A Phase 2b/3 Double Blind Safety and Efficacy Study of Injectable Cabotegravir Compared to Daily Oral Tenofovir Disoproxil Fumarate/Emtricitabine For Pre-Exposure Prophylaxis in HIV-Uninfected Men and Transgender Women Who Have Sex With Men
Phase: PHASE2
Conditions: HIV Infections
Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

 
HPTN 083 
A Phase 2b/3 Double Blind Safety and Efficacy Study of Injectable Cabotegravir Compared to Daily Oral 
Tenofovir Disoproxil Fumarate/Emtricitabine (TDF/FTC), For Pre-Exposure Prophylaxis in HIV-
Uninfected Cisgender Men and Transgender Women who have Sex with Men 
 
DAIDS Document ID: 20725 
 
A Study by the HIV Prevention Trials Network 
 
Sponsored by: 
Division of AIDS, National Institute of Allergy and Infectious Diseases 
 
Pharmaceutical Support Provided by: 
ViiV Healthcare 
Gilead Sciences, Inc  
 
IND # 122, 744 
 
Protocol Chair: 
Raphael J. Landovitz, M.D., M.Sc. 
 
Protocol Co-Chair: 
Beatriz Grinsztejn, M.D., Ph.D. 
 
Final Version 3.0 
October 31, 2019 
  

 
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October 31, 2019 
 
HPTN 083 
A Phase 2b/3 Double Blind Safety and Efficacy Study of Injectable Cabotegravir Compared to 
Daily Oral Tenofovir Disoproxil Fumarate/Emtricitabine (TDF/FTC), for Pre-Exposure 
Prophylaxis in HIV-Uninfected Cisgender Men and Transgender Women who have Sex with Men 
TABLE OF CONTENTS 
TABLE OF CONTENTS .........................................................................................................................................2 
PROTOCOL SIGNATURE PAGE ........................................................................................................................6 
LIST OF ABBREVIATIONS AND ACRONYMS ................................................................................................7 
PROTOCOL TEAM ROSTER .............................................................................................................................11 
TERMINOLOGY FOR CABOTEGRAVIR AND TDF/FTC FORMULATIONS ..........................................16 
SCHEMA ................................................................................................................................................................17 
OVERVIEW OF STUDY DESIGN AND RANDOMIZATION SCHEME......................................................22 
1.0 
INTRODUCTION .....................................................................................................................................23 
1.1 BACKGROUND AND RATIONALE ..................................................................................................................23 
1.2 OVERVIEW OF ORAL CABOTEGRAVIR (ORAL CAB) AND LONG-ACTING INJECTABLE (CAB LA) ..............24 
1.3 DOSE RATIONALE ........................................................................................................................................26 
1.4 CLINICAL EXPERIENCE TO DATE: ORAL CAB AND CAB LA .....................................................................35 
1.5 HEPATIC AND CENTRAL NERVOUS SYSTEM ADVERSE EVENTS .................................................................38 
1.6 BACKGROUND OF TDF/FTC FOR PRE-EXPOSURE PROPHYLAXIS ...............................................................39 
1.7 RATIONALE FOR STUDY DESIGN .................................................................................................................41 
1.8 RATIONALE FOR BONE MINERAL DENSITY SUBSET ...................................................................................42 
1.9 RECRUITING AND RETAINING MOST AT RISK POPULATIONS .....................................................................42 
1.10 HIV AND RISK REDUCTION COUNSELING ...................................................................................................43 
1.11 ADHERENCE COUNSELING AND MONITORING ............................................................................................43 
1.12 RATIONALE FOR USE OF ORAL LEAD-IN PRIOR TO INJECTABLE DOSING ......................................................44 
1.13 RATIONALE FOR EXPLORING CROSS-SEX HORMONE THERAPY AND PREP MEDICATION DRUG-DRUG 
INTERACTIONS .............................................................................................................................................44 
1.14 RATIONALE FOR WEB-BASED SEXUAL HEALTH PROMOTION SCORE DURING SCREENING .......................44 
1.15 RATIONALE FOR COLLECTING AND ANALYZING METABOLIC PARAMETERS .............................................45 
2.0 
STUDY OBJECTIVES AND DESIGN ...................................................................................................46 
2.1 PRIMARY OBJECTIVES: ................................................................................................................................46 
2.2 SECONDARY OBJECTIVES: ...........................................................................................................................46 
2.3 TERTIARY OBJECTIVES: ...............................................................................................................................46 
2.4 EXPLORATORY OBJECTIVES: .......................................................................................................................47 
2.5 STUDY DESIGN AND OVERVIEW ..................................................................................................................47 

 
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3.0 
STUDY POPULATION ............................................................................................................................49 
3.1 INCLUSION CRITERIA ...................................................................................................................................49 
3.2 EXCLUSION CRITERIA ..................................................................................................................................50 
3.3 RECRUITMENT PROCESS ..............................................................................................................................51 
3.4 CO-ENROLLMENT GUIDELINES ...................................................................................................................51 
3.5 PARTICIPANT RETENTION ............................................................................................................................52 
3.6 PARTICIPANT WITHDRAWAL .......................................................................................................................52 
4.0 
STUDY PRODUCT CONSIDERATIONS .............................................................................................54 
4.1 STUDY PRODUCT REGIMENS/ADMINISTRATION/FORMULATION CONTENT ................................................54 
4.2 STUDY PRODUCT FORMULATIONS ..............................................................................................................54 
4.3 STUDY PRODUCT PREPARATION..................................................................................................................55 
4.4 STUDY PRODUCT ACQUISITION AND ACCOUNTABILITY .............................................................................60 
4.5 TOXICITY MANAGEMENT ............................................................................................................................60 
4.6 CONCOMITANT, PROHIBITED, AND PRECAUTIONARY MEDICATIONS .........................................................60 
4.7 OTHER STUDY PRODUCT DISPENSING CONSIDERATIONS ...........................................................................63 
5.0 
STUDY PROCEDURES ...........................................................................................................................64 
5.1 SCREENING ..................................................................................................................................................64 
5.2 STEP 1:  WEEK 0 - ENROLLMENT .................................................................................................................65 
5.3 STEP 1:  WEEKS 2 AND 4 – ORAL SAFETY VISITS ........................................................................................67 
5.4 STEP 2:  WEEKS 5 – FIRST INJECTION VISIT IN STEP 2 .................................................................................69 
5.5 STEP 2:  WEEK 6 – SAFETY VISIT FOLLOWING FIRST INJECTION ..................................................................69 
5.6 STEP 2:  ALL REMAINING VISITS WHERE INJECTIONS OCCUR - WEEKS 9, 17, 25, 33, 41, 49, 57, 65, 73, 81, 
89, 97, 105, 113, 121, 129, 137, 145 ............................................................................................................70 
5.7 STEP 2:  ALL REMAINING SAFETY VISITS, WITH WEEK 10 OCCURRING 1 WEEK AFTER THE WEEK 9 
INJECTION, AND EVERY 2 WEEKS AFTER EACH INJECTION VISIT THEREAFTER AS - WEEKS 10, 19, 27, 35, 
43, 51, 59, 67, 75, 83, 91, 99, 107, 115, 123, 131, 139, 147 ..........................................................................71 
5.8 WEEK 153, LAST VISIT OF STEP 2/ DAY 0, FIRST VISIT OF STEP 3 ..............................................................72 
5.9 STEP 3:  OPEN-LABEL TDF/FTC ..................................................................................................................74 
5.10 VISIT WINDOWS ..........................................................................................................................................75 
5.11 PROCEDURES FOR CONTINUED ORAL AND INJECTABLE DOSING ................................................................75 
5.12 PROCEDURES FOR PARTICIPANTS WHO DO NOT COMPLETE THE FULL COURSE OF INJECTIONS ...............75 
5.13 PLANNED UNBLINDING OF STUDY PARTICIPANTS ......................................................................................76 
5.14 PARTICIPANTS WITH SUSPECTED OR CONFIRMED HIV INFECTION, AT SCREENING, ENROLLMENT, OR 
FOLLOW-UP .................................................................................................................................................77 
5.15 SEXUALLY TRANSMITTED INFECTIONS .......................................................................................................78 
5.16 HEPATITIS B AND HEPATITIS C ...................................................................................................................78 
5.17 INTERIM CONTACTS AND VISITS AND MISSED VISITS ................................................................................79 
5.18 CRITERIA FOR EARLY TERMINATION OF STUDY PARTICIPATION ...............................................................79 
5.19 PHARMACOKINETIC MONITORING ..............................................................................................................79 
5.20 OTHER CONSIDERATIONS FOR PREMATURE TRANSITION FROM STEP 2 TO STEP 3.....................................79 
6.0 
SAFETY MONITORING AND ADVERSE EVENT (AE) REPORTING ..........................................81 
6.1 SAFETY MONITORING ..................................................................................................................................81 
6.2 CLINICAL DATA REVIEW .............................................................................................................................81 
6.3 ADVERSE EVENT DEFINITION AND REPORTING ..........................................................................................82 
6.4 EXPEDITED ADVERSE EVENT REPORTING ...................................................................................................82 
6.5 SOCIAL IMPACT REPORTING ........................................................................................................................83 

 
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7.0 
STATISTICAL CONSIDERATIONS .....................................................................................................85 
7.1 REVIEW OF STUDY DESIGN .........................................................................................................................85 
7.2 CONSIDERATIONS IN NON-INFERIORITY TRIALS .........................................................................................85 
7.3 JUSTIFICATION OF THE NON-INFERIORITY MARGIN ....................................................................................86 
7.4 RE-ASSESSING THE NI MARGIN AT THE COMPLETION OF THE TRIAL ..........................................................91 
7.5 ENDPOINTS ..................................................................................................................................................93 
7.6 SAMPLE SIZE AND INTERIM MONITORING...................................................................................................94 
7.7 ACCRUAL AND RETENTION .........................................................................................................................97 
7.8 RANDOM ASSIGNMENT ................................................................................................................................97 
7.9 BLINDING .....................................................................................................................................................98 
7.10 DATA AND SAFETY MONITORING BOARD OVERSIGHT AND STUDY MONITORING COMMITTEE OVERSIGHT
 .....................................................................................................................................................................98 
7.11 STATISTICAL ANALYSIS ..............................................................................................................................98 
8.0 
HUMAN SUBJECTS CONSIDERATIONS .........................................................................................104 
8.1 ETHICAL REVIEW .......................................................................................................................................104 
8.2 INFORMED CONSENT .................................................................................................................................104 
8.3 INCENTIVES ...............................................................................................................................................104 
8.4 CONFIDENTIALITY .....................................................................................................................................104 
8.5 COMMUNICABLE DISEASE REPORTING REQUIREMENTS ...........................................................................105 
8.6 STUDY DISCONTINUATION ........................................................................................................................105 
9.0 
LABORATORY SPECIMENS AND BIOHAZARD CONTAINMENT ...........................................106 
9.1 LOCAL LABORATORY SPECIMENS .............................................................................................................106 
9.2 STORED SPECIMENS ...................................................................................................................................107 
9.3 QUALITY CONTROL AND QUALITY ASSURANCE PROCEDURES ................................................................108 
9.4 SPECIMEN STORAGE AND POSSIBLE FUTURE RESEARCH TESTING ...........................................................109 
9.5 BIOHAZARD CONTAINMENT ......................................................................................................................109 
10.0 
ADMINISTRATIVE PROCEDURES ...................................................................................................110 
10.1 PROTOCOL REGISTRATION ........................................................................................................................110 
10.2 STUDY ACTIVATION ..................................................................................................................................110 
10.3 STUDY COORDINATION .............................................................................................................................110 
10.4 STUDY MONITORING .................................................................................................................................111 
10.5 PROTOCOL COMPLIANCE ...........................................................................................................................111 
10.6 INVESTIGATOR'S RECORDS ........................................................................................................................112 
10.7 USE OF INFORMATION AND PUBLICATIONS ...............................................................................................112 
11.0 
REFERENCES ........................................................................................................................................113 

 
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APPENDICES I - IV ............................................................................................................................................120 
APPENDIX IA: SCHEDULE OF PROCEDURES AND EVALUATIONS – SCREENING; STEP 1 – BLINDED DAILY ORAL 
PILLS ..........................................................................................................................................................121 
APPENDIX IB: SCHEDULE OF PROCEDURES AND EVALUATIONS - STEP 2 – BLINDED INJECTIONS + BLINDED 
DAILY ORAL PILLS ....................................................................................................................................123 
APPENDIX IC: SCHEDULE OF PROCEDURES AND EVALUATIONS - STEP 3 – OPEN LABEL DAILY ORAL TDF/FTC 
POST-LAST INJECTION ...............................................................................................................................125 
APPENDIX ID: SCHEDULE OF PROCEDURES AND EVALUATIONS FOR ANNUAL VISITS .....................................126 
APPENDIX IE: HIV TESTING ALGORITHM AT THE SCREENING VISIT: ...............................................................127 
APPENDIX IF: HIV TESTING ALGORITHM AT THE ENROLLMENT VISIT: ...........................................................128 
APPENDIX IG: HIV TESTING ALGORITHM AT FOLLOW-UP VISIT: .....................................................................129 
APPENDIX II: SCHEDULE FOR ADDITIONAL PROCEDURES FOR ENROLLED PARTICIPANTS WHO HAVE A 
REACTIVE OR POSITIVE HIV TEST RESULT (INCLUDING HIV CONFIRMATORY VISIT) .............................130 
APPENDIX III: TOXICITY MANAGEMENT ...........................................................................................................131 
APPENDIX IV: SAMPLE SCREENING AND ENROLLMENT INFORMED CONSENT FORM .......................................142 
 

 
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PROTOCOL SIGNATURE PAGE 
 
HPTN 083 
A Phase 2b/3 Double Blind Safety and Efficacy Study of Injectable Cabotegravir Compared to 
Daily Oral Tenofovir Disoproxil Fumarate/Emtricitabine (TDF/FTC), for Pre-Exposure 
Prophylaxis in HIV-Uninfected Cisgender Men and Transgender Women who have Sex with Men 
DAIDS Document ID # 20725 
Version 3.0 
October 31, 2019 
 
 
 
 
I will conduct this 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 US 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. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Name of Investigator of Record  
Signature of Investigator of Record 
Date 

 
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HPTN 083 
A Phase 2b/3 Double Blind Safety and Efficacy Study of Injectable Cabotegravir 
Compared to Daily Oral Tenofovir Disoproxil Fumarate/Emtricitabine (TDF/FTC), for 
Pre-Exposure Prophylaxis in HIV-Uninfected Cisgender Men and Transgender Women 
who have Sex with Men 
LIST OF ABBREVIATIONS AND ACRONYMS 
 
ABC/3TC 
abacavir/lamivudine 
AE 
adverse event 
AIDS 
acquired immunodeficiency syndrome 
ART 
antiretroviral therapy 
ARV 
antiretroviral 
AST 
aspartate aminotransferase 
ALT 
alanine aminotransferase 
AUC 
area under the curve 
BCRP 
breast cancer resistance protein 
BGRG 
Black Gay Research Group 
BMD 
bone mineral density 
BMSM 
black men who have sex with men 
BUN 
blood urea nitrogen 
CAB 
cabotegravir, oral and LA formulations 
CAB LA 
long-acting injectable formulation of cabotegravir 
CABG 
coronary artery bypass grafting 
CBC 
complete blood count 
CBO 
community-based organizations 
CDC 
(US) Centers for Disease Control and Prevention 
CFR 
(US) Code of Federal Regulations 
CI 
confidence interval 
CK or CPK 
creatine phosphokinase 
CLIA 
Clinical Laboratory Improvement Amendments 
Cmax 
maximum or “peak” concentration of a drug observed after its 
administration 
CMC 
Clinical Management Committee 
Cmin 
minimum or “trough” concentration of a drug observed after its 
administration and just prior to the administration of a subsequent dose 
CPQA 
Clinical Pharmacology Quality Assurance  
CPK 
creatine phosphokinase 
CRF 
Case Report Form 
CRM 
Clinical Research Manager 
CRPMC 
Clinical Research Products Management Center 
CT 
Chlamydia trachomatis 
DAERS 
DAIDS Adverse Event Reporting System 
DAIDS 
Division of AIDS 
DAIDS-ES 
DAIDS Enterprise System 

 
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HPTN 083 
A Phase 2b/3 Double Blind Safety and Efficacy Study of Injectable Cabotegravir 
Compared to Daily Oral Tenofovir Disoproxil Fumarate/Emtricitabine (TDF/FTC), for 
Pre-Exposure Prophylaxis in HIV-Uninfected Cisgender Men and Transgender Women 
who have Sex with Men 
LIST OF ABBREVIATIONS AND ACRONYMS 
 
DAIDS PRO 
DAIDS Protocol Registration Office 
DAIDS RSC 
DAIDS Regulatory Support Center 
DBS 
dried blood spot 
DSMB 
Data and Safety Monitoring Board 
DXA 
dual-energy X-ray absorptiometry 
EAE 
expedited adverse event 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
ÉCLAIR 
A Phase IIa Study to Evaluate the Safety, Tolerability and 
Acceptability of Long Acting Injections of the HIV Integrase Inhibitor, 
GSK1265744, in HIV Uninfected Men 
EQA 
External Quality Assurance 
FDA 
(US) Food and Drug Administration 
FEM-PrEP 
Phase 3, double-blind, randomized, placebo-controlled effectiveness 
and safety study among 3900 women at high risk of HIV infection at 6 
sites in 4 African countries 
FTC 
Emtricitabine 
FTC-TP 
emtricitabine triphosphate 
GC 
Neisseria gonorrheae 
GT 
Genital tract 
HBcAb 
hepatitis B virus core antibody 
HBsAb 
hepatitis B virus surface antibody 
HBsAg 
hepatitis B surface antigen 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HDL 
high-density lipoprotein 
HDPE 
high density polyethylene 
HIV 
human immunodeficiency virus 
HIV RNA 
HIV test using a ribonucleic acid 
HIV-1 
human immunodeficiency virus type 1 
HPTN 
HIV Prevention Trials Network 
HPTN LC 
(HPTN) Laboratory Center 
HPTN LDMS 
(HPTN) Laboratory Data Management System 
HPTN LOC 
(HPTN) Leadership and Operations Center 
HPTN SDMC 
(HPTN) Statistical and Data Management Center 
HR 
hazard ratio 
HSV 
herpes simplex virus 

 
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HPTN 083 
A Phase 2b/3 Double Blind Safety and Efficacy Study of Injectable Cabotegravir 
Compared to Daily Oral Tenofovir Disoproxil Fumarate/Emtricitabine (TDF/FTC), for 
Pre-Exposure Prophylaxis in HIV-Uninfected Cisgender Men and Transgender Women 
who have Sex with Men 
LIST OF ABBREVIATIONS AND ACRONYMS 
 
IATA 
International Air Transport Association 
ICF 
informed consent form 
ID 
Identification 
IM 
Intramuscular 
IND 
investigational new drug 
IoR 
Investigator of Record 
iPrEX OLE 
iPrEx Open Label Extension 
IQA 
(DAIDS) Immunology Quality Assurance 
IQR 
interquartile range 
IRB 
Institutional Review Board 
ISR 
injection site reaction 
LA 
long-acting (injectable) 
LATTE-2 
A Phase IIb, Dose Ranging Study of Oral GSK1265744 in 
Combination With Nucleoside Reverse Transcriptase Inhibitors for 
Induction of Human Immunodeficiency Virus -1 (HIV-1) Virologic 
Suppression Followed by an Evaluation of Maintenance of Virologic 
Suppression When Oral GSK1265744 is Combined With Oral 
Rilpivirine in HIV-1 Infected, Antiretroviral Therapy Naive Adult 
Subjects 
LDL 
low-density lipoprotein 
LFTs 
liver function tests 
LGBT 
lesbian, gay, bisexual, and transgender 
MSM 
men who have sex with men 
NGO 
non-governmental organization 
NI 
non-inferiority 
NIAID 
(US) National Institute of Allergy and Infectious Diseases 
NNRTI 
non-nucleoside reverse transcriptase inhibitor 
NRTI 
nucleoside reverse transcriptase inhibitor 
OHRP 
Office for Human Research Protections 
Oral CAB 
oral formulation of cabotegravir 
PA-IC90 
protein-adjusted 90% inhibitory concentration 
PAT 
presence at the table 
PEP 
post-exposure prophylaxis 
PI 
package insert 
Pgp 
permeability glycoprotein 
PK 
Pharmacokinetic 
PO 
by mouth/orally 

 
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HPTN 083 
A Phase 2b/3 Double Blind Safety and Efficacy Study of Injectable Cabotegravir 
Compared to Daily Oral Tenofovir Disoproxil Fumarate/Emtricitabine (TDF/FTC), for 
Pre-Exposure Prophylaxis in HIV-Uninfected Cisgender Men and Transgender Women 
who have Sex with Men 
LIST OF ABBREVIATIONS AND ACRONYMS 
 
PrEP 
pre-exposure prophylaxis 
PROUD 
PRe-exposure Option for reducing HIV in the UK: an open-label 
randomisation to immediate or Deferred daily Truvada for HIV 
negative gay men 
PSMILE 
PTCA 
Patient Safety Monitoring and International Laboratory Evaluation 
percutaneous transluminal coronary angioplasty 
PY 
person-years 
QA 
quality assurance 
QC 
quality control 
RE 
regulatory entity 
RNA 
ribonucleic acid 
RPV 
rilpivirine 
RPV LA 
rilpivirine long-acting (injectable) 
SAE 
serious adverse events 
SC 
subcutaneous 
SHIV 
simian human immunodeficiency virus 
SMC 
Study Monitoring Committee 
SOP 
standard operating procedure 
SSP 
Study Specific Procedures Manual 
STI 
sexually transmitted infection 
TBili 
total bilirubin 
TCID 
tissue culture infective dose 
TDF 
tenofovir disoproxil fumarate 
TDF/FTC 
tenofovir/emtricitabine (trade name: Truvada®) 
TFV 
tenofovir 
TFV-DP 
tenofovir diphosphate 
TGW 
transgender women 
TP 
triphosphate 
UKNEQAS 
United Kingdom National External Quality Assessment Service 
ULN 
upper limit of normal 
US 
United States of America 
VCT 
voluntary counselling and testing 
VOICE 
Vaginal and Oral Interventions to Control the Epidemic 
VQA 
(DAIDS) Virology Quality Assurance 
WHO 
World Health Organization 
 

 
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HPTN 083 
A Phase 2b/3 Double Blind Safety and Efficacy Study of Injectable Cabotegravir Compared to 
Daily Oral Tenofovir Disoproxil Fumarate/Emtricitabine (TDF/FTC), for Pre-Exposure 
Prophylaxis in HIV-Uninfected Cisgender Men and Transgender Women who have Sex with Men 
PROTOCOL TEAM ROSTER 
Adeola Adeyeye MD, MPA, CCFP, 
LCDR, U.S. Public Health Service Medical 
Officer, Clinical Prevention Research 
Branch   
Prevention Sciences Program, Division of 
AIDS, NIAID, NIH 
5601 Fishers Lane, Room 8B36, MSC 9831 
Rockville, MD  20852-9831 
Phone: 240-669-5005 
Cell: 240-619-9365 
Email: adeyeyeao@niaid.nih.gov  
 
Cheryl Blanchette, BS 
HPTN Leadership and Operations Center 
Community Programs Associate 
FHI 360 
359 Blackwell Street, Suite 200 
Durham, NC 27701  
Phone: 919-544-7040, ext. 11359 
Fax: 919-544-0207 
Email: ccokley@fhi360.org 
 
Todd Brown, MD 
Associate Professor of Medicine 
Division of Endocrinology and Metabolism  
Johns Hopkins University 1830  
East Monument Street, Suite 333  
Baltimore, MD 21287  
Phone: 410-502-6888  
Fax: 410-955-8172 
Email: tbrown27@jhmi.edu 
Leslie Cottle, BA 
HPTN SDMC Protocol Manager 
SCHARP-FHCRC 
1100 Fairview Avenue N, LE-400 
PO Box 19024 
Seattle, WA 98109 
Phone: 206-667-7405 
Fax: 206-667-4812 
Email:  leslie@scharp.org 
 
Carlos del Rio, MD 
Emory University  
Rollins School of Public Health 
1518 Clifton Rd NE, Room 754 
Atlanta, GA 30322 
Phone: 404-727-1557  
Fax:  404-727-1278  
Email: cdelrio@emory.edu     
 
Deborah Donnell, PhD 
HPTN SDMC  
SCHARP-FHCRC  
1100 Fairview Avenue N, LE-400 
PO Box 19024 
Seattle, WA 98109 
Phone:  206-667-5661  
Fax:  206-667-4812 
Email: deborah@scharp.org 
 
Joseph Eron, MD  
Professor of Medicine 
University of North Carolina at Chapel Hill 
Division of Infectious Diseases 
130 Mason Farm Rd; CB 7215 
Chapel Hill, NC 27599-7215 
Phone: 919-843-2722 
Fax: 919-966-6714 
Email: jeron@med.unc.edu 
 

 
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HPTN 083 
A Phase 2b/3 Double Blind Safety and Efficacy Study of Injectable Cabotegravir Compared to 
Daily Oral Tenofovir Disoproxil Fumarate/Emtricitabine (TDF/FTC), for Pre-Exposure 
Prophylaxis in HIV-Uninfected Cisgender Men and Transgender Women who have Sex with Men 
PROTOCOL TEAM ROSTER 
Susan Eshleman, MD, PhD  
HPTN Laboratory Center Virologist 
Johns Hopkins Univ. School of Medicine  
720 Rutland Avenue 
Ross Bldg., Room 646 
Baltimore, MD 21205 
Phone: 410-614-4734 
Fax: 410-502-9244 
Email: seshlem@jhmi.edu  
 
Sheldon Fields, PhD, RN, FNP-BC, 
AACRN, FAANP, FNAP, FAAN 
Dean and Professor 
School of Health Professions 
New York Institute of Technology 
Northern Boulevard, P.O. Box 8000 
Ryland Building, Room 347, Old Westbury 
Campus 
Old Westbury, NY, 11568-8000 
Phone: 516.686.3939  
Email: Sheldon.Fields@nyit.edu 
 
Kailazarid Gomez-Feliciano, MPM 
Senior Clinical Research Manager 
FHI 360 
PO Box 21059 
Durham, NC 27703 USA 
Phone: 919-544-7040, Ext. 11282 
Email: kgomez@fhi360.org 
 
Beatriz Grinsztejn, MD, PhD 
Protocol Co-Chair 
Instituto de Pesquisa Clinica Evandro 
Chagas-Fiocruz 
Avenida Brasil 4365 
Rio de Janeiro, Brasil 
Phone: 55-21-2270-7064 
Fax: 55-21-25644933 
Mobile: 55-21-981584631 
Email: gbeatriz@ipec.fiocruz.br 
 
Brett Hanscom, PhD 
HPTN SDMC  
SCHARP-FHCRC  
1100 Fairview Avenue N 
PO Box 19024 
Seattle, WA 98109 
Phone: 206.667.4534 
Email: bhanscom@fredhutch.org 
 
Craig W. Hendrix, MD 
Johns Hopkins University 
Blalock 569 
600 N. Wolfe St. 
Baltimore, MD 21287 
Phone: 410-955-9707 
Fax: 410-955-9708 
Email: chendrix@jhmi.edu 
 
 
 

 
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HPTN 083 
A Phase 2b/3 Double Blind Safety and Efficacy Study of Injectable Cabotegravir Compared to 
Daily Oral Tenofovir Disoproxil Fumarate/Emtricitabine (TDF/FTC), for Pre-Exposure 
Prophylaxis in HIV-Uninfected Cisgender Men and Transgender Women who have Sex with Men 
PROTOCOL TEAM ROSTER
Tim Holtz, MD, MPH 
Captain, US Public Health Service 
Deputy Director, Office of AIDS Research, 
DPCPSI, OD 
National Institutes of Health 
5601 Fishers Lane, Room 2F46 
Rockville, MD 20852-1792 
Phone: +1-240-627-3210 
Fax: +1-301-496-2119 
Email: timothy.holtz@nih.gov 
  
Andrea Jennings, BA 
Clinical Research Manager 
HPTN Leadership and Operations Center 
FHI 360 
359 Blackwell Street, Suite 200 
Durham, NC 27701 
Phone: 919-544-7040 x11566 
Email: ajennings@fhi360.org 
 
Raphael J. Landovitz, MD, MSc 
Protocol Chair 
UCLA Center for Clinical AIDS Research & 
Education 
11075 Santa Monica Blvd, Suite 100 
Los Angeles, CA 90025 
Phone: 310 825-3782  
Fax: 310 477-7657  
Email: rlandovitz@mednet.ucla.edu 
 
María del Rosario Leon Rhandomy 
HPTN Community Working Group 
Representative 
Barranco/San Miguel CRS, IMPACTA 
Av Almirante Miguel Grau 1010 Barranco, 
Lima 4, Peru 
Phone: + (51) 993512516 
Email: rleon@impactaperu.org 
 
David Margolis, MD, MPH  
ViiV Healthcare  
5 Moore Drive 
Durham NC, 27709 
Phone: 919-483-7869 
Fax:  919-315-6359 
Email: 
david.a.margolis@viivhealthcare.com 
Marybeth McCauley, MPH  
HPTN Leadership and Operations Center 
Senior Clinical Program Manager 
FHI 360 
1825 Connecticut Avenue, NW 
Washington, DC 20009 
Phone: 202-884-8340 
Fax: 202-884-8400 
Email: mmccauley@fhi360.org 
Nittaya Phanuphak, MD, PhD 
Chief, Prevention Department 
Thai Red Cross AIDS Research Centre 
104 Rajdamri Road, Pathumwan 
Bangkok 10330 Thailand 
Phone:  +662 253 0996 
Fax: +662 253 0998 
Email:  nittaya.p@trcarc.org  
 
 

 
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HPTN 083 
A Phase 2b/3 Double Blind Safety and Efficacy Study of Injectable Cabotegravir Compared to 
Daily Oral Tenofovir Disoproxil Fumarate/Emtricitabine (TDF/FTC), for Pre-Exposure 
Prophylaxis in HIV-Uninfected Cisgender Men and Transgender Women who have Sex with Men 
PROTOCOL TEAM ROSTER 
Christina Psaros, PhD 
Massachusetts General Hospital  
One Bowdoin Square 
Boston, MA 02114 
Phone: 617-726-7458  
Fax: 617-724-8690 
Email: cpsaros@mgh.harvard.edu 
Paul Richardson, MSc  
HPTN Laboratory Center Senior QA/QC 
Coordinator 
Johns Hopkins Univ. Dept. of Pathology 
Pathology Building 306 
600 N. Wolfe St. 
Baltimore, MD 21287 
Phone: 410-502-0435 
Fax: 410-614-0430 
Email: pricha18@jhmi.edu 
 
Alex Rinehart, PhD 
ViiV Healthcare 
5 Moore Drive 
Durham, NC 27709 
Phone:  919-483-2085 (office) 
Phone: 919-599-7551 (mobile) 
Email: alex.r.rinehart@viivhealthcare.com 
 
James Rooney, MD 
Gilead Sciences  
333 Lakeside Drive 
Foster City, CA 94404 
Phone: 650-522-5708  
Fax: 650-522-5854 
Email: jim.rooney@gilead.com 
 
Steve Safren, PhD 
University of Miami and Fenway Health 
5665 Ponce de Leon Boulevard 
P.O. Box 248185 
Miami, FL  33146-2510 
Phone: 305-243-3471 or 305-284-2818  
Email: ssafren@miami.edu 
 
Hyman M. Scott, MD MPH 
Research Scientist 
Bridge HIV/ San Francisco Department of 
Public Health 
25 Van Ness Avenue, Suite 100, San 
Francisco, CA 94102 
Phone: 415-437-7483 
Fax: 415-431-7029 
Email: hyman.scott@sfdph.org 
 
Pich Seekaew 
HPTN Community Working Group 
Representative 
Thai Red Cross AIDS Research Centre 
104 Rajdumri Rd. Pathumwan. Bangkok, 
Thailand 10330 
Phone: (+66) 909182447 
Email: pich@trcarc.org  
 
Katherine Shin, Pharm.D. 
Senior Pharmacist 
Pharmaceutical Affairs Branch, Division of 
AIDS 
5601 Fishers Lane, Room 9D30, MSC 9829 
Rockville, MD 20852-9829 
Overnight Mail: Rockville, MD 20852-9831 
Phone: 240-627-3047 
Fax: 301-402-1506 
Email: kashin@niaid.nih.gov 

 
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HPTN 083 
A Phase 2b/3 Double Blind Safety and Efficacy Study of Injectable Cabotegravir Compared to 
Daily Oral Tenofovir Disoproxil Fumarate/Emtricitabine (TDF/FTC), for Pre-Exposure 
Prophylaxis in HIV-Uninfected Cisgender Men and Transgender Women who have Sex with Men 
 
PROTOCOL TEAM ROSTER
Kimberly Smith, MD, MPH 
ViiV Healthcare 
5 Moore Drive 
Durham, NC 27709 
Phone: 919-315-9825 
Email: 
kimberly.y.smith@viivhealthcare.com 
 
William Spreen, PhD 
ViiV Healthcare 
5 Moore Drive 
Durham, NC 27709 
Phone: 919-483-1393 
Fax: 919-315-5263 
Email: william.r.spreen@viivhealthcare.com 
Jeremy Sugarman, MD, MPH  
HPTN Ethics Working Group 
Representative 
Harvey M. Meyerhoff Professor of Bioethics 
and Medicine 
Johns Hopkins Berman Institute of Bioethics    
1809 Ashland Ave. 
Deering Hall, Room 203 
Baltimore, MD 21205 
Phone:  410-614-5634 
Fax:  410-614-5360 
Email: jsugarman@jhu.edu 
 
Philip Sullivan, MPH, MLS (ASCP)CM 
HPTN Laboratory Center Lab QC/QA 
Coordinator 
600 N. Wolfe Street  
Pathology 311 
Baltimore, MD 21287 
Phone: 410-502-5720 
Email: psulli22@jhmi.edu 
 
 
 

 
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HPTN 083 
TERMINOLOGY FOR CABOTEGRAVIR AND TDF/FTC FORMULATIONS 
Compound Name or 
Abbreviation 
Comments 
Cabotegravir or CAB 
When written as shown, this is the ViiV 
Healthcare compound under study and refers to 
the parent compound, irrespective of formulation, 
usually in the context of pharmacokinetic 
measurement.     
Oral CAB 
When written as shown, this refers to the oral 
tablet formulation of cabotegravir.    
CAB LA 
When written as shown, this refers to the long-
acting injectable formulation of cabotegravir. 
TDF/FTC (tenofovir 
disoproxil 
fumarate/emtricitabine 
When written as shown, this refers to the 
antiretroviral drug tenofovir/emtricitabine (trade 
name: Truvada®), manufactured by Gilead 
Sciences, Inc. 
TFV (tenofovir) 
When written as shown, this is the inactive, de-
esterified form of TDF. This form of the drug is 
measured in plasma and other body fluids.   
TFV-DP (tenofovir 
diphosphate) 
When written as shown, this is the active, 
phosphorylated form of tenofovir that is generated 
in cells. This is the form of the drug that is 
measured in cells (including PBMCs and RBCs). 
It is rapidly dephosphorylated to the inactive form 
outside of cells, and has a very short half-life 
outside of cells in tissue 
FTC-TP (emtricitabine 
triphosphate) 
When written as shown, this is the active form of 
FTC that is generated in cells. This is the form 
measured in cells (including PBMCs and RBCs).   
 

 
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HPTN 083 
A Phase 2b/3 Double Blind Safety and Efficacy Study of Injectable Cabotegravir Compared to 
Daily Oral Tenofovir Disoproxil Fumarate/Emtricitabine (TDF/FTC), for Pre-Exposure 
Prophylaxis in HIV-Uninfected Cisgender Men and Transgender Women who have Sex with Men 
SCHEMA 
Purpose: 
To evaluate the safety and efficacy of the injectable agent, cabotegravir (CAB LA), for 
pre-exposure prophylaxis (PrEP) in HIV-uninfected cisgender men and transgender 
women who have sex with men (MSM and TGW). 
 
Design: 
Multi-site, double blind, two-arm, randomized (1:1), controlled non-inferiority trial of the 
efficacy of CAB LA compared to daily oral tenofovir disoproxyl fumarate 
(TDF)/emtricitabine (FTC) for HIV prevention. 
 
Population: HIV-uninfected MSM and TGW at risk for acquiring HIV infection, ages 18 or older. 
 
Study Size: 
Approximately 5000, 2500 per arm. 
 
Study 
Duration: 
Due to staggered timelines of study activation at the participating sites, the overall study 
duration is approximately 7.5 years.   
 
Individual participants will be followed on blinded study products for three years from 
the date of enrollment during Steps 1 and 2.  After completion of blinded study products, 
participants will then receive 48 weeks of open label TDF/FTC during Step 3 – for a total 
of four years of follow-up for any individual participant. 
 
In Step 1, participants will receive blinded daily oral tablets for 5 weeks.  
 
In Step 2, participants will receive injections (as a single injection at two time points 4 
weeks apart and every 8 weeks thereafter) and daily oral tablets until Week 153, which is 
approximately three years from the date of the Enrollment visit.  
All participants will all be simultaneously unblinded after the last participant concludes 
their participation in Step 2. 
 
In Step 3, participants will receive study-provided open-label daily oral TDF/FTC for  48 
weeks. The timeline for the 48 weeks of open label TDF/FTC for Step 3 begins 8 weeks 
from the last administered injection of Step 2, irrespective of actual date of TDF/FTC 
initiation.   
 
Study 
Sites: 
Study sites are listed in the Study Specific Procedures (SSP) Manual, and include sites in 
the Americas, Asia, and South Africa.    
 
 
 

 
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HPTN 083 
A Phase 2b/3 Double Blind Safety and Efficacy Study of Injectable Cabotegravir Compared to 
Daily Oral Tenofovir Disoproxil Fumarate/Emtricitabine (TDF/FTC), for Pre-Exposure 
Prophylaxis in HIV-Uninfected Cisgender Men and Transgender Women who have Sex with Men 
SCHEMA (continued) 
Study  
Regimen: 
Once randomized to one of two arms, participants will move through the following steps 
(active drugs are shown in bold text): 
Step 1:   
Arm A – Daily oral CAB (30 mg tablets) and oral TDF/FTC placebo for five weeks 
Arm B – Daily oral TDF/FTC (300 mg/200 mg fixed-dose combination tablets) and oral 
CAB placebo for five weeks 
A participant that becomes HIV-infected during Step 1 of the study will permanently 
discontinue study product and will be terminated from the study and referred for HIV-
related care.  
Step 2:  
Arm A – CAB LA (600 mg as a single intramuscular [IM] injection at two time points 4 
weeks apart and every 8 weeks thereafter) and daily oral TDF/FTC placebo to 
Week 153   
Arm B – Daily oral TDF/FTC (300/200 mg fixed-dose combination tablets) and IM 
placebo at two time points 4 weeks apart and every 8 weeks thereafter 
(matching vehicle, identical volume as active injectable product in Arm A) to 
Week 153   
A participant that becomes HIV-infected during Step 2 of the study will permanently 
discontinue study product, be placed on immediate suppressive ART, and will be 
followed at quarterly intervals for 52 weeks after their last injection prior to diagnosis of 
HIV in order to test for safety parameters, as well as CD4 cell count and HIV viral load. 
After 52 weeks, they will be terminated from the study and transitioned to continued 
HIV-related care.   
Step 3:   
Both arms:  Open-label daily oral TDF/FTC will start at Week 153 (last day of Step 2) 
/Day 0 (first day of Step 3) and continue for 48 weeks.   
All participants will be transitioned to locally-available HIV prevention services, 
including services for PrEP, if available, at the end of their participation in the study, or if 
they transition to annual visits in Step 1 or Step 2, or if at the discretion of the primary 
care physician, they transition to Step 3 on study but off study-provided TDF/FTC.   
 

 
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A participant with confirmed HIV infection during Step 3 will be placed on ART and 
followed at least for the duration of Step 3, with possible additional assessments and 
follow-up to be determined by the members of the 083HIV@hptn.org group.     

 
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HPTN 083 
A Phase 2b/3 Double Blind Safety and Efficacy Study of Injectable Cabotegravir Compared to 
Daily Oral Tenofovir Disoproxil Fumarate/Emtricitabine (TDF/FTC), for Pre-Exposure 
Prophylaxis in HIV-Uninfected Cisgender Men and Transgender Women who have Sex with Men 
SCHEMA (continued) 
Primary 
Objectives: 
 
• To compare HIV incidence among participants randomized to oral CAB/CAB LA 
(oral lead in and injections) vs. oral TDF/FTC (Steps 1 and 2) 
• To compare the safety of oral CAB/CAB LA vs. oral TDF/FTC  
Secondary 
Objectives: 
 
• To compare HIV incidence among participants receiving CAB LA injections vs. oral 
TDF/FTC (each step independently and all steps in aggregate) 
• To compare HIV incidence among participants receiving CAB LA injections vs. oral 
TDF/FTC (Steps 1, 2, and 3 combined) 
• To compare HIV incidence among participants randomized to CAB LA injections vs. 
oral TDF/FTC while taking open label TDF/FTC (Step 3 only, descriptive) 
• To compare the change in risk of HIV acquisition between CAB and oral TDF/FTC 
strategies (Arm A and Arm B) as participants progress from Step 2 to Step 3 
• To compare HIV incidence among the subgroups of participants receiving oral 
CAB/CAB LA vs. oral TDF/FTC by region, age, race, ethnicity, baseline risk, and 
gender identity 
• To compare changes in renal function, liver function, and bone mineral density 
(BMD) among participants receiving oral CAB/CAB LA vs. oral TDF/FTC 
• To evaluate and compare rates of HIV drug resistance among participants who 
acquire HIV infection during the study among participants receiving oral CAB/CAB 
LA vs oral TDF/FTC 
• To compare the acceptability of and preferences for CAB LA vs. oral TDF/FTC 
• To compare changes in weight, blood pressure, pulse, fasting glucose, and fasting 
lipids among participants receiving oral CAB/CAB LA vs. oral TDF/FTC 
Tertiary 
Objectives: 
• To examine the association between levels of adherence and HIV incidence 
• To compare and describe the rates, patterns, and correlates of adherence to CAB LA 
vs oral TDF/FTC, in aggregate and by psychosocial/demographic variables  

 
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• To estimate changes in sexual-risk behavior as measured by self-report and rates of 
incident gonorrhea, chlamydia, and syphilis in the study population 
• To compare the resource utilization and programmatic costs of long-acting injectable 
PrEP vs. daily oral PrEP vs. no PrEP for HIV uninfected MSM and TGW in the US, 
Brazil, and South Africa  
• To use mathematical simulation to project the short- and long-term clinical impact, 
cost projections, budgetary impact, and incremental cost-effectiveness of long-acting 
injectable PrEP vs. daily oral PrEP vs. no PrEP for HIV uninfected MSM and TGW 
in the US, Brazil, and South Africa  
Exploratory 
Objectives: 
 
• To perform secondary laboratory assessments that may include evaluation of factors 
related to HIV infection, hepatitis infection, or sexually transmitted infections (STIs); 
antiretroviral (ARV) drug use; pharmacogenomics; characterization of HIV in 
infected participants; and evaluation of laboratory assays related to the study 
objectives  
• To explore possible drug-drug interactions between cross-sex hormone therapy 
(csHT) and cabotegravir and TDF/FTC in a subset of TGW taking commonly 
prescribed cross-sex hormone therapy regimens 

 
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HPTN 083 
A Phase 2b/3 Double Blind Safety and Efficacy Study of Injectable Cabotegravir Compared to 
Daily Oral Tenofovir Disoproxil Fumarate/Emtricitabine (TDF/FTC), for Pre-Exposure 
Prophylaxis in HIV-Uninfected Cisgender Men and Transgender Women who have Sex with Men 
OVERVIEW OF STUDY DESIGN AND RANDOMIZATION SCHEME 
 
 
 
 
 
 
 

 
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1.0 
INTRODUCTION 
1.1 
Background and Rationale 
Cabotegravir LA (CAB LA) is a long-acting injectable integrase inhibitor, also known as GSK 
1265744 LA or 744 LA. This is a Phase 2b/3 study designed to establish the efficacy of CAB LA 
for pre-exposure prophylaxis (PrEP) in HIV-uninfected men who have sex with men (MSM) and 
in transgender women (TGW). Small single-dose and multiple-dose studies and Phase 2a 
safety/tolerability studies have been performed for CAB LA. This PrEP efficacy study is the next 
developmental investigation of CAB LA in healthy, HIV-uninfected MSM and TGW. CAB LA 
is the first antiretroviral (ARV) drug being studied as an intervention for HIV prevention prior to 
regulatory approval of the drug for HIV treatment. A parallel development program for use of 
cabotegravir (oral and injectable) for treatment of HIV-infected individuals is currently in Phase 
2b studies with a salutary safety and efficacy profile to date. 
The study of systemic ARV drug use for both HIV treatment and prevention has provided 
consistent and compelling evidence of efficacy.1-9 A challenge in the use of current oral ARV 
formulations for both indications is the requirement for adherence to daily or near-daily dosing 
strategies.10,11 In healthy HIV-uninfected and HIV –infected individuals, sustaining adherence 
over time becomes increasingly challenging.12 In the treatment setting, sub-optimal adherence to 
an ARV treatment (ART) regimen can lead not only to ART failure, but also to the development 
of HIV drug resistance.13-16 HIV transmission in the setting of ARV PrEP is relatively rare; the 
majority of transmission events have occurred in the context of absent or sub-therapeutic drug 
levels, indicating poor adherence. Resistance to PrEP agents has been observed in individuals 
who initiated PrEP with undiagnosed primary HIV infection.1,4,17 Resistance appears to emerge 
less frequently in individuals who acquire HIV infection after initiating a PrEP regimen;1,4,9,17-21 
however, recent studies using more sensitive drug resistance tests have revealed the presence of 
minority variants with resistance mutations in some individuals.17,18 In these cases, resistance 
may arise in individuals with suboptimal PrEP adherence who become infected, but continue to 
take their PrEP regimen before their HIV infection is diagnosed.18 
Despite tremendous therapeutic advances in HIV treatment and prevention, the HIV epidemic 
persists worldwide.22 The United States (US) Food and Drug Administration (FDA) approved 
oral tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) for PrEP and the US Centers for 
Disease Control and Prevention (CDC) and the World Health Organization (WHO) have offered 
guidance for its use.23,24 The safety and efficacy of TDF/FTC in combination with other ARV 
drugs for ART,25-29 and results from TDF/FTC PrEP studies in a rhesus macaque simian-HIV 
(SHIV) exposure model,30,31 supported the development and evaluation of TDF/FTC for PrEP. 
Five randomized clinical trials (RCTs) have evaluated oral TDF or TDF/FTC as PrEP.1,4,8,20,21 
These five trials differ in several ways, but suboptimal adherence,32,33 with a daily pill regimen 
was noted in all five studies. In fact, the FEM-PrEP and VOICE trials, both conducted in 
sexually-active, young women in sub-Saharan Africa and requiring adherence to a daily regimen, 
were either stopped for futility or showed no efficacy on completion. On further investigation, 
very poor adherence by trial participants to study product was confirmed in both studies. 
Analyses of the available RCT data suggest a strong correlation between adherence to study 
product and observed efficacy. The iPrEX open label extension (iPrEX OLE) suggests that 
individuals with sustained adherence averaging 4-7 doses of TDF/FTC PrEP weekly conferred 

 
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100% protection;34 however the impact of timing of HIV exposures relative to missed doses on 
protective efficacy remains to be clarified. Recent open-label data from the United Kingdom 
PROUD study suggests that in particularly high-incidence populations of MSM, daily oral 
TDF/FTC can be as effective as 86% compared to a strategy of “standard of care” risk reduction 
and deferred TDF/FTC.35 A strategy of “on demand” TDF/FTC, using a 2-dose pre-coital dose 
and then daily dosing until the completion of sexual activity, followed by two additional daily 
doses, also demonstrated 86% reduction in HIV acquisition compared to a placebo intervention, 
but the mean monthly use was 16 tablets (IQR 12-24) with a median 10 sexual partners per 
month  roughly equating to 4 or more doses per week. Notably, only 43% of the study 
participants were able to adhere to the pre- and post-coital dosing as prescribed.36 While TDF-
based PrEP provides an exciting new prevention tool, adherence to daily oral dosing has proven 
a challenging obstacle to consistent, preventive success. There are several additional reasons why 
alternative PrEP agents are needed, including: 1) TDF/FTC causes side effects that may impede 
adherence;4 2) TDF/FTC has been associated with increased creatinine levels and decreased bone 
density;37-39 and 3) TDF/FTC is a key component of many first-line ART regimens;40 resistance 
that might emerge with its use as a PrEP agent is highly undesirable. 
PrEP may only reach its full potential with agents that do not depend on daily or near-daily 
pill-taking. The development of alternative agents for PrEP, and/or more adherence-friendly 
schedules for currently available agents, could increase prevention choices and increase 
acceptability. Long-acting injectable agents have the potential to prevent HIV acquisition 
without relying on adherence to a daily oral regimen.41 Injectable agents have been used by 
women for contraception, although adherence even to quarterly injections is imperfect. In the 
US, insurance claims showed that only 41.4% of new users had a second injection at three 
months.42 Data from Brazil show that 64% of injectable contraception users discontinued use in 
the first 12 months, 27% related to side effects.43 Increased choice in type and method of 
delivery of contraceptive methods has increased acceptability.44 It is our hypothesis that 
expanded choices for HIV prevention will similarly increase utilization, satisfaction, and 
effectiveness. 
1.2 
Overview of Oral Cabotegravir (Oral CAB) and long-acting injectable (CAB LA)  
Cabotegravir (GSK 1265744) is an investigational HIV integrase strand transfer inhibitor 
(INSTI) that has attributes favorable for both HIV treatment and prevention indications. 
Currently in Phase 2 clinical trials, it was initially selected for development based on its potential 
for a high genetic barrier to resistance and a PK profile that allows low-dose, once-daily oral 
dosing or monthly to quarterly parenteral dosing using a nanosuspension formulation. An oral 
tablet version of cabotegravir (oral CAB) is also under development as lead-in therapy to 
establish acute safety and tolerability in individual subjects prior to switching to the long-acting 
formulation. CAB LA has a plasma half-life of 21 to 50 days in healthy HIV-uninfected adults.  
1.2.1 Non-human Primate Studies relevant to rectal exposures 
CAB LA has demonstrated activity in preventing SHIV infection in non-human primate 
models45. 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. 

 
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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 LA 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 cabotegravir protein-adjusted 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 1 to 3 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 cabotegravir were 
approximately 20% of plasma levels.45  Additionally, a penile SHIV infection model in rhesus 
macaques demonstrated 93% protective efficacy of CAB LA against penile exposures to SHIV.46   
1.2.2 Metabolism 
Cabotegravir 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 via the 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).  
1.2.3 Preclinical Studies 
The cabotegravir toxicology package supports the careful conduct of clinical studies with 
cabotegravir up to the no observed adverse effect level (NOAEL) exposure in the 39-week 
monkey toxicity study (Week 39 gender mean area under the curve (AUC0-24) and Cmax of 547 
g·h/mL and 34.6 g: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·h/mL). 
In a rat pre- and postnatal development (PPN) study, female pregnant rats were administered 0.5, 
5 or 1000 mg/kg of oral CAB daily from gestation day 6 to postnatal day 21 (without dosing to 
the offspring directly). In the high-dose (1000 mg/kg/day) group, there was an increased number 
of rat offspring dead at birth (2.9% stillborn vs. 0.7% in control) and offspring that died during 
the early post-natal period (10.2% dead or missing on post-natal day 2-4 vs. 0.7% in control). 
This resulted in a decrease in rat offspring viability during post-natal day 1-4 (87.4% vs. 98.9%) 
and a corresponding decrease in live litter size on post-natal day 4 (10 offspring/litter vs. 11.5 in 
control on post-natal day 4). There were no treatment-related findings in the 0.5 or 5 mg/kg/day 
groups. Clinical dosing in HPTN 077, a safety, tolerability, and pharmacokinetics of CAB LA in 
HIV uninfected, at 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. 

 
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1.3 
Dose Rationale 
1.3.1 Oral CAB  
CAB is readily absorbed following oral administration in healthy and HIV infected participants 
with a median Tmax of approximately 2 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.47,48 In LAI116482 
(LATTE), the Phase 2b study in HIV-infected, ART-naïve adult participants,49 suppression of 
HIV replication was accomplished with oral CAB at doses of 10 mg to 60 mg once daily in 
combination with 2 nucleoside reverse transcriptase inhibitors (NRTIs), and was maintained 
below 50c/mL at similar rates across oral CAB 10 mg to 60mg doses through >72 weeks when 
combined with oral rilpivirine (RPV). The geometric mean individual average plasma C 
following oral CAB 10 mg and 30mg once daily were 1.35 g/mL, 8-fold above PA-IC90, and 
4.2g/mL, 25-fold above PA-IC90, respectively.   
CAB 30mg once daily has been used as the oral lead-in in both ECLAIR and LATTE-2, where it 
achieved a similar pre-dose CAB concentration at baseline as observed in LATTE. The 
geometric mean (CVb%) Cmax following CAB 30mg once daily is 7.5g/mL (28%), which 
provides adequate safety coverage for the predicted median (90%PI) peak concentrations 
following CAB LA of 4.0g/mL (1.8, 8.9g/mL). Therefore, CAB 30mg once daily has been 
selected for the oral lead-in regimen for this study. 
Relevant pharmacokinetic parameters following oral administration are listed in Table 1. 
1.3.2 CAB LA  
Following a single IM or subcutaneous (SC) injection of CAB LA, plasma drug concentrations 
increased rapidly over the first week, followed by a general trend to plateau for the remainder of 
the 12-week follow-up period. Data from the ÉCLAIR study (which administered three serial 
injections of 800 mg CAB LA IM every 12 weeks [as 2 x 400 mg IM at each injection]) have 
shown that in some individuals (14 out of 83, 17%), CAB was detectable in plasma at 52 weeks 
post last injection.50  The CAB concentrations in these study participants ranged from 29-105 
ng/ml; these values fall between the lower limit of quantitation (LOQ) of 25 ng/ml and 1 x PA-
IC90 (166 ng/ml).  
Additional data through 76 weeks post last injection (an additional 24 weeks longer than the 
current follow-up of 52-weeks post last injection) in HPTN 077 (which administers CAB LA 800 
mg IM every 12 weeks in Cohort 1 and CAB LA 600 mg IM every 8 weeks after two initial 
injections four weeks apart in Cohort 2) suggests that the median time from the last injection to 
CAB levels falling below the limits of quantitation (25 ng/mL) were  43.7 (range 20-4-152.5) 
weeks for males and 67.3 (range 17.7-225.5) weeks for females. 

 
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The CAB LA PrEP dose has been selected to deliver adequate drug concentrations to prevent 
sexual transmission of HIV. The proposed dosing schedule for evaluation in humans is based on 
maintaining CAB LA plasma concentrations well above the PA-IC90 value of 0.166 g/mL, a 
concentration range shown to have significant antiviral activity.  
A small cohort of healthy participants receiving two quarterly doses (Q12W) of CAB LA 800 
mg IM achieved a geometric mean (CVb%) Ctau (C) of 1.11 g/mL (139%), approximately 6.7-
fold above the PA-IC90 and between the 5 mg and 10 mg oral doses (Table 1). These data, as 
well other PK data following CAB LA following single or repeat doses ranging from 100mg to 
800mg IM, were included in the initial population PK model. Based on the initial population PK 
model, CAB LA 800 mg IM given every 12 weeks (Q12W) was predicted to achieve a mean 
concentration above the 1.35 g/mL target based on 10 mg daily oral dosing with the lower 
bound of the 90% confidence interval (CI) at ~4-fold PA-IC90. The overall range of predicted 
CAB C values following CAB LA 800 mg IM was similar to that following once daily dosing of 
oral CAB 10 mg.  
The Phase 2a 201120 (ÉCLAIR) study was undertaken to evaluate PK and safety following 
Q12W CAB LA 800mg IM doses in healthy male participants. Evaluation of PK data from 
ÉCLAIR showed that 30 to 37% of CAB LA C values were 4-fold PA-IC90 following each of 
the three quarterly injections while 15 to 31% were below the PA-IC90. Graphical evaluation of 
the CAB plasma concentration-time profiles suggests that absorption was more rapid among 
participants in the ÉCLAIR study than that observed in prior studies, resulting in higher peak and 
lower trough concentrations (Figure 1). Of note, the CAB LA nanosuspension formulation has 
remained essentially unchanged throughout the clinical development program, indicating that 
other factors are contributing to the observed PK differences. Given this information, a regimen 
of CAB LA 800mg Q12W may not maintain sufficient exposures in all participants, particularly 
in males. The ongoing Phase 2a study HPTN 077, which is similar to ÉCLAIR, studying CAB 
LA 800mg IM Q12W in healthy male and female participants, was amended to enroll a second 
cohort with dosing of CAB LA 600 mg IM at two time points 4 weeks apart and every 8 weeks 
(Q8W) thereafter for 5 injection visits. A similar regimen (CAB LA 800mg IM initial dose 
followed by 600mg IM at two time points 4 weeks apart and Q8W thereafter) has been evaluated 
in HIV infected participants (n=115; 107 males and 8 females) in combination with rilpivirine 
(RPV) LA in study 200056 (LATTE-2). This regimen achieved a mean CAB C of 1.53g/mL 
(median 1.45 g/mL) at Week 32 (Figure 2), above the geometric mean C value for the 10mg 
oral dose in LATTE. At Week 32, the proportion of participants maintaining suppression of HIV 
in the Q8W arm was 95% as compared to 94% in the Q4W arm (CAB LA 800mg IM initial dose 
followed by 400mg IM every 4 weeks from Week 4, n=115). 
The CAB population PK model has been updated with PK data from ÉCLAIR (an additional 94 
males) and LATTE-2 (an additional 230 participants; 216 males and 14 females), significantly 
increasing the data in the population PK dataset. The absorption rate constant following CAB LA 
was increased approximately 2-fold (4.54 x 10-4 hr-1 to 9.19 x 10-4 hr-1; i.e., more rapid 
absorption) and resulted in higher peak to trough ratios than previously observed.   
Simulations based on the updated population PK model have been conducted to evaluate several 
potential dosing regimens. The proposed regimen for this study is CAB LA 600mg IM as a 
single injection at two time intervals 4 weeks apart and every 8 weeks thereafter (Figure 3). This 

 
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dosing regimen is predicted to yield a median steady-state C in males of approximately 1.35 
g/mL, which is approximately 8-fold above PA-IC90 (Figure 3), with C above the PA-IC90 for 
95% of participants, and 4-fold above PA-IC90 for 80% of participants (Figure 4). A one-week 
delay in dosing of 600mg IM at steady state resulted in a drop in the median C to 1.08g/mL, 
and the 5th percentile to 0.10g/mL, with 92% of C values remaining above the PA-IC90 
(Figure 5).   
 
Relevant PK parameters following CAB LA in healthy and HIV infected subjects and following 
simulations based on the initial and updated population PK models are listed in Table 1.  
Additionally, pharmacokinetic analyses from HPTN 077, evaluating the 600mg IM dose of CAB 
LA at 8-week intervals after an initial 4-week interval between the first two injections, also 
support the choice of that dose for the Phase 3 studies of CAB LA for HIV prevention.51     

 
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Table 1:  Summary of Cabotegravir Pharmacokinetic Parameters Following Oral and LA (IM) 
Administration and Pharmacokinetic Simulations in Healthy and HIV-Infected Participants 
 
Route 
Study 
Population 
N 
Cabotegravir 
Regimen 
Cabotegravir PK Parameter  
C or C0 
(g/mL) 
Cmax 
(g/mL) 
AUC (0-) 
(g•h/mL) 
Geomean IQ 
C0 or C/PA- 
IC-90b 
Oral Data 
Ph2a - ITZ112929 
HIV infected 
N=7 
5 mg oral once 
daily x10 d 
monotherapy 
0.57 
[33%] 
1.02 
[25%] 
17.7 
[31%] 
3.4 
Ph2b - LAI116482 
(LATTE) 
HIV infected 
N=14 
10 mg oral once 
daily with 
2NRTIs 
1.35 
[45%] 
(n=57) 
2.77 
[33%] 
45.7 
[32%] 
8.1 
Ph2b - LAI116482 
 (LATTE) 
HIV infected 
N=12 
30 mg oral once 
daily with 2 
NRTIs 
4.20 
[40%] 
(n=53) 
7.49 
[28%] 
134 
[32%] 
25 
LA Data 
Ph1 - LAI115428 
HVs  
N=9 
800 mg IM every 
12weeks x 2 
(2nd dose 
interval) 
1.11 
[139%] 
3.35 
[56%] 
4417 
[53%] 
6.7 
Ph2a - 201120 
(ECLAIR) 
HVsc 
800 mg IM every 
12 weeks x 3 
(third dose) 
(n=85) 
0.387 
[150%] 
(n=66) 
4.91 
[67%] 
4021 
[36%] 
2.3 
 
Ph2b – 200056 Q4W 
(LATTE-2a) 
HIV infected 
(N=115) 
800mg IM Day 1, 
400mg IM W4, 
then Q4W 
following 30 mg 
PO QD with 2 
NRTIs  lead-in 
2.30 
(0.85 – 5.0) 
(W32, 
n=85) 
3.40 
(1.64- 
9.05) 
(W25, 
n=86) 
NDc 
13.9 
Ph2b – 200056 Q8W 
(LATTE-2a) 
HIV infected(n=115) 
800mg IM LD, 
600mg IM W4, 
W8, then Q8W 
following 30 mg 
PO QD with 2 
NRTIs  lead-in 
1.45 
(0.21 – 3. 
9) 
(W32, 
n=84) 
3.36 
(0.75- 
12.4) 
(W25, 
n=87) 
NDd 
8.7 
Modeling and Simultation 
PopPK simulation 
 (Initial PopPK 
model) (N=1000) 
800 mg IM every 
12 weeks x 5 
(last dose) 
1.57 
[56%] 
NDd 
NDd 
9.5 
PopPK simulationa 
(Current PopPK 
model) (N=10000) 
600 mg IM Day1, 
600 mg IM W4, 
then Q8W 
1.3 
(0.18, 2.84) 
4.0 
(1.8, 8.9) 
NDd 
8.0 
a. Data presented as geometric mean, [CVb%], LATTE-2 data presented as median (range), Current 
Population PK model predictions median (90% prediction interval (PI)) 
b. PA-IC90=0.166 g/mL  
c. Healthy volunteers 
d. Not Determined 

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

 
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Figure 2:Mean (SD) Plasma CAB Concentration-Time Profile following CAB LA Q8W 
Regimen (800mg IM Loading Dose, 600mg IM W4, W8, then Q8W) in 200056 (LATTE-2)  
 
Time (Weeks) 
0 1
4
8
12
16
20
2425
28
32
Plasma CAB ( g/mL)
0.1
1
10
Mean (SD)
Min, Max values
1x PA-IC90 (1.66 g/mL)
4x PA-IC90 (0.664 g/mL)
Geometric Mean C 10mg PO (LATTE, 1.35 g/mL)

 
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Figure 3: Simulated Median (90% PI) Plasma CAB Concentration-Time Profile for the 
Proposed Regimen (600mg IM Day 1, W4 and Q8W) in Males based on Updated 
Population PK Model (linear scale) 
 

 
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Figure 4: Simulated Plasma CAB Concentration-Time Profile for the Proposed Regimen 
(600mg IM Day 1, W4 and Q8W) in Males based on Updated Population PK Model 
(semilog scale) 
 
 
 

 
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Figure 5: Simulated Plasma CAB Concentration-Time Profile for the Proposed Regimen 
(600mg IM Day 1, W4 and Q8W) with a One-Week Delay in Dosing at Steady State (W44) 
in Males based on Updated Population PK Model (semilog scale) 
 
 

 
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1.4 
Clinical Experience to Date: Oral CAB and CAB LA 
Through 1 July 2015, approximately 1056 adult participants have been exposed to at least one 
dose of CAB (oral and/or long acting) across 18 completed or ongoing Phase 1 and Phase 2 
clinical trials.   
Oral CAB has been studied at doses between 5 mg - 150 mg in HIV-uninfected and HIV-infected 
adults. The oral formulation of GSK 1265744 has been generally well-tolerated as single or 
repeated doses in clinical studies of HIV-uninfected adults. Among the HIV-uninfected and 
HIV-infected participants who received oral formulations ranging from 5 mg-150 mg in Phase 1 
and 2a studies, eleven participants receiving oral CAB were withdrawn due to potentially drug-
related adverse events (AEs), including dizziness, leucopenia, and aspartate aminotransferase 
and alanine aminotransferase [AST/ALT]/gamma-glutamyltransferase increases, CPK increases 
and fatigue. No drug-related Grade 3 or Grade 4 clinical AEs or serious adverse events (SAEs) 
have been reported to date in Phase 1 and 2a studies.52 One death from anoxic brain injury as a 
result of status epilepticus was reported in the HIV-infected Phase 2b treatment study; the event 
was in the clinical context of recreational drug use, but contribution from oral CAB could not be 
ruled out. 
One hundred thirty-six (136) 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. Five non-drug-related SAEs have been reported: foot 
osteomyelitis, uterine fibroids, appendicitis, elective hysterectomy, and seizure. An additional 94 
participants have received CAB LA as 800 mg IM injections every 12 weeks in the ongoing 
201120 (ÉCLAIR) study. One participant was withdrawn from CAB LA therapy due to a pre-
existing prostate cancer diagnosis, a non-drug-related adverse event. 
Injection site reactions (ISR) occurred in the majority of participants following IM (76% 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).52 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.52  
A Phase 2a safety and acceptability study (ÉCLAIR), designed similarly to HPTN 077, is 
currently in the follow-up phase of the study at 10 US-based sites. In this study, 205 individuals 
were screened in order to enroll and randomize 127 HIV-uninfected low-risk men. Participants 
received daily oral CAB 30 mg or daily oral placebo in a randomized 5:1 ratio during the 4-week 
oral lead-in phase. One participant randomized to active study product (oral CAB and CAB LA) 
withdrew prior to the oral lead-in due to being incarcerated. During the oral lead-in, eleven 
participants withdrew prior to their first injection, all of whom were randomized to CAB LA, 
seven for adverse events 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) randomized to CAB LA completed all three of their injections. The participant on the 
placebo arm that did not complete all three injections reached a protocol-defined stopping 
criteria, subject acquired HIV, after his second injection. Four participants on the CAB LA arm 
withdrew after their second injection, citing injection tolerability as a primary reason. Three 
other participants discontinued study participation after receiving injections, for non-AE and 
non-injection-related reasons. 

 
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Fifteen participants experienced a Grade 1 or higher abnormality of 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 744LA 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.  
Two Phase 2b clinical trials are in progress (GSK protocol LAI116482 [LATTE] and 200056 
[LATTE-2]). In the LAI116482 study 181 participants were randomized to receive oral CAB 
(10, 30, or 60 mg once-daily, blinded doses) in combination with either TDF/FTC or abacavir-
lamivudine.48 (ABC/3TC). An additional 62 participants were randomized to a control arm of 
open-label efavirenz (EFV) 600 mg once daily in combination with one of the two NRTIs. A 
week 24 interim analysis demonstrated good initial efficacy and safety of CAB in combination 
with NRTIs. The overall response rate across the three dosing arms of oral CAB were 87% <50 
c/mL (FDA snapshot analysis) with minimal differences between oral CAB doses; the control 
arm response rate was 74% <50 c/mL. In the “maintenance” phase, participants randomized to 
any of the CAB doses who had viral loads < 50c/mL prior to week 24 were transitioned to a 
regimen maintaining their 744 dosing but substituting oral rilpivirine 25 mg daily for the 
nucleosides. Efavirenz-treated participants were kept on their “induction” regimen of dual 
nucleosides with efavirenz. 96-week data (representing 72 weeks of maintenance dosing)) 
showed virologic suppression (<50 c/mL) rates via snapshot analysis to be 79%, 85% and 93% 
for oral CAB 10mg, 30mg, and 60mg daily, and 83% for the efavirenz control participants. One 
participant randomized to oral CAB 10mg who successfully transitioned to rilpivirine plus oral 
CAB 10 mg daily experienced virologic failure at week 48 in the context of subtherapeutic 
(<50% expected) CAB and rilpirivine plasma levels (partially confounded by an extreme calorie-
restricted diet during weeks 40-48) and developed treatment-emergent high-level integrase 
(Q148R) and NNRTI (E138Q) resistance.49  
Safety results through week 144 support continuation of all three oral CAB dosing arms. There 
have been no deaths, oral CAB-related SAEs or clinically significant AE trends identified to date 
in LAI116482. The most common clinical drug related AEs to date have been headache (15%), 
nausea (17%) and diarrhea (10%) with few oral CAB AEs leading to withdrawal from the study 
(744 - 4% vs EFV - 15%). Two HIV-infected participants receiving oral CAB 60 mg + 
ABC/3TC with pre-existing steatohepatitis developed an ALT >10x upper limit of normal 
(ULN) 4 weeks and 8 weeks after study initiation. Both participants remained asymptomatic with 
normal bilirubin levels and hepatic function, and ALT levels normalized after drug 
discontinuation. No other participants have required dose adjustment or discontinuation due to a 
change in transaminases through week 96. One participant receiving oral CAB and rilpivirine 25 
mg developed ALT values >10x ULN at Week 96 likely due to acute Hepatitis C infection. 
Plasma exposures after administration of CAB LA are expected to remain between the oral CAB 
10 mg and 30 mg exposures. At this stage of development, a lead-in of oral CAB is being 
employed to determine safety and tolerability in individual participants, prior to the transition to 
CAB LA. The accumulated efficacy and safety data with oral CAB and CABLA in HIV-infected 
and HIV-uninfected participants supports continued clinical development for HIV treatment and 
PrEP. 

 
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A second Phase 2b study in HIV-infected, antiretroviral naïve adults (LATTE-2) is ongoing, 
with 310 participants enrolled to receive oral CAB 30mg + ABC/3TC for 20 weeks followed by 
a long acting regimen containing CAB LA + TMC278LA or continuation of oral medications. 
Data from this study is limited and preliminary. One participant with Hepatitis C infection and 
underlying stage 3/4liver fibrosis received oral CAB 30mg + ABC/3TC and developed possible 
drug induced liver injury and a second subject on oral CAB 30 mg + ABC/3TC, with 
steatohepatitis, developed possible drug induced liver injury approximately 6 months after 
initiating oral CAB. Two deaths have occurred on study, one due to a motor vehicle accident 
(unrelated to study products), and as noted above, one due to anoxic brain injury from status 
epilepticus in the setting of recreational drug use; contribution from oral CAB could not be ruled 
out. 
Cumulative exposures of CAB, through October 2018, are shown in Table 2.   
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 
 
 

 
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1.4.1 Evidence for Clinically Significant Anti-viral Activity in HIV-infected Individuals 
As described above, two Phase 2b clinical trials are ongoing (GSK protocol LAI116482 
[LATTE] and 200056 [LATTE-2]). In the LATTE study, 181 participants were randomized to 
receive oral CAB (10, 30, or 60 mg once-daily, blinded doses) in combination with either 
TDF/FTC or abacavir-lamivudine (ABC/3TC).49 An additional 62 participants were randomized 
to a control arm of open-label efavirenz (EFV) 600 mg once daily in combination with one of the 
two NRTIs. A week 24 interim analysis demonstrated good initial efficacy and safety of oral 
CAB in combination with NRTIs. The overall response rate across the three dosing arms of oral 
CAB were 87% <50 c/mL (FDA snapshot analysis) with minimal differences between oral CAB 
doses; the control arm response rate was 74% <50 c/mL. In the “maintenance” phase, 
participants randomized to any of the oral CAB doses who had viral loads <50 c/mL prior to 
week 24 were transitioned to a regimen maintaining their oral CAB dosing but substituting oral 
rilpivirine (RPV) 25 mg daily for the NRTI. EFV-treated participants were kept on their 
“induction” regimen of dual NRTIs with EFV. 96-week data (representing 72 weeks of 
maintenance dosing) showed virologic suppression (<50 c/mL) rates via snapshot analysis to be 
79%, 85% and 93% for oral CAB administered at 10 mg, 30 mg, and 60 mg daily, and 83% for 
the EFV control participants. One participant randomized to oral CAB 10 mg who successfully 
transitioned to RPV plus oral CAB 10 mg daily experienced virologic failure at week 48 in the 
context of sub therapeutic (<50% expected) CAB and RPV plasma levels (partially confounded 
by an extreme calorie-restricted diet during weeks 40-48), and developed treatment-emergent 
high level integrase (Q148R) and non-nucleoside reverse transcriptase inhibitor (NNRTI) 
resistance with the E138Q mutation.49 Two additional participants experienced virologic failure 
on CAB-containing therapy with evidence of NNRTI-resistance only (K101K/E and E183E/K at 
weeks 48 and 72, respectively).53  Two phase 3 trials of CAB LA + RPV LA administered at 4-
week intervals for maintenance of virologic suppression in HIV-infected individuals have been 
presented (ATLAS, FLAIR), wherein CAB LA + RPV LA was found to be non-inferior to oral 
ART in both naïve treatment settings (after ABC/3TC/DTG induction to suppression) and as 
non-failure switch from stably suppressive ART; an additional phase 3b trial of CAB LA + RPV 
LA administered at 8-week intervals for maintenance of virologic suppression in HIV infected 
individuals is ongoing (ATLAS-2M). 
1.4.2 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. Median rectal tissue concentrations were ≤8% of plasma 
concentrations (range 0-20%).54 Further tissue studies using single and multiple doses of the 800 
mg IM dose are ongoing. 
1.5 
Hepatic and Central Nervous System Adverse Events 
As part of the early phase development of cabotegravir (Phase 2a HPTN 077, Phase 2b LATTE 
and LATTE-2), some participants developed transaminase elevations, which were clinically 
asymptomatic and resolved rapidly with cessation of study product.   
In a single-dose study, a healthy male volunteer with a history of prior seizure activity (one 
episode 14 years prior), on no anti-epileptic medication, experienced an unwitnessed seizure 

 
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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 an MRI was unrevealing for pathology. An 
EEG was consistent with benign juvenile epilepsy; the participant recovered without additional 
events.   
A second participant in the ongoing Phase 2b LATTE-2 trial of HIV-infected individuals 
received oral ABC/3TC with CAB 30mg 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 ICU, 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 third 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 30mg (or placebo) was administered for 4 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 did not receive additional IP dosing. 
1.6 
Background of TDF/FTC for Pre-exposure Prophylaxis  
In 2010, results became available from the first efficacy trial of an ARV-based PrEP, known as 
“iPrEX”.4  Close to 2,500 HIV-uninfected MSM and transgendered women who have sex with 
men in South Africa, South America, Thailand, and the US were randomized to daily oral 
TDF/FTC or placebo. Overall 44% fewer incident HIV infections occurred in the TDF/FTC 
group (36 incident infections) compared to the placebo group (64 incident infections). A key 
finding of the study was that drug detection in blood (intracellular and plasma levels) was highly 
correlated with protection among those who self-reported TDF/FTC use on at least 90% of days, 
incident HIV infection was 73% lower when compared with the placebo arm. AEs were similar 
between the two groups, with Grade 3 and 4 events occurring among 12% of participants in each 
arm. Some Grade 2 and higher AEs were reported significantly more frequently in the TDF/FTC 
arm than the placebo arm: moderate nausea (22 vs. 10 events) and unintentional weight loss (34 
vs. 19 events). Serum creatinine elevations occurred more frequently in the TDF/FTC arm than 
placebo arm (25 vs. 14 events). All elevations in the serum creatinine level resolved after 
discontinuation of study drug. There were 10 participants who were HIV infected at enrollment, 
of whom three had FTC-resistant infections. There were no TDF-resistant infections. Of the 
participants who became infected during follow-up, no FTC or TDF resistance was detected. Of 
interest, participants in the study reported increased condom use and decreased number of sexual 
partners. The Partners PrEP Study enrolled 4,758 HIV-serodiscordant African heterosexual 
couples and compared TDF once daily and TDF/FTC once daily regimens to placebo. The TDF 

 
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and TDF/FTC PrEP demonstrated definitive reduced risk of HIV acquisition, by 67% (P<0.001) 
and 75% (P<0.001) respectively, in these men and women.1 The CDC TDF-2 trial showed that 
daily TDF/FTC was safe and effective for prevention of HIV infection among African 
heterosexual men and women compared to placebo.8 In a modified intent-to-treat analysis that 
excluded three participants who were HIV-infected at enrollment, the overall protective efficacy 
was 62.2% (P=0.03); an “as-treated” analysis demonstrated a protective efficacy of 77.9% 
(P=0.01).9 In all of these studies, PrEP regimens were well-tolerated. 
After consideration of these results (primarily iPrEX and Partners PrEP), the US FDA, in July 
2012, approved Truvada® (TDF/FTC fixed dose combination) “to be taken once daily and used 
in combination with safer sex practices to reduce the risk of sexually acquired HIV-1 infection in 
adults who do not have HIV but are at high risk of becoming infected.”55   
Modeling data based the iPrEX dataset estimate that the protective efficacy for those who took 
the TDF/FTC 7 days per week (as prescribed) had 99% reduction in the risk of HIV acquisition; 
those who took 4 doses per week had 96% reduction, and those who took 2 doses per week had 
76% protection;56 further, in the iPrEX Open Label Extension (OLE) study, no seroconversions 
were observed among MSM and TGW who had intraerythrocytic TFV-DP levels consistent with 
4-7 doses per week.34 
Despite these estimates of high-levels of efficacy when taken as prescribed, it remains clear that 
many populations have challenges achieving the level of adherence to daily oral tablets required 
for these high levels of protection. Studies in African women in particular (FEM-PrEP, VOICE) 
have failed to demonstrate protective efficacy for oral TDF-based PrEP due to a combination of 
low-levels of adherence and a need for greater adherence fidelity to achieve HIV protection from 
vaginal exposures compared to rectal exposures.57,58 
In addition to adherence challenges inherent to daily oral tablet regimens, additional concerns 
related to the safety of TDF-based PrEP have propelled the evaluation of additional agents (and 
delivery systems) for potential use in prevention settings: TDF/FTC is used commonly in ARV 
regimens for treatment of HIV-infected individuals, and viral strains that are resistant to TDF 
and/or FTC exist and are transmitted in the community. Across randomized Phase 3 PrEP 
studies, the rate of HIV seroconversion with resistant virus among active-exposed participants 
was 0.06%,1,4,9,17-21 although rates of resistant virus generated by the initiation of TDF-based 
PrEP during occult primary HIV infection was approximately 25%. 
Concerns also remain about longer-term side effects of these drugs, including renal toxicity and 
decreased bone mineral density (BMD). Renal toxicity occurs with TDF use, including acute 
renal failure and Fanconi’s syndrome.59,60 Across Phase 3 randomized studies, the rate of Grade 
2-4 confirmed creatinine elevations was approximately 0.2%, with no documented cases of renal 
dysfunction requiring dialysis or permanent renal dysfunction.1,9,20,21,61  BMD changes of 
approximately 1% were seen in dual-energy X-ray absorptiometry (DXA) subsets of MSM who 
received 48 weeks of TDF-based PrEP with some reversion towards baseline after PrEP 
medication withdrawal; no interventions have been shown to mitigate such bone loss to 
date.37,62,63 Fractures were not observed to be associated with observed levels of BMD loss.   

 
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1.7 
Rationale for Study Design  
This study is a Phase 2b/3 randomized double-blind non-inferiority trial of CAB-LA versus 
TDF/FTC designed to evaluate the ability of long-acting injectable Cabotegravir (CAB LA) to 
prevent HIV infection in high-risk transgender women (TGW) and men who have sex with men 
(MSM) when used as pre-exposure prophylaxis (PrEP). A non-inferiority trial comparing CAB 
LA to an active control group taking oral TDF/FTC is appropriate because robust evidence now 
exists supporting a strong protective effect of oral TDF/FTC against rectal exposure to HIV4,35,36 
and the US FDA has approved licensure of TDF/FTC for HIV prevention in high risk 
populations. The WHO has provided guidance suggesting that the current level of evidence for 
MSM and TGW is sufficient for placebo-controlled designs to be unacceptable.64 Although 
TDF/FTC has been shown to be effective, adherence to a daily oral regimen can be difficult in 
many settings, and no efficacy was observed when adherence was low (FEM-PrEP, VOICE).  
An effective, long-acting PrEP agent could offer substantial advantages in achieving sustained 
efficacy because of increased convenience and higher adherence. 
A non-inferiority design has been selected because TDF/FTC has been shown to be highly 
effective in high-risk MSM populations so that it is sufficient to establish that CAB-LA has 
similar effectiveness to TDF/FTC, particularly if CAB-LA is shown to be safe and effective, and 
to have an adherence advantage over daily TDF/FTC. Using existing randomized, controlled trial 
data for TDF/FTC in MSM populations an appropriately robust non-inferiority margin can be 
established that would substantially preserve clinical efficacy in a randomized comparison of 
CAB-LA to oral TDF/FTC.65 The proposed randomized trial does also allow for establishing 
superiority of CAB-LA in the event that it is substantially more effective than TDF/FTC. 
The study is double blind to achieve a direct comparison of the two drugs in the absence of the 
additional differential effect of adherence to daily pills and difference in risk behavior. With the 
double blind, all participants are required to take a daily pill and receive the injections, thus 
differences in pill adherence between the arms are likely to be small (based on prior trials). HIV 
risk is also expected to be similar in both groups. An un-blinded trial was considered; however, 
the strong potential for knowledge of the active agent to modify daily adherence, retention in the 
trial and risk behavior was judged to threaten the interpretability of the study. A double-blind 
trial of CAB-LA, with all participants offered TDF/FTC could also be considered, but this would 
not lead to licensure of CAB-LA as a single agent with a potential for a long-acting drug without 
the adherence burden of daily drug dosing. 
Although treatment paradigms for HIV typically include three or more agents in order to achieve 
durable suppression of viral replication, HIV prevention using ARVs agents does not obligate 
three or even multiple agents. For example, the Partners PrEP study demonstrated statistically 
similar prophylaxis efficacy against HIV acquisition among heterosexual men and women for 
tenofovir monotherapy and TDF/FTC dual therapy.   
There is a risk that too few HIV infections will occur in the trial to be able to definitively 
establish non-inferiority. This could occur if the population was not truly at risk for HIV, or if 
both products were highly effective in preventing HIV: that is, that adherence to TDF/FTC was 
high and CAB-LA was similarly effective. We plan to establish whether adherence to TDF/FTC 
is high by measuring intraerythrocytic TFV-DP levels, relying on the robust database for 

 
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TDF/FTC that allows extrapolation of intraerythrocytic TFV-DP level data to levels of protective 
efficacy. Risk behavior and non-HIV STIs will be carefully monitored to provide a benchmark 
for HIV-exposure risk of the enrolled population and to support the statistical design 
assumptions.   
1.8 
Rationale for Bone Mineral Density Subset 
As noted above, bone mineral density (BMD) loss was associated with receipt of TDF-based 
PrEP in HIV-uninfected participants, making BMD loss one of three “signature” toxicities of 
TDF/FTC-based PrEP (including a gastrointestinal “start-up” syndrome and potential 
nephrotoxicity). Although there are no data to suggest that integrase inhibitors as a class or CAB 
specifically should impact BMD, it has not been studied. In order to evaluate further the risk-
benefit of a long-acting injectable compared to daily oral TDF/FTC, it is critical to compare the 
known toxicity profile of TDF/FTC to any comparator agent. 
At sites that have the ability to perform DXA scans, 175 participants in each arm (350 
participants in total) will be offered participation in a DXA subset. DXA evaluations will be 
conducted for subset participants at Enrollment and Weeks 57 and 105. An additional informed 
consent will be required for subset participation. The subset will be competitively enrolled until 
350 baseline DXA scans are obtained. 
1.9 
Recruiting and Retaining Most At Risk Populations 
The study aims to recruit a large population of highest-risk individuals from a broad geography. 
Sites will implement wide-reaching educational efforts, community engagement, and multimedia 
advertising including rapidly changing and adaptive social media strategies to reach most-at risk 
populations. Participant retention during prolonged follow-up will be accomplished using study-
visit incentives as permitted by local IRBs at the maximum permissible level. 
The study will be targeted towards most at-risk populations of MSM and TGW in each 
geographic setting (i.e., those with highest HIV incidence). In the US, this will entail close 
collaboration with community and leadership of the African-American and Latino MSM 
communities, as well as the transgender community. Such collaborations are being planned or 
have already occurred, including planned discussions with the Black Gay Research Group 
(BGRG) and the Black Caucus within the HPTN, as well as engagement with the transgender 
community at a transgender workshop that took place during the HPTN Annual Meeting in June 
2015. In the US, HPTN 061, a cohort engaging African American MSM in a longitudinal 
observational study, found localized epidemics where HIV incidence among young (age 18-29) 
Black MSM was 5.9%, and approximately 3% overall for the population.66 US recruitment in 
this study will be guided by the recommendations set forth by the Black Caucus on future 
research with BMSM, including using the “Presence at the Table”67 strategy at US sites at the 
time of initiation.  
In order to target most at-risk populations, sites will be encouraged to enroll the majority of 
participants 30 years of age and younger. Additionally, the protocol will strive to enroll 50% of 
the US-based recruitment with Black MSM, particularly young (<30 years) Black MSM. Efforts 
to enrich enrollment with young Black MSM will be a focus of education and outreach at US 

 
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based sites. The study overall will strive to enroll 10% TGW, and again, efforts to enrich 
enrollment with TGW will be a focus of education and outreach at all sites. 
Within South America, young MSM and TGW have the highest risk of HIV infection.68 Previous 
studies in the region have found that this population has a high willingness and acceptability for 
the use of PrEP.69 To help identify potential study participants, alliances will be made between 
the study team and local specialized resources, including Lesbian/Gay/Bisexual/Transgender-
based non-governmental organizations, trans-advocacy and support groups and mobile HIV 
testing units. Because of the work with iPrEX and other PrEP studies underway in the region, the 
foundation for many of these recruitment partnerships has already been established across South 
America. Recent epidemiologic data from 3 voluntary counseling and testing sites in Rio de 
Janeiro found 24.8% (95% CI 19.9-29.7) prevalence among MSM, and conservatively estimated 
incidence among MSM to be 8.55% (95% CI 4.36-12.74).70 MSM and TGW in Brazil have a 
very high willingness to use PrEP to prevent HIV.71  
A cohort of 718 MSM/TW in Peru showed an HIV incidence was 3.6 cases per 100 person-
years, with HIV incidence being highly associated with having an incident STI (aHR 3.73).72 In 
Thailand, the situation is similar, with MSM at high risk of HIV infection and younger MSM at 
even higher risk. MSM cohorts from 2006-2013 found HIV incidence rates of 5–6 per 100 PY, 
with incidence among MSM aged 24 years or less to be 7 per 100 PY.73 The overall HIV 
incidence rate among MSM is 180 times as high as the estimated incidence of 0.03% in 2011 
among adults in Thailand.74 Risk factors for HIV infection in this population have been found to 
be younger age, drug use for sexual pleasure, inconsistent condom use, group sex, and 
seropositivity for herpes simplex virus type 1 and 2 (HSV-1, HSV-2) and syphilis at baseline.60 
The MSM population has a high willingness to participate in PrEP trials, and the civil society 
links between community-based organizations and researchers are strong. Interest in injectable 
forms of PrEP is high among MSM community-based organizations. 
Sub-Saharan Africa was long believed to have an exclusively heterosexual epidemic. 
Nevertheless, HIV rates have been found to be higher than the background male population rates 
in both gay-identified and non-identified MSM. HIV prevalence rates of up to 50% have been 
described.75-79 
1.10 HIV and Risk Reduction Counseling 
HIV testing and risk reduction counseling will be provided at each study visit, in accordance 
with local standards of care, and will include messaging about consistent condom use, and the 
known effectiveness of daily oral TDF/FTC when taken with high adherence. Condoms and 
lubricant will be offered to all participants at each study visit. In addition, counseling will 
emphasize the unknown efficacy of the injectable study product in preventing HIV infection. 
1.11 Adherence Counseling and Monitoring  
It is clear that the effectiveness of daily oral TDF/FTC is tightly correlated with adherence.  
Therefore, a critical component of the comparison between daily oral TDF/FTC and CAB LA 
will be participants’ ability/willingness to take a daily pill compared to a clinic-administered 
injection at two time points 4 weeks apart followed by every 8 weeks thereafter. To evaluate the 

 
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clinical applicability of this difference, the study will provide adherence support at baseline and 
at all follow-up visits for all participants in a manualized/standardized fashion commensurate 
with an intervention that could be easily implemented in diverse clinical settings. Any participant 
who has self-reported or actual returned pill-count evidence of challenges with adherence to AT 
MINIMUM the level of 4 doses weekly will be provided an individualized adherence 
intervention designed to problem-solve individual barriers to adherence. 
When approximately 50% of the study population has enrolled, a random sample of plasma 
and/or dried blood spot (DBS) specimens from TDF/FTC-arm participants from a variety of time 
points will be assayed for drug levels (TFV in plasma and/or intra-erythrocytic TFV-DP in 
DBS). If adherence rates suggest adherence levels <50-60%, additional adherence support for 
daily oral tablets will be provided to all participants. 
1.12 Rationale for use of oral lead-in prior to injectable dosing 
The CAB LA formulation has a pharmacokinetic decay rate that exposes the injected individual 
to detectable levels of cabotegravir for up to a year or more after an injection (see Section 1.3.2). 
In order to maximally identify any acute toxicity prior to administration of a non-dialyzable, 
non-removable depot injection, a 5-week lead-in period of daily oral (short acting) cabotegravir 
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 4 weeks of oral drug 
exposure. The 5-week exposure in this study is designed to provide uninterrupted study product 
coverage while awaiting return of the Week 4 safety laboratory assessments.   
1.13 Rationale for exploring cross-sex hormone therapy and PrEP medication drug-drug 
interactions 
Although no drug-drug interactions would be expected between the components of TDF/FTC or 
CAB and cross-sex hormone therapy (csHT) in HIV-uninfected individuals, there are currently 
no data to support that assumption. Lower TFV-DP levels observed in TGW in the iPrEX OLE 
study, which were attributed to poor adherence may, in fact, be partly attributable to drug-drug 
interactions.34 Focus groups among TGW have also noted a high level of interest in interactions 
between PrEP agents and csHT. TGW will often prioritize csHT use above other health 
concerns, further emphasizing the importance of formally evaluating such drug-drug 
interactions.80 In order to best characterize interactions, csHT regimens would need to be limited 
to most-common regimens composed of oral 17-beta estradiol, with or without spironolactone or 
progestagens. PK data (plasma TFV and/or TFV-DP levels) and plasma CAB levels from a 
subset of TGW participants taking stable regimens of csHT and a subset of TGW not taking 
csHT from each arm could then be compared. 
 
1.14 Rationale For Web-Based Sexual Health Promotion Score During Screening 
SexPro is a web-based tool that provides participants with a sexual health promotion score. The 
SexPro score was developed to estimate short-term HIV acquisition risk using data from several 
large cohorts of MSM in the United States and South America. 81-85 Different models were 
developed for North and South America, based on data from these two populations. In particular, 

 
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these models reflect differences in demographic and substance use effects on HIV acquisition 
and required tradeoffs between goodness of fit and delivering interpretable risk information. 
From this, two separate SexPro interfaces were created: one for North American MSM (available 
in English and Spanish), and one for South American MSM (in Spanish and Portuguese). 
Participants answer a brief questionnaire including age, race/ethnicity (US only), behavioral risk 
factors, substance use, and history of sexually transmitted diseases (gonorrhea, chlamydia, and 
syphilis) which are used to calculate their personalized HIV risk score reflecting their likelihood 
of HIV acquisition at six months. Scores range from 1 (highest risk) to 20 (lowest risk) based 
upon a positive sexual health promotion framing. The SexPro score for the North American 
model has been subsequently validated in two contemporary longitudinal cohorts of MSM – 
HPTN 061 and HVTN 505 – and shows good model fit, especially among Black MSM in HPTN 
061.86 A SexPro score of 16 or lower showed good sensitivity (75.4%) and specificity (51.8%) in 
HVTN 505. All HIV seroconversions in HPTN 061 occurred below this value; this cut-off was 
chosen to identify MSM at high risk for HIV infection, and to maximize sensitivity of the tool 
for Black MSM in the US. The SexPro score, using a score cut-off of 16 or lower, will be used in 
addition to the current behavioral risk inclusion criteria for the US-based cohort; participants 
who do not qualify on the basis of the current behavioral risk will be eligible with a risk score of 
16 or lower. This recognizes that young men of color in the US are at risk of acquiring HIV with 
less self-reported risk than older white men. SexPro will also be administered to MSM outside of 
US but will not be used as part of the inclusion criteria, as this has not yet been validated in 
separate cohorts. 
 
1.15 Rationale For Collecting and Analyzing Metabolic Parameters  
Data increasingly support the association of integrase inhibitors with weight gain in the setting of 
HIV infection. 87,88 The precise mechanism is unknown, is noted to be greater in Black 
participants, in women, and in those with lower CD4 cell counts, and appear to be additionally 
contributed to by the choice of nucleoside analogue reverse transcriptase inhibitors (NRTIs) used 
as part of the treatment regimen. The contribution of the HIV-associated inflammatory milieu is 
also unknown.  HPTN 077 did not find a difference between CAB and placebo arms for weight 
gain for any population.89 The HPTN 083 study will capture participant data for weight in a 
standardized way to evaluate changes between study product arms.  Per FDA guidance, 
additional metabolic parameters (including but not limited to weight, pulse, blood pressure and 
fasting glucose/lipids) will also be analyzed for changes between study arms.90   
 

 
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2.0 
STUDY OBJECTIVES AND DESIGN 
2.1 
Primary Objectives:  
• To compare HIV incidence among participants randomized to oral CAB/CAB LA (oral 
lead in and injections) vs. oral TDF/FTC (Steps 1 and 2) 
• To compare the safety of oral CAB/CAB LA vs. oral TDF/FTC (Steps 1 and 2) 
2.2 
Secondary Objectives: 
• To compare HIV incidence among participants receiving CAB LA injections vs. oral 
TDF/FTC (each step independently and all steps in aggregate) 
• To compare HIV incidence among participants receiving CAB LA injections vs. oral 
TDF/FTC (Steps 1, 2, and 3 combined) 
• To compare HIV incidence among participants receiving CAB LA injections vs. oral 
TDF/FTC (Step 3 only, descriptive) 
• To estimate the change in hazard of HIV acquisition between CAB and oral TDF/FTC 
strategies (Arm A and Arm B) as participants progress from Step 2 to Step 3 
• To compare HIV incidence among the subgroups of participants receiving oral 
CAB/CAB LA vs. oral TDF/FTC by region, age, race, ethnicity, baseline risk, and gender 
identity  
• To compare changes in renal function, liver function, and bone mineral density (BMD) 
among participants receiving oral CAB/CAB LA vs. oral TDF/FTC 
• To evaluate and compare rates of HIV drug resistance among participants who acquire 
HIV infection during the study among participants receiving oral CAB/CAB LA vs oral 
TDF/FTC 
• To compare the acceptability of and preferences for CAB LA vs. oral TDF/FTC 
• To compare changes in weight, blood pressure, pulse, fasting glucose, and fasting lipids 
among participants receiving oral CAB/CAB LA vs. oral TDF/FTC 
2.3 
Tertiary Objectives: 
• To examine the association between levels of adherence and HIV incidence 
• To compare and describe the rates, patterns, and correlates of adherence to CAB LA vs 
oral TDF/FTC, in aggregate and by psychosocial/demographic variables.  
• To estimate changes in sexual-risk behavior as measured by self-report and rates of 
incident gonorrhea, chlamydia, and syphilis in the study population 
• To compare the resource utilization and programmatic costs of long-acting injectable 
PrEP vs. daily oral PrEP vs. no PrEP for HIV uninfected MSM and TGW in the US, 
Brazil, and South Africa 

 
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• To use mathematical simulation to project the short- and long-term clinical impact, cost 
projections, budgetary impact, and incremental cost-effectiveness of long-acting 
injectable PrEP vs. daily oral PrEP vs. no PrEP for HIV uninfected MSM and TGW in 
the US, Brazil, and South Africa  
2.4 
Exploratory Objectives: 
• To perform secondary laboratory assessments that may include evaluation of factors 
related to HIV infection, hepatitis infection, or sexually transmitted infections (STIs); 
antiretroviral (ARV) drug use; pharmacogenomics; characterization of HIV in infected 
participants; and evaluation of laboratory assays related to the study objectives  
• To explore possible drug-drug interactions between cross-sex hormone therapy (csHT) 
and cabotegravir and TDF/FTC in a subset of TGW taking commonly prescribed cross-
sex hormone therapy regimens    
2.5 
Study Design and Overview 
This is a Phase 2b/3, randomized, multi-site, two-arm, study of CAB LA compared to daily oral 
TDF/FTC for HIV prevention. Approximately 5000 participants will be enrolled, randomized 1:1 
to Arm A and Arm B through the following 3 steps: 
Step 1: 
• Arm A - Daily oral CAB (30 mg tablets) and daily oral placebo for TDF/FTC for 5 
weeks.   
• Arm B - Daily oral TDF/FTC and daily oral placebo for CAB for 5 weeks. 
Any participant that becomes HIV-infected during Step 1 of the study will permanently 
discontinue study product and will be terminated from the study and referred for HIV-related 
care.  Participants in Step 1 who do not transition to Step 2 for any reason other than HIV 
infection will remain blinded to their study assignment and be asked to attend annual visits until 
they each individually complete 3 years of follow-up from the time of Enrollment.   
Step 2: 
• Arm A – Injections of CAB LA at two time points four weeks apart and every 8 weeks 
thereafter beginning at Week 5, and daily oral placebo for TDF/FTC. Injections will 
consist of 600 mg of CAB LA administered as one 3 mL injection.   
• Arm B: Daily oral TDF/FTC and injections of placebo for CAB LA on the same schedule 
as Arm A beginning at week 5. Injections will consist of the same volume (3 mL) as Arm 
A participants.   
This step will continue until three years of follow-up, to Week 153, for each participant, with the 
last injection provided and the last blinded oral study product dispensed at Week 145.  
Participants who prematurely discontinue blinded study products during Step 2 (having received 
at least one injection) for any reason other than HIV infection will transition to Step 3 and 

 
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receive 48 weeks of study-provided open label TDF/FTC, followed by annual follow-up until 
three years from the date of Enrollment. For these participants, the timepoint at which they 
transition to Step 3 will determine whether they will be asked to attend annual visits following 
the completion of Step 3; if the completion of Step 3 post-dates three years from the date of 
Enrollment, annual follow-up is not required.   
All participants will also be simultaneously unblinded after the last participant concludes their 
participation in Step 2. 
Any participant that becomes HIV infected during Step 2 of the study will permanently 
discontinue study product and will be followed at quarterly intervals for approximately 48 weeks 
in order to test for safety parameters, as well as CD4 cell count and HIV viral load.       
Step 3:   
 Participants who complete the full three years of follow-up in Step 2 at the Week 153 visit will 
ideally begin Step 3 on the same day, which will be considered Day 0 of Step 3.  On this day, 
participants will begin study-provided open-label daily oral TDF/FTC for 48 weeks (for Arm A, 
to “cover the tail”). For participants who prematurely transition to Step 3 before completing three 
years of follow-up in Step 2 , Step 3 will start no later than 8 weeks after their last injection (the 
timing of the last injection visit and duration of provision of daily oral TDF/FTC may vary 
according to when the last participant reaches their final Step 2 visit or if the study endpoints are 
reached earlier).  
All participants will be transitioned to locally-available HIV prevention services, including 
services for PrEP, if available, when their participation in the study ends, or if they transition to 
annual visits in Step 1 or Step 2, or if at the discretion of the primary care physician, they 
transition to Step 3 on study but off study-provided TDF/FTC.  
Participants with confirmed HIV infection during Step 3 will be followed at least for the duration 
of Step 3, with possible additional assessments and follow-up to be determined by the 
083HIV@hptn.org group.   
All participants will receive HIV testing with pre- and post-test counseling, risk-reduction 
counseling, and be offered condoms and lubricant (lubricant will be offered per local standards). 
All participants will be followed according to the Schedule of Evaluations and Procedures 
provided in Appendices I a-c, and in the event of HIV infection, according to Appendix II.   
2.5.1 Participating Sites/Institutions 
Participating sites are listed in the SSP Manual, and are located in Asia, North and South 
America, and South Africa. 
2.5.2 Study Duration 
The study will last approximately 7.5 years total, with individual participants being followed for 
approximately 4.0 years total. Accrual will require approximately 3.5 years.   
 

 
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3.0 
STUDY POPULATION 
Approximately five thousand (5000) HIV-uninfected MSM and TGW will be included in this 
study. Each site will be asked to work with their Community Advisory Board and outreach, 
education and recruitment teams to develop a recruitment plan appropriate for their local 
population. Participants will be selected for the study according to the criteria in Sections 3.1 and 
3.2. Study participants will be recruited as described in Section 3.3. Requirements related to 
participant retention and withdrawal from the study are described in Sections 3.5 and 3.6, 
respectively. Individual sites will be given enrollment targets such that overall cross-site 
enrollment meets overall protocol goals.    
3.1 
Inclusion Criteria 
Participants who meet all of the following criteria are eligible for inclusion in this study: 
• MSM and TGW, 18 years or older at the time of screening (male at birth) 
• Willing to provide informed consent for the study 
• At high risk for sexually acquiring HIV infection based on self-report of at least one of 
the following:  
o Any condomless receptive anal intercourse in the 6 months prior to enrollment 
(condomless anal intercourse within a monogamous HIV seronegative concordant 
relationship does not meet this criterion)   
o More than five partners in the 6 months prior to enrollment (regardless of condom use 
and HIV serostatus, as reported by the enrollee) 
o Any stimulant drug use in the 6 months prior to enrollment 
o Rectal or urethral gonorrhea or chlamydia or incident syphilis in the 6 months prior to 
enrollment 
o SexPro score of ≤ 16 (US sites only)  
• In general good health, as evidenced by the following laboratory values, which must be 
from specimens obtained within 45 days prior to study enrollment:   
o Non-reactive / negative HIV test results* 
o Hemoglobin > 11 g/dL,  
o Absolute neutrophil count > 750 cells/mm3 
o Platelet count ≥ 100,000/mm3  
o Calculated creatinine clearance ≥ 60 mL/minute using the Cockcroft-Gault equation 
(use sex at birth for calculation) 
o Although not protocol exclusionary, sites should carefully consider the 
advisability of enrolling participants with calculated creatinine clearance between 
60-70 mL/min, as limited changes in creatinine clearance during study conduct 

 
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will lead to protocol-mandated product holds and may alter the risk-benefit 
considerations of study participation 
o Alanine aminotransferase (ALT) < 2 times the upper limit of normal (ULN) 
o Total bilirubin < 2.5 times ULN 
o Hepatitis B virus (HBV) surface antigen (HBsAg) negative 
o HCV Ab negative 
o No Grade 3 or higher laboratory abnormalities on any laboratory tests obtained at 
screening, including tests obtained as part of a panel of tests ordered to obtain the 
protocol-required laboratory test results. 
*All HIV test results from the Screening visit must be obtained and must all be 
negative/non-reactive. This includes testing for acute HIV infection, which must be 
performed within 14 days of Enrollment. In addition, at least one HIV test result obtained 
at the Enrollment visit must be obtained prior to provision of study product and must be 
negative/non-reactive. Individuals who have one or more reactive or positive HIV test 
results will not be enrolled, even if subsequent confirmatory testing indicates that they are 
not HIV-infected (see SSP Manual).    
• No medical condition that, in the opinion of the study investigator, would interfere with 
the conduct of the study (e.g., provided by self-report, or found upon medical history and 
examination or in available medical records)  
• Willing to undergo all required study procedures  
3.2 
Exclusion Criteria 
Participants who meet any of the following criteria will be excluded from this study: 
• One or more reactive or positive HIV test result at Screening or Enrollment, even if HIV 
infection is not confirmed 
• Active or recent use of any illicit intravenous drugs (“recent” defined as in the 90 days 
prior to enrollment) 
• Co-enrollment in any other interventional research study or other concurrent studies that 
may interfere with this study (as provided by self-report or other available 
documentation. Exceptions may be made if appropriate after consultation with the CMC.) 
• Past or current participation in HIV vaccine trial. An exception will be made for 
participants that can provide documentation of receipt of placebo (not active arm). Note:  
Past participation in a monoclonal antibody study is not exclusionary, effective as of 
Version 1.0 of HPTN 083.   
• 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 
 

 
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• Inflammatory skin conditions that compromise the safety of intramuscular (IM) 
injections, per the discretion of the Investigator of Record. Mild skin conditions may not 
be exclusionary at the discretion of the Investigator of Record or designee in consultation 
with the CMC 
• Has a tattoo or other dermatological condition overlying the buttock region which in the 
opinion of the IoR or designee, in consultation with the CMC, 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) 
• Coagulopathy (primary or iatrogenic) which would contraindicate IM injection 
(concomitant anticoagulant or anti-platelet therapy use should be discussed with the 
CMC) 
• Active or planned use of prohibited medications as described in the Investigator’s 
Brochure or listed in the SSP Manual (provided by self-report or obtained from medical 
history or medical records). In particular, future use of TDF/FTC at any point during the 
study.    
• Known or suspected allergy to study product components (active or placebo), including 
egg or soy products (egg and soy products are contained in Intralipid) 
• Surgically-placed or injected buttock implants or fillers, per self-report. Contact the CMC 
for guidance regarding questions about individual cases. 
• Alcohol or substance use that, in the opinion of the study investigator, would jeopardize 
the safety of the participant on study (e.g., provided by self-report, or found upon medical 
history and examination or in available medical records).     
• History of seizure disorder, per self-report 
• QTc interval (B or F) > 500 msec 
3.3 
Recruitment Process 
Sites will be responsible for developing appropriate recruitment processes that are geared toward 
their respective local communities. See also Section 1.9. All advertising materials must undergo 
approval by each participating site’s Institutional Review Board (IRB)/Ethics Committee (EC).  
3.4 
Co-Enrollment Guidelines 
In general, participants in this study will not be allowed to take part in other concurrent research 
studies during their participation in the study. This is due in part to concerns about participant 
study burden, American Red Cross-mandated limitations on per-unit-time phlebotomized blood 
volumes, to avoid potential unblinding of this or other studies, and to avoid confounding in the 
interpretation of the study data. The Clinical Management Committee (CMC) should be 
consulted for any possible exceptions.   

 
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3.5 
Participant Retention 
Once a participant enrolls in this study, the study site will make every effort to retain him or her 
for the entire follow-up period. Optimally, participant retention procedures will be established 
such that loss rates do not exceed the range that would allow the incidence rate of the primary 
study outcome to be reliably estimated (i.e., a maximum of 7.5% per year as assumed in the 
sample size calculation). Study site staff are responsible for developing and implementing local 
standard operating procedures to target this goal. Components of such procedures may include: 
• Thorough explanation of the study-visit schedule and procedural requirements during the 
informed consent process and re-emphasis at each study visit. 
• Thorough explanation of the importance of both arms 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. 
• Immediate and multifaceted follow-up on missed visits. 
• Mobilization of trained staff to complete in-person contact with participants at their 
homes and/or other community locations. 
• Regular communication with the study community at large to increase awareness about 
HIV/AIDS and explain the purpose of HIV prevention research and the importance of 
completing research study visits. 
• Incentives or reimbursements as permitted by local IRB/ECs  
3.6 
Participant Withdrawal 
Regardless of the participant retention methods described in Section 3.5, participants may 
voluntarily withdraw from the study for any reason at any time. In general, participants should 
not be withdrawn from the study during the blinded, randomized portion of the study except in 
the case of a) withdrawal of consent; b) death; c) extreme/unusual circumstances to protect 
participant safety; or d) if they are unwilling or unable to comply with required study procedures.  
Any such safety-related participant terminations should only be implemented after consultation 
with the Protocol Chair, Division of AIDS (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 also may be withdrawn if the study sponsor, government or regulatory authorities 
(including Office for Human Research Protections [OHRP] and the FDA) or site IRBs terminate 
the study prior to its planned end date. 
Every reasonable effort will be made to complete a final evaluation of participants who terminate 
from the study prior to the final protocol-dictated study week, and study staff will record the 
reason(s) for all withdrawals from the study in participants’ study records.   

 
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3.6.1 Premature Termination Visits  
In general, for participants who withdraw consent from the study prematurely during a study visit, 
the requirements for that visit should be completed to the extent possible except for provision of 
study product and will be considered their final visit. When possible, a plan should be made to 
provide final laboratory results to the participant. For participants who inform the site in between 
visits that they wish to withdraw consent from the study, sites should make every effort to have the 
participant return any unused study product.  

 
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4.0 
STUDY PRODUCT CONSIDERATIONS 
4.1 
Study Product Regimens/Administration/Formulation Content 
Study Product Regimens 
Step 1 - Participants will be randomized 1:1 to one of two study arms: 
• Arm A:  Oral CAB tablets 30 mg, one tablet orally daily for five weeks, with or without 
food AND placebo for TDF/FTC tablets, one tablet orally daily for 5 weeks, with or 
without food 
• Arm B:  TDF/FTC 300 mg/200 mg fixed dose combination tablet, one tablet orally daily 
for five weeks, with or without food AND placebo for oral CAB tablet, orally daily for 5 
weeks, with or without food 
Step 2 – Blinded injections and blinded daily oral pills:   
• Arm A:  CAB LA 600 mg administered as one 3 mL (600 mg) intramuscular IM injection 
in the gluteal muscle at two time points 4 weeks apart and every 8 weeks thereafter, AND 
placebo for TDF/FTC tablet, one tablet orally daily with or without food   
• Arm B:  TDF/FTC 300 mg/200 mg fixed dost combination tablet, one tablet orally daily, 
with or without food AND placebo for CAB LA (Intralipid 20% fat emulsion infusion) 
administered as one 3mL intramuscular (IM) injection in the gluteal muscle as two time 
points 4 weeks apart and every 8 weeks thereafter 
Step 3:  All participants transitioned to this step, including those who permanently discontinue 
receiving injections before their Step 2 participation in the study ends, will receive open-label 
TDF/FTC 300 mg/200 mg fixed dose combination tablets, one tablet orally daily for up to 48 
weeks.   
4.2 
Study Product Formulations 
4.2.1 Oral Products 
CAB 30 mg tablets (blinded) are formulated as white to almost white oval-shaped coated tablets 
for oral administration. The tablets are packaged in high density polyethylene (HDPE) bottles 
with child-resistant closure that include an induction seal. The bottles contain 30 tablets and a 
desiccant. The tablets must be stored in the original container. The bottles are to be stored up to 
30°C (86o F) and protected from moisture. 
 
Placebo for CAB 30 mg tablets (blinded) are formulated as white to almost white oval-shaped 
coated tablets to visually match the CAB tablets. The tablets are packaged in high density 
polyethylene (HDPE) bottles with child-resistant closure that include an induction seal. The 
bottles contain 30 tablets and a desiccant. The tablets must be stored in the original container. 
The bottles are to be stored up to 30°C (86°F) and protected from moisture. 
 

 
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TDF 300 mg/FTC 200 mg tablets (blinded) are capsule-shaped, film-coated blue tablets that 
must be stored in the original container. Each bottle contains a silica gel desiccant canister to 
protect the product from humidity. The bottles are to be stored up to 25°C (77°F). Excursions are 
permitted between 15° to 30°C (59 to 86°F).  
 
Placebo for TDF 300 mg/FTC 200 mg tablets (blinded) are capsule-shaped, film-coated blue 
tablets that visually match the TDF/FTC tablets. The tablets must be stored in the original 
container. Each bottle contains a silica gel desiccant to protect the product from humidity. The 
bottles are to be stored up to 25o C (77°F). Excursions are permitted between 15°C to 30°C (59 
to 86°F). 
 
TDF 300 mg/FTC 200 mg tablets (open-label) are capsule-shaped, film-coated blue tablets that 
must be stored in the original container. Each bottle contains a silica gel desiccant canister to 
protect the product from humidity. The bottles are to be stored at 25°C (77°F). Excursions are 
permitted between 15° to 30°C (59 to 86°F).  The TDF/FTC fixed dose combination tablet 
containing 300 mg of TDF and 200 mg of FTC is available as Truvada® and is approved by the 
U.S. FDA for treatment and prevention of HIV-1 infection. Further information on Truvada® is 
available in the current package insert.91 
 
4.2.2 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 Investigator’s Brochure (IB), which will be 
provided by the DAIDS Regulatory Support Center (RSC). 
 
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 2 mL or 3 mL glass 
vial. Each vial is for single use containing 2 mL (400 mg) or 3 mL (600 mg) and does not require 
dilution prior to administration. CAB LA injectable suspension is to be stored up to 30°C (86°F), 
do not freeze. 
 
Placebo for CAB LA Injectable Suspension will be Intralipid 20% fat emulsion infusion which is 
packaged in 100 mL IV bags. Intralipid 20% fat emulsion infusion IV bags are to be stored 
below 25°C (77°F), do not freeze. 
 
4.3 
Study Product Preparation  
4.3.1 Preparation of the Oral Study Product 
The oral products for this study will be provided with customary two-part structure which 
includes a tear-off portion containing the un-blinded-product identification (i.e., active or 
placebo). 
 
Prior to dispensing, the un-blinded portion of the tear-off label must be removed and attached to 
the participant specific pharmacy record such as participant prescription or participant specific 

 
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study product accountability record. The permanently affixed section of the label will remain on 
the original container. 
 
The site pharmacist will label the bottle with a participant specific label prior to dispensing. The 
participant specific label must be in accordance with the local regulations and the DAIDS 
Pharmacy Guidelines manual. 
 
The pharmacist will prepare the participant-specific study product and dispense sufficient 
quantity to last until the next follow-up visit plus approximately one-month buffer supply. 
Pharmacists will record dispensations on the Pharmacy Accountability Logs. 
 
4.3.2 Preparation of Injectable Study Product  
The site pharmacist(s) must be proficient in the preparation of injectable study products using 
aseptic technique under a pharmacy biological safety cabinet (BSC) Class II or better. Local 
regulations and site institutional policies and procedures for use of personal protective 
equipment, such as gloves, gowns, masks, and safety glasses, must be followed. 
 
Preparation of Active Injectable Study Product (CAB LA 600 mg/3 mL) 
 
The designated pharmacy personnel will follow the steps below for preparation of active 
injectable study product, CAB LA injectable suspension. In Step 2 of the study, for the 
participants in Arm A, one syringe containing 3 mL (600 mg) of CAB-LA must be prepared 
using aseptic technique under a pharmacy BSC/Isolator. 
 
Materials required for preparation and administration of CAB LA 600mg; 3 mL dose: 
1. One CAB LA 600 mg/3 mL vial or two CAB LA 400 mg/2 mL vials 
2. Becton Dickenson (BD) 3-mL syringe, Leur-Lok Tip, Product No.: 309657 or equivalent 
3. Becton Dickinson (BD) 5-mL Syringe, Luer-Lok Tip, Product No.: 309646 or equivalent 
4. Needle for aspiration: BD general use sterile hypodermic needle, 21G x 1½ inch (e.g. 
PrecisionGlide Needle, Product No.: 305165 or equivalent) 
5. Needle for intramuscular injection: BD IM sterile hypodermic needle, 23G x 1½ inch (e.g. 
PrecisionGlide Needle, Product No.: 305194 or equivalent).  Refer to the HPTN 083 SSP 
for further details on appropriate needle gauge size and length to use for IM administration. 
 
Preparation Steps: 
 
1. Remove two vials of CAB LA (400 mg/2 mL per vial) or one vial of CAB LA (600 mg/3 mL 
per vial) from storage.  If the vials are stored in the refrigerator (2°C to 8°C), remove vial(s) 
from the refrigerator and wait at least 15 minutes to equilibrate to room temperature. 
 
2. Vigorously shake the vial(s) for a full 10 seconds by shaking the vial(s) with long arm 
movements. 
 
3. Invert the vial(s) and inspect to ensure uniform suspension.  If solid remains undispersed, 
repeat Steps 2-3 until all material is uniformly suspended. 
 

 
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NOTE: It is normal to see small air bubbles at the end of shaking the vial for re-suspension. 
 
4. Using aseptic technique under a pharmacy BSC/isolator, flip off the plastic cap from the vial. 
Wipe the top of the vial with an alcohol pad (isopropyl alcohol 70% or similar) and allow to 
dry. Do not touch the rubber stopper at any time. 
 
5. Remove a 3 mL or 5 mL size syringe and 21G x 1½ inch (or equivalent) needle for 
aspiration.  Attach the needle to the Luer connection of the syringe. 
 
6. With the needle sheath on, pull the syringe plunger rod to allow approximately 1 mL of air 
into the syringe. Remove the needle sheath.  
 
7. With the vial in the inverted position and the syringe with the needle in the upright position, 
push the needle through the vial stopper and inject approximately 1 mL of air into the vial.  
 
8. While keeping the syringe with the needle in the upright position, withdraw needed volume 
of CAB LA suspension from the vial(s) into the syringe  
• Withdraw total of 3 mL (600 mg) of CAB LA suspension from the vial(s) into a syringe. 
o If using two CAB LA 400 mg/2 mL vials to prepare the dose, a second new 
aspiration needle should be used to withdraw suspension from the second vial. 
Remove the first needle that was used to withdraw the suspension out of the first 
vial and discard properly. Attach the new 21G x 1½ inch needle (or equivalent) to 
the syringe already containing suspension per instructions in Step 5 and repeat 
Steps 6 and 7 to withdraw the remaining needed volume from the second vial. 
 
Since the suspension can contain some air after having shaken the vial, withdraw enough 
suspension from the vial in order to be able to de-aerate the syringe properly. 
 
9. Remove the needle that was used to withdraw the suspension out of the vial and discard the 
needle properly. 
 
10. Place an overlay around the prepared syringe to maintain the blind. 
 
11. Attach a 23G x 1½ inch (or equivalent) needle to the Luer connection of the prepared CAB 
LA syringe for IM injection for the participant. Alternatively, the site pharmacist can attach a 
syringe cap to the prepared syringe. The study staff can then attach the appropriate needle for 
administration to the prepared syringe in the clinic before administration. 
 
NOTE: The participant-specific prepared CAB LA in a syringe is to be de-aerated by 
administrator prior to injection so that the correct volume can be administered. 
 
De-aerate the syringe by first tapping with a finger against the syringe and then by 
moving the plunger rod carefully forward with the needle in an upright position until the 
first drop of suspension appears.  Remove the excess suspension in order to administer 
the correct volume (3 mL).  If needed, collect the excess suspension in a beaker to avoid 
spilling. 

 
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12. Record the time that the suspension was withdrawn from the vial and into the syringe in the 
participant’s pharmacy log.  This is the time of preparation. 
 
13. Label the prepared syringe containing 3 mL (600 mg) of CAB-LA in a blinded fashion as 
“CAB LA 600 mg or Placebo for CAB LA”, including the volume (3 mL), route (IM), 
participant’s PTID, date and time of preparation, and date and time of expiration. Follow the 
DAIDS Pharmacy guidelines and local regulations for preparing the participant specific 
label. 
 
After withdrawal of the CAB-LA suspension from the vial into a syringe, it is recommended to 
inject the suspension immediately. Do not exceed 2 hours between withdrawing the contents of 
the vial(s) into a syringe (Step 8) and administration to the study participant.  
 
The prepared CAB LA study product in a syringe must be stored at controlled room temperature 
between 20°C to 25°C (68°F-77°F) from the time it is withdrawn into a syringe to the time it is 
administered. 
 
Any entered vials or expired filled syringes should be disposed of in accordance with 
institutional or pharmacy policy. 
 
Preparation of Placebo Injectable Study Product (Intralipid 20%/ 3 mL syringe) 
 
The designated pharmacy personnel will follow the steps below for preparation of placebo 
injectable study product. Placebo for CAB LA injectable suspension is Intralipid 20% fat 
emulsion infusion. In Step 2 of the study, for the participants in Arm B, one syringe containing 
3mL of intralipid 20% fat emulsion infusion will be prepared using aseptic technique under a 
pharmacy BSC/Isolator. 
 
Materials required for preparation and administration Placebo for CAB LA (Intralipid 20%) 3 
mL dose: 
1. One 100 mL IV bag of intralipid 20% fat emulsion  
2. Becton Dickenson (BD) 3-mL syringe, Leur-Lok Tip, Product No.: 309657 or equivalent 
3. Becton Dickinson (BD) 5-mL Syringe, Luer-Lok Tip, Product No.: 309646 or equivalent 
4. Needle for aspiration: BD general use sterile hypodermic needle, 21G x 1½ inch (e.g. 
PrecisionGlide Needle, Product No.: 305165 or equivalent) 
5. Needle for intramuscular injection: BD IM sterile hypodermic needle, 23G x 1½ inch (e.g. 
PrecisionGlide Needle, Product No.: 305194 or equivalent) 
 
Preparation Steps: 
 
1. Remove one 100 mL IV bag of Intralipid 20% from storage. If the bags are stored in the 
refrigerator (2°C to 8°C), remove bag from the refrigerator and wait at least 15 minutes to 
equilibrate to room temperature. 
 

 
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2. Using aseptic technique under a pharmacy BSC/ Isolator, wipe the additive port of the 
infusion bag with an alcohol pad (isopropyl alcohol 70% or similar) and allow to dry. 
 
3. Remove a 3 mL or 5 mL size syringe and 21G x 1½ inch (or equivalent) needle for 
aspiration. Attach the needle to the Luer connection of the syringe.  
 
4. Remove the needle sheath.   
 
5. Push the needle through the additive port of the infusion bag and withdraw 3mL of Intralipid 
20% into the syringe. 
   
6. Since the suspension can still contain some air, withdraw enough suspension from the 
Intralipid 20% IV bag in order to be able to de-aerate the syringe properly. 
 
7. Remove the needle that was used to withdraw the suspension out of the Intralipid IV bag and 
discard the needle properly. 
 
8. Place an overlay around the dosing syringe to maintain the blind. 
 
9. Attach a 23G x 1½ inch (or equivalent) needle to the Luer connection of the prepared 
Intralipid 20% (placebo) syringe for IM injection for the participant. Alternatively, the site 
pharmacist can attach a syringe cap to the prepared syringe. The study staff can then attach 
the appropriate needle for administration to the prepared syringe in the clinic before 
administration. 
 
NOTE: The participant-specific prepared Intralipid 20% syringe is to be de-aerated by 
administrator prior to injection so that the correct volume can be administered. 
 
De-aerate the syringe by first tapping with a finger against the syringe and then by 
moving the plunger rod carefully forward with the needle in an upright position until the 
first drop of suspension appears.  Remove the excess suspension in order to administer 
the correct volume (3 mL).  If needed, collect the excess suspension in a beaker to avoid 
spilling. 
 
10. Record the time the suspension was withdrawn from the Intralipid 20% IV bag into the 
syringe in the participant’s pharmacy log.  This is the time of preparation. 
 
11. Label the prepared syringe containing 3 mL of Intralipid 20% suspension in a blinded fashion 
as “CAB LA 600 mg or Placebo for CAB LA”, including the volume (3 mL), route (IM), 
participant’s PTID, date and time of preparation, and date and time of expiration. Follow the 
DAIDS Pharmacy guidelines and local regulations for preparing the participant specific 
label. 
 
12. Any entered IV bag or expired filled syringes should be disposed of in accordance with 
institutional or pharmacy policy. 
 

 
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After withdrawal of the Intralipid 20% suspension from the IV bag into a syringe, it is 
recommended to inject the suspension immediately.  Do not exceed 2 hours between 
withdrawing from the IV bag into a syringe (Step 5) and administration to the study participant.  
The prepared Placebo for CAB LA study product in a syringe must be stored at controlled room 
temperature between 20° C to 25° C (68° F-77° F) from the time it is withdrawn into a syringe to 
the time it is administered. 
 
4.4 
Study Product Acquisition and Accountability 
Cabotegravir (CAB) 30 mg tablets, Placebo for CAB tablets, and Cabotegravir Long Acting 
(CAB LA) injectables are manufactured and provided by ViiV Healthcare. Intralipid 20% IV 
bags are manufactured by Fresenius Kabi and provided by ViiV Healthcare. TDF 300 mg/FTC 
200 mg tablets and Placebo for TDF/FTC tablets are manufactured and provided by Gilead 
Sciences, Inc. 
 
4.4.1 Study Product Acquisition 
All study products (active drug and placebo) will be supplied by 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.    
4.4.2 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. At US clinical research sites, all unused study products must be returned to the 
CRPMC after the study is completed, terminated or otherwise instructed by the study sponsor. 
The procedures to be followed are provided in the Pharmacy Guidelines and Instructions for 
DAIDS Clinical Trials Networks. The site pharmacist at non-US clinical research sites must 
follow the instructions in the Pharmacy Guidelines and Instructions for DAIDS Clinical Trials 
Networks DAIDS Pharmaceutical Affairs for the destruction of unused study products. 
 
4.5 
Toxicity Management 
Toxicity management guidelines can be found in Appendix III.    
4.6 
Concomitant, Prohibited, and Precautionary Medications 
As noted in the SSP Manual Section 9, a variety of medications including rifampicin, rifapentine 
and rifabutin are contraindicated for concurrent use with cabotegravir. If treatment for any 
condition requiring the use of a prohibited medication (including but not limited to TB or LTBI) 
is planned, blinded study product should be held. Depending on which step the participant is in, 
the participant will be offered study-provided open label TDF/FTC during the course of 
prohibited medication use and may return to blinded study product once the prohibited 
medication use is completed.  This is also applicable to any participant who stopped blinded 

 
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study product prior to all relevant national and local approvals of Version 3.0 of the protocol.  
Sites must contact the CMC for clinical guidance on implementation of this blinded study 
product hold, concurrence on the appropriateness of planned resumption of blinded study 
products upon prohibited medication completion, and resumption of blinded study products 
when/if appropriate.  Section 9 of the SSP provides guidance regarding the visit schedule during 
the use of study-provided open label TDF/FTC while using a prohibited medication.     
 
As also outlined in the SSP Manual Section 9, non-study provided TDF/FTC or TAF/FTC for 
PrEP is not permitted during any portion of HPTN 083.  Exceptions to this include that non-
study provided PrEP may be used per primary care physician discretion during annual follow-up 
(when participants are off study-provided product per protocol) and during Step 3 in 
circumstances in which a participant is not on study-provided open label TDF/FTC per protocol 
(e.g., in the case of an AE).    
The precautionary and prohibited medications are: 
 
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 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 

 
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o dabigatran 
o dalteparin 
o enoxaparin 
o fondaparinux 
o heparin 
o lepirudin 
o prasugrel 
o rivaroxaban 
o ticagrelor 
o ticlopidine 
o warfarin 
• Oral formulation precautions 
o Antacid products containing divalent cations (e.g., aluminum, calcium, and magnesium) 
must be taken at least 2 hours before or at least 4-6 hours after the oral CAB 
administration  
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) 
Intralipid 20% fat emulsion: There are no precautionary/prohibited medications in the current 
package insert for Intralipid 20% fat emulsion. 
 
Additional information regarding recommended, prohibited, and precautionary concomitant 
medications can be found in the cabotegravir IB and the Truvada® PI.   
 
The precautionary and prohibited medications listed above are also included in Section 9 of the 
SSP Manual; refer to that section for other information.   
   

 
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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). Alcohol and recreational or 
street drug use reported by a participant during the study will be recorded in the participant’s 
study chart only (and not captured on the concomitant medication log for inclusion in the study 
database).  
4.7 
Other Study Product Dispensing Considerations 
While it is not required, it is recommended that sites dispense two bottles of each study product 
(TDF/FTC or placebo and CAB or placebo) at Week 0, two bottles of oral TDF/FTC or placebo 
at Week 5, and three bottles at each dispensation visit throughout Step 2 to ensure an extra month 
supply between visits. Participants should be advised to bring open bottles to appointments, 
finish an open bottle before opening a new one, and should not combine or transfer pills between 
open bottles. A formal pill count is not required in Step 2 (or Step 3), but an open bottle can be 
used to assist with determining refill quantity (that is, whether there is sufficient remaining oral 
study product supply in the participant’s possession that only two bottles need be dispensed and 
still maintain a three-month supply in the participant’s possession). 
 
It is important to dispense all study products at each visit at which study product dispensation is 
scheduled per protocol. For example, if during Step 2 a participant reports for an injection visit 
but refuses the injection or does not receive the injection for any other reason, oral study product 
should not be dispensed. Participants should either receive all study products at each visit where 
study product is scheduled to be dispensed, or no study products. 
 
 

 
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5.0 
STUDY PROCEDURES 
Overviews of the study visit and procedures schedules are presented in Appendix IA, Appendix 
IB, Appendix IC, and Appendix ID, and Appendix II in the event of suspected and confirmed 
HIV infection. Appendix IE, Appendix IF, and Appendix IG include the required HIV testing 
algorithm for screening, enrollment and follow-up, respectively (these are also included in the 
SSP). Presented below is additional information on visit-specific study procedures. Detailed 
instructions to guide and standardize all study procedures across sites are included in the SSP 
Manual. 
5.1 
Screening 
It is the responsibility of the local site to determine the best approach to screening.  For each 
participant, independent written informed consent will be obtained before any study procedures 
are initiated. Screening procedures may occur over one or more visits. The SSP Manual provides 
additional information regarding the procedures outlined below, including clinical and laboratory 
procedures and requirements. Enrollment must occur within 45 days of specimen collection 
(except for HIV RNA, which must be collected, and results obtained within 14 days before 
enrollment) for the clinical and laboratory evaluation and procedures outlined below. The 
following evaluations and procedures will occur as part of screening: 
Administrative, Behavioral, and Regulatory Procedures  
• Informed consent 
• Administer SexPro assessment (US only for inclusion purposes; South American sites 
only for data collection purposes currently) 
• Locator information 
• HIV counseling 
• Offer condoms and lubricant 
Clinical Procedures 
• Target medical history (including bleeding history) and targeted physical exam for 
ascertainment of eligibility, and concomitant medications 
• ECG (will serve as baseline value) 
• Blood collection 
Laboratory Evaluations 
• HIV testing (see SSP Manual), including testing for acute HIV infection within 14 days 
prior to enrollment 
• Hepatitis testing (HBsAg and HCVAb testing required at Screening) 
• CBC with differential 

 
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• Chemistry testing (creatinine is the only required chemistry at Screening)  
• Liver function testing (LFT) (ALT and total bilirubin are the only required LFTs at 
Screening) 
• Plasma storage (can be discarded if participant does not enroll utilizing sample lists 
provided by the HPTN SDMC in consultation with the HPTN LC)  
Sites will follow the HIV testing algorithm for Screening included in the SSP Manual. If a 
reactive/positive result is obtained for any HIV test, the person is not eligible for the study.  
Additional testing to confirm suspected HIV infection during Screening will be performed in 
accordance with local guidelines. If HIV infection is confirmed, participants will receive 
counseling and be referred for appropriate care, as necessary.   
Individuals deemed not eligible will be informed that they do not meet the elibility criteria for 
the study and will be referred for appropriate medical care, if necessary.   
Potential participants may be rescreened once at the discretion of the IoR or their designee.  
Further re-screening for administrative reasons may be permitted with the approval of the CMC. 
However, potential participants with clinically-significant cardiovascular disease as outlined in 
the exclusion criteria in Section 3.2, or any reactive HIV test, may not be re-screened. 
Participants with symptoms concerning for acute HIV infection (per IoR or designee) may be re-
screened in consultation with the CMC once appropriate testing has ruled out acute HIV 
infection.      
Eligible participants should be reminded that the use of anticoagulant and/or antiplatelet 
medications as outlined in the SSP Manual are prohibited within 7 days before and 7 days after 
injections. Reminders should be built in to the concomitant medication history.     
5.2 
Step 1:  Week 0 - Enrollment 
Administrative, Behavioral, and Regulatory Procedures  
• Locator information 
• Demographic information (sites may collect this information at Screening at IoR 
discretion) 
• Randomization 
• HIV counseling 
• Offer condoms and lubricant 
• Baseline acceptability assessment 
• Baseline behavioral assessment 
• Adherence counseling 

 
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Clinical Procedures 
• Complete medical history and complete physical exam, per section 9 of the SSP Manual, 
including concomitant medications, as well as height, weight, blood pressure, and pulse 
data entry into Medidata Rave (the complete medical history and complete physical exam 
may be performed during screening at the discretion of the Investigator of Record or their 
designee).  Note: The collection of height is a one-time data entry into Medidata Rave.      
• For BMD Subset only:  DXA scan, and dietary calcium and Vitamin D assessment.  The 
scan may be performed -30 days/+7 days of enrollment.  
• Blood collection (collect prior to administration of study product) 
• Urine collection for urinalysis  
• Urine collection for Neisseria gonorrheae (GC) and Chlamydia trachomatis (CT)  
• Rectal swab for GC/CT testing  
• Dispense oral study product (enough for 5 weeks) (Dosing should begin on the day of 
Enrollment or no later than 24 hours after Enrollment)  
Laboratory Evaluations 
• HIV testing (see SSP Manual) 
• Hepatitis B testing (HBsAb and HBcAb required at enrollment) 
• CBC with differential 
• Chemistry testing (see Appendix IA) 
• Liver function testing (see Appendix IA) 
• Fasting lipid profile and fasting glucose (participants should be fasting for at least 8 
[preferably 12] hours prior to sample collection) (see Appendix IA) 
• Syphilis serology 
• BMD Subset only:  25-OH-Vitamin D  
• Urine GC/CT testing    
• Rectal swab GC/CT testing  
• Urinalysis (protein and glucose) 
• Plasma storage 
• Whole blood storage for Pharmacogenomics testing (at the discretion of the study site).  
For sites that store samples for this testing, participants must provide specific consent). 
NOTE 1: All HIV test results including testing for acute HIV testing from Screening 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, LFTs, lipid profile, 

 
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hematology testing, and urinalysis from this visit are NOT required prior to the issue of study 
product.   
NOTE 2: Throughout this section, the CASI and interviewer-administered assessments are 
referred to as “behavioral” and “acceptability” assessments. Refer to the SSP Manual Schedule 
of Forms for the schedule of CASI and interviewer-administered assessments. 
5.3 
Step 1:  Weeks 2 and 4 – Oral Safety Visits   
Administrative, Behavioral, and Regulatory Procedures 
• Locator information 
• HIV counseling 
• Offer condoms and lubricant 
• Adherence counseling  
• Pill count 
Clinical Procedures 
• Targeted medical history and targeted physical exam, including concomitant medications, 
as well as weight, blood pressure, and pulse data entry to Medidata Rave 
• Blood collection 
Laboratory Evaluations 
• HIV testing (see SSP Manual) 
• CBC with differential 
• Chemistry testing (see Appendix IA) 
• Liver function testing (see Appendix IA) 
• Plasma storage  
• DBS storage (Week 4 only)  
NOTES for Weeks 2 and 4:   
All HIV test results from previous visits and at least one HIV test result from the current visit 
must be available and reviewed. If any of these tests is reactive/positive, study drug should be 
discontinued.   
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 2, study drug may continue to Week 4. If the repeat value is < Grade 2 at Week 

 
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4, the participant may proceed to Step 2 injection phase. If repeated value is Grade 2 or higher at 
Week 4, study product should be stopped, and the participant will be followed annually until 
three years from the date of Enrollment. 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. If an etiology for elevated ALT is identified or persistent without explanation, the CMC may 
direct an alternate interval for follow-up.  
A Grade 3 or higher ALT abnormality reported at Week 2 or Week 4, regardless of relatedness to 
the study product, will prohibit a participant from entering the injection phase of the study, and 
the participant will be followed annually until three years from the date of Enrollment.  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. If an etiology for elevated ALT is identified or 
persistent without explanation, the CMC may direct an alternate interval for follow-up. 
Excluding ALT, any grade 3 clinical or laboratory AE observed prior to Week 5 will prompt 
consultation with the CMC prior to any injectable dosing.    
Grade 3 adverse events deemed related to study product, or a Grade 3 ALT, or any Grade 4 
adverse event will lead to permanent study product discontinuation, and the participant will be 
followed annually until three years from the date of Enrollment. AEs will be followed until 
resolution (< grade 1) in consultation with the CMC. 
Note the following for cases of exercise-induced CK abnormalities: Cases of CK abnormality at 
the Grade 3 or higher level accompanied by ALT abnormalities of Grade 3 or lower up to and 
including Grade 3 should be brought to the attention of the CMC for adjudication of further 
management and further administration of study product. Grade 4 elevations in ALT, regardless 
of CK elevation will prompt permanent discontinuation of study product and the participant will 
be followed annually until three years from the date of Enrollment. All such cases must be 
reported to the CMC. 
The Week 4 visit must take place within 120 days of study enrollment. Participants with pill 
counts resulting in less than 50% adherence as assessed by pill count at the Week 4 visit will not 
be allowed to transition to Step 2. These participants will be asked to report for annual visits until 
three years from the date of Enrollment. Refer to Section 5 of the SSP for instructions regarding 
participants who forget to bring their pill bottles to the Week 4 visit.     
For participants who do not transition to Step 2 as outlined above, the following procedures will 
take place (see also Appendix ID) 
• Review/update locator information  
• Targeted medical history and targeted physical exam, with concomitant medications 
update  
• HIV pre and post-test counseling  
• HIV testing, plasma storage, DBS storage  
• Offer condoms and lubricant   

 
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5.4 
Step 2:  Weeks 5 – First injection visit in Step 2 
Administrative, Behavioral, and Regulatory Procedures  
• Locator information 
• HIV counseling 
• Offer condoms and lubricant  
• Behavioral assessment 
• Adherence counseling 
Clinical Procedures 
• Targeted medical history and targeted physical exam, including concomitant medications, 
as well as weight, blood pressure, and pulse data entry into Medidata Rave 
• Blood collection 
• Administer injection 
• Dispense pills 
Laboratory Evaluations 
• HIV testing (see SSP Manual) 
• Plasma storage 
NOTE 1: All HIV test results from previous visits and at least one HIV test result from the Week 
5 visit must be available and confirmed to be negative/non-reactive PRIOR to injection of study 
product. The injection must not be given if any HIV test is reactive/positive.  
Results from all Week 4 clinical and laboratory evaluations (e.g., chemistry, LFTs, hematology) 
must be available and be reviewed by the IoR or their designee prior to injection.   
NOTE 2:   Refer to Section 5 of the SSP regarding instructions for split visits where the 
injection was not administered during the first half of the split visit, and for merged visits where 
in unforeseen circumstances, a safety visit and an injection visit occur on the same day. 
5.5 
Step 2:  Week 6 – Safety visit following first injection  
Administrative, Behavioral, and Regulatory Procedures  
• Locator information 
• HIV counseling 
• Offer condoms and lubricant 
• Adherence counseling 

 
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Clinical Procedures 
• Targeted medical history and targeted physical exam, and concomitant medications 
• Blood collection 
• ISR evaluation 
Laboratory Evaluations 
• HIV testing (see SSP Manual) 
• CBC with differential 
• Chemistry testing (see Appendix IB)  
• Liver function testing (see Appendix IB) 
• Plasma storage  
5.6 
Step 2:  All remaining visits where injections occur - Weeks 9, 17, 25, 33, 41, 49, 57, 65, 73, 
81, 89, 97, 105, 113, 121, 129, 137, 145 
Administrative, Behavioral, and Regulatory Procedures  
• Locator information 
• HIV counseling 
• Offer condoms and lubricant 
• Behavioral assessment (only at Weeks 9, 17, 25, 33, 41, 49, 57, 65, 73, 81, 89, 97, 105, 
121, 137) 
• Acceptability assessment (only at Weeks 17, 41, 65, 89, 137) 
• Adherence counseling 
Clinical Procedures 
• Targeted medical history and targeted physical exam, including concomitant medications, 
as well as weight, blood pressure, and pulse data entry to Medidata Rave 
• ECG (only at Weeks 57, 105) 
• BMD Subset only (only at Weeks 57 and 105):  DXA scan, and dietary calcium and 
Vitamin D assessment.  These scans may be performed -/+ 8 weeks of each visit).   
Note: If a participant in the BMD subset prematurely transitions out of Step 2 to Step 3 or 
annual visits, and the transition occurs close to the Week 57 or Week 105 DXA 
timepoints, the CMC may authorize that a DXA be performed    
• Blood collection 
• Urine collection for urinalysis (only at Weeks 57, 105) 

 
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• Urine collection for GC/CT testing (only at Weeks 33, 57, 81, 105, 129) 
• Rectal swab for GC/CT testing (only at Weeks 33, 57, 81, 105, 129)  
• Administer injection 
• Dispense pills  
Laboratory Evaluations 
• HIV testing (see SSP Manual) 
• HCV testing (only at Weeks 57, 105) 
• CBC with differential 
• Chemistry testing (see Appendix IB) 
• Liver function testing (see Appendix IB) 
• Fasting lipid profile and fasting glucose (only at Weeks 57, 105) (see Appendix IB) 
• Syphilis serologic testing (only at Weeks 33, 57, 81, 105, 129) 
• Urinalysis (only at Weeks 57, 105) 
• Urine GC/CT testing (only at Weeks 33, 57, 81, 105, 129) 
• Rectal swab GC/CT testing (only at Weeks 33, 57, 81, 105, 129)  
• Plasma storage 
• DBS storage 
NOTE 1: All HIV test results from previous visits and at least one HIV test result from the 
current injection visit must be available and confirmed to be negative/non-reactive PRIOR to 
injection of study product. The injection must not be given if any HIV test is reactive/positive.  
Results from the other laboratory evaluations (e.g., chemistry, LFTs, hematology) from the visit 
prior to the injection visit must be available and be reviewed by the IoR or designee prior to 
injection. 
NOTE 2:   Refer to Section 5 of the SSP regarding instructions for split visits where the 
injection was not administered during the first half of the split visit, and for merged visits where 
in unforeseen circumstances, a safety visit and an injection visit occur on the same day. 
5.7 
Step 2:  All remaining safety visits, with Week 10 occurring 1 week after the Week 9 
injection, and every 2 weeks after each injection visit thereafter as - Weeks 10, 19, 27, 35, 43, 
51, 59, 67, 75, 83, 91, 99, 107, 115, 123, 131, 139, 147  
Administrative, Behavioral, and Regulatory Procedures  
• Locator information 
• HIV counseling 

 
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• Offer condoms and lubricant 
• Adherence counseling 
Clinical Procedures 
• Targeted medical history and targeted physical exam, and concomitant medications 
• Blood collection 
• ISR evaluation 
Laboratory Evaluations 
• HIV testing (see SSP Manual) 
• CBC with differential 
• Chemistry testing (see Appendix IB) 
• Liver function testing (see Appendix IB) 
• Plasma storage 
Note:  Refer to Appendix II for any participant who becomes infected with HIV during Step 2.   
5.8 
Week 153, Last Visit of Step 2/ Day 0, First Visit of Step 3 
The final visit of Step 2 will take place at Week 153, which is also Day 0 of Step 3. An injection will not 
be administered at this visit and blinded oral study product will not be dispensed at this visit.  All other 
procedures required for Week 153/Day 0 will be performed.  Any remaining blinded oral study product 
will be collected from the participant as part of the conclusion of Step 2.  Open-label oral product will be 
dispensed at this visit as part of Day 0 of Step 3.  The procedures required at Week 153 (except for 
administration of the injection) and results of testing from Week 153 will also apply to Day 0 of Step 3 
unless otherwise noted below and otherwise directed by the CMC.  Additionally, if the Week 153 visit is 
missed or has already occurred or passed at the time Version 3.0 of the protocol is approved and 
implemented at a site, the final visit of Step 2/first visit of Step 3 will take place at the next visit the 
participant attends; the CMC may be contacted if additional guidance is required in these cases, though 
this is not required.       
 
Administrative, Behavioral, and Regulatory Procedures 
 
• Locator information 
• HIV counseling 
• Offer condoms and lubricant 
• Behavioral assessment 
• Adherence counseling 

 
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Clinical Procedures 
 
• Targeted medical history and targeted physical exam, including concomitant medications 
as well as weight, blood pressure, and pulse data entry to Medidata Rave 
• ECG  
• Blood collection 
• Urine collection for urinalysis  
• Urine collection for GC/CT testing  
• Rectal swab for GC/CT testing   
• Collect any unused blinded oral study product  
• Dispense OPEN-LABEL oral TDF/FTC pills  
Laboratory Evaluations 
 
• HIV testing (see SSP Manual) 
• HCV testing  
• CBC with differential 
• Chemistry testing (see Appendix IB) 
• Liver function testing (see Appendix IB) 
• Syphilis serologic testing  
• Urinalysis  
• Urine GC/CT testing  
• Rectal swab GC/CT testing  
• Plasma storage 
• DBS storage 
NOTE:  If a participant in Step 2 transitions prematurely to Step 3 or misses the Week 153 visit, the 
procedures listed above will be performed as part of the last visit of Step 2 (whenever that occurs)/Day 0 
of Step 3 to the extent possible. All assessments are identical to Week 153/Day 0 listed above with the 
following exceptions:   
• Behavioral assessment – do not administer if done within the last month before entering 
Step 3   
• Acceptability assessment (not listed above) – this should be administered at this visit if it 
was not done in the last 6 months before entering Step 3 
• Urine collection and testing for GC/CT – do not collect/do not perform test if testing 
occurred within 3 months prior to entering Step 3 

 
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• Rectal swab collection and testing for GC/CT – do not collect/do not perform test if 
testing occurred within 3 months prior to entering Step 3 
• Syphilis testing – do not perform test if testing occurred within 3 months prior to entering 
Step 3  
5.9 
Step 3:  Open-label TDF/FTC  
(Weeks 12, 24, 36, 48)  
Administrative, Behavioral, and Regulatory Procedures  
• Locator information (Week 48 location information to be collected for reporting of or 
follow up safety labs/HIV testing after study exit) 
• HIV counseling 
• Offer condoms and lubricant 
• Behavioral assessment (only Weeks 24 and 48; if conducted within the last month before 
entering Step 3, conduct at Weeks 12, 24, and 48).       
• Adherence counseling (Weeks 12, 24, and 36) 
Clinical Procedures 
• Targeted medical history and targeted physical exam, including concomitant medications, 
as well as weight, blood pressure, and pulse data entry to Medidata Rave 
• Blood collection 
• Urine collection for GC/CT testing (Weeks 24, 48) 
• Rectal swab collection for GC/CT testing (Weeks 24, 48) 
• Dispense pills (Weeks 12, 24, 36) 
Laboratory Evaluations 
• HIV testing (see SSP Manual) 
• Chemistry testing (only at Weeks 24 and 48) (see Appendix IC) 
• Liver function testing (only at Weeks 24 and 48) (see Appendix IC) 
• Syphilis testing (only at Weeks 24, 48) 
• Urine GC/CT testing (only at Weeks 24, 48)    
• Rectal swab GC/CT testing (only at Weeks 24, 48)  
• Plasma storage 

 
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NOTE: All HIV test results from previous visits and at least one HIV test result from the current 
visit must be available and confirmed to be negative/non-reactive PRIOR to provision of study 
pills.    
Results from the clinical and laboratory evaluations (e.g., chemistry, LFTs, hematology) must be 
available and be reviewed by the IoR or their designee prior to provision of study pills.    
5.10 Visit Windows 
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 injections 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. 
Additionally, and as already outlined above, the windows for the DXA subset are -30/+ 7 days 
for Enrollment, and +/- 8 weeks for Weeks 57 and 105.  
It is not required to contact the CMC for out of target visit window injection visits provided that 
they are a minimum of 6 weeks from the last injection and a maximum of 15 weeks from the 
prior injection, and for the Week 9 injection, when it is a minimum of 3 weeks from the Week 5 
injection and a maximum of 11 weeks from the Week 5 injection. It is required to contact the 
CMC for guidance in cases outside of these parameters.  
It is not required to contact the CMC for out of target window safety visits no matter when they 
occur; however, an injection visit may never be completed without a preceding safety visit being 
completed and all the assessments being resulted and protocol-allowable. 
5.11 Procedures for Continued Oral and Injectable Dosing 
Appendix III, Toxicity Management, must be referred to regarding general toxicity management, 
as well as specific clinical and laboratory toxicity management guidelines, including directions 
regarding temporary and permanent study product holds.        
5.12 Procedures for Participants Who Do Not Complete the Full Course of Injections 
Participants in Step 1 of the study who are unable to transition to Step 2 of the study for any 
reason other than HIV infection will be asked to attend annual visits until three years from the 
date of Enrollment. These participants will remain blinded to their original randomized 
assignment until all participants complete Step 2 of the study. Participants with confirmed HIV 
infection during Step 1 of the study will not transition to Step 2 of the study but will be referred 
for care and will be terminated from the study.  
Participants in Step 2 of the study that prematurely stop receiving injections due to any reason 
other than HIV infection will be asked to transition to Step 3 of the study and receive 48 weeks 
of open label TDF/FTC, (or may be transitioned to Step 3 off study product for safety reasons 
due to an AE or condition where open label TDF/FTC is contraindicated), followed by annual 
follow-up until three years from the date of Enrollment (see note below). The timepoint during 

 
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Step 2 that a participant transitions to Step 3 will determine whether they will be asked to attend 
annual visits following the completion of Step 3. If the completion of open label TDF/FTC for 
Step 3 post-dates three years from the date of Enrollment, no further annual follow-up is 
required. Once a participant has completed three years of follow-up, they will then be 
transitioned to local prevention services. These participants will remain blinded to their original 
randomized assignment until all participants complete Step 2 of the study. Participants in Step 2 
of the study with confirmed HIV infection will be followed according to Appendix II.   
Note:  Participants who wish to prematurely discontinue injections in Step 2 due to an injection 
site reaction AE must follow procedures detailed in Appendix III, Guidance for Injection Site 
Reactions (ISRs) prior to discontinuation of Step 2 procedures. 
Sites should contact 083HIV@hptn.org for guidance regarding study visit procedures for 
participants that become HIV-infected during Step 3 of the study.    
For participants that transition to annual visits as outlined above, the following procedures will 
take place (see also Appendix ID): 
• Review/update locator information  
• Targeted medical history and targeted physical exam, with concomitant medications 
update  
• HIV pre and post-test counseling  
• Blood collection  
• HIV testing, plasma storage, DBS storage  
• Offer condoms and lubricant 
5.13 Planned Unblinding of Study Participants  
When the last participant completes scheduled Step 2 follow-up, and when all corresponding 
procedures at the HPTN SDMC, LC, and LOC have been completed, the study will be 
unblinded.  
5.13.1 Emergency Unblinding for Medical Reasons 
If, in the judgment of the site investigator of record (IoR), or in the judgment of the 
participant’s medical provider and the site IoR, a medical event is of sufficient extreme 
severity that it requires the immediate unblinding of a participant, the site IoR may proceed 
with unblinding a participant per the instructions in Appendix VI of the SSP (Unblinding 
Medical Emergency) and any separate applicable instructions provided by the HPTN SDMC.  
Emergency unblinding is expected to be extremely rare. It should only occur in the setting of 
a potentially life-threatening clinical event, and if knowing the participant’s treatment 
assignment would affect decisions regarding the participant’s immediate medical 
management. Both conditions must be satisfied.   

 
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5.14 Participants with Suspected or Confirmed HIV Infection, at Screening, Enrollment, or 
Follow-Up 
5.14.1 Screening and Enrollment 
HIV testing will be performed to identify participants with HIV infection.  Individuals who have 
one or more reactive or positive HIV tests at the Screening or Enrollment visit are not eligible to 
participate in this study. Furthermore, at the Screening and Enrollment visit (at Enrollment, prior 
to randomization; and for sites that do split enrollment visits due to physical location constraints, 
prior to administration of study product), 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 will be included in the SSP Manual.   
5.14.2 Follow-up (after study Enrollment) 
Frequent testing for HIV acquisition during the study period 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. Therefore, HIV testing will be performed at all scheduled study 
visits. In addition, if a participant has signs or symptoms consistent with acute HIV infection (see 
above), or expresses a concern about recent HIV acquisition, HIV testing will be performed 
using a ribonucleic acid (RNA) test that, in the opinion of the Investigator of Record or designee, 
is able to detect early HIV infection. If possible, an assay that is US FDA-cleared for early HIV 
diagnosis such as the Aptima HIV-1 RNA Qualitative Assay should be used.   
Regardless of whether HIV RNA testing is used for diagnostic testing, HIV acquisition after 
study enrollment must be confirmed in all cases using two independent samples collected on 
different days.   
Participants who have any reactive or positive HIV test result during follow-up visits will have 
further testing to confirm infection, as described in the SSP Manual and Appendix II. Samples 
from participants with confirmed HIV infection should be sent both to a local laboratory for 
resistance testing to assist with clinical management (results from resistance testing performed in 
local laboratories should not be reported to the HPTN SDMC or the HPTN LC). If a participant 
has a reactive or positive HIV test, the participant will not receive additional doses of study 
products pending further direction regarding testing and continued participation in the study from 
designated study team members (see SSP for email alias regarding suspected HIV infection), 
including the HPTN LC. Refer to the SSP Manual for instructions regarding HIV testing. 
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. 
Participants with confirmed HIV infection during Step 2 will not receive additional injections or 
oral study product and will be followed per the Schedule of Evaluations and Procedures in 
Appendix II for approximately 52 weeks, and will also follow the toxicity management 
guidelines in Appendix III. An Investigator can request unblinding from the HPTN SDMC 
directly to a participant’s primary care provider in the event a participant becomes infected with 

 
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HIV during the study; the randomized assignment will not be provided to the site where the 
participant was enrolled and followed. See Section 7.9 and the SSP Manual. In addition, sites 
will have a standard operating procedure (SOP) that outlines a plan in the event that a participant 
becomes HIV infected during any Step of the study, and in particular during Step 2 of the study, 
which must include the participant’s facilitation into locally-available immediate suppressive 
ART treatment to prevent persistent-monotherapy-related resistance complications for a 
minimum of 52 weeks post-final injection. The sites will not be responsible for the actual 
provision/payment of ART.  ART or funds for provision of ART will not be provided by the 
study. 
Participants with confirmed HIV infection during Step 3 will be followed at least for the duration 
of Step 3, with possible additional assessments and follow-up to be determined by the 
083HIV@hptn.org group. 
It should be noted that all reactive/positive HIV test results will be reviewed by an independent 
HIV Endpoint Adjudication Committee whose responsibility is to determine whether the test 
results meet the primary endpoint of the study of HIV infection.    
5.15 Sexually Transmitted Infections 
Testing for GC/CT and syphilis will occur throughout the study. Testing will be performed at the 
local laboratory. For rectal swabs, if testing cannot be performed at the local laboratory, testing 
at another laboratory may be arranged (see SSP Manual). 
Participants will be referred for treatment of STIs as per local guidelines. Symptomatic screening 
for STIs beyond what is required by the protocol will be performed at a site’s discretion and 
costs associated may come out of each site’s respective per participant study reimbursements.   
Any positive/reactive laboratory test results for syphilis from the time of study enrollment and 
any positive/reactive test during the study must be referred to the CMC for adjudication 
accompanied by any prior testing and treatment results.  The communication with the CMC 
should occur prior to the subsequent study visit at which the positive/reactive testing is resulted. 
Cases of syphilis discovered prior to study participation should be documented as a pre-existing 
condition.  
Sites will report STIs into the study database on the Adverse Event e-CRF as well as the STI e-
CRF.  Further instructions regarding reporting STIs into the database are included in Section 9 of 
the SSP.     
5.16 Hepatitis B and Hepatitis C 
Testing for HBV and HCV will be performed at Screening (HBsAg and HCAb). Persons whose 
screening tests results are not negative will be excluded from study participation and will be 
referred to their primary provider for management. Persons with a positive HCV antibody test at 
Screening will be excluded from the study, even if confirmatory HCV RNA is undetectable. At 
Enrollment, participants will be tested for HBV surface antibody (HBsAb), and HBV Core 
antibody (HBcAb). Participants who do not have evidence of immunity to HBV (e.g., negative 
HBsAb) will be referred for HBV vaccination. For participants who do not have evidence of 

 
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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 only.      
For enrolled individuals, HCV antibody testing will be performed at scheduled visits while on 
Step 2 (see Appendix IB). Incident HCV infection during follow-up will not mandate 
discontinuation of study product absent other requirements per Appendix III- Toxicity 
Management.       
5.17 Interim Contacts and Visits and Missed Visits 
Interim contacts and visits (those between regularly scheduled follow up visits) may be 
performed at participant request or as deemed necessary by the investigator or designee at any 
time during the study.  
Some interim visits may occur for administrative reasons. For example, the participant may have 
questions for study staff. Interim visits at which no data are collected are not documented on case 
report forms. 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 case 
report form, and provide or refer the participant to appropriate medical care.   
In general, when a visit is missed altogether and a participant reports to the site for 
the next scheduled visit, the procedures from the missed visit that are not also 
required for the current visit should be performed. 
Refer to the SSP Manual for further details regarding management of such visits. 
5.18 Criteria for Early Termination of Study Participation 
Refer to Section 3.6 of the protocol.   
5.19 Pharmacokinetic Monitoring 
Plasma and DBS will be collected throughout the study for pharmacokinetic assessments. The 
specimen type(s) used to assess adherence to TDF/FTC will be determined by the HPTN LC.  
Results of this testing will not be provided to study sites or participants.  
5.20 Other Considerations for Premature Transition from Step 2 to Step 3    
In other circumstances prompting premature transition from Step 2 to Step 3, if a return to Step 2 
blinded study products is feasible and desirable, contact the CMC for guidance on the 
permissibility and operationalization of such a resumption of blinded study products.  For 
example, a participant may transition prematurely to Step 3 due to relocation to an area where 
there is no HPTN 083 clinical site; if this participant were to relocate again to an area where 
there is an HPTN 083 clinical site (including back to the original location), he or she could be 

 
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considered for a return to Step 2, with resumption of blinded study products, in consultation with 
the CMC.  Protocol-mandated premature transitions to Step 3 for adverse clinical or laboratory 
events are not eligible for return to Step 2 blinded study products, even if the adverse event has 
resolved.

 
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6.0 
SAFETY MONITORING AND ADVERSE EVENT (AE) REPORTING 
6.1 
Safety Monitoring 
Close cooperation between the Protocol Chair, study site Investigator(s), DAIDS Medical 
Officer, LOC Clinical Research Manager, SDMC Biostatistician, SDMC Clinical Affairs Staff, 
HPTN LC, and other study team members will be necessary in order to monitor participant 
safety and to respond to occurrences of toxicity in a timely manner. The team will have regularly 
scheduled conference calls during the period of study implementation, and additional ad hoc 
calls will be convened if required. 
The study site Investigators are responsible for continuous close monitoring and management of 
AEs in conjunction with IoRs. 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 Clinical Management Committee (CMC – 
outlined below) if unexpected concerns arise. 
A sub-group of the Protocol Team, including the Protocol Chair, DAIDS Medical Officer, and 
other site investigators will serve as members of the CMC. The CMC provides support to sites 
regarding individual participant clinical management (e.g., questions related to eligibility, 
toxicity management, clinical holds of study drug, etc.). Sites will be instructed to not solicit 
guidance from the CMC regarding HIV seroconversions in order to ensure to the extent possible 
that the team is blinded to the number of infections occurring in the study. The HPTN LC will be 
available for questions regarding HIV confirmation testing. 
6.2 
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 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. 
The SDMC will prepare routine study conduct and safety reports for the SMC, which will meet 
by conference call approximately every 6 months and will review accrual and retention data, as 
well as safety data. 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, which will 
meet at least annually to review safety and efficacy data.   

 
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6.3 
Adverse Event 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 e-CRF AEs (Grade 1 and 
higher clinical AEs, as well as Grade 2 and higher laboratory AEs, and any AE (clinical or 
laboratory) that leads to a study product hold (temporary or permanent) will be captured on AE 
e-CRFs) reported by or observed in enrolled (defined as after randomization has occurred) 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, Version 2.1 
corrected, July 2017.  STIs will be dually reported on the AE e-CRF as well as the STI e-CRF 
(see Section 9 of the SSP for further details related to STI reporting into the study database).      
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 AE to study product will be assessed as specified in 
Version 2.0, January 2010 of the DAIDS Expedited Adverse Event (EAE) Reporting Manual.   
6.4 
Expedited Adverse Event Reporting 
Requirements, definitions, and methods for expedited reporting of adverse events are outlined in 
Version 2.0 of the DAIDS EAE Manual, which is available on the DAIDS Regulatory Support 
Center (RSC) website at https://rsc.niaid.nih.gov/clinical-research-sites/manual-expedited-
reporting-adverse-events-daids.   
6.4.1 Reporting to DAIDS 
The DAIDS Adverse Event Reporting System (DAERS), an internet-based reporting system, 
must be used for EAE reporting to DAIDS. In the event of system outages or technical 
difficulties, EAEs may be submitted via the DAIDS EAE form. This form is available on the 
DAIDS RSC website at https://rsc.niaid.nih.gov/clinical-research-sites/paper-eae-reporting. For 
questions about DAERS, please contact CRMSSupport@niaid.nih.gov. Site queries may also be 
sent with the DAERS application itself. 

 
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For questions about EAE reporting, please contact the RSC at DAIDSRSCSafetyOffice@tech-
res.com. 
6.4.2 Reporting Requirements for this Study 
The Serious Adverse Event (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 required for each study participant from enrollment until their 
follow-up in the study ends. After this time, sites must report to DAIDS serious, unexpected, 
clinical suspected adverse drug reactions, as defined in Version 2.0 of the DAIDS EAE manual, 
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 or placebo; 
CAB LA injectable suspension (200mg/mL) or placebo; TDF/FTC fixed dose combination tablet 
containing 200 mg of FTC and 300 mg of TDF or placebo (also outlined in Section 4.0). 
In addition to submitting EAE information to the DAIDS Safety Office via DAERS, the site 
investigator may be required to submit AE and EAE information to local regulatory agencies or 
other local authorities. 
Information on Grade 1 and higher AEs will be included in reports to the US FDA, and other 
government and regulatory authorities as applicable. Site staff will report information regarding 
AEs to their IRB in accordance with all applicable regulations and local IRB requirements. 
6.4.3 Grading Severity of Events 
The Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, 
Corrected Version 2.1, July 2017, will be used for determining and reporting the severity of 
adverse events. 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. 
6.5 
Social Impact Reporting 
It is possible that participants' involvement in the study could become known to others, and that a 
social impact may result (i.e., because participants could be perceived as being HIV-infected or 
at risk or "high risk" for HIV infection). For example, participants could be treated unfairly, or 
could have problems being accepted by their families and/or communities. A social impact that 
is reported by the participant and judged by the IoR/designee to be serious or unexpected will be 

 
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reported to the responsible site’s IRBs at least annually, or according to their individual 
requirements. Social impacts will be collected and reported on CRFs during regular visits. In the 
event that a participant reports a social impact, 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 CAB in exploring the social context 
surrounding instances of social impacts, to minimize the potential occurrence of such an impact. 
 

 
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7.0 
STATISTICAL CONSIDERATIONS 
7.1 
Review of Study Design 
This is a Phase 2b/3 randomized, multi-site, two-arm, double-blinded, double-dummy study of 
the safety and efficacy of CAB LA vs. TDF/FTC for MSM and TGW. Eligible participants will 
be randomized 1:1 to receive either oral CAB/CAB LA or matching placebo or daily oral 
TDF/FTC or matching placebo, and move through 3 steps. Participants will be assigned either 
active cabotegravir or active TDF/FTC – no participant will receive placebo only. In Step 1, 
study participants will receive oral tablets for 5 weeks, followed by entering Step 2 and 
undergoing a single injection at two time points 4 weeks apart and every 8 weeks thereafter and 
daily oral tablets for a total of 3 years. In Step 3, all participants will receive open-label daily oral 
TDF/FTC for up to 48 weeks.  Participants will therefore be followed for 3 years on blinded 
study product and 48 weeks on open-label daily oral TDF/FTC. All participants will transition to 
local HIV prevention services after their completion of Step 3.    
7.2 
Considerations in Non-Inferiority Trials 
Large, high-quality clinical trials have previously established that TDF/FTC can be a highly 
effective HIV PrEP agent when adherence to the drug is high (iPrEx, TDF2, Partners-PrEP, and 
presumably PROUD and IPERGAY). When good evidence exists that supports the use of a 
readily available, FDA-approved product, and in particular when the endpoint of interest is 
serious (such as HIV infection), it is generally considered unethical to conduct a placebo-
controlled trial. The International Conference on Harmonization guidance E10 on Choice of 
Control Group and Related Issues in Clinical Trials (ICH E10) states:  
In cases where an available treatment is known to prevent serious harm, such as death or 
irreversible morbidity in the study population, it is generally inappropriate to use a placebo 
control. [The term “generally” leaves room for a placebo control if the known effective treatment 
is very toxic.]  
In addition, recent guidance from UNAIDS/WHO on Ethical Considerations in Biomedical HIV 
Prevention Trials (Guidance Point 15) states that “the use of a placebo control arm is ethically 
acceptable in a biomedical HIV prevention trial only when there is no HIV prevention modality 
of the type being studied that has been shown to be effective in comparable populations.” 
Providing a placebo in the context of HIV PrEP would be the same as withholding the effective 
drug, TDF/FTC, which is nontoxic and has few serious side effects (iPrEx, TDF2, Partners-PrEP, 
PROUD, iPERGAY). Therefore, rather than comparing CAB LA to placebo, a non-inferiority 
trial is proposed to evaluate whether CAB LA is not unacceptably worse than (“non-inferior” to) 
the active comparator TDF/FTC. If CAB LA is shown to be non-inferior to TDF/FTC, it can be 
inferred with reasonable certainty that CAB LA is effective. 
7.2.1 Constancy 
A positive result in a non-inferiority trial must be interpreted with caution. Establishing non-
inferiority could mean either that both treatments are similarly effective, or that both treatments 
are similarly ineffective. In order to assure that a positive trial indicates efficacy, it is critical to 
select a study population in which the standard regimen has been shown to work and is expected 

 
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to work in the future. The term “constancy” is often used to describe the degree to which the 
active control is effective in a new study population. A critical factor defining constancy for 
TDF/FTC is drug adherence. TDF/FTC efficacy (as with most drugs) is highly dependent on 
adherence, hence the degree to which CAB LA would be judged to be effective based on a 
comparison with oral TDF/FTC would depend heavily on observed TDF/FTC adherence.   
Although there is some suggestion that oral TDF/FTC may have higher efficacy for rectal 
exposures than for vaginal exposures, strong evidence does not yet exist to conclude this.   
Regardless, HPTN 083 will recruit only TGW and MSM, both of whom are expected to have the 
highest risk of HIV acquisition based on rectal exposure, and prior studies suggest that TDF/FTC 
is effective in this population. 
7.3 
Justification of the Non-inferiority Margin 
The protocol design is based on a pre-specified NI margin that preserves 50% of the lower bound 
of proven efficacy in this risk population, using a combination of statistical, prevention and 
clinical judgment. This section describes the data that support the margin, the effect of different 
adherence assumptions on the choice of margin and interprets the margin as an absolute increase 
in number of infections.  
7.3.1 Selecting a Non-inferiority Margin (M1 versus M2) 
The non-inferiority margin is the degree to which the experimental intervention can have lower 
efficacy than the active control, but not be considered “clinically unacceptably worse.” Defining 
the non-inferiority margin requires knowledge of the effect size provided by the active control, 
preferably based on multiple high-quality controlled trials. This is the M1 margin. It also requires 
an assessment of the “clinically acceptable” degree of inferiority, or the proportion of the active 
drug effect that must be preserved. This is the M2 margin, which is always stricter than M1. 
When defining the effect size of TDF/FTC, it is fortunate to have results from five large, high-
quality, controlled trials (iPrEX, TDF2, Partners-PrEP, VOICE, FEM-PrEP), as well as two 
smaller studies in MSM (PROUD and iPERGAY) which allow to estimate TDF/FTC efficacy. 
Meta-analysis can be used to combine results from existing trials, and estimate confidence 
bounds (see Section 7.3.2). 
A standard practice to define the margin is to define M1, or the active-control efficacy, as the 
lower bound of the 95% confidence interval for the efficacy estimate for placebo compared to 
the standard of care (TDF/FTC). The lower bound is used as a conservative estimate of efficacy, 
acknowledging both the uncertainties associated with sampling variation and the potential that 
the constancy assumption may not be perfectly met in a new study. M2 is defined relative to this 
M1. In a successful trial, the upper 95% confidence bound on the relative efficacy (experimental 
treatment versus active control) will fall below the pre-specified non-inferiority margin. This 
method, requiring that the upper bound of the NI study’s 95% CI falls below some fraction of the 
lower bound of the 95% CI from the originator’s studies is referred to as the “95-95” method. 
The key question is where to determine the M2 margin. Clinical judgment comes into play when 
defining this margin. One metric for acceptability of the margin is the absolute effect: in this 
setting, the number of additional infections per (e.g.) 10,000 patient years of exposure in the 

 
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studied population were cabotegravir to be licensed. A second metric is the relative 
effectiveness: to set M2 to preserve a fixed proportion of M1, e.g., select M2 to preserve at least 
half of the (lower bound of) active-control efficacy. Both measures should be taken into account. 
Because it is believed to be clinically and ethically important that a new PrEP modality provide 
not just minimal efficacy, but also preserve a meaningful amount of TDF/FTC’s effect, the 
protocol is designed using an M2 margin that preserved 50% of the M1 margin. 
7.3.2 Deriving the M1 Margin Using Meta-analysis of Existing PrEP Trial Results 
Estimating efficacy for the active control in a non-inferiority trial requires results from prior 
trials, if available, and meta-analysis is often used to combine those prior results. It is fortunate 
to have five large, high-quality, controlled trials (iPrEX, TDF2, Partners-PrEP, VOICE, FEM-
PrEP), as well as two smaller studies in MSM (PROUD and iPERGAY), all of which can be 
incorporated in to meta-analytic models. The difficulty, however, is that these existing trials were 
conducted in widely varying populations with widely varying levels of adherence. To satisfy the 
constancy assumption, TDF/FTC efficacy must be estimated using settings that closely match the 
setting of the proposed study. Given the heterogeneity between existing PrEP trials, directly 
combining the results from those trials (e.g., using fixed-effects meta-analysis) may not be 
appropriate.   
Several approaches are possible. First, the iPrEX trial is the only major trial of TDF/FTC among 
MSM and TGW in study locations that are similar to the locations planned for HPTN 083: the 
iPrEx study locations were primarily in the Americas, but also included participants from 
Thailand and South Africa. Based on transmission risk factors and demographic similarities, it 
could make sense to use the iPrEx results alone to estimate TDF/FTC efficacy and the 
corresponding non-inferiority margin. However, the adherence level to TDF/FTC in iPrEx was 
only moderate (reported as 51%1). After publication of iPrEx results, and in combination with 
the strong positive results from Partners PrEP, TDF2, iPERGAY, and PROUD, there is broad 
confidence in TDF/FTC. This confidence may translate into higher overall adherence in HPTN 
083, and consequently increase TDF/FTC’s efficacy in HPTN 083 as compared to iPrEx. 
A second option would be to combine the results from the three trials conducted in MSM, 
namely iPrEx, iPERGAY, and PROUD. The latter two trials are relatively small, but their higher 
efficacy presumably resulted from higher adherence (not published), and the combined results 
from these three trials (using a fixed-effects meta-analysis) may represent an average effect that 
better represents TDF/FTC efficacy in a more adherent population. The two smaller studies, 
however, were conducted in MSM recruited in England (PROUD), Canada and France 
(iPERGAY), a population that is quite different demographically than the iPrEx population.    
A third option is to use the results from the five large trials and explicitly model TDF/FTC 
adherence as an effect moderator. By using a mixed-effects modeling approach, the meta-
analysis can account for the known heterogeneity between study populations (random effects 
component), and explicitly estimate the relationship between adherence and efficacy (fixed 
                                                 
1 Defined as the proportion of specimens with quantifiable drug > 10 ng/mL in 43 matched control specimens from HIV-
uninfected participants randomized to Truvada. 
 

 
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effects component). A broad range of adherence levels is represented in these trials, and this 
makes it possible to estimate efficacy at moderate (e.g., 55%) or moderately high (e.g., 75%) 
levels of adherence without extrapolating beyond the range of observed data2. Incorporating 
results from all five major trials should provide a more robust, precise estimate of TDF/FTC 
efficacy than estimates based on fewer or smaller studies, and the ability to estimate efficacy at 
specific adherence levels allows for computing a non-inferiority margin tailored to the projected 
adherence levels in HPTN 083. 
The iPrEx study alone gives a Placebo-versus-TDF/FTC estimate (95% C.I.) equal to 1.79 (1.20, 
2.67) yielding a M2 non-inferiority margin of 1.09. A fixed-effects (using inverse variance 
weighting) meta-analysis of the three MSM trials gives a larger Placebo-versus-TDF/FTC 
relative risk (95% C.I.) of 2.20 (1.52, 3.18), which gives a M2 non-inferiority margin equal to 
1.23. A mixed-effects meta-analysis.92of the five major PrEP trials reveals a range of potential 
TDF/FTC efficacy depending on adherence (Table 3), and a corresponding range of non-
inferiority bounds. Figure 6 shows the individual efficacy results and the results of the random 
effect meta-analysis with adherence as an effect modifier. 
                                                 
2 Adherence measures for the published trials are based on proportion of samples with detectable drug concentrations 
measured in a randomly selected subset of HIV-infected controls randomized to Truvada. This generally corresponds to 
evidence of TDF/FTC taken within 2-3 days of the visit.  

 
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Figure 6: A Random Effects Meta-analysis of PrEP Trials with Adherence as Effect 
Modifier   
 
 
Table 3: The M2 non-inferiority margins based on fixed and random effects meta-
analysis 
Fixed Effects 
Trials Included 
Placebo/TDF/FTCRR 
95%LB 
95%UB 
NI Margin 
(M2=50%) 
iPrEx 
1.79 
1.20 
2.67 
1.09 
iPrEx, PROUD, 
iPERGAY 
2.20 
1.52 
3.18 
1.23 
Mixed Effects: Includes five major placebo controlled trials of TDF/FTC as PrEP, 
adjusting for measured drug adherence as an effect moderator. 
TDF/FTC Adherence2 
Placebo/TDF/FTCRR 
95%LB 
95%UB 
NI Margin 
(M2=50%) 
40% 
1.26 
1.02 
1.57 
1.01 
50% 
1.61 
1.30 
1.98 
1.14 
60% 
2.04 
1.59 
2.62 
1.26 
70% 
2.59 
1.88 
3.57 
1.37 

 
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Of note is the similarity between the 1.23 margin given by the combined three MSM studies, as 
compared with the 1.26 margin given by the mixed-effects model at 60% adherence. As 
expected, the mixed-effects model that includes all five major trials gives a more precise 
estimate (narrower confidence interval), and it is reassuring the two estimates are well aligned.   
7.3.3 Selection of the NI Margin. 
The random effects meta-analysis suggests that different NI margins could be justified depending 
on TDF/FTC adherence. In addition, given that injection of CAB LA should confer an adherence 
advantage, the relative efficacy of CAB LA vs TDF/FTC may increase as TDF/FTC adherence 
decreases. Table 4 describes potential pairings of NI margins and relative risks for assumed 
levels of adherence to daily TDF/FTC. These choices imply differing sample sizes, expressed 
here as the total number of events required.  
Table 4: Number of Events Required for a Non-inferiority Trial of CAB-LA vs TDF/FTC, Under a 
Range of Non-inferiority Margins Implied by Different Levels of Adherence to TDF/FTC, and 
Relative Risks that Decrease as Adherence Increases. 
TDF/FTC 
Adherence 
NI 
Margin 
CAB LA 
vs 
TDF/FT
C 
Non-treated HIV-incidence of 
4% 
Non-treated HIV-incidence of 
5% 
# of 
Events 
Needed 
for 90% 
Power 
TDF/FTC 
Incidence* 
CAB LA 
incidence 
TDF/FTC 
Incidence 
CAB LA 
incidenc
e 
45% 
1.08 
0.65 
2.82% 
1.83% 
3.52% 
2.29% 
164 
50% 
1.14 
0.65 
2.50% 
1.62% 
3.12% 
2.03% 
134 
55% 
1.20 
0.75 
2.21% 
1.66% 
2.77% 
2.08% 
191 
57.5% 
1.23 
0.75 
2.09% 
1.56% 
2.61% 
1.95% 
172 
60% 
1.26 
0.75 
1.96% 
1.47% 
2.45% 
1.84% 
157 
70% 
1.37 
0.85 
1.54% 
1.31% 
1.93% 
1.64% 
185 
75% 
1.43 
0.85 
1.37% 
1.16% 
1.71% 
1.46% 
156 
* Using effectiveness estimates from meta-analysis 
 
The current trial design is designed with a NI margin of 1.23. Using the random effects modeling 
of the 5 major trials with an adherence biomarker assessment this corresponds to an assumption 
of ~55-60% TDF/FTC adherence. This is also the estimated effect from the fixed effect 
modeling of the three MSM studies.  
7.3.4 The NI margin: Absolute Difference in Proportion Infected 
A non-inferiority margin also requires consideration of the “acceptable” number of additional 
infections per (e.g.) 10,000 patient years of exposure in the studied population were cabotegravir 
to be licensed on the basis of a finding of non-inferiority. In this trial design, because it is 
assumed CAB LA is somewhat more effective that TDF/FTC, a non-inferiority finding requires 
an observed relative risk less than one, i.e., fewer infections with CAB LA than TDF/FTC.  
Nonetheless, respecting the interpretation of the 95-95 rule, the prevention impact implied by the 
upper 95% confidence limit is presented.  

 
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In Table 5, the number of additional HIV infections that would be expected among people 
treated with CAB LA as compared to TDF/FTC if the risk ratio were equal to the margin (i.e., 
the worst case scenario) is computed. Note that this corresponds to the upper bound of the trial’s 
95% confidence interval, which would be more extreme than the risk ratio actually observed in 
the trial. For example, if a 1.23 margin were ruled out just at the boundary under the proposed 
trial design, 90 infections in the TDF/FTC arm and 82 in the CAB LA arm (i.e., a RR = 0.91) 
would be observed, but the upper 95% confidence limit would imply CAB LA could be as much 
as 23% worse than TDF/FTC. This corresponds to the potential for 48 additional infections per 
10,000 person years on CAB LA vs TDF/FTC at the NI margin. Note that, without treatment, the 
expected number of infections for background rates of 4% and 5% incidence is 400 and 500, 
respectively.  
Table 5: Prevention Impact Implied by the Choice of Non-inferiority Margin Under Selected 
TDF/FTC Adherence and Relative Risk Assumptions.   
TDF/FTC
Adherence 
NI 
Margin 
RR of 
CAB LA 
vs 
TDF/FTC 
RR 
Trial results if just rule 
out the NI margin 
Implied prevention impact 
Observed† 
CAB 
Infections 
Observed 
TDF/FTC 
Infections 
Additional CAB Infections per 
10,000 pyrs implied at the NI 
margin§ 
4% HIV 
Incidence* 
5% HIV 
Incidence* 
45% 
1.08 
0.65 
73  
91  
23 
28 
50% 
1.14 
0.65 
60  
74 
35  
44 
55% 
1.20 
0.75 
91  
100 
44  
55 
57.5% 
1.23 
0.75 
82  
90 
48  
60 
60% 
1.26 
0.75 
75  
82 
51  
64 
70% 
1.37 
0.85 
94  
91 
57  
71 
75% 
1.43 
0.85 
80  
76 
59  
74  
† Observed number of events in the trial if the upper bound of the 95% CI is at the NI margin.  
* Background HIV incidence in the untreated study population; per arm incidence and total number of events for each row as 
in Table 4. 
§ Estimated at the upper 95% confidence bound exactly equal to the NI margin. Additional infections computed as (TDF/FTC 
incidence x NI margin – TDF/FTC incidence) x 10,000. 
 
7.4 
Re-assessing the NI margin at the Completion of the Trial 
The study is designed with a fixed non-inferiority margin specified in advance. However, the 
appropriate margin at completion could be broader or narrower than that specified in the 
protocol. For low levels of TDF/FTC adherence, HPTN 083 may demonstrate superior efficacy 
of directly observed, injectable, long-acting therapy. A narrow non-inferiority margin is 
consistent with the trial objectives in this setting. For high levels of TDF/FTC adherence, the rate 
of infection on TDF/FTC is expected to be low and a comparatively higher M2 margin expressed 
as an RR may still lead to an acceptable non-inferiority margin.  

 
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The study will obtain a rigorous, objective, assessment of adherence to TDF/FTC from dried 
blood spots and/or plasma throughout the trial. At the completion of the trial, to assist in the 
interpretation of the relative efficacy results of CAB-LA vs TDF/FTC, a post-trial NI margin 
using a fully pre-specified algorithm will be computed. Using pre-existing, external data 
incorporating all available randomized, placebo controlled trials with known TDF/FTC 
adherence and efficacy, a pre-specified algorithm to derive the meta-analytic estimate of the M2 
boundary corresponding to the TDF/FTC adherence observed in HPTN 083 will be used. Full 
details of the pre-specified algorithm will be provided in a separate document, updated with all 
available relevant data on adherence and efficacy prior to the final analysis of the trial. 
If observed adherence is higher than 65% or lower than 50%, this recomputed NI margin will be 
a critical secondary analysis to gauge the prevention efficacy of CAB LA.  
7.4.1 Justification for Recomputing the NI Margin 
The fixed NI margin selected for the study design is justified by a meta-analysis combining trials 
that in all likelihood had different adherence levels. Whether this NI margin establishes that 
CAB LA is substantial better than placebo depends on the actual adherence to TDF/FTC in the 
current study. In reality, the selected NI margin of 1.23 could either be insufficient to establish 
CAB LA prevents HIV infection or be overly conservative. 
Table 6 details the absolute change in HIV incidence that would be implied under CAB LA if the 
true efficacy of CAB LA is lower than TDF/FTC by the upper bound of the CAB LA/TDF/FTC 
relative-risk confidence bound, i.e., when true relative efficacy of TDF/FTC vs CAB LA is equal 
to the non-inferiority margin. This is the worst-case-scenario expected based on a clinical trial 
that just concludes non-inferiority. 
Higher than expected TDF/FTC adherence: If adherence to TDF/FTC is as high as 75%, 
efficacy similar to that seen in PROUD and iPERGAY would be anticipated. In this case, even 
assuming CAB LA were a modest 15% more effective than TDF/FTC (i.e. RR = 0.85), a 172 
event trial has only 46% power to rule out a HR of 1.23, under reasonable assumptions of 
implied efficacy of TDF/FTC. As Table 4 suggests, if adherence is 75%, a larger margin of 1.43 
could be justified. Against this margin, a 172 endpoint trial would retain 82% power. Table 6 
illustrates the absolute increase in infection rates implied by this margin. In 75% adherence 
setting, assuming a background incidence of 5/100 PY, we expect TDF/FTC incidence to be 
reduced to 1.7/100 PY; the upper bound of the CAB LA incidence in a NI trial with a 1.43 
margin would be 2.4/100 PY, still substantially lower than 5/100 PY and an absolute increase of 
0.7/100 PY compared to TDF/FTC.  
Lower than expected TDF/FTC adherence: If adherence to TDF/FTC is as low as 40%, we 
anticipate efficacy lower than that seen in iPrEX, in which case the trial has >99% power to rule 
out a HR of 1.23 if the RR of CAB LA to TDF/FTC is 0.75. However, as Table 6 indicates, if 
adherence is 40%, ruling out a HR of 1.23 would likely not provide adequate evidence for 
effectiveness of CAB-LA over placebo. In this lower adherence setting, the justified NI margin is 
close to 1.0, implying that CAB-LA should have to achieve close to superiority relative to 
TDF/FTC to ensure it is in fact better than placebo. Table 6 illustrates that the 1.23 bound in this 

 
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scenario corresponds to an expected incidence rate with Cabotegravir of 4.9/100 PY - virtually 
the same as no treatment at all. 
Table 6: HIV incidence Under Cabotegravir if the True Efficacy of Cabotegravir is Lower than 
TDF/FTC by the Upper Bound of the CAB/TDF/FTC Relative-risk Confidence Bound, i.e., when 
true relative efficacy of TDF/FTC vs Cabotegravir is equal to the non-inferiority margin.  (This is 
the worst-case-scenario expected based on a clinical trial that just concludes non-inferiority, i.e., the 
upper confidence bound equals the NI margin.) Background HIV incidence rate without PrEP 
assumed to be 5/100 PY. 
TDF/FTC 
Adherence 
Implied 
TDF/FTC 
Efficacy* 
Implied 
HIV 
Incidence 
On 
TDF/FTC 
HIV Incidence on CAB if true CAB/TDF/FTC efficacy equals the NI 
Margin ("Worst Case Scenario")** 
NI Margin 
1.01 
1.08 
1.14 
1.2 
1.23 
1.26 
1.32 
1.37 
1.43 
0.4 
21% 
4.0% 
4.0% 
4.3% 
4.5% 
4.7% 
4.9% 
5.0% 
5.2% 
5.4% 
5.6% 
0.45 
30% 
3.5% 
3.5% 
3.8% 
4.0% 
4.2% 
4.3% 
4.4% 
4.6% 
4.8% 
5.0% 
0.5 
38% 
3.1% 
3.1% 
3.3% 
3.5% 
3.7% 
3.8% 
3.9% 
4.1% 
4.2% 
4.4% 
0.55 
45% 
2.8% 
2.8% 
3.0% 
3.1% 
3.3% 
3.4% 
3.5% 
3.6% 
3.8% 
3.9% 
0.575 
48% 
2.6% 
2.6% 
2.8% 
3.0% 
3.1% 
3.2% 
3.3% 
3.4% 
3.6% 
3.7% 
0.6 
51% 
2.5% 
2.5% 
2.6% 
2.8% 
2.9% 
3.0% 
3.1% 
3.2% 
3.4% 
3.5% 
0.65 
57% 
2.2% 
2.2% 
2.3% 
2.5% 
2.6% 
2.6% 
2.7% 
2.8% 
2.9% 
3.1% 
0.7 
61% 
2.0% 
2.0% 
2.1% 
2.2% 
2.3% 
2.4% 
2.5% 
2.6% 
2.7% 
2.8% 
0.75 
66% 
1.7% 
1.7% 
1.8% 
1.9% 
2.0% 
2.1% 
2.1% 
2.2% 
2.3% 
2.4% 
* Based on meta analysis of five major TDF/FTC PrEP trials, TDF/FTC efficacy is predicted based on adherence. 
** For the level of TDF/FTC efficacy listed in each row, the column header of the highlighted cell contains the 
corresponding M2 non-inferiority margin.  
 
7.5 
Endpoints 
7.5.1 Primary Endpoint 
• Number of documented incident HIV infections in Steps 1 and 2 
• Grade 2 or higher clinical and laboratory adverse events  
7.5.2 Secondary Endpoints 
• Number of documented incident HIV infections in Step 2 
• Number of documented incident HIV infections in Steps 1, 2, and 3 
• Number of documented incident HIV infections in Step 3 
• Number of documented incident HIV infections in Step 2 and 3 
• Kidney function as measured by: changes from baseline in creatinine and creatinine 
clearance 

 
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• Liver function as measured by:  changes from baseline and Grade 3 or 4 liver-related AEs 
(laboratory assessment of ALT, AST, TBili, CPK or clinical assessment of 
jaundice/icterus). 
• Bone mineral density (DXA subset) as measured by:  Changes in Z-score from baseline 
and DXA criteria for osteopenia and osteoporosis  
• Resistance mutations to study products (including but not limited to K65R, M184V/I, 
Q148R) among seroconverters 
• Acceptability scale assessments 
• Weight, blood pressure, pulse, fasting glucose, and fasting lipids 
7.5.3 Tertiary Endpoints  
• Adherence to study product during step 2: For CAB-LA/Placebo CAB-LA scheduled 
injections received; for TDF/FTC/Placebo TDF/FTC pill dispensing  
• Plasma and/or DBS levels of TDF in participants randomized to TDF/FTC   
• Number of sexual partners (primary and non-primary), number of coital acts, number of 
non-condom protected anal intercourse acts (insertive and receptive)  
• STIs (rectal and urinary GC/CT, syphilis [adjudicated]) 
• Resource utilization:  Clinical visits, acuity visits (related to toxicity) hospital days 
(related to toxicity), standard laboratory monitoring, laboratory/radiography events 
(related to toxicity 
• Cost-effectiveness:  1-5 year budgetary impact, lifetime expectancy, lifetime costs 
projections and incremental cost-effectiveness, stratified by country 
7.6 
Sample Size and Interim Monitoring 
Assuming CAB LA is 25% more effective than TDF/FTC, approximately 174 observed HIV-
infections will provide 90% power to rule out a non-inferiority margin of HR=1.23, with type-I 
error alpha = 0.025 (see Figure 7 below). This non-inferiority margin is an M2 margin based on 
an inverse-variance weighted meta-analysis of three randomized controlled trials of TDF/FTC 
versus placebo in MSM: iPrex, iPERGAY, and PROUD4, 35-36. The M2 margin is defined as the 
reduced bound that is designed to preserve a clinically acceptable amount of the benefit provided 
by the active control (TDF/FTC). Setting M2 to be 50% of M1 (on the log scale in the case of 
hazard ratios) is considered to be conservative. M1 is defined as the lower limit of the 95% 
confidence interval around the placebo versus active-control HR estimate (1.39, based on the 
meta-analysis). Once the stated number of HIV-infections have been observed, non-inferiority 
will be established if the estimated CAB LA versus TDF/FTC hazard ratio point estimate is 
approximately 0.90 or less (indicating a 10% or better advantage of CAB LA over TDF/FTC), 
and superiority will be established if the hazard ratio point estimate is approximately 0.74 or less 
(indicating a 26 % or better advantage of CAB LA over TDF/FTC). The power to detect 
superiority is 47%. 

 
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The number of enrolled participants needed to observe the target number of HIV-infections 
depends on the background HIV incidence in the study populations, the efficacy of CAB LA and 
TDF/FTC in these populations, the dropout rate, and the study duration. Assuming (a) annual 
HIV incidence for the TDF/FTC arm is 2.0% (similar to the 1.8% incidence observed in the 
iPrex OLE study); (b) CAB LA is 25% more protective than TDF/FTC; and (c) the annual 
dropout rate is 7.5%, then approximately 5000 individuals will be needed to enroll and be 
followed for an average of 2.5 years. See Figure 8 below.    
Interim monitoring will be conducted by an independent DSMB on a regular schedule, with 
safety review approximately every 6 months, and at least annually. Formal interim analyses will 
be planned approximately 4 times during the study, using the Lan-DeMets modification of the 
O’Brien-Fleming stopping bounds to control alpha spending. Superiority bounds will be used for 
early stopping for favorable risk-to-benefit ratio for CAB LA; non-inferiority bounds will be 
used for early stopping for unfavorable risk-to-benefit ratio. Thus, the study will continue if non-
inferiority is established but superiority remains plausible, however the study may end early if 
non-inferiority is ruled implausible or if inferiority is established.  
As this is the first large-scale phase 2b/3 study of IM administration of a biomedical intervention 
for prevention of sexual HIV transmission, an early feasibility check will be employed whereby 
after approximately 250 participants have completed 3 injections (Week 29), a treatment-blinded 
analysis of injection feasibility will be conducted and reported to the SMC and DSMB. 
Enrollment of the remaining study participants will be deemed feasible if ≥ 75% of those 250 
participants remain engaged in the trial and have not declined further injections. Enrollment will 
not be paused for this feasibility assessment, with the condition that no more than approximately 
25% of the planned full study population will be enrolled prior to completion of the assessment. 
The trial will be terminated at the first occurrence of any of the following: 1) The accrual of 172 
incident HIV endpoints; 2) completion of 11,800 person-years of follow-up; or 3) reaching a 
stopping boundary.    
Details of the interim monitoring approach and stopping rules will be further described in the 
Interim Monitoring Plan. 

 
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Figure 7: Indicates the number of observed HIV infections required to achieve 90% power 
for superiority and non-inferiority (NI) designs with NI margins of 1.09 and 1.23. The X-
axis shows the relative efficacy of CAB LA vs TDF/FTC, the quantity that this trial is 
designed to estimate. 
 
 

 
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Figure 8: Indicates the total number of people needed to achieve the number of events 
required for a non-inferiority design (rule out HR of 1.23) under different assumptions of 
background incidence (i.e. HIV incidence without blinded use of TDF/FTC) and different 
TDF/FTC efficacy.  The X-axis shows the relative efficacy of CAB LA vs TDF/FTC, the 
quantity that this trial is designed to estimate. 
 
7.7 
Accrual and Retention 
Approximately 5000 participants will be enrolled in approximately 3.5 years and followed for a 
maximum of 3.0 years on blinded study product, followed by 1 year on open-label study product, 
for a total of a maximum of 4.0 years of follow-up. An average annual retention rate of at least 
92.5% percent will be targeted.  
7.8 
Random Assignment 
Enrolled participants will be randomized to one of two study arms in a 1:1 ratio. Randomization 
will be stratified by study site, race, and ethnicity, and a permuted blocks design will be used to 

 
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ensure balanced treatment assignments within study site. The randomization scheme will be 
generated, operationalized and maintained by the HPTN SDMC. Additional details regarding the 
process of randomization will be included in the SSP Manual. All endpoints will be analyzed 
according to a participant’s original blinded randomization assignment, regardless of timing of 
endpoint occurrence. 
7.9 
Blinding   
Study site staff, with the exception of the site Pharmacist of Record or their designee, and 
participants will be blinded to the random assignments. Blinding will be maintained until the trial 
is completed or stopped, i.e., the trial is stopped early, or the required number of endpoints or 
person years has been met. At a specified time directed by the HPTN SDMC, participants will be 
notified of their treatment assignment. In addition, as noted in Section 5.14.2, an Investigator can 
request unblinding to the HPTN SDMC in the event that a participant becomes infected with 
HIV during the study, and the SDMC will assist in directly providing the participant’s primary 
health care provider the randomized arm assignment information per their SOP; the randomized 
assignment will not be provided to the site where the participant was enrolled and followed. 
 
7.10 Data and Safety Monitoring Board Oversight and Study Monitoring Committee Oversight 
NIAID Data and Safety Monitoring Board oversight is planned for this study. Monitoring 
guidance will be detailed in a separate Interim Monitoring Plan. In addition, approximately every 
6 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 MOP. 
7.11 Statistical Analysis 
This section briefly describes the final study analyses, unblinded as to treatment arm assignment. 
Detailed technical specifications of the statistical analyses will be described in a separate 
Statistical Analysis Plan.  
7.11.1 Analyses of Primary Efficacy Objective 
• To compare HIV incidence among participants randomized to oral CAB/CAB LA (oral lead 
in and injections) vs. oral TDF/FTC (Steps 1 and 2) 
MITT:  A modified intent-to-treat will be used as the primary assessment for the efficacy 
comparison, thus all participants who receive at least one dose of oral study product will 
contribute to the primary analyses. Any participant determined to be HIV infected prior to 
receiving study product will be omitted from the analysis.   
The HIV incidence rate will be calculated as the total number of participants with confirmed 
incident HIV infection during study follow-up of Step 1 and Step 2 divided by the person-years 
accumulated in each arm. 95% CIs will be calculated based on Poisson distribution assumptions. 

 
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Treatment efficacy will be estimated as TE= 1 - HR. The Hazard Ratio comparing CAB-LA vs 
TDF/FTC and 95% confidence intervals will be estimated using Cox proportional hazards with 
treatment arm as the only covariate, stratified by site. 
Per protocol: A per protocol estimate of treatment efficacy will be conducted as a secondary 
analysis in the non-inferiority context of active control, as a verification that a similar HR 
estimate is obtained in the compliant population. Compliance will be defined as: Adherent by 
administration and plasma TDF concentrations: In CAB LA arm, from the time of receipt of the 
injection the participant is considered adherent for 8 weeks. In the TDF/FTC arms, from time of 
dispensing pills the participant is considered adherent if plasma TDF concentrations are 
detectable at 8 weeks. Each HIV testing interval (time period between determining HIV status 
through study testing) will be defined as compliant if participant has TDF levels consistent with 
4 or more doses per week by appropriate pharmacokinetic laboratory assays. 
Estimates will be computed as follows: 
• Time varying compliance: Compliance will be a time-dependent covariate, and the HR 
for efficacy CAB-LA vs TDF/FTC during periods of compliance will be estimated using 
Cox proportional hazards with an interaction term between study arm and compliance. 
The estimate of efficacy will be the HR for CAB-LA vs TDF/FTC in the compliant 
periods. 
• 
Estimate in the compliant cohort: The compliant cohort is defined as those participants 
who were adherent >80% of their time on study. The same methods as detailed for the 
primary analysis will be used for estimating effectiveness on the compliant cohort. 
Evidence of confounding in this cohort will result in an analysis that is adjusted for 
additional baseline risk covariates.  
7.11.2 Analyses of Primary Safety Objective 
• To compare the safety of oral CAB/CAB LA vs. oral TDF/FTC  
Local reactions 
The number and percentage of participants experiencing local reactions to the injections will be 
tabulated by severity and treatment arm and the percentages displayed graphically by arm. For a 
given local reaction type, each participant’s reaction will be counted once under the maximum 
severity for all injection visits. In addition, to the individual reaction types, the maximum 
severity of local pain or tenderness, induration or erythema, and of systemic symptoms will be 
calculated. Kruskal-Wallis tests will be used to test for differences in severity between arms.  
AEs and SAEs  
AEs will be summarized using MedDRA System Organ Class and preferred terms. Tables will 
show by treatment arm the number and percentage of participants experiencing an AE within a 
System Organ Class or within preferred term category by severity. For the calculations in these 
tables, a participant with multiple AEs within a category will be counted once under the 

 
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maximum severity. Formal statistical testing comparing arms is not planned since interpretation 
of differences must rely heavily upon clinical judgment.  
A listing of SAEs reported to the DAIDS Regulatory Support Center (RSC) Safety Office will 
provide details of the events including severity, time between onset and last dosing, and 
cumulative number of doses received.  
Local laboratory values  
Box plots of local laboratory values will be generated for baseline values and for values 
measured during the course of the study by treatment arm and visit. Each box plot will show the 
first quartile, the median, and the third quartile. Outliers (values outside the box plot) will also be 
plotted. If appropriate, horizontal lines representing boundaries for abnormal values will be 
plotted.  
The number (percentage) of participants with local laboratory values recorded as meeting Grade 
2 AE criteria or above as specified in the DAIDS AE Grading Table will be tabulated by 
treatment arm for follow-up time points. Reportable clinical laboratory abnormalities without an 
associated clinical diagnosis will also be included in the tabulation of AEs described above.  
7.11.3 Analyses of Secondary Objectives 
• To compare HIV incidence among participants receiving CAB LA vs. oral TDF/FTC (each 
step independently and all steps in aggregate). 
• To compare HIV incidence among participants receiving CAB LA injections vs. oral 
TDF/FTC (Steps 1, 2, and 3 combined) 
The same methods as detailed for the primary analysis will be used for estimating effectiveness 
for these secondary objectives. For step 2 only, during the double blind phase, persons who do 
not initiate Step 2 and infections that occur in Step 1 will be omitted from the assessment of 
relative efficacy. For comparison across all three steps, all infections observed on trial will be 
included in the estimate of efficacy.  
• To compare HIV incidence among participants randomized to CAB LA injections vs. oral 
TDF/FTC while taking open label TDF/FTC (Step 3 only, descriptive) 
HIV incidence rates will be compared between arms for all participants after initiating open label 
FTC/TDF. Only events occurring during Step 3 will be included in the comparison. 
• To compare the change in risk of HIV acquisition between CAB and oral TDF/FTC 
strategies (Arm A and Arm B) as participants progress from Step 2 to Step 3 
Change in HIV incidence rates will be compared between arms during Step 2 and Step 3. In 
addition, the change in HIV incidence rates in each arm will be compared as the study 
participant’s transition from the double blind to open label phases of the study intervention.  

 
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• To compare HIV incidence among the following subgroups of participants receiving oral 
CAB/CAB LA vs. oral TDF/FTC; region, age, race, ethnicity, and baseline risk 
The same methods as detailed for the primary analysis will be used for estimating effectiveness 
in each of the subgroups defined by the stated baseline characteristics. A test for significant 
interaction between intervention arm and subgroup will be conducted as a test of effect 
modification. 
• To compare changes in renal function, liver function, and bone mineral density (BMD) 
among participants receiving oral CAB/CAB LA vs. oral TDF/FTC. 
Global test of association: The number of participants by highest graded AE recorded for each 
renal and liver endpoint will be compared between arms using a Chi-squared test (or Fisher 
exact, if expected cell frequency is < 5). 
Dose dependent association: The number of renal and liver function AEs within weeks 1-4 after 
injection will be compared with the number in weeks 5-8 in the CAB LA arm using a Chi-
squared test.  
Cumulative Exposure: To assess the risk of increasing severity in renal, liver and bone mineral 
density with increased exposure, summary statistics will be presented by treatment arm and time 
point, as well as changes from baseline for post-enrollment values.  
• To evaluate and compare rates of HIV drug resistance among participants who acquire HIV 
infection during the study among participants receiving oral CAB/CAB LA vs. oral 
TDF/FTC. 
The number, proportion and types of resistance will be reported by arm for all HIV 
seroconverters, separately for each Step of the trial.  No formal statistical test will be performed. 
• To evaluate the acceptability of and preferences for CAB LA vs. oral TDF/FTC. 
Descriptive statistics will be used to summarize acceptability measures and preferences over the 
course of the study. Acceptability scores for each product will be compared between the arms 
(i.e. for CAB LA vs. Placebo CAB LA and TDF/FTC vs. Placebo TDF/FTC) using linear mixed 
effects model with study arm as a fixed effect.   
• To compare changes in weight, blood pressure, pulse, fasting glucose, and fasting lipids 
among participants receiving oral CAB/CAB LA vs. oral TDF/FTC 
Change from baseline (enrollment) for weight, blood pressure, pulse, fasting glucose, and fasting 
lipids will be computed at each follow-up visit where these measures are collected.  The mean 
changes will be plotted over time by treatment arm for visits where participants remained on 
blinded, protocol-specified treatment.  (Per-protocol analysis). A linear mixed model will be fit 
with categorical intervals for time in study, treatment and time by treatment interaction to 
evaluate time trends in each arm and the association between treatment and biological measures.  
Categorical models will also be used to assess changes over time in BMI category, proportion of 
participants with 5% or more weight change, and occurrence of new diabetes diagnoses.  

 
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Differences in time trends and treatment effects will be explored for demographic and clinical 
subgroups, including race/ethnicity, age, baseline smoking status, baseline BMI, and baseline 
weight. 
7.11.4 Analyses of Tertiary Objectives 
• To examine the association between levels of adherence and HIV incidence 
HIV incidence and 95% CI will be estimated within periods defined by levels of adherence, and 
cohorts of adherers. 
• To compare and describe the rates, patterns, and correlates of adherence to CAB LA vs oral 
TDF/FTC, in aggregate and by psychosocial/demographic variables.  
Adherence rates will be calculated for the active drug using proportion injections received for 
CAB LA, and proportion of study time within 8 weeks of injection; and for TDF/FTC using 
proportion of visits where TDF pharmacokinetic laboratory assessment categorizes the 
participant as having taken at least 4 doses per week, and proportion of study time where pills 
were taken according to pill counts. Descriptive statistics will be used.  
Adherence rates will be calculated for each blinded study group using proportion of injections 
received for CAB LA/Placebo CAB LA and proportion of study time where pills were taken 
according to pill counts for TDF/FTC. Statistical comparisons between the arms will use logistic 
regression with GEE methods to account for repeated assessments.  
Detailed description of the patterns and psychosocial and demographic variables to be assessed 
as correlates will be described in the Statistical Analysis Plan.  
• To estimate changes in sexual-risk behavior as measured by self-report and rates of incident 
gonorrhea, chlamydia, and syphilis in the study population. 
Each sexual risk behavior will be assessed using a repeated measure approach to estimate effect 
of randomization arm on sexual behavior post-randomization. If statistically significant 
imbalance is observed at baseline, the model will be adjusted for the respective baseline 
covariate. Sexual behavior will additionally be assessed by perceived randomization assignment, 
as well as by actual randomization assignment using appropriate random effects regression 
models. For count outcomes, a Poisson-type regression model will be used to assess differences 
in rate; for binomial outcomes and logistic-type regression will be used.    
Incident rates of STIs will be compared between arms using a HR estimated by Cox proportional 
hazards, with an Anderson-Gill approach for repeated events, assuming STIs are treated and 
resolve at each study visit. 
• To compare the resource utilization and programmatic costs of long-acting injectable PrEP 
vs. daily oral PrEP vs. no PrEP for HIV uninfected MSM and TGW in the US, Brazil and 
South Africa  

 
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For each study arm, a standardized data collection instrument will be used which asks about 
resource utilization retrospectively since the prior visit including queries regarding additional 
outpatient, emergency department or inpatient visits (with duration), and laboratory/radiology 
visits. Resource utilization can be ascribed to be related to study (e.g., drug toxicity) or 
unrelated (e.g., trauma-related fracture).  If different by study arm (or by country), resource 
utilization will be multiplied by country-specific unit costs to provide country-specific unit costs 
for differences in resources used.  Country specific unit costs will also be applied to generate 
overall programmatic costs (e.g., personnel, baseline laboratory resources, space).  
• To use mathematical simulation to project the short- and long-term clinical impact, cost 
projections, budgetary impact, and incremental cost-effectiveness of long-acting injectable 
PrEP vs. daily oral PrEP vs. no PrEP for HIV uninfected MSM and TGW in the US, Brazil, 
and South Africa 
The Cost-effectiveness of Preventing AIDS Complication-US and International models 
(CEPAC I), will be used and populated with data specific for each of the countries -- US, Brazil, 
and South Africa.  The model will be updated, specified, programmed and debugged for 
simulations specific to this protocol. It will further be parameterized with efficacy and resource 
utilization data obtained from the trial.  We will use total cohort data where there are not 
statistically significant differences between country-level data.  We will use country-specific 
data where those difference occur.  For each country, the model will have the capacity to 
generate outcomes including: 1-, 5-, 10-year survival, life expectancy, per person lifetime costs 
(and a breakdown of where those costs occurred), 1- and 5- year budgetary impact, as well as 
incremental cost-effectiveness.  This will allow for comparison of cost-effectiveness outcomes 
across regions of analysis with differences in baseline incidence, costing structures and gross 
domestic products (willingness/ability to pay). 
 
 

 
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8.0 
HUMAN SUBJECTS CONSIDERATIONS 
8.1 
Ethical Review 
This protocol and the template informed consent form contained in Appendix IVand any 
subsequent modifications — will be reviewed and approved by the HPTN Scientific Review 
Committee and DAIDS Prevention Science Review Committee 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, in accordance with the current DAIDS Protocol 
Registration Policy and Procedure Manual. 
8.2 
Informed Consent 
Written informed consent will be obtained from each study participant. Each study site is 
responsible for developing study informed consent forms for local use, based on the template in 
Appendix IV that describes the purpose of the study, the procedures to be followed, and the risks 
and benefits of participation, in accordance with all applicable regulations. If applicable, the 
study site also is responsible for translating the template form into local languages, and verifying 
the accuracy of the translation by performing an independent back-translation. 
Participants will document their provision of informed consent by signing their informed consent 
forms. (Further details regarding DAIDS requirements for documenting the informed consent 
process can be found in the DAIDS Standard Operating Procedure for Source Documentation.)   
All participants will be offered a copy of their informed consent form. 
8.3 
Incentives 
Pending IRB approval, participants will be compensated for their time and effort in this study, 
and/or be reimbursed for travel to study visits and time away from work. Site-specific 
reimbursement amounts will be specified in the study informed consent forms. 
8.4 
Confidentiality 
All study-related information will be stored securely at the study site. All participant information 
will be stored in locked file cabinets in areas with access limited to study staff. All laboratory 

 
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specimens, reports, study data collection, process, and administrative forms will be identified by 
a coded number only to maintain participant confidentiality. All records that contain names or 
other personal identifiers, such as locator forms and informed consent forms, will be stored 
separately from study records identified by code number. All local databases will be secured 
with password-protected access systems. Forms, lists, logbooks, appointment books, and any 
other listings that link participant ID numbers to other identifying information will be stored in a 
separate, locked file in an area with limited access. 
Participant’s study information will not be released without the written permission of the 
participant, except as necessary for monitoring by the NIAID and/or its contractors; 
pharmaceutical sponsors; representatives of the HPTN LOC, SDMC, and/or LC; the US FDA, 
OHRP, other U.S., local and international regulatory entities, and/or site IRBs.   
For sites located in the US, the HPTN will obtain a Certificate of Confidentiality from the US 
Department of Health and Human Services that will be applicable for this study. Sites may 
register under the Certificate through the HPTN LOC once they have obtained local IRB 
approvals for the study. This Certificate protects study staff from being compelled to disclose 
study-related information by any Federal, State or local civil, criminal, administrative, 
legislative, or other body. 
8.5 
Communicable Disease Reporting Requirements 
Study staff will comply with all applicable local requirements to report communicable diseases 
identified among study participants to local health authorities. Participants will be made aware of 
all reporting requirements during the study informed consent process. 
8.6 
Study Discontinuation 
The study also may be discontinued at any time by NIAID, the HPTN, the pharmaceutical 
sponsors, the US FDA, other government or regulatory authorities (OHRP), or site IRBs/ECs. 

 
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9.0 
LABORATORY SPECIMENS AND BIOHAZARD CONTAINMENT 
Laboratory procedures are described below, in Appendix IA, Appendix IB, Appendix IC: 
Section 5.0. Additional tests to be performed at subsequent visits for participants who have a 
reactive or positive HIV test result are described in Appendix II.  
9.1 
Local Laboratory Specimens 
The following types of tests will be performed at the local laboratory:  
• HIV testing (see SSP Manual) 
• HBV and HCV testing to include HBsAg, HBsAb, HBcAb, HCV antibody tests   
• CBC with differential and platelets 
• Chemistry testing (BUN/urea, creatinine, CPK, glucose, calcium, phosphorous, amylase, 
lipase 
• LFTs (AST, ALT, total bilirubin, alkaline phosphatase) 
• Fasting lipid profile (total cholesterol, high-density lipoprotein (HDL), triglycerides, low-
density lipoprotein (LDL) – calculated or measured  
• 25-OH-Vitamin D  
• Syphilis serologic testing 
• Urinalysis (protein and glucose) 
• Urine for GC/CT NAAT testing  
• Rectal swabs for GC/CT NAAT testing; for sites that cannot perform this testing, 
arrangements may be made for testing at another laboratory (see SSP Manual)  
• Plasma storage 
• DBS storage 
• Whole blood storage for pharmacogenomic testing (sites may choose to opt out of this 
testing if is not acceptable to local regulatory bodies or for other reasons approved by the 
protocol team) 
• HIV viral load (if HIV infected) 
• CD4 cell count (if HIV infected) 
• Real-time resistance testing for clinical management (if HIV infected) 
If the HIV testing algorithm includes HIV rapid testing, that testing may be performed in the 
clinic or laboratory.  
Each study site will adhere to standards of good laboratory practice, the HPTN MOP, the SSP 
Manual and local standard operating procedures (SOPs) for proper collection, processing, 
labeling, transport, and storage of specimens to the local laboratory. Specimen collection, testing, 

 
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and storage at the local laboratory will be documented using the HPTN Laboratory Data 
Management System (LDMS) as described in the SSP Manual. 
All specimens will be shipped in accordance with International Air Transport Association 
(IATA) specimen shipping regulations. All shipments will be documented using the HPTN 
LDMS as described in the SSP Manual. 
9.2 
Stored Specimens 
Plasma and DBS will be stored at the local site throughout the study. In addition, whole blood 
samples will be stored at the Enrollment visit at sites that agree to store such samples for 
pharmacogenomic testing. 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. 
9.2.1 Virology 
The HPTN LC will perform QA testing, including testing to determine HIV infection status in 
selected cases. Additional assays may be performed at the HPTN LC or a laboratory designated 
by the HPTN LC. This testing may include the following tests for participants who acquire HIV 
infection: HIV viral load, HIV resistance testing, HIV subtyping, and other tests to characterize 
HIV viruses and/or the host response to HIV infection. Results will not be returned to the sites or 
study participants, with the exception of HIV testing (if results obtained at the HPTN LC do not 
agree with site results).  
Resistance testing will be performed at the HPTN LC or a laboratory designated by the HPTN 
LC. This testing will be performed retrospectively at the end of the study. Results of this testing 
will not be returned to study sites. Because real-time resistance testing may be needed for clinical 
management in the event of HIV infection, each site will have an SOP as to how they will 
accomplish real-time local or regional resistance testing to assist with clinical decision making; 
separate specimens should be collected for that testing.   
9.2.2 Pharmacology 
Plasma and DBS samples for drug levels will be collected throughout the study from all 
participants, although PK testing may be limited to a subset of the samples.  
Plasma and DBS samples will be processed and frozen locally for subsequent shipment to the 
HPTN LC following procedures outlined in the SSP Manual. Pharmacology testing will be 
performed at the HPTN LC or at an outside laboratory designated by the HPTN LC. The primary 
pharmacologic assessments will be performed using assays that have been validated and 
approved by the Clinical Pharmacology Quality Assurance (CPQA) Committee. Results will not 
be returned to the sites or study participants. 
NOTE: Samples may be unblinded at the HPTN Laboratory Center (Pharmacology Laboratory 
only), so the relevant assays are only performed on participants who received the study product. 

 
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Stored plasma may also be tested for the presence of other ARV drugs or other substances. 
9.2.3 Pharmacogenomics 
Blood samples collected for pharmacogenomics testing will be analyzed for genetic 
polymorphisms associated with study drug exposure. Assays will be performed at the HPTN LC.  
Sites and individual participants may choose to opt out of this testing. For sites that will conduct 
this testing, results will not be returned to the sites or study participants. 
9.2.4 GC/CT Rectal Swab Storage (Non US Sites Only) 
Rectal swab testing for GC/CT NAAT will occur throughout the study at 6-month intervals at 
sites that have this capacity. If the site does not have a validated NAAT assay, arrangements may 
be made for testing at another laboratory (see SSP Manual). 
9.3 
Quality Control and Quality Assurance Procedures 
Study sites will document that their laboratories are certified under the Clinical Laboratory 
Improvement Amendments Act of 1988 (CLIA-certified) and/or participate in DAIDS-sponsored 
External Quality Assurance (EQA) programs, or other QA methods as deemed appropriate by the 
HPTN LC. 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. 
9.3.1 QC for HIV Diagnostic Testing 
Before performing HIV diagnostic testing, all sites must validate their HIV testing procedures, 
and the validation studies must be approved by the HPTN LC.  Local laboratories will perform 
testing for HIV diagnosis at Screening, Enrollment, and all follow-up visits. Algorithms for HIV 
diagnostic testing are provided in the SSP Manual. 
Throughout the course of the study, the HPTN LC 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 inform site staff of the samples selected for QA testing, and site staff will 
ship the selected specimens to 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. 
9.3.2 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 Schedule of Procedures and Evaluations. Non-US 
laboratories performing these tests will be monitored by Patient Safety Monitoring and 

 
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International Laboratory Evaluation (pSMILE) and must demonstrate successful participation in 
the relevant EQA programs. US sites should send these tests to CLIA-certified laboratories and 
must participate in EQA programs. 
9.3.3 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 UNKEQAS program and must demonstrate successful 
participation in these programs. US sites must use CLIA-certified laboratories; participation in 
the IQA program is recommended.    
9.3.4  Quality Assurance for HIV RNA Testing 
Local laboratories may also perform HIV RNA/viral load testing 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. US sites must use CLIA-certified laboratories; participant in the VQA program is 
recommended. 
9.4 
Specimen Storage and Possible Future Research Testing 
Study sites will store specimens collected in this study at least through the end of the study. In 
addition, at sites that allow this type of storage, study participants will be asked to provide 
written informed consent for these samples to be stored after the end of the study for possible 
future non-protocol listed testing. The specimens of participants who do not consent to long-term 
storage and additional testing will be destroyed after all of the protocol specified testing 
(including assessments at the HPTN LC) has been completed.  
Samples from participants who did not successfully enroll in the study may be discarded if 
participant does not enroll utilizing sample lists provided by the HPTN SDMC in consultation 
with the HPTN LC. 
9.5 
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). 
 

 
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10.0 ADMINISTRATIVE PROCEDURES 
10.1 Protocol Registration 
Initial Registration of the protocol by the DAIDS Protocol Registration Office (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) approved, as appropriate, by their local institutional 
review board (IRB)/ethics committee (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 Regulatory Support Center (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 informed consent forms (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/protocol-registration. 
10.2 Study Activation 
Pending successful protocol registration and submission of all required documents, the HPTN 
LOC staff will “activate” a site. Study implementation may not be initiated until a study 
activation notice is provided to the site by the HPTN LOC. In addition, if study “activation” is 
determined to be necessary for any subsequent amendments, study implementation may not be 
initiated until a study activation notice is provided to the site by the HPTN LOC. 
10.3 Study Coordination 
DAIDS holds the Investigational New Drug (IND) application for this study. Copies of all 
regulatory documents submitted to this IND by DAIDS will be forwarded to ViiV Healthcare 
and Gilead Sciences, Inc. for cross-referencing with the company’s other INDs for the study 
product(s). Assignment of all sponsor responsibilities for this study will be specified in a Clinical 

 
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Trials Agreement executed by DAIDS and ViiV Healthcare, and DAIDS and Gilead Sciences, 
Inc. 
Study implementation will be directed by this protocol as well as the SSP Manual. The SSP 
Manual, which will include links to the DAIDS SOPs for Source Documentation and Essential 
Documents, as well as links to the Manual for Expedited Reporting of Adverse Events 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. 
Electronic study case report forms will be developed by the study team and HPTN SDMC.  Data 
will be transferred to the HPTN SDMC, entered, and cleaned using the MediData Rave 
electronic data management system. Quality control reports and 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, case report 
forms), as well as observe the performance of study procedures. Investigators also will allow 
inspection of all study-related documentation by authorized representatives of the HPTN LOC, 
HPTN SDMC, HPTN LC, NIAID, ViiV Healthcare, Gilead Sciences, Inc., site IRBs/ECs, and 
other US, local, and international regulatory authorities. 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 
Regulatory Support Center (RSC) prior to implementing the amendment. 

 
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10.6 Investigator's Records 
The Investigator 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 Investigator 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 and at least three years after the completion of research. 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. Study records include administrative 
documentation — including protocol registration documents and all reports and correspondence 
relating to the study — as well as documentation related to each participant screened and/or 
enrolled in the study — including informed consent forms, locator forms, case report forms, 
notations of all contacts with the participant, and all other source documents. 
Completion of a clinical research study occurs when the following activities have been completed: 
 
• 
All research-related interventions or interactions with human subjects (e.g. when all subjects are 
off study);  
• 
All protocol-required data collection of identifiable private information described in the IRB/EC-
approved research plan;  
• 
All analysis of identifiable private information described in the IRB/EC-approved research plan;  
• 
Primary analysis of either identifiable private or de-identified information.  
 
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, DAIDS, ViiV Healthcare, Gilead Sciences, Inc. for review prior to submission. 
 

 
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53. Margolis D, et al. Cabotegravir and Rilpivirine as 2 Drug Oral Maintenance Therapy:  Latte 
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56. Anderson PL, Glidden DV, Liu A, et al. Emtricitabine-tenofovir concentrations and pre-
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59. Gupta SK, Anderson AM, Ebrahimi R, et al. Fanconi syndrome accompanied by renal 
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emtricitabine/tenofovir disoproxil fumarate use for HIV pre-exposure prophylaxis. AIDS 
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62. Kasonde M, Niska RW, Rose C, et al. Bone mineral density changes among HIV-uninfected 
young adults in a randomised trial of pre-exposure prophylaxis with tenofovir-emtricitabine 
or placebo in Botswana. PloS one 2014;9:e90111. 
63. Mulligan K, Glidden DV, Anderson PL, et al. Effects of Emtricitabine/Tenofovir on Bone 
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66. Koblin BA, Mayer KH, Eshleman SH, et al. Correlates of HIV acquisition in a cohort of 
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67. HIV Prevention Trials Network Black Caucus Scientific Report Identifying Research Gaps 
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69. Peinado J, Lama JR, Galea JT, et al. Acceptability of oral versus rectal HIV preexposure 
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the International Association of Providers of AIDS Care 2013;12:278-83. 
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71. Hoagland B, Veloso V, De Boni R, et al. Awareness and willingness to take pre-exposure 
prophylaxis (PrEP) among men who have sex with men and transgender women: preliminary 
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Prevention 2015; Vancouver, Canada. 

 
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72. Castillo R, Konda KA, Leon SR, et al. Human Immunodeficiency Virus (HIV) and Sexually 
Transmitted Infection (STI) incidence and associated risk factors among high-risk MSM and 
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75. Beyrer C, Baral SD, van Griensven F, et al. Global epidemiology of HIV infection in men 
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76. Burrell E, Mark D, Grant R, Wood R, Bekker LG. Sexual risk behaviours and HIV-1 
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77. Price MA, Rida W, Mwangome M, et al. Identifying at-risk populations in Kenya and South 
Africa: HIV incidence in cohorts of men who report sex with men, sex workers, and youth. J 
Acquir Immune Defic Syndr 2012;59:185-93. 
78. Rispel LC, Metcalf CA, Cloete A, Reddy V, Lombard C. HIV prevalence and risk practices 
among men who have sex with men in two South African cities. J Acquir Immune Defic 
Syndr 2011;57:69-76. 
79. Sanders EJ, Okuku HS, Smith AD, et al. High HIV-1 incidence, correlates of HIV-1 
acquisition, and high viral loads following seroconversion among MSM. AIDS 2013;27:437-
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80. Sevelius JM, Patouhas E, Keatley JG, Johnson MO. Barriers and facilitators to engagement 
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81. Koblin BA, Chesney MA, Husnik MJ, et al. High-risk behaviors among men who have sex 
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82. Koblin BA, Mayer KH, Noonan E, et al. Sexual risk behaviors, circumcision status and pre-
existing immunity to adenovirus type 5 among men who have sex with men participating in a 
randomized HIV-1 vaccine efficacy trial: Step Study. J Acquir Immune Defic Syndr 2012. 
83. Bartholow BN, Goli V, Ackers M, et al. Demographic and behavioral contextual risk groups 
among men who have sex with men participating in a phase 3 HIV vaccine efficacy trial: 
implications for HIV prevention and behavioral/biomedical intervention trials. J Acquir 
Immune Defic Syndr 2006;43:594-602. 
84. Buchbinder SP, Vittinghoff E, Heagerty PJ, et al. Sexual Risk, Nitrite Inhalant Use, and Lack 
of Circumcision Associated With HIV Seroconversion in Men Who Have Sex With Men in 
the United States. J Acquir Immune Defic Syndr 2005;39:82-9.  

 
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85. Sanchez J, Lama JR, Peinado J, et al. High HIV and ulcerative sexually transmitted infection 
incidence estimates among men who have sex with men in Peru: awaiting for an effective 
preventive intervention. J Acquir Immune Defic Syndr 2009;51 Suppl 1:S47-51. 
86. Scott H, Vittinghoff E, Irvin R, et al. Development and Validation of the Personalized Sexual 
Health Promotion (SexPro) HIV Risk Prediction Model for Men Who Have Sex with Men in 
the United States. AIDS Behav. 2019. 
87. The NAMSAL ANRS 12313 Study Group. Dolutegravir-based or low-dose efavirenz–based 
regimen for the treatment of HIV-1. N Engl J Med. 2019.88.  
88. Venter WDF, Moorhouse M, Sokhela S, et al. Dolutegravir plus two different prodrugs of 
tenofovir to treat HIV. N Engl J Med. 2019. 
89. Landovitz RJ, et al. Cabotegravir is Not Associated with Weight Gain in HIV-uninfected 
Individuals in HPTN 077. Clin Infect Dis. 2019 May 24 
90. Hill A, et al. Are new antiretroviral treatments increasing the risks of clinical obesity? J Virus 
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91. Gilead Package Insert For Truvada. at 
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Chichester ; New York: John Wiley & Sons Ltd; 2000. 
     
 
 

 
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APPENDICES I - IV 

 
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Appendix IA: Schedule of Procedures and Evaluations – Screening; Step 1 – Blinded Daily Oral Pills 
 
Screening 
Step 1  
DAY 0/Enrollment 
WEEK 2 
WEEK 4 
ADMINISTRATIVE, BEHAVIORAL, REGULATORY 
Informed consent  
X 
 
 
 
SexPro assessment (US sites only for inclusion; 
South American sites only for data collection) 
X 
 
 
 
Locator information 
X 
X 
X 
X 
Demographic information 
 
X 
 
 
Randomization 
 
X 
 
 
HIV counseling  
X 
X 
X 
X 
Offer condoms and lubricant  
X 
X 
X 
X 
Baseline acceptability assessment  
 
X 
 
 
Baseline behavioral assessment 
 
X 
 
 
Adherence counseling/pill count (Pill count 
Week 2 and 4 only) 
 
X 
X 
X 
CLINICAL EVALUATIONS & PROCEDURES 
History (including bleeding history at 
Screening), con meds, physical exam 
X 
X 
X 
X 
Height7, weight, blood pressure, pulse data entry 
to Medidata Rave 
 
X 
X 
X 
ECG (screening ECG can serve as baseline 
value) 
X 
 
 
 
DXA (BMD subset only, 175 per arm), to 
include dietary calcium and Vitamin D 
assessment  
 
X 
 
 
Blood collection 
X 
X 
X 
X 
Urine collection for urinalysis  
 
X 
 
 
Urine collection for urinalysis GC/CT testing 
 
X 
 
 
Rectal swab for GC/CT testing1  
 
X 
 
 
Dispense Pills (enough for 5 weeks)  
 
X 
 
 
LOCAL LABORATORY EVALUATIONS & PROCEDURES 
HIV testing2 
X 
X 
X 
X 
HBV and HCV testing3 
X 
X 
 
 
CBC with differential 
X 
X 
X 
X 
Chemistry testing4  
X 
X 
X 
X 
Liver function tests5 
X  
X 
X 
X 
Fasting glucose and fasting lipid profile6  
 
X 
 
 
Syphilis serologic testing 
 
X 
 
 
BMD subset only:  25-OH-Vitamin D 
 
X 
 
 

 
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Screening 
Step 1  
DAY 0/Enrollment 
WEEK 2 
WEEK 4 
Urine GC/CT testing 
 
X 
 
 
Rectal swab GC/CT testing1 
 
X 
 
 
Urinalysis (protein and glucose) 
 
X 
 
 
Plasma storage 
X 
X 
X 
X 
DBS storage  
 
 
 
X 
Whole blood storage  
 
X 
 
 
 
FOOTNOTES FOR APPENDIX IA 
1 If testing cannot be performed at the local laboratory, testing at another laboratory will be considered (see SSP Manual).   
2 The HIV testing algorithm is provided in Appendices IE-G and the SSP Manual. If HIV rapid testing is indicated, this testing may be performed in the clinic or the 
laboratory.   
3 HBsAg and HCV antibody testing are required at Screening. At Enrollment, HBsAb and HBcAb required; no HCV testing required at Enrollment.      
4 Creatinine required at screening; at and after enrollment, BUN/Urea, creatinine, CPK, calcium, phosphorous, glucose, amylase, and lipase are required.  
5 ALT and bilirubin required at screening; at and after enrollment, AST, ALT, total bilirubin, and alkaline phosphatase are required.  
6 Total cholesterol, HDL, triglycerides, and LDL (either calculated or measured). Participants should have fasted for at least 8 hours, preferably 12 hours, prior to sample 
collection. 
7  Height is a one-time measurement required to be captured in the source documents at enrollment as part of the complete physical exam.  The height 
measurement should be entered into MediData Rave when the database is updated to capture the measurement.   
 

 
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Appendix IB: Schedule of Procedures and Evaluations - Step 2 – Blinded Injections + Blinded Daily Oral Pills 
WEEKS (shaded 
column = 
injection/ dispense 
pills visit) 
5
6
9
10
17
19
25
27
33
35
41
43
49
51
57
59
65
67
73
75
81
83
89
91
97
99
105
107
113
115
121
123
129
131
137
139
145
147
Week 153/ 
Day 0* 
Locator Information 
X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X 
X 
HIV Counseling 
X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X 
X 
Condoms and 
lubricant 
X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X 
X 
Acceptability 
Assessment 
 
 
 
 X  
 
 
 
 X  
 
 
 
 X  
 
 
 
 X  
 
 
 
 
 
 
 
 
 
 X  
 
 
 
Behavioral 
Assessment 
X  X  X  X  X  X  X  X  
 
 X  
 
 X  
 
 X  
 
 X  
 
 X  
 
 
X 
Adherence Counseling X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X 
X 
History, concomitant 
medications, physical 
exam 
X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X 
X 
Weight, blood 
pressure, pulse data 
entry to Medidata 
Rave 
X  X  X  X  X  X  X  X  X  X  X  X  X  X  X  X  X  X  X  
X 
ECG 
 
 
 
 
 
 
 
 
 
 
 
 
 
 X  
 
 
 
 
 
 
 
 
 
 X  
 
 
 
 
 
 
 
 
 
 
X 
DXA (subset only, 175 
per arm)1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 X  
 
 
 
 
 
 
 
 
 
 X  
 
 
 
 
 
 
 
 
 
 
 
Blood Collection 
X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X 
X 
Urine collection for 
urinalysis testing 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X  
 
 
 
 
 
 
 
 
 
 X  
 
 
 
 
 
 
 
 
 
 
X 
Urine collection for 
GC/CT testing 
 
 
 
 
 
 
 
 X  
 
 
 
 X  
 
 
 
 X  
 
 
 
 X  
 
 
 
 X  
 
 
 
 
X 
Rectal swab for 
GC/CT testing2 
 
 
 
 
 
 
 
 X  
 
 
 
 X  
 
 
 
 X  
 
 
 
 X  
 
 
 
 X  
 
 
 
 
X 
Injection/Dispense 
pills 
X  X  X  X  X  X  X  X  X  X  X  X  X  X  X  X  X  X  X  
 
ISR evaluation 
 X  X  X  X  X  X  X  X  X  X  X  X  X  X  X  X  X  X  X 
 
 
 
 

 
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WEEKS (shaded 
column = 
injection/ dispense 
pills visit) 
5
6
9
10
17
19
25
27
33
35
41
43
49
51
57
59
65
67
73
75
81
83
89
91
97
99
105
107
113
115
121
123
129
131
137
139
145
147
Week 153/ 
Day 0* 
HIV testing3 
X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X 
X 
HCV testing4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 X  
 
 
 
 
 
 
 
 
 
 X  
 
 
 
 
 
 
 
 
 
 
X 
CBC with differential  X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X 
X 
Chemistry testing5 
 X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X 
X 
Liver function tests6 
 X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X 
X 
Fasting glucose and 
fasting lipid profile7  
 
 
 
 
 
 
 
 
 
 
 
 
 
 X  
 
 
 
 
 
 
 
 
 
 X  
 
 
 
 
 
 
 
 
 
 
 
Syphilis serologic 
testing 
 
 
 
 
 
 
 
 X  
 
 
 
 X  
 
 
 
 X  
 
 
 
 X  
 
 
 
 X  
 
 
 
 
X 
Urine GC/CT testing 
 
 
 
 
 
 
 
 X  
 
 
 
 X  
 
 
 
 X  
 
 
 
 X  
 
 
 
 X  
 
 
 
 
X 
Rectal swab GC/CT 
 
 
 
 
 
 
 
 X  
 
 
 
 X  
 
 
 
 X  
 
 
 
 X  
 
 
 
 X  
 
 
 
 
X 
Urinalysis 
 
 
 
 
 
 
 
 
 
 
 
 
 
 X  
 
 
 
 
 
 
 
 
 
 X  
 
 
 
 
 
 
 
 
 
 
X 
Plasma storage 
X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X 
X 
DBS storage 
 
 X  X  X  X  X  X  X  X  X  X  X  X  X  X  X  X  X  X  
X 
FOOTNOTES FOR APPENDIX IB 
*See Appendix IC and corresponding footnotes for Step 3 Day 0 
1 To include dietary calcium and Vitamin D assessment 
2 If testing cannot be performed at the local laboratory, testing at another laboratory will be considered (see SSP Manual).   
3 The HIV testing algorithm is provided in Appendices IE-G and the SSP Manual. If HIV rapid testing is indicated, this testing may be performed in the clinic or the 
laboratory.   
4 Testing does not need to be repeated if infection was documented at a prior visit.  HCV Ab testing is required.   
5 Required chemistry testing: BUN/Urea, creatinine, CPK, calcium, phosphorous, glucose, amylase, and lipase.  
6 Required LFTs: AST, ALT, total bilirubin, and alkaline phosphatase.  
7 Required for lipid profile: Total cholesterol, HDL, triglycerides, and LDL (either calculated or measured). Participants should have fasted for at least 8 hours, preferably 
12 hours, prior to sample collection.

 
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Appendix IC: Schedule of Procedures and Evaluations - Step 3 – Open Label Daily Oral TDF/FTC Post-Last Injection  
Procedures 
Week 153/ Day0* 
Week 12 
Week 24 
Week 36 
Week 48 
ADMINISTRATIVE, BEHAVIORAL, REGULATORY 
 
Locator Information 
X 
X 
X 
X 
X 
HIV Counseling 
X 
X 
X 
X 
X 
Offer Condoms and lubricant 
X 
X 
X 
X 
X 
Acceptability Assessment2 
X 
 
 
 
 
Behavioral Assessment (if done 
in last 4 weeks, skip D0 and 
start at W12) 
X 
 
X 
 
 
X 
Adherence Counseling 
X 
X 
X 
X 
 
CLINICAL EVALUATIONS & PROCEDURES 
 
History, concomitant 
medications, physical exam 
X 
X 
X 
X 
X 
Weight, blood pressure, pulse 
data entry to Medidata Rave 
X 
X 
X 
X 
X 
Blood Collection 
X 
X 
X 
X 
X 
Urine collection for GC/CT 
testing  
X1 
 
X 
 
X 
Rectal swab for GC/CT testing3  
X1 
 
X 
 
X 
Dispense pills 
X 
X 
X 
X 
 
LOCAL LABORATORY EVALUATIONS & PROCEDURES 
HIV testing4 
X 
X 
X 
X 
X 
Chemistry testing5  
 
 
X 
 
X 
Liver function tests6 
 
 
X 
 
X 
Syphilis serologic testing 
X1 
 
X 
 
X 
Urine GC/CT testing 
X1 
 
X 
 
X 
Rectal swab GC/CT testing 
X1 
 
X 
 
X 
Plasma storage 
X 
X 
X 
X 
X 
FOOTNOTES FOR APPENDIX IC 
*For participants who transition to Step 3 prematurely, the timeline for Day 0 begins 8 weeks after that participant’s last injection, even if the participant does not report to the 
Day 0 visit (or the Week 12 visit, etc.). The timeline for Step 3 continues whether or not a participant attends visits. Sites may contact the CMC for questions regarding 
participants who transition to Step 3 prematurely who are then subsequently missing, though it is not required to do so. For participants who transition to Step 3 at Week 153, 
the first day of Step 3 begins at Week 153 and is also considered Day 0 of Step 3.              
1 Skip Day 0 if testing has occurred within last 3 months of Day 0 and do only at Weeks 24 and 48. 
2Administer acceptability assessment at Day 0 as final assessment if not done in the previous 6 months on Step 2, to include a brief preference assessment 
3 If testing cannot be performed at the local laboratory, testing at another laboratory will be considered (see SSP Manual).   
4 The HIV testing algorithm is provided in Appendices IE-G and the SSP Manual. If HIV rapid testing is indicated, this testing may be performed in the clinic or the 
laboratory.   
5 Required chemistry testing:  BUN/Urea, creatinine, CPK, calcium, phosphorous, glucose, amylase, and lipase.  
6 Required LFTs:  AST, ALT, total bilirubin, and alkaline phosphatase.  

 
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Appendix ID: Schedule of Procedures and Evaluations for Annual Visits 
The procedures listed below are for the following participants: 
• Participants in Step 1 who do not transition to Step 2 for any reason other than HIV infection 
will be asked to attend annual visits until three years from the date of Enrollment.  
• Participants in Step 2 who prematurely stop receiving injections for any reason other than 
HIV infection will transition to Step 3, complete the required 48 weeks of follow-up in Step 
3, and will then be asked to attend annual visits until three years from the date of Enrollment. 
The timepoint during Step 2 that a participant transitions to Step 3 will determine whether 
they will be asked to attend annual visits following the completion of Step 3. If the 
completion of open label TDF/FTC for Step 3 post-dates three years from the date of 
Enrollment, no further annual follow-up is required. 
In both cases above, these participants will remain blinded to their original randomized assignment until 
all participants complete Step 2 of the study.     
 
 
Procedure 
Annual Visit 
Locator information  
X 
Offer condoms and lubricant 
X 
HIV counseling (pre- and post-test) 
X 
Targeted history, con meds, physical exam 
X 
Blood collection 
X 
HIV testing 
X 
Plasma storage 
X 
DBS storage 
X 
 
 

 
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Appendix IE: HIV Testing Algorithm at the Screening Visit: 
 
 

 
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Appendix IF: HIV Testing Algorithm at the Enrollment Visit: 
 

 
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Appendix IG: HIV Testing Algorithm at Follow-up Visit: 
 

 
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Appendix II: Schedule for Additional Procedures for Enrolled Participants who have a Reactive 
or Positive HIV Test Result (including HIV confirmatory visit) 
Note 1:  The procedures listed for the HIV Confirmation Visit apply to participants who become 
infected at any time during the study.  The procedures listed for Weeks 12, 24, 36, and 48 apply 
only to participants with confirmed HIV infection during Step 2 of the study.  Participants with 
confirmed HIV infection in Step 3 of the study may undergo similar procedures as listed in Weeks 
12, 24, 26, and 48, and will be determined by the members of 083HIV@hptn.org.    
Note 2:  Procedures for discordant or discrepant HIV test results are outlined in the SSP. 
 
HIV 
Confirmation 
Visit 
Week 12 
Week 24 
Week 36 
Week 486 
ADMININISTRATIVE, BEHAVIORAL, REGULATORY 
Locator information  
X 
X 
X 
X 
X 
Offer condoms and lubricant 
X 
X 
X 
X 
X 
HIV counseling  
X 
 
 
 
 
CLINICAL EVALUATIONS AND PROCEDURES 
History, con meds, 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 
 
 
 
 
1 The HIV confirmation testing algorithm is to be performed on a different day from the initial reactive/positive sample.  The 
specifics 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 will not be used for real-
time/local resistance testing.   
3 Required chemistry testing: BUN/Urea, creatinine, CPK, calcium, phosphorous, glucose, amylase, and lipase.  
4 Required LFTs: AST, ALT, total bilirubin, and alkaline phosphatase.  
5 Stored plasma will be used for Quality Assurance testing at the HPTN LC and for other assessments described in Section 
9.0. Assessments will be performed retrospectively; results will not be returned to study sites or participants, except as noted 
in Section 9.0. 
6 The Week 48 visit should be timed as closely as possible to 52 weeks after the participant received their last injection.      
 

 
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Appendix III: Toxicity Management 
Toxicity Management General Guidance 
In general, the IoR has the discretion to hold study product at any time if she/he feels that 
continued product use would be harmful to the participant, or interfere with treatment deemed 
clinically necessary according to the judgment of the IoR. In addition, a Clinical Management 
Committee (CMC) will be 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. Investigators also 
should consult the CMC for further guidance in restarting study product or progressing to 
permanent discontinuation. Revealing a participant’s blinded status will occur only for 
individuals who become HIV infected and choose to initiate antiretroviral therapy, or in the case 
of a medical management decision (as approved by DAIDS), or as outlined in Section 5.13.1 of 
the protocol and Appendix VI of the SSP regarding unblinding in the event of an immediate 
medical emergency. 
The following general guidance refers to all AEs except for ALT, creatinine clearance (absolute 
and change from baseline), and CPK. Refer to the tables below for specific guidance about these 
laboratory abnormalities.  
Grade 1 or 2 
In general, participants who develop a Grade 1 or 2 AE regardless of relatedness to study 
product, and that is not specifically addressed in the Table below may continue use of the study 
product per protocol.             
Grade 3 
Any grade 3 or higher clinical or laboratory AE observed prior to Week 5 will prompt 
consultation with the CMC prior to any injectable dosing. Participants who develop a Grade 3 
AE or toxicity that is not specifically addressed in the Table below and is judged to be related to 
study product by the Investigator, study product use should be temporarily discontinued in 
consultation with the CMC. In general, and unless otherwise decided in consultation with the 
CMC, the investigator should re-evaluate the participant until resolution of the toxicity. 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 Investigator must consult the CMC for further guidance on holding of study product, 
frequency of reevaluation or progression to permanent discontinuation of the study product. For 
Grade 3 AEs deemed unrelated to study product, the CMC should be consulted for further 
management recommendations. Additionally, for Grade 3 or higher abnormalities at Week 0 
(study enrollment), consult the CMC for guidance regarding follow up and ongoing study 
product administration.   

 
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Grade 4 
Any grade 4 or higher clinical or laboratory AE observed prior to Week 5 will prompt 
consultation with the CMC prior to any injectable dosing. Participants who develop a Grade 4 
AE or toxicity that is not specifically addressed below (regardless of relationship to study 
product) should have the study product temporarily discontinued. The Investigator must consult 
the CMC and continue the temporary study product hold until a recommendation is obtained 
from the CMC. In general, study product use will not be resumed if the Grade 4 AE is considered 
related to study product use. If, in consultation with the CMC, study product use is resumed and 
the same Grade 4 AE recurs at Grade 4 level at any time, study product must then be 
permanently discontinued. 
General Criteria for Discontinuation of Study Product 
Participants may voluntarily discontinue the study products for any reason at any time.   
Investigators 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. Investigators 
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 hepatitis B virus (HBV) infection   
Participants in Step 2 who prematurely and permanently discontinue study product should be 
asked to continue to be followed according to the applicable Schedule of Evaluations and 
Procedures of Step 3. 
Study product will be temporarily withheld from a participant for any of the following reasons: 
• Report of use of prohibited concomitant medications as described in the SSP Manual.  
Study product use may resume upon consultation with the CMC and when the participant 
reports that he/she is no longer taking the prohibited medication, provided other reasons 
for temporary study product hold/permanent discontinuation do not apply. The CMC 

 
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should be consulted in all cases where a participant reports taking a prohibited product 
during the course of the study.   
• The participant is unable or unwilling to comply with required study procedures such as 
HIV testing and routine laboratory assessments, or otherwise might be put at undue risk 
to their safety and well-being by continuing study product use, according to the judgment 
of the IoR. The IoR must consult the CMC on all temporary study product holds 
instituted for this reason for further guidance on resuming study product use, continuing 
the temporary hold, or progressing to permanent discontinuation.   
• The participant has one or more reactive HIV test results, or expresses a concern about 
having acute HIV infection. Criteria for resuming use of study product in these 
circumstances are defined in the protocol and SSP Manual. 
Participants who temporarily or permanently discontinue study product during the oral phase will 
be instructed to return all study products as soon as possible. 
Note the following for cases of exercise-induced CK abnormalities: Cases of CK abnormality, 
presumed to be exercise induced, at the Grade 3 or higher level accompanied by ALT 
abnormalities of Grade 3 or lower up to and including Grade 3 should be brought to the attention 
of the CMC for adjudication of further management and further administration of study product. 
Grade 4 elevations in ALT, regardless of CK elevation will prompt permanent discontinuation of 
study product and the participant will be followed annually until three years from the date of 
Enrollment. All such cases must be reported to the CMC. 

 
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Guidance on Toxicity Management for Specified Toxicities: 
Nausea, Vomiting, and Diarrhea 
CONDITION AND 
SEVERITY1 
IMMEDIATE 
ACTION 
FOLLOW-UP AND MANAGEMENT2 
Nausea, Vomiting, and Diarrhea 
Grade 1 and 2 
Continue study 
product (reminder 
to take study 
product with food) 
Treat symptomatically with hydration, oral 
antiemetic therapies or antiemetic suppositories at 
the discretion of the Investigator. The Investigator 
should order any clinically relevant laboratory 
analyses (per judgment of the Investigator). 
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 Investigator 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 
CONDITION AND 
SEVERITY1 
STUDY 
PRODUCT USE 
FOLLOW-UP AND MANAGEMENT2 
ELEVATIONS in ALT  
Grade 2 and higher 
Oral phase (Step 1): 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 2, study drug may 
continue to Week 4. If the repeat value is < Grade 2 at Week 4, the 
participant may proceed to Step 2 injection phase. If the repeat value is 
Grade 2 or higher at Week 4, study product should be stopped, and the 
participant will be followed annually until three years from the date of 
Enrollment. 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.  If an etiology for elevated ALT is identified or 
persistent without explanation, the CMC may direct an alternate interval 
for follow-up.    
A Grade 3 or higher ALT abnormality reported at Week 2 or Week 4, 
regardless of relatedness to the study product, will prohibit a participant 
from entering the injection phase of the study, and the participant will be 
followed annually until three years from the date of Enrollment. 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. If 
an etiology for elevated ALT is identified or persistent without 
explanation, the CMC may direct an alternate interval for follow-up.    
  
Note the following for cases of exercise-induced CK abnormalities:  
Cases of CK abnormality, presumed to be exercise induced, at the Grade 
3 or higher level accompanied by ALT abnormalities of Grade 3 or 
lower up to and including Grade 3 should be brought to the attention of 
the CMC for adjudication of further management and further 
administration of study product. Grade 4 elevations in ALT, regardless 
of CK elevation will prompt permanent discontinuation of study product 
and the participant will be followed annually until three years from the 
date of Enrollment. All such cases must be reported to the CMC.   

 
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CONDITION AND 
SEVERITY1 
STUDY 
PRODUCT USE 
FOLLOW-UP AND MANAGEMENT2 
ELEVATIONS in ALT  
Grade 2 and higher 
Injection phase (Step 2): 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. If an etiology for elevated ALT is 
identified or persistent without explanation, the CMC may direct an 
alternate interval for follow-up.    
Participants who are permanently discontinued from study product 
should continue to be followed on study/off study product, following the 
Step 3 Schedule of Evaluations for Arm A. 
Note the following for cases of exercise-induced CK abnormalities:  
Cases of CK abnormality, presumed to be exercise induced, at the Grade 
3 or higher level accompanied by ALT abnormalities of Grade 3 or 
lower up to and including Grade 3 should be brought to the attention of 
the CMC for adjudication of further management and further 
administration of study product. Grade 4 elevations in ALT, regardless 
of CK elevation will prompt permanent discontinuation of study product.  
Open-label phase (Step 3):  Participants outlined above who transition 
to Step 3 will be followed per the Schedule of Procedures and 
Evaluations for Step 3 except for provision of study product.   
When Step 3 concludes in these cases, the participant will be followed 
annually until three years from the date of Enrollment. The timepoint 
during Step 2 that a participant transitions to Step 3 will determine 
whether they will be asked to attend annual visits following the 
completion of Step 3. If the completion of open label TDF/FTC for Step 
3 post-dates three years from the date of Enrollment, no further annual 
follow-up is required. All such cases must be reported to the CMC.   

 
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Guidance on Toxicity Management for Specified Toxicities: 
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 referred for 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.  

 
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Guidance on Toxicity Management for Specified Toxicities: 
 
Creatinine Clearance 
NOTE:  Adverse events related to creatinine clearance should be based on examination of BOTH 
the absolute creatinine clearance AND the change in creatinine clearance from baseline 
(Enrollment/ Visit 2.0). When gradable, only the higher grade of these two assessments should 
be entered on the Adverse Event e-CRF. Clinical Management of Grade 3 and Grade 4 changes 
in creatinine clearance should follow the “Toxicity Management General Guidance” ONLY 
when the absolute creatinine clearance is < 90 mL/min. That is, changes in creatinine clearance 
of >30% from baseline that DO NOT result in an absolute creatinine clearance < 90 mL/min do 
NOT need to be reported to the CMC or more frequent clinical monitoring.  Additionally, 
changes in creatinine clearance of > 30% that are accompanied by a creatinine that remains 
within normal limits also do not need to be reported to the CMC and do not require more 
frequent clinical monitoring.    
 
CONDITION AND 
SEVERITY 
STUDY PRODUCT 
USE 
FOLLOW-UP AND MANAGEMENT 
CREATININE CLEARANCE 
Estimated CrCl< 60 mL/min 
Discontinue study 
product temporarily 
If the calculated creatinine clearance is 
<60mL/min, it should be confirmed within 1 week 
of the receipt of the results, and the CMC should 
be consulted for adjudication and recommendation 
for further testing and follow-up.   
Confirmed CrCl< 60 mL/min  
Permanently 
discontinue study 
product  
If the calculated creatinine clearance is confirmed 
to be <60 mL/min, the study product must be 
permanently discontinued and the CMC notified.  
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 
Investigator must consult the CMC for further 
guidance on resuming study product use, 
continuing the hold temporarily, or progressing to 
permanent discontinuation. 
If the investigator 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 (CK or CPK) 
CONDITION AND 
SEVERITY\ 
STUDY PRODUCT USE 
FOLLOW-UP AND MANAGEMENT 
Creatine Phosphokinase 
Grade 1 and 2 
Continue study product 
A Grade 2 or lower elevation does not 
warrant retesting or changes to study product 
use. 
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 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. If after retesting, a Grade 3 
elevation persists, consult the CMC for 
guidance. 
Grade 4 
Continue study product until 
repeat test results are 
available  
Grade 4 elevations in CPK should have a 
repeat assessment within 2 weeks at least 24 
hours after the subject has abstained from 
exercise. For persistent Grade 4 CPK 
elevations that are symptomatic (myalgias, 
muscle pain, dark urine, or clinically 
significant changes in creatinine clearance, 
defined in consultation with the CMC) 
should have study product discontinued. 
Otherwise, the CMC will provide guidance 
on frequency of additional CPK monitoring 
and ongoing study product use.   

 
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Guidance on Toxicity Management for Specified Toxicities: 
QTc – Criteria for Permanent Discontinuation of Study Product 
A participant that meets either criterion below will have study product stopped, but will remain 
in study follow-up. The QT (QTc) correction formula used to determine study product 
discontinuation should be the same one used throughout the study. For example, either Bazett’s 
(QTcB) or Fridericia (QTcF) correction formula may be used, as long as the same formula is 
used throughout for a given participant. 
• QTc > 550 msec, OR 
• Change from baseline: QTc >60 msec 
Study product discontinuation decisions are to be determined by the Investigator of Record or 
designee in consultation with the CMC. A decision to permanently discontinue study product 
will be based on an average QTc value of triplicate ECGs. If an ECG demonstrates a prolonged 
QT interval, obtain two more ECGs within one hour, and then use the averaged QTc values of 
the three ECGs to determine whether the participant should permanently discontinue study 
product.   
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.  Starting at the point of when Version 
3.0 is implemented at an individual site, sites should document all interventions that have been 
attempted to mitigate injection site reactions, which should include at a minimum: 
1. Pre-treatment (prior to injection administration) warm compresses 
2. Topical or oral pre-treatment with NSAID preparations, unless contraindicated 
3. Immediate post-injection massage to injection location 
4. Post-treatment warm or cold compresses 
5. Post-treatment NSAID or other analgesic preparations, topically or orally 
Such interventions and their outcome should be documented in the source documents and the 
CMC consulted prior to discontinuation of Step 2 follow-up.  A proactive and comprehensive 
approach to mitigating ISRs should be undertaken, with premature transition from Step 2 to Step 
3 being reserved for refractory cases in extreme circumstances. 
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 

 
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the study site staff immediately if there is any worsening of symptoms or if further systemic 
signs or symptoms develop. Antihistamines, topical corticosteroids, or antipruritic agents may be 
prescribed.  
Participants with Grade ≥3 allergic reactions that are considered to be related to study product 
should permanently discontinue study product and continue to be followed on study/off study 
product. Participants should be treated as clinically appropriate and followed until resolution of 
the AE. 
 

 
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Appendix IV: Sample Screening and Enrollment Informed Consent Form 
HPTN 083 
A Phase 2b/3 Double Blind Safety and Efficacy Study of Injectable Cabotegravir Compared to 
Daily Oral Tenofovir Disoproxil Fumarate/Emtricitabine (TDF/FTC), For Pre-Exposure 
Prophylaxis in HIV-Uninfected Cisgender Men and Transgender Women who have Sex with 
Men 
Version 3.0 
October 31, 2019 
DAIDS Document ID: 20725 
 
Sponsored by: Division of AIDS, United States (US) National Institute of Allergy and Infectious 
Disease, US National Institutes of Health.  Study products are provided by ViiV Healthcare and Gilead 
Sciences, Inc.  
PRINCIPAL INVESTIGATOR: [Insert Name] 
PHONE:  [Insert Number] 
GENERAL OVERVIEW 
You are being asked to take part in an investigational research study related to the Human 
Immunodeficiency Virus, or HIV.  HIV is the virus that causes Acquired Immunodeficiency Syndrome, 
or AIDS. 
This study is being offered to approximately 5000 HIV-uninfected men who have sex with men (MSM) 
and transgender women (TGW) that have sex with men in Asia, North and South America, and South 
Africa. Before you decide whether to join the study, we would like to explain the purpose of the study, 
the risks and benefits to you, and what is expected of you. 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by U.S. 
Law. This Web site will not include information that can identify you. At most, the Web site will 
include a summary of the results. You can search this Web site at any time. 
There may be no direct benefits for you if you participate in this study. There also may be some risks 
with taking part in the study. Before you can make an informed decision about whether to take part in 
this study, you should understand the possible risks and potential benefits of being in this study. This 
informed consent form gives information about the study that will be discussed with you. Once you 
understand the study, and if you agree to take part, you will be asked to sign your name on this form.   

 
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Your participation is voluntary 
This consent form gives information about the study that will be discussed with you. Once you 
understand the study, and if you agree to take part, you will be asked to sign your name or make your 
mark on this form. You will be offered a copy of this form to keep.  
Before you learn about the study, it is important that you know the following: 
• Your participation is voluntary. You do not have to take part in any of the tests or 
procedures in the study. 
• You may decide not to take part in the study, or you may decide to leave the study at any 
time. [You will continue to receive the same services that you can get at [insert clinic 
name]].   
• If you decide not to take part in the study, you can still join another study at a later time if 
there is one available and you qualify. 
• You cannot join this study if you are taking part in another study of drugs or medical 
devices. You are asked to tell the study staff about any other studies you are taking part in 
or thinking of taking part in. This is very important for your safety.   
BACKGROUND AND PURPOSE OF THE STUDY 
You are being asked to participate in this study because you are at risk of getting infected with HIV.  
Ideally, as part of routine medical care, ways to decrease your risk of getting infected with HIV would 
be discussed with you. [Sites to include next sentence if Truvada is locally available]: A treatment you 
might be offered to decrease your risk of getting HIV is a pill call Truvada (TDF/FTC). It is one pill that 
contains two drugs, one called emtricitibine [FTC] and the other called tenofovir disoproxil fumarate 
[TDF]). It is approved by the U.S. Food and Drug Administration (FDA) for the treatment of HIV and 
also to prevent people from getting HIV.  [Non-US sites to fill in the current status of approval of 
TDF/FTC here]. The US FDA is the regulatory group that oversees the approval of all drugs in the US.  
The approval of TDF/FTC for the prevention of HIV is based in part on a previous study in men who 
have sex with men (MSM) and transgender women (TGW) who have sex with men, called iPrEX. The 
iPrEX trial enrolled close to 2,500 HIV-uninfected MSM and TGW who were at risk for getting HIV, to 
see whether TDF/FTC would lower their chances of getting HIV. The study showed that it did. The 
study also showed that people that took the drugs more regularly were more likely to not get HIV than 
those who did not take the drugs regularly. TDF/FTC is supposed to be taken every day in order to 
provide the highest chance of not getting HIV. 
The main purpose of this study is to try to find out if a new drug, called cabotegravir (CAB), is as safe 
and will work as well as TDF/FTC in protecting you from getting HIV. CAB is available in the form of 
a pill and as an injection (shot). Researchers do not yet know if this injectable drug will work to protect 
people from getting HIV. This is why we are doing this study. In this study, you will take pills every 
day, and you will be get a shot every 8 weeks, after first getting two shots given one month apart.    

 
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STUDY GROUPS 
If you decide to be in this study, you will be placed in to 1 of 2 groups. Each group will have 
approximately 2500 people in it.  You will be followed for approximately four years, and include up to 
approximately 47visits to this clinic over that time.  
Each person in each group will get injections and a daily pill.  Injections are given as one shot in the 
buttock. The shot is given over time like this: you get one shot, then a month later you get another shot, 
and then after that you get a shot every two months. The pill should be taken every day.   
The first group will get the real CAB drug in a pill and injections, and the second group will get the real 
TDF/FTC drug in a pill and an injection with no study drug in it. We do not want you or the study 
researchers to know which group you are in, because we want to know which drug works better to 
protect you from getting HIV. By not knowing, then we do not favor one group over the other.  In order 
to do this, each group will also get placebos of the injections and the pills. Placebos look and feel like 
the real drug, but they do not contain any of the active (“real”) drug or any other medicines. The placebo 
for the CAB injection is a nutrition infusion called Intralipid. The placebo for the pills will look, feel and 
taste the same as the real pills.     
The study group that you will be in will be chosen randomly, like flipping a coin.  You cannot choose 
your group, and the study staff cannot choose your group for you. You have an equal chance of being 
placed in one of the two groups. Both groups are very important to the study. In this study, you and the 
study researchers will NOT know which group you are in until the study is over.       
No matter what group you are in, you must remember that we do not know if CAB works to protect you 
from getting HIV. We do know that taking TDF/FTC on a daily basis can be more than 90% protective 
against getting HIV infection. It is important to remember neither daily TDF/FTC nor CAB will protect 
you from getting sexually transmitted infections, like gonorrhea, chlamydia, syphilis, warts, or herpes.  
One of the best things you can do to protect yourself from getting HIV during sex is to us a condom 
every time you have sex. 
The groups look like this, and each group moves through 3 Steps in the study [sites may show a graphic 
to depict the groups and the steps] like this:   
Group A – this group gets real CAB pills and injections: 
o Step 1: Real CAB pill AND placebo pill for TDF/FTC (2 pills total) every day for 5 
weeks 
o Step 2: Real CAB injections given as one shot, then another shot a month later, and then 
every 2 months after that AND placebo pill for TDF/FTC every day up to three years 
after enrollment  
o Step 3: Real TDF/FTC pill every day for about a year, then move to local HIV prevention 
services  
 
Group B – this group gets real TDF/FTC pills:    

 
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o Step 1: Real TDF/FTC pill AND placebo pill for CAB (2 pills total) every day for 5 
weeks  
o Step 2: Placebo CAB injection AND real TDF/FTC pill everyday up to three years after 
enrollment 
o Step 3: Real TDF/FTC pill every day for about a year, then move to local HIV prevention 
services  
In Step 1, everyone starts the study by taking pills for 5 weeks. This is to see if you have any serious 
side effects to the study drugs before you start getting the shots.   
In Step 2, everyone takes pills and gets shots. This step will continue until three years after enrollment.   
In Step 3, which starts on the same day as the last day of Step 2, everyone gets the real TDF/FTC every 
day for about a year, then your participation in the study will end and we will refer you to local HIV 
prevention services.  There are no current plans for the study to offer the injectable CAB drug to study 
participants after the completion of the study.     
If the results of this study show that CAB works to prevent HIV, we will tell you that and let you know 
if it may become available in your local area. Often times it can take a long while for a new drug to 
become available to the public once it has been shown that it works in a study like this.   
STUDY PROCEDURES 
Screening Visit 
Your screening visit may occur after you read, discuss, understand, and sign this form, or will we 
schedule it for you at another time. We will help you understand the form and answer your questions 
before you sign this form. The procedures done for the screening visit will take about [site to fill in time 
required], and may be done at one or more visits.   
At this visit, the study staff will:  
• Ask you where you live and other questions about you, your medical health, your sexual 
practices, including if you are at a higher risk of getting HIV, and whether you use 
alcohol or drugs. [Sites in US to add this here:  We will ask you to answer some 
additional questions about sexual practices using an assessment called SexPro, which 
may provide additional information about your HIV risk, and whether this study is 
appropriate for you.]  [Sites in South America to add this here:  We will ask you to 
answer some additional questions about sexual practices using an assessment called 
SexPro, which may provide additional information about your HIV risk.] 
• Give you a brief physical exam to make sure you are healthy. 
• Talk with you about HIV and ways to protect yourself from getting it and offer condoms 
and lubricant. 
• Have an electrocardiogram (ECG) scan, which is a test to monitor your heart. 

 
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• Collect ~XX mL (about x teaspoons) of blood for HIV testing, Hepatitis B and C testing, 
to check your general health, to check the health of your liver, and for storage for study-
related testing. 
• [Sites participating in the DXA substudy to include this:] We may ask you to be a part of 
a group that gets a bone mineral density-energy x-ray absorptimetry (DXA) scan. A DXA 
scan is a special kind of x-ray using a small amount of radiation, allowing the doctor to 
see parts of the body better than a regular x-ray. We know that TDF/FTC may cause 
thinning or softening of bones in some people. We want to see whether there are changes 
to your bones during the study, and the DXA scan lets us evaluate your bones.  We want 
to see if this is different between the TDF/FTC and CAB treatments. The scan will be 
done at the Enrollment visit (this visit), and 2 other times during the study (Weeks 57 and 
105). The results of the DXA scans will be given to you at the end of the study. 
The results of the HIV test will be available [site to insert timeframe of RNA testing, and also EIA 
testing if being used]. You will be contacted about the results of your other tests when they are available. 
Confirmation of Eligibility: 
Once all the results of the screening tests are known, the following will happen within 45 days after 
screening: 
• You will be told your test results and what they mean. 
• If you have a positive HIV, hepatitis B or C test you will not be eligible for the study, and 
you will be referred for the appropriate medical care (sites to add specifics about this 
here as necessary).  
• If you are negative for HIV but the results from the other blood tests show that you might 
have some health problems, you may not be eligible for the study. Study staff will refer 
you to available sources of medical care and other services you may need. Later, if these 
problems resolve, you may be able to come back to find out if you are eligible at that 
time. 
Step 1:  Enrollment Visit (Week 0) 
If you are eligible for this study and decide to take part in the study, you will be asked to return for the 
enrollment visit. This visit will last about xx hours. During the visit, the study staff will: 
• Confirm where you live and how to contact you. 
• Ask you some questions about yourself, like your age, and your racial/ethnic group [sites 
that want to collect this during screening should move this to screening section.] 
• Talk with you about HIV and ways to protect yourself from getting it. 
• Give you a complete physical exam, to include measuring your height, weight, blood 
pressure, pulse, and ask you about any other medicines you are taking.   
• Collect a urine sample to see if there is sugar or protein in your urine. 

 
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• Collect ~XX mL (about x teaspoons) of blood for:  HIV testing, Hepatitis B testing, 
syphilis, to check how much cholesterol is in your blood (a fatty substance in your 
blood), to check your general health, to check the health of your liver, and for storage for 
study-related testing and long-term storage (if you provide consent) [Sites to delete if 
long term storage is not allowed]. [Sites to add this if allowed at your site. If not, delete:  
Additionally, if you provide consent, we will use a sample of your blood to see how the 
drugs work in your body by looking at your genes. Information about the testing related 
to your genes is found later in this consent form.] For the cholesterol test, you will be 
instructed to not eat or drink anything other than what the study staff tell you is 
acceptable for 8-12 hours before your blood is drawn. 
• Ask you questions about your sexual behavior. 
• Ask you questions about your opinions about taking pills and getting injections. 
• Perform a swab of your rectum and collect urine for gonorrhea and chlamydia. 
• [Sites participating in DXA substudy to include this: If you agreed to be part of the DXA 
subset, you will undergo a DXA scan [Note to sites participating in the DXA substudy - 
the first DXA may occur 30 days before the  Enrollment visit or 7 days after in order to 
allow for flexibility in scheduling.] 
• We may ask you to be a part of a group that gets a bone mineral density-energy x-ray 
absorptimetry (DXA) scan. A DXA scan is a special kind of x-ray using a small amount 
of radiation, allowing the doctor to see parts of the body better than a regular x-ray. The 
subset will include 350 participants. The scan will be done at the Enrollment visit and 2 
other times during the study (Weeks 57 and 105). If  you are in this group, we will also 
check your blood to see how much Vitamin D is in it, and will ask you about your diet to 
see if you are eating foods with calcium in it.  We will tell you if the DXA subset is no 
longer available to participate in.  [Sites that do not participate in the DXA subset to 
delete this entire bullet item].    
• Randomize you into one of the two study groups.  
• Give you your study pills, and explain how to take them, and any side effects they may 
cause.   
• Have a discussion about any challenges of taking a pill every day.  
• Give you the results of tests when they are available. 
• Offer you condoms and lubricants. 
Step 1:  Weeks 2 and 4 Visits 
These visits will last about XX.  During these visits, the study staff will: 
• Confirm where you live and how to contact you. 
• Talk with you about HIV and ways to protect yourself from getting it.  
• Count your pills, and talk with you about ways to help you take your pills.    

 
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• Give you a brief physical exam, to include measuring your weight, blood pressure, pulse, 
and ask you if you have experienced any side effects from the study drugs, and ask you 
about any other medicines you are taking. 
• Collect ~XX mL (about x teaspoons) of blood for HIV testing, to check your general 
health, the health of your liver and kidneys, and for storage. 
• Have a discussion to help work through any challenges of taking a pill every day; if it 
seems to you or to the study staff that you are having challenges, we will try to help by 
working through these with you. 
• Give you the results of your blood tests when they are available. 
• Offer you condoms and lubricant. 
If you have a side effect from the pills, or if you do not take enough of your pills, you may 
not be able to get the shots. If this happens, we will ask you to attend a visit once a year for 
three years from the time you enrolled in the study. The procedures for those visits are 
outlined later in this consent form document [sites may also list the procedures here].    
Step 2:  Week 5 Visit – Visit for first injection 
This visit will last up X hours.  During this visit, the study staff will: 
• Confirm where you live and how to contact you. 
• Give you a brief physical exam, to include measuring your weight, blood pressure, pulse, 
ask you if you have experienced any side effects from the study drugs, and ask you about 
any other medicines you are taking. 
• Talk with you about HIV and ways to protect yourself from getting it. 
• Collect ~XX mL (about x teaspoons) of blood for HIV testing and for storage. 
• Ask you to answer questions about your sexual behavior. 
• Give you your study pills, and explain how to take them, and any side effects they may 
cause.    
• Administer the first shot in your buttock 
• Have a discussion to help work through any challenges of taking a pill every day; if it 
seems to you or to the study staff that you are having challenges, we will try to help by 
working through these with you. 
• Give you the results of your blood test when they are available. 
• Offer you condoms and lubricant. 

 
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Step 2:  All other visits where injections occurs:  Week 9, 17, 25, 33, 41, 49, 57, 65, 73, 81, 89, 97, 
105, 113, 121, 129, 137, 145, 153 (an injection is not given at Week 153 but is a study visit), 
In this step of the study, there will be approximately 19 visits where you will receive a shot and study 
pills. Injections will be given approximately every 2 months (8 weeks) after the first two are given one 
month (4 weeks) apart. These visits will last up to XX hours. During these visits, the study staff will: 
[Note:  Sites may remove Week numbers in the text below if easier to depict it in a table or refer to the 
Schedule of Procedures and Evaluations].   
• Confirm where you live and how to contact you. 
• Talk with you about HIV and ways to protect yourself from getting it. 
• Give you a brief physical exam, to include measuring your weight, blood pressure, pulse. 
Ask you if you have experience any side effects from the shots you received, and ask you 
about any other medicines you are taking. 
• Collect ~XX mL (about x teaspoons) of blood for:   
o HIV testing, to check your general health, the health of your liver, and for storage 
(every injection visit) 
o HCV testing about every year (Weeks 57, 105 and 153 only) 
o Syphilis testing about every 6 months throughout Step 2 (Weeks 33, 57, 81, 105, 
129 and 153 only) 
o Testing to see how much cholesterol is in your blood two times during the study, 
one year apart (Weeks 57 and 105 only). For the cholesterol test, you will be 
instructed to not eat or drink anything other than what the study staff tell you is 
acceptable for 8-12 hours before your blood is drawn.    
• Collect a urine sample to see if there is sugar or protein in your urine about every year for 
3 years (Weeks 57, 105, and 153 only). 
• Ask you to answer questions about your sexual behavior at every injection visit for about 
2 years, and then every other injection visit for the rest of Step 2 (Weeks 5, 9, 17, 25, 33, 
41, 49, 57, 65, 73, 81, 89, 97, 105, 121, 137, 153) 
• Ask you questions about how you feel about taking pills and getting injections about 
every 6 months for two years and then once more a year later (Weeks 17, 41, 65, 89 and  
137 ). 
• [Sites to include only for those sites participating in DXA subset:] If you had a DXA scan 
(x-ray) when you started the study, we will ask you to have two more, about a year apart 
from each other (Weeks 57 and 105 only). We will also ask you questions about what 
you eat and if you take any vitamins or other supplements.   
• Ask you to have an ECG scan about every year for 3 years (Weeks 57, 105, and 153 
only). 
• Perform a swab of your rectum and collect urine for gonorrhea and chlamydia about 
every 6 months throughout Step 2 (Weeks 33, 57, 81, 105, 129, and 153 only). 

 
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• Give you your study pills, and explain how to take them, and any side effects they may 
cause (at all injections visits).   
• At Week 153 only or if you move to Step 3 early, collect any unused blinded oral study 
product  
• Give you a shot (at all injection visits except for Week 153).  
• Give you the results of your blood tests when they are available (at all injection visits). 
• Have a discussion to help work through any challenges of taking a pill every day; if it 
seems to you or to the study staff that you are having challenges, we will try to help by 
working through these with you (at all injection visits). 
• Offer you condoms and lubricant (at all injection visits). 
Step 2:  Post-Injection Visits:  Weeks 6, 10, 19, 27, 35, 43, 51, 59, 67, 75, 83, 91, 99, 107, 115, 123, 
131, 139, 147 
[Note:  Sites may remove Week numbers in the text below if easier to depict it in a table or refer to the 
Schedule of Procedures and Evaluations].   
There will be up to approximately 19 visits following each visit where you got a shot. These visits will 
last up to XX hours. During these visits, the study staff will: 
• Confirm where you live and how to contact you. 
• Talk with you about HIV and ways to protect yourself from getting it. 
• Give you a brief physical exam. Ask you if you have experience any side effects from the 
shots you received, and ask you about any other medicines you are taking. 
• Collect ~XX mL (about x teaspoons) of blood for HIV testing, to check your general 
health, the health of your liver, the amount of the study drug that is in your blood, and for 
storage. 
• Offer you condoms and lubricant. 
Step 3:  If you stopped getting injections early, you will go to Step 3.  If you got all of your 
injections, you will go to Step 3 at Week 153 of Step 2, which is the same visit as Day 0 of Step 3.  
This step includes 4 more visits over about a year (Week 12, 24, 36, and 48).    
Each visit will last up to XX hours.  During these visits, the study staff will: 
• Confirm where you live and how to contact you. 
• Talk with you about HIV and ways to protect yourself from getting it. 
• Give you a brief physical exam, to include measuring your weight, blood pressure, pulse, 
and ask you about any other medicines you are taking 
• Collect ~XX mL (about x teaspoons) of blood for HIV testing, syphilis testing, to check 
your general health, the health of your liver, the amount of the study drug in your blood, 

 
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and for storage. Note: Blood will be collected for syphilis testing at Day 0 (which is the 
same as Step 2 Week 153), and Weeks 24 and 48.  However, if you have had syphilis 
testing within 3 months of joining this part of the study, you will only have this done at 
Week 24 and Week 48.   
• Perform a swab of your rectum and collect urine for gonorrhea and chlamydia (Day 0 
(same as Step 2 Week 153), Week 24 and 48 only). If you have had this test within 3 
months of joining this part of the study, you will only have this done at Week 24 and 
Week 48 only. 
• Give you your study pills, and explain how to take them, and any side effects they may 
cause (Day 0, Weeks 12, 24, and 36 only). 
• Ask you to answer questions about your sexual behavior (Day 0, Week 12, 24 and 48 
only). 
• Ask you questions about what it was like getting the injections and taking the study pills 
(this will only be asked if you have not been asked this in the few months before you 
started this step).   
• Have a discussion to help work through any challenges of taking a pill every day; if it 
seems to you or to the study staff that you are having challenges, we will try to help by 
working through these with you. 
• Give you condoms and lubricant. 
If you move into Step 3 prematurely, some of the procedures above may not have to be performed, 
which will depend on when during the study you moved into Step 3.  The procedures that may not have 
to be performed are: asking you about questions about your sexual behavior, urine collection and testing 
for GC/CT, and rectal swab collection and testing for GC/CT and syphilis testing.   
It may be necessary for additional visit(s) and procedures in the event of unforeseen or unanticipated 
events or results; for example, you may have a side effect that requires repeat testing on your blood to 
ensure that the study drugs continue to be safe for you to use.  Or, sometimes the results of some tests 
are not clear and additional testing is needed in order to confirm a test result.  There also may be 
difficulties in sample shipping, processing, or testing; and/or if you are experiencing any symptoms or 
changes in your physical condition.  There also may be a time that you are not able to complete all of the 
procedures in a visit and you have to come back the next day or another day, and additional blood may 
be needed when you come back in order to complete the requirements of the visit.  In the event of any of 
these unforeseen or unanticipated results, we will explain to you what will happen and what procedures 
will need to be done. 
After these visits are over, we will help you seek additional HIV prevention care [sites to add 
information here or elsewhere in the consent form].  
Annual Visits 
Procedures for HIV testing every year if you do not get shots or have completed or been in Step 3: 

 
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As we mentioned, the study begins with taking pills only for five weeks before you can start with the 
shots. During this time, you may get a side effect that would result in not moving to the part of the study 
where the shots are given. Or, you may not have taken enough of the pills. If any of this happens, you 
would not get shots, and we would ask you to attend a visit once a year until three years from your date 
of Enrollment in order to test you for HIV.   
If you do get shots but stop getting them early, you will move to Step 3 of the study where you will get 
real TDF/FTC for approximately a year and come in for visits every three months for approximately a 
year.  After that time, we will help you find prevention services in the local area, and we will ask you to 
attend a visit once a year until three years from your date of Enrollment in order to test you for HIV.   
The procedures for these visits every year while Step 2 of the study is still ongoing are:    
• Confirm where you live and how to contact you. 
• Talk with you about HIV and ways to protect yourself from getting it. 
• Give you a brief physical exam, and ask you about any medicines you are taking.  
• Collect ~XX mL (about x teaspoons) of blood for HIV testing, the amount of the study drug in 
your blood, and for storage. 
• Give you condoms and lubricant.  
 
As we mentioned at the beginning of the consent form, you can decide to not participate in the study at 
any time during the study.  If you decide this during a study visit, that study visit may be your last study 
visit.  If you decide this in between visits, we will ask you to return any unused study pills.   
Procedures if you become infected with HIV during the study 
If you get HIV during the Step 1 of the study, you will stop taking your study pills, and you will be 
referred for local care and treatment of HIV and will be discontinued from the study. If you get HIV 
during Step 2 of the study (while you are getting shots), you will stop taking the study drugs and getting 
shots and we will ask you to come back for a visit every 3 months for about a year. During these visits 
we will take xx amount of blood [sites to fill in] to check your immune system, the amount of HIV in 
your blood, the health of your blood and liver, and for storage. We also will give you a brief physical 
exam during these visits, and ask you about any other medications that you are taking. If you get HIV 
during Step 3 of the study, you will stop taking the TDF/FTC (Truvada), and will be referred for local 
care and treatment of HIV.  We may ask you to come in for additional visits to check on your health.         
Permanently Stopping Your Study Product 
There may be certain situations that occur where you will no longer get the study drugs while in the 
study, either because you decide you do not want to any longer, you get HIV, or the drugs are no longer 
safe for you to take. We may ask you to continue to come to the study visits even if you no longer get 
shots or take pills. We will fully explain to you what will be expected if you permanently stop taking the 
study drugs. 

 
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USE OF STUDY SAMPLES 
In addition to the laboratory tests performed at each study visit, samples from all study participants will 
be used for other testing that is part of this study. This will include testing related to HIV and other 
infections, including testing for the drugs used in this study and other anti-HIV medications. If you get 
infected with HIV or hepatitis B or C during the study, some the stored blood may also be used to study 
the HIV and hepatitis virus, and the body’s response to these infections. If you are taking sex hormones, 
your stored samples may also be used to study whether these medications interact with the anti-HIV 
medications used in this study. The samples used for this testing will be labeled with your study number 
and will be tested at special laboratory facilities that may be located in the US and other countries outside 
of [insert site country]. Results of this specialized testing will not be returned to the study site or you. 
POSSIBLE FUTURE TESTS [Sites may require a separate consent form for this] 
If you agree, your stored samples may also be used for future research related to HIV infection, hepatitis 
infection, and other infections transmitted through sex, and to better understand laboratory tests related to 
this study. [For sites that opt in for pharmacogenomics testing:] If you agree, your stored samples may 
also be used to study genes related to HIV infection and use of anti-HIV medications to prevent HIV 
infection. This testing is described in more detail below. You can agree to have your samples used for 
future research, even if you do not agree to have your samples used to study genes. 
The stored samples will be labeled with your study number and will be tested at special laboratory facilities 
that may be located in the US and other countries outside of [insert site country]. Only approved 
researchers will have access to them. Results from this testing will not be returned to the study site or you. 
You will be asked to sign at the end of this consent form to give permission to use your stored samples 
for future research. Even if you do not give permission to store your blood for possible future research, 
you can still be in this study. You may also withdraw your consent to use your stored samples for future 
research at any time. We will then destroy your samples after all of the study-related testing has been 
completed. If you agree to have your stored samples used for future research, your left over blood will be 
stored for an indefinite period of time after the study ends.  
RISKS AND/OR DISCOMFORTS 
Study Medications 
The side effects of cabotegravir include:   
• Headache 
• Diarrhea 
• Fatigue 
• Muscle aches 
• Nausea 
• Fever  
• Dizziness 

 
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• Runny nose 
• Sore throat 
• Upper respiratory tract infection 
• Vomiting (being sick)  
• Difficulty sleeping 
• Abnormal dreams/nightmares 
• Depression 
• Flatulence (gas or wind)  
• Increase in the level of enzymes in the muscles (creatine phosphokinase) 
• With the CAB that you get as a shot, some people in other studies have said they had pain, 
irritation, skin redness, bumps, swelling, itching, bruising in the area where they got the shot, 
some of which lasted a few weeks before resolving. 
There have been some people who were taking this medicine who have had liver side effects. Some of 
these people were HIV-infected (HIV positive) and some had damage to their liver before taking the 
CAB study medication. While taking the study medication, their blood tests showed that their liver was 
irritated, although they felt well. The medications were stopped, and the liver blood tests returned to 
normal. In this study, anyone with HIV-infection, Hepatitis C (or B), or any liver irritation will not be 
allowed to be in the study.   
Some people who have had a prior history of seizures (epilepsy) have had seizures (spells) while taking 
CAB. One person who did not have a previous history of seizures died after prolonged seizures. If you 
have ever had a seizure you will not be allowed to be in the study. 
The shots you receive in this study are long acting, meaning they stay in your body for a long time – as 
long as a year or more. If you develop a side effect to the study drug after the shot, there will be no way 
to remove the drug from your body. If you are in Group A, the group that gets the real CAB, we will 
monitor your health for a year after your last injection. If you get infected with HIV while on the real 
CAB, it is possible that real CAB and other HIV drugs that are like it may not work to fight the virus. 
If you develop a symptom from these drugs while the drugs are still in your body, every effort will be 
made to treat the side effects. The amount of drug will decrease overtime and will eventually disappear. 
We will update you on any new side effects that we see in this study and other on-going studies, if those 
side effects appear to have come from the drug. If you have questions concerning the additional study 
drug side effects, please ask the medical staff at your site. As stated above, some of these risks are seen 
in HIV infected people taking these medications. It is not known if these side effects will occur as often 
and it could be that some of these side effects might be more or less serious in HIV uninfected people. 
Side effects of TDF/FTC include:   
Lactic acidosis (elevated lactic acid levels in the blood) and severe hepatomegaly (enlarged liver) with 
steatosis (fatty liver) that may result in liver failure, other complications or death have been reported 

 
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with the use of antiretroviral nucleoside analogues alone or in combination. The liver complications and 
death have been seen more often in women on these drug regimens. Some nonspecific symptoms that 
might indicate lactic acidosis include: unexplained weight loss, stomach discomfort, nausea, vomiting, 
fatigue, cramps, muscle pain, weakness, dizziness and shortness of breath. 
Other side effects include:   
• Upset stomach (nausea), vomiting, gas, loose or watery stools   
• Abdominal pain  
• Generalized weakness 
• Dizziness  
• Depression 
• Headache 
• Shortness of breath 
• Increased cough 
• Runny nose  
• Allergic reaction: symptoms may include fever, rash, itching, upset stomach, vomiting, loose or 
watery stools, abdominal pain, achiness, shortness of breath, a general feeling of illness or a 
potentially serious swelling of the face, lips, and/or tongue. 
• Skin darkening of the palms of hands and/or soles (bottom) of feet  
• Bone pain and bone changes such as thinning and softening which may increase the risk of 
breakage (this side effect goes away after stopping TDF/FTC) 
• Muscle pain and muscle weakness 
• Sleeping problems; unusual dreams; tiredness 
• Worsening or new kidney damage or failure  
• Liver problems. If you are developing liver problems, you may have one or more of the 
following symptoms:  
o Abnormal liver function tests, which could mean liver damage 
o Yellowing of the skin or whites of your eyes,  
o Dark urine,  
o Pain on the right side of your stomach,  
o Loss of appetite, upset stomach or vomiting,  
o Pale colored stools, 
o Itchy skin. 
• Increases in pancreatic enzyme (substances in the blood), which could mean a problem with the 
pancreas 

 
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• Increased triglycerides  
• Increased creatine phosphokinase (CPK), which could mean muscle damage 
Side effects of Intralipid when used as an intramuscular injection placebo include headache, anxiety, 
insomnia, vomiting, nausea, constipation, extremity pain, agitation, diarrhea, sedation, nasopharyngitis, 
upper respiratory infection, cough, urinary tract infection, decreased weight, and increased muscle tone. 
When Intralipid is given as an intravenous infusion (into a vein directly) for nutrition, the following side 
effects have been reported (note that these side effects have not been reported when Intralipid is 
administered through an intramuscular injection): 
Immediate or early adverse reactions, each of which has been reported to occur in clinical trials  less 
than 1% of the time:  trouble breathing, blue appearance to the skin at where the injection was given, 
allergic reactions, elevated levels of fat in your blood,  increased chances of getting blood clots, nausea, 
vomiting, headache, flushing, increase in temperature, sweating, sleepiness, pain in the chest and back, 
slight pressure over the eyes, dizziness, and irritation at the site of the infusion;  
Delayed adverse reactions such as:  large liver, yellowing of the skin and eyes, large spleen, low blood 
cell counts, increases in liver function tests, and overloading syndrome (seizures, fever, increase in white 
blood count, large liver, large spleen, and shock). 
Possible Injection Side Effects:  
 
The injections will be given in the muscles of your buttocks (bottom “cheeks”).  The injection could be 
given too deeply or not deeply enough, missing the muscle and entering your skin, blood, or a nerve.  
The risk of this is unknown but may result in higher levels of the injected medication in your system.     
Getting injections could also cause some people to feel lightheaded or feel like they might pass out, or 
‘faint’.  This reaction, called a ‘vasovagal reaction’, can occur with many medical procedures and 
resolves quickly.   
 
Blood Draws 
Taking blood samples may cause some pain, bruise your arm, or make you feel lightheaded.  In rare 
cases you may faint. There is also a slight chance of infection when blood is drawn. You may be 
nervous while you are waiting for your test results, particularly your HIV and sexually transmitted 
infection tests. You will receive counseling before and after these tests to help address your concerns. 
Rectal Swabs 
You may experience pain or discomfort in your rectum from the swab. In some cases, you may have 
some bleeding. 

 
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Sensitive Questions 
The questions we will ask you about your sexual behavior may make you feel uneasy. However, you do 
not have to answer any question that you do not want to and you can stop answering the questions at any 
time. 
DXA Scan [Only sites participating in the DXA subset to include this section] 
If you receive the scan, note the following: We are exposed to radiation on a daily basis both from 
natural (sun and earth) and man-made sources. The average radiation dose from these sources for those 
living in the United States is 363 millirem per year. Exposure of up to 5,000 millirem of radiation is 
allowed in individuals who use radiation in their work (such as Radiologic Technologists and 
radiologists). Also, there is no evidence that a dose up to 5,000 millirem per year is associated with any 
risk. The radiation dose that you will receive from the DXA scans done for this research is less than 1% 
of this annual limit for radiation workers (if you receive the scans). The scanning machines will not 
cause any physical discomfort other than from having to lie still on the table for the duration of the test.  
ECG 
ECG patches may cause a skin reaction such as redness or itching. You may also experience localized 
skin discomforts and/or hair loss associated with the placement of ECG leads. 
Genetic Testing 
[Sites that are able to conduct this testing should keep this section included; otherwise, this should be 
removed, as well as the signature lines on the signature page] 
We want to look at your genes that affect how your body changes and removes the drug used in this 
study. Gene differences between people can lead to different amounts of drug in the body. This may 
affect how well a drug protects people from HIV infection. If you consent, we will test your blood to get 
information about how your genes may have affected the drug levels in your body. The tests we will use 
to look at your genes are research tests and will be performed in a research laboratory. All of the 
samples will be identified with a coded number. The laboratory doing the testing will not know who you 
are. The results obtained for individual study participants (like you) will not be reported to the study 
sites or back to you. However, the combined results of the testing for all of the study participants will be 
available to the study sites and to the study participants at their request, once the analysis has been 
completed. 
We also may also use your samples and information for more complete genetic testing. For example, 
researchers may do “genome-wide association studies,” also known as GWAS. A genome is all of your 
genes in total. Genes are made of even smaller “building blocks” that are arranged in a specific order.  
Many diseases can result from changes to this order or “sequence.” These changes may somewhat 
explain why some people get diseases like cancer or diabetes while others do not. These changes may 
partly explain the body’s response to disease and treatment. We are interested in understanding if the 
way the study medication interacts with your body has anything to do with your particular genes. 
We may find information as we do this study that raises important other questions as to the safety of the 
study medication - - this new information may require that we do additional testing of left-over study 

 
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samples. We will let you know right away if we find any new information or any new concerns develop 
about the medication as the study continues. 
Your genetic information may also be shared for future research purposes and may be stored in a central 
genetic database, but your personal information (like your name or anything else about you) will not be 
shared.     
Social 
There may also be some social risks to participating in this study. You may feel embarrassed or 
uncomfortable with some of the questions you will be asked, some of the procedures that will be done, 
or some of the test results that you will receive. The questions we will ask you about your sexual 
behavior may make you feel uneasy. However, you do not have to answer any question that you do not 
want to and you can stop answering the questions at any time. You may also experience stigma as a 
result of being involved in a study about HIV because people may assume that you are HIV-infected. In 
addition, there may be uncommon or previously unknown risks that might occur. You should report any 
problems to the researchers immediately. 
Confidentiality 
We will make every effort to protect your confidentiality during the study. However, it is possible that 
others may learn that you are part of this study and they may think that you are infected with HIV or are 
at high risk for infection with HIV. Because of this you could have trouble finding or keeping a job.  
You could also have problems with your family, friends and community. 
HIV Infection 
We told you earlier that we do not know if CAB works to protect you from getting HIV. If you are in the 
group that gets the real CAB, you still may be at risk of getting HIV. We do know that taking TDF/FTC 
every day can be very effective at preventing HIV infection. If it is not taken every day, you may not be 
well protected. Because of these risks, it is very important that you use condoms every time you have 
sex, no matter what group you are in. 
Because the study medication is itself being studied to be an HIV treatment medication, if you become 
HIV infected while taking the study medication, there is a chance that other drugs used to treat HIV 
infection might not work. This is called drug resistance. 
To reduce the possibility of developing drug resistance, you will be asked to work with your local study 
clinic team to begin HIV treatment after your last study medication injection. The study will not provide 
this treatment but may be able to help you find and/or pay for that treatment. 
BENEFITS 
There may be no direct benefit for you if you participate in the study. TDF/FTC is known to protect 
against getting HIV if taken daily as directed. CAB has not been shown to protect against getting HIV, 
which is the reason we are doing this study. Neither you nor we will know which real drug you are 
getting in this study.   

 
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We will test you for HIV, hepatitis B and hepatitis C during this study, and other sexually transmitted 
infections. We will refer you for Hepatitis B vaccination if it is indicated. The counseling you get during 
this study may help you to avoid HIV and other sexually transmitted infections. If you have or become 
infected with HIV, this counseling may help you to learn how to better care for yourself and avoid 
passing HIV to your sexual partners. If you become HIV infected, or have another sexually transmitted 
infection, we will refer you for care and/or treatment. During the study you will also have other tests to 
check on the health of your blood, and liver. If any health problems are found, you will be referred for 
care. At every visit you will be offered condoms and lubricant free of charge.   
You or others in your community may benefit from this study later. The information gathered during 
this study may help to prevent the spread of HIV. This may be beneficial to you and your community.   
NEW INFORMATION 
You will be told any new information learned during this study that might affect your willingness to stay 
in the study. For example, if information becomes available that shows that the medication may be 
causing bad effects, you will be told about this. You will also be told when the results of the study may 
be available, and how to learn about them.   
WHY YOU MAY BE WITHDRAWN FROM THE STUDY WITHOUT YOUR CONSENT 
You may be withdrawn from the study without your consent if any of the following occur:  
• You are unable or unwilling to follow all of the study procedures or instructions.   
• You could be harmed by continuing to take the pill or getting an injection. 
• The study is stopped or canceled. 
• The study staff feels that staying in the study would be harmful to you. 
• You are not able to attend clinic visits or complete all of the study procedures. 
• Other reasons, as decided by the study staff.  
ALTERNATIVES TO PARTICIPATION 
[Sites to include/amend the following if applicable: There may be other studies going on here or in the 
community that you may be eligible for. If you wish, we will tell you about other studies that we know 
about. There also may be other places where you can go for HIV counseling and testing. We will tell 
you about those places if you wish.] 
COSTS TO YOU 
There will be no cost to you for study related visits, study products, physical examinations, laboratory 
tests, or other procedures specifically related to the study.    

 
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REIMBURSEMENT 
You will receive [sites to fill in] for your time, effort, and travel to and from the clinic at each scheduled 
visit.  
CONFIDENTIALITY 
To keep your information private, your samples will be labeled with a code that can only be traced 
back to your study clinic. Your name, where you live, and other personal information will be 
protected by the study clinic. The results of any tests done on these samples will not be included 
in your health records without your permission. Every effort will be made to keep your personal 
information confidential, but we cannot guarantee absolute confidentiality. Your personal information 
may be disclosed if required by law. 
Efforts will be made to keep your study records and test results confidential to the extent permitted by 
law.  However, we cannot guarantee absolute confidentiality. You will be identified by a code, and 
personal information from your records will not be released without your written permission. Any 
publication of this study will not use your name or identify you personally. However, your 
records may be reviewed, under guidelines of the United States Federal Privacy Act, by the United 
States Food and Drug Administration (FDA); the sponsor of the study (United States National Institutes 
of Health [NIH]), the [insert name of site] Institutional Review Board (IRB), Ethic Committee (EC) 
study staff, study monitors, the companies that make the drugs used in this study, and (insert applicable 
local authorities]. 
[For US sites only to include] 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, such as the court system, about 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 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. 
The study staff will also use your personal information, if needed, to verify that you are not taking part 
in any other research studies. This includes other studies conducted by [site name] and studies conducted 
by other researchers that study staff know about.  
Your records may be reviewed by: 
 
• US FDA 
• US NIH 
• US Department of Heath and Human Services (DHHS), Office of Human Research 
Protection (OHRP) 
• [insert names of applicable IRBs/ECs/other local eview bodies as applicable] 

 
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• Study staff 
• Study monitors 
• Companies that makes the study drug (ViiV Healthcare and Gilead Sciences, Inc.) 
• Other U.S., local, and international regulatory entities may also review study records 
[Sites to include/amend the following if applicable:] [Local/state/national] regulations require study 
staff to report the names of people who test positive for [HIV and other infections] passed during sex to 
the [local health authority]. Outreach workers from the [health authority] may then contact you about 
informing your partners, since they also should be tested. If you do not want to inform your partners 
yourself, the outreach workers will contact them, according to the confidentiality guidelines of the 
[health authority]. 
RESEARCH-RELATED INJURY 
[Sites to specify institutional policy:] It is unlikely that you will be injured as a result of study 
participation. If you are injured, the [institution] will give you immediate necessary treatment for your 
injuries. You [will/will not] have to pay for this treatment. You will be told where you can get additional 
treatment for your injuries. There is no program to pay money or give other forms of compensation for 
such injuries either through this institution or the NIH. You do not give up any legal rights by signing 
this consent form. 
PROBLEMS OR QUESTIONS 
If you ever have any questions about the study, or if you have a research-related injury, you should 
contact [insert name of the investigator or other study staff] at [insert telephone number and/or physical 
address]. 
If you have questions about your rights as a research participant, you should contact [insert name or title 
of person on the IRB or other organization appropriate for the site] at [insert physical address and 
telephone number]. 
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 083 
A Phase 2b/3 Double Blind Safety and Efficacy Study of Injectable Cabotegravir Compared to 
Daily Oral Tenofovir Disoproxil Fumarate/Emtricitabine (TDF/FTC), For Pre-Exposure 
Prophylaxis in HIV-Uninfected Cisgender Men and Transgender Women who have Sex with Men 
Version 3.0 
October 31, 2019 
SCREENING AND ENROLLMENT CONSENT 
Insert signature blocks as required by the local IRB:] If you have read this consent form, or had it read 
and explained to you, and you understand the information, and you voluntarily agree to join the study, 
please sign your name or make your mark below. Also, please indicate by providing your initials in the 
spaces below the additional sample collection, genetic testing, or long-term storage that you agree to. 
________ 
I agree to take part in this study.  
________ 
I agree to have samples of my blood stored and used for future testing.    
________ 
I do not agree to have samples of my blood stored and used for future testing.  
________ 
I agree to allow my blood to be tested to see how my genes make the drug work in my 
body. 
________ 
I do not agree to allow my blood to be tested to see how my genes make the drug work in 
my body. 
________ 
[Sites that participating in the DXA subset to add this]:  I agree to take part in the DXA 
subset. 
________ 
[Sites that are participating in the DXA subset to add this]:  I do not agree to take part in 
the DXA subset. 
________ 
[Sites that are participating in the DXA subset to add this]:  I have been told that the DXA 
subset is no longer available for participation. 
 
 
 
 
 
 
 
 
____________________________________ 
Participant Name (print) 
 
 
Participant Signature and Date 
 
 
 
 
 
 
 
 
 
____________________________________ 
Study Staff Conducting 
 
 
Study Staff Signature and Date 
Consent Discussion (print) 

 
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____________________________________ 
Witness Name (print)  
 
 
Witness Signature and Date 
(As appropriate)