Conditions: HIV Infections
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 55
Healthy volunteers: yes

Brief summary:
This study will establish the minimum safety, tolerability and acceptability data needed to support the use of cabotegravir long-acting injection (CAB LA) in an adolescent population, potentially transforming the field of HIV prevention for young people.

Detailed description:
This study will enroll sexually-active, healthy, HIV-uninfected adolescents assigned female sex at birth. Total participant commitment for the entire study is approximately 1.5 years.

This study will take place in three steps. In Step 1, participants will receive daily oral CAB tablets for 5 weeks. In Step 2, participants will receive a series of five intramuscular (IM) injections of CAB LA, administered at 8-week intervals after a 4-week loading dose (injections at Weeks 5, 9, 17, 25 \& 33). A safety visit will follow each injection to ascertain safety data, including injection site reactions. In Step 3, all participants who have received at least one injection will be followed quarterly (every 3 months) for 48 weeks after their last injection. Participants will receive oral TDF/FTC for daily use for 48 weeks or join and open-label extension CAB study in their area, if available.

Participants will attend about 18 study visits throughout the study. Visits may include physical examinations, blood collection, urine collection, vaginal swab collection, risk reduction and adherence counseling, and behavioral or acceptability assessments.

Arms:
arm 1: In Step 1, participants will receive one CAB tablet orally every day for 5 weeks. In Step 2, participants will receive an intramuscular (IM) injection of CAB LA at Weeks 5, 9, 17, 25, and 33. In Step 3, participants will receive a TDF/FTC tablet orally every day for 48 weeks or join an open-label extension CAB study in their area, if available.

Interventions: intervention 1: Oral cabotegravir (CAB) intervention 2: CAB LA intervention 3: Oral tenofovir disoproxil fumarate/emtricitabine (TDF/FTC)
Intervention descriptions: intervention 1: 30 mg tablets intervention 2: Administered as one 3 mL (600 mg) IM injection in the gluteal muscle at two time points 4 weeks apart and every 8 weeks thereafter intervention 3: 300 mg/200 mg fixed-dose combination tablets

Protocol document:
Prot_ICF_002.pdf: 
 
 
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 HPTN 084-01: 
Safety, Tolerability and Acceptability of Long-Acting Cabotegravir (CAB LA) for the Prevention 
of HIV among Adolescent Females – A Sub-study of HPTN 084 
 
 
 
DAIDS Document ID: 38655 
 
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), Eunice Kennedy Shriver National Institute of Child Health and Human Development 
(NICHD), 
US National Institutes of Health (NIH) 
 
Support Provided by: 
ViiV Healthcare 
 
 
 
 
IND Holder: 
DAIDS, NIAID, NIH 
 
IND #: 122,744 
 
Protocol Chair: 
Sybil Hosek, PhD 
 
Protocol Co-Chair: 
Lynda Stranix-Chibanda, MBChB, MMED 
 
 
FINAL, Version 1.0 
14 October 2019 
 
 
 
 
 


 
 
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TABLE OF CONTENTS 
 
PROTOCOL TEAM ROSTER ............................................................................................................. 10 
SCHEMA ................................................................................................................................................. 15 
 
INTRODUCTION....................................................................................................................... 16 
1.1 Background and Rationale ............................................................................................................ 16 
1.2 Overview of Oral CAB and CAB LA ........................................................................................... 18 
1.3 Metabolism ................................................................................................................................... 19 
1.4 Preclinical Studies ......................................................................................................................... 19 
1.5 Dose Rationale .............................................................................................................................. 20 
1.6 Genital Tract (GT) Tissue Levels after Oral and Injectable Administration ................................ 22 
1.7 Pediatric Dosing ............................................................................................................................ 22 
1.8 Pregnancy and Pregnancy Prevention with CAB Use .................................................................. 24 
1.9 Hepatic and Central Nervous System Adverse Events ................................................................. 26 
1.10 Weight gain ................................................................................................................................... 27 
1.11 Rationale for use of Oral Run-in Prior to Injectable Dosing ........................................................ 27 
 
STUDY OBJECTIVES AND DESIGN ..................................................................................... 27 
2.1 Primary Objectives........................................................................................................................ 27 
2.2 Secondary Objectives.................................................................................................................... 27 
2.3 To evaluate the pharmacokinetics of CAB LA. Study Design and Overview.............................. 28 
 
STUDY POPULATION ............................................................................................................. 29 
3.1 Inclusion Criteria .......................................................................................................................... 29 
3.2 Exclusion Criteria ......................................................................................................................... 30 
3.3 Recruitment Process...................................................................................................................... 32 
3.4 Co-Enrollment Guidelines ............................................................................................................ 32 
3.5 Participant Retention ..................................................................................................................... 32 
3.6 Participant Withdrawal ................................................................................................................. 33 
 
STUDY PRODUCT CONSIDERATIONS ............................................................................... 33 
4.1 Study Product Regimens/Administration/Formulation Content ................................................... 33 
4.2 Study Product Acquisition and Accountability............................................................................. 36 
4.3 Toxicity Management ................................................................................................................... 36 
4.4 Concomitant, Prohibited, and Precautionary Medications ........................................................... 36 
 
STUDY PROCEDURES ............................................................................................................ 39 


 
 
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5.1 Screening....................................................................................................................................... 39 
5.2 Enrollment..................................................................................................................................... 39 
5.3 Step 1, Oral Run-in Phase: Safety Visits ...................................................................................... 40 
5.4 Transitioning from Step 1 to Step 2 .............................................................................................. 41 
5.5 Step 2, Injection Phase: Injection Visits ....................................................................................... 42 
5.6 Step 2, Injection Phase: Safety Visits ........................................................................................... 42 
5.7 Step 3, Follow-up Phase ............................................................................................................... 42 
5.8 Standard of Care (SOC) Counseling for all Participants .............................................................. 43 
5.9 Injection Visit Windows ............................................................................................................... 44 
5.10 Procedures for Injectable Dosing .................................................................................................. 44 
5.11 Participants with Suspected or Confirmed HIV Infection at Screening, Enrollment, or  Follow-
Up 44 
5.12 STIs ............................................................................................................................................... 45 
5.13 HBV and HCV .............................................................................................................................. 45 
5.14 Contraception ................................................................................................................................ 46 
5.15 Pregnancy ...................................................................................................................................... 46 
5.16 Behavioral and Acceptability Assessments .................................................................................. 47 
5.17 Interim Contacts and Visits ........................................................................................................... 47 
5.18 Criteria for Early Termination of Study Participation .................................................................. 48 
 
SAFETY MONITORING AND AE REPORTING ................................................................. 48 
6.1 AE Definition and Reporting ........................................................................................................ 48 
6.2 EAE Reporting .............................................................................................................................. 49 
6.3 Safety Monitoring ......................................................................................................................... 50 
6.4 Clinical Data Review .................................................................................................................... 51 
6.5 Social Harms and Social Benefits Reporting ................................................................................ 51 
6.6 Critical Events Reporting .............................................................................................................. 52 
 
STATISTICAL CONSIDERATIONS ...................................................................................... 52 
7.1 Review of Study Design ............................................................................................................... 52 
7.2 Endpoints ...................................................................................................................................... 52 
7.3 Sample Size ................................................................................................................................... 53 
7.4 Randomization .............................................................................................................................. 54 
7.5 Blinding......................................................................................................................................... 54 
7.6 Data and Safety Monitoring Analysis ........................................................................................... 54 
7.7 Secondary Analyses ...................................................................................................................... 56 
7.8 Qualitative Analysis ...................................................................................................................... 56 
 
HUMAN SUBJECTS CONSIDERATIONS ............................................................................ 57 
8.1 Ethical Review .............................................................................................................................. 57 
8.2 Informed Consent.......................................................................................................................... 57 
8.3 Incentives ...................................................................................................................................... 59 
8.4 Confidentiality .............................................................................................................................. 59 
8.5 Communicable Disease and Statutory Rape Reporting Requirements ......................................... 59 
8.6 Study Discontinuation ................................................................................................................... 59 
 
LABORATORY SPECIMENS AND BIOHAZARD CONTAINMENT .............................. 59 


 
 
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9.1 Local Laboratory Specimens ........................................................................................................ 60 
9.2 Stored Specimens .......................................................................................................................... 61 
9.3 Virology ........................................................................................................................................ 61 
9.4 Pharmacology ............................................................................................................................... 61 
9.5 Quality Control and Quality Assurance Procedures ..................................................................... 62 
9.6 QC for HIV Diagnostic Testing .................................................................................................... 62 
9.7 Quality Assurance for General Laboratory Testing ...................................................................... 62 
9.8 Quality Assurance for CD4 Cell Count Testing ........................................................................... 62 
9.9 Quality Assurance for HIV RNA Testing ..................................................................................... 62 
9.10 Specimen Storage and Possible Future Research Testing ............................................................ 63 
9.11 Biohazard Containment ................................................................................................................ 63 
 
ADMINISTRATIVE PROCEDURES ...................................................................................... 63 
10.1 Protocol Registration .................................................................................................................... 63 
10.2 Study Activation ........................................................................................................................... 64 
10.3 Study Coordination ....................................................................................................................... 64 
10.4 Study Monitoring .......................................................................................................................... 64 
10.5 Protocol Compliance ..................................................................................................................... 65 
10.6 Investigator's Records ................................................................................................................... 65 
10.7 Use of Information and Publications ............................................................................................ 65 
 
REFERENCES ............................................................................................................................ 66 
 
APPENDICES I - X .................................................................................................................... 69 
12.1 APPENDIX I. SCHEDULE OF EVALUATIONS – ORAL PHASE (Step 1) ............................ 70 
12.2 APPENDIX II. SCHEDULE OF EVALUATIONS – INJECTION PHASE (Step 2) ................. 72 
12.3 APPENDIX III. SCHEDULE OF EVALUATIONS –FOLLOW-UP PHASE (Step 3) .............. 74 
12.4 APPENDIX IV: SCHEDULE OF ADDITIONAL PROCEDURES FOR REACTIVE/POSITIVE 
HIV TESTS ........................................................................................................................................... 76 
12.5 APPENDIX V:  SCHEDULE OF EVALUATIONS FOR PREGNANT PARTICIPANTS ....... 78 
12.6 APPENDIX VI: TOXICITY MANAGEMENT ........................................................................... 79 
12.7 APPENDIX VII: SAMPLE INFORMED CONSENT with PARENT/GUARDIAN 
PERMISSION ....................................................................................................................................... 88 
12.8 APPENDIX VIII: SAMPLE INFORMED CONSENT FOR SPECIMEN STORAGE AND 
FUTURE USE with PARENT/GUARDIAN PERMISSION ............................................................ 103 
12.9 APPENDIX IX: SAMPLE INFORMED CONSENT FOR ADOLESCENT INTERVIEWS with 
PARENT/GUARDIAN PERMISSION .............................................................................................. 108 
12.10 
APPENDIX X: SAMPLE INFORMED CONSENT FOR PARENT/GUARDIAN 
INTERVIEW ...................................................................................................................................... 113 
 
 
 


 
 
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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 
BUN 
blood urea nitrogen 
C 
Celsius 
C 
trough concentration 
CAB 
cabotegravir, oral and LA formulations 
CAB LA 
long-acting injectable formulation of cabotegravir 
CABG 
CASI 
coronary artery bypass grafting 
computer-assisted self-interview 
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 Committee 
CPK 
creatine phosphokinase 
CRF 
case report form 
CRM 
Clinical Research Manager 
CRPMC 
CRS 
Clinical Research Products Management Center 
Clinical Research Site 
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 Center 


 
 
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DMPA 
depot medroxyprogesterone acetate 
DSMB 
DTG 
Data and Safety Monitoring Board 
Dolutegravir 
EAE 
expedited adverse event 
EC 
Ethics Committee 
ECLAIR 
 
EE 
Phase IIa Safety and PK Study of Cabotegravir LA in HIV-
Uninfected Men at Low Risk for Sexual Acquisition of HIV 
Infection 
Ethinyl estradiol 
EFD 
early fetal development 
EFV 
efavirenz 
EQA 
FACTS 
external quality assurance 
Follow-on African Consortium for Tenofovir Studies 
FDA 
(US) Food and Drug Administration 
FEM-PrEP 
 
FSH 
Pre-exposure Prophylaxis Trial for HIV Prevention among 
African Women 
Follicular stimulating hormone 
FTC 
emtricitabine 
FTC-TP 
emtricitabine triphosphate 
GC 
Neisseria gonorrhoeae 
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 
IATA 
International Air Transport Association 
IB 
Investigator Brochure 
ICF 
informed consent form 
ID 
IDI 
Identification 
In-depth interview 
IM 
IMPAACT 
Intramuscular 
International Maternal Pediatric Adolescent AIDS Clinical Trials 
Network 
IND 
investigational new drug 


 
 
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INSTI 
integrase strand transfer inhibitor  
IoR 
Investigator of Record  
IP 
Intraperitoneal 
iPrEX OLE 
iPrEx Open Label Extension 
IQA 
(DAIDS) Immunology Quality Assurance 
IRB 
Institutional Review Board 
ISR 
injection site reaction 
IUD 
intrauterine device 
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 
LH 
LNG 
liver function tests 
luteinizing hormone 
Levonorgestrel 
LOC 
LLQ 
MedDRA 
MO 
(HPTN) Leadership and Operations Center 
Lower limit of quantification 
Medical Dictionary for Regulatory Activities 
Medical Officer 
MOP 
Manual of Operations 
MRC 
MRI 
(HPTN) Manuscript Review Committee 
Magnetic resonance imaging 
MSM 
men who have sex with men 
NAAT 
nucleic acid amplification test 
NET-EN 
NICHD 
Norethisterone enanthate 
Eunice Kennedy Shriver National Institute of Child Health and 
Human Development 
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 
PEP 
Protocol Analyte List 
Post-exposure prophylaxis 
PI 
package insert 
Pgp 
permeability glycoprotein 
PK 
Pharmacokinetic 
PO 
by mouth/orally 
PPN 
pre- and postnatal development 


 
 
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PrEP 
pre-exposure prophylaxis 
PROUD 
Pre-exposure Prophylaxis to Prevent Acquisition of HIV-1 
Infection 
pSMILE 
Patient Safety Monitoring and International Laboratory 
Evaluation 
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) 
SAE 
SAHPRA 
serious adverse events 
South African Health Products Regulatory Authority 
SC 
Subcutaneous 
SDMC 
(HPTN) Statistics and Data Management Center 
SHIV 
simian human immunodeficiency virus 
SMC 
SMS 
Study Monitoring Committee 
Short message service 
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 
SUSAR 
sexually transmitted infection 
suspected unexpected serious adverse reaction 
TBili 
total bilirubin 
TCID 
tissue culture infective dose 
TDF 
tenofovir disoproxil fumarate 
TENOFOVIR/EMTRICITABINE 
(TRADE NAME: TDF/FTC, 
TRUVADA®) 
tenofovir/emtricitabine (trade name: 
TENOFOVIR/EMTRICITABINE (TRADE NAME: TDF/FTC, 
TRUVADA®)®) 
TFV 
Tenofovir 
TFV-DP 
tenofovir diphosphate 
TGW 
Tmax 
transgender women 
time after drug administration when maximum drug concentration 
in serum is reached 
TP 
UGT 1A1 
UKNEQAS 
Triphosphate 
Uridine Diphosphate Glucuronyltransferase Type 1A1 
United Kingdom National External Quality Assessment Service 
ULN 
upper limit of normal 
US 
United States of America 
VOICE 
Vaginal and Oral Interventions to Control the Epidemic 


 
 
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VQA 
(DAIDS) Virology Quality Assurance 
WHO 
YKP 
YMSM 
World Health Organization 
Youth Key Populations 
Young men who have sex with men 
 
 
 
 


 
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PROTOCOL TEAM ROSTER 
 
PROTOCOL CHAIR: 
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: +001 312 864 8030 
Fax: +001 312 864 9203 
Email: shosek@cookcountyhhs.org 
 
PROTOCOL CO-CHAIR: 
Lynda Stranix-Chibanda, MBChB, MMED 
Department of Paediatrics and Child Health 
College of Health Sciences 
University of Zimbabwe 
Harare 
Zimbabwe 
Phone: +263 24 2704890 
Fax: +263 24 2704897 
Email: lstranix@uzchs-ctrc.org 
Adeola Adeyeye, MD, MPA 
Medical Officer 
Prevention Science Program 
DAIDS, NIAID, NIH 
Room 8B36 MSC 9832 
5601 Fishers Lane  
Rockville, MD 20852-9831 
United States 
Phone:  +001 240 669 5005  
Cell: +001 240 619 9365 
Email: adeola.adeyeye@nih.gov  
   
Bill G. Kapogiannis, MD  
Eunice Kennedy Shriver National Institute of Child 
Health and Human Development (NICHD) 
BG 6710B RM 2150 
6710B Rockledge Dr. 
Bethesda, MD 20817  
United States 
Phone: +001 301 402 0698 
Fax: +001 301 480 3882 
Email: bill.kapogiannis@nih.gov 
Erica Hamilton, MPH 
HPTN LOC 
Clinical Research Manager II 
FHI 360 
359 Blackwell Street, Suite 200 
Durham, NC 27701 
United States 
Phone: +001 919 544 7040, Ext. 11295 
Email: ehamilton@fhi360.org 
 
Scott Rose, BS  
HPTN LOC 
Clinical Research Project Manager  
FHI 360 
359 Blackwell Street, Suite 200 
Durham, NC 27701 
United States 
Phone: +001 919 544 7040, Ext. 11378  
Email: srose@fhi360.org  
 
 
 


 
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Irene Rwakazina, PharmD, CCRP, RPh 
Pharmacist, Pharmaceutical Affairs Branch 
Office of Clinical Site Oversight (OCSO) 
Division of AIDS/NIAID/NIH 
5601 Fishers Lane 
Room 9E14 MSC 9830 
Rockville, MD 20852-9830 
United States 
Phone: +001 301 761 7269 
Fax: +001 240 627 3112 
Email: irene.rwakazina@nih.gov 
 
Lynda Emel, PhD 
HPTN SDMC Associate Director 
SCHARP-FHCRC  
1100 Fairview Avenue N, LE-400 
PO Box 19024 
Seattle, WA 98109 
United States 
Phone:  +001 206 667 5803 
Fax:  +001 206 667 4812 
Email: lemel@scharp.org    
 
Mark Marzinke, PhD, DABCC 
HPTN Laboratory Center 
Johns Hopkins University 
Department of Pathology  
1800 Orleans Street 
Sheikh Zayed Tower, Room B1-1020G 
Baltimore, MD 21287  
United States 
Phone: +001 443 287 7516 
CPAL Office: +001 410 550 9702 
Email:  mmarzin1@jhmi.edu 
 
Estelle M. Piwowar-Manning, BS, MT 
Johns Hopkins University  
Pathology Building, Room 313  
600 North Wolfe Street  
Baltimore, MD 21287, USA 
United States 
Phone: +001 410 614 6736  
Fax: +001 410 614 0430 
Email: epiwowa@jhmi.edu 
 
Alex Rinehart, PhD 
ViiV Healthcare 
5 Moore Drive 
Durham, NC 27709 
United States 
Phone:  +001 919 483 2085 (office) 
Phone: +001 919 599 7551 (mobile) 
Email: alex.r.rinehart@viivhealthcare.com 
 
Cindy McCoig, MD 
ViiV Healthcare 
Severo Ochoa, 2 
28760 Tres Cantos, Madrid 
Spain 
Phone: +34 608 831 611 
Email: cynthia.c.mccoig@viivhealthcare.com 
 
Nirupama Sista, PhD 
HPTN LOC Director 
359 Blackwell Street, Suite 200 
Durham, NC 27701 
United States  
Phone: +001 919 405 1454 
Fax: +001 919 405 1402 
Email: nsista@fhi360.org 
Linda-Gail Bekker, MBChB, DTMH, DCH, FCP 
Desmond Tutu HIV Centre 
Institute of Infectious Disease & Molecular 
Medicine 
University of Cape Town Faculty of Health Sciences 
Cape Town, 7925 
South Africa 
Phone: +27 021 6506970 
Fax: +27 021 6506959 
Email: Linda-Gail.Bekker@hiv-research.org.za 
 
 
 
 


 
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James Hughes, PhD 
HPTN SDMC  
SCHARP-FHCRC  
University of Washington 
Department of Biostatistics 
MS# 357232 
Seattle, WA 98195 
United States 
Phone:  +001 206 616 2721  
Fax:  +001 206 667 4812 
Email: hughes@scharp.org   
  
Shahar Zangeneh, PhDHPTN SDMC  
SCHARP-FHCRC  
MS# M2-C200 
Seattle, WA 98195 
United States 
Phone:  +001 206 657 7049  
Fax:  +001 206 667 4812 
Email: saharzz@scharp.org 
 
Sinead Delany-Moretlwe, MBBCh, PhD, 
DTM&H 
Wits Reproductive Health and HIV Institute 
CRS (WRHI CRS) 
University of the Witwatersrand 
Hillbrow Health Precinct 
22 Esselen Street 
Johannesburg, 2001 
South Africa 
Phone:  +27 11 358 5414 
Fax:  +27 86 426 5575 
Email: sdelany@wrhi.ac.za 
 
Raphael J. Landovitz, MD, MSc 
UCLA Center for Clinical AIDS Research & 
Education 
11075 Santa Monica Blvd, Suite 100 
Los Angeles, CA 90025 
United States 
Phone: +001 310 825 3782  
Fax: +001 310 477 7657  
Email: rlandovitz@mednet.ucla.edu 
 
 
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: +001 410 614 6763 
Email: yagyei1@jhmi.edu 
Ethel D. Weld, MD 
HPTN Laboratory Center 
Johns Hopkins University  
Division of Clinical Pharmacology 
600 North Wolfe Street, Osler 508 
Baltimore, MD 21287 
United States 
Phone: +001 410 502 8129 
Fax: +001 410 955 9708    
Email: eweld@jhmi.edu 
 
Kathleen M. MacQueen, PhD, MPH 
Senior Social Scientist 
Behavioral, Epidemiological & Clinical Sciences 
FHI 360 
359 Blackwell Street, Suite 200 
Durham, NC  27701 USA  
United States 
Phone: +001 919 544 7040, Ext. 11587  
Email: kmacqueen@fhi360.org 
 
Tanette Headen 
HPTN LOC 
Clinical Research Assistant 
FHI 360 
359 Blackwell Street, Suite 200 
Durham, NC 27701 
United States 
Phone: +001 919 544 7040, Ext. 11297 
Email: theaden@fhi360.org 
 
Lisa Hightow-Weidman 
University of North Carolina at Chapel Hill 
Heather Noble, MPH 
HPTN SDMC Clinical Data Manager 


 
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130 Mason Farm Road, CB#215 
Chapel Hill, NC 27599 
United States 
Phone: +001 919 843 0033 
Email: lisa_hightow@med.unc.edu 
SCHARP-FHCRC  
Vaccine and Infectious Disease Division 
1100 Fairview Ave N 
PO Box 19024  
Seattle, WA 98109 
United States 
Phone: +001 206 667 3329  
Email: hnoble@scharp.org 
 
Marcus Bryan, M.Ed 
Sr. Community Program Manager III (HPTN, 
MTN, IMPAACT) 
FHI 360 
359 Blackwell Street, Suite 200 
Durham, NC 27701 
United States 
Phone: +001 919 544 7040, Ext. 11678 
Fax: +001 919 544 7261 
Cell: +001 919 638 9850 
Email: mbolton@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: +001 206 709 3407  
Email: Lut.VanDamme@gatesfoundation.org 
 
 


 
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Protocol Signature Page 
 
Version 1.0, dated 14 October 2019 
DAIDS Document ID: 38655 
 
A Study of the HIV Prevention Trials Network (HPTN) 
 
Sponsored by: 
Division of AIDS (DAIDS), United States (US) National Institute of Allergy and Infectious Diseases 
(NIAID), Eunice Kennedy Shriver National Institute of Child Health and Human Development 
(NICHD), 
US National Institutes of Health (NIH) 
 
Support Provided by: 
ViiV Healthcare 
 
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 (DD/MM/YYYY) 
 
 
 
 
 


 
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HPTN 084-01: 
Safety, Tolerability and Acceptability of Long-Acting Cabotegravir (CAB LA) for the Prevention 
of HIV among Adolescent Females – A Sub-study of HPTN 084 
 
SCHEMA 
 
Purpose:  
To establish the minimum safety, tolerability and acceptability data needed to support the use of 
cabotegravir long-acting injection (CAB LA) in an adolescent population, potentially transforming the 
field of HIV prevention for young people. 
  
 
Design:  
A Phase IIB single arm, open label safety, tolerability, and acceptability study 
  
 
Population:   
Sexually-active, healthy female adolescents aged below 18 years.  
 
Study Size:    
Approximately 50. 
 
Study Duration:  
Participant recruitment will take approximately 12 months. Oral study product will be administered for 5 
weeks, followed by 34 weeks on injectable product then quarterly visits for 48 weeks after final 
injection. All participants who have received at least one injection will be followed for 48 weeks after 
their last injection. Waning levels of cabotegravir (the PK tail) will be covered with locally sourced oral 
TENOFOVIR/EMTRICITABINE (TRADE NAME: TDF/FTC, TRUVADA®) for daily use for 48 
weeks. Total study duration per participant will be approximately 21 months. 
 
Study Sites:  
 
 
 
Ward 21 CRS, Johannesburg, South Africa; Spilhaus CRS, Harare, Zimbabwe; MU-JHU Research 
Collaboration (MUJHU CARE LTD) CRS, Kampala, Uganda 
 
Study Regimen:  
Step 1 – oral cabotegravir (30mg tablet); Step 2 – injectable cabotegravir 3 mL (600 mg) intramuscular 
(IM) injection; Step 3 – TENOFOVIR/EMTRICITABINE (TRADE NAME: TDF/FTC, TRUVADA®) 
(300mg/200mg tablet) 
 
Primary Objectives:  
• To evaluate the safety, tolerability and acceptability of CAB LA in healthy HIV-uninfected 
female adolescents aged below 18 years. 
Secondary Objectives: 
• To examine adherence to and timeliness of injections over time among adolescent 
participants provided CAB LA and information regarding its safety and unknown efficacy. 
• To examine patterns of sexual risk behavior over time among adolescent participants 
provided CAB LA and information regarding its safety and unknown efficacy. 
• To evaluate the safety of CAB LA for up to 48 weeks of follow-up after final injection. 


 
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• To characterize the pharmacokinetics of CAB LA. 
 
 INTRODUCTION 
1.1 Background and Rationale 
The burden of HIV infection worldwide is disproportionately borne by youth. 
Despite reductions in other age groups, the number of deaths attributable to HIV is rising in the 
adolescent age group, with AIDS being the leading cause of death among adolescents in Africa and the 
second leading cause for adolescents worldwide.1 Between 2005 and 2012, the number of AIDS-related 
deaths decreased by 30% for all ages except adolescents, who experienced a 50% increase in that same 
period. Youth are over-represented in the current HIV epidemic: in 2017, nearly 2000 of the 5000 new 
HIV infections which occur globally each day are in individuals aged 24 years or younger (one-third of 
these new HIV infections occur in youth aged 15 to 24).2 Among youth, there are also key populations 
that bear disproportionate burdens of HIV and are the most vulnerable. These key populations (YKPs) 
include young men who have sex with men (YMSM) globally and adolescent/young adult women in 
Sub-Saharan Africa.3  
Girls and young women between 15 and 30 years old have an extraordinarily high incidence, 
particularly in countries such as South Africa.4-6 The most recent household survey confirms the 
feminization of the epidemic nationally in that country, with adolescent girls 15 to 19 years of age four 
times more likely to be infected than their male counterparts.6 In recent HIV prevention trials, annual 
HIV incidence was 5-6% in South African young women, even in the context of counseling, condom 
provision and STI treatment.7-9 HIV prevention and decreasing HIV-related deaths depend critically on 
reaching adolescents, engaging them in HIV prevention research, and ensuring access to HIV prevention 
products via regulatory approvals. 
Oral Pre-exposure Prophylaxis is highly efficacious against HIV, but poor adherence has limited its 
effectiveness for youth.  
Tenofovir-based ARV regimens have been shown to significantly reduce HIV acquisition among men 
who have sex with men (MSM), heterosexual men and women, injection drug users and HIV sero-
discordant couples.10-13 Given the growing body of evidence about its effectiveness, including 
encouraging “real world” demonstration projects14,15, oral daily PrEP is now recommended for HIV 
prevention by the US Centers for Disease Control and Prevention (CDC), the World Health 
Organization (WHO) and a growing number of countries worldwide16,17. 
As with many daily medication regimens, the effectiveness of oral PrEP is highly dependent on 
adherence to the prescribed drugs. This appears to be particularly true for adolescents and young adults. 
In at least two clinical trials of women, oral PrEP did not show a decreased risk of HIV transmission and 
these results appeared to be related to poor adherence among study participants.7,18 In the FEM-PrEP 
study, for example, only 12% of women had serum drug levels associated with good adherence 
throughout trial participation.18 Similarly, the VOICE trial7 failed to show efficacy of either oral PrEP or 
daily vaginal gel, largely attributable to very low rates of adherence among a cohort of young women. 
Trials of other short-acting prevention technologies have also been negatively impacted by low 
adherence among the youngest participants. The FACTS 001 licensure trial18 for tenofovir gel that 
followed CAPRISA 004 recently reported no effect on HIV acquisition among a large sample of young 


 
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South African women, primarily because participants struggled to adhere to the prescribed regimen.9 
Furthermore, results from two recent randomized trials of the dapivirine vaginal ring, which showed 
modest efficacy overall, demonstrated consistently low adherence among women under the age of 21, 
which attenuated the overall protective effect of the intervention.8,19 
For youth, PrEP may only reach its full potential with drugs that do not depend on daily or near-daily 
pill-taking. 
Challenges with adherence to medication are commonplace among adolescents, regardless of whether it 
is adherence to a treatment or prevention regimen. Non-adherence among youth is often a reflection of 
both the biological and behavioral transitions that occur during this developmental time, including 
increased autonomy from parents/caregivers, increased importance of peers and corresponding 
vulnerability to peer influence and stigma, and undeveloped cognitive capacity for organization and 
planning. Rates of adherence among adolescents and young adults with chronic illnesses requiring daily 
medication, such as HIV, diabetes, and cancer are consistently low, with estimates often about 50% 
overall.20,21 Similarly, rates of adherence to oral prevention strategies, such as contraception, 
demonstrate similar challenges to daily adherence. Many studies have found that continuation rates are 
lower and pregnancy rates are higher among adolescents using oral contraception versus long-acting 
contraceptives.22,23 Just as increased choice in type and method of delivery of contraceptive methods has 
increased acceptability and effectiveness for contraception24,25, we believe that expanded choices for 
HIV prevention will similarly increase utilization, satisfaction, and effectiveness. 
A recent discrete choice experiment conducted in Kenya and South Africa26, which was designed to 
assess preferences for prevention technologies among young women ages 18 to 30 years, found that an 
injection every 2 to 3 months was preferred over daily oral pills, and that there was desire for multi-
purpose prevention technologies combining contraception with prevention of HIV. The development of 
alternative agents for PrEP, with more adherence-friendly schedules, 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 regimen27.  
Adult safety data on long-acting cabotegravir (CAB LA) will need to be expanded to adolescents in 
order to license the product for adolescents under the age of 18 
Currently, two parent protocols (HPTN 083 and HPTN 084) are being conducted globally. HPTN 083 is 
a study being done to evaluate the efficacy of CAB LA for PrEP in HIV-uninfected MSM and TGW, 
ages 18 and older, and is enrolling approximately 4500 MSM and TGW in the Americas, Asia and 
South Africa. HPTN 084 is a study being done to evaluate the safety and efficacy of CAB LA, compared 
to daily oral TENOFOVIR/EMTRICITABINE (TRADE NAME: TDF/FTC, TRUVADA®), for PrEP in 
approximately 3,200 HIV-uninfected women ages 18 to 45 years old in sub-Saharan Africa who are at 
risk for acquiring HIV. 
Historically, medical treatments applied to children were often based upon testing done only in adults, 
rendering evidence-based treatments less available to children due to their exclusion from studies. Since 
1996, one goal of the National Institutes of Health as well as the US FDA has been to increase the 
participation of children in research so that adequate data can be developed to support treatment (and 
prevention) modalities for disorders and conditions that affect adults as well as children. In order for 
adolescents to access safe and effective new biomedical HIV prevention products at the same time that 
these products are approved and marketed for adults, the scientific development and testing of these 
products for adolescents must proceed concurrently.28 Similarly, adolescents are often excluded from 


 
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prevention intervention trials due to concerns from regulatory or ethics boards as well as investigator 
concerns around the complexity of recruitment/retention and/or fear that adolescent difficulties will 
adversely impact the primary outcomes of the trial.29,30 This exclusion from large Phase 3 trials as well 
as hesitancy to launch youth-focused bridging trials only exacerbates the gaps in HIV prevention 
intervention availability and access, which continues to fuel the HIV epidemic among vulnerable young 
people.  
This trial has been designed as an open label clinical trial. An unblended, single arm trial is most 
developmentally-appropriate for youth, while also minimizing participant and staff burden. The design 
of the parent trials (HPTN 083 and HPTN 084) is quite complicated. They are double-blind, double 
dummy trials with a complex visit schedule and a lengthy commitment for participant completion. The 
team feels it is unreasonable to request this type of commitment and burden from vulnerable youth (and 
their parents/caregivers), when efficacy data can be extrapolated from the parent studies. Furthermore, 
open label prevention studies have demonstrated that product adherence improves when participants 
know what they are taking and can be counseled about the unblinded product.31,32,33 
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 Dated 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 bimonthly 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 participants prior to switching to the long-acting 
formulation. CAB LA has an absorption half-life of 21 to 50 days in 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 


 
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CAB prevented SHIV infection in two non- human primate models. In one study which used 
medroxyprogesterone acetate (Depo-Provera) to increase the risk of infection,35 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 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. 
CAB 
LA PK Profiles following Q8W Dosing in Males and Females (HPTN077, Cohort 2)) 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).  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).  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 post-natal study, CAB exposure during pregnancy resulted in increased offspring 
mortality at the highest dose tested (1000mg/kg/day). This is in excess of the established safety limit 
(NOAEL) of 5mg/kg/day. The NOAEL is >20 fold the predicted clinical Cmax and AUC exposures in 
humans for both HIV treatment and prevention. The mechanism for the reduction in viable pups at this 


 
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supratherapeutic dose up to 4 days post-partum is unknown. 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.   
An oral tablet version of CAB has been developed as lead-in therapy to establish acute safety and 
tolerability in individual participants prior to switching to the long-acting formulation. Oral CAB has 
been studied at doses between 5 mg and 150 mg in HIV-uninfected and HIV-infected adults. The oral 
formulation of CAB has been generally well-tolerated as single or repeated doses in clinical studies of 
HIV-uninfected adults. CAB 30 mg once daily has been used as the oral lead-in in the ECLAIR (Phase 
IIa Safety and PK Study of Cabotegravir LA in HIV-uninfected Men), LATTE-2 (CAB + RPV as Long-
Acting Maintenance Therapy), HPTN 077 (A Phase IIa Safety, Tolerability and Acceptability Study of 
an Investigational Injectable HIV Integrase Inhibitor for PrEP in HIV Uninfected Men and Women) 
studies, and 4 Phase III studies in adults  - 2 PrEP studies, HPTN 083 and HPTN 084, and 2 treatment 
studies (201584 (FLAIR) and 201585 (ATLAS)). Therefore, CAB 30mg once daily has been selected 
for the oral run-in regimen for this study. 
 CAB LA  
Through October 2018, approximately 4236 adult participants have been exposed to at least one dose of 
CAB (oral and/or LA) across 18 completed or ongoing Phase 1, 2 & 3 clinical trials (see Table 1).  
The regimen proposed for this study was evaluated in HPTN 077 Cohort 2.  For the HPTN 077 study, 
participants were low-risk HIV-uninfected individuals at eight sites globally, randomized (3:1) to daily 
oral CAB 30mg (or placebo) for four weeks (W), followed by CAB (or PBO) 800mg IM at W5, 17, and 
29 (Cohort 1) or 600 mg IM at W5, 9, 17, 25, and 33 (Cohort 2]). One hundred ten participants enrolled 
in Cohort 1, 89 in Cohort 2. Ninety-four percent of participants completed the oral phase, 89% received 
at least one injection, and 75% completed all injections, which did not differ by arm, cohort or sex. Over 
41 weeks, injection site pain and injection site reactions (ISR) were more common in CAB vs. placebo. 
No other differences were found in safety or tolerability. ISR led to injection discontinuation in 2/134 


 
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(1.5%).  Cohort 2 dosing consistently achieved plasma trough targets whereas Cohort 1 dosing did not. 
Overall, CAB was well tolerated among low-risk HIV-uninfected men and women. Pharmacokinetics 
supported the development of CAB for HIV prevention using 600 mg IM every 8 weeks with a 4-week 
loading dose for all sexes. 
In HPTN 077, overall 65% of the study participants were female. Median BMI was 28 kg/m2 in female 
participants and 25 kg/m2 in male participants. Among participants in Cohort 1 (who received a split 
injection of CAB-LA 800mg IM q12 weeks), males had a higher geometric mean Cmax after the first 
injection, but significantly lower trough concentrations than female participants after all three injections. 
Trough CAB concentrations were below 4X PA-IC90 in 72%, 35%, and 32% of male participants at 
weeks 17, 29, and 41, respectively. In contrast, trough CAB concentrations in female participants were 
largely at goal throughout the trial, with 24%, 5% and 0% of female participants having trough 
concentrations below 4X PA-IC90 at weeks 17, 29, and 41. In Cohort 2 (CAB LA 600mg IM q 8 
weeks), male participants achieved significantly higher CAB Cmax, AUC0-tau, and Ctrough after the first 
injection than female participants (and overall, participants with lower BMI were observed to have 
significantly higher trough concentrations after the first injection). However, CAB trough concentrations 
< 4X PA-IC90 (between 1 and 4X the PA-IC90) were observed in 5%, 20%, 20%, 16%, and 11% of 
male participants after injections 1, 2, 3, 4, and 5, respectively.  For female participants, 21%, 5%, 3%, 
0%, and 3% had CAB trough concentrations below 4X PA-IC90 after injections 1, 2, 3, 4, and 5, 
respectively.  
Figure 1. CAB LA PK Profiles following Q8W Dosing in Males and Females (HPTN077, Cohort 
2) 
 
 
During the 76-week follow-up phase of the HPTN 077 study39, differences were observed in the median 
time to undetectable cabotegravir levels between men and women: 42.7 weeks (range 20.4-134) in men 
as compared to 66.3 weeks (range 17.7-182) in women. CAB was detected in plasma in 22% of men and 
63% of women at 60 weeks and 13% of men and 44% of women at 76 weeks post the last injection). 


 
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The observed pharmacokinetics in HPTN 077 supported the development of CAB for HIV prevention 
using 600mg IM every 8 weeks with a 4-week loading dose for all sexes.40 Although the medium 
waning PK tail for women participating in HTPN 077 was 66.3 weeks, the HPTN 084-01 team has 
determined that participants in this trial should receive TENOFOVIR/EMTRICITABINE (TRADE 
NAME: TDF/FTC, TRUVADA®) for 48 weeks, in order to mimic the parent trial, HPTN 084. 
1.6 Genital Tract (GT) Tissue Levels 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%).41 Further tissue 
studies using single and multiple doses of the 800 mg IM dose are currently ongoing.   
1.7 Pediatric Dosing 
Currently, there is no previous clinical trial experience with oral CAB or CAB LA in humans under 18 
years of age. However, the IMPAACT 2017 began enrolling in April 2019. IMPAACT 2017 is a Phase 
I/II, multi‐center, open‐label, non‐comparative study to confirm the dose and evaluate the safety, 
tolerability, acceptability, and PK of oral CAB, long-acting injectable CAB (CAB LA), and long-acting 
injectable RPV (RPV LA) administered monthly among up to 155 virologically suppressed HIV‐1 
infected children and adolescents aged 12 to <18. 
In HPTN 077, 89 healthy females received an oral lead-in (OLI) of CAB 30 mg once daily x 4 weeks 
prior to initiating CAB LA injections.  These participants had a median weight of 71 kg, and 6 weighed  
 50 kg.  Therefore, administration of the OLI to participants  50 kg is expected to achieve exposures 
within the range of prior experience, and PK will not be evaluated following oral administration in this 
study.  Following a 1-week washout, 40 of 89 female participants in HPTN 077 received the proposed 
CAB LA Q8W regimen (Figure 1).    
A population PK model (n=1647) that included data from HPTN 077 (n=134, 89 females, 45 males) and 
15 other studies was used to predict exposures following the proposed CAB LA Q8W regimen in 
adolescents.  Gender and BMI are significant covariates affecting the absorption rate following IM 
administration and were retained in the model to extrapolate to smaller adolescent females expected to 
enroll in HPTN 084-01.  Model predicted concentrations in adolescent females (simulated with median 
weight and BMI of 59 kg and 22 kg/m2, respectively) to enroll in HPTN 084-01 are similar to adult 
females in HPTN 077 and below oral dosing, and therefore are expected to be safe in this population 
(Table 1).  Greater than >95% are expected to achieve trough concentrations > 4x PA-IC90 following 
the 5th injection.  This regimen is currently being evaluated in uninfected adult males and females in 
HTPN 083 and HPTN 084, respectively, and has maintained HIV suppression in infected adults when 
combined with RPV LA (LATTE-2). 


 
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Table 1. Predicted CAB Parameters following Injection 5 of the CAB LA 600mg IM Q8W 
Regimen in Female Adolescents compared with Predicted and Observed Data in Female 
Adults in HPTN 077  
Plasma CAB 
Parameter 
((g/mL) 
Female Participants in HPTN 
077 
Median 
(range) 
Predicted Exposures 
Female Adolescents 50kg  
Predicted 
Parameters  
30 mg Once 
Daily 
Observed Data 
600mg IM 
Q8W 
(Injection 5)  
Median 
(90% PI) 
Peds:Adults 
Relative Exposure 
Vs 30mg 
Vs 
600mg 
Oral Cmax or  
C,Wk 34 
(1-week post Inj5) 
9.1 
(4.4 - 18.1) 
3.3 
(1.7 - 8.2) 
3.9 
(2.0, 6.8) 
0.4 
1.2 
Oral C or  
C,Wk 41  
(8-weeks post Inj5) 
5.4 
(2.3 - 12.0) 
2.1 
(0.62 - 4.6) 
2.3 
(1.3, 3.8) 
0.4 
1.1 
 
Plasma CAB concentrations are expected to be detectable in a majority of subjects for one year 
following the final injection.   
Based on adult dosing data and pharmacokinetic modeling, oral CAB 30mg and CAB LA 600mg IM are 
expected to be safe in adolescents and have been selected as the initial regimen for IMPAACT 2017 
study - the same as the adult CAB regimen in current Phase III studies. While somewhat higher CAB 
plasma concentrations are expected in lower weight adolescent participants, the safety and tolerability 
seen in adults at the higher oral CAB dose of 60 mg daily and CAB LA dose of 800mg q 8 weeks 
tempers any safety concerns.  
This protocol will enroll using a weight-based approach rather than age based. This allows for an 
eventual adolescent indication for LA CAB in adolescents at-risk, regardless of age. The supplemental 
adolescent indication for Truvada® was entirely weight-based (down to 35 kg) for adolescents at risk of 
HIV. Also, by not specifying a lower limit of age, this allows sites the flexibility to enroll participants 
that meet the behavioral and physical criteria necessary to qualify. Each site will have ethics review and 
will consider these criteria in light of community standards; and each investigator of record will be able 
to determine whether a candidate is appropriate for enrollment or not. These decisions will then be made 
with consideration for the local context of each site/community, rather than arbitrarily choosing what 
age should be the lower limit. Additionally, we need to acquire more data for use of this product in 
adolescents under 50 kg.  
Dose adjustments are not anticipated for this protocol. However, a pre-specified weight-based analysis 
from Cohort 1 of IMPAACT 2017 is scheduled to compare dosing safety above and below 50kg (110 
lbs.). The HPTN 084-01 protocol team will review these findings when data is available to determine 
whether the dose of the oral and injectable CAB study products must be revised. In that case, the new 
doses will be specified in a letter of amendment. 


 
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Table 2. 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 
 
1.8 Pregnancy and Pregnancy Prevention with CAB Use 
There is no requirement to exclude women of reproductive potential from clinical trials of CAB based 
on reproductive toxicity 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 
levonorgestrel (LNG) or ethinyl estradiol (EE) containing combination oral contraceptive.42 There were 
no apparent differences in pharmacodynamic assessments of follicular stimulating hormone (FSH), 
luteinizing 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 


 
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implantable forms of hormonal contraceptives and CAB to date. Progestin-only products, such as 
injectable NET-EN and DMPA, and etonogestrel implants are commonly prescribed, specifically in 
SSA. Although the metabolic pathways for such products are complex and vary somewhat from ethinyl 
estradiol and levonorgestrel, no pharmacokinetic drug-drug interaction between CAB and progestin-only 
contraceptives is anticipated.43 HPTN 077 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.43 
 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.44 
This was based on information received from the Botswana NICHD-funded Tsepamo Birth Outcomes 
Surveillance Study, the largest body of data related to birth outcomes following the use of DTG in 
pregnancy. 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/TENOFOVIR/EMTRICITABINE (TRADE NAME: TDF/FTC, TRUVADA®) as first line 
treatment 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/TENOFOVIR/EMTRICITABINE (TRADE NAME: TDF/FTC, TRUVADA®). Almost all women 
on DTG-based and EFV-based ART took these drugs in combination with 
TENOFOVIR/EMTRICITABINE (TRADE NAME: TDF/FTC, TRUVADA®). More than 95% of 
women in Botswana deliver in a hospital, and obstetric records were available for >99% of women. The 
Tsepamo surveillance study is conducted at 8 of the largest public maternity wards across Botswana 
(representing ~45% of the total births in the country). Research assistants abstract ART data from the 
maternity card for all consecutive in-hospital deliveries (both HIV-infected and HIV-uninfected 
women). Each newborn, whether stillborn or live-born, undergoes a systematic infant surface 
examination that is completed by trained nurse midwives. Reports and photographs (where available) of 
major abnormalities are reviewed by an experienced medical geneticist who is blinded to exposure 
information. During a preliminary unscheduled analysis of the Tsepamo data collected between August 
15, 2014 and May 1, 2018, which was undertaken at the request of colleagues who were preparing for a 
WHO meeting, the investigators found 4 cases of neural tube defects in babies of 426 women who 
became pregnant while taking DTG (prevalence 0.9%). This rate compares to a 0.1% risk of neural tube 
defects in infants born to women taking other antiretroviral medicines at the time of conception. Data is 
expected on the pregnancy outcomes of an additional 600 women in the Tsepamo study who were taking 
DTG around the time of conception. A follow-up analysis of 1729 pregnant women in the same 
observational cohort in Botswana found that there was no difference in the risk for any adverse birth 
outcome among children born to women on dolutegravir as compared to those on efavirenz (33.2% vs 
35% for DTG and EFV, respectively; aRR 0.95, 95% CI 0.88-1.03). There was also no difference in the 
occurrence of any severe birth outcome (10.7% for women on DTG versus 11.3% for women on EFV; 
aRR 0.94, 95% CI 0.81-1.11).45 More data are also expected to be forthcoming from other studies of 
DTG in pregnancy. These data will provide more information on the safety of DTG for women of 
childbearing age. 


 
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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, in keeping with a class effect. 
Cabotegravir was evaluated in a complete package of reproductive toxicology studies, including 
embryo-fetal 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.  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 using CAB LA.  
1.9 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 (LAI116815), 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.  
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 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.   


 
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1.10 
Weight gain 
There is emerging evidence from randomized trials that the use of integrate inhibitors could lead to 
significant increases in body weight.46 Two trials of raltegravir and three involving dolutegravir all 
observed greater weight gain increases in integrase containing regimens. These effects appear to vary by 
gender and race, with highest increases observed in women and those of black race. The mechanism for 
this needs to be fully elucidated. These data are from populations receiving treatment and more data is 
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).47  
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.   
 
 STUDY OBJECTIVES AND DESIGN 
2.1 Primary Objectives  
• To evaluate the safety, tolerability and acceptability of CAB LA in healthy, HIV-
uninfected female adolescents aged below 18 years. 
 
2.2 Secondary Objectives 
• To examine adherence to and timeliness of injections over time among adolescent 
participants provided CAB LA and information regarding its safety and unknown 
efficacy.  
• To examine patterns of sexual risk behavior over time among adolescent participants 
provided CAB LA and information regarding its safety and unknown efficacy. 
• To evaluate the safety of CAB LA for 48 weeks of follow-up after final injection. 


 
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2.3 To evaluate the pharmacokinetics of CAB LA. Study Design and Overview 
We propose a single arm, open label, safety, tolerability, and acceptability study (n=50) in sexually-
active, healthy adolescents assigned female sex at birth. We have chosen to enroll an adolescent 
population that is sexually-active, yet not at the highest risk for HIV exposure due to several reasons. 
First, this is the first protocol to study a new prevention product (CAB LA) among adolescent minors – 
and the primary outcome of interest is safety. Safety studies within a new population with an unproven 
product typically enroll “healthy” volunteers. The adult safety study for CAB LA was HPTN 077, which 
enrolled lower risk adults in a manner similar to the approach adopted for these sub-studies. Second, 
adolescents are considered a vulnerable population and the efficacy of CAB LA has yet to be proven. 
Thus, a young person at very high risk would potentially benefit more from oral 
TENOFOVIR/EMTRICITABINE (TRADE NAME: TDF/FTC, TRUVADA®), which is highly 
efficacious and approved for use by adolescents to prevent HIV infection. Finally, adolescent sexual 
activity is highly variable and we will likely see individual variation in sexual risk over the course of the 
study visits. Should promising efficacy data from adult populations become available during the 
implementation of this study, the protocol team will consult with the DSMB to consider broadening the 
sexual risk criteria to enroll high-risk adolescents. 
Study participation includes, Step 1: a 5-week oral CAB 30mg QD safety lead-in followed by a series of 
5 intramuscular (IM) injections of 3 mL (600 mg) administered at 8-week intervals after a 4-week 
loading dose (injections at weeks 5, 9, 17, 25 & 33) in Step 2. Adherence support strategies (e.g., 
counseling, reminders, pill cases) will be included to support pill-taking during the first five weeks and 
to support retention during the injectable phase. A safety visit will follow each injection to ascertain 
pharmacokinetic-peak safety data, including injection site reactions. Step 3: A blood draw visit, the +8 
Week Visit, will follow the last injection to monitor CAB drug levels. All participants who have 
received at least one injection will be followed for 48 weeks after their last injection. Waning levels of 
cabotegravir (the PK tail) will be covered with locally sourced oral TENOFOVIR/EMTRICITABINE 
(TRADE NAME: TDF/FTC, TRUVADA®) for daily use for 48 weeks. Behavioral and acceptability 
data will be collected via computer-assisted self-interview (CASI).  
Participants who 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. 
Finally, in-depth qualitative interviews will be conducted at the end of the product exposure period 
(Week 34) with 10 participants (total, across sites) to explore issues of acceptability and preference for 
oral tablets and/or injections. Additionally, up to 10 parents/guardians of participants will be asked to 
participate in in-depth interviews to explore facilitators and barriers to adolescent enrollment in 
biomedical clinical trials as well as parental acceptability of injectable prevention products for 
adolescents.   
As previously mentioned, we have chosen an unblinded, single arm trial because it is most 
developmentally-appropriate for adolescents and minimizes participant and staff burden, while also 
offering a more streamlined visit schedule than the parent protocols and, hopefully, promoting study 
drug adherence. 
 Participating Sites/Institutions 
Participating sites are listed in the Schema and in the SSP Manual. 


 
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 Study Duration 
The initial phase, Step 1, will be an oral lead-in phase of 5 weeks. After that, follow up on study product 
will be for 34 weeks followed by quarterly visits for 48 weeks after the final injection. Total participant 
commitment for the entire study is approximately 87 weeks, or approximately 1.5 years. We anticipate 
recruitment for the study will take approximately 12 months. 
 
 STUDY POPULATION 
We are using clinical sites that have proven ability to enroll and retain adolescent participants, astute 
awareness of the developmental and cultural issues experienced by adolescents, as well as outstanding 
productivity with previous bio-behavioral clinical trials. Participants will be recruited from the clinical 
sites’ patient populations, through community-based venues by working with sites’ community partners 
and Community Advisory Boards, as well as through social media and/or other technology-based 
recruitment methods successfully used in our previous PrEP studies for adolescents. 
Approximately 50 participants 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 
Female adolescents who meet the following criteria are eligible for inclusion in this study: 
 Assigned female at birth;  
 At enrollment, below 18 years of age;* 
 At enrollment, body weight ≥ 50 kg (110 lbs.);* 
 Willing to provide written informed assent/consent for the study and/or able to obtain 
written parental/guardian informed consent;  
• If not of legal age or otherwise not able to provide independent informed consent as 
determined by site SOPs, local laws and regulations, and consistent with site IRB/EC 
policies and procedures: Parent or legal guardian is willing and able to provide 
written informed consent for study participation and potential participant is willing 
and able to provide written assent for study participation  
• If of legal age or otherwise able to provide independent informed consent as 
determined by site SOPs, local laws and regulations, and consistent with site IRB/EC 
policies and procedures: Willing and able to provide written informed consent for 
study participation 
 Self-reported sexual activity with a male (oral, anal or vaginal) in the past 12 months; 


 
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 In general, good health, as evidenced by the following laboratory values:  
• Non-reactive / negative HIV test results**,  
• Absolute neutrophil count > 799 cells/mm3,  
• Platelet count ≥ 100,000/mm3,  
• Hemoglobin > 11g/dL, 
• Calculated creatinine clearance ≥ 60 mL/minute using the modified Schwartz 
equation, 
• Alanine aminotransferase (ALT) < 2.0 times the upper limit of normal (ULN) (< 
grade 1) and total bilirubin (Tbili) ≤ 2.5 x ULN, 
• Hepatitis B virus (HBV) surface antigen (HBsAg) negative) and accepts vaccination,  
• HCV Antibody negative;  
 Willing to undergo all required study procedures; 
 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 Enrollment 
and before initiating study product; 
 Must agree to use a reliable form of long acting contraception, during the trial and for 48 
weeks after stopping the long acting injectable, or 30 days after stopping oral study product, 
from the list below: 
• Intrauterine device (IUD) or intrauterine system (IUS) that meets <1% failure rate as 
stated in the product label 
• 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).  
*Please see Section 1.7 for explanation. 
**HIV-uninfected, based on HIV test results obtained at Screening and 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. 
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). 
3.2 Exclusion Criteria 
Female adolescents with any of the following criteria will be excluded from the study: 


 
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 Co-enrollment in any other HIV interventional research study or other concurrent studies 
which may interfere with this study (as provided by self-report or other available 
documentation); 
 Currently receiving PrEP from a non-study source; 
 Past or current participation in HIV vaccine trial with exception for participants who can 
provide documentation of receipt of placebo; 
 Exclusively had sex with biological females in lifetime; 
 In the last 6 months (at the time of screening):  
• self-reported unprotected anal or vaginal intercourse with someone known to be HIV-
infected, 
• self-reported illicit injection drug use of any kind or stimulant use (including inhaled 
nitrate, cocaine in any form, methamphetamine, or non-physician prescribed 
pharmaceutical-grade stimulants),  
• active or planned use of any substance use which would, in the opinion of the site 
investigator, interfere with study participation (including herbal remedies), as 
described in the IB or listed in the SSP, and/ or Protocol Section 4.4,  
• self-report of greater than 5 different sexual partners (anal or vaginal), regardless of 
use of protection or knowledge of HIV status in last 6 months 
 Known history of 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 intramuscular (IM) injections;  
 Tattoo or other dermatological condition overlying the buttock region that may interfere 
with interpretation of injection site reactions;  
 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);  
 Known history of clinically significant bleeding;  
 A history of seizure disorder, per self-report;  
 Medical, social or other condition that, in the opinion of the site investigator, would interfere 
with the conduct of the study or safety of the participant (e.g., provided by self-report, or 
found upon medical history and examination or in available medical records);  


 
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 Plans to move out of the geographic area within the next 18 months or otherwise unable to 
participate in study visits, according to the site investigator; 
 Pregnant or currently breastfeeding at the time of screening or intends to become pregnant 
and/or breastfeed while on study. 
3.3 Recruitment Process 
The study will be targeted towards at-risk, sexually active adolescent populations of female adolescents 
in SSA. Enrollment will occur over approximately 12 months. 
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 young 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 
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) limitations on per-unit-time phlebotomized blood volumes, and 3) to avoid confounding in 
the interpretation of the study data.  
3.5 Participant Retention 
Once a participant enrolls in this study, the study site will make every effort to retain the participant for 
the entire follow-up period. 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 adherence/retention 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/WhatsApp/text messaging. 
• Immediate and multifaceted follow-up on missed visits, including 
SMS/WhatsApp/text messaging. 
• Mobilization of trained staff to complete in-person contact with participants at their 
homes and/or other community locations. 


 
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• 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, US government or regulatory 
authorities (including Office for Human Research Protections [OHRP] and the FDA), site IRBs/ECs and 
other regulatory bodies, or ViiV terminate the study prior to its planned end date. 
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 study product in participants’ study records. In such cases, the IoR or designee 
must contact the CMC for guidance regarding final evaluation procedures.     
 
 STUDY PRODUCT CONSIDERATIONS 
Site pharmacists should consult the Pharmacy Guidelines and Instructions for DAIDS Clinical Trials 
Networks for standard pharmacy operations. Refer to study schema on page 15 for an overview of steps 
and study design, and to the investigator’s brochures (IBs) for further information about the study 
products. 
 
4.1 Study Product Regimens/Administration/Formulation Content 
Study Product Regimens 
Step 1 – Oral Run-in Phase  
• CAB  30 mg tablet, one tablet orally once daily for five weeks, with or without food  
Step 2 – Injection Phase  
• CAB LA 600 mg administered as one 3 mL (600 mg) IM injection in the gluteal muscle 
at weeks 5, 9, 17, 25, and 33 (5 injections administered at 8-week intervals after a 4-week 
loading dose) 
• A safety visit will follow each injection to ascertain safety data, including injection site 
reactions 
Step 3 – Follow-up Phase 


 
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All participants who have received at least one injection will be followed for 48 weeks after their last 
injection, beginning with a blood draw visit, the +8 Week Visit, that will follow eight weeks after the 
last injection to monitor CAB drug levels. Waning levels of cabotegravir (the PK tail) will be covered 
with locally sourced oral tenofovir/emtricitabine (TENOFOVIR/EMTRICITABINE (TRADE NAME: 
TDF/FTC, TRUVADA®)) for daily use for 48 weeks.  
 Oral Product 
Step 1 - Oral CAB tablets 30 mg are formulated as white to almost white oval-shaped film-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 
bottles should be stored up to 30oC (86oF) and protected from moisture.    
Step 3 – TENOFOVIR/EMTRICITABINE (TRADE NAME: TDF/FTC, TRUVADA®) is a fixed dose 
combination tablet containing 200 mg of emtricitabine (FTC) and 300 mg of tenofovir disoproxil 
fumarate (TDF) in each tablet. The tablets must be stored as per the manufacturer’s recommendation. 
Refer to the package insert for recommended storage conditions. 
 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 3 mL (600mg) vial. The total amount 
to be administered to each participant is 3 mL (600 mg) per intramuscular (IM) injection. The 
formulation does not require dilution prior to administration. CAB LA injectable suspension is to be 
stored up to 30oC (86oF), do not freeze.  
The investigational pharmacist(s) must be proficient in the preparation of study products using aseptic 
technique under a pharmacy biological safety cabinet (BSC) Class II or better isolator. 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.  
One syringe containing 3 mL (600 mg) of CAB LA study product must be prepared using aseptic 
technique under a pharmacy BSC/isolator.  
Materials required for preparation and administration: 
1. One CAB LA 600 mg/3 mL vial 
2. Becton Dickinson (BD) 5-mL Syringe, Luer-Lok Tip, Product No.: 309646 or equivalent 
3. Needle for aspiration: BD general use sterile hypodermic needle, 21G x 1½ inch (e.g. 
    PrecisionGlide Needle, Product No.: 305165 or equivalent) 
4. Needle for intramuscular injection: BD IM sterile hypodermic needle, 23G x 1½ inch 
    (e.g. PrecisionGlide Needle, Product No.: 305194 or equivalent) 


 
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Preparation Steps: 
 
1 Remove one CAB LA 600 mg/3 mL vial from storage. If vials are stored in the refrigerator 
(2°C to 8°C), remove vial from the refrigerator and wait at least 15 minutes to equilibrate to 
room temperature. 
2. Vigorously shake the vial for a full 10 seconds, by shaking the vial with long arm movements. 
3. Invert the vial 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 and allow to dry. Do not touch the rubber stopper 
at any time. 
5. Remove a 5-mL syringe and a 21G x 1½ inch 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. Push the needle through the vial stopper and inject approximately 1 mL of air into the vial.   
8. Withdraw the entire contents of the vial into the syringe. Since the suspension can contain 
some air after having shaken the vial, withdraw all suspension from the vial in order to be able 
to de-aerate the syringe properly. 
9. Record the time that the suspension was withdrawn from the vial into the syringe. 
10. Remove the needle that was used to withdraw the suspension into the syringe and discard the 
needle.  
11. Attach a 23G x 1½ inch needle for intramuscular injection to Luer connection of the syringe. 
Remove the needle sheath from the needle. 
12. De-aerate the syringe by first tapping a finger against the syringe and then by moving the 
plunger rod carefully forward with the needle in the 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 in order to avoid spilling. 
 
After withdrawal of the 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 into a 
syringe (Step 8) and administration to the study participant.   
 
The prepared CAB LA suspension in a syringe must be stored at controlled room temperature between 
20°C to 25°C 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. 
IM Dosing Considerations 


 
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IM injections are administered into the gluteus muscle (gluteus medius method preferred) using a needle 
of appropriate gauge and length (recommended 1.5” 23-gauge needle for CAB LA).  The needle should 
be long enough to reach the muscle mass and prevent study drug from seeping into subcutaneous tissue, 
but not so long as to involve underlying nerves, blood vessels, or bone.  Variable needle lengths and/or 
needles with different gauge (21 to 25 gauge) are permitted if needed to accommodate individual body 
type.  Longer needle lengths may be required for participants with higher body mass indexes (BMIs, 
example > 30), to ensure that injections are administered intramuscularly as opposed to subcutaneously.  
4.2 Study Product Acquisition and Accountability 
The CAB study products (oral and LA injectable) for Steps 1 and 2 are being provided by ViiV 
Healthcare. For Step 3, the sites will provide locally sourced TENOFOVIR/EMTRICITABINE 
(TRADE NAME: TDF/FTC, TRUVADA®) for 48 weeks after the participants’ last CAB LA injection. 
 Study Product Acquisition 
The CAB study products (oral and LA injectable) 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.    
TENOFOVIR/EMTRICITABINE (TRADE NAME: TDF/FTC, TRUVADA®) will be obtained locally 
by the site. Contraceptive products will be provided by the sites.  
 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 destroyed 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. 
4.3 Toxicity Management 
Toxicity management guidelines can be found in Appendix VI.    
4.4 Concomitant, Prohibited, and Precautionary Medications 
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 package insert (PI - for 
Truvada®) and investigator’s brochure (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 Truvada PI or cabotegravir IB, it 
is required that the HPTN 084 CMC be notified for recommendations for continuing or stopping (or 
holding) study product.     


 
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Experimental agents not otherwise specified in the SSP Manual may not be administered. Precautionary 
and prohibited medications (as of the time this section of the SSP was written) pare listed below. 
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  
 
Truvada®: 
• 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: 
o drugs that are eliminated by active tubular secretion (e.g. drug, cidofovir, ganciclovir, 
valacyclovir, valganciclovir, aminoglycosides (e.g., gentamicin), and high-dose or multiple 
NSAIDS), as these may increase concentrations of emtricitabine, tenofovir, and/or the co-
administered drug.   
o 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 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.  
Further information regarding prohibited and precautionary concomitant medications, including 
rifampin, can be found in the SSP Manual and IB. The SSP Manual will be revised (as a whole or as a 
Memorandum of Changes) and re-issued when changes are made.   
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).  
 


 
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 STUDY PROCEDURES 
Overviews of the study visit and procedures schedules are presented in Appendices I, II, III and 
Appendix IV (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.  Written informed 
consent and/or assent (as appropriate) will be obtained before any study procedures are initiated. Both 
clinical and laboratory evaluations will occur at this visit (see Appendix 1). 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 30 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/indeterminate 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.   
Contraception counselling and provision must be initiated before or at the week 2 visit in Step 1 so that 
the method is in place prior to transition to Step 2.  
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 may be permitted with prior 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 Enrollment  
Baseline/Enrollment/Week 0 Visit 
Both clinical and laboratory evaluations will occur at this visit, along with behavioral and acceptability 
assessments (see Appendix 1 ).  
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 provision of study product.  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 enrollment. 


 
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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 form. 
Participants will meet with study staff to receive education and information about the adherence during 
the oral phase, identify potential barriers to adherence for the participant, and decide on adherence 
support strategies that will facilitate adherence. During counseling, participants will be offered 
supportive tools such as discrete pill containers, mobile reminder tools including text messaging and/or 
mobile app alerts, and weekly telephone check-ins from study teams. 
All behavioral assessment measures will be programmed into CASI. Measures have been previously 
used either in adolescent biomedical prevention trials or in the Phase III adult trials of cabotegravir.  
A pregnancy test must be conducted on the same day that study product is dispensed, and the test must 
be confirmed to be negative prior to dispensing.   
At the end of this visit, participants will be dispensed oral cabotegravir, with first dose directly observed 
by study staff. Study product must be dispensed with instruction to participants. 
5.3  Step 1, Oral Run-in Phase: Safety Visits   
Oral Run-in Safety Visits at Weeks 2 and 4  
There will be 2 brief follow-up visits during the oral phase of cabotegravir for the purpose of safety and 
adherence checks. Both clinical and laboratory evaluations will occur at these visits (see Appendix 1). 
Adherence counseling will be provided at both Weeks 2 and 4 to address barriers to daily pill taking, as 
well as remind participants of adherence support options available to them. Pill counts will occur at 
these visits and participants will take a dose directly observed by study staff at each of these visits. 
Participants with pill counts resulting in less than 50% adherence at the Week 4 visit will not be allowed 
to transition to Step 2. Anyone not moving to Step 2 will be terminated from the study. 
Investigators should contact the CMC at 084-01cmc@hptn.org if a participant has 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.  Participants with significant, negative 
side effects to oral study product will not continue on to Step 2, the Injection Phase.  See Table 5.1 for 
brief instruction and Appendix VI, Toxicity Management for detailed instruction on participant 
management.  All AEs are to be followed until the return to < Grade 2. 
 
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 


 
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Grade 2 AE, excluding ALT 
Proceed with SOE and to Step 2 
Grade 2 ALT 
At Enrollment or Week 2 → continue oral product, repeat 
ALT labs in 1 week 
At Week 4→ continue oral CAB, repeat ALT labs in 1 week 
 
If result is < Grade 1, participant may move to Step 2 if 
otherwise qualifies; 
If result is > Grade 2, permanently discontinue oral CAB, do 
not move to Step 2 and repeat ALT weekly until < Grade 1, 
then terminate from study 
Grade 3 AE, excluding ALT & 
CPK 
Report to CMC and if determined to be: 
• Related AE→ permanently stop oral product, follow 
until stabilizes and then terminate from study 
• NOT related AE→ follow CMC guidance 
Grade 3 ALT 
Report to CMC  
 
Permanently discontinue oral CAB, do not move to Step 2 
and repeat ALT weekly until < Grade 1, then terminate from 
study 
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 until stabilizes and then 
terminate from study 
Grade 4 ALT 
Report to CMC 
Regardless of CPK permanently stop oral product, repeat 
ALT labs weekly until < Grade 1, then terminate from study 
Grade 4 CPK + < Grade 3 ALT 
Report to CMC for adjudication 
 
5.4 Transitioning from Step 1 to Step 2 
Conditions in Step 1 that could disqualify a participant from transitioning to Step 2 are as follows: 


 
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• Pill count suggestive of less than 50% adherence at the Week 4 visit; 
• Missed or delayed Week 4 visit; 
• Not on effective long-term contraception at the Week 4 visit; 
• Any suspected or confirmed pregnancy (see SSP and Section 5.16); 
• Specific AEs per Table 5.1Error! Reference source not found.; 
• At substantial risk of HIV infection and/or qualifies for oral PrEP by local guidelines; 
• Any HIV reactive/positive test (see SSP and Section 5.12). 
 
If any of the above conditions occur, investigators should notify the HPTN 084-01 CMC at 084-
01cmc@hptn.org within one week of awareness for final determination of fitness to enter Step 2.  
 Early Discontinuation in Step 1 
Participants who do not enter Step 2 will discontinue study follow-up. Prior to termination, study staff 
will complete study evaluations due at the Week 4 visit in Appendix I, if possible. All appropriate 
referrals will be made to primary care service providers for sexual reproductive health and HIV 
prevention. Participants should continue contraception for at least 30 days following the last dose of oral 
CAB. 
5.5 Step 2, Injection Phase: Injection Visits  
Injection Phase Injection Visits at Weeks 5, 9, 17, 25, and 33  
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. The injection 
may NOT be given if any HIV test is reactive/positive. For management of participants with an HIV-
positive test, see Section 5.10. 
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. Results from STI tests do not need to be reviewed prior to provision of study product. For 
management of participants with AEs, see Appendix VI, Toxicity Management. 
During Step 2, the injection phase of the study, all participants will have brief safety visits one week 
after each injection. Both clinical and laboratory evaluations will occur at both the injection visits and 
the safety visits as well as CASI administration for either behavioral or acceptability assessments (see 
Appendix II. Schedule of Evaluations for Injection– Step 2). 
5.6 Step 2, Injection Phase: Safety Visits  
Injection Phase Safety Visits at Week 6, 10, 18, 26, and 34 
During the injection phase of the study, all participants will have brief safety visits one week after each 
injection. Blood will also be collected at these visits to monitor drug levels of CAB. A three-month 
supply of TENOFOVIR/EMTRICITABINE [TRADE NAME: TDF/FTC, TRUVADA®]) will be 
provided at Week 34. 
5.7 Step 3, Follow-up Phase 
Follow-up Phase  


 
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All participants will be followed quarterly for 48 weeks following their last injection.  
Step 3 will begin with the +8 Week Visit, in which participants who receive the Week 33 injection will 
return for a blood draw eight weeks afterwards, in order to monitor drug levels of CAB. Participants 
who do not receive the week 33 injection will have a +8 Week Visit after their last injection visit and 
continue to be followed per the Step 3 Follow-up Phase (see Appendix III).  
Both clinical and laboratory evaluations will occur during follow-up phase visits as well as CASI 
administration for either behavioral or acceptability assessments (see Appendix III. Schedule of 
Evaluations for Follow-up Phase – Step 3). Participants will also be monitored for increased HIV 
transmission risk behavior during this time and open-label oral PrEP provided at the clinical sites. 
5.8 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.  
Increase in Risk for HIV Infection 
At any time during study participation, any participant whose risk for HIV increases such that they 
qualify for PrEP by local guidelines, and desire to start PrEP, will permanently discontinue study 
product and receive ongoing risk reduction counselling. Step 1 participants will be switched to open 
label TENOFOVIR/EMTRICITABINE (TRADE NAME: TDF/FTC, TRUVADA®) PrEP and not 
transition to Step 2. They will be referred for further HIV prevention services and exit the study. Step 2 
participants will switch to open label TENOFOVIR/EMTRICITABINE (TRADE NAME: TDF/FTC, 
TRUVADA®)PrEP and remain in follow-up in Step 3. All cases should be communicated to the HPTN 
084-01 CMC at 084-01cmc@hptn.org.  
 
Post-exposure Prophylaxis (PEP) 
At any time during study participation, any participant who express concern about a potential HIV 
exposure will be referred for PEP services. Any participant receiving PEP will temporarily hold study 
product. Participants may qualify to resume study product dosing and remain in follow-up, after 
consultation with the HPTN 084-01 CMC at 084-01cmc@hptn.org. 
 Adherence Counseling and Monitoring 
The study will provide adherence support/counseling at baseline and at all follow-up visits for all 
participants and will be tailored to participants’ current study Step. During Step 1, participants will 
receive counseling focused on adherence to the oral CAB and messages about ensuring adequate dosing 
for safety prior to proceeding to Step 2. During Step 2, the importance of returning for injection visits on 
or as close to the scheduled date as practical will be emphasized. During Step 3, the focus will be on 
adherence to oral TENOFOVIR/EMTRICITABINE (TRADE NAME: TDF/FTC, TRUVADA®) PrEP. 
Throughout the study, participants will be reminded that efficacy of CAB LA for HIV prevention has 
yet to be established.  


 
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5.9 Injection Visit Windows 
The visit windows for all visits, including injection visits, are outlined in the SSP Manual. Refer to SSP 
for instruction on managing participants who report to clinic outside of injection window. 
The target visit windows for all visits, including injection visits, are outlined in the SSP Manual. In 
brief, the target visit window for injection visits for the Week 5 and 9 injections is +/- 3 days and is +/- 7 
days for all other injection visits. Visits conducted outside of the target visit windows are allowable 
without restriction and are also defined in the SSP Manual for scheduling guidance. Each study visit, 
including the injection visit, should ideally be conducted within the target date range. When that is not 
possible, visits outside of the target dates may be completed.  
5.10 
Procedures for Injectable Dosing 
Refer to Appendix VI, 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.        
5.11 
Participants with Suspected or Confirmed HIV Infection at Screening, Enrollment, or 
 
Follow-Up 
All participants with preliminary positive HIV test results at screening or throughout the study will be 
actively linked with care and treatment from their choice of primary HIV service provider. Each of the 
clinical study sites have adolescent-friendly HIV care clinics available.  
 Screening and Enrollment 
HIV testing will be performed to identify participants with HIV infection. Individuals who have one or 
more reactive / positive HIV tests at Screening or Enrollment are not eligible to participate in this study. 
Furthermore, at Screening and Enrollment 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 outlined in the SSP Manual.   
 After Study Enrollment 
Frequent testing for HIV acquisition during the study period (at all study visits in Step 1 and 3, and at all 
injection visits in Step 2) specified in the schedules of evaluation) 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. 
Whenever 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.   


 
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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, including the HPTN LC and the CMC. Refer to the SSP Manual for instructions further 
information. 
Step 1 – Oral Phase 
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 – Injection Phase 
Participants with confirmed HIV infection during Step 2 will not receive additional injections and will 
be followed per the SOE in Appendices II and III quarterly for 48 weeks. In addition, sites will have a 
standard operating procedure (SOP) that outlines a plan to facilitate immediate initiation of non-study 
ART and link with appropriate HIV services in the event that a participant becomes HIV-infected during 
any Step of the study, and in particular during Step 2 of the study, to prevent emergence of drug 
resistance. 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 – Follow-up Phase 
Participants with confirmed HIV infection during Step 3 will not receive oral 
TENOFOVIR/EMTRICITABINE (TRADE NAME: TDF/FTC, TRUVADA®) and will be followed per 
the SOE in Appendix III quarterly through study exit. In addition, sites will have a standard operating 
procedure (SOP) that outlines a plan to facilitate immediate initiation of non-study ART and link with 
appropriate HIV services in the event that a participant becomes HIV-infected during any Step of the 
study, and in particular during Step 2 of the study, to prevent emergence of drug resistance. 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. 
 
5.12 
STIs 
Testing for Neisseria gonorrhoeae (GC)/Chlamydia trachomatis (CT)and syphilis will occur throughout 
the study. Testing will be performed at local laboratories. Symptomatic screening for STIs beyond what 
is required by the protocol will be at a site’s discretion. Participants will be referred for treatment of 
STIs as per local standard of care.   
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. Participants will be tested for Hepatitis B surface antibody (HBsAb), and Hepatitis B core 


 
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antibody (HBcAb, total) at Screening or Enrollment. Participants who do not have evidence of immunity 
to HBV (e.g., negative HBsAb) will be offered HBV vaccination, ideally starting at week 2. For 
participants who do not have evidence of HBV immunity at Enrollment, HBV testing should be repeated 
at the discretion of the IoR or designee during the study if clinically indicated, if the participant has 
elevated AST/ALT results (elevated level at discretion of IoR or designee), or if the participant 
expresses a concern about having acquired HBV infection after enrollment. 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 II). Incident HCV infection during follow-up will not mandate discontinuation of study 
product absent other requirements per Appendix VI - Toxicity Management.       
5.14 
Contraception 
Contraception Requirements 
Because oral 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 a reliable form of 
long acting contraception during the trial and for 48 weeks after stopping the long acting injectable, or 
30 days after stopping oral study product. Study approved methods of contraception are outlined in 
Section 3.1 and are as follows: 
• Intrauterine device (IUD) or intrauterine system (IUS) that meets <1% failure rate as 
stated in the product label 
• 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).  
All participants will be actively encouraged to also use condoms for prevention of HIV and other STIs.  
Contraceptive Service Provision  
Study staff will provide contraceptive services to enrolled participants throughout the duration of study 
participation. Participants must be using one of the study-approved contraceptive methods by the Week 
2 visit in Step 1 to transition to Step 2. 
Verification of Contraceptive Use 
Study staff should confirm adequate contraception at each visit. 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 084-01 CMC at 084-01cmc@hptn.org for further guidance.  
All participants who are not currently pregnant and decide to discontinue long acting contraception for 
any reason will immediately discontinue study product (oral CAB or CAB LA injections). In all such 
cases, contact the HPTN 084-01 CMC at 084-01cmc@hptn.org for further guidance. 
5.15 
Pregnancy 
Participants are assessed for pregnancy throughout Steps 1, 2 and 3 as specified in the schedules of 
evaluation. Participants with a positive pregnancy test during a study visit or as reported by the 


 
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participant between study visits must be reported to the CMC within seven days of site awareness. 
Administration of study product (oral CAB or CAB LA injections) will be held immediately and open 
label TENOFOVIR/EMTRICITABINE (TRADE NAME: TDF/FTC, TRUVADA®) offered. 
Confirmation of pregnancy at a subsequent visit at least 4 weeks after the initial pregnancy test is 
required.  
 
All participants who are confirmed 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 tests may be done as indicated.  The preceding services will be covered by 
the study. All findings and pregnancy outcomes will be collected and reported. The site IoR or designee 
will refer pregnant participants to all applicable pregnancy-related services and will provide 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.  
 
Confirmed Pregnancies in Step 1 
These participants will permanently discontinue oral CAB and will not transition to Step 2. They will 
skip to Step 3, be provided open label TENOFOVIR/EMTRICITABINE (TRADE NAME: TDF/FTC, 
TRUVADA®) as PrEP and be reviewed every 12 weeks until delivery. If pregnancy is not confirmed on 
subsequent testing, Step 1 participants will exit the study. Site staff will refer to their SOP for detailed 
management. 
Confirmed Pregnancies in Steps 2 and 3 
Participants in Step 2 with confirmed pregnancy will permanently discontinue CAB LA injections and 
transition to Step 3 to be followed by the study every 12 weeks for 48 weeks after the last CAB LA 
injection or delivery whichever comes last. Open label TENOFOVIR/EMTRICITABINE (TRADE 
NAME: TDF/FTC, TRUVADA®)will be provided for 48 weeks after the last CAB injection. Site staff 
will refer to their SOP for detailed management.  
5.16 
Behavioral and Acceptability Assessments 
Behavioral assessment questions have been previously used either in adolescent biomedical prevention 
trials or in the Phase III adult trials of cabotegravir.  Behavioral assessment areas include sexual risk 
behavior, substance use, study product adherence and stigma associated with HIV and prevention 
technologies. 
Acceptability assessments of CAB LA will be administered via brief behavioral surveys.  The surveys 
will include, but not be limited to, questions about participants’ attitudes/beliefs towards CAB LA as 
well as product and study-related motivations. All measures will be programmed into CASI. 
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.  


 
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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.   
 
5.18 
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, other regulatory bodies or ViiV terminate the study prior to its planned end 
date. Study staff will record the reason(s) for all withdrawals in participants’ study records. 
 
 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 all AEs (Grade 1 and 
higher, and any AE that leads to a study product hold (temporary or permanent) will be captured on 
CRFs) 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 AE reporting period for this study is from Enrollment (Week 0) until follow-up in the study ends. 
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.   


 
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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.  
6.2 EAE Reporting 
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). 
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.  
The study agents for the purposes of EAE reporting are: Oral CAB 30 mg oral tablet; CAB LA 
injectable suspension 3 mL (600 mg) intramuscular (IM) injectable suspension. 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 DAIDS RSC website: 
https://rsc.niaid.nih.gov/clinical-research-sites/paper-eae-reporting. For questions about EAE reporting, 
please contact the DAIDS 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 results:   
• 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).  
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. 


 
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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. 
6.3 Safety Monitoring 
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 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).34 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.34  
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. 
The ECLAIR study, conducted at 10 US sites, screened 205 individuals 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.32 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 in the injection phase 
discontinued study participation 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.  


 
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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.).  
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 Safety Monitoring Committee (SMC), 
which will meet by conference call approximately every 6 months and will review accrual and retention 
data, as well as other aspects of study conduct. More frequent or ad hoc reviews of safety data may be 
conducted by the SMC as needed. 
This study also will be monitored by a NIAID Data and Safety Monitoring Board (DSMB), along with 
the parent protocols, 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 and Social Benefits 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 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.   


 
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Social harms and benefits 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, which are outcomes reported by the participant as a benefit to them as a result of being in 
the study (e.g., improvement in relationships), 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/criticaleventsmanual.pdf.  
 
 STATISTICAL CONSIDERATIONS 
7.1 Review of Study Design 
This is a single arm, open label, safety, tolerability, and acceptability study of CAB LA for prevention of 
HIV-acquisition in sexually-active, HIV-uninfected adolescents (<18 years old at time of enrollment).  
The study includes a 5-week oral CAB 30mg QD safety lead-in followed by a series of 5 intramuscular 
(IM) injections of 3 mL (600 mg) of CAB LA administered at 8-week intervals after a 4-week loading 
dose (injections at weeks 5, 9, 17, 25 & 33). Follow up on study product (oral and injectable) will occur 
for 34 weeks.  All participants who have received at least one injection will be followed for 48 weeks 
after their last injection. Waning levels of cabotegravir (the PK tail) will be covered with locally sourced 
oral TENOFOVIR/EMTRICITABINE (TRADE NAME: TDF/FTC, TRUVADA®) for daily use for 48 
weeks.  
The sample size for this study will be set to enroll approximately 50 participants. The sample size for 
this protocol (n=50) is the number of participants agreed upon by the industry sponsor and regulators in 
order to provide supplementary safety and behavioral data on adolescents in collaboration with the 
HPTN 083 and HPTN 084 adult trials. The primary aims of the study are focused on safety, tolerability, 
and acceptability of this long-acting product.  
Finally, in-depth qualitative interviews will be conducted with 10 participants total across all sites after 
Week 34 to explore issues of acceptability and preference for oral tablets and/or injections. Additionally, 
up to 10 parents/guardians of participants (total, across all sites) will be asked to participate in in-depth 
interviews to explore facilitators and barriers to adolescent enrollment in biomedical clinical trials.  
7.2 Endpoints 
 Primary Endpoints 


 
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• Safety endpoint: Proportion of participants experiencing any Grade 2 or higher 
clinical adverse events (AEs) and laboratory abnormalities among participants who 
receive at least one injection of CAB LA 
• Tolerability endpoint: Proportion of participants who receive at least 1 injection and 
who discontinue receiving injections prior to the full course of injections due to 
intolerability of injection, frequency of injections or burden of study procedures 
• Acceptability endpoints: Proportion of participants who complete all scheduled 
injections and proportion of participants who receive at least one injection whom 
would consider using CAB LA for HIV prevention in the future  
 
 Secondary Endpoints 
• Plasma CAB pharmacokinetics  
• Proportion of participants experiencing Grade 2 or higher clinical AEs and laboratory 
abnormalities in the 48 weeks following final injection  
• Proportion of injection visits that occurred “on-time”  
• Change from enrollment of self-reported sexual behavior (number of sexual partners, 
increased episodes of unprotected vaginal or anal intercourse) during the study period  
7.3 Sample Size  
The sample size for this protocol (n=50) is the number of participants agreed upon by the industry 
sponsor and regulators in order to provide supplementary safety and behavioral data on adolescents in 
collaboration with the HPTN 083 and HPTN 084 adult trials. The goal of the safety evaluation for this 
study is to identify safety concerns associated with CAB LA. 
Since each of the primary endpoints is a proportion, Table 2. Width of 95% confidence interval for 
estimated proportion as a function of the true proportion, assuming a sample size of 50. shows the 
precision (confidence interval width) that will be obtained for each endpoint with a sample size of 50. 
Table 2. Width of 95% confidence interval for estimated proportion as a function of the true 
proportion, assuming a sample size of 50. 
True proportion 
Width of 95% CI 
0.1 
± 0.083 
0.2 
± 0.11 
0.3 
± 0.13 
0.4 
± 0.14 
0.5 
± 0.14 
 
The study will recruit participants to ensure that at least 50 participants progress to the injection phase. 


 
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7.4 Randomization 
There is no treatment randomization due to this study being a single arm, open label trial. 
7.5 Blinding 
 Participants and site staff will be unblinded throughout the trial. 
7.6 Data and Safety Monitoring Analysis 
 Study Monitoring Committee  
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). 
 Primary Analyses 
All participants who receive at least one injection will contribute to the primary analyses. The safety and 
tolerability will be analyzed in aggregate. When the use of descriptive statistics to assess group 
characteristics or differences is required, the following methods will be used: for categorical variables, 
the number and percent in each category; for continuous variables, the mean, median, standard 
deviation, quartiles and range (minimum, maximum).  
 Safety Endpoints 
The primary safety analysis will include Grade 2 or higher clinical and laboratory events that occur from 
the initial injection to 48 weeks after the last injection among participants who receive at least one 
injection. Secondary safety analyses will include the same definition applied over the oral phase only 
(week 0 to week 4) and the aggregate oral+injectable+follow-up period. 
To assess safety, the number and the percent of participants experiencing each safety endpoint will be 
tabulated. Each participant will contribute once in each category (for example, only for the highest 
severity AE for each participant) for the calculation of event rates. Exact binomial confidence intervals 
will be calculated for each safety endpoint.   
 Injection Site Reaction (ISR)  
The number and percentage of participants experiencing each type of injection site reaction sign or 
symptom will be tabulated by severity. For a given sign or symptom, each participant’s ISR will be 
counted once under the maximum severity for all injection visits as well as by each successive injection. 
In addition, we will report the proportion of injections (over all participants) that resulted in an ISR. A 
95% CI (using a robust variance) will be computed. 
 AEs and Serious Adverse Events (SAEs) 


 
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AEs will be tabulated using MedDRA preferred terms. The number and percentage of participants 
experiencing each specific AE (All AEs, Grade 2 or higher, and SAEs) will be tabulated by severity and 
by relationship to study product. For the calculations in these tables, each participant’s AEs will be 
counted once as the maximum severity and relationship to study product. AEs leading to temporarily or 
permanently stopping drug will also be summarized. AEs will be summarized for those that are 
treatment emergent during LA dosing separately from those that are treatment emergent during oral 
dosing and also for those that are treatment emergent across the entire treatment phase of the study 
(combining both LA and oral dosing).   
A listing of EAEs reported to the DAIDS RSC Safety Office will provide details of the events including 
severity, relationship to study product, time between onset and last injection, number of injections 
received, and a summary of the event. 
 Tolerability 
To assess tolerability, the number and the percent of participants who receive at least one injection and 
discontinue receiving injections prior to the full course due to intolerability of injection (including but 
not limited to ISR), frequency of injections, or burden of procedures or any AE will be tabulated. 
 Acceptability 
To assess acceptability, the number and percentage of participants who complete all scheduled injections 
will be described. Additionally, the number and the percent of participants who receive at least one 
injection that would consider using CAB LA for HIV prevention in the future will be tabulated. 
Acceptability will be assessed by age and in aggregate.  
Acceptability of CAB LA will also be assessed through administration of brief behavioral surveys and 
qualitative interviews.  The surveys will include, but not be limited to, questions about participants’ 
attitudes/beliefs towards CAB LA; product and study-related motivations. In addition, a subset of 
participants will be invited to take part in qualitative assessments of acceptability in order to provide 
more holistic and contextualized information on motivations, attitudes and experiences using injectable 
PrEP, reasons for and circumstances related to product and/or study discontinuation, and future 
intentions related to PrEP use. 
A subset of 10 willing participants will complete an in-depth interview (IDI) to be scheduled after the 
Week 34 visit. In addition, up to 10 parents of participants will be invited to participate in in-depth 
interviews that will explore facilitators and barriers to adolescent participation in biomedical HIV 
prevention trials. When conducting a qualitative exploration, the sampling method should be designed to 
include a range of possible perspectives on the phenomenon under study, thus ideal qualitative samples 
are purposive in nature. For this study, we will utilize a purposive sampling strategy, which will allow 
for consideration of the concepts of range, saturation/redundancy, and stratification in the sampling 
frame. We will ask sites to identify potential participants as well as parents/caregivers who would be 
interested in and comfortable with sharing their experiences with the study product as well as study 
procedures. Data on acceptability and factors affecting adherence will be collected during the IDI, 
including questions that explore the use and the acceptability of both the oral and injectable CAB, along 
with examination of preference for pills or injections. Additional interview topics will include 
challenges to study participation as well as product use. We will also discuss with participants the 
acceptability of parental involvement in the consent process.  


 
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These interviews will be conducted by a trained study interviewer and will follow a semi-structured 
questionnaire guide. They will be approximately 30-60 minutes in duration and will be conducted in an 
area that maximizes participant privacy and confidentiality. Participants may be compensated for the 
completion of the in-depth interview. These interviews will be recorded for analysis and transcribed. 
 
 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 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 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. 
7.7 Secondary Analyses 
 Sexual Risk Behaviors 
Change in sexual risk behavior (number of sexual partners, episodes of unprotected anal and/or vaginal 
intercourse) during the injection phase will be measured by summarizing the change from baseline by 
visit. Sexual risk behavior will be analyzed in aggregate.   
 Plasma Drug-Level Concentrations  
Descriptive analyses of plasma concentration of CAB LA will be performed using mean, median, 
standard deviation, coefficient of variation (%CV) and range, for example. Graphical displays of the 
data based on appropriate techniques (e.g., boxplots, histograms, kernel density estimates, probability 
plots, scatterplots) will be generated to visually explore distributional properties of the data. Statistics 
and graphical displays will be produced for plasma concentrations within and across timepoints. In 
addition, proportion of participants with plasma CAB concentrations <LLQ, between LLQ and PA-
IC90, 1-4X PA-IC90, and >4X PA-IC90 will be calculated at pre-specified time points after the final 
injection. 
In addition to concentration summaries, parameters may be derived by non-compartmental methods.  
Details of the analysis will be described in the study Reporting and Analysis Plan (RAP), separately.   
7.8 Qualitative Analysis  
All qualitative interviews will be conducted by trained interviewers, digitally-recorded, transcribed and 
translated into English (as needed), and then uploaded into a qualitative software analysis program (such 
as NVivo 12.) The Protocol Chair and her team will follow a process of reading, coding, data display 
and data reduction in order to explore in greater depth participants’ attitudes towards and experiences 
with the product. Data coding and analysis will be both iterative and interactive processes. The team will 
first read all interview transcripts in order to increase familiarity with the data. Next, the team will 
assign a priori codes and create emergent codes. Transcripts will then be re-read to create pattern codes 
that connect subsequent concepts under larger headings. Consistent patterns in meaning, concepts, and 
themes across all interviews will be identified, and detailed memos/data matrices will be developed to 


 
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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, parent or other social relationships) influence acceptability and interest in future use of an 
injectable PrEP product. Comparative analyses will be conducted to clarify differences that may exist 
for any subgroups of adolescents. Coding and analytic activities will be discussed during qualitative data 
analysis meetings, and discrepancies in coding and interpretation will be resolved through consensus. A 
similar analytic approach will be followed for parent/guardian interviews.  
 
 HUMAN SUBJECTS CONSIDERATIONS 
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 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 
This section provides details regarding informed consent and assent requirements and procedures for 
adolescents. Site investigators and their designees will be required to determine participant age and 
ability to provide independent informed consent for study participation consistent with IRB/EC policies 
and procedures. Each site must establish SOPs, roles, and responsibilities for completing these 
determinations, and study staff involved in completing these determinations must have documented 
training in the relevant policies and procedures prior to initiating study activity.  
Written informed consent and written assent will be obtained for study participation as follows:  
• If the potential participant is of legal age or otherwise able to provide independent 
informed consent as determined by site SOPs, local laws and regulations, and 
consistent with site IRB/EC policies and procedures: The potential participant must 
provide written informed consent for study participation.  
• If the potential participant is not of legal age to provide independent informed 
consent as determined by site SOPs and local laws and regulations: Parent, legal 
guardian, or other legally authorized representative must provide written informed 


 
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permission for study participation and the potential participant must provide written 
assent for study participation.  
Note: IRB/EC risk determinations will guide whether the consent of one or both parents may be required 
for this study. All IRB/EC requirements must be followed.  
• During study follow-up, if such a participant reaches the legal age and is able to 
provide independent informed consent as determined by site SOPs: The participant 
must then provide written informed consent to continue study participation. 
Written informed consent and assent (as applicable) for participation will be obtained before any study-
specific procedures are performed. The informed consent process will include information exchange, 
detailed discussion, and formal assessment of understanding of all required elements of informed 
consent, including the potential risks, benefits, and alternatives to study participation. The process will 
describe what is known about the safety and tolerability of the study products and participants and 
parents/guardians will be extensively counseled on the importance of adherence to the study product 
regimen and study visit schedule. The approach adopted by the site will be tailored to adolescents, 
utilizing a variety of supporting materials, and may be spread over multiple sessions to foster sufficient 
understanding of the study prior to making the decision to take part.   
Appendix VI provides sample informed consent/assent forms for obtaining parent or legal guardian 
permission and adolescent assent for study participation. Appendices VII, VIII and IX provide sample 
informed permission and assent forms for specimen storage and future use, adolescent qualitative 
interviews and parent/legal guardian interviews. All sample informed consent and assent forms may be 
modified by sites to meet IRB/EC requirements. If the participant, parent, or guardian (as applicable) is 
unable to read, the process for consenting illiterate participants, as defined or approved by the local 
IRB/EC, should be followed.  
As indicated above, parental consenting requirements at each site will depend on the IRB/EC risk 
determination and all IRB/EC requirements will be followed. Participants enrolling in the study as 
minors will generally require permission from a parent or guardian.  
In general, each participant is expected to take part in the informed consent process with his or her 
parent or legal guardian, and both the assent of the participant and the permission of the parent or legal 
guardian will be required for all consent decisions. For example, if the participant does not provide 
assent, or the parent or legal guardian does not provide permission, the participant will not be enrolled in 
the study.  
Should the consenting parent (or guardian) of a participant no longer be available for any reason, sites 
should follow the guidelines and procedures described by their IRBs/ECs. Study sites may continue to 
provide care for the participant as needed and appropriate (outside of the study), consistent with local 
standard of care.  
Participants may also reach the legal age of consent during follow-up. In this case, written informed 
consent for continued participation will be obtained from participants once they reach legal age at their 
next study visit. If participants do not consent for continued study participation, they should be 
discontinued from the study.  
Each study site is responsible for developing study informed consent forms for local use that describes 
the purpose of the study, the procedures to be followed, and the risks and benefits of participation, in 


 
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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 and assent by signing their informed 
consent forms. 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 other responsibilities. This includes the time 
and effort of parents or legal guardians who bring their child to the study visits. 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. 
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; representatives of the HPTN 
LOC, HPTN SDMC, and/or HPTN LC; site IRBs/ECs; other local, US, or international regulatory 
authorities; the government or regulatory authorities (including the OHRP and US FDA); or ViiV.  
8.5 Communicable Disease and Statutory Rape Reporting Requirements 
Study staff will comply with all applicable local requirements to report communicable diseases 
identified among study participants to local health authorities and will comply with applicable local laws 
regarding the reporting requirements of sexual activity of minors that can be considered statutory rape. 
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, government or regulatory 
authorities (including the OHRP and US FDA), site IRBs/ECs or if appropriate, the SAHPRA, or ViiV. 
This would be done primarily due to safety concerns for the participants or due to an earlier-than-
expected indication of product efficacy or study futility. 
 
 LABORATORY SPECIMENS AND BIOHAZARD CONTAINMENT 
Laboratory procedures are described below and in Appendices I and II. Refer to Appendix IV for any 
participant who has a reactive or positive HIV test after Enrollment. 


 
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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  
• Plasma storage 
• 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 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.  
 
Each study site will adhere to standards of good laboratory practice, 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.  


 
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9.2 Stored Specimens 
Plasma will be stored at the local site throughout the study and after until discard approval is given by 
DIADS, the PI, and the HPTN LC. 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. 
9.3 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 diagnostic 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.   
9.4 Pharmacology 
Blood samples will be collected throughout the study from all participants and assayed for plasma CAB 
concentrations. PK sample times include pre-dose trough samples at W5, W9, W17, W25, and W33 
(final concentration in injection phase) and 1-week post injection samples at W6, W10, W18, W26, 
W34.  In addition, follow-up samples will be collected at +8, +24, +36 and +48-weeks following the 
final injection (Appendix II and Appendix III) and at HIV confirmatory visit (Appendix IV).   
Plasma 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 (reference assay validation report). Results will not be returned 
to the study participants or study sites. 
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 (reference assay validation report). Results will not be returned 
to the study participants or study sites. Plasma and DBS will be collected in Step 3 and if a study 
participant seroconverts for potential pharmacologic analysis of plasma TFV and DBS TFV-DP 
concentrations, respectively, to assess PrEP adherence.   
Stored plasma may also be tested for the presence of other ARV drugs or other concomitant 
medications. 
 


 
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9.5 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. 
9.6 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 per 
the SSP. The HPTN LC, with guidance from the SDMC, will select a random sample of stored 
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. 
9.7 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 Patient Safety Monitoring and International Laboratory Evaluation (pSMILE) and must 
demonstrate successful participation in the relevant EQA programs.  
9.8 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 the DAIDS Immunology Quality Assurance 
(IQA) program and UKNEQAS program and must demonstrate successful participation in these 
programs.       
9.9 Quality Assurance for HIV RNA Testing 
Local laboratories may also perform HIV RNA/viral load testing (platform and 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.  


 
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9.10 
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, study participants will be 
asked to provide written informed consent for the collected 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 and approval from the protocol team and 
network leadership is provided.    
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. 
9.11 
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. 
 
 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/clinical-research-sites/daids-protocol-
registration-policy-and-procedures-manual. 


 
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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 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 ViiV 
Healthcare. 
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 Medidata Rave electronic data 
management system. 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 


 
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documentation by authorized representatives of the HPTN LOC, HPTN SDMC, HPTN LC; NIAID 
and/or its contractors; site IRBs/ECs; other local or international regulatory authorities (including the 
OHRP and US FDA); or, if appropriate, ViiV. A site visit log will be maintained at each study site to 
document all visits. 
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, 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. 
This includes 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, and ViiV Healthcare for review prior to submission.  
 


 
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 REFERENCES 
 
1. 
World Health Organization. Department of Maternal Newborn Child and Adolescent Health. 
Health for the world’s adolescents: A second chance in the second decade. Summary. Geneva, 
Switzerland: WHO, Department of Maternal, Newborn, Child and Adolescent Health;2014. 
2. 
UNAIDS. Global HIV & AIDS statistics — 2018 fact sheet. 2018. 
3. 
UNAIDS. The Gap Report – July 2014 Geneva: Switzerland.2014. 
4. 
Cowan F, Pettifor A. HIV in adolescents in sub-Saharan Africa. Current Opinion in HIV and 
AIDS. 2009;4(4):288-293. 
5. 
Abdool Karim Q, Kharsany ABM, Leask K, et al. Prevalence of HIV, HSV-2 and pregnancy 
among high school students in rural KwaZulu-Natal, South Africa: a bio-behavioural cross-
sectional survey. Sexually Transmitted Infections. 2014;90(8):620-626. 
6. 
Shisana O, Rehle T, Simbayi LC, al. e. South African National HIV Prevalence, Incidence and 
Behaviour Survey, 2012. . Cape Town, South Africa. 2014. 
7. 
Marrazzo JM, Ramjee G, Richardson BA, et al. Tenofovir-Based Preexposure Prophylaxis for 
HIV Infection Among African Women. Obstetrical & Gynecological Survey. 2015;70(7):444-
446. 
8. 
Baeten JM, Palanee-Phillips T, Brown ER, et al. Use of a Vaginal Ring Containing Dapivirine 
for HIV-1 Prevention in Women. New England Journal of Medicine. 2016;375(22):2121-2132. 
9. 
Rees H, S. D-M, Baron D, et al. Facts 001 Phase III Trial of Pericoital Tenofovir 1% Gel for 
HIV Prevention in Women. . Paper presented at: Conference on Retroviruses and Opportunistic 
Infections (CROI). February 23-26 2015., 2015; Seattle, WA, USA. . 
10. 
Baeten JM, Donnell D, Ndase P, et al. Antiretroviral prophylaxis for HIV prevention in 
heterosexual men and women. N Engl J Med. 2012;367(5):399-410. 
11. 
Choopanya K, Martin M, Suntharasamai P, et al. Antiretroviral prophylaxis for HIV infection in 
injecting drug users in Bangkok, Thailand (the Bangkok Tenofovir Study): a randomised, 
double-blind, placebo-controlled phase 3 trial. The Lancet. 2013;381(9883):2083-2090. 
12. 
Grant RM, Lama JR, Anderson PL, et al. Preexposure chemoprophylaxis for HIV prevention in 
men who have sex with men. N Engl J Med. 2010;363(27):2587-2599. 
13. 
Thigpen MC, Kebaabetswe PM, Paxton LA, et al. Antiretroviral Preexposure Prophylaxis for 
Heterosexual HIV Transmission in Botswana. New England Journal of Medicine. 
2012;367(5):423-434. 
14. 
Grant RM, Anderson PL, McMahan V, et al. Uptake of pre-exposure prophylaxis, sexual 
practices, and HIV incidence in men and transgender women who have sex with men: a cohort 
study. The Lancet Infectious Diseases. 2014;14(9):820-829. 
15. 
McCormack S, Dunn DT, Desai M, et al. Pre-exposure prophylaxis to prevent the acquisition of 
HIV-1 infection (PROUD): effectiveness results from the pilot phase of a pragmatic open-label 
randomised trial. The Lancet. 2016;387(10013):53-60. 
16. 
WHO. Guideline on when to start Antiretroviral Therapy and on Pre-Exposure Prophylaxis for 
HIV. 2015. 
17. 
U.S. Public Health Service. Preexposure prophylaxis for the prevention of HIV infection in the 
United States - 2017 update. A clinical practice guideline. . 2018. 
18. 
Van Damme L, Corneli A, Ahmed K, et al. Preexposure Prophylaxis for HIV Infection among 
African Women. New England Journal of Medicine. 2012;367(5):411-422. 
19. 
Nel A, Haazen W, Nuttall J, Romano J, Rosenberg Z, van Niekerk N. A safety and 
pharmacokinetic trial assessing delivery of dapivirine from a vaginal ring in healthy women. 
AIDS. 2014;28(10):1479-1487. 


 
HPTN 084-01, FINAL Version 1.0 
 
67 of 117 
14 October 2019 
20. 
Murphy DA, Wilson CM, Durako SJ, Muenz LR, Belzer M. Antiretroviral medication adherence 
among the REACH HIV-infected adolescent cohort in the USA. AIDS Care. 2001;13(1):27-40. 
21. 
LaGreca AM, Schuman W. Adherence to prescribed medical regimens.  . In: Roberts MC, ed. 
Handbook of Pediatric Psychology. 2nd ed. New York, NY, USA.: Guilford Press.; 1995. 
22. 
Rome E. Use of long-acting reversible contraceptives to reduce the rate of teen pregnancy. 
Cleveland Clinic Journal of Medicine. 2015;82(suppl 1):S8-S12. 
23. 
Rosenberg MJ, Waugh MS, Meehan TE. Use and misuse of oral contraceptives: Risk indicators 
for poor pill taking and discontinuation. Contraception. 1995;51(5):283-288. 
24. 
Bureau PR. 2019 Family Planning Data Sheet. . Washington, DC, USA.2019. 
25. 
Reece M, Herbenick D, Schick V, Sanders SA, Dodge B, Fortenberry JD. Condom Use Rates in 
a National Probability Sample of Males and Females Ages 14 to 94 in the United States. The 
Journal of Sexual Medicine. 2010;7:266-276. 
26. 
Minnis AM, Browne EN, Boeri M, et al. Young Women's Stated Preferences for Biomedical 
HIV Prevention: Results of a Discrete Choice Experiment in Kenya and South Africa. J Acquir 
Immune Defic Syndr. 2019;80(4):394-403. 
27. 
Spreen WR, Margolis DA, Pottage JC. Long-acting injectable antiretrovirals for HIV treatment 
and prevention. Current Opinion in HIV and AIDS. 2013;8(6):565-571. 
28. 
Hume M, Lewis LL, Nelson RM. Meeting the goal of concurrent adolescent and adult licensure 
of HIV prevention and treatment strategies. Journal of Medical Ethics. 2017;43(12):857-860. 
29. 
Bekker LG, Slack C, Lee S, Shah S, Kapogiannis B. Ethical issues in adolescent HIV research in 
resource-limited countries. J Acquir Immune Defic Syndr. 2014;65 Suppl 1:S24-28. 
30. 
Shah SK, Allison SM, Kapogiannis BG, Black R, Dawson L, Erbelding E. Advancing 
independent adolescent consent for participation in HIV prevention research. J Med Ethics. 
2018;44(7):431-433. 
31. 
Glidden DV, Amico KR, Liu AY, et al. Symptoms, Side Effects and Adherence in the iPrEx 
Open-Label Extension. Clin Infect Dis. 2016;62(9):1172-1177. 
32. 
Spinner CD, Boesecke C, Zink A, et al. HIV pre-exposure prophylaxis (PrEP): a review of 
current knowledge of oral systemic HIV PrEP in humans. Infection. 2016;44(2):151-158. 
33. 
Mujugira A, Baeten J, Kidoguchi L, et al. High levels of viral suppression among East African 
HIV-infected women and men in serodiscordant partnerships initiating antiretroviral therapy 
with high CD4 counts and during pregnancy. AIDS Res Hum Retroviruses. 2018;34(2):140-147. 
34. 
Radzio J, Spreen W, Yueh YL, et al. The long-acting integrase inhibitor GSK744 protects 
macaques from repeated intravaginal SHIV challenge. Science Translational Medicine. 
2015;7(270):270ra275-270ra275. 
35. 
Andrews CD, Spreen WR, Mohri H, et al. Long-Acting Integrase Inhibitor Protects Macaques 
from Intrarectal Simian/Human Immunodeficiency Virus. Science. 2014;343(6175):1151-1154. 
36. 
Min S, DeJesus E, McCurdy L, et al. Pharmacokinetics (PK) and safety in healthy and HIV-
infected subjects and short-term antiviral efficacy of S/GSK 1265744, a next generation once 
daily HIV integrase inhibitor [Abstract no. H-1228]. Paper presented at: 9th Interscience 
Conference on Antimicrobial Agents and Chemotherapy 2009; San Francisco, CA. 
37. 
Spreen W, Min S, Ford SL, et al. Pharmacokinetics, safety, and monotherapy antiviral activity of 
GSK1265744, an HIV integrase strand transfer inhibitor. HIV clinical trials. 2013;14(5):192-
203. 
38. 
Margolis D, Brinson C, Eron J, et al. 744 and Rilpivirine as Two-Drug Oral Maintenance 
Therapy: LAI116482 (LATTE) Week 48 Results. Abstract 91LB. Paper presented at: 21st 
Conference on Retrovirus and Opportunistic Infections 2014; Boston, MA. 
39. 
Landovitz RJ, Eron JJ, Grinsztein G, al. e. Tail-phase safety, tolerability and pharmacokinetics of 
long-acting injectable cabotegravir in HIV-uninfected individuals: HPTN 077 final results. . 


 
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14 October 2019 
Paper presented at: HIV Research for Prevention (HIV R4P). October 21-25 2018., 2018; 
Madrid, Spain. 
40. 
Landovitz RJ, Li S, Grinsztejn B, et al. Safety, tolerability, and pharmacokinetics of long-acting 
injectable cabotegravir in low-risk HIV-uninfected individuals: HPTN 077, a phase 2a 
randomized controlled trial. PLoS Med. 2018;15(11):e1002690. 
41. 
Spreen W, Ford SL, Chen S, et al. GSK1265744 pharmacokinetics in plasma and tissue after 
single-dose long-acting injectable administration in healthy subjects. Journal of acquired 
immune deficiency syndromes (1999). 2014;67(5):481-486. 
42. 
Trezza C, Ford SL, Gould E, et al. Lack of effect of oral cabotegravir on the pharmacokinetics of 
a levonorgestrel/ethinyl oestradiol-containing oral contraceptive in healthy adult women. British 
Journal of Clinical Pharmacology. 2017;83(7):1499-1505. 
43. 
Blair CS, Li S, Chau G, et al. Hormonal Contraceptives Do Not Alter Cabotegravir PK in HIV 
Uninfected Women: HPTN 077. Conference on Retroviruses and Opportunistic Infections 
(CROI); 2019; Seattle, WA, USA. 
44. 
EMA. New study suggests risk of birth defects in babies born to women on HIV medicine 
dolutegravir. 2018. 
45. 
Zash R, Jacobson DL, Diseko M, et al. Comparative safety of dolutegravir-based or efavirenz-
based antiretroviral treatment started during pregnancy in Botswana: an observational study. 
Lancet Glob Health. 2018;6(7):e804-e810. 
46. 
Hill A, Waters L, Pozniak A. Are new antiretroviral treatments increasing the risks of clinical 
obesity? J Virus Erad. 2019;5(1):41-43. 
47. 
Landovitz RJ, Zangeneh SZ, Chau G, et al. Cabotegravir is Not Associated with Weight Gain in 
HIV-uninfected Individuals in HPTN 077. Clin Infect Dis. 2019. 
 


 
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 APPENDICES I - X 


 
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12.1 
APPENDIX I. SCHEDULE OF EVALUATIONS – ORAL PHASE (Step 1) 
 
WEEKS in Study 
(Shaded column = dispense oral product) 
 
Screening 
WEEK 0 
Enrollment 
WEEK 
2 
WEEK 
4 
ADMINISTRATIVE, BEHAVIORAL, REGULATORY 
Informed consent  
X 
 
 
 
Locator information 
X 
X 
X 
X 
Demographic information 
 
X 
 
 
HIV prevention counseling  
X 
X 
X 
X 
Offer condoms  
X 
X 
X 
X 
Behavioral/Acceptability Assessment (CASI)  
 
X 
 
X 
CLINICAL EVALUATIONS & PROCEDURES 
Dispense study product (enough for 5 weeks) 
 
X 
 
 
Observe participant take oral study product1 
 
X 
X1 
X1 
Adherence counseling/pill count (pill count Weeks 2 and 4 only) 
 
X 
X 
X 
Contraception counselling and provision or verification of use 
X 
X 
X 
X 
Medical history, con meds, targeted physical exam (with weight)2 
X 
X 
X 
X 
Hep B vaccination (if needed)3 
 
 
X 
 
Blood collection 
X 
X 
X 
X 
Urine and/or vaginal swab collection  
X 
X 
X 
X 
LOCAL LABORATORY EVALUATIONS & PROCEDURES 
HIV testing4 
X 
X 
X 
X 
Pregnancy testing5 
X 
X 
X 
X 
HBV and HCV testing6 
X 
X 
 
 
CBC with differential 
X 
X 
X 
X 
Chemistry testing7  
X 
X 
X 
X 
Liver function tests8 
X 
X 
 
X 
Fasting lipid profile9 
 
X 
 
 
Syphilis testing 
X 
 
 
 
GC/CT testing (urine or vaginal swab) 
X 
 
 
 
Urinalysis (protein and glucose) 
 
X 
 
 
Plasma storage10  
X 
X 
X 
X 
 
FOOTNOTES FOR APPENDIX I: 
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. 
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 The HIV testing algorithm is provided in the SSP Manual. Testing for acute HIV must be negative and must be performed within 14 
days prior to 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 and reviewed the same day as sample collection and before product is administered.  
5 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. Confirmation of pregnancy at a subsequent visit at least 4 weeks after the 
initial pregnancy test is required. Participants with confirmed pregnancies will permanently discontinue oral CAB and will not 
transition to Step 2. They will skip to Step 3, be provided open label TENOFOVIR/EMTRICITABINE (TRADE NAME: TDF/FTC, 
TRUVADA®) as PrEP and be reviewed every 12 weeks until delivery. If pregnancy is not confirmed on subsequent testing, Step 1 
participants will exit the study. Site staff will refer to their SOP for detailed management. 


 
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6 Participants will be tested for Hepatitis B surface antibody (HBsAb), and Hepatitis B core antibody (HBcAb, total) at Screening or 
Enrollment. HbsAg and HCV Ab must be resulted and reviewed prior to enrollment. 
7 At Screening: Creatinine. At and after enrollment: BUN/urea, creatinine, CPK, calcium, phosphorous, glucose, amylase, and lipase. 
8 At Screening: ALT and TBili. At and after Enrollment: AST, ALT, total bilirubin, and alkaline phosphatase.  
9 Total cholesterol, HDL, triglycerides, and LDL (either calculated or measured). Participants must have fasted for at least 8 hours, 
preferably 12 hours, prior to sample collection. Do not collect or test if <8 hrs fasting.  
10 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 SSP. Samples cannot be used 
by site or other lab for local purposes without specific instructions from the LC w/CMC consult. 
 
 
 
 
  
 


 
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12.2 
APPENDIX II. SCHEDULE OF EVALUATIONS – INJECTION PHASE (Step 2) 
 
WEEKS in Study  
(shaded column = injection visit) 
Wk 
5 
Wk 
6 
Wk 
9 
Wk 
10 
Wk 
17 
Wk 
18 
Wk 
25 
Wk 
26 
Wk 
33 
Wk 
34 
ADMINISTRATIVE, BEHAVIORAL, REGULATORY 
Locator information 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HIV prevention counseling 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Condoms per local SOC 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Behavioral/Acceptability assessment (CASI) 
X 
 
X 
 
X 
 
X 
 
X 
 
Qualitative interviews begin (approximately) 
 
 
 
 
 
 
 
 
 
X 
CLINICAL EVALUATIONS & PROCEDURES 
Adherence, HIV prevention/risk reduction 
counselling 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Contraception counselling and provision or 
verification of use 
X 
 
X 
 
X 
 
X 
 
X 
 
Medical history1, concomitant medications, targeted 
physical exam 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hep B vaccination (if needed) 2 
 
X 
 
 
 
 
 
 
X 
 
Blood collection 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urine collection 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Injections for all participants 
X 
 
X 
 
X 
 
X 
 
X 
 
ISR evaluation 
 
X 
 
X 
 
X 
 
X 
 
X 
Provision of TENOFOVIR/EMTRICITABINE 
(TRADE NAME: TDF/FTC, TRUVADA®) 
provision (3 months’ worth) 
 
 
 
 
 
 
 
 
 
X 
LOCAL LABORATORY EVALUATIONS & PROCEDURES 
HIV testing3 
X 
 
X 
 
X 
 
X 
 
X 
 
Pregnancy testing4 
X 
 
X 
 
X 
 
X 
 
X 
 
CBC with differential 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Chemistry testing5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Liver function testing6 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Fasting lipid profile7 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Syphilis testing 
 
 
 
 
 
 
 
 
X 
 
GC/CT testing (urine or vaginal swab) 
 
 
 
 
X 
 
 
 
X 
 
Urinalysis (protein, glucose) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Plasma storage8 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
FOOTNOTES FOR APPENDIX II: 
1 Medical history must include pulse, blood pressure, weight and Body Mass Index (BMI) calculated at each visit.  
2 The initial dose of the HBV 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. 
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 and reviewed the same day as sample collection and before product is 
administered.  
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. Confirmation of pregnancy at a subsequent visit at least 4 weeks after 
the initial pregnancy test is required. Participants with confirmed pregnancies will permanently discontinue oral CAB and will not 
complete Step 2. They will skip to Step 3, be provided open label TENOFOVIR/EMTRICITABINE (TRADE NAME: TDF/FTC, 
TRUVADA®) as PrEP and be reviewed every 12 weeks until delivery. Site staff will refer to their SOP for detailed management. 
5 BUN/urea, creatinine, CPK, calcium, phosphorous, glucose, amylase, and lipase. 
6 AST, ALT, TBili, and alkaline phosphatase.  


 
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7 Total cholesterol, HDL, triglycerides, and LDL (either calculated or measured). Participants must have fasted for at least 8 hours, 
preferably 12 hours, prior to sample collection. Do not collect or test if <8 hrs fasting.  
8  Stored plasma will be used for Quality Assurance testing and other assessments at the HPTN LC (see Section 9), including potential 
assay for plasma CAB concentrations. Assessments will be performed retrospectively; results will not be returned to study sites or 
participants, except as noted in the SSP Manual.


 
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APPENDIX III. SCHEDULE OF EVALUATIONS –FOLLOW-UP PHASE (Step 3) 
 
WEEKS SINCE LAST INJECTION  
Wk 
+8 
Wk 
+12 
Wk 
+24 
Wk 
+36 
Wk 
+48 
Early 
Discontinuation 
ADMINISTRATIVE, BEHAVIORAL, REGULATORY 
 
Locator information 
X 
X 
X 
X 
X 
X 
HIV prevention & risk reduction counseling 
X 
X 
X 
X 
X 
X 
Condoms per local SOC 
X 
X 
X 
X 
X 
X 
Behavioral/Acceptability assessment (CASI) 
 
X 
X 
X 
X 
X 
CLINICAL EVALUATIONS & PROCEDURES 
 
Qualitative interviews begin (approximately) 
 
X 
 
 
 
 
Contraception counselling and provision or 
verification of use 
 
X 
X 
X 
X 
 
Medical history1, concomitant medications, 
targeted physical exam 
 
X 
X 
X 
X 
X 
Hep B vaccination (if needed) 2 
 
 
 
 
 
 
Blood collection 
X 
 
X 
X 
X 
X 
Urine collection 
 
X 
X 
X 
X 
X 
Provision of 
TENOFOVIR/EMTRICITABINE (TRADE 
NAME: TDF/FTC, TRUVADA®) (3 months’ 
worth) 
 
X 
X 
X 
 
 
LOCAL LABORATORY EVALUATIONS & PROCEDURES 
 
HIV testing3 
 
X 
X 
X 
X 
X 
Pregnancy testing4 
 
X 
X 
X 
X 
X 
CBC with differential 
 
X 
X 
X 
X 
X 
Chemistry testing5 
 
X 
X 
X 
X 
X 
Liver function testing6 
 
X 
X 
X 
X 
X 
Fasting lipid profile7 
 
X 
 
 
 
 
Syphilis testing 
 
 
 
X 
 
 
GC/CT testing (urine or vaginal swab) 
 
X 
X 
X 
X 
X 
Urinalysis (protein, glucose) 
 
X 
X 
X 
X 
 
Plasma storage8 
X 
X 
X 
X 
X 
X 
DBS storage 
 
X 
X 
 
X 
 
 
FOOTNOTES FOR APPENDIX III: 
1 Medical history must include pulse, blood pressure, weight and Body Mass Index (BMI) calculated at each visit. 
. 2 The initial dose of the HBV 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. 
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 and reviewed the same day as sample collection and 
before product is administered. 
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. Confirmation of pregnancy at a subsequent 
visit at least 4 weeks after the initial pregnancy test is required. Participants with confirmed pregnancies in Step 3 will 
continue to be followed by the study every 12 weeks for 48 weeks after the last CAB LA injection or delivery, whichever 
comes last. Open label TENOFOVIR/EMTRICITABINE (TRADE NAME: TDF/FTC, TRUVADA®) will be provided for 
48 weeks after the last CAB injection. Site staff will refer to their SOP for detailed management. 


 
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5 BUN/urea, creatinine, CPK, calcium, phosphorous, glucose, amylase, and lipase. 
6 AST, ALT, TBili, and alkaline phosphatase. 
7 Total cholesterol, HDL, triglycerides, and LDL (either calculated or measured). Participants must have fasted for at least 8 
hours, preferably 12 hours, prior to sample collection. Do not collect or test if <8 hrs fasting.  
8 Stored plasma will be used for Quality Assurance testing and other assessments at the HPTN LC (see Section 9), including 
potential assay for plasma CAB concentrations. Assessments will be performed retrospectively; results will not be returned to 
study sites or participants, except as noted in SSP 


 
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12.4 
APPENDIX IV: 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.  They are completed in addition to the 
procedures included in Appendix II. The procedures listed for Weeks 12, 24, 36, and 48 
apply to participants who acquire HIV infection after having one or more injections.  
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 protocol team. 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.   
 
FOOTNOTES FOR APPENDIX IV: 
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.     
2 Sites will 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.  
Participants who acquire HIV infection in Steps 2 and 3 only 
HIV 
Confirmation 
Visit 
Week 12 
Week 24 
Week 36 
Week 48 
ADMININISTRATIVE, BEHAVIORAL, REGULATORY 
Locator information  
X 
X 
X 
X 
X 
Offer condoms  
X 
X 
X 
X 
X 
HIV counseling  
X 
 
 
 
 
CLINICAL EVALUATIONS AND PROCEDURES 
Targeted history, con meds, 
targeted physical exam 
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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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) including 
potential assay for plasma CAB concentrations. Assessments will be performed retrospectively; results will not be returned to 
study sites or participants, except as noted in Section 9.0. 
 
 
 
 
 


 
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12.5 
APPENDIX V:  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) 
Quarterly Visit 
4 
(48 weeks since 
first positive 
pregnancy test) 
ADMINISTRATIVE, BEHAVIORAL, REGULATORY 
Locator information 
X 
X 
X 
X 
X 
HIV prevention and risk 
reduction counseling 
X 
X 
X 
X 
X 
Offer Condoms per local SOC 
X 
X 
X 
X 
X 
Behavioral/Acceptability 
assessment (CASI)  
X 
X 
X 
 X 
X 
CLINICAL EVALUATIONS & PROCEDURES 
Medical history, concomitant 
medications, targeted physical 
exam  
 X 
X 
X 
X 
X 
Blood collection 
X 
X 
X 
X 
X 
Urine collection  
X 
X 
X 
X 
X 
Vaginal swab collection1 
  
X 
  
X 
X 
 Provision of 
TENOFOVIR/EMTRICITABINE 
(TRADE NAME: TDF/FTC, 
TRUVADA®) 
 X 
 X  
X  
X 
 
LOCAL LABORATORY EVALUATIONS & PROCEDURES 
HIV testing2 
X 
X 
X 
X 
X 
Pregnancy testing3 
X 
  
  
  
 
Chemistry testing4 
X 
 X 
X 
 X 
X 
Liver function testing5 
 X  
 X 
X 
 X 
X 
Urinalysis (protein, glucose) 
X 
 
 
 
 
Plasma storage6 
X 
X 
X 
X 
X 
 
FOOTNOTES FOR APPENDIX V: 
1 GC/CT NAAT testing may be performed using urine or a vaginal swab.   
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) including 
potential assay for plasma CAB concentrations. Assessments will be performed retrospectively; results will not be returned to 
study sites or participants, except as noted in Section 9.0.  
 
 


 
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APPENDIX VI: 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. Refer to the table below for specific 
guidance for ALT. 
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 temporary study product 
hold until a recommendation is obtained from the CMC.  
 


 
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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 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 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 permanently 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 or HBV 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 Protocol Section 4.4.  
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. 


 
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Oral Phase: 
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. 
Injection Phase: 
Participants who have received at least one injection and refuse further injections or discontinue due to 
an AE will be transitioned to quarterly follow-up. 
 
 
 


 
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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  
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 viral 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.   
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 the 
injection phase. If the repeat value is Grade 2 or higher at Week 4, study 
product should be stopped, and the participant will be discontinued from 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 or higher ALT abnormality, regardless of relatedness 
to the study product, will result in permanent 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.   
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 will be followed 
for 48 weeks post-last injection. 


 
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GUIDANCE ON TOXICITY MANAGEMENT FOR SPECIFIED TOXICITIES: 
Creatinine Clearance 
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 
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 for 48 weeks post-last injection. 
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 quarterly. Participants should be 
treated as clinically appropriate and followed until resolution of the AE. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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12.7 
APPENDIX VII: SAMPLE INFORMED CONSENT with PARENT/GUARDIAN 
PERMISSION  
INFORMED CONSENT STATEMENT FOR RESEARCH 
 
HPTN 084-01: 
Safety, Tolerability and Acceptability of Long-Acting Cabotegravir (CAB LA) for the Prevention 
of HIV among Female Adolescents – A Sub-study of HPTN 084 
 
FINAL, Version 1.0 
14 October 2019 
DAIDS Document ID: 38655 
 
 
Sponsored by: Division of AIDS (DAIDS), United States (US) National Institute of Allergy and 
Infectious Diseases (NIAID), Eunice Kennedy Shriver National Institute of Child Health and Human 
Development (NICHD), US National Institutes of Health (NIH) 
 
Study product provided by: ViiV Healthcare 
 
PRINCIPAL INVESTIGATOR: [Insert Name] 
PHONE: [Insert Number] 
 
If you are a parent or legal guardian of a child participating on this study, throughout this document 
“you(r)” = “your child”. 
 
Key Information:  
The first two pages of this document include summary information about this study that will help 
you decide whether or not you should participate. More detailed information is provided after this 
summary section.   
 
 
About this research  
You are being asked to join a research study.  Scientists do research to answer important questions 
which might help change or improve the way we do things in the future.  This consent form explains the 
research study and your part in the study.  Please read it carefully and take as much time as you need. 
Ask your study doctor or the study team to explain any words or information that you do not understand.  
You may take this description home and discuss it with your family or friends to help you decide.   
 
Taking part in this research study is voluntary 
You may choose not to take part in the study or may choose to leave the study at any time.  Deciding not 
to participate, or deciding to leave the study later, will not result in any penalty or loss of benefits to 
which you are entitled and will not affect your relationship with [insert appropriate entity (e.g., hospital, 
clinic)].  
 
Important Information  
This information gives you an overview of the research.  More information about these topics may be 
found in the pages that follow.   


 
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1. Why is this research being done? 
There is a new medication called cabotegravir (CAB) that can treat people who have HIV infection. 
CAB is also being tested to see if it can protect people from getting HIV. In this study, we want to 
know if it is safe and acceptable for adolescent girls who do not have HIV to take CAB. For more 
information, please see the What is this Study About section below.   
 
2. What will happen to me during the study? 
You will move through the study in 3 steps: 
• Step 1: You will take one CAB pill every day for five weeks 
• Step 2: You will receive a total of 5 CAB injections over 6 months 
• Step 3: You will come to the clinic for study visits quarterly for up to one year. 
 
Different procedures are done at different study visits. The procedures include: 
• Physical examinations – We will examine you to check on your health by measuring height, 
weight, temperature and blood pressure.  
• Questions – We will ask general questions about your age, living situation, medical health, 
and as well as beliefs about HIV, opinions about taking pills and getting injections, sexual 
behavior, and any alcohol or drug use. 
• Counselling – We will discuss ways to protect you from getting HIV and offer condoms. We 
will discuss any challenges you have taking the CAB pill or attending study visits. 
• Contraception and Pregnancy – Even if you are not currently sexually active, you must agree 
to use a long-acting, reversible type of contraception. We will provide you with 
contraception and related counselling throughout this study and test you for pregnancy. 
• CAB pills or injection – During Step 1, we will explain how to take the study pills, watch you 
take a study pill, and explain any side effects the pills may cause. In Step 2, the CAB 
injection will be given into your buttock.  
• Laboratory tests – We will collect blood, urine and vaginal swabs to test for HIV, Hepatitis, 
liver and kidney health, cholesterol, and sexually transmitted infections. 
• HIV Prevention – We will offer you Truvada tablets as PrEP after you stops the CAB 
injections.  
 
For more information on each procedure and when it happens, please see the What Will I have to Do 
in the Study section below.   
 
3. How long will I participate in the study? 
If you decide to join the study, participation will last about 1.5 years and include a maximum of 18 
study visits at this clinic. 
 
4. Will I benefit from the study? 
It is possible that you may benefit from taking part in this study; however, there is no guarantee that 
it will help you. You will get information about your health and the results of the tests, as well as 
treatment for sexually transmitted infections. The counseling you get during this study may help you 
avoid HIV and other sexually transmitted infections. For more information, please see What are the 
Potential Benefits of Taking Part in the Study section below. 
 
5. Will taking part in this study expose me to risks? 


 
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Taking part in this research may expose you to risks. We may not know or understand all the risks at 
this time.  Some people may experience side effects or discomfort, some of which may be serious. It 
is very important that you understand the risks in this research study before you decide whether you 
will participate. For details and a list of risks you should know about, please see the What Are the 
Risks of Taking Part in the Study section below. 
 
6. Will I be paid to participate? 
Payment for your time or travel is available if you decide that you will take part in this study.  For 
more information, please see the What Will I Get for Taking Part in this Study section below.  
 
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.   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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HPTN 084-01: 
Safety, Tolerability and Acceptability of Long-Acting Cabotegravir (CAB LA) for the Prevention 
of HIV among Female Adolescents – A Sub-study of HPTN 084 
 
FINAL, Version 1.0  
14 October 2019 
DAIDS Document ID: 38655 
 
 
Sponsored by: Division of AIDS (DAIDS), United States (US) National Institute of Allergy and 
Infectious Diseases (NIAID), Eunice Kennedy Shriver National Institute of Child Health and Human 
Development (NICHD), US National Institutes of Health (NIH) 
   
Study product provided by: ViiV Healthcare 
 
PRINCIPAL INVESTIGATOR: [Insert Name] 
PHONE: [Insert Number] 
 
If you are a parent or legal guardian of a child participating on this study, throughout this document 
“you(r)” = “your child”. 
 
INTRODUCTION 
We invite you to take part in a research study about PrEP for Human Immunodeficiency Virus (HIV). 
PrEP is short for Pre-Exposure Prophylaxis. Pre-exposure means before being exposed to HIV. 
Prophylaxis is the way people prevent a disease from infecting them. With PrEP for HIV, medications 
are being developed to prevent people from getting infected if they are exposed to HIV.  
 
This form gives information about what it means to join the study. Please read it, or have it read to you, 
and ask any questions that you may have. You can take as much time as you need to fully understand the 
study. We will ask questions to see if we have explained the study clearly. After you understand the 
study, if you decide that you will take part, we will ask you to sign or make your mark on this form. You 
will be offered a copy to keep. Because you are still a minor, we must have permission from a parent or 
guardian for you to take part. This process is called “informed consent.” 
 
WHAT IS THIS STUDY ABOUT? 
In this study, we want to know if it is safe and acceptable for adolescent women who do not have HIV to 
take an anti-HIV drug called cabotegravir (CAB). We would also like to look at the tolerability, or side 
effects, of CAB. CAB is a new medicine that is still being studied. Other studies showed that CABcan 
treat people who have HIV infection, but we do not know if CAB could also be used as PrEP to protect 
people from getting HIV. First, we must study if CAB is safe for people who do not have HIV. CAB 
comes in the form of a pill and also as an injection [sites may insert appropriate term commonly used 
e.g. (shot)]. CAB pills and injections are not yet approved for the treatment or prevention of HIV 
infection by the US FDA or [add local drug regulatory authority]. CAB injections are not HIV 
vaccinations. 
 
You are being invited to join this study because you live in sub-Saharan Africa, where young women are 
at high risk of getting infected with HIV – as many as five to ten out of 100 each year. This study will be 


 
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offered to about 50 women under 18 years old across several study sites in Africa. The person in charge 
of the study at [insert site name] is [insert name of IoR]. The United States National Institutes of Health 
is paying for the study. 
 
Some of the questions that we want to answer with this study are: 
• Is it safe for adolescent women to take CAB pills and CAB injections? 
• Is it acceptable and practical for adolescent women to use CAB for HIV prevention? 
• Are adolescent women able to make it to the clinic for injection appointments? 
• What do parents/guardians think about their daughters using CAB for HIV prevention? 
 
This study will not show us if CAB prevents new infections with HIV. There are other studies being 
done that will answer that question, but those studies only involve adults. Currently, the only known 
way to prevent HIV infection from sex is to use condoms and/or take the PrEP pill called 
TENOFOVIR/EMTRICITABINE (TRADE NAME: TDF/FTC, TRUVADA®) every day. But, some 
people have a hard time remembering to take a pill every day, so it is a good idea to have other HIV 
prevention options. If the CAB injections work, people could get injections every 8 weeks and would 
not have to remember to take a pill every day. It is important that we learn what happens when 
adolescent women use CAB for HIV prevention and whether it is safe and acceptable. 
 
A description of this study will be available on www.ClinicalTrials.gov. This website will not include 
information that can identify you. At most the website will include a summary of the results. You can 
search this website at any time. 
 
DO I HAVE TO JOIN THIS STUDY? 
You do not have to be in this study. The study staff can tell you about other places where you can get the 
care you need even if you do not join the study. If you join the study today, you can still change your 
mind later and leave the study at any time for any reason without penalty. 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. 
 
You can’t join this study if you are taking part in another study of drugs, HIV vaccines, or medical 
devices. You must 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. [Some sites may have biometric fingerprint screening 
and, if so, sites should add information regarding that here.] 
 
HOW LONG WILL THE STUDY LAST? 
If you decide to join the study, participation will last about 1.5 years and include about18 study visits at 
this clinic. You will move through the study in 3 steps: 
 
• Step 1: You will take one CAB pill every day for five weeks 
• Step 2: You will receive a total of 5 CAB injections over 6 months 
• Step 3: You will come to the clinic for study visits quarterly for up to one year 
 
 
WHAT WILL I HAVE TO DO IN THE STUDY? 


 
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If you want to be in this study, you will sign this consent form before you begin the study.  
 
Study Visit Schedule 
• Screening (1 visit) – First, we will find out if you qualify to be in the study.  
• Step 1 (3 visits) – If you qualify and decide to join the study, you will swallow 1 CAB tablet 
every day for 5 weeks starting at the Entry, or Enrollment, Visit. Step 1 is done to make sure 
your body is tolerating the CAB well, so you should take the tablets every day.  You will come 
back for a medical check-up at weeks 2 and 4. If Step 1 goes well for you, then you will move to 
Step 2. 
• Step 2 (10 visits) – If you qualify, you will get the first CAB injection at week 5, then again at 
weeks 9, 17, 25 and 33 (5 injection visits). You will come back to the study clinic for a brief 
check-up 1 week after each injection at weeks 6, 10, 18, 26 and 34 (5 safety visits). You will also 
come back to the study clinic for a blood draw 8 weeks after the last injection.  
• Step 3 (5 visits) – After a blood draw 8 weeks after your last injection, you will come to the 
clinic quarterly (every 3 months) for almost a year to check how you are doing and to see how 
long CAB remains in your body after your last injection (+8, +12, +24, +36, +48 weeks). In most 
people, CAB disappears from the body slowly over 6 months, but it may last for a year or so. 
During this Step, you will be provided with TENOFOVIR/EMTRICITABINE (TRADE NAME: 
TDF/FTC, TRUVADA®) to take daily, so we will be following you to see how well things are 
going on oral PrEP and doing bloodwork, as well as HIV and other STI testing. 
 
You will be in the study for about 1.5 years. Your parent/guardian does not need to come with you to the 
study visits. The study visits will take from 1 to 4 hours each [sites to modify accordingly]. It is 
important that you attend all of these study visits. If you do not come for a scheduled visit or if a test 
result comes back abnormal, study staff will contact you or visit you. We will ask for your address and 
contact information so that we will be able to get in touch with you. You should not join the study if it’s 
not okay for study staff to contact you and visit you where you stay. If at any time you feel sick, you 
should let the study staff know right away and we may ask you to come back for a check-up.  
 
Study Visit Procedures 
 
Different procedures are done at different study visits. We will now explain each of the procedures and 
then show you which ones are done at which visits.  
 
• Physical examinations – We will examine you to check on your health by measuring height, 
weight, temperature and blood pressure. At each study visit, we will check on whether CAB may 
be causing side effects. We will also tell you what to do if you have side effects. 
• Questions – We will ask general questions about your age, living situation, medical health, and 
any medications or vitamins that you takes. At some visits, you will also answer questions on a 
computer about your beliefs about HIV, opinions about taking pills and getting injections, sexual 
behavior, and any alcohol or drug use (we call these questions “CASI” for computer-assisted 
self-interview). 


 
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• Counselling – We will discuss ways to protect you from getting HIV and offer condoms. We will 
talk to you about plans in the next year for becoming pregnant. We will discuss any challenges 
you have about taking the CAB pill or attending study visits. 
• Contraception and pregnancy – We will provide you with contraception throughout this study 
free of charge because we do not know if CAB will harm a baby. Even if you are not currently 
sexually active, you must agree to use a long-acting, reversible type of contraception. These 
include implants, injectables, and intrauterine devices (IUD). You must agree to use one of these 
forms of contraception during the study and for 48 weeks (almost a year) after stopping CAB 
injections because CAB remains in the body for a long time. If you leave the study early (in Step 
1), you must agree to use contraception for 30 days after stopping oral study product. Study staff 
will discuss with you and help choose a method of contraception that will work best for you. At 
the majority of visits, we will check your contraception, test you for pregnancy (urine test) [site 
insert sample type] and offer you condoms. 
• 
CAB pills or injection – During Step 1, we will explain how to take the study pills, watch you 
take a study pill, and explain any side effects the pills may cause. In Step 2, the CAB injection 
will be given into your buttock.  
 
• Laboratory tests – We will collect blood, urine and a vaginal swab. Some of these tests are done 
right away and we will tell you the results when they are available. The HIV results will be 
available before you are given CAB each time. Other tests are stored and then done later in a 
batch. More details are shown in the table below this section. Some tests are done in laboratories 
in another country, so your samples may be shipped there for testing. The laboratory tests are 
done for the following reasons: 
 
o Blood – To check for infections (HIV, hepatitis B and C, Syphilis), your general health, 
the health of the liver and kidneys, the amount of cholesterol (a fatty substance in your 
blood) and the amount of the study drug that is in your blood. How much blood is taken 
depends on which tests are due at each visit and is between 1 and 4 teaspoons each time 
(5-20mL). Study staff will tell you more about fasting before the cholesterol test. 
o Urine – To test if there is sugar or protein in your urine and for sexually transmitted 
infections and pregnancy. [Sites to distinguish if prenancy testing is done via urine or 
plasma/serum.] 
o Vaginal swab – To test for sexually transmitted infections. 
 
• Hepatitis B vaccination – At Week 2 or soon thereafter, you will be given the hepatitis B 
vaccination if testing shows you are not already immune. Additional vaccination (boosters) will 
be given at approximately Weeks 6 and 33.  
• HIV Prevention – We do not know for sure if CAB will protect you from getting HIV. Also, the 
amount of CAB remaining in the body disappears slowly after you stops the CAB injections – it 
can last in the body for about one year, so you must use other ways of preventing HIV if you are 
at risk of infection. For this reason, we will offer you TENOFOVIR/EMTRICITABINE 


 
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(TRADE NAME: TDF/FTC, TRUVADA®) tablets as PrEP after you stop the CAB injections. 
Before you leave the study, we will help you find a place where you can continue getting HIV 
prevention care [sites to add information here or elsewhere in the consent form].   
 
Tables of Study Visit Procedures 
 
Step 1 – to see if your body is tolerating the CAB well 
 
 screening entry Week 2 Week 4 
Receive pills (5 weeks’ worth) 
 
√ 
 
 
Pill count 
 
 
√ 
√ 
Questions/CASI 
√ 
√ 
√ 
√ 
Counselling 
√ 
√ 
√ 
√ 
Physical exam 
√ 
√ 
√ 
√ 
Blood 
√ 
√ 
√ 
√ 
Urine 
√ 
√ 
 
 
Vaginal swab 
√ 
 
 
 
CAB pills 
 
√ 
√ 
√ 
 
Step 2 – to give you the CAB injections and check your health (grey columns mean injection weeks) 
 
 
Week 
5 
Week 
6 
Week 
9 
Week 
10 
Week 
17 
Week 
18 
Week 
25 
Week 
26 
Week 
33 
Week 
34 
Questions/
CASI 
√ 
 
√ 
 
√ 
 
√ 
 
√ 
 
Counselling 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
Brief 
physical 
exam 
√ 
 
√ 
 
√ 
 
√ 
 
√ 
 
√ 
 
√ 
 
√ 
 
√ 
 
√ 
Blood 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
Urine 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
Vaginal 
swab 
 
 
 
 
√ 
 
 
 
√ 
 
CAB 
injection 
√ 
 
√ 
 
√ 
 
√ 
 
√ 
 
 
Step 3 Follow-Up Visits – to see how long the CAB remains in your body 
 
 +8 Weeks +12 Weeks +24 Weeks +36 Weeks +48 Weeks 
Questions/CASI 
 
√ 
√ 
√ 
√ 
Counselling 
√ 
√ 
√ 
√ 
√ 
Brief physical exam 
 
√ 
√ 
√ 
√ 
Blood 
√ 
 
√ 
√ 
√ 
Urine 
 
√ 
√ 
√ 
√ 
Vaginal swab 
 
√ 
√ 
√ 
√ 
PrEP pills offered 
 
√ 
√ 
√ 
 
 


 
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Permanently Stopping Study Medicine 
 
CAB pills are only given in Step 1, and then stopped permanently. If you need to leave the study before 
you receive any CAB injections, we’d still like to do a final study visit, which will include the same 
activities as the Step 3 Follow-Up Visits. If you permanently stop taking CAB after you had at least 1 
CAB injection, then you will move straight to Step 3 follow-up visits, if you agree to stay in the study. 
 
WHAT IF I BECOME INFECTED WITH HIV? 
Being in this study will not cause HIV infection, but you could become infected with HIV through sex 
or other activities while in this study. If you get HIV infection, you will stop using CAB, but you should 
still come for the study visits to make sure that you are doing okay. The study staff will counsel you and 
refer you for HIV treatment and other available services, but the study will not pay for this treatment. 
We will share any test results that will help you get the treatment you need. Testing, which will take an 
additional 1-3 mL of blood, 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. 
 
Tables of Study Visit Procedures if you become infected with HIV during Step 2 or Step 3 
If you become infected with HIV infection before your first injection, you will have the oral CAB 
stopped permanently and will be referred to local HIV-related care and exit from the study. 
 
WHAT IF I BECOME PREGNANT? 
You should not fall pregnant while receiving CAB. During the study you will use contraception. If there 
is a reason you can’t use contraception or if you wish to be pregnant in the next two years, you should 
not join the study. The reason for this is because the World Health Organization recommends that 
women should not fall pregnant when using a medicine similar to CAB, called Dolutegravir, until more 
information is available about using these drugs during pregnancy. If you become pregnant during this 
study, you will stop CAB injections and we will refer you to available maternity care. CAB will 
probably last in your body and the baby’s body throughout the pregnancy up until delivery. If you are 
still pregnant after your last study visit, we will ask your doctor to provide updates on the progress of the 
pregnancy. The outcome of the pregnancy is important to the study, so we would like updates for the 
first year of your baby’s life. The study doctor will share this information with the study sponsor for 
safety monitoring follow-up. 
 
• If you become pregnant in Step 1: 
 
HIV 
Confirmation 
Visit 
+12 
weeks 
=24 
weeks 
+36 weeks 
+48 weeks 
Questions/CASI 
√ 
√ 
√ 
√ 
√ 
Counselling  
√ 
 
 
 
 
Brief physical exam 
√ 
√ 
√ 
√ 
√ 
Blood  
√ 
√ 
√ 
√ 
√ 


 
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o You will permanently discontinue oral CAB and will not transition to Step 2. You will skip 
to Step 3, be provided TENOFOVIR/EMTRICITABINE (TRADE NAME: TDF/FTC, 
TRUVADA®) tablets as PrEP, and visit us every 12 weeks until delivery. If your pregnancy 
is not confirmed on subsequent testing, you will exit the study.  
• If you become pregnant in Steps 2 and 3: 
o If you become pregnant in Step 2, you will permanently discontinue CAB LA injections and 
transition to Step 3 to be followed by the study every 12 weeks for 48 weeks after the last 
CAB LA injection or delivery, whichever comes last. You will be provided with 
TENOFOVIR/EMTRICITABINE (TRADE NAME: TDF/FTC, TRUVADA®) tablets as 
PrEP  for 48 weeks after the last CAB injection.  
 
WHAT OTHER TESTS WILL BE DONE? 
After all the laboratory tests mentioned above for this study have been done, there may be some of your 
samples left over. We want to keep these in storage for future tests related to HIV and other infections, 
including testing for the medications used in this study and other anti-HIV medications, or tests about 
your genes. There is a separate informed consent form with more information about this. We will not 
use DNA from your stored samples to study your whole genetic sequence (also called your "genome"). 
 
WHAT ARE THE RISKS OF TAKING PART IN THIS STUDY? 
Taking part in this study may involve some risks and discomfort. 
 
• Risk from Blood Draws – The needle can cause pain, swelling, bruising, or bleeding from the 
needle site. Drawing blood can cause fainting or infection, but this is very rare. 
 
• Risk from Receiving CAB Injections – People who got CAB injections in other studies had pain, 
skin irritation, skin redness, bumps, swelling, itching, or bruising at the spot where they got the 
shot. Most reactions go away in a week or less but sometimes they can last a long time. The 
injection could be given too deeply or not deeply enough, missing the muscle and entering your 
skin, blood, or a nerve. Everything possible will be done to decrease this risk, including watching 
you for problems during the study. If we think that the injection was not given the right way, you 
might be asked to stay in the clinic up to 2 hours [sites to modify] after the injection to watch 
how you are doing. Receiving injections can cause some people to feel lightheaded or feel like 
they might pass out, or 'faint'.  This is called a 'vasovagal reaction' and it can occur with many 
medical procedures but usually resolves quickly. 
 
• Risk of CAB Side Effects – All medications can cause side effects. Some side effects are minor; 
others can be severe. Some side effects are common; others are rare. Some people who take 
medication have some of the side effects. Other people have different side effects, or no side 
effects. The most common side effects for CAB are listed below. It is not known if CAB, other 
drugs or the patient’s other health problems caused these side effects. There may be other side 
effects that we do not know about now. This may be especially true for adolescents, because this 
is the first study of CAB in adolescents.  


 
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Very Common Side Effects of CAB 
Common Side Effects of CAB 
• Nausea (feeling sick to the stomach) 
• Diarrhea or loose stools 
• Runny nose, sore throat/Upper respiratory tract 
infection 
• Headache 
• Fever 
• Lack of energy 
 
• Rash 
• Itching  
• Vomiting (being sick) 
• Stomach pain and discomfort  
• Problems sleeping  
• Abnormal dreams/nightmares 
• Feeling light headed 
• Depression 
• Passing gas or wind 
• Joint or muscle pain 
• Increase in the level of enzymes made in the muscles 
(creatine phosphokinase) 
 
Some of the people who received CAB in other studies also had abnormal liver tests. In most 
people, this was explained by other things such as a new virus infection with Hepatitis. Very few 
people did not have another possible reason, so it is possible that a mild form of liver damage 
happened from taking CAB.  In those people, the liver tests got better after stopping CAB, 
showing that any damage was temporary. Seizures have been seen (rarely) in people who had 
CAB. They are not thought to be caused by CAB, but the study staff will ask you about them. 
We have an information sheet about CAB and its side effects for you to keep. 
 
• Risk of HIV Resistance to CAB – We do not know if using CAB for PrEP will mean that CAB 
will not work to treat the HIV  if you get infected with HIV during the study or in the future (this 
is called drug resistance). Drug resistance usually occurs when the amount of a medicine in the 
body is too low to kill the virus. You will have low levels of CAB in the body for about one year 
after the last injection, or if you don’t  get the injections when they are due. This is why it is very 
important that you use other methods to protect against HIV infection whenever you are  at risk, 
like using condoms and TENOFOVIR/EMTRICITABINE (TRADE NAME: TDF/FTC, 
TRUVADA®) PrEP pills.   
 
• Risks potentially related to TENOFOVIR/EMTRICITABINE (TRADE NAME: TDF/FTC, 
TRUVADA®) for PrEP - Like all other medicines, you may have symptoms or side effects 
while taking PrEP. 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. In past 
PrEP research studies, nausea and diarrhea were the most common side effects, but happened in 
only about 10% or 1 in 10 people. Nausea and diarrhea mainly happened in the first month and 
then went away. A small number (<1% or 1 out of 100 people) in PrEP studies showed a small 
decrease in how their kidneys work, but this stopped when the people stopped taking the drug. 
Other side effects were very rare and have always gotten better when the drug was stopped.  
 
• Risks of Asking Sensitive Questions – You may feel uncomfortable when we ask personal 
questions. You do not have to answer any question that you do not want to and you can stop 
answering the questions at any time.  
 


 
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• 
Risk of Disclosure of Private Information – We will make every effort to keep your information 
private and confidential. 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 HIV. Because of this you 
may feel stigma, stress or embarrassment. We will not share any information about you or your 
health with anyone, even your parent/guardian, without talking to you first, except when [sites to 
insert relevant information about any legal obligations for disclosure, for example…your life is thought 
to be in danger 
 
• Other Risks – There may be uncommon or previously unknown risks that might occur. You 
should report any problems to the researchers immediately. 
 
WHAT ARE THE BENEFITS OF TAKING PART IN THIS STUDY? 
You may not get direct benefit from being in this study. You will get information about your health and 
the results of the tests, as well as treatment for sexually transmitted infections and free contraception. 
The counseling you get during this study may help you avoid HIV and other sexually transmitted 
infections. 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.   
 
ARE THERE ANY COSTS TO ME FOR TAKING PART IN THIS STUDY? 
You will pay no money to be in the study.    
 
WHAT OTHER CHOICES DO I HAVE? 
It is possible that TENOFOVIR/EMTRICITABINE (TRADE NAME: TDF/FTC, TRUVADA®) PrEP 
is available in your local area for HIV prevention. Because we do not know if CAB injections will 
protect you against HIV, if you prefer to take PrEP instead of joining the study, 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.] 
 
WILL I BE TOLD IF THERE IS NEW INFORMATION? 
You will be told about any new information learned during the course of the study that might cause you 
to change your mind about being in the study. At the end of the study, you will be told when study 
results may be available and how we will let you know about the results. 
 
ARE THERE ANY REASONS WHY I MAY BE ASKED TO STOP TAKING PART IN THIS 
STUDY? 
You may be withdrawn from the study if any of the following occur:  
• You are unable or unwilling to attend clinic visits and/or follow all of the study procedures or 
instructions.   
• You could be harmed by continuing to take the pills or getting an injection. 
• The study is stopped or canceled. 
• The study staff feels that staying in the study would be harmful to you. 
• Other reasons, as decided by the study staff.  


 
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WHAT WILL I GET FOR TAKING PART IN THIS STUDY? 
You will receive [sites to fill in] for your time, effort, and travel to and from the clinic at each scheduled 
visit.  
 
HOW WILL MY PRIVACY BE PROTECTED? 
To keep your information private, your samples will be labeled with a code that can only be traced 
back to the study clinic. Your name, where you live, and other personal information will be 
protected by the study clinic. The results of any tests done 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 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 US, local and 
international regulatory entities may also review your study records, as well as the [insert name of site 
here] Institutional Review Board (IRB), Ethics Committee (EC), study staff, study monitors, the 
company that makes CAB, and [insert applicable local authorities]. 
 
Groups that oversee the study include:  
• 
[insert name of site IRB/EC] 
• 
[insert name of site drug regulatory authority] 
• 
[insert name of other site regulatory entities] 
• 
Representatives of the HPTN 
• 
The United States National Institutes of Health and its study monitors 
• 
The United States Food and Drug Administration 
• 
The United States Office for Human Research Protections 
• 
Other U.S., local, and international regulatory entities 
• 
ViiV Healthcare (the company that makes CAB) 
 
The study staff and these groups are required to keep study records private and confidential. The results 
of the study may be presented publicly or published.  However, no presentation or publication will use 
your name or identify you personally. Your study information may be given to other authorities if 
required by law, including diagnoses of sexually transmitted infections. [Sites add more specific detail 
here as needed; example follows:] For example, we are required to follow state laws and report any risk 
of harm to you or others. This would include sexual activity with an adult while you are a minor. 
 
In addition to the efforts made by the study staff to help keep your personal information confidential, we 
have obtained a Certificate of Confidentiality from the U.S. Federal Government. This Certificate 
protects researchers from being forced to tell people who are not connected with this study your 
participation. The Certificate of Confidentiality does not prevent you from releasing information about 
yourself and your participation in the study. The Certificate cannot be used to resist a demand for 
information from personnel of the United States Government that is used for auditing or evaluation of 
federally funded projects or for information that must be disclosed in order to meet the requirements of 


 
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the federal Food and Drug Administration (FDA). Even with the Certificate of Confidentiality, if the 
study staff learns of possible child abuse and/or neglect or a risk of harm to you or others, we will tell 
the proper authorities. 
 
WHAT HAPPENS IF I AM INJURED DURING THE STUDY? 
Your health is important to us.  We will make every effort to protect your well-being and minimize 
risks.  It is possible, however, that you could have an illness or injury that is study-related.  This means 
that the illness or injury occurred as a direct result of the study procedures or the study drug.  
 
[Sites may modify this paragraph to reflect local institutional policies; information regarding coverage 
available through clinical trial insurance obtained by the site should be included if applicable; the 
statement regarding no program for compensation through the NIH may not be removed.]  If a study-
RELATED illness or injury occurs, we will treat you or tell you where you can get treatment.  The cost 
for this treatment may be charged to you or your insurance company.  There is no program for 
compensation either through [site name or] the U.S. National Institutes of Health. 
 
WHO DO I CONTACT IF I HAVE PROBLEMS OR QUESTIONS ABOUT THE STUDY? 
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 CAB member] at [insert physical address and telephone 
number]. 


 
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SIGNATURE PAGE 
HPTN 084-01: 
Safety, Tolerability and Acceptability of Long-Acting Cabotegravir (CAB LA) for the Prevention 
of HIV among Female Adolescents – A Sub-study of HPTN 084 
 
FINAL, Version 1.0 
14 October 2019 
DAIDS Document ID: 38655 
 
SCREENING AND ENROLLMENT CONSENT 
 
 
WHAT DOES YOUR SIGNATURE ON THIS CONSENT FORM MEAN? 
Your signature on this form means that: 
• You understand the information given to you in this form,  
• You accept the provisions in the form, on behalf of your child, and  
• You agree to permit your child to join the study  
 
You will not give up any of your child’s legal rights by signing this consent form. 
 
CONSENT FOR MINOR TO TAKE PART IN THIS STUDY 
In consideration of all of the above, I give my consent for my child to participate in this research study.  
I will be given a copy of this informed consent document to keep for my records.  I agree to let my child 
take part in this study. 
 
Write your initials or make your mark below. 
 
______________________________ 
________________________________________ 
Name of Participant (print) 
 
 
Signature and Date 
 
 
 
 
 
 
PARENT/GUARDIAN INFORMED CONSENT                               
 
________________________ 
Relationship to participant 
 
 
 
 
 
 
 
____________________________________ 
Name (print)  
 
 
 
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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12.8 
APPENDIX VIII: SAMPLE INFORMED CONSENT FOR SPECIMEN STORAGE AND 
FUTURE USE with PARENT/GUARDIAN PERMISSION  
 
 
HPTN 084-01: 
Safety, Tolerability and Acceptability of Long-Acting Cabotegravir (CAB LA) for the Prevention 
of HIV among Female Adolescents – A Sub-study of HPTN 084 
 
FINAL, Version 1.0 
14 October 2019 
DAIDS Document ID: 38655 
 
Sponsored by: Division of AIDS (DAIDS), United States (US) National Institute of Allergy and 
Infectious Diseases (NIAID), Eunice Kennedy Shriver National Institute of Child Health and Human 
Development (NICHD), US National Institutes of Health (NIH) 
   
Study product provided by: ViiV Healthcare 
 
PRINCIPAL INVESTIGATOR: [Insert Name] 
PHONE: [Insert Number] 
 
INTRODUCTION 
You have decided to let your child join the study named above. As part of the study, she will have 
blood, urine and vaginal swabs collected. After all the tests for this study have been done for her, there 
may be some of the samples left over. We call these left over samples. The HPTN would like to keep 
these left over samples and use them for other research in the future. This form gives information about 
use of left over samples. Please read it, or have it read to you, and ask any questions you may have. 
After we discuss the information with you, you will record your decisions on use of extra samples at the 
end of the form.  
 
1. It is your decision whether or not to allow the left over samples to be used.  
You are free to say yes or no, and to change your mind at any time. Your decision will not affect her 
participation in the study. If you say no, all left over samples will be destroyed.  
 
2. If you agree, her leftover samples will be kept in a repository.  
[Sites should insert one of the two options shown below. Choose/adapt the second option if local 
regulations do not permit storage of samples for future research use in the United States.] 
 
A repository is a secure facility that is used to store samples. The HPTN repository is in the United 
States. If you agree to have left over samples stored, the samples will be kept in this repository. There is 
no limit on how long the samples will be kept [sites may insert time limits or additional site-specific 
requirements here if required by local authorities]. 
 
A repository is a secure facility that is used to store samples. The HPTN has a repository in the United 
States. However, our local regulations require that left over samples be stored in our country. Therefore, 
we will keep the samples here at our laboratory. There is no limit on how long the samples will be kept 


 
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[sites may insert time limits or additional site-specific requirements here if required by local 
authorities]. 
 
3. Left over samples could be used for different types of research.  
Left over samples may be used for research on HIV and other infections, including testing for the 
medicines used in this study and other anti-HIV medicines, the immune system, and other diseases. The 
research may be done in the United States or in other locations. If you agree, the left over samples could 
also be used for research that looks at your child’s genes. Genes are passed to children from their birth 
parents. They affect how people look and how their bodies work. Differences in people’s genes can help 
explain why some people get a disease while others do not. Your child’s samples would only be used to 
look at genes related to how the body responds to the medicines used in this study and the immune 
system. These tests would not include whole genome sequencing (WGS). 
 
Any research done with the left over samples must be reviewed and approved by the HPTN. The 
research must also be approved by an ethics committee. The role of an ethics committee is to review the 
research plan and protect the rights and well-being of the people whose samples will be used.  
 
The research done with left over samples is not expected to give any information relevant to your child’s 
health. Therefore, the results will not be given to the study staff or to you. The results also will not be 
placed in your child’s study records. 
 
4. There is little risk to your child.  
When left over samples are used for research, they are labeled with a code number only. To protect your 
child’s privacy, no names are used. However, information such as age, gender, HIV status, and other 
health information may be linked to the samples. There may be some risks from tests of your child’s 
genes. If others found out the results of these tests, they could treat your child badly or unfairly. 
However, this is almost impossible because the results will not be given to the study staff or to you, and 
will not be in her study records. 
 
Any identifiers will be removed from the identifiable private information or biospecimens and, after 
removal, the information or biospecimens can be used for future research studies or distributed to 
another investigator for future research studies without additional informed consent. 
 
5. There may be no benefit to you or your child.  
By allowing your child’s left over samples to be used for research, she will be part of the search for new 
information that may benefit people in the future. However, the research done with the extra samples is 
not expected to directly benefit your child in any way.  
 
6. You will not be paid for use of your child’s samples. 
There is no cost to you for use of your child’s left over samples. The samples will not be sold, and you 
will not be paid for use of the samples. It is possible that research done with the samples could lead to a 
new discovery or a new product. If this happens, there is no plan to share any money with you or your 
child.  
 
7. Information from research using extra samples may be reviewed by groups that oversee the 
research. 
These groups include:   


 
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• [insert name of site IRB/EC] 
• [insert name of site drug regulatory authority] 
• [insert name of other site regulatory entities] 
• Representatives of the HPTN  
• The United States National Institutes of Health and its study monitors 
• The United States Food and Drug Administration 
• The United States Office for Human Research Protections 
• Other U.S., local, and international regulatory entities 
• ViiV Healthcare (the company that makes CAB) 
The people who do research with the left over samples and the groups listed above are required to make 
efforts to keep information private and confidential. 
 
The results of research done with the left over samples may be presented publicly or published. 
However, no presentation or publication will use your child’s name or identify her personally.  
 
8. If you have questions, concerns, or problems at any time, use these contacts. 
• If you have questions about use of your child’s left over samples:  
[insert name and telephone number of investigator or other study staff].  
 
• If you later change your mind about use of your child’s left over samples:  
[insert name and telephone number of investigator or other study staff].  
 
• If you have questions about your child’s rights as a research participant or concerns about how she is 
being treated in the study:  
[insert name and telephone number of IRB/EC contact person or other appropriate 
person/organization].  
 
 
 
 


 
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PARENT/GUARDIAN SIGNATURE PAGE 
 
HPTN 084-01: 
Safety, Tolerability and Acceptability of Long-Acting Cabotegravir (CAB LA) for the Prevention 
of HIV among Female Adolescents – A Sub-study of HPTN 084 
 
FINAL, Version 1.0 
14 October 2019 
DAIDS Document ID: 38655 
 
 
SPECIMEN STORAGE AND FUTURE USE INFORMED CONSENT 
 
Before deciding about storage of laboratory specimens, make sure you have read this form, or had it 
read to you, and that all of your questions have been answered.  You should feel that you understand 
your options and the possible risks and benefits before making your decision. You and your child do not 
give up any rights by signing this form. 
 
For your child’s leftover samples, write your initials or make your mark next to your choice 
(choose only one). 
 
__________ I allow my child’s leftover samples to be used for research on HIV and other infections, 
including testing for the medicines used in this study and other anti-HIV medicines, the immune system, 
and other diseases. I also allow my child’s samples to be used for tests of his or her genes.  
 
__________ allow my child’s leftover samples to be used for research on HIV and other infections, 
including testing for the medicines used in this study and other anti-HIV medicines, the immune system, 
and other diseases. I do not allow my baby’s samples to be used for tests of his or her genes.  
 
__________ I do not allow my child’s leftover samples to be used for any research.  
 
 
 
 
 
 
 
 
 
Participant Name (print) 
 
 
 
 
 
PARENT/GUARDIAN INFORMED CONSENT                               
 
 
________________________ 
Relationship to participant 
 
 
 
 
 
 
 
 
____________________________________ 
Name (print)  
 
 
 
Signature or Mark 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) 
 
 


 
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12.9 
 APPENDIX IX: SAMPLE INFORMED CONSENT FOR ADOLESCENT INTERVIEWS 
with PARENT/GUARDIAN PERMISSION  
 
HPTN 084-01: 
Safety, Tolerability and Acceptability of Long-Acting Cabotegravir (CAB LA) for the Prevention 
of HIV among Female Adolescents – A Sub-study of HPTN 084 
 
FINAL, Version 1.0 
14 October 2019 
DAIDS Document ID: 38655 
 
Sponsored by: Division of AIDS (DAIDS), United States (US) National Institute of Allergy and 
Infectious Diseases (NIAID), Eunice Kennedy Shriver National Institute of Child Health and Human 
Development (NICHD), US National Institutes of Health (NIH) 
   
Study product provided by: ViiV Healthcare 
 
PRINCIPAL INVESTIGATOR: [Insert Name] 
PHONE: [Insert Number] 
 
INTRODUCTION 
You are being asked to take part in a sub-study of the HPTN 084-1 research study that involves 
completing an interview. Joining this sub-study is voluntary. You may refuse to join, or you may 
withdraw your consent to be in this sub-study for any reason. Before you decide whether to join this 
sub-study we would like to explain the purpose of the interview, the risks and benefits to you and what 
is expected of you.  
  
This consent form gives information about being in the sub-study. We will help you to understand the 
form and answer your questions before you sign this form. Once you understand the sub-study, and if 
you agree to take part, you will be asked to sign your name or make your mark on this form. You will be 
offered a copy of this form to keep. Because you are a child, your parent/guardian must also give their 
permission.  
 
Note for parent/guardian – In this form, we use ‘you’ to refer to your child. 
 
Participation is voluntary 
Before you learn about the sub-study, it is important that you know the following: 
Your participation is voluntary. You do not have to take part in this sub-study if you do not want to. 
You may decide not to take part in the sub-study, or you may decide to leave this sub-study at any time 
without losing your regular medical care. 
You are not not required to participate in these interviews in order to remain in the rest of the HPTN 
084-1 study. 
 
About the sub-study 
The HPTN 084-1 study is being done to find out if it is safe and acceptable for adolescent women who 
do not have HIV to take a new HIV medicine called cabotegravir (CAB) as PrEP to prevent HIV. This 
sub-study will ask young women what they like and do not like about getting CAB injections. We will 


 
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also ask questions to find out what makes some young women more or less interested in starting PrEP. 
Finally, we will ask about difficulties you had getting CAB injections and things that made that easier. 
 
Entering the sub-study 
In order to understand better what makes it easier or harder for young women in this study to get CAB 
injections as directed, we will be doing interviews with up to 10 young women at participating sites. 
You have been selected to take part in one interview sometime after your last CAB injection.  
 
What will happen during the interview 
The interview will be led by a member of the research team that you do not work with during the study. 
It should take about 1 hour and your parent/guardian will not be there. [To be modified to reflect site 
practices: The interview will take place in a location that the study staff have determined will provide 
you with privacy and confidentiality such as the clinic, or another appropriate place. The study team 
will talk with you about this so you know where to go for the interview].  
 
During the interview we will ask you questions about:  
• How and when you decided to join the HPTN 084-1 study,  
• Whether you feel that you personally are at risk of HIV,  
• How you made daily pill-taking part of your routine in Step 1,  
• Where you kept your CAB pills,  
• Whether you talked to your family members, peers, or partner(s) about being in this study or 
getting CAB injections in Step 2,  
• If you had any bad effects from the CAB injections, and if this influenced your decision to keep 
getting the injections,  
• If you are taking daily TENOFOVIR/EMTRICITABINE (TRADE NAME: TDF/FTC, 
TRUVADA®) pills, how you feel about being on PrEP, and  
• Other related topics.  
 
If any of the questions make you upset, either you or the interviewer may stop the interview at any time. 
You will also be provided with contact and referral information if any of the questions raise issues that 
you would like to talk about later. 
 
Benefits of the sub-study 
There may be no benefit from being in the sub-study. You may not receive any other direct benefit from 
being in this part of the study; however, you or others in your community may benefit from this study 
later.  
 
Risk of the sub-study 
There is little risk from the interview. To minimize any discomfort and to protect your privacy the 
interview will be conducted in a private area that will allow you to speak comfortably without being 
overheard. Although we hope that you will be comfortable answering all of the questions openly and 
honestly, please keep in mind that you may refuse to answer any of the questions, or stop the interview 
completely, at any time. The greatest risk may involve your privacy and confidentiality. The steps that 
the study team have taken to protect your privacy are described below.  
 


 
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Other information about the sub-study 
 
Privacy – 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, or 
anything else that might identify you personally, will not be used in any publication of information 
about this study.  
 
To help assure that we get the best understanding possible from your answers during the interview, the 
entire interview will be audio-recorded. After the interview is finished, the recording will be typed 
(called a transcript) by people who know how to do this. All identifying information will be removed 
from the transcript. Your name will not be included on the transcript. These recordings will be destroyed 
after all analysis is completed. 
 
Your records may be reviewed by the following groups, involved with the study: 
• 
[insert name of site IRB/EC] 
• 
[insert name of site drug regulatory authority] 
• 
[insert name of other site regulatory entities] 
• 
Representatives of the HPTN  
• 
The United States National Institutes of Health and its study monitors 
• 
The United States Food and Drug Administration 
• 
The United States Office for Human Research Protections 
• 
Other U.S., local, and international regulatory entities 
• 
ViiV Healthcare (the company that makes CAB) 
 
 
If the study staff learns that you are at risk of harm, we will tell the proper authorities as we are required 
to do by the law. We are also required to follow state laws regarding reporting of sexual activity of 
minors with adults.  
 
New Information – You will be told any new information learned during this study that might affect 
your willingness to stay in the study. You will also be told when the results of the study may be 
available, and how to learn about them.  
 
Alternatives to participating 
You can talk to the study staff at any time about your experiences in the study, without taking part in the 
sub-study interview. 
 
There are no costs to you for being in the sub-study 
There will be no cost to you for participating in the in-depth interview, and you will not receive payment 
for being interviewed. [Insert information about compensation/reimbursement here, e.g., You will be 
reimbursed for the cost of transport to the clinic for the interview. You will be given (specify amount). 
 
Whom to contact 
If you have questions, concerns, or problems at any time, use these contacts. 
 


 
HPTN 084-01, FINAL Version 1.0 
 
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• If you have questions about the sub-study:  
[insert name and telephone number of investigator or other study staff] 
 
• If you have questions about your rights as a research participant or concerns about how you are 
being treated in the sub-study:  
[insert name and telephone number of IRB/EC contact person or other appropriate 
person/organization] 
 
• If you have any health or other problems that may be related to sub-study participation:  
[insert name and telephone number of investigator or other study staff] 
 
• If you want to leave the sub-study:  
[insert name and telephone number of investigator or other study staff] 
 
 
 


 
HPTN 084-01, FINAL Version 1.0 
 
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14 October 2019 
SIGNATURE PAGE  
ADOLESCENT IN-DEPTH INTERVIEW INFORMED CONSENT FORM  
 
HPTN 084-01: 
Safety, Tolerability and Acceptability of Long-Acting Cabotegravir (CAB LA) for the Prevention 
of HIV among Female Adolescents – A Sub-study of HPTN 084 
 
FINAL, Version 1.0 
14 October 2019 
DAIDS Document ID: 38655 
 
If you decide to join this sub-study, sign or make your mark below. Before deciding whether to join this 
study, make sure you have read this form, or had it read to you, and that all of your questions have been 
answered. You should feel that you understand the study, its risks and benefits, and what is expected of 
you if you decide to join. You can ask questions or request more information at any time. You do not 
give up any rights by signing this form. 
 
ADOLESCENT ASSENT 
 
Write your initials or make your mark below. 
 
________ 
I agree to be interviewed for HPTN 084-01 and to have the interview audiotaped. 
 
 
______________________________ 
________________________________________ 
Name of Participant (print) 
 
 
Signature and Date 
 
 
 
 
 
 
 
 
 
 
 
 
PARENT/GUARDIAN INFORMED CONSENT                               
 
________________________ 
Relationship to participant 
 
 
 
 
 
 
 
 
____________________________________ 
Name (print)  
 
 
 
Signature and Date 
 
 
 
 
 
 
 
 
____________________________________ 
Study Staff Conducting 
 
 
Study Staff Signature and Date 
Consent Discussion (print) 
 
 
 
 
 
 
 
 
____________________________________ 
Witness Name (print)  
 
 
Witness Signature and Date 
(As appropriate) 


 
HPTN 084-01, FINAL Version 1.0 
 
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12.10 APPENDIX X: SAMPLE INFORMED CONSENT FOR PARENT/GUARDIAN 
INTERVIEW  
 
 
HPTN 084-01: 
Safety, Tolerability and Acceptability of Long-Acting Cabotegravir (CAB LA) for the Prevention 
of HIV among Female Adolescents – A Sub-study of HPTN 084 
 
FINAL, Version 1.0 
14 October 2019 
DAIDS Document ID: 38655 
 
Sponsored by: Division of AIDS (DAIDS), United States (US) National Institute of Allergy and 
Infectious Diseases (NIAID), Eunice Kennedy Shriver National Institute of Child Health and Human 
Development (NICHD), US National Institutes of Health (NIH) 
   
Study product provided by: ViiV Healthcare 
 
PRINCIPAL INVESTIGATOR: [Insert Name] 
PHONE: [Insert Number] 
 
INTRODUCTION 
You are being asked to take part in a sub-study of the HPTN 084-1 research study that involves 
completing an interview. Joining this sub-study is voluntary. You may refuse to join, or you may 
withdraw your consent to be in this sub-study for any reason. Before you decide whether to join this 
sub-study we would like to explain the purpose of the interview, the risks and benefits to you and what 
is expected of you.  
  
This consent form gives information about being in the sub-study. We will help you to understand the 
form and answer your questions before you sign this form. Once you understand the sub-study, and if 
you agree to take part, you will be asked to sign your name or make your mark on this form. You will be 
offered a copy of this form to keep.  
 
Participation is voluntary 
Before you learn about the sub-study, it is important that you know the following: 
Your participation is voluntary. You do not have to take part in this sub-study if you do not want to. 
You may decide not to take part in the sub-study, or you may decide to leave this sub-study at any time 
without losing your regular medical care. 
You are not not required to participate in these interviews in order for your child to to remain in the rest 
of the HPTN 084-1 study. 
 
About the sub-study 
The HPTN 084-1 study is being done to find out if it is safe and acceptable for adolescent women who 
do not have HIV to take a new HIV medicine called cabotegravir (CAB) as PrEP to prevent HIV. This 
sub-study will ask young women what they like and do not like about getting CAB injections. We will 
also ask their parents/guardians questions to find out what it is like to have a child getting CAB 
injections and things that made that easier, and that is why you have been chosen to take part. 


 
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Entering the sub-study 
We will be doing interviews with up to 10 parents/guardians at participating sites (total, across sites). 
You have been selected to take part in one interview sometime after your child’s last CAB injection.  
 
What will happen during the interview 
The interview will be led by a member of the research team that you do not work with during the study. 
It should take about 1 hour and your child will not be there. [To be modified to reflect site practices: The 
interview will take place in a location that the study staff have determined will provide you with privacy 
and confidentiality such as the clinic, or another appropriate place. The study team will talk with you 
about this so you know where to go for the interview].  
 
During the interview we will ask you questions about:  
• How and when you decided to allow your child to join the HPTN 084-1 study,  
• Whether you feel that they personally are at risk of HIV,  
• Whether you talked to your children about sexual activity or preventing HIV and pregnancy,  
• If your child had any bad effects from being in the HPTN 084-1 study, and if this influenced 
your decision to keep coming for the study visits,  
• Other related topics.  
If any of the questions make you upset, either you or the interviewer may stop the interview at any time. 
You will also be provided with contact and referral information if any of the questions raise issues that 
you would like to talk about later. 
 
Benefits of the sub-study 
There may be no benefit from being in the sub-study. You may not receive any other direct benefit from 
being in this part of the study; however, you or others in your community may benefit from this study 
later.  
 
Risk of the sub-study 
There is little risk from the interview. To minimize any discomfort and to protect your privacy the 
interview will be conducted in a private area that will allow you to speak comfortably without being 
overheard. Although we hope that you will be comfortable answering all of the questions openly and 
honestly, please keep in mind that you may refuse to answer any of the questions, or stop the interview 
completely, at any time. The greatest risk may involve your privacy and confidentiality. The steps that 
the study team have taken to protect your privacy are described below.  
 
Other information about the sub-study 
Privacy – 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, or 
anything else that might identify you personally, will not be used in any publication of information 
about this study.  
 
To help assure that we get the best understanding possible from your answers during the interview, the 
entire interview will be audio-recorded. After the interview is finished, the recording will be typed 
(called a transcript) by people who know how to do this. All identifying information will be removed 
from the transcript. Your name will not be included on the transcript. These recordings will be destroyed 


 
HPTN 084-01, FINAL Version 1.0 
 
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after all analysis is completed. 
 
Your records may be reviewed by the following groups, involved with the study: 
• 
[insert name of site IRB/EC] 
• 
[insert name of site drug regulatory authority] 
• 
[insert name of other site regulatory entities] 
• 
Representatives of the HPTN  
• 
The United States National Institutes of Health and its study monitors 
• 
The United States Food and Drug Administration 
• 
The United States Office for Human Research Protections 
• 
Other U.S., local, and international regulatory entities 
• 
ViiV Healthcare (the company that makes CAB) 
 
 
If the study staff learns that you are at risk of harm, we will tell the proper authorities as we are required 
to do by the law. 
 
New Information – You will be told any new information learned during this study that might affect 
your willingness to stay in the study. You will also be told when the results of the study may be 
available, and how to learn about them.  
 
Alternatives to participating 
You can talk to the study staff at any time about your child’s experiences in the study, without taking 
part in the sub-study interview. 
 
There are no costs to you for being in the sub-study 
There will be no cost to you for participating in the in-depth interview, and you will not receive payment 
for being interviewed. [Insert information about compensation/reimbursement here, e.g., You will be 
reimbursed for the cost of transport to the clinic for the interview. You will be given (specify amount).] 
 
Who to contact 
If you have questions, concerns, or problems at any time, use these contacts. 
 
• If you have questions about the sub-study:  
[insert name and telephone number of investigator or other study staff] 
 
• If you have questions about your rights as a research participant or concerns about how you are 
being treated in the sub-study:  
[insert name and telephone number of IRB/EC contact person or other appropriate 
person/organization] 
 
• If you have any health or other problems that may be related to sub-study participation:  
[insert name and telephone number of investigator or other study staff] 


 
HPTN 084-01, FINAL Version 1.0 
 
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14 October 2019 
 
• If you want to leave the sub-study:  
[insert name and telephone number of investigator or other study staff] 
 
 
 


 
HPTN 084-01, FINAL Version 1.0 
 
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14 October 2019 
 
SIGNATURE PAGE  
PARENT/GUARDIAN IN-DEPTH INTERVIEW INFORMED CONSENT FORM  
 
HPTN 084-01: 
Safety, Tolerability and Acceptability of Long-Acting Cabotegravir (CAB LA) for the Prevention 
of HIV among Female Adolescents – A Sub-study of HPTN 084 
 
FINAL, Version 1.0 
14 October 2019 
DAIDS Document ID: 38655 
 
If you decide to join this sub-study, sign or make your mark below. Before deciding whether to join this 
study, make sure you have read this form, or had it read to you, and that all of your questions have been 
answered. You should feel that you understand the study, its risks and benefits, and what is expected of 
you if you decide to join. You can ask questions or request more information at any time. You do not 
give up any rights by signing this form. 
 
 
Write your initials or make your mark below. 
 
 
________ 
I agree to be interviewed for HPTN 084-1 and to have the interview audiotaped 
 
 
______________________________ 
____________________________________ 
Name of Participant (print) 
 
 
Signature and Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
____________________________________ 
Study Staff Conducting 
 
 
Study Staff Signature and Date 
Consent Discussion (print) 
 
 
 
 
 
 
 
 
____________________________________ 
Witness Name (print)  
 
 
Witness Signature and Date 
(As appropriate) 
 
 
 

SAP_001.pdf: 
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STATISTICAL ANALYSIS PLAN 
Safety, Tolerability and Acceptability of Long-Acting 
Cabotegravir (CAB LA) for the Prevention of HIV among 
Adolescent Females – A Sub-study of HPTN 084 
HPTN 084-01 
Effective Date: Date of latest signature 
Version: 3.0




 
 
 
 
 
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TABLE OF CONTENTS 
1. 
LIST OF ABBREVIATIONS AND ACRONYMS .................................................................... 4 
2. 
INTRODUCTION ............................................................................................................ 5 
2.1 
GENERAL DESIGN CONSIDERATIONS ........................................................................................... 5 
2.2 
STUDY OBJECTIVES AND ENDPOINTS ........................................................................................... 6 
2.3 
RANDOMIZATION .................................................................................................................... 7 
2.4 
BLINDING .............................................................................................................................. 8 
2.5 
SAMPLE SIZE AND POWER ........................................................................................................ 8 
3. 
GENERAL DATA ANALYSIS CONSIDERATIONS ................................................................ 8 
3.1 
ANALYSIS SET(S) ..................................................................................................................... 8 
3.2 
STATISTICAL ANALYSIS ISSUES .................................................................................................... 9 
4. 
INTERIM ANALYSIS AND DATA MONITORING COMMITTEE ........................................... 9 
5. 
GENERAL ANALYSIS METHODS ..................................................................................... 9 
6. 
TRIAL PARTICIPANT DISPOSITION ................................................................................. 9 
6.1 
DISPOSITION OF PARTICIPANTS .................................................................................................. 9 
6.2 
TREATMENT EXPOSURE .......................................................................................................... 12 
6.3 
PROTOCOL DEVIATIONS ......................................................................................................... 13 
7. 
BASELINE DATA .......................................................................................................... 13 
8. 
EFFICACY/EFFECTIVENESS ANALYSES .......................................................................... 14 
9. 
SAFETY ANALYSES ...................................................................................................... 15 
9.1 
ADVERSE EVENTS AND DEATHS ................................................................................................ 16 
9.2 
LABORATORY EVALUATIONS .................................................................................................... 16 
9.3 
OTHER SAFETY MEASURES ...................................................................................................... 16 
10. 
IMMUNOGENICITY ANALYSES .................................................................................... 16 
11. 
PHARMACOKINETIC ANALYSES ................................................................................... 16 
12. 
SECONDARY ENDPOINTS ............................................................................................ 16 
13. 
REFERENCES .............................................................. ERROR! BOOKMARK NOT DEFINED. 
14. 
CHANGE HISTORY ....................................................................................................... 18 


 
 
 
 
 
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LIST OF ABBREVIATIONS AND ACRONYMS  
Term/Abbreviation 
Definition 
ADaM 
Analysis Dataset Model 
AEs 
Adverse Events  
AESI 
AEs of Special Interest 
ALT 
Alanine Aminotransferase  
AST  
Aspartate Aminotransferase 
CAB LA 
Long-Acting Cabotegravir 
CABG 
Coronary Artery Bypass Grafting  
CASI 
Computer Assisted Self Interview 
CBC 
Complete Blood Count 
CMC  
Clinical Management Committee 
CPK 
Creatine Phosphokinase 
CRF  
Case Report Forms 
CV 
Coefficient of Variation 
DAIDS 
Division of AIDS 
EC  
Ethics Committee 
FDA  
(US) Food and Drug Administration 
GEE 
Generalized Estimating Equations 
HBsAg 
Hepatitis B Virus Surface Antigen 
HBV 
Hepatitis B Virus  
HDL  
HighDensity Lipoprotein 
IM 
Intramuscular 
IoR  
Investigator of Record 
IRB  
Institutional Review Board 
ISR 
Injection Site Reaction 
IUD 
Intrauterine Device 
IUS 
Intrauterine System 
LDL 
Low Density Lipoprotein 
MO  
Medical Officer 
NIAID 
National Institute of Allergy and Infectious Diseases 
NICHD 
National Institute of Child Health and Human Development 
OHRP  
Office for Human Research Protections 
OLE 
Open Label Extension 
PTCA 
Percutaneous Transluminal Coronary Angioplasty 


 
 
 
 
 
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SD 
Standard Deviation 
SMC 
Safety Monitoring Committee 
SPDSMP 
Study Progress and Data Safety Monitoring Plan 
STI 
Sexually Transmitted Infection 
Tbili 
Total Bilirubin  
ULN 
Upper Limit of Normal 
US 
United States 
WBC 
White Blood Cell 
WHO 
World Health Organization 
βHCG 
Beta Human Chorionic Gonadotropin  
2. INTRODUCTION 
This SAP is intended to describe the final primary and secondary analyses upon completion of HPTN084-
01. Sections of the SCHARP SAP template had to be adapted here to reflect the distinct single-arm 
outcomes, as opposed to the more common multi-arm studies that the template was designed for. Key 
variable definitions are included in appendix B.  
2.1 General Design Considerations 
HPTN084-01 is a phase IIB single arm trial designed to establish the minimum safety, tolerability and 
acceptability data needed to support the use of cabotegravir long-acting injection (CAB LA) in an 
adolescent population, potentially transforming the field of HIV prevention for young people. The study 
target population is sexually-active, healthy female adolescents aged below 18 years. The study target is 
to enroll more than 50 participants with at least 50 participants receiving at least one injection. Participant 
recruitment will take approximately 12 months. 
Study participation includes:  
Step 1: a 5-week oral CAB 30mg QD safety lead-in followed by  
Step 2: a series of 5 intramuscular (IM) injections of 3 mL (600 mg) cabotegravir administered at 
8-week intervals after a 4-week loading dose (injections at weeks 5, 9, 17, 25 & 33). Adherence 
support strategies (e.g., counseling, reminders, pill cases) will be included to support pill-taking 
during the first five weeks and to support retention during the injectable phase. A safety visit will 
follow each injection to ascertain pharmacokinetic-peak safety data, including injection site 
reactions.  
Step 3: A blood draw visit, the +8 Week Visit, will follow the last injection to monitor CAB drug 
levels, with additional blood collection at the +24, +36, and +48 Week Visits. All participants 
who have received at least one injection will be followed for 48 weeks after their last injection. 
Waning levels of cabotegravir (the PK tail) will be covered with locally sourced oral 
Tenofovir/emtricitabine (Trade name: TDF/FTC, Truvada®) for daily use for 48 weeks. Both 
clinical and laboratory evaluations will occur during follow-up phase visits, and behavioral and 
acceptability data will be collected via computer-assisted self-interview (CASI). Total participant 
commitment for the entire study is up to 87 weeks, or approximately 1.5 years 


 
 
 
 
 
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Alternative to Step 3-Open Label Extension: Participants may be offered the opportunity to join 
an open label extension (OLE) CAB study at any time following completion of Step 2, if such a 
study is being implemented in their area at the time. 
We anticipate recruitment for the study will take approximately 12 months. Participants who discontinue 
study product during Step 2 for any reason other than HIV infection or study product related AE 
occurrence will be transitioned to open label TDF/FTC for 48 weeks. 
There are in total three study sites: Ward 21 CRS, Johannesburg, South Africa; Spilhaus CRS, Harare, 
Zimbabwe; MU-JHU Research Collaboration (MUJHU CARE LTD) CRS, Kampala, Uganda. 
Study is sponsored by Division of AIDS (DAIDS), United States (US) National Institute of Allergy and 
Infectious Diseases (NIAID), Eunice Kennedy Shriver National Institute of Child Health and Human 
Development (NICHD), US National Institutes of Health (NIH), IND number is 122,744. Protocol Chair 
is Sybil Hosek, PhD and Protocol Co-chair is Lynda Stranix-Chibanda, MBChB, MMED. 
2.2 Study Objectives and Endpoints 
Primary objectives:  
• 
To evaluate the safety, tolerability and acceptability of CAB LA in healthy, HIV-uninfected 
female adolescents aged below 18 years 
Secondary objectives: 
• 
To examine adherence to and timeliness of injections over time among adolescent participants 
provided CAB LA and information regarding its safety and efficacy 
• 
To examine patterns of sexual risk behavior over time among adolescent participants provided 
CAB LA and information regarding its safety and efficacy 
• 
To evaluate the safety of oral CAB during step 1 (oral phase) as well as all study products during 
the aggregate oral+injectable period for all enrolled participants 
• 
To characterize the pharmacokinetics of CAB LA 
• 
Additional exploratory analyses will be done with the laboratory and clinical data, including 
resistance mutations 
To achieve the primary and secondary objective, the planned primary and secondary endpoints are:  
 
Primary endpoints: 
1. Safety endpoint: Proportion of participants experiencing any Grade 2 or higher clinical adverse 
events (AEs) and laboratory abnormalities from adverse event reporting among participants who 
receive at least one injection of CAB LA. Laboratory abnormalities include grade 2 or above on 
tests include (CRF: Chemistry Panel, Fasting Lipid Test Results, Urinalysis, Hematology): 
a. Renal function: Creatinine, Creatinine clearance 
b. Hematology: Hemoglobin, Platelets, WBC, Neutrophils, Lymphocytes 
c. Liver function: Alkaline phosphatase, AST, ALT, Total bilirubin 
d. Electrolytes: Phosphorus, Calcium 
e. Other chemistries: CPK, Glucose, Amylase, Lipase 
f. Urine test: Protein, Glucose 
g. Fasting Lipid Test Results: Total cholesterol, Triglycerides, LDL, HDL 
 


 
 
 
 
 
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2. Tolerability endpoint: Proportion of participants who receive at least 1 injection and who 
discontinue receiving injections prior to the full course of injections due to intolerability of 
injection, frequency of injections or burden of study procedures. Reasons for intolerability may 
include: 
1. Injection site reaction 
2. Participant refused further participation1 
3. Participant lost to follow-up 
4. Participant is unwilling or unable to comply with required study procedures 
5. Participant refused further study product use 
6. Participant unable to adhere to visit schedule  
1Excluding cases in which reason for termination is unrelated to intolerability 
 
• 
Acceptability endpoint: Proportion of participants who complete all scheduled injections and 
proportion of participants who receive at least one injection who would consider using CAB LA 
for HIV prevention in the future. This endpoint will be evaluated using CASI questionnaires at 
the last injection visit (Step 2, week 33) For participants who do not have acceptability data at the 
Step 2, week 33 visit (either due to a change in when the questionnaire items were administered2, 
missed the final injection visit, or discontinue injections early)and continue to step 3, 
acceptability endpoints are evaluated during the follow up phase (step 3, week +12). The primary 
acceptability outcome is: 
a. If you wanted to protect yourself from getting HIV, which of the following product(s) 
would you prefer to use? 
▪ 
Prefer not using a product 
▪ 
Condoms only 
▪ 
Oral PrEP pills only 
▪ 
Injectable PrEP only 
▪ 
Condoms and oral PrEP pills together 
▪ 
Condoms and injectable PrEP together 
▪ 
Prefer not to answer 
2The CASI survey was updated to include acceptability endpoints at the Step 2, week 33 visit on 
01NOV2021 for all sites, since the addition of OLE could have otherwise precluded this endpoint 
from being captured (for participants who never begin Step 3). At this time, 6 participants had 
already completed their Step 2, week 33 visit. 
Secondary endpoints: 
• 
Plasma CAB pharmacokinetics  
• 
Proportion of participants experiencing Grade 2 or higher clinical AEs and laboratory 
abnormalities in the oral phase and the aggregate oral and injection phases 
• 
Proportion of injection visits that occurred “on-time”  
• 
Change from enrollment of self-reported sexual behavior (number of sexual partners, increased 
episodes of vaginal or anal sex without a condom) during the oral and injection phases  
• 
Presence of ART resistance among HIV seroconverters   
2.3 Randomization 
There is no treatment randomization as this study is a single arm, open label trial. 


 
 
 
 
 
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2.4 Blinding 
Participants and site staff will be unblinded throughout the trial. 
2.5 Sample Size and Power 
The expected sample size available for analysis for this protocol (n=50) is the number of participants 
agreed upon by the industry sponsor and regulators in order to provide supplementary safety and 
behavioral data on adolescents in collaboration with the HPTN 083 and HPTN 084 adult trials. The goal 
of the safety evaluation for this study is to identify safety concerns associated with CAB LA. 
Width of 95% confidence interval for 
estimated proportion as a 
function of the true 
proportion, assuming a 
sample size of 50. 
True proportion 
Width of 95% CI 
0.1 
± 0.083 
0.2 
± 0.11 
0.3 
± 0.13 
0.4 
± 0.14 
0.5 
± 0.14 
 
Since each of the primary endpoints is a proportion, Width of 95% confidence interval for estimated 
proportion as a function of the true proportion, assuming a sample size of 50. shows the precision 
(confidence interval width) that will be obtained for each endpoint with a sample size of 50. 
Recognizing that some participants will not reach the first injection visit and/or may not receive any study 
injections due to personal or clinical concerns, the study will continue to recruit participants until it is 
clear that at least 50 participants will progress to the injection phase.  Experience in the parent study 
HPTN 084 suggests that only a small proportion of participants will fail to reach the injection stage, and it 
is expected that approximately 5-7 additional enrollees may be needed in order to reach 50 participants in 
the injection phase. 
3. GENERAL DATA ANALYSIS CONSIDERATIONS 
3.1 Analysis Set(s) 
Primary and secondary analyses will be carried out among the following populations:  
 
Screened Population: Includes all participants who were screened for potential enrollment. 
 
Injection Population: Includes enrolled female adolescents who receive at least one injection of CAB LA. 
 
Safety Population: Includes enrolled participants who began step 1 (oral phase). 
 
Enrolled Population: Includes all enrolled participants.  


 
 
 
 
 
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Seroconverter Population: Includes all enrolled participants who seroconverted during the study. 
 
TDF/FTC Population: All enrolled participants who were provided TDF/FTC during the study. 
 
3.2 Statistical Analysis Issues 
AEs will be tabulated using MedDRA preferred terms. The number and percentage of participants 
experiencing each specific AE (All AEs, Grade 2 or higher, and SAEs) will be tabulated by severity and 
by relationship to study product. For the calculations in these tables, each participant’s AEs will be 
counted once as the maximum severity and relationship to study product. AEs leading to temporarily or 
permanently stopping drug will also be summarized.  
 
Methods for imputation of missing dates are described in Appendix C. 
4. INTERIM ANALYSIS AND DATA MONITORING COMMITTEE 
See: Study progress and safety data monitoring plan (SPDSMP) for a detailed description of the study 
monitoring committee (SMC) and the data safety monitoring board (DSMB) reports for this study.  
5. GENERAL ANALYSIS METHODS 
Within the single arm, all primary and secondary outcome proportions with 95% CIs will be calculated. 
6. TRIAL PARTICIPANT DISPOSITION 
6.1 Disposition of Participants 
The study will recruit participants to ensure that at least 50 participants progress to the injection phase, 
therefore more than 50 participants will be screened and enrolled. 
 
 


 
 
 
 
 
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Consort Diagram (numbers to be determined) 
 
 
 
 
 
 
Screened  
n = x 
Enrolled 
n = x 
Excluded (x) 
• 
Did not meet all inclusion 
criteria (x) 
• 
Declined to participate (x) 
• 
Lost to follow-up (x) 
• 
Other (x) 
Step 1 (Oral Phase) 
n = x 
visit 1: x/x (x%) 
visit 2: x/x (x%) 
Step 2 (Injection Phase) 
n = x 
Injection 1: x/x (x%) 
Injection 2: x/x (x%) 
Injection 3: x/x (x%) 
Injection 4: x/x (x%) 
Injection 5: x/x (x%) 
Did not begin Step 2 (x) 
• 
Any HIV reactive/positive test (x) 
• 
Any suspected or confirmed 
pregnancy (x) 
• 
Participant request (x) 
• 
Product discontinuation due to 
disqualifying condition1 (x) 
• 
Lost to follow-up (x) 
• 
Other (x) 
Step 3 (Follow Up) 
n = x 
visit 1: x/x (x%) 
visit 2: x/x (x%) 
visit 3: x/x (x%) 
visit 4: x/x (x%) 
visit 5: x/x (x%) 
Open Label Extension 
n = x  
visit 1: x/x (x%) 
visit 2: x/x (x%) 
visit 3: x/x (x%) 
visit 4: x/x (x%) 
visit 5: x/x (x%) 
(x) 
(x) 


 
 
 
 
 
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1Conditions in Step 1 that could disqualify a participant from transitioning to Step 2 are as follows:  
• 
Pill count suggestive of less than 50% adherence at the Week 4 visit 
• 
Missed or delayed Week 4 visit 
• 
Not on effective long-term contraception at the Week 4 visit 
• 
Grade 2 ALT at week 4, or grade 3 and above ALT anytime in step 1 
• 
Grade 3 AE that related to study product anytime in step 1, excluding ALT & CPK 
• 
Grade 4 AE anytime in step 1, excluding ALT & CPK 
• 
At substantial risk of HIV infection and/or qualifies for oral PrEP by local guidelines 
• 
HIV reactive or positive test  
• 
Confirmed pregnancy 
 
 
Participant enrollment inclusion and exclusion criteria (see study protocol)  
A. Inclusion Criteria 
1) Assigned female at birth 
2) At enrollment, below 18 years of age 
3) 
aAt enrollment, body weight ≥ 35 kg (77 lbs.) 
4) Willing to provide written informed assent/consent for the study and/or able to obtain written 
parental/guardian informed consent 
5) Self-reported sexual activity with a male (oral, anal or vaginal) in the past 12 months 
6) In general, good health, as evidenced by the following laboratory values:  
a. Non-reactive / negative HIV test results  
b. Absolute neutrophil count > 799 cells/mm3 
c. Platelet count ≥ 100,000 cells/mm3 
d. Hemoglobin > 11g/dL 
e. Calculated creatinine clearance ≥ 60 mL/minute using the modified Schwartz equation 
f. Alanine aminotransferase (ALT) < 2.0 times the upper limit of normal (ULN) (< grade 1) and 
total bilirubin (Tbili) ≤ 2.5 x ULN 
g. Hepatitis B virus (HBV) surface antigen (HBsAg) negative) and accepts vaccination 
h. HCV Antibody negative 
7) Willing to undergo all required study procedures 
8) 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 Enrollment and before initiating 
study product 
9) Must agree to use a reliable form of long acting contraception, during the trial and for 48 weeks 
after stopping the long acting injectable, or 30 days after stopping oral study product, from the list 
below: 
a. Intrauterine device (IUD) or intrauterine system (IUS) that meets <1% failure rate as 
stated in the product label  
b. 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). 
10) bIf currently on PrEP from a non-study source, willing to stop said PrEP prior to enrollment and 
agree to switch to oral CAB for the lead-in period and CAB LA injections. 
 
B. Exclusion Criteriac 


 
 
 
 
 
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1) Co-enrollment in any other HIV interventional research study or other concurrent studies which 
may interfere with this study (as provided by self-report or other available documentation) 
2) Past or current participation in HIV vaccine trial with exception for participants who can provide 
documentation of receipt of placebo 
3) Exclusively had sex with biological females in lifetime 
4) In the last 6 months (at the time of screening):  
a. active or planned use of any substance use which would, in the opinion of the site 
investigator, interfere with study participation (including herbal remedies) 
5) Known history of 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 
6) Inflammatory skin conditions that compromise the safety of intramuscular (IM) injections 
7) Tattoo or other dermatological condition overlying the buttock region that may interfere with 
interpretation of injection site reactions 
8) 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) 
9) Known history of clinically significant bleeding 
10) A history of seizure disorder, per self-report 
11) Medical, social or other condition that, in the opinion of the site investigator, would interfere with 
the conduct of the study or safety of the participant (e.g., provided by self-report, or found upon 
medical history and examination or in available medical records) 
12) Plans to move out of the geographic area within the next 18 months or otherwise unable to 
participate in study visits, according to the site investigator 
13) Pregnant or currently breastfeeding at the time of screening or intends to become pregnant and/or 
breastfeed while on study 
 
a Letter of Amendment (LoA) #1 (03 December 2020): Decreased weight criterion from > 50 kg 
(110 lbs) to > 35 kg (77 lbs). 
b LoA #1: Added new inclusion criterion #10. 
c LoA #1: Removed exclusion criterion “Currently receiving PrEP from a non-study source” has 
been removed. Three exclusion criteria have been removed, to broaden the sexual risk profile for 
participants, due to the superiority results from HPTN 084: In the last 6 months (at the time of 
screening): 1. self-reported unprotected anal or vaginal intercourse with someone known to be 
HIV infected. 2. self-reported illicit injection drug use of any kind or stimulant use (including 
inhaled nitrate, cocaine in any form, methamphetamine, or non-physician prescribed 
pharmaceutical-grade stimulants) 3. self-report of greater than 5 different sexual partners (anal or 
vaginal), regardless of use of protection or knowledge of HIV status in last 6 months. 
6.2 Treatment Exposure 
During step 1 (oral phase) staff are required to observe participants take one pill at enrollment, week 2 
and week 4. Pill counts will occur at visits for week 2 and 4.  
 
All injections during step 2 (injection phase) will be administered (and therefore directly observed) by 
study staff. Injections will be considered “on-time” if they occur in the visit window, described in the 
secondary analyses (section 12).  
 


 
 
 
 
 
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Blood samples will be collected throughout the study from all participants and assayed for plasma CAB 
concentrations. PK sample times include pre-dose trough samples at W5, W9, W17, W25, and W33 
(final concentration in injection phase) 1-week post injection samples at W6, W10, W18, W26, 
W34, with a final sample at +8-weeks following the final injection. For participants advancing to Step 3 
(and not the OLE), additional follow-up samples will be collected at +24, +36 and +48-weeks following 
the final injection and at HIV confirmatory visit.    
6.3 Protocol Deviations 
Protocol deviations will be summarized in regular reports to the SMC, the details of which are available 
in the SPDSMP.  Serious protocol deviations may result in participants being terminated from the trial 
and/or being excluded from analyses.  The decision to exclude participant data from the analyses will be 
made based on independent review.  
7. BASELINE DATA  
The following data will be described overall, and by site: 
 
Demographics (Table 1): 
• 
Age (continuous – mean, SD, median, min max; categorical (<16, ≥ 16): n (%)) 
• 
Gender 
• 
Sexual orientation 
• 
Race  
• 
Weight (continuous – mean, SD, median, min max; categorical (<50 kg, ≥50 kg): n (%)) 
• 
BMI  
o Age standardized BMI z-score (continuous – mean, SD, median, min max) 
o Classification as obese, overweight, normal, thinness, severe thinness based on z-score 
• 
Housing security* 
o -Do you have a regular place or home where you stay and store your things? (yes/no) 
• 
Food security* 
o In the past 6 months, how frequently did you worry that your household would not have 
enough food? 
 
Sexual behavior/HIV prevention (Table 2): 
• 
Sexual behaviors*: 
During the past month the participant had:  
o a primary partner  
o a primary partner who is reported to be HIV positive or unknown  
o transactional sex with a man  
o number of male sex partners  
o number of  male sex partners who are reported to be HIV positive 
o number of episodes of vaginal sex (median (Q1, Q3))  
o number of episodes of vaginal sex without condom (median (Q1, Q3))  
o number of episodes of anal sex 
o number of episodes of anal sex without condom 
• 
Sexually transmitted infections (STIs): 
o Syphilis 
o Gonorrhea  
o 
Chlamydia  


 
 
 
 
 
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• 
HIV risk perception*:  
o How much do you personally feel at risk of getting infected with HIV? 
 
Mental health (Table 3): 
• 
Depression indices1 
o CES-D-10* (continuous – mean, SD, median, min max; categorical (≤10: not depressed, 
>10: depressed): n (%)) 
o PHQ9 (continuous – mean, SD, median, min max; categorical (none-minimal, mild, 
moderate, moderately severe, severe): n (%)) 
• 
Intimate partner violence (IPV)* 
o In the past 6 months, have any of your partners punched, slapped, kicked, bit you, or 
caused you any type of physical harm? 
o In the past 6 months, have any of your partners insulted, ignored or humiliated you, 
yelled at you, or made you feel ashamed or bad about yourself? 
o In the past 6 months, have any of your partners forced you to have sex or perform any 
sexual act, or touched you sexually in any way that you did not want? 
o In the past 6 months, have any of your partners made you feel afraid, unsafe or in danger? 
• 
Primary care post traumatic stress disorder screening questionnaire (PC-PTSD-4)* (continuous – 
mean, SD, median, min max; categorical (≤2: no PTSD, >2: potential PTSD): n (%)) 
• 
alcohol/substance use* 
o How often do you have a drink containing alcohol? 
o How often do you have six or more drinks on one occasion? 
o In the past month, did you have a drink containing alcohol just before or during sex? 
o In the past month, how often have you used each of the following substances? 
▪ 
Cannabis (Also called marijuana, pot, grass, dakka, dagga or hash) 
▪ 
Amphetamine-type stimulants (For example Tik/Crystal Meth, ecstasy, speed, or 
diet pills) 
▪ 
Prescription drugs for non-prescription purposes (For example codeine (including 
cough syrup), efavirenz, valium) 
 
1Internal consistency of Depression Index summaries (addendum to Table 3): 
1. Tabular cross-frequency of the categories for CES-D-10/PHQ9 
2. Scatterplot of the values of either index, with color-coding based on whether they agree on 
qualitative risk of depression 
 
*CASI questionnaire variables  
8. PRIMARY ANALYSES  
For each of the three primary endpoints the number and proportion of participants will be computed along 
with corresponding exact 95% confidence intervals where applicable. Endpoint descriptions are available 
in section 2.2. 
 
8.1 Safety endpoint analysis 
 
Population: Injection population 
Analysis description: Number and percent of participants experiencing any Grade 2 or higher clinical 
adverse events (AEs) or laboratory abnormalities (reported as adverse events) from the first injection 
visit to 8 weeks after the last Step 2 injection visit or week 41, whichever comes first. 


 
 
 
 
 
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8.2 Tolerability endpoint analysis 
 
Population: Injection population 
Analysis description: Number and percent of participants who receive at least 1 injection and who 
discontinue receiving injections prior to the full course of injections due to intolerability of injection 
or burden of study procedures. Reasons for intolerability may include:   
 
1. Injection site reaction 
2. Burden of study procedure 
i. 
Participant refused further participation 
ii. 
Participant is unwilling or unable to comply with required study procedures 
iii. 
Participant refused further study product use 
iv. 
Participant unable to adhere to visit schedule  
 
8.3 
Acceptability endpoint analysis 
 
8.3.1 
Completion of scheduled injections  
 
Population: Injection population and Enrolled population 
Analysis description: Number and percent of participants who complete all scheduled injections1  
 
1Definition of completing all scheduled injections for participants who are confirmed 
pregnant, confirmed HIV seroconverted, or discontinue product due to the following 
reasons: 
• 
Death 
• 
Early study closure 
• 
HBV infection 
 
During Step 1: 
Enrolled population: completed all 0 of 0 scheduled injections 
Injection population: not applicable, did not receive injection 
 
During Step 2: 
both enrolled and injection: completed all injections whose target window closed prior to 
pregnancy/seroconversion/product discontinuation date   
 
8.3.2 
Preferred method for HIV prevention  
 
Population: Injection population  
Analysis description: Number and percent of participants who choose ‘injectable PrEP’ or ‘condoms 
and injectable PrEP’ when asked the question “If you wanted to protect yourself from getting HIV, 
which of the following product(s) would you prefer to use?” 
9. SAFETY ANALYSES  
See section 8.1 above.  In addition to the primary safety outcomes (grade 2 or higher), AEs and laboratory 
data will be summarized in the closed DSMB report (described in the SPDSMP).  
 


 
 
 
 
 
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9.1 Adverse Events and Deaths  
Adverse events of special interest (AESI) will be summarized in the Clinical Study Report. Planned AESI 
summaries for the CSR are described in Appendix A.  
9.2 Laboratory Evaluations  
Population: Safety population 
Description: Laboratory findings for CBC (hemoglobin, platelets, WBC, neutrophils, lymphocytes), 
chemistries (urea, creatinine, CPK, glucose, calcium, phosphorous, amylase, lipase), 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. Baseline laboratory values will be summarized by site using: median, 
1st and 3rd quartiles, and min and max. Change from baseline in laboratory values will be summarized at 
follow up visits using: median, and 1st and 3rd quartile. Summaries involving values and changes from 
baseline at scheduled visit time points will consider values from scheduled visits only, and in the case of 
missing values, results will not be carried forward from interim (unscheduled) visits.  For summaries and 
analyses involving changes in laboratory values over time or maximum change from baseline (e.g. shift 
tables), values from interim (unscheduled) visits will also be considered.  
9.3 Other Safety Measures  
10. IMMUNOGENICITY ANALYSES 
NA 
11. PHARMACOKINETIC ANALYSES 
Plasma will be collected during Steps 1 and 2 for pharmacologic assessment of CAB concentrations.  
Plasma and DBS will also be collected for participants entering Step 3. If a study participant seroconverts 
during Step 3, pharmacologic analysis of plasma will be performed to assess PrEP adherence; plasma 
TFV and intraerythrocytic TFV-DP collected as DBS will be used to interpret TDF/FTC adherence 
during Step 3. Analysis details are provided in the current version of the Pharmacokinetics Analysis Plan. 
12. SECONDARY ANALYSES 
For binary secondary endpoints, the number and proportion of endpoints will be computed along with 
corresponding 95% exact confidence intervals where applicable.   Endpoint descriptions are available in 
section 2.2. Note: Some secondary analyses will not be included in the Clinical Study Report, and the 
Clinical Study Report will not generally provide 95% confidence intervals for secondary analyses.  
 
12.1 Plasma CAB pharmacokinetics 
 
Analysis details are provided in the current version of the Pharmacokinetics Analysis Plan. 
 
12.2 Proportion of participants experiencing Grade 2 or higher clinical AEs and laboratory 
abnormalities in the oral phase and over the aggregate oral and injection phase 


 
 
 
 
 
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Population: Safety population 
Analysis description: Number and percent of participants experiencing any Grade 2 or higher 
clinical adverse events (AEs) or laboratory abnormalities from:  
1. enrollment to week 5 (oral phase (step 1), including interim visits). 
2. enrollment to 8 weeks following the last injection received (aggregate over oral+injection 
phases (step 1-step 2) including interim visits) 
 
12.3 Proportion of participants receiving 1 or more injections experiencing Grade 2 or higher 
clinical AEs and laboratory abnormalities from initial injection to 36 weeks later 
 
Population: Injection population 
Analysis description: Number and percent of participants experiencing any Grade 2 or higher 
clinical adverse events (AEs) or laboratory abnormalities from the first injection visit to 
approximately 36 weeks later regardless of whether participants received all 5 injections. For 
participants receiving all 5 injections, the end date is 8 weeks following the week 33 injection 
visit. For participants discontinuing study product early and moving on to Step 3, the end date is 
36 weeks after the initial injection. Participants who terminate early are included in the analysis 
and censored at the date of termination.     
 
12.4 Proportion of injection visits that occurred “on-time” 
 
Population: Injection population 
Analysis description: Number and percent of injection visits (up to 5 per participant) that occur 
“on-time”1, using the number of injections given as the denominator. This will be presented along 
with the total number and percent of injections given, among all intended injections (i.e. 5 
injections per participant).  
 
1The target injection date is defined by the W5 visit i.e. for the initial injection, the target 
injection date is 0 days (same day), and is +28, +84, +140, +196 days from the W5 visit for 
injections 2-5, respectively. The target visit window for injection visits for the week 5 
injection is 0 to 3 days after the W5 visit (if the injection could not be done on the same day 
as the W5 visit), for all other injection visits (W9, W17, W25, W33) the target window is +/-
3 days from the target injection date. Injection dates happening within the target window are 
considered “on-time”. 
  
 
12.5 Change from enrollment of self-reported sexual behavior (number of sexual partners, 
increased episodes of vaginal or anal sex without a condom) during the study period 
 
Note: This secondary analysis will not be included in the Clinical Study Report. 
 
Population: Enrolled population 
Analysis description: We will use generalized estimating equations (GEE) with robust variance to 
model change in self-reported sexual behavior from enrollment (W0) to follow up visits (W4, 
W5, W9, W17, W25, W33, W+12, W+24, W+36, W+48), with an indicator variable for all on-
study visits (i.e. enrollment visit = 0) to measure change in the outcome behavior. We will model 
count outcomes (number of sexual partners, number of episodes of vaginal sex without a 
condom) using a poisson model and binary outcomes (any episodes of anal sex without a 
condom) using a logistic model.  


 
 
 
 
 
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12.6 Evaluate rates of HIV drug resistance among participants who acquire HIV infection during 
the study  
 
Population: Seroconverter population 
Analysis description: Data from steps 1, 2, and 3 will be included. The number of cases of drug 
resistance will be summarized. All cases of drug resistance among incident HIV infections will be 
described. 
13. AD HOC ANALYSIS 
 
13.1 Change from enrollment of age-standardized BMI z-score during the oral and injection 
phases 
 
Population: Injection population1 
 
Analysis description: We will test a null hypothesis that there is no change in age-standardized 
BMI z-score, using the one-sample Wilcoxon signed-rank test applied to participant-level 
difference in BMI z-score as measured at the enrollment and W33 visits. In addition we will 
estimate the mean change in BMI z-score from baseline and 95% confidence interval.  
 
We will include summary descriptions of change in age-standardized BMI z-scores from 
enrollment (W0) to follow up visits (W4, W5, W9, W17, W25, W33), including tabular 
summaries of actual and change (relative to enrollment) values at each visit (mean, SD, median, 
min max) as well as the number and percent falling into standardized categorizations for the 
following groups: obesity (z-score >2SD), overweight (1SD< z-score ≤2SD), normal (-2SD< z-
score ≤1SD), thinness (-2SD< z-score ≤-3SD), severe thinness (z-score <-3SD). We will present 
graphical summaries of change in BMI z-scores at each visit using a line plot of median change 
values, including vertical bars at each visit representing interquartile ranges (including a text 
annotation of the P-value for change in BMI above the W33 visit). A second graph will include a 
stacked bar chart at each timepoint, with number and percent in each standardized BMI category 
defined above.  
 
1For participants who become pregnant, excludes participant-visits occurring after confirmed 
pregnancy date. Missed injections will be summarized or included as a footnote. 
 
14. CHANGE HISTORY  
 
Version 
Affected 
Section(s) 
Activity Description 
Number 
Effective 
Date 
1.0 
 
22/02/2021 
All sections 
Creation of SAP v 1.0 


 
 
 
 
 
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2.0 
Date of 
last 
signature 
2, 3, 6, 7-9, 
11, 12 
Revisions based on new alternative to Step 3 (OLE CAB 
study). Added study populations and definitions. Updated 
consort diagram, primary and secondary 
outcomes/analyses, including addition of secondary 
outcome 12.6. Revisions/edits based on feedback from 
SCHARP external partners at GSK/PXL/Viiv. 
3.0  
Date of 
last 
signature 
2, 6, 7, 8.3.1, 
11, 12.1, 
12.5, 13, 16, 
17 
Minor revisions throughout. Updates to consort diagram, 
acceptability endpoint definition, and reference to PK 
analysis plan. Additional details to account for changes to 
schedule of visits and data collection, due to new OLE. 
Added sections: 13 (ad hoc analysis), appendices B and C 
(variable definitions and imputation of missing data).  
 
 
 


 
 
 
 
 
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15. APPENDIX A – Adverse Events of Special Interest 
Adverse events of special interest (AESI) have been determined for CAB based on pre-clinical and 
clinical experience, along with information for the integrase inhibitor class of HIV medications safety 
profile. These are adverse events for which more detailed summaries of event characteristics are of 
interest. 
The identification and classification of AESI will be based on MedDRA preferred terms as specified in 
the ADRG (Analysis Data Reviewers Guide).  The current MedDRA version used for the preferred terms 
in the ADRG is v24.1.  Preferred terms will be updated in the ADRG if a new version becomes available 
before the database lock. 
Table 1 below shows the adverse events of special interest identified and reasons for including. 
 
Table 1 
Adverse Events of Special Interest (Clinical Study Report only) 
AESI 
Product Implicated Reason for Including as AESI 
Hepatic Safety Profile: Assessment of risk of 
hepatoxicity 
CAB 
Clinical, Class, Regulatory 
Interest,  
Hypersensitivity Reactions (HSR) 
CAB 
Class, Regulatory Interest,  
Rash 
CAB 
Class, Regulatory Interest 
Neuropsychiatric Events  
• 
Suicidal Ideation/Behaviour 
• 
Depression 
• 
Bipolar Disorder 
• 
Psychosis 
• 
Mood Disorders 
• 
Anxiety 
• 
Sleep Disorders 
CAB 
Clinical, Class, Regulatory 
Interest,  
Injection Site Reactions (ISR) 
CAB 
Clinical, Regulatory Interest 
Seizures and Seizure-like events 
CAB 
Clinical, Regulatory Interest 
Weight Gain 
CAB 
Clinical, Class, Regulatory 
Interest 
Rhabdomyolysis 
CAB 
Clinical, Class, Regulatory 
Interest 
Pancreatitis 
CAB 
Clinical, Therapeutic Area, 
Regulatory Interest 
Impact on Creatinine 
CAB 
Regulatory Interest, 
Therapeutic Area  
Safety in Pregnancy  
CAB 
Regulatory Interest, Class 


 
 
 
 
 
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Hyperglycaemia/new onset diabetes mellitus 
CAB 
Observation from 083, Class 
  
Common ISR adverse events are defined by MedDRA preferred terms including injection site pain, 
injection site induration, injection site nodules and preferred terms of any other ISR exceeding the threshold 
as specified in the ADRG. ISRs are summarized and listed regardless of IP relationship.  
Separate outputs will be created for each one of the AESIs described in Table 3 to explore the data in 
more detail. Outputs will summarize Adverse events that occurred during Step 1 and/or Step 2 of the 
study.  
Event Characteristics: The characteristics of all event occurrences during the post-baseline period will 
be summarized, which looks at event characteristics (serious, drug-related, leading to withdrawal, or 
Grade 3/4, fatal), number of events per participant, outcome, maximum grade or intensity and action 
taken.  
Time to First Event (TTFE): A tabular summary of time of onset and duration of first event will be 
produced.  
Duration of Events: The total duration of time a subject experience the adverse events in question will 
also be summarized.   
In addition, Pyrexia Plus includes PT: (Chills – 10008531, Feeling of Body Temperature Change - 
10061458, Feeling Hot - 10016334, Body Temperature Increased - 10005911, Pyrexia - 10037660, 
Influenza Like Illness - 10022004, Fever – 10016558) will be summarized in relation to timing of 
previous injection. 
No formal statistical comparison planned for AESI.  
 
16. APPENDIX B – Variable Definitions 
1. CES-D-10 (score/categories)  
 
Create a score based on 10 items below (in CASI questionnaire): 
 
In the list below, please indicate how often you have felt this way during the past week by ticking the 
appropriate box for each question: 
 
1. I was bothered by things that usually don't bother me. 
2. I had trouble keeping my mind on what I was doing. 
3. I felt depressed. 
4. I felt that everything I did was an effort. 
5. I felt hopeful about the future. 
6. I felt fearful or afraid. 
7. My sleep was restless. 
8. I was happy. 
9. I felt lonely. 
10. I could not "get going”, I did not feel motivated. 
 
 
 
 
 


 
 
 
 
 
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Scoring: 
 
Rarely or none of the 
time (less than 1 day) 
Some or a little of the 
time (1‐2 days) 
Occasionally or a moderate 
amount of time (3‐4 days) 
All of the time 
(5‐7 days) 
Questions 
5 & 8 
3 
2 
1 
0 
All other 
questions 
0 
1 
2 
3 
 
The total score is calculated by finding the sum of 10 items. Score as ‘missing’ if 1 or more items are 
missing/prefer not to answer. Any score ≥10 is considered depressed. 
 
2. PHQ-9 (score/categories)  
 
Create a score based on values from 9 questions (Not at all = 0, Several days = 1, More than half the days 
= 2, Nearly every day = 3): 
 
    Over the last 2 weeks, how often have you been bothered by the following problems? 
 
1. Little interest or pleasure in doing things 
2. Feeling down, depressed, or hopeless 
3. Trouble falling or staying asleep, or sleeping too much 
4. Feeling tired or having little energy 
5. Poor appetite or overeating 
6. Feeling bad about yourself - or that you are a failure or have let yourself or your family down", 
7. Trouble concentrating on things, such as reading the newspaper or watching television", 
8. Moving or speaking so slowly that other people could have noticed. Or the opposite - being so 
fidgety or restless that you have been moving around a lot more than usual 
9. Thoughts that you would be better off dead, or of hurting yourself 
 
PHQ-9 score obtained by adding score for each question (total points). Score as ‘missing’ if 1 or more 
items are missing. Then categories of depression severity are created from the total score according to: 0-
4: None-minimal, 5-9: Mild, 10-14: Moderate, 15-19: Moderately Severe 20 – 27: Severe.  
 
3. PC-PTSD-4 (score/categories)  
 
Create a score based on values from 4 questions (yes = 1, no = 0): 
 
In your life, have you ever had any experience that was so frightening, horrible, or upsetting that, in the 
past month, you: 
 
1. Have had nightmares about it or thought about it when you did not want to? 
2. Tried hard not to think about it or went out of your way to avoid situations that reminded you of it? 
3. Were constantly on guard, watchful, or easily frightened? 
4. Felt empty, numb or detached from others, activities, or your surroundings? 


 
 
 
 
 
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If missing or prefer not to answer any questions, then code score as missing. For non-missing scores, a 
score of 0-2 fails to indicate PTSD, and ≥ 3 indicates the potential for PTSD, which can be determined by 
a clinical interview.  
 
4. Age-standardized BMI z-score 
 
Based on World Health Organization (WHO) tool:  
 
(1)      https://www.who.int/tools/growth-reference-data-for-5to19-years/indicators/bmi-for-age.  
 
With instructions for calculations (see section “Computation of centiles and z-scores”, link to pdf: 
“instructions in English”): 
 
(2)      https://cdn.who.int/media/docs/default-source/child-growth/growth-reference-5-19-
years/computation.pdf?sfvrsn=c2ff6a95_4 
 
 
Age-specific values of necessary parameters L(t), M(t), and S(t) can be downloaded from the website (1) 
(see section: “Expanded tables for constructing national health cards” link to dataset “z-scores: 
girls”)  
 
Categorical BMI classification based on age-standardized BMI z-score as follows:  
• 
Obesity: >+2 
• 
Overweight: >+1 and ≤+2 
• 
Normal: >-2 and ≤+1 
• 
Thinness: >-3 and ≤-2 
• 
Severe thinness: ≤-3 
17. APPENDIX C – Imputation of missing dates 
Missing Start and Stop Dates for Prior and Concomitant Medication, and Medical History 
The Assumption is to consider the most conservative judgment when imputing. 
 
Start date: 
When imputing a start date ensure that the new imputed date is sensible i.e. is prior to the end 
date and the general rules are: 
1. If start date is completely missing, start date will not be imputed 
2. If year and month are present and day is missing, set day to the 1st day of month.  
3. If year and day are present and month is missing, then set month to January. 
4. If year is present and month and day are missing, set month and day to January 1st.  
 
Stop date: 
1. If end date is completely missing, end date will not be imputed 
2. If year and month are present and day is missing, set day to the last day of month. 
3. If year and day are present and month is missing, set month to December 
4. If year is present and month and day are missing, set month and day to December 31st. 
 


 
 
 
 
 
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Missing Start and Stop Dates for Adverse Events (including ISRs) 
The Assumption is to consider the most conservative judgment when imputing. 
 
Start date: 
1. If start date is completely missing, start date is set to date of first dose. 
2. If (year is present, and month and day are missing) or (year and day are present, and month is 
missing): 
a. If year = year of first dose, then set month and day to month and day of first dose. 
b. If year < year of first dose, then set month and day to December 31st. 
c. If year > year of first dose, then set month and day to January 1st. 
3. If month and year are present and day is missing: 
a. If year = year of first dose and 
i. If month = month of first dose, then set day to day of first dose date. 
ii. If month < month of first dose, then set day to last day of month. 
iii. If month > month of first dose, then set day to 1st day of month. 
b. If year < year of first dose, then set day to last day of month. 
c. If year > year of first dose, then set day to 1st day of month. 
 
Stop date: 
If the outcome of the AE was ongoing or unknown, then the rules outlined below will not be applied. 
 
1. If stop date is completely missing, stop date is set to date of study discontinuation. 
2. If (year is present, and month and day are missing) or (year and day are present, and month is 
missing): 
a. If year = year of study discontinuation, then set month and day to month and day of study 
discontinuation. 
b. If year < year of study discontinuation, then set month and day to December 31st. 
c. If year > year of study discontinuation, then set month and day to December 31st. 
3. If month and year are present and day is missing: 
a. If year = year of study discontinuation and 
i. If month = month of study discontinuation, then set day to day of study 
discontinuation date 
ii. If month < month of study discontinuation, then set day to last day of month. 
iii. If month > month of study discontinuation, then set day to last day of month. 
b. If year < year of study discontinuation, then set day to last day of month. 
c. If year > year of study discontinuation, then set day to last day of month. 
 
Missing Start and Stop Dates for Protocol Deviations 
The Assumption is to consider the most conservative judgment when imputing. 
 
Start date: 
When imputing a start date ensure that the new imputed date is sensible i.e. is prior to the end date 
and the general rules are: 
 
1. If start date is completely missing, start date will not be imputed 
2. If (year is present, and month and day are missing) or (year and day are present, and month is 
missing), set month and day to January 1st. 


 
 
 
 
 
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3. If year and month are present and day is missing, set day to the 1st day of month.  
 
Stop date: 
1. If end date is completely missing, end date will not be imputed 
2. If (year is present, and month and day are missing) or (year and day are present, and month is 
missing), set month and day to December 31st. 
3. If year and month are present and day is missing, set day to the last day of month.