSA, are HIV-uninfected, and have sex 
with men.  
 
Before you decide whether to join the study, we will explain the purpose of the study, the risks and 
benefits, and what is expected of you.  This form includes all of that information in the later pages. 
A description of this study will be available on www.ClinicalTrials.gov, as required by US 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. 
Before you learn more about the study, it is important that you know the following: 
• Your participation is voluntary. You do not have to participate in the study. 
• If you join the study and later on want to stop participating, you may leave the study at any time. 
You will continue to receive the same services that you would normally get here at [insert clinic 
name].   
• If you decide not to take part in this study, you can join another study at a later time if one is 
available and you qualify for it. 

 
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• You cannot join this study if you are taking part in another study of drugs, HIV vaccines,  or 
medical devices. You are asked to tell the study staff about any other studies you are taking part 
in or thinking of taking part in. This is very important for your safety.   
So that you can make an informed decision about participating in this study, we will explain all of the 
possible risks and benefits of this study. It is important that you understand there may be no direct 
benefit to participating in this study and there may be some risks associated with taking part in the study.  
The information included in this form will be discussed with you and you may ask as many questions as 
you wish after you review it.  
Once you understand the study, and if you decide to take part, you will be asked to sign your name or 
make your mark on this form. You will be offered a copy of this form to keep.  
BACKGROUND AND PURPOSE OF THE STUDY 
Women in SSA are at high risk for HIV, and new methods of HIV prevention are needed. Current HIV 
prevention methods for women include condoms or pre-exposure prohylaxis (PrEP). Taking medication 
to prevent becoming HIV-infected is called “PrEP.” 
The main purpose of this study is to find out if a new drug called cabotegravir (CAB), an antiretroviral 
used as PrEP, will protect women from getting HIV. CAB comes in the form of a pill and also as an 
injection (shot). CAB has shown to be effective in treating HIV, but researchers do not yet know if CAB 
protects people from getting HIV.  Neither CAB pills nor CAB injections are approved by the US FDA 
for the treatment and prevention of HIV infection. CAB pills and CAB injections are considered 
investigational drugs. In this study, we want to find out whether the injection form of CAB, which is 
active for a longer time in the body than the pill form, can protect people from HIV. 
In this study, CAB injections (the long acting form of CAB) are given as one injection in the buttocks.  
The first two doses are given four weeks apart.  After these first two doses, an injection will be given 
every eight weeks.  Over the course of the study, and depending on what point in time you join the 
study, you could receive up to 24 injections.  The injections are NOT HIV vaccinations.  
CAB pills are also used in the study.  CAB pills are taken every day for five weeks to make sure that no 
one has a bad reaction to CAB before getting an injection.  The injection form of CAB (the long acting 
form) is active in the body for weeks.  It is important to take the CAB pills because once an injection of 
the long acting CAB is given, the drug takes a long time to leave the body.   
 
Researchers want to study the long acting, injection form of CAB, as an alternative method of HIV 
prevention.  Right now, there is a pill approved by the US Food and Drug Administration (FDA), the 
South African Health Products Regulatory Authority (SAHPRA), [or country-specific regulatory 
agency], and recommended by the World Health Organization that can be taken daily by people who do 
not have HIV but are at risk to become infected.  [Non-US sites to fill in the current status of approval 
for TDF/FTC here.]  That pill contains two drugs called “TDF” and “FTC.”  For the TDF/FTC pill to 
work best at preventing HIV infection, it must be taken every day.  When taken every day, TDF/FTC 
can be more than 90% protective against HIV infection.  However, some people have a hard time 
remembering to take a daily pill, so it is a good idea to have another HIV prevention option.  If the CAB 
injections work, people could get injections every eight weeks and would not have to remember to take a 
pill every day. 

 
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This research study will evaluate the safety of oral CAB followed by injectable CAB versus daily oral 
TDF/FTC.  It will also see which drug works better to prevent HIV. 
 
STUDY GROUPS 
If you decide to be in this study, you will be placed into one of two groups, either Group A or Group B.  
Each group will have about 1,600 women in it.  The study group that you will be in will be chosen 
randomly, like flipping a coin.  You cannot choose your group, and the study staff cannot choose your 
group for you. You have an equal chance of being placed in Group A or in Group B.  Both groups are 
very important to the study. You will not be told which group you are in and study clinic staff will not 
know which group you are in either. 
 
We do not want you or the study researchers to know which group you are in, because we want to know 
which drug works better to protect you from getting HIV. By not knowing, then we do not favor one 
group over the other.   
 
Each person in each group will get injections and a daily pill.  The pill must be taken every day to 
protect against HIV.  Injections are given as one shot in the buttock. The shot is given over time like 
this: you get one shot, then a month later you get another shot, and then after that you get a shot every 
two months.  
 
There are two types of study pills used.  One pill will be the active (“real”) product.  The other type of 
pill is called a “placebo” (“dummy”) pill that will look and feel like the real product, but it will not 
contain any of the “active” (“real”) drug or any other medicines.   
 
There are also two types of injections used in the study.  One injection will be the “active” (“real”) 
product. The other type of injection is called a “placebo” (“dummy”) that will look and feel like the real 
product, but it will not contain any of the active (“real”) drug or any other medicines.   
 
In order to keep the groups secret, women in both groups will get the same number of pills and the same 
number of injections. One study group will get the real CAB drug in a pill and CAB injections plus 
“placebo” TDF/FTC pills, and the second group will get the real TDF/FTC pills and “placebo” CAB 
pills and CAB injections. The placebo for the CAB injection is a nutrition injection called Intralipid.  
 
Both groups will move through three steps (stages) in the study.  The steps look like this [sites may show 
a graphic to depict the groups and the steps]:   
• Group A: This group gets CAB pills and CAB injections plus TDF/FTC placebo pills. 
o Step 1: CAB pill plus a TDF/FTC placebo pill every day for five weeks  
o Step 2: CAB injections given as a shot, then another shot a month later, and then every 2 
months after that up to three and half years plus a TDF/FTC placebo pill every day 
o Step 3: TDF/FTC pill every day for about a year, then move to local HIV prevention 
services  
 

 
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• Group B: This group gets TDF/FTC pills plus placebo CAB pills and placebo CAB injections.   
o Step 1: TDF/FTC pill plus placebo CAB pill every day for five weeks  
o Step 2: TDF/FTC pill everyday plus placebo CAB injections up to three and a half years 
o Step 3: TDF/FTC pill every day for about a year, then move to local HIV prevention 
services. 
If you decide to join the study, at the most, your participation could last up to 4.5 years and include a 
maximum of 36 study visits at this clinic.  Most of those visits would happen about every two months.  
We do not know exactly how long you will participate because we do not how long the study will 
continue after you join it.  Some women will join early in the study and others may join as long as two 
years after the first women join.  As the study goes on, we will keep you updated you on how long your 
participation will be. 
No matter what group you are in, neither daily TDF/FTC nor CAB will protect you from getting 
sexually transmitted infections, like gonorrhea, chlamydia, syphilis, warts, or herpes.  Neither TDF/FTC 
nor CAB will prevent pregnancy. One of the best things you can do to protect yourself from getting 
HIV or other sexually transmitted infections during sex is to use a condom every time you have 
sex. 
STUDY PROCEDURES 
Screening Visit Activities 
Your screening visit may occur after you read, discuss, understand, and sign this form. We will help you 
understand the form and answer all of your questions before you sign it. The procedures done for the 
screening visit will take about [site to fill in time required], and may be done at one or more visits.   
During the screening visit, the study staff will:  
• Ask you where you live and other questions about you, your medical health, your sexual 
practices, including if you are at a higher risk of getting HIV, and whether you use alcohol or 
drugs. 
• Give you a brief physical exam to make sure you are healthy. 
• Talk with you about HIV and ways to protect yourself from getting it and offer condoms. 
• Collect ~XX mL (about x teaspoons) of blood for HIV testing, hepatitis B and C testing, to 
check your general health, to check the health of your liver, and for storage for study-related 
testing. 
• Test you for pregancy [site insert sample type, blood vs. urine] and talk to you about your plans 
in the next years for becoming pregnant as well as available forms of long acting contraception. 
We will require proof of contraception if you have received it elsewhere. 
 
The results of the HIV test will be available [site to insert timeframe of RNA testing, and also EIA 
testing if being used]. You will be contacted about the results of your other tests when they are available. 

 
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Step 1 Visit Activities 
Step 1:  Enrollment Visit (Week 0) Activities 
If you are eligible for this study and decide to take part in it, you will be asked to return for the 
enrollment visit within a specific window of time after the screening visit (usually within two weeks). 
This visit will last about xx hours, [sites to add appropriate timeframe]. During the visit, the study staff 
will: 
• Confirm where you live and how to contact you. 
• Ask you some questions about yourself, like your age, and your racial/ethnic group [sites that 
want to collect this during screening should move this to screening section.] 
• Talk with you about HIV and ways to protect yourself from getting it. 
• Give you a complete physical exam, to include measuring your height, weight, temperature, 
blood pressure, ask you about any other medicines you are taking, and whether you use alcohol 
or drugs.   
• Collect a urine sample to see if there is sugar or protein in your urine. This sample may also be 
used to test for pregnancy or for sexually transmitted infections. 
• Collect ~XX mL (about x teaspoons) of blood for:  HIV testing, hepatitis B testing, hepatitis C, 
and syphilis testing, to check how much cholesterol is in your blood (a fatty substance in your 
blood), to check your general health, to check the health of your liver, and for storage for study-
related testing and long-term storage (if you provide consent) [Sites to delete if long term storage 
is not allowed]. [Sites to add this if allowed at your site. If not, delete:  Additionally, if you 
provide consent, we will use a sample of your blood to see how the HIV drugs work in your body 
by looking at your genes. Information about the testing related to your genes is found later in 
this consent form.] For the cholesterol test, you will be instructed to not eat or drink anything 
other than what the study staff tell you is acceptable for 8-12 hours before your blood is drawn. 
• Test you for pregancy [site insert sample type, blood vs. urine]. This testing may be done using a 
blood or urine sample. 
• Talk with you about long term contraception.  If you are not currently utilizing implants, 
injections or intrauterine devices we will offer them to you in the clinic or refer you for services. 
We will require proof of contraception if you have received it elsewhere. If you are receiving a 
long-acting injectable contraceptive, we will also require proof that you received your most 
recent dose. 
• Ask you questions about your sexual behavior. 
• Ask you questions about your opinions about taking pills and getting injections. 
• Test a vaginal swab to test for sexually transmitted infections; urine may also be used for some 
of this testing.  
• Randomize you into one of the two study groups.  
• Give you your study pills, explain how to take them, watch you take one, and explain any side 
effects they may cause.   
• Have a discussion about any challenges of taking a pill every day.  

 
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• Give you the results of tests when they are available. 
• Offer you condoms. 
Step 1:  Weeks 2 and 4 Visit Activities 
These visits will last about XX minutes.  During these visits, the study staff will: 
• Confirm where you live and how to contact you. 
• Talk with you about HIV and ways to protect yourself from getting it.  
• Site staff will count your study pills, watch you take one, and talk with you about ways to help 
you remember to take your pills. If it seems to you or to the study staff that you are having 
challenges, we will try to help by working through these with you. 
• Give you a brief physical exam, ask you if you have experienced any side effects from the study 
drugs, and ask you about any other medicines you are taking. 
• Collect ~XX mL (about x teaspoons) of blood for HIV testing, to check your general health, the 
health of your kidneys, the amount of the study drug that is in your blood, and for storage.  Blood 
will also be used to test liver health at Week 4. 
• At Week 2 but not Week 4, you will be given the hepatitis B vaccination if testing shows you are 
not already immune (first vaccination at Week 2, and then boosters at approximately Weeks 6 
and 33). 
• Test you for pregnancy [site insert sample type, blood vs. urine]. 
• Talk with you about long term contraception.  If you are not currently utilizing implants, 
injections or intrauterine devices we will offer them to you in the clinic or refer you for services. 
We will require proof of contraception if you have received it elsewhere. If you are receiving a 
long-acting injectable contraceptive, we will also require proof that you received your most 
recent dose. 
• Give you the results of your blood tests when they are available. 
• Offer you condoms. 
 
Step 2 Visit Activities 
Step 2:  Visit Activities 
In this step of the study, there may as many as 24 visits during which participants will receive injections 
and pills. The number of these visits in Step 2 is dependent on when you join the study.   
In Step 2 of the study, everybody will also attend 4 safety visits that will take place at Weeks 6, 13, 21 
and 42. 
At all Step 2 visits, the following activities will occur: 
• Confirm where you live and how to contact you. 
• Talk with you about HIV and ways to protect yourself from getting it. 

 
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• Give you a brief physical exam. Ask you if you have experienced any side effects from the study 
drugs (either the pills or shots). Everyone will be asked about any other medicines they are 
taking, and whether they use alcohol or drugs. 
• Collect ~XX mL (about x teaspoons) of blood for HIV testing, the amount of the study drug that 
is in your blood, and for storage. 
• Test you for pregnancy [site insert sample type, blood vs. urine]. 
• Talk with you about long term contraception.  If you are not currently utilizing implants, 
injections or intrauterine devices we will offer them to you in the clinic or refer you for services. 
We will require proof of contraception if you have received it elsewhere. If you are receiving a 
long-acting injectable contraceptive, we will also require proof that you received your most 
recent dose.  
• Give you the results of your blood tests when they are available. 
• Offer you condoms. 
 
Step: 2: Week 5 Visit Activities 
This visit will last up X hours.  During this visit, in addition to the activities described above for all Step 
2 visits, the study staff will: 
• Ask you to answer questions about your sexual behavior. 
• Staff will give you more pills. Staff will also count your leftover pills and talk with you 
about ways to help you take your pills. If it seems to you or to the study staff that you are 
having challenges, we will try to help by working through these with you.   
• The first shot will be given in your buttock.  
 
Step 2:  CAB LA Injection or TDF/FTC Dispensing Visit Activities 
These visits will take place at Weeks 9, 17, 25, 33, 41, 49, 57, 65, 73, 81, 89, 97, 105, 113, 121, 129, 
137, 145, 153, 161, 169, 177, 185.  [Note:  Sites may remove Week numbers in the text if easier to depict 
it in a table or refer to the Schedule of Procedures and Evaluations].  
These visits will last up to XX hours. During these visits, in addition to the activities described above for 
all Step 2 visits, the study staff will: 
• Collect ~XX mL (about x teaspoons) of blood for:   
o Hepatitis C testing about every year (Weeks 57, 105 and 153 only) 
o Syphilis testing about every 6 months throughout Step 2 (Weeks 33, 57, 81, 105, 129, 
153 and 177 only) 
o Testing to see how much cholesterol is in your blood two times during the study, one 
year apart (Weeks 57 and 105 only). For the cholesterol test, you will be instructed to not 
eat or drink anything other than what the study staff tell you is acceptable for 8-12 hours 
before your blood is drawn.    

 
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• Collect a urine sample to see if there is sugar or protein in your urine about every year for 3 years 
(Weeks 57, 105, and 153 only). 
• Ask you to answer questions about your sexual behavior at every visit for about 2 years, and then 
every other visit for the rest of Step 2 (Weeks 9, 17, 25, 33, 41, 49, 57, 65, 73, 81, 89, 97, 105, 
121, 137, 153, 169, 185 only) 
• Staff will give you more pills. Staff will also count your leftover pills and talk with you about 
ways to help you take your pills. If it seems to you or to the study staff that you are having 
challenges, we will try to help by working through these with you.  
 
• A shot will be given in your buttock. Shots will be given approximately every 2 months (8 
weeks) after the first two are given.   
• Ask you questions about how you feel about taking pills and getting injections about every 6 
months for two years and then once more a year later (Weeks 17, 41, 65, 89, 137 and 185). 
• Test a vaginal swab for sexually transmitted infections about every 6 months throughout Step 2 
(Weeks 33, 57, 81, 105, 129, 153 and 177 only). 
• Talk with you about long term contraception.  If you are not currently utilizing implants, 
injections or intrauterine devices we will offer them to you in the clinic or refer you for services. 
We will require proof of contraception if you have received it elsewhere. If you are receiving a 
long-acting injectable contraceptive, we will also require proof that you received your most 
recent dose. 
 
Step 2:  Weeks 6, 13, 21 and 42 Safety Visit Activities 
In this step of the study, there will be 4 safety visits following each injection visit. The visits will take 
place at Weeks  6, 13, 21 and 42.[Note:  Sites may remove Week numbers in the text if easier to depict it 
in a table or refer to the Schedule of Procedures and Evaluations].   
These visits will last up to XX hours. During these visits, the study staff will: 
• count your pills and talk with you about ways to help you take your pills. If it seems to 
you or to the study staff that you are having challenges, we will try to help by working 
through these with you. 
• Talk  with you about long term contraception.  If you are not currently utilizing implants, 
injections or intrauterine devices we will offer them to you in the clinic or refer you for 
services. We will require proof of contraception if you have received it elsewhere.  
If you are receiving a long-acting injectable contraceptive, we will also require proof that 
you received your most recent dose.  
 
Step 3 Visit Activities 
Step 3:  Follow-up Visits 
Step 3 includes 5 visits over about a year (Step 3: Day 0, Weeks 12, 24, 36, and 48).   Each visit will last 
up to XX hours.  During these visits, the study staff will: 
• Confirm where you live and how to contact you. 

 
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• Talk with you about HIV and ways to protect yourself from getting it. 
• Give you a brief physical exam and ask you about any other medicines you are taking.  
• Collect ~XX mL (about x teaspoons) of blood for HIV testing, syphilis testing, to check your 
general health, the health of your liver, the amount of the study drug in your blood, and for 
storage. 
• Test you for pregnancy [site insert sample type, blood vs. urine]. 
• Talk with you about long term contraception.  If you are not currently utilizing implants, 
injections or intrauterine devices we will offer them to you in the clinic or refer you for services. 
We will require proof of contraception if you have received it elsewhere. If you are receiving a 
long-acting injectable contraceptive, we will also require proof that you received your most 
recent dose.  
• Test a vaginal swab for sexually transmitted infections (Day 0, Week 24 and 48 only). If you 
have had these tests within 3 months of joining this part of the study, you will only have this 
done at Week 24 and Week 48 only; urine may also be used for some of this testing. 
• You will be given TDF/FTC pills. Staff will count your leftover pills and talk with you about 
ways to help you take your pills. If it seems to you or to the study staff that you are having 
challenges, we will try to help by working through these with you.  (Day 0, Weeks 12, 24, and 36 
only). 
• Ask you to answer questions about your sexual behavior (Day 0, Week 12, 24 and 48 only). 
• Ask you questions about what it was like getting the injections and taking the study pills (this 
will only be asked if you have not been asked this in the few months before you started this step).   
• Offer you condoms. 
While you are attending study visits, sitting in the waiting room or attending events with other 
participants, staff members may take notes on what is said about using the study pills, injections or 
taking part in this study. We are doing this to help us learn more about women’s experiences with taking 
study medication. We will not record your name or participant ID on these notes. 
 
After these visits are over, we will help you seek additional HIV prevention care [sites to add 
information here or elsewhere in the consent form].   
[This text is only relevant for sites which will do the Contraceptive Sub-study: 
Injectable Contraceptive Sub-Study  
A subset of approximately 180 participants will be invited to join the Contraceptive Sub-Study.  The 
sub-study will help researchers find out if CAB LA has any impact on implant (etonogestrel) and 
injectable contraceptives (NET- EN and DMPA).  No additional study visits are required.  However, 
there is an additional blood draw at four of the study visits: Enrollment visit and then at Weeks 25, 49 
and 73.] 
 
[This text is only relevant for the four sites which will do the Qualitative Sub-study: 
Qualitative Sub-Study  

 
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At a subset of approximately four sites, a qualitative sub-study will be done. This sub-study will help us 
understand how the women in the study feel about the injectable product and other HIV prevention 
methods. We will collect their opinions during interviews.   We will also observe the waiting room for 
up to an hour at about four different times each year. Each time the waiting room is observed notes will 
be taken about topics of discussion and any information participants wish to share.  No identifying 
information (such as a woman’s name or birthdate) will be written down about the participants observed.  
 
Women who are invited to participate in the qualitative sub-study will also need to sign a separate 
consent form that fully explains the sub-study.]  
 
Procedures if you become infected with HIV during the study 
During the study, if you have a positive HIV test result the site will have you come back for an 
additional visit (s).  The site will also need to draw some more blood from you.  The additional blood 
will be used for further testing to confirm whether you have become infected with HIV. 
 
• If you get HIV during Step 1 of the study, you will stop taking any study pills and you will be 
referred for local care and treatment of HIV and will be discontinued from the study.  
• If you get HIV during Step 2 of the study, you will stop taking any study drug and you will be 
referred for local care and treatment of HIV. You will stop receiving the injections and stop 
taking study pills. 
We will ask you to come back for a visit every 3 months for about a year. During these visits we 
will take xx amount of blood [sites to fill in] to check your immune system, the amount of HIV 
in your blood, the health of your blood and liver, and for storage. We also will give you a brief 
physical exam during these visits, and ask you about any other medications that you are taking. 
We will also update your contact information and offer you with condoms. 
• If you get HIV during Step 3 of the study, you will stop taking the TDF/FTC.  People in both 
groups will be referred for local care and treatment of HIV.  We may ask you to come in for 
additional visits to check on your health.         
Testing will be done to see if your HIV is resistant to any drugs that are used to treat HIV infection. This 
testing will help select the best drugs to treat your HIV infection. 
Permanently Stopping Your Study Product 
There may be certain situations that occur where you will no longer get the study drugs while in the 
study.  For example, you may decide you do not want to take study drug any more, you may get HIV, or 
we may find out the drugs are no longer safe for you to take. We may ask you to continue to come to the 
study visits even if you no taking pills or getting shots. Depending on the reason that study product is 
stopped, you may be asked to come to the site at least once a year for HIV testing until the study ends. 
We will fully explain to you what will be expected if you permanently stop taking the study drugs.   
 
USE OF STUDY SAMPLES 

 
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In addition to the laboratory tests performed at each study visit, further study-related testing may be 
performed on samples. This will include testing related to HIV and other infections, including testing for 
the drugs used in this study and other anti-HIV medications. If you get infected with HIV or hepatitis B 
or C during the study, some the stored blood may also be used to study the HIV and hepatitis virus, and 
the body’s response to these infections. The samples used for this testing will be labeled with your study 
number and will be tested at special laboratory facilities that may be located in the US and other 
countries outside of [insert site country]. Results of this specialized testing will not be returned to the 
study site or you. 
POSSIBLE FUTURE TESTS  [Sites may require a separate consent form for this] 
If you agree, your stored samples may also be used for future research related to HIV infection, hepatitis 
infection, and other infections, and to better understand laboratory tests related to this study. [For sites 
that opt in for pharmacogenomics testing:] If you agree, your stored samples may also be used to study 
genes related to HIV infection and use of anti-HIV medications to prevent HIV infection. This testing is 
described in more detail below. You can agree to have your samples used for future research, even if 
you do not agree to have your samples used to study genes. 
The stored samples will be labeled with your study number and will be tested at special laboratory 
facilities that may be located in the US and other countries outside of [insert site country]. Only 
approved researchers will have access to them. Results from this testing will not be returned to the study 
site or you. You will be asked to sign at the end of this consent form to give permission to use your 
stored samples for future research. Even if you do not give permission to store your blood for possible 
future research, you can still be in this study. You may also withdraw your consent to use your stored 
samples for future research at any time. We will then destroy your samples after all of the study-related 
testing has been completed. If you agree to have your stored samples used for future research, your left 
over blood will be stored for an indefinite period of time after the study ends.  Results from possible 
future tests will not be given to either the site or to you. 
 
RISKS AND/OR DISCOMFORTS 
Study Medications 
The side effects of CAB include:   
Headaches, diarrhea, and fatigue. With the CAB that you get as an injection, people in other studies 
have said they had pain, irritation, skin redness, bumps, swelling, itching, bruising where they got the 
injection. Other reported side effects include muscle aches, irritated nasal passages, runny nose, sore 
throat, upper respiratory tract infection, difficulty sleeping, abnormal dreams/nightmares, depression, 
increase in the level of enzymes in the muscle (creatine phosphokinase), nausea, vomiting (being sick), 
flatulence (gas or wind), fever and dizziness. There have been some people who were taking this 
medicine who have had liver side effects.  Some of these people were HIV-infected (HIV positive) and 
some, but not all, had damage to their liver before taking the CAB study medication. While taking the 
study medication, their blood tests showed that their liver was irritated, although they felt well. The 
medications were stopped, and the liver blood tests returned to normal. In this study, anyone with HIV-
infection, Hepatitis C (or B), or any liver irritation will not be allowed to be in the study.   
 
Some people who have had a prior history of seizures (epilepsy) have had seizures (spells) while taking 
CAB. One person who did not have a previous history of seizures died after prolonged seizures. If you 
have ever had a seizure you will not be allowed to be in the study. 

 
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The injections you receive in this study are long acting, meaning they can potentially stay in your body 
as long as a year or more, although for most people the drug is processed and eliminated from the body 
within 6 months. If you are in the group that gets the CAB, we will monitor your health for a year after 
your last injection. If you get infected with HIV while on the CAB, it is possible that HIV may be 
resistant to CAB and other HIV drugs that are like it, called integrase inhibitors, may not work to fight 
the virus. For this reason, we will ask you to take an oral PrEP pill daily to reduce your chance of 
becoming infected with HIV. 
If you develop a symptom from these drugs while the drugs are still in your body, every effort will be 
made to treat the side effects. The amount of drug will decrease overtime and will eventually disappear. 
We will update you on any new side effects that we see in this study and other on-going studies, if those 
side effects appear to have come from the drug. If you have questions concerning the additional study 
drug side effects, please ask the medical staff at your site. As stated above, some of these risks are seen 
in HIV-infected people taking these medications. It is not known if these side effects will occur as often 
and it could be that some of these side effects might be more or less serious in HIV-uninfected people. 
The side effects of Intralipid include:   
Side effects of Intralipid when used as an intramuscular injection placebo include headache, anxiety, 
difficulties with sleeping feeling restless or sleepy, stomach upset, extremity pain, upper respiratory 
infection, cough, urinary tract infection, decreased weight, and increased muscle tone. 
 
Side effects of TDF/FTC include:   
Like all other medicines, you may have symptoms or side effects while taking TDF/FTC. These 
symptoms or sides effects may be due to participation in the study or due to illnesses that have no 
relation to the study, like a cold or flu. You should tell the staff at the study clinic about any symptoms 
that you feel while you are participating in the study. You will be given a telephone number so you can 
contact the clinic. You should call them if you/she experience any symptoms.  
 
In TDF/FTC research studies, nausea and diarrhea were the most common side effects, but happened in 
only about 10% or one in ten people. Nausea and diarrhea mainly happened in the first month and then 
went away. A small number (<1% or one in one hundred people) in these PrEP studies showed a slight 
decline in their kidney function, but this stopped when the people stopped taking the drug.  
 
Other side effects, such as changes in bone mineral density (how much calcium and other minerals are in 
your bone which keep them strong) were very rare in people taking the drug who did not have HIV and 
have gotten better when the drug was stopped.  
You could have these side effects or other side effects that we do not know about. Please tell the staff 
here if you have any side effect that bothers you or does not go away.  
Blood Draws 
Taking blood samples may cause some pain, bruise your arm, or make you feel lightheaded.  In rare 
cases you may faint. There is also a slight chance of infection when blood is drawn. You may be 
nervous while you are waiting for your test results, particularly your HIV and sexually transmitted 
infection tests. You will receive counseling before and after these tests to help address your concerns. 

 
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Possible Injection (Shot) Side Effects:  
The shots will be given in the muscles of your buttocks (bottom “cheeks”).  The shot could be given too 
deeply or not deeply enough, missing the muscle and entering your skin, blood, or a nerve.  The risk of 
this is unknown, but may result in higher or lower levels of the injected study medication in your 
system.     
  
Getting shots could also cause some people to feel lightheaded or feel like they might pass out, or 
‘faint’.  People may also ‘see black spots’, sweat, or feel sick to their stomach.  This reaction, called a 
‘vasovagal reaction’, can occur with many medical procedures and usually passes quickly.   
 
Sensitive Questions 
The questions we will ask you about your sexual behavior may make you feel uneasy. However, you do 
not have to answer any question that you do not want to and you can stop answering the questions at any 
time. 
Genetic Testing 
[Sites that are able to conduct this testing should keep this section included; otherwise, this should be 
removed, as well as the signature lines on the signature page] 
We want to look at your genes that affect how your body changes and removes the drug used in this 
study. Gene differences between people can lead to different amounts of drug in the body. This may 
affect how well a drug protects people from HIV infection. If you consent, we will test your blood to get 
information about how your genes may have affected the drug levels in your body. The tests we will use 
to look at your genes are research tests and will be performed in a research laboratory. All of the 
samples will be identified with a coded number. The laboratory doing the testing will not know who you 
are. The results obtained for individual study participants (like you) will not be reported to the study 
sites or back to you. However, the combined results of the testing for all of the study participants will be 
available to the study sites and to the study participants at their request, once the analysis has been 
completed. 
Your genetic information may also be shared for future research purposes and may be stored in a central 
genetic database, but your personal information (like your name or anything else about you) will not be 
shared.     
Social 
There may also be some social risks to participating in this study. You may feel embarrassed or 
uncomfortable with some of the questions you will be asked, some of the procedures that will be done, 
or some of the test results that you will receive. The questions we will ask you about your sexual 
behavior may make you feel uneasy. However, you do not have to answer any question that you do not 
want to and you can stop answering the questions at any time. You may also experience stigma as a 
result of being involved in a study about HIV because people may assume that you are HIV-infected. In 
addition, there may be uncommon or previously unknown risks that might occur. You should report any 
problems to the researchers immediately. 
Confidentiality 

 
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We will make every effort to protect your confidentiality during the study. However, it is possible that 
others may learn that you are part of this study and they may think that you are infected with HIV or are 
at high risk for infection with HIV. Because of this you could have trouble finding or keeping a job.  
You could also have problems with your family, friends and community. 
This study has been reviewed and approved by a local IRB (an Ethics Committee).  The name of your 
local IRB is [  site to insert IRB info here   ].   The IRB is a committee that watches over the safety and 
rights of research participants. 
HIV Infection 
We told you earlier that we do not know if CAB works to protect you from getting HIV.  If you are in 
the group that gets the CAB, you still may be at risk of getting HIV.  We do know that taking TDF/FTC 
every day can be very effective at preventing HIV infection.  If it is not taken every day, you may not be 
well protected.  Neither of these methods prevent pregnancy or sexually transmitted infections. Because 
of these risks, you may still need to use condoms every time you have sex, no matter what group you are 
in.   
Because the study medication is itself being studied to be an HIV treatment medication, if you become 
HIV-infected while taking the study medication, there is a chance that other drugs used to treat HIV 
infection might not work. This is called drug resistance. If you become infected, we will test your HIV 
for resistance to help guide treatment decisions for your HIV infection. 
To reduce the possibility of developing drug resistance, you will be asked to work with your local study 
clinic team to begin HIV treatment after your last study medication injection. The study will not provide 
this treatment but may be able to help you find and/or pay for that treatment. 
PREGNANCY 
To participate in this study, you must agree not to become pregnant.  You must agree to use a reliable 
form of long acting contraception (either injectables, implants or IUD/IUS) during the trial and for 52 
weeks after stopping injections, or for 30 days after stopping oral study product. If you have received 
your contraception at another site which is not this study clinic, we may ask you to provide proof that 
you are on an effective long-acting contraceptive method.  If you wish to be pregnant in the next few 
years, you should not participate in this research study.  
 
We would like you to be cautious about falling pregnant. We do not yet know how CAB LA might 
affect a baby during pregnancy. There are few data from humans on the effects of CAB in pregnancy. 
Most of the information we have comes from animal studies.  In studies done in pregnant rats and their 
newborns, using very high amounts of CAB, there were more baby rats that died when they were born or 
right after they were born.  This did not happen to the baby rats when the mother got lower amounts of 
the drug, or no drug.  The amount of CAB that we are giving in this study is expected to be more than 7-
times lower than the amount given to the pregnant rats.  We do not know whether what happened to the 
baby rats has any impact on what will happen in pregnant humans taking this drug.  That is why if you 
are female and participating in this study, you cannot be pregnant, and we want you to take long acting 
contraception the entire time you are in the study and also for a year after.   
 
We do not know if CAB can cause birth defects in babies.  Birth defects have not been found in any 
animal studies of CAB so far.  We have information from a different study conducted in Botswana with 

 
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dolutegravir (DTG), a medicine that is similar to but not the same as cabotegravir (CAB), the medicine 
being studied in HPTN 084.  In that study, some women living with HIV were taking DTG for treatment 
of HIV infection around the time of conception.  That study, known as the Tsepamo study, collected 
information on 153,899 deliveries at government hospitals throughout Botswana from August 2014 
April 2020 and reported on babies that had birth defects of the spinal cord and brain (neural tube 
defects).  These defects occur early on in the development of the pregnancy.  
 
The latest results show that about 2 out of 1000 infants born to women who used DTG around the time 
of conception had a neural tube defect, compared to 1 in 1000 infants born to women using any non-
DTG regimen. The difference between the two groups is not statistically significant. When this new 
unexpected finding was first reported in May 2018, there were concerns that the rate of nervous system 
defects in babies of mothers using dolutegravir at the start of pregnancy was much higher than for other 
antiretroviral drugs. However, we now know that the difference in the rate of these birth defects between 
the two groups is essentially the same.  
  
Cabotegravir is not the same as dolutegravir, and we still do not know if CAB can cause birth defects in 
babies. We share this information with you so that you can be cautious about becoming pregnant, and so 
that you can decide if you want to participate in the HPTN 084 study.  
 
During the study, you will receive counseling about your options for preventing pregnancy. You can 
receive some forms of contraception from the study clinic or be referred to an appropriate clinic for 
contraception.  
 
• If you change your mind after enrolling in the study and do wish to become pregnant prior to 
Week 5, we will ask you to stop study product and continue with follow up visits only.   
• If you change your mind and desire to become pregnant at any time point after Week 5, we will 
stop giving you injections as we don’t know how CAB LA might impact a baby.  You will be 
started on open-label oral TDF/FTC (“open-label” means you will know you are receiving 
TDF/FTC) and followed at the regularly scheduled study visits until either the end of your 
pregnancy or breastfeeding period.   
 
If you decide to re-start your long-acting contraception and you are still in Step 2, you may be allowed 
to restart your blinded study pills and injections provided all other safety requirements are met.   
 
If you become pregnant during the study, we will refer you for obstetric care.  We will stop giving you 
injections, we will tell you and your doctor which study group you were assigned to and switch you to 
open-label TDF/FTC. We will refer you for an ultrasound and evaluation by an obstetric specialist 
approximately 12 weeks into your pregnancy so that we can examine the health of your unborn baby.  
Ultrasound imaging uses sound waves and allows an inside view of soft tissues and 
body cavities without the use of invasive techniques. There is no evidence that any danger occurs from 
doing an ultrasound during pregnancy.  The study will not pay for the ultrasound.  If the ultrasound 
shows anything unusual we will refer you for further care. 
 
Your study schedule will be reduced and we will only ask you to come to clinic one time every 12 
weeks during your pregnancy and until your baby is 1 year of age or you have stopped breastfeeding. 
During these study visits, we will collect blood and urine samples and at some visits we will also collect 

 
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vaginal swabs. We will perform some, but not all, of the same study lab tests you agreed to.  Although 
you will stop injections, if you were receiving CAB it is likely that the levels of CAB will last in your 
body throughout your pregnancy up until delivery.  If available at this site, you may be offered 
enrollment in a separate study to measures levels of cabotegravir in the babies of mothers who received 
cabotegravir injections. Once your pregnancy has ended and you have completed breastfeeding you may 
resume taking the study product you were allocated to (injection OR pills) and resume your previous 
visit schedule, provided that you agree to use an approved long-acting contraceptive method. If you do 
not wish to use an approved long-acting contraceptive method, then we will ask you to continue taking 
open-label TDF/FTC for up to 48 weeks after your last CAB LA injection and attending quarterly study 
visits. After that we will ask to see you at least once a year for HIV testing until the study has ended. 
 
If you are still pregnant after your last visit, we will ask you or your doctor to provide updates on the 
progress of your pregnancy and its outcome for the first year of the baby’s life. The study doctor will 
make this information available to the study sponsor for safety monitoring follow-up.   
 
BENEFITS 
There may be no direct benefit for you if you participate in the study.  
 
TDF/FTC is known to protect people from getting HIV if taken daily as directed. The recent results from 
the HPTN 083 study comparing CAB to TDF/FTC conducted in men who have sex with men and 
transgender women at 43 sites globally showed that participants given daily TDF/FTC pills had about 
three times the number of HIV infections compared to participants getting long-acting CAB.  CAB has 
not yet been shown to protect against HIV infection in cisgender women, which is the reason we are 
doing this study.  
Neither you nor we will know which real drug you are getting in this study. We will test you for HIV, 
hepatitis B and hepatitis C during this study, and other sexually transmitted infections. We will refer you 
for Hepatitis B vaccination if it is indicated. The counseling you get during this study may help you to 
avoid HIV and other sexually transmitted infections. If you have or become infected with HIV, this 
counseling may help you to learn how to better care for yourself and avoid passing HIV to your sexual 
partners. If you become HIV-infected, or have another sexually transmitted infection, we will refer you 
for care and/or treatment. During the study you will also have other tests to check on the health of your 
blood, and liver. If any health problems are found, you will be referred for care. At every visit you will 
be offered condoms free of charge.   
You or others in your community may benefit from this study later. The information gathered during 
this study may help to prevent the spread of HIV. This may be beneficial to you and your community.   
NEW INFORMATION 
You will be told any new information learned during this study that might affect your willingness to stay 
in the study. For example, if information becomes available that shows that the medication may be 
causing bad effects, you will be told about this. You will also be told when the results of the study may 
be available, and how to learn about them.   
WHY YOU MAY BE WITHDRAWN FROM THE STUDY WITHOUT YOUR CONSENT 
You may be withdrawn from the study without your consent if any of the following occur:  

 
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• You are unable or unwilling to follow all of the study procedures or instructions.   
• You could be harmed by continuing to take the pill or getting an injection. 
• The study is stopped or canceled. 
• The study staff feels that staying in the study would be harmful to you. 
• You are not able to attend clinic visits or complete all of the study procedures. 
• Other reasons, as decided by the study staff.  
ALTERNATIVES TO PARTICIPATION 
It is possible that TDF/FTC is available in your local area as an HIV prevention method.  Because we do 
not know if CAB LA will protect you against HIV, if you prefer to take TDF/FTC instead of joining the 
study where you may receive CAB LA instead, ask the clinic staff to refer you for HIV prevention 
medical services.  
 
[Sites to include/amend the following if applicable: There may be other studies going on here or in the 
community that you may be eligible for. If you wish, we will tell you about other studies that we know 
about. There also may be other places where you can go for HIV counseling and testing. We will tell you 
about those places if you wish.] 
 
COSTS TO YOU 
There will be no cost to you for study related visits, study products, physical examinations, laboratory 
tests, or other procedures specifically related to the study.    
 
REIMBURSEMENT 
You will receive [sites to fill in] for your time, effort, and travel to and from the clinic at each scheduled 
visit.  
CONFIDENTIALITY 
To keep your information private, your samples will be labeled with a code that can only be traced 
back to your study clinic. Your name, where you live, and other personal information will be 
protected by the study clinic. The results of any tests done on these samples will not be included 
in your health records without your permission. Every effort will be made to keep your personal 
information confidential, but we cannot guarantee absolute confidentiality. Your personal information 
may be disclosed if required by law. 
Efforts will be made to keep your study records and test results confidential to the extent permitted by 
law.  However, we cannot guarantee absolute confidentiality. You will be identified by a code, and 
personal information from your records will not be released without your written permission. Any 
publication of this study will not use your name or identify you personally. However, your 
records may be reviewed, under guidelines of the United States Federal Privacy Act, by the United 
States Food and Drug Administration (FDA); the sponsor of the study (United States National Institutes 
of Health [NIH]), other U.S., local, and international regulatory entities may also review study records, 
as well as the [insert name of site] Institutional Review Board (IRB), Ethic Committee (EC) study staff, 

 
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study monitors, the companies that make the drugs used in this study, and (insert applicable local 
authorities]. 
The study staff will also use your personal information, if needed, to verify that you are not taking part 
in any other research studies. This includes other studies conducted by [site name] and studies conducted 
by other researchers that study staff know about.  
Your records may be reviewed by: 
 
• US FDA 
• US NIH 
• US Department of Heath and Human Services (DHHS), Office of Human Research Protection 
(OHRP) 
• other U.S., local, and international regulatory entities 
• [insert names of applicable IRBs/ECs/other local eview bodies as applicable] 
• Study staff 
• Study monitors 
• Companies that makes the study drug (ViiV Healthcare and Gilead Sciences, Inc.) 
[Sites to include/amend the following if applicable:] [Local/state/national] regulations require study 
staff to report the names of people who test positive for [HIV and other infections] passed during sex to 
the [local health authority]. Outreach workers from the [health authority] may then contact you about 
informing your partners, since they also should be tested. If you do not want to inform your partners 
yourself, the outreach workers will contact them, according to the confidentiality guidelines of the 
[health authority]. 
RESEARCH-RELATED INJURY 
[Sites to specify institutional policy:] It is unlikely that you will be injured as a result of study 
participation. If you are injured, the [institution] will give you immediate necessary treatment for your 
injuries. You [will/will not] have to pay for this treatment. You will be told where you can get additional 
treatment for your injuries. There is no program to pay money or give other forms of compensation for 
such injuries either through this institution or the NIH. You do not give up any legal rights by signing 
this consent form. 
 
PROBLEMS OR QUESTIONS 
If you ever have any questions about the study, or if you have a research-related injury, you should 
contact [insert name of the investigator or other study staff] at [insert telephone number and/or physical 
address]. 
If you have questions about your rights as a research participant, you should contact [insert name or title 
of person on the IRB or other organization appropriate for the site] at [insert physical address and 
telephone number]. 

 
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If you have questions about who to contact at the research site, you should contact [insert name of the 
investigator or community educator or CAB member] at [insert physical address and telephone number]. 
SIGNATURE PAGE 
HPTN 084: 
A Phase 3 Double Blind Safety and Efficacy Study of Long-Acting Injectable Cabotegravir 
Compared to Daily Oral TDF/FTC for Pre-Exposure Prophylaxis in HIV-Uninfected Women  
 
FINAL Version 
Protocol Version 3.0, dated 12August2021 
DAIDS Document ID: 38070 
 
 
SCREENING AND ENROLLMENT CONSENT 
Insert signature blocks as required by the local IRB:] If you have read this consent form, or had it read 
and explained to you, and you understand the information, and you voluntarily agree to join the study, 
please sign your name or make your mark below. Samples will be stored from all study participants for 
study-related testing. Also, please indicate by providing your initials in the spaces below if you agree to 
long-term sample storage for other future testing and/or use of your samples for genetic testing. 
________ 
I agree to take part in this study.    
________ 
I agree to have samples of my blood stored long-term for future testing.    
________ 
I do not agree to have samples of my blood stored and long-term for future testing.  
________ 
I agree to allow my blood to be tested to see how my genes make drugs work in my body. 
________ 
I do not agree to allow my blood to be tested to see how my genes make drugs work in my 
body. 
[________     I agree to take part in the Contraceptive Sub-study.  *If relevant to site.] 
 
[________     I do not agree to take part in the Contraceptive Sub-study.  *If relevant to site.] 
 
 
 
 
 
 
 
 
 
____________________________________ 
Participant Name (print) 
 
 
Participant Signature and Date 
 
 
 
 
 
 
____________________________________ 
 
Study Staff Conducting 
 
 
Study Staff Signature and Date 
Consent Discussion (print) 
 
 
 
 
 
 
 
____________________________________ 
Witness Name (print)  
 
 
Witness Signature and Date 

 
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(As appropriate) 
 
Appendix V: Sample Qualitative Informed Consent Form  
HPTN 084: 
A Phase 3 Double Blind Safety and Efficacy Study of Long-Acting Injectable Cabotegravir 
Compared to Daily Oral TDF/FTC for Pre-Exposure Prophylaxis in HIV-Uninfected Women 
 
FINAL Version 
Protocol Version 3.0, dated 12August2021 
DAIDS Document ID: 38070 
 
 
Sponsored by: Division of AIDS, United States (US) National Institute of Allergy and Infectious 
Disease, US National Institutes of Health.   
 
Study products are provided by ViiV Healthcare and Gilead Sciences, Inc. Additional support is 
provided by the Bill & Melinda Gates Foundation (BMGF).  
 
PRINCIPAL INVESTIGATOR: [Insert Name] 
PHONE:  [Insert Number] 
GENERAL OVERVIEW 
You have been invited to take part in a qualitative substudy for the HPTN 084 main study.  The goal of 
the qualitative substudy is to understand how you feel about topics related to this study, HIV risk and 
HIV prevention methods.  The substudy will include one to three interviews during which you will be 
asked to share your experiences about participating in HPTN 084. This qualitative substudy is being 
conducted in four of the HPTN 084 sites in Africa. It will include a total of 80-110 women. 
 
The interviews will be led by a trained and experienced interviewer. We are interested in learning about 
your thoughts, opinions, and experiences with being a part of the study. For example, we would like to 
know how you decided to join the study. We would also like to know what you like and do not like 
about the injections (shots) and about the oral pills.  Finally, we would like to know how you feel about 
contraception and getting pregnant during the study. We hope that the information learned from this 
study will help us to better understand what kind of HIV prevention options women prefer. 
 
What happens if you do not want to join the qualitative interviews? 
Before you learn more about the study it is important that you know the following: 
 
• You do not have to join the qualitative interview.  
• If you join the qualitative interview study but later decide later you want to stop, you can stop 
taking part at any time.  
• Whether or not you take part in the qualitative interview study, you can still participate in the 
main study (HPTN 084).  Also you will still continue to receive the same services you get at 

 
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[insert clinic]. 
 
 
 
What will happen if you do want to join the qualitative interview study? 
If you decide to join the qualitative interview study, you will be asked to participate in a minimum of 
one and a maximum of 3 interviews during the time that you participate in HPTN 084.  Each interview 
will be conducted by a trained interviewer and last from one hour to one and a half hours.  The 
interviewer will contact you to arrange the next interview. In general, interviews will occur when you 
move to another stage of the HPTN 084 study.   
 
The information that you share during the qualitative interviews will be treated confidentially. 
The interviews will be audio-recorded to help assure that we get the best understanding possible 
from each discussion. This recording will be used to make a written transcript of the interview. The 
recording and transcript will only have a Participant ID number. No identifying information will be 
included in the written transcript.  
 
Although we hope that you will be comfortable answering all of the questions and talking openly 
and honestly, please keep in mind that you do not have to answer any of the questions.  You may 
stop participating completely at any time.   
 
What are the potential benefits? 
You will not receive any direct benefit from being in the qualitative interviews; however, you or 
others in your community may benefit from this study later. The information gathered during this 
study may help to prevent HIV and other infections. This may be beneficial to you and your 
community. 
 
What are the possible risks or discomforts? 
The questions we will ask you may make you feel uncomfortable. Your partner or others may not 
like for you to talk about the study and how it affects your home life.  We hope that the qualitative 
interview procedures described above will minimize your discomfort when discussing sensitive 
topics. However, the greatest risk may involve your privacy and confidentiality. Additional steps 
that the study team has taken to protect your privacy are described below.   
 
How will your privacy be protected? 
Every effort will be made to keep your personal information confidential.  Your personal information 
(name, address, phone number) will be protected by the research clinic. Your name, and anything 
else that might identify you personally, will not be used in any publication of information about this 
study.   
  
Your records may be reviewed by the sponsor of the study (US National Institutes of Health  
(NIH) their representatives), US FDA, US Department of Heath and Human Services (DHHS), Office of 
Human Research Protection (OHRP) and other government and local, US and International regulatory 
entities, authorized representatives of US NIH and/or its contractors, [insert names of applicable 
IRBs/ECs/other local review bodies as applicable] IRB, study staff, study monitors, and companies that 
makes the study drug (ViiV Healthcare and Gilead Sciences, Inc.). 

 
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We cannot guarantee absolute confidentiality.   
 
A description of this study will be available on www.ClinicalTrials.gov, as required by US 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. 
 
What are the alternatives to participating in this study? 
You do not have to participate in the interviews. 
 
Reasons why you may be withdrawn from the study without your consent 
Your participation in the interviews may be ended early without your consent for the following reasons: 
• The research study, or the qualitative part of the research study, is stopped or canceled. 
• The study staff feels that participating in the interviews would be harmful to you. 
 
What happens if you are injured by this research? 
It is unlikely that you will be injured as a result of taking part in a qualitative interview.  If you are 
injured, the [institution] will give you the treatment needed for your injuries.  You [will/will not] have to 
pay for this treatment.  You will be told where you can get additional treatment for your injuries.  There 
is no program to pay money or give other forms of compensation for such injuries through the United 
States NIH.  You do not give up any legal rights by signing this consent form. 
 
Who can you contact if you have any questions? 
We are happy to answer any questions that you may have.  It may be that you have questions about your 
rights as a study participant or that you think you have been injured because you were in this study.  In 
this case you can contact [insert name of the investigator or other study staff] at [insert telephone 
number and physical address].   
 
If you have any questions or concerns about whether you should join this study, or your rights as a 
research participant, you should contact [insert name or title of person on the IRB/EC or other 
organization appropriate for the site] at [insert physical address and telephone number].     
 
What is the cost of study participation? 
There is no cost to you for being in this study.  You will receive [insert local amount] for your time, 
effort, and travel to and from the clinic for each study visit.   
 
 

 
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SIGNATURE PAGE 
 
HPTN 084:  
A Phase 3 Double Blind Safety and Efficacy Study of Long-Acting Injectable Cabotegravir 
Compared to Daily Oral TDF/FTC for Pre-Exposure Prophylaxis in HIV-Uninfected Women 
 
FINAL Version 
Protocol Version 3.0, dated 12August2021 
DAIDS Document ID: 38070 
 
 
Sponsored by: Division of AIDS, United States (US) National Institute of Allergy and Infectious 
Disease, US National Institutes of Health.   
 
Study products are provided by ViiV Healthcare and Gilead Sciences, Inc. Additional support is 
provided by the Bill & Melinda Gates Foundation (BMGF).  
 
PRINCIPAL INVESTIGATOR: [Insert Name] 
PHONE:  [Insert Number] 
Study Participation 
If you have read this consent form, or had it read and explained to you, and you understand the 
information, and you voluntarily agree to join the study, please sign your name or make your mark 
below. 
 
____________________ 
________________________ 
______________ 
Participant Name (print) 
Participant Signature 
Date 
 
 
 
For staff:  I have explained the purpose of the screening to the volunteer and have answered all of her 
questions. To the best of my knowledge, she understands the purpose, procedures, risks and benefits of 
this study.  
 
____________________ 
________________________ 
______________ 
Study Staff Conducting  
Study Staff Signature 
Date 
Consent Discussion (print) 
 
 
 
 
 
 
 
 
 

 
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Appendix VI: Guidance on study conduct during the COVID-19 pandemic 
 
PRIORITIZATION OF STUDY VISIT PROCEDURES 
 
• Sites with full capacity to conduct study visits in-person at the study clinic should continue to do so 
in full compliance with the protocol.  
• Sites with limited capacity to conduct in-person study visits should prioritize assessments as 
determined by the site Investigator of Record (IoR) (e.g., urgent safety testing, HIV testing, 
provision of study product, etc.).  
• Sites with no capacity to conduct in-person visits may conduct telephonic or video-based 
assessments remotely at the discretion of the IoR (and following all institutional approval 
requirements), and may include targeted medical history (including ascertainment of AEs), HIV and 
adherence counseling, interviewer administered surveys, etc. The content of these visits should be 
determined by the site IoR.  
 
Note: If locally available, feasible, and at the discretion of the IoR, home HIV self-tests can be 
sourced and distributed to participants for participant use, and results demonstrated by video or 
photo-sharing to study sites as corroborative evidence of testing and test results. Such photos should 
be placed in the participant research record. Absence of home-testing results will NOT be considered 
a protocol deviation, nor reportable.   
 
• Sites that are able may also conduct study visits — in full or in part — off-site if permitted by 
applicable government, health authority, and institutional policies. This is including but not limited 
to home-based visits. Where this option is permitted, site staff should communicate with participants 
to determine in advance where and when such visits will take place, with adequate protections for 
safety, privacy, and confidentiality. Offsite visit procedures should be conducted by site staff who 
are adequately qualified and trained to conduct the procedures, as determined by the site Investigator 
of Record (IoR), with attention paid to occupational health, biohazard containment, and specimen 
and data chain of custody. These staff should also be adequately qualified and trained to immediately 
assess and/or manage any adverse events or social impacts that may occur during the visits. If 
adverse events requiring further evaluation or management are identified during an off-site visit, 
staff conducting the visit should arrange for appropriate clinical management, in consultation with 
the IoR or designee as needed. NOTE: Step 2 BLINDED study product cannot be provided at an off-
site visit. 
 
 
Finalized Guidance for STEPS 1, 2 and 3 sent out 17 April 2020 
These recommendations are made with the goal of ensuring both participant and staff safety and 
respecting the public health recommendations to minimize disease transmission.   
  
 
1. Screening and enrollment were paused until further notice at all sites effective close of business 
local time Tuesday, March 17, 2020.  This means that any screening and enrollment 

 
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appointments scheduled have to be deferred until after the pause is lifted.  
 
2. For participants on study, follow-up visits should continue to ensure safety of the participants in 
alignment with local guidance and protocol where possible. We encourage all sites to plan for 
contingencies regarding HPTN 084 participants on study. 
 
3. In the event that CRS operations are diminished or suspended entirely, and where conduct of 
study visits is not possible either because of staffing or operational concerns, please note the 
following: 
a. For participants in Step 1 (applicable to sites in South Africa and Eswatini), we 
recommend that where safe and feasible, participants be transitioned to step 2. At some 
sites, it may be possible to conduct week 4 testing and receive same-day results. In this 
case, sites may then proceed to complete week 5 procedures at that visit if protocol 
requirements for transition to step 2 are met.  
 
Where it is not possible to complete week 4 visits, participants should continue study 
product. Site staff should provide participants with sufficient product to cover this time 
period and ensure that they have sufficient contraceptive protection. Please counsel 
participants on the need to adopt additional HIV and pregnancy preventive measures if 
they are unable to return to site per schedule, and to record their pill taking and when that 
ended. We will follow routine procedures for assessing the transition to step 2 for delayed 
week 4/5.  
 
We do not anticipate significant product-related adverse events during this period, but if 
participants report significant symptoms, they should contact the site by phone. The IoR 
may consult the CMC, but in case responses are delayed, the IoR may use clinical 
judgement to hold or continue product. 
 
b. For participants in step 2: Sufficient product should be provided to cover the 8-week 
interval between injections plus a buffer of 30 days per the SSP - even for visits prior to 
week 41. This may allow the visit interval to extend up to 12 weeks. Contraception 
coverage should be verified to cover the entire interval.  
 
Participants need to receive both blinded study products during step 2. If injections 
cannot be administered, oral product should also be held. In this scenario, participants are 
advised to take additional measures to prevent HIV infection and exposure by all means 
available until they can return to study site. If they use non-study provided open-label 
PrEP during this period they should be encouraged to keep a log of dates of use should 
they use this option. 
 
c. For participants in step 3: we recommend continuation on daily unblinded oral product. 
Where participants cannot report for quarterly visits, participants should continue study 
product and where possible sites should explore delivery of product directly to 
participants from site investigational pharmacies.  If not feasible, participants should be 
counselled to use other available means to protect themselves against HIV exposure and 
infection and pregnancy prevention until they are able to return to study participation. 

 
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IoRs can use their judgement about ongoing dispensation of oral product in these 
extraordinary circumstances without routine HIV and creatinine testing, based on known 
previous renal function, risk and adherence. Self-testing for HIV may also be useful in 
this setting if practical. The same guidance would apply to pregnant participants.  
 
d. For participants in step 2 where early pregnancy cannot be excluded including a lapse in 
contraception, we suggest providing the participant with up to four weeks of TDF/FTC. 
The site can provide the participant with a pregnancy test kit to repeat pregnancy testing 
at home. Where the second test is negative, see guidance re step 2. Where the test is 
positive, see guidance re step 3.    
 
e. For annual follow up: Annual visits should be delayed until study conduct can be 
resumed at the site. 
 
 
4. PLEASE NOTE:  These measures may not all be needed at your site immediately and are to be 
deployed as needed. Before any of these above is implemented, and should you update your 
plans, please inform the people copied on this email, including your site-specific DAIDS OCSO 
Program Officer. Please note that additional guidance was issued to CTU PIs and CRS leaders 
regarding considerations for visits during this extraordinary time (see attachment).  
 
5. Please follow Data Communique #8, sent on 2 April 2020, regarding data collection procedures 
and documentation of missed visits or missed procedures, and any associated protocol 
deviations. 
 
6. Please consider whether partial or full participant reimbursements may be provided for 
telephonic visits during this pandemic.  This decision must be made in conjunction with your 
IRB and CTU. 
 
7. Finally, as the situation unfolds in our countries, sites will also need to consider procedures for 
symptom screening, isolation of suspected cases and linkage to testing based on national 
guidelines. It may be useful to anticipate these contingencies ahead of time. 
 
 
STUDY PRODUCT CONSIDERATIONS 
• For emergency cases, and if possible given local considerations, the Pharmacy Guidelines and 
Instructions for DAIDS Clinical Trials Networks permits shipment or courier of oral study product 
from the site directly to participants. The pharmacist should refer to the section on “Shipping Study 
Product to a Participant” in this manual for detailed procedures. If this method is to be implemented, 
each site pharmacist must develop appropriate procedures for the shipment or courier of oral study 
product to identified participant in accordance with these guidelines and must include appropriately 
documented chain of custody. This method should only be used if permissible per local institutional 
and IRB/EC policies.   
 
• All questions related to study product management should be directed to Katie Shin – 
kashin@niaid.nih.gov.  

 
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DOCUMENTATION 
• Site-specific contingency plans, and the implementation thereof, should be documented in essential 
document files for HPTN 084.  
• Participant-specific documentation should be entered in participant study charts in real-time to the 
extent possible.  
 
• Specific guidance regarding coding visits and instructions therein is forthcoming from SCHARP in a 
separate communication to all sites.  
 
• In consultation with the Division of AIDS, the HPTN Network is developing comprehensive 
guidance for documenting and/or reporting protocol deviations that may occur due to limited site 
capacity to conduct study visits or procedures during the COVID-19 pandemic. Once this Network-
level guidance is available, it will be provided in a separate communication to all sites. 
 
 

 
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Appendix VII: Study conduct post 5 November 2020 DSMB meeting (LoA #4) 
All modifications included in this Letter of Amendment are based on results of a pre-planned interim efficacy and 
safety review by the National Institute of Allergy and Infectious Diseases (NIAID) Multinational Data and Safety 
Monitoring Board (DSMB).  On 5 November 2020, the NIAID Multinational DSMB was in agreement that the 
primary question of whether long-acting cabotegravir prevents HIV infection has been answered in the affirmative 
and was highly statistically significant.  Because of these results, the DSMB recommended that blinded portion of 
the study be stopped, participants unblinded to their study allocation and that the trial results be made available as 
soon as possible.  The study’s sponsor (NIAID) accepted the Board’s recommendation.  A full protocol 
amendment will be developed; however, the modifications specified below reflect an interim approach to be 
employed until that amendment is finalized and approved by the sponsor and the IRBs/ECs/other national and 
local regulatory authorities.  
 
The immediate modifications are summarized below:    
 
• 
No further screening or enrollment will occur under Version 2.0 of the protocol, dated November 6, 2019, 
meaning that the portion of the LoA that outlines the recommendation for an increase to 3,350 participants in 
LoA #3 is null and void.  
  
• 
Investigators of Record (IoR) will be provided the randomization assignment for their enrolled participants.  
Each site IoR will then be responsible for informing participants of her randomization assignment as soon as 
is feasible following approval of a Participant Letter to be administered at the time of unblinding.   
 
• 
Upon being informed of randomized study drug assignment, participants still receiving study drug will no 
longer receive the respective placebo study product and will be offered to continue the active study drug to 
which they were originally assigned until further notice as follows:        
 
o Participants in Step 1:  If any participants remain in Step 1, contact the HPTN 084 Clinical 
Management Committee for guidance. (084cmc@hptn.org). 
 
o Participants in Step 2 assigned to active CAB LA: These participants will be offered to continue 
active CAB LA on the current Step 2 study visit schedule.   
 
o Participants in Step 2 assigned to active oral TDF/FTC:  These participants will be offered to 
continue active TDF/FTC on the current Step 2 study visit schedule.  These participants will be 
offered CAB when it becomes available.    
 
o Participants in Step 3 will continue visits per the current Step 3 visit schedule.  Participants who 
reach the final visit of Step 3 prior to obtaining additional CAB drug supply will transition to 
annual follow-up and be referred to local HIV prevention services.  When CAB supply is 
obtained, these participants will be contacted and offered CAB. 
 
o In consultation with the study’s Clinical Management Committee (CMC), participants who have 
already completed or terminated study participation for reasons other than HIV infection, an 
adverse event assessed as related to study product, or other exclusionary reasons as identified by 
the CMC, will be offered to re-enroll via the upcoming full amendment of the protocol.       
 
• 
Upon implementation of LoA #4, participants who choose to continue study follow-up as outlined above will 
follow the current applicable Step-associated Schedule of Procedures and Evaluations with the exception of 

 
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pill counts at Weeks 2 and 4 and dispensing blinded product and placebo.  Only unblinded products will be 
dispensed. 
Sample HPTN 084 Participant Letter/Information Sheet 
 
 
PRINCIPAL INVESTIGATOR: 
[Insert PI Name/Affiliation]  
 
 
Dear HPTN 084 Participant:  
 
The purpose of this letter is to share with you some important results from the HPTN 084 study that have become 
available after a recent Data and Safety Monitoring Board (DSMB) meeting on 5 November 2020.  The DSMB is 
an independent group that reviews studies and their results while they are happening to ensure the safety and well-
being of the study participants.  After reading this letter, if you have any questions about this information, we 
encourage you to talk to the site staff.   
 
The HPTN 084 Study:  
 
The HPTN 084 study is being done at 20 sites in South Africa, Botswana, Eswatini, Zimbabwe, Malawi, Uganda 
and Kenya and has enrolled 3,224 participants with [X] at this site.   
 
As you know, the purpose of the study is to try to find out if a new drug called cabotegravir (CAB), is as safe and 
will work better than TDF/FTC in protecting you from getting HIV.  As a reminder, TDF/FTC is approved by the 
U.S. Food and Drug Administration (FDA) [and insert local country if applicable] for the treatment of HIV and 
also to prevent people from getting HIV.   
All participants in this study were put into one of two groups by chance (like the flip of a coin):   
 
• 
Group 1:  Real CAB drug and TDF/FTC placebo (pill that does not have TDF/FTC)  
 
• 
Group 2: Real TDF/FTC drug and CAB placebo (injections that do not have CAB) 
 
 
Results of the DSMB review:  
 
At the DSMB meeting on 5 November 2020, the DSMB found that both CAB and TDF/FTC were very good at 
preventing new HIV infections.  They also found that both CAB and daily TDF/FTC pills were safe and well 
tolerated.  They saw that CAB was much better at preventing HIV than TDF/FTC. Participants given daily 
TDF/FTC pills had approximately nine times the number of HIV infections than participants getting long-acting 
cabotegravir shots (real CAB, also called CAB LA).  The DSMB recommended that the blinded part of the study 
be stopped, that participants be informed of their study group, and that the results be made public.  
 
The HPTN 084 study will continue.  The study team wants you to keep coming to this clinic for follow up visits 
and procedures.  In the near future, the protocol will be amended to allow for slight changes to the study visit 
requirements depending on which active product you are taking and whether you change from TDF/FTC to CAB.  
You will be given the information and offered an updated consent form at that time.  For now, you will stay in the 
group that you were put in at the beginning of the study.  We will tell you what this group is at your visit today.  
 
[To be inserted for sites with participants on Step 1:  If you are in the first part of the study (Step 1) and you are 
on real CAB, you will finish Step 1 and then you will come to the clinic for your first injection and then four weeks 

 
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later for another injection, and then every 8 weeks after that.  If you are on real TDF/FTC, you will finish Step 1 
and then come to the clinic every 8 weeks.]   
 
If you are in part of the study where you are getting injections (Step 2), you will come to the clinic as originally 
planned which is about every 8 weeks.  Participants assigned to real CAB will continue to receive real CAB 
injections but will no longer receive TDF/FTC placebo pills.  
 
Participants assigned to real TDF/FTC will continue to receive real TDF/FTC pills but will no longer receive 
CAB placebo injections.  If this is the real TDF/FTC group, we want to remind you that TDF/FTC works very 
well to prevent HIV infection if it is taken as prescribed.   
 
If you are in the group that got real TDF/FTC and you want to get CAB, you will be offered CAB when it is 
available. The study team is working to get more CAB for participants that want it.  The study team will also let 
you know how long you will stay in the study, the new study visits and study procedures now that we have this 
new information. Any changes in the study must be approved by a group of people that protect your rights and 
safety (insert regulatory authorities and Ethics Committees as appropriate).  This group oversees research at this 
clinic.  We will tell you of any decisions about changes in the study and fully explain any changes to you.  
 
Staying in HPTN 084 is entirely your choice.  You may choose to leave the study now or at any time in the future 
without losing any of the care you get at this [or name local referral clinic or other required local language] 
clinic.   
 
If you have any questions now or later about the information in this letter, you may ask the study staff or contact 
me directly.  We will do our best to answer your questions or concerns.   
 
Your participation in the HPTN 084 study has led to a very important discovery about a new way to prevent HIV 
infection.  Staying in this study will help to increase our knowledge.  Thank you for participating in HPTN 084.  
 
Sincerely,  
 
[Insert name and contact information of Investigator of Record] 
 
____________________________________________________________________________________ 
 
If you have read this letter, or have had it read and explained to you, and understand the information, please sign your 
name or make your mark below.   
 
 
 
 
____________________________________ 
Participant Name (print) 
 
 
Participant Signature and Date 
 
 
 
 
 
 
____________________________________ 
Study Staff Conducting  
 
 
Study Staff Signature and Date 
Consent Discussion (print) 
 
 
 
 
 
____________________________________ 
Witness Name (print) 
 
 
 
Witness Signature and Date 
(As appropriate) 

 
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Appendix VIII: Procedures for Offering Open Label (OL) Cabotegravir- The Next Part of HPTN 
084 
Background, Purpose and Overview, Description of Steps 
 
1. 
Background 
Given the results of the HPTN 084 trial1, in keeping with the Data and Safety Monitoring Board 
(DSMB) recommendations after the 5 November 2020 review to discontinue the blinded portion 
of the trial, and in keeping with the HPTN 083 trial results and DSMB recommendations, HPTN 
084 is amending the version 2.0 protocol to add an open-label (OL) evaluation of long-acting 
cabotegravir (CAB LA) for all participants, irrespective of original study arm. Please note that as 
an interim measure between the DSMB’s recommendation and this full protocol amendment, a 
Letter of Amendment (LoA) (LoA #4 dated 16 November 2020) was issued.  That LoA ended 
the blinded portion of the study and included a descriptive Dear Participant Letter. This full 
protocol amendment will permit participants to choose which of the two active study agents 
(CAB LA or TDF/FTC) they wish to take for a 48-week OL evaluation. In addition, it makes 
provision for participants to continue active dosing with CAB LA through pregnancy and 
breastfeeding upon reconsent. 
The procedures for the amendment and an addendum to the main informed consent form (ICF) 
are contained within this Appendix.  The amended protocol signature page is within the main 
body of the protocol.  The only other changes made to the main body of the protocol were to 
incorporate previously issued updates to the v2.0 protocol made via Clarification Memo (CM) 
and LoAs.  Specifically, the main protocol was edited to include changes made by the previously 
issued: 
• CM#1, Version 1.0 dated 22Jan2020 
• LoA#1, Version 1.0 dated 23June2020 
• LoA#2, Version 1.0 dated 10Sep2020 
• CM#2, Version 1.0 dated 16Sep2020 
• LoA#3, Version 1.0 dated 22Oct2020 
• LoA#4, Version 1.0 dated 16Nov2020 
 
A few minor wording changes were made to Sections 9.0, Laboratory Specimens and Biohazards 
Containment to reflect a network change in quality assurance. A footnote was added to Appendix 
1b (Schedule of Evaluations- Step 2.  Injection Phase), to address participants who reach  Week 
185 on Step at a site awaiting implementation of this amendment.  No other changes were made 
to the main body of the protocol.    
    
 
 

 
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2. 
Purpose and Overview  
The purpose of this Appendix is to provide instructions for the OL portion of the study. 
Participants will be offered the opportunity to either take OL CAB LA 600 mg IM every eight 
weeks (with the exception of participants who previously discontinued CAB LA for confirmed 
safety reasons) or to take OL daily TDF/FTC.  Participants switching from TDF/FTC or re-
starting CAB LA may choose to start CAB LA immediately or they may start at a later time 
point but no later than 24 weeks after they begin the OL portion of the study.  Participants 
initiating CAB LA during this amendment will be permitted to choose between an oral lead-in 
(OLI) prior to the first injection or initiating injections immediately. Participants may also 
choose to discontinue study products, (e.g., if they have reduced HIV risk); participants 
discontinuing study products will be asked to continue in follow-up for 48 weeks off of study 
product.  Below are two images illustrating the options participants will have during the open-
label portion of the study.    
 
* Note that participants who elect to stop taking CAB LA injections will be offered 48 weeks of TDF/FTC to 
cover the PK tail. 
 
 
 
 

 
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* Note that participants who elect to stop taking CAB LA injections will be offered 48 weeks of TDF/FTC to 
cover the PK tail. 
 
This Appendix includes procedures for new Steps, Step 4 (OL CAB LA or OL TDF/FTC) and 
Step 5 (OL TDF/FTC following premature discontinuation of CAB LA), the respective visit 
schedule for each participant group, updated toxicity management instructions, an updated 
sample ICF, and other relevant information from the original protocol that pertains to study 
procedures for Steps 4 and 5. Please note, this section also contains an SOE for following 
pregnant and breastfeeding participants. 
Implementation of this Appendix will go into effect at a given site when: 1) all required 
IRB/EC/other regulatory entity approvals are in place; 2) adequate supply of cabotegravir for this 
purpose has been received at the site; 3) the site has confirmed that training of all active 
personnel for Version 3.0 has been completed; and 4) the site receives notification from the 
DAIDS Protocol Registration Office that the site-specific informed consent addendum is 
approved and indicates successful completion of the amendment protocol registration process.  
The HPTN Leadership and Operations Center (LOC) will issue an approval notice to begin 
implementation of Version 3.0 upon confirmation that all items outlined above are in place.      
 
2.1 
Duration  
For the majority of participants, the HPTN 084 OL component will last a minimum of 
approximately 48 weeks and a maximum of 52 weeks, per participant.  In specific circumstances, 
participants may be in the study for longer timeframes: 

 
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• Participants starting/re-starting CAB LA who elect to do the oral run-in will be followed 
for 56 weeks.  These participants will complete 4 weeks of an oral run-in plus a 4-week 
injection loading period.   
• Only a minority of participants will be followed for up to 100 weeks (those who 
discontinue CAB LA prematurely during the OL component and are offered 48 weeks of 
TDF/FTC to cover the pharmacokinetic (PK) “tail").  
• Pregnant participants may be enrolled in the study for up to 148 weeks (four-week OLI 
optional, plus 48 weeks OL CAB LA (and only if pregnancy occurs within 8 weeks of 
last injection) plus 96 weeks of follow-up through pregnancy and post-partum period 
with final assessment of infant outcome at 48 weeks post-partum). 
 
The OL evaluation period will be 48 weeks of either OL study product (CAB LA or TDF/FTC).  
Following that initial 48-week period participants will take one of two paths: 
 
1) Participants who elected to take OL TDF/FTC will have completed all study activities and 
will be provided information to access local Pre-Exposure Prophylaxis (PrEP) programs.   
2) Participants who elected to take OL CAB LA may choose to transition to locally available 
CAB LA (through a post-trial access program) or to a local PrEP program. These participants 
will have completed all study activities, unless they are pregnant. 
2.2 
Study sites and population  
Only participants at sites who participated in the original HPTN 084 study, or participants in the 
adolescent sub-study HPTN 084-01 will be included.  HPTN 084-01 participants may transition 
to this HPTN 084 protocol amendment any time after Step 2 of HPTN 084-01. 
 
2.3 
Special considerations:  
Optional Oral Lead-In (OLI): Following review of the preliminary safety data from HPTN 
083, HPTN 084 and safety data across the entire CAB LA clinical program, ViiV Healthcare has 
agreed to permit an optional OLI in the OL extension for participants switching from TDF/FTC 
to CAB LA.  
Justification for an optional OLI:  
Based on the totality of the safety data obtained during Step 1 of HPTN 083 (n=2281 participants 
in the CAB group Step 1 Safety population, of whom 2117 were included in the Step 2 Safety 
population), no significant concerns regarding safety or tolerability of oral CAB have been 
identified.  A review of AEs, SAEs, Grade 3 or 4 AEs, AEs leading to discontinuation of study 
drug, and drug-induced liver injury (DILI) cases in participants receiving CAB do not indicate 
any specific safety concerns that would require mandatory use of OLI to mitigate severe adverse 
drug reactions (ADRs) prior to initiating CAB LA. 
 

 
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To date, the OLI has been included in the CAB LA clinical development program to reduce the 
theoretical risk of a severe adverse drug reaction following initiation of CAB LA. The duration 
up to five weeks of OLI for HPTN 084 was selected given that approximately 80-90% of severe 
hypersensitivity drug-related reactions (in general, and not necessarily for CAB) occur within the 
first four weeks of dosing. HPTN 084 was launched approximately three years ago, in November 
2017, and HPTN 083 was launched in December 2016. A total of 7,143 subjects have received at 
least 1 dose of CAB oral or LA through 18 October 2020 in ViiV sponsored and supported 
studies, of whom 6,279 of these received CAB LA.  Approximately 90,000 CAB injections have 
been administered to date.  No confirmed hypersensitivity cases were reported in the CAB 
treatment program in HIV infected patients.  The AE data for the combined OLI CAB + 
rilpivirine (RPV) periods in Phase 3 Studies 201584 (FLAIR), 201585 (ATLAS), and 207966 
(ATLAS-2M) did not identify any new AE trends. One case of possible DILI was identified 
during OLI in a participant for ATLAS-2M (Overton, Lancet 2020 article2 and additional 
Sponsor information). Based on FLAIR Week 124 results, CAB + RPV LA with or without an 
OLI, was found to be a well-tolerated, safe and effective maintenance regimen up to Week 
124.  Switching directly to CAB + RPV LA was comparable in terms of safety and tolerability to 
treatment with OLI (cite Glasgow 2020 presentation).3   
 
An OLI is not required for achievement of therapeutic concentrations on initiation of injections 
or at steady state.  The contribution of oral dosing to the profile is limited to the first week 
following the final OLI dose and has no impact on trough levels 4-weeks following the initiation 
injection as observed in HIV-infected participants [geometric mean (5th, 95th percentile):  1.43 
µg/mL (0.403, 3.90) without OLI, 1.56 µg/mL (0.551, 3.61) with OLI], which were similar to 
observed values for uninfected participants in HPTN083 where OLI dosing was stopped 1 day 
prior to initiation injections [1.86 µ/mL (0.43, 4.73)].  Initiation of injections without OLI did not 
impact efficacy in HIV-1 infected participants in the CAB-LA/RPV-LA treatment program 
[plasma HIV-1 RNA ≥50 c/mL 24-weeks after initiation: 1 of 111 (0.9%) participants without 
OLI compared with 1 of 121 (0.8%) participants with OLI]. 
 
The CAB LA HIV prevention program, relative to the treatment program, has unique 
considerations that need to be better understood to fully inform the risk/benefit of using CAB LA 
as PrEP. People using PrEP are HIV un-infected and desire PrEP to protect themselves.  
Adherence to oral PrEP is difficult for many, and suboptimal oral adherence during the OLI in 
HPTN 083 may have played a role in three incident cases in the CAB LA arm during the OLI 
period.4  In addition to adherence challenges, many countries are also resource constrained.  
Access to providers and to PrEP may be limited. Operationally, countries may desire simplified 
programs once CAB LA is available. 
 
In the HIV treatment arena, the evaluation of an optional OLI dosing was first undertaken in a 
controlled clinical trial setting. Our proposal for an optional OLI approach in the prevention 
arena, rather than outright removal of the oral lead-in period, will allow us to explore 
considerations around participant choice, provider choice and comfort level, uptake and 
utilization, and safety data collection in detail in a trial setting.  
 
Pregnancy: Following a review of available safety data, the long-acting, reversible 
contraceptive (LARC) requirement for the OL evaluation of HPTN 084 will be relaxed to allow 

 
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for more real-world approach to fertility intentions.  Participants will not be required to take any 
form of contraception during the OL Steps 4 and 5, although they will be counselled about risks 
and benefits of CAB use during pregnancy and breastfeeding and about ways to avoid pregnancy 
if they so desire. Participants who become pregnant during the HPTN 084 OL will be permitted 
to continue active dosing with CAB LA, after they provide additional consent.  
Justification for relaxed contraceptive requirements and CAB LA dosing during 
pregnancy: Addressing the use of CAB LA for HIV PrEP in pregnancy is important and timely. 
Women in high HIV prevalence settings may be at increased risk for HIV when planning to 
conceive, and need HIV prevention options, like PrEP that go beyond condoms. Pregnancy may 
also be a vulnerable period for HIV acquisition. A systematic review in 2018 that included 37 
studies contributing 100,758 person-years of follow-up estimated that the average HIV incidence 
in pregnant and breastfeeding women was 3.6 per 100 person years. This HIV incidence is 
consistent with the threshold recommended for offer of PrEP in at-risk populations. While the 
review did not find any evidence of excess HIV risk associated with pregnancy and 
breastfeeding, there was significant heterogeneity in the data.5 Pregnancy and breastfeeding are 
periods marked by significant biological and behavioral changes that may have varying effects 
on the risk of HIV.  Pregnancy is associated with biological changes including higher 
concentrations of estrogen and progesterone that may promote a cascade of synergistic changes 
in the female genital tract, including changes in C-C chemokine receptor type 5 (CCR5) and  
C-X-C chemokine receptor type 4 (CXCR4) expression, increased inflammation, decreased 
integrity of the vaginal epithelium, and alterations in vaginal microbiota, all of which have been 
associated with increased HIV acquisition susceptibility.6 An analysis of prospective data from 
2,751 HIV serodiscordant couples found that the per-coital act probability of HIV acquisition 
was higher in late pregnancy and early post-partum compared to the non-pregnant state, after 
adjusting for sexual behavior, leading authors to hypothesize that this increased risk may be due 
to biological changes that occur in the late pregnancy and post-partum period.7 These biological 
changes and associated risks may be offset in some settings by changes in sexual behavior and 
reduced frequency of sexual intercourse. The direction of an observed association between 
pregnancy and the breastfeeding and HIV, may therefore depend on the context as well as the 
balance of these behavioral and biological factors.5 Nevertheless, preventing HIV in high-risk 
populations who are also at risk for pregnancy remains a priority for reducing both maternal and 
infant morbidity and mortality. As access to PrEP expands, data on the safety, acceptability and 
dosing requirements of PrEP agents during pregnancy are a priority. 
 
During the blinded portion of HPTN 084 it was not possible to continue dosing with blinded 
study product during pregnancy. In May 2018, the study protocol was modified to require all 
participants of child-bearing potential to use a long-acting reversible contraceptive (LARC); all 
participants who became pregnant discontinued blinded product and were transitioned to OL 
TDF/FTC for the duration of pregnancy. This was in response to a safety signal observed in 
women living with HIV and using dolutegravir (DTG) around the time of conception in the 
Tsepamo study. (see section 1.7.1) Since the initial reports from the Tsepamo study, studies done 
in several other cohorts have not confirmed this safety signal.7  These studies however have been 
conducted in high-income countries (e.g., Canada, Germany, France, and the UK) and have 
included few exposed pregnancies. Neural Tube Defect (NTD) cases have also been reviewed 
using pharmacovigilance databases; one review lacked sufficient data on DTG exposure in 
pregnant women necessary to make any conclusion.8 A subsequent review of NTD data from the 

 
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World Health Organization (WHO) pharmacovigilance database that includes 20 million case 
safety reports from over 130 million countries did not find strong support for the NTD signal 
associated with DTG use.9  In 2020, updated data from expanded and ongoing surveillance in 
Botswana (where the original Tsepamo study was conducted) between April 1, 2019, and April 
30, 2020, revealed a decrease in the NTD prevalence difference between women receiving DTG 
and those receiving other antiretrovirals from 0.20% in the earlier report to 0.09%, a difference 
that is not statistically significant.10   
 
Current guidance from WHO recommends the use of DTG in pregnant women and those of 
child-bearing potential, and encourages counselling of women so that they can make an informed 
choice about treatment based on an understanding of the risks and benefits associated with their 
choice.11  While structurally similar, cabotegravir is not the same as DTG. Pre-clinical studies 
did not find any effect of CAB on embryofetal development (see section 1.7 of original 
protocol). In HPTN 084, prior to 5 November 2020, pregnancy incidence in the context of LARC 
use was 1.3 per 100 person years (95% confidence interval [CI] 1.0, 1.7). Of 50 confirmed 
pregnancies, 27 (54%) had confirmed pregnancy outcomes while the remainder were ongoing. 
Reassuringly, no congenital anomalies were observed.1 
 
Data on the safety and PK of CAB LA in pregnant women compared to non-pregnant women are 
critical. In particular, data on PK are important for informing the need for dose adjustments in 
pregnancy. Drug metabolism may be altered during pregnancy. Pregnant women experience 
unique physiological changes that may result in clinically significant alterations in drug PK and 
pharmacodynamics. With respect to long-acting injectable antiretroviral products, the following 
physiological changes beginning early in gestation may be relevant: (a) large changes in total 
body water and fat, increasing drug distribution volume; (b) decreased albumin and increased 
alpha-1 acid glycoprotein (AAG) concentrations that may cause clinically relevant changes in 
drug protein binding; (c) increased cardiac output, ventilation, and hepatic and renal blood flow 
which may impact drug metabolism and elimination; and (e) increased concentrations of 
endogenous glucocorticoids that may affect the activity of hepatic enzyme systems that regulate 
drug metabolism. 12-17 These physiological changes have the potential to result in lower drug 
exposures with consequent loss of HIV protection if significant. While few data exist, an analysis 
of samples from three women living with HIV who received CAB LA with RPV during ViiV-
sponsored trials provide some reassurance. Although CAB LA was discontinued at the time of 
pregnancy confirmation, the rate of decline of CAB concentrations during the PK tail in 
pregnancy was within the expected range for non-pregnant women. The CAB LA PK profile is 
primarily determined by its absorption rate, which appears to be unaffected by changes in 
metabolic enzymatic profile.18 More data in a larger sample size could confirm this.   
 
Data on CAB LA concentrations in breastmilk are extremely limited. In pre-clinical pre- and 
post-natal development studies in female rats, no effect of CAB on lactation was seen at any 
dose.19 There was also no effect on rat pup growth and development, or AEs with exposure to 
CAB in maternal milk. Data from DTG may provide some indication of expected breast milk 
concentrations. In 17 breastfeeding mothers, the median ratio of DTG in breast milk to maternal 
plasma was 0.03. Their infants had a median maximum DTG concentration of 66.7 ng/mL (range 
21–654 ng/mL) and a median minimum concentration of 60.9 ng/mL (range 16.3–479 ng/mL) at 
a median age of 10 days (range 7–18 days). It appears that elimination by newborn infants is 

 
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prolonged but no AEs have been reported and DTG has been used safely in HIV-positive 
mothers during breastfeeding.20  Collection of similar data on CAB concentrations in breastmilk 
and infant plasma will be important for providing clear guidance to health care providers and 
PrEP users about CAB use during breastfeeding, particularly if HIV risk is elevated in the early 
post-partum period and effective PrEP is required. These data may also be informative for 
women who may breastfeed for a prolonged period (up to 2 years) but who also want an 
effective method of HIV prevention.    
 
Historically, pregnant women have been seen as a vulnerable population and excluded from 
clinical trials in order to protect the mother and fetus from potential harm. The consequence of 
this exclusion, however, has been off-label use of medicines in pregnancy in the absence of 
robust evidence of safety, PK and efficacy of during this period. More recently there has been a 
recognition that pregnant women are better served through targeted enrollment in research that 
meets their needs, and that is able to provide appropriate protections within the framework of a 
clinical trial where adequate monitoring can take place.21 The HPTN 084 amendment provides 
an opportunity to offer participants the chance to reconsent to active CAB LA dosing during 
pregnancy and breastfeeding, while ensuring adequate monitoring of safety in both mother and 
infant.  These data will provide important information on acceptability, tolerability, safety and 
PK of CAB LA during pregnancy and breastfeeding prior to widescale implementation in 
demonstration projects and national programs where extensive monitoring may be limited.  
 
3. 
Description of Steps 4 and 5 
3.1 
 Overview 
All participants will be offered OL CAB LA, except for those participants who discontinued 
CAB LA for safety reasons earlier in the study. Participants who permanently discontinued study 
products during the blinded portion of the study due to HIV infection, HBV infection or for a 
study product-related AE that would deem the continuation or initiation of CAB unsafe are NOT 
eligible to restart or begin CAB.  The CMC may be contacted for questions related to study 
product AEs of concern for participants interested in continuing or initiating CAB and whether it 
is safe to do so.   
All participants will be followed for at least 48 weeks in Step 4 (unless they decline consent for 
further participation).  Step 5 will be offered to all participants who receive at least one injection 
of CAB LA in Step 4 but who prematurely discontinue CAB LA in Step 4.  In Step 5 participants 
will be followed for 48 weeks on OL TDF/FTC to cover the CAB LA tail. Details of Steps 4 and 
5 are included below. 
An addendum to the main informed consent form is included in this Appendix and will 
document the participant’s continued participation in the OL portion of the study.  A site may opt 
to discuss the choice of participating in the OL evaluation via telephone or telemedicine at the 
discretion of the Investigator of Record (IoR) and if allowable by local ethics committees. If this 
discussion does occur off-site and the participant chooses to continue in the study, once the 
participant reports to the study site, product dispensation can only occur after signature of the 
addendum informed consent form.  Contact the CMC (084cmc@hptn.org) for guidance if there 

 
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are other scenarios for a discussion about choice and obtaining informed consent that are not 
outlined here.      
The following Steps will be followed during the OL evaluation: 
 
1) Step 4a- Procedures for Participants Initially Randomized to TDF/FTC Who Elect to Move 
to OL CAB LA with Optional Oral Lead-in first 
2) Step 4b- Procedures for Participants Initiating or Re-starting CAB LA without the Optional 
Oral Lead-in; the Initial Dose Visit  
3) Step 4c- Procedures for Participants on Maintenance Doses of CAB LA or TDF/FTC 
4) Step 4d- Procedures for Pregnant/Breastfeeding Participants  
5) Step 5-  Procedures for Participants Taking OL TDF/FTC for 48 Weeks after Premature CAB 
LA discontinuation 
 
Step 4 
During Step 4c, all participants will be followed for 48 weeks, irrespective of OL study product 
choice (CAB LA or TDF/FTC), at visits every eight weeks for a total of six visits. 
 
Participants who were taking CAB LA during the original study will move directly into Step 4c 
(if they wish to continue taking CAB LA). 
 
Participants who transition from TDF/FTC or re-start CAB LA may choose from two options 
before starting Step 4c: 
 
Option A: Step 4a- Participants will receive daily oral CAB pills for four weeks 
prior to starting injectable CAB LA. Once Step 4a is completed, participants will 
move to Step 4b. 
 
Option B: Step 4b- Participants will start immediately with injectable CAB LA.  
Once a participant completes Step 4b, she will move to Step 4c four weeks later 
for the first injection of the 48-week OL evaluation.  
 
Step 4d is for participants who become pregnant in Step 4 and first 8 weeks of Step 5, who 
have had at least one CAB LA injection ever: This step does not apply to participants who 
have never received a CAB LA injection. At the first pregnancy test positive visit, participants 
will have their pregnancy confirmed on a second independent sample. Participants should be 
counselled about the risks and benefits of continuing CAB through pregnancy and breastfeeding, 
and offered an opportunity to re-consent to receive CAB LA injections during pregnancy. 
Participants who need more time to consider their decision can have their CAB LA injection 
temporarily deferred, within the remaining visit window. Participants who decline to continue 
CAB LA during pregnancy and breastfeeding will be offered OL TDF/FTC. All pregnant 
participants who have had at least one CAB LA injection will be followed up in accordance with 
the pregnancy schedule of evaluations in Step 4d. CAB LA injections will be administered every 
eight weeks in those that consent.  Additional safety assessments and PK samples will be 
collected at study visits four weeks after every injection.  
 

 
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At delivery, a maternal blood sample and cord blood sample will be collected from the mother, 
and where feasible an infant blood sample will be collected (week 0). During the post-partum 
period blood and breastmilk samples will be collected from the mother, and blood samples from 
the infant per the Step 4d SOE. Infant outcomes will be assessed at delivery up to approximately 
12 months later (Week 48 of Step 4d).  
 
Participants who do not have a live birth outcome will be followed up in accordance with Step 4c 
visits. Pregnancy outcome data will still be collected in these participants at the time of the 
pregnancy outcome.  
 
Participants who have never received a CAB LA injection will be followed up through Step 4c 
and through to pregnancy outcome. They will remain on the Step 4c SOE. 
 
All participants who complete Steps 4c or d will have the option to link to a CAB LA access 
program or local HIV prevention program if preferred.  
 
Step 5 
Only participants who received OL CAB LA in Step 4 and who discontinue CAB LA early for 
safety or other reasons will have the option to transition to Step 5. 
During Step 5, participants will be followed for 48 weeks on OL TDF/FTC according to the Step 
5 SOE. Once participants complete Step 5 they will be offered information for local 
PrEP/standard of care HIV prevention programs. 
 
 

 
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a.  Step 4a 
 
Appendix VIII: Schedule of Evaluations for Step 4a-Procedures for Participants Initially 
Randomized to TDF/FTC Who Elect to Move to OL CAB LA with Optional Oral Lead-in first 
 
 
DAY 0/ 
of Step 4a 
ADMINISTRATIVE, BEHAVIORAL, REGULATORY 
Informed consent  
X 
Locator information 
X 
Offer CAB LA and counseling on 
direct to inject vs. oral lead in 
X 
Acceptability assessment  
X 
Behavioral assessment 
X 
HIV prevention counseling  
X 
Offer condoms  
X 
CLINICAL EVALUATIONS & PROCEDURES 
Medical history, con meds, targeted 
physical exam (with pulse, BP, weight 
and BMI calculated at each visit) 
X 
Blood collection 
X 
Urine collection1    
X 
For those who select oral lead in: 
Dispense study product (enough for 4 
weeks) 
X 
Adherence counseling2  
X 
LOCAL LABORATORY EVALUATIONS & PROCEDURES 
HIV testing3 
X 
HIV viral load testing4 
X 
Pregnancy testing1 
X 
CBC with differential, if not done in 
Step 4a 
X 
Chemistry testing5  
X 
Liver function tests6 
X 
Fasting lipid profile, if not done in 
Step 4a7 
X 
Plasma storage8,9  
X 
DBS storage9 
X 
 
1 Pregnancy testing may be performed in the clinic or the laboratory. Results must be available the same day as sample 
collection and before product is administered. Testing may be performed using a urine, plasma, or serum sample. The assay 
used for pregnancy testing must have a limit of detection of 25 mIU/mL or lower. Pregnancy testing is not required at 
subsequent visits if a positive result is obtained and the participant is still pregnant. 
2 Refer to the SSP Manual.  
3 The HIV testing algorithm and instruction for VL testing are provided in the SSP Manual. HIV rapid testing may be 
performed in the clinic or the laboratory.  At least one HIV test must be available the same day as sample collection and 
before product is administered.  
4   This testing will be performed for all study participants, regardless of HIV status or the results of other HIV tests. 
This testing must be performed with an assay with a lower limit of quantification of 50 copies/mL or lower.     
5 Albumin, BUN/urea, creatinine. Additional testing may be required if abnormalities of clinical significance are 
detected. 

 
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6 AST, ALT, total bilirubin.  
7 Total cholesterol, HDL, triglycerides, and LDL (either calculated or measured). Participants should have fasted for at 
least 8 hours, preferably 12 hours, prior to sample collection. If participants are not fasting, do not order the lipid 
testing. Participants may return for testing or it can be performed at next visit 
8 Stored plasma may be used for Quality Assurance testing, possible HSV-2 testing and other assessments at the HPTN 
LC.  
9 Assessments on stored samples will be performed retrospectively; results will not be returned to study sites or 
participants, except as noted in the SSP. 
 
 
 

 
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b.  Step 4b 
 
Appendix VIII: Schedule of Evaluations for Step 4b- Procedures for Participants Initiating or Re-
starting CAB LA without the Optional Oral Lead-in; the Initial Dose Visit  
 
 
DAY 0 of Step 4b 
ADMINISTRATIVE, BEHAVIORAL, REGULATORY 
Informed consent, if not obtained in Step 4a  
X 
Locator information 
X 
Offer CAB LA and counseling on direct to inject vs. oral 
lead in, if not done in Step 4a 
X 
Acceptability assessment, if not done in Step 4a  
X 
Behavioral assessment, if not done in Step 4a 
X 
HIV prevention counseling  
X 
Offer condoms  
X 
CLINICAL EVALUATIONS & PROCEDURES 
Medical history, con meds, targeted physical exam (with 
pulse, BP, weight and BMI calculated at each visit) 
X 
Blood collection 
X 
Urine collection1    
X 
Adherence counseling2   
X 
Dispense and administer CAB LA  + 
X 
LOCAL LABORATORY EVALUATIONS & PROCEDURES 
HIV testing3 
X 
HIV viral load testing 4 
X 
Pregnancy testing1 
X 
CBC with differential, if not done in Step 4a 
X 
Chemistry testing5  
X 
Liver function tests6 
X 
Fasting lipid profile, if not done in Step 4a7 
X 
Plasma storage8,9  
X 
DBS storage9 
X 
 
+ All participants initiating or re-starting CAB LA, will receive their initial CAB LA injection during Step 4b.  The 
second injection will occur during Step 4c.  The second injection must be given 4 weeks after the initial injection. 
 
1 Pregnancy testing may be performed in the clinic or the laboratory. Results must be available the same day as sample 
collection and before product is administered. Testing may be performed using a urine, plasma, or serum sample. The assay 
used for pregnancy testing must have a limit of detection of 25 mIU/mL or lower. Pregnancy testing is not required at 
subsequent visits if a positive result is obtained and the participant is still pregnant.  
2 Refer to the SSP Manual.  
3 The HIV testing algorithm and instruction for VL testing are provided in the SSP Manual. HIV rapid testing may be 
performed in the clinic or the laboratory.  At least one HIV test must be available the same day as sample collection and 
before product is administered.  
4  This testing will be performed for all study participants, regardless of HIV status or the results of other HIV tests. This 
testing must be performed with an assay with a lower limit of quantification of 50 copies/mL or lower.     

 
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5 Albumin, BUN/urea, creatinine. Additional testing may be required if abnormalities of clinical significance are 
detected. 
6 AST, ALT, total bilirubin.  
7 Total cholesterol, HDL, triglycerides, and LDL (either calculated or measured). Participants should have fasted for at 
least 8 hours, preferably 12 hours, prior to sample collection. If participants are not fasting, do not order the lipid 
testing. Participants may return for testing or it can be performed at next visit 
8 Stored plasma may be used for Quality Assurance testing, possible HSV-2 testing and other assessments at the HPTN 
LC.  
9 Assessments on stored samples will be performed retrospectively; results will not be returned to study sites or 
participants, except as noted in the SSP. 

 
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c. Step 4c 
 
Appendix VIII: Schedule of Evaluations for Step 4c- Procedures for Participants on Maintenance 
Doses of CAB LA or TDF/FTC 
 
Time on OL Study 
Product  
 
Week 0 of 
Step 4c+ 
 
Wee k 8 
 
Week 16 
 
Week 24 
 
Week 32 
 
Week 40 
 
Week 48 
Informed Consent** 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Locator information 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Acceptability assessment 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
Behavioral assessment 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
HIV prevention counseling 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Offer condoms per local SOC 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
CLINICAL EVALUATIONS & PROCEDURES 
Medical history, concomitant 
medications, targeted physical 
exam (with pulse, BP, weight and 
BMI calculated at each visit) 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Blood collection 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Urine collection1    
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Vaginal swab collection2 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
Adherence counseling3  
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Dispense/administer product as is 
appropriate 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
LOCAL LABORATORY EVALUATIONS & PROCEDURES 
HIV testing4 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
HIV viral load testing5 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Pregnancy testing1  
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
CBC with differential, if not done 
in Step 4a or 4b 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
Chemistry testing, if not done in 
Step 4a or 4b6 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
Liver function testing7 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
Fasting lipid profile8 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Syphilis testing 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
Vaginal GC/CT and TV testing2 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
Urinalysis (protein, glucose) 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
Plasma storage9,10 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
DBS storage10      
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
** for those that have not already re-consented as part of step 4 a or b 
** for those that have not already re-consented as part of step 4 a or b 
+   For participants transitioning from Step 4b this will not be Week 0 of CAB LA. This is Week 0 of Step 4c but must 
implemented 4 weeks after the initial injection for women who completed Step 4b.  

 
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1 Pregnancy testing may be performed in the clinic or the laboratory. Results must be available the same day as sample 
collection and before product is administered. Testing may be performed using a urine, plasma, or serum sample. The assay 
used for pregnancy testing must have a limit of detection of 25 mIU/mL or lower. Pregnancy testing is not required at 
subsequent visits if a positive result is obtained and the participant is still pregnant. If a participant has a positive pregnancy 
test, follow her according to Step 4d. 
2 GC/CT and TV testing to be done only if not performed in the past 3 months.  GC/CT NAAT testing may be performed 
using urine or a vaginal swab; TV testing is performed using a vaginal swab.  If a woman is menstruating, the swab may be 
collected at a later visit and all testing u9sing the swab may be performed at that later visit.  
3 Refer to the SSP Manual.  
4 The HIV testing algorithm is provided in the SSP Manual.  HIV rapid testing testing may be performed in the clinic or the 
laboratory.  At least one HIV test must be available the same day as sample collection and before product is administered.  
5  This testing will be performed for all study participants, regardless of HIV status or the results of other HIV tests. This 
testing must be performed with an assay with a lower limit of quantification of 50 copies/mL or lower.     
6 Only for those that did not have this collected in steps 4a and b. Albumin, BUN/urea, creatinine.  Additional testing may be 
required if abnormalities of clinical significance are detected. 
7 AST, ALT, total bilirubin.  
8 Total cholesterol, HDL, triglycerides, and LDL (either calculated or measured). Participants should have fasted for at 
least 8 hours, preferably 12 hours, prior to sample collection. If participants are not fasting, do not order the lipid 
testing. Participants may return for testing or it can be performed at next visit. 
9 Stored plasma may be used for Quality Assurance testing, possible HSV-2 testing and other assessments at the HPTN 
LC.  
10 Assessments on stored samples will be performed retrospectively; results will not be returned to study sites or 
participants, except as noted in the SSP.  
 
 
 

 
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d. Step 4d 
 
Participants who become pregnant during Step 4 and who received at least one CAB LA injection during 
HPTN 084 are eligible to participate in the Pregnancy and Infant Sub-Study.  In addition, participants in 
Step 5 who received a CAB LA injection within 8 weeks of pregnancy confirmation may join the 
Pregnancy and Infant Sub-Study. All participants interested in participating in Step 4d will be provided 
informed consent for this Step prior to any study activities. 
 
Appendix VIII: Schedule of Evaluations for Step 4d- Procedures for Pregnant/Breastfeeding 
Participants 
Time on Pregnancy  
and Infant Sub-
study 
Week 0 
Wee k 4 
Week 8 
Week 12 
Week 16 
Week 20 
Week 24 
Week 28 
Week 32 
Week 36 
Week 40 
Delivery 
Week 2, pp 
Week 4, pp 
Week 8, pp 
Week 16 pp 
Week 24, pp 
Week 32, pp 
Week 40, pp 
Week 48, pp 
Maternal assessments 
Informed Consent 
X                     
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Locator information 
X  X  X  X  X  X  X  X  X  X  X  
 
 
 
 
 
 X  X  X  X  X  
X 
Acceptability assessment 
X      X          X     
 
 
 
 
 
 
 
 
 
 
 X  
 
 
 
 
X 
Behavioral assessment 
X  X  X  X  X  X  X  X  X  X  X  
 
 
 
 
 
 X  X  X  X  X  
X 
HIV prevention counseling X  X  X  X  X  X  X  X  X  X  X  
 
 
 
 
 
 X  X  X  X  X  
X 
Offer condoms per local 
SOC 
X  X  X  X  X  X  X  X  X  X  X  
 
 
 
 
 
 X  X  X  X  X  
X 
Medical history, 
concomitant medications 
(including folate intake) 
X  X 
 
X  X  X  X  X 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
 
 
 
X  X  X  X  
X  
X 
Targeted physical exam 
including antenatal 
assessment per SOC 
X  X 
 
X  X  X  X  X 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
Ultrasound or refer to 
ultrasound 
 
     X               
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood collection  
X  X  X  X  X  X  X  X  X  X  X  X  X  X  X  X  X  X  X  
X 
Urine collection 1 
X   
  
  
  
  
 X         
 
 
 
 
 
 
 X  X  X  X  X  
X 
Vaginal swab collection1  
X            X         
 
 
 
 
 
 
 X  
 
 
 
 
 
 
 
 
X 
Breastmilk Collection, 
5mLs4 
 
                    
 
 
 X  X  X  X  X  
 
 
 
 
 
Adherence counseling2   
X  X  X  X  X  X  X  X  X  X  X  
 
 
 
 
 
 X  X  X  X  X  
X 
Contraceptive counseling 
 
                    
 
 
 
 
 
 
 X  X  X  X  X  
X 
Dispense/administer study 
product, as is appropriate 
X    X    X    X    X    X  
 
 
 
 
 
 X  X  X  X  
 
 
X 
ISR Assessment, only for 
PPTs receiving CAB LA 
injections 
 
 X    X    X    X    X   
 
 
 
 
 
 
 X  
 
 
 
 
 
 
 
 
X 
HIV testing3 
X  X  X  X  X  X  X  X  X  X  X  X  X  X  X  X  X  X  X  
X 
HIV viral load testing 4 
X  X  X  X  X  X  X  X  X  X  X  X  X  X  X  X  X  X  X  
X 
Pregnancy testing5   
 
                    
 
 
 
 
 
 
 X  X  X  X  X  
X 
CBC with differential 
X            X      X   
 
 
 
 
 
 
 X  
 
 
 
 
 
 
 
 
X 

 
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Time on Pregnancy  
and Infant Sub-
study 
Week 0 
Wee k 4 
Week 8 
Week 12 
Week 16 
Week 20 
Week 24 
Week 28 
Week 32 
Week 36 
Week 40 
Delivery 
Week 2, pp 
Week 4, pp 
Week 8, pp 
Week 16 pp 
Week 24, pp 
Week 32, pp 
Week 40, pp 
Week 48, pp 
Chemistry testing6    
X            X      X   
 
 
 
 
 
 
 X  
 
 
 
 
 
 
 
 
X 
Liver function testing7  
X            X      X   
 
 
 
 
 
 
 X  
 
 
 
 
 
 
 
 
X 
Syphilis testing 
X            X         
 
 
 
 
 
 
 X  
 
 
 
 
 
 
 
 
X 
Vaginal GC/CT and TV 
testing1 
X            X         
 
 
 
 
 
 
 X  
 
 
 
 
 
 
 
 
X 
Urinalysis (protein, glucose) X            X      X   
 
 
 
 
 
 
 X  
 
 
 
 
 
 
 
 
X 
Plasma storage8,9    
X  X  X  X  X  X  X  X  X  X   
 X  X  X  X  X  X  X  X  
X 
Breastmilk storage9,10 
 
                    
 
 
 X  X  X  X  X  
 
 
 
 
 
DBS storage for women on 
TDF/FTC only9,11 
X  X  X  X  X  X  X  X  X  X   
 X  
 
 X  X  X  X  
 
 
 
 
 
 
 
                    
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Infant assessments 
Pregnancy outcome 
assessment including 
abbreviated infant 
examination12 
 
  
 
        
         
 
 
 
 
 
 
 X  
 
 
 
 
 
 
 
 
X 
Infant feeding history 
 
                    
 
 
 
 
 
 
 X  X  X  
 
 
 
 
 
Infant HIV testing, if the 
mother is confirmed to 
have HIV infection13 
 
  
 
        
         
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cord blood storage9,14 
 
                    
 X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Infant plasma storage9,14 
 
                    
 X  X  X  X  X  X  
 
 
 
 
X 
 
NOTE: PK analysis will be performed on cord blood and infant plasma samples at an offsite laboratory.  
 
1  GC/CT NAAT testing may be performed using urine or a vaginal swab; TV testing is performed using a vaginal swab.  If a 
woman is menstruating, the swab may be collected at a later visit and all testing using the swab may be performed at that 
later visit.  
2 Refer to the SSP Manual.  
3 The HIV testing algorithm is provided in the SSP Manual. If HIV rapid testing is indicated, this testing may be performed in 
the clinic or the laboratory.  At least one HIV test must be available the same day as sample collection and before product is 
administered.   
4  This testing will be performed for all study participants, regardless of HIV status or the results of other HIV tests. This 
testing must be performed with an assay with a lower limit of quantification of 50 copies/mL or lower.     
5 Pregnancy testing may be done if indicated.  Pregnancy testing may be performed in the clinic or the laboratory. Testing 
may be performed using a urine, plasma, or serum sample. The assay used for pregnancy testing must have a limit of 
detection of 25 mIU/mL or lower. Pregnancy testing is not required at subsequent visits if a positive result is obtained and the 
participant is still pregnant.  
6 Albumin, BUN/urea, creatinine. 
7  AST, ALT, total bilirubin 
8 Stored plasma may be used for Quality Assurance testing and other assessments at the HPTN LC (see Section 9). 
9Assessments on stored samples will be performed retrospectively; results will not be returned to study sites or 
participants, except as noted in the SSP.  
10 Breastmilk collection does not need to be performed if the mother is not breastfeeding or producing milk.  
11 DBS will be stored for participants who elect to receive TDF/FTC. Processing and storage procedures will be described in 
detail in the SSP. Assessments will be performed retrospectively; results will not be returned to study sites or participants. 

 
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12 Whenever feasible, use delivery notes plus complete assessment in clinic. 
13  If HIV testing indicates that an infant has HIV infection, a second confirmatory visit should be conducted to confirm HIV 
infection in the infant. If infant infection is confirmed, resistance testing should be performed locally using a separate 
(additional) infant sample collected for this purpose. 
14 Samples will be used for PK analysis and may be used for other assessments, including virology testing. 
 
 
 
 
 

 
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e.  Step 5 
 
Appendix VIII: Schedule of Evaluations for Step 5- Procedures for Participants Taking OL 
TDF/FTC for 48 Weeks after Premature CAB LA discontinuation 
Time in Step 5 
Step 5, 
Day 0* 
Step 5,  
Week 12 
Step 5,  
Week 24 
Step 5,  
Week 36 
Step 5,  
Week 48 
ADMINISTRATIVE, BEHAVIORAL, REGULATORY 
 
Locator information 
X 
X 
X 
X 
X 
Acceptability assessment 
X 
 
 
 
X 
Behavioral assessment (if done in 
last 4 weeks, skip D0 and start at 
W12) 
X 
 
X 
 
 
X 
HIV prevention counseling 
X 
X 
X 
X 
X 
Offer condoms  
X 
X 
X 
X 
X 
CLINICAL EVALUATIONS & PROCEDURES 
 
Medical history, concomitant 
medications, targeted physical 
exam (with pulse, BP, weight 
and BMI calculated at each 
visit)  
X 
X 
X 
X 
X 
Blood collection 
X 
X 
X 
X 
X 
Urine collection  
X7 
X 
X 
X 
X 
Vaginal swab collection1  
X 7 
 
X 
 
X 
Adherence counseling2  
X 
X 
X 
X 
 
Dispense pills to all 
participants 
X 
X 
X 
X 
 
LOCAL LABORATORY EVALUATIONS & PROCEDURES 
HIV testing 3 
X 
X 
X 
X 
X 
HIV viral load testing4 
X 
X 
X 
X 
X 
Pregnancy testing5   
X 
X 
X 
X 
X 
Chemistry testing6   
X 
 
X 
 
X 
Liver function testing7 
X 
 
 
 
X 
Syphilis testing 
X7 
 
X 
 
X 
GC/CT and TV testing1 
X7 
 
X 
 
X 
Plasma storage8,9 
X 
X 
X 
X 
X 
DBS storage9 
X 
X 
X 
X 
X 
 
FOOTNOTES FOR Step 5, SOE 
* Day 0 of Step 5 should be scheduled no later than 8 weeks after the last injection.  Attempts should be made to bring the 
participant in earlier rather than later than the target date.  See SSP Manual for further details.       
1 GC/CT NAAT testing may be performed using urine or a vaginal swab; TV testing is performed using a vaginal swab.  If a 
woman is menstruating, the swab may be collected at a later visit and all testing using the swab may be performed at that 
later visit.  
2  Refer to the SSP Manual. 
3 The HIV testing algorithm is provided in the SSP Manual. If HIV rapid testing is indicated, this testing may be performed in 
the clinic or the laboratory.  At least one HIV test must be available the same day as sample collection and before product is 
administered.  
4  This testing will be performed for all study participants, regardless of HIV status or the results of other HIV tests. This 
testing must be performed with an assay with a lower limit of quantification of 50 copies/mL or lower.     
5 Pregnancy testing may be performed in the clinic or the laboratory at all visits where this testing is indicated. Results must 
be available the same day as sample collection and before product is administered. Testing may be performed using a urine, 
plasma, or serum sample. The assay used for pregnancy testing must have a limit of detection of 25 mIU/mL or lower. 

 
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Pregnancy testing is not required at subsequent visits if a positive result is obtained and the pregnancy is still ongoing. For  
Step 5, ONLY PARTICIPANTS WHO HAVE RECEIVED CAB LA WITHIN THE PAST EIGHT WEEKS may join the 
pregnancy sub-study (see Step 4d).Pregnancy outcome data will be collected from participants who join Step 4d. 
6 Chemistry testing includes: Albumin, BUN/Urea, creatinine. Skip Day 0 if testing has occurred within the last 3 months of 
Day 0, and do only at Weeks 24 and 48.  
7  Liver function testing includes: AST, ALT, Total bilirubin.  
8 Stored plasma may be used for Quality Assurance testing and other assessments at the HPTN LC. 
9 Assessments on stored samples will be performed retrospectively; results will not be returned to study sites or participants, 
except as noted in the SSP. 
 
 
 

 
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Schedule of Additional Procedures for Women with Reactive/ Positive HIV Tests 
 
It is possible that some participants may test positive for HIV during the OL portion of this trial.  
Site staff will follow procedures, see below, to confirm a participant’s HIV status and must 
contact the HIV alias group (084HIV@hptn.org) for guidance.   
 
Participants with a confirmed HIV infection must be linked to care as soon as possible (care is 
not provided by the study) and subsequently, the IOR must confirm that the participant has 
achieved viral suppression on antiretroviral treatment.  The participant’s ART regimen must be 
documented as concomitant medication.  Once viral suppression is confirmed, the participant 
will be terminated from the study. 
 
Note 1:  The procedures listed for the HIV Confirmation Visit apply to participants who acquire 
HIV infection at any time during the study.  Procedures will be determined by the members of 
084HIV@hptn.org.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Participants who acquire HIV infection 
HIV Confirmation 
Visit 
ADMININISTRATIVE, BEHAVIORAL, 
REGULATORY 
Locator information  
X 
Offer condoms  
X 
HIV counseling  
X 
CLINICAL EVALUATIONS AND PROCEDURES 
History, con meds, physical 
exam (with pulse, BP, weight 
and BMI calculated at each 
visit) 
X 
Blood collection 
X 
LOCAL LABORATORY EVALUATIONS 
HIV testing1 
X 
CD4 cell count  
X 
HIV viral load testing2 
X 
HIV resistance testing3 
X 
Chemistry testing4 
X 
Liver function testing5 
X 
Plasma storage6,7 
X 
DBS Storage7 
X 

 
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1 The HIV confirmatory visit must be held on a different day from the visit where the participant had their initial 
reactive/positive HIV test.  The testing algorithm for the HIV Confirmation Visit is provided in the SSP Manual. If HIV rapid 
testing is included in the HIV testing algorithm, this testing may be performed in the clinic or the laboratory.    Additional 
HIV testing may be requested by the 084HIV alias committee. 
2 This testing must be performed with an assay with a lower limit of quantification of 50 copies/mL or lower. 
3 Sites may collect specimens for resistance testing at a local laboratory to assist with clinical management; results from 
resistance testing performed at local laboratories will not be reported to the SDMC.  Stored plasma may not be used real-
time/local resistance testing; additional samples must be collected for this testing.     
4 Required chemistry testing: Albumin, BUN/urea, creatinine,  
5 Required LFTs: AST, ALT, total bilirubin,  
6 Stored plasma will be used for Quality Assurance testing and other assessments at the HPTN LC.   
7 Assessments on stored samples will be performed retrospectively; results will not be returned to study sites or participants, 
except as noted in the SSP.  Additional HIV testing may be requested by the 084 HIV alias committee. 
 
 
 
 
 
 

 
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A. Information in the Main Protocol that is Not Relevant to Protocol, Version 3.0       
  
Many sections of text, but not all, from the original/main protocol are no longer applicable; they pertain 
specifically to the original study design under protocol versions 1.0 and 2.0.  Material from the original 
protocol that is not relevant to this amendment is delineated in this Section, Section A (Information in 
the Main Protocol that is Not Relevant to Protocol, Version 3.0, dated 12 August 2021).  
 
Information from the following sections of the protocol are not relevant to Protocol Version3.0, dated 
12 August 2021: 
• Schema  
• Overview of Study Design and Randomization Scheme  
• Section 1.1 through Section 1.6, Section 1.8 through 1,11 
• Section 2.0, in full  
• Section 3.0: Sections 3.1, 3.2 and 3.3  
• Section 4.0: Section 4.5 
• Section 5.0: Section 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.9, 5.13, 5.15, and 5.18  
• Section 6.6 
• Section 7.0 in full (analyses from endpoints outlined are ongoing and pertain to the original study 
design and are not repeated in this Appendix) 
• Section 9.0 in full (all relevant information from this section of the protocol is included in the 
updated SSP section pertaining to this Appendix) 
• Section 10.2 
 
B. Information in the Main Protocol that is Relevant to Protocol, Version 3.0       
  
Material from the original protocol that is relevant to this amendment is delineated in this Section, 
Section B (Information in the Main Protocol that is Relevant to Protocol, Version 3.0, dated 12 August 
2021).  
 
The following front matter of Protocol, Version 3.0, dated 12 August 2021 is applicable:  
 
• Title page  
• Table of Contents 
• Protocol Signature Page  
• List of Abbreviations and Acronyms 
• Protocol Team Roster 
• Terminology for Cabotegravir and TDF/FTC Formulations  
 
SECTION 3.0 (MODIFIED FROM THE MAIN PROTOCOL) 
3.4 
Co-Enrollment:   
Participants may join a COVID-19 vaccine or treatment study, provided that participant study 
burden and American Red Cross-mandated limitations on per-unit-time phlebotomized blood 
volumes are not exceeded.  There is no need to consult the CMC for participation in this type of 

 
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COVID study.  However, the CMC should be consulted for participation in any other 
biomedical/intervention or observational study.  Co-enrollment in IMPAACT 2026 is prohibited. 
3.5 
Participant Retention:   
Sites will continue to implement all existing retention strategies and are encouraged to develop 
new strategies as needed.    
3.6 
Participant Withdrawal:    
Participants may voluntarily withdraw from the study for any reason at any time.  Participants 
may be withdrawn from the study if the study sponsor, government or regulatory authorities 
(including Office for Human Research Protections [OHRP] and the FDA) or site IRBs/ECs or if 
ViiV/Gilead terminate the study prior to its planned end date. Every reasonable effort will be 
made to complete a final evaluation of participants who terminate from the study prior to the 
final protocol-dictated study week, and study staff will record the reason(s) for all withdrawals 
from the study in participants’ study records.  In such cases, the IoR or designee must contact the 
CMC for guidance regarding final evaluation procedures.     
SECTION 4.0 (MODIFIED FROM THE MAIN PROTOCOL)        
4.1 
Study Product Regimens/Administration/Formulation Content:   
Study Product Regimens 
 
Step 4 
Step 4a -  CAB 30 mg tablets 
• Oral CAB  tablets, 30 mg, one tablet orally daily for four weeks, with or without food  
Step 4b – CAB LA 600 mg 
• CAB LA 600 mg administered as one 3 mL (600 mg) IM injection in the gluteal muscle 
one time 
 
Step 4c – CAB LA 600 mg   OR   TDF 300 mg/FTC 200 mg tablets 
• CAB LA 600 mg administered as one 3 mL (600 mg) IM injection in the gluteal muscle 
every 8 weeks for no longer than a total of 48 weeks 
• TDF/FTC 300 mg/200 mg fixed dose combination tablet, one tablet orally daily, with or 
without food for no longer than a total of 48 weeks 
 
Step 4d – CAB LA 600 mg   OR   TDF 300 mg/FTC 200 mg tablets 
• CAB LA 600 mg administered as one 3 mL (600 mg) IM injection in the gluteal muscle 
every 8 weeks for the duration of the pregnancy and up to 48 weeks after delivery 
• TDF/FTC 300 mg/200 mg fixed dose combination tablet, one tablet orally daily, with or 
without food for the duration of the pregnancy and up to 48 weeks after delivery 
 
Step 5 
Step 5- TDF 300 mg/FTC 200 mg tablets 

 
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• TDF/FTC 300 mg/200 mg fixed dose combination tablet, one tablet orally daily, with or 
without food for no longer than a total of 48 weeks 
 
The CAB study product (oral and LA injectable) being tested in this study is investigational and 
not yet approved by the US FDA for the prevention of HIV-1 infection.   Injectable CAB-LA in 
combination with RPV-LA (CABENUVA®) is approved for the treatment of HIV-1 infection by 
the U.S. FDA. 
Further information on the study product is available in the Investigator’s Brochure (IB), which 
will be provided by the DAIDS Regulatory Support Center (RSC). 
Oral Study Products    
• Cabotegravir (CAB) 30 mg tablets are formulated as white to almost white oval-shaped 
coated tablets for oral administration. The tablets are packaged in high density polyethylene 
(HDPE) bottles with child-resistant closure that include an induction seal. The bottles contain 
30 tablets and a desiccant. The tablets must be stored in the original container. The bottles are 
to be stored up to 30° C (86o F) and protected from moisture. 
 
• TDF 300 mg/FTC 200 mg tablets are capsule-shaped, film-coated blue tablets that must be 
stored in the original container. Each bottle contains a silica gel desiccant canister to protect 
the product from humidity. The bottles are to be stored at 25° C (77° F). Excursions are 
permitted between 15° to 30°C (59 to 86°F).  The TDF/FTC fixed dose combination tablet 
containing 300 mg of tenofovir disoproxil fumarate (TDF) and 200 mg of emtricitabine 
(FTC) is available as Truvada® and is approved by the U.S. FDA for treatment and 
prevention of HIV-1 infection. Further information on Truvada® is available in the current 
package insert. 
 
Injectable Study Product 
• CAB LA is formulated as a sterile white to slightly pink colored suspension containing 200 
mg/mL of CAB LA for administration by IM. The product is packaged in a 2mL or 3 mL 
glass vial.  Each vial is for single use containing 2mL (400 mg), or 3mL (600mg), and does 
not require dilution prior to administration. CAB LA injectable suspension is to be stored up 
to 30o C (86oF), do not freeze.  
4.2 
Study Product Preparation: 
Prescription 
A prescription for all unblinded study product signed by an authorized prescriber must be 
provided to the site pharmacist prior to preparation of study product.  The prescription must 
include the Step number (4a, 4b, 4c, 4d or 5) and a notation if the participant is switching 
between CAB arm and TDF/FTC arm.  
 
Study Product Preparation  
The site pharmacist must consult the Pharmacy Guidelines and Instructions for DAIDS Clinical 
Trials Networks for standard pharmacy operations.   
 

 
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Preparation of Oral Study Product  
CAB 30 mg Oral Product 
The pharmacist will take the following steps to prepare and dispense un-blinded active oral CAB 
to the participant: 
 
1) Retrieve oral active CAB 30mg tablet bottle with two part-label from Step 2 supply. 
 
2) Retain both the un-blinded part and the blinded part of the two-part label on 
the CAB bottle. Do not tear off the un-blinded part of the two-part label from the 
bottle. 
 
3) Place pharmacist-prepared, participant- specific, un-blinded label in such a way 
 
that the blinded part of the two-part label on the bottle is covered. 
 
The pharmacist prepared, participant-specific, un-blinded oral active CAB bottle will have the 
manufacturer’s unblinded part of the two-part label and site pharmacist generated participant 
specific un-blinded label visible on the prepared bottle before dispensation. 
The participant specific label must be in accordance with the local regulations and the DAIDS 
Pharmacy Guidelines manual. 
The pharmacist will dispense sufficient quantity to last until the next follow-up visit plus 
approximately one-month buffer supply. Pharmacists will record dispensations on the Pharmacy 
Accountability Logs. 
 
TDF/FTC (300 mg/200mg) Oral Product   
The pharmacist will take the following steps to prepare and dispense un-blinded active oral 
TDF/FTC to the participant:  
 
1) Retrieve oral active TDF 300 mg/FTC 200 mg with two-part label from Step 2 
supply.  
2) Retain both the un-blinded part and the blinded part of the two-part label on the 
TDF/FTC bottle. Do not tear off the un-blinded part of the two-part label from the 
bottle.   
3) Place pharmacist prepared participant-specific un-blinded label in such a way that 
the blinded part of the two-part label on the bottle is covered.   
 
The pharmacist-prepared, participant-specific, un-blinded oral active TDF/FTC bottle will have 
the manufacturer’s unblinded part of the two-part label and site pharmacist generated participant-
specific un-blinded label visible on the prepared bottle before dispensation. 
Alternatively, retrieve open-label oral active TDF/FTC supply from Step 3 supply if the site no 
longer has oral active TDF/FTC bottles with a two-part label from Step 2 supply. Place 
pharmacist prepared participant-specific un-blinded label on the bottle and dispense 

 
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The participant specific label must be in accordance with the local regulations and the DAIDS 
Pharmacy Guidelines manual. 
The pharmacist will dispense sufficient quantity to last until the next follow-up visit plus 
approximately one-month buffer supply. Pharmacists will record dispensations on the Pharmacy 
Accountability Logs. 
Injectable CAB LA 600 mg/3mL  
The site pharmacist(s) must be proficient in the preparation of injectable study products using 
aseptic technique under a pharmacy biological safety cabinet (BSC) Class II or better. Local 
regulations and site institutional policies and procedures for use of personal protective 
equipment, such as gloves, gowns, masks, and safety glasses, must be followed. 
The designated site pharmacy personnel will follow the steps below for preparation of active 
injectable study product, CAB LA injectable suspension. In Steps 4b, 4c and 4d of the study ((as 
is appropriate), one syringe containing 3 mL (600 mg) of CAB-LA must be prepared using 
aseptic technique under a pharmacy BSC/Isolator. 
Materials required for preparation and administration of CAB LA 600mg; 3 mL dose: 
• One CAB LA 600 mg/3 mL vial or two CAB LA 400 mg/2 mL vials 
• Becton Dickenson (BD) 3-mL syringe, Luer-Lok Tip, Product No.: 309657 or equivalent 
• Becton Dickinson (BD) 5-mL Syringe, Luer-Lok Tip, Product No.: 309646 or equivalent 
• Needle for aspiration: BD general use sterile hypodermic needle, 21G x 1½ inch (e.g. 
PrecisionGlide Needle, Product No.: 305165 or equivalent) 
• Needle for intramuscular injection: BD IM sterile hypodermic needle, 23G x 1½ inch (e.g. 
PrecisionGlide Needle, Product No.: 305194 or equivalent).  Refer to the HPTN 083 SSP for 
further details on appropriate needle gauge size and length to use for IM administration. 
 
Preparation Steps: 
• Remove two vials of CAB LA (400 mg/2 mL per vial) or one vial of CAB LA (600 mg/3 mL 
per vial) from storage.  If the vials are stored in the refrigerator (2°C to 8°C), remove vial(s) 
from the refrigerator and wait at least 15 minutes to equilibrate to room temperature. 
 
• Hold the vial firmly and vigorously shake the vial(s) for a full 10 seconds. 
 
• Invert the vial(s) and inspect to ensure uniform suspension.  If solid remains undispersed, 
repeat vigorous shaking and inversion until all material is uniformly suspended. 
 
o NOTE: It is normal to see small air bubbles at the end of shaking the vial for re-
suspension. 
 
• Using aseptic technique under a pharmacy BSC/isolator, flip off the plastic cap from the vial. 
Wipe the top of the vial with an alcohol pad (isopropyl alcohol 70% or similar) and allow to 
dry. Do not allow anything to touch the rubber stopper after wiping it. 
 

 
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• Remove a 3 mL or 5 mL size syringe and 21G x 1½ inch (or equivalent) needle for 
aspiration.  Attach the needle to the Luer connection of the syringe. 
 
• With the needle sheath on, pull the syringe plunger rod to allow approximately 1 mL of air 
into the syringe. Remove the needle sheath.  
 
• With the vial in the inverted position and the syringe with the needle in the upright position, 
push the needle through the vial stopper and inject approximately 1 mL of air into the vial.  
 
• While keeping the syringe with the needle in the upright position, withdraw needed volume 
of CAB LA suspension from the vial(s) into the syringe.  
 
• Withdraw total of 3 mL (600 mg) of CAB LA suspension from the vial(s) into a syringe. 
o If using two CAB LA 400 mg/2 mL vials to prepare the dose, a second new aspiration 
needle should be used to withdraw suspension from the second vial. Remove the first 
needle that was used to withdraw the suspension out of the first vial and discard 
properly. Attach the new 21G x 1½ inch needle (or equivalent) to the syringe already 
containing suspension per instructions above to withdraw the remaining needed 
volume from the second vial. 
 
o Since the suspension can contain some air after having shaken the vial, withdraw 
enough suspension from the vial in order to be able to de-aerate the syringe properly. 
 
• Remove the needle that was used to withdraw the suspension out of the vial and discard the 
needle properly. 
 
• Attach a 23G x 1½ inch (or equivalent) needle to the Luer connection of the prepared CAB 
LA syringe for IM injection for the participant. Alternatively, the site pharmacist can attach a 
syringe cap to the prepared syringe. The study staff can then attach the appropriate needle for 
administration to the prepared syringe in the clinic before administration. 
 
o NOTE: The participant-specific prepared CAB LA in a syringe is to be de-aerated by 
administrator prior to injection so that the correct volume can be administered. 
 
▪ De-aerate the syringe by first tapping with a finger against the syringe and 
then by moving the plunger rod carefully forward with the needle in an 
upright position until the first drop of suspension appears.  Remove the excess 
suspension in order to administer the correct volume (3 mL).  If needed, 
collect the excess suspension in a beaker to avoid spilling. 
 
• Record the time that the suspension was withdrawn from the vial and into the syringe in the 
participant’s pharmacy log.  This is the time of preparation. 
• The overlay tape that covers the syringe barrel of the prepared unblinded, injectable CAB LA 
in a syringe is not required 
 

 
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• Label the prepared syringe containing 3 mL (600 mg) of CAB-LA as “CAB LA 600 mg per 
3 mL”, including the volume (3 mL), route (IM), participant’s PTID, date and time of 
preparation, and date and time of expiration. Follow the DAIDS Pharmacy guidelines and 
local regulations for preparing the participant specific label. 
 
After withdrawal of the CAB-LA suspension from the vial into a syringe, it is recommended 
to inject the suspension immediately. Once the CAB LA suspension has been drawn into the 
syringe, the medication can remain in the syringe for up to 2 hours before injecting. If 2 
hours are exceeded, the medication, syringes, and needles must be discarded.  
 
The prepared CAB LA study product in a syringe must be stored at controlled room 
temperature between 20°C to 25°C (68°F-77°F) from the time it is withdrawn into a syringe 
to the time it is administered. 
 
Any entered vials or expired filled syringes should be disposed of in accordance with 
institutional or pharmacy policy. 
 
4.3 
Study Product Acquisition and Accountability   
CAB 30 mg tablets and CAB LA injectables are manufactured and provided by ViiV Healthcare.  
TDF 300 mg/FTC 200 mg tablets and Placebo for TDF/FTC tablets are manufactured and 
provided by Gilead Sciences, Inc. 
All study products will be supplied through the National Institute of Allergy and Infectious 
Diseases (NIAID) Clinical Research Products Management Center (CRPMC). The study site 
pharmacist can obtain all the study products through the CRPMC by following the instructions in 
the Pharmacy Guidelines and Instructions for DAIDS Clinical Trial Networks, and instructions 
in the SSP Manual.    
The site pharmacist is required to maintain complete records of all study products received from 
the CRPMC and subsequently dispensed to study participants. All study products must be stored 
in the pharmacy. At US clinical research sites, all unused study products must be returned to the 
CRPMC after the study is completed, terminated or otherwise instructed by the study sponsor. 
The procedures to be followed are provided in the Pharmacy Guidelines and Instructions for 
DAIDS Clinical Trials Networks. The site pharmacist at non-US clinical research sites must 
follow the instructions in the Pharmacy Guidelines and Instructions for DAIDS Clinical Trials 
Networks DAIDS Pharmaceutical Affairs for the destruction of unused study products. 
4.4  Other Study Product Dispensing Considerations 
While it is not required, it is recommended that sites dispense an additional bottle of study 
product (TDF/FTC or CAB) to ensure an extra month supply between visits.  For example, for 
participants initiating CAB, sites should dispense two bottles of oral CAB to cover the 4-week 
period prior to the first injection.  Participants should be advised to bring open bottles to 
appointments, finish an open bottle before opening a new one, and should not combine or 
transfer pills between open bottles. Formal pill counts are not required under the procedures of 
this Appendix. 

 
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4.6 
Concomitant, Prohibited, and Precautionary Medications 
All concomitant medications/preparations (prescription and non-prescription) including 
alternative/complementary medications/preparations (e.g., herbs, vitamins, etc.) will be collected 
in the study participant’s chart and on study case report forms (CRFs).  
In order to avoid AEs caused by drug interactions, whenever a concomitant medication is taken, 
site staff must review the concomitant medication's and study product’s most recent PI for 
TDF/FTC and the IB for cabotegravir to obtain the most current information on drug interactions 
and contraindications.  Concomitant medications (prescription and non-prescription) should be 
administered only as medically necessary during the study.  
 
For any precautionary or prohibited drug listed in the TDF/FTC PI or cabotegravir IB, it is 
required that the HPTN 084 CMC be notified for recommendations for continuing or stopping 
(or holding) study product.     
Experimental agents not otherwise specified in the SSP Manual may not be administered. 
Precautionary and prohibited medications (as of the time this section was written) are listed 
below. 
Cabotegravir: 
• Not to be administered concurrently: 
o Cytotoxic chemotherapy or radiation therapy 
o barbiturates 
o carbamazepine 
o oxcarbazepine 
o phenytoin 
o pheonobarbital 
o rifabutin 
o rifampin 
o rifapentine 
o St. John’s wort 
NOTE: Prohibition of concurrent immunomodulators and systematically administered 
immunomodulators has been removed per the updated IB, version 10.0, Effective Date 06 
January 2021.  Co-administration of methotrexate and CAB LA is now permitted. 
• Prohibited within 7 days before and 7 days after an injection 
o high dose aspirin (>325 mg per day) 
o anagrelide 
o apixaban 
o argatroban 
o bivalirudin 

 
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o clopidogrel 
o dabigatran 
o dalteparin 
o enoxaparin 
o fondaparinux 
o heparin 
o lepirudin 
o prasugrel 
o rivaroxaban 
o ticagrelor 
o ticlopidine 
o warfarin 
• Oral formulation precautions 
o Antacid products containing divalent cations (e.g., aluminum, calcium, and magnesium) 
must be taken at least 2 hours before or at least 4-6 hours after the oral CAB 
administration  
TDF/FTC (Truvada®): 
• Not to be administered concurrently: 
o emtricitabine or tenofovir disoproxil fumarate (e.g. ATRIPLA®, COMPLERA®, 
EMTRIVA, GENVOYA®, ODEFSEY®, STRIBILD®, or VIREAD, Descovy). 
o lamivudine (e.g. Combivir, Dutrebis, Epivir, Epivir-HBV, Epivir A/F, Epzicom, 
Triumeq, or Trizivir) 
o adefovir (e.g. HEPSERA®) 
o tenofovir alafenamide (e.g. Vemlidy) 
o didanosine (e.g. Videx EC) 
o atazanavir (e.g. Reyataz, Evotaz (atazanari/cobicistat)) 
o ledipasvir/sofosbuvir (e.g. HARVONI®) 
o darunavir (e.g. Prezista) 
o lopinavir/ritonavir (e.g. Kaletra) 
o orlistat (e.g. Alli, Xenical) 
 
Additional information regarding recommended, prohibited, and precautionary concomitant 
medications can be found in the cabotegravir IB and the Truvada® PI.   
Refer to SSP for NSAIDS and considerations for co-administration of precautionary and 
prohibited medications. 
   

 
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SECTION 5.0 (MODIFIED FROM THE MAIN PROTOCOL)        
Procedures for protocol version 3.0, dated 12 August 2021, are included in the Schedules of 
Evaluation for Steps 4a, 4b, 4c, 4d, and 5.  The HIV testing algorithm is included in the updated 
SSP.  Sites will refer to that and will follow the Schedule of Additional Procedures for 
Reactive/Positive HIV Tests as is appropriate.  
5.8 
Injection Visit Windows 
Target windows for all visits are outlined in the SSP Manual.  It is not required to contact the 
CMC regarding visit window timing as long as injections are administered in accordance with 
the below: 
- For the Week 0 injection of Step 4c, the injection must be given with a minimum of 3 weeks’ 
time and a maximum of 10-12 weeks’ time from the injection in Step 4b. 
- For all other injections during Steps 4c and 4d, injections must be given with a minimum of 3 
weeks.  
An injection visit may never be completed without preceding safety laboratory assessments 
being completed and all the assessments being resulted and protocol-allowable. 
The CMC must be contacted for guidance for any scenarios that deviate from the above 
parameters. 
5.10  Procedures for Participants in Step 4 Who Do Not Complete the Full Course of Study 
Product 
Premature Discontinuations for Step 4a  
Participants in Step 4a of the study who are unable to transition to Steps 4b and 4c for any reason 
AND who have not had a dose of CAB LA in the past 48 weeks – including HIV infection - will 
be referred to local care and terminated from the study.    
Premature Discontinuations for Steps 4b and 4c  
Participants in Step 4b or 4c of the study who prematurely stop injections will transition to Step 
5, unless study product is discontinued for HIV infection or for an AE/circumstance where OL 
TDF/FTC is contraindicated.  Participants for whom OL TDF/FTC is contraindicated will be 
followed according to the SOE for Step 5, excluding study product dispensing and adherence 
counseling. 
Participants with HIV infection detected in Steps 4b or 4c will be followed per the Schedule of 
Additional Procedures for Reactive/Positive HIV Tests. 
5.11 
Participants with Suspected of Confirmed HIV Infection 
Refer to the updated SSP as well as the Schedule of Additional Procedures for Reactive/Positive 
HIV Tests in this protocol Appendix. 

 
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Sites will continue to contact the 084HIV@hptn.org email alias any time a participant has a 
reactive HIV test result for guidance regarding clinical management or other questions.      
5.12 
STIs 
 
Testing for Neisseria gonorrhoeae (GC)/Chlamydia trachomatis (CT), Trichomonas vaginalis 
(TV) and syphilis will occur throughout the study. Testing will be performed at local 
laboratories.  
Participants will be referred for treatment of STIs as per local guidelines. Symptomatic screening 
for STIs beyond what is required by the protocol will be at a site’s discretion and cost.   
Testing may be adjusted or prioritized at the discretion of the site investigator if there is a 
potential for shortage of supplies for collection and testing. Please see CDC recommendation 
September 8 2020.  https://www.cdc.gov/std/general/DCL-Diagnostic-Test-Shortage.pdf. 
5.14 
Pregnancy 
Confirmed Pregnancies 
Participants with a positive pregnancy test will require confirmation of pregnancy at a 
subsequent visit at least TWO weeks later. All pregnancies that occur during the course of the 
study must be reported to the CMC within seven days of site awareness (either upon 
confirmation by urine or blood pregnancy testing during a study visit or as reported by the 
participant between study visits). Site staff will refer to their SOP for detailed management. 
The site IoR or designee will refer pregnant participants to all applicable pregnancy-related 
services and will be provided a letter to obstetric services detailing participation in the trial; 
however, sites will not be responsible for paying for pregnancy-related care.  The site IoR or 
designee will counsel any participants who become pregnant regarding possible risks to the fetus 
according to site-specific SOPs.   
 
Participants who have received at least one injection of CAB LA during HPTN 084 or HPTN 
084-01, or who received an injection within the previous eight weeks and are in Step 5 are 
eligible to join the Pregnancy and Infant Sub-Study.  Procedures in Step 4d for 
Pregnant/Breastfeeding Participants must be followed. 
5.16  Acceptability Assessments 
Acceptability of CAB LA and daily use of TDF/FTC will be continued to be assessed through 
administration of brief behavioral surveys conducted every six months during this 
amendment.  The surveys will include, but not be limited to, questions about participants’ 
attitudes/beliefs towards CAB LA and TDF/FTC; product-related preferences and choice. In 
addition, the qualitative sub-study, conducted in four sites, will continue with some additional 
modifications.  
 
 
 

 
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Qualitative Sub-study 
Qualitative sub-study participants who were recruited during the blinded trial (both “continuing” 
participants and those recruited as “special cases”) will be invited for a final interview. This final 
interview will explore women’s preferences and choice of PrEP product (or no product), 
including how her perception of HIV risk, desires for pregnancy, partner dynamics or other 
contexts influence that choice. The interview will also elicit recommendations for additional 
information and service delivery strategies that might support women’s access and use of CAB 
LA and PrEP more generally beyond clinical trial settings.  
Several additional activities will be conducted within the qualitative sub-study, including 
interviews with male partners and other key informants and up to two participatory workshops. 
As is appropriate, separate informed consent will be collected. 
1. In each site, a total of 5-6 male partners of qualitative sub-study participants will be invited 
to participate in a qualitative interview. The qualitative study team in each site will identify 
sub-study participants who represent different product-related experiences and who would be 
interested/willing to facilitate their partner’s engagement in the study. Male partner 
interviews will explore disclosure and/or couple decision-making about trial participation and 
product use, perceived risks and benefits of injectable and oral PrEP use, questions about 
product use during pregnancy, use by a partner, and impact of trial participation on couple 
relationship.  
 
2. In each site, a total of 5-6 community-based healthcare providers and/or other key informants 
(CBO stakeholders or others) will be invited to participate in a qualitative interview to 
explore perceptions about CAB LA and other PrEP modalities, required information, tools 
and strategies to integrate delivery of CAB LA into other services, and perspectives about 
how to increase demand for and uptake of injectable and oral PrEP within different 
populations (e.g., adolescents and young women, pregnant and breastfeeding women etc).   
 
3. Finally, teams in each site will convene one to two participatory workshops that include a 
mix of participants who represent target end-user group(s), providers and community 
representatives. They will review findings from the qualitative sub-study, make use of design 
strategies (e.g., personnas, journey maps, scenario development); and draft potential 
messages and/or strategies that support uptake, use and/or transitions between PrEP products, 
including CAB LA.    
5.17  Interim Contacts and Visits 
Refer to SSP Appendix for guidance.   
5.19  Criteria for Early Termination of Study Product 
Participants may voluntarily withdraw from the study for any reason at any time. Site IoRs may, 
with the agreement of the CMC, Protocol Chairs, DAIDS MO, and study statistician withdraw 
participants before their scheduled termination visit to protect their safety, the safety of the staff, 
and/or if participants are unable or unwilling to comply with study procedures. Participants also 
may be withdrawn if the study sponsors, government or regulatory authorities (including the 

 
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OHRP and US FDA), or site IRBs/ECs or ViiV/Gilead terminate the study prior to its planned 
end date. Study staff will record the reason(s) for all withdrawals in participants’ study records. 
SECTION 6.0 (NOT MODIFIED FROM THE MAIN PROTOCOL)        
6.1 
 AE Definition and Reporting 
An AE is defined as any untoward medical occurrence in a clinical research participant 
administered an investigational product and which does not necessarily have a causal 
relationship with the investigational product. As such, an AE can be an unfavorable or 
unintended sign (including an abnormal laboratory finding, for example), symptom or disease 
temporally associated with the use of an investigational product, whether or not considered 
related to the product. 
Study participants will be provided a 24-hour telephone number and contact information and 
instructed to contact the study clinician to report any AEs they may experience. For life-
threatening events, they will also be instructed to seek immediate emergency care. Where 
feasible and medically appropriate, participants will be encouraged to seek evaluation where the 
study clinician is based, and to request that the clinician be contacted upon their arrival. With 
appropriate permission of the participant, whenever possible, records from all non-study medical 
providers related to AEs will be obtained and required data elements will be recorded on study 
CRFs. All participants reporting an AE will be followed clinically, until the AE resolves (returns 
to baseline) or stabilizes. 
Study site staff will document in source documents and the appropriate CRF AEs  reported by or 
observed in enrolled study participants regardless of severity and presumed relationship to study 
product. AE severity will be graded per the DAIDS Table for Grading Adult and Pediatric 
Adverse Events, Corrected Version 2.1, July 2017. This version will be used for the entire 
duration of the study. 
The expedited AE reporting period for this study is from Enrollment (Week 0) until follow-up in 
the study ends. 
After the protocol-defined AE reporting period, unless otherwise noted, only SUSARs as defined 
in Version 2.0 of the EAE Manual will be reported to DAIDS if the study staff become aware of 
the events on a passive basis (from publicly available information). 
 
Relatedness is an assessment made by a study clinician of whether or not the event is related to 
the study agent. The relationship of all AEs to study product will be assessed as specified in 
Version 2.0, January 2010 of the DAIDS EAE Reporting Manual.   
6.2 
 EAE Reporting 
Requirements, definitions, and methods for expedited reporting of AEs are outlined in Version 
2.0 of the DAIDS EAE Manual, which is available at https://rsc.niaid.nih.gov/clinical-research-
sites/manual-expedited-reporting-adverse-events-daids. 

 
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6.2.1  Reporting to DAIDS 
The DAIDS Adverse Event Reporting System (DAERS), an internet-based reporting system, 
must be used for EAE reporting to DAIDS. In the event of system outages or technical 
difficulties, EAEs may be submitted via the DAIDS EAE form. For questions about DAERS, 
please contact CRMSSupport@niaid.nih.gov. Site queries may also be sent with the DAERS 
application itself. 
If the DAERS website or site internet is non-functional, sites will submit expedited AEs by 
documenting the information on the current DAIDS EAE form. This form is available on the 
RSC website:  https://rsc.niaid.nih.gov/clinical-research-sites/paper-eae-reporting. For questions 
about EAE reporting, please contact the RSC at DAIDSRSCSafetyOffice@tech-res.com. 
6.2.2  Reporting Requirements for This Study 
The SAE Reporting Category, as defined in Version 2.0 of the DAIDS EAE manual, will be used 
for this study (the definition of an SAE is also included in the manual).   
In addition to SAEs, sites will report in an expedited manner the following:   
• ALT ≥ 3xULN AND total bilirubin ≥ 2xULN (must be both in order to require expedited 
reporting) 
• Any seizure event 
These reporting requirements are for each study participant from Enrollment (Week 0) until 
follow-up in the study ends. After this time, sites must report serious, unexpected, clinical 
suspected adverse drug reactions if the study site becomes aware of the event on a passive basis, 
i.e., from publicly available information. 
The study agents for the purposes of EAE reporting are: Oral CAB 30 mg oral tablet; CAB LA 
injectable suspension (200 mg/mL); TDF/FTC fixed dose combination tablet containing 200 mg 
of FTC and 300 mg of TDF (also outlined in Section 4.0). 
In addition to submitting EAE information to the DAIDS Safety Office via DAERS, the site 
investigator may be required to submit AE and EAE information to local regulatory agencies or 
other local authorities. 
Information on Grade 1 and higher AEs will be included in reports to the US FDA, and other 
government and regulatory authorities as applicable. Site staff will report information regarding 
AEs to their IRB in accordance with all applicable regulations and local IRB requirements. 
6.2.3  Grading Severity of Events 
The Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, 
Corrected Version 2.1, July 2017, will be used for the entire duration of the study for 
determining and reporting the severity of AEs. The DAIDS grading table is available on the 

 
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DAIDS RSC website at https://rsc.niaid.nih.gov/clinical-research-sites/daids-adverse-event-
grading-tables. 
6.3 
 Safety Monitoring 
Close cooperation between the Protocol Chair, study site Investigator(s), DAIDS Medical 
Officer, LOC Clinical Research Manager, SDMC Biostatistician, SDMC Clinical Affairs Staff, 
HPTN LC, and other study team members will be necessary in order to monitor participant 
safety and to respond to occurrences of toxicity in a timely manner.  
The study site Investigators are responsible for continuous close monitoring and management of 
AEs. Sites are required to have detailed SOPs describing methods for AE reporting and toxicity 
management to ensure that AEs are reported and managed in accordance with the protocol and 
for alerting the CMC (outlined below) if unexpected concerns arise. 
A sub-group of the Protocol Team, including the Protocol Chair, DAIDS Medical Officer, and 
other site investigators will serve as members of the CMC. The CMC provides support to sites 
regarding individual participant clinical management (e.g., questions related to eligibility, 
toxicity management, clinical holds of study drug, etc.). Sites will be instructed to not solicit 
guidance from the CMC regarding HIV seroconversions in order to ensure to the extent possible 
that the team is blinded to the number of infections occurring in the study. The HPTN LC will be 
available for questions regarding HIV confirmation testing. 
6.4 
 Clinical Data Review 
A multi-tiered safety review process will be followed for the duration of this study. The study 
site investigators are responsible for the initial evaluation and reporting of safety information at 
the participant level, and for alerting the CMC if unexpected concerns arise.   
Participant safety data is also monitored by the SDMC Clinical Affairs staff who review 
incoming safety data for completeness and consistency on an ongoing basis. Events identified as 
questionable, inconsistent, or unexplained will be queried for verification.  
AE reports submitted in an expedited manner to the DAIDS Safety Office will be forwarded to 
the DAIDS Medical Officer for review and possible reporting to the FDA as a Safety Report. 
The SDMC will prepare routine reports of study conduct for the Study Monitoring Committee 
(SMC), which will meet by conference call approximately every 6 months. More frequent or ad 
hoc reviews may be conducted by the SMC as needed. 
This study also will be monitored by a NIAID Data and Safety Monitoring Board (DSMB), 
which will meet at least annually to review safety and efficacy data.  More frequent or ad hoc 
reviews of safety data may be conducted by the DSMB as needed.  
6.5 
 Social Harms Reporting 
It is possible that participants' involvement in the study could become known to others, and that a 
social harm may result (i.e., because participants could be perceived as being HIV-infected or at 

 
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"high risk" for HIV infection).  For example, participants could be treated unfairly, or could have 
problems being accepted by their families and/or communities.  These are social harm 
events.  Social harms events are those negative events that a participant reports as affecting them 
as a result of being involved in a research study, not the researcher’s opinion of how they 
perceive an event has affected a participant.  A social harm that is reported by the participant and 
judged by the IoR/designee to be serious or unexpected will be reported to the responsible site’s 
IRBs at least annually, or according to their individual requirements.  Social harms will be 
collected and reported on CRFs during regular visits.  In the event that a participant reports a 
social harm, every effort will be made by study staff to provide appropriate care and counseling 
to the participant as necessary, and/or referral to appropriate resources for the safety of the 
participant.  Each site will provide such care and counseling in accordance with standardized 
guidance in the SSP Manual.  While maintaining participant confidentiality, study sites may 
engage their Community Advisory Board in exploring the social context surrounding instances 
of social harms, to minimize the potential occurrence of such an impact. In addition to social 
harms, any benefits of study participation will also be collected and reported into the database. 
SECTION 7.0 (MODIFIED FROM THE MAIN PROTOCOL) 
Throughout this section the start of OL Cab LA period will be defined as the (site-specific) date 
that the OLE extension is approved for those originally randomized to the Cab LA arm and as the 
date that a participant begins use of Cab (injectable or OLI) for those originally randomized to the 
TDF/FTC arm.  
 
Participants will be censored from the OL Cab efficacy and safety analyses using an On-Blinded-
Study-Product (OBSP) approach i.e. at the end of study participation or 10 weeks after the date of 
last Cab injection (6 weeks, if only one injection has been given), whichever comes first. 
 
ITT analyses of Cab vs TDF/FTC incidence will be restricted to the blinded and unblinded study 
periods. OBSP estimates of Cab incidence will use data from the blinded, unblinded and OLE 
periods. 
 
OLE objectives: 
• To estimate the incidence of HIV among participants who use CAB LA, combining blinded, 
unblinded and OL periods 
 
The number of infections and cumulative person-years will be computed by combining the total 
follow-up time of those randomized to the CAB LA arm together with the follow-up time from 
start of OL Cab LA in those randomized to the TDF/FTC arm. The HIV incidence rate will be 
calculated as the total number of participants with confirmed incident HIV infection follow-up, 
divided by the accumulated person-years. OBSP censoring will be used. Corresponding 95% CIs 
will be calculated based on Poisson assumptions. Additional estimates will be made for each 
subperiod (blinded, unblinded, OL). 
• To evaluate the safety of open-label CAB LA with and without an oral lead-in over 48 weeks 
 

 
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We will tabulate all AEs with maximum grade >2 for those receiving OL CAB LA overall 
among those with and without an oral lead-in. Event rates and 95% robust confidence intervals 
will be calculated using a log-linear model for counts using log(person-time) as an offset, 
assuming a Poisson distribution and using a robust variance (i.e. generalized estimating 
equations). OBSP censoring will be used. 
 
Laboratory findings for CBC, chemistries (urea, creatinine, glucose, calcium), liver function 
(AST, ALT, total bilirubin, alkaline phosphatase) and fasting lipid profile (total cholesterol, 
triglycerides, HDL, LDL) will be reported by grade, as defined in the “Division of AIDS 
(DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events”. The proportion 
of laboratory findings qualifying as Grade 2 or above will be presented. Laboratory values as 
median, 1st and 3rd quartiles, min and max.  
 
In a supplementary analysis we will compare AE rates during the OL CAB LA period to AE 
rates in the CAB LA arm and the TDF/FTC arm (separately) during the blinded and unblinded 
periods. 
• To evaluate the acceptability (uptake, continuation, discontinuation) of OL CAB LA over 48 
weeks  
 
The proportion of participants who start/continue CAB LA during the OL period will be reported 
overall and by original randomization arm, along with 95% CI. Time from initiation of injections 
to discontinuation, defined as not receiving an injection within 12 weeks of the prior injection, 
will be plotted using the product limit method i) using all follow-up time on CAB LA (blinded, 
unblinded and OL) and ii) for those starting CAB LA during the OL period only.  
 
• To estimate the incidence of pregnancy among participants during the OL period 
 
Tables will summarize the number of pregnancies and pregnancy rate. The pregnancy rate and 
95% robust confidence interval will be calculated from a log-linear model for counts using 
log(person-time) (excluding time spent pregnant) as an offset, assuming a Poisson distribution, 
and using a robust variance (i.e. generalized estimating equations). 
• To evaluate safety and infant outcomes among pregnant participants  
 
Safety events, as described above, will be tabulated before, during and up to 24 weeks after 
pregnancy for women who become pregnant. Events will be reported overall and separately for 
women who did and did not receive CAB injections during pregnancy. Infant outcomes will be 
tabulated and all congenital anomalies individual reported. 
• To evaluate the PK of CAB LA among pregnant participants, combining blinded, unblinded 
and OL periods  
 
The mean and SD of log CAB LA PK concentrations before, during and after (up to 24 weeks 
postpartum) pregnancy will be described, combining data from the blinded, unblinded and OL 
periods (since injections were discontinued when pregnancy was confirmed in the blinded and 
unblinded periods, these data will contribute primarily to PK during the tail phase). Specifically, 

 
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plots of PK concentrations  as a function of time since last injection will be provided, separately 
for pre-pregnant, pregnant and postpartum periods, using the data from all women who become 
pregnant. A linear mixed model with log drug concentration  as the outcome and time since last 
injection, pregnancy (yes/no), baseline BMI, and a pregnancy x time since last injection 
interaction will be fit with random effects (intercept and slope) for each participant. The effect of 
pregnancy as a on mean PK concentrations and as a modifier of time since last injection will be 
tested using  = 0.05. 
• To describe the diagnostic test profile, PK, HIV drug resistance, and response to 
antiretroviral treatment in those who become infected after CAB LA exposure, combining 
blinded, unblinded and OL periods 
 
The number of cases of drug resistance will be summarized by period (blinded, unblinded, OL) 
for those receiving CAB LA who become infected. Case reports including information on testing 
profile, resistance, drug resistance and response to treatment will be developed for each 
confirmed incident infection in for those who receive CAB. 
• To characterize pharmacokinetics and duration of detectable drug among those who 
discontinue CAB LA injections, combining blinded, unblinded and OL periods. 
 
Starting with the third (17 week) injection (to allow steady state to be achieved), we will tabulate 
and plot the mean and SD of log CAB LA levels as a function of time since the last injection. 
Data will be presented overall and separately by pregnancy status. These data will be input into a 
mechanistic PK model and estimated parameter values from the fitted model will be reported.  
 
• To evaluate concentration in breastmilk and infants among women who receive CAB LA 
injections during pregnancy and/or the early post-partum period. 
 
We will present descriptive statistics (median, quartiles, geometric mean) of cabotegravir 
concentrations in breastmilk and infant plasma samples collected at multiple time points 
following delivery among women who receive CAB LA injections during pregnancy and 
breastfeeding.  We will also summarize infant plasma/maternal plasma ratios and breast 
milk/maternal plasma ratios to help understand drug transfer and deposition, respectively. 
 
SECTION 8.0 (NOT MODIFIED FROM THE MAIN PROTOCOL)        
8.1 
 Ethical Review 
This protocol and the template informed consent form contained in Appendix IV— and any 
subsequent modifications — will be reviewed and approved by the HPTN Scientific Review 
Committee (SRC) and DAIDS Prevention Science Review Committee (PSRC) with respect to 
scientific content and compliance with applicable research and human subjects regulations.  
The protocol, site-specific informed consent form, participant education and recruitment 
materials, and other requested documents — and any subsequent modifications — also will be 

 
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reviewed and approved by the ethical review bodies responsible for oversight of research 
conducted at the study site.  
Subsequent to initial review and approval, the responsible IRBs/ECs will review the protocol at 
least annually. The Investigator will make safety and progress reports to the IRBs/ECs at least 
annually, and within three months of study termination or completion. These reports will include 
the total number of participants enrolled in the study, the number of participants who completed 
the study, all changes in the research activity, and all unanticipated problems involving risks to 
human subjects or others. Study sites are responsible for the submission of continuing review to 
the DAIDS Protocol Registration Office (PRO), in accordance with the current DAIDS Protocol 
Registration Policy and Procedure Manual. 
8.2 
 Informed Consent 
Written informed consent for the OL amendment will be obtained from each study participant. If 
a participant becomes pregnant, consent will also be obtained from her before joining the 
Pregnancy-Infant Sub-Study.  Each study site is responsible for developing study informed 
consent forms for local use, based on the template in Appendix IV that describes the purpose of 
the study, the procedures to be followed, and the risks and benefits of participation, in 
accordance with all applicable regulations. If applicable, the study site also is responsible for 
translating the template form into local languages, and verifying the accuracy of the translation 
by performing an independent back-translation. 
Participants will document their provision of informed consent by signing their informed consent 
forms. (Further details regarding DAIDS requirements for documenting the informed consent 
process can be found in the DAIDS Standard Operating Procedure for Source Documentation.)   
All participants will be offered a copy of their informed consent form. 
8.3 
 Incentives 
Pending IRB approval, participants will be compensated for their time and effort in this study, 
and/or be reimbursed for travel to study visits and time away from work. Site-specific 
reimbursement amounts will be specified in the study informed consent forms. 
8.4 
 Confidentiality 
All study-related information will be stored securely at the study site. All participant information 
will be stored in locked file cabinets in areas with access limited to study staff. All laboratory 
specimens, reports, study data collection, process, and administrative forms will be identified by 
a 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 
separately from study records identified by code number. All local databases will be secured 
with password-protected access systems. Forms, lists, logbooks, appointment books, and any 
other listings that link participant ID numbers to other identifying information will be stored in a 
separate, locked file in an area with limited access. 

 
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Participant’s study information will not be released without the written permission of the 
participant, except as necessary for monitoring by the NIAID and/or its contractors; 
pharmaceutical sponsors; representatives of the HPTN LOC, SDMC, and/or LC; the government 
or other local, US, or international regulatory authorities (including the OHRP and US FDA), 
site IRBs/ECs or ViiV/Gilead.  
8.5 
 Communicable Disease Reporting Requirements 
Study staff will comply with all applicable local requirements to report communicable diseases 
identified among study participants to local health authorities. Participants will be made aware of 
all reporting requirements during the study informed consent process. 
8.6 
 Study Discontinuation 
The study also may be discontinued at any time by NIAID, the HPTN, the study sponsors, 
government or regulatory authorities (including the OHRP and US FDA), site IRBs/ECs or if, 
ViiV/Gilead. This would be done primarily due to safety concerns for the patients or due to an 
earlier-than-expected indication of product efficacy or study futility. 
SECTION 10.0 (MODIFIED FROM THE MAIN PROTOCOL)        
10.1  Protocol Registration 
Full protocol amendments require submission of a protocol registration packet to the DAIDS 
PRO. DAIDS PRO WILL review and approve site-specific ICFs for the Version 3.0 protocol 
amendment. Upon receiving final IRB/EC and any other applicable RE approval(s) for an 
amendment, sites must submit documents to DAIDS PRO and must wait for written approval 
prior to implementation. Sites will receive a Registration Notification when the DAIDS PRO 
receives a complete registration packet.  A copy of the Amendment Registration Notification 
should be retained in the site’s regulatory files.   
For additional information on the protocol registration process and specific documents required 
amendment registrations, refer to the current version of the DAIDS Protocol Registration 
Manual, which can be found at https://rsc.niaid.nih.gov/networks-protocol-teams/protocol-
templates. 
10.3  Study Coordination 
DAIDS holds the Investigational New Drug (IND) application for this study. Copies of all 
regulatory documents submitted to this IND by DAIDS will be forwarded to ViiV Healthcare 
and Gilead Sciences, Inc. for cross-referencing with the company’s other INDs for the study 
product(s). Assignment of all sponsor responsibilities for this study will be specified in a Clinical 
Trials Agreement executed between DAIDS and each of the collaborating partners (ViiV 
Healthcare, and Gilead Sciences, Inc.). 
Study implementation will be directed by this protocol as well as the SSP Manual. The SSP 
Manual, which will include links to the DAIDS SOPs for Source Documentation and Essential 
Documents, as well as links to the Manual for Expedited Reporting of AEs to DAIDS and the 

 
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DAIDS Toxicity Tables, will outline procedures for conducting study visits; data and forms 
processing; AE assessment, management and reporting; dispensing study products and 
documenting product accountability; and other study operations. 
Study CRFs will be developed by the study team and HPTN SDMC.  Data will be transferred to 
the HPTN SDMC, entered, and cleaned using the HPTN SDMC.  Queries routinely will be 
generated and distributed to the study sites for verification and resolution. 
Close coordination between protocol team members will be necessary to track study progress, 
respond to queries about proper study implementation, and address other issues in a timely 
manner. Rates of accrual, adherence, follow-up, and AE incidence will be monitored closely by 
the team as well as the HPTN SMC. The protocol team’s CMC will address issues related to 
study eligibility and AE management and reporting as needed to assure consistent case 
management, documentation, and information-sharing across sites. 
10.4  Study Monitoring 
On-site study monitoring will be performed in accordance with DAIDS policies.  Study monitors 
will visit the site to: 
• verify compliance with human subjects and other research regulations and guidelines;  
• assess adherence to the study protocol, study-specific procedures manual, and local 
counseling practices; and 
• confirm the quality and accuracy of information collected at the study site and entered 
into the study database. 
Site investigators will allow study monitors to inspect study facilities and documentation (e.g., 
informed consent forms, clinic and laboratory records, other source documents, CRFs), as well 
as observe the performance of study procedures. Investigators also will allow inspection of all 
study-related documentation by authorized representatives of the HPTN LOC, HPTN SDMC, 
HPTN LC, NIAID, government or other local, US, or international regulatory authorities/entities 
(including the OHRP and US FDA). site IRBs/ECs or ViiV/Gilead A site visit log will be 
maintained at each study site to document all visits. 
10.4.1  Remote Study Monitoring 
Due to ongoing travel restrictions during the COVID-19 pandemic, some sites are unable to 
accommodate onsite monitoring visits. Remote monitoring visits to date consist of quality review 
of study data available in the Electronic Data Capture system without verification to 
corresponding source documents. Review of source documentation is a critical component of 
ensuring data integrity.  
Monitoring visits may be conducted on-site or remotely. Remote visits may include remote 
source document verification using methods specified for this purpose by NIAID. Remote 
monitoring visits may be performed in place of, or in addition to onsite visits to ensure the safety 
of study participants and data integrity22. 
 

 
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Other secure platforms that are 21 CFR Part 11 compliant may be utilized, as allowed by the 
DAIDS Office of Clinical Site Oversight (OCSO). 
 
Four options listed below will enable the facilitation of remote source document verification, 
which may vary site by site.  All offered are HIPAA and 21 CFR Part 11 compliant.  
Option #1 - Veeva SiteVault Platform- This platform is available for sites to self-subscribe at no 
cost from Veeva Systems. There is no software to download and the only requirement is internet 
access. Sites will upload source documents to this secure platform and assign permissions to 
monitors to access these data for a limited period of time. For sites that are already using this 
platform in some capacity, they can add specific DAIDS studies to their existing account. In the 
event that this platform is being used by another entity within the institution, the site can request 
access to the platform following their internal procedures. However, sites that are not currently 
using Veeva SiteVault, can obtain additional information by visiting 
https://www.veeva.com/products/sitevault/ or sign up to try at sites.veeva.com. Veeva SiteVault 
may require a signed agreement between the site and Veeva Systems. 
Option #2 - Site Controlled SharePoint or Cloud-Based Portal-Some sites may already have a 
platform which allows for sharing of participant source documents, which could be extended to 
allow monitor’s access. This option must be 21CRF 11 and HIPAA compliant as applicable. 
Option #3 – Direct Access to Electronic Medical Records by Monitors- This option may be 
feasible for sites that use Electronic Medical Records, and whose institutional policy allows for 
direct access of the site’s Electronic Medical Record to monitors for a limited period of time. 
Please contact your institution’s Security Officer for required approvals and any agreements to 
facilitate remote access to participant source documents. 
Option #4 - Medidata Rave Imaging Solution- This option does not require additional purchase 
of software and sign-on is through each site’s existing single iMedidata account. Sites will 
upload source documents to this secure platform and monitor permission and access is assigned 
by the SDMC. There is ongoing discussion regarding the implementation timeline for MediData 
Rave Imaging Solutions, and the SDMC will contact sites regarding demonstration of this 
solution. 
10.5  Protocol Compliance 
The study will be conducted in full compliance with the protocol. The protocol will not be 
amended without prior written approval by the Protocol Chair and DAIDS Medical Officer. All 
protocol amendments must be submitted to and approved by the relevant IRB(s) and the DAIDS 
RSC prior to implementing the amendment. 
10.6  Investigator's Records 
The IoR will maintain, and store in a secure manner, complete, accurate, and current study 
records throughout the study. In accordance with Federal regulations, for each of the 
investigational products tested, the IoR will retain all study records for at least two years 
following the date of marketing approval for the study product for the indication in which it was 
studied, or if other applicable laws, regulations, policies, or other requirements (e.g., State, 

 
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country-specific, and local laws, and sponsor or institutional policies) exist, the most stringent 
retention period will be followed. If no marketing application is filed, or if the application is not 
approved, the records must be retained for two years after the US FDA is notified that the IND is 
discontinued, or if other applicable laws, regulations, policies, or other requirements (e.g., State, 
country-specific, and local laws, and sponsor or institutional policies) exist, the most stringent 
retention period will be followed. Study records include administrative documentation — 
including protocol registration documents and all reports and correspondence relating to the 
study — as well as documentation related to each participant screened and/or enrolled in the 
study — including informed consent forms, locator forms, CRFs, notations of all contacts with 
the participant, and all other source documents. 
10.7  Use of Information and Publications 
Publication of the results of this study will be governed by HPTN policies. Any presentation, 
abstract, or manuscript will be submitted by the Investigator to the HPTN Manuscript Review 
Committee (MRC), DAIDS, ViiV Healthcare, Gilead Sciences, Inc., and BMGF for review prior 
to submission.  
 
TOXICITY MANAGEMENT (MODIFIED- APPENDIX III IN MAIN PROTOCOL) 
Toxicity Management General Guidance 
In general, the IoR has the discretion to hold study product at any time if she/he feels that 
continued product use would be harmful to the participant, or interfere with treatment deemed 
clinically necessary according to the judgment of the IoR. In addition, a CMC has been 
established for this study. The CMC’s responsibilities will include consultation and decision-
making regarding management of toxicities and study product administration, including product 
resumption following the occurrence of certain types of toxicities and/or permanent 
discontinuation. Throughout this appendix are examples of AEs that require consultation with 
the CMC; in all such cases, the CMC should be notified as soon as possible and ideally within 72 
hours of site awareness of the AE in question. IoRs also should consult the CMC for further 
guidance in restarting study product or progressing to permanent discontinuation.  
The following general guidance refers to all AEs except for ALT, creatinine clearance (absolute 
and change from baseline), and CPK. Refer to the tables below for specific guidance about these 
laboratory abnormalities. 
Grade 1 or 2 
In general, participants who develop a Grade 1 or 2 AE regardless of relatedness to study 
product, and that is not specifically addressed elsewhere in the protocol or in the Tables below 
may continue use of the study product per protocol.             
Grade 3 
For participants who develop a Grade 3 AE or toxicity that is not specifically addressed 
elsewhere in the protocol or in the Tables below and is judged to be related to study product by 
the IoR, study product use should be temporarily discontinued in consultation with the CMC. In 

 
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general, and unless otherwise decided in consultation with the CMC, the IoR should re-evaluate 
the participant until resolution of the toxicity.  
 
Related: 
For Grade 3 AEs deemed related to study product, the study product should be 
permanently discontinued if improvement to severity ≤ Grade 2 cannot be documented 
within 4 weeks of receipt of the initial result. If study product is resumed and the same 
Grade 3 AE recurs at any time, the IoR must consult the CMC for further guidance on 
holding of study product, frequency of reevaluation or progression to permanent 
discontinuation of the study product.   
 
Unrelated: 
For Grade 3 AEs deemed unrelated to study product, the CMC should be consulted for 
further management recommendations.  
Grade 4 
Any Related, Grade 4 or higher clinical or laboratory AE observed prior to first injection (i.e. in 
STEP 4a) will prompt permanent study product discontinuation. 
Participants who develop a Related, Grade 4 AE or toxicity that is not specifically addressed 
elsewhere in the protocol or in the Tables below (regardless of relationship to study product) 
must have the study product temporarily discontinued. The IoR must consult the CMC and 
continue the temporary study product hold until a recommendation is obtained from the CMC.  
 
In general, study product use will not be resumed if the Grade 4 AE is considered related to 
study product use. If, in consultation with the CMC, study product use is resumed and the same 
Grade 4 AE recurs at Grade 4 level at any time, study product must then be permanently 
discontinued. 
General Criteria for Discontinuation of Study Product 
Participants may voluntarily discontinue the study product for any reason at any time.   IoRs will 
permanently discontinue participants from study product per protocol for any of the specific 
criteria below, which may be further clarified in the SSP Manual. IoRs also may also temporarily 
or permanently discontinue participants for reasons not shown here or in the SSP Manual (e.g., to 
protect participants’ safety and/or if participants are unable or unwilling to comply with study 
product use procedures). In such cases, the IoR or designee must first query the CMC for review. 
The CMC will provide a written response to the site indicating whether the CMC has 
recommended temporary or permanent discontinuation of study product based on careful review 
of all relevant data. It should be noted that the safety of the participant should always take 
precedence, and therefore, an IoR may determine that study product be temporarily discontinued 
before the CMC has time to respond. This is acceptable, and in such cases, the CMC should be 
notified as soon as possible regarding the nature of the case and the course of action taken.   
The criteria for permanent discontinuation of study product use for an individual participant are: 
• Study product-related toxicity requiring permanent discontinuation of study product per the 
guidelines above and below 

 
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• Completion of regimen as defined in the protocol 
• Request by participant to terminate study product 
• Clinical reasons determined by the IoR  
• Acquires HIV infection  
Study product will be temporarily withheld from a participant for any of the following reasons: 
• Report of use of prohibited concomitant medications as described in the SSP Manual.  Study 
product use may resume upon consultation with the CMC and when the participant reports that 
she is no longer taking the prohibited medication, provided other reasons for temporary study 
product hold/permanent discontinuation do not apply. The CMC should be consulted in all cases 
where a participant reports taking a prohibited product during the course of the study.   
• The participant is unable or unwilling to comply with required study procedures such as HIV 
testing and routine laboratory assessments, or otherwise might be put at undue risk to their safety 
and well-being by continuing study product use, according to the judgment of the IoR. The IoR 
must consult the CMC on all temporary study product holds instituted for this reason for further 
guidance on resuming study product use, continuing the temporary hold, or progressing to 
permanent discontinuation.   
• The participant has one or more reactive HIV test results, or expresses a concern about having 
acute HIV infection. Criteria for resuming use of study product in these circumstances are 
defined in the protocol and SSP Manual. 
Participants who temporarily or permanently discontinue study product and are taking pills 
(either TDF/FTC or oral CAB) will be instructed to return all study products as soon as possible.   
 

 
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Guidance on Toxicity Management for Specified Toxicities: 
Nausea, Vomiting, and Diarrhea 
 
CONDITION AND 
SEVERITY 
IMMEDIATE 
ACTION 
FOLLOW-UP AND MANAGEMENT 
Nausea, Vomiting, and Diarrhea 
Grade 1 and 2 
Continue study 
product (reminder to 
take oral study 
product with food) 
Treat symptomatically with hydration, oral 
antiemetic therapies or antiemetic suppositories at 
the discretion of the IoR. The IoR should order any 
clinically relevant laboratory analyses (per 
judgment of the IoR). 
Grade ≥ 3  
Discontinue study 
product temporarily 
Participants with Grade  3 nausea, vomiting, or 
diarrhea, for which an alternative etiology is not 
established, must discontinue the study product 
temporarily until Grade 2 or lower and be treated 
symptomatically. Should condition(s) not improve 
to Grade ≤ 2 within 7 days, the IoR should consult 
the CMC for guidance on continuing the temporary 
discontinuation or progressing to permanent 
discontinuation of study product. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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Guidance on Toxicity Management for Specified Toxicities: 
ALT 
Note for all Grades:  
All study participants will be negative for HBsAg at study entry, and participants who enter the 
study without evidence of immunity to HBV will be provided HBV vaccination. Therefore, pre-
existing HBV infection is not likely to be a cause of AST/ALT elevations. 
Careful assessments should be done to rule out the use of alcohol, lactic acidosis syndrome, non-
study medication-related product toxicity, herbal medications/supplements, or infectious 
hepatitis as the cause of elevation in AST or ALT of any Grade. The participant must be 
carefully assessed for any symptoms or signs of hepatotoxicity, including fatigue, malaise, 
anorexia and nausea, jaundice, acholic stools, right upper quadrant pain, or hepatomegaly. If the 
AST/ALT elevation is considered most likely to be due to concomitant illness or medication, 
standard management, including discontinuation of the likely causative agent, if possible, should 
be undertaken. If symptoms or signs of clinical hepatitis are present, study product must be held 
or discontinued. In addition, all participants with elevated values should be considered for testing 
for hepatitis A, B, and C infection.  Contact the CMC for further guidance on investigation and 
study product administration. 
Note the following for cases of exercise-induced CPK abnormalities:   
Note the following for cases of exercise-induced CPK abnormalities: Cases of CPK abnormality 
> Grade 3 or higher, presumed to be exercise induced, accompanied by < Grade 3 ALT must be 
brought to the attention of the CMC for adjudication of further management and further 
administration of study product. Grades 3 and 4 elevations in ALT, regardless of CK elevation 
will prompt permanent discontinuation of study product and the participant will be followed 
annually for HIV testing only until the conclusion of Step 2 of the study. All such cases must be 
reported to the CMC.   
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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Guidance on Toxicity Management for Specified Toxicities: 
 
CONDITION AND 
SEVERITY 
FOLLOW-UP AND MANAGEMENT 
ELEVATIONS in ALT  
Grade 3 and higher 
Oral CAB (Step 4a): A Grade 3 ALT abnormality reported at Week 4, 
regardless of relatedness to the study product, will prohibit a participant 
from entering the injection phase (Step 4b) of the study, and the participant 
will be permanently discontinued from the study. All such cases must be 
reported to the CMC. Prior to discontinuation, participants will be followed 
every two weeks for ALT assessments until they return to < Grade 1. If an 
etiology for elevated ALT is identified or persistent without explanation, 
the CMC may direct an alternate interval for follow-up, or return to clinical 
care.    
Grade 3 and higher 
Injectable CAB (Step 4c): For Grade 3 and higher ALT, study product 
will be permanently discontinued.  Repeat testing should be performed as 
soon as possible, and participants should be followed every two weeks until 
levels are ≤ Grade 1. If an etiology for elevated ALT is identified or 
persistent without explanation, the CMC may direct an alternate 
interval for follow-up, or in rare cases where alternative etiology has 
been identified and ALT has resolved to Grade 1 or lower, restart of 
study product.    
Participants who are permanently discontinued from study product will be 
transitioned to local clinical care for clinical management and local 
prevention services and terminated from the study per CMC direction.  
Open label TDF/FTC (Step 5):  Participants will be followed per the 
Schedule of Procedures and Evaluations for Step 5; for participants who 
have transitioned to Step 5 from Step 4c, the decision whether it is safe to 
provide oral TDF/FTC will be made with guidance from the CMC. 
When Step 5 concludes in these cases, the participant will be referred to 
local prevention services.  Note that Step 5 concludes at Week 48 for all 
participants transitioning from Step 4c.   

 
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Guidance on Toxicity Management for Specified Toxicities: 
 
Creatinine Clearance, only applicable to TDF/FTC recipients 
Changes in creatinine clearance, in CAB recipients should be managed per clinical standards of care, 
unless attributed by the IoR to SP, in which case the below toxicity management guidelines should 
apply. 
NOTE:  Adverse events related to creatinine clearance should be based on examination of BOTH the 
absolute creatinine clearance AND the change in creatinine clearance from baseline (Enrollment/ 
Visit 2.0). When gradable, only the higher grade of these two assessments should be entered on the 
Adverse Event e-CRF. Clinical Management of Grade 3 and Grade 4 changes in creatinine clearance 
should follow the “Toxicity Management General Guidance” ONLY when the absolute creatinine  
clearance is < 90 mL/min. That is, changes in creatinine clearance of >30% from baseline that DO 
NOT result in an absolute creatinine clearance < 90 mL/min do NOT need to be reported to the 
CMC or more frequent clinical monitoring. Additionally, changes in creatinine clearance of > 30% 
that are accompanied by a creatinine that remains within normal limits also do not need to be 
reported to the CMC and do not require more frequent clinical monitoring.    
 
CONDITION AND 
SEVERITY 
IMMEDIATE 
ACTION 
FOLLOW-UP AND MANAGEMENT 
CREATININE CLEARANCE 
Estimated CrCl< 60 mL/min 
Discontinue study 
product temporarily 
If the calculated creatinine clearance is 
<60mL/min, it should be confirmed within 1 week 
of the receipt of the results, and the CMC should 
be consulted for adjudication and recommendation 
for further testing and follow-up.   
Confirmed CrCl< 60 mL/min  
Permanently 
discontinue study 
product  
If the calculated creatinine clearance is confirmed 
to be <60 mL/min, the CMC must be notified and 
the study product must be discontinued.  
Participants who fail to have a confirmed test 
within 2 weeks of receiving the initial result, 
should be discontinued from use of the study 
product until CMC adjudication and 
recommendation for further testing and follow-up. 
Re-testing result is             
≥60 mL/min 
Consult CMC for 
guidance 
If re-testing yields a result ≥ 60 mL/min, the IoR 
must consult the CMC for further guidance on 
resuming study product use, continuing the hold 
temporarily, or progressing to permanent 
discontinuation. 
If the IoR in consultation with the CMC has 
determined that the case has stabilized, it may be 
possible to decrease the frequency of follow-up 
laboratory testing in addition to resumption of 
study product.  
 

 
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Guidance on Toxicity Management for Specified Toxicities: 
 
Creatine Phosphokinase (CPK) 
Note the following for cases of exercise-induced CPK abnormalities:   
Note the following for cases of exercise-induced CPK abnormalities: Cases of CPK abnormality > 
Grade 3 or higher, presumed to be exercise induced, accompanied by < Grade 3 ALT must be brought to 
the attention of the CMC for adjudication of further management and further administration of study 
product. Grades 3 and 4 elevations in ALT, regardless of CK elevation will prompt permanent 
discontinuation of study product and the participant will be followed annually for HIV testing only until 
the conclusion of Step 2 of the study. All such cases must be reported to the CMC.   
CONDITION AND 
SEVERITY 
IMMEDIATE ACTION 
FOLLOW-UP AND MANAGEMENT 
Creatine Phosphokinase 
Grade 3  
Continue study product until 
repeat test results are 
available 
A Grade 3 or higher elevation in CPK should 
result in a repeat assessment within 2-4 
weeks to ensure the result is transient or due 
to exercise and will not require a change in 
study treatment. A history regarding use of 
products known to cause increase of CPK 
(such as statins) physical activity or exercise 
preceding the CPK evaluation should be 
obtained.  
Grade 4 
Continue study product until 
repeat test results are 
available if the elevation is 
thought to be possibly or 
probably related to study 
product. 
Grade 4 elevations in CPK should have a 
repeat assessment after the subject has 
abstained from exercise for >24 hours. For 
persistent Grade 4 CPK elevations that are 
considered possibly or probably related to the 
study product, study product should be 
discontinued and the participant should be 
followed on study/off study product.   
 
 
 
Guidance on Toxicity Management for Specified Toxicities: 
Guidance for Injection Site Reactions (ISRs) 
ISR discomfort can be managed if the reaction is interfering with the participant’s ability to 
perform activities of daily living.  Recommended interventions include: 
• Pre-treatment (prior to injection administration) warm compresses 
• Topical or oral pre-treatment with NSAID preparations, unless contraindicated 
• Immediate post-injection massage to injection location 
• Post-treatment warm or cold compresses 

 
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• Post-treatment NSAID or other analgesic preparations, topically or orally 
A proactive and comprehensive approach to mitigating ISRs should be undertaken, with 
premature transition from Step 4c to Step 5 being reserved for refractory cases in extreme 
circumstances.  The CMC should be notified of such transitions. 
 
Guidance for Allergic Reactions 
Participants may continue to receive oral or injectable study product for Grade 1 or 2 allergic 
reactions at the discretion of the IoR or designee. The participant should be advised to contact 
the study site staff immediately if there is any worsening of symptoms or if further systemic 
signs or symptoms develop. Antihistamines, topical corticosteroids, or antipruritic agents may be 
prescribed.  
Participants with Grade ≥3 allergic reactions that are considered to be related to study product 
should permanently discontinue study product and continue to be followed on study/off study 
product. Participants should be treated as clinically appropriate and followed until resolution of 
the AE. 
 
 
 

 
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ADDENDUM TO THE MAIN SAMPLE INFORMED CONSENT FORM 
HPTN 084: 
A Phase 3 Double Blind Safety and Efficacy Study of Long-Acting Injectable Cabotegravir 
Compared to Daily Oral TDF/FTC for Pre-Exposure Prophylaxis in HIV-Uninfected Women  
 
 
FINAL Version 
Protocol Version 3.0, dated 12August2021 
DAIDS Document ID: 38070 
 
 
 
Sponsored by: Division of AIDS, United States (US) National Institute of Allergy and Infectious 
Disease, US National Institutes of Health.   
 
Study products are provided by ViiV Healthcare and Gilead Sciences, Inc. Additional support is 
provided by the Bill & Melinda Gates Foundation (BMGF). 
 
PRINCIPAL INVESTIGATOR: [Insert Name] 
PHONE:  [Insert Number] 
You are currently taking part in either HPTN 084 (for adult women) or HPTN 084-01 for adolescent 
girls).  This consent form update contains information to help you decide if you want to participate in 
the “open label” portion of HPTN 084.   
Your participation is voluntary 
This consent form gives you information about the next part of this study, the “open label” piece. Once 
you understand the next part, and if you agree to take part, you will be asked to sign your name or make 
your mark on this form. You will be offered a copy of this form to keep. Your continued participation in 
this research is voluntary. You may decide to not take place in the next part of the study now or at any 
time without a loss of benefits to which you are otherwise entitled.  We will also review the information 
in the main consent form that you already signed (either for HPTN 084 or for HPTN 084-01), if you 
would like us to do that. 
 
Important information 
This information gives you an overview of the research. More information about these topics may be 
found in the pages that follow. 
1. 
Why is this research being done? 
We’d like to learn more about women’s HIV prevention choices including during pregnancy and 
breastfeeding now that we know that CAB LA is safe and effective in preventing HIV infection in 
women.  

 
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2. 
How long will I participate in the study? 
For most participants the study will last an additional 7 visits over 48 weeks (11 months). If you choose 
to start or re-start CAB you may take 1-2 extra visits over 8 weeks over and above the 48 weeks. If you 
become pregnant you will be asked to be in follow up until your baby is one year old. If you have had at 
least one CAB injection you will be asked to attend additional visits during pregnancy and after delivery 
for a total of 19 visits. 
 
3. 
What will happen to me during the study? 
Participants can choose to stay on their current study medication or to change. We will offer participants 
who received TDF/FTC the chance to take CAB LA if they wish for an additional 48 weeks. Participants 
starting or re-starting CAB can choose to start injections directly or to take 30 days or oral CAB pills 
first before starting injections. We would like you to continue your study visits even if you choose 
neither TDF/FTC or CAB LA. 
 
You will be asked to come for study visits every 8 weeks. At each of these visits we will ask you 
questions about your health, the medications you are taking, any side effects of study medications, and 
any alcohol or drug use. We will talk with you about ways to avoid HIV. We will ask you about your 
plans to become pregnant and ways to avoid pregnancy if you wish. We will not require you to use long 
acting contraceptives anymore. We will collect blood samples for HIV, syphilis, drug level testing and 
to test your general health. We will collect urine samples for pregnancy testing and to test the health of 
your kidneys. We will collect vaginal samples to test for sexually transmitted infections (STIs) You will 
be given your preferred study medication and offered condoms. If you are having trouble taking your 
oral pills or attending your injection visits on time we will talk with you about strategies to help with 
that.  
 
4. 
Will I benefit from the study? 
You will receive information about your health and access to effective HIV prevention, including oral or 
injectable PrEP, as well as treatment for STIs. The counselling you receive may help you to avoid HIV, 
STIs or pregnancy. If you become pregnant you and your baby will receive monitoring during 
pregnancy and breastfeeding.  
 
5. 
Will taking part in the study expose me to risks? 
Taking part in research may expose you to some risks. We know that both CAB LA and TDF/FTC are 
safe and well tolerated in women. Injection site reactions were the most common side effect in women 
receiving CAB LA. The risks are similar to those described during the blinded part of the study. 
 
[Sites: For pregnant women only.   
 
If you become pregnant during the study and choose to take CAB LA during pregnancy and while 
breastfeeding, we want to be sure you know that while we think CAB LA will be safe for your baby 
there is not much information available yet.  The lack of information is why we are doing this study.  So 
far, in the women who have become pregnant and breastfed their babies while taking CAB LA, no 
problems in their babies have occurred.   
 
We do know that in studies of another drug, called dolutegravir, which is very similar to CAB LA no 

 
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nursing babies had any problems.  These babies were breastfed by mothers who had HIV and were 
taking dolutegravir as treatment.  Small amounts of dolutegravir were found in the breastmilk.  It is 
possible some CAB LA may pass to a baby through breastmilk.]   
 
6. 
Will I be paid to participate? 
You will be reimbursed for costs associated with your visits, as was done in the blinded part of the 
study. 
 
7. 
Will it cost me anything to participate? 
There is no cost to you for taking part in this study. 
 
Please review the rest of this document for details about these topics and additional things you 
should know before making a decision about whether you will participate in this research 
New Information about CAB LA 
We now know for certain that CAB LA is effective in preventing people from getting infected with HIV, 
the virus that causes AIDS. 
As a quick reminder, in November 2020, an independent Data Safety and Monitoring Board or DSMB 
checked the HPTN 084 study data and found that both CAB and TDF/FTC were very good at preventing 
new HIV infections.  They also found that both CAB and daily TDF/FTC pills were safe and well 
tolerated.  They saw that CAB was much better at preventing HIV than TDF/FTC. Participants given 
daily TDF/FTC pills had approximately nine times the number of HIV infections than participants 
getting long-acting cabotegravir injections (real CAB, also called CAB LA).  The DSMB recommended 
that the blinded part of the study be stopped, that participants be informed of their study group, and that 
the results be made public. Study teams shared the data with their country regulators and with their 
permission, have begun to tell participants which study product they were taking.  
 
Since we first shared the study results with you, we have some new updates based on the testing of 
samples in those people that became infected with HIV. One of the reasons that women in the CAB LA 
group had fewer infections is because it may be easier to take an injection every 8 weeks than a pill 
every day. TDF/FTC works very well when taken daily but it cannot protect you if you do not take it 
every day.  The participants in HPTN 084 in the TDF/FTC group who became infected with HIV were 
not taking TDF/FTC every day.  We know they weren’t taking pills every day because we measured the 
amount of study drug in their blood. We know that some people find it hard to take a pill every day. 
Four women in the CAB LA group in HPTN 084 became infected with HIV.  Two women became 
infected before they received any CAB LA injections. When we measured the amount of drug in their 
blood, we learned that they weren’t taking their oral pills every day.  Two other participants became 
infected with HIV while receiving injections; one of those participants was late for several of her 
injections and this may have led to her becoming infected with HIV. All participants who became 
infected with HIV were counselled about starting antiretroviral therapy.  
Did any participants develop HIV infections that were resistant to CAB LA? 
None of the participants who received CAB LA and later became infected with HIV had any resistance 
to CAB or other drugs like CAB called integrase inhibitors. For example, dolutegravir which is 
commonly used to treat HIV infection in many parts of Sub-Saharan Africa, is an integrase inhibitor. 
Resistance means that the drug, and sometimes other drugs like it, might not work as well to control the 

 
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HIV infection as part of HIV treatment.  In another study however called HPTN 083 that involved men 
who have sex with men and transgender women, they did see several cases of resistance to CAB LA and 
other drugs like CAB LA called integrase inhibitors. These people all had to use different anti-retroviral 
drugs that are not like CAB to control their HIV.  
In HPTN 084, one participant in the TDF/FTC group who became infected with HIV had resistance to 
FTC. Similarly, in HPTN 083 several people in the TDF/FTC group has resistance to one or both drugs. 
What happens next?  
We’d like to offer you the chance to continue taking CAB LA or TDF/FTC for the next 48 weeks. We 
want to learn more about women’s HIV prevention choices now that we know that CAB LA is safe and 
works to prevent HIV.   We also want to learn more about CAB LA use during pregnancy and 
breastfeeding. In the next part of the study, the “open-label” part of the study you will be able to:   
• Stay on CAB LA if you are already on it    
• Stay on TDF/FTC if you are already on it  
• Switch to CAB LA if you are on TDF/FTC and it is safe for you to do so 
• Start or re-start CAB LA if you have been on the annual visit schedule and it is deemed safe 
for you to take CAB LA  
• Stop from CAB LA to TDF/FTC  
If you think you are no longer at risk for HIV, you may stop both study product. We’d still like you to 
come for study visits for 48 weeks. Study staff will take with you and help you to decide whether you 
are at risk for HIV and still need to take pre-exposure prophylaxis or PrEP (either oral or injectable) to 
prevent HIV.  
 
What will happen during the open-label part of the study? 
If you decide to continue with the study you will have visits similar to those in the earlier part of the 
study.  Most study visits will be spaced eight weeks apart (every other month). These next study visits 
will happen for at least 48 weeks (11 months).  If you become pregnant you may be on study for longer 
(1 year and 10 months).   
 
If you choose CAB LA injections 
• If you were previously receiving CAB LA injections during the blinded part of HPTN 084 and 
you choose to continue CAB LA injections you will be in the next part of the study for 48 weeks.  
You will have at least seven more study visits.  These visits will be spaced eight weeks apart.  At 
the end of 48 weeks, if you want to keep taking CAB LA you can choose to move to locally 
provided CAB LA that is not part of the study.  Your participation in the study will end.  If you 
prefer, we can refer you to a local HIV prevention program for ongoing PrEP access. 
 
 
End of study participation; move 
to local HIV prevention services 
CAB LA injections for 48 weeks 

 
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• If you were previously receiving TDF/FTC during the blinded part of HPTN 084, or if you 
stopped taking CAB LA injections (and it is safe for you to restart), and you choose to take CAB 
LA injections during the open-label part of the study you will be in the next part of the study for 
either 52 or 56 weeks.  You will have 8 or 9 more study visits.  . These visits will be spaced eight 
weeks apart, except for the first two injections which are 4 weeks apart.     At the end of all these 
visits, your participation in the study will end. You would have the choice then to join a locally 
available program for CAB LA injections (the company that makes CAB LA is working to make 
it available locally for study participants). If you prefer, we can refer you to a local HIV 
prevention program for ongoing PrEP access. 
To start you on CAB LA injections you may choose from two options:  
 
Option 1- start injections directly 
 
 
 
 
 
Option 2- take oral pills for 30 days and then start injections 
 
 
 
 
During the blinded part of the study, you may remember that everyone was required to take cabotegravir 
pills before getting injections. This process was in place because we did not have enough information 
then about CAB LA to know if it was safe to start getting injections right away.  Based on what we 
learned in the blinded part of the study, we now know that it is safe to begin injections right away.  
However, if you feel more comfortable taking 30 days of cabotegravir pills first you may do so. [Note to 
sites:  If your IRB/EC requires this step, or if the IoR requires this step, then update this language to 
make it non-optional]. 
 
If you choose TDF/FTC pills 
• If you choose to take TDF/FTC pills, you will be in the next part of the study for 48 weeks.  You 
will have a total of seven more study visits.  At the end of the 48 weeks, your participation in the 
study will be over.  If you prefer, we can refer you to a local HIV prevention program for 
ongoing PrEP access. 
Take 30 
days of 
CAB pills 
End of study 
participation; 
move to local HIV 
prevention 
services 
CAB LA 
injections for 
48 weeks 
Get your first 
injection 
4 weeks 
End of study 
participation; move 
to local HIV 
prevention services 
  
CAB LA 
injections for 48 
weeks 
Get your first injection 
4 weeks 

 
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What will happen during open-label study visits? 
During the new, open-label part of the study clinic visits will be very similar to those you are used to.  
Because you will be allowed to choose between CAB LA and TDF/FTC and some people may switch 
products, the number of study visits will depend on each person’s choices.  Visits will be spaced eight 
weeks apart and will last for at least 48 weeks.  Below are descriptions of what will happen depending 
on participant choices. 
 
For people that stay on their current study medication,  
During the study visits we will:  
• At the first visit we will talk with you about your choice of study products. 
• Confirm where you live and how to contact you. 
• Ask you questions. We will ask about about your sexual behavior, how your health is, whether 
you have experienced any side effects from taking study medication, whether you have taken any 
other medicines, and whether you have used alcohol or drugs. We will also ask how you feel 
about taking pills or getting injections at the first visit and then at weeks 24 and 48. 
• Give you a brief physical exam.  
• Collect blood samples. We will collect ~XX mL (about x teaspoons) of blood for HIV testing,  to 
measure the amount of the study drug that is in your blood, and for storage.  At this visit, and 
every 6 months we will also collect ~XX mL (about x teaspoons) of blood to testing your general 
health, including the on the health of your liver, and for syphilis. 
• At Week 48, we will also collect ~XX mL (about x teaspoons) of blood to check how much 
cholesterol is in your blood (a fatty substance in your blood.  For this cholesterol test, you will be 
instructed to not eat or drink anything other than what the study staff tell you is acceptable for 8-
12 hours before your blood is drawn. 
• Collect urine samples to Test you for pregnancy [site insert sample type, blood vs. urine]. At 
your first visit, and every 6 months we will also test to see if there is sugar or protein in your 
urine. 
• Collect vaginal swabs at the first visit and every 6 months to test for sexually transmitted 
infections.  
• Provide you with the results of your tests and talk with you about what they mean. Talk with you 
about HIV and ways to protect yourself from getting it.  
• Talk with you about ways to avoid pregnancy if you wish to. 
• If it seems to you or to the study staff that you are having challenges taking the pills or attending 
study visits, we will try to help by working through these with you.  
TDF/FTC pills for 48 weeks 
End of study participation; 
move to local HIV prevention 
services 

 
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• Staff will give you study medication (pills or injections) and offer you condoms. 
 
For people that choose to start or re-start CAB LA  
 
• Option 1 – start injections directly 
In addition to the procedures above, if you choose to start taking injections directly, we will check 
your previous results to make sure that it is safe to start CAB LA. After you receive your first CAB 
LA injection, you will be asked to return to the clinic in four weeks where you will receive your 
second CAB LA injection. Once you have received two CAB LA injections, at four weeks apart, the 
CAB LA levels in your body will be high enough to let you space injections out to every eight 
weeks.  From this point in the study, you will have at least seven more study visits. 
• Option 2 - take oral pills for 30 days and then start injections 
If you chose to take 30 days of CAB pills, you will complete the visit procedures listed above and 
will be given pills to take daily for 30 days. You will be asked to return to the clinic after the pills 
are finished.  The study procedures listed above will be repeated and you will receive your first CAB 
LA injection.  
After you receive your first CAB LA injection, you will be asked to return to the clinic in four weeks 
where you will receive your second CAB LA injection. Once you have received two CAB LA 
injections, at four weeks apart, the CAB LA levels in your body will be high enough to let you space 
injections out to every eight weeks.  From this point in the study, you will have at least seven more 
study visits. 
 What happens if you need to stop taking CAB LA during the injection period? 
During the open-label part of the study, if you stop taking CAB LA because of a safety concern we will 
offer you TDF/FTC for 48 more weeks to cover the CAB LA “tail”.  If you remember, this is to protect 
you from potentially developing resistant HIV infection if you become HIV infected while the levels of 
CAB in your blood are decreasing. We know from our HPTN 084 study results that this risk is very 
small. Please note that that we will only cover the tail for this sub-group of women who stop CAB LA 
early. While you are taking TDF/FTC, you will return the clinic for a total of five more visits spaced 12 
weeks apart.  At that point, your participation in the study will end. If you prefer, we can refer you to a 
local HIV prevention program for ongoing PrEP access. 
 
During these visits we will: 
• Confirm where you live and how to contact you. 
• Talk with you about HIV and ways to protect yourself from getting it. 
• Offer you condoms. 
• At the first visit and at the last visit, we will ask you and about how you feel about taking pills. 
We will ask you if you have experienced any side effects from the TDF/FTC.   At the first visit 

 
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and again at Weeks 24 and 48, we will also ask you questions about your sexual behavior. 
Everyone will be asked about any other medicines they are taking, and whether they use alcohol 
or drugs. 
• Give you a brief physical exam and ask how your health is.  
• Collect ~XX mL (about x teaspoons) of blood for HIV testing, to measure the amount of the 
study drug that is in your blood, and for storage.   
• Collect ~XX mL (about x teaspoons) of blood at the first visit and at Week 24 and Week 48 for 
checking your general health. 
• Collect ~XX mL (about x teaspoons) of blood at the first visit and Week 48 to check the health 
of your liver. 
• Give you the results of your blood tests when they are available. 
• Test you for pregnancy [site insert sample type, blood vs. urine]. 
• Test a vaginal swab for sexually transmitted infections at the first visit and then at Week 24 and 
Week 48.  
• If it seems to you or to the study staff that you are having challenges taking the pills or attending 
study visits, we will try to help by working through these with you.  
• Staff will give you more pills. 
At this point, your participation in the study will end.  We will refer to locally provided HIV prevention 
services. 
 
What happens if you become pregnant during the next part of this study? 
 
During HPTN 084, women were required to be on a long-acting, reversible contraceptive (LARC).  This 
was because:  
1) we did not know how well CAB LA worked in women and  
2) a report from Botswana was released raising the possibility that a drug called dolutegravir (DTG) may 
have caused a very serious birth defect of the spinal cord and the brain in women who were taking DTG 
at the time they became pregnant for treatment of HIV. DTG is similar to CAB LA so we wanted to be 
careful during HPTN 084. Ever since the first Botswana report, doctors have continued to monitor 
babies born to mothers who have taken DTG during pregnancy.  It now seems much less likely that 
DTG was the cause of the birth defects in babies. We now know that the difference in the rate of birth 
defects in mothers who took DTG and those that used other antiretrovirals for HIV treatment is 
essentially the same. Other studies that study large groups of pregnant women that use medications, 
including DTG during have not found this problem. CAB LA is not the same as DTG. CAB LA has not 
been shown to cause birth defects in animal studies. In blinded portion of HPTN 084 there were 50 
confirmed pregnancies; none of the babies born to women in HPTN 084 had any birth defects. 
 
Now that we know that CAB LA is safe and works to prevent HIV in women, we no longer will require 
you to use a LARC during this study. We will talk with you about ways to avoid pregnancy if you wish 

 
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to do so. We will test for pregnancy at every study visit.  If you do become pregnant, please note that we 
will refer you to a clinic that routinely manages pregnant women; the study will not pay for this medical 
care. 
We know that many women wish to conceive safely, but are worried about the risk of HIV during 
pregnancy and breastfeeding. If you become pregnant during the study you will be given the chance to 
continue taking CAB LA injections during pregnancy and breastfeeding. If you prefer, you can switch to 
TDF/FTC.  TDF/FTC has been used much longer than CAB LA and is not known to cause any health 
problems for babies.  All women who become pregnant in the study will be followed up. We would like 
to know about the health of your baby when born and again at one year of age. 
For women who have received at least one CAB LA injection in this study, we would like you to invite 
you to complete additional study visits during pregnancy and for about one year after the birth of your 
baby. You will have 11 study visits that are very similar to study visits that occurred before you were 
pregnant. Those study visits will happen every 4 weeks.  You will receive your preferred study product 
every 8 weeks as before. We will ask you to sign this form to confirm that you agree to these additional 
visits for you and your infant. 
[This section is only for women who become pregnant and have ever received a CAB LA injection. 
Study activities for women who become pregnant 
Most study activities will be very similar to previous visits.  During these visits we will do the 
following: 
• At the first visit we will talk with you about your choice of study products.  If you have been 
taking CAB LA and wish to continue taking it, you may do so after providing consent by signing 
the end of this form. 
• Confirm where you live and how to contact you. 
• Ask you questions. We will ask about about your sexual behavior, how your health is, whether 
you have experienced any side effects from taking study medication, whether you have taken any 
other medicines, and whether you have used alcohol or drugs. We will also ask how you feel 
about taking pills or getting injections at the first visit and then at weeks 12 and 32. 
• Give you a brief physical exam.  
• Collect blood samples. We will collect ~XX mL (about x teaspoons) of blood for HIV testing 
and to measure the amount of the study drug that is in your blood, and for storage.   
• We will collect ~XX mL (about x teaspoons) of blood at the first visit and again at Weeks 24 and 
36 to test your general health, including the on the health of your liver.  
• Collect urine samples at the first visit and again at Weeks 24 and 36 to see if there is sugar or 
protein in your urine. 
• Collect vaginal swabs at the first visit and again at Week 24 to test for sexually transmitted 
infections. 
• Provide you with the results of your tests and talk with you about what they mean. Talk with you 
about HIV and ways to protect yourself from getting it.  

 
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• [Sites to include this if local SOC permits offer of condoms.      At each study visit we will offer 
you condoms.] 
Here are some study activities that will be new and are specific to pregnancy: 
At the visit where your pregnancy test is positive, we will  
• confirm your pregnancy on a second sample 
• collect a swab to test for sexually transmitted infections 
• talk with you about whether you want to continue with CAB LA injections or whether you want 
to start TDF/FTC. If you are not sure, you can take some time to think about it and return for 
your injection visit at a later date (within the visit window). You can start TDF/FTC then if you 
prefer. 
• If you choose to take CAB LA injections during pregnancy, we will check the injection location 
carefully at the following visit s: Weeks 4, 12, 20, 28 and 36. 
- At Week 12, we will either perform an ultrasound to check on the baby (or refer you to a local office 
for this). 
-At Week 24, we will test you for sexually transmitted infections like syphilis, chlamydia, gonorrhea and 
trichomonas.  
 
At Delivery 
Please know that we do not want to disrupt the special time that you spend with your new baby, family 
and friends.  We would like to know about the health of you and your baby at the time of delivery. If 
you choose to deliver in a healthcare facility, we would like to make arrangements ahead of time with 
the facility to collect some blood from you, some blood from the umbilical cord and some blood from 
the baby.  
After Delivery 
Once you have your baby, you will have 8 more study visits. These visits will happen at Weeks 2, 4, 8, 
16, 24, 32, 40 and 48. We will use these visits to check on the health of you and your baby.  
Study visits are very similar to study visits that occurred before you were pregnant. For example, at 
Weeks 8 and 48 we will do a targeted physical exam, vaginal swab collection, and blood collection to 
check on your general health, including liver health. 
 
Here are some study activities that will be new and others that are similar to those that occurred during 
previous visits: 
 
-At Weeks 24 and 48, we will ask how you feel about taking pills or getting injections. 
- At Weeks 2, 4, 8, 16 and 24 we collect 5mLs (1 teaspoon) of breastmilk to learn about levels of CAB 
in breastmilk.  

 
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-At Weeks 8, 16, 24, 32 40 and 48 we will collect urine to test you for pregnancy and at Weeks 8 and 48 
we will also check the amount of sugar and protein in your urine. 
-At Week 8 and again at Week 48, we will test you for sexually transmitted infections like syphilis, 
chlamydia, gonorrhea and trichomonas.  
 
-If you choose to take CAB LA injections during breastfeeding, we will check the injection location 
carefully at Week 8 and Week 48. 
What happens to babies during study visits? 
We would love the opportunity to meet your baby and to collect some information about them.  With the 
information we have right now, we think it is unlikely that CAB LA causes problems for babies.  If we 
can examine babies born to moms in this study, the information will help us and will help other women 
in the future.   
 
You can bring your baby to the same study visits that you attend after delivery.  Those visits happen at 
Weeks 2, 4, 8, 16, 24, 32, 40 and 48.  Here is what happens at those visits: 
 
-We would like to do a brief infant exam at Week 8 and Week 48. 
-We would like to ask you about your baby’s eating habits at Weeks 8, 16 and 24. 
-We would like to collect a small amount of blood from your baby at Weeks 2, 4, 8, 16, 24 and 48. 
At the end of 48 weeks your participation in the study will end.  At that time, if you want to keep taking 
CAB LA you can choose to move to locally provided CAB LA that is not part of the study.  The 
company making CAB LA is working to offer it to study participants after this research study ends. If 
you prefer, we can refer you to a local HIV prevention program. 
[End of section only for women who become pregnant.] 
What happens if you become infected with HIV during this part of the study? 
If you become infected with HIV during this next part of the study, you will be immediately referred for 
local care and treatment of HIV.  We will not provide care for HIV infection as part of this study. 
We will ask you to come back to the study clinic for a few appointments.  At the first visit, we will 
confirm your contact information, we will offer you condoms, provide HIV counseling, do a physical 
exam and collect blood.  Some blood will be stored, if you agree to that.  The rest of the blood will be 
used to help us better understand how the infection occurred and how the early course of infection may 
be impacted by the study drug you were taking. This includes testing for HIV resistance. If you get 
infected with HIV while on CAB, you might need to take medications that are not like CAB to treat the 
HIV infection. We will also want to make sure that the amount of HIV virus in your blood is responding 
well to treatment.  Once we have confirmed that your HIV is responding well to treatment, you 
participation in the study will end. 
Problems or Questions 

 
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If you ever have any questions about the study, or if you have a research-related injury, you should 
contact [insert name of the investigator or other study staff] at [insert telephone number and/or physical 
address]. 
If you have questions about your rights as a research participant, you should contact [insert name or title 
of person on the IRB or other organization appropriate for the site] at [insert physical address and 
telephone number]. 
If you have questions about who to contact at the research site, you should contact [insert name of the 
investigator or community educator or Community Advisor Board member] at [insert physical address 
and telephone number]. 
 
 
 
 
 
 
 

 
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SIGNATURE PAGE 
HPTN 084: 
A Phase 3 Double Blind Safety and Efficacy Study of Long-Acting Injectable Cabotegravir 
Compared to Daily Oral TDF/FTC for Pre-Exposure Prophylaxis in HIV-Uninfected Women  
 
FINAL Version 
Protocol Version 3.0, dated 12August2021 
DAIDS Document ID: 38070 
 
[The section immediately below is only for ADULTS who participated in HPTN 084 or 
HPTN 084-01.  The signature block for minors is further down the page.] 
[Insert signature blocks as required by the local IRB:]  
If you have read this addendum to the main consent form, or had it read and explained to you, and you 
understand the information, and you voluntarily agree to continue in this part of the study, please sign 
your name or make your mark below. Also, please indicate by providing your initials in the spaces below 
the additional sample collection, genetic testing, or long-term storage that you agree to. 
 
 
________ 
I agree to take part in this OL amendment of the HPTN 084 of the study.  
________ 
I do not agree to take part in this OL amendment of the HPTN 084 of the study.    
________ 
I agree to have samples of my blood stored long-term for future testing.    
________ 
I do not agree to have samples of my blood stored and long-term for future testing.  
________ 
I agree to allow my blood to be tested to see how my genes make drugs work in my body. 
________ 
I do not agree to allow my blood to be tested to see how my genes make drugs work in my 
body. 
 
[________     I agree to continue taking part in the Contraceptive Sub-study.  *If relevant] 
 
[________     I do not agree to continue taking part in the Contraceptive Sub-study.  *If relevant] 
 
 
 
 
 
 
 
 
____________________________________ 
Participant Name (print) 
 
 
Participant Signature and Date 
 
 
 
 

 
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____________________________________ 
Study Staff Conducting 
 
 
Study Staff Signature and Date 
Consent Discussion (print) 
 
 
 
 
 
 
 
 
 
____________________________________ 
Witness Name (print)  
 
 
Witness Signature and Date 
(As appropriate) 
 
[End of the ADULT, OL amendment Signature Block.] 
 
 
 
[The section below is only for MINORS who participated in HPTN 084-01.] 
[Insert signature blocks as required by the local IRB:]  
If you have read this addendum to the main consent form, or had it read and explained to you, and you 
understand the information, and you voluntarily agree to continue in this part of the study, please sign 
your name or make your mark below. Also, please indicate by providing your initials in the spaces below 
the additional sample collection, genetic testing, or long-term storage that you agree to. 
 
 
________ 
I agree to take part in this OL amendment of the HPTN 084 of the study.  
________ 
I do not agree to take part in this OL amendment of the HPTN 084 of the study.    
________ 
I agree to have samples of my blood stored long-term for future testing.    
________ 
I do not agree to have samples of my blood stored and long-term for future testing.  
________ 
I agree to allow my blood to be tested to see how my genes make drugs work in my body. 
________ 
I do not agree to allow my blood to be tested to see how my genes make drugs work in my 
body. 
 
 
 
 
 
 
 
 
 
____________________________________ 
Participant Name (print) 
 
 
Participant Signature and Date 
 

 
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____________________________________ 
Parent or Guardian Name (print)  
Parent or Guardian Name Signature and Date 
 
 
 
 
 
 
 
 
____________________________________ 
Study Staff Conducting 
 
 
Study Staff Signature and Date 
Consent Discussion (print) 
 
 
 
 
 
 
 
 
 
____________________________________ 
Witness Name (print)  
 
 
Witness Signature and Date 
(As appropriate) 
 
 
[End of the MINOR, OL amendment Signature Block.] 
 
 
 
[This consent section is separate because it is ONLY for participants who 1) become 
pregnant during the OL amendment, 2) who have received at least one CAB LA 
injection, and 3) want to join the Pregnancy Infant Sub-study.  Only women meeting 
the criteria need to read and complete the below.] 
 
[Insert signature blocks as required by the local IRB:] 
 If you have read this addendum to the main consent form, or had it read and explained to you, and you 
understand the information, and you voluntarily agree to join the Pregnancy Infant Sub-Study, please 
sign your name or make your mark below. Also, please indicate by providing your initials in the spaces 
below whether you agree for your baby to participate. 
________ 
I agree to take part in the Pregnancy Infant Sub-Study of the HPTN 084 OL amendment.  
________ 
I do not agree to take part in the Pregnancy Infant Sub-Study of the HPTN 084 OL 
amendment.  
________ 
I agree to take CAB LA injections during the pregnancy and while breastfeeding. 
________ 
I do not agree to take CAB LA injections during the pregnancy and while breastfeeding. 
 
________ 
I agree to let the team collect blood from me.   

 
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________ 
I do not agree to let the team collect blood from me. 
 
________ 
I agree to let the team collect some blood from the umbilical cord at delivery.   
________ 
I do not agree to let the team collect some blood from the umbilical cord at delivery.   
 
________ 
I agree to let the team collect blood from my baby.   
________ 
I do not agree to let the team collect blood from my baby. 
 
________ 
I agree to let the team collect breastmilk samples.   
________ 
I do not agree to let the team collect breastmilk samples.   
 
 
________ 
I agree to let the team store umbilical cord blood, blood from my baby and breastmilk  
samples for future research.   
________ 
I do not agree to let the team store umbilical cord blood, blood from my baby and 
breastmilk  samples for future research.   
 
 
[Immediately below is a signature block for ADULT participants.  There is a separate 
signature block for pregnant, minor participants further down.] 
 
 
 
 
 
 
 
 
____________________________________ 
Participant Name (print) 
 
 
Participant Signature and Date 
 
 
 
 
 
 
 
 
 
 
____________________________________ 
Study Staff Conducting 
 
 
Study Staff Signature and Date 
Consent Discussion (print) 
 
 
 
 
 
 
 
 
 
____________________________________ 
Witness Name (print)  
 
 
Witness Signature and Date 
(As appropriate) 

 
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[End of the ADLUT Pregnancy Infant Sub-Study Signature Block.] 
 
 
 
 
 
 
 
[Immediately below is a signature block for MINOR  participants.  There is a separate 
signature block for pregnant, adult participants above.] 
 
 
 
 
 
 
 
 
____________________________________ 
Participant Name (print) 
 
 
Participant Signature and Date 
 
 
 
 
 
 
 
 
____________________________________ 
Parent or Guardian Name (print)  
Parent or Guardian Name Signature and Date 
 
 
 
 
 
 
 
 
____________________________________ 
Study Staff Conducting 
 
 
Study Staff Signature and Date 
Consent Discussion (print) 
 
 
 
 
 
 
 
 
 
____________________________________ 
Witness Name (print)  
 
 
Witness Signature and Date 
(As appropriate) 
 
 
 
[End of the MINOR Pregnancy Infant Sub-Study Signature Block.] 
 
 
 

 
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REFERENCES TO OLE APPENDIX  
1. 
S Delany-Moretlwe, JP Hughes, P Bock, et al. Long acting injectable cabotegravir is safe and 
effective in preventing HIV infection in cisgender women: interim results from HPTN 084. Paper 
presented at: R4P; January, 2021; Online. 
2. 
Overton ET, Richmond G, Rizzardini G, et al. Long-acting cabotegravir and rilpivirine dosed 
every 2 months in adults with HIV-1 infection (ATLAS-2M), 48-week results: a randomised, 
multicentre, open-label, phase 3b, non-inferiority study. Lancet. 2021;396(10267):1994-2005. 
3. 
Susan Swindells, Thomas Lutz, Lelanie Van Zyl, et al. Cabotegravir + Rilpivirine Long-Acting 
as HIV-1 Maintenance Therapy: ATLAS Week 96 Results. HIV Glasgow – Virtual, 5–8 October 2020; 
2020. 
4. 
Marzinke MA, Grinsztejn B, Fogel JM, et al. Characterization of HIV infection in cisgender men 
and transgender women who have sex with men receiving injectable cabotegravir for HIV prevention: 
HPTN 083. J Infect Dis. 2021. 
5. 
Graybill LA, Kasaro M, Freeborn K, et al. Incident HIV among pregnant and breast-feeding 
women in sub-Saharan Africa: a systematic review and meta-analysis. Aids. 2020;34(5):761-776. 
6. 
Thomson KA, Hughes J, Baeten JM, et al. Increased Risk of HIV Acquisition Among Women 
Throughout Pregnancy and During the Postpartum Period: A Prospective Per-Coital-Act Analysis 
Among Women With HIV-Infected Partners. The Journal of Infectious Diseases. 2018;218(1):16-25. 
7. 
Thomson KA, Hughes J, Baeten JM, et al. Increased Risk of HIV Acquisition Among Women 
Throughout Pregnancy and During the Postpartum Period: A Prospective Per-Coital-Act Analysis 
Among Women With HIV-Infected Partners. J Infect Dis. 2018;218(1):16-25. 
8. 
Chouchana L, Beeker N, Treluyer JM. Is There a Safety Signal for Dolutegravir and Integrase 
Inhibitors During Pregnancy? J Acquir Immune Defic Syndr. 2019;81(4):481-486. 
9. 
van De Ven NS, Pozniak AL, Levi JA, et al. Analysis of Pharmacovigilance Databases for 
Dolutegravir Safety in Pregnancy. Clin Infect Dis. 2020;70(12):2599-2606. 
10. 
R. Zash, L. Holmes, M. Diseko, et al. Update on neural tube defects with antiretroviral exposure 
in the Tsepamo study, Botswana. IAS; 2020; Virtual. 
11. 
In: World Health Organization. Policy brief: update of recommendations on first- and second-
line antiretroviral regimens.; 2019. 
12. 
Odagiri E, Ishiwatari N, Abe Y, et al. Hypercortisolism and the resistance to dexamethasone 
suppression during gestation. Endocrinol Jpn. 1988;35(5):685-690. 
13. 
Markham A. Bictegravir: First Global Approval. Drugs. 2018;78(5):601-606. 
14. 
J C, SK W, S C, Vu A XD, H M. Pharmacokinetics of Bictegravir Adminstered Twice Daily in 
Combination with Rifambin.  25th Conference on Retroviruses and Opportunistic Infections. Paper 
presented at: CROI2018; Boston, MA. 
15. 
Zhang H, Custodio JM, Wei X, et al. CLINICAL PHARMACOLOGY OF THE HIV 
INTEGRASE STRAND TRANSFER INHIBITOR BICTEGRAVIR. Paper presented at: CROI2017; 
Seattle, WA. 
16. 
Kityo C, Hagins D, Koenig E, A. A. Switching to Bictegravir/Emtricitabine/Tenfovir Alfenimide 
(B/F/TAF) in Women. Paper presented at: CROI2018; Boston, MA. 
17. 
Gallant J, Lazzarin A, Mills A, et al. Bictegravir, emtricitabine, and tenofovir alafenamide versus 
dolutegravir, abacavir, and lamivudine for initial treatment of HIV-1 infection (GS-US-380-1489): a 
double-blind, multicentre, phase 3, randomised controlled non-inferiority trial. Lancet. 
2017;390(10107):2063-2072. 

 
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18. 
Parul Patel, Shanker Thiagarajah, Susan Ford, et al. CABOTEGRAVIR PHARMACOKINETIC 
TAIL IN PREGNANCY AND NEONATAL OUTCOMES. Paper presented at: CROI2020; Boston, 
MA. 
19. 
GSK1265744, Cabotegravir. In: 11 V, ed. Investigator’s Brochure. February 2021. 
20. 
Waitt C, Orrell C, Walimbwa S, et al. Safety and pharmacokinetics of dolutegravir in pregnant 
mothers with HIV infection and their neonates: A randomised trial (DolPHIN-1 study). PLoS Med. 
2019;16(9):e1002895. 
21. 
Risa M Hoffman, Rosie Mngqibisa, Dawn Averitt, Currier JS. Accelerating drug discovery for 
pregnant and lactating women living with HIV. JIAS. 2021;Volume24(3). 
22.  
FDA Guidance on Conduct of Clinical Trials of Medical Products During the COVID-19 Public 
Health Emergency: Guidance for Industry, Investigators, and Institutional Review Boards, March 2020, 
Updated on January 27, 2021. Accessed at: https://www.fda.gov/media/136238/download