Clinical trial NCT02178800
Conditions: HIV Infections
Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Start date: 2015-02-01; Completion date: 2018-07-13
Enrollment: 199 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study will evaluate the safety, tolerability, and pharmacokinetics (which is how the body interacts with drugs) of an investigational, injectable HIV medicine (GSK1265744) in healthy, HIV-uninfected adults.

Detailed description:
This study will evaluate GSK1265744, which is an investigational, injectable HIV medicine. The purpose of this study is to evaluate the safety, tolerability, and pharmacokinetics of GSK1265744 in healthy, HIV-uninfected adults.

This study will enroll two cohorts of participants (Cohort 1 and Cohort 2). Within each cohort, participants will be randomly assigned to one of two groups: Group 1 will receive GSK1265744 tablets (also called oral 744) and injections (also called GSK1265744 long acting or 744LA), and Group 2 will receive placebo tablets and injections. Participants in Cohort 1 will attend several study visits through Week 81 or Week 105. Participants in Cohort 2 will attend several study visits through Week 85 or Week 109. From study entry through Week 4, participants in both cohorts will take a GSK1265744 tablet (Group 1) or a placebo tablet (Group 2) once a day. For 1 week after participants stop taking their assigned tablets, study researchers will assess safety and tolerability. If no safety or tolerability concerns are identified, participants will enter the injection phase of the study. Participants in Cohort 1 will receive two injections of GSK1265744 (Group 1) or placebo (Group 2) at Weeks 5, 17, and 29. Participants in Cohort 2 will receive one injection of GSK1265744 (Group 1) or placebo (Group 2) at Weeks 5, 9, 17, 25, and 33.

All study visits will include HIV counseling, a physical examination, a medical history review, and a blood collection. Select study visits will include adherence counseling, central nervous system (CNS) symptom assessment, behavioral and acceptability assessments, a urine collection, an electrocardiogram (ECG), and rectal and/or vaginal swabs.

Arms: arm 1: Participants in Cohorts 1 and 2 will receive one GSK1265744 tablet orally every day from study entry through Week 4. They will then receive an injection of GSK1265744-at Weeks 5, 17, and 29 for participants in Cohort 1 and at Weeks 5, 9, 17, 25, and 33 for participants in Cohort 2. arm 2: Participants in Cohorts 1 and 2 will receive one placebo tablet orally every day from study entry through Week 4. They will then receive an injection of placebo-at Weeks 5, 17, and 29 for participants in Cohort 1 and at Weeks 5, 9, 17, 25, and 33 for participants in Cohort 2.
Interventions: intervention 1: GSK1265744 Tablets intervention 2: Injectable GSK1265744 intervention 3: Placebo for GSK1265744 Tablets intervention 4: Injectable Placebo for GSK1265744
Intervention descriptions: intervention 1: 30-mg tablets, taken orally intervention 2: Cohort 1: 800-mg injection, administered as two 400-mg intramuscular (IM) gluteal injections

Cohort 2: 600-mg injection, administered as one IM gluteal injection intervention 3: Taken orally intervention 4: Cohort 1: Sodium Chloride for Injection USP, 0.9%; administered as two 400-mg IM gluteal injections

Cohort 2: Sodium Chloride for Injection USP, 0.9%; administered as one 600-mg IM gluteal injection

Protocol documents:
Prot_001.pdf: 
 
HPTN 077 
 
A Phase IIa Study to Evaluate the Safety, Tolerability and Pharmacokinetics of the Investigational 
Injectable HIV Integrase Inhibitor, GSK1265744, in HIV-uninfected Men and Women 
 
 
DAIDS Document ID: 11964 
 
 
A Study by the HIV Prevention Trials Network 
 
 
Sponsored by: 
Division of AIDS, US National Institute of Allergy and Infectious Diseases 
 
Pharmaceutical Support Provided by: 
ViiV Healthcare 
 
IND # 122,744 
 
Protocol Chair: 
Raphael J. Landovitz, M.D., M.Sc. 
 
Final Version 3.0  
October 13, 2015  


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HPTN 077 
A Phase IIa Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of the 
Investigational Injectable HIV Integrase Inhibitor, GSK1265744, in HIV-uninfected Men and 
Women 
 
 
TABLE OF CONTENTS 
 
LIST OF ABBREVIATIONS AND ACRONYMS ................................................................................................... 5 
PROTOCOL TEAM ROSTER .................................................................................................................................. 8 
TERMINOLOGY FOR GSK1265744 FORMULATIONS.................................................................................... 11 
SCHEMA .................................................................................................................................................................... 12 
OVERVIEW OF STUDY DESIGN AND RANDOMIZATION SCHEME ......................................................... 15 
1.0 
INTRODUCTION ............................................................................................................................................ 16 
1.1 
BACKGROUND AND RATIONALE .....................................................................................................................16 
1.2 
OVERVIEW OF GSK1265744 ORAL (ORAL 744) AND LONG ACTING INJECTABLE (744LA) .............................17 
1.3 
DOSE RATIONALE ..........................................................................................................................................20 
1.4 
CLINICAL EXPERIENCE TO DATE – GSK1265744...........................................................................................26 
1.5 
RISK ASSESSMENT FOR GSK1265744 ............................................................................................................30 
1.6 
ACCEPTABILITY .............................................................................................................................................31 
1.7 
SEXUAL RISK BEHAVIOR ................................................................................................................................31 
1.8 
RATIONALE FOR PLACEBO-CONTROLLED STUDY DESIGN ..............................................................................31 
2.0 
STUDY OBJECTIVES AND DESIGN .......................................................................................................... 33 
2.1 
PRIMARY OBJECTIVE ......................................................................................................................................33 
2.2 
SECONDARY OBJECTIVES ...............................................................................................................................33 
2.3 
EXPLORATORY OBJECTIVES ...........................................................................................................................33 
2.4 
STUDY DESIGN AND OVERVIEW .....................................................................................................................34 
3.0 
STUDY POPULATION ................................................................................................................................... 35 
3.1 
INCLUSION CRITERIA .....................................................................................................................................35 
3.2 
EXCLUSION CRITERIA ....................................................................................................................................36 
3.3 
RECRUITMENT PROCESS .................................................................................................................................38 
3.4 
CO-ENROLLMENT GUIDELINES ......................................................................................................................38 
3.5 
PARTICIPANT RETENTION ...............................................................................................................................38 
3.6 
PARTICIPANT WITHDRAWAL ..........................................................................................................................38 
4.0 
STUDY PRODUCT CONSIDERATIONS .................................................................................................... 40 
4.1 
STUDY PRODUCT REGIMENS/ADMINISTRATION/FORMULATION CONTENT ....................................................40 
4.2 
STUDY PRODUCT ACQUISITION AND ACCOUNTABILITY .................................................................................41 
4.3 
TOXICITY MANAGEMENT ...............................................................................................................................41 
4.4 
CONCOMITANT, PROHIBITED, AND PRECAUTIONARY MEDICATIONS ..............................................................41 
5.0 
STUDY PROCEDURES .................................................................................................................................. 42 
5.1 
SCREENING:  BOTH COHORTS .........................................................................................................................42 
5.2 
WEEK 0: ENROLLMENT – BOTH COHORTS .....................................................................................................43 
5.3 
WEEKS 2 AND 4:  ORAL SAFETY VISITS (WEEK 4 IS POST-ORAL SAFETY VISIT) – BOTH COHORTS ...............44 
5.4 
FIRST INJECTION VISIT:  BOTH COHORTS - WEEK 5 .......................................................................................45 
5.5 
SAFETY VISITS: COHORT 1 - WEEK 6, 9, 13; COHORT 2 - WEEK 6 ONLY ........................................................45 
5.6 
SECOND INJECTION VISIT:  COHORT 1 – WEEK 17; COHORT 2 – WEEK 9 .......................................................46 


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5.7 
SAFETY VISITS:  COHORT 1 - WEEK 18 AND 23; COHORT 2 – WEEK 10 AND 13 .............................................46 
5.8 
THIRD INJECTION VISIT:  COHORT 1 – WEEK 29; COHORT 2 – WEEK 17 ........................................................47 
5.9 
SAFETY VISITS: COHORT 1 – WEEK 30 AND 35; COHORT 2 – WEEK 18 AND 21 .............................................48 
5.10 FOURTH INJECTION VISIT:  COHORT 2 ONLY - WEEK 25 .................................................................................48 
5.11 SAFETY VISITS:  COHORT 2 ONLY – WEEK 26 AND 29 ....................................................................................49 
5.12 FIFTH INJECTION VISIT:  COHORT 2 ONLY – WEEK 33 ....................................................................................49 
5.13 SAFETY VISITS:  COHORT 2 ONLY – WEEKS 34 AND 37 ..................................................................................50 
5.14 PRIMARY ENDPOINT VISIT:  BOTH COHORTS - WEEK 41 ................................................................................50 
5.15 TAIL PHASE VISITS:  BOTH COHORTS – WEEK 53, 65, 77 ...............................................................................51 
5.16 FINAL VISIT:  COHORT 1 – WEEK 81; COHORT 2 – WEEK 85 .......................................................................51 
5.17 INJECTION VISIT WINDOWS ............................................................................................................................52 
5.18 PROCEDURES FOR CONTINUED ORAL AND INJECTABLE DOSING ....................................................................52 
5.19 PROCEDURES FOR PARTICIPANTS WHO DO NOT COMPLETE THE FULL COURSE OF INJECTIONS ....................52 
5.20 PLANNED UNBLINDING OF STUDY PARTICIPANTS ..........................................................................................52 
5.21 PARTICIPANTS WITH SUSPECTED OR CONFIRMED HIV INFECTION, AT SCREENING, ENROLLMENT, 
OR FOLLOW-UP  .......................................................................................................................................................52 
5.22 SEXUALLY TRANSMITTED INFECTIONS ..........................................................................................................54 
5.23 PREGNANCY ...................................................................................................................................................54 
5.24 CHANGES IN REPORTED HIV/STI RISK STATUS DURING FOLLOW-UP ...........................................................55 
5.25 HEPATITIS B AND HEPATITIS C ......................................................................................................................55 
5.26 INTERIM CONTACTS AND VISITS ....................................................................................................................55 
5.27 CRITERIA FOR EARLY TERMINATION OF STUDY PARTICIPATION ....................................................................55 
5.28 PHARMACOKINETICS ......................................................................................................................................56 
6.0 
SAFETY MONITORING AND ADVERSE EVENT (AE) REPORTING ................................................. 57 
6.1 
SAFETY MONITORING ....................................................................................................................................57 
6.2 
CLINICAL DATA REVIEW ................................................................................................................................57 
6.3 
ADVERSE EVENT DEFINITION AND REPORTING ..............................................................................................57 
6.4 
EXPEDITED ADVERSE EVENT REPORTING ......................................................................................................58 
6.5 
SOCIAL IMPACT REPORTING ...........................................................................................................................59 
7.0 
STATISTICAL CONSIDERATIONS ............................................................................................................ 60 
7.1 
REVIEW OF STUDY DESIGN ............................................................................................................................60 
7.2 
SAMPLE SIZE ..................................................................................................................................................61 
7.3 
ACCRUAL, FOLLOW-UP, AND RETENTION ......................................................................................................65 
7.4 
RANDOM ASSIGNMENT ..................................................................................................................................65 
7.5 
BLINDING 65 
7.6 
DATA AND SAFETY MONITORING ANALYSIS .................................................................................................66 
8.0 
HUMAN SUBJECTS CONSIDERATIONS .................................................................................................. 71 
8.1 
ETHICAL REVIEW ...........................................................................................................................................71 
8.2 
INFORMED CONSENT ......................................................................................................................................71 
8.3 
INCENTIVES ....................................................................................................................................................71 
8.4 
CONFIDENTIALITY ..........................................................................................................................................71 
8.5 
COMMUNICABLE DISEASE REPORTING REQUIREMENTS .................................................................................72 
8.6 
STUDY DISCONTINUATION .............................................................................................................................72 
9.0 
LABORATORY SPECIMENS AND BIOHAZARD CONTAINMENT .................................................... 73 
9.1 
LOCAL LABORATORY SPECIMENS ..................................................................................................................73 
9.2 
STORED SPECIMENS .......................................................................................................................................74 
9.3 
QUALITY CONTROL AND QUALITY ASSURANCE PROCEDURES .......................................................................75 
9.4 
SPECIMEN STORAGE AND POSSIBLE FUTURE RESEARCH TESTING .................................................................76 
9.5 
BIOHAZARD CONTAINMENT ...........................................................................................................................76 
 
 


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10.0 ADMINISTRATIVE PROCEDURES............................................................................................................ 77 
10.1 PROTOCOL REGISTRATION .............................................................................................................................77 
10.2 STUDY ACTIVATION .......................................................................................................................................77 
10.3 STUDY COORDINATION ..................................................................................................................................77 
10.4 STUDY MONITORING ......................................................................................................................................78 
10.5 PROTOCOL COMPLIANCE ................................................................................................................................78 
10.6 INVESTIGATOR'S RECORDS .............................................................................................................................78 
10.7 USE OF INFORMATION AND PUBLICATIONS ....................................................................................................78 
11.0 REFERENCES ................................................................................................................................................. 79 
APPENDICES I-XIII ................................................................................................................................................ 83 
APPENDIX I: SCHEDULE OF PROCEDURES AND EVALUATIONS – FOR PARTICIPANTS 
WHO COMPLETE ALL THREE INJECTIONS IN COHORT 1 ....................................................................... 84 
APPENDIX II: SCHEDULE OF PROCEDURES AND EVALUATIONS – FOR PARTICIPANTS 
WHO COMPLETE TWO INJECTIONS ONLY IN COHORT 1 ........................................................................ 87 
APPENDIX III: SCHEDULE OF PROCEDURES AND EVALUATIONS – FOR PARTICIPANTS 
WHO COMPLETE ONE INJECTION ONLY IN COHORT 1 ........................................................................... 89 
APPENDIX IV: SCHEDULE OF PROCEDURES AND EVALUATIONS – FOR PARTICIPANTS 
WHO COMPLETE ALL FIVE INJECTIONS IN COHORT 2 ........................................................................... 91 
APPENDIX V: SCHEDULE OF PROCEDURES AND EVALUATIONS – FOR PARTICIPANTS 
WHO COMPLETE FOUR INJECTIONS ONLY IN COHORT 2 ...................................................................... 94 
APPENDIX VI: SCHEDULE OF PROCEDURES AND EVALUATIONS – FOR PARTICIPANTS 
WHO COMPLETE THREE INJECTIONS ONLY IN COHORT 2 .................................................................... 95 
APPENDIX VII: SCHEDULE OF PROCEDURES AND EVALUATIONS – FOR PARTICIPANTS 
WHO COMPLETE TWO INJECTIONS ONLY IN COHORT 2 ........................................................................ 98 
APPENDIX VIII: SCHEDULE OF PROCEDURES AND EVALUATIONS – FOR PARTICIPANTS 
WHO COMPLETE ONE INJECTION ONLY IN COHORT 2 ......................................................................... 100 
APPENDIX IX: SCHEDULE FOR ADDITIONAL LABORATORY PROCEDURES FOR ENROLLED 
PARTICIPANTS WHO HAVE A REACTIVE POSITIVE HIV TEST RESULT…………………………….. 101 
APPENDIX X:  RISK ASSESSMENT AND MITIGATION STRATEGY........................................................ 103 
APPENDIX XI: TOXICITY MANAGEMENT .................................................................................................... 106 
APPENDIX XII: SAMPLE SCREENING AND ENROLLMENT INFORMED CONSENT FORM 
FOR PARTICIPANTS ENROLLING UNDER VERSION 3.0 ........................................................................... 115 
APPENDIX XIII: SAMPLE HPTN 077 PARTICIPANT LETTER/INFORMATION SHEET FOR 
PARTICIPANTS ENROLLED UNDER VERSION 2.0 ...................................................................................... 133 
 


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A Phase IIa Study to Evaluate the Safety, Tolerability and Pharmacokinetics of the Investigational 
Injectable HIV Integrase Inhibitor, GSK1265744, in HIV-uninfected Men and Women  
LIST OF ABBREVIATIONS AND ACRONYMS 
 
3TC 
 
 
lamivudine 
Oral 744 
 
oral formulation of GSK1265744  
744LA  
 
long-acting injectable formulation of GSK1265744  
ABC/3TC 
 
abacavir/lamivudine 
AE 
 
 
adverse event 
AIDS  
 
acquired immunodeficiency syndrome 
ALT 
 
 
alanine aminotransferase 
ART  
 
antiretroviral therapy 
ARV  
 
antiretroviral 
AST 
 
 
aspartate aminotransferase 
AUC  
 
area under the curve 
AUDIT 
 
Alcohol Use Disorders Identification Test 
AV 
 
 
atrioventricular 
BCRP  
 
breast cancer resistance protein  
CAB  
 
Community Advisory Board 
CABG  
 
coronary artery bypass grafting 
CBC  
 
complete blood count 
CDC  
 
(US) Centers for Disease Control and Prevention 
CFR 
 
 
(US) Code of Federal Regulations 
CI 
 
 
confidence interval 
CLIA  
 
Clinical Laboratory Improvement Amendments 
CMC  
 
Clinical Management Committee 
Cmax 
 
 
maximum or “peak” concentration of a drug observed after its  
 
 
 
 
administration 
Cmin 
 
 
minimum or “trough” concentration of a drug observed after its  
 
 
 
 
administration and just prior to the administration of a subsequent dose 
CPK  
 
creatine phosphokinase 
CPQA  
 
Clinical Pharmacology Quality Assurance Committee 
CRF 
 
 
Case Report Form 
CROI  
 
Conference on Retroviruses and Opportunistic Infections 
CRPMC 
 
(NIAID) Clinical Research Products Management Center 
DAERS 
 
DAIDS Adverse Event Reporting System 
DAIDS 
 
Division of AIDS 
DAIDS ES 
 
DAIDS Enterprise System 
DAIDS PRO  
DAIDS Protocol Registration Office 
DDI 
 
 
drug-drug interaction 
DNA  
 
deoxyribonucleic acid 
EAE 
 
 
expedited adverse event 
EC 
 
 
Ethics Committee 
ECG  
 
electrocardiogram 
EQA  
 
external quality assurance 


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ETR 
 
 
etravirine 
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 
FSH 
 
 
follicle-stimulating hormone 
GI 
 
 
gastrointestinal 
GSK  
 
GlaxoSmithKline 
HBV  
 
hepatitis B virus 
HCV  
 
hepatitis C virus 
HDPE  
 
high density polyethylene 
HIV 
 
 
human immunodeficiency virus 
HIV-1 IIIB 
 
human immunodeficiency virus type 1 IIIB strain 
HIV-1 NL-432 
human immunodeficiency virus type 1 NL-432 strain 
LC 
 
 
HIV Prevention Trials Network 
 
 
 
(HPTN) Laboratory Center 
LDMS  
 
Laboratory Data Management System 
LOC  
 
(HPTN) Leadership and Operations Center 
MOP  
 
(HPTN) Manual of Operations 
SDMC  
 
(HPTN) Statistical and Data Management Center 
HSR  
 
hypersensitivity reaction 
IATA  
 
International Air Transport Association 
ICAAC 
 
Interscience Conference on Antimicrobial Agents and Chemotherapy 
ID 
 
 
identification 
IM 
 
 
intramuscular 
IND 
 
 
investigational new drug 
iPrEx 
Phase 3, safety and effectiveness trial of once-daily TDF/FTC in gay men, 
transgender women and other men who have sex with men in six countries 
IQA 
 
 
(DAIDS) Immunology Quality Assurance 
IRB 
 
 
Institutional Review Board 
ISR 
 
 
injection site reaction 
IUD 
 
 
intrauterine device 
IUS 
 
 
intrauterine system 
LA 
 
 
long-acting (injectable) 
LAP 
 
 
long-acting parenteral 
LC 
 
 
Laboratory Center 
MT-2  
 
lymphocyte cells 
NIAID  
 
National Institute of Allergy and Infectious Diseases 
NIH 
 
 
National Institutes of Health 
NOAEL 
 
no observed adverse effect level 
NRTI  
 
nucleoside/nucleotide reverse transcriptase inhibitors 
OHRP  
 
Office for Human Research Protections 
PA-IC50 
 
protein-adjusted 50% inhibitory concentration 
 
PA-IC90 
 
protein-adjusted 90% inhibitory concentration 
PBMC  
 
peripheral blood mononuclear cells 
PCTA  
 
percutaneous transluminal coronary angioplasty 


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PEG 
 
 
polyethylene glycol 3350 
PEP 
 
 
post-exposure prophylaxis 
Pgp 
 
 
permeability glycoprotein 
PK 
 
 
pharmacokinetic 
PO 
 
 
by mouth/orally 
PrEP  
 
pre-exposure prophylaxis 
QA 
 
 
quality assurance 
QC 
 
 
quality control 
qd 
 
 
once daily dose 
QRS  
 
interval from the beginning of the Q wave to the end of the S wave 
QTc 
 
 
corrected QT 
RE 
 
 
relative effect; Regulatory Entity  
RNA  
 
ribonucleic acid 
RPV  
 
rilpivirine 
RSC 
 
 
(DAIDS) Regulatory Support Center 
SAE 
 
 
serious adverse event 
SC 
 
 
subcutaneous 
SCHARP-FHCRC 
Statistical Center for HIV/AIDS Research and Prevention – Fred 
Hutchinson Cancer Research Center 
SD 
 
 
standard deviation 
SHIV  
 
simian human immunodeficiency virus 
SMC  
 
Study Monitoring Committee 
SSA 
 
 
sub-Saharan Africa 
SSP 
 
 
Study Specific Procedures Manual 
TDF 
 
 
tenofovir disoproxil fumarate 
TDF/FTC 
 
tenofovir disoproxil fumarate/emtricitabine 
TDF 
 
 
tenofovir 
ULN  
 
upper limit of normal 
UKNEQAS 
 
United Kingdom National External Quality Assessment Service 
US 
 
 
United States of America 
VQA  
 
(DAIDS) Virology Quality Assurance 
WHO  
 
World Health Organization 
WPW  
 
Wolf Parkinson White syndrome 
 


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HPTN 077 
A Phase IIa Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of the 
Investigational Injectable HIV Integrase Inhibitor, GSK1265744, in HIV-uninfected Men and 
Women  
PROTOCOL TEAM ROSTER 
Namandje Bumpus, PhD  
HPTN Laboratory Center Pharmacologist  
Department of Pharmacology and Molecular 
Sciences 
Johns Hopkins University School of Medicine 
725 N. Wolfe Street, Biophysics 307A 
Baltimore, MD 21205 
Phone: 410-955-0562 
Fax: 410-955-3023 
Email: nbumpus1@jhmi.edu  
 
Mike Cohen, MD 
HPTN Co-PI 
University of North Carolina School of 
Medicine 
Department of Medicine 
Division of Infectious Diseases  
130 Mason Farm Road 
Bioinformatics Bldg. 
Chapel Hill, NC 27599 
Phone: 919-966-2536 
Fax: 919-966-6714 
Email: myron_cohen@med.unc.edu  
  
Cheryl Cokley, BS  
HPTN Leadership and Operations Center 
Community Program Manager 
FHI 360 
359 Blackwell Street, Suite 200 
Durham, NC 27701  
Phone: 919-544-7040, ext. 11515 
Fax: 919-544-0207 
Email: ccokley@fhi360.org  
 
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 
 
Vanessa Elharrar, MD, MPH  
DAIDS Medical Officer 
Prevention Science Program 
DAIDS/NIAID/NIH 
5601 Fishers Lane, Rm 8B39, MSC 9830 
Bethesda, MD 20892 
Phone: 240-292-4787 
Email: elharrarva@niaid.nih.gov  
 
Joseph Eron, MD  
Site Investigator 
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  
 
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  
 


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Beatriz Grinsztejn, MD, PhD 
Site Investigator 
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  
 
Mina Hosseinipour, MD, MPH 
Site Investigator 
Clinical Director 
UNC Project  
Tidziwe Center 
Kamuzu Central Hospital 
100 Mzimba Road 
Private Bag A/104 
Lilongwe, Malawi 
Phone: 265-1-755-056 
Fax: 265-1-755-954 
Email: minach@med.unc.edu  
 
Quarraisha Abdool Karim, PhD 
Site Investigator 
CAPRISA  
2nd Floor Doris Duke Medical Research Institute 
Nelson R Mandela School of Medicine 
University of KwaZuu-Natal 
Private Bag 7 
Congella 4013 
South Africa 
Phone: 27-31-2604550 
Fax:  27-31-2604566 
Email: abdoolq2@ukzn.ac.za  
 
Raphael J. Landovitz, MD, MSc 
Protocol Chair 
UCLA Center for Clinical AIDS Research & 
Education 
9911 W. Pico Blvd, Suite 980 
Los Angeles, CA 90035 
Phone: 310-557-1894  
Fax: 310-557-1899  
Email: rlandovitz@mednet.ucla.edu   
Sue Li, PhD  
HPTN SDMC Protocol Statistician  
Fred Hutchinson Cancer Research Center 
1100 Fairview Avenue N, M2-C200 
PO Box 19024  
Seattle, WA 98109 
Phone: 206-667-7066  
Fax: 206-667-6352 
Email: sli@scharp.org 
 
Albert Liu, MD, MPH 
Site Investigator 
Director, HIV Prevention Intervention Studies 
Bridge HIV, San Francisco Department of 
Public Health 
25 Van Ness Avenue, Suite 100 
San Francisco, CA 94102 
Phone: 415-437-7408 
Fax: 415-431-7029 
Email: albert.liu@sfdph.org  
 
Manya Magnus, PhD, MPH 
Site Investigator 
George Washington University  
School of Public Health and Health Services 
Department of Epidemiology and Biostatistics 
950 New Hampshire Avenue 
Washington, DC 20052 
Phone: 202-994-3024 
Fax: 202-994 0082   
Email: manyadm@gwu.edu  
 
David Margolis, MD, MPH  
GlaxoSmithKline  
5 Moore Drive 
Durham NC, 27709 
Phone: 919-483-7869 
Fax:  919-315-6359 
Email: david.a.margolis@gsk.com  
 
 
 
 
 
 
 


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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  
 
Ravindre Panchia, MBBCh 
Site Investigator 
Soweto HPTN CRS 
Chris Hani Baragwanath Hospital 
Soweto, South Africa 
Phone: 27-11-9899711 
Fax: 27-11-9899877 
Email: panchiar@phru.co.za  
 
Paul Richardson, MSc  
HPTN Laboratory Center 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 
 
William Spreen, PhD 
GlaxoSmithKline   
5 Moore Drive 
Phone: 919-483-1393 
Fax: 919-315-5263 
Email: william.r.spreen@gsk.com 
Durham, NC 27709 
 
Britt Stancil, BS 
GlaxoSmithKline   
5 Moore Drive 
Durham, NC 27709 
Phone:  919-483-5561 
Fax:  919-483-0272   
Email:  Britt.n.shahan@gsk.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 
 
Betsy Tolley, MA, PhD 
FHI 360 
359 Blackwell Street, Suite 200 
Durham, NC 27701, USA 
Phone: 919-544-7040, Ext. 11334 
Fax: 919-405-1402 
Email: btolley@fhi360.org 
 
Phaedrea Watkins, MBA 
HPTN Leadership and Operations Center 
Clinical Research Manager 
FHI 360 
359 Blackwell St, Suite 200 
Durham, NC 27701 
Phone: 919-544-7040, ext. 11596 
Fax: 919-405-1402 
Email: pwatkins@fhi360.org 
 
Michelle Wildman, Pharm D 
Protocol Pharmacist 
Division of AIDS/NIAID/NIH 
5601 Fishers Lane, Room 9E15 
Bethesda, MD  20892 
Phone:  240-627-3058 
Email:  michelle.wildman@nih.gov 
 


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HPTN 077 
A Phase IIa Study to Evaluate the Safety, Tolerability and Pharmacokinetics of the Investigational 
Injectable HIV Integrase Inhibitor, GSK1265744, in HIV-uninfected Men and Women  
 
TERMINOLOGY FOR GSK1265744 FORMULATIONS 
Compound 
Name or 
Abbreviation 
Comments 
GSK1265744  
When written as shown, this is the ViiV Healthcare 
compound under study, and refers to the oral or long-acting 
(LA) formulation.  Also when written as shown, it refers to 
plasma concentrations following both oral and LA 
formulations.   
 
Oral 744 
When written as shown, this refers to the oral formulation of 
GSK1265744.    
744LA 
When written as shown, this refers to the long-acting 
injectable formulation of GSK1265744. 
 
 


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HPTN 077 
A Phase IIa Study to Evaluate the Safety, Tolerability and Pharmacokinetics of the Investigational 
Injectable HIV Integrase Inhibitor, GSK1265744, in HIV-uninfected Men and Women  
SCHEMA 
Purpose: 
To evaluate the safety, tolerability, pharmacokinetics and acceptability of the injectable 
agent, GSK1265744 long-acting injectable (744LA), in healthy, HIV-uninfected men and 
women. 
Design: 
Multi-site, double-blind, two-arm, randomized, placebo-controlled trial of the safety, 
tolerability, and acceptability of 744LA.  
Population: HIV-uninfected men and women at low to minimal risk for acquiring HIV infection, ages 
18 to 65. 
Study Size: Approximately 194 men and women, randomized 3:1, with approximately 145 in the active 
drug arm, and approximately 49 in the placebo arm. It is anticipated that approximately 
60% of the enrolled participants will be women.  Two cohorts will be enrolled (Cohort 1 
and Cohort 2).  Cohort 1 will include approximately 106 participants (approximately 40 
men and 66 women), and Cohort 2 will include approximately 88 participants 
(approximately 35 men and 53 women).      
Study  
Participants will be randomized to receive daily oral GSK1265744 (30 mg tablets) or 
Regimens: daily oral placebo for 4 weeks, followed by a one-week washout, to assess safety and 
tolerability before they receive injections. After safety and tolerability assessments from 
the oral phase have been completed (if no concerns are identified), participants will enter 
the injection phase of the study.  Cohort 1 will receive two intra-muscular (IM) gluteal 
injections of 744LA (800 mg, administered as two 400 mg injections) or placebo (matching 
vehicle control) at three study visits performed at 12-week intervals (Week 5, 17, and 29).  
Cohort 2 will receive a single IM gluteal injection of 744LA (600 mg or placebo) at five 
study visits, with the first two occurring 4 weeks apart (Weeks 5 and 9), and the remaining 
three at 8-week intervals (Weeks 17, 25, and 33).        
Study 
Duration: 
Approximately 3 years.  Accrual will require approximately 16 to 24 weeks (4 – 6 months) 
for each cohort. Participants in both cohorts will receive oral tablets for 4 weeks, followed 
by a 1 week wash out period.  Cohort 1 will then receive intra-muscular (IM) injections at 3 
time points over 24 weeks (6 months); Cohort 2 will receive IM injections at 5 time points 
over 28 weeks (7 months).  Participants in the active study product arm will be followed 
for 52 weeks (12 months) after their last injection.  Participants in the placebo arm will be 
followed until 52 weeks after their last injection or until the last participant in the active 
study product arm of Cohort 2 completes their Week 41 visit, whichever comes first, after 
which the cohorts will be unblinded to assess the primary endpoint.  When all procedures 
related to unblinding are completed, participants in the placebo arms of both cohorts will 
no longer be followed.  
   
Study 
HIV Prevention Trials Network (HPTN)-affiliated Clinical Trial Units (CTUs) and/or 
Sites: 
Clinical Research Sites (CRSs) participating in this study will be listed in the SSP Manual, 
and will include sites in Brazil, sub-Saharan Africa (SSA), and the United States (US).      


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HPTN 077 
A Phase IIa Study to Evaluate the Safety, Tolerability and Pharmacokinetics of the 
Investigational Injectable HIV Integrase Inhibitor, GSK1265744, in HIV-uninfected Men and 
Women 
SCHEMA (Continued) 
 
Primary Objectives:  
 
 Evaluate the safety and tolerability of the injectable agent GSK1265744 long acting (744LA) 
injectable (800 mg dose administered at three time points at 12 week intervals), through Week 41 
in HIV-uninfected men and women. 
 Evaluate the safety and tolerability of the injectable agent GSK1265744 long acting (744LA) 
injectable (600 mg dose administered at two time points at 4 week intervals, followed by three 
time points at 8 week intervals), through Week 41 in HIV-uninfected men and women. 
 
Secondary Objectives: 
 
 Evaluate the safety and tolerability of GSK1265744 (daily oral 744 + 744LA) for 52 weeks of 
follow-up after final injection (each cohort will be analyzed separately) 
 Evaluate the safety and tolerability of oral 744 from Week 0 to Week 5 
 Evaluate the pharmacokinetics of 744LA administered at three time points as 800 mg IM every 
12 weeks for 52 weeks of follow-up after final injection  
 Evaluate the pharmacokinetics of 744LA administered at five time points as 600 mg IM at two 
time points every 4 weeks followed by three time points every 8 weeks for 52 weeks of follow-
up after final injection  
 Evaluate differential pharmacokinetics of 744LA in participants by age, gender, race, ethnicity, 
weight, body mass index (BMI), and smoking status 
 Evaluate the acceptability of 744LA injections   
 Evaluate the effect of 744LA on sexual risk behavior by change from enrollment over time 
during the study period  
 Evaluate HIV incidence and antiretroviral drug resistance, in participants who acquire HIV 
infection during the study  
 Evaluate the safety, tolerability and pharmacokinetics of 744LA in the subset of women who use 
a hormone-based contraceptive 
Exploratory Objectives: 
 
 
 Explore relationships between safety parameters and GSK1265744 concentrations and/or 
participant demographic factors 
 Explore genetic factors that may impact the pharmacokinetics of 744LA 


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 Perform secondary laboratory assessments which 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  
 
 
 


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HPTN 077 
A Phase IIa Study to Evaluate the Safety and Pharmacokinetics of the Investigational 
Injectable HIV Integrase Inhibitor, GSK1265744, in HIV-uninfected Men and Women 
OVERVIEW OF STUDY DESIGN AND RANDOMIZATION SCHEME  
COHORT 1 
 
W = Week 
 
 
COHORT 2 
 
W = Week 
 


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1.0 
INTRODUCTION 
1.1 
Background and Rationale 
HPTN 077 is a Phase IIa study designed to establish the safety, tolerability, and multiple-dose 
pharmacokinetics of GSK1265744 in low-risk HIV-uninfected men and women.  Following 
small single-dose and multiple-dose studies of a long-acting nanosuspension formulation 
(744LA), this study is the next developmental investigation of the 744LA nanosuspension in 
healthy, HIV negative, low-risk for HIV acquisition men and women.  While preventive and 
therapeutic efficacy have yet to be definitively established, the goal of the product development 
pathway (by way of planned future Phase 3 studies) to establish the efficacy, safety, and 
tolerability of 744LA for HIV prevention.  A parallel developmental pathway is being pursued 
for HIV therapeutic use. 
The study of systemic antiretroviral therapy (ART) for both HIV treatment and prevention has 
provided consistent and compelling evidence of efficacy1-8.  A challenge in the use of oral 
formulations for each indication is user dependence on adherence to the dosing strategy9.10.  In 
healthy uninfected individuals and infected individuals with therapeutic success, sustaining 
adherence with time becomes increasingly challenging11.  In addition to treatment failure, one of 
the concerning sequellae of treatment non-adherence is the development of resistant HIV 
quasispecies12-15.  HIV seroconversion in the context of ART use for prevention has been a rare 
occurrence, with the overwhelming majority of seroconversions occurring in the context of 
subtherapeutic drug levels belying non-adherence.  Resistance has therefore not been frequently 
seen in such prevention failures, absent selective drug pressure – and almost exclusively in cases 
in which the therapeutic agent was begun during occult primary HIV infection 2,3.  
New ART drugs continue to be developed, and an exciting advance is the formulation of new 
drugs in long-acting slow release injectable formulations16.  This has significant implications for 
patients who have achieved therapeutic success on oral medication and need to maintain this 
over many years or for HIV uninfected persons who are at risk of acquiring HIV.  
Despite these advances in both treatment and prevention, the HIV epidemic persists worldwide17. 
Oral tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) was recently approved by the 
United States (US) Food and Drug Administration (FDA) for PrEP and the US Centers for 
Disease Control and Prevention (CDC) and the World Health Organization (WHO) have offered 
interim guidance about its use18,19. The safety and efficacy of TDF/FTC in combination with 
other antiretroviral (ARV) drugs for antiretroviral therapy (ART)20-24, and results from TDF/FTC 
PrEP in a rhesus macaque rectal simian-HIV (SHIV) exposure model25,26, supported the 
development and evaluation of TDF/FTC for PrEP. Six randomized clinical trials (RCTs) have 
evaluated oral TDF or TDF/FTC as PrEP2,3,27-30.  These six trials differ in several ways, but 
suboptimal adherence31,32 with a daily pill regimen was noted in the FEM-PrEP28,  iPrEx2, and 
VOICE30 trials.  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.  Both, on further investigation, 
confirmed very poor adherence by trial participants to study product.   Analyses of the available 
randomized controlled trial data suggests a strong correlation between adherence to study 
product and observed efficacy.  While the TDF-based therapy provides an exciting new 
prevention tool, there are several reasons why alternative PrEP agents are needed, including: 1) 
TDF/FTC causes side effects that may impede adherence2; 2) TDF/FTC has been  associated 
with increased creatinine levels and decreased bone density33-35; 3) Tenofovir (TDF) does not 
concentrate in the cervix or vagina after a single dose, and this may reduce “forgiveness” in the 
protection of women if doses are missed;36 and 4) TDF/FTC is a key component of many first-
line ART regimens, so resistance that might emerge with its use for PrEP is highly undesirable.37 
PrEP may only reach its full potential with agents that do not depend on daily pill-taking. 
Therefore, development of alternative agents for PrEP, including long-acting injectable agents, is 


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desirable. Such agents have the potential to prevent HIV acquisition without relying on 
adherence to a daily oral regimen.  Injectable agents are being used by women for contraception. 
In the future, an effective PrEP agent has the potential to be combined with an effective 
contraceptive for prevention of both pregnancy and HIV infection, and would be a valuable tool 
for HIV prevention in women in resource-limited settings, including sub-Saharan Africa, which 
bear the majority of prevalent and incident HIV/AIDS cases worldwide. 
The evaluation of the GSK1265744 long-acting injectable integrase inhibitor (744LA) for PrEP 
during this relatively early stage of clinical development addresses an important issue.  It is 
imperative that HIV-uninfected individuals who are offered PrEP receive a safe and well-
tolerated agent; a significant number of persons who are at high risk of acquiring HIV infection 
are currently unable to effectively use oral agents or condoms to prevent transmission30, 38.  
Developing alternative options for PrEP remains a high priority. PrEP development has to date 
been restricted to agents that have already been shown to be well-tolerated and safe in subjects 
with HIV infection who benefit directly from the proven antiviral activity of these agents. The 
parallel development plan of 744LA for the treatment of HIV infection will provide expedited 
safety and tolerability data to support development of this drug as a PrEP agent.  Further, the 
therapeutic utility of long-acting agents for treatment of HIV is dependent on availability and co-
administration of the agent with other long-acting formulated agents to create a fully-suppressive 
long-acting ART combination to realize and exploit the potential of the improved 
pharmacokinetics (PK).   
1.2 
Overview of GSK1265744 oral (oral 744) and long acting injectable (744LA)  
The majority of information contained in this section is a summary of information contained in 
the GSK1265744 Investigator’s Brochure, Effective Date 01 December 2014, unless otherwise 
noted. 39 
GSK1265744 is an investigational HIV-1 integrase strand transfer inhibitor that possesses 
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 pharmacokinetic (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 GSK1265744 (oral 744) 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.  744LA has a plasma half-life of 21 to 50 days in healthy HIV-uninfected adults, 
supporting a quarterly dosing interval when used for PrEP.  
744LA has demonstrated activity in preventing SHIV infection in non-human primate models40.  
In a preclinical study evaluating the potential of 744LA for PrEP, eight male rhesus macaques 
were injected with 744LA (50 mg/kg intramuscularly [IM]) at two time points, 1 week prior to 
the first virus exposure and 4 weeks later. An additional eight male macaques were untreated and 
served as placebo controls. All animals were challenged intra-rectally each week with 
SHIV162p3 (50 tissue culture infective dose [TCID]50) for up to eight exposures. All eight 
placebo macaques became infected after a median of two rectal exposures (range 1 to 7). Of the 
eight 744LA-treated macaques, none had detectable systemic viremia 10 weeks after the last 
virus challenge. In these protected animals, the plasma concentrations of 744LA throughout the 
period of virus challenges were comparable to clinically relevant concentrations in humans. 
After acquisition of these proof-of-concept results, a follow-up study was performed to confirm 
the initial findings and determine plasma levels of GSK1265744 at which protection is no longer 
maintained during repeated low-dose intrarectal SHIV challenge in male macaques. Twelve male 
macaques were injected with 744LA 50 mg/kg IM one week prior to the first viral challenge. 
Four animals remained untreated as placebo controls, with one placebo animal beginning viral 
challenge every 4 weeks. All animals were challenged rectally each week with SHIV162p3 (50 
TCID50) until infection was established. Of the 12 male macaques treated with 744LA, none had 


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detectable systemic viremia following the first 4 weekly challenges confirming the previous 
observation that monthly administration of 744LA protects male macaques against repeated 
intrarectal low-dose SHIV challenge. Thereafter, 744LA-treated animals became infected after 6 
to 17 challenges compared with 1 to 7 challenges for the 12 placebo controls (4 in-study and 8 
historical from initial study). One dose of 744LA delayed infection by 5 to 10 (median 8) 
challenges compared with untreated controls. The percent of challenges resulting in infection 
were calculated relative to the plasma GSK1265744 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 viral 
challenges resulted in infection in control animals; rectal tissue levels of 744 were approximately 
20% of plasma levels41 ,42.   
Intravaginal challenge studies with GSK1265744 in pigtail macaques demonstrated that 3 
monthly injections of 50 mg/kg of 744LA, protected against infection by 12 cycles of weekly 
vaginal SHIV challenges.  Protection was durably demonstrated out to 28 weeks; vaginal fluid 
744 concentrations were 16-26% of plasma concentrations.  Placebo injected animals became 
infected after identical vaginal challenges after an average of 2-4 challenges43.  
1.2.1 In Vitro Studies 
GSK1265744, is a potent inhibitor of HIV integrase in vitro. It inhibits integrase-catalyzed viral 
deoxyribonucleic acid (DNA) strand transfer with half maximal inhibitory concentration (IC50) 
values in the nanomolar range (3.0 to 13.0 nM).  GSK1265744 is a potent antiviral agent when 
tested in a variety of in vitro assays.  Additionally, the IC50 values of GSK1265744 for viral 
replication were also in the low nanomolar concentration range for National Institutes of Health 
(NIH) reference strains (24 HIV-1 strains and 3 HIV-2 strains in peripheral blood mononuclear 
cell (PBMC) assays; 3 HIV-1 strains in monocyte-derived macrophage assays). The protein 
adjusted IC50 (PA-IC50) was estimated to be 102 nM in HIV-1 IIIB infected MT-4 cells.  
Exposure of MT-2 cells infected with HIV-1 IIIB to GSK1265744 for up to 112 days did not 
produce any highly resistant mutants.  No amino acid substitutions in the integrase (IN) region 
were selected when passaging the wild type HIV-1 NL-432 in the presence of 6.4 nM 
GSK1265744 for 56 days. 
1.2.2 Metabolism 
The protein binding of GSK1265744 in rat, dog, monkey and human plasma and serum was high 
(>99%).  GSK1265744 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.  After oral administration of GSK1265744 to 
rats, radioactivity was slowly absorbed, widely distributed to tissues and minimally associated 
with blood cellular components.  Elimination of radioactivity was slow with most tissues 
containing low but quantifiable radioactivity at 28 days.  Following oral administration of 
GSK1265744 to mice and rats, GSK1265744 was the principal component in plasma of both 
species, representing up to 99.4% and 92.3% of the plasma radioactivity, respectively.  
Elimination of drug-related material occurred predominantly via the feces, with the majority of 
the absorbed radioactivity secreted into the bile.  Renal excretion was minimal, with less than 1% 
of the dose eliminated in the urine.  The primary route of biotransformation in mice and rats was 
conjugation with glucuronic acid (M1), similar to its metabolism in human hepatocytes.  Overall, 
these findings suggest that metabolism represents a significant route of clearance for absorbed 
GSK1265744 in the mouse and rat.   


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1.2.3 Preclinical Studies 
The GSK1265744 toxicology package supports the careful conduct of clinical studies with 
GSK1265744 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/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 GSK1265744 injectable suspension up to the mean Cmax plasma 
concentration observed at the NOAEL in the 39-week monkey oral GSK1265744 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 744LA 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 744 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 postnantal 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 is approximately 7 fold below the NOAEL in 10-day-old 
rat offspring.  Importantly, an early fetal development (EFD) study in rats was negative. 
1.2.4 Pharmacokinetics 
The PK of GSK1265744 in both healthy HIV-uninfected subjects and HIV-infected subjects 
supports once daily administration with oral dosing and once monthly or longer dosing with the 
LA formulation. 
Oral 744 dosing: 
 
Following oral administration of single doses to healthy subjects, oral 744 was readily absorbed 
with the maximum concentration achieved between 0.5 and 2.0 hours when dosed as solution 
and between 1.5 and 3.5 hours when dosed as tablet in the fasted state.  Following repeat dose 
administration for 14 days, GSK1265744 AUC (0-tau), Cmax, C, and Cmin increased 
proportionally to increase in dose.  Available data support time invariant PK.  The effective half-
life was estimated to be 40 hours.  GSK1265744 has a low potential for drug interactions. Co-
administration of oral 744 and etravirine (ETR) had no effect on the PK of oral 744.  A 
designated cardiac safety study is on-going to evaluate QT prolongation.   
744LA dosing: 
 
Following a single IM or SC injection of 744LA, 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.  GSK1265744 was detected in plasma up to 48 weeks.  When the dose was 
administered as two equally divided injections, total drug release was increased so that Cmax was 
greater than dose proportional and there was a more pronounced decay in drug concentrations 
over time.  However, overall extent of exposure (AUC0-tau) was similar. Following single dose 
744LA administration, mean absorption-limited apparent terminal phase half-life ranged from 21 
to 50 days, reflecting elimination from the depot site (absorption from depot site) rather than the 
systemic circulation.   
744LA PK has been evaluated in Phase 1 studies following repeat administration in healthy HIV-
uninfected subjects.  Following a loading dose of 800 mg IM and three monthly (every 28 days) 
maintenance doses, the third monthly 200 mg SC, 200 mg IM and 400 mg IM injections 


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achieved geometric mean plasma Cτ of .61g/mL, 1.72 g/mL, and 3.22 g/mL –  9.7-, 10-, and 
19-fold above the PA-IC90 (0.166 g/mL), respectively. Following two quarterly 800 mg IM 
doses, geometric mean plasma GSK1265744 Cτ was 1.11 g/mL, 6.7-fold above the PA-IC90.   
The phase 2a ÉCLAIR study evaluated 800mg IM quarterly x 3 doses in N=127 healthy male 
study participants. Preliminary evaluation of PK data from that study showed that only 
30 to 37% of reportable CAB trough concentrations were 4x PA-IC90 following each of the 
three injections, and 15 to 31% were below 1x PA-IC90.  Graphical evaluation of the CAB 
concentration-time profiles suggests that drug absorption from the depot injection site was more 
rapid in ÉCLAIR than observed in prior studies, resulting in higher peaks and lower troughs 
(Figure 3).   
The rationale for extended follow-up in this study (52 weeks after last injection) is two-fold:  The 
first is to assess safety events during the prolonged interval during which drug levels have been 
demonstrated to be detectable in blood plasma in order to best characterize the safety profile of 
744LA.  The second is to characterize in detail any HIV infections that might occur during a 
period of declining blood plasma drug levels, including viral resistance profiles and response to 
antiretroviral therapy treatment.   
Plans for suppressive ART treatment for participants who acquire HIV infection during the study 
are detailed in Section 5.21.   
1.2.5 Pharmacogenomics 
The purpose of the pharmacogenomic analysis will be to determine whether genetic 
polymorphisms play a role in governing the variability among participants in the PK and 
pharmacodynamics (PD) of GSK1265744 when potentially used for HIV prevention in the 
future.  Pharmacogenomics will be an exploratory end point in this study. Genome wide 
association studies will be performed and compared to PK parameters. The genes to be analyzed 
will include those that encode the UDP-glucuronosyltransferase family of enzymes since these 
proteins play a role in the clearance of GSK1265744 via the conjugation of glucuronic acid.  
1.3 
Dose Rationale 
Rationale for Cohort 1:   
The Cohort 1 744LA dose rationale is based on the objective to deliver adequate drug 
concentrations to prevent sexual transmission of HIV. The proposed dose schedule for evaluation 
in humans is based on maintaining 744LA plasma concentrations well above the PA-IC90 value 
of 0.166 g/mL, a concentration range shown to have significant antiviral activity. In a short-
term monotherapy study seven HIV-infected subjects received oral 744 5 mg once daily for 10 
days44, 45.  Geometric mean Day 10 C was 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 baseline of -2.2 
log10 c/mL.  In LAI116482, the Phase IIb study in HIV-1 infected, antiretroviral therapy naïve 
adult subjects46, suppression of HIV infection was accomplished with oral 744 at doses of 10 mg 
to 60 mg once daily in combination with 2 nucleotide reverse transcriptase inhibitors (NRTIs), 
and suppression of HIV has been maintained through 96 weeks using a dual regimen of oral 744 
and rilpivirine (RPV) at oral 744 10 mg and higher.  The geometric mean individual average 
predose concentration following oral 744 10 mg once daily was 1.35 g/mL.  Following two 
quarterly doses (12-weeks apart) of 744LA 800 mg IM in healthy participants (n=10), geometric 
mean (trough concentration) C was approximately 1.11 g/mL, approximately 6.7-fold above 
the PA-IC90 and between the 5 mg and 10 mg oral doses (Table 1).  Furthermore, based on 
population PK modeling and simulation, 744LA 800 mg IM every 12 weeks achieves a mean 
concentration above the 1.35 g/mL target based on 10 mg daily oral dosing and the lower 
bound of the 90% confidence interval (CI) is at 4-fold PA-IC90 (Figure 1).  The overall range in 


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predicted 744LA C values following 744LA 800 mg IM is similar to that following once daily 
dosing of oral 744 10 mg (Figure 2).  
Lastly, a one week delay in dosing at steady state for 800 mg IM every 12 weeks is predicted to 
result in a geometric mean C that is 10% lower than for dosing that is administered on schedule 
while remaining above the 1.35 g/mL target (Table 1).  Thus, the 800 mg IM every 12 weekly 
dosing schedule was expected to maintain geometric mean plasma concentrations well above the 
PA-IC90 value throughout the dosing interval and in a range of 5-10 mg oral doses with 
demonstrated antiviral activity.  
Table 1: Summary of GSK1265744 Pharmacokinetic Parameters Following Oral 
Administration in HIV- Infected Subjects and IM Administration in 
HIV-Uninfected Subjects 
Route 
Study 
Population 
N 
GSK 
1265744 
Regimen 
GSK1265744 PK Parametera  
C or C0 
(g/mL) 
Cmax 
(g/mL) 
AUC(0-) 
(g h/mL) 
Geomean IQ 
C0 or C:PA-IC-90 
Oral 
ITZ111451 
HIV 
N=7 
5 mg PO qdb  
0.57 
[33%] 
1.02 
[25%] 
17.7 
[31%] 
3.4 
Oral 
LAI116482 
HIV 
N=14 
10 mg PO 
qdb  
1.35 
[45%] 
(n=57) 
2.77 
[33] 
45.7 
[32] 
8.1 
IM 
LAI115428 
HVsc  
N=9 
800 mg IM 
every 
12weeks x 2 
(2nd dose 
interval) 
1.11 
[139%] 
3.35 
[56%] 
4,417 
[53%] 
6.7 
IM 
PopPK 
simulation 
HVs 
800 mg IM 
every 12 
weeks x 5 
(last dose) 
1.57 
[56%] 
NDd 
NDd 
9.5 
IM 
PopPK 
simulation 
HVs 
800 mg IM 
every 12 
weeks x 5 
(last dose 
with 1w 
delay) 
1.41 
[60%] 
NDd 
NDd 
8.5 
a. Data presented as geometric mean, [CVb%] 
b. By mouth, once daily 
c. Healthy volunteers 
d. Not Determined 
 
 
 


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Figure 1: Predicted Mean (90% CI) 744LA Concentration-Time Profile Following 
800 mg IM Every 12 Weeks x 5 in HIV-Uninfected Subjects Compared 
to Oral Target (1.35 µg/ml) based on 10 mg Oral Daily Dosing  in HIV-
Infected Subjects and to 4 times the PA-IC90 (0.664 µg/ml)  
 
 
Figure 2: Predicted 744LA Trough Concentrations Following 800 mg IM Every 12 
Weeks in HIV-Uninfected Subjects Compared to Oral Daily Dosing of 
10mg   
 
White line: median; Solid box: interquartile range (IQR); Whiskers: ±1.5 IQR; 
Horizontal lines: outliers  
 
 
 
 
Time(weeks)
Mean Concentration (90%CI)
0
10
20
30
40
50
60
0
2
4
6
8
10
0.644 ug/mL
1.35 ug/mL
0
1
2
3
4
5
800 Q12wks
Oral 10mg
(n=1000)
(n=1000)
Predicted Ctroughs (ug/mL)
1.35 ug/mL
0.644 ug/mL


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Rationale for Cohort 2:  
 
An analogous study to HPTN 077 (201120, ÉCLAIR) was undertaken to evaluate 744LA 800mg 
quarterly at three time points in healthy male participants, with results becoming available during 
the conduct of the HPTN 077 study.  Preliminary evaluation of PK data from that study showed 
only 30 to 37% of reportable 744 trough plasma concentrations were 4x PA-IC90 following 
each of the three injections, and 15 to 31% were below 1x PA-IC90.  Graphical evaluation of the 
744 concentration-time profiles suggests that absorption was more rapid among participants in 
the ÉCLAIR study than observed in prior studies and the related Phase 2 population PK model, 
resulting in higher peak and lower trough concentrations (Figure 3). Of note, the 744LA 
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 744LA 800mg every 12 weeks, particularly in 
male subjects, may not maintain sufficient exposures in all participants, and an amendment to the 
HPTN 077 dosing schedule in the protocol will enable evaluation of a second regimen (Cohort 2) 
in both males and females at low risk of acquiring HIV infection.   
 
The 744 Phase 2 population PK model has been updated with ÉCLAIR PK data, significantly 
increasing the dataset in the model, and preliminary results indicate absorption from the injection 
site (Ka LA) has increased ~50% overall and ~2-fold for ÉCLAIR participants, specifically, 
relative to the original model.  Further modeling efforts to understand which covariates may be 
influencing this increase in absorption are ongoing. Simulations of the 744LA 800mg every 12 
weeks regimen have been re-run with the updated PK model and now reflect the predicted 
troughs below targets, particularly in males as observed in the ÉCLAIR study (Figure 4).  The 
proposed regimen for Cohort 2 in this study is 744LA 600mg at Week 5, four weeks later at 
Week 9, and then every 8 weeks thereafter at three more time points (Week 5, 9, 17, 25 and 33).  
Simulations of this regimen, based on the updated PK model, predict that steady state trough 
concentrations will achieve targets in both males and females (Figure 5).  This regimen will 
enable evaluation of a 600mg LA dose, which has not been studied previously without an 800mg 
LA loading dose, with the understanding that a higher loading dose may be required in future 
studies of participants at higher risk of acquiring HIV infection, particularly females who on 
average demonstrate slower 744LA absorption rates.  
 
Lastly, a similar regimen has been administered to HIV infected participants in 200056 (LATTE-
2).  In that study, 744LA 800mg was administered as a loading dose, and two subsequent 
monthly doses of 744 LA 600mg were administered prior to initiating the every 8 week dosing 
starting at Week 8.  Preliminary data for this every 8 week regimen in LATTE-2 were not 
available at the time of the population PK update but have been evaluated graphically by gender 
(Figure 6).  On average, this regimen has achieved clinical targets in both males and females, 
further supporting the selection of an every 8 week regimen, for inclusion in the HPTN 077 
study. 
 


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Figure 3.  Mean (SD) Plasma 744 (CAB) following 744LA 800mg IM Q12W in ÉCLAIR        
and in original Phase 2 Dose Rationale Model Predictions (Sparse Time Points)  
 
 
Figure 4.  Simulated Concentration-Time profiles following 744 (CAB) LA 800 IM Q12W 
in Males and Females based on updated PopPK Model 
 
 
Legend:  Red Line = Median, Blue band = IQR (25th/75th percentiles), Light blue band = 
10th/90th percentiles, Pink band =5th/95th percentiles 
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)
Plasma CAB (g/mL)
Males
Females


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Figure 5.  Simulated Concentration-Time profiles following 744 (CAB) LA 600mg IM at Day 1, 
Week 4 and Q8W thereafter in Males and Females based on updated PopPK Model 
 
 
Legend:  Red Line = Median, Blue band = IQR (25th/75th percentiles), Light blue band = 
10th/90th percentiles, Pink band =5th/95th percentiles 
 
Plasma CAB (g/mL)
Males
Females


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Figure 6.  Preliminary Concentration-Time Profiles following the 744 (CAB) LA Q8W Regimen in 
Males and Females (LATTE-2) 
 
 
 
 
 
1.4 
Clinical Experience to Date – GSK1265744 
Through 1 July 2015, approximately 1056 adult subjects 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 744 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 744 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. 46  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 744 could not be 
ruled out. 
One hundred thirty six (136) healthy participants from completed studies have received single or 
repeat doses of 744 LA in Phase 1 studies at doses ranging from 100-800 mg administered as 
single or split IM or SC injections.  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 
Time (Weeks)
0 1
4
8
12
16
20
2425
28
32
32
Plasma CAB ( g/mL)
1
10
Males on Q8W (LATTE2, n=104)
Females on Q8W (LATTE2, n=8))
8x PA-IC90 (1.35 g/mL)
4x PA-IC90 (0.664 g/mL)


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rash. Five non-drug-related SAEs have been reported: foot osteomyelitis, uterine fibroids, 
appendicitis, elective hysterectomy, and seizure. An additional 94 participants have received  
744 LA as 800 mg IM injections every 12 weeks in the ongoing 201120 (ÉCLAIR) study. One 
participant was withdrawn from 744 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 subjects 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).46  ISRs related to 744LA 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%)C 2013).  Median IM ISR 
durations were approximately 5 days for pain and erythema, and approximately 22 days for 
nodules46.  
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 744 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 744 and 744LA) 
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 744LA, seven 
for adverse events and four for other reasons. Ninety-four (94) participants received at least one 
injection of 744LA 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 744LA 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 744LA arm withdrew after 
their second injection, citing injection tolerability as a primary reason.  Three other participants 
discontinued study participation after receiving injections, for non-AE and non injection-related 
reasons. 
Fifteen participants experienced a Grade 1 or higher 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 744 (10, 
30, or 60 mg once-daily, blinded doses) in combination with either TDF/FTC or abacavir-
lamivudine.47 (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 744 in combination 
with NRTIs. The overall response rate across the three dosing arms of oral 744 were 87% <50 
c/mL (FDA snapshot analysis) with minimal differences between oral 744 doses; the control arm 
response rate was 74% <50 c/mL.  In the “maintenance” phase, participants randomized to any 
of the 744 doses who had viral loads < 50c/mL prior to week 24 were transitioned to a regimen 


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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 744 10mg, 
30mg, and 60mg daily, and 83% for the efavirenz control participants.  One participant 
randomized to 744 10mg who successfully transitioned to rilpivirine plus 744 10 mg daily 
experienced virologic failure at week 48 in the context of subtherapeutic (<50% expected) 744 
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) resistance48.  
Safety results through week 96 support continuation of all three oral 744 dosing arms. There 
have been no deaths, oral 744 drug-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 744 AEs leading to withdrawal from the 
study (744 - 4% vs EFV - 15%). Two HIV-infected participants receiving oral 744 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 744 and rilpivirine 25 
mg developed ALT values >10x ULN at Week 96 likely due to acute Hepatitis C infection. 
Plasma exposures after administration of 744LA are expected to remain between the oral 744 10 
mg and 30 mg exposures.  At this stage of development, a lead-in of oral 744 is being employed 
to determine safety and tolerability in individual participants, prior to the transition to 744LA.  
The accumulated efficacy and safety data with oral 744 and 744 LAHIV-infected and HIV-
uninfected participants supports continued clinical development for HIV treatment and PrEP. 
A second Phase 2b study in HIV-infected, antiretroviral naïve adults is currently underway 
(LATTE-2), with 310 participants enrolled to receive oral 744 30mg  + ABC/3TC for 20 weeks 
followed by a long acting regimen containing 744 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 744 30mg + ABC/3TC and 
developed possible drug induced liver injury and a second subject on oral 744 30  mg + 
ABC/3TC, with steatohepatitis, developed possible drug induced liver injury approximately 6 
months after initiating oral 744.  See details below under Hepatic Safety.   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 744 could not be ruled out. 
 


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Cumulative exposures of GSK1265744, through 01 July 2015, are shown in Table 2.  
 
 
Table 2: Cumulative GSK1265744 Exposure Estimates from Phase 1 through Phase 2b 
Clinical Studies Up To 01 July 2015 
Treatment Population/Dose 
Duration 
Completed 
Ongoing/ 
Concludeda 
Total 
HIV uninfected healthy subjects 
351 
200 
551  
5 to 150 mg 
Single dose 
115 
37 
152 
10 to 30 mg once daily 
10 to 28 days 
138 
163b 
301 
150 mg every 12 hours 
3 doses 
40 
0 
40 
100 – 800 mg IM/SC LA 
Max 252 days 
136c 
114d 
250 
HIV-infected subjects 
15 
490 
505 
5 to 30 mg once daily (Ph IIa) 
10 days 
15 
0 
15 
10 to 60 mg once daily (Ph 
IIb) 
Max 1022 daysi 
0 
181 
181 
30 mg once daily (Ph IIb) 
Max 394 days 
0 
309 
309 
Up to 800 mg IM LAe 
Max 232 daysh 
 
229f 
229 
Total 
366 
690b 
1056 
Single dose oral (5 to 150 mg) 
 
115 
37 
152 
Repeat dose once daily oral 
(10 to 60 mg) 
- 
153 
653 
806 
150 mg oral every 12 hours x 3 
 
40 
0 
40 
Single or repeat dose LA (100 
– 800 mg) 
- 
136c 
343g 
479 
a. Concluded studies: study completed through follow-up; and/or clinical study report is in preparation 
b. Approximately 10 are on placebo in study 201103 
c. 78 received both oral and LA dosing 
d. 114 received both oral and LA dosing and approximately 5 are on placebo from study 201103  
e. Includes 400 mg Q4W and 600 mg Q8W dosing 
f. Subset that received 30 mg once daily in study 200056 
g. 343 received both oral and LA dosing and approximately 5 are on placebo from study 201103 
h. Detectable CAB concentrations can remain for up to 52 weeks following the last CAB injection 
i. As of 28 Dec 2014, all participants had transitioned to oral 744 30 mg in the Open-Label phase of study LAI116482 (LATTE), 
therefore, the longer durations apply to the 30 mg dose only 
 
 
 
Hepatic Safety 
 
As part of the early phase development of GSK 1265744, two participants in the HIV Treatment 
Phase IIb LAI116482 (LATTE) study developed Grade 4 transaminase elevations.  Both were 
HIV-infected, had pre-existing steatohepatitis, and had Grade 1 ALT/AST elevations at 
screening/entry.  Both were treated with ABC/3TC + 744 60 mg PO QD as part of “induction 
therapy” in the LATTE-1 study.   Laboratory assessments at week 2, and again at week 4 (for 
one of the two) were normal.  One participant at Week 4, and the other at Week 8 (day 57) 
demonstrated ALT elevations 12x ULN and 8x ULN respectively.  Bilirubin remained normal, 
as did coagulation parameters, and the participants were clinically asymptomatic.  Oral 744 was 
withdrawn and ALT/AST returned to normal 5 and 8 weeks thereafter, respectively.  
 
A third participant in the HIV Treatment Phase 2b 200056 (LATTE-2) study developed Grade 4 
transaminase elevations, and also > Grade 2 bilirubin elevation. This participant was HIV/HCV 
co-infected, with portal hypertension and Grade 3-4 fibrosis on Fibroscan but normal screening 


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transaminase levels.  He was begun on ABC/3TC (600 mg/300 mg) + 744 30 mg PO QD. On 
Day 35 of treatment the participant developed ALT 5 x ULN, which peaked one week later at 7 x 
ULN.  Drug was withdrawn and the ALT/AST and bilirubin have normalized. The participant 
was clinically asymptomatic.  A fourth participant receiving 744 30 mg PO + ABC/3TC 
developed an ALT >5x ULN after approximately one year on therapy which lead to 
discontinuation of oral therapy, with resolution of ALT values.  Initial ALT elevations were 
detected approximately 6 months after initiating therapy.  This participant was noted to have 
steatohepatitis on ultrasound imaging and did not develop evidence of hepatic dysfunction.  Oral 
744 could not be ruled out as a contributing factor to the observed liver injury. 
 
Central Nervous System Safety 
In a single-dose study, a healthy male volunteer with a history of prior seizure activity (one 
episode 14 years prior), on no anti-epileptic medication, experienced an unwitnessed seizure 
event 270 days after a single injection of CAB LA 400 mg IM.  Plasma levels of CAB were 
undetectable for 4 months prior to the seizure event.  The event occurred in the context of 
consumption of approximately 10 cans of beer, and 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 is not planned for additional IP dosing. 
 
1.5 
Risk Assessment for GSK1265744 
Since GSK1265744 is still in clinical development and exposure in humans with or without HIV 
infection is limited, the clinical safety profile in humans has yet to be fully elucidated.  Refer to 
Appendix X, which outlines the risks that have primarily been identified during routine 
preclinical testing and/or in the clinical trial experience to date and are considered of potential 
relevance to clinical usage in the context of this protocol.  Summaries of findings from both 
clinical and non-clinical studies conducted with GSK1265744 also can be found in the 
Investigator’s Brochure. 


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1.6 
Acceptability  
Acceptability has been conceptualized as individuals’ willingness and ability to use a product 
over time and, when available, in the context of a range of alternative choices.49-51 In both the 
fields of HIV prevention and contraception, individuals’ decisions to initiate use of a product, 
and their ability to adhere to and sustain use of that product is strongly influenced by their 
knowledge and beliefs about the product, attitudes towards and experiences of product attributes 
and how product use fits their social/sexual context – especially in comparison to other 
prevention methods.   As apparent from recent microbicide and PrEP clinical trials, product-
related acceptability is also intertwined with the clinical trial context, including a person’s 
understanding of the study product efficacy (which may be a placebo) and attitudes towards 
other trial requirements. Such factors may lead to differences between within-trial acceptability 
and likelihood of using a product outside of a trial context.  
While assessing acceptability in a low-risk population may not be representative of the target 
population for PrEP, given the novelty of this investigational approach, it is believed that 
capturing limited and focused information on acceptability is warranted.  Acceptability will be 
assessed through a questionnaire, including questions related to health outcomes 52,53, assessed 
after initiation of each injection. Semi-structured interviews may be conducted at select sites 
regarding their experience with study treatment.  These would be conducted under a separate 
IRB/EC approved consent.  Participation in such interviews would be optional. 
 
1.7 
Sexual Risk Behavior 
Concern for “risk compensation” – a compensatory increase in numbers of sexual partners or 
unprotected sex acts engendered by perceived protection of a biomedical agent – has been a 
major concern regarding all ART-based, microbicide, and vaccine agents, including male 
circumcision.  In the Phase III placebo-controlled trials of oral and vaginal microbicide products, 
such risk compensation was not observed; however, placebo-controlled studies do not provide 
the optimal method for evaluating effects of investigational products on such behavior.54 Open-
label demonstration projects are currently ongoing to better inform the field.  The open-label 
continuation of the Partners-PrEP study provided one of the first opportunities to assess behavior 
change after study unblinding; in this study of serodiscordant heterosexual couples in Kenya and 
Uganda, there was an increase in rates of non-primary sexual partnering post-unblinding55.  
Mathematical modeling has suggested that even small increases in sexual risk behavior have the 
potential to abrogate the prophylactic efficacy of even a potent PrEP agent56.  Assessment of 
sexual risk behavior change in response to a long-acting prophylactic agent would be particularly 
important to the field, especially with regard to cost-efficacy, risk-benefit, and implementation 
issues.   
Sexual risk behavior will be assessed at baseline (prior to initiation of oral 744 and again prior to 
initiation of 744LA), and throughout the injection phase of the study and follow-up at quarterly 
intervals. 
1.8 
Rationale for Placebo-Controlled Study Design 
The placebo-controlled trial (PCT) study design is a rigorous method of evaluating therapeutic 
options for safety and efficacy, but is ethically controversial when effective alternatives to the 
study agent exist.  International debate has resulted in guidance to help inform such clinical trial 
designs57.  
In the case of 744LA for HIV prevention, the effective comparator that could be considered is 
daily TDF/FTC.  Although daily oral TDF/FTC has been demonstrated to be effective in MSM 
and transgender women globally and heterosexual men and women in Africa, clinical trial 
efficacy has not translated into effectiveness due to poor adherence to daily dosing 28, 30.   The 
lack of understanding of the likely many socio-cultural, economic, and contextual correlates of 


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adherence to daily oral PrEP is, in large part, the genesis for the push to develop novel PrEP 
agents and delivery systems such as the one being investigated in the current protocol.  
A PCT study design may be appropriate in specific scenarios.  One of these scenarios is when 
withholding treatment poses negligible risk to participants.58  
In this trial, although there is a proven effective strategy for ART-based PrEP as noted above, 
participants in the current protocol will be specifically selected for being at low to minimal risk 
of HIV acquisition.  Participants will be particularly screened through the lens that 
randomization to the placebo arm would be acceptable to both the Investigator of Record (IoR) 
and participant – that is, for the well-being of the participant, lack of access to oral PrEP that is 
known to be safe and effective would not be expected to be problematic during the course of the 
trial. 
Careful selection of the study population, for whom it will be determined by both the IoR at the 
site, study staff, and the participant that the participant’s HIV risk-mitigation strategies and 
partner profile abrogate the need for further HIV prevention support from TDF/FTC-based PrEP 
will be employed.  Additionally, condoms and sexual health counseling will be provided to 
participants in both arms.  In this way, risk associated with assignment to the placebo arm is 
minimized. 
While meeting such criteria justifies the use of placebo control, it is insufficient rationale alone; 
there must also be sound methodological reasons for PCT. GSK1265744 has to date had 
relatively limited HIV-uninfected human exposure 39, and there is need to establish the safety, 
tolerability, acceptability, and impact on sexual risk behavior of the injectable preparation.  As 
the alternative comparator (if active comparator were to be employed) is an oral daily 
preparation, this would not only confound the acceptability and sexual risk behavior outcomes of 
the study, it would be providing an intervention to individuals who do not carry an indication for 
its use; that is, those not deemed at “significant” risk for HIV acquisition do not meet the US 
FDA or CDC guidance for TDF/FTC PrEP use. 
 
 


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2.0 
STUDY OBJECTIVES AND DESIGN 
2.1 
Primary Objective 
 Evaluate the safety and tolerability of the injectable agent GSK1265744 long acting 
(744LA) injectable (800 mg dose administered at three time points at 12 week intervals), 
through Week 41 in HIV-uninfected men and women. 
 Evaluate the safety and tolerability of the injectable agent GSK1265744 long acting 
(744LA) injectable (600 mg dose administered at two time points at 4 week intervals, 
followed by three time points at 8 week intervals), through Week 41 in HIV-uninfected 
men and women. 
2.2 
Secondary Objectives 
 Evaluate the safety and tolerability of GSK1265744 (daily oral 744 + 744LA) for 52 
weeks of follow-up after final injection (each cohort will be analyzed separately) 
 Evaluate the safety and tolerability of oral 744 from Week 0 to Week 5 
 Evaluate the pharmacokinetics of 744LA administered at three time points as 800 mg IM 
every 12 weeks for 52 weeks of follow-up after final injection  
 Evaluate the pharmacokinetics of 744LA administered at five time points as 600 mg IM 
at two time points every 4 weeks followed by three time points every 8 weeks for 52 
weeks of follow-up after final injection  
 Evaluate differential pharmacokinetics of 744LA in participants by age, gender, race, 
ethnicity, weight, body mass index (BMI), and smoking status 
 Evaluate the acceptability of 744LA injections   
 Evaluate the effect of 744LA on sexual risk behavior by change from enrollment over 
time during the study period  
 Evaluate HIV incidence and antiretroviral drug resistance, in participants who acquire 
HIV infection during the study  
 Evaluate the safety, tolerability and pharmacokinetics of 744LA in the subset of women 
who use a hormone-based contraceptive 
2.3 
Exploratory Objectives 
 Explore relationships between safety parameters and GSK1265744 concentrations and/or 
participant demographic factors 
 Explore genetic factors that may impact the pharmacokinetics of 744LA 
 Perform secondary laboratory assessments which 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  
 


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2.4 
Study Design and Overview 
This is a Phase 2a, randomized, multi-site, two-arm, double-blind study of the safety, tolerability, 
pharmacokinetics, and acceptability of 744LA.  Eligible participants will be enrolled into two 
cohorts, and will begin an oral lead-in phase in which they will be randomized to receive daily 
oral 744 (30 mg tablets) or matching placebo for 4 weeks, followed by a one week washout 
period, to assess safety prior to receiving 744LA.  Following final safety lab assessments from 
the oral regimen phase, participants will enter the injection phase and receive IM injections of 
744LA or placebo at three time points at 12 week intervals in Cohort 1, and five time points at 4 
and 8 week intervals in Cohort 2.   
Approximately 194 participants will be divided into two dose cohorts and will be randomized to 
two arms in a ratio of 3:1 as follows:  
Cohort 1 
Arm 1:  Approximately 79 participants will receive daily oral 744 (30 mg tablets) for 4 weeks, 
followed by a one week washout period, to establish safety and tolerability, followed by intra-
muscular (IM) gluteal injections of 800 mg of 744LA (administered as two sequential 400 mg 
gluteal injections) at three time points at 12 week intervals as:  Week 5, Week 17, and Week 29.    
Arm 2:  Approximately 27 participants will receive daily oral matching placebo and IM 
injections of vehicle-matched placebo on the same schedule as Arm 1.   
Cohort 2 
Arm 1:  Approximately 66 participants will receive daily oral 744 (30 mg tablets) for 4 weeks, 
followed by a one week washout period, to establish safety and tolerability, followed by intra-
muscular (IM) gluteal injections of 600 mg of 744LA (administered as one 600 mg gluteal 
injection) at five time points at 4 and 8 week intervals as:  Week 5, Week 9, Week 17, Week 25, 
and Week 33.    
Arm 2:  Approximately 22 participants will receive daily oral matching placebo and IM 
injections of vehicle-matched placebo on the same schedule as Arm 1.   
All participants will receive HIV testing with pre- and post-test counseling, in addition to risk-
reduction counseling and condoms and lubricant. All participants will be followed according to 
the Schedule of Evaluations and Procedures provided in Appendices I-IX. 
2.4.1 Participating Sites/Institutions 
Participating sites are listed in the SSP Manual, and are located in Brazil, SSA, and the US. 
2.4.2 Study Duration 
This study will be approximately 3 years in length.  Accrual will require approximately 16-24 
weeks (4-6 months) for each cohort.  Study participants in both cohorts will receive oral tablets 
for 4 weeks, followed by a one-week washout period.  Cohort 1 will then receive injections at 
three points over 24 weeks (6 months); Cohort 2 will receive injections at five time points over 
28 weeks (7 months).  Participants in the active study product arms will be followed for 52 
weeks following their last injection.  Participants in the placebo arm will be followed until 52 
weeks after their last injection or until the last participant in the active study product arm in 
Cohort 2 completes their Week 41 visit, whichever comes first, after which the cohorts will be 
unblinded to assess the primary endpoint.  When all procedures related to unblinding are 
completed, participants in the placebo arm of the respective cohort will no longer be followed.    


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3.0 
STUDY POPULATION 
Approximately 194 hundred HIV-uninfected men and women will be included in this study.  A 
parallel study is being conducted in the US in men who have sex with men; as such, this study 
will enroll a higher proportion of women (60%).  Each site will be asked to work with their 
community advisory boards (CABs) 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 and assigned to a study arm as described in Section 7.5.  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 and gender distribution targets 
commensurate with study population needs, adjusted for local epidemiology, such that overall 
cross-site enrollment meets overall protocol goals.   Enrollment targets may be substantially 
different in terms of gender distribution across sites. 
3.1 
Inclusion Criteria 
Participants who meet all of the following criteria are eligible for inclusion in this study: 
 Men and women, 18-65 years old at the time of screening   
 Willing to provide informed consent for the study 
 In the last 12 months (at the time of screening):   
o No self-reported unprotected anal or vaginal intercourse with someone known to be 
HIV-infected or of unknown HIV infection status  
o No self-reported stimulant use (cocaine [including crack], methamphetamine, or non-
physician prescribed pharmaceutical-grade stimulants) or inhaled nitrate 
o No self-reported illicit injection drug use of any kind  
o No self-reported diagnosis of GC, CT, incident syphilis, bacterial vaginosis, or 
trichomoniasis 
o Not reporting greater than or equal to 5 different sexual partners, regardless of use of 
protection or knowledge of HIV status 
 
Note:  "Unknown HIV status” is defined as a partner not known to be HIV infected or 
HIV uninfected by the potential participant (as assessed by the Investigator of Record or 
designee).  The Clinical Management Committee (CMC) – refer to Section 6.1 for further 
information regarding the CMC – should be contacted regarding any questions about how 
to apply or interpret the risk eligibility criteria.  The SSP Manual should also be referred 
to for additional guidance regarding appropriate categorization of participants as low risk.   
 
 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 ≥ 70 mL/minute using the Cockcroft-Gault equation 
o Alanine aminotransferase (ALT) and aspartate aminotransferase (AST)  < upper limit 
of normal (ULN) 
o Total bilirubin < Grade 1 and direct bilirubin < ULN 
o Hepatitis B surface antigen (HBsAg) negative 
o Hepatitis C Ab negative 
 


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Note:  Chemistry and hematology parameters which do not meet the inclusion criteria 
above may be repeated once during screening.  
 
*HIV uninfected, based on HIV test results obtained at Screening and just prior to 
randomization at the Enrollment visit.  All HIV test results from the Screening visit must 
be obtained and must all be negative/non-reactive.  This includes testing for acute HIV 
infection, which must be performed within 14 days of Enrollment.  In addition, at least 
one HIV test result obtained at the Enrollment visit must be obtained prior to 
randomization in to the study 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.  Refer to SSP Manual.    
 
 No alcohol or substance use that, in the opinion of the study investigator, would interfere 
with the conduct of the study (e.g., provided by self-report, or found upon medical history 
and examination or in available medical records).  See Section 3.2 for additional 
exclusion criteria related to substance use.   
 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  
 
Additional requirements for all women: 
 
 If of reproductive potential (defined as pre-menopausal women who have not had a 
sterilization procedure per self-report, such as hysterectomy, bilateral oophorectomy, 
tubal ligation or salpingectomy), must have a negative urine pregnancy test performed 
(and results known) within 48 hours before initiating the protocol-specified medication(s) 
at enrollment.  Women are considered menopausal if they have not had a menses for at 
least 12 months and have a follicle stimulating hormone (FSH) level of greater than 40 
IU/L; if FSH testing is not available, they must have had amenorrhea for 24 or more 
consecutive months.  (FSH testing is not a protocol requirement.) 
 If of reproductive potential and participating in sexual activity that could lead to 
pregnancy, women must agree to use a form of contraception during the trial and for 30 
days after stopping the oral study medication or for 52 weeks after stopping the long 
acting injectable from the list below: 
o Intrauterine device (IUD) or intrauterine system (IUS) that meets <1% failure rate as 
stated in the product label 
o Hormone-based contraceptive 
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 
 Any active sexually transmitted infection detected by laboratory testing at Screening  
 Co-enrollment in any other HIV interventional research study or other concurrent studies 
which may interfere with this study (as provided by self-report or other available 
documentation. 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). 


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 Use of ART (e.g., for non-occupational post-exposure prophylaxis [PEP] or PrEP) in the 
90 days prior to study entry 
 Clinically significant cardiovascular disease, including:  
o ECG (one repeat ECG is allowed during screening; may be performed on the same 
day) with: 
 heart rate  < 45 or > 100 beats per minute for men, and <50 or >100 beats per 
minute for women  
 QRS duration >120 msec 
 QTc interval (B or F) > 450 msec 
 evidence of previous myocardial infarction (pathologic Q waves, S-T segment 
changes (except early repolarization)) 
 any clinically significant conduction abnormality (including but not specific to left 
or right complete bundle branch block, AV block [2nd degree (type II) or higher], 
Wolf Parkinson White [WPW] syndrome) (Any question of clinical significance 
should be referred to the CMC for adjudication) 
 sinus pauses > 3 seconds 
 any clinically significant arrhythmia which, in the opinion of the Investigator of 
Record or designee, will interfere with the safety for the individual participant (any 
question of clinical significance should be referred to the CMC for adjudication) 
 or history of non-sustained (3 consecutive ventricular ectopic beats on ECG at 
screening or entry) or sustained ventricular tachycardia 
o 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 
o Systolic blood pressure at screening outside the range of 90-140 mmHg or diastolic 
blood pressure is outside the range of 45-90 mmHg (confirmed on repeat 
measurement) 
 Underlying skin disease or currently active skin disorder (e.g., infection, inflammation, 
dermatitis, eczema, psoriasis, urticaria).  Mild cases of localized acne or folliculitis or 
other mild skin condition 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) 
 A score of > 8 on the WHO Alcohol Use Disorders Identification Test (AUDIT) at 
screening.  Note:  A score of > 8 indicates a medium to high level of problem alcohol use. 
 For women, pregnant or currently breastfeeding, or intends to become pregnant and/or 
breastfeed during the study 
 A history of seizure disorder, by self-report 
 


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3.3 
Recruitment Process 
Sites will be responsible for developing appropriate recruitment processes that are geared toward 
their respective local communities.  All advertising materials must undergo approval by each 
participating site’s Institutional Review Board (IRB)/Ethics Committee (EC).  
3.4 
Co-Enrollment Guidelines 
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.  Any requests for co-enrollment in observational studies should 
be directed to the CMC. 
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 allow the incidence rate of the primary study 
outcome to be reliably estimated (i.e., a maximum of 10% 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. 
3.6 
Participant Withdrawal 
Regardless of the participant retention methods described in Section 3.5, participants may 
voluntarily withdraw from the study for any reason at any time. The Investigator also may 
withdraw participants from the study in order to protect their safety and/or if they are unwilling 
or unable to comply with required study procedures after consultation with the Protocol Chair, 
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. 


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Every reasonable effort will be made to complete a final evaluation of participants who terminate 
from the study prior to the final protocol-dictated study week, and study staff will record the 
reason(s) for all withdrawals from the study in participants’ study records.  In such cases, the 
Investigator of Record or designee must contact the CMC for guidance regarding final evaluation 
procedures.     
 
 


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4.0 STUDY PRODUCT CONSIDERATIONS 
4.1 
Study Product Regimens/Administration/Formulation Content 
Study Product Regimens 
 
Both Cohorts:   
Oral lead-in phase:  Participants will be randomized 3:1 to one of two study arms: 
Arm 1:  GSK1265744 tablets 30 mg – one tablet orally daily for 4 weeks, with or without food 
Arm 2:  Placebo for GSK1265744 – one tablet orally daily for 4 weeks, with or without food 
Injectable phase:  After a one week washout period to assess safety, participants will begin 
injections (with the same randomization as the oral lead-in phase) as:  
Cohort 1:   
Arm 1:  GSK1265744 (744 LA) 800 mg administered as two 2 mL (400 mg) IM injections in the 
gluteal muscle at Weeks 5, 17 and 29  
Arm 2:  Placebo for GSK1265744 (744 LA Placebo) administered as two 2 mL (400 mg) 
injections in the gluteal muscle at Weeks 5, 17 and 29  
Cohort 2:   
Arm 1:  GSK1265744 (744 LA) 600 mg administered as one 3mL (600 mg) IM injections in the 
gluteal muscle at Weeks 5, 9, 17, 25 and 33  
Arm 2:  Placebo for GSK1265744 (744 LA Placebo) administered as one 3 mL (600 mg) 
injections in the gluteal muscle at Weeks 5, 9, 17, 25 and 33  
Study Product Formulations 
Oral product:   
GSK1265744 tablets 30 mg 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 a desiccant.  The 
bottles should be stored up to 25 degrees Celsius (25o C) and protected from moisture.     
Placebo tablets for GSK1265744 are formulated as white to almost white oval-shaped coated 
tablets to visually match the active GSK1265744 tablets.  The tablets are packaged in high 
density polyethylene (HDPE) bottles with child-resistant closure that include an induction seal. 
The bottles contain a desiccant.  The bottles should be stored up to 25 degrees Celsius (25o C) 
and protected from moisture.   
Injectable Suspension:   
The GSK1265744LA is formulated as a sterile white to slightly colored suspension containing 
400mg/2mL of GSK1265744 for administration by intramuscular (IM).  The product is packaged 
in a 3 mL vials.  Each vial is for single use containing a nominal fill of 2mL (400 mg), and does 
not require dilution prior to administration.  The GSK1265744LA injectable suspension is to be 
stored at 2 degrees celsius to 30 degrees celsius (2o C – 30o C), do not freeze.  


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Placebo for GSK1265744 Injectable Suspension will be Sodium Chloride for Injection USP, 
0.9%.   
Syringes containing active and placebo study product will be covered with an overlay by the 
study Pharmacist of Record or designee prior to dispensing in order to maintain the blind, as per 
the SSP Manual. 
The study product 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, which will be provided by the DAIDS 
Regulatory Support Contract (RSC). 
4.2 
Study Product Acquisition and Accountability 
 
Study product is being provided by ViiV Healthcare.     
 
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.    
Study Product Accountability 
 
The site pharmacist is required to maintain complete records of all study products received from 
the CRPMC and subsequently dispensed to study participants. All study products must be stored 
in the pharmacy. All unused study products must be returned to the CRPMC after the study is 
completed, terminated or otherwise instructed by the study sponsor. The procedures to be 
followed are provided in the Pharmacy Guidelines and Instructions for DAIDS Clinical Trials 
Networks. 
4.3 
Toxicity Management 
Toxicity management guidelines can be found in Appendix XI.  
4.4 
Concomitant, Prohibited, and Precautionary Medications 
Information regarding prohibited and precautionary concomitant medications can be found in the 
SSP Manual.  The SSP Manual will be revised (as a whole or as a Memorandum of Changes) 
and re-issued when changes are made.   
All concomitant medications/preparations (prescription and non-prescription) including 
alternative/complementary medications/preparations (e.g., herbs, vitamins, etc.) taken within 30 
days prior to enrollment and anytime thereafter during study participation will be collected in the 
study participant’s chart and on study case report forms (CRFs).  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).  
 
 


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5.0 
STUDY PROCEDURES 
Overviews of the study visit and procedures schedules for both cohorts are presented in 
Appendices I-VIII (Cohort 1, Appendices I-III; Cohort 2, Appendices IV-VIII).  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:  Both Cohorts 
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 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 
 Locator information 
 HIV counseling 
 Administer AUDIT questionnaire 
 Offer condoms and lubricant 
 
Clinical Procedures 
 Target medical history (including bleeding history) and targeted physical exam for 
ascertainment of eligibility, and concomitant medications 
 ECG 
 Blood collection 
 Urine collection for GC/CT testing (men and women) 
 Urine pregnancy testing for women of reproductive potential 
 Vaginal swab collection for GC/CT testing (optional alternate collection for women if 
urine not used) 
 
Laboratory Evaluations 
 HIV testing (see SSP Manual)., including testing for acute HIV infection within 14 days 
prior to enrollment 
 Hepatitis testing:  HBsAg, HBsAb, HBcAb, HCAb 
 CBC with differential 
 Chemistry testing (see Appendix I or IV) 
 Liver function testing (AST, ALT, total and direct bilirubin, and alkaline phosphatase) 
 Syphilis testing 
 GC/CT testing (urine for men and either urine or vaginal swab for women)   
 Plasma storage 
 Urine pregnancy testing (for women of reproductive potential)  
 
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.   
Participants who have a positive test result for a sexually transmitted infection (STI) at Screening 
are not eligible for enrollment; all positive results will be reported per local legal reporting 


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guidance and referred for appropriate care and treatment.  STI treatment will not be provided by 
the study protocol. 
If a participant is deemed eligible after Screening, they will be asked to return to the site for 
Enrollment.  Those who are 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.  
However, potential participants with clinically significant cardiovascular disease as outlined in 
the exclusion criteria in Section 3.2, or having symptoms consistent with acute HIV infection 
(per IoR or designee) or a reactive HIV test may not be re-screened.   
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 
Week 0: Enrollment – Both Cohorts 
Administrative, Behavioral, and Regulatory Procedures  
 Locator information 
 Demographic information 
 Randomization 
 HIV counseling 
 Offer condoms and lubricant 
 Adherence counseling 
 Behavioral Assessment 
 Acceptability Assessment 
 
Clinical Procedures 
 Complete medical history and complete physical exam, including concomitant 
medications (may be performed during screening at the discretion of the Investigator of 
Record or their designee) 
 ECG 
 Blood collection (collect prior to administration of study product) 
 Urine collection for urinalysis  
 Urine pregnancy testing for women of reproductive potential 
 Rectal swab for GC/CT testing (men and women) (at US sites, may be performed during 
Screening at the discretion of the Investigator of Record or his/her designee) 
 Provide oral drug  
 
Laboratory Evaluations 
 HIV testing (see SSP Manual) 
 CBC with differential 
 Chemistry testing  
 Liver function testing (AST, ALT, total bilirubin, alkaline phosphatase) 
 Fasting lipid profile (participants should be fasting for at least 8 [preferably 12] hours 
prior to sample collection) 
 Urinalysis (protein and glucose) 
 GC/CT testing (rectal swab for men and women); for non-US sites, to be batched and 
shipped to the HPTN Laboratory Center for testing (see SSP for details).  For US sites, to 
be performed locally.   
 Plasma storage 
 Sample storage for Pharmacogenomic testing (at the discretion of the study site).  For 
sites that store samples for this testing, participants must provide specific consent). 
 


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NOTE: 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. In addition, for women of reproductive potential, a 
pregnancy test result from the Enrollment visit must be available and confirmed to be negative 
PRIOR to the provision of study product.  Results from the chemistry testing, LFTs, lipid profile, 
hematology testing, and urinalysis from this visit are NOT required prior to the issue of study 
product.   
5.3 
Weeks 2 and 4:  Oral Safety Visits (Week 4 is Post-Oral Safety Visit) – Both Cohorts  
Administrative, Behavioral, and Regulatory Procedures 
 Locator information 
 HIV counseling 
 Offer condoms and lubricant 
 Adherence counseling (Week 2 only) 
 Returned pill count 
 
Clinical Procedures 
 Targeted medical history and targeted physical exam, including concomitant medications 
and central nervous system (CNS) symptoms assessment 
 ECG (Week 4 only) 
 Blood collection 
 Urine collection for urine pregnancy testing for women of reproductive potential 
 
Laboratory Evaluations 
 HIV testing (see SSP Manual) 
 CBC with differential 
 Chemistry testing 
 Liver function testing (AST, ALT, total bilirubin, alkaline phosphatase) 
 Plasma storage  
 
NOTES for Week 2:   
- All HIV test results from previous visits and at least one HIV test result from the Week 2 visit 
must be available and reviewed at this visit. If any of these tests is reactive/positive, study drug 
should be discontinued (see also Section 5.21). In addition, for women of reproductive potential, 
a pregnancy test result from the Week 2 visit must be available and confirmed to be negative 
PRIOR to the provision of study product.  Results from other laboratory tests (e.g., chemistry, 
LFTs, hematology) from the Week 2 visit are NOT required prior to the issue of study product.   
- A Grade 1 AST/ALT abnormality reported at Week 2, regardless of relatedness to the study 
product, should be confirmed within one week.  Study drug may continue until the confirmatory 
results are available.  If the repeat value is < Grade 1, study drug may continue to Week 4.  If the 
repeat value is Grade 1 or higher, study product should be stopped, and the participant will be 
prohibited from entering the injection phase of the study, and will be terminated from the study.   
All such cases must be reported to the CMC.  In addition, participants will be followed with 
weekly AST/ALT assessments until they return to < Grade 1.   
- A Grade 2 or higher AST/ALT abnormality reported at Week 2 of the oral phase, regardless of 
relatedness to the study product, will prohibit a participant from entering the injection phase of 
the study, and the participant will be terminated from the study.   All such cases must be reported 
to the CMC.  In addition, participants will be followed with weekly AST/ALT assessments until 
they return to < Grade 1.   


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NOTE for Week 4:  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 the first injection at Week 5.  A Grade 1 (unconfirmed) or higher AST/ALT abnormality 
reported at Week 4 during the oral phase, regardless of relatedness to the study product, will 
prohibit a participant from entering the injection phase of the study, and the participant will be 
terminated from the study.  All such cases must be reported to the CMC.  In addition, 
participants will be followed with weekly AST/ALT assessments until they return to < Grade 1.     
NOTE for Weeks 2 and 4: The CMC should be contacted for guidance regarding pill counts 
resulting in less than 75% adherence prior to the Week 5 First Injection Visit, or any other 
concerns regarding adherence.      
5.4 
First Injection Visit:  Both Cohorts - Week 5  
Administrative, Behavioral, and Regulatory Procedures  
 Locator information 
 HIV counseling 
 Offer condoms and lubricant  
 Behavioral assessment 
 
Clinical Procedures 
 Targeted medical history and targeted physical exam, including concomitant medications 
and CNS symptoms assessment 
 Blood collection 
 Urine pregnancy testing for women of reproductive potential 
 Administer injection (with counseling) 
 
Laboratory Evaluations 
 HIV testing (see SSP Manual) 
 CBC with differential 
 Chemistry testing  
 Liver function testing (AST, ALT, total bilirubin, alkaline phosphatase) 
 Plasma storage (must be drawn PRIOR to the injection) 
NOTE:   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.  
For women of reproductive potential, a pregnancy test result from the Week 5 visit must be 
available and confirmed to be negative PRIOR to injection of study product.  The injection must 
not be given if the pregnancy test is positive.  
Results from the other laboratory evaluations (e.g., chemistry, LFTs, hematology) from the 
Week 5 visit are NOT required prior to injection.   
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.   
5.5 
Safety Visits: Cohort 1 - Week 6, 9, 13; Cohort 2 - Week 6 only  
Administrative, Behavioral, and Regulatory Procedures  
 Locator information 
 HIV counseling 
 Offer condoms and lubricant 
 Acceptability assessment (Week 6 only) 
 


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Clinical Procedures 
 Targeted medical history and targeted physical exam, and concomitant medications and 
CNS symptoms assessment 
 ECG (Week 6 and 9 only for Cohort 1, and Week 6 only for Cohort 2) 
 Blood collection 
 ISR evaluation 
 
Laboratory Evaluations 
 HIV testing (see SSP Manual) 
 CBC with differential 
 Chemistry testing  
 Liver function testing (AST, ALT, total bilirubin, alkaline phosphatase) 
 Plasma storage 
 
5.6 
Second Injection Visit:  Cohort 1 – Week 17; Cohort 2 – Week 9 
Administrative, Behavioral, and Regulatory Procedures  
 Locator information 
 HIV counseling 
 Offer condoms and lubricant 
 Behavioral assessment 
 
Clinical Procedures 
 Targeted medical history and targeted physical exam, including concomitant medications 
and CNS symptoms assessment 
 Blood collection 
 Urine pregnancy testing for women of reproductive potential 
 Administer injection (with counseling) 
 
Laboratory Evaluations 
 HIV testing (see SSP Manual) 
 CBC with differential 
 Chemistry testing  
 Liver function testing (AST, ALT, total bilirubin, alkaline phosphatase) 
 Plasma storage (must be drawn PRIOR to the injection) 
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 injection of 
study product. The injection must not be given if any HIV test is reactive/positive.  
For women of reproductive potential, a pregnancy test result from the current visit must be 
available and confirmed to be negative PRIOR to injection of study product.  The injection must 
not be given if the pregnancy test is positive.  
Results from the other laboratory evaluations (e.g., chemistry, LFTs, hematology) from the 
current visit are NOT required prior to injection.   
Results from all the previous safety visit clinical and laboratory evaluations (e.g., chemistry, 
LFTs, hematology) must be available and be reviewed by the IoR or designee prior to injection.   
5.7 
Safety Visits:  Cohort 1 - Week 18 and 23; Cohort 2 – Week 10 and 13 
Administrative, Behavioral, and Regulatory Procedures  
 Locator information 
 HIV counseling 
 Offer condoms and lubricant 


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 Tolerability/Acceptability assessment (Cohort 1 – Week 18 only; Cohort 2 – Week 10  
only) 
 
Clinical Procedures 
 Targeted medical history and targeted physical exam, including concomitant medications 
and CNS symptoms assessment 
 ECG (Cohort 1 - Week 23 only; Cohort 2 – Week 13 only)  
 Blood collection 
 ISR evaluation 
 
Laboratory Evaluations 
 HIV testing (see SSP Manual) 
 CBC with differential 
 Chemistry testing  
 Liver function testing (AST, ALT, total bilirubin, alkaline phosphatase) 
 Plasma storage 
 
5.8 
Third Injection Visit:  Cohort 1 – Week 29; Cohort 2 – Week 17 
Administrative, Behavioral, and Regulatory Procedures  
 Locator information 
 HIV counseling 
 Offer condoms and lubricant 
 Behavioral assessment 
 
Clinical Procedures 
 Targeted medical history and targeted physical exam, including concomitant medications 
and CNS symptoms assessment 
 Blood collection 
 Urine collection for GC/CT testing (men and women) (Cohort 1 only) 
 Urine pregnancy testing for women of reproductive potential 
 Rectal swab collection for GC/CT testing (men and women) (Cohort 1 only) 
 Vaginal swab collection for GC/CT testing (optional alternate collection for women if 
urine is not used) (Cohort 1 only) 
 Administer injection (with counseling) 
 
Laboratory Evaluations 
 HIV testing (see SSP Manual) 
 CBC with differential 
 Chemistry testing (see Appendix I or IV). 
 Liver function testing (AST, ALT, total bilirubin, alkaline phosphatase) 
 Syphilis testing (Cohort 1 only) 
 GC/CT testing:  Urine for men and either urine or vaginal swab for women.  For rectal 
swab GC/CT testing for men and women, non-US sites will batch and ship to the HPTN 
Laboratory Center for testing (see SSP for details); US sites will perform testing locally.  
(Cohort 1 only) 
 Plasma storage (must be drawn PRIOR to the injection) 
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 injection of study 
product. The injection must not be given if any HIV test is reactive/positive.  
For women of reproductive potential, a pregnancy test result from the current visit must be 
available and confirmed to be negative PRIOR to injection of study product.  The injection must 
not be given if the pregnancy test is positive.  


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Results from the other laboratory evaluations (e.g., chemistry, LFTs, hematology) from the 
current visit are NOT required prior to the injections.   
Results from the previous safety visit clinical and laboratory evaluations (e.g., chemistry, LFTs, 
hematology) must be available and be reviewed by the IoR or their designee prior to the 
injection.    
5.9 
Safety Visits: Cohort 1 – Week 30 and 35; Cohort 2 – Week 18 and 21 
Administrative, Behavioral, and Regulatory Procedures  
 Locator information 
 HIV counseling 
 Offer condoms and lubricant 
 Tolerability/Acceptability assessments (Cohort 1 -Week 30 only, Cohort 2 -Week 18 
only) 
 
Clinical Procedures 
 Targeted medical history and targeted physical exam, including concomitant medications 
and CNS symptoms assessment 
 ECG (Cohort 1 - Week 35 only; Cohort 2 – Week 21 only)  
 Blood collection 
 ISR evaluation 
 
Laboratory Evaluation: 
 HIV testing (see SSP Manual) 
 CBC with differential 
 Chemistry testing  
 Liver function testing (AST, ALT, total bilirubin, alkaline phosphatase) 
 Plasma storage 
  
5.10 
Fourth Injection Visit:  Cohort 2 only - Week 25  
Administrative, Behavioral, and Regulatory Procedures  
 Locator information 
 HIV counseling 
 Offer condoms and lubricant 
 Behavioral assessment 
 
Clinical Procedures 
 Targeted medical history and targeted physical exam, including concomitant medications 
and CNS symptoms assessment 
 Blood collection 
 Urine collection for GC/CT testing (men and women) 
 Urine pregnancy testing for women of reproductive potential 
 Rectal swab collection for GC/CT testing (men and women) 
 Vaginal swab collection for GC/CT testing (optional alternate collection for women if 
urine is not used) 
 Administer injection (with counseling) 
 
Laboratory Evaluations 
 HIV testing (see SSP Manual) 
 CBC with differential 
 Chemistry testing  
 Liver function testing (AST, ALT, total bilirubin, alkaline phosphatase) 
 Syphilis testing 


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 GC/CT testing:  Urine for men and either urine or vaginal swab for women.  For rectal 
swab GC/CT testing for men and women, non-US sites will batch and ship to the HPTN 
Laboratory Center for testing (see SSP for details); US sites will perform testing locally.   
 Plasma storage (must be drawn PRIOR to the injection) 
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 injection of study 
product. The injection must not be given if any HIV test is reactive/positive.  
For women of reproductive potential, a pregnancy test result from the current visit must be 
available and confirmed to be negative PRIOR to injection of study product.  The injection must 
not be given if the pregnancy test is positive.  
Results from the other laboratory evaluations (e.g., chemistry, LFTs, hematology) from the 
current visit are NOT required prior injection.   
Results from the previous safety visit clinical and laboratory evaluations (e.g., chemistry, LFTs, 
hematology) must be available and be reviewed by the IoR or their designee prior to the 
injection.    
5.11 
Safety Visits:  Cohort 2 only – Week 26 and 29  
Administrative, Behavioral, and Regulatory Procedures  
 Locator information 
 HIV counseling 
 Offer condoms and lubricant 
 Tolerability/Acceptability assessments (Week 26 only) 
 
Clinical Procedures 
 Targeted medical history and targeted physical exam, including concomitant medications 
and CNS symptoms assessment 
 ECG (Week 29 only) 
 Blood collection 
 ISR evaluation 
 
Laboratory Evaluation: 
 HIV testing (see SSP Manual) 
 CBC with differential 
 Chemistry testing  
 Liver function testing (AST, ALT, total bilirubin, alkaline phosphatase) 
 Plasma storage 
 
5.12 
Fifth Injection Visit:  Cohort 2 only – Week 33  
Administrative, Behavioral, and Regulatory Procedures  
 Locator information 
 HIV counseling 
 Offer condoms and lubricant 
 Behavioral assessment 
 
Clinical Procedures 
 Targeted medical history and targeted physical exam, including concomitant medications 
and CNS symptoms assessment 
 Blood collection 
 Urine pregnancy testing for women of reproductive potential 
 Administer injection (with counseling) 


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Laboratory Evaluations 
 HIV testing (see SSP Manual) 
 CBC with differential 
 Chemistry testing  
 Liver function testing (AST, ALT, total bilirubin, alkaline phosphatase) 
 Plasma storage (must be drawn PRIOR to the injection) 
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 injection of study 
product. The injection must not be given if any HIV test is reactive/positive.  
For women of reproductive potential, a pregnancy test result from the current visit must be 
available and confirmed to be negative PRIOR to injection of study product.  The injection must 
not be given if the pregnancy test is positive.  
Results from the other laboratory evaluations (e.g., chemistry, LFTs, hematology) from the 
current visit are NOT required prior injection.   
Results from the previous safety visit clinical and laboratory evaluations (e.g., chemistry, LFTs, 
hematology) must be available and be reviewed by the IoR or their designee prior to the 
injection.    
5.13 
Safety Visits:  Cohort 2 only – Weeks 34 and 37 
Administrative, Behavioral, and Regulatory Procedures  
 Locator information 
 HIV counseling 
 Offer condoms and lubricant 
 Tolerability/Acceptability assessments (Week 34 only) 
 
Clinical Procedures 
 Targeted medical history and targeted physical exam, including concomitant medications 
and CNS symptoms assessment 
 ECG (Week 37 only) 
 Blood collection 
 ISR evaluation 
 
Laboratory Evaluation: 
 HIV testing (see SSP Manual) 
 CBC with differential 
 Chemistry testing  
 Liver function testing (AST, ALT, total bilirubin, alkaline phosphatase) 
 Plasma storage  
5.14 
Primary Endpoint Visit:  Both Cohorts - Week 41 
Administrative, Behavioral, and Regulatory Procedures  
 Locator information 
 HIV counseling 
 Offer condoms and lubricant 
 Behavioral assessment 
 
Clinical Procedures 
 Targeted medical history and targeted physical exam, including concomitant medications 
and CNS symptoms assessment 


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 Blood collection 
 Urine collection for urinalysis  
 Urine pregnancy testing for women of reproductive potential 
 
Laboratory Evaluations 
 HIV testing (see SSP Manual) 
 CBC with differential 
 Chemistry testing  
 Liver function testing (AST, ALT, total bilirubin, alkaline phosphatase) 
 Fasting lipid profile (Participants should be fasting for at least 8 [preferably 12] hours 
prior to sample collection) 
 Urinalysis (protein and glucose) 
 Plasma storage  
5.15 
Tail Phase Visits:  Both Cohorts – Week 53, 65, 77 
Administrative, Behavioral, and Regulatory Procedures  
 Locator information 
 HIV counseling 
 Offer condoms and lubricant 
 Behavioral assessment 
 
Clinical Procedures 
 Targeted medical history and targeted physical exam, including concomitant medications 
and CNS symptoms assessment 
 Blood collection 
 Urine collection for GC/CT testing (men and women at week 53 only) 
 Urine  pregnancy testing for women of reproductive potential 
 Rectal swab collection for GC/CT testing (men and women at week 53 only) 
 Vaginal swab collection for GC/CT testing (optional alternate collection for women if 
urine is not used; Week 53 only)  
 
Laboratory Evaluations 
 HIV testing (see SSP Manual) 
 Liver function testing (AST, ALT, total bilirubin, alkaline phosphatase) 
 Syphilis testing (Week 53 only) 
 GC/CT testing (Week 53 only):  Urine for men and either urine or vaginal swab for 
women.  For rectal swab GC/CT testing for men and women, non-US sites will batch and 
ship to the HPTN Laboratory Center for testing (see SSP for details); US sites will 
perform testing locally.   
 Plasma storage  
5.16 
Final Visit:  Cohort 1 – Week 81; Cohort 2 – Week 85 
Administrative, Behavioral, and Regulatory Procedures 
 HIV counseling 
 Offer condoms and lubricant 
 
Clinical Procedures 
 Targeted medical history and targeted physical exam, including concomitant medications 
and CNS symptoms assessment 
 Blood collection 
 Urine pregnancy testing for women of reproductive potential 
 
Laboratory Evaluations 


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 HIV testing (see SSP Manual) 
 Liver function testing (AST, ALT, total bilirubin, alkaline phosphatase) 
 Plasma storage  
5.17 
Injection Visit Windows 
The visit windows for all visits, including injection visits, are outlined in the SSP Manual.  In 
brief, the visit window for injection visits is +/- 3 days.  If a participant is unable to report to the 
visit during this time frame, or if the participant misses their appointment within this time frame, 
the CMC must be contacted for consultation regarding whether rescheduling outside of the visit 
window is allowable.  
    
5.18   Procedures for Continued Oral and Injectable Dosing 
Appendix XI, 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.  Study product guidelines in the event 
of HIV infection and pregnancy are outlined in Sections 5.21 and 5.23, respectively.      
 
5.19 
Procedures for Participants Who Do Not Complete the Full Course of Injections 
Participants who do not receive the full course of injections in either cohort will be followed per 
the relevant Schedule of Evaluations and Procedures (Appendices II and III for Cohort 1; 
Appendices V-VIII for Cohort 2).      
Participants who are unable to receive the first injection for any reason will be terminated from 
the study.  If the reason is due to HIV infection or pregnancy, refer to Section 5.21 and 5.23, 
respectively.   
5.20 
Planned Unblinding of Study Participants  
When the last participant on the active study product arm in Cohort 2 completes his or her Week 
41 visit (Cohort 2), and when key study procedures at the HPTN SDMC, LC, and LOC have 
been completed, both cohorts will be unblinded.  Participants will be unblinded at their next 
study visit following final confirmation from the HPTN SDMC that all corresponding unblinding 
procedures have been completed.  Participants in the placebo arm will no longer be required to 
complete any further follow-up visits once they have been unblinded.  Active study product arm 
participants will complete their follow-up per the appropriate Schedule of Evaluations and 
Procedures.   
As previously noted, due to differences in timing of study initiation across the participating sites, 
as well as the ratio of active product arm vs. placebo arm participants being enrolled, it is likely 
that some placebo participants will complete their full follow-up visit schedule. 
Additional information will be outlined in the SSP Manual.   
5.21 
Participants with Suspected or Confirmed HIV Infection, at Screening, Enrollment, or 
Follow-Up 
The CMC must be notified of any possible HIV exposures as reported by the participant during 
the study, as well as any reactive or positive HIV test result identified at Enrollment or follow-
up.   
Screening and Enrollment 


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HIV testing will be performed to identify participants with HIV infection, and to identify 
participants whose HIV results may be equivocal (which could complicate HIV diagnosis at 
follow-up visits).  Individuals who have one or more reactive or positive HIV tests at Screening 
or Enrollment are not eligible to participate in this study. Furthermore, at the Screening and 
Enrollment (at Enrollment, prior to randomization), individuals with any signs or symptoms 
consistent with acute (pre-seroconversion) HIV infection will not be enrolled.  Signs and 
symptoms consistent with acute HIV infection will be included in the SSP Manual.   
Follow-up (after study Enrollment) 
 
Frequent testing for HIV acquisition during the study period will help prevent dosing with the 
investigational 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 an 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 IX. Samples 
from participants with confirmed HIV infection may be sent to a local laboratory for resistance 
testing to assist with clinical management; results from resistance testing performed in local 
laboratories will not be reported to the HPTN Statistical and Data Management Center (SDMC).  
The participant will not receive additional doses of study drug if they have a reactive or positive 
HIV test, even if further testing indicates that they do not have HIV infection.   
In the event that a participant has a reactive or positive HIV test at Week 2, 4, or 5, study product 
will be discontinued and the participant will be followed for an additional two visits - Weeks 17 
and 29 -  and will be terminated from the study at the Week 29 visit.  See the SSP Manual for 
details regarding the Week 17 and 29 visit procedures and specimens to be collected in the event 
of HIV infection during the oral phase.         
Participants who have a reactive or positive HIV test after Week 5 (that is, have had at least one 
injection) will not receive additional injections and will be followed per the appropriate Schedule 
of Evaluations and Procedures, on study, but off study product.   
For participants with confirmed HIV infection during follow-up, the treatment assignment will 
be provided to a subset of the CMC as outlined in the SSP Manual.  This is necessary due to the 
limited information available regarding the study product considering it is investigative in nature, 
and this subset of the CMC may assist the site with the appropriate follow-up care, including 
HIV treatment recommendations.   
Sites will have a standard operating procedure (SOP) that outlines a plan in the event that a 
participant becomes HIV infected during the study, to include the participant’s facilitation into 
immediate suppressive ART treatment to prevent persistent-monotherapy-related resistance 
complications for a minimum of 52 weeks post-final 744LA injection.  At the end of the 52 
weeks, participants will be transitioned to a local HIV care clinic where ART provision could be 
continued (if the participant desires to stay on ART). 
 


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Administration of PEP in cases of possible HIV exposure should be expedited at the site level.  
Such action should be simultaneously and immediately reported to the CMC for assistance with 
additional clinical and behavioral management plans, as well as decisions about further 
administration of study medication and follow-up schedules. 
 
5.22 Sexually Transmitted Infections 
Testing for GC/ CT in men (urine) and women (urine or vaginal swab), and syphilis will occur at 
Screening and approximately every 6 months – see Scheduled of Procedures and Evaluations.  
Testing will be performed at the local laboratory. Testing for GC/ CT in men and women (rectal 
swab), will occur at Enrollment and approximately every 6 months – see Schedule of Procedures 
and Evaluations.  At US sites, testing will be performed at the local laboratory. At non US sites, 
samples will be stored for non-real-time, batched testing at the HPTN LC or designated 
laboratory.    
 
Treatment for STIs will be referred for treatment as per local guidelines.  Symptomatic screening 
for STIs beyond what is required by the protocol will be at a site’s discretion.   
 
5.23 Pregnancy 
Because this is an investigational agent, receipt of study product by female study participants of 
reproductive potential requires use of an effective method of contraception as outlined in Section 
3.1.  All participants should also use male or female condoms for prevention of HIV and other 
sexually transmitted infections (STIs).  As needed, study staff will provide contraceptive 
counseling to enrolled participants throughout the duration of study participation and will 
facilitate access to contraceptive services through direct service delivery and/or active referrals to 
local service providers.  Study staff also will provide participants with male and/or female 
condoms and lubricant and counseling on use of condoms.   
Female participants of reproductive potential will have pregnancy testing performed as outlined 
in the Schedule of Evaluations and Procedures.  Participants will be encouraged to report all 
signs or symptoms of pregnancy to study staff.   
Any pregnancy that occurs during the course of a female participant’s participation in the study 
should be reported to the CMC upon site awareness (either upon confirming via urine pregnancy 
testing during a study visit or as reported by the participant between study visits).  In the event 
that a female participant has a positive pregnancy test at Weeks 2, 4, or 5, study product will be 
discontinued and the participant will be followed approximately every 12 weeks starting at the 
Week 17 visit until pregnancy outcome is reached.  Once pregnancy outcome is reached, the 
participant will be terminated from the study.  The CMC should be contacted regarding visit 
procedures and specimens to be collected at follow-up visits in the event of pregnancy during the 
oral phase.    
Participants who have a positive pregnancy test or report a desire to become pregnant at any 
other time point after Week 5 (that is, have had at least one injection) will not receive additional 
injections (regardless of pregnancy outcome) and will be followed per the appropriate Schedule 
of Evaluations and Procedures, on-study but off study product.   
The site IoR or designee will counsel any participants who become pregnant regarding possible 
risks to the fetus according to site-specific SOPs.  Participants may not enroll if they are 
currently breastfeeding and study product should be discontinued if any participant identifies that 
she is breastfeeding after enrollment.  The site IoR or designee also will refer the participant to 


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all applicable services; however, sites will not be responsible for paying for pregnancy-related 
care.   
Participants who are pregnant at their last study visit will continue to be followed (if they agree) 
until the pregnancy outcome is ascertained or it is determined that the pregnancy outcome cannot 
be ascertained.  All pregnancy outcomes will be reported on relevant Case Report Forms (CRFs).  
Outcomes meeting criteria for expedited adverse event (EAE) reporting also will be reported. 
5.24 Changes in Reported HIV/STI Risk Status During Follow-Up 
Changes in HIV and STI risk status (i.e., increase in risk) during the oral or injection phases of 
the study as reported by the participant upon interviewer-administered questionnaires or as 
deemed by the IoR upon history and physical exam, should be brought to the attention of the 
CMC in order to adjudicate the appropriateness of a) further dosing b) risk reduction counseling 
and/or c) referral for appropriate services (substance use, mental health, intimate partner 
violence).  No further study product should be administered from the time the site is made aware 
of the change in risk status until the CMC has provided guidance on appropriate management.        
 
5.25 Hepatitis B and Hepatitis C 
Testing for HBV will be performed at Screening (HBsAg, HBsAb, and HBcAb). Persons with a 
positive HBsAg test will be excluded from the study and will be referred to their primary 
provider for management. 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 HBV immunity at Screening, 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.   
HCV antibody testing will be performed at Screening.  Persons with a positive HCV antibody 
test will be excluded from the study.  Refer to the SSP Manual for persons who are isolated 
HBCAb positive.      
5.26 Interim Contacts and Visits 
Interim contacts and visits (those between regularly scheduled follow up visits) may be 
performed at participant request or as deemed necessary by the investigator or designee at any 
time during the study. All interim contacts and visits will be documented in participants’ study 
records and on applicable CRFs.  
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.   
5.27 Criteria for Early Termination of Study Participation 
Participants may voluntarily withdraw from the study for any reason at any time.  Site IoRs may, 
with the approval of the CMC, withdraw participants before their scheduled termination visit to 
protect their safety, and/or if participants are unable or unwilling to comply with study 
procedures.  Participants also may be withdrawn if the study sponsors, government or regulatory 
authorities (including the OHRP and US FDA), or site IRBs terminate the study prior to its 


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planned end date.  Study staff will record the reason(s) for all withdrawals in participants’ study 
records. 
5.28 Pharmacokinetics 
Cohort 1:  Blood samples will be collected during the oral lead-in phase of the study for 
determination of plasma concentrations of GSK1265744 following oral dosing.  Blood samples 
for PK analysis will also be collected starting on the first day of the first injection phase prior to 
the injection and every visit thereafter.  At each injection visit a blood sample will be collected 
prior to the injections at Weeks 5, 17 and 29, and one week post-injection at Weeks 6, 18, and 
30, and at week 41. The sample collected 12 weeks following each injection will serve as the 
pre-dose sample for the subsequent dosing interval (except for after the 3rd injection visit, i.e., the 
sample will be collected, but will not serve as a pre-dose sample because injections will be 
completed after the 3rd injection).  Two additional samples will be collected 4 and 8 weeks after 
the first injection (Weeks 9 and 13), and one additional sample will be collected 6 weeks 
following the second and third injections (Weeks 23 and 35).  PK samples will be collected 
during the oral phase at Week 2 and 4, and every 12 weeks at Weeks 35, 53, 65, 77 and 81 until 
participants reach 52 weeks post-third injection (these collections are modified for participants 
who receive less than three injections [see Appendices II and III]).   
Cohort 2:  Blood samples will be collected during the oral lead-in phase of the study for 
determination of plasma concentrations of GSK1265744 following oral dosing.  Blood samples 
for PK analysis will also be collected starting on the first day of the first injection phase prior to 
the injection and every visit thereafter, as indicated in Appendices IV-VIII.  At each injection 
visit a blood sample will be collected prior to the injections at Weeks 5, 9, 17, 25, and 33.  The 
sample collected 4 or 8 weeks following each injection will serve as the pre-dose sample for the 
subsequent dosing interval (except for after the 5rh injection visit, i.e., the sample will be 
collected, but will not serve as a pre-dose sample because injections will be completed after the 
5th injection).  Two additional samples will be collected 1 and 4 weeks after each of the four   
injections, beginning with the Week 9 injection (Weeks 10, 13, 18, 21, 26, 29, 34, 37). 
Additionally, a single PK sample will be obtained 1 week after the Week 5 loading dose (Week 
6). PK samples also will be collected during the oral phase at Week 2 and 4, and at follow-up 
phase visits (week 41, 53, 65, 77, and 85) until participants reach 52 weeks post-fifth injection 
(these collections are modified for participants who receive less than five injections [see 
Appendices V-VIII).   
The actual date and time of each blood sample collection will be recorded, as well as the time of 
each injection.  The timing of PK samples may be altered and/or PK samples may be obtained at 
additional time points to ensure thorough PK monitoring.  Details of PK blood sample collection 
(including volume to be collected), processing, storage and shipping procedures are provided in 
the SSP Manual. 
Concentrations of GSK1265744 will be determined in plasma using an approved, validated 
analytical methodology.  
 
 


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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 Laboratory Center (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, site 
clinicians, and the SDMC Clinical Affairs Safety Associate will serve as members of the CMC.  
The CMC provides support to site clinicians regarding individual participant clinical 
management (e.g., questions related to eligibility, toxicity management, clinical holds of study 
drug, permanent discontinuations, etc.).  In addition, for trials such as this with no DSMB 
oversight, the HPTN Study Monitoring Committee (SMC) may also review safety data in 
aggregate. 
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 (SMC reviews), 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 safety data by study arm 
(unblinded) during a closed meeting.  More frequent or ad hoc reviews of safety reports may be 
conducted by the SMC as needed.  A recommendation to stop the trial may be made by the SMC 
at any such time that the team agrees an unacceptable type and/or frequency of AEs has been 
observed. If at any time a decision is made to discontinue the study product in all participants, 
DAIDS will notify the US FDA, as well as the site IoRs, who will notify the responsible IRBs 
expeditiously. 
6.3 
Adverse Event Definition and Reporting 
An adverse event (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. 


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Study participants will be provided a 24-hour telephone number and contact information and 
instructed to contact the study clinician to report any AEs they may experience.  For life-
threatening events, they will also be instructed to seek immediate emergency care.  Where 
feasible and medically appropriate, participants will be encouraged to seek evaluation where the 
study clinician is based, and to request that the clinician be contacted upon their arrival.  With 
appropriate permission of the participant, whenever possible, records from all non-study medical 
providers related to AEs will be obtained and required data elements will be recorded on study 
CRFs.  All participants reporting an AE will be followed clinically, until the AE resolves (returns 
to baseline) or stabilizes. 
Study site staff will document in source documents and the appropriate CRF all AEs (Grade 1 
and higher) reported by or observed in enrolled study participants regardless of severity and 
presumed relationship to study product.  AE severity will be graded per the DAIDS Table for 
Grading Adult and Pediatric Adverse Events, Version 2.0, November 2014. This version will be 
used for the entire duration of the study.   
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 (or most current version) 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 (or latest version) of the DAIDS EAE Manual, which is available on the DAIDS 
Regulatory Support Center (RSC) website at http://rsc.tech-
res.com/safetyandpharmacovigilance.   
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.  For questions about DAERS, 
please contact DAIDS-ES at DAIDS-ESSupport@niaid.nih.gov.  Site queries may also be sent 
with the DAERS application itself. 
Where DAERS has not been implemented, sites will submit expedited AEs by documenting the 
information on the current DAIDS EAE form.  This form is available on the RSC website:  
http://rsc.tech-res.com/safetyandpharmacovigilance/.  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: 
 
 ALT≥3xULN AND total bilirubin≥2xULN (.must be both in order to require expedited 
reporting) 
 Any seizure event    
 


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These reporting requirements are required for each study participant from enrollment (week 0) 
until their follow-up in the study ends.  After this time, sites must report serious, unexpected, 
clinical suspected adverse drug reactions if the study site becomes aware of the event on a 
passive basis, i.e., from publicly available information.   
 
The study agents for the purposes of EAE reporting are GSK1265744 30 mg oral tablet or 
placebo and 744LA injectable suspension (200mg/mL) or placebo (also outlined in Section 4.1.). 
   
Grading Severity of Events 
 
The Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, 
Version 2.0, November 2014, will be used for the entire duration of the study for determining 
and reporting the severity of adverse events.  The DAIDS grading table is available on the 
DAIDS RSC website at http://rsc.tech-res.com/safetyandpharmacovigilance.   
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. 
6.5 
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 
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 2a, randomized, multi-site, two-arm, double-blinded study of the safety, 
tolerability, pharmacokinetics and acceptability of 744LA.  Eligible participants will be 
randomized 3:1, stratified by gender and region (US and non US sites), to receive GSK1265744 
or matching placebo, and placed into one of two cohorts.  Participants will receive daily 30 mg 
oral 744 tablets or matching placebo for 4 weeks, followed by a one-week washout period, to 
assess for safety and tolerability prior to receiving injections. Following clinical review of safety 
lab assessments from the oral regimen phase, participants will enter the injection phase and 
receive IM injections of 744LA or placebo at three time points at 12 week intervals (Cohort 1), 
or five time points at 4 and 8 week intervals (Cohort 2).  Participants in the active drug arms will 
be followed for 52 weeks following their last injection.  Participants in the placebo arms will be 
followed until 52 weeks after their last injection or until the last participant in the active study 
product arm of Cohort 2 completes their Week 41 visit, whichever comes first, at which time the 
cohorts will be unblinded to assess the primary endpoint.  When all procedures related to 
unblinding are completed, participants in the placebo arm will no longer be followed.    
Approximately 194 participants will be placed into two dose cohorts and will be randomized to 
one of the two study arms with an active GSK 744 to placebo ratio of 3:1, stratified by gender 
and region (US and non US), as follows: 
Cohort 1 
Arm 1:  Approximately 79 participants will receive daily oral 744 (30 mg tablets) for 4 weeks, 
followed by a one week washout period, to establish safety and tolerability, followed by intra-
muscular (IM) gluteal injections of 800 mg of 744LA (administered as two sequential 400 mg 
gluteal injections) at three time points at 12 week intervals as:  Week 5, Week 17, and Week 29.    
Arm 2:  Approximately 27 participants will receive daily oral matching placebo and IM 
injections of vehicle-matched placebo on the same schedule as Arm 1.   
Cohort 2 
Arm 1:  Approximately 66 participants will receive daily oral 744 (30 mg tablets) for 4 weeks, 
followed by a one week washout period, to establish safety and tolerability, followed by intra-
muscular (IM) gluteal injections of 600 mg of 744LA (administered as one 600 mg gluteal 
injection) at five time points at 4 and 8 week intervals as:  Week 5, Week 9, Week 17, Week 25, 
and Week 33.    
Arm 2:  Approximately 22 participants will receive daily oral matching placebo and IM 
injections of vehicle-matched placebo on the same schedule as Arm 1.   
7.1.1 Primary Endpoint 
Safety endpoint:  Proportion of participants experiencing any Grade 2 or higher clinical AEs and 
laboratory abnormalities that occur from the initial injection to Week 41 among participants who 
receive at least one injection (injectable phase only) 
Tolerability endpoint:  Proportion of participants who receive at least 1 injection and who 
discontinue receiving injections prior to the full course of injections due to intolerability of 
injection (including but not limited to ISR), frequency of injections, burden of study procedures, 
or any AE. 
These cohorts may be aggregated for an overall analysis if appropriate.   


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7.1.2 Secondary Endpoints 
The following endpoints will be analyzed by cohort and in aggregate, unless otherwise noted:  
 
 Proportion of participants who discontinue either oral or injectable study product for reasons 
of toxicity, tolerability, or acceptability prior to completion of the full oral and injectable 
phases 
 Proportion of participants experiencing Grade 2 or higher clinical AEs and laboratory 
abnormalities during 52 weeks following final injection (safety) and any AE that leads to 
discontinuation (tolerability) during the aggregate oral and injectable phases  
 Proportion of participants experiencing Grade 2 or higher clinical AEs and laboratory 
abnormalities (safety) and any AE that leads to discontinuation (tolerability) in the oral phase 
and washout period 
 Plasma drug levels of GSK1265744 at designated time points after each injection of 744LA 
(by cohort only) 
 Plasma drug levels of GSK1265744 at designated time points after each injection of 744LA 
stratified by age, gender, race, ethnicity, weight, BMI, and smoking status (by cohort only)  
 Proportion of participants willing to use an injectable agent such as the study product for 
HIV prevention in the future  
 Change from enrollment of self-reported sexual behavior (number of sexual partners, 
episodes of unprotected anal and/or vaginal intercourse) during the study period using a 
standardized assessment tool (in aggregate only) 
 Number of incident HIV infections through the study period, including number with  
treatment emergent resistance 
 Proportion of injectable hormonal-contraception-using female participants who reach a safety 
or tolerability endpoint as defined above 
7.1.3 Exploratory Endpoints 
 Relationships between observed AEs and pharmacokinetic parameters (including but not 
limited to GSK1265744 Cmax and Cmin and AUC) and participant demographic data  
(individual and in aggregate)  
 Relationships between pharmacogenetics (evaluated by Genome Wide Association Study 
[GWAS], which will inform subsequent targeted analyses) and pharmacokinetic parameters 
or incidence of AEs (any and by organ class and individual AE)    
7.2 
Sample Size 
It is expected that at least 168 (124 in 744LA and 44 in placebo) out of 194 participants (106 in 
Cohort 1 and 88 in Cohort 2) will complete the primary endpoint visit assuming that the annual 
retention rate is approximately 90% and the percentage of the participants who will not be 
advanced to the injection phase due to their elevated AST/ALT (grade ≥1) during the oral phase 
is 5% (at most according to ÉCLAIR data). The following power calculations are based on the 
sample size of 168 (124 in 744LA and 44 in placebo) for the combined two cohorts as well as the 
sample size of 67 in 744LA for Cohort 1 and 57 in 744LA for Cohort 2.    
The goal of the safety evaluation for this study is to identify safety concerns associated with 
744LA overall (combined Cohort 1 and Cohort 2) and 744LA in individual cohort (Cohort 1 or 
Cohort 2).  The ability of the study to detect SAEs (See Section 6.3) can be expressed by the true 
event rate above which at least 1 SAE would likely be observed and the true event rate below 


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which no events would likely be observed. Specifically, for the 744LA arm of the study (n 
=124), there is a 90% chance of observing at least 1 event if the true rate of such an event is 
1.9% or more, and there is a 90% chance of observing no events if the true rate is <0.01%.  For 
the placebo arm (n=44), there is a 90% chance of observing at least 1 event if the true rate of 
such an event is 5.1% or more, and there is a 90% chance of observing no events if the true rate 
is 0.2% or less.  
Probabilities of observing 0, 1 or more, and 2 or more events among the arms (N=168; 124 in 
744LA arm, and 44 in placebo arm) are presented in Table 3 for a range of true adverse event 
rates. These calculations provide a more complete picture of the sensitivity of this study design 
to identify potential safety concerns with 744LA.  
Table 3: Probability of observing 0 events, 1 or more events, and 2 or more events, among 
both arms in the combined cohorts: the 744LA arm (n=124) and the placebo arm (n=44), 
for different true event rates. 
True 
event rate 
(%) 
Pr(0/124) 
Pr(1+/124) 
Pr(2+/124) 
Pr(0/44) 
Pr(1+/44) 
Pr(2+/44) 
0.5 
53.7 
46.3 
12.8 
80.2 
19.8 
2.1 
1 
28.8 
71.2 
35.2 
64.3 
35.7 
7.2 
2.5 
4.3 
95.7 
81.9 
32.8 
67.2 
30.1 
5 
0.2 
99.8 
98.7 
10.5 
89.5 
65.3 
10 
<0.1 
>99.9 
>99.9 
1 
99 
94.3 
15 
<0.1 
>99.9 
>99.9 
0.1 
99.9 
99.3 
20 
<0.1 
>99.9 
>99.9 
<0.1 
>99.9 
99.9 
 
For the 744LA arm in Cohort 1 (n=67), there is a 90% chance of observing at least 1 event if the 
true rate of such an event is 3.4% or more, and there is a 90% chance of observing no events if 
the true rate is 0.1% or less.   For the 744LA arm in Cohort 2 (n=57), there is a 90% chance of 
observing at least 1 event if the true rate of such an event is 4% or more, and there is a 90% 
chance of observing no events if the true rate is 0.1% or less.    
Probabilities of observing 0, 1 or more, and 2 or more events among the 744LA arm in two 
cohorts (n1=67 and n2=57) are presented in Table 3a for a range of true adverse event rates. 
These calculations provide a more complete picture of the sensitivity of this study design to 
identify potential safety concerns with 744LA (in 800mg or 600mg dose).  
Table 3a: Probability of observing 0 events, 1 or more events, and 2 or more events, among 
the 744LA arm in two cohorts (n1=67 and n2=57)   
True 
event 
rate (%) 
Pr(0/67) 
Pr(1+/67) 
Pr(2+/67) 
Pr(0/57) 
Pr(1+/57) 
Pr(2+/57) 
0.5 
71.5 
28.5 
4.5 
75.1 
24.9 
3.3 
1 
51 
49 
14.5 
56.4 
43.6 
11.1 
2.5 
18.3 
81.7 
50.2 
23.6 
76.4 
41.9 
5 
3.2 
96.8 
85.4 
5.4 
94.6 
78.5 
10 
0.1 
99.9 
99.3 
0.2 
99.8 
98.2 
15 
<0.1 
>99.9 
>99.9 
0 
>99.9 
99.9 
20 
<0.1 
>99.9 
>99.9 
<0.1 
>99.9 
99.9 
 


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The primary safety endpoint is the proportion of participants experiencing any Grade 2 or higher 
clinical AEs and laboratory abnormalities that occur from the initial injection to 41 weeks among 
participants who receive at least one injection. The precision with which the true event rate can 
be estimated from the observed data depends on the underlying true event rate and the sample 
size.  Table 4 shows the two-sided 95% confidence intervals for the true event rate based on 
various values for the observed event rates, given the sample size of 124 in the 744LA arm and 
44 in the placebo arm in the combined cohorts. Calculations are done using the score test 
method.59  
Table 4. Two-sided 95% confidence intervals based on observing a particular rate of event 
for the 744LA arm (n=124) and the placebo arm(n=44) in the combined cohorts 
Observed Event 
Rate (%) 
95% CI (744LA arm) 
95% CI (Placebo arm) 
0 
(0, 3) 
(0, 8) 
2.5 
(0.8, 6.9) 
(0.4, 11.8) 
5 
(2.2, 10.2) 
(1.3, 15.1) 
10 
(5.6, 16.2) 
(3.6, 21.2) 
15 
(10, 22.7) 
(7.9, 29.4) 
20 
(14, 28.1) 
(11.2, 34.5) 
25 
(18.2, 33.3) 
(14.6, 39.4) 
 
Table 4a shows the two-sided 95% confidence intervals for the true event rate based on various 
values for the observed event rates, given the sample size of 67 in 744LA arm in Cohort 1 and 57 
in 744LA arm in Cohort 2. 
Table 4a. Two-sided 95% confidence intervals based on observing a particular rate of event 
for the 744LA arm in Cohort 1 (n=67) and Cohort 2 (n=57) 
Observed Event 
Rate (%) 
95% CI (744LA arm in 
Cohort 1) 
95% CI (744 LA arm in 
Cohort 2) 
0 
(0, 5.4) 
(0, 6.3) 
2.5 
(0.8, 10.2) 
(0.3, 9.3) 
5 
(1.5, 12.4) 
(1.8, 14.4) 
10 
(5.2, 20) 
(4.9, 21.1) 
15 
(8.3, 25.3) 
(8.5, 27.4) 
20 
(11.7, 30.4) 
(11.1, 31.3) 
25 
(16.5, 36.9) 
(15.2, 37.1) 
 
The safety and toxicity rates of participants using 744LA and the rates for those using placebo 
will not be formally compared. A sample size of 168 participants (124 in 744LA and 44 in 
placebo) in the combined cohorts assuming 90% retention rate per year will assure with 83% 
power that a 95% confidence interval for the difference between the study drug and placebo 
safety and toxicity rates has an upper limit no more than 10% when the true toxicity rates for 
744LA and placebo are both 5%. Table 5 displays two-sided 95% confidence interval for 
different assumptions on the safety and toxicity rates in the active product and placebo arms for a 
study of this sample size combined from the two cohorts.  


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Table 5: Two-sided 95% Confidence Intervals for the Difference between 744LA and 
Placebo Safety Rates (n=124 in the 744LA arm and n=44 in the placebo arm) 
Assumed rate 
in placebo arm 
Assumed rate in 744LA arm 
1% 
5% 
7.5% 
10.0% 
12.5% 
15.0% 
1% 
(-3.4, 3.4) 
(-0.8, 8.8) 
(1, 12) 
(3, 15) 
(5, 18) 
(7.1, 20.9) 
5% 
- 
(-7.5, 7.5) 
(-5.4, 10.4) 
(-3.3, 13.3) 
(-1.2, 16.2) 
(1, 19) 
7.5% 
- 
- 
(-9.1, 9.1) 
(-6.9, 11.9) 
(-4.7, 14.7) 
(-2.5, 17.5) 
10.0% 
- 
- 
- 
(-10.3, 
10.3) 
(-8.1, 13.1) 
(-5.9, 15.9) 
12.5% 
- 
- 
- 
- 
(-11.4, 
11.4) 
(-9.1, 14.1) 
15.0% 
- 
- 
- 
- 
- 
(-12.3, 
12.3) 
 
Tables 5a and 5b shows the two-sided 95% confidence interval for different assumptions on the 
safety and toxicity rates in the active product arm in each of two cohorts and the placebo arm 
combined from the two cohorts.   
Table 5a: Two-sided 95% Confidence Intervals for the Difference of Safety Rates between 
the 744LA arm in Cohort 1 (n=67) and the Placebo arm (combined from the 
placebo arms of both cohorts) (n=44) 
Assumed rate 
in placebo arm 
Assumed rate in 744LA arm 
1% 
5% 
7.5% 
10.0% 
12.5% 
15.0% 
1% 
(-3.8, 3.8) 
(-2, 10) 
(-0.5, 13.5) 
(1.2, 16.8) 
(3.1, 19.9) 
(5, 23) 
5% 
- 
(-8.3, 8.3) 
(-6.5, 11.5) 
(-4.6, 14.6) 
(-2.7, 17.7) 
(-0.7, 20.7) 
7.5% 
- 
- 
(-10, 10) 
(-8.1, 13.1) 
(-6.1, 16.1) 
(-4.1, 19.1) 
10.0% 
- 
- 
- 
(-11.4, 
11.4) 
(-9.4, 14.4) 
(-7.3, 17.3) 
12.5% 
- 
- 
- 
- 
(-12.6, 
12.6) 
(-10.5, 
15.5) 
15.0% 
- 
- 
- 
- 
- 
(-13.6, 
13.6) 
 
Table 5b Two-sided 95% Confidence Intervals for the Difference of Safety Rates between 
744LA arm in Cohort 2 (n=57) and the Placebo arm (combined from the placebo 
arms from both cohort) (n=44) 
Assumed rate 
in placebo arm 
Assumed rate in 744LA arm 
1% 
5% 
7.5% 
10.0% 
12.5% 
15.0% 
1% 
(-3.9, 3.9) 
(-2.4, 10.4) 
(-0.9, 13.9) 
(0.7, 17.3) 
(2.4, 20.6) 
(4.3, 23.7) 
5% 
- 
(-8.6, 8.6) 
(-6.9, 11.9) 
(-5.1, 15.1) 
(-3.2, 18.2) 
(-1.3, 21.3) 
7.5% 
- 
- 
(-10.4, 
10.4) 
(-8.5, 13.5) 
(-6.6, 16.6) 
(-4.6, 19.6) 
10.0% 
- 
- 
- 
(-11.8, 
11.8) 
(-9.8, 14.8) 
(-7.8, 17.8) 
12.5% 
- 
- 
- 
- 
(-13, 13) 
(-11, 16) 
15.0% 
- 
- 
- 
- 
- 
(-14, 14) 
 
The tolerability of 744LA will be measured by the proportion (with 95% CI) of participants who 
terminate from receiving injections prior to the full course due to AE, intolerability of injection, 
frequency of injections, or burden of procedures related to injections out of those participants 
that received at least one injection by treatment arm.  The values of Table 4 show (in addition to 


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confidence intervals for safety) two-sided 95% confidence intervals for the true tolerability rate 
based on various possible observed rates, given the sample size of 124 participants in the 744LA 
arm. Table 4a similarly also shows two-sided 95% confidence intervals for true tolerability rate 
based on various possible observed rates, given the sample size of 67 (57) participants in the 
744LA arm in Cohort 1 (Cohort 2). 
The acceptability of 744LA will be measured by the proportion (with 95% CI for the 744 LA 
arm) of participants who would consider using 744LA for HIV prevention in the future. This 
endpoint will be measured at the end of the study on every enrolled participant (including those 
who terminated product use during the trial). Table 6 shows two-sided 95% confidence intervals 
for true acceptance rate based on various possible observed rates, given the sample size of 124 
participants in the active 744LA arm from the two cohorts and the sample size of 67 and 57 
participants in the active 744LA arm in Cohort 1 and 2, respectively.   
Table 6: 95% Confidence Intervals for the True Acceptance Rate Given Possibly 
Observed Rates in the 744LA arm overall (n=124) and by cohort (n=67, 57) 
Observed Event 
Rate 
95% CI for True 
Event Rate 
(n=124) 
95% CI for 
True Event 
Rate (n=67) 
95% CI for 
True Event 
Rate (n=57) 
50% 
(41.3, 58.7) 
(39.1, 62.3) 
(36.6, 61.7) 
70% 
(61.6, 77.5) 
(58.3, 79.8) 
(57.3, 80.5) 
80% 
(71.9, 86) 
(69.6, 88.3) 
(68.7, 88.9) 
90% 
(83.8, 94.4) 
(80, 94.8) 
(78.9, 95.1) 
95% 
(89.8, 97.8) 
(87.6, 98.5) 
(85.6, 98.2) 
 
7.3 
Accrual, Follow-up, and Retention 
A total of approximately 194 participants will be enrolled in approximately 16 to 24 weeks for 
each cohort. Study participants will receive oral tablets for 4 weeks, followed by a 1 week wash 
out period, followed by receipt of injections at 3 time points (Cohort 1) or 5 time points (Cohort 
2) over 24 weeks.  Participants in the active drug arm will be followed for 52 weeks (12 months) 
after their last injection.  Participants in the placebo arm will be followed until 52 weeks after 
their last injection or until the last participant in the active study product arm completes their 
primary endpoint visit, whichever comes first, at which time the cohorts will be unblinded to 
assess the primary endpoint.  From that point on, placebo participants will no longer be followed. 
The protocol team will be targeting an average annual retention rate of 85-90 percent.  
 
7.4 
Random Assignment 
Enrolled participants will be randomized to one of two study arms with an active GSK1265744 
to placebo ratio of 3:1 in two cohorts.  The arm randomization will be stratified by gender and 
region (US and non-US sites) and done in blocks to ensure balanced treatment assignments 
within each gender and region in each cohort.  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. 
7.5 
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 last 
participant enrolled in to the active drug arm in both cohorts has completed their primary 
endpoint visit, and when all data related to the primary endpoint visit has been entered into the 
database, as well as cleaned and verified.  At a specified time directed by the HPTN SDMC, 


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participants will be unblinded to their treatment assignment, and participants in the placebo arm 
will no longer need to be followed.  Participants in the active study product arm will continued to 
be followed for 52 weeks after their last injection.  In addition, as noted in Section 5.21, an 
Investigator can request unblinding to the CMC in the event that a participant becomes infected 
with HIV during the study, and the CMC will assist in the treatment of the participant’s HIV 
infection. 
NOTE:  Samples may be unblinded in the HPTN Pharmacology Laboratory (only), so the 
relevant assays are only performed on participants who received the study product. 
7.6 
Data and Safety Monitoring Analysis 
7.6.1 Study Monitoring Committee 
Data and Safety Monitoring Board oversight is not planned for this study.  The HPTN SMC will 
conduct interim reviews of study progress, including rates of participant accrual, visit retention, 
completion of primary and main secondary endpoint collection, and, in a closed report, safety 
data by arm.  The frequency and content of SMC reviews will be determined prior to the start of 
the study and outlined in the SSP Manual.   
7.6.2 Primary Analyses 
All participants who receive at least one injection will contribute to the primary analyses.  The 
safety and tolerability will be analyzed by cohort and in aggregate.   
When the use of descriptive statistics to assess group characteristics or differences is required, 
the following methods will be used: for categorical variables, the number and percent in each 
category; for continuous variables, the mean, median, standard deviation, quartiles and range 
(minimum, maximum). Within-treatment group assessment of the change from the baseline 
measurement to a follow-up measurement will be analyzed using McNemar test (for categorical 
response variables) or the paired t-test or Wilcoxon signed-ranks test (for continuous variables).  
When use of formal testing to assess differences between users of the placebo arm and users of 
744LA is required, the following methods will be used: for binomial response variables, chi-
square tests and logistic regression (or exact testing methods); for continuous variables, t-tests 
and linear regression or nonparametric methods if data are non-normal.  


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To assess the adequacy of the randomization, participants in each of the two arms will be 
compared for baseline characteristics including demographics and laboratory measurements 
using descriptive statistics only. 
Safety Endpoints 
The primary safety analysis will include Grade 2 or higher clinical and laboratory events that 
occur from the initial injection to 12 weeks (Cohort 1) or 8 weeks (Cohort 2) after the last 
injection among participants who receive at least one injection.  Secondary safety analyses will 
include the same definition applied over the oral phase only (week 0 to week 5) and the 
aggregate oral+injectable+follow-up period. 
To assess safety, the number and the percent of participants experiencing each safety endpoint 
will be tabulated by study arm.  Each participant will contribute once in each category (for 
example, only for the highest severity AE for each participant) for the calculation of event rates.  
Exact binomial confidence intervals will be calculated for each safety endpoint for each arm and 
Fisher’s exact test used to test for differences in event rates between the two arms.  No formal 
treatment comparisons will be performed in this study, so any p-values that are calculated should 
only be used as a descriptive statistic. No formal multiple comparison adjustments will be 
employed for safety endpoints. 
Injection Site Reaction (ISR)  
The number and percentage of participants experiencing each type of injection site reaction sign 
or symptom will be tabulated by severity.  For a given sign or symptom, each participant’s ISR 
will be counted once under the maximum severity for all injection visits as well as by each 
successive injection. 
AEs  
AEs will be tabulated using MedDRA preferred terms.  The number and percentage of 
participants experiencing each specific AE (All AEs, Grade 2 or higher, and SAEs) will be 
tabulated by severity and by relationship to study product.  For the calculations in these tables, 
each participant’s AEs will be counted once as the maximum severity and relationship to study 
product.  AEs leading to temporarily or permanently stopping drug will also be summarized by 
treatment.  AEs will be summarized for those that are treatment emergent during LA dosing 
separately from those that are treatment emergent during oral dosing and also for those that are 
treatment emergent across the entire treatment phase of the study (combining both LA and oral 
dosing).   
A listing of EAEs reported to the DAIDS RSC Safety Office will provide details of the events 
including severity, relationship to study product, time between onset and last injection, number 
of injections received, and a summary of the event. 
Tolerability 
To assess tolerability, the number and the percent of participants who receive at least one 
injection and discontinue receiving injections prior to the full course due to intolerability of 
injection (including but limited to ISR), frequency of injections, or burden of procedures or any 
AE will be tabulated by study arm. Chi-square test will be used to compare the proportion of 
participants who terminated from receiving the full course of injections due to any of the above 
reasons between the two study arms. 


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7.6.3 Secondary Analyses 
Acceptability 
To assess acceptability of the 744LA, the proportion (with 95% CI for the 744LA arm) of 
subjects who would consider using 744LA for HIV prevention in the future will be calculated 
among all enrolled participants  (including those who terminated product use during the trial) and 
summarized by treatment arm. Acceptability will be assessed by cohort and in aggregate.     
A questionnaire modeled after the HIV Treatment Satisfaction Questionnaire (HIVTSQ) will 
also be used to assess participant acceptability and satisfaction to the treatment.  For each 
question the responses will be summarized by the proportion of participants reporting the 
response on the Likert scale out of all those that answered the question by visit and treatment 
arm.  An overall treatment satisfaction score will be calculated for each participant by visit.  
These total scores will be summarized by visit and treatment arm. 
Sexual Risk Behaviors 
 
Change in sexual risk behavior (number of sexual partners, episodes of unprotected anal and/or 
vaginal intercourse) during the injection phase will be measured by summarizing the change 
from baseline by visit and treatment arm.  Sexual risk behavior will be analyzed in aggregate.   
HIV Incidence 
HIV incidence rate will be calculated as the total number of participants with confirmed HIV 
infection during study follow-up divided by the person-years accumulated in each arm.  95% CIs 
will be calculated based on Poisson distribution assumptions.  HIV incidence will be assessed by 
cohort and in aggregate.   
Pharmacokinetics  
Plasma GSK1265744 concentration-time data will be analyzed by noncompartmental methods 
using WinNonlin Professional 5.2 or higher, Phoenix (Pharsight Corporation) or comparable 
software.  Individual plasma PK parameters for each injection interval will be determined, 
including:  area under the plasma concentration time curve over the dosing interval (AUC(0-)), 
maximum observed concentration (Cmax), time to maximum observed concentration (tmax), 
concentration at the end of the dosing interval (C), apparent terminal phase half-life for 744LA 
administration (t½) and lambda z as a measure of absorption rate constant (z) if data allow.  
Pharmacokinetics will be analyzed by cohort only.   
Descriptive statistics will be used to summarize GSK1265744 concentration by time and plasma 
PK parameters.  Unless stated otherwise, descriptive summaries will include n, mean, standard 
deviation (SD), coefficient of variation (%CV), median, minimum, and maximum for continuous 
variables, n and percent for categorical variables, and geometric mean, 95% confidence interval 
(CI), and the between-subject CV (%CVb) for the loge-transformed PK parameters. 
Accumulation of GSK1265744 will determined by using point estimates and confidence 
intervals for difference in least squares means for the comparisons of AUC(0-), Cmax, and C as 
follows: 
 


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Table 7: 
Summary of Comparisons of AUC(0-), Cmax, and C 
Comparison 
Test 
Reference 
Accumulation 
AUC(0-), the last injection (Week 
29-41 in Cohort 1, or Week 33-41 in 
Cohort 2) 
AUC(0-), the first injection 
(Week 
5-17 in Cohort 1) and the second 
injection (Week 9-17 in Cohort 2) 
Cmax, last injection 
Cmax, first injection 
C, the injection (Week 41 for both 
cohorts) 
C, the first injection (in Cohort 
1) or the second injection (in 
Cohort 2) (Week 17) 
 
The difference in pharmacokinetic parameters, AUC(0-), Cmax, and C, between the two 
different time points will be tested using paired t-test if the data or log transferred data appear to 
be normally distributed and using Wilcoxon signed rank test if the data or log transferred data are 
not normally distributed.   
Time to steady state will be assessed by comparing plasma concentration at Week 41 (C 
following the last injection) to previous C concentrations at Weeks 17 and 29 in Cohort 1, or 
previous C concentrations at Week 17, 25, and 33 in Cohort 2.  This may be accomplished by 
visual inspection of graphical data or by calculating the point estimate and confidence interval 
for the slope for log(C) by injection visit and cohort.    
Injectable Hormonal Contraception Usage 
Safety and Tolerability analyses described above will be performed on the subset of female 
participants who self-report the use of injectable hormonal-based contraception at study entry or 
at any time during the study period.  Proportions of such women meeting safety or tolerability 
endpoints will be compared a) across study arms b) to women in the active study arm who are do 
not report the use of injectable hormonal contraception c) to the overall study population 
randomized to active GSK1265744.  
7.6.4 Exploratory Analyses 
Pharmacokinetics/Pharmacodynamics 
 
The relationship between GSK1265744 PK parameters and demography (age, gender, race, 
ethnicity, weight, BMI, smoking status) or PD endpoints (conversion to HIV-infected status, 
safety parameters) may be explored. 
Pharmacogenomic Analysis 
 
Specific genes may be studied that encode the drug targets, drug mechanism of action pathways, 
drug metabolizing enzymes, or drug transporters or which may underpin AEs, disease risk, or 
pharmacokinetics or drug response. These candidate genes may include a common set of 
absorption, distribution, metabolism, and excretion genes that are studied to determine the 
relationship between gene variants and pharmacokinetics or safety parameters. In addition, future 
research may identify other enzymes, transporters, proteins, or receptors that may be involved in 
response to GSK1265744.  The genes that may code for these proteins may also be studied.  
Results of any pharmacogenomics investigations performed will be reported either as part of the 
main clinical study report or as a separate report. A detailed description of any analysis elected to 
be performed will be documented in the study statistical analysis plan or in a separate 
pharmacogenomics statistical analysis plan, as appropriate. 


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7.6.5 Interim Analysis/Interim Meta-Analysis 
An interim analysis will be performed when 50% of the participants have completed their 
primary endpoint visit (Week 41). All data available at that time will be included in the analysis. 
Pharmacokinetic data will be analyzed when approximately 50% of Cohort 1 reaches Week 29 
(two troughs) for Cohort 1 participants, and when approximately 50% of Cohort 2 reaches Week 
17 (two troughs) for Cohort 2. For the interim analysis, unblinded summaries from the analysis 
will be provided to others as pre-specified by the HPTN SMC and to the US FDA.  All members 
of the protocol team, including GSK and ViiV Healthcare, as well as study participants will 
remain blinded to individual participant treatment assignment.  The data from this analysis may 
also be combined with the interim data from a similar study being conducted by GSK, if needed 
and appropriate.  Pooled summaries will also be provided to the study team to share with 
regulators.  Specifics regarding study monitoring by the SMC and provision of data summaries, 
their review, and the estimated timing and guidance that will be used to determine regimen safety 
will be determined by the HPTN SMC, Protocol Chair, and ViiV Healthcare.  Additional ad-hoc 
pharmacokinetic analyses, as required to inform regulatory interactions, may be conducted.      
 
 


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8.0 
HUMAN SUBJECTS CONSIDERATIONS 
8.1 
Ethical Review 
This protocol and the template informed consent form contained in Appendix XII and XIII — 
and 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 XII and XIII that describes the purpose of the study, the procedures to be followed, 
and the risks and benefits of participation, in accordance with all applicable regulations.  If 
applicable, the study site also is responsible for translating the template form into local 
languages, and verifying the accuracy of the translation by performing an independent back-
translation. 
Participants will document their provision of informed consent by signing their informed consent 
forms.  (Further details regarding DAIDS requirements for documenting the informed consent 
process can be found in the DAIDS Standard Operating Procedure for Source Documentation.)   
All participants will be offered a copy of their informed consent form. 
8.3 
Incentives 
Pending IRB approval, participants will be compensated for their time and effort in this study, 
and/or be reimbursed for travel to study visits and time away from work. Site-specific 
reimbursement amounts will be specified in the study informed consent forms. 
8.4 
Confidentiality 
All study-related information will be stored securely at the study site.  All participant 
information will be stored in locked file cabinets in areas with access limited to study staff.  All 
laboratory specimens, reports, study data collection, process, and administrative forms will be 
identified by a coded number only to maintain participant confidentiality.  All records that 
contain names or other personal identifiers, such as locator forms and informed consent forms, 
will be stored separately from study records identified by code number.  All local databases will 
be secured with password-protected access systems.  Forms, lists, logbooks, appointment books, 
and any other listings that link participant ID numbers to other identifying information will be 
stored in a separate, locked file in an area with limited access. 


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Participant’s study information will not be released without the written permission of the 
participant, except as necessary for monitoring by the NIAID and/or its contractors; GSK and 
ViiV Healthcare; representatives of the HPTN LOC, SDMC, and/or LC; the US FDA, OHRP, 
other government and regulatory authorities, 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. 
 
 


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9.0 
LABORATORY SPECIMENS AND BIOHAZARD CONTAINMENT 
Laboratory procedures are described below, Appendices I-VIII, and Section 5.0; additional tests 
to be performed at a subsequent visit for participants who have a reactive or positive HIV test 
result are described in Appendix IX. 
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 hepatitis B surface antigen (HBsAg), hepatitis B 
surface antibody (HBsAb), hepatitis B core antibody (HBcAb) and hepatitis C antibody 
(HCV) tests   
 CBC with differential and platelets 
 Chemistry testing (BUN/urea, Na, K, Cl, CO2, CPK, creatinine, total protein, glucose, 
calcium, phosphorous, amylase, lipase, magnesium) 
 LFTs (AST, ALT, total and direct bilirubin, alkaline phosphatase) 
 Fasting lipid profile (total cholesterol, HDL, triglycerides, LDL – calculated or measured 
(participants should be fasting for at least 8 [preferably 12] hours prior to sample 
collection) 
 Syphilis serologic testing (men and women) 
 Urine for GC/CT testing for men and women. (may be replaced with a vaginal swab in 
women if desired) 
 Urinalysis (protein and glucose) 
 Urine test for pregnancy* 
 Rectal swabs for GC/CT for men and women (for non-US sites, batch and ship to the 
HPTN LC; for US sites, testing will be performed locally) 
 Plasma storage 
 Plasma storage for Pharmacology testing 
 Sample 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) 
 Following a positive or reactive HIV test result:  HIV viral load, CD4 cell count, HIV 
resistance testing at a local laboratory (real-time resistance testing for clinical 
management is optional, at the site’s discretion), plasma storage. 
If the HIV testing algorithm includes HIV rapid testing, that testing may be performed in the 
clinic or laboratory. Urine pregnancy testing may be performed in the clinic or the laboratory. 
*All women of reproductive potential will have a urine βHCG test for pregnancy (sensitivity of ≤ 
25 mIU/mL) at each visit. Pregnancy testing is not required at subsequent visits if a woman had a 
positive pregnancy test at a previous visit and is still pregnant. 
Each study site will adhere to standards of good laboratory practice, the HPTN LC Manual, the 
SSP and local SOPs for proper collection, processing, labeling, transport, and storage of 
specimens to the local laboratory.  Specimen collection, testing, and storage at the local 
laboratory will be documented using the HPTN Laboratory Data Management System (LDMS) 
as described in the SSP Manual. 
All specimens will be shipped in accordance with International Air Transport Association 
(IATA) specimen shipping regulations.  All shipments will be documented using the HPTN 
LDMS as described in the SSP Manual. 


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9.2 
Stored Specimens 
As described in Section 5.0, and indicated in Appendices I-VIII, plasma will be stored at the 
local site at every visit.  In addition, blood samples will be stored at the Enrollment visit for 
participants who consent to 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 US 
laboratory designated by the HPTN LC.  Rectal swab samples may also be shipped to the HPTN 
LC for testing.  The HPTN LC may ask sites to store other specimen types for STI testing at the 
HPTN LC if the site is not able to perform the testing.     
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) and the exception for resistance test results, noted below.  
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.  If real-time resistance 
testing is needed for clinical management, that testing should be arranged by the site outside of 
the study; separate specimens should be collected for that testing. For sites that do not have the 
capacity for local resistance testing for clinical care, results from resistance testing may be 
provided at the end of the study at the request of the site IoR, with approval of the HPTN LC and 
Protocol Chair. Results from specialized resistance testing (e.g., minority variants analysis, if 
performed) will not be returned to study sites. 
Pharmacology 
 
Plasma samples for drug levels will be collected beginning at Week 2 through and including the 
last study visit at Week 81 (Cohort 1) and Week 85 (Cohort 2).  These samples will collected 
from all participants, although PK testing may be limited to a subset of the samples.  
Plasma 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 in the HPTN Pharmacology Laboratory (only), so the 
relevant assays are only performed on participants who received the study product. 
Stored plasma may also be tested for the presence of other ARV drugs or other substances. 
Pharmacogenomics 
 
Blood samples collected for Pharmacogenomic testing will be analyzed for genetic 
polymorphisms associated with study drug exposure.  Assays will be performed at the HPTN 
LC.  Sites may choose to opt out of this testing. For sites that do allow this testing, results will 
not be returned to the sites or study participants. 


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GC/CT Rectal Swab Storage (Non US Sites Only) 
 
Testing for GC/CT in men and women (rectal swab), will occur at scheduled visits 
approximately every 6 months.  At US sites, testing will be performed at the local laboratory. At 
non-US sites, samples will be stored for non-real-time, batched testing at the HPTN LC or 
designated laboratory.   
 
9.3 
Quality Control and Quality Assurance Procedures 
Study sites will document that their laboratories are certified under the Continuous Laboratory 
Improvement 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 
be determined by 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 chemistry, LFT, lipid profile, hematology, urinalysis and 
pregnancy testing as indicated in Appendices I-VIII.  Non-US laboratories performing these tests 
must demonstrate successful participation in the relevant EQA programs as deemed appropriate 
by the HPTN LC. 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 IX. Non-
US laboratories performing these tests will be monitored by the DAIDS Immunology Quality 
Assurance (IQA) program and United Kingdom National External Quality Assessment Service 
(UKNEQAS) 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 IX or 
for evaluation of possible acute HIV infection.  Non-US laboratories performing these tests will 


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be monitored by the DAIDS Virology Quality Assurance (VQA) program and must demonstrate 
successful participation in this program.  Alternately HIV RNA/viral load testing for clinical 
purposes can be done per local standard of care. US sites must use CLIA-certified laboratories; 
participation in the VQA program is recommended. For participants who become HIV infected, 
HIV RNA/viral load analysis will be performed retrospectively at the HPTN LC; results from 
this testing will not be returned to study sites or participants. 
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 and the primary research paper has 
been published.  
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. 
  
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 http://rsc.tech-res.com/protocolregistration/. 
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 some cases the Division of AIDS 
has provided activation approval via email, which is also acceptable documentation of 
activation.) 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 GlaxoSmithKline 
and ViiV Healthcare for cross-referencing with the company’s other INDs for the study 
product(s). Assignment of all sponsor responsibilities for this study will be specified in a Clinical 
Trials Agreement executed by DAIDS and ViiV Healthcare. 
Study implementation will be directed by this protocol as well as the SSP Manual. The SSP 
Manual, which will include links to the DAIDS SOPs for Source Documentation and Essential 
Documents, as well as links to the Manual for Expedited Reporting of 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.   


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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 HPTN SDMC DataFax 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 Study Monitoring Committee.  The CMC (as described in Section 
6.1) 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, site IRBs/ECs, and US regulatory 
authorities (OHRP and US FDA). 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. 
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.  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. 
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, and ViiV Healthcare, for review prior to submission. 


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APPENDICES I-XIII 


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Appendix I: Schedule of Procedures and Evaluations – For Participants Who Complete All Three Injections in Cohort 1  
 
Screen 
Oral Phase 
1-WEEK WASHOUT 
Injection And Tail Phase Follow-up 
Day 
0 
Enr 
Week 
2 
Safety 
Week 4 
Post 
Oral 
Drug 
Week 
5 
First 
Injection 
Week 
6, 9, 
13 
Safety 
Week 
17 
Second 
Injection 
Week 
18, 23 
Safety 
Week 
29 
Third 
Injection 
Week 
30, 35 
Safety 
Week 41 
Primary 
Endpoint 
Week 
53, 65, 
77 
Tail 
Phase 
Week 
81 
Final 
Visit 
ADMINISTRATIVE, BEHAVIORAL, REGULATORY 
 
 
Informed consent  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Locator information 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Demographic information 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
HIV counseling  
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Offer condoms and lubricant  
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Acceptability assessments (Weeks 0,  
6, 18, 30 only)15 
 
X 
 
 
 
 
X 
 
X 
 
X 
 
 
 
Behavioral assessment 
 
X 
 
 
 
X 
 
X 
 
X 
 
X 
X 
 
Adherence counseling/pill count1 
 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
AUDIT questionnaire 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
CLINICAL EVALUATIONS & PROCEDURES 
 
 
History (including bleeding history 
at Screening), con meds, physical 
exam2 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CNS symptom assessment 
 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECG3 
X 
X 
 
X 
 
 
X 
 
X 
 
X 
 
 
 
Blood collection 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urine collection for GC/CT testing 
men and women5 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
Urine collection for urinalysis 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
Urine pregnancy testing4 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
Rectal swab for GC/CT testing men 
and women5 
 
X 
 
 
 
 
 
 
 
X 
 
 
X 
 
Vaginal swab for GC/CT testing5  
(Optional alternate collection for 
women if urine not used) 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
Provide oral study drug  
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Administer injection6  
 
 
 
 
 
X 
 
X 
 
X 
 
 
 
 
ISR evaluation 
 
 
 
 
 
 
X 
 
X 
 
X 
 
 
 
LOCAL LABORATORY EVALUATIONS & PROCEDURES 
 
 
HIV testing7 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HBV and HCV testing8 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
CBC with differential 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
 


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Screen 
Oral Phase 
1-WEEK WASHOUT 
Injection And Tail Phase Follow-up 
Day 
0 
Enr 
Week 
2 
Safety 
Week 4 
Post 
Oral 
Drug 
Week 
5 
First 
Injection 
Week 
6, 9, 
13 
Safety 
Week 
17 
Second 
Injection 
Week 
18, 23 
Safety 
Week 
29 
Third 
Injection 
Week 
30, 35 
Safety 
Week 41 
Primary 
Endpoint 
Week 
53, 65, 
77 
Tail 
Phase 
Week 
81 
Final 
Visit 
Chemistry testing9 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
 
LFTs (AST, ALT, total bilirubin, [at 
screening only, direct bilirubin in 
addition to total] alkaline 
phosphatase) 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Fasting lipid profile10  
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
Syphilis serologic testing men and 
women5 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
Urine/ vaginal swab GC/CT testing 
men and women5 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
Rectal swab GC/CT testing5 
 
X 
 
 
 
 
 
 
 
X 
 
 
X 
 
Urinalysis11 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
Plasma storage12 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Plasma storage for Pharmacology 
testing13   
 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Sample storage for 
Pharmacogenomic testing14 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
FOOTNOTES FOR APPENDIX I 
1 Adherence counseling will be performed at Day 0 and Week 2; pill counts will be performed at Week 2 and 4. 
2 Targeted history and physical exam for ascertainment of eligibility at Screening, including a bleeding history at Screening; complete history and physical exam at Enrollment only; targeted history and physical exam at all 
other follow-up visits.  Refer to the SSP Manual for procedures and evaluations included in the targeted and full physical exams.  Sites may perform the complete physical exam and history required at Enrollment during 
Screening per the discretion of the IoR or designee.  
3 A 12-lead ECG will be performed at Screening, Enrollment, and Weeks 4, 6, 9, 23, and 35.   
4 Urine pregnancy testing is required for women of reproductive potential only. The assay used must have sensitivity of ≤25 mIU/mL βHCG. At the oral dosing visits (Day 0, Week 2 and Week 4) and injection visits (Weeks 
5, 17, and 29), a urine pregnancy test must be performed and pregnancy must be ruled out PRIOR to administering the study product. Urine pregnancy testing may be performed in the clinic or the laboratory. Pregnancy 
testing is not required if a positive result was obtained at a prior visit and the participant is still pregnant.  Refer to the SSP Manual for instructions regarding follow-up of participants with a positive pregnancy test result at 
Weeks 2, 4, or 5; also see Section 5.23 of the protocol.    
5 Refer to the SSP Manual for details regarding STI testing. STI testing (urine and/or vaginal swab for GC/CT, syphilis testing), will be performed at Screening and Weeks 29 and 53.  Rectal swabs for GC/CT will be 
performed at enrollment (or for US sites, at screening per IoR discretion) and weeks 29 and 53. For non-US sites, rectal swabs will be batched and shipped to the HPTN LC for testing (see SSP Manual); for US sites, testing 
will be performed locally.   
6 Administer injection with counseling, including review of prohibited medications, after confirmation of negative pregnancy and HIV testing per SSP. 
7 The HIV testing algorithm 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.  Participants who have one or more 
reactive or positive HIV test result (any assay) at Screening or Enrollment are not eligible to participate in the study, even if they are confirmed to be HIV-uninfected. Additional testing is required for participants who have a 
reactive or positive HIV test after Enrollment (see Appendix 1X and the SSP Manual). In all cases, HIV acquisition after Enrollment must be confirmed using two specimens collected on different dates (see SSP Manual). 
HIV testing does not need to be performed after confirmation of HIV infection (based on results from samples collected on two separate dates).  Refer to SSP Manual for instructions regarding follow-up for participants who 
have a reactive or positive HIV test at Weeks 2, 4 or 5; also see Section 5.21 of the protocol.   
8Testing for hepatitis B virus (HBV) and hepatitis C virus (HCV) includes hepatitis B surface antigen (HBsAg), hepatitis B surface antibody (HBsAb), hepatitis B core antibody (HBcAb), and hepatitis C antibody (HCAb).   


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9 Chemistry testing includes: BUN, urea, Na, K, Cl, CO2, CPK, creatinine, total protein, glucose, calcium, phosphorous, amylase, lipase, and magnesium. 
10 The fasting lipid profile includes 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. 
11 Urinalysis includes protein and glucose; this testing may be performed in the clinic or the laboratory.  Results from urinalysis are not needed prior to enrollment. 
12 Stored plasma will be used for Quality Assurance testing at the HPTN LC and for other assessments described in Section 9.2. These assessments will be performed retrospectively; results will not be returned to study sites 
or participants, except as noted in Section 9.2.  
13 Plasma samples collected for Pharmacology testing at Weeks 5, 17, and 29 must be drawn PRIOR to injection of study product.   Refer to the SSP Manual). 
14 Specimens will be stored at Enrollment for Pharmacogenomic testing only at sites that opt to include this testing (See SSP Manual for further details). 
15 All acceptability assessments may not be performed at all sites.  The assessments are listed below.  Also, refer to Section 9 and 11 of the SSP Manual.      
 
Baseline Acceptability Questionnaire – Enrollment 
 
Follow-Up Acceptability Questionnaire – Weeks 6, 18, and 30 
 
Study Medication Satisfaction Questionnaire – Weeks 6, 18, and 30 
 
Study Medication Satisfaction Change Questionnaire – Week 18 only 
 
Behavioral Questionnaire – Enrollment and Weeks 5, 17, 29, 41, 53, 65, and 77 


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Appendix II: Schedule of Procedures and Evaluations – For Participants Who Complete Two Injections Only in Cohort 1 
 
Injection And Tail Phase Follow-up 
Week 5 
First  
Injection 
Week 
6, 9, 13 
Safety 
Week 17 
Second 
Injection 
Week 18, 
23 
Safety 
Week 29 
Follow Up 
Week 41 
Follow Up 
Week 53 
Follow Up 
Week 65 
Follow Up 
Week 69 
Final 
ADMINISTRATIVE, BEHAVIORAL, REGULATORY 
Locator information 
X 
X 
X 
X 
X 
X 
X 
X 
 
HIV counseling  
X 
X 
X 
X 
X 
X 
X 
X 
X 
Offer condoms and lubricant  
X 
X 
X 
X 
X 
X 
X 
X 
X 
Acceptability assessment (Week 6 
and 18 only)15 
 
X 
 
X 
 
 
 
 
 
Behavioral assessment 
X 
 
X 
 
X 
X 
X 
X 
 
CLINICAL EVALUATIONS & PROCEDURES 
History, con meds, physical exam2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CNS symptom assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECG3 
 
X 
 
X 
 
 
 
 
 
Blood collection 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urine collection for GC/CT testing 
men and women5  
 
 
 
 
X 
 
X 
 
 
Urine collection for urinalysis11 
 
 
 
 
 
X 
 
 
 
Urine pregnancy testing 4 
X 
 
X 
 
X 
X 
X 
X 
X 
Rectal swab for GC/CT testing 
men and women5 
 
 
 
 
X 
 
X 
 
 
Vaginal swab for GC/CT testing5 
(Optional alternate collection for 
women if urine not used) 
 
 
 
 
X 
 
X 
 
 
Administer injection6 
X 
 
X 
 
 
 
 
 
 
ISR evaluation 
 
X 
 
X 
 
 
 
 
 
LOCAL LABORATORY EVALUATIONS 
HIV testing7 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CBC with differential 
X 
X 
X 
X 
X 
X 
 
 
 
Chemistry testing9 
X 
X 
X 
X 
X 
X 
 
 
 
LFTs (AST, ALT, total bilirubin, 
alkaline phosphatase) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Fasting lipid profile10 
 
 
 
 
 
X 
 
 
 


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Injection And Tail Phase Follow-up 
Week 5 
First  
Injection 
Week 
6, 9, 13 
Safety 
Week 17 
Second 
Injection 
Week 18, 
23 
Safety 
Week 29 
Follow Up 
Week 41 
Follow Up 
Week 53 
Follow Up 
Week 65 
Follow Up 
Week 69 
Final 
Syphilis serologic testing men and 
women5 
 
 
 
 
X 
 
X 
 
 
Urine/vaginal swab GC/CT testing 
men and women5 
 
 
 
 
X 
 
X 
 
 
Urinalysis11 
 
 
 
 
 
X 
 
 
 
Plasma storage12 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Plasma storage for Pharmacology 
testing13   
X 
X 
X 
X 
X 
X 
X 
X 
X 
SEE FOOTNOTES FOR APPENDIX I 
 
 


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Appendix III: Schedule of Procedures and Evaluations – For Participants Who Complete One Injection Only in Cohort 1 
 
Injection And Tail Phase Follow-up 
Week 5 
First 
Injection 
Week 6, 9, 13 
Safety 
Week 17 
Follow Up 
Week 29 
Follow Up 
Week 41 
Follow Up 
Week 53 
Follow Up 
Week 57 
Final 
Visit 
ADMINISTRATIVE, BEHAVIORAL, REGULATORY 
Locator information 
X 
X 
X 
X 
X 
X 
X 
HIV counseling  
X 
X 
X 
X 
X 
X 
X 
Offer condoms and lubricant  
X 
X 
X 
X 
X 
X 
X 
Tolerability/Acceptability 
Assessment  (Week 6 only)15 
 
X 
 
 
 
 
 
Behavioral assessment 
X 
 
X 
X 
X 
X 
 
CLINICAL EVALUATIONS & PROCEDURES 
History, con meds, physical exam2 
X 
X 
X 
X 
X 
X 
X 
CNS symptom assessment 
X 
X 
X 
X 
X 
X 
X 
ECG3 
 
X 
 
 
 
 
 
Blood collection 
X 
X 
X 
X 
X 
X 
X 
Urine collection for GC/CT testing 
men and women5 
 
 
 
X 
 
X 
 
Urine collection for urinalysis11 
 
 
 
 
X 
 
 
Urine pregnancy testing4 
X 
 
X 
X 
X 
X 
X 
Rectal swab for GC/CT testing men 
and women5 
 
 
 
X 
 
X 
 
Vaginal swab for GC/CT testing5   
(Optional alternate collection for 
women if urine not used) 
 
 
 
X 
 
X 
 
Administer injection6 
X 
 
 
 
 
 
 
ISR Evaluation 
 
X 
 
 
 
 
 
LOCAL LABORATORY EVALUATIONS 
HIV testing7 
X 
X 
X 
X 
X 
X 
X 
CBC with differential 
X 
X 
X 
X 
X 
 
 
Chemistry testing9 
X 
X 
X 
X 
X 
 
 
LFTs (AST, ALT, total bilirubin, 
alkaline phosphatase) 
X 
X 
X 
X 
X 
X 
X 
Fasting lipid profile10 
 
 
 
 
X 
 
 


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Injection And Tail Phase Follow-up 
Week 5 
First 
Injection 
Week 6, 9, 13 
Safety 
Week 17 
Follow Up 
Week 29 
Follow Up 
Week 41 
Follow Up 
Week 53 
Follow Up 
Week 57 
Final 
Visit 
Syphilis serologic testing men and 
women5 
 
 
 
X 
 
X 
 
Urine/vaginal swab GC/CT testing 
men and women5 
 
 
 
X 
 
X 
 
Rectal swab GC/CT testing5 
 
 
 
X 
 
X 
 
Urinalaysis11 
 
 
 
 
X 
 
 
Plasma storage12 
X 
X 
X 
X 
X 
X 
X 
Plasma storage for Pharmacology 
testing13   
X 
X 
X 
X 
X 
X 
X 
SEE FOOTNOTES FOR APPENDIX I 
 
 


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Appendix IV: Schedule of Procedures and Evaluations – For Participants Who Complete All Five Injections in Cohort 2  
 
Screen 
Oral Phase 
1-WEEK WASHOUT 
Injection And Tail Phase Follow-up 
Day 
0 
Enr 
Wk 2 
Safety 
Week 4 
Post 
Oral 
Drug 
Wk 5  
1st 
Inj 
Wk 
 6 
Safety 
Wk 
 9 
2nd 
Inj  
Wk  
10, 13 
Safety 
Wk  
17 
3rd 
Inj 
Wk 
18, 21 
Safety 
Wk 
25 
4th 
Inj 
Wk 
26, 29 
Safety 
Wk 
33 
5th 
Inj 
 
Wk 
34, 37 
Safety 
Wk 41  
1o 
Endpt 
Wk 
53, 
65, 
77 
Tail  
Wk 
85 
Final 
Visit 
ADMINISTRATIVE, BEHAVIORAL, REGULATORY 
Informed consent  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Locator information 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Demographic information 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HIV counseling  
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Offer condoms and lubricant  
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Acceptability assessments 
(Weeks 0,  6, 10, 18, 26, and 
34 only)15 
 
X 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
Behavioral assessment 
 
X 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
Adherence counseling/pill 
count1 
 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AUDIT questionnaire 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CLINICAL EVALUATIONS & PROCEDURES 
History (including bleeding 
history at Screening), con 
meds, physical exam2 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CNS symptom assessment 
 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECG3 
X 
X 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
Blood collection 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urine collection for GC/CT 
testing men and women5 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
Urine collection for urinalysis 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Urine pregnancy testing4 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
Rectal swab for GC/CT 
testing men and women5 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
Vaginal swab for GC/CT 
testing5  (Optional alternate 
collection for women if urine 
not used) 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
Provide oral study drug  
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Administer injection6  
 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
ISR evaluation 
 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 


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Screen 
Oral Phase 
1-WEEK WASHOUT 
Injection And Tail Phase Follow-up 
Day 
0 
Enr 
Wk 2 
Safety 
Week 4 
Post 
Oral 
Drug 
Wk 5  
1st 
Inj 
Wk 
 6 
Safety 
Wk 
 9 
2nd 
Inj  
Wk  
10, 13 
Safety 
Wk  
17 
3rd 
Inj 
Wk 
18, 21 
Safety 
Wk 
25 
4th 
Inj 
Wk 
26, 29 
Safety 
Wk 
33 
5th 
Inj 
 
Wk 
34, 37 
Safety 
Wk 41  
1o 
Endpt 
Wk 
53, 
65, 
77 
Tail  
Wk 
85 
Final 
Visit 
LOCAL LABORATORY EVALUATIONS & PROCEDURES 
HIV testing7 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HBV and HCV testing8 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CBC with differential 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Chemistry testing9 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
LFTs (AST, ALT, total 
bilirubin, [at screening only, 
direct bilirubin in addition to 
total] alkaline phosphatase) 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Fasting lipid profile10  
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Syphilis serologic testing men 
and women5 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
Urine/ vaginal swab GC/CT 
testing men and women5 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
Rectal swab GC/CT testing5 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
Urinalysis11 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Plasma storage12 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Plasma storage for 
Pharmacology testing13   
 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Sample storage for 
Pharmacogenomic testing14 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
FOOTNOTES FOR APPENDIX IV 
1 Adherence counseling will be performed at Day 0 and Week 2; pill counts will be performed at Week 2 and 4. 
2 Targeted history and physical exam for ascertainment of eligibility at Screening, including a bleeding history at Screening; complete history and physical exam at Enrollment only; targeted history and physical exam at all 
other follow-up visits.  Refer to the SSP Manual for procedures and evaluations included in the targeted and full physical exams.  Sites may perform the complete physical exam and history required at Enrollment during 
Screening per the discretion of the IoR or designee.  
3 A 12-lead ECG will be performed at Screening, Enrollment, and Weeks 4, 6, 13, 21, 29, and 37 
4 Urine pregnancy testing is required for women of reproductive potential only. The assay used must have sensitivity of ≤25 mIU/mL βHCG. At the oral dosing visits (Day 0, Week 2 and Week 4) and injection visits (Weeks 
5, 9, 17, 25, and 33), a urine pregnancy test must be performed and pregnancy must be ruled out PRIOR to administering the study product. Urine pregnancy testing may be performed in the clinic or the laboratory. Pregnancy 
testing is not required if a positive result was obtained at a prior visit and the participant is still pregnant.  Refer to the SSP Manual for instructions regarding follow-up of participants with a positive pregnancy test result at 
Weeks 2, 4, or 5; also see Section 5.23 of the protocol.    
5 Refer to the SSP Manual for details regarding STI testing. STI testing (urine and/or vaginal swab for GC/CT, syphilis testing), will be performed at Screening and Weeks 25 and 53.  Rectal swabs for GC/CT will be 
performed at enrollment (or for US sites, at screening per IoR discretion) and weeks 25 and 53. For non-US sites, rectal swabs will be batched and shipped to the HPTN LC for testing (see SSP Manual); for US sites, testing 
will be performed locally.   
6 Administer injection with counseling, including review of prohibited medications, after confirmation of negative pregnancy and HIV testing per SSP Manual. 


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7 The HIV testing algorithm 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.  Participants who have one or more 
reactive or positive HIV test result (any assay) at Screening or Enrollment are not eligible to participate in the study, even if they are confirmed to be HIV-uninfected. Additional testing is required for participants who have a 
reactive or positive HIV test after Enrollment (see Appendix IX and the SSP Manual). In all cases, HIV acquisition after Enrollment must be confirmed using two specimens collected on different dates (see SSP Manual). 
HIV testing does not need to be performed after confirmation of HIV infection (based on results from samples collected on two separate dates).  Refer to SSP Manual for instructions regarding follow-up for participants who 
have a reactive or positive HIV test at Weeks 2, 4 or 5; also see Section 5.21 of the protocol.   
8Testing for hepatitis B virus (HBV) and hepatitis C virus (HCV) includes hepatitis B surface antigen (HBsAg), hepatitis B surface antibody (HbsAb), hepatitis B core antibody (HbcAb), and hepatitis C antibody (HCAb).   
9 Chemistry testing includes: BUN, urea, Na, K, Cl, CO2, CPK, creatinine, total protein, glucose, calcium, phosphorous, amylase, lipase, and magnesium. 
10 The fasting lipid profile includes 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. 
11 Urinalysis includes protein and glucose; this testing may be performed in the clinic or the laboratory.  Results from urinalysis are not needed prior to enrollment. 
12 Stored plasma will be used for Quality Assurance testing at the HPTN LC and for other assessments described in Section 9.2. These assessments will be performed retrospectively; results will not be returned to study sites 
or participants, except as noted in Section 9.2.  
13 Plasma samples collected for Pharmacology testing at Weeks 5, 9, 17, 25, and 33 must be drawn PRIOR to injection of study product.   Refer to the SSP Manual). 
14 Specimens will be stored at Enrollment for Pharmacogenomic testing only at sites that opt to include this testing (See SSP Manual for further details). 
15 All acceptability assessments may not be performed at all sites.  The assessments are listed below.  Also, refer to Section 9 and 11 of the SSP Manual.      
 
Baseline Acceptability Questionnaire – Enrollment 
 
Follow-Up Acceptability Questionnaire – Weeks 6, 10, 18, 26, and 34 
 
Study Medication Satisfaction Questionnaire – Weeks 6, 10, 18, 26, and 34 
 
Study Medication Satisfaction Change Questionnaire – Week 10 only 
 
Behavioral Questionnaire – Enrollment and Weeks 5, 9, 17, 25, 33, 41, 53, 65, and 77 


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Appendix V: Schedule of Procedures and Evaluations – For Participants Who Complete Four Injections Only in Cohort 2 
 
Injection And Tail Phase Follow-up 
Week 5 
First  
Injection 
Week 
6  
Safety 
Week 9 
Second 
Injection 
Week 10, 
13 
Safety 
Week 17 
Third 
Injection 
Week 18, 
21 Safety 
 
Week 25  
Fourth 
Injection 
Week 26, 
29 
Safety 
 
Week 41, 
53, 65  
Follow Up 
Week 77 
Final 
ADMINISTRATIVE, BEHAVIORAL, REGULATORY 
Locator information 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
HIV counseling  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Offer condoms and lubricant  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Acceptability assessment (Week 6, 
10, 18, and 26 only)1 
 
X 
 
X 
 
X 
 
X 
 
 
Behavioral assessment  
X 
 
X 
 
X 
 
X 
 
X 
 
CLINICAL EVALUATIONS & PROCEDURES 
History, con meds, physical exam 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CNS symptom assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECG (Week 6, 13, 21, and 29 only) 
 
X 
 
X 
 
X 
 
X 
 
 
Blood collection 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urine collection for GC/CT testing 
men and women2 
 
 
 
 
 
 
X 
 
X 
 
Urine collection for urinalysis3 
 
 
 
 
 
 
 
 
X 
 
Urine pregnancy testing4 
X 
 
X 
 
X 
 
X 
 
X 
X 
Rectal swab for GC/CT testing 
men and women2 
 
 
 
 
 
 
X 
 
X 
 
Vaginal swab for GC/CT testing 
(Optional alternate collection for 
women if urine not used)2 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
Administer injection5 
X 
 
X 
 
X 
 
X 
 
 
 
ISR evaluation 
 
X 
 
X 
 
X 
 
X 
 
 
LOCAL LABORATORY EVALUATIONS 
HIV testing6 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CBC with differential (Week 41 
only) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Chemistry testing7  (Week 41 only) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
LFTs (AST, ALT, total bilirubin, 
alkaline phosphatase) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Fasting lipid profile8 
 
 
 
 
 
 
 
 
X 
 


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Injection And Tail Phase Follow-up 
Week 5 
First  
Injection 
Week 
6  
Safety 
Week 9 
Second 
Injection 
Week 10, 
13 
Safety 
Week 17 
Third 
Injection 
Week 18, 
21 Safety 
 
Week 25  
Fourth 
Injection 
Week 26, 
29 
Safety 
 
Week 41, 
53, 65  
Follow Up 
Week 77 
Final 
Syphilis serologic testing men and 
women2 
 
 
 
 
 
 
X 
 
X 
 
Urine/vaginal swab GC/CT testing 
men and women2 
 
 
 
 
 
 
X 
 
X 
 
Rectal swab GC/CT testing2 
 
 
 
 
 
 
X 
 
X 
 
Urinalysis3 
 
 
 
 
 
 
 
 
X 
 
Plasma storage9 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Plasma storage for Pharmacology 
testing10   
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
FOOTNOTES FOR APPENDIX V 
1 All assessments may not be performed at all sites.  The assessments for this visit schedule are listed below.  Also, refer to Section 9 and 11 of the SSP Manual.      
•Follow-Up Acceptability Questionnaire – Weeks 6, 10, 18, 26 
•Study Medication Satisfaction Questionnaire – Weeks 6, 10, 18, 26 
•Study Medication Satisfaction Change Questionnaire – Week 10 only 
•Behavioral Questionnaire – Weeks 5, 9, 17, 25, 41, 53, and 65 
2 Refer to the SSP Manual for details regarding STI testing. STI testing (urine and/or vaginal swab for GC/CT, syphilis testing), will be performed at Weeks 25 and 53.  Rectal swabs for GC/CT will be 
performed at 25 and 53. For non-US sites, rectal swabs will be batched and shipped to the HPTN LC for testing (see SSP Manual); for US sites, testing will be performed locally.   
3 Week 41 only.  Urinalysis includes protein and glucose; this testing may be performed in the clinic or the laboratory.  
4 Urine pregnancy testing is required for women of reproductive potential only. The assay used must have sensitivity of ≤25 mIU/mL βHCG. At the injection visits (Weeks 5, 9, 17, 25), a urine 
pregnancy test must be performed and pregnancy must be ruled out PRIOR to administering the study product. Urine pregnancy testing may be performed in the clinic or the laboratory. Pregnancy 
testing is not required if a positive result was obtained at a prior visit and the participant is still pregnant.  Refer to the SSP Manual for instructions regarding follow-up of participants with a positive 
pregnancy test result at Week 5; also see Section 5.23 of the protocol.    
5 Administer injection with counseling, including review of prohibited medications, after confirmation of negative pregnancy and HIV testing per SSP Manual. 
6 The HIV testing algorithm is provided in the SSP Manual. If HIV rapid testing is included in the HIV testing algorithm, this testing may be performed in the clinic or the laboratory.  Additional 
testing is required for participants who have a reactive or positive HIV test after Enrollment (see Appendix IX and the SSP Manual). In all cases, HIV acquisition after Enrollment must be confirmed 
using two specimens collected on different dates (see SSP Manual). HIV testing does not need to be performed after confirmation of HIV infection (based on results from samples collected on two 
separate dates).  Refer to SSP Manual for instructions regarding follow-up for participants who have a reactive or positive HIV test at Week 5; also see Section 5.21 of the protocol.   
7 Chemistry testing includes: BUN, urea, Na, K, Cl, CO2, CPK, creatinine, total protein, glucose, calcium, phosphorous, amylase, lipase, and magnesium. 
8 Week 41 only.  The fasting lipid profile includes 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. 
9 Stored plasma will be used for Quality Assurance testing at the HPTN LC and for other assessments described in Section 9.2. These assessments will be performed retrospectively; results will not be 
returned to study sites or participants, except as noted in Section 9.2.  
10 Plasma samples collected for Pharmacology testing at Weeks 5, 9, 17, and 25 must be drawn PRIOR to injection of study product.   Refer to the SSP Manual. 
Appendix VI: Schedule of Procedures and Evaluations – For Participants Who Complete Three Injections Only in Cohort 2 


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Injection And Tail Phase Follow-up 
Week 5 
First  
Injection 
Week 
6 
Safety 
Week 9 
Second 
Injection 
Week 10, 13 
Safety 
 
Week 17 
Third 
Injection 
 
Week 18, 21 
Safety 
Week 29, 41, 
53  
Follow Up 
Week 69 
Final 
ADMINISTRATIVE, BEHAVIORAL, REGULATORY 
Locator information 
X 
X 
X 
X 
X 
X 
X 
 
HIV counseling  
X 
X 
X 
X 
X 
X 
X 
X 
Offer condoms and lubricant  
X 
X 
X 
X 
X 
X 
X 
X 
Acceptability assessment (Week 6, 
10, and 18 only)1 
 
X 
 
X 
 
X 
 
 
Behavioral assessment  
X 
 
X 
 
X 
 
X 
 
CLINICAL EVALUATIONS & PROCEDURES 
History, con meds, physical exam 
X 
X 
X 
X 
X 
X 
X 
X 
CNS symptom assessment 
X 
X 
X 
X 
X 
X 
X 
X 
ECG (Week 6, 13, 21 only) 
 
X 
 
X 
 
X 
 
 
Blood collection 
X 
X 
X 
X 
X 
X 
X 
X 
Urine collection for GC/CT 
testing men and women2  
 
 
 
 
 
 
X 
 
Urine collection for urinalysis3 
 
 
 
 
 
X 
X 
 
Urine pregnancy testing4 
X 
 
X 
 
X 
 
X 
X 
Rectal swab for GC/CT testing 
men and women2 
 
 
 
 
 
X 
X 
 
Vaginal swab for GC/CT testing5 
(Optional alternate collection for 
women if urine not used)2 
 
 
 
 
 
X 
X 
 
Administer injection5 
X 
 
X 
 
X 
 
 
 
ISR evaluation 
 
X 
 
X 
 
X 
 
 
LOCAL LABORATORY EVALUATIONS 
HIV testing6 
X 
X 
X 
X 
X 
X 
X 
X 
CBC with differential (Week 29 
and 41 only) 
X 
X 
X 
X 
X 
X 
X 
 
Chemistry testing7 (Week 29 and 
41 only) 
X 
X 
X 
X 
X 
X 
X 
 
LFTs (AST, ALT, total bilirubin, 
alkaline phosphatase) 
X 
X 
X 
X 
X 
X 
X 
X 
Fasting lipid profile8 
 
 
 
 
 
 
X 
 


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Injection And Tail Phase Follow-up 
Week 5 
First  
Injection 
Week 
6 
Safety 
Week 9 
Second 
Injection 
Week 10, 13 
Safety 
 
Week 17 
Third 
Injection 
 
Week 18, 21 
Safety 
Week 29, 41, 
53  
Follow Up 
Week 69 
Final 
Syphilis serologic testing men and 
women2 
 
 
 
 
 
X 
X 
 
Urine/vaginal swab GC/CT testing 
men and women2 
 
 
 
 
 
X 
X 
 
Rectal swab GC/CT testing2 
 
 
 
 
 
X 
X 
 
Urinalysis3 
 
 
 
 
 
 
X 
 
Plasma storage9 
X 
X 
X 
X 
X 
X 
X 
X 
Plasma storage for Pharmacology 
testing10   
X 
X 
X 
X 
X 
X 
X 
X 
FOOTNOTES FOR APPENDIX VI 
1 All assessments may not be performed at all sites.  The assessments for this visit schedule are listed below.  Also, refer to Section 9 and 11 of the SSP Manual.      
•Follow-Up Acceptability Questionnaire – Weeks 6, 10, 18, 
•Study Medication Satisfaction Questionnaire – Weeks 6, 10, 18,  
•Study Medication Satisfaction Change Questionnaire – Week 10 only 
•Behavioral Questionnaire – Weeks 5, 9, 17, 29, 41, and 53  
2 Refer to the SSP Manual for details regarding STI testing. STI testing (urine and/or vaginal swab for GC/CT, syphilis testing), will be performed at Weeks 21 and 53.  Rectal swabs for GC/CT will be 
performed at 21 and 53. For non-US sites, rectal swabs will be batched and shipped to the HPTN LC for testing (see SSP Manual); for US sites, testing will be performed locally.   
3 Week 41 only.  Urinalysis includes protein and glucose; this testing may be performed in the clinic or the laboratory.  
4 Urine pregnancy testing is required for women of reproductive potential only. The assay used must have sensitivity of ≤25 mIU/mL βHCG. At the injection visits (Weeks 5, 9, 17), a urine pregnancy 
test must be performed and pregnancy must be ruled out PRIOR to administering the study product. Urine pregnancy testing may be performed in the clinic or the laboratory. Pregnancy testing is not 
required if a positive result was obtained at a prior visit and the participant is still pregnant.  Refer to the SSP Manual for instructions regarding follow-up of participants with a positive pregnancy test 
result at Week 5; also see Section 5.23 of the protocol.    
5 Administer injection with counseling, including review of prohibited medications, after confirmation of negative pregnancy and HIV testing per SSP Manual. 
6 The HIV testing algorithm is provided in the SSP Manual. If HIV rapid testing is included in the HIV testing algorithm, this testing may be performed in the clinic or the laboratory.  Additional 
testing is required for participants who have a reactive or positive HIV test after Enrollment (see Appendix IX and the SSP Manual). In all cases, HIV acquisition after Enrollment must be confirmed 
using two specimens collected on different dates (see SSP Manual). HIV testing does not need to be performed after confirmation of HIV infection (based on results from samples collected on two 
separate dates).  Refer to SSP Manual for instructions regarding follow-up for participants who have a reactive or positive HIV test at Week 5; also see Section 5.21 of the protocol.   
7 Chemistry testing includes: BUN, urea, Na, K, Cl, CO2, CPK, creatinine, total protein, glucose, calcium, phosphorous, amylase, lipase, and magnesium. 
8 Week 41 only.  The fasting lipid profile includes 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. 
9 Stored plasma will be used for Quality Assurance testing at the HPTN LC and for other assessments described in Section 9.2. These assessments will be performed retrospectively; results will not be 
returned to study sites or participants, except as noted in Section 9.2.  
10 Plasma samples collected for Pharmacology testing at Weeks 5, 9, and 17 must be drawn PRIOR to injection of study product.   Refer to the SSP Manual. 


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Appendix VII: Schedule of Procedures and Evaluations – For Participants Who Complete Two Injections Only in Cohort 2 
 
Injection And Tail Phase Follow-up 
Week 5 
First 
Injection 
Week 6  
Safety 
 
Week 9  
Second 
Injection 
Week 10, 13 
Safety 
Week 27 
Follow Up 
Week 41 
Follow Up 
Week 53 
Follow Up 
Week 61 
Final 
Visit 
ADMINISTRATIVE, BEHAVIORAL, REGULATORY 
Locator information 
X 
X 
X 
X 
X 
X 
X 
 
HIV counseling  
X 
X 
X 
X 
X 
X 
X 
X 
Offer condoms and lubricant  
X 
X 
X 
X 
X 
X 
X 
X 
Acceptability Assessment  
(Week 6 and 10 only)1 
 
X 
 
X 
 
 
 
 
Behavioral assessment 
X 
 
X 
 
X 
X 
X 
 
CLINICAL EVALUATIONS & PROCEDURES 
History, con meds, physical 
exam 
X 
X 
X 
X 
X 
X 
X 
X 
CNS symptom assessment 
X 
X 
X 
X 
X 
X 
X 
X 
ECG (Week 6 and 13 only) 
 
X 
 
X 
 
 
 
 
Blood collection 
X 
X 
X 
X 
X 
X 
X 
X 
Urine collection for GC/CT 
testing men and women2 
 
 
 
 
X 
 
X 
 
Urine collection for urinalysis3 
 
 
 
 
 
X 
 
 
Urine pregnancy testing4 
X 
 
X 
X 
X 
X 
X 
X 
Rectal swab for GC/CT testing 
men and women2 
 
 
 
 
X 
 
X 
 
Vaginal swab for GC/CT testing   
(Optional alternate collection for 
women if urine not used)2 
 
 
 
 
X 
 
X 
 
Administer injection5 
X 
 
X 
 
 
 
 
 
ISR Evaluation 
 
X 
 
X 
 
 
 
 
LOCAL LABORATORY EVALUATIONS 
HIV testing6 
X 
X 
X 
X 
X 
X 
X 
X 
CBC with differential 
X 
X 
X 
X 
X 
X 
 
 
Chemistry testing7 
X 
X 
X 
X 
X 
X 
 
 
LFTs (AST, ALT, total bilirubin, 
alkaline phosphatase) 
X 
X 
X 
X 
X 
X 
X 
X 


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Injection And Tail Phase Follow-up 
Week 5 
First 
Injection 
Week 6  
Safety 
 
Week 9  
Second 
Injection 
Week 10, 13 
Safety 
Week 27 
Follow Up 
Week 41 
Follow Up 
Week 53 
Follow Up 
Week 61 
Final 
Visit 
Fasting lipid profile8 
 
 
 
 
 
X 
 
 
Syphilis serologic testing men 
and women2 
 
 
 
 
X 
 
X 
 
Urine/vaginal swab GC/CT 
testing men and women 
 
 
 
 
X 
 
X 
 
Rectal swab GC/CT testing2 
 
 
 
 
X 
 
X 
 
Urinalysis3 
 
 
 
 
 
X 
 
 
Plasma storage9 
X 
X 
X 
X 
X 
X 
X 
X 
Plasma storage for 
Pharmacology testing10   
X 
X 
X 
X 
X 
X 
X 
X 
FOOTNOTES FOR APPENDIX VII 
1 All assessments may not be performed at all sites.  The assessments for this visit schedule are listed below.  Also, refer to Section 9 and 11 of the SSP Manual.      
•Follow-Up Acceptability Questionnaire – Weeks 6, 10 
•Study Medication Satisfaction Questionnaire – Weeks 6, 10  
•Study Medication Satisfaction Change Questionnaire – Week 10 only 
•Behavioral Questionnaire – Weeks 5, 9, 27, 41, 53  
2 Refer to the SSP Manual for details regarding STI testing. STI testing (urine and/or vaginal swab for GC/CT, syphilis testing), will be performed at Weeks 27 and 53.  Rectal swabs for GC/CT will be 
performed at 27 and 53. For non-US sites, rectal swabs will be batched and shipped to the HPTN LC for testing (see SSP Manual); for US sites, testing will be performed locally.   
3 Urinalysis includes protein and glucose; this testing may be performed in the clinic or the laboratory.  
4 Urine pregnancy testing is required for women of reproductive potential only. The assay used must have sensitivity of ≤25 mIU/mL βHCG. At the injection visits (Weeks 5, 9, a urine pregnancy test 
must be performed and pregnancy must be ruled out PRIOR to administering the study product. Urine pregnancy testing may be performed in the clinic or the laboratory. Pregnancy testing is not 
required if a positive result was obtained at a prior visit and the participant is still pregnant.  Refer to the SSP Manual for instructions regarding follow-up of participants with a positive pregnancy test 
result at Week 5; also see Section 5.23 of the protocol.    
5 Administer injection with counseling, including review of prohibited medications, after confirmation of negative pregnancy and HIV testing per SSP Manual. 
6 The HIV testing algorithm is provided in the SSP Manual. If HIV rapid testing is included in the HIV testing algorithm, this testing may be performed in the clinic or the laboratory.  Additional 
testing is required for participants who have a reactive or positive HIV test after Enrollment (see Appendix IX and the SSP Manual). In all cases, HIV acquisition after Enrollment must be confirmed 
using two specimens collected on different dates (see SSP Manual). HIV testing does not need to be performed after confirmation of HIV infection (based on results from samples collected on two 
separate dates).  Refer to SSP Manual for instructions regarding follow-up for participants who have a reactive or positive HIV test at Week 5; also see Section 5.21 of the protocol.   
7 Chemistry testing includes: BUN, urea, Na, K, Cl, CO2, CPK, creatinine, total protein, glucose, calcium, phosphorous, amylase, lipase, and magnesium. 
8 Week 41 only.  The fasting lipid profile includes 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. 
9 Stored plasma will be used for Quality Assurance testing at the HPTN LC and for other assessments described in Section 9.2. These assessments will be performed retrospectively; results will not be 
returned to study sites or participants, except as noted in Section 9.2.  
10 Plasma samples collected for Pharmacology testing at Weeks 5 and 9, must be drawn PRIOR to injection of study product.   Refer to the SSP Manual. 


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Appendix VIII: Schedule of Procedures and Evaluations – For Participants Who Complete One Injection Only in Cohort 2 
 
Injection And Tail Phase Follow-up 
Week 5 
First 
Injection 
Week 6 
Safety 
Week 9 
Follow Up 
Week 13 
Follow Up 
Week 27 
Follow Up 
Week 41 
Follow Up 
Week 53 
Follow Up 
Week 57 
Final 
Visit 
ADMINISTRATIVE, BEHAVIORAL, REGULATORY 
Locator information 
X 
X 
X 
X 
X 
X 
X 
X 
HIV counseling  
X 
X 
X 
X 
X 
X 
X 
X 
Offer condoms and lubricant  
X 
X 
X 
X 
X 
X 
X 
X 
Acceptability Assessment  (Week 
6 only)1 
 
X 
 
 
 
 
 
 
Behavioral assessment 
X 
 
 
X 
X 
X 
X 
 
CLINICAL EVALUATIONS & PROCEDURES 
History, con meds, physical exam 
X 
X 
X 
X 
X 
X 
X 
X 
CNS symptom assessment 
X 
X 
X 
X 
X 
X 
X 
X 
ECG (Week 6 only) 
 
X 
 
 
 
 
 
 
Blood collection 
X 
X 
X 
X 
X 
X 
X 
X 
Urine collection for GC/CT 
testing men and women2 
 
 
 
 
X 
 
X 
 
Urine collection for urinalysis3 
 
 
 
 
 
X 
 
 
Urine pregnancy testing4 
X 
 
X 
X 
X 
X 
X 
X 
Rectal swab for GC/CT testing 
men and women2 
 
 
 
 
X 
 
X 
 
Vaginal swab for GC/CT testing   
(Optional alternate collection for 
women if urine not used)2 
 
 
 
 
X 
 
X 
 
Administer injection5 
X 
 
 
 
 
 
 
 
ISR Evaluation 
 
X 
 
 
 
 
 
 
LOCAL LABORATORY EVALUATIONS 
HIV testing6 
X 
X 
X 
X 
X 
X 
X 
X 
CBC with differential 
X 
X 
X 
X 
X 
X 
 
 
Chemistry testing7 
X 
X 
X 
X 
X 
X 
 
 
LFTs (AST, ALT, total bilirubin, 
alkaline phosphatase) 
X 
X 
X 
X 
X 
X 
X 
X 
Fasting lipid profile8 
 
 
 
 
 
X 
 
 


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Injection And Tail Phase Follow-up 
Week 5 
First 
Injection 
Week 6 
Safety 
Week 9 
Follow Up 
Week 13 
Follow Up 
Week 27 
Follow Up 
Week 41 
Follow Up 
Week 53 
Follow Up 
Week 57 
Final 
Visit 
Syphilis serologic testing men and 
women2 
 
 
 
 
X 
 
X 
 
Urine/vaginal swab GC/CT 
testing men and women2 
 
 
 
 
X 
 
X 
 
Rectal swab GC/CT testing2 
 
 
 
 
X 
 
X 
 
Urinalysis3 
 
 
 
 
 
X 
 
 
Plasma storage9 
X 
X 
X 
X 
X 
X 
X 
X 
Plasma storage for Pharmacology 
testing10   
X 
X 
X 
X 
X 
X 
X 
X 
FOOTNOTES FOR APPENDIX VIII 
1 All assessments may not be performed at all sites.  The assessments for this visit schedule are listed below.  Also, refer to Section 9 and 11 of the SSP Manual.      
•Follow-Up Acceptability Questionnaire – Weeks 6 only 
•Study Medication Satisfaction Questionnaire – Weeks 6 only   
•Study Medication Satisfaction Change Questionnaire – Week 9 only 
•Behavioral Questionnaire – Weeks 5, 9, 27, 41, 53  
2 Refer to the SSP Manual for details regarding STI testing. STI testing (urine and/or vaginal swab for GC/CT, syphilis testing), will be performed at Weeks 27 and 53.  Rectal swabs for GC/CT will be 
performed at Weeks 27 and 53. For non-US sites, rectal swabs will be batched and shipped to the HPTN LC for testing (see SSP Manual); for US sites, testing will be performed locally.   
3 Urinalysis includes protein and glucose; this testing may be performed in the clinic or the laboratory.  
4 Urine pregnancy testing is required for women of reproductive potential only. The assay used must have sensitivity of ≤25 mIU/mL βHCG. At the injection visits (Weeks 5, 9, a urine pregnancy test 
must be performed and pregnancy must be ruled out PRIOR to administering the study product. Urine pregnancy testing may be performed in the clinic or the laboratory. Pregnancy testing is not 
required if a positive result was obtained at a prior visit and the participant is still pregnant.  Refer to the SSP Manual for instructions regarding follow-up of participants with a positive pregnancy test 
result at Week 5; also see Section 5.23 of the protocol.    
5 Administer injection with counseling, including review of prohibited medications, after confirmation of negative pregnancy and HIV testing per SSP Manual. 
6 The HIV testing algorithm is provided in the SSP Manual. If HIV rapid testing is included in the HIV testing algorithm, this testing may be performed in the clinic or the laboratory.  Additional 
testing is required for participants who have a reactive or positive HIV test after Enrollment (see Appendix IX and the SSP Manual). In all cases, HIV acquisition after Enrollment must be confirmed 
using two specimens collected on different dates (see SSP Manual). HIV testing does not need to be performed after confirmation of HIV infection (based on results from samples collected on two 
separate dates).  Refer to SSP Manual for instructions regarding follow-up for participants who have a reactive or positive HIV test at Week 5; also see Section 5.21 of the protocol.   
7 Chemistry testing includes: BUN, urea, Na, K, Cl, CO2, CPK, creatinine, total protein, glucose, calcium, phosphorous, amylase, lipase, and magnesium. 
8 Week 41 only.  The fasting lipid profile includes 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. 
9 Stored plasma will be used for Quality Assurance testing at the HPTN LC and for other assessments described in Section 9.2. These assessments will be performed retrospectively; results will not be 
returned to study sites or participants, except as noted in Section 9.2.  
10 Plasma samples collected for Pharmacology testing at Week 5 must be drawn PRIOR to injection of study product.   Refer to the SSP Manual. 


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Appendix IX: Schedule for Additional Laboratory Procedures for Enrolled Participants who have 
a Reactive Positive HIV Test Result (HIV Confirmation Visit – to be performed on a different day 
from the initial reactive/positive sample) 
HIV Confirmation Visit  
ADMININISTRATIVE, BEHAVIORAL, REGULATORY 
Locator information  
X 
Offer condoms and lubricant 
X 
HIV counseling  
X 
CLINICAL EVALUATIONS AND PROCEDURES 
Blood collection  
X 
LOCAL LABORATORY EVALUATIONS 
HIV testing1 
X 
CD4 cell count  
X 
HIV viral load testing 
X 
HIV resistance testing2 
X2 
Plasma storage3 
X 
1 The HIV testing algorithm for the HIV Confirmation Visit is provided in the SSP Manual. If HIV rapid 
testing is included in the HIV testing algorithm, this testing may be performed in the clinic or the 
laboratory.   
2 Sites may collect specimens for resistance testing at a local laboratory to assist with clinical 
management; results from resistance testing performed at local laboratories will not be reported to the 
SDMC.  Stored plasma may not be used real-time/local resistance testing.   
3 Stored plasma will be used for Quality Assurance testing at the HPTN LC and for other assessments 
described in Section 9.2. These assessments will be performed retrospectively; results will not be 
returned to study sites or participants, except as noted in Section 9.2. 
 
 


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Appendix X:  Risk Assessment and Mitigation Strategy 
Potential Risk of Clinical Significance 
Data/Rationale for Risk 
Mitigation Strategy 
Elevated Liver Transaminases (ALT/AST) 
See section 1.4 on Hepatic Safety. 
Liver transaminases will be closely monitored 
throughout this study, and liver chemistry 
stopping criteria will be adopted. All instances 
of liver transaminase elevations of Grade 1 and 
above will be followed to resolution. This risk 
will also be mitigated by exclusion criteria. In 
addition, an oral lead-in period is being 
implemented in this study, where all subjects 
will receive oral 744 for 4 weeks, to determine 
individual safety and tolerability, prior to the 
administration of 744LA.  For management of 
Grade 1 or higher AST/ALT, refer to Section 5.3 
and Appendix XI.    
Injection Site Reactions (ISRs) 
The occurrence of injection site reactions (ISRs) 
was identified in rats and monkeys at all dose 
levels of 744LA and associated with both the IM 
and SC route of administration. In humans, 
experience to date has demonstrated that ISRs 
occur in the majority of exposed subjects, but 
are generally mild (Grade 1) and include 
tenderness, erythema, or nodule formation of 
several days duration. Reactions to date have 
been well tolerated and have not to date been 
associated with subject withdrawal. 
Subjects will be closely monitored for ISRs, 
particularly for signs of pain, tenderness, 
infections, erythema, swelling, induration, or 
nodules (granulomas or cysts) throughout the 
study. Specialist dermatology consultation will 
be sought if warranted for individual subjects. 
Creatine Phosphokinase (CPK) 
Elevations 
Occurrences of asymptomatic, transient 
instances of elevations of CPK levels have been 
observed in Phase I studies and an ongoing 
Phase 2b study with oral 744 at dose levels of 
10, 30 and 60 mg (LAI116482). These generally 
appeared to be related to physical activity, were 
not associated with clinical symptoms and 
returned to pre-treatment levels in all cases. No 
subject has required a discontinuation of 
GSK1265744 as a result of a CPK elevation. 
Rhabdomyolysis of uncertain cause has been 
included in labeling for a currently available 
integrase inhibitor (raltegravir), but has not been 
seen in any subject receiving GSK1265744 to 
Standard laboratory monitoring. 


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Potential Risk of Clinical Significance 
Data/Rationale for Risk 
Mitigation Strategy 
date. 
Bone Marrow Depletion 
This risk was demonstrated in high dose (1,000 
mg/kg/day) oral 744 monkey study, but was not 
apparent from studies conducted in rats or at 
lower dose levels in monkeys. Blood disorders 
such as anemia and leucopenia are labeled for 
other drugs of the integrase inhibitor class. No 
signal for bone marrow depletion has been 
identified to date through Phase 2b. 
Doses used within this study will result in many 
fold lower level exposure compared to the effect 
level in primates. Careful monitoring of adverse 
hematological events will occur during study 
conduct. AEs will be managed appropriately 
including, but not limited to, withdrawal of 744 
(oral or LA), and will be followed to resolution, 
as per Sponsor’s standard medical monitoring 
practices.  
Gastrointestinal (GI) Intolerability   
The risk identified in a monkey toxicity study at 
the highest administered dose of oral 744 and 
considered related to local irritation (rather than 
a systemic effect) leading to morbidity 
associated with clinical signs of intolerance. 
Careful monitoring of adverse GI events will 
occur throughout the study. AEs will be 
managed appropriately including, but not limited 
to, withdrawal of 744, and will be followed to 
resolution, as per Sponsor’s standard medical 
monitoring practices.    
Hypersensitivity Reactions (HSR) 
While there have been no clinical cases of 
hypersensitivity to GSK1265744, there is a 
theoretical risk of systemic or severe 
hypersensitivity reactions with or without 
hepatic symptoms. The long exposures 
anticipated after a 744LA injection may 
complicate the management of a drug 
hypersensitivity reaction, were it to occur. 
This risk of developing a hypersensitivity 
reaction post administration of 744LA will be 
minimized by the use of an oral 744 lead-in to 
determine individual safety and tolerability prior 
to the introduction of 744LA. Any reactions 
would be managed per standard clinical 
guidelines.   
Drug-Drug Interactions (DDIs) 
Residual concentrations of GSK1265744 would 
remain in the systemic circulation of subjects 
who stopped treatment (e.g., for tolerability 
issues or treatment failure) for prolonged periods 
(months). Subjects discontinuing a 744LA 
regimen may be at risk for developing DDIs 
many weeks after discontinuing injectable 
therapy. Of note, evidence to date indicates that 
significant DDIs with GSK1265744 and other 
antiretrovirals are unlikely to occur. 
None needed at this time. All subjects will be 
informed of prohibited medications throughout 
the study and updates provided as needed to 
participants. 


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Potential Risk of Clinical Significance 
Data/Rationale for Risk 
Mitigation Strategy 
Development of Resistance in the Setting of 
HIV Acquisition 
Residual concentrations of GSK1265744 would 
remain in the systemic circulation of participants 
who stopped 744LA (e.g., for tolerability issues 
or treatment withdrawal) for prolonged periods 
(months).  Participants discontinuing a 744LA 
regimen may be at risk for developing resistance 
to GSK1265744 many weeks after discontinuing 
injectable therapy were they to become newly 
infected with HIV.  
The risk of HIV acquisition should be 
minimized in this study on the basis of inclusion 
of participants at lower risk for acquiring HIV. 
All participants will be provided HIV counseling 
and testing throughout the study, as well as 
provision of condoms and lubricant. 
Additionally, participants will be followed for 
52 weeks from the time of the last injection with 
744LA. Participants who acquire HIV on study 
will be referred for appropriate care. 
 
 


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APPENDIX XI: 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.   (A full 
description of the CMC’s role and responsibilities is included in the SSP Manual).   
The following general guidance refers to all AEs except for AST/ALT.  Refer to the section 
below “Specific Guidance on Transitioning from Oral to Injectable Phase”, as well as to the table 
below for specific guidance for AST/ALT. 
Grade 1 or 2 
 
In general, participants who develop a Grade 1 or 2 AE regardless of relatedness to study 
product, and that is not specifically addressed in the Table below may continue use of the study 
product per protocol.  See an exception to this under “Specific Guidance on Transitioning from 
Oral to Injectable Phase”.             
Grade 3 
 
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.  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. 
Grade 4 
 
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. 
 


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Specific Guidance on Transitioning from Oral to Injectable Phase 
  
A Grade 1 AST/ALT abnormality reported at Week 2, regardless of relatedness to the study 
product, should be confirmed within one week.  Study drug may continue until the confirmatory 
results are available.  If the repeat value is < Grade 1, study drug may continue to Week 4.  If the 
repeat value is Grade 1 or higher, study product should be stopped, and the participant will be 
prohibited from entering the injection phase of the study, and will be terminated from the study.   
All such cases must be reported to the CMC.  In addition, participants will be followed with 
weekly AST/ALT assessments until they return to < Grade 1.   
A Grade 2 or higher AST/ALT abnormality reported at Week 2 of the oral phase, regardless of 
relatedness to the study product, will prohibit a participant from entering the injection phase of 
the study, and the participant will be terminated from the study.   All such cases must be reported 
to the CMC.  In addition, participants will be followed with weekly AST/ALT assessments until 
they return to < Grade 1.   
Excluding AST and ALT, any grade 3 clinical or laboratory AE observed prior to Week 5 will 
prompt consultation with the CMC prior to any injectable dosing.   Excluding AST and ALT, 
Grade 3 adverse events deemed after CMC consultation to clearly not be related to study product 
may be permissible to continue to injectable dosing provided  
a) Documented resolution to ≤ Grade 1 prior to injectable dosing, and 
b) Approval of the CMC.    
 
Grade 3 adverse events deemed related to study product, or a Grade 3 AST or ALT, or any Grade 
4 adverse event will lead to study discontinuation prior to injectable dosing.  AEs will be 
followed until resolution in consultation with the CMC. 
 
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   


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 Pregnancy or expresses a desire to become pregnant 
 
Participants in the injection phase who prematurely and permanently discontinue study product 
should be asked to continue to be followed according to the applicable Schedule of Evaluations 
and Procedures (Appendices I - VIII).     
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 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 SSP Manual and Section 5.21 of the protocol. 
Participants who temporarily or permanently discontinue study product during the oral phase will 
be instructed to return all study products as soon as possible. 
 


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Guidance on Toxicity Management for Specified Toxicities: 
 
Nausea, Vomiting, and Diarrhea 
CONDITION AND  
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: 
 
AST/ALT 
 
CONDITION AND  
SEVERITY1 
STUDY 
PRODUCT USE 
FOLLOW-UP AND MANAGEMENT2 
ELEVATIONS in AST/ALT 
(New clinical finding or increase from baseline clinical finding only) 
Grade 1 and higher 
Oral phase:  A Grade 1 AST/ALT abnormality reported at Week 2, 
regardless of relatedness to the study product, should be confirmed 
within one week.  Study drug may continue until the confirmatory 
results are available.  If the repeat value is < Grade 1, study drug may 
continue to Week 4.  If the repeat value is Grade 1 or higher, study 
product should be stopped, and the participant will be prohibited from 
entering the injection phase of the study, and will be terminated from 
the study.   All such cases must be reported to the CMC.  In addition, 
participants will be followed with weekly AST/ALT assessments until 
they return to < Grade 1.   
A Grade 2 or higher AST/ALT abnormality reported at Week 2 of the 
oral phase, regardless of relatedness to the study product, will prohibit a 
participant from entering the injection phase of the study, and the 
participant will be terminated from the study.   All such cases must be 
reported to the CMC.  In addition, participants will be followed with 
weekly AST/ALT assessments until they return to < Grade 1 
 
Injection phase:  The CMC should be notified as soon as possible.  For a 
Grade 1 AST/ALT, the CMC will determine whether further injections may 
be given in cases where levels are < Grade 1 prior to the next scheduled 
injection.  Unless otherwise specified by the CMC, for Grade 1 and 2 
AST/ALT, repeat testing should be performed weekly until levels are < Grade 
1.  For Grade 2 and higher AST/ALT, study product will be permanently 
discontinued.  For Grade 3 and 4 AST/ALT, repeat testing should be 
performed as soon as possible, and participants should be followed weekly 
until levels are < Grade 1.  Participants who are permanently discontinued 
from stud product should continue to be followed on study/off study product, 
following the appropriate Schedule of Evaluations (based on number of 
injections received).   
 
Note the following for cases of exercise-induced CK abnormalities:  Cases of 
CK abnormality, presumed attributable to exercise, at the Grade 3 or higher 
level accompanied by ALT/AST abnormalities of Grade 3 or lower 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 or 
AST, regardless of CK elevation will prompt permanent discontinuation of 
study product.  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 
 
CONDITION AND  
SEVERITY1 
STUDY PRODUCT 
USE 
FOLLOW-UP AND MANAGEMENT2 
CREATININE CLEARANCE 
Estimated CrCl< 50 mL/min 
Discontinue study 
product temporarily 
If the calculated creatinine clearance is <50mL/min, 
it should be confirmed within 1 week of the receipt 
of the results, and the CMC should be consulted 
Confirmed CrCl< 50 mL/min  
Permanently 
discontinue study 
product  
If the calculated creatinine clearance is confirmed to 
be <50 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 
permanently discontinued from use of the study 
product and the CMC is notified. 
Re-testing result is             
≥50 mL/min 
Consult CMC for 
guidance 
If re-testing yields a result ≥ 50 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  
SEVERITY1 
STUDY PRODUCT USE 
FOLLOW-UP AND MANAGEMENT2 
Creatine Phosphokinase 
Grade 3  
 
Continue study product until 
repeat test results are available 
 
A Grade 3 or higher elevation in CPK should 
result in a repeat assessment within 2-4 weeks 
to ensure the result is transient or due to 
exercise and will not require a change in study 
treatment. A history regarding use of products 
known to cause increase of CPK (such as 
statins) physical activity or exercise preceding 
the CPK evaluation should be obtained.  
 
Grade 4 
Continue study product until 
repeat test results are available 
if the elevation is thought to 
be possibly or probably related 
to study product. 
Grade 4 elevations in CPK should have a 
repeat assessment after the subject has 
abstained from exercise for >24 hours. For 
persistent Grade 4 CPK elevations that are 
considered possibly or probably related to the 
study product, study product should be 
discontinued and the participant should be 
followed on study/off study product.   
 
(See section on ALT/AST abnormalities for 
important notes on ALT/AST abnormalities 
accompanying CK elevations) 
 
 


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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 correction formula used to determine study product discontinuation should be the 
same one used throughout the study. 
 QTcB > 500 msec, OR 
 Change from baseline: QTcB >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.  
Guidance for Allergic Reactions 
 
Participants may continue to receive oral or injectable study product for Grade 1 or 2 allergic reactions 
at the discretion of the IoR or designee. The participant should be advised to contact the study site staff 
immediately if there is any worsening of symptoms or if further systemic signs or symptoms develop. 
Antihistamines, topical corticosteroids, or antipruritic agents may be prescribed.  
Participants with Grade ≥3 allergic reactions that are considered to be related to study product should 
permanently discontinue study product and continue to be followed on study/off study product.  
Participants should be treated as clinically appropriate and followed until resolution of the AE. 
 


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APPENDIX XII: SAMPLE SCREENING AND ENROLLMENT INFORMED CONSENT FORM 
FOR PARTICIPANTS ENROLLING UNDER VERSION 3.0 
 
A Phase IIa Study to Evaluate the Safety, Tolerability and Pharmacokinetics of the 
Investigational Injectable HIV Integrase Inhibitor, GSK1265744, in HIV-uninfected Men and 
Women 
 
(HPTN 077) 
 
Version 3.0 
October 13, 2015 
DAIDS Document ID: 11964 
 
Sponsored by:  Division of AIDS, United States (US) National Institute of Allergy and Infectious 
Diseases, US National Institutes of Health. Study products are provided by ViiV Healthcare  
PRINCIPAL INVESTIGATOR: [Insert Name] 
PHONE:  [Insert Number] 
Introduction 
You are being asked to take part in an investigational research study related to the safety of a new drug 
that is hoped to be used one day to treat or prevent Human Immunodeficiency Virus, or HIV.  HIV is the 
virus that causes Acquired Immunodeficiency Syndrome, or AIDS.   
This study is being offered to approximately 194 men and women in Africa, and North and South 
America.  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 study will be available on www.ClinicalTrials.gov, as required by US law. This 
web site will not include information that can identify you. At most, the web site will include a summary 
of the results. You can search this web site at any time. 
 
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.   
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. 


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 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.   
 If you are a woman and are pregnant or breastfeeding, or wish to become pregnant during the 
course of the study, you are not eligible to be in this study.   
Purpose of the study 
The purpose of this study is to find out whether a new drug is safe.  The drug is being developed for 
both the treatment and prevention of HIV.   The drug being used in this study has not been approved for 
use by the US Food and Drug Administration (FDA), which is the part of the US government that 
approves medicines.  The drug is called GSK 1265744 (GSK 744 for short), and it is a type of drug 
called an antiretroviral drug.  Antiretroviral drugs usually come in the form of pills, but newer kinds are 
becoming available as an injection, or a shot.      
In this study, we want to find out whether the pill and injection form of the drug is safe, as well as how 
people who get the drug respond to it (meaning, does it make you feel sick).  Another reason we are 
doing this study is to find out whether people in the study are willing to receive the injections (shots) of 
the new drug and how they feel about it.  .   
You are being asked to participate in this study because you are at very low risk of getting HIV.  We do 
not know whether the drug being used in this study will prevent a person from getting HIV, and that is 
why we need volunteers who have little to no risk of getting HIV.  [If required or desired, sites to 
include here or other section as appropriate the protocol and site-specific risk criteria].      
Even though you are at low risk, we have to remind you every time we see you for your study visits that 
one of the best things that you can do to protect yourself against getting HIV during sex is to use a 
condom every time you have sex. 
We will also ask you to let us know if your risk for getting HIV has changed while you are in the study, 
and also to let us know whether you think that you may have been exposed to HIV through sex or 
intravenous drugs.    
If you think you are at risk for getting HIV, you should not participate in this study.   
STUDY GROUPS 
There are two study groups in this study. Each group has two arms. The first group (Group 1) has 
already been enrolled in the study.  If you decide to take part in the study, you will be enrolled into the 
second study group (Group 2). 
The groups and arms look like this: 
 Group 1  
o Arm 1:  People in this arm get pills and shots that have the GSK 744 drug in it, and people get 
shots every 12 weeks, at 3 time points.   


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o Arm 2:  People in this arm get pills and shots at the same time points as above, but they do not 
have the GSK 744 drug in it.  This is called a placebo.  The placebo forms of the drug 
typically look like the active or “real” drug, but they do not have the drug or any other 
medicine in them.   
There are approximately 106 people enrolled into Group 1.    
 Group 2  
o Arm 1:  People in this arm get pills and shots that have the GSK 744 drug in it.  People get a 
shot at 5 time points – the first two are 4 weeks apart and the next 3 are every 8 weeks.  It is 
given as one shot in the buttock.   
o Arm 2:  This arm gets the placebo pills and shots at the same time points as above.   
There will be approximately 88 people in Group 2.   
Reason For the Two Groups 
Recently, the ÉCLAIR study, a very similar study to this one, got some results.  ÉCLAIR is studying 
over 100 men in the United States.  These men got GSK 744 the same way as Group 1 in this study.  So 
these men got the drug every 12 weeks, at 3 time points.  ÉCLAIR showed that the drug did not last in 
the blood for the full 12 weeks.  Since we want to see if this drug can protect people from getting HIV, 
we need to find out how long this rug lasts in between shots.  We need this information to see if people 
can stay protected.  That is why we have Group 2 in HPTN 077.  We want to study a different dose of 
the drug and give it at a different length of time between shots.  The group that we are asking you to 
enroll in will get a shot of 600 mg of GSK 744 at two time points 4 weeks apart, and then at 3 time 
points 8 weeks apart (Week 5 ,9, 17, 25, ands 33).  The amount of drug is smaller in Group 2 than Group 
1 (600 mg instead of 800 mg). The amount is smaller since the shots occur closer together in time in 
Group 1 than they do in Group 2.  Whether you get the real drug or the placebo is chosen randomly, like 
flipping a coin.  You cannot choose which one you get and the study staff cannot choose it for you.     
No matter what group you are in, three out of four people (or 75%) will get pills and shots that have the 
GSK 744 drug in it.   One out of four people (or 25%) will get the placebo, which does not have the 
GSK 744 drug in it.  [Sites may insert another way to describe the 3:1 randomization that may be more 
appropriate to the local population]. 
The study staff and you will not know whether you got the real drug or placebo until a planned time later 
during the study.  When that time is reached, we will let everyone know which one they got.  Your 
participation in the study may have ended by the time, but we will contact you to let you know.   
If you did not receive the GSK 744 drug and you are still in the study when we let everyone know what 
they got, that will be the time that your participation in the study will end.  Even if you did not get the 
GSK 744 drug, your participation is very important because it gives us a chance to compare what 
happens to you with a person that did get the drug.       
STUDY PROCEDURES 
If you decide to join the study, you will be asked to come to this clinic up to 22 times over the course of 
up to two years.      


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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]. 
At this visit, the study staff will:   
 Ask you where you live and other questions about you, your medical health and if you are taking 
any medicines, your sexual practices, and whether you use alcohol or drugs for eligibility 
purposes. 
 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. 
 We will ask you to have an electrocardiogram (ECG) scan, which is a test to monitor your heart. 
 Test for three sexually transmitted infections called gonorrhea, chlamydia, and syphilis.  For 
gonorrhea and chlamydia, this will be done with urine if you are a man, or urine or a  swab of 
your vagina or cervix if you are a woman. Blood will be collected for syphilis testing. 
 For women of childbearing potential:  Collect XX mL of urine for pregnancy testing. 
 Collect ~XX mL (about x teaspoons) of blood for HIV testing, hepatitis B testing, hepatitis C 
testing, syphilis, 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). 
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.  If you have gonorrhea, chlamydia, or syphilis, you will not be eligible for the study and you 
will be referred for treatment.  A small amount of blood will be stored from this visit. No other samples 
collected at the time of screening will be kept or used for any other tests other than those listed above. 
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 test or a positive test for hepatitis B infection, 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 both HIV, hepatitis B infection, but the results from the other blood or urine 
tests show that you might have some health problems, or that you may be pregnant, 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 can come back to find out if you are 
eligible at that time. 
 You will be given referrals for other health services if you need them.  


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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 ethnic group. 
 Talk with you about HIV and ways to protect yourself from getting it. 
 Give you a complete physical exam, to include measuring your height, weight, temperature, 
blood pressure, and ask you about any other medicines you are taking.   
 Perform an ECG scan. 
 For women of childbearing potential:  Collect ~XX mL of urine for pregnancy testing. 
 Test for gonorrhea and chlamydia by using a swab of  your rectum. [US sites opting to perform 
this testing at screening to remove this from here and place in screening section]. 
 Collect a urine sample to see if there is sugar or protein in your urine. 
 Collect ~XX mL (about x teaspoons) of blood for:  HIV testing, to check how much 
cholesterol is in your blood (a fatty substance in your blood), to check your general health, to 
check the health of your liver, and for storage for study-related testing and long-term storage 
(if you provide consent).  [Sites that opt to collect samples for Pharmcogenomic testing to 
add this language here:  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 
regarding 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, using other 
products, as well as your opinions about being in a study. 
 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.    
 Give you the results of your blood tests when they are available. 
 Give you condoms and lubricants. 
 
Weeks 2 and 4 Visits  
This visit will last about xx hours. During this visit, the study staff will: 
 Confirm where you live and how to contact you. 
 Give you a brief physical exam, ask you if you have experienced any side effects from the study 
product, and ask you about any other medicines you are taking.  During the Week 4 visit, we will 
also remind you about certain drugs that you should not take a week before your injection.   


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 Ask you to have an ECG scan (Week 4 only). 
 Collect ~XX mL (about x teaspoons) of blood for HIV testing, to check your general health, the 
health of your liver, the amount of study product in you, and for storage for study-related testing 
and long-term storage (if you provide consent). 
 For women of childbearing potential:  Collect ~XX mL of urine for pregnancy testing. 
 Talk with you about HIV and ways to protect yourself from getting it and count your pills.  
 Ask you whether you have questions about taking your study pills. (Week 2 only) 
 Give you the results of your blood tests when they are available. 
 Give you condoms and lubricant. 
 
Week 5 Visit 
This visit will last xx hours.  During this visit, the study staff will: 
 Confirm where you live and how to contact you. 
 Give you a brief physical exam, ask you if you have experienced any side effects from the study 
product, and ask you about any other medicines you are taking.  We will also remind you about  
certain drugs that you should not take for one week after the injection.   
 Talk with you about HIV and ways to protect yourself from getting it. 
 For women of childbearing potential:  Collect ~XX mL of urine for pregnancy testing. 
 Collect ~XX mL (about x teaspoons) of blood for HIV testing, to check your general health, the 
health of your liver, the amount of study product in you, and for storage for study-related testing 
and long-term storage (if you provide consent). 
 Ask you questions about your sexual behavior. 
 Administer the a shot (your clinician will discuss the injection site with you). Give you the 
results of your blood tests when they are available. 
 Give you condoms and lubricants. 
 
Week 6 Visit 
This visit will last up to xx hours.  During this visit, 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 experienced any side effects from the shots 
you received, and ask you about any other medicines you are taking. At the Week 13 visit, we 
will remind you about certain drugs that you should not take one week before your injection.    
 Ask you to have an ECG scan.  


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 Collect ~XX mL (about x teaspoons) of blood for HIV testing, to check your general health, the 
health of your liver, the amount of study product in you, and for storage for study-related testing 
and long-term storage (if you provide consent). 
 Ask you questions about the shots you received at the previous visit. 
 Give you the results of your blood tests when they are available. 
 Give you condoms and lubricant. 
 
Week 9 Visit 
This visit will last about xx hours.  During this visit, 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 experienced any side effects from the shots 
you received, and ask you about any other medicines you are taking.  We will also remind you 
about certain drugs that you should not take for one week after the injection.     
 For women of childbearing potential:  Collect ~XX mL of urine for pregnancy testing. 
 Collect ~XX mL (about x teaspoons) of blood for HIV testing, to check your general health, the 
health of your liver, the amount of study product in you, and for storage for study-related testing 
and long-term storage (if you provide consent). 
 Ask you questions about your sexual behavior. 
 Administer the shot (your clinician will discuss the injection site with you).  
 Give you the results of your blood tests when they are available. 
 Give you condoms and lubricant. 
 
Weeks 10 and 13 Visits 
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 experienced any side effects from the shots 
you received, and ask you about any other medicines you are taking.  At the Week 23 visit, we 
will also remind you about certain drugs that you should not take one week before your next 
injection.   
 Ask you to have an ECG scan (Week 13 only). 
 Collect ~XX mL (about x teaspoons) of blood for HIV testing, to check your general health, the 
health of your liver, the amount of study product in you, and for storage for study-related testing 
and long-term storage (if you provide consent). 


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 Ask you questions about the shot you received at the previous visit (Week 10 only). 
 Give you condoms and lubricant. 
 
Week 17 Visit 
This visit will last about xx hour.  During this visit, the study staff will: 
 Confirm where you live and how to contact you. 
 Give you a brief physical exam, ask you if you have experienced any side effects from the shot 
you received, and ask you about any other medicines you are taking.  We will also remind you 
about certain drugs that you should not take one week after the injection.   
 Talk with you about HIV and ways to protect yourself from getting it. 
 For women of childbearing potential:  Collect ~XX mL of urine for pregnancy testing. 
 Collect ~XX mL (about x teaspoons) of blood for HIV testing, to check your general health, the 
health of your liver, the amount of study product in you, and for storage for study-related testing 
and long-term storage (if you provide consent). 
 Ask you questions about your sexual behavior. 
 Administer a shot (your clinician will discuss the injection site with you). Give you the results of 
your blood tests when they are available. 
 Give you condoms and lubricant. 
 
Weeks 18 and 21 Visits 
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 experienced any side effects from the shot 
you received, and ask you about any other medicines you are taking.   
 Ask you to have an ECG scan (Week 21 only). 
 Collect ~XX mL (about x teaspoons) of blood for HIV testing, to check your general health, the 
health of your liver, the amount of study product in you, and for storage for study-related testing 
and long-term storage (if you provide consent). 
 Ask you about the shot you received at the previous visit (Week 18 only). 
 Give you condoms and lubricant. 
 
 
 


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Week 25 Visit 
This visit will last xx hours.  During this visit, the study staff will: 
 Confirm where you live and how to contact you. 
 Give you a brief physical exam, ask you if you have experienced any side effects from the study 
product, and ask you about any other medicines you are taking.  We will also remind you about  
certain drugs that you should not take for one week after the injection.   
 Talk with you about HIV and ways to protect yourself from getting it. 
 For women of childbearing potential:  Collect ~XX mL of urine for pregnancy testing. 
 Collect ~XX mL (about x teaspoons) of blood for HIV testing, to check your general health, the 
health of your liver, the amount of study product in you, and for storage for study-related testing 
and long-term storage (if you provide consent). 
 Test you for three sexually transmitted infections called gonorrhea, chlamydia, and syphilis.  For 
gonorrhea and chlamydia, this will be done with urine if you are a man.    If you are a woman, 
this will be done with urine or a swab of your vagina or cervix. For men and women we will also 
test using a swab of your rectum. Blood will be collected for syphilis testing. 
 Ask you questions about your sexual behavior. 
 Administer the shot (your clinician will discuss the injection site with you).  
 Give you the results of your blood tests when they are available. 
 Give you condoms and lubricants. 
 
Weeks 26 and 29 Visits 
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 experienced any side effects from the shot 
you received, and ask you about any other medicines you are taking.   
 Ask you to have an ECG scan (Week 29 only). 
 Collect ~XX mL (about x teaspoons) of blood for HIV testing, to check your general health, the 
health of your liver, the amount of study product in you, and for storage for study-related testing 
and long-term storage (if you provide consent). 
 Ask you about the shot you received at the previous visit (Week 26 only). 
 Give you condoms and lubricant. 
 
 


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Week 33 Visit 
This visit will last about xx hour.  During this visit, the study staff will: 
 Confirm where you live and how to contact you. 
 Give you a brief physical exam, ask you if you have experienced any side effects from the shot 
you received, and ask you about any other medicines you are taking.  We will also remind you 
about certain drugs that you should not take one week after the injection.   
 Talk with you about HIV and ways to protect yourself from getting it. 
 For women of childbearing potential:  Collect ~XX mL of urine for pregnancy testing. 
 Collect ~XX mL (about x teaspoons) of blood for HIV testing, to check your general health, the 
health of your liver, the amount of study product in you, and for storage for study-related testing 
and long-term storage (if you provide consent). 
 Ask you questions about your sexual behavior. 
 Administer a shot (your clinician will discuss the injection site with you). Give you the results of 
your blood tests when they are available. 
 Give you condoms and lubricant. 
 
Weeks 34 and 37 Visits 
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 experienced any side effects from the shot 
you received, and ask you about any other medicines you are taking.   
 Ask you to have an ECG scan (Week 37 only). 
 Collect ~XX mL (about x teaspoons) of blood for HIV testing, to check your general health, the 
health of your liver, the amount of study product in you, and for storage for study-related testing 
and long-term storage (if you provide consent). 
 Ask you about the shot you received at the previous visit (Week 34 only). 
 Give you condoms and lubricant. 
 
 
 
 
 


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Week 41 Visit  
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 experienced any side effects from the shots 
you received, and ask you about any other medicines you are taking.   
 For women of childbearing potential:  Collect ~XX mL of urine for pregnancy testing. 
 Collect a urine sample to see if there is sugar or protein in your urine.  
 Collect ~XX mL (about x teaspoons) of blood for HIV testing, to check your general health, to 
check how much cholesterol is in your blood (a fatty substance in your blood), the health of your 
liver, the amount of study drug is in your blood, and for storage for study-related testing and 
long-term storage (if you provide consent). 
 Ask you questions about your sexual behavior.   
 Give you condoms and lubricant. 
 
Weeks 53, 65, and 77 Visits 
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 experienced any side effects from the shots 
you received, and ask you about any other medicines you are taking.   
 For women of childbearing potential:  Collect ~XX mL of urine for pregnancy testing. 
 Collect ~XX mL (about x teaspoons) of blood for HIV testing, to check the health of your liver, 
the amount of study drug in you, and for storage for study-related testing and long-term storage 
(if you provide consent). 
 At Week 53 only, we will test for three sexually transmitted infections called gonorrhea, 
chlamydia, and syphilis.  For gonorrhea and chlamydia, this will be done with urine if you are a 
man.    If you are a woman, this will be done with urine or a swab of your vagina or cervix. For 
men and women we will also test using a swab of your rectum. Blood will be collected for 
syphilis testing. 
 Ask you questions about your sexual behavior.   
 Give you condoms and lubricant. 
 
 


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Week 85, Final Visit 
These visits will last up to xx hours.  During this visit, the study staff will: 
 Talk with you about HIV and ways to protect yourself from getting it. 
 Give you a brief physical exam, ask you if you have experienced any side effects from the study 
shots you received, and ask you about any other medicines you are taking.   
 For women of childbearing potential:  Collect ~XX mL of urine for pregnancy testing. 
 Collect ~XX mL (about x teaspoons) of blood for HIV testing, to check the health of your liver, 
the amount of product in you, and for storage for study-related testing and long-term storage (if 
you provide consent). 
 Give you condoms and lubricants. 
 
Permanently Stopping Your Study Product If you permanently stop being on the study drug during 
the study for any reason, we may ask you to continue to come for your visits, but on a modified 
schedule.  We will fully explain to you what will be expected if you permanently stop getting the study 
drug. 
 
Sample Storage 
 
Each time blood is taken during a study visit, we will test some of it here in our laboratory at the site, 
and some of it will be stored for testing at designated laboratories in the United States.  [Non-US sites to 
add:  Swabs or other samples may also be sent for STI testing at designated laboratories in the United 
States].  
POSSIBLE FUTURE TESTS [Sites that are able to do this per country or IRB regulations to keep 
this included; otherwise, this should be removed, as well as the signature line for it on the signature 
page] 
Some of the blood that you give during this study may be left over after all of the study tests are 
completed.  We would like to keep this blood for an indefinite amount of time for future testing that may 
be unrelated to this study, but still related to HIV. You will be asked to sign at the end of this consent 
form to give permission for this. This blood will be stored and tested at designated laboratories in the 
United States.  Even if you do not give permission to store your blood after the study, you can still be in 
this study. You may also withdraw your consent for specimen storage at any time.    
RISKS AND/OR DISCOMFORTS 
Study Medications 
The drug being used in this study is currently being used in other people participating in similar studies. 
Those studies have reported side effects of the study drug, such as headaches, dizziness, upset stomach, 
rash, liver problems, fatigue, or injection site reaction (pain, irritation, skin redness, bumps, swelling, 
itching, bruising). Other reported side effects were nausea, stomach cramps, constipation, and right hand 
pain.   


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There have been some people who were taking this medicine in other studies who have had liver side 
effects.  All of these people were HIV-infected (HIV positive) and they all had some damage to their 
liver before taking the GSK 744 study medication.  In those studies, 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 are normal.  In HPTN 077, 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 
GSK 744.  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 in the study.  We will ask you about any neurologic 
symptoms during the study.      
In studies done in pregnant rats and their newborns, using very high amounts of GSK 744, there were 
more baby rats that died when they were born or right after they were born.  This did not happen to the 
baby rats when the mother got lower amounts of the drug, or no drug.  The amount of GSK 744 that we 
are giving in this study is expected to be more than 7-times lower than the amount given to the pregnant 
rats.  Birth defects have not been found in any animal studies of GSK 744 so far.  We do not know 
whether what happened to the baby rats has any impact on what will happen in pregnant humans taking 
this drug.  That is why if you are female and participating in this study, you cannot be pregnant, and we 
want you to take birth control the entire time you are in the study and also for a year after.  If you 
become pregnant, we will not give you any more study medication and we will ask you to stay in the 
study so that we can follow you carefully. 
 
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. 
There is a risk of local pain, bruising, swelling and rarely, an infection may occur at the injection site 
(where you got the shot). 
The shots you receive in this study are long acting, meaning they stay in your body for a long time. One 
single shot can stay in your body for up to one year. 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. You will be in the study for up to 85 
weeks. This is so that we can monitor your health for a year after your last injection.  
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. 
HIV Infection 
If you test positive for HIV during the study you will be asked to stop taking your study medication, but 
will continue to be followed in the study.  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 for at least one year after your last study medication injection.  The 


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study will not provide this treatment but may be able to help you find and/or pay for that treatment for 
the one-year treatment period. 
Pregnancy 
As mentioned above, there are no studies of pregnant women taking the drug being used in this study.  If 
you are pregnant, you are not eligible to be in this study. 
If you can get pregnant and are engaging in sexual activity that could lead to pregnancy, you must agree 
to use a form of contraception (an IUD or hormone-based contraceptive) during the trial.  If you stop 
being in the study during or right after the first part of the study, which is the part where you take the 
pills only, then you have to be on contraception for 30 days after taking your last pill.  If you stay in the 
study and get injections, then you have to be on contraception for one year after your last shot.    
If you express desire to become or become pregnant after joining the study, you will no longer receive 
the study product.  
If you become pregnant during the first part of the study, which is the part where you take pills only, you 
will not get any shots, and we will follow you until your pregnancy is over, and then your participation 
in the study will end.  If you become pregnant after you have had at least one shot, you will continue to 
be followed on study, but you will not get any more shots.   
If you are still pregnant when the study ends, we will still contact you and/or review your medical 
records until the outcome of your pregnancy is known by site staff.   
Not all contraceptive choices can prevent HIV transmission, and some may actually increase the risk of 
getting HIV.  We will talk with you throughout the study about ways to protect yourself from getting 
HIV.  You should also discuss with your health care provider and the study clinic staff ways to maintain 
effective contraception during your participation in the study.     
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 HIV test result.  If the tests show that you have HIV, you may 
worry about your health and future.  You will receive counseling before and after the test to help address 
your concerns.  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.   
Rectal Swabs, and Vaginal/Cervical Swabs (for women only) 
You may experience pain or discomfort form the rectal or vaginal/cervical swab.  In some cases, you 
may have some bleeding. 
Other Testing and Genetic Testing 
[Sites that are able to do this per country or IRB/EC regulations to keep this section included; 
otherwise, this should be removed, as well as the signature lines for it on the signature page] 


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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 
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.     
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. 
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. 
BENEFITS 
We will test you for HIV and hepatitis B and C during this study.  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 during the study, or have another 


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sexually transmitted infection, we will refer you for care and/or treatment as described earlier, and you 
will continue to be followed in the study.  At the screening visit we will also check if you have hepatitis 
B infection.  If needed, we will refer you for hepatitis B vaccination.  During the study you will have 
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 receive condoms and lubricant free of charge.   
You may not receive any other direct benefit from being in this study; however, 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 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.    
REIMBURSEMENT 
You will receive [$xx] for your time, effort, and travel to and from the clinic at each scheduled visit.  


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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.  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), study staff, study monitors, 
the companies that make the drugs used in this study, other government and regulatory authorities, 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. Any publication of this study will not use your name or 
identify you personally. 
Your records may be reviewed by: 
 US FDA 
 US NIH 
 US Department of Heath and Human Services (DHHS), Office of Human Research Protection 
(OHRP) 
 Other government and regulatory authorities 
 [insert names of applicable IRBs/ECs/other local eview bodies as applicable] 
 Study staff 
 Study monitors 
 The company  that makes the study drug (ViiV Healthcare) 
[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 


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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 
A Phase IIa Study to Evaluate the Safety, Tolerability and Pharmacokinetics of the 
Investigational Injectable HIV Integrase Inhibitor, GSK1265744, in HIV-uninfected Men and 
Women 
(HPTN 077) 
Version 3.0 
October 13, 2015 
DAIDS Document ID: 11964 
 
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. [Sites to add and edit the following sentence as it 
pertains to your site, e.g., if you are not allowing genetic testing, then do not include the words “genetic 
testing” in the sentence:  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 related to HIV 
infection.    
________ 
I do not agree to have samples of my blood stored and used for future testing related to 
HIV infection.  
________ 
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. 
________ 
I agree to allow my genetic information to be shared for future research purposes and for 
this information to be stored in a central genetic database. 
________ 
I do not agree to allow my genetic information to be shared for future research purposes 
or for this information to be stored in a central genetic database. 
   
 
 
 
____________________________________ 
Participant Name (print) 
 
 
Participant Signature and Date 
 
 
 
 
____________________________________ 
Study Staff Conducting 
 
 
Study Staff Signature and Date 
Consent Discussion (print) 
 
 
 
 
____________________________________ 
Witness Name (print)  
 
 
Witness Signature and Date 
(As appropriate) 


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APPENDIX XIII: SAMPLE HPTN 077 PARTICIPANT LETTER/INFORMATION SHEET 
FOR PARTICIPANTS ENROLLED UNDER VERSION 2.0 
 
A Phase IIa Study to Evaluate the Safety, Tolerability and Pharmacokinetics of the 
Investigational Injectable HIV Integrase Inhibitor, GSK1265744, in HIV-uninfected Men and 
Women 
 
(HPTN 077) 
 
Version 3.0 
October 13, 2015 
DAIDS Document ID: 11964 
 
Sponsored by:  Division of AIDS, United States (US) National Institute of Allergy and Infectious 
Diseases, US National Institutes of Health. Study products are provided by ViiV Healthcare 
Dear HPTN 077 Participant: 
We told you when you joined the study that we would tell you if we had any new information about this 
study or others that may impact you.  The purpose of this letter is to share with you five pieces of 
information from this study, from another study called ÉCLAIR, and also from other studies in animals.   
1.  ÉCLAIR is very similar to this study, and is being conducted in the United States in men only.  It is 
fully enrolled and is much farther along in progress than this study.  It uses the same dose (30 mg) of the 
pill-version of GSK 1265744 for 4-weeks, the and the same injectable form of the drug in the same 
amount (800 mg), at the same time in between shots (every 12 weeks) at three time points, and for the 
same purpose, to test whether it is safe and how people respond to it.     
In HPTN 077 and the ÉCLAIR study, the shots are given every 12 weeks because that is how long 
earlier studies in animals and humans showed that it lasted at high levels in the blood.  But, those studies 
did not involve a large number of animals or people. In the ÉCLAIR study that enrolled over 100 men, 
they recently did a planned check on the levels of drug in the blood of the participants, and it showed in 
some participants that the drug did not last at high levels for the entire 12 weeks.  Since it is hoped that 
this drug can eventually be used to protect people from getting HIV, it is important to find out how long 
the drug lasts in between shots so that people can remain protected.   
Because of these findings, in HPTN 077, we have decided to enroll a second group of participants that 
will test a slightly different dose of the same drug (600 mg) GSK1265744, given as a shot every 8 
weeks.  We plan to enroll about 88 participants in this new second group, in addition to the 
approximately 105 participants we currently have in the first group.  This will allow us to know whether 
this dose every 8 weeks is safe and whether it lasts in the blood at high levels between shots.  A lower 
dose was chosen since the shots are closer together in time (every 8 weeks instead of every 12 weeks).  
Your participation in the HPTN 077 study is very important because we still need to know that the 800 
mg dose every 12 weeks that what was found in the ÉCLAIR study in men was correct, and also to see if 
the same is true in women.   
2.  Some people who have had a prior history of seizures (epilepsy) have had seizures (spells) while 
taking GSK 744.  One person who did not have a previous history of seizures died after prolonged 
seizures.  You may have already been contacted by us to see if you have ever had a seizure.  If you have, 


HPTN 077 Final Version 3.0   
135 of 136 
October 13, 2015 
and you have not finished getting all of your shots, you will not get any more shots, and we will ask you 
to continue in the study.  If you have gotten all of your shots, we will continue to follow you in the 
study. Either way, we will ask you about any neurologic symptoms during the study.      
3.  In studies done in pregnant rats and their newborns, using very high amounts of GSK 744, there were 
more baby rats that died when they were born or right after they were born.  This did not happen to the 
baby rats when the mother got lower amounts of the drug, or no drug.  The amount of GSK 744 that we 
are giving in this study is expected to be more than 7-times lower than the amount given to the pregnant 
rats.  Birth defects have not been found in any animal studies of GSK 744 so far.  We do not know 
whether what happened to the baby rats has any impact on what will happen in pregnant humans taking 
this drug.  That is why if you are female and participating in this study, you cannot be pregnant, and we 
want you to take birth control the entire time you are in the study and also for a year after.  If you 
become pregnant, we will not give you any more study medication and we will ask you to stay in the 
study so that we can follow you carefully. 
4.  We told you when you started the study that there have been some people who were taking this 
medicine in other studies who have had liver side effects.  All of these people were HIV-infected (HIV 
positive) and they all had some damage to their liver before taking the GSK 744 study medication.  In 
those studies, 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 are normal.  That is 
why anyone in HPTN 077 will not be able to participate if they have HIV-infection, Hepatitis C (or B), 
or any liver irritation.    
5.  We told you that the study drug was being provided by GlaxoSmithKline and ViiV Healthcare.  Only 
ViiV Healthcare is providing the study drug now.   
We will continue to update you on any new information, including side effects that we see in this study 
and other on-going studies, and if those side effects appear to have come from the drug.   
The HPTN 077 study team wants you to continue in the study.   Your continued participation in HPTN 
077 is, as it has always been, entirely voluntary.  
 
If you have any questions now or later about the information provided in this letter, you may ask the 
study staff or contact me directly.  We will do our best to answer any questions or concerns that you 
may have.   
 
Your participation in the HPTN 077 will lead to important discoveries that will hopefully lead to better 
prevention methods for protection against HIV infection.  Thank you for participating in HPTN 077.  
 
Sincerely,  
 
[Insert name and contact information of Investigator of Record] 
 
 
 
 


HPTN 077 Final Version 3.0   
136 of 136 
October 13, 2015 
If you have read this letter, or have had it read and explained to you, and understand the information, please 
sign your name below.   
   
________ 
I agree to continue to take part in this study.  
________ 
I do not agree to continue to take part in this study.   
   
 
 
 
____________________________________ 
Participant Name (print) 
 
 
Participant Signature and Date 
 
 
 
 
____________________________________ 
Study Staff Conducting 
 
 
Study Staff Signature and Date 
Consent Discussion (print) 
 
 
 
 
____________________________________ 
Witness Name (print)  
 
 
Witness Signature and Date 
(As appropriate) 
 
 

SAP_000.pdf: 
CONFIDENTIAL 
 
Protocol HPTN 077 
Statistical Analysis Plan 
December 17, 2014 
Page 1 of 32 
 
 
 
STATISTICAL ANALYSIS PLAN 
Protocol HPTN 077 
A Phase IIa Study to Evaluate the Safety, Tolerability and Pharmacokinetics of the 
Investigational Injectable HIV Integrase Inhibitor, GSK1265744, in HIV-uninfected Men and 
Women 
 
April 09, 2018 
Version 2.2 
Prepared by 
 
 
Sue Li 
HPTN SDMC Statistician 
 
Gordon Chau 
SCHARP Statistical Research Associate 
 
 
 
 
 


 
CONFIDENTIAL 
 
HPTN 077 
Statistical Analysis Plan 
2 
 
SAP Modification History 
SAP modified SAP v1 according to the protocol HPTN 077 final version 3.0 that includes the 
second cohort.    
SAP v2.1 modified SAP v2 according to Letter of Amendment #3 to HPTN 077.   
SAP v2.2 updated tables and figures templates for the final study report and added an algorithm 
of defining the phase for AEs  
 
 
 
 


 
CONFIDENTIAL 
 
HPTN 077 
Statistical Analysis Plan 
3 
 
Table of Contents 
1 
INTRODUCTION .............................................................................................................................. 6 
2 
PROTOCOL SUMMARY.................................................................................................................. 6 
2.1 
Title ..................................................................................................................................... 6 
2.2 
Primary Objectives .............................................................................................................. 6 
2.3 
Study Product Regimens/Administration/Formulation Content .......................................... 6 
2.4 
Schema ............................................................................................................................... 7 
3 
OBJECTIVES AND ENDPOINTS .................................................................................................... 9 
3.1 
Primary Objectives and Endpoints ...................................................................................... 9 
3.2 
Secondary Objectives and Endpoints ................................................................................. 9 
3.3 
Exploratory Objectives and Endpoints .............................................................................. 10 
4 
STUDY DESIGN ............................................................................................................................ 11 
4.1 
Participants ....................................................................................................................... 11 
4.2 
Design ............................................................................................................................... 11 
4.3 
Study Duration .................................................................................................................. 11 
4.4 
Study Visits ....................................................................................................................... 11 
4.5 
Allowable Visit Windows ................................................................................................... 12 
4.6 
Study Sites ........................................................................................................................ 12 
4.7 
Randomization .................................................................................................................. 12 
4.8 
Blinding ............................................................................................................................. 13 
5 
PLANNED ANALYSES .................................................................................................................. 13 
5.1 
Interim Analysis ................................................................... Error! Bookmark not defined. 
5.2 
Primary Analysis ............................................................................................................... 14 
5.3 
Final Analysis .................................................................................................................... 14 
6 
STUDY POPULATIONS ................................................................................................................ 14 
6.1 
Screened Population ......................................................................................................... 14 
6.2 
Randomized Population .................................................................................................... 14 
6.3 
Safety Population .............................................................................................................. 14 
6.4 
Primary/Injectable Safety Population ................................................................................ 15 
6.5 
Pharmacokinetic Concentration Population ...................................................................... 15 
6.6 
Pharmacokinetic Parameter Population ........................................................................... 15 
6.7 
Pharmacogenomic Population .......................................................................................... 15 
7 
ASSESSMENT WINDOWS ........................................................................................................... 15 
7.1 
Treatment Periods ............................................................................................................. 15 
7.2 
Baseline Definition ............................................................................................................ 16 
8 
DATA HANDLING/MANAGEMENT ............................................................................................... 16 
8.1 
Premature Withdrawal and Missing Data ......................................................................... 16 
8.1.1 
Premature Withdrawal ......................................................................................... 16 


 
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HPTN 077 
Statistical Analysis Plan 
4 
 
8.1.2 
Methods for Missing Data .................................................................................... 16 
8.2 
Derived and Transformed Data ......................................................................................... 16 
8.2.1 
Age ....................................................................................................................... 16 
8.2.2 
Changes from the Baseline .................................................................................. 17 
8.2.3 
Corrected QT Intervals ......................................................................................... 17 
9 
STATISTICAL DATA ANALYSES .................................................................................................. 17 
9.1 
Analysis Tools ................................................................................................................... 17 
9.2 
Analysis Variables ............................................................................................................. 17 
9.3 
General Approach ............................................................................................................. 17 
9.4 
Baseline Characteristics ................................................................................................... 18 
9.5 
Safety Analysis .................................................................................................................. 18 
9.5.1 
Injection Site Reaction (ISR) ................................................................................ 18 
9.5.2 
AEs ....................................................................................................................... 18 
9.5.3 
Local Laboratory Values ...................................................................................... 19 
9.5.4 
Other Safety Measures ........................................................................................ 19 
9.5.5 
Safety Endpoint .................................................................................................... 20 
9.5.6 
Reasons for Treatment Discontinuation and Early Study Termination ................ 20 
9.6 
Tolerability ......................................................................................................................... 21 
9.7 
Pharmacokinetics .............................................................................................................. 21 
9.7.1 
Association between Pharmacokinetics and Baseline Characteristics ................ 21 
9.8 
Study Medication Satisfaction Questionnaire ................................................................... 22 
9.9 
Acceptability Questionnaire .............................................................................................. 22 
9.10 
Sexual Risk Behaviors ...................................................................................................... 22 
9.11 
HIV Incidence .................................................................................................................... 23 
9.12 
Evaluate the Safety, Tolerability and Pharmacokinetics of 744LA in the Women Who Use 
Injectable Hormonal Contraception ................................................................................... 23 
9.13 
Exploratory Analyses ........................................................................................................ 24 
10 
SMC REPORTS ............................................................................................................................. 24 
10.1 
Study Conduct Report (SMC Open Report) ..................................................................... 24 
10.1.1  List of Tables ........................................................................................................ 24 
10.1.2  List of Graphs ....................................................................................................... 25 
10.2 
Safety Tables and Graphs (SMC Close Report) ............................................................... 25 
10.2.1  List of Tables ........................................................................................................ 25 
10.2.2  List of Graphs ....................................................................................................... 26 
11 
FINAL STUDY REPORT (FSR) ..................................................................................................... 27 
11.1 
Study Population Summary .............................................................................................. 27 
11.1.1  Lists of Tables ...................................................................................................... 27 
11.2 
Safety and Tolerability Analysis ........................................................................................ 28 
11.2.1  Lists of Tables ...................................................................................................... 28 
 


 
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HPTN 077 
Statistical Analysis Plan 
5 
 
11.2.2  List of Figures ....................................................................................................... 28 
11.3 
Pharmacokinetic and Other Secondary Analyses ............................................................ 29 
11.3.1  List of Tables ........................................................................................................ 29 
11.3.2  List of Figures ....................................................................................................... 29 
12 
ATTACHMENTS ............................................................................................................................ 30 
13 
REFERENCE ................................................................................................................................. 31 
 
 
 


 
CONFIDENTIAL 
 
HPTN 077 
Statistical Analysis Plan 
6 
 
1 
INTRODUCTION  
 
This Statistical Analysis Plan (SAP) provides details on planned study statistical analyses 
and reports for HPTN 077. This SAP is required prior to the first analysis and must be 
approved by the protocol chair and reviewed by GSK statistician. The plan might be 
updated if needed prior to any interim analyses and before the final analysis. Any updates 
will be archived. The contents of SAP are based on the protocol HPTN 077 final version 3.0 
and are modified to extend the tail visits according to Letter of Amendment #3.  
2 
PROTOCOL SUMMARY 
2.1 Title  
 
A Phase IIa Study to Evaluate the Safety, Tolerability and Pharmacokinetics of the 
Investigational Injectable HIV Integrase Inhibitor, GSK1265744, in HIV-uninfected Men and 
Women 
2.2 Primary Objectives  
 
 
Evaluate the safety and tolerability of the injectable agent GSK1265744 long acting 
(744LA) injectable (800 mg dose administered at three time points at 12 week intervals), 
through Week 41 in HIV-uninfected men and women. 
 
Evaluate the safety and tolerability of the injectable agent GSK1265744 long acting 
(744LA) injectable (600 mg dose administered at two time points at 4 week intervals, 
followed by three time points at 8 week intervals), through Week 41 in HIV-uninfected 
men and women. 
2.3 Study Product Regimens/Administration/Formulation Content 
 
Study Product Regimens 
Both Cohorts: 
Oral lead-in phase:  Participants will be randomized 3:1 to one of two study arms: 
 
Arm 1:  GSK1265744 tablets 30 mg – one tablet orally daily for 4 weeks, with or 
without food 
 
Arm 2:  Placebo for GSK1265744 – one tablet orally daily for 4 weeks, with or 
without food 
Injectable phase:  After a one week washout period to assess safety, participants will begin 
injections (with the same randomization as the oral lead-in phase) as:  
Cohort 1: 
 
Arm 1:  GSK1265744 (744 LA) 800 mg administered as two 2 mL (400 mg) IM 
injections in the gluteal muscle at Weeks 5, 17, and 29  


 
CONFIDENTIAL 
 
HPTN 077 
Statistical Analysis Plan 
7 
 
 
Arm 2:  Placebo for GSK1265744 (744 LA Placebo) administered as two 2 mL  
injections in the gluteal muscle at Weeks 5, 17, and 29  
Cohort 2:   
 
Arm 1:  GSK1265744 (744 LA) 600 mg administered as one 3mL (600 mg) IM 
injections in the gluteal muscle at Weeks 5, 9, 17, 25 and 33  
 
Arm 2:  Placebo for GSK1265744 (744 LA Placebo) administered as one 3 mL 
injections in the gluteal muscle at Weeks 5, 9, 17, 25 and 33  
Study Product Formulations 
Oral product:   
 
GSK1265744 tablets 30 mg 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 a desiccant.  The bottles should be stored up to 25 
degrees Celsius (25o C) and protected from moisture.     
 
Placebo tablets for GSK1265744 are formulated as white to almost white oval-
shaped coated tablets to visually match the active GSK1265744 tablets.  The 
tablets are packaged in high density polyethylene (HDPE) bottles with child-
resistant closure that include an induction seal. The bottles contain a desiccant.  
The bottles should be stored up to 25 degrees Celsius (25o C) and protected from 
moisture.   
Injectable Suspension:   
 
The GSK1265744LA is formulated as a sterile white to slightly colored suspension 
containing 400mg/2mL of GSK1265744 for administration by intramuscular (IM).  Th 
e product is packaged in a 3 mL vials.  Each vial is for single use containing a 
nominal fill of 2mL (400 mg), and does not require dilution prior to 
administration.  The GSK1265744LA injectable suspension is to be stored at 2 
degrees Celsius to 30 degrees Celsius (2o C – 30o C), do not freeze.  
 
Placebo for GSK1265744 Injectable Suspension will be Sodium Chloride for 
Injection USP, 0.9%.   
Syringes containing active and placebo study product will be covered with an overlay by the 
study Pharmacist of Record or designee prior to dispensing in order to maintain the blind, 
as per the SSP Manual. 
The study product 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, which will be provided by the DAIDS 
Regulatory Support Contract (RSC). 
2.4 Schema 
Cohort 1 


 
CONFIDENTIAL 
 
HPTN 077 
Statistical Analysis Plan 
8 
 
 
    W = Week 
Cohort 2 
 
 
 
 
 
 
 
 
 
The 110 participants in Cohort 1 and 90 participants in Cohort 2 were randomized to one of the 
two study arms with an active GSK 744 to placebo ratio of 3:1, stratified by gender and region 
(US and non US), as follows: 
Cohort 1 
Arm 1:  82 participants received daily oral 744 (30 mg tablets) for 4 weeks, followed by an one 
week washout period, to establish safety and tolerability, followed by intra-muscular (IM) gluteal 
injections of 800 mg of 744LA (administered as two sequential 400 mg gluteal injections) at 
three time points at 12 week intervals as:  Week 5, Week 17, and Week 29.    
Arm 2:  28 participants received daily oral matching placebo and IM injections of vehicle-
matched placebo on the same schedule as Arm 1.   
 


 
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HPTN 077 
Statistical Analysis Plan 
9 
 
Cohort 2 
Arm 1:  Approximately 66 participants will receive daily oral 744 (30 mg tablets) for 4 weeks, 
followed by a one week washout period, to establish safety and tolerability, followed by intra-
muscular (IM) gluteal injections of 600 mg of 744LA (administered as one 600 mg gluteal 
injection) at five time points at 4 and 8 week intervals as:  Week 5, Week 9, Week 17, Week 25, 
and Week 33.    
Arm 2:  Approximately 22 participants will receive daily oral matching placebo and IM 
injections of vehicle-matched placebo on the same schedule as Arm 1.   
All participants will receive HIV testing with pre- and post-test counseling, in addition to risk-
reduction counseling and condoms and lubricant. All participants will be followed according to 
the Schedule of Evaluations and Procedures provided in HPTN077 protocol Appendices I-IV. 
3 
OBJECTIVES AND ENDPOINTS 
3.1 
Primary Objectives and Endpoints 
 
Primary Objective 
 
Evaluate the safety and tolerability of the injectable agent, GSK1265744 long acting 
(744LA) injectable (800 mg dose administered at three time points at 12 week intervals) 
through Week 41 in HIV-uninfected men and women 
 
Evaluate the safety and tolerability of the injectable agent GSK1265744 long acting 
(744LA) injectable (600 mg dose administered at two time points at 4 week intervals, 
followed by three time points at 8 week intervals), through Week 41 in HIV-uninfected 
men and women. 
Primary Endpoints 
Safety endpoint:  Proportion of participants experiencing any Grade 2 or higher clinical 
AEs and laboratory abnormalities that occur from the initial injection to 12 weeks after the 
last injection among participants who receive at least one injection (injectable phase only) 
Tolerability endpoint:  Proportion of participants who receive at least 1 injection and who 
discontinue receiving injections prior to the full course of 3 injections due to intolerability of 
injection (including but not limited to ISR), frequency of injections, burden of study 
procedures, or any AE. 
These cohorts may be aggregated for an overall analysis if appropriate.   
3.2 Secondary Objectives and Endpoints 
 
Secondary Objectives 
 
 
Evaluate the safety and tolerability of GSK1265744 (daily oral 744 + 744LA) for 76 
weeks of follow-up after final injection (each cohort will be analyzed separately) 
 
Evaluate the safety and tolerability of oral 744 from Week 0 to Week 5 


 
CONFIDENTIAL 
 
HPTN 077 
Statistical Analysis Plan 
10 
 
 
Evaluate the pharmacokinetics of 744LA administered as 800 mg IM every 12 weeks 
for 52 weeks of follow-up after final injection  
 
Evaluate differential pharmacokinetics of 744LA in participants by age, gender, race, 
ethnicity, weight, body mass index (BMI), and smoking status 
 
Evaluate the acceptability of 744LA injections   
 
Evaluate the effect of 744LA on sexual risk behavior by change from enrollment for  
repeat assessments to during the study period  
 
Evaluate HIV incidence and antiretroviral drug resistance, if any participants acquire 
HIV infection during the study  
 
Evaluate the safety, tolerability and pharmacokinetics of 744LA in the subset of 
women who use a hormone-based contraceptive 
Secondary Endpoints 
 
 
Proportion of participants who discontinue either oral or injectable study product for 
reasons of toxicity, tolerability, or acceptability prior to completion of the full oral and 
injectable phases 
 
Proportion of participants experiencing Grade 2 or higher clinical AEs and laboratory 
abnormalities during 52 weeks following final injection (safety) and any AE that leads 
to discontinuation (tolerability) during the aggregate oral and injectable phases  
 
Proportion of participants experiencing Grade 2 or higher clinical AEs and laboratory 
abnormalities (safety) and any AE that leads to discontinuation (tolerability) in the 
oral phase and washout period 
 
Plasma drug levels of GSK1265744 at designated time points after each injection of 
744LA (by cohort only) 
 
Plasma drug levels of GSK1265744 at designated time points after each injection of 
744LA stratified by age, gender, race, ethnicity, weight, BMI, and smoking status 
 
Proportion of participants willing to use an injectable agent such as the study product 
for HIV prevention in the future 
 
Change from enrolment of self-reported sexual behaviour (number of sexual 
partners, episodes of unprotected anal and/or vaginal intercourse) during the study 
period using a standardized assessment tool (in aggregate only) 
 
Number of incident HIV infections through the study period, including number with  
treatment emergent resistance 
 
Proportion of injectable hormonal-contraception-using female participants who reach 
a safety or tolerability endpoint as defined above 
3.3 
Exploratory Objectives and Endpoints 
 
Exploratory Objectives 
 


 
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HPTN 077 
Statistical Analysis Plan 
11 
 
 
Explore relationships between safety parameters and GSK1265744 concentrations 
and/or participant demographic factors 
 
Explore genetic factors that may impact the pharmacokinetics of 744LA 
 
Perform secondary laboratory assessments which 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 
Exploratory Endpoints 
 
 
Relationships between observed AEs and pharmacokinetic parameters (including but 
not limited to GSK1265744 Cmax and Cmin and AUC) and participant demographic 
data  (individual and in aggregate)  
 
Relationships between pharmacogenetics (evaluated by Genome Wide Association 
Study [GWAS], which will inform subsequent targeted analyses) and 
pharmacokinetic parameters or incidence of AEs (any and by organ class and 
individual AE)    
4 
STUDY DESIGN 
4.1 
Participants 
 
200 men and women at low to minimal risk for acquiring HIV infection, ages 18 to 65, 
randomized 3:1, with approximately 150 in the active drug arm, and 50 in the placebo 
arm. It is anticipated that approximately 60% of the enrolled participants will be women.   
4.2 
Design 
 
This is a multi-site, double-blind, two-arm, randomized, placebo-controlled trial of the 
safety, tolerability, and acceptability of 744LA.  
4.3 
Study Duration 
 
 Approximately 3 years.  Accrual will require approximately 16 to 24 weeks (4 – 6 
months) for each cohort.  Study participants in both cohorts will receive oral tablets for 4 
weeks, followed by a 1 week wash out period. Cohort 1 will then receive intra-muscular 
injections at 3 time points over 24 weeks (6 months); cohort 2 will receive intra-muscular 
injections at five time points over 28 weeks (7 months).  Participants in the active study 
product arm will be followed for 76 weeks (18 months) after their last injection.  Participants 
in the placebo arm will be followed until 76 weeks after their last injection or until the last 
participant in the active study product arm in cohort 2 completes their Week 41 visit, 
whichever comes first, at which time the study will be unblinded to assess the primary 
endpoint.  When all procedures related to unblinding are completed, participants in the 
placebo arm will no longer be followed.   
4.4 
Study Visits 
Cohort 1: 


 
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HPTN 077 
Statistical Analysis Plan 
12 
 
 
Week 0: enrollment visit 
 
Weeks 2 and 4: oral phase safety visits 
 
Week 5: the first injection visit 
 
Weeks 6, 9, 13: safety visits after the 1st injection 
 
Week 17: the second injection visit 
 
Weeks 18 and 23: safety visits after the 2nd injection 
 
Week 29: the third injection 
 
Weeks 30, and 35: safety visits after the 3rd injection 
 
Week 41: primary endpoint visit  
 
Weeks 53, 65, 77, 89, 101: tail phase safety visit 
 
Week 105: final study visit.   
Cohort 2: 
 
Week 0: enrollment visit 
 
Weeks 2 and 4: oral phase safety visits 
 
Week 5: the first injection visit 
 
Week 6: safety visits after the 1st injection 
 
Week 9: the second injection visit 
 
Weeks 10 and 13: safety visits after the 2nd injection 
 
Week 17: the third injection visit 
 
Weeks 18 and 21: safety visits after the 3nd injection 
 
Week 25: the forth injection 
 
Weeks 26, and 29: safety visits after the 4th injection 
 
Week 33: the fifth injection visit 
 
Week 34 and 37: safety visits after the 5th injection 
 
Week 41: primary endpoint visit  
 
Weeks 53, 65,  77, 89, 101: tail phase safety visit 
 
Week 109: final study visit.   
 
4.5 
Allowable Visit Windows 
 
The allowable visit windows for all visits, including injection visits, are outlined in Section 
12 Data Management of SSP Manual.  The allowable visit windows are pre-specified 
around the targeted visit windows. If a participant is unable to report to the visit during this 
time frame, or if a participant misses his/her appointment within the visit time frame, the 
CMC must be contacted for consultation regarding whether rescheduling outside of the 
visit window is allowable. Visits that occur outside of the allowable visit windows are coded 
either late or early.  
4.6 
Study Sites 
  
HIV Prevention Trials Network (HPTN)-affiliated Clinical Trial Units (CTUs) and/or 
Clinical Research Sites (CRSs) participating in this study is listed in the SSP Manual, and 
include sites in Brazil, sub-Saharan Africa (SSA), and the United States (US).      
4.7 
Randomization 
 
Enrolled participants are randomized to one of two study arms with an active 
GSK1265744 to placebo ratio of 3:1 in two cohorts. The arm randomization is stratified by 


 
CONFIDENTIAL 
 
HPTN 077 
Statistical Analysis Plan 
13 
 
gender and region (US and non-US sites) and done in blocks to ensure balanced 
treatment assignments within each gender and region (US and non-US).  The 
randomization scheme is generated, operationalized and maintained by HPTN SDMC 
using Frontier Science & Technology Research Foundation, Inc. (FSTRF) system. 
Additional details regarding the process of randomization are included in the SSP 
Manual. 
4.8 
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 last participant enrolled in to the active drug arm in cohort 2 has completed their 
Week 41 visit (the time point of the primary endpoint of the study), and when all data 
related to the Week 41 visit has been entered into the database, as well as cleaned and 
verified.  At a specified time directed by the HPTN SDMC, participants will be unblinded 
to their treatment assignment, and participants in the placebo arm will no longer need to 
be followed.  Participants in the active study product arm will continued to be followed for 
52 weeks after their last injection.   
5 
PLANNED ANALYSES 
5.1 
SMC Report  
The HPTN Study Monitoring Committee (SMC) will be utilized in this study to ensure 
objective medical and/or statistical review of safety issues in order to protect the ethical 
and safety interests of participants and to protect the scientific validity of the study. The 
SMC will conduct interim reviews of the study data approximately every 6 months. Study 
data including rates of subject accrual, visit retention, progression of primary and main 
secondary endpoint assessments, data collection and laboratory issues will be shared by 
the study team with the SMC in an open session.  In a closed report, safety data by 
unblinded treatment arm will be provided to the SMC by HPTN SDMC in the closed report.  
The first SMC review will be conducted when approximately 50% of the subjects complete 
Week 17 (second injection) and at least every six months thereafter.  
5.2 
Interim Analysis 
An interim analysis will be performed when 50% of the participants have completed their 
primary endpoint visit (Week 41). All data available at that time will be included in the 
analysis. Pharmacokinetic data will be analyzed when approximately 50% of Cohort 1 
reaches Week 29 (two troughs) for Cohort 1 participants, and when approximately 50% of 
Cohort 2 reaches Week 17 (two troughs) for Cohort 2. 
With the approval from HPTN SMC, the unblinded summaries of the safety and 
pharmacokinetic data from the analysis may also be provided to the key members of the 
protocol team and possibly to regulatory agencies to facilitate an initiation of a phase III 
trial.  All members of the protocol team, including GSK and ViiV Healthcare, as well as 
study participants will remain blinded to individual participant treatment assignment.  The 
data from this analysis may also be combined with the interim data from a similar study 
being conducted by GSK/ViiV, if needed and appropriate.  Pooled summaries will also be 
provided to the study team to share with regulators.  
To maintain the integrity of the clinical study, only the following staff may be unblinded at 
these SMC interim analyses, as deemed necessary by the SMC: selected clinical 


 
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HPTN 077 
Statistical Analysis Plan 
14 
 
pharmacometrician, programmer, and statisticians who will use unblinded 744 
concentrations to build the population PK models, and staff who will incorporate safety 
data from this analysis into regulatory documents for other studies of 744. The primary 
study team (medical monitor, clinical study team leader, operational scientist, data 
manager) should remain blinded until all subjects complete the week 41 visit and the data 
has been entered and cleaned and all major protocol violators have been identified. The 
primary study team will only receive unblinded summary tables and figures for the planned 
interim analysis. 
5.3 Primary Analysis 
 
A clinical database will be authorized and released for reporting on the unblinded 41-week 
safety and tolerability results that encompass the primary endpoints of this study. These 
findings will be used for internal decision making, possible reporting at scientific meetings, 
and as needed for regulatory submissions. 
5.4 Final Analysis 
 
The final planned analyses will be performed after all participants have completed the 
follow-up phase and after database freeze. 
 
6 
STUDY POPULATIONS 
 
The data collected from the enrolled participants will be analyzed according to the actual 
treatment that the participants have received.  A subset of the enrolled participants might 
be evaluated in some analyses. For instance, in the primary safety analysis, the safety 
data from the participants who have completed at least one injection will be analyzed. We 
define this subset of the enrolled participants as the Injectable/Primary Safety Population 
below in Section 6.4.    
6.1 Screened Population 
 
The Screened Population will consist of all participants who are screened for inclusion in 
the study.  
6.2 Randomized Population 
 
The Randomized Population will consist of all participants who meet the study criteria and 
are randomly assigned to a treatment in the study at the enrollment date.   
6.3 Safety Population 
 
The Safety Population will consist of the participants who are enrolled in the study and 
have received at least one dose of the study product. In the analyses, the participants will 
be grouped based on the initial randomization assignments regardless how many doses of 
the study product they have received.  


 
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6.4 Primary/Injectable Safety Population 
 
The Primary/Injectable Safety Population is a subset of the Safety Population that consists 
of the participants who have received at least one injection of study product. In the 
analyses, the participants will be grouped based on the initial randomization assignment 
regardless how many injections they have received.  
6.5 Pharmacokinetic Concentration Population 
 
The Pharmacokinetic Concentration Population will consist of the participants in the 
Injectable Safety Population who have plasma sample(s) collected for PK assay. 
 
6.6 Pharmacokinetic Parameter Population 
 
The Pharmacokinetic Parameter Population will consist of the participants in the Injectable 
Population who are also assigned to receive the 744 study product and have available 
samples for PK assay. 
 
6.7 Pharmacogenomic Population 
 
The Pharmacogenomic Population will be determined later.  
 
7 
ASSESSMENT WINDOWS 
7.1 Treatment Periods 
 
Adverse events, laboratory, vital signs and liver events will be assessed and denoted 
within the treatment periods that are defined below.    
Oral Phase is defined as the time between the enrollment date (Week 0) and the day of 
the 1st injection (Week 5) or the day of withdrawal, whichever comes first.   
Injection Phase is defined as the time between the first injection and the 12 weeks visit 
after the last injection.  For the participants who complete all three injections, the injection 
phase assessment window is the time between Week 5 and Week 41 visits. For the 
participants who complete the two injections, the injection phase assessment window is 
the time between Week 5 visit and Week 29 visit.  For the participants who complete only 
the first injection, the injection phase assessment window is the time between Week 5 visit 
and Week 17 visit.   
Tail Phase is defined as the time between Week 41 to Week 105/109 for ITT analysis. 
However, for per protocol analysis such as pharmacokinetics analysis, for the participants 
who did not complete full injections (3 injections for cohort 1 and 5 injections for cohort 2), 
the tail phase assessment window starts at the 12th (the 8th) weeks after the last injection 
for cohort 1 (cohort 2) to the last follow-up visit.   


 
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On-Treatment is defined as the time between the beginning of the oral phase and the end 
of the follow-up phase (from the participants’ enrollment day to the participants’ last day 
subject’s last day in the study).  
 
7.2 Baseline Definition 
 
The data collected at the enrolment date will be considered as the baseline data for 
minoring and evaluating the safety, tolerability, and acceptability of the investigating study 
product and other analyses unless it is specified.  In some cases, the assessments at 
Week 5 prior to the first injection will be considered as the baseline.    
 
8 
DATA HANDLING/MANAGEMENT 
 
All data will be collected and saved in CRF database and laboratory database. The details 
of data collection and data management are provided in Section 12 Data Management in 
SSP.  
 
8.1 Premature Withdrawal and Missing Data 
8.1.1 
Premature Withdrawal 
The reason(s) for withdrawal from the study must be recorded by the investigator in the 
CRF, including the participant’s reason for withdrawn consent. Withdrawn participants will 
not be replaced. All available data from those who withdraw from the study earlier will be 
included in the analyses according to the study populations defined in Section 6. In the 
case that the study is prematurely discontinued, all available data will be used in the 
analyses that are still considered appropriate. 
 
8.1.2 
Methods for Missing Data 
Missing data will occur when any requested data is not provided, leading to blank fields on 
the collection instrument. Answers such as “Not applicable” and “Not evaluable” are not 
considered to be missing data and should be displayed as such. Missing data will occur if 
the participants will miss visits and withdraw from the study prior to complete the study 
regimen.   
8.2 Derived and Transformed Data 
 
8.2.1 
Age 
 
The participants’ date of birth or age will be recorded in CRF. If the age is not recorded in 
CRF, the age will be calculated based on the date of birth and the date of the completion 
of the CRF. In a case that the date of birth will be used in the calculation of the age, if the 
date of birth is partial missing, the missing month will be imputed by June; the missing day 


 
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will be imputed as the 30th; Otherwise, if the date of birth is missing completely, the date of 
birth will not be imputed and the age will be missing.   
 
8.2.2 
Changes from the Baseline 
 
For the variables that the changes from the baseline will be evaluated in the analyses, the 
changes will be calculated by subtracting the baselines values of the variables from the 
values at post-baseline visits.  If the baseline or the post-baseline value is missing, then 
the change from the baseline will be missing. 
 
8.2.3 
Corrected QT Intervals 
The corrected QT interval measured by Bazett’s (QTcB) or Fridericia’s (QTcF) will be 
recorded in CRF.  
 
9 
STATISTICAL DATA ANALYSES  
 
All data from enrolled participants will be analyzed according to the Analysis Populations 
described in Section 6.  
9.1 
Analysis Tools 
 
Analyses for primary endpoints will be performed in SAS. All other descriptive and 
inferential statistical analyses will be performed using SAS and/or R statistical software. 
9.2 
Analysis Variables 
 
The analysis variables consist of baseline participant characteristics, safety, tolerability, 
acceptability, sexual risk behavioral, and pharmacokinetics for primary, secondary, and 
exploratory analyses.   
9.3 
General Approach 
 
When the use of descriptive statistics to summarize the study populations’ characteristics 
is required, the following statistics will be used: for categorical variables, the number and 
percent in each category; for continuous variables, the mean, median, standard deviation, 
quartiles and range (minimum, maximum). When the use of a statistical test to assess the 
difference between two different time points within each the treatment arm is required, the 
following tests will be used: for categorical variables, McNemar test; for continuous 
variables the paired t-test or Wilcoxon signed-ranks test.  When use of a statistical test to 
assess the differences between the two treatment arms is required, the following 
tests/models will be used: for binomial response variables, chi-square tests (Fisher Exact 
test will be used if there are cells with less than 5) or logistic regression models if other 
covariates need to be adjusted in the model; for continuous variables, t-test if the data are 
normal distributions) or nonparametric Wilcox rank sum test if data are not normally 


 
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distributed or linear regression models if other covariates need to be adjusted. Additional 
analyses will also be performed and described below.  
To assess the adequacy of the randomization, participants in each of the two arms will be 
compared for baseline characteristics including demographics and laboratory 
measurements. 
9.4 
Baseline Characteristics  
 
A table that includes the baseline characteristic variables of the enrolled participants will 
be presented. Summary statistics appropriate for the measurement scale will be used to 
describe the distribution of these variables. These summary statistics will be presented in 
tables by cohort and study arm among the enrolled participants in the oral phase and as 
well as among the participants that will be enrolled in the injection phase. Baseline 
characteristics will be compared between two study arms using chi-square test for 
categorical variables such as gender and using t-test or for continuous variables. The 
summary tables will be also stratified by US sites and Non-US sites to see whether 
theses baseline measures differ by US sites vs international sites. The comparisons 
between the two treatment arms will be adjusted for sites (US vs. Non-US) if the 
differences are observed between US and Non-US sites.  
9.5 
Safety Analysis 
 
Safety data will be analyzed using the data from the safety populations described above 
respectively for each safety analysis.  Safety will be analyzed by cohort and in aggregate.   
9.5.1 
Injection Site Reaction (ISR)  
 
The number and percentage of participants experiencing each type of ISR sign or 
symptom will be tabulated by severity and treatment arm. For a given sign or symptom, 
each participant’s ISR will be counted once under the maximum severity for all injection 
visits as well as by each successive injection. ISR other characteristics will be 
summarized by treatment arm and injection.  
If a participant is observed with any inflammation symptom, the participant’s temperature 
will be taken and reported in ISR CRF.  The temperature will be graded according to the 
DAIDS Grading Table 2014 V2.0 and will tabulated by study arm by each injection and 
compared between the two arms using Chi-square test.       
9.5.2 
AEs  
 
AEs will be summarized using MedDRA system organ class and preferred terms.  The 
number and percentage of participants experiencing each specific AE within a System 
Organ Class or within preferred term will be tabulated by severity or by relationship to 
study product within each treatment arm.  For the calculations in these tables, a 
participant with multiple AEs within a category during the evaluating phase of the study 
will be counted once under the maximum severity or the strongest recorded causal 
relationship to study product.  AEs will be summarized for those that will occur during the 
injection phase separately from those that will occur during the oral phase and as well as 
for those that will occur during the entire treatment phase of the study (the oral and the 


 
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injection phase).  AEs leading to temporarily or permanently stopping drug will also be 
summarized by treatment arm.   
A listing of EAEs reported to the DAIDS RSC Safety Office will provide details of the 
events including severity, relationship to study product, time between onset and last 
injection, number of injections received, and a summary of the event. 
9.5.3 
Local Laboratory Values 
 
Scatter plots of some local laboratory values measured during the course of the study vs. 
the values at the baseline. If appropriate, horizontal/vertical lines representing boundaries 
for abnormal values will be plotted. 
For each local laboratory measure, summary statistics will also be presented by 
treatment arm and visit time, as well as changes from baseline for post-enrollment 
values. Clinical laboratory abnormalities without an associated clinical diagnosis will also 
be reported as AEs and will be included in the tabulation of AEs described above. 
In addition, the number (percentage) of participants with local laboratory values recorded 
as meeting Grade 1 AE criteria or above as specified in the DAIDS AE Grading Table 
(see Section 6.4.2 of the protocol) will be tabulated by treatment arm for each safety visit 
time point. In addition to SAEs, a list of the participants with the results: ALT≥3xULN and 
bilirubin≥2xULN will be provided.  
9.5.4 
Other Safety Measures 
9.5.4.1 
12-Lead ECG 
 
The 12-lead electrocardiogram (ECG) findings will be summarized and listed by visit and 
treatment arm. Corrected QTc intervals will also be summarized by category for change 
from baseline: <30, ≥30 to <60, and ≥60 (described in table of ECG values of potential 
clinical importance below) by treatment group at each scheduled visit and for the 
maximum post baseline values. QTc interval is reported in CRF using one of the reporting 
methods, Bazett and Fridericia, and is denoted here by QTcB and QTcF, respectively.  
 
Table 1. ECG Values of Potential Clinical Importance 
ECG Parameter 
(QTcB/QTcF) 
Potential Clinical 
Importance Range  
Increase from baseline  
<30 
Increase from baseline  
≥30 to <60 
Increase from baseline  
≥60 
 
In addition, the number (percentage) of participants with ECG values recorded as 
meeting AE criteria will be tabulated by severity and the relationship to study product and 
compared between treatment arms using the method as described above. 
 
9.5.4.2 
Liver Events 
 


 
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Separate summaries will be presented for liver chemistry tests (AST, ALT, ALK PHOS, 
and bilirubin): Summary of maximum treatment emergent toxicities for oral phase, 
injection phase and oral+injection; Summary of changes in baseline toxicity to maximum 
toxicity for oral phase, injection phase and oral+injection.  
By-subject listing of liver events and time of event relative to treatment will be produced. 
Box plots of liver chemistries (AST, ALT, ALP, and bilirubin) by treatment arm and visit. 
Scatter plots of maximum liver chemistries during oral (injection phase or oral+injection) 
phase vs. baseline. Matrix plot of maximum of liver chemistries on-treatment in oral, 
injection, or oral+injection phase will all be generated.  
Kaplan-Meier plot of the time to first occurrence of grade 1 or greater elevation in 
ALT/AST will be generated by treatment arm during the oral, injection or oral+injection 
phase.   
In addition, the number (percentage) of participants with liver chemistry values recorded 
as meeting AE criteria will be tabulated by severity and the relationship to study product 
and compared between the treatment arms as described above.  
 
9.5.5 Safety Endpoint 
 
Primary safety endpoint is the proportion of participants experiencing any Grade 2 or 
higher clinical AEs or laboratory abnormalities since the initial injection to 12 weeks (8 
weeks) after the last injection in Cohort 1 (Cohort 2) among the participants who 
complete at least one injection to evaluate the safety of the 744 injectable during the 
injection phase.  A secondary safety endpoint is the proportion of Grade 2 or higher 
clinical AEs or laboratory abnormalities occurred from the initial injection to 76 weeks in 
both cohorts after last injection among the participants who complete at least one 
injection to evaluate the safety of the 744 injectable in long term; the proportion of Grade 
2 or higher AEs or laboratory abnormalities occurred during the oral phase (Weeks 0-5) 
among all enrolled participants to evaluate the safety of the oral 744 product; and the 
proportion of Grade 2 or higher AEs or laboratory abnormalities occurred during the 
whole study period among the all enrolled participants to evaluate the safety of the oral 
and injectable product. The proportions of endpoints and the %95 confidence intervals 
will be estimated for each treatment arm. The 95% CIs will be estimated using Wilson 
score method1. The proportions of endpoints will be compared between the treatment 
arms using Fisher Exact test.   
In addition, the safety endpoint rate might be calculated for each treatment arm and 
compared between the treatment arms.  The safety endpoint rate is the number of the 
participants who have experienced Grade 2 or higher clinical AEs or laboratory 
abnormalities during the study period (defined in each safety analysis) divided by the 
person-time-at-risk throughout the observation period within the study period.  
The 95% exact confidence interval of the safety event rate will be calculated for each 
treatment arm, assuming the rate follows the Poisson distribution.  The safety event rate 
will be compared between the treatment arms using exact Poisson test.    
9.5.6 Reasons for Treatment Discontinuation and Early Study Termination 
 


 
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The number and percentage of participants who discontinue the study treatment and who 
terminate the study early will be tabulated by reasons and the treatment arm separately 
for the oral phase and the injection phase by cohort and in aggregate. 
 
9.6 
Tolerability 
 
To assess tolerability of 744 LA, the proportion (with 95% CI) of subjects who terminate 
from receiving injections prior to the full course due to AEs, intolerability of injection, 
frequency of injections, or burden of procedures related to injections out of those subjects 
that received at least one injection by cohort and treatment arm will be provided. The 
proportion will be compared between the treatment arms by cohort and in aggregate 
using Fisher Exact test.   
9.7 
Pharmacokinetics  
 
Plasma GSK1265744 concentration-time data will be analyzed by noncompartmental 
methods using WinNonlin Professional 5.2 or higher, Phoenix (Pharsight Corporation) or 
comparable software.  Individual plasma PK parameters for each injection interval will be 
determined which include the area under the plasma concentration time curve over the 
dosing interval (AUC(0-)), maximum observed concentration (Cmax), time to maximum 
observed concentration (tmax), concentration at the end of the dosing interval (C), 
apparent terminal phase half-life for 744LA administration (t½) and lambda z as a measure 
of absorption rate constant (z) if data allow among the participants in the 744 arm. The 
pharmacokinetic parameters will be generated by the scientist from HPTN Core 
Laboratory.  
The summary statistics of pharmacokinetic parameters, AUC(0-), Cmax, and C, will be 
presented by injection. The means of the pharmacokinetic parameters (after log-
transformation) and their 95% CIs will be displayed by visit weeks and cohort. The 
pharmacokinetic parameters, AUC(0-), Cmax, and C in different injection intervals will be 
compared using paired t-test if the data or log transferred data appear to be normally 
distributed and using Wilcoxon signed rank test if the data or log transferred data are not 
normally distributed.  
Time to steady state will also be assessed by comparing plasma concentration, C, at 
Week 41 (following third injection) to previous C concentrations at Weeks 17 and 29 (at 
Weeks 17, 25, and 29) in Cohort 1 (Cohort 2).   General estimation equation (GEE) 
regression model will be used to test any difference in the concentration over time and a 
trend.  
9.7.1 Association between Pharmacokinetics and Baseline Characteristics 
 
To evaluate differential pharmacokinetics of 744LA in participants by age, gender, race, 
ethnicity, weight, body mass index (BMI), and smoking status, we will use GEE 
regression model to account the correlations of the PK parameters following three 
injections in Cohort 1 or five injections in Cohort 2. The analysis will be performed 
separately for each cohort. The associations between the PK parameters and the 
predictors will be tested   in univariate models (include one predictor in each model) and 


 
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in a multivariate model (include all predictors). Each model will be adjusted for sites (US 
vs. Non-US sites) by cohort.     
9.8 
Study Medication Satisfaction Questionnaire 
 
The Study Medication Satisfaction Questionnaire (SMSQ) will also be used to assess 
subject tolerability and satisfaction to the study medication in this trial. The SMSQ is a 
modified version of the current HIV Treatment Satisfaction Questionnaire (HIVTSQ) that 
does not include questions pertaining to treatment but rather study medication. The 
SMSQ is a 12-item self-reported scale that measures overall satisfaction with medication, 
general satisfaction/clinical, satisfaction with lifestyle/ease, and each individual 
satisfaction. This study uses the SMSQs (status version) and the SMSQc (change 
version).  
The SMSQs will be administered at the following time points: Week 6, Week 18, and 
Week 30 in Cohort 1 and Weeks 6, 10, 18, 26, and 34 in Cohort 2. The SMSQc will be 
administered at Week 18 in Cohort 1 and Week 10 in Cohort 2.  
 
For each question the responses will be summarized by the proportion of participants 
reporting the response on the Likert scale out of all those that answered the question at 
visit by the treatment arm.  An overall treatment satisfaction score will be calculated for 
each participant at each visit.  To evaluate the participants’ experience of the medication 
with injection comparing to the experience of medication with tablets during the first 4 
weeks of the study, the score derived from SMSQc will be summarized by treatment arm 
and compared between the treatment arms using t-test and using the linear regression 
model to adjust for site effect (US sites vs. Non-US sites). To evaluate the participants’ 
experience of the medication with injection, the scores derived from SMSQs will be 
summarized by treatment arm and visit and compared between the treatment arms over 
time using GEE model to account for the correlations of the scores over time and will be 
evaluated the changes over time within the treatment arms.  The analyses will be done by 
Cohort and in aggregate.  
9.9 
Acceptability Questionnaire 
 
Baseline acceptability questionnaire (BAQ) will be administered at baseline Week 0 visit 
in both cohorts. Follow-up acceptability questionnaire (FAQ) will be administered at 
Weeks 6, 18, and 30 in Cohort 1; at Weeks 6, 10, 18, 26, and 34 in Cohort 2.   
The scores will be derived from the items in BAQ/FAQ at each visit and then will be 
compared between the treatment arms.  The scores derived from BAQ will be 
summarized and compared between the treatment arms using t-test and using the linear 
regression model to adjust for site effect (US sites vs. Non-US sites). The scores derived 
from FAQ will be summarized and compared between the treatment arms using GEE 
model to account for the correlations of the scores over time and will be evaluated the 
changes over time within the treatment arms. The data will be analyzed by cohort and in 
aggregate.   
9.10 Sexual Risk Behaviors 
 
To assess the 744LA effect on sexual risk behavior by change from enrollment during the 
study period, the behavioral questionnaire (BQ) will be administered at the baseline (at 


 
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enrollment date) and at each injection visit week (Weeks 5, 17, 29 in Cohort 1 and 5, 9, 
17, 25, 33 in Cohort 2) and tail visit weeks 41, 53, 65 and 77.   
We will first assess whether or not there is any change in the sexual risk behavior at 
Week 5 from enrollment within each treatment arm and whether or not the change differs 
between the 744LA arm and the placebo arm. Then we will assess whether or not there 
is any change in the sexual risk behavior during the injection phase from the baseline (at 
Week 5) within each treatment arm and whether or not the change differs between the 
treatment arms over time using GEE model. The sexual risk behavior variables, such as 
the number of sexual partners, the number of total sexual acts, the episodes of 
unprotected anal and/or vaginal intercourse, the number of unprotected sexual acts with 
HIV seropositive partner(s) in the past 3 months, are as the outcomes and are assumed 
with a negative binomial distribution. The treatment and time are as covariates. Both 
analyses will be stratified by gender and adjusted for other demographic variables such 
as age and race/ethnicity. Robust standard errors will be used to account for within-
person correlation. In the second analysis, time is treated as a continuous variable 
measured in 3 months; a linear and quadratic time and time interactions with the 
treatment are included in the model to test a linear or a quadratic trend in the self-
reporting risk behavior in the past 3 months during the injection phase in each arm and to 
test the difference between the treatment arms.  The data will be analyzed in aggregate.  
9.11 HIV Incidence 
HIV incidence rate will be calculated as the total number of participants with confirmed 
HIV infection during study follow-up divided by the person-years accumulated in each 
arm.  95% CIs will be calculated based on Poisson distribution assumptions. In addition, 
exact tests based on the Poisson distribution will be used to compare HIV incidence rate 
between the treatment arms.    
9.12 Evaluate the Safety, Tolerability and Pharmacokinetics of 744LA in the Women Who 
Use Injectable Hormonal Contraception  
 
The safety and tolerability analyses described above will be performed on the subset of 
female participants who self-report the use of injectable hormonal-based contraception at 
study entry or at any time during the study period.  Proportions of such women meeting 
safety or tolerability endpoints will be compared a) across treatment arms b) to the women 
in the 744LA arm who are do not report use of injectable hormonal contraception c) to the 
overall study population randomized to active GSK1265744. The comparisons in a) are to 
evaluate the safety and tolerability of the 744LA injection in the women who report use of 
injectable hormonal-based contraception between the two treatment arms. The 
comparisons in b) are to evaluate the safety and tolerability of the 744LA injection between 
the women who report the use of injectable hormonal-based contraception and the women 
who are do not report the use of injectable hormonal-based contraception. The 
comparisons in c) are to evaluate the safety and tolerability of the women who report the 
use of injectable hormonal-based contraception in contrast to the rest of the enrolled 
participants in the study.  All comparisons will be done using the Fisher exact test.  The 
data will be analyzed by cohort and in aggregate.  


 
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9.13 Exploratory Analyses 
Pharmacokinetics/Pharmacodynamics 
The relationship between GSK1265744 PK parameters and demography variables (age, 
gender, race, ethnicity, weight, BMI, smoking status) or PD endpoints (conversion to HIV-
infected status, safety parameters) may be explored. 
Pharmacogenomics Analysis 
Specific genes may be studied that encode the drug targets, drug mechanism of action 
pathways, drug metabolizing enzymes, or drug transporters or which may underpin AEs, 
disease risk, or pharmacokinetics or drug response. These candidate genes may include 
a common set of absorption, distribution, metabolism, and excretion genes that are 
studied to determine the relationship between gene variants and pharmacokinetics or 
safety parameters. In addition, future research may identify other enzymes, transporters, 
proteins, or receptors that may be involved in response to GSK1265744.  The genes that 
may code for these proteins may also be studied.   
A detailed statistical analysis plan will be documented separately once the 
pharmacogenomics study plan is finalized.   
 
10 SMC REPORTS 
10.1 Cohort data will be analyzed and presented separately in all SMC report periods.  If 
appropriate, they will be analyzed jointly in the last SMC report period. Study 
Conduct Report (SMC Open Report) 
10.1.1 List of Tables  
 
 
Accrual summary by site and by gender   
 
Accrual summary and accrual by calendar month and by site  
 
Specimen collection by pre-specified specimen collection visits and site 
 
Retention by study visit and by site  
 
Baseline demographics for total and by site  
 
Completion of behavioral assessment questionnaire (BQ) by study visit and site  
 
Completion of Study Medication Satisfaction questionnaire (SMSQ) by study visit 
and site  
 
Completion of Baseline Acceptability questionnaire (BAQ) by site and completion 
of Follow-up Acceptability questionnaire (FAQ) by study visit and site 
 
Adherence as measured by pill counts during 4 weeks of oral phase by study 
visit (Weeks 2 and 4) and site  


 
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 
Adherence as measured by self-report at Week 4 by site  
 
Completion of injections by study visit and site  
 
Baseline sexual risk behavior  
 
Study product holds and earlier discontinuations by site   
 
Reasons for early discontinuation of study regimen during the oral phase by site  
 
Reasons for not advancing to injection phase by site  
 
Reasons for early discontinuation of study regimen during the injection phase by 
site  
 
Social harms/impacts summary 
 
Pregnancy listing 
 
10.1.2 List of Graphs  
 
Accrual graph by calendar month – total 
 
Accrual graph by calendar month - by site 
 
10.2 Safety Tables and Graphs (SMC Close Report) 
10.2.1 List of Tables 
 
 
Permanent discontinuation of study regimen during the oral phase (Weeks 0-5) 
by treatment arm  
 
Permanent discontinuation of study regimen during the injection phase (Weeks 
5-41) by treatment arm  
 
Permanent discontinuation of study regimen during the tail phase (Weeks 41-
105/109) by treatment arm  
 
List of early discontinuation of study regimen (reason, study week) 
 
Grade 3 or higher adverse events by treatment arm during the oral phase 
(Weeks 0-5) 
 
Proportion of Grade 2 or higher adverse events by treatment arm during the oral 
phase (Weeks 0-5)  
 
Adverse events by severity and relationship to study product during the oral 
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 
Adverse events by MedDRA preferred term ordered by system organ class 
during the oral phase by treatment arm (Weeks 0-5) 
 
listing of Grade 3 or above adverse events during the oral phase by treatment 
arm (Weeks 0-5) with details of the events including severity, relationship to the 
study product, on-set date, outcome, duration, the enrollment date and days 
since the enrollment.  
 
Grade 1 or above AST/ALT by treatment arm during the oral phase (Weeks 0-5) 
 
Grade 2 or higher adverse events by treatment arm during the injection phase 
(Weeks 5-41) 
 
Number and percentage of adverse events by severity and relationship to study 
product during the injection phase (Weeks 5-41) 
 
Adverse events by MedDRA preferred term ordered by system organ class 
during the injection phase (Weeks 5-41) 
 
Injection site reaction (ISR) adverse events during the injection phase by BMI 
(above/below median BMI) (Weeks 5-41) 
 
Grade 1 or above AST/ALT by treatment arm during the injection phase (Weeks 
5-41) 
 
Adverse events by MedDRA preferred term ordered by system organ class 
during the injection phase (Weeks 5-105/109) 
 
listing of Grade 3 or above adverse events during the whole injection phase 
(Weeks 5-81) with details of the events including severity, relationship to the 
study product, on-set date, outcome, duration, last injection date, and the number 
of injections prior to the event 
 
Adverse events by severity and relationship to study product and treatment arm 
during the whole injection phase (Weeks 5-105/109) 
 
Grade 1 or above AST/ALT by treatment arm during the whole injection phase 
(Weeks 5-105/109) 
 
HIV infection status by study arm 
 
 
 
10.2.2 List of Graphs 
 
 
Kaplan-Meier curves of time to permanent discontinuation by treatment arm (For 
those who complete the study and currently stay in the study, their time to 
permanent discontinuation will be censored at the last visit date) 
 
Box plots of maximum liver chemistries (AST, ALT, ALP, and bilirubin) by 
treatment arm and visit during oral, injection, and oral+injection phase.  
 


 
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 
Scatter plots of maximum liver chemistries during oral, injection, and 
oral+injection phase vs. baseline.  
 
 
Matrix plot of maximum of liver chemistries during the oral, the injection, and the 
oral+injection phase.  
 
 
Shift plot of some laboratory measure at each visit week vs. baseline during the 
oral, injection, and oral+injection phase.  
 
 
Cumulative incidence curve of the time to first occurrence of grade 1 or greater 
elevation in ALT/AST will be generated by treatment arm during the oral, injection 
and  oral+injection phase.   
 
11 FINAL STUDY REPORT (FSR) 
The data will be analyzed by cohort and in aggregate (if it is appropriate).  
11.1 Study Population Summary  
 
All study population characteristics will be provided for table and by treatment arm  
11.1.1 Lists of Tables 
Table 1    Summary of study populations 
 
Table 2    Summary of subject accountability:  Study conclusion record 
 
Table 3    Summary of baseline demographic characteristics 
 
Table 4    Summary of baseline risk behavior 
 
Table 5    Summary of baseline concomitant medications  
Table 6    Summary of important protocol deviations 
Table 7    Summary of exposure to randomized investigational product 
 


 
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11.2 Safety and Tolerability Analysis 
11.2.1 Lists of Tables 
Table 8     Permanent discontinuation of study regimen by treatment arm (a) during the 
oral phase, (b) during the injection phase, and (c) during the on-treatment 
 
Table 9      Adverse experiences by MedDRA preferred term and severity (ordered by 
system organ class) (a) during the oral phase, (b) during the injection phase, 
(c) during the tail phase, and (d) during the on-treatment 
 
Table 10  Adverse experiences by MedDRA preferred term and severity – including 
severe, potential life-threatening or fatal events only (a) during the oral phase, 
(b) during the injection phase, (c) during the tail phase, and (d) during the on-
treatment  
Table 11  Adverse experiences by MedDRA preferred term and relationship to study 
product (a) during the oral phase, (b) during the injection phase, (c) during 
the tail phase, and (d) during the on-treatment  
Table 12  Elevation of liver chemistry and other lab test events (a) during the oral phase, 
(b) during the injection phase, (c) during the tail phase, and (d) during the on-
treatment   
Table 13  Summary of Injection Site Reaction Characteristics  
 
Table 14 Summary of characteristics of common ISR symptoms   
Table 15 Summary of change in laboratory test at follow up from baseline by visit and 
cohort  
 
Table 16 Summary of ECG values by treatment arm and visit 
 
Table 17  Summary of maximum change in corrected QTc intervals by category for 
change from baseline 
 
Table 18   Listing of expedited adverse events (EAE) or serious adverse events (SAE) 
with the details of the events including severity, relationship to study product, 
time between onset and last injection, number of injections received (if the 
events occurring after the 1st injection), and a summary of the event  
Table 19   Proportion of participants experiencing any Grade 2 or higher clinical AEs and 
laboratory abnormalities that occur (a) during the oral phase, (b) during the 
injection phase (c) during the tail phase, and (d) during the on-treatment 
period 
 
Table 20  The proportion of participants who discontinue the study product for reasons of 
toxicity, tolerability, or acceptability (a) prior to completion of the full oral 
phase and (b) prior to completion of the full injection phase. 
 
11.2.2 List of Figures 
 


 
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Figure 1    Kaplan-Meier curves of time to permanent discontinuation by treatment arm 
(For those who complete the study and currently stay in the study, their time 
to permanent discontinuation will be censored at the last visit date) 
 
Figure 2    Kaplan-Meier curves of time to permanent discontinuation by treatment arm 
(For those who enter the injection phase and currently stay in the study, their 
time to permanent discontinuation will be censored at the last visit date) 
 
Figure 3    Shift scatter plot of some laboratory measures at each visit week vs. baseline 
Figure 4    Box plots of maximum some laboratory measures (AST, ALT, ALP, total 
bilirubin, CPK, Creatinine, Creatinine clearance) elevation from baseline by 
treatment arm and phase  
Figure 5    Scatter plots of maximum liver chemistries (a) during the oral (b) during the 
injection (c) during the tail phase and (d) during the on-treatment phase vs. 
baseline.  
Figure 6    Matrix plot of maximum of liver chemistries (a) during the oral (b) during the 
injection (c) during the tail phase and (d) during the on-treatment phase 
 
Figure 7    Cumulative incidence plot of the time to first occurrence of grade 1 or greater 
elevation in ALT/AST will be generated by treatment arm (a) since the 
enrolment date and (b) since the first injection date 
 
 
 
11.3 Pharmacokinetic and Other Secondary Analyses 
11.3.1 List of Tables  
 
Table 21   Summary of pharmacokinetic parameters by injection 
Table 22   Assess the time to steady state of the plasma drug concentration, C  
Table 23   Associations of sex at birth (or BMI) with pharmacokinetic parameters   
Table 24  Change in sexual risk behavior (number of sexual partners) from baseline  
 
Table 25  HIV incidences during the study   
Table 26  Reported pregnancies by treatment arm and cohort  
 
Table 27  The proportion of women experiencing any Grade 2 or higher AEs (a) prior to 
completion of the full oral phase and (b) prior to completion of the full injection phase --- 
among the women who use any injectable hormonal contraception  (combined cohort) 
Table 28  The proportion of the women who discontinue the study product for reasons of 
toxicity, tolerability, or acceptability (a) prior to completion of the full oral phase and (b) 
prior to completion of the full injection phase—among the women who use any injectable 
hormonal contraception 
 
Table 29  Summary of pharmacokinetic parameters by injection and cohort —among the 
women who use any injectable hormonal contraception 
 
 
11.3.2 List of Figures 
 


 
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Figure 8    Plot of plasma CAB concentration over time by cohort   
Figure 9    Percentage of participants who experienced ISR by arm, injection and cohort  
Figure 10   Plot of change in sexual risk behavior over time from the baseline by 
treatment arm and cohort  
 
12 ATTACHMENTS 
 The tables shell: the tables listed in Section 11.  
 The figures shell: the figures listed in Section 11.   
 


 
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13 REFERENCE 
1.  
Agresti A, Coull BA. Approximate Is Better than “Exact” for Interval Estimation of Binomial 
Proportions. Am Stat. 1998;52(2):119–126.  
 
 
 


 
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Appendix 
Definition of Derived Variables and Study Populations  
Study Populations: 
Randomized population:  randomized=1 if Screnr = 1 (Form SO-1 006, screening 
outcome) 
Oral safety analysis population: randomized=1 and PCpdn>0 and PCpbrp="No", or 
PCpdn>Pcnumpil if PCpbrp="Yes" (Form PC-1 134, Pill count) 
Primary/Injectable safety analysis population: randomized=1 and Iaingiv=1 for week5 
(Form IA-1 126, Injection administration) 
Derived Variables: 
BMI=weight (in kg)/ height(in cm)*height(in cm)  (Form LLR-1152, Local Laboratory 
Results)  
Algorithm of defining the phase for AEs  
The phase (oral or injection) of AEs was determined based on the AE on-set date and 
the first injection date as follows.    
For AEs with a complete onset date (no missing on day, month, or year) 
  1. If the AE onset date is before of the first injection date, then the phase of the AE is 
oral. 
  2. If the AE onset date is after the first injection date, then phase of the AE is injection. 
  3. If the AE onset date is on the same data as the first injection date, then: 
     a. If the AE is Injection site reaction, then the phase of the AE is injection. 
     b. If the AE is not Injection site reaction, then the phase is oral. 
For the AEs with an incomplete onset date (missing day, day is not mandated) 
  1. If the onset date is before the first injection date determined by the month and the 
year of the onset date, then the phase is oral. 
  2. If the onset date of the AE is after of the first injection date determined by the 
month and the year of the onset date, then the phase is injection. 
  3. If the month and year in the AE onset date match to the month and year in the first 
injection date, then: 
   a. the sites determined whether the AE occurred before or after the first injection. 
   b. If the sites could not determine, PI determined which phase the AE should be.