Conditions: HIV Infections
Keywords: GSK1265744 Pre-Exposure Prophylaxis Human immunodeficiency virus Cabotegravir Pharmacokinetics
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 48
Healthy volunteers: yes

Brief summary:
The pre-exposure prophylaxis (PrEP) is an important component in the overall strategy for prevention of HIV infection. Cabotegravir (CAB) is an integrase strand transfer inhibitor currently in development for treatment and prevention of HIV infection. CAB possesses attributes that allow formulation and delivery as a LA parenteral product. CAB is being developed as both oral and long acting (LA) injectable formulations. This study is designed to evaluate the PK, safety, tolerability, and acceptability of CAB LA in adult HIV uninfected Chinese male subjects at low risk for HIV acquisition. Eligible subjects will receive oral CAB during oral phase of the study followed by CAB LA intramuscular (IM) injection during injection phase of the study. Approximately 60 subjects will be screened, of which, approximately 48 subjects will enter the oral phase and 40 subjects will enter the injection phase of the study. The maximum study duration will be approximately 89 weeks including oral phase, injection phase and follow-up phase.

Detailed description:

Arms:
arm 1: Eligible subjects will receive oral doses of CAB 30 milligrams (mg) tablets once daily for 4 weeks followed by IM injectable suspension of CAB LA 600 mg at Week 5, Week 9, Week 17, Week 25 and Week 33. There will be an approximately 1-week washout period between the last oral dose and the first injection of CAB at Week 5.

Interventions: intervention 1: Oral CAB intervention 2: CAB LA
Intervention descriptions: intervention 1: CAB tablet will be formulated as white to almost white, oval shaped, film coated 30 mg tablets, administered orally once daily. The CAB tablets will be packaged in bottles containing 30 tablets each. intervention 2: CAB LA is a sterile white to slightly colored suspension containing 200 mg/mL of CAB as free acid for administration by IM injection in gluteus medius.

Protocol document:
Prot_000.pdf: 
2016N293702_01
CONFIDENTIAL
ViiV Healthcare and the GlaxoSmithKline group of companies
206898
1
TITLE PAGE
Protocol Title: An Open Label, Phase 1 Study to Evaluate the PK, Safety, Tolerability 
and Acceptability of Long Acting Injections of the HIV Integrase Inhibitor, Cabotegravir 
(CAB; GSK1265744) in HIV Uninfected Chinese Men
Protocol Number: 206898
Short Title: A Phase 1 Safety, Tolerability, Acceptability, and PK study of CAB 
(GSK1265744) LA in Healthy HIV-Uninfected Chinese Men
Compound Number:
GSK1265744
This study is sponsored by ViiV Healthcare.  GlaxoSmithKline is implementing and 
managing all aspects of this study.
Sponsor Name and Legal Registered Address: 
ViiV Healthcare
980 Great West Road
Brentford
Middlesex, TW8 9GS
UK
Copyright 2018 ViiV Healthcare and the GlaxoSmithKline group of companies.  All 
rights reserved.  Unauthorized copying or use of this information is prohibited.


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Authors:
, Director Clinical Pharmacology Modeling and Simulation, GlaxoSmithKline 
(GSK)
, Director of Clinical Pharmacology, ViiV Healthcare
, Clinical Development, ViiV Healthcare
, Aaron Diamond AIDS Research Center
, University of California at San Francisco
, Clinical Development Director, GSK 
, Project Physician, GSK
, Statistician, GSK
, GSK
, GSK
, GSK
, GSK
Medical Monitors Name and Contact Information
Refer to the study reference manual (SRM) for additional study contact information.
ViiV Implementation Statement
This study is sponsored by ViiV Healthcare.  GlaxoSmithKline is implementing and 
managing all aspects of this study.
Regulatory Agency Identifying Number(s): Version 1.0
Approval Date: 06-JUN-2018
PPD
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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
DOCUMENT HISTORY
Document
Date
Amendment 1
06-JUN-2018
Original Protocol
20-JUL-2017
Amendment 1 [06-June-2018]
Overall Rationale for the Amendment:
This is an amendment to the original protocol.
This amendment has been made to create consistency across protocol sections, and edit 
wording related to pharmacokinetic sampling for more clarity.
(Note: ‘Additions’ are underlined and ‘deletions’ are striked off)


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Section # and Name
Description of Change
Brief Rationale
2. SCHEDULE OF 
ACTIVITIES (SoA)
Drug screen was previous mentioned at 
footnote ‘a’ of SoA table.  An 
additional line of urine drug screen is 
added to the main table.
An additional line of Urine chemistry
assessment at day1 is added for 
baseline assessment  
Additional line for oral phase diary card
at day 1.
Updated footnote ‘n’: All PK samples 
will be collected prior to CAB LA 
injections at Week 5, 9, 17, 25, and 
33 with the exception of 1-week post 
injection samples at Weeks 6, 10, 18, 
26, 34, week 37(2 4-week post 
injection sample) and Week 41
Added for more clarity
It is added since, Appendix 4 
Adverse Events-
Proteinuria mentioned that, 
‘change from Baseline 
value for abnormal urine 
microalbumin/creatinine 
ratio’ 
Additional assessment
Updated the schedule PK 
sampling post injection
5.1. Overall Design
4 PK Pharmacokinetic sampling 
following CAB LA IM injections will start 
on just prior to the first injection at 
Week 5 (Injection Phase) and prior to 
each subsequent injection with limited 
PK sampling between injection visits 
(for complete PK sampling schedule 
refer to SoA, Table 1).
Added for more clarity
7.1.3. GSK1265744 –
Injectable 
Suspension (CAB 
LA)
IM injections should be administered at 
a 90 degree angle into the gluteus 
medius muscle using a 1.5” – 2.5” 21-
25 gauge needle (or sizes outside of 
this suggested range based on 
investigator judgement)
Text added around the 
dimensions of injection 
needle use for CAB LA 
injection
7.6. Treatment 
Compliance
CAB LA dosing is expected to occur in 
a window ±3 Days any time within the 
scheduled dose week.
Mentioned the specific 
window period for CAB LA 
dosing
8.1. Discontinuation 
of Study Treatment
Participants who discontinue treatment 
during the injection phase should enter 
the be followed up phase for at least 56 
weeks after their last injection as per 
Minor edits for more clarity


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Section # and Name
Description of Change
Brief Rationale
the schedule of activities.
8.2.2. Withdrawal of 
Informed Consent
Added new section with following 
points:
If the participant withdraws consent for 
disclosure of future information, the 
sponsor may retain and continue to 
use any data collected before such a 
withdrawal of consent.
If a participant withdraws from the 
study, he/she may request 
destruction of any samples taken and 
not tested, and the investigator must 
document this in the site study 
records.
Refer to the SoA for data to be 
collected at the time of study 
discontinuation and follow-up and for 
any further evaluations that need to 
be completed.
Updated separate withdrawal 
criteria due to withdrawal of 
Informed consent
9.3. Treatment of 
Overdose
Amended
For the Oral Phase of this study, any 
dose of CAB greater than 30 mg 1 
tablet (30mg) within a day 24 hour time 
period [±12 hours] will be considered 
an overdose.
Updated for more clarity
9.5. 
Pharmacokinetics
Amended
The last oral dose will be administered 
on day 28 before after the final PK 
sample with subsequent safety and 
central lab assessment on the same 
day.
Updated the time point for PK 
sampling
12.2. Appendix 2: 
Clinical Laboratory 
Tests
Under Clinical Chemistry: Added
Glomerular Filtration Rate (GFR)
Phosphate
Lactate Dehydrogenase (LDH)
Under Urine Chemistry: Added
Microalbumin
The following tests were 
mentioned in the protocol, but 
not listed under Appendix 2


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Section # and Name
Description of Change
Brief Rationale
Creatinine
Microalbumin/creatinine ratio
12.2. Appendix 2: 
Clinical Laboratory 
Tests
Other Screening Tests-Deleted 
HIV serology (4th generation HIV test)
HIV RNA
Removed from screening
12.10. Appendix 10: 
HIV-Prevention 
Treatment 
Satisfaction 
Questionnaire 
(change): (HIV-
PrevTSQc)
Amended
For the past 4 months 10 weeks you 
have been taking part in a study of 
treatment to prevent HIV.
To be consistent with SoA 
table
Throughout
Minor editorial and document formatting 
revisions 
Updated the abbreviation table.
Minor, therefore have not 
been summarized
Corrections/clarifications


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TABLE OF CONTENTS
PAGE
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE.....................................4
1.
SYNOPSIS.............................................................................................................11
2.
SCHEDULE OF ACTIVITIES (SOA).......................................................................15
3.
INTRODUCTION....................................................................................................19
3.1.
Study Rationale ..........................................................................................19
3.2.
Background ................................................................................................20
3.3.
Benefit/Risk Assessment ............................................................................21
3.3.1.
Risk Assessment .........................................................................22
3.3.2.
Other Clinically Relevant Information...........................................27
3.3.3.
Benefit Assessment.....................................................................27
3.3.4.
Overall Benefit: Risk Conclusion..................................................27
4.
OBJECTIVES AND ENDPOINTS...........................................................................28
5.
STUDY DESIGN ....................................................................................................29
5.1.
Overall Design ............................................................................................29
5.2.
Number of Participants ...............................................................................30
5.3.
Participant and Study Completion...............................................................30
5.4.
Scientific Rationale for Study Design ..........................................................30
5.5.
Dose Justification........................................................................................30
6.
STUDY POPULATION...........................................................................................37
6.1.
Inclusion Criteria.........................................................................................37
6.2.
Exclusion Criteria........................................................................................38
6.3.
Lifestyle Restrictions...................................................................................39
6.4.
Screen Failures...........................................................................................39
7.
TREATMENTS.......................................................................................................40
7.1.
Treatments Administered............................................................................40
7.1.1.
Study Treatments ........................................................................40
7.1.2.
GSK1265744 – Tablet (CAB).......................................................40
7.1.3.
GSK1265744 – Injectable Suspension (CAB LA).........................40
7.2.
Dose Modification .......................................................................................41
7.3.
Method of Treatment Assignment ...............................................................41
7.4.
Blinding.......................................................................................................41
7.5.
Preparation/Handling/Storage/Accountability..............................................42
7.6.
Treatment Compliance................................................................................42
7.7.
Concomitant Therapy..................................................................................43
7.7.1.
Permitted Medications and Non-Drug Therapies..........................43
7.7.2.
Prohibited Medications and Non-Drug Therapies.........................43
7.8.
Treatment after the End of the Study ..........................................................44
8.
DISCONTINUATION CRITERIA.............................................................................44
8.1.
Discontinuation of Study Treatment ............................................................44
8.1.1.
Liver Chemistry Stopping Criteria ................................................44
8.1.2.
Temporary Discontinuation ..........................................................45


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8.1.3.
Follow up visits for participants withdrawn from IM dosing...........45
8.1.4.
Rechallenge.................................................................................46
8.1.4.1.
Study Treatment Restart or Rechallenge....................46
8.2.
Withdrawal from the Study..........................................................................46
8.2.1.
Withdrawal from the Study Treatment..........................................46
8.2.2.
Withdrawal of Informed Consent..................................................47
8.3.
Lost to Follow Up........................................................................................47
9.
STUDY ASSESSMENTS AND PROCEDURES .....................................................47
9.1.
Efficacy Assessments.................................................................................48
9.2.
Adverse Events...........................................................................................48
9.2.1.
Time Period and Frequency for Collecting AE and SAE 
Information...................................................................................48
9.2.2.
Method of Detecting AEs and SAEs.............................................49
9.2.3.
Follow-up of AEs and SAEs.........................................................49
9.2.4.
Regulatory Reporting Requirements for SAEs .............................49
9.2.5.
Cardiovascular and Death Events................................................50
9.3.
Treatment of Overdose...............................................................................50
9.4.
Safety Assessments ...................................................................................51
9.4.1.
Physical Examinations.................................................................51
9.4.2.
Injection site reaction ...................................................................51
9.4.3.
HIV Counseling............................................................................51
9.4.4.
Acquisition of HIV During the Study .............................................52
9.4.5.
Vital Signs....................................................................................52
9.4.6.
Electrocardiograms......................................................................52
9.4.7.
Clinical Safety Laboratory Assessments ......................................52
9.5.
Pharmacokinetics .......................................................................................53
9.6.
Pharmacodynamics ....................................................................................54
9.7.
Genetics .....................................................................................................54
9.8.
Biomarkers .................................................................................................54
9.9.
Health Economics OR Medical Resource Utilization and Health 
Economics..................................................................................................54
10. STATISTICAL CONSIDERATIONS........................................................................54
10.1.
Sample Size Determination ........................................................................54
10.1.1.
Hypotheses..................................................................................54
10.1.2.
Sample Size Considerations........................................................55
10.2.
Populations for Analyses ............................................................................55
10.3.
Statistical Analyses.....................................................................................55
10.3.1.
Primary Analyses.........................................................................56
10.3.1.1.
Safety Analyses..........................................................56
10.3.1.1.1.
Injection Site Reaction (ISR)...................56
10.3.1.1.2.
AEs.........................................................56
10.3.1.2.
Pharmacokinetic Analysis...........................................56
10.3.2.
Secondary Analyses ....................................................................58
10.3.3.
Pharmacokinetic/Pharmacodynamic Analyses.............................58
10.3.4.
Pharmacogenetics.......................................................................58
10.3.5.
Other Analyses ............................................................................58
10.3.6.
Interim Analyses ..........................................................................58
11. REFERENCES.......................................................................................................59


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12. APPENDICES........................................................................................................61
12.1.
Appendix 1: Abbreviations and Trademarks................................................61
12.2.
Appendix 2: Clinical Laboratory Tests.........................................................64
12.3.
Appendix 3: Study Governance Considerations..........................................66
12.4.
Appendix 4: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting .......................................70
12.5.
Appendix 5: Schedule for Additional Laboratory Procedures for 
Enrolled Participants who have a Reactive Positive HIV Test Result 
(Post-HIV Confirmation Visit) ......................................................................78
12.6.
Appendix 6: Liver Safety: Required Actions and Follow-up 
Assessments ..............................................................................................79
12.7.
Appendix 7: Division of AIDS Table for Grading the Severity of Adult 
and Pediatric Adverse Events Version  2.1, March 2017.............................81
12.8.
Appendix 8: Toxicity Management ............................................................111
12.9.
Appendix 9: HIV Testing Algorithm and Management of HIV 
Infection in Study Participants...................................................................116
12.10. Appendix 10: HIV-Prevention Treatment Satisfaction Questionnaire 
(change): (HIV-PrevTSQc)........................................................................117
12.11. Appendix 11: Daily Diary Card for Symptoms at Injection Area.................119
12.12. Appendix 12: Protocol Amendment History...............................................123


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1.
SYNOPSIS
Protocol Title: An Open Label, Phase 1 Study to Evaluate the PK, Safety, Tolerability 
and Acceptability of Long Acting Injections of the HIV Integrase Inhibitor, Cabotegravir 
(CAB; GSK1265744) in HIV Uninfected Chinese Men.
Short Title: A Phase 1 Safety, Tolerability, Acceptability, and PK study of GSK1265744 
LA in Healthy HIV-Uninfected Chinese Men.
Rationale:
Cabotegravir (CAB, GSK1265744) is an integrase strand transfer inhibitor currently in 
development for treatment and prevention of HIV infection.  CAB has been formulated as 
a long-acting injectable nanosuspension (CAB LA) with a favorable pharmacokinetic 
(PK) profile supporting monthly or less frequent administration and the potential to 
overcome barriers to adherence associated with daily oral antiretroviral therapy (ART) 
and pre-exposure prophylaxis (PrEP).  Two regimens of CAB LA (400 mg IM every 4 
weeks [Q4W] and 600 mg IM every 8 weeks [Q8W]) are being evaluated in ongoing 
Phase 2b and 3 treatment studies with long-acting rilpivirine (RPV LA) in HIV infected 
individuals, both dosing regimens demonstrating efficacy rates >90% for 48-weeks.  
CAB LA 600 mg IM Q8W, starting 4-weeks following an initial 600 mg IM loading 
dose, has been selected for evaluation in Phase 3 PrEP studies in uninfected males and 
transgender females (HPTN083) and in females (HPTN084) at high risk of HIV infection 
via sexual transmission.  These studies will be conducted in the Americas, Africa and in 
Asian regions excluding China.  The PK profile following CAB LA 600 mg IM Q8W 
observed in healthy and HIV infected individuals achieves concentrations associated with 
protection against acquisition of Simian/Human Immunodeficiency Virus (SHIV) and 
Simian Immunodeficiency Virus (SIV) via genital tract challenges in nonhuman primate 
models and has maintained suppression of HIV in >90% of infected individuals for 48 
weeks when coadministered with RPV LA.  
This study will evaluate the proposed PrEP regimen in uninfected Chinese male adults at
low risk of HIV infection to confirm dosing prior to larger scale PrEP studies in Chinese 
individuals at high risk of HIV infection.  Plasma CAB PK may be impacted by 
differences in elimination from the systemic circulation and absorption from the injection 
site.  CAB undergoes metabolism primarily by uridine diphosphosphate-
glucuronosyltransferase (UGT) 1A1 conjugation. Approximately ~10-15% of the Han 
Chinese population carry a *6 allele of UGT1A1 which may result in reduced 
metabolism and ~30-50% higher CAB concentrations than those with wild type 
UGT1A1.  Overall, the impact on average exposure is likely to be less than 10% higher 
for the Chinese population when compared to other populations.  Body morphology and 
fat distribution may affect absorption of CAB LA from the injection site.  Males of lower 
body mass index (BMI) often exhibit faster absorption and lower trough concentrations 
than those of higher BMI.  Despite potential differences in absorption and elimination in 
Chinese individuals, the impact on plasma CAB PK is expected to be minimal, and the 
safety profile of oral CAB and CAB LA offers considerable allowance for any increase in 
plasma concentrations due to PK differences.  This study will confirm dose selection for 
Phase 3 PrEP studies in Chinese males.  


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Objectives and Endpoints:
Objectives
Endpoints
Primary
Evaluate the safety and tolerability of the 
injectable agent, cabotegravir 
(GSK1265744) long acting (CAB LA) 
injectable (600 mg dose administered every 
4 weeks for 2 doses followed by every 8 
weeks for 3 doses) through Week 5-41 in 
HIV-1 uninfected Chinese men.
Safety and tolerability parameters, 
including adverse events, clinical 
laboratory tests, study withdrawals due to 
AEs, vital signs assessments, and 
evaluation of injection site reactions 
(ISRs).
Evaluate the plasma pharmacokinetics of 
CAB following repeat oral administration
(Day 1 to Week 4) and CAB LA IM 
injections throughout the Injection Phase 
(Weeks 5-41).
Plasma CAB PK parameters following 
repeated once daily oral administration 
(Day1-Week 4) include (as permitted by 
the data): C, AUC(0-), Cmax, tmax, 
CL/F, Vss, t1/2, and λz.
  
Plasma CAB PK parameters following 
CAB LA IM administration (Week 5-Week 
41) include (as permitted by the data): C, 
AUC(0-), Cmax and tmax.
Secondary
Evaluate the plasma pharmacokinetics of 
CAB LA trough the Injection and Long-
term Follow-up Phases (Week 5-89)
Plasma CAB PK parameters following 
CAB LA IM administration (Week 5-Week 
89) as permitted by the data including C, 
AUC(0-), Cmax, tmax, CL/F, Vss, t1/2, 
and λz.
Evaluate the safety and tolerability of oral 
CAB in HIV uninfected Chinese men
during the oral lead-in Phase (Day 1 to 
Week 4)
Safety and tolerability parameters, 
including adverse events, study 
withdrawals due to AEs, vital signs 
assessments, and clinical laboratory 
assessments.
Evaluate the acceptability of CAB LA 
injections through 41 weeks.
Injection discontinuation rate, the number
and severity of ISRs and additional 
acceptability measures.
Explore concentration-effect relationships 
for various safety and tolerability 
parameters if relevant.
Evaluation of relationships between 
significant safety and tolerability 
parameters and CAB PK may be explored.
AE: Adverse events, AUC (0- ): Area under the plasma concentration time curve over the dosing interval, 
C: Concentration at the end of the dosing interval, Cmax: Maximum observed concentration, Tmax: Time 
of occurrence of Cmax, τ:  Dosing interval, λz: Apparent terminal phase rate constant, CL/F: Oral 
clearance, Vss: volume of distribution at steady state, t1/2: Terminal absorption elimination half-life
Overall Design:
This is an open label (OL) Phase 1, multi-site, study to evaluate the PK, safety, 
tolerability, and acceptability of CAB LA in adult HIV uninfected Chinese male 
participants at low risk for HIV acquisition.  Eligible participants will receive both daily 


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oral CAB and CAB LA.  Participants will receive daily oral CAB (30 mg tablets) for 
4 weeks during the Oral Phase of the study, to assess for safety and tolerability prior to 
receiving CAB LA injections.  Oral dosing will end and clinical and laboratory safety 
evaluations will be conducted at Week 4.  Following confirmation of safety results from 
Week 4, participants will enter the Injection Phase at Week 5and receive five CAB LA 
600 mg IM injections administered at 8-week intervals, with the first 2 doses given 
4 weeks apart, as indicated in below figure. Serial plasma pharmacokinetic sampling 
over 24 h will be performed before the last oral dose to characterize steady-state PK 
parameters in an approximately 16 participants.  Sparse PK sampling during CAB LA 
administration will start on the first day of the Injection Phase prior to the first injection 
and every visit thereafter. Participants will be followed for 56 weeks following their last 
injection.
206898 Study Schematic
Number of Participants:
Approximately 60 participants will be screened in order to ensure that approximately 48 
participants will enter the oral phase and approximately 40 participants will enter the
injection phase of the study. Participants will be enrolled from multiple sites in China. 
Participation will be limited to participants who are male at birth, with a target of at least 
60% men who have sex with men.
Treatment Groups and Duration:
Participants will receive daily oral CAB (30 mg tablets) for 4 weeks.  Following 
confirmation of oral CAB safety and tolerability at the Week 4 visit, participants will 
enter the injection phase and receive CAB LA 600 mg (3 mL) IM injections at the 
following time points: Week 5, Week 9, Week 17, Week 25 and Week 33. In addition,
approximately 16 participants will participate in serial PK sampling at the end of the oral 
lead in, prior to receiving CAB LA injections.


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A participant may withdraw from the study treatment at any time at his/her own request, 
or may be withdrawn at any time at the discretion of the Investigator for safety, 
behavioral or administrative reasons. Participants that are discontinued prematurely from 
the injection phase will enter the post treatment period for one year following their last 
injection unless consent is withdrawn. Study treatment restart or rechallenge after the 
stopping criteria are met by any participant is not allowed.


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2.
SCHEDULE OF ACTIVITIES (SOA)
Table 1
SCHEDULE OF ACTIVITIESq
Clinical Assessments
Screeninga
Oral 
Phasem
Injection Phase
Follow-
up 
Phase & 
Final 
Visit
Day 1
Day 28 (Week 4)
Day 35 (Week 5)
Injection 1
Day 42 (Week 6)
Week 9
Injection 2
Week 10
Week 17
Injection 3
Week 18
Week 25
Injection 4
Week 26
Week 33
Injection 5
Week 34
Week 37
Week 41
Week 53, 65, 77
Week 89
Written informed consent
X
Inclusion/Exclusion criteriab
X
Demographic information
X
Full physical exam/medical historyc
X
X
Brief physical exam
X
X
X
X
X
X
X
X
X
X
X
X
X
Height/weight/BMId
X
X
Medication/drug/alcohol history
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
Dispense oral study medication (with 
counseling)e
X
Drug accountability (pill counts)
X
X
CAB LA Injection (with counseling)
X
X
X
X
X
HIV-PrevTSQcf
X
Oral phase diary card
X


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Clinical Assessments
Screeninga
Oral 
Phasem
Injection Phase
Follow-
up 
Phase & 
Final 
Visit
Day 1
Day 28 (Week 4)
Day 35 (Week 5)
Injection 1
Day 42 (Week 6)
Week 9
Injection 2
Week 10
Week 17
Injection 3
Week 18
Week 25
Injection 4
Week 26
Week 33
Injection 5
Week 34
Week 37
Week 41
Week 53, 65, 77
Week 89
ISR AE Diaryg
X
X
X
X
X
AE 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
SAE review (SAE will be collected 
from the signing of ICF)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant medication check
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Vital signsh
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Qualitative HIV RNA by NAATi
X
HIV PoC testj
X
X
X
X
X
X
X
X
X
X
ECGk
X
HbsAg and HbsAb, HCV Antibody
X
Hematology/Chemistry testing
X
X
X
X
X
X
X
X
X
X
X
Urinalysis
X
X
Urine drug screen
X
Urine chemistry
X
Urine screen for Chlamydia and 
gonorrhea
X
Liver Chemistry Testsl
X
Fasting lipid profile
X
X
Coagulation testing
X
X


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Clinical Assessments
Screeninga
Oral 
Phasem
Injection Phase
Follow-
up 
Phase & 
Final 
Visit
Day 1
Day 28 (Week 4)
Day 35 (Week 5)
Injection 1
Day 42 (Week 6)
Week 9
Injection 2
Week 10
Week 17
Injection 3
Week 18
Week 25
Injection 4
Week 26
Week 33
Injection 5
Week 34
Week 37
Week 41
Week 53, 65, 77
Week 89
TRUST for Syphilis screen
X
Plasma for CAB concentrationm,n,o
Xm
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Plasma storage samplep
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
AE: Adverse events, BMI: Body mass index, CAB: Cabotegravir, CAB LA: Cabotegravir long-acting, ECG: Electrocardiogram, HbsAg: Hepatitis B surface antigen, HIV: Human 
Immunodeficiency Virus, HCV: Hepatitis C Virus, ISR: Injection site reactions, SAE: Serious adverse event, HIV-PrevTSQc:  HIV-Prevention Treatment Satisfaction Questionnaire 
(change): TRUST: Toluidine Red Unheated Serum Test, RNA: Ribonucleic acid.
a.
Screening (including drug screen) is to be performed within 30 days of the first dose in the Oral Phase of the study. See Appendix 2
b.
Inclusion/exclusion criteria will be fully assessed at the Screening visit. Changes between the screening visit and the Day 1 visit should be assessed to ensure eligibility, including 
additional assessments performed at Day 1.
c.
A full physical exam will be performed at Week 89.
d.
Weight will be collected at Screening and at Week 89. Height and BMI will be collected at Screening only.
e.
Oral phase consists of 28 days with a 7 day washout period between Day 28 (last oral dose) and Day 35 (first injection visit).
f.
HIV-PrevTSQc: HIV-Prevention Treatment Satisfaction Questionnaire (change) will be given at Week 10 only (after 2nd injection).
g.
ISR AE 7 Day Post Injection Diary will be distributed at the injection visit at Week 5, 9, 17, 25 and 33 and returned to the clinic at weeks 6, 10, 18, 26, and 34. For participants 
having ISR on the last day of week 5, 9, 17, 25 and 33, additional ISR AE Weeks 2 – 12 Post Injection Diary will be distributed at weeks 6,10, 18, and 26,34. Participants will be 
asked to bring the diary to each clinic visit.
h.
Vital sign measurements will be performed following 5 minutes of rest.
i.
Qualitative HIV Nucleic Acid Amplification Testing (NAAT) will be performed at Screening.  See Appendix 9 for the HIV testing algorithm at screening, Day 1 and during the 
course of the study.
j.
HIV PoC (Point of care) test will be performed at each time point during the course of the study and must be reviewed prior to IM dosing. See Appendix 9 for the HIV testing 
algorithm at screening, Day 1 and during the course of the study. 
k.
ECGs will be performed following 5 minutes of rest in a semi-supine position.
l.
Liver Chemistry Tests include Alanine aminotransferase (ALT), Aspartate aminotransferase (AST), Bilirubin total and direct.


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m.
Oral Pharmacokinetic (PK) sampling at trough will be collected for all subjects prior to dose within 20 to 28 hours following oral administration the day prior. Intensive oral PK 
sampling will be collected from approximately16 participants as shown in Table 2.
n.
PK sampling for Injection phase: All PK samples will be collected prior to CAB LA injections at Week 5, 9, 17, 25, and 33 with the exception of 1-week post injection samples at 
Weeks 6, 10, 18, 26, 34, week 37(4-week post injection sample) and Week 41
o.
Long-term follow up PK samples: PK sampling during follow up will occur at, Week 53, 65, 77, and 89.
p.
Additional testing is required for participants who have a reactive or positive HIV test after enrolment. Stored plasma from the visit previous to the positive test should be tested for 
HIV using the 4th generation HIV test to best estimate time of infection. HIV acquisition must be confirmed by either western blot, HIV ½ Multispot or the Geenius HIV Confirmation 
½ Assay, and HIV RNA.
q.
Visit may occur in a window ±3 Days
Table 2
SCHEDULE OF INTENSIVE ORAL PK APPROXIMATELY 16 PARTICIPANTS) a,b
Day 25
Day 26 
Day 27
Day 28
Check-
in
Oral dose 
administered   
(e.g. 8AM)
Prior to 
oral dose 
(e.g. 
7:55AM)
Oral dose 
administered  
(e.g. 8AM)
1-
hour 
post 
dose 
(e.g. 
9AM)
2-hour 
post 
dose 
(e.g. 
10AM)
3-hour 
post 
dose 
(e.g. 
11AM)
4-hour 
post 
dose 
(e.g. 
12AM)
8-
hour 
post 
dose 
(e.g. 
4PM)
24-
hour 
post 
dose 
(e.g. 
8AM)
Oral dose 
administered 
(e.g. after 8 
AM)
Plasma for 
CAB 
concentration
X
X
X
X
X
X
X
a.
PK sampling may occur 15min
b.
Central lab tests for the intensive oral PK subjects refer to Table 1. 


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3.
INTRODUCTION
Acquired Immune Deficiency Syndrome (AIDS) is a syndrome of immune deficiency 
caused by human infection with HIV, concurrence of series of opportunistic infections 
and tumours and leading to death in severe cases.
HIV infection can be transmitted sexually, through blood transfusions, contaminated 
needles, perinatally, and via breast feeding. High-risk groups include some populations 
of men who have sex with men (MSM), intravenous drug users, those frequently 
transfused with unscreened blood and blood products and the infants delivered by HIV-
infected mothers.
Cabotegravir (CAB, GSK 1265744) is an investigational HIV integrase strand transfer 
inhibitor (INSTI) that has attributes favourable for both HIV treatment and prevention 
indications. CAB is being developed as both oral and long acting injectable 
formulations. Long-acting antiretroviral agents, capable of being administered on an 
infrequent basis, may improve adherence to therapy and extend opportunities for 
effective HIV prevention. Cabotegravir possesses attributes that allow formulation and 
delivery as a long-acting parenteral (LA) product. These include high-level intrinsic 
antiviral activity, low systemic clearance, low daily dose requirement, low aqueous 
solubility, and a high melting point (permitting micronization or nanomilling). To date, 
results of preclinical and clinical evaluation of CAB as a LA formulation support 
continued investigation of this approach.
3.1.
Study Rationale
Preexposure prophylaxis (PrEP) is an important component in the overall strategy for 
prevention of HIV infection. Oral tenofovir disproxil fumarate/emtricitabine (TDF/FTC) 
was recently approved by the United States (US) Food and Drug Administration (FDA) 
for PrEP and the Centers for Disease Control and Prevention (CDC) and the World 
Health Organization (WHO) have offered interim guidance about TDF/FTC as a PrEP 
treatment. While the TDF/FTC combination provides an exciting prevention tool, 
adherence to daily oral therapy as prevention is challenging. Decreased effectiveness has 
been observed in some randomized placebo-controlled PrEP clinical trials with TDF/FTC
when adherence is suboptimal.
CAB LA has been formulated into a long acting therapy. Efficacy in non-human primate 
models supports its further evaluation as a PrEP therapy in participants at risk of 
acquiring HIV. As monotherapy, CAB LA may be able to be dosed once every 8 weeks 
(after 2 monthly loading doses) and is anticipated to provide high level protection by 
addressing the adherence challenges associated with oral administration.
This study will evaluate the proposed PrEP regimen in uninfected Chinese male adults of 
low risk of HIV infection to confirm dosing prior to larger scale PrEP studies in Chinese 
individuals of higher risk of HIV infection.  Plasma CAB PK may be impacted by 
differences in elimination from the systemic circulation and absorption from the injection 
site.  CAB undergoes metabolism primarily by uridine diphosphosphate-
glucuronosyltransferase (UGT) 1A1 conjugation. Approximately ~10-15% of the Han 


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Chinese population carry a *6 allele of UGT1A1 which may result in reduced 
metabolism and ~30-50% higher CAB concentrations than those with wild type 
UGT1A1.  The impact of differences in metabolism on average exposure is likely to be 
less than 10% higher for the Chinese population when compared to other populations.
Body morphology and fat distribution may affect absorption of CAB LA from the 
injection site.  Males of lower BMI often exhibit faster absorption and lower trough 
concentrations than those of higher BMI.  Despite potential differences in absorption and 
elimination in Chinese individuals, the impact on plasma CAB PK is expected to be 
minimal, and the safety profile of oral CAB and CAB LA offers considerable allowance 
for any increase in plasma concentrations due to PK differences.  This study will serve to 
confirm dose selection for Phase 3 PrEP studies in Chinese males
3.2.
Background
The investigational product CAB possesses attributes that permit its evaluation for both 
HIV treatment and prevention indications.  CAB LA is currently in Phase 3 for both the 
treatment indication (in combination with RPV LA) dosed every 4 weeks (Q4W) and the 
PrEP indication dosed every 8 weeks (Q8W). Two regimens are being evaluated for 
treatment, specifically 400mg IM Q4W and 600mg Q8W, both after a beginning 4-weeks
oral lead-in period for safety/tolerability assessment followed by administration of long-
acting IM injections.  The loading dose strategy for both the Q4W and Q8W regimens
were modified for Phase 3 studies without change to the corresponding maintenance dose 
strategy evaluated in Phase 2b; both Q4W and Q8W regimens maintained >90% 
suppression of HIV for at least 48 weeks. 
CAB LA 600mg IM Q8W, starting 4-weeks following a first dose of 600mg IM, was 
selected for Phase 3 PrEP trials in males and transgender women (HPTN083) and 
females (HPTN084).  Both studies will compare CAB LA to daily oral TDF/FTC to 
assess any advantage of long-acting administration to overcome adherence challenges 
associated with oral PrEP.  Concentrations following the proposed regimen have been 
associated with protection in non-human primate models.
Two Phase 2A PreP studies have assessed potential CAB LA regimens for evaluation in 
Phase 3 PrEP trials.  The first was a randomized, placebo-controlled, double-blind, 
multicenter US study (Study 201120, ECLAIR) in healthy men at low risk of acquiring 
HIV-1 to assess the safety, tolerability, acceptability, and PK of CAB LA given 
intramuscularly (IM). Participants were randomized in a 5 to 1 ratio to receive oral CAB 
30 mg daily or matching placebo for 4 weeks. Following a safety assessment, 
participants received three CAB long-acting (LA) 800 mg (2 x 400 mg split IM injection) 
or saline intramuscular IM injections at 12-week intervals. Most participants (CAB LA, 
n=106; placebo, n=21) were MSM (83%) and Caucasian (56%). During the injection 
phase, Grade 2 or higher adverse events were experienced by more participants in the 
CAB LA group (n=75 [80%]) compared with placebo (n=10 [48%]; p<0.01), with the 
majority attributed to injection-site pain (CAB LA, n=55 participants [59%]; none with 
placebo). The median duration of injection site pain was 5.4 days. Only 4 participants 
terminated participation prematurely due to injection intolerability. Geometric mean 
trough concentrations were lower than predicted and did not achieve the target presumed 
to offer clinical benefit. Overall, 68 participants (79%) reported willingness to continue 


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CAB LA injections. In this US study CAB LA injection was well tolerated through 
Week 41, despite the high incidence of mild-to-moderate injection-site reactions.
HPTN077 (201103), an analogous study to ECLAIR, is an ongoing Phase 2 study 
evaluating PK and safety of CAB LA in men and women at low risk of HIV acquisition.  
Two regimens are being assessed in separate cohorts, including 800mg IM Q12W for 
three doses as well as CAB LA 600mg IM Q8W, with a second dose 4weeks following 
an initial 600mg IM dose, for a total of five doses.  The Q8W regimen was selected based 
on modeling and simulation that included data from Phase 2 PrEP and treatment studies 
and was predicted to achieve clinical targets in male and female subjects.  This study will 
evaluate the selected Phase 3 CAB LA 600 mg IM Q8W PreP dosing regimen in Chinese 
male adults of low risk of HIV acquisition prior to initiating PrEP trials in those of higher 
risk of infection.
3.3.
Benefit/Risk Assessment
More detailed information about the known and expected benefits and risks and 
reasonably expected adverse events of CAB may be found in the Investigator Brochure 
[(GlaxoSmithKline Document Number RH2009/00003/06, 2016].


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3.3.1.
Risk Assessment
Potential Risk of 
Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Drug Induced Liver 
Injury (DILIs)
A small proportion of participants in the CAB program 
to date (total exposure approximately 1644 to 01 April
2017) have developed transaminitis (elevated liver 
transaminases characterized by predominant Alanine 
aminotransferase [ALT] elevation).  In most
participants, transient transaminitis was explained by 
acute hepatitis C infection (majority) and other 
systemic infections. In a small number of participants, 
there was not an alternative explanation, suggesting a 
mild form of DILI without hepatic dysfunction which 
resolved upon withdrawal of treatment with CAB. Of 
the four participants with suspected of DILI identified 
in Phase 2 HIV treatment studies, all were receiving 
oral CAB. 

Exclusion criteria as described in Section 6.2
will prohibit participants with significant liver 
impairment based on screening liver chemistry 
including transaminases (ALT and aspartate 
aminotransferase [AST]) as well as on prior 
medical history. Participants with a history of 
chronic liver disease with ongoing 
inflammation and/or fibrosis will be excluded. 

A 4-week oral lead- in Phase is being 
implemented in this study, where all 
participants will receive oral CAB prior to the 
administration of IM CAB to assess individual 
tolerance to systemic drug.

Liver transaminases (ALT and AST) will be 
closely monitored throughout this study (refer 
to SoA Table 1) and the liver chemistry 
stopping criteria will be adopted as described in 
Section 8.1.1 of this protocol. Participants will 
be withdrawn from CAB treatment where no 
compelling alternative cause is identified and 
DILI is suspected.

Participants who develop ALT ≥3 times the 
upper limit of normal (ULN) while on study 
must consult with Medical Monitor prior to 
initiation or continuation of CAB LA.


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Potential Risk of 
Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Injection Site 
Reactions (ISRs)
Clinical experience to date has demonstrated ISRs 
occur in the majority of participants receiving CAB LA 
but are generally mild (Grade 1) or moderate (Grade 2) 
and include events of pain, tenderness, erythema, or 
nodule formation of several days duration (median
duration for individual events <1 week). ISRs may 
occur more than once in an individual participant 
receiving multiple injections. Although some Grade 3 
ISRs were reported, overall ISRs have been well 
tolerated and have not to date been associated with an 
excess of participants withdrawing.  None of the ISRs 
reported to date was serious and no clinically 
significant complications were reported.

Administration advice will be given to 
minimize risk of poor administration technique 
giving rise to injection site reactions. Advice 
on care, monitoring, natural course, and 
treatment of ISRs is given in study 
documentation 

Advice will be given to participants on care of 
injection site on day/days immediately post 
administration, including use of analgesia, 
compresses where appropriate.

Participants will be closely monitored for ISRs 
particularly for signs of pain, tenderness, 
infections, erythema, swelling, induration, or 
nodules (granulomas or cysts) throughout the 
study. 
Hypersensitivity 
Reactions (HSR)
Hypersensitivity reactions have been reported as 
uncommon occurrences with integrase inhibitors, 
including the closely related compound dolutegravir, 
and were characterized by rash, constitutional findings, 
and sometimes, organ dysfunction, including liver 
injury. 
While there have been no clinical cases of 
hypersensitivity to CAB, there is a theoretical risk of 
systemic or severe hypersensitivity reactions with or 
without hepatic symptoms associated with use of IM 
CAB. The long exposures anticipated after IM CAB 
injection may complicate the management of a drug 

The risk of developing a hypersensitivity 
reaction post administration of IM CAB will be 
minimized by the use of a 4-week oral lead-in 
of oral CAB to determine individual tolerance
prior to the introduction of IM CAB. 

Clinical assessments, laboratory tests (including 
liver transaminases) and vital signs will be 
performed throughout this study (refer to SoA 
Table 1). Results from these assessments may 
aid early detection of HSR. 

Oral CAB will be withdrawn immediately for 


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Potential Risk of 
Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
hypersensitivity reaction, were it to occur.
cases with suspected HSR during the oral CAB 
lead-in phase and would not proceed to the 
injection phase. Participants in the injection 
phase would not receive further injections. 
During oral and IM CAB treatment, any HSR 
reactions that occur would be managed 
supportively.
Development of 
Resistance following 
discontinuation of 
CAB LA
Residual concentrations of CAB LA would remain in 
the systemic circulation of participants who stopped 
study product (e.g. for tolerability issues or treatment 
withdrawal) for varying and in some instances 
prolonged periods (months). Participants discontinuing 
a LA regimen may be at risk for developing resistance 
to CAB many weeks after discontinuing injectable 
therapy were they to become newly infected with 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 
56 weeks from the time of the last injection 
with CAB.  Participants who acquire HIV on 
study will be referred for appropriate care.
Drug-Drug 
Interactions (DDIs)
For a complete listing of permitted and prohibited 
concurrent medications for CAB and CAB LA, refer to 
Section 7.7
CAB and CAB LA should not be co-administered with 
the following medicinal products, as significant 
decreases in CAB plasma concentrations may occur 
(due to UGT enzyme induction), which may result in 
loss of therapeutic effect of CAB.
-
the anticonvulsants carbamazepine, 

All participants will be informed of prohibited 
medications throughout the study and updates 
provided as needed via the informed consent.


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Potential Risk of 
Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
oxcarbazepine, phenobarbital, phenytoin
-
the antimycobacterials rifampicin, 
rifapentine, rifabutin
-
St John’s wort (Hypericum perforatum).
Oral CAB administration only: Antacid products 
containing divalent cations (e.g., aluminium, calcium 
and magnesium) must be taken at least 2 hours before 
or at least 4 hours after CAB.
Participants discontinuing a LA regimen may be at risk 
for developing DDIs many weeks after discontinuing 
injectable therapy.
Study Procedures
Risks of ECG pad 
removal
Participants will be required to have ECG tracings at 
screening. Some discomfort and rash may occur where 
the ECG pads are removed.
All ECGs will be conducted by experienced personnel 
and contact time for the pads on the skin will be kept to 
a minimum.
Venipuncture as used 
for blood sample 
collection
Complications from venipuncture include swelling, 
bleeding, bruising and infection

These risks will be minimized using current 
standard of care techniques for venipuncture.


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Potential Risk of 
Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Other 
Social Harms
Participation in the study could lead to social harms 
that may include loss of privacy, stigmatization, 
interference with gainful employment, and coercion. 
Information regarding social harms will be solicited 
during every 8 week study visits after enrollment in the 
study and will be recorded in log form on case report 
forms (CRFs). In addition, social harms may be 
identified by other study staff, including recruiters, 
receptionists, nurses, physicians, pharmacist, and 
others. All social harms will be brought to the 
attention of the on-site medical officer and reported 
according to AE reporting guidelines described in 
Section 12.4. An investigative committee will review 
social harm reports and determine appropriate follow-
up, including modifying the study protocol and/or 
procedures as necessary. Participants who report social 
harms will be referred to speak with a social worker 
and/or a study counselor.

Participants who report social harms will be 
referred to speak with a social worker and/or a 
study counselor.


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3.3.2.
Other Clinically Relevant Information
Additional details concerning safety observations from clinical studies and for which a 
causal association has not been established or which are of minimal clinical significance 
may be found in the Investigator’s Brochure (GlaxoSmithKline Document number
RH2009/00003/06 IB Version 6)
Adverse Events of Special Interest:
Seizure
Three cases of seizures have occurred in the CAB program cumulatively through 15 May 
2016.  Two of the cases occurred in HIV uninfected subjects with a prior history of 
seizure and one case involved a subject in study 200056 with circumstantial and 
anecdotal evidence of illicit drug use. Overall, there is not convincing evidence that 
cabotegravir exposure may be causally associated with seizure or with reduction of 
seizure threshold, due to the low frequency of reports, the confounders present in the 
cases received to date and lack of any pre-clinical signal or identified plausible 
mechanism. However, seizure and seizure-like events are considered as AEs of special 
interest for close monitoring in future studies. Subjects with recent history of, or recent 
treatment for seizure or determined to have a high risk of seizures, including participants 
with an unstable or poorly controlled seizure disorder will be excluded from study 
participation. For further details refer study reference manual (SRM).
All cases of prior seizure history should be discussed with the Medical Monitor prior to 
enrolment
3.3.3.
Benefit Assessment
Participants in the study will benefit from HIV education and prevention counseling
efforts. In addition they will receive access to chemoprophylaxis CAB LA which may be 
effective in reducing HIV acquisition in adherent individuals. Participants will also be 
screened for sexually transmitted infections (STIs) and referred for treatment, and receive 
screening for hepatitis B and C.
3.3.4.
Overall Benefit: Risk Conclusion
Safety risks in this study are addressed through study design and careful, long term 
monitoring.  Participants in this study will be at risk, though low, for acquisition of HIV 
on the basis of the inclusion criteria, and could receive a therapeutic benefit, as well as 
receiving surveillance of HIV acquisition and other sexually transmitted infections, and
will have access to additional prevention counseling.  The benefit/risk profile for the 
continued development of the CAB LA injection and oral formulations as mono-therapy 
in pre-exposure prophylaxis for horizontal HIV transmission in HIV negative patients 
remains favorable.


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4.
OBJECTIVES AND ENDPOINTS
Objectives
Endpoints
Primary
Evaluate the safety and tolerability of the 
injectable agent, cabotegravir 
(GSK1265744) long acting (CAB LA) 
injectable (600 mg dose administered every 
4 weeks for 2 doses followed by every 8 
weeks for 3 doses) through Week 5-41 in 
HIV-1 uninfected Chinese men.
Safety and tolerability parameters, 
including adverse events, clinical 
laboratory tests, study withdrawals due to 
AEs, vital signs assessments, and 
evaluation of injection site reactions 
(ISRs).
Evaluate the plasma pharmacokinetics of 
CAB following repeat oral administration 
(Day 1 to Week 4) and CAB LA IM 
injections throughout the Injection Phase 
(Weeks 5-41).
Plasma CAB PK parameters following 
repeated once daily oral administration 
(Day1-Week 4) include (as permitted by 
the data): C, AUC(0-), Cmax, tmax, 
CL/F, Vss, t1/2, and λz.
  
Plasma CAB PK parameters following 
CAB LA IM administration (Week 5-Week 
41) include (as permitted by the data): C, 
AUC(0-), Cmax and tmax.
Secondary
Evaluate the plasma pharmacokinetics of 
CAB LA trough the Injection and Long-
term Follow-up Phases (Week 5-89)
Plasma CAB PK parameters following 
CAB LA IM administration (Week 5 -
Week 89) as permitted by the data 
including C, AUC(0-), Cmax, tmax, 
CL/F, Vss, t1/2, and λz.
Evaluate the safety and tolerability of oral 
CAB in HIV uninfected Chinese men
during the oral lead-in Phase (Day 1 to 
Week 4)
Safety and tolerability parameters, 
including adverse events, study 
withdrawals due to AEs, vital signs 
assessments and clinical laboratory 
assessments.
Evaluate the acceptability of CAB LA 
injections through 41 weeks.
Injection discontinuation rate, the number
and severity of ISRs and additional 
acceptability measures.
Explore concentration-effect relationships 
for various safety and tolerability 
parameters if relevant.
Evaluation of relationships between 
significant safety and tolerability 
parameters and CAB PK may be explored.
AE: Adverse events, AUC (0- ): Area under the plasma concentration time curve over the dosing interval, 
C: Concentration at the end of the dosing interval, Cmax: Maximum observed concentration, Tmax: Time 
of occurrence of Cmax, τ: Dosing interval, λz: Apparent terminal phase rate constant, CL/F: Oral clearance, 
Vss: volume of distribution at steady state, t1/2: Terminal absorption elimination half-life.


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5.
STUDY DESIGN
5.1.
Overall Design
Protocol waivers or exemptions are not allowed with the exception of immediate safety 
concerns that may arise after the oral administration of CAB.  Therefore, adherence to the 
study design requirements, including those specified in the SoA Table (Table 1), is 
essential and required for study conduct. 
This study is an open label (OL) Phase 1, multi-site, study to evaluate the PK, safety, 
tolerability, and acceptability of CAB LA in adult male participants (Figure 1).  Eligible 
participants will receive OL CAB LA.  Participants will receive daily oral CAB (30 mg 
tablets) for 4 weeks during the Oral Phase of the study, to assess for safety and 
tolerability prior to receiving CAB LA injections.  Serial PK will also be performed 
during the oral phase to characterize plasma PK parameters of distribution and 
elimination.  Following safety assessments after 4 weeks of oral dosing, participants will 
enter the Injection Phase at Week 5 and receive IM injections of CAB LA (Figure 1).  
CAB LA 600mg will be administered as a single 3-mL IM injection.  Subjects who 
volunteer to participate in the intensive PK assessment will have serial blood sampling 
for measurement of plasma CAB concentrations following oral administration over a 24 h 
window starting on Day 27 and ending on Day 28 (Table 2). Pharmacokinetic sampling 
following CAB LA IM injections will start on just prior to the first injection at Week 
5(Injection Phase) and prior to each subsequent injection with limited PK sampling 
between injection visits (for complete PK sampling schedule refer to SoA , Table 1). 
Starting at 8 weeks post last injection, participants will be seen once every 12 weeks for 
48 weeks during the follow-up phase.
Figure 1
Study Design


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5.2.
Number of Participants
Approximately 60 participants will be screened in order to ensure that approximately 48 
participants will enter the oral phase and approximately 40 participants will enter the 
injection phase of the study.  The participants will be enrolled from multiple sites in 
China.  Participation will be limited to participants who are male at birth, with a target of 
at least 60% men who have sex with men. For further details, refer to Section 10.
If participants prematurely discontinue the oral phase of the study, additional replacement 
participants may be recruited at the discretion of the Sponsor.  Participants who enter the 
injection phase of the study will not be replaced. 
5.3.
Participant and Study Completion
A participant is considered to have completed the study if he/she has completed all 
phases of the study including week 89.
The end of the study is defined as the participant completing the week 89 visit.
5.4.
Scientific Rationale for Study Design
The currently proposed study will evaluate a CAB LA 600 mg IM Q8W dosing regimen 
is appropriate, in a Chinese population.
5.5.
Dose Justification
Oral CAB 30 mg once daily has been selected as the oral lead-in dose prior to initiating 
CAB LA IM injections.  Following this dose in HIV infected participants, geometric 
mean Cand Cmax were 4.2 g/mL and 7.5 g/mL, respectively. Oral CAB 60 mg once 
daily was safe and well tolerated in Phase 2 treatment studies and achieves geometric 
mean Cand Cmax of 7.9 g/mL and 12 g/mL, offering coverage for increased 
exposures in Chinese males due to any potential decrease in UGT1A1 metabolism.  The 
oral lead-in period will be conducted from Day 1 through Week 4 of the study.  Since 
participants are of low risk of HIV acquisition, oral dosing will be discontinued during 
safety assessments after the oral lead-in and prior to the first injection at Week 5.
The CAB LA dose rationale is based on the objective of delivering adequate drug 
concentrations to prevent sexual transmission of HIV.  The proposed dose schedule for 
evaluation in humans is based on maintaining plasma CAB concentrations above the PA-
90% of the maximum inhibitory concentration (IC90) value of 0.166 g/mL which 
demonstrated a 97% protective efficacy of Simian/Human Immunodeficiency Virus
(SHIV) transmission in male macaques.  Plasma CAB concentrations >4 x PA-IC90 
(0.664 g/mL) demonstrated 100% protection against intra-rectal SHIV transmission 
[Andrews, 2014] and was predicted to provide 90% probability of in vivo protection after 
seven intra-vaginal SIVmac251 challenges in female rhesus macaques [Spreen, 2015]. 
CAB LA has been administered following single and repeat IM injections to non-HIV 
infected adult males and females (n=186) and following repeat IM injections to HIV 


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infected participants (n=230).  Relevant PK parameters observed following repeat 
administration of CAB LA to adults are presented in Table 3.
Table 3
Summary of CAB PK Parameters following Repeat Dose 
Administration of CAB LA to Healthy and HIV-infected Subjects
Population
Study
CAB LA 
Regimen
Dosing 
Interval
Plasma CAB  PK Parameter
(Geometric mean [95%CI] (CVb%)
AUC(0- ) 
(g•h/mL)
Cmax
(g/mL)
C
(g/mL)
Tmaxa
(day post 
last dose)
Healthy 
Subjects
LAI115428
800 mg IM/
400 mg IM 
Q4W
(n=10)
D1-W4
1252
[836, 1873]
(61)
2.74
[1.72 4.35]
(72)
1.78
[1.35, 2.36]
(41)
6
(6 – 28)
W4-W8
2010
[1619, 2494]
(31)
3.79
[2.89, 4.99]
(40)
2.60
[2.20, 3.07]
(24)
6
(2 – 28)
W8-W12
2182
[1798, 2647]
(28)
4.03
[3.05, 5.30]
(40)
2.69
[2.21, 3.27]
(28)
6
(2 – 28)
W12-W16
2473
[2063, 2965]
(26)
4.41
[3.55, 5.48]
(31)
3.27
[2.71, 3.94]
(27)
6
(2 – 13)
800 mg IM 
Q12W x2
(n=10)
D1-W12
2917
[2045, 4161]
(53)
2.70
[1.49, 4.88]
(99)
0.74
[0.41, 1.32]
(97)
16.5
(2 – 83)
W12-W24
(n=9)
4468
[3058, 6528]
(52)
3.31
[2.18, 5.04]
(59)
1.10
[0.50, 2.46]
(140)
15
(6 – 42)
201120
ECLAIR
800 mg IM 
Q12W x3
(n=93)
D1-W12
(n=93)
3415
[3140, 3714]
(42.5)
4.26
[3.64, 4.98]
(88.6)
0.302b
[0.237, 0.385]
(157)
7.76
(4.95 – 57.0)
W12-W24
(n=89)
3873
[3543, 4235]
(44.3)
5.22
[4.52, 6.04]
(78.0)
0.331c
[0.253, 0.435]
(165)
6.97
(3.83 – 75.0)
W24-W36
(n=85)
4021
[3728, 4337]
(36.2)
4.91
[4.31, 5.60]
(66.6)
0.387d
[0.296, 0.505]
(150)
6.99
(5.63 – 43.0)
HIV 
Infected 
Subjects
200056
LATTE2
800 mg IM/ 
400 mg IM 
Q4W
(n=115)
W24-W28
(n=97)
1858e
[1719, 2007]
(37)
3.50 
[3.2, 3.8]
(39)
2.35f
[2.2, 2.5]
(32)
6.9
(0 – 29)
W40-W44
(n=95)
2017g
[1847, 2203]
(41)
3.50j  
[3.3, 3.8]
(37)
2.56h  
[2.4, 2.7]
(32)
6.9 
(0 – 28)
800 mg IM/ 
600 mg IM 
Q8W
(n=115)
W24-W32
(n=98)
3037i
[2786, 3310]
(42)
3.55
[3.2, 3.9]
(56)
1.43j
[1.3, 1.6]
(54)
6.9 
(0 – 59)
W40-W48
(n=104)
3027k
[2762, 3322]
(47)
3.33 
[3.1, 3.6]
(47)
1.49 
[1.4, 1.6]
(42)
7.0 
(0 –  57)


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a.
median (range)
b.
n=84
c.
n=71
d.
n=66
e.
n=84
f.
n=108
g.
n=80
h.
n=98
i.
n=86
j.
n=100
k.
n=112
PK data from the ECLAIR (201120) study showed only 30 to 37% of reportable CAB 
plasma trough concentrations were 4x PA-IC90 following each of the three injections, 
and 15 to 31% were below 1x PA-IC90 [Markowitz, 2016].  Graphical evaluation of the 
CAB concentration-time profiles suggests that absorption was more rapid among 
participants in the ECLAIR study than predicted, resulting in higher peak and lower 
trough concentrations.  In the LATTE-2 (200056) study, CAB LA was evaluated in 
combination with Rilpivirine (RPV) LA at two dosing frequencies Q4W and Q8W.  The 
Q8W regimen included an 800 mg loading dose and two subsequent monthly doses of 
CAB LA 600mg prior to initiating an every 8-week dosing interval starting at Week 8.  
On average, this Q8W regimen achieved clinical targets in both males and females
(Figure 2), supporting the selection of an every 8-week regimen for PrEP.  
Figure 2
Observed Mean (SD) Concentration-Time Data following CAB LA 
Q8W in HIV infected subjects (200056 (LATTE-2)
Week
0 1
4
8
12
16
20
2425
28
32
32
36
4041
44
48
48
Plasma CAB (g/mL)
0.1
1
10
100
800mg IM LD, 600mg IM W4, W8 and Q8W
PA-IC90 (0.166g/mL)
10mg PO QD C (LATTE, 1.35g/mL)


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A population PK analysis has been performed to select doses for study in Phase 3 trials in 
treatment and PrEP using NONMEM 7.2 (ICON Development Solutions, Ellicott City, 
Maryland, USA) with data from eight Phase 1 and 2a studies plus the two Phase 2b 
studies 201120 (ÉCLAIR) and 200056 (LATTE-2). A total of 416 participants provided 
data following CAB LA IM administration, with approximately 50% of data obtained 
from LATTE-2, ~20% from ECLAIR and ~30% from Phase 1/2a studies.  A two-
compartment model with first order absorption characterized the observed data well.  
High BMI (>30 kg/m2) and female sex were associated with slower absorption rates.  
BMI and formulation change helped explain a minor amount of the variability of KA LA.  
Scaling of central volume and systemic clearance by weight also improved model fit.  
Model performance was assessed using various goodness-of-fit criteria, including a 
visual inspection of diagnostic scatter plots, successful minimization, completion of 
covariance step, and precision of the parameter estimates.  A visual predictive check was 
used to validate the model.
The model was used to simulate the median (90% prediction interval (PI)) CAB 
concentration-time profile for the selected CAB LA PrEP regimen of 600mg IM Day 1, 
Week 4, then Q8W.  The simulated profile for this regimen for male participants is 
shown in Figure 3.  At steady state, 50% are predicted to achieve trough concentrations 
above the geometric mean trough following the 10 mg oral dose of 1.35g/mL (8-fold 
PA-IC90), which was shown to be efficacious in maintaining viral suppression when 
coadministred with in RPV 25mg once daily in LATTE, and 95% are predicted to 
achieve trough concentrations above PA-IC90. A one week delay in dosing of 600mg IM 
at steady state resulted in a drop in the median Cto 1.08g/mLwith 92% of Cvalues 
remaining above the PA-IC90, supporting a maximum one week delay in dosing. Phase 
3 PrEP trials with the selected CAB LA dose have started in late 2016.


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Figure 3
Simulated* Median (90% Prediction Interval [PI]) Plasma CAB 
Concentrations versus Time for the Selected CAB LA Q8W Regimen 
(600 mg IM Day 1, Week 4, then Q8W) in Male Subjects with normal 
UGT function
Above simulation includes oral lead-in dosing up to and includeing the day of the first injection.  In this 
study, however, there will be an approximately 1-week washout between the last oral dose and the first 
injection at Week 5. 
Although race is not a significant covariate, Asian participants comprise only ~2.5% of 
the IM data in the current population pharmacokinetic (PK) model.  Variability in the 
CAB LA profile is driven by absorption rate constant (which is impacted by gender and 
BMI) and systemic clearance, which can be affected by metabolic pathways and body 
size measures (weight).  Adult Asian males are assumed to be similar in size to those in 
the model.  Differences in UGT metabolism may, however, play a role in disposition of 
CAB LA in Asian participants.
Metabolism of CAB primarily involves UGT1A1, with a minor contribution from 
UGT1A9. Carriage of the UGT1A1 *28 (common) and *37 (African ancestry), and *6 
(East Asian populations) alleles results in decreased UGT1A1 enzyme activity compared 
to wild type enzyme activity (UGT1A1 *1/*1 [Barbarino, 2014]. The clinical impact of 
reduced UGT1A1 enzyme activity varies between medicines. Reduced UGT1A1 enzyme 


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activity is associated with significant changes in disposition of irinotecan and its 
metabolites and, consequently, increased risk of treatment-induced toxicities [Stingl, 
2014; Fujita, 2010]. In contrast, carriage of UGT1A1 polymorphisms that reduce 
enzyme activity have a modest effect on the oral integrase inhibitor (INI) dolutegravir 
exposure and its safety [Chen, 2014]. 
The UGT1A1*28 polymorphism has been reported to be associated with 
hyperbilirunemia induced by several drugs, is known to cause reduced UGT1A1
expression and predisposes individuals to Gilbert’s syndrome, a benign form of episodic 
jaundice [Bosma, 1995; Raijmakers, 2000; Danoff, 2004; VOTRIENT Package Insert 
2015, TASIGNA Package Insert, 2015].  Mild (grade 1 to 2), nonprogressive bilirubin 
(TBL) increases observed in a small subset of patients in LATTE might be a consequence 
of cabotegravir acting as a substrate of UGT1A1 [Margolis, 2015].
A pharmacogenetic (PGx) study was undertaken to evaluate the effect of UGT1A1 and 
UGT1A9 genotypes on exposure and tolerability in participants receiving oral CAB in six 
studies.  The PGx analysis specifically examined 1) PK measurements from participants
in Phase 1 and 2 studies treated with oral CAB 30 mg once daily for at least 8 days; and 
2) selected tolerability endpoints using participants treated with oral CAB from a Phase 2 
study.
Genetically predicted UGT1A1 activity was significantly associated with steady-state 
oral CAB 30mg PK parameters C, AUC, and Cmax, with mean values of C, AUC, 
and Cmax ~1.5, 1.4 and 1.3-fold, respectively, higher in participants with low relative 
versus normal predicted activity. Based on the cumulative CAB PK and safety data 
collected to date, this magnitude of increase in CAB exposure is not anticipated to have a 
clinically relevant impact and does not change the understood benefit-risk profile of 
30mg oral CAB.
Genetically predicted UGT1A1 activity was significantly associated with change from 
baseline TBL, but not ALT. None of the five participants who had maximum on-
treatment TBL≥1.5xULN in this dataset, had genetically predicted normal UGT1A1 
activity; all carried one or more reduced function UGT1A1 alleles.
The UGT1A9 genetic variant (*1B) was not associated with any PK endpoints analyzed 
or with maximum on-treatment ALT, but was moderately associated with maximum on-
treatment TBL. After accounting for genetically predicted UGT1A1 activity within the 
same model, UGT1A9 *1B is no longer significantly associated with change from 
baseline TBL, which suggests that the association between UGT1A9 and TBL may be 
due to the correlation between UGT1A1 and UGT1A9. Further details of the Pgx 
analysis are provided in Section 27.4 of the China Investigational New Drug (IND).
Based on the pharmacogenetics analysis, a 1.4-fold increase in AUC (0- ) would 
correspond to a ~30% reduction in CL.  Therefore, participants carrying a *6 allele (~10-
15% in Han Chinese population) are predicted to have higher CAB concentrations 
following CAB LA than those (of same size and gender) with wild type UGT1A1.  
Simulated median (90% PI) of the proposed PrEP regimen in male participants with 
reduced UGT function (30% decreased CL) is shown in Figure 4.  Median predicted 


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steady state Chas increased from 1.35 g/mL to 1.8 g/mL.  The median predicted 
steady state Cmax (1-week post injection concentration) increased from 4 g/mL to 
5.5 g/mL, and the 95th percentile from 8.7 g/mL to 11.8 g/mL, within the range 
studied following oral CAB in HIV infected participants (LATTE). Given the overall 
good tolerability and safety profile of CAB, it is unlikely that any increase in 
concentrations will produce AEs.  However, there may be a predisposition to increased 
liver function tests (total bilirubin) in those carrying the genetic variants.  
Figure 4
Simulated* Median (90% Prediction Interval [PI]) Plasma CAB 
Concentrations versus Time for the Selected CAB LA Q8W Regimen 
(600 mg IM Day 1, Week 4, then Q8W ) in Male Subjects with 
Reduced UGT Function


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6.
STUDY POPULATION
Protocol waivers or exemptions are not allowed with the exception of immediate safety 
concerns that may arise after the oral administration of CAB.
Specific information regarding warnings, precautions, contraindications, adverse events, 
and other pertinent information on the investigational regimen or other study treatment 
that may impact participant eligibility is provided in the current Investigator’s Brochures 
(IB) for CAB (GlaxoSmithKline Document Number RH2009/00003/06, 2016).
Deviations from inclusion and exclusion criteria are not allowed because they can 
potentially jeopardize the scientific integrity of the study, regulatory acceptability or 
participant safety. Therefore, adherence to the criteria as specified in the protocol is 
essential.
6.1.
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria 
apply:
AGE
1. Participant must be 18 to 65 years of age inclusive, at the time of signing the 
informed consent
TYPE OF PARTICIPANT AND DIAGNOSIS INCLUDING DISEASE SEVERITY
2. Participants are male at birth
3. Participants who have non-reactive POC HIV test and undetectable HIV-1 RNA at 
screening.
4. At risk of acquiring HIV, defined as having at least one casual male or female sex 
partner in the past 24 months
5. Healthy as determined by a responsible and experienced physician, based on a 
medical evaluation including medical history, physical examination, laboratory tests 
and cardiac monitoring at the time of screening;
INFORMED CONSENT
6. Capable of giving written informed consent, which includes compliance with the 
requirements and restrictions listed in the consent form.
OTHER
7. Agree to appropriate use of contraceptive measures during heterosexual intercourse.

All participants should be counselled on safer sexual practices including the 
use and benefit/risk of effective barrier methods (e.g., male condom) to reduce 
the risk of sexually transmitted infections.
8. Willing to undergo all required study procedures


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6.2.
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply
CONCURRENT CONDITIONS/MEDICAL HISTORY (INCLUDES LIVER 
FUNCTION) 
1. Current or chronic history of liver disease, or known hepatic or biliary abnormalities 
(with the exception of Gilbert's syndrome or asymptomatic gallstones).
2. History of the following cardiac diseases: myocardial infarction, congestive heart 
failure, documented hypertrophic cardiomyopathy, sustained ventricular tachycardia.
3. Active skin disease or disorder (i.e., infection, inflammation, dermatitis, eczema, drug 
rash, 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 Medical Monitor.
4.
Participants determined by the Investigator to have a high risk of seizures, 
including participants with an unstable or poorly controlled seizure disorder. A 
participant with a prior history of seizure may be considered for enrolment if the 
Investigator believes the risk of seizure recurrence is low.  All cases of prior seizure 
history should be discussed with the Medical Monitor prior to enrolment.
5. Any medical condition, including psychiatric conditions that in the judgment of the 
investigator would interfere with the participant’s ability to complete study 
procedures.
6. Participant who, in the investigator's judgment, poses a significant suicide risk.
CONCOMITANT MEDICATIONS
7. Use of antiretroviral (ARV) therapy (e.g., for Post exposure prophylaxis [PEP] or 
PrEP) in the past 30 days.
8. Use of high dose aspirin or any other anticoagulant or antiplatelet medication that 
would interfere with the ability to receive IM injections.
RELEVANT HABITS
9. Assessed by the Investigator of Record or designee as being at “high risk” for HIV 
infection. This may include one or more of the following:

The negative partner in an HIV serodiscordant couple where the HIV infected 
partner is not suppressed.

Men who exchange sex for goods or money.

Men who have engaged in any condomless anal intercourse within the past 6 
months.

Men who have had greater than 5 male or female sexual partners within the past 6 
months

Men who have had a sexually transmitted disease within the past 6 months.

Any other behaviour assessed by the investigator as “high risk”.
10. History of drug or alcohol consumption that in the opinion of the Principal 
Investigator will interfere with study participation.


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11. Ongoing intravenous drug use – episodic use or any use in the past 90 days is 
exclusionary (as assessed by the study investigator).
DIAGNOSTIC ASSESSMENTS AND OTHER CRITERIA
12. One or more reactive HIV test results at screening or enrolment, even if HIV 
infection is not confirmed. Negative HIV RNA must also be documented at 
screening.
13. Co-enrolment in any other HIV interventional research study (provided by self-report 
or other available documentation) or prior enrolment and receipt of the active arm 
(i.e., NOT a placebo) of a HIV vaccine trial (provided by available documentation).
14. Any of the following laboratory values during the screening period:

Positive Hepatitis C antibody result

Positive Hepatitis B surface antigen (HBsAg)

Hemoglobin <11 g/dL

Absolute neutrophil count <750 cells/mm3

Platelet count ≤100,000 cells/mm3

Presence of a coagulopathy as defined by an international normalized ratio(INR)>1.5 
or a partial thromboplastin time (PTT) >45sec

Calculated creatinine clearance <60 mL/minute using the Cockcroft-Gault equation

A single repeat test is allowed during the Screening period to verify a result, with the 
exception of HIV tests.
15. Participants with an alanine aminotransferase (ALT), alkaline phosphatase (ALP) or 
bilirubin ≥1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is 
fractionated and direct bilirubin <35%).
16. The participant has a tattoo or other dermatological condition overlying the gluteus 
region which may interfere with interpretation of injection site reactions .
6.3.
Lifestyle Restrictions
Participants will abstain from strenuous exercise for 24 hours before each blood 
collection for clinical laboratory test.
6.4.
Screen Failures
Participants who do not meet all inclusion, exclusion and any other eligibility criteria will
be considered Screen Failures. Basic study data will be collected for all screened
participants including the reason for screen failure to meet the Consolidated Standards of 
Reporting Trials (CONSORT) publishing requirements and to respond to queries from 
regulatory authorities. Participants are allowed to rescreen once but the participant will 
be assigned a new participant number. Participants who are administered oral CAB (or
oral phase) and subsequently withdrawn from the study, for any reason, may not be re-
screened.


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7.
TREATMENTS
Study treatment is defined as any investigational treatment intended to be administered to 
a study participant according to the study protocol.
7.1.
Treatments Administered
7.1.1.
Study Treatments
Table 4
Study Treatments
Study Treatment
Product Name:
Oral CAB
CAB-LA
Dosage Formulation
Tablet
Sterile Suspension for
Injection Vial
Unit dose 
strength(s)/Dosage level(s):
30 mg tablet
Dose level = 1 tablet
200 mg/mL sterile 
suspension
Dose level = 
600 mg (3 mL)
Route of Administration
Oral
Intramuscular injection
Dosing instructions
Administer orally, once 
daily. Dose at same time 
daily without regard to 
food with water
Intramuscular Injection.
See instructions in Study 
Reference Manual (SRM)
for preparation and 
administration
Packaging and Labeling
Study Treatment will be 
provided in high density
polyethylene (HDPE) 
container. Each container 
will be labeled as required 
per country requirement.
Study Treatment will be 
provided in USP Type I 
glass vial with a 13 mm
gray stopper and an orange 
colored plastic flip off 
overseal. Each vial will be 
labeled as required per 
country requirement.
USP United States Pharmacopeia
7.1.2.
GSK1265744 – Tablet (CAB)
The investigational product (IP) CAB is manufactured by GlaxoSmithKline (GSK) and is 
formulated as white to almost white oval shaped film coated 30 mg tablets for oral 
administration, packaged in HDPE bottles with child-resistant closure that include an 
induction seal.  The CAB tablets will be packaged in bottles containing 30 tablets each.
Participants must keep all IP in its original package container. CAB tablets are to be 
stored up to 30°C and protected from moisture.
7.1.3.
GSK1265744 – Injectable Suspension (CAB LA)
The IP CAB LA is manufactured by GSK and is a sterile white to slightly colored
suspension containing 200 mg/mL of CAB as free acid for administration by IM 
injection. The product is packaged in a 3 mL USP Type I glass vial with a 13 mm gray 
stopper and an orange colored plastic flip off overseal. Each vial is for single use 


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containing a withdrawable fill of 2.0 mL, and does not require dilution prior to 
administration. CAB LA injectable suspension is to be stored at up to 30°C, do not 
freeze. Participants will be assigned to study treatment in accordance with the schedule 
mentioned in SoA (Table 1).
Vials of CAB LA are supplied as a suspension and need no further dilution or
reconstitution. However, sites should gently invert the vials a few times to re-suspend
sediments and allow bubbles to subside, and then use a syringe to withdraw the required
volume of suspension for IM injection.
All injections must be given intramuscularly in the gluteus medius. Sites may use their
discretion as to where in the gluteus muscle each injection is given according to
individual participant circumstance. The time of injection will be captured in the 
electronic case report form (eCRF).
IM injections should be administered at a 90 degree angle into the gluteus medius muscle
using a 1.5” – 2.5” 21-25 gauge needle (or sizes outside of this suggested range based on 
investigator judgement). The needle should be long enough to reach the muscle mass and 
ensure an IM injection, but not so long as to involve underlying nerves, blood vessels, or 
bone. Longer needle lengths will be required for participants with higher BMIs, to ensure 
that injections are administered intramuscularly as opposed to subcutaneously. BMI, 
needle gauge, and length will be collected in the eCRF.
For participants with a higher BMI the investigator should consider using a longer needle, 
see SRM for details.
In the event of suspected intravenous administration, a PK sample will also be drawn 
approximately 2 hours post dose for evaluation of CAB plasma concentrations. Detailed 
dosing instructions can be found in the SRM.
7.2.
Dose Modification
Dose modification will not be permitted in this study.  Data from this study may be the 
basis of future dose modifications for subsequent studies. 
7.3.
Method of Treatment Assignment
This will be an open label, non-randomized, single arm study. Participants will receive 
daily oral CAB (30 mg tablets) for 4 weeks during the Oral Phase of the study and IM 
injections of 600 mg of CAB LA at Week 5, Week 9, Week 17, Week 25 and Week 33
during the Injection phase. For details of dosing refer to Section 2.
7.4.
Blinding
This will be an open label, non-randomized, single arm study.


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7.5.
Preparation/Handling/Storage/Accountability

The investigator or designee must confirm appropriate temperature conditions have 
been maintained during transit for all study treatment received and any discrepancies 
are reported and resolved before use of the study treatment.

Only participants enrolled in the study may receive study treatment and only 
authorized site staff may supply or administer study treatment. All study treatments 
must be stored in a secure, environmentally controlled, and monitored (manual or 
automated) area in accordance with the labeled storage conditions with access 
limited to the investigator and authorized site staff.

The investigator, institution, or the head of the medical institution (where applicable) 
is responsible for study treatment accountability, reconciliation, and record 
maintenance (i.e., receipt, reconciliation, and final disposition records).  Take
adequate precautions to avoid direct eye or skin contact. In the case of unintentional 
occupational exposure notify the monitor, Medical Monitor and/or GSK study 
contact.

Further guidance and information for the final disposition of unused study treatment 
are provided in the SRM.

Under normal conditions of handling and administration, study treatment is not 
expected to pose significant safety risks to site staff.

A Material Safety Data Sheet (MSDS)/equivalent document describing occupational 
hazards and recommended handling precautions either will be provided to the 
investigator, where this is required by local laws, or is available upon request from 
GSK.
7.6.
Treatment Compliance

When participants are dosed at the site, they will receive study treatment directly 
from the investigator or designee, under medical supervision.  The date and time of 
each dose administered in the clinic will be recorded in the source documents.  The 
dose of study treatment and study participant identification will be confirmed at the 
time of dosing by a member of the study site staff other than the person 
administering the study treatment.  

During the oral dosing phase, compliance will be assessed through querying the 
participant during the site visits and documented in the source documents and CRF.  
A record of the number of CAB tablets dispensed to and taken by each participant 
must be maintained and reconciled with study treatment and compliance records.  
Treatment start and stop dates, including dates for treatment delays and/or dose 
reductions will also be recorded in the CRF.

CAB LA 600 mg at weeks 5, 9 and every 8 weeks up to 33 weeks will be 
intramuscularly administered to participants at the site.  Administration will be 
documented in the source documents and reported in the CRF.
Note:

CAB LA dosing is expected to occur in a window ±3 Days


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
CAB LA dosing may occur without consultation from the medical monitor if 
performed within this dosing window.
Any request for dosing to occur outside of the dose week must be discussed and agreed
with the medical monitor prior to dosing. In the event of a late dose, a revised dosing
schedule for subsequent dosing may be required and will be communicated to the site
staff at the time of approval for continued dosing.
7.7.
Concomitant Therapy
Any medication or vaccine (including over-the-counter or prescription medicines, 
vitamins, and/or herbal supplements including traditional Chinese medicines) that the 
participant is receiving at the time of enrolment or receives during the study must be 
recorded along with:

reason for use

dates of administration including start and end dates

dosage information including dose and frequency
The Medical Monitor should be contacted if there are any questions regarding 
concomitant or prior therapy.
7.7.1.
Permitted Medications and Non-Drug Therapies
Not applicable.
7.7.2.
Prohibited Medications and Non-Drug Therapies
Experimental agents not otherwise specified in the protocol, cytotoxic chemotherapy, 
antiretroviral therapy, or radiation therapy may not be administered. Systemically 
administered immunomodulators are prohibited.
The following medications could significantly decrease the levels of CAB in the blood 
due to enzyme induction and therefore must not be administered concurrently: 

carbamazepine

oxcarbazepine

phenobarbital

phenytoin

rifabutin

rifampin

rifapentine

St. John’s wort
The following medications are anticoagulant/antiplatelet medications and could interfere 
with the ability to receive intramuscular injections. Their use is prohibited within 7 days 
before and for 7 days after the injection:


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
high dose aspirin

anagrelide

apixaban

argatroban

bivalirudin

clopidogrel

dabigatran

dalteparin

enoxaparin

fondaparinux

heparin

lepirudin

prasugrel

rivaroxaban

ticagrelor

ticlopidine

warfarin
7.8.
Treatment after the End of the Study
Participants will not receive any additional treatment after completion of the study.
8.
DISCONTINUATION CRITERIA
8.1.
Discontinuation of Study Treatment
Participants who discontinue study treatment during the oral phase will be withdrawn 
from the study. Participants who discontinue treatment during the injection phase should 
be followed up for at least 56 weeks after their last injection as per the schedule of 
activities.
8.1.1.
Liver Chemistry Stopping Criteria
Liver chemistry stopping and increased monitoring criteria have been designed to 
assure participant safety and evaluate liver event etiology (in alignment with the FDA 
premarketing clinical liver safety guidance). These protocol guidelines are in alignment 
with FDA premarketing clinical liver safety guidance: 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf.
Discontinuation of study treatment for abnormal liver tests is required when 

a participant meets one of the conditions outlined in the algorithm
or 

when in the presence of abnormal liver chemistries not meeting protocol-specified
stopping rules, the investigator believes study treatment discontinuation  is in the 


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best interest of the participant Phase I Liver Chemistry Stopping Criteria – Liver 
Stopping Event Algorithm
Continue Study Treatment 
Discontinue Study Treatment 
*INR value not applicable to subjects on anticoagulants 
ALT ≥3xULN 
No
Yes
Must refer to Liver Safety Required Actions and Follow up Assessments  section in the Appendix
Report as an SAE if possible Hy’s Law case: ALT≥3xULN and  Bilirubin≥2xULN (>35% direct)  or 
INR>1.5, if measured*
Liver Safety Required Actions and Follow up Assessments Section can be found in 
Appendix 6 .
8.1.2.
Temporary Discontinuation
Temporary discontinuation is not allowed.
8.1.3.
Follow up visits for participants withdrawn from IM dosing
Participants that are withdrawn from study treatment will continue to be followed for 56
Weeks. All participants who have received at least 1 injection will be followed as per the 
follow-up phase of the study. Starting eight weeks post last injection, participants will be 
seen once every 12 weeks for up to 48 weeks.
At each visit the following long term follow up procedures will be performed:

HIV POC test

HIV counselling

Offer condoms and lubricant

Adverse event and SAE review

Concomitant medication review

Liver function tests

Plasma sample for drug level

Plasma sample for storage
Final visit will be performed at 56 weeks post last injection (see Section 2) Week 89.


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8.1.4.
Rechallenge
8.1.4.1.
Study Treatment Restart or Rechallenge
Study treatment restart or rechallenge after the stopping criteria are met by any 
participant participating in this study is not allowed.
8.2.
Withdrawal from the Study
8.2.1.
Withdrawal from the Study Treatment
A participant may withdraw from the study treatment at any time at his/her own request, 
or may be withdrawn at any time at the discretion of the Investigator for safety, 
behavioral or administrative reasons. Participants that are discontinued from treatment
during the Oral Phase will end their participation at that time. Participants that are 
discontinued from treatment during the Injection phase will enter the post treatment 
period unless consent is withdrawn.  All participants who have received at least 1 
injection of CAB LA will be followed as per the follow-up phase of the study. Starting 
eight weeks post last injection, participants will be seen once every 12 weeks for up to 48
weeks. Every effort should be made to complete the early termination study procedures 
and observations if the participant does not enter post-treatment follow-up.
Any laboratory parameter that meets the stopping criteria should be repeated once to 
confirm the value prior to withdrawal
Reasons for study treatment discontinuation during the Oral or Injection Phase may 
include: 

Confirmed HIV acquisition 

Any clinically significant AE deemed to require discontinuation of investigational 
product

Grade 3 or higher rash or Grade 2 rash with evidence of systemic involvement 

Grade 2 or higher allergic reaction

Post entry co-enrolment in an HIV prevention study 

Use of PrEP during the course of the study

Behaviors assessed by the investigator as being at “high risk” for HIV infection 
during the course of the study
These thresholds assume that participants are asymptomatic with respect to these 
changes. In the presence of clinically significant symptoms, lower thresholds for these 
parameters may need to be used for consideration of possible withdrawal of participants
from the study treatment, after consultation between the Principal Investigator and a 
Medical Monitor.
Before discontinuing a participant from investigational product(s), the Investigator must 
contact the Medical Monitor. In the event that the investigator is unable to reach the 


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Medical Monitor, the Investigator, at his or her discretion, may withhold investigational 
product(s) from a participant until the Medical Monitor or designee can be contacted.
8.2.2.
Withdrawal of Informed Consent

If the participant withdraws consent for disclosure of future information, the 
sponsor may retain and continue to use any data collected before such a 
withdrawal of consent.

If a participant withdraws from the study, he/she may request destruction of any 
samples taken and not tested, and the investigator must document this in the site 
study records.

Refer to the SoA for data to be collected at the time of study discontinuation and
follow-up and for any further evaluations that need to be completed.
8.3.
Lost to Follow Up
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic for a 
required study visit:

The site must attempt to contact the participant and reschedule the missed visit 
as soon as possible and counsel the participant on the importance of maintaining 
the assigned visit schedule and ascertain whether or not the participant wishes to 
and/or should continue in the study.

Before a participant is deemed lost to follow up, the investigator or designee 
must make every effort to regain contact with the participant (where possible, 3 
telephone calls and, if necessary, a certified letter to the participant’s last known 
mailing address or local equivalent methods). These contact attempts should be 
documented in the participant’s medical record.
Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up
9.
STUDY ASSESSMENTS AND PROCEDURES

Study procedures and their timing are summarized in the SoA (Section 2)

Protocol waivers or exemptions are not allowed 

Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or 
discontinue study treatment.

Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.


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
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening 
log to record details of all participants screened and to confirm eligibility or record 
reasons for screening failure, as applicable. Sites will follow the HIV testing 
algorithm for Screening detailed in Appendix 9 and included in the SRM.  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. Participants with reactive screening tests for HIV will 
receive counselling and be referred for further testing and appropriate management.  

Procedures conducted as part of the participant’s routine clinical management (e.g., 
blood count) and obtained before signing of Informed consent form (ICF) may be 
utilized for screening or baseline purposes provided the procedure met the protocol-
specified criteria and was performed within the time frame defined in the SoA (Table 
1).

The maximum amount of blood collected from each participant over the 
duration of the study, including any extra assessments that may be required, will 
not exceed 1500 mL.

Repeat or unscheduled samples may be taken for safety reasons or for technical 
issues with the samples.
9.1.
Efficacy Assessments
In this study only pharmacokinetic and safety parameters will be evaluated, efficacy 
assessment is not applicable.
9.2.
Adverse Events
The definitions of an AE or SAE can be found in Appendix 4.
The investigator and any designees are responsible for detecting, documenting, and 
reporting events that meet the definition of an AE or SAE and remain responsible for 
following up AEs that are serious, considered related to the study treatment or the study, 
or that caused the participant to discontinue the study treatment (see Section 8).
Seizures or suspected seizures are to be reported to GSK promptly (within 24 hours of 
learning of the event) for evaluation and possible onward reporting (see Section 3.3.2).  
Any seizures and suspected seizures that meet the definition of an AE or SAE should be 
reported in these forms.
9.2.1.
Time Period and Frequency for Collecting AE and SAE 
Information

All SAEs will be collected from the signing of the ICF until the final follow-up 
visit at the time points specified in the SoA (Section 2).

All AEs will be collected from the start of treatment until the final follow-up 
visit at the time points specified in the SoA (Section 2).


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
Medical occurrences that begin before the start of study treatment but after 
obtaining informed consent will be recorded on the Medical History/Current 
Medical Conditions section of the case report form (CRF) not the AE section, 
unless it is an SAE.

All SAEs will be recorded and reported to the sponsor or designee immediately
and under no circumstance should this exceed 24 hours, as indicated in 
Appendix 4. The investigator will submit any updated SAE data to the sponsor 
within 24 hours of it being available.

Investigators are not obligated to actively seek AEs or SAEs in former study 
participants. However, if the investigator learns of any SAE, including a death, 
at any time after a participant has been discharged from the study, and he/she 
considers the event to be reasonably related to the study treatment or study 
participation, the investigator must promptly notify the sponsor.

The method of recording, evaluating, and assessing causality of AE and SAEs 
and the procedures for completing and transmitting SAE reports are provided in 
Appendix 4.
9.2.2.
Method of Detecting AEs and SAEs
Care will be taken not to introduce bias when detecting AE and/or SAE. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about 
AE occurrence. Appropriate questions include:

“How are you feeling?” 

“Have you had any (other) medical problems since your last visit/contact?” 

“Have you taken any new medicines, other than those provided in this study, since 
your last visit/contact”
9.2.3.
Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All SAEs, and non-serious AEs of special 
interest (as defined in Section 12.4), will be followed until the event is resolved, 
stabilized, otherwise explained, or the participant is lost to follow-up (as defined in 
Section 8.3). Further information on follow-up procedures is given in Appendix 4.
9.2.4.
Regulatory Reporting Requirements for SAEs

Prompt notification by the investigator to the sponsor of a SAE is essential so 
that legal obligations and ethical responsibilities towards the safety of 
participants and the safety of a study treatment under clinical investigation are 
met. 

The sponsor has a legal responsibility to notify both the local regulatory 
authority and other regulatory agencies about the safety of a study treatment 
under clinical investigation. The sponsor will comply with country-specific 
regulatory requirements relating to safety reporting to the regulatory authority, 


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Institutional Review Boards (IRB)/Independent Ethics Committees (IEC), and 
investigators.

Investigator safety reports must be prepared for suspected unexpected serious 
adverse reactions (SUSAR) according to local regulatory requirements and 
sponsor policy and forwarded to investigators as necessary.

An investigator who receives an investigator safety report describing a Serious 
adverse event (SAE) or other specific safety information (e.g., summary or 
listing of SAE) from the sponsor will review and then file it along with the 
Investigator’s Brochure and will notify the IRB/IEC, if appropriate according to 
local requirements.
9.2.5.
Cardiovascular and Death Events
For any cardiovascular events detailed in Appendix 4 and all deaths, whether or not they 
are considered SAEs, specific Cardiovascular (CV) and Death sections of the CRF will 
be required to be completed.  These sections include questions regarding cardiovascular 
(including sudden cardiac death) and non-cardiovascular death. 
The CV CRFs are presented as queries in response to reporting of certain CV Medical 
Dictionary for Regulatory Activities (MedDRA) terms.  The CV information should be 
recorded in the specific cardiovascular section of the CRF within one week of receipt of a 
CV Event data query prompting its completion.  
The Death CRF is provided immediately after the occurrence or outcome of death is 
reported. Initial and follow-up reports regarding death must be completed within one 
week of when the death is reported.
9.3.
Treatment of Overdose
For the Oral Phase of this study, any dose of CAB greater than 1 tablet (30 mg) within a 
day will be considered an overdose. For the Injection Phase, any dose of CAB LA 
greater than 600 mg will be considered an overdose. GSK does not recommend specific 
treatment for an overdose. The investigator will use clinical judgment to treat any 
overdose In the event of an overdose, the investigator or treating physician should:
1.
Contact the Medical Monitor immediately.
2.
For oral overdose, closely monitor the participant for AE/SAE and laboratory 
abnormalities (at least 14 days). For injection overdose monitor the participant for 
AE/SAE and laboratory abnormalities as per the SoA.
3.
For oral overdose, obtain a plasma sample for PK analysis within 14 days from the 
date of the last dose of study treatment if requested by the Medical Monitor 
(determined on a case-by-case basis).
4.
Document the quantity of the excess dose as well as the duration of the overdosing in 
the CRF.


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Decisions regarding dose interruptions or modifications will be made by the investigator 
in consultation with the Medical Monitor based on the clinical evaluation of the 
participant.
9.4.
Safety Assessments
Planned time points for all safety assessments are provided in the SoA (Section 2).
9.4.1.
Physical Examinations

A complete physical examination will include, at a minimum, assessment of the 
(Skin, Cardiovascular, Respiratory, Gastrointestinal and Neurological) systems.
Height and weight will also be measured and recorded.

A brief physical examination will include, at a minimum assessments of the (Skin, 
lungs, cardiovascular system, and abdomen [Liver and spleen]).

Investigators should pay special attention to clinical signs related to previous serious 
illnesses.
9.4.2.
Injection site reaction
Injection site reactions will be recorded via ISR diaries and managed through investigator 
assessment throughout the study. All ISRs that are either serious, Grade 3 or higher, or 
persisting beyond 2 weeks must be discussed with the Medical Monitor to determine 
etiology and assess appropriate continued study participation.  Digital photographs may 
be documented where possible on all participants who have an injection site reaction, 
with observable findings, that is either serious or Grade 3 or higher, or that persists 
beyond 2 weeks. Dermatology will be consulted on all participants who have an 
injection site reaction considered serious, Grade 3 or above, or if clinically significant 
and persistent beyond 30 days and others if the Investigator or Medical Monitor feels it is 
medically necessary. Details regarding photo collection and any other follow up will be 
given by the Medical Monitor at the time of assessment. 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. The required 
intervention should be documented on the appropriate eCRF page.
9.4.3.
HIV Counseling
Participants will be assessed for HIV risk behaviors at each visit and should be provided
with risk-reduction counseling. This should also include assessing sexually transmitted
diseases symptoms (testing and treating to be applied, as needed). If a significant change
in risk from baseline is identified during the study, the investigator should discuss
continuing participation with the medical monitor. Participants with documented risk 
behaviors requiring the use of PEP should have study treatment withdrawn and managed 
as per Section 8.2. 


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9.4.4.
Acquisition of HIV During the Study
A participant with a positive POC test will have additional samples collected at the same
visit to confirm the acquisition of HIV. A confirmatory test either western blot, HIV ½ 
Multispot or the Geenius HIV Confirmation ½ Assay, and HIV RNA will be performed.
Further information on interpretation is available in the SRM.  Participants who become 
HIV-infected during the course of this study will be referred to care. It is the 
responsibility of the principal investigator to refer the HIV positive participant to an 
appropriate center for HIV care. Investigator will guide HIV positive participants to start 
suppressive HIV treatment as soon as possible to minimize the risk of development of 
drug resistance. A post-HIV confirmation visit will be scheduled and procedures will be 
performed as outlined in Appendix 5. Participants who become infected with HIV-1 
during the Injection Phase should enter the follow-up phase and be managed as per 
Section 8.2.
9.4.5.
Vital Signs
Vital signs will be measured in a semi-supine position after 5 minutes rest and will 
include temperature, systolic and diastolic blood pressure, and pulse rate and respiratory 
rate. Three readings of blood pressure and pulse will be taken. The first reading should 
be rejected. The second and third readings should be averaged to give the measurement 
to be recorded in the CRF.
9.4.6.
Electrocardiograms
A single 12-lead ECG will be obtained at screening as outlined in the SoA (Section 2) 
using an ECG machine that automatically calculates the heart rate and measures PR, 
QRS, QT, and corrected QT interval (QTc) intervals. 
9.4.7.
Clinical Safety Laboratory Assessments

Refer to Appendix 2 for the list of clinical laboratory tests to be performed and 
to the SoA for the timing and frequency. 

The investigator must review the laboratory report, document this review, and 
record any clinically relevant changes occurring during the study in the AE 
section of the CRF. The laboratory reports must be filed with the source 
documents.

All laboratory tests with values considered clinically significantly abnormal 
during participation in the study or within 14 days after last dose of oral study 
treatment or 56 weeks following their last injection, should be repeated until the 
values return to normal or baseline or are no longer considered significantly 
abnormal by the investigator or medical monitor. 

If such values do not return to normal/baseline within a period of time judged 
reasonable by the investigator, the aetiology should be identified and the sponsor 
notified.


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
All protocol-required laboratory assessments, as defined in Appendix 2, must be 
conducted in accordance with the laboratory manual and the SoA.

Blood plasma samples for storage will be collected as indicated in the Section 2
(SoA).  Stored plasma will also be collected from participants who acquire HIV
infection, these assessments include: CAB PK measurements, CD4 count, Viral 
Load, resistance testing, HIV sub typing, characterization of the virus and/or the 
host response to infection.
As these assessments will be performed 
retrospectively; results will not be returned to study sites or participants. An 
HIV confirmatory visit will be scheduled (Appendix 5).
9.5.
Pharmacokinetics

Intensive oral CAB PK will be measured in approximately 16 subjects. These 
subjects will spend three continuous nights at the clinic.  Subjects will check in on 
Day 25 and will take the Day 26 oral dose (e.g. 8 AM) at the clinic. Sample 
collections on Day 27 following oral dose (e.g. 8 AM) at the clinic. Sample 
collections on Day 27 following observed oral CAB dosing in the clinic will be 
obtained before oral dose (e.g. 7:55 AM), and following dose administration at 1, 
2, 3, 4, 8 -hour post-dose and on Day 28, 24-hour post the Day 27 dose 
Approximately 2mL of blood samples will be collected at each of these time 
points.
The last oral dose will be administered on day 28 after the final PK 
sample with subsequent safety and central lab assessment on the same day. For 
study subjects not participating in the intensive PK part of the study, they will 
come in only for day 28 visit for pre-dose PK sampling (approximately 20 to 28 
hours after the dose taken at home the day prior) as well as safety and central lab 
assessment.

Blood samples will be processed to harvest plasma within 1hr of sample 
collection.
Samples collected for analyses of study treatment, plasma
concentration may also be used to evaluate safety or efficacy aspects related to 
concerns arising during or after the study.

Determination of CAB concentration in plasma will be performed in Covance 
Pharmaceutical R&D (Shanghai) Co., Ltd under the monitoring of 
GlaxoSmithKline. CAB concentrations will be determined in plasma using an 
approved, validated analytical methodology. A method validation report will be 
generated to demonstrate the details in validation assessments. 

Once the plasma has been analyzed for CAB, any remaining plasma to be 
used may be analyzed for other compound-related metabolites and the results 
reported under a separate protocol.

All pharmacokinetic analyses will be performed under the direction and 
supervision of the Antiviral Group of Clinical Pharmacology Modelling and 
Simulation (CPMS) at GlaxoSmithKline.  Individual plasma PK parameters will 
be determined by non-compartmental methods using WinNonlin Professional 5.2 
or higher, Phoenix (Certara Corporation) or comparable software.  


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
PK parameters following oral administration may include 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), oral clearance (CL/F) and 
steady state volume (Vss). Following CAB LA administration, individual plasma 
PK parameters for specific injection intervals of the Week 5-41 injection phase of 
the study will be determined where applicable, and may include: 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), and apparent terminal phase 
half-life for CAB LA administration (t½) and lambda z as a measure of absorption 
rate constant (z) if data allow. Plasma levels of CAB will be measured during 
the Follow-up phase between weeks 41 to 89 to determine λz and t1/2 for the final 
injection interval starting at Week 33.
9.6.
Pharmacodynamics
Blood draws are listed in the SoA and Section 9.5 to assess the relationship between drug 
levels and or the emergence of adverse events (HIV acquisition).
9.7.
Genetics
Genetics are not evaluated in this study.
9.8.
Biomarkers
Biomarkers are not evaluated in this study
9.9.
Health Economics OR Medical Resource Utilization and 
Health Economics
Health Economics/Medical Resource Utilization and Health Economics parameters are 
not evaluated in this study
10.
STATISTICAL CONSIDERATIONS
10.1.
Sample Size Determination
10.1.1.
Hypotheses
No formal statistical hypotheses will be evaluated. The study is designed to evaluate the 
PK, safety, tolerability, and acceptability of the injectable agent, CAB LA (600 mg dose 
administered at 8-week intervals after 2 initial doses 4 weeks apart) in HIV-uninfected 
men in China where at least 60% of the men are of a population who have sex with men. 
Where appropriate, an estimation approach will be taken, and point estimates and 
confidence intervals will be constructed.


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10.1.2.
Sample Size Considerations
The sample size of 40 participants given the CAB LA treatment was chosen to ensure an 
adequate evaluation of safety, tolerability and pharmacokinetics data in this population 
prior to moving into a large phase 3 study.
10.2.
Populations for Analyses
For purposes of analysis, the following populations are defined:
Population
Description
All Subjects Screened 
Population
The All Subjects Screened Population will include all 
subjects who consent to participate in the clinical study. 
Subjects in this population will be used for disposition 
summary
Safety Population
The Safety Population will include all subjects who receive at 
least one dose of the study treatment.  Subjects in this 
population will be used for all demographic and safety 
summaries or listings.
Oral Pharmacokinetic 
(PK) Population
The Oral PK Population will include those subjects in the 
Safety population for whom at least one evaluable intensive
Oral PK sample will be obtained and analyzed.  Oral 
pharmacokinetic samples that may be affected by protocol 
deviations will be reviewed by the study team and determined 
whether the or not the sample will be excluded.  All Oral PK 
analyses will be based on this analysis population.
Injection 
Pharmacokinetic (PK) 
Population
The Injection PK Population will include all subjects in the 
Safety population for whom at least one evaluable Injection 
PK sample will be obtained and analyzed.  Injection 
pharmacokinetic samples that may be affected by protocol 
deviations will be reviewed by the study team and determined 
whether or not the sample will be excluded.  All Injection PK 
analyses will be based on this analysis population.
10.3.
Statistical Analyses
The primary safety analysis and PK analyses including both oral phase and injection 
phase through Weeks 5 to 41 will be performed after all ongoing participants complete 
the Week 41 visit and datasets have been authorized. Other secondary analyses as 
mentioned, where appropriate, will also be performed. The end of study analysis will be 
performed after all ongoing participants complete the Week 89 visit.


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Data will be listed and summarized according to GSK reporting standards, where 
applicable. Listings will be sorted by participant, study period or phase, visit, actual 
study day, and time if applicable. Summary tables and figures will be presented by visit 
and time if applicable.
The baseline or pre-dose assessment is the last available assessment prior to the time of 
the first dose unless it is specified otherwise. If there are multiple assessments collected 
at the same scheduled time, the average of these assessments will be used. For tabulated 
safety summaries, only the scheduled assessments will be included in the summary tables 
or as noted in the Reporting and Analysis Plan (RAP).
Complete details of the planned analysis will be documented in the RAP.
10.3.1.
Primary Analyses
10.3.1.1.
Safety Analyses
All safety analyses will be performed on the Safety Population. 
The primary safety analysis will include Grade 2 or higher clinical and laboratory events 
that occur from the initial injection to 8 weeks after the last injection among participants
who receive at least one injection.  In an extended safety analysis, all data from enrolled 
participants will be analyzed regardless of how many injections they receive.
To assess safety, the number and the percentage of participants experiencing each safety 
endpoint will be tabulated.  Each participant will contribute once in each category (i.e., 
only for the highest severity AE for each participant) for the calculation of event rates.
10.3.1.1.1. 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.
10.3.1.1.2. AEs
AEs will be tabulated using MedDRA preferred terms.  The number and percentage of 
participants experiencing each specific AEs (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 under the maximum severity or 
the strongest relationship to study product.  AEs leading to withdrawal will also be 
summarized.  AEs will be summarized for those that are treatment emergent during LA 
dosing separately from those that are treatment emergent during oral dosing and also for 
those that are treatment emergent across the entire treatment phase of the study 
(combining both LA and oral dosing). 
10.3.1.2.
Pharmacokinetic Analysis
Plasma PK parameters will be generated in accordance to Section 9.5. 


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Concentration-time data summaries should include number (n), mean, standard deviation 
(SD), coefficient of variation (%CV), geometric mean, geometric mean coefficient of 
variation (% CVb), 95% CI, median, minimum, and maximum.  Concentration-time data 
will be summarized using all data for each planned visit regardless of timing as well as 
for evaluable data that falls within allowable windows for each visit (to be defined in the 
RAP).  Unless stated otherwise, descriptive summaries will include number (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-participant CV (% CVb) 
for the loge-transformed PK parameters.
Accumulation of plasma CAB following CAB LA will be determined by using point 
estimates and confidence intervals for difference in least squares means for the following 
comparison:  
Comparison
Test 
Reference 
Accumulation
1 week post injection concentrations 
Week 34
1 week post injection concentrations 
Week 6
Time to steady state will be assessed by comparing plasma concentration of CAB at 
Week 41 (Cfollowing 5th injection) to previous Cconcentrations at Weeks 17, 25, and 
33.  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 week for Weeks 25 
through 41.


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10.3.2.
Secondary Analyses
Acceptability
To assess acceptability of the CAB LA, the proportion (with 95% CI) of participants who 
would consider using CAB LA for HIV prevention in the future will be calculated among 
all enrolled participants (including those who terminated product use during the trial).  
Participants will be asked if they would consider using CAB LA for HIV prevention in 
the future at their Week 41 visit or at their withdrawal visit, whichever occurs first.
Tolerability 
To assess tolerability of CAB LA, the proportion 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.
A questionnaire will also be used to assess participant tolerability and satisfaction to the 
treatment.  For each question the responses will be summarized by the proportion of 
participants reporting the response out of all those that answered the question.  An overall 
treatment satisfaction score will be calculated for each participant.  
10.3.3.
Pharmacokinetic/Pharmacodynamic Analyses
The relationship between CAB PK parameters and demography (age, weight, gender, 
race, and ethnicity) or pharmacodynamic (PD) (e.g., safety parameter) may be explored.
10.3.4.
Pharmacogenetics
Pharmacogenetic analysis will not be conducted in this study.
10.3.5.
Other Analyses
PK, pharmacodynamic, and biomarker exploratory analyses will be described in the 
reporting and analysis plan. The population PK analysis and pharmacodynamic analyses
will be presented separately from the main clinical study report (CSR). 
10.3.6.
Interim Analyses
No interim analysis is planned for this study.


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11.
REFERENCES
Andrews CD, Spreen WR, Mohri H, Moss L, Ford S, Gettie A, et al. Long-Acting 
Integrase Inhibitor Protects Macaques from Intrarectal Simian/Human Immunodeficiency 
Virus. Science. 2014; 343:1151-1154.
Barbarino JM, Haidar CE, Klein TE, Altman RB. Pharm GKB summary: very important 
pharmacogene information for UGT1A1. Pharmacogenet Genomics. 2014;24:177.
Bosma PJ, Chowdhury JR, Bakker C, Gantla S, de Boer A, Oostra BA, et al. The genetic 
basis of the reduced expression of bilirubin UDP-glucuronosyltransferase 1 in Gilbert's 
syndrome. N Engl J Med. 1995;2:333.
Chen S, St Jean P, Borland J, Song I, Yeo AJ, Piscitelli S, et al. Evaluation of the effect 
of UGT1A1 polymorphisms on dolutegravir pharmacokinetics. Pharmacogenomics. 
2014;19:229.
Danoff TM, Campbell DA, McCarthy LC, Lewis KF, Repasch MH, Saunders AM, et.al. 
A Gilbert's syndrome UGT1A1 variant confers susceptibility to tranilast-induced 
hyperbilirubinemia. Pharmacogenomics J. 2004;4:49.
Fujita K, Sparreboom A. Pharmacogenetics of irinotecan disposition and toxicity: a 
review. Curr Clin Pharmacol. 2010;5:209-17.
GlaxoSmithKline Document Number RH2009/00003/06: GSK1265744 (Cabotegravir)
Clinical Investigator's Brochure, Version 06, December 2016.
Margolis D, Brinson C, Smith G, de Vente J, Hagins D, Eron J, et. al.  Cabotegravir plus 
rilpivirine, once a day, after induction with cabotegravir plus nucleoside reverse 
transcriptase inhibitors in antiretroviral-naive adults with HIV-1 infection (LATTE): a 
randomised, phase 2b, dose-ranging trial. Lancet Infect Dis. 2015; 15: 1145-55.
Markowitz M, Frank I; Grant R, Mayer KH; Margolis DA.; Hudson KJ, et al.  ÉCLAIR: 
Phase 2A Safety and PK Study of Cabotegravir LA in HIV-Uninfected Men, Conference 
Dates and Location: February 22–25, 2016 | Boston, Massachusetts, Abstract Number: 
106.
Raijmakers MT, Jansen PL, Steegers EA, Peters WH. Association of human liver 
bilirubin UDP-glucuronyltransferase activity with a polymorphism in the promoter region 
of the UGT1A1 gene. J Hepatol. 2000;33:348.
Spreen WR, Lowry A, Pal R, Yun Lan Y, Ford S, Richardson-Harman N, et al. 
Correlation of in vivo cabotegravir concentration & prevention of SIV in macaques. 
Conference on Retroviruses and Opportunistic Infections, Seattle, WA. 2015, 23-26. 
Abstract 966LB.
Stingl JC, Bartels H, Viviani R, Lehmann ML, Brockmöller J. Relevance of UDP-
glucuronosyltransferase polymorphisms for drug dosing: A quantitative systematic 
review. Pharmacol Ther. 2014;141:92-116.


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TASIGNA (nilotinib) Product Information. 2015.
VOTRIENT (pazopanib) Product Information. 2015.


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12.
APPENDICES
12.1.
Appendix 1: Abbreviations and Trademarks
AE
Adverse Event
AIDS
Acquired Immune Deficiency Syndrome
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase 
ANC
Absolute Neutrophil Count
ARV
Antiretroviral
ART
Antiretroviral therapy
AST
Aspartate aminotransferase
AUC
Area under concentration-time curve
AUC(0-)
Area under the plasma concentration time curve over the 
dosing interval t
BMI
Body mass index
BUN
Blood urea nitrogen
CAB
Cabotegravir
CAB LA
Cabotegravir long-acting
CDC
US Centers for Disease Control and Prevention 
CI
Confidence interval
CL
Systemic clearance of parent drug
CL/F
Apparent clearance following oral dosing
Cmax
Maximum observed concentration 
Cτ
Pre-dose (trough) concentration at the end of the dosing 
interval
CPK
Creatine phosphokinase
CRF
Case Report Form
CV
Coefficient of variance
%CV
Percent coefficient of variation
%CVb
between-participant CV 
DAIDS
Division of Acquired Immunodeficiency Syndrome
DDIs
Drug-Drug Interactions
DILI
Drug Induced Liver Injury
eCRF
Electronic Case Report Form
ECG
Electrocardiogram
FDA
Food and Drug Administration 
FTC
Emtricitabine
GFR
Glomerular Filtration Rate
GGT
Gamma glutamyltransferase
GLP
Good Laboratory Practice
GLS
Geometric Least-Squares
GSK
GlaxoSmithKline
GSK1265744
Cabotegravir (Both oral and LA formulations)
HBsAg
Hepatitis B surface antigen
HBV
Hepatitis B Virus


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HCV
Hepatitis C Virus
HDPE
High density polyethylene
HIV
Human Immunodeficiency Virus
HIV-
PrevTSQc
HIV-Prevention Treatment Satisfaction Questionnaire 
change
HSR
Hypersensitivity Reactions
h/hr
Hour(s)
IB
Investigator’s Brochure
IC50
Half maximal inhibitory concentration
IC90 or IC90
90% of the maximum inhibitory concentration
ICF
Informed consent form
IEC
Independent Ethics Committee
IgG
Immunoglobulin G
IM
Intramuscular 
IND
Investigational New Drug
INI
Integrase inhibitor
INR
International normalized ratio
INSTI
Integrase strand transfer inhibitor
IP
Investigational Product
IRB
Institutional Review Board
ISR
Injection site reactions
LA
Long acting
LDH
Lactate dehydrogenase
LFT
Liver Function Test
z
Terminal phase rate constant
µg
Microgram
µL
Microliter
MCH
Mean corpuscular hemoglobin
MCHC
Mean corpuscular hemoglobin concentration
MCV
Mean corpuscular volume
MedDRA
Medical Dictionary for Regulatory Activities
MSDS
Material Safety Data Sheet
MSM
Men who have sex with men
n
Number
NAAT
Nucleic Acid Amplification Testing
OL
Open Label
PD
Pharmacodynamic
PGx
Pharmacogenetics
PI
Prediction interval
PK
Pharmacokinetic
PEP
Post exposure prophylaxis
POC
Point of care
PrEP
Pre-exposure prophylaxis
PTT
Partial thromboplastin time


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Q4W
Every 4 weeks
Q8W
Every 8 weeks
RAP
Reporting and Analysis Plan
RNA
Ribose nucleic acid
RPV
Rilpivirine
SAE
Serious adverse event(s)
SD
Standard deviation
SGOT
Serum glutamic-oxaloacetic transaminase
SGPT
Serum glutamic pyruvic transaminase
SHIV
Simian/Human Immunodeficiency Virus
SIV
Simian Immunodeficiency Virus
SRM
Study Reference Manual
STI
Sexually transmitted infection
SOA
Schedule of Activity
t½
Terminal phase half-life
τ
Dosing interval
TDF
Tenofovir disproxilfumarate
tmax
Time of occurrence of Cmax
UGT
Uridine diphosphosphate-glucuronosyltransferase
ULN
Upper limit of normal
UK
United Kingdom
US
United States
USP
United States Pharmacopeia
ViiV
ViiV Healthcare 
Vss
Volume of distribution at steady state
WHO
World Health Organization
Trademark Information
Trademarks of ViiV Healthcare
Trademarks not owned by ViiV
Healthcare
NONE
MedDRA
Phoenix
WinNonlin


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12.2.
Appendix 2: Clinical Laboratory Tests

The tests detailed in Table 5 will be performed by the central laboratory.

Local laboratory results are only required in the event that the central laboratory 
results are not available in time for either study treatment administration and/or 
response evaluation. If a local sample is required, it is important that the sample 
for central analysis is obtained at the same time.

Protocol-specific requirements for inclusion or exclusion of participants are 
detailed in Section 6 of the protocol.

Additional tests may be performed at any time during the study as determined 
necessary by the investigator or required by local regulations.
Table 5
Protocol-Required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet Count
RBC Indices:
MCV
MCH
% Reticulocytes
MCHC
WBC count with 
Differential:
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
RBC Count
Hemoglobin
Hematocrit
WBC Count (absolute)
Reticulocyte Count
Clinical 
Chemistry1,2
BUN
Potassium
Aspartate 
Aminotransferase
(AST)/ Serum 
Glutamic-
Oxaloacetic 
Transaminase
(SGOT)
Total and direct 
bilirubin
Creatinine
Sodium
Alanine 
Aminotransferase
(ALT)/ Serum 
Glutamic-Pyruvic 
Transaminase
(SGPT)
Total Protein
Glucose non 
fasting except 
for day 1 and 
week 41
Calcium
Alkaline 
phosphatase
Creatine 
phosphokinase 
(CPK)
Total CO2
Gamma 
glutamyltransferase 
(GGT)
Calculated 
creatinine 
clearance –
Cockcroft-Gault 
equation
Uric Acid


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Laboratory 
Assessments
Parameters
Albumin
Chloride
Glomerular 
Filtration Rate 
(GFR)
phosphate
Lactate 
Dehydrogenase 
(LDH)
Lipid Panel2
Total 
Cholesterol
High-density 
lipoprotein (HDL)
Low Density 
Lipoprotein (LDL)
Triglyceride
Coagulation 
Panel
Prothrombin
Time (PT)
PTT
International
normalized
ratio (INR)
Routine 
Urinalysis

Specific gravity

pH, glucose, protein, blood, ketones, (bilirubin, urobilinogen, nitrite, 
leukocyte esterase) by dipstick

Microscopic examination (if blood or protein is abnormal)
Urine 
Chemistry

Microalbumin

Creatinine

Microalbumin/creatinine ratio
Other 
Screening 
Tests

HIV POC test; if positive will be confirmed by western blot, HIV ½ Multispot
or the Geenius HIV Confirmation ½ Assay, and HIV RNA.

Hepatitis B surface antigen [HBsAg] and antibody[HBsAb], Hepatitis C 
(HCV)

Syphilis, Urine screening for Chlamydia, Gonorrhea screen.  A positive 
TRUST for syphilis screen will reflex to a treponemal confirmation test.

Urine drug screen (to include at minimum: amphetamines, barbiturates, 
cocaine, opiates, cannabinoids and benzodiazepines).
NOTES:
1.
Details of liver chemistry stopping criteria and required actions and follow-up assessments after liver 
stopping or monitoring event are given in Section 8.1 and Appendix 6. All events of ALT 3 × upper limit of 
normal (ULN) and bilirubin 2 × ULN (>35% direct bilirubin) or ALT 3 × ULN and international normalized 
ratio (INR) >1.5, if INR measured, which may indicate severe liver injury (possible Hy’s Law), must be 
reported as an SAE (excluding studies of hepatic impairment or cirrhosis).
2.
Test will be performed in the fasting state.


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12.3.
Appendix 3: Study Governance Considerations
Regulatory and Ethical Considerations

This study will be conducted in accordance with the protocol and with:

Consensus ethical principles derived from international guidelines 
including the Declaration of Helsinki and Council for International 
Organizations of Medical Sciences (CIOMS) International Ethical 
Guidelines

Applicable ICH Good Clinical Practice (GCP) Guidelines

Applicable laws and regulations

The protocol, protocol amendments, ICF, Investigator Brochure, and other 
relevant documents (e.g., advertisements) must be submitted to an IRB/IEC by 
the investigator and reviewed and approved by the IRB/IEC before the study is 
initiated. 

Any amendments to the protocol will require IEC/IRB approval before 
implementation of changes made to the study design, except for changes 
necessary to eliminate an immediate hazard to study participants. 

The investigator will be responsible for the following:

Providing written summaries of the status of the study to the IRB/IEC 
annually or more frequently in accordance with the requirements, policies, 
and procedures established by the IRB/EC

Notifying the IRB/IEC of SAE or other significant safety findings as 
required by IRB/IEC procedures

Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, European 
regulation 536/2014 for clinical studies (if applicable), and all other 
applicable local regulations
Informed Consent Process

The investigator or his/her representative will explain the nature of the study to 
the participant or his/her legally authorized representative and answer all 
questions regarding the study. 

Participants must be informed that their participation is voluntary. Participants
or their legally authorized representative will be required to sign a statement of 
informed consent that meets the requirements of 21 CFR 50, local regulations, 
ICH guidelines, Health Insurance Portability and Accountability Act (HIPAA) 
requirements, where applicable, and the IRB/IEC or study center. 

The medical record must include a statement that written informed consent was 
obtained before the participant was enrolled in the study and the date the written 
consent was obtained. The authorized person obtaining the informed consent 
must also sign the ICF.


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
Participants must be re-consented to the most current version of the ICF(s) 
during their participation in the study. 

A copy of the ICF(s) must be provided to the participant or the participant’s 
legally authorized representative. 

Participants who are rescreened are required to sign a new ICF.
The ICF may contain a separate section that addresses the use of remaining mandatory 
samples for optional exploratory research in accordance with SOP-GSKF-410. The
investigator or authorized designee will explain to each participant the objectives of the 
exploratory research. Participants will be told that they are free to refuse to participate 
and may withdraw their consent at any time and for any reason during the storage period.
A separate signature will be required to document a participant's agreement to allow any 
remaining specimens to be used for exploratory research. Participants who decline to 
participate will not provide this separate signature.
Data Protection

Participants will be assigned a unique identifier by the sponsor. Any participant 
records or datasets that are transferred to the sponsor will contain the identifier 
only; participant names or any information which would make the participant 
identifiable will not be transferred. 

The participant must be informed that his/her personal study-related data will be 
used by the sponsor in accordance with local data protection law. The level of 
disclosure must also be explained to the participant. 

The participant must be informed that his/her medical records may be examined 
by Clinical Quality Assurance auditors or other authorized personnel appointed 
by the sponsor, by appropriate IRB/IEC members, and by inspectors from 
regulatory authorities.
Committees Structure
Not applicable
Publication Policy

The results of this study may be published or presented at scientific meetings. If 
this is foreseen, the investigator agrees to submit all manuscripts or abstracts to 
the sponsor before submission. This allows the sponsor to protect proprietary 
information and to provide comments.

The sponsor will comply with the requirements for publication of study results. 
In accordance with standard editorial and ethical practice, the sponsor will 
generally support publication of multicenter studies only in their entirety and not 
as individual site data. In this case, a coordinating investigator will be 
designated by mutual agreement.

Authorship will be determined by mutual agreement and in line with 
International Committee of Medical Journal Editors authorship requirements.


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Dissemination of Clinical Study Data

Where required by applicable regulatory requirements, an investigator signatory 
will be identified for the approval of the clinical study report.  The investigator 
will be provided reasonable access to statistical tables, figures, and relevant 
reports and will have the opportunity to review the complete study results at a 
GSK site or other mutually-agreeable location.

GSK will also provide the investigator with the full summary of the study 
results.  The investigator is encouraged to share the summary results with the 
study participants, as appropriate.

The procedures and timing for public disclosure of the results summary and for 
development of a manuscript for publication will be in accordance with GSK 
Policy.
Data Quality Assurance

All participant data relating to the study will be recorded on printed or electronic 
CRF unless transmitted to the sponsor or designee electronically (e.g., 
laboratory data). The investigator is responsible for verifying that data entries 
are accurate and correct by physically or electronically signing the CRF. 

The investigator must maintain accurate documentation (source data) that 
supports the information entered in the CRF. 

The investigator must permit study-related monitoring, audits, IRB/IEC review, 
and regulatory agency inspections and provide direct access to source data 
documents. 

The sponsor or designee is responsible for the data management of this study 
including quality checking of the data. 

Study monitors will perform ongoing source data verification to confirm that 
data entered into the CRF by authorized site personnel are accurate, complete, 
and verifiable from source documents; that the safety and rights of participants 
are being protected; and that the study is being conducted in accordance with the 
currently approved protocol and any other study agreements, ICH GCP, and all 
applicable regulatory requirements. 

Records and documents, including signed ICF, pertaining to the conduct of this 
study must be retained by the investigator for 25 years after study completion 
unless local regulations or institutional policies require a longer retention period. 
No records may be destroyed during the retention period without the written 
approval of the sponsor. No records may be transferred to another location or 
party without written notification to the sponsor. 
Source Documents

Source documents provide evidence for the existence of the participant and 
substantiate the integrity of the data collected. Source documents are filed at the 
investigator’s site.


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
Data reported on the CRF or entered in the eCRF that are transcribed from 
source documents must be consistent with the source documents or the 
discrepancies must be explained. The investigator may need to request previous 
medical records or transfer records, depending on the study. Also, current 
medical records must be available.

Definition of what constitutes source data can be found in Data Quality Plan.
Study and Site Closure
GSK or its designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of GSK. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study 
supplies have been collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time, provided there is reasonable 
cause and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include 
but are not limited to:

Failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsor's procedures, or GCP guidelines

Inadequate recruitment of participants by the investigator

Discontinuation of further study treatment development


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12.4.
Appendix 4: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting
Definition of AE
AE Definition

An AE is any untoward medical occurrence in a clinical study participant, temporally 
associated with the use of a study treatment, whether or not considered related to the 
study treatment.

NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a study treatment.
Events Meeting the AE Definition 

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (e.g., ECG, radiological scans, vital signs 
measurements), including those that worsen from baseline, considered clinically 
significant in the medical and scientific judgment of the investigator (i.e., not related 
to progression of underlying disease).

Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study treatment administration even 
though it may have been present before the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication. Overdose per se will not be reported as an 
AE/SAE unless it is an intentional overdose taken with possible suicidal/self-
harming intent. Such overdoses should be reported regardless of sequelae.
Events NOT Meeting the AE Definition 

Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition.

The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the 
participant’s condition.

Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that 
leads to the procedure is the AE.

Situations in which an untoward medical occurrence did not occur (social and/or 


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convenience admission to a hospital).

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen.
Cardiovascular Events (CV) Definition:

Myocardial infarction/unstable angina

Congestive heart failure

Arrhythmias

Valvulopathy

Pulmonary hypertension

Cerebrovascular events/stroke and transient ischemic attack

Peripheral arterial thromboembolism

Deep venous thrombosis/pulmonary embolism

Revascularization
AEs of Special Interest:
Diarrhea
Participants with Grade 1 or 2 diarrhea may continue study treatment without 
interruption. Participants with diarrhea of any toxicity grade may be treated 
symptomatically with anti-motility agents; however, the recommended daily dose of the 
chosen anti-motility agent must not be exceeded.  If symptoms persist or get worse on the 
recommended daily dose of the chosen anti-motility agent, then the anti-motility agent 
must be discontinued and consultation made with the Medical Monitor.
For participants with Grade 3 diarrhea that is unresponsive to the recommended dose of 
the anti-motility agents and for which an alternative etiology (e.g., infectious diarrhea) is 
not established, the treatment with the anti-motility agent and IP must be interrupted until 
resolution of diarrhea to Grade 2 or Baseline, after which IP and background ART may 
be resumed after discussion and agreement with the Medical Monitor.  If Grade 3 
diarrhea recurs within 28 days upon the resumption of IP, the IP should be permanently 
discontinued and the participant withdrawn from the study.  
If loperamide is used for treatment of diarrhea, local prescribing information should be 
followed with respect to dose and frequency of administration.  Loperamide dosing 
should not exceed local prescribing information.


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Hypertriglyceridemia/ Hypercholesterolemia
Samples for lipid measurements must be obtained in a fasted state according to the SoA 
table (Section 2).  Participants who experience asymptomatic triglyceride or cholesterol 
elevations may continue to receive IP.  Clinical management of participants with 
hypertriglyceridemia/hypercholesterolemia should not be based upon non-fasting samples 
(obtained in the fed state).  A confirmatory fasting triglyceride and/or cholesterol level 
should be obtained prior to the institution of medical therapy for hyperlipidemia.  Isolated 
Grade 3 and Grade 4 lipid abnormalities do not require withdrawal of IP.
Please see the Recommendations of the Adult AIDS Clinical Trial Group Cardiovascular 
Disease Focus Group [Dube, 2003] for full discussion of management of hyperlipidemia
in the context of HIV therapy.
Decline in Renal Function
Participants who experience an increase in serum creatinine from Baseline of 45 
micromoles/liter (Mol/L) (or 0.5 milligrams/deciliter [mg/dL]) should return for a 
confirmatory assessment within 2 to 4 weeks.  A urinalysis and urine albumin/creatinine 
and urine total protein/albumin ratios should also be done at this confirmatory visit.  If 
the creatinine increase is confirmed, the investigator should contact the study medical 
monitor to discuss additional follow-up and medical management.
Participants who have a decline in the estimated GFR (using the CKD-EPI method) of 
>50% from Baseline must return for a confirmatory assessment as soon as possible 
[Levey, 2009].  A urinalysis and urine albumin/creatinine and urine protein/creatinine 
ratios should also be done at this confirmatory visit. If the estimated GFR has declined 
by >50% (confirmed), then study drug should be withheld and the investigator should 
contact the study medical monitor to discuss the rationale for restarting study drugs (if 
appropriate).  Consideration for confounding factors (e.g., background therapy, other 
medications, dehydration, and concurrent conditions) should be taken into account, and a 
nephrology consult may be obtained.  
Proximal Renal Tubule Dysfunctions
Proximal Renal Tubule Dysfunctions (PRTD) is defined as:
Confirmed rise in serum creatinine of ≥0.5 mg/dL from Baseline AND serum phosphate 
<2.0 mg/dL;
Either of the above accompanied by any two of the following:
Glycosuria (≥250 mg/dL) in a non-diabetic;
Low serum potassium (<3 mEq/L);
Low serum bicarbonate (<19 mEq/L).


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Participants meeting criteria for PRTD must return for a confirmatory assessment within 
2 weeks of diagnosis. A urinalysis should also be performed at the time of the 
confirmatory assessment.  If PRTD is confirmed participants should have study drug 
withheld and the investigator should contact the Study medical monitor to discuss the 
rationale for restarting study drugs (if appropriate).  Consideration for confounding 
factors (e.g. other medications, dehydration, concurrent conditions) should be taken into 
account, and a nephrology consult may be obtained. 
Proteinuria
Participants with an abnormal urine microalbumin/creatinine ratio (>0.3 mg/mg, 
>300 mg/g, or >34 mg/mmol) that represents a change from Baseline and no associated 
increase in creatinine, should have a repeat spot urine microalbumin/creatinine ratio 
performed within 2-4 weeks. If confirmed, then consideration should be given to 
additional evaluation after consultation with the study medical monitor. Additional 
evaluation may include a 24-hour urine protein and creatinine measurement and 
nephrology referral.
Participants with an abnormal urine albumin/creatinine ratio (>0.3 mg/mg, 300 mg/g, or 
>34 mg/mmol and representing a change from Baseline) and a serum creatinine increase 
>45 μmol/L (or 0.5 mg/dL) should have confirmation of both results within 2 weeks. If 
confirmed, the study medical monitor should be contacted immediately. Agreement on 
further management should be agreed between the investigator and medical monitor. 


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Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (e.g., hospitalization for signs/symptoms of the disease under study, 
death due to progression of disease).
A SAE is defined as any untoward medical occurrence that, at any dose:
a.
Results in death
b.
Is life-threatening
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event,
which hypothetically might have caused death, if it were more severe.
c.
Requires inpatient hospitalization or prolongation of existing hospitalization
In general, hospitalization signifies that the participant has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or 
outpatient setting. Complications that occur during hospitalization are AE. If a 
complication prolongs hospitalization or fulfils any other serious criteria, the event is 
serious. When in doubt as to whether “hospitalization” occurred or was necessary, the 
AE should be considered serious.
Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an AE.
d.
Results in persistent disability/incapacity

The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.

This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (e.g., sprained ankle) which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect
f.
Other situations:

Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the participant or may require medical or surgical intervention to prevent 
one of the other outcomes listed in the above definition. These events should usually 
be considered serious.
Examples of such events include invasive or malignant cancers, intensive treatment 
in an emergency room or at home for allergic bronchospasm, blood dyscrasias or 


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convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse.
Recording AE and SAE
AE and SAE Recording

When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g., hospital progress notes, laboratory, and diagnostics reports) 
related to the event.

The investigator will then record all relevant AE/SAE information in the CRF.

It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to GSK in lieu of completion of the GSK /AE/SAE CRF page.

There may be instances when copies of medical records for certain cases are 
requested by GSK. In this case, all participant identifiers, with the exception of the 
participant number, will be redacted on the copies of the medical records before 
submission to GSK.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not 
the individual signs/symptoms) will be documented as the AE/SAE.
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and assign it to 1 of the following categories: 

Mild: An event that is easily tolerated by the participant, causing minimal discomfort 
and not interfering with everyday activities.

Moderate: An event that causes sufficiently discomfort and interferes with normal 
everyday activities.

Severe: An event that prevents normal everyday activities. An AE that is assessed as 
severe should not be confused with an SAE. Severe is a category utilized for rating 
the intensity of an event; and both AE and SAE can be assessed as severe.
An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes 
as described in the definition of an SAE, NOT when it is rated as severe.
Assessment of Causality

The investigator is obligated to assess the relationship between study treatment and 
each occurrence of each AE/SAE.

A "reasonable possibility" of a relationship conveys that there are facts, evidence, 
and/or arguments to suggest a causal relationship, rather than a relationship cannot 
be ruled out.


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
The investigator will use clinical judgment to determine the relationship.

Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study treatment 
administration will be considered and investigated.

The investigator will also consult the Investigator’s Brochure (IB) and/or Product 
Information, for marketed products, in his/her assessment.

For each AE/SAE, the investigator must document in the medical notes that he/she 
has reviewed the AE/SAE and has provided an assessment of causality.

There may be situations in which an SAE has occurred and the investigator has 
minimal information to include in the initial report to GSK. However, it is very 
important that the investigator always make an assessment of causality for 
every event before the initial transmission of the SAE data to GSK.

The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality 
assessment.

The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.
Follow-up of AE and SAE

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by GSK to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, 
or consultation with other health care professionals.  If a participant dies during 
participation in the study or during a recognized follow-up period, the investigator 
will provide GSK with a copy of any post-mortem findings including histopathology.

New or updated information will be recorded in the originally completed CRF.

The investigator will submit any updated SAE data to GSK within 24 hours of 
receipt of the information.
Reporting of SAE to GSK
SAE Reporting to GSK via Electronic Data Collection Tool

The primary mechanism for reporting SAE to GSK will be the electronic data 
collection tool.

If the electronic system is unavailable, then the site will use the paper SAE data 
collection tool (see next section) in order to report the event within 24 hours.

The site will enter the SAE data into the electronic system as soon as it becomes 
available.


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
After the study is completed at a given site, the electronic data collection tool will be 
taken off-line to prevent the entry of new data or changes to existing data.

If a site receives a report of a new SAE from a study participant or receives updated 
data on a previously reported SAE after the electronic data collection tool has been 
taken off-line, then the site can report this information on a paper SAE form (see 
next section) or to the medical monitor by telephone.

Contacts for SAE reporting can be found in the study reference manual.
SAE Reporting to GSK via Paper CRF

Facsimile transmission of the SAE paper CRF is the preferred method to transmit 
this information to the medical monitor.

In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by overnight 
mail or courier service.

Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames.

Contacts for SAE reporting can be found in the study reference manual.
References
Dube MP, Stein JH, Aberg JA, Fichtenbaum CJ, Gerber JG, Tashima KT et al.
Guidelines for the evaluation and management of dyslipidemia in human
immunodeficiency virus (HIV)-infected adults receiving antiretroviral therapy:
recommendations of the HIV Medical Association of the Infectious Disease Society of
America and the Adult AIDS Clinical Trials Group. Clin Infect Dis 2003; 37(5):613-27.
Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF, Feldman HI, et.al. A new
equation to estimate glomerular filtration rate. Ann Int Med. 2009; 150: 604-12.


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12.5.
Appendix 5: Schedule for Additional Laboratory Procedures 
for Enrolled Participants who have a Reactive Positive HIV 
Test Result (Post-HIV Confirmation Visit)
Post-HIV Confirmation Visit
Refer for care 
X
Offer condoms and lubricant
X
HIV counseling
X
Clinical Evaluation and Procedures
Blood collection for plasma storage1
X
Schedule follow up visits2
X
CD4 cell count 
X
HIV viral load 
X
HIV resistance testing
X
(1) Stored plasma samples will be collected from participants who acquire HIV infection, 
these assessments may include PK assessment, CD4, resistance testing, HIV subtyping,
characterization of the virus and/or the host response to infection. These assessments will 
be performed retrospectively; results will not be returned to study sites or participants.
(2) Participants will continue to be followed every 12 weeks (Section 8.1.3)


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12.6.
Appendix 6: Liver Safety: Required Actions and Follow-up 
Assessments
Phase 1 Liver chemistry stopping criteria have been designed to assure participant safety 
and to evaluate liver event etiology (in alignment with FDA premarketing clinical liver 
safety guidance).  
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf
Phase 1 liver chemistry stopping criteria and required follow up assessments
Liver Chemistry Stopping Criteria 
ALT-absolute
ALT≥3xULN
If ALT≥3xULN AND bilirubin1,2 2xULN (>35% direct bilirubin) or  INR >1.5, 
Report as an SAE.
See additional Actions and Follow Up Assessments listed below
Required Actions and Follow up Assessments 
Actions
Follow Up Assessments

Immediately discontinue study treatment

Report the event to GSK within 24 hours

Complete the liver event CRF, and complete 
an SAE data collection tool if the event also 
meets the criteria for an SAE2

Perform liver event follow up assessments 

Monitor the participant until liver chemistries 
resolve, stabilize, or return to within baseline 
(see MONITORING below)
MONITORING:
If ALT≥3xULN AND bilirubin 2xULN or INR 
>1.5

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments within  24 
hrs

Monitor participants twice weekly until liver 
chemistries resolve, stabilize or return to 
within baseline

A specialist or hepatology consultation is 

Viral hepatitis serology3

Obtain INR and recheck with each liver 
chemistry assessment until the 
transaminases values show downward 
trend

A blood sample for pharmacokinetic (PK) 
analysis will be obtained at every visit, and 
therefore, should be available to match 
with Liver Function Test (LFT) findings.  An 
additional PK sample should be obtained 
at the same time as any unscheduled LFT 
assessment. 

Serum creatine phosphokinase (CPK) and 
lactate dehydrogenase (LDH).

Fractionate bilirubin, if total 
bilirubin2xULN

Obtain complete blood count with 
differential to assess eosinophilia

Record the appearance or worsening of 
clinical symptoms of liver injury, or 
hypersensitivity e.g., fatigue, decreased 
appetite, nausea, vomiting, abdominal 


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Liver Chemistry Stopping Criteria 
recommended
If ALT≥3xULN AND bilirubin < 2xULN and INR 
≤1.5:

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments within 24-
72 hrs

Monitor participants weekly until liver 
chemistries resolve, stabilize or return to 
within baseline
pain, jaundice, fever, or rash, on the AE
report form

Record use of concomitant medications on 
the concomitant medications report form 
including acetaminophen, herbal remedies, 
other over the counter medications.

Record alcohol use on the liver event 
alcohol intake case report form
If ALT≥3xULN AND bilirubin 2xULN  or 
INR >1.5:

Anti-nuclear antibody, anti-smooth muscle 
antibody, Type 1 anti-liver kidney 
microsomal antibodies, and quantitative 
total immunoglobulin G (IgG) or gamma 
globulins.

Liver imaging (ultrasound, magnetic 
resonance, or computerized tomography) 
and /or liver biopsy to evaluate liver 
disease; complete Liver Imaging and/or 
Liver Biopsy CRF forms.
1.
Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not 
immediately available, discontinue study treatment for that participant if ALT 3xULN and bilirubin 2xULN. 
Additionally, if serum bilirubin fractionation testing is unavailable, record presence of detectable urinary bilirubin on 
dipstick, indicating direct bilirubin elevations and suggesting liver injury. 
2.
All events of ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) or ALT 3xULN and INR>1.5, if INR 
measured, which may indicate severe liver injury (possible ‘Hy’s Law’), must be reported as an SAE (excluding 
studies of hepatic impairment or cirrhosis); INR measurement is not required and the threshold value stated will 
not apply to participants receiving anticoagulants
3.
Hepatitis A IgM antibody; Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM); Hepatitis C RNA; 
Cytomegalovirus IgM antibody;  Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain 
heterophile antibody or monospot testing);  Hepatitis E IgM antibody 
4.
Record the date/time of the PK blood sample draw and the date/time of the last dose of study treatment prior to 
PK blood sample draw on the CRF. If the date or time of the last dose is unclear, provide the participant’s best 
approximation. If the date/time of the last dose cannot be approximated OR a PK sample cannot be collected in 
the time period indicated above, do not obtain a PK sample. Instructions for sample handling and shipping are in 
the SRM.
References
James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA etal..
Pharmacokinetics of Acetaminophen-Adduct in Adults with Acetaminophen Overdose 
and Acute Liver Failure. Drug Metab Dispos 2009; 37:1779-1784.


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12.7.
Appendix 7: Division of AIDS Table for Grading the Severity 
of Adult and Pediatric Adverse Events Version 2.1, March 
2017
VERSION 2.1, March 2017
The Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse 
Events (“DAIDS AE Grading Table”) is a descriptive terminology which can be utilised 
for Adverse Event (AE) reporting.  A grading (severity) scale is provided for each AE 
term.
Estimating Severity Grade for Parameters Not Identified in the Grading Table
The functional table below should be used to grade the severity of an AE that is not 
specifically identified in the grading table. In addition, all deaths related to an AE are to 
be classified as grade 5
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
Clinical adverse
event NOT
identified 
elsewhere in the
grading table
Mild symptoms
causing no or 
minimal 
interference
with
usual social & 
functional
activities with
intervention not
indicated
Moderate symptoms
causing greater
than minimal
interference with
usual social &
functional
activities with
intervention 
indicated
Severe symptoms
causing inability
to perform usual
social & 
functional
activities
with
intervention
or 
hospitalization 
indicated
Potentially life-
threatening
symptoms causing
inability to
perform basic 
self-care functions 
with intervention
indicated to
prevent permanent
impairment, 
persistent
disability, or death
Major Clinical Conditions 
Cardiovascular
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
Arrhythmia
(by ECG or physical
examination)
Specify 
type, if 
applicable
No symptoms
AND No
intervention 
indicated
No symptoms
AND Non-urgent 
intervention 
indicated
Non-life-
threatening 
symptoms AND
Non-urgent
intervention
indicated
Life-threatening 
arrhythmia OR
Urgent 
intervention
indicated


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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
Blood Pressure
Abnormalities1
Hypertension
(with the lowest
reading taken
after repeat 
testing during a
visit)
≥ 18 years of
age
140 to < 160
mmHg systolic
OR
90 to < 100
mmHg diastolic
≥ 160 to < 
180 
mmHg
systolic OR
≥ 100 to < 
110 
mmHg
diastolic
≥ 180 mmHg
systolic
OR ≥ 110 mmHg 
diastolic
Life-threatening 
consequences in a 
participant not 
previously
diagnosed with
hypertension (e.g., 
malignant
hypertension) OR
Hospitalization 
indicated
< 18 years of
age
> 120/80 mmHg
≥ 95th to < 99th 
percentile + 5
mmHg adjusted
for age, height,
and gender 
(systolic and/or 
diastolic)
≥99th percentile
+5mmHg adjusted 
for age, height, 
and gender
(systolic
and/or diastolic)
Life-threatening 
consequences in a 
participant not 
previously
diagnosed with
hypertension (e.g., 
malignant
hypertension) OR
Hospitalization 
indicated
Hypotension
No symptoms
Symptoms 
corrected with
oral fluid 
replacement
Symptoms AND IV
fluids indicated
Shock requiring use 
of vasopressors or 
mechanical
assistance to 
maintain blood
pressure
Cardiac Ischemia
or
Infarction
Report only one
NA
NA
NA
New symptoms
with ischemia 
(stable angina)
OR New testing
consistent with
ischemia
Unstable angina 
OR Acute
myocardial 
infarction
Heart Failure
No symptoms
AND Laboratory
or cardiac imaging 
abnormalities
Symptoms with
mild to moderate 
activity or
exertion
Symptoms at rest
or with minimal
activity or
exertion (e.g., 
hypoxemia) OR
Intervention
indicated
(e.g., 
oxygen)
Life-threatening 
consequences OR
Urgent intervention 
indicated (e.g., 
vasoactive
medications,
ventricular assist
device, heart
transplant)


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1 Blood pressure norms for children < 18 years of age can be found in: Expert Panel on Integrated 
Guidelines for Cardiovascular Health and Risk Reduction in Children and Adolescents. Pediatrics 
2011;128;S213; originally published online November 14, 2011; DOI: 10.1542/peds.2009-2107C
Cardiovascular
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
Hemorrhage
(with
significant
acute blood
loss)
NA
Symptoms AND
No transfusion
indicated
Symptoms
AND
Transfusion of
≤2 units packed
RBCs indicated
Life-threatening 
hypotension OR
Transfusion of > 2
units packed RBCs 
(for children, packed
RBCs
> 10 cc/kg) indicated
Prolonged PR 
Interval or AV
Block
Report only one
> 16 years of age
PR interval 0.21 to
< 0.25 seconds
PR interval ≥ 
0.25 seconds 
OR Type I
2nd degree AV
block
Type II 2nd
degree AV block
OR Ventricular
pause ≥
3.0 seconds
Complete AV block
≤ 16 years of age 1st degree AV
block
(PR interval
> normal for
age and rate)
Type I 2nd degree
AV block
Type II 2nd
degree AV block
OR Ventricular
pause ≥
3.0 seconds
Complete AV block
Prolonged QTc
Interval2
0.45 to 0.47
seconds
> 0.47 to
0.50 
seconds
> 0.50 seconds OR
≥ 0.06 seconds 
above baseline
Life-threatening 
consequences (e.g., 
Torsade de pointes, 
other associated
serious ventricular
dysrhythmia)
Thrombosis or
Embolism
Report only one
NA
Symptoms AND
No intervention 
indicated
Symptoms
AND
Intervention 
indicated
Life-threatening 
embolic event (e.g., 
pulmonary
embolism, 
thrombus)
2 As per Bazett’s formula


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Dermatologic
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
Alopecia (scalp only) Detectable by
study 
participant, 
caregiver, or 
physician AND
Causing no or 
minimal
interference
with usual social
& functional
activities
Obvious on
visual inspection
AND Causing
greater than 
minimal
interference with
usual social & 
functional
activities
NA
NA
Bruising
Localized to
one area
Localized to
more than one 
area
Generalized
NA
Cellulitis
NA
Non-parenteral 
treatment
indicated (e.g.,
oral antibiotics, 
antifungals, 
antivirals)
IV treatment 
indicated
(e.g., IV 
antibiotics, 
antifungals, 
antivirals)
Life-threatening 
consequences (e.g., 
sepsis, tissue 
necrosis)
Hyperpigmentation
Slight or
localized 
causing no or 
minimal 
interference
with usual
social &
functional
activities
Marked or 
generalized
causing greater
than minimal 
interference with 
usual social & 
functional
activities
NA
NA
Hypopigmentation
Slight or
localized 
causing no or 
minimal 
interference
with usual
social &
functional
activities
Marked or 
generalized
causing greater
than minimal 
interference with 
usual social & 
functional
activities
NA
NA
Petechiae
Localized to
one area
Localized to
more than one 
area
Generalized
NA


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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
Pruritus3
(without skin lesions)
Itching causing
no or minimal 
interference
with usual social
& functional
activities
Itching causing 
greater than
minimal 
interference with 
usual social & 
functional
activities
Itching causing 
inability to
perform usual
social & 
functional
activities
NA
Rash
Specify 
type, if 
applicable
Localized rash
Diffuse rash
OR Target
lesions
Diffuse rash
AND Vesicles 
or limited 
number of
bullae or 
superficial 
ulcerations of 
mucous 
membrane 
limited to one 
site
Extensive or
generalized bullous
lesions OR Ulceration
of mucous membrane 
involving
two or more 
distinct mucosal
sites OR
Stevens-Johnson
syndrome OR
Toxic epidermal
necrolysis
3 For pruritus associated with injections or infusions, see the Site Reactions to Injections and Infusions
section (page 23 in source DAIDS Table).
Endocrine and Metabolic
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
Diabetes Mellitus
Controlled
without 
medication
Controlled with 
medication OR
Modification of 
current
medication 
regimen
Uncontrolled
despite treatment 
modification OR
Hospitalization
for immediate 
glucose control
indicated
Life-threatening 
consequences (e.g., 
ketoacidosis, 
hyperosmolar non-
ketotic coma, end
organ failure)
Gynecomastia
Detectable by
study 
participant, 
caregiver, or 
physician AND
Causing no or 
minimal
interference with 
usual social & 
functional
activities
Obvious on
visual inspection
AND Causing
pain with greater
than minimal 
interference with 
usual social & 
functional
activities
Disfiguring
changes AND
Symptoms 
requiring
intervention or
causing inability
to perform usual
social
& 
functional 
activities
NA


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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
Hyperthyroidism
No symptoms
AND Abnormal 
laboratory value
Symptoms 
causing greater
than minimal 
interference with 
usual social & 
functional
activities OR
Thyroid 
suppression
therapy indicated
Symptoms 
causing 
inability to
perform usual
social & 
functional
activities OR
Uncontrolled 
despite 
treatment 
modification
Life-threatening 
consequences 
(e.g., thyroid
storm)
Hypothyroidism
No symptoms
AND Abnormal 
laboratory value
Symptoms 
causing greater
than minimal 
interference with 
usual social & 
functional
activities OR
Thyroid 
replacement
therapy indicated
Symptoms 
causing 
inability to
perform usual
social & 
functional
activities OR
Uncontrolled 
despite 
treatment 
modification
Life-threatening 
consequences 
(e.g., myxedema 
coma)
Lipoatrophy4
Detectable by
study 
participant, 
caregiver, or 
physician AND
Causing no or 
minimal
interference
with usual
social &
functional
activities
Obvious on
visual inspection
AND Causing
greater than 
minimal
interference with
usual social & 
functional
activities
Disfiguring
changes
NA
Lipohypertrophy5
Detectable by
study 
participant, 
caregiver, or 
physician AND
Causing no or 
minimal
interference with 
usual social & 
functional
activities
Obvious on
visual inspection
AND Causing
greater than 
minimal
interference with
usual social & 
functional
activities
Disfiguring
changes
NA
4 Definition: A disorder characterized by fat loss in the face, extremities, and buttocks.
5 Definition: A disorder characterized by abnormal fat accumulation on the back of the neck, breasts, and
abdomen


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Gastrointestinal
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
Anorexia
Loss of appetite 
without
decreased oral
intake
Loss of appetite 
associated with 
decreased oral intake 
without significant 
weight loss
Loss of
appetite 
associated with 
significant
weight loss
Life-threatening 
consequences OR
Aggressive 
intervention 
indicated (e.g., tube 
feeding, total
parenteral nutrition)
Ascites
No symptoms
Symptoms AND
Intervention 
indicated (e.g.,
diuretics, therapeutic 
paracentesis)
Symptoms recur
or persist
despite 
intervention
Life-
threatening 
consequences
Bloating or 
Distension
Report only one
Symptoms 
causing no or
minimal 
interference with 
usual social & 
functional
activities
Symptoms causing 
greater than minimal 
interference with 
usual social & 
functional activities
Symptoms 
causing inability
to perform usual
social & 
functional
activities
NA
Cholecystitis
NA
Symptoms AND
Medical intervention 
indicated
Radiologic, 
endoscopic,
or operative
intervention
indicated
Life-threatening 
consequences 
(e.g., sepsis,
perforation)
Constipation
NA
Persistent 
constipation 
requiring regular use 
of dietary 
modifications, 
laxatives, or enemas
Obstipation
with manual
evacuation 
indicated
Life-threatening 
consequences 
(e.g., 
obstruction)
Diarrhea
≥ 1 year of age
Transient 
or 
intermitten
t episodes 
of
unformed stools 
OR Increase of ≤ 
3 stools over
baseline
24 h
i d
Persistent episodes 
of unformed to 
watery stools OR
Increase of 4 to  6 
stools over baseline 
per 24-hour period
Increase of ≥ 7 
stools per 24-
hour period OR
IV fluid 
replacement 
indicated
Life-threatening 
consequences 
(e.g., hypotensive 
shock)


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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
< 1 year of age
Liquid stools 
(more unformed
than usual) but
usual number of
stools
Liquid stools with 
increased number of 
stools OR Mild 
dehydration
Liquid stools with 
moderate 
dehydration
Life-threatening 
consequences (e.g., 
liquid stools resulting
in severe 
dehydration, 
hypotensive shock)
Dysphagia or
Odynophagia
Report only
one and 
specify 
location
Symptoms but
able to eat usual
diet
Symptoms causing 
altered dietary intake 
with no intervention 
indicated
Symptoms causing 
severely altered 
dietary intake with 
intervention
indicated
Life-threatening 
reduction in oral
intake
Gastrointestinal
Bleeding
Not requiring 
intervention
other than iron 
supplement
Endoscopic 
intervention 
indicated
Transfusion  
indicated
Life-threatening 
consequences 
(e.g., hypotensive 
shock)
Mucositis or 
Stomatitis
Report only
one and 
specify 
location
Mucosal erythema
Patchy 
pseudomembranes or 
ulcerations
Confluent
pseudomembranes 
or ulcerations OR
Mucosal bleeding 
with minor trauma
Life-threatening 
consequences (e.g., 
aspiration, choking)
OR Tissue necrosis 
OR Diffuse 
spontaneous mucosal
bleeding
Nausea
Transient (< 24 
hours) or 
intermittent
AND No or
minimal 
interference
with oral intake
Persistent nausea 
resulting in
decreased oral intake 
for 24 to 48 hours
Persistent nausea 
resulting in
minimal oral
intake for > 48 
hours OR
Rehydration 
indicated (e.g.,
IV fluids)
Life-threatening 
consequences 
(e.g., hypotensive 
shock)
Pancreatitis
NA
Symptoms with 
hospitalization not 
indicated
Symptoms
with 
hospitalization 
indicated
Life-threatening 
consequences 
(e.g., circulatory
failure, 
hemorrhage,
sepsis)
Perforation
(colon or rectum)
NA
NA
Intervention 
indicatedP
Life-
threatening 
consequences 


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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
Proctitis
Rectal discomfort 
with no
intervention 
indicated
Symptoms causing 
greater than minimal 
interference with 
usual social & 
functional activities 
OR Medical 
intervention 
indicated
Symptoms causing 
inability to
perform usual
social & functional
activities OR
Operative 
intervention
indicated
Life-threatening 
consequences 
(e.g., perforation)
Rectal Discharge
Visible discharge
Discharge requiring 
the use of pads
NA
NA
Vomiting
Transient or 
intermittent
AND No or
minimal 
interference
with oral intake
Frequent episodes 
with no or mild 
dehydration
Persistent
vomiting resulting
in orthostatic 
hypotension OR
Aggressive 
rehydration
indicated (e.g., IV
fluids)
Life-threatening 
consequences 
(e.g., hypotensive 
shock)
Musculoskeletal
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY LIFE-
THREATENING
Arthralgia
Joint pain
causing no or
minimal 
interference
with usual social
& functional
activities
Joint pain causing 
greater than
minimal 
interference with 
usual social & 
functional
activities
Joint pain
causing 
inability to
perform usual
social & 
functional
activities
Disabling joint pain 
causing inability to 
perform basic self-care 
functions
Arthritis
Stiffness or joint 
swelling causing
no or minimal 
interference
with usual social
& functional
activities
Stiffness or joint 
swelling causing 
greater than
minimal 
interference with 
usual social & 
functional
activities
Stiffness or
joint swelling
causing 
inability to
perform usual
social & 
functional
activities
Disabling joint stiffness 
or swelling causing 
inability to perform
basic self-care functions


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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY LIFE-
THREATENING
Myalgia
(generalized)
Muscle pain 
causing no or 
minimal 
interference
with usual
social &
functional
activities
Muscle pain
causing greater
than minimal 
interference with 
usual social & 
functional
activities
Muscle pain
causing inability
to perform usual
social & 
functional
activities
Disabling muscle pain 
causing inability to 
perform basic self-care 
functions
Osteonecrosis
NA
No symptoms 
but with
radiographic 
findings AND
No operative 
intervention 
indicated
Bone pain with 
radiographic 
findings OR
Operative 
intervention
indicated
Disabling bone pain 
with radiographic 
findings causing 
inability to perform
basic self-care functions
Osteopenia6
≥ 30 years of age
BMD t-score
-2.5 to -1
NA
NA
NA
< 30 years of age
BMD z-score
-2 to -1
NA
NA
NA
Osteoporosis6
≥ 30 years of age
NA
BMD t-score < -2.5 Pathologic 
fracture (e.g.,
compression 
fracture causing
loss of vertebral
height)
Pathologic fracture 
causing life-threatening 
consequences
< 30 years of age
NA
BMD z-score < -2
Pathologic 
fracture (e.g.,
compression 
fracture causing
loss of vertebral
height)
Pathologic fracture 
causing life-threatening 
consequences
6 BMD t and z scores can be found in: Kanis JA on behalf of the World Health Organization Scientific 
Group (2007). Assessment of osteoporosis at the primary health-care level. Technical Report. World
Health Organization Collaborating Centre for Metabolic Bone Diseases, University of Sheffield, UK.
2007: Printed by the University of Sheffield


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Neurologic
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
Acute CNS Ischemia NA
NA
Transient
ischemic attack
Cerebral vascular 
accident (e.g.,
stroke with
neurological 
deficit)
Altered Mental
Status (for
Dementia, see 
Cognitive,
Behavioral, or 
Attentional
Disturbance below)
Changes causing
no or minimal 
interference with 
usual social & 
functional
activities
Mild lethargy or 
somnolence 
causing greater
than minimal 
interference with 
usual social & 
functional
activities
Confusion,
memory 
impairment,
lethargy, or 
somnolence 
causing inability
to perform usual
social & 
functional 
activities
Delirium OR
Obtundation
OR Coma
Ataxia
Symptoms 
causing no or
minimal 
interference with 
usual social & 
functional
activities OR No
symptoms with
ataxia detected 
on examination
Symptoms 
causing greater
than minimal 
interference with 
usual social & 
functional
activities
Symptoms 
causing 
inability to
perform usual
social & 
functional
activities
Disabling symptoms 
causing inability to 
perform basic self-
care functions
Cognitive,
Behavioral, or 
Attentional 
Disturbance 
(includes dementia 
and attention 
deficit disorder)
Specify type, if
applicable
Disability
causing no or
minimal 
interference
with usual social
& functional
activities OR
Specialized 
resources not 
indicated
Disability causing 
greater than
minimal 
interference with 
usual social & 
functional
activities OR
Specialized 
resources on part-
time basis 
indicated
Disability
causing 
inability to
perform usual
social & 
functional
activities OR
Specialized 
resources on a 
full- time basis 
indicated
Disability causing 
inability to
perform
basic self-care
functions
OR
Institutionalization 
indicated


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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
Developmental
Delay
< 18 years of
age
Specify type, if
applicable
Mild
developmental 
delay, either
motor or
cognitive, as 
determined by 
comparison with
a developmental 
screening tool 
appropriate for
the setting
Moderate 
developmental
delay, either
motor or 
cognitive, as 
determined by 
comparison with a 
developmental 
screening tool 
appropriate for the 
setting
Severe
developmental
delay, either
motor or
cognitive, as 
determined by 
comparison
with a 
developmental
screening tool 
appropriate for
the setting
Developmental 
regression, either
motor or cognitive, as 
determined by 
comparison with a 
developmental 
screening tool 
appropriate for the 
setting
Headache
Symptoms 
causing no or
minimal 
interference
with usual social
& functional
activities
Symptoms 
causing greater
than minimal 
interference with 
usual social & 
functional
activities
Symptoms 
causing 
inability to
perform usual
social & 
functional
activities
Symptoms 
causing inability
to perform
basic self-care
functions
OR Hospitalization 
indicated  OR
Headache with
significant impairment
of alertness or other
neurologic function
Neuromuscular 
Weakness 
(includes 
myopathy and 
neuropathy)
Specify type, if
applicable
Minimal muscle 
weakness 
causing no or
minimal 
interference
with usual social
& functional
activities OR No
symptoms with
decreased 
strength on 
examination
Muscle weakness 
causing greater
than minimal
interference with
usual social & 
functional
activities
Muscle 
weakness 
causing inability
to perform usual
social
& 
functional 
activities
Disabling muscle 
weakness causing 
inability to
perform
basic self-care
functions OR
Respiratory muscle 
weakness impairing
ventilation
Neurosensory 
Alteration
(includes 
paresthesia and
painful 
neuropathy)
Specify type, if
applicable
Minimal
paresthesia 
causing no or 
minimal
interference
with usual social
& functional
activities
OR No
symptoms 
with sensory 
alteration on 
examination
Sensory alteration
or paresthesia 
causing greater
than minimal 
interference with 
usual social & 
functional
activities
Sensory
alteration or 
paresthesia 
causing inability
to perform usual
social & 
functional
activities
Disabling sensory 
alteration or
paresthesia causing
inability to perform
basic self-care 
functions


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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
Seizures
New Onset
Seizure
≥ 18 years of
age
NA
NA
1 to  3 seizures
Prolonged and
repetitive seizures 
(e.g., status 
epilepticus) OR
Difficult to control
(e.g., refractory
epilepsy)
< 18 years of
age (includes 
new or pre-
existing febrile 
seizures)
Seizure lasting < 
5 minutes with < 
24 hours 
postictal state
Seizure lasting 5 to
<
20 minutes with
< 24 hours 
postictal state
Seizure lasting
≥ 20 minutes 
OR > 24 hours 
postictal state
Prolonged and
repetitive seizures 
(e.g., status 
epilepticus) OR
Difficult to control
(e.g., refractory
epilepsy)
Pre-existing
Seizure
NA
Increased
frequency from
previous level of
control without 
change in seizure 
character
Change in
seizure 
character either
in duration or
quality (e.g.,
severity or 
focality)
Prolonged and
repetitive seizures 
(e.g., status 
epilepticus) OR
Difficult to control
(e.g., refractory
epilepsy)
Syncope
Near syncope 
without loss of 
consciousness 
(e.g., pre-
syncope)
Loss of 
consciousness 
with no
intervention 
indicated
Loss of 
consciousness 
AND
Hospitalization
or intervention
required
NA
Pregnancy, Puerperium, and Perinatal
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
Stillbirth (report
using mother’s 
participant ID)
Report only one
NA
NA
Fetal death 
occurring at ≥ 
20 weeks 
gestation
NA
Preterm Birth
(report using
mother’s 
participant ID)
Live birth at 34 to
< 37 weeks 
gestational
age
Live birth at 28 to
< 34 weeks 
gestational
age
Live birth at 24 to
< 28
weeks 
gestational
age
Live birth at < 24
weeks gestational age


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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
Spontaneous 
Abortion or 
Miscarriage7
(report using
mother’s 
participant ID)
Report only one
Chemical 
pregnancy
Uncomplicated 
spontaneous 
abortion or
miscarriage
Complicated 
spontaneous 
abortion or
miscarriage
NA
7 Definition: A pregnancy loss occurring at < 20 weeks gestational age
Psychiatric
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
Insomnia
Mild difficulty 
falling asleep, 
staying asleep,
or waking up
early causing
no or minimal 
interference
with usual
social &
functional
activities
Moderate 
difficulty falling
asleep, staying
asleep, or 
waking up early 
causing more 
than
minimal
interference with
usual social & 
functional
activities
Severe difficulty 
falling asleep,
staying asleep, or
waking up early
causing
inability to
perform usual
social &
functional
activities
requiring
intervention or
hospitalization
NA
Psychiatric 
Disorders 
(includes anxiety, 
depression,
mania, and 
psychosis)
Specify disorder
Symptoms
with 
intervention
not indicated
OR Behavior
causing no or
minimal 
interference
with usual
social & 
functional
activities
Symptoms with 
intervention 
indicated OR
Behavior causing 
greater than
minimal 
interference with 
usual social & 
functional
activities
Symptoms with 
hospitalization 
indicated OR
Behavior
causing 
inability to
perform usual
social & 
functional
activities
Threatens harm to self 
or others OR Acute 
psychosis OR
Behavior causing
inability to perform
basic self-care 
functions


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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
Suicidal Ideation or
Attempt
Report only one
Preoccupied
with thoughts 
of death AND
No wish to kill
oneself
Preoccupied
with thoughts 
of death AND
Wish to kill 
oneself with no 
specific plan or 
intent
Thoughts of
killing oneself
with partial
or complete plans
but no attempt to
do so OR
Hospitalization
indicated
Suicide attempted
Respiratory
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
Acute 
Bronchospasm
Forced
expiratory 
volume in 1
second or peak
flow reduced to
≥ 70 to < 80%
OR Mild
symptoms
with intervention
not indicated
Forced
expiratory 
volume in 1
second or peak
flow 50 to
< 70% OR
Symptoms with
intervention
indicated OR
Symptoms 
causing greater
than minimal 
interference with
usual social &
functional activities
Forced
expiratory 
volume in 1
second or peak
flow 25 to
< 50% OR
Symptoms 
causing
inability to
perform usual
social & 
functional
activities
Forced expiratory 
volume in 1 second
or peak flow < 25%
OR Life-threatening 
respiratory or 
hemodynamic 
compromise OR
Intubation
Dyspnea or 
Respiratory
Distress
Report only one
Dyspnea on 
exertion with no
or minimal 
interference
with usual
social &
functional
activities OR
Wheezing OR
Minimal increase 
in
respiratory rate
for age
Dyspnea on
exertion causing
greater than 
minimal
interference with
usual social & 
functional
activities OR
Nasal flaring OR
Intercostal
retractions OR
Pulse oximetry
90 to < 95%
Dyspnea at rest 
causing inability
to perform usual
social
& functional
activities OR
Pulse oximetry
< 90%
Respiratory failure 
with ventilator support 
indicated (e.g., CPAP, 
BPAP, intubation)


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Sensory
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
Hearing Loss
≥ 12 years of age
NA
Hearing aid
or 
intervention
not indicated
Hearing aid or 
intervention
indicated
Profound bilateral 
hearing loss (> 80 dB 
at
2 kHz and above) OR
Non-serviceable 
hearing
(i.e., >50 dB
audiogram and <50%
speech 
discrimination)
< 12 years of age
(based on a 1, 2, 3, 4,
6 and 8
kHz 
audiogram)
> 20 dB 
hearing loss 
at ≤ 4 kHz
> 20 dB hearing
loss at > 4 kHz
> 20 dB 
hearing loss at 
≥ 3 kHz in one 
ear with
additional
speech language
related
services 
indicated
(where 
available) OR
Hearing loss 
sufficient to
indicate 
therapeutic 
intervention, 
including
hearing aids
Audiologic indication
for cochlear implant
and additional speech-
language related
services indicated
(where available)
Tinnitus
Symptoms 
causing no or
minimal 
interference
with usual social
& functional
activities with
intervention not
indicated
Symptoms 
causing greater
than minimal 
interference with 
usual social & 
functional
activities with
intervention 
indicated
Symptoms 
causing 
inability to
perform usual
social & 
functional
activities
NA
Uveitis
No symptoms
AND Detectable 
on examination
Anterior uveitis 
with symptoms 
OR Medical
intervention 
indicated
Posterior or
pan- uveitis OR
Operative 
intervention
indicated
Disabling visual loss 
in affected eye(s)


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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
Vertigo
Vertigo causing
no or minimal 
interference
with usual social
& functional
activities
Vertigo causing 
greater than
minimal 
interference with 
usual social & 
functional
activities
Vertigo
causing 
inability to
perform usual
social & 
functional
activities
Disabling vertigo 
causing inability to 
perform basic self-
care functions
Visual Changes
(assessed from baseline)
Visual
changes 
causing no or 
minimal 
interference
with usual
social &
functional
activities
Visual changes 
causing greater
than minimal
interference with
usual social & 
functional
activities
Visual
changes 
causing
inability to 
perform usual
social
& functional
activities
Disabling visual loss 
in affected eye(s)
Systemic
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY LIFE-
THREATENING
Acute Allergic
Reaction
Localized
urticaria (wheals)
with no medical
intervention 
indicated
Localized
urticaria with
intervention 
indicated OR
Mild 
angioedema
with no
intervention 
indicated
Generalized
urticaria OR
Angioedema with 
intervention
indicated OR
Symptoms of
mild
bronchospasm
Acute anaphylaxis 
OR Life-threatening 
bronchospasm OR
Laryngeal edema
Chills
Symptoms causing
no or minimal 
interference with
usual social &
functional activities
Symptoms 
causing greater
than minimal 
interference
with usual
social &
functional
activities
Symptoms 
causing 
inability to
perform usual
social & 
functional
activities
NA


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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY LIFE-
THREATENING
Cytokine Release
Syndrome8
Mild signs and 
symptoms
AND Therapy
(i.e., antibody
infusion) 
interruption not 
indicated
Therapy (i.e., 
antibody
infusion) 
interruption 
indicated AND
Responds
promptly to
symptomatic 
treatment OR
Prophylactic 
medications 
indicated for ≤
24 hours
Prolonged
severe signs and
symptoms OR
Recurrence of 
symptoms
following initial
improvement
Life-threatening 
consequences 
(e.g., requiring
pressor or 
ventilator support)
Fatigue or 
Malaise
Report only one
Symptoms causing
no or minimal 
interference with
usual social &
functional activities
Symptoms 
causing greater
than minimal 
interference
with usual
social &
functional
activities
Symptoms 
causing 
inability to
perform usual
social & 
functional
activities
Incapacitating
symptoms of fatigue or
malaise causing
inability to perform
basic self-care 
functions
Fever (non-
axillary 
temperatures 
only)
38.0 to < 38.6°C or
100.4 to < 101.5°F
≥ 38.6 to <
39.3°C
or ≥ 101.5 to
< 102.7°F
≥ 39.3 to < 40.0°C
or
≥ 102.7 to <
104.0°F
≥ 40.0°C or ≥ 104.0°F
Pain9 (not
associated with
study agent 
injections and
not specified
elsewhere)
Specify location
Pain causing no
or minimal
interference with
usual social & 
functional
activities
Pain causing 
greater than 
minimal 
interference
with usual
social &
functional
activities
Pain causing
inability to
perform usual 
social & 
functional 
activities
Disabling pain causing 
inability to perform
basic self-care
functions OR
Hospitalization
indicated
Serum Sickness10 Mild signs 
and 
symptoms
Moderate signs 
and symptoms
AND
Intervention 
indicated (e.g., 
antihistamines)
Severe signs and 
symptoms AND
Higher level 
intervention
indicated (e.g.,
steroids or IV 
fluids)
Life-threatening 
consequences 
(e.g., requiring
pressor or 
ventilator support)
Underweight11
> 5 to 19 years 
of
age
WHO BMI z-score
< -1 to -2
WHO BMI z-
score
< -2 to -3
WHO BMI z-score
< -3
WHO BMI z-score
< -3 with life-
threatening 
consequences


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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY LIFE-
THREATENING
2 to 5 years of
age
WHO BMI z-score
< -1 to -2
WHO Weight-
for- height z-
score
< -2 to -3
WHO Weight-
for- height z-
score < -3
WHO Weight-for-
height z-score < -3 with
life- threatening
consequences
< 2 years of age
WHO BMI z-score
< -1 to -2
WHO Weight-
for- length z-
score
< -2 to -3
WHO Weight-
for- length z-
score < -3
WHO Weight-for-
length z-score < -3 with
life- threatening
consequences
Unintentional 
Weight Loss 
(excludes 
postpartum 
weight loss)
NA
5 to < 9% loss 
in body weight
from baseline
≥ 9 to < 20%
loss in body
weight from 
baseline
≥ 20% loss in body 
weight from baseline 
OR Aggressive 
intervention indicated
(e.g., tube feeding, total
parenteral nutrition)
8 Definition: A disorder characterized by nausea, headache, tachycardia, hypotension, rash, and/or shortness 
of breath.
9 For pain associated with injections or infusions, see the Site Reactions to Injections and Infusions section
(page 23 in source DAIDS Table).
10 Definition: A disorder characterized by fever, arthralgia, myalgia, skin eruptions, lymphadenopathy,
marked discomfort, and/or dyspnea
11 WHO reference tables may be accessed by clicking the desired age range or by accessing the following
URLs:
http://www.who.int/growthref/who2007_bmi_for_age/en/ for participants > 5
to 19 years of age and 
http://www.who.int/childgrowth/standards/chart_catalogue/en/ for those ≤ 5
years of age.
Urinary
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
Urinary Tract
Obstruction
NA
Signs or
symptoms of
urinary tract 
obstruction
without 
hydronephrosis 
or renal
dysfunction
Signs or
symptoms of 
urinary tract 
obstruction with 
hydronephrosis 
or renal
dysfunction
Obstruction
causing life-
threatening 
consequences


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Site Reactions to Injections and Infusions
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
Injection Site Pain
or
Tenderness
Report only one
Pain or
tenderness 
causing no or 
minimal
limitation of
use of limb
Pain or tenderness 
causing greater
than minimal
limitation of use 
of limb
Pain or
tenderness 
causing inability
to perform usual
social
& functional
activities
Pain or tenderness 
causing inability to 
perform basic self-
care function OR
Hospitalization 
indicated
Injection Site 
Erythema or 
Redness12
Report only one
> 15 years of age
2.5 to < 5 cm in 
diameter OR
6.25 to
< 25 cm2
surface area
AND
Symptoms 
causing no or
minimal
interference with 
usual social & 
functional
activities
≥ 5 to < 10 cm in 
diameter OR ≥ 25
to
< 100 cm2
surface area OR
Symptoms 
causing greater
than minimal
interference
with usual social &
functional
activities
≥ 10 cm in
diameter OR ≥ 
100 cm2 surface 
area OR
Ulceration OR
Secondary
infection OR
Phlebitis OR
Sterile abscess 
OR Drainage 
OR Symptoms 
causing inability
to perform usual
social & 
functional
activities
Potentially life-
threatening 
consequences 
(e.g., abscess,
exfoliative 
dermatitis,
necrosis involving
dermis or deeper
tissue)
≤ 15 years of age
≤ 2.5 cm
in 
diameter
> 2.5 cm in
diameter with < 
50% surface area 
of the extremity 
segment involved 
(e.g., upper arm
or thigh)
≥ 50% surface 
area of the 
extremity 
segment involved 
(e.g., upper arm
or thigh) OR
Ulceration OR
Secondary 
infection OR
Phlebitis OR
Sterile
abscess OR
Drainage
Potentially life-
threatening 
consequences 
(e.g., abscess,
exfoliative 
dermatitis,
necrosis involving
dermis or deeper
tissue)
Injection Site
Induration or 
Swelling
Report only one
> 15 years of
age
Same as for 
Injection
Site 
Erythema
or Redness,
> 15 years 
of age
Same as for 
Injection Site 
Erythema or 
Redness, > 15
years of age
Same as for 
Injection Site 
Erythema or 
Redness, > 15
years of age
Same as for Injection 
Site Erythema or 
Redness, > 15 years 
of age


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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
≤15 years of age
Same as for 
Injection Site 
Erythema or 
Redness, ≤ 15
years of age
Same as for 
Injection Site 
Erythema or 
Redness, ≤ 15
years of age
Same as for 
Injection Site 
Erythema or 
Redness, ≤ 15
years of age
Same as for Injection 
Site Erythema or 
Redness, ≤ 15 years
of age
Injection Site 
Pruritus
Itching localized
to the injection
site that is 
relieved 
spontaneously
or in
< 48 hours 
of 
treatment
Itching beyond
the injection site 
that is not
generalized OR
Itching localized
to the injection
site requiring ≥ 
48 hours 
treatment
Generalized 
itching causing
inability
to 
perform
usual
social
& 
functional 
activities
NA
12 Injection Site Erythema or Redness should be evaluated and graded using the greatest single diameter or 
measured surface area.
Laboratory Values*
Chemistries
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
Acidosis
NA
pH ≥ 7.3 to < LLN
pH < 7.3
without life-
threatening 
consequences
pH < 7.3 with life-
threatening 
consequences
Albumin,
Low
(g/dL;
g/L)
3.0 to < LLN
30  to < LLN
≥ 2.0 to < 3.0
≥ 20  to < 30
< 2.0
< 20
NA
Alkaline 
Phosphatase, 
High
1.25 to <
2.5 x ULN
2.5  to < 5.0 x ULN
5.0 to < 10.0 x
ULN
≥ 10.0 x ULN
Alkalosis
NA
pH > ULN to ≤ 7.5
pH > 7.5
without life-
threatening 
consequences
pH > 7.5 with life-
threatening 
consequences
ALT or SGPT,
High
Report only one
1.25 to <
2.5 x ULN
2.5 to < 5.0 x ULN
5.0  to < 10.0 x
ULN
≥ 10.0 x ULN


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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
Amylase 
(Pancreatic) or
Amylase (Total),
High
Report only one
1.1  to < 1.5 x
ULN
1.5  to < 3.0 x ULN
3.0  to < 5.0 x
ULN
≥ 5.0 x ULN
AST or SGOT,
High
Report only one
1.25 to <
2.5 x ULN
2.5  to < 5.0 x ULN
5.0  to < 10.0 x
ULN
≥ 10.0 x ULN
Bicarbonate, Low
(mEq/L; mmol/L)
16.0 to <  LLN
16.0 to <  LLN
11.0 to < 16.0
11.0 to < 16.0
8.0  to < 11.0
8.0  to < 11.0
< 8.0
< 8.0
Bilirubin
Direct
Bilirubin13, 
High
> 28 days of age
NA
NA
> ULN with
other signs 
and symptoms 
of
hepatotoxicity.
> ULN with life-
threatening 
consequences (e.g., 
signs and symptoms of 
liver failure)
≤ 28 days of age ULN to ≤ 1 mg/dL > 1 to ≤ 1.5 mg/dL
> 1.5 to ≤2
mg/dL
> 2 mg/dL
Total Bilirubin,
High
> 28 days of
age
1.1 to < 1.6 x
ULN
1.6 to < 2.6 x ULN
2.6 to < 5.0 x
ULN with
other signs 
and symptoms 
of 
hepatotoxicity.
≥ 5.0 x ULN with life-
threatening 
consequences (e.g., 
signs and symptoms of 
liver failure).
≤ 28 days of age See Appendix 
A  in Source 
DAIDS TAble. 
Total Bilirubin
for Term and
Preterm 
Neonates
See Appendix A
in Source 
DAIDS Table. 
Total Bilirubin
for Term and
Preterm 
Neonates
See 
Appendix A
in Source 
DAIDS 
Table. Total
Bilirubin for 
Term and
Preterm 
Neonates
See Appendix A in 
Source DAIDS TAble.
Total Bilirubin for
Term and Preterm
Neonates
Calcium, High
(mg/dL; mmol/L)
≥ 7 days of age
10.6  to < 11.5
2.65 to < 2.88
11.5 to < 12.5
2.88 to < 3.13
12.5  to < 13.5
3.13 to < 3.38
≥ 13.5
≥ 3.38
< 7 days of age
11.5 to < 12.4
2.88 to < 3.10
12.4 to < 12.9
3.10 to < 3.23
12.9 to < 13.5
3.23 to < 3.38
≥ 13.5
≥ 3.38


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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
Calcium (Ionized),
High
(mg/dL; mmol/L)
> ULN to < 6.0
> ULN to < 1.5
6.0 to < 6.4
1.5 to < 1.6
6.4 to < 7.2
1.6 to < 1.8
≥ 7.2
≥ 1.8
Calcium, Low
(mg/dL; mmol/L)
≥ 7 days of age
7.8  to < 8.4
1.95 to < 2.10
7.0  to < 7.8
1.75 to < 1.95
6.1  to < 7.0
1.53 to < 1.75
< 6.1
< 1.53
< 7 days of age
6.5  to < 7.5
1.63 to < 1.88
6.0 to < 6.5
1.50 to < 1.63
5.50 to < 6.0
1.38 to < 1.50
< 5.50
< 1.38
Calcium (Ionized),
Low
(mg/dL; mmol/L)
< LLN to 4.0
< LLN to 1.0
3.6 to < 4.0
0.9 to < 1.0
3.2 to < 3.6
0.8 to < 0.9
< 3.2
< 0.8
Cardiac 
Troponin I, 
High
NA
NA
NA
Levels consistent with 
myocardial infarction 
or unstable angina as 
defined by the local 
laboratory
Creatine Kinase,
High
3 to < 6 x ULN
6 to < 10x ULN
10 to < 20 x
ULN
≥ 20 x ULN
Creatinine, High
*Report only one
1.1 to 1.3 x ULN
> 1.3 to 1.8 x ULN 
OR Increase to 1.3
to
< 1.5 x
participant’s 
baseline
> 1.8  to < 3.5
x ULN OR
Increase to 1.5
to < 2.0 x 
participant’s
baseline
≥ 3.5 x ULN OR
Increase of ≥ 2.0 x
participant’s baseline
Creatinine 
Clearance14
or eGFR, Low
*Report only one
NA
< 90 to 60 ml/min
or ml/min/1.73 m2
OR
10 to < 30%
decrease from
participant’s 
baseline
< 60 to 30
ml/min or 
ml/min/1.73
m2
OR
30 to < 50% 
decrease from 
participant’s
baseline
< 30 ml/min or 
ml/min/1.73 m2
OR
≥ 50% decrease from 
participant’s baseline or 
dialysis needed
Glucose
(mg/dL; mmol/L)
Fasting, High
110 to 125
6.11 to < 6.95
> 125 to 250
6.95 to < 13.89
> 250 to 500
13.89 to < 27.75
≥ 500
≥ 27.75
Nonfasting, High
116 to 160
6.44 to < 8.89
> 160 to 250
8.89 to < 13.89
> 250  to 500
13.89  to < 27.75
≥ 500
≥ 27.75


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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
Glucose, Low
(mg/dL; mmol/L)
≥ 1 month of age
55  to 64
3.05 to <3.55
40  to < 55
2.22 to < 3.05
30  to < 40
1.67 to < 2.22
< 30
< 1.67
< 1 month of age
50 to 54
2.78 to < 3.00
40 to < 50
2.22 to < 2.78
30 to < 40
1.67 to < 2.22
< 30
< 1.67
Lactate, High
ULN to < 2.0
x ULN
without 
acidosis
≥ 2.0 x ULN
without acidosis
Increased
lactate with pH 
< 7.3 without
life- threatening 
consequences
Increased lactate with 
pH < 7.3 with life-
threatening 
consequences
Lipase, High
1.1  to < 1.5 x
ULN
1.5  to < 3.0 x ULN
3.0  to < 5.0 x
ULN
≥ 5.0 x ULN
Lipid Disorders
(mg/dL; mmol/L)
Cholesterol,
Fasting, High
≥ 18 years of
age
200  to < 240
5.18 to < 6.19
240  to < 300
6.19 to < 7.77
≥ 300
≥ 7.77
NA
< 18 years of
age
170  to < 200
4.40 to < 5.15
200 to < 300
5.15 to < 7.77
≥ 300
≥ 7.77
NA
LDL, Fasting,
High
≥ 18 years of
age
130  to < 160
3.37 to < 4.12
160 to < 190
4.12 to < 4.90
≥ 190
≥4.90
NA
> 2 to < 18
years of age
110  to < 130
2.85 to < 3.34
130 to < 190
3.34 to < 4.90
≥ 190
≥ 4.90
NA
Triglycerides,
Fasting, High
150 to 300
1.71 to 3.42
>300  to 500
>3.42 to 5.7
>500 to < 1,000
>5.7 to 11.4
> 1,000
> 11.4
Magnesium15,
Low
(mEq/L;
mmol/L)
1.2  to < 1.4
0.60 to < 0.70
0.9  to < 1.2
0.45 to < 0.60
0.6  to < 0.9
0.30 to < 0.45
< 0.6
< 0.30
Phosphate, Low
(mg/dL; mmol/L)
> 14 years of age
2.0 to < LLN
0.65 to < LLN
1.4 to < 2.0
0.45 to < 0.65
1.0 to < 1.4
0.32 to < 0.45
< 1.0
< 0.32
1 to 14 years of
age
3.0  to < 3.5
0.97 to < 1.13
2.5  to < 3.0
0.81 to < 0.97
1.5  to < 2.5
0.48 to < 0.81
< 1.5
< 0.48


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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
< 1 year of age
3.5  to < 4.5
1.13 to < 1.45
2.5  to < 3.5
0.81 to < 1.13
1.5  to < 2.5
0.48 to < 0.81
< 1.5
< 0.48
Potassium, High
(mEq/L; mmol/L)
5.6  to < 6.0
5.6  to < 6.0
6.0  to < 6.5
6.0  to < 6.5
6.5  to < 7.0
6.5  to < 7.0
≥ 7.0
≥ 7.0
Potassium, Low
(mEq/L; mmol/L)
3.0  to < 3.4
3.0  to < 3.4
2.5  to < 3.0
2.5  to < 3.0
2.0  to < 2.5
2.0  to < 2.5
< 2.0
< 2.0
Sodium, High
(mEq/L; mmol/L)
146  to < 150
146  to < 150
150  to < 154
150  to < 154
154  to < 160
154  to < 160
≥ 160
≥ 160
Sodium, Low
(mEq/L; mmol/L)
130  to < 135
130  to < 135
125  to < 130
125  to < 130
121  to < 125
121  to < 125
≤ 120
≤ 120
Uric Acid, High
(mg/dL; mmol/L)
7.5  to < 10.0
0.45 to < 0.59
10.0 to < 12.0
0.59 to < 0.71
12.0 to < 15.0
0.71 to < 0.89
≥ 15.0
≥ 0.89
*Reminder: An asymptomatic abnormal laboratory finding without an accompanying AE should not be 
reported to DAIDS in an expedited time frame unless it meets protocol-specific reporting requirements.
13 Direct bilirubin > 1.5 mg/dL in a participant < 28 days of age should be graded as grade 2, if < 10% of
the total bilirubin
14 Use the applicable formula (i.e., Cockcroft-Gault in mL/min or Schwartz, MDRD, CKD-Epi in
mL/min/1.73m2). Sites should choose the method defined in their study and when not specified, use the 
method most relevant to the study population.
*Reminder: Choose the method that selects for the higher grade
15 To convert a magnesium value from mg/dL to mmol/L, laboratories should multiply by 0.4114
Hematology
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
Absolute CD4+
Count, Low
(cell/mm3; cells/L)
> 5 years of age
(not HIV infected)
300 to < 400
300 to < 400
200 to <  300
200 to < 300
100 to < 200
100  to < 200
< 100
< 100


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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
Absolute 
Lymphocyte
Count, Low
(cell/mm3;
cells/L)
> 5 years of
age 
(not HIV infected) 
600  to < 650
< 0.600 x 109 to < 
0.650 x 109
500  to < 600
0.500 x 1099 to 
< 0.600 x 109
350 to < 500
0350 x 109 to 
< 0.500 x 109
< 350
< 0.350 x 109
Absolute 
Neutrophil
Count (ANC),
Low
(cells/mm3;
cells/L)
> 7 days of
age
800 to 1,000
0.800 x 109 to
1.000 x 109
600 to 799
0.600 x 109 to
0.799 x 109
400 to 599
0.400 x 109 to
0.599 x 109
< 400
< 0.400 x 109
2 to 7 days of age
1,250 to 1,500
1.250 x 109 to
1.500 x 109
1,000 to 1,249
1.000 x 109 to
1.249 x 109
750 to 999
0.750 x 109 to
0.999 x 109
< 750
< 0.750 x 109
≤ 1 day of age
4,000 to 5,000
4.000 x 109 to
5.000 x 109
3,000 to 3,999
3.000 x 109 to
3.999 x 109
1,500 to 2,999
1.500 x 109 to
2.999 x 109
< 1,500
< 1.500 x 109
Fibrinogen,
Decreased
(mg/dL; g/L)
100  to < 200
1.00 to < 2.00
OR
0.75 to < 
1.00 x LLN
75  to < 100
0.75 to < 1.00
OR
≥ 0.50 to < 
0.75 x LLN
50  to < 75
0.50 to < 0.75
OR
0.25 to < 
0.50 x LLN
< 50
< 0.50
OR
< 0.25 x LLN
OR Associated
with gross bleeding
Hemoglobin16,
Low
(g/dL; mmol/L)17
≥ 13 years of age
(male only)
10.0 to 10.9
6.19 to 6.76
9.0 to < 10.0
5.57 to < 6.19
7.0 to < 9.0
4.34 to < 5.57
< 7.0
< 4.34
≥ 13 years of age
(female only)
9.5 to 10.4
5.88 to 6.48
8.5 to < 9.5
5.25 to < 5.88
6.5 to < 8.5
4.03 to < 5.25
< 6.5
< 4.03
57 days of age to
< 13 years of
age
(male and female)
9.5 to 10.4
5.88 to 6.48
8.5 to < 9.5
5.25 to < 5.88
6.5 to < 8.5
4.03 to < 5.25
< 6.5
< 4.03
36 to 56 days of
age
(male and female)
8.5 to 9.6
5.26 to 5.99
7.0 to < 8.5
4.32 to < 5.26
6.0 to < 7.0
3.72 to < 4.32
< 6.0
< 3.72


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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
22 to 35 days of
age
(male and female)
9.5 to 11.0
5.88 to 6.86
8.0 to < 9.5
4.94 to < 5.88
6.7 to < 8.0
4.15 to < 4.94
< 6.7
< 4.15
8 to ≤ 21 days of
age
(male and female)
11.0 to 13.0
6.81 to 8.10
9.0 to < 11.0
5.57 to < 6.81
8.0 to < 9.0
4.96 to < 5.57
< 8.0
< 4.96
≤ 7 days of age
(male and female)
13.0 to 14.0
8.05 to 8.72
10.0 to < 13.0
6.19 to < 8.05
9.0 to < 10.0
5.59 to < 6.19
< 9.0
< 5.59
INR, High
(not on
anticoagulation
therapy)
1.1  to < 1.5 x
ULN
1.5  to < 2.0 x ULN 2.0  to < 3.0 x
ULN
≥ 3.0 x ULN
Methemoglobin
(% hemoglobin)
5.0  to < 10.0%
10.0 to < 15.0%
15.0 to < 20.0%
≥ 20.0%
PTT, High
(not on
anticoagulation
therapy)
1.1  to < 
1.66 x
ULN
1.66 to < 
2.33 x ULN
2.33 to < 
3.00 x
ULN
≥ 3.00 x ULN
Platelets, Decreased
(cells/mm3;
cells/L)
100,000  to
< 125,000
100.000 x 109 to
< 125.000 x 109
50,000 to
< 100,000
50.000 x 109 to
< 100.000 x 109
25,000 to
< 50,000
25.000 x 109 to
< 50.000 x 109
< 25,000
< 25.000 x 109
PT, High
(not on
anticoagulation
therapy
1.1  to < 
1.25 x
ULN
1.25 to <
1.50 x ULN
1.50 to <
3.00 x ULN
≥ 3.00 x ULN
WBC,
Decreased
(cells/mm3;
cells/L)
> 7 days of
age
2,000 to 2,499
2.000 x 109 to
2.499 x 109
1,500 to 1,999
1.500 x 109 to
1.999 x 109
1,000 to 1,499
1.000 x 109 to
1.499 x 109
< 1,000
< 1.000 x 109
≤ 7 days of age
5,500 to 6,999
5.500 x 109 to
6.999 x 109
4,000 to 5,499
4.000 x 109 to
5.499 x 109
2,500 to 3,999
2.500 x 109 to
3.999 x 109
< 2,500
< 2.500 x 109


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16 Male and female sex are defined as sex at birth. For transgender participants 13 years of age who have 
been on hormone therapy for more than 6 consecutive months grade hemoglobin based on the gender with 
which they identify (i.e., a transgender female should be graded using the femaile sex at birth hemoglobin 
laboratory values).
17 The most commonly used conversion factor to convert g/dL to mmol/L is 0.6206. For grading
hemoglobin results obtained by an analytic method with a conversion factor other than 0.6206, the result
must be converted to g/dL using appropriate conversion factor for the particular laboratory
Urinalysis
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
Glycosuria
(random 
collection tested
by dipstick)
Trace to 1+ or
≤ 250 mg
2+ or ˃ 250 to
≤ 500 mg
> 2+ or > 500 mg
NA
Hematuria (not to
be reported based
on dipstick
findings or on 
blood believed to
be of menstrual
origin)
6 to < 10 RBCs
per high power
field
≥ 10 RBCs per
high power field
Gross, with or 
without clots OR
With RBC casts 
OR Intervention 
indicated
Life-
threatening 
consequences
Proteinuria
(random 
collection tested
by dipstick)
1+
2+
3+  or higher
NA
Appendix A: Total Bilirubin Table for Term and Preterm Neonates
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
Total Bilirubin18,
High
(mg/dL;
µmol/L)19
Term Neonate20
< 24 hours of
age
4 to < 7
68.4 to < 119.7
7 to < 10
119.7 to < 171
10  to < 17
171  to < 290.7
≥ 17
≥ 290.7
24 to < 48
hours of age
5 to < 8
85.5 to < 136.8
8 to < 12
136.8 to < 205.2
12  to < 19
205.2  to < 324.9
≥ 19
≥ 324.9


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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY 
LIFE-
THREATENING
48 to < 72
hours of age
8.5 to < 13
145.35 to < 222.3
13 to < 15
222.3 to < 256.5
15  to < 22
256.5  to < 376.2
≥ 22
≥ 376.2
72 hours to < 7
days of age
11 to < 16
188.1 to < 273.6
16 to < 18
273.6 to < 307.8
18  to < 24
307.8  to < 410.4
≥ 24
≥ 410.4
7 to 28 days of
age
(breast feeding)
5 to < 10
85.5 to < 171
10 to < 20
171 to < 342
20 to < 25
342 to < 427.5
≥ 25
≥ 427.5
7 to 28 days of
age
(not breast
feeding)
1.1 to < 1.6 x ULN
1.6 to < 2.6 x ULN
2.6 to < 5.0 x ULN ≥ 5.0 x ULN
Preterm
Neonate20
35 to < 37
weeks 
gestational
age
Same as for Total
Bilirubin, High,
Term Neonate 
(based
on days of age).
Same as for Total
Bilirubin, High,
Term Neonate 
(based
on days of age).
Same as for Total
Bilirubin, High,
Term Neonate 
(based
on days of age).
Same as for Total
Bilirubin, High,
Term Neonate 
(based
on days of age).
32 to < 35
weeks 
gestational age 
and
< 7 days of age
NA
NA
10 to < 14
171 to < 239.4
≥ 14
≥ 239.4
28 to < 32
weeks 
gestational age 
and
< 7 days of age
NA
NA
6 to < 10
102.6 to < 171
≥ 10
≥ 171
< 28 weeks 
gestational age 
and
< 7 days of age
NA
NA
5 to < 8
85.5 to < 136.8
≥ 8
≥ 136.8
7 to  28 days of
age
(breast feeding)
5 to < 10
85.5 to < 171
10 to < 20
171 to < 342
20 to < 25
342 to < 427.5
≥ 25
≥ 427.5
7 to 28 days of
age
(not breast
feeding)
1.1 to < 1.6 x ULN
1.6 to < 2.6 x ULN
2.6 to < 5.0 x ULN ≥ 5.0 x ULN


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18 Severity grading for total bilirubin in neonates is complex because of rapidly changing total bilirubin
normal ranges in the first week of life followed by the benign phenomenon of breast milk jaundice after
the first week of life. Severity grading in this appendix corresponds approximately to cut-offs for
indications for phototherapy at grade 3 and for exchange transfusion at grade 4.
19 A laboratory value of 1 mg/dL is equivalent to 17.1 µmol/L.
20 Definitions: Term is defined as ≥ 37 weeks gestational age; near-term, as ≥ 35 weeks  gestational age; 
preterm, as < 35 weeks gestational age; and neonate, as 0 to 28 days of age.
Reference
U.S. Department of Health and Human Services, National Institutes of Health, National 
Institute of Allergy and Infectious Diseases, Division of AIDS. Division of AIDS 
(DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events, Version 
2.1. [March 2017]. Available from: https://rsc.tech-res.com/docs/default-
source/safety/daids-ae-grading-table-mar2017.pdf (accessed 26 May 2017).


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12.8.
Appendix 8: Toxicity Management
ANEMIA
Grade 1 (mild) hemoglobin decrease:
Any hemoglobin decrease meeting the definition of Grade 1 must be repeated with the 
following additional tests:
1.   peripheral blood smear
2.
indirect bilirubin
(abnormal if increased >50% from baseline)
3.
haptoglobin
(abnormal if 25 mg/dL)
4.
reticulocyte count
(abnormal if 4%) 
If the additional tests are within the normal range, participants may continue study 
medication.  If one or more of the additional tests is abnormal or suggestive of hemolytic 
anemia as specified above, participants will permanently discontinue study medication 
and be withdrawn from the trial.  Participants should be followed up until resolution of 
anemia.
Grade 2 (moderate) hemoglobin decrease:
Any hemoglobin decrease meeting the definition of Grade 2 must be repeated with the 
following additional tests:
1. peripheral blood smear
2. indirect bilirubin
(abnormal if increased > 50% from baseline)
3. haptoglobin
(abnormal if 25 mg/dL)
4. reticulocyte count
(abnormal if 4%) 
If the additional tests are within the normal range, participants may continue study 
medication.  If one or more of the additional tests is abnormal or suggestive of hemolytic 
anemia as specified above, participants will permanently discontinue study medication 
and be withdrawn from the trial.  Consultation with a Hematologist should be considered.  
Participants should be followed up until resolution of anemia.
Grade 3 (severe) or Grade 4 (potentially life threatening) hemoglobin decrease:
Any hemoglobin decrease meeting the definition of Grade 3 or 4 must be repeated with 
the following additional tests:
1. peripheral blood smear
2. indirect bilirubin
3. haptoglobin
4. reticulocyte count 


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Participants will permanently discontinue study medication and be withdrawn from the 
trial.  Consultation with a Hematologist should be considered.  Participants should be 
followed up until resolution of anemia.
TOTAL BILIRUBIN ELEVATION
Grade 1 (mild) bilirubin elevation (1.1 - 1.5 times ULN) or Grade 2 (moderate 
- 1.6-2.5 times ULN):
Any bilirubin value above the upper limit of normal must be repeated and fractionated 
(direct and indirect bilirubin).  Participants may continue study medication.  Participants
should be followed up until resolution (return to baseline) of elevation.
Grade 3 (severe – 2.6-5.0 times ULN) or 4 (life-threatening - > 5.0 times ULN) 
bilirubin elevation:
Any bilirubin value above the upper limit of normal must be repeated and fractionated 
(direct and indirect bilirubin).  Participants will permanently discontinue study 
medication and be withdrawn from the trial.  Participants should be followed up until 
resolution (return to baseline) of bilirubin elevation.
AST AND ALT ELEVATION
See Section 12.6.
RASH
Grade 1 rash (Localized macular rash):
Participants with Grade 1 rash should be evaluated by the Investigator immediately.  A 
dermatologist may be consulted and a biopsy may be obtained if recommended by the 
dermatologist.  The study drug should be permanently discontinued if the following signs 
or symptoms are noted at any time:
1. Temperature >38.5°C
2. Lymphadenopathy
3. Pharyngitis
4. Any indication of internal organ involvement (hepatitis, nephritis)
In the absence of the above signs or symptoms, participants with Grade 1 rash may 
continue the study drug at the discretion of the Investigator.  The participant should be 
advised to contact the Investigator immediately if there is any worsening of the rash, if 
any systemic signs or symptoms worsen, or if mucosal ulceration develops. If the rash is 
considered to be most likely due to concomitant illness or non-study medication, standard 
management, including discontinuation of the likely causative agent, should be 
undertaken. If no other causative factor is found after clinical evaluation, the participant
may be treated symptomatically until the rash resolves. Antihistamines, topical 
corticosteroids or antipruritic agents may be prescribed.  The participant should remain 
on the study to be followed for safety and PK as outlined in Section 2.


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Grade 2 rash (Diffuse macular, maculopapular, or morbilliform rash OR Target 
lesions):
Participants with Grade 2 rash should be evaluated by the Investigator immediately.  
Digital photographs should be obtained.  A dermatologist may be consulted and a biopsy 
may be obtained if recommended by the dermatologist.  The study drug should be 
permanently discontinued if the following signs or symptoms are noted at any time:

Temperature > 38.5°C

Lymphadenopathy

Pharyngitis

Any indication of internal organ involvement (hepatitis, nephritis)
In the absence of the above signs or symptoms, participants with Grade 2 rash may 
continue the study drug at the discretion of the Investigator.  It should be noted that oral 
mucosal erosions may be part of a Grade 2 rash.  Any mucosal ulceration increases the 
severity of the rash to at least Grade 3.  The participant should be advised to contact the 
Investigator immediately if there is any worsening of the rash, if any systemic signs or 
symptoms worsen, or if mucosal ulceration develops. If the rash is considered to be most 
likely due to concomitant illness or non-study medication, standard management, 
including discontinuation of the likely causative agent, should be undertaken. If no other 
causative factor is found after clinical evaluation, the participant may be treated 
symptomatically until the rash resolves. Antihistamines, topical corticosteroids or 
antipruritic agents may be prescribed.  The participant should remain on the study to be 
followed for safety and PK as outlined in Section 2.
Grade 3 rash (Diffuse macular, maculopapular, or morbilliform rash with vesicles 
or limited number of bullae OR Superficial ulcerations of mucous membrane 
limited to one site):
Participants with a Grade 3 rash will permanently discontinue the study medication.  The 
participant should be evaluated in the physician’s office immediately and should be seen 
in the physician’s office or contacted by phone every 2 days until the rash resolves.  A 
dermatologist should be consulted and digital photographs and a biopsy should be 
obtained.  Antihistamines, topical corticosteroids or antipruritic agents may be prescribed 
at the discretion of the Investigator. The participant should be advised to contact the 
Investigator immediately if there is any worsening of the rash, if any systemic signs or 
symptoms appear, or if mucosal involvement develops.  The participant should remain on 
the study to be followed for safety and PK as outlined in Section 2.
Grade 4 rash (Extensive or generalized bullous lesions OR Stevens-Johnson 
syndrome OR Ulceration of mucous membrane involving two or more distinct 
mucosal sites OR Toxic epidermal necrolysis (TEN):
Participants with a Grade 4 rash will permanently discontinue the study medication.  A 
dermatologist should be consulted and digital photographs and a biopsy should be 
obtained.  Sponsor and PPD Medical Monitor should be notified of this serious adverse 
event within 24hr via phone or fax.  The participant should be closely followed everyday 
until resolution of the reaction.  The participant should remain on the study to be 
followed for safety and PK as outlined in Section 2.


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ALLERGIC REACTION
Grade 1 allergic reaction (Pruritis without rash):
Participants with Grade 1 allergic reaction should be evaluated by the Investigator 
immediately.  The study drug should be permanently discontinued if the following signs 
or symptoms are noted at any time:
1. Temperature > 38.5°C
2. Eosinophilia
3. Respiratory involvement including bronchospasm, laryngospasm, or angioedema
4. Any indication of internal organ involvement (hepatitis, nephritis)
In the absence of the above signs or symptoms, participants with Grade 1 allergic 
reaction may continue the study drug at the discretion of the Investigator.  The participant
should be advised to contact the Investigator immediately if there is any worsening of the 
allergic reaction and/or if any systemic signs or symptoms worsen.  If the allergic 
reaction is considered to be most likely due to concomitant illness or non-study 
medication, standard management, including discontinuation of the likely causative 
agent, should be undertaken.  If no other causative factor is found after clinical 
evaluation, the participant may be treated symptomatically until the rash resolves. 
Antihistamines, topical corticosteroids or antipruritic agents may be prescribed.  The 
participant should remain on the study to be followed for safety and PK as outlined in 
Section 2.
Grade 2 allergic reaction (Localized urticaria):
Participants with Grade 2 allergic reaction should be evaluated by the Investigator 
immediately.  The study drug should be permanently discontinued if the following signs 
or symptoms are noted at any time:
1. Temperature > 38.5°C
2. Eosinophilia
3. Respiratory involvement including bronchospasm, laryngospasm, or angioedema
4. Any indication of internal organ involvement (hepatitis, nephritis)
In the absence of the above signs or symptoms, participants with Grade 2 allergic 
reaction may continue the study drug at the discretion of the Investigator.  The participant
should be advised to contact the Investigator immediately if there is any worsening of the 
allergic reaction and/or if any systemic signs or symptoms worsen.  If the allergic 
reaction is considered to be most likely due to concomitant illness or non-study 
medication, standard management, including discontinuation of the likely causative 
agent, should be undertaken.  If no other causative factor is found after clinical 
evaluation, the participant may be treated symptomatically until the rash resolves. 
Antihistamines, topical corticosteroids or antipruritic agents may be prescribed.  The 
participant should remain on the study to be followed for safety and PK as outlined in 
Section 2.


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Grade 3 allergic reaction (Generalized urticaria or angioedema):
Participants will permanently discontinue the study medication and be withdrawn from 
the trial.  Participants will be treated as clinically appropriate.  Participants should be 
followed up until resolution of the adverse event and standard management should be 
undertaken.
Grade 4 allergic reaction (Anaphylaxis):
Participants will permanently discontinue the study medication and be withdrawn from 
the trial.  Participants will be treated as clinically appropriate.  Participants should be 
followed up until resolution of the adverse event and standard management should be 
undertaken.
Revised ACTG Toxicity 
Grade
Definitions
Investigator Action
Grade 1
Pruritus without rash
May continue therapy
Grade 2
Localized urticaria
May continue therapy
Grade 3
Generalized urticaria
Angioedema
Discontinue Therapy
Grade 4
Anaphylaxis
Discontinue Therapy


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12.9.
Appendix 9: HIV Testing Algorithm and Management of HIV 
Infection in Study Participants
HIV testing at Day 1 and the subsequent visits will use POC HIV testing kits in 
accordance with local standard operating procedures. Additional testing is required 
for participants who have a reactive or positive HIV test after enrolment.  Stored 
plasma from the visit previous to the positive test should be tested for HIV using the 
4th generation HIV test to best estimate time of infection. HIV acquisition must be 
confirmed by either western blot, HIV ½ Multispot or the Geenius HIV Confirmation 
½ Assay, and HIV RNA (Branson, 2014).
Reference:
Branson BM., Owen  SM., Wesolowski LG et al. CDC Reference Guide: Laboratory 
Testing for the Diagnosis of HIV Infection: Updated Recommendations. June 27, 2014.


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12.10.
Appendix 10: HIV-Prevention Treatment Satisfaction 
Questionnaire (change): (HIV-PrevTSQc)
For the past 10 weeks you have been taking part in a study of treatment to prevent HIV.  
The study began with 4 weeks of tablet treatment followed by five CAB LA 600 mg IM 
injections administered at 8-week intervals, with the first 2 doses given 4 weeks. Today 
we would like to know how your experience of your current prevention treatment with 
injections compares with your experience of prevention treatment with tablets during the 
first 4 weeks of the study. Please answer each question by circling a number on each of 
the scales. If you have experienced no change in your satisfaction with treatment, please 
circle ‘0’.
CCI - This section contained Clinical Outcome Assessment data collection questionnaires or indices, which are protected by 
third party copyright laws and therefore have been excluded.


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Please make sure that you have circled one number on each of the scales.
Thank you for taking the time to complete this questionnaire.
CCI - This section contained Clinical Outcome Assessment data collection questionnaires or indices, which are protected by 
third party copyright laws and therefore have been excluded.


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12.11.
Appendix 11: Daily Diary Card for Symptoms at Injection 
Area
GENERAL INSTRUCTIONS
An injection is another word for "shot" or "jab" and is how you have been receiving your 
study medication. This diary card will help us understand any symptoms you may have in 
the area where you receive the injections.
How to complete this Diary Card
•
Make all the entries in black ink with a ball point pen. 
•
Print neatly so that your answers can be read easily. 
•
Complete dates as Day Month Year. Example: 15 October 2013 write 15 OCT 13. 
•
If you make a mistake, draw a single line through it. 
•
Additional Instructions
•
Complete the Diary Card every day. 
•
Some sections have a number scale. Use these scales to help you describe your symptoms. 
•
Please call the study site if you develop any symptoms which interfere with normal everyday 
activities, any temperature >38.3C, or any symptoms which cause you concern. 
HOW TO DESCRIBE YOUR SYMPTOMS
Symptoms may appear around the area where you receive the injections. On the day you get the 
injections and for each day after, check the area where the injection was given for any itching, 
pain or any other symptoms. If you have any symptoms, complete ALL of the columns for that 
day. If you do not have any symptoms for that day, tick ( ) NO under the Symptoms column. 
Leave the remaining columns blank for that day.
Pain:
•
Using the scale of 0-3, tick (  ) the number in the box that best describes the
worst pain you feel around the area you received the injection.
0 =  No pain or tenderness 
1 = Pain or tenderness that is easily tolerated and does not interfere with your normal, 
everyday activities 
2 =  Pain or tenderness that interferes with your normal, everyday activities 
3 =  Pain or tenderness that prevents your normal, everyday activities 
Itching: 
•
Using the scale of 0-3, tick ( ) the number in the box that best describes the worst itching 
around the injection area you felt that day. 
0 =  No itching 
1 = Itching at the injection area that is easily tolerated and does not interfere with your 
normal, everyday activities 
2 = Itching at and around the injection area that interferes with your normal, everyday 
activities 
3 = Itching in a large area around the injection area that prevents your normal, everyday 
activities 


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Other Symptoms:
•
Using a mirror and your hand, check for any bruising, skin firmness, discoloration, 
or bump in the area where you received the injection. 
•
Tick ( ) NO if you do not see or feel any of these other symptoms, or the appropriate word 
abbreviation for the symptoms that you do see or feel. 
NO =  None
BR = Bruising
BU =  Bump
D
= Discoloration
R
= Redness
SF
= Skin firmness
SW = Swelling
W
=
Warm to 
touch
Home Treatment:
•
Please tick ( ) the appropriate word abbreviation. If you used or applied any treatment for 
your symptoms at the area of the injection at home, on your own, or with family/caregiver 
assistance. 
NO =  None
AP = Acetaminophen/paracetamol 
D
= Diphenhydramine 
T  =  Topical anti-itch cream or ointment such as 
hydrocortisone/ diphenhydramine/TCM pain patch, etc.
W
=  Warm compress (heating pad)
C
=  Cold compress (cold pack or ice pack)
I
=   Ibuprofen
Exercise Habits:
For the week following your injection, please record your exercise habits.
•
Tick ( ) YES if you performed any cardiovascular activity this week, then tick all activities 
you performed and record the total duration of your cardiovascular activities for the entire 
week (in minutes). Tick ( ) NO if you did not perform any cardiovascular activities this 
week. 
•
Tick ( ) YES if you performed any strength training exercise this week, then record the total 
duration of your strength training exercise for the entire week (in minutes). Tick ( ) NO if 
you did not perform any strength training exercises this week. 
•
Tick ( ) YES if you performed any other strenuous activity this week, then record the total 
duration for the entire week (in minutes) of your other strenuous activity. Tick ( ) NO if you 
did not perform any other strenuous activity this week. 


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CONFIDENTIAL
Final - 17 JAN14
Protocol Identifier
Subject Identifier
DAILY DIARY CARD FOR
Visit Description
206898
INJECTION AREA SYMPTOMS
(   )Week 5      ( )Week 9     (   )Week 17      (   )Week 25     
(   )Week 33
Symptoms
Pain
Itching
Other Symptoms
Day
Date
?
(0 - 3)
(0 - 3)
Home Treatment
0= No pain or tenderness
0 = No itching
NO = None
NO = None
1=
Pain or tenderness that is 
easily
1 = Itching at the injection area that 
is
BR = Bruising
AP = Acetaminophen/paracetamol
tolerated and does not 
interfere
easily tolerated and does 
not
BU = Bump
  I= Ibuprofen
with your normal, 
everyday
interfere with your 
normal,
D = Discoloration
D = Diphenhydramine (Benadryl)
2=
activities
everyday 
activities
R = Redness
Top = Topical anti-itch cream or
Pain or tenderness that
2 = Itching at and around the 
injection
SF = Skin firmness
ointment such as 
hydrocortisone/
interferes with your 
normal,
area that interferes with 
your
SW = Swelling
diphenhydramine, TCM 
painpatch etc.
everyday activities
normal, everyday 
activities
W = Warm to touch
W = Warm compress (heating pad)
3= Pain or tenderness that 
prevents
3 = Itching in a large area that 
prevents
C = Cold compress (cold pack or 
ice
your normal, everyday 
activities
your normal, everyday activities
pack)
DD/MMM/YY
Yes
No
0
1
2
3
0
1
2
3
NO BR BU D
R SF SW W NO AP/I D Top W
C
e.g
15 OCT 13
First
Day
Second
Day
Third
Day
Fourth
Day


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Fifth
Day
Sixth
Day
Seventh
Day
If you have ongoing symptoms when you turn in this diary card, please continue to record the symptoms on the next diary card the study staff gives to you, until you no longer have the symptom.
Did you perform any cardiovascular activity this 
week?
Total Weekly
Did you perform any 
strength
Total Weekly Did you perform any other Total Weekly
Duration
training exercise this 
week?
Duration
strenuous activity this 
week?
Duration
Yes No Run Walk Bike Swim Aerobic
Elliptical-
Stairs
Other
(minutes)
Yes
No
(minutes)
Yes
No
(minutes)
20
20


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12.12.
Appendix 12: Protocol Amendment History
The Protocol Amendment Summary of Changes Table for the current amendment is 
located directly before the Table of Contents (TOC).

SAP_001.pdf: 
CONFIDENTIAL
The GlaxoSmithKline group of companies
206898
1
Division
:
Worldwide Development
Information Type
:
Reporting and Analysis Plan (RAP)
Title
:
Reporting and Analysis Plan for 206898: An Open Label, 
Phase 1 Study to Evaluate the PK, Safety, Tolerability and 
Acceptability of Long Acting Injections of the HIV Integrase 
Inhibitor, Cabotegravir (CAB; GSK1265744) in HIV 
Uninfected Chinese Men
Compound Number
:
GSK1265744
Effective Date 
:
22-APR-2019
Description:

The purpose of this RAP is to describe the planned analyses and output to be 
included in the Clinical Study Report for Protocol 206898.

This RAP is intended to describe the safety, tolerability, and pharmacokinetic (PK) 
analyses required for the study. 

This RAP will be provided to the study team members to convey the content of the 
Statistical Analysis Complete (SAC) deliverable.
Author’s Name and Functional Area: 
22-APR-2019
Senior Biostatistician, PPD
22-APR-2019
Pharmacokineticist (Biostatistics, PPD)
Approved by: 
22-APR-2019
Statistics Leader, GSK
22-APR-2019
Manager Statistics
Copyright 2019 the GlaxoSmithKline group of companies. All rights reserved. 
Unauthorised copying or use of this information is prohibited.
 
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TABLE OF CONTENTS
PAGE
1.
REPORTING & ANALYSIS PLAN SYNOPSIS.........................................................5
2.
SUMMARY OF KEY PROTOCOL INFORMATION ..................................................8
2.1.
Changes to the Protocol Defined Statistical Analysis Plan............................8
2.2.
Study Objective(s) and Endpoint(s)...............................................................8
2.3.
Study Design ................................................................................................9
2.4.
Statistical Hypotheses.................................................................................10
3.
PLANNED ANALYSES ..........................................................................................11
3.1.
Interim Analyses .........................................................................................11
3.2.
Final Analyses ............................................................................................11
4.
ANALYSIS POPULATIONS ...................................................................................12
4.1.
Protocol Deviations.....................................................................................13
5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA HANDLING 
CONVENTIONS.....................................................................................................14
6.
STUDY POPULATION ANALYSES .......................................................................15
6.1.
Overview of Planned Analyses ...................................................................15
6.1.1.
Disposition...................................................................................15
6.1.2.
Demographics .............................................................................15
6.1.3.
Medical History ............................................................................16
6.1.4.
Prior and Concomitant Medications .............................................16
6.1.5.
Protocol Deviation........................................................................16
7.
PRIMARY STATISTICAL ANALYSES....................................................................17
7.1.
Safety Analyses of CAB LA ........................................................................17
7.1.1.
Injection Site Reaction .................................................................17
7.1.2.
Adverse Events............................................................................18
7.1.3.
Clinical Laboratory Tests .............................................................19
7.1.4.
Vital Sign Assessments ...............................................................19
7.1.5.
Death...........................................................................................20
7.2.
Tolerability Analyses of CAB LA .................................................................21
7.3.
Primary Pharmacokinetic Analyses.............................................................22
7.3.1.
Overview of Planned Primary Pharmacokinetic Analyses ............22
7.3.2.
Primary Drug Concentration Measures ........................................22
7.3.3.
Primary Pharmacokinetic Parameters..........................................23
7.3.3.1.
Deriving Primary Pharmacokinetic Parameters...........23
7.3.3.2.
Statistical Analysis of Primary Pharmacokinetic 
Parameters.................................................................24
8.
SECONDARY STATISTICAL ANALYSES .............................................................25
8.1.
Secondary Pharmacokinetic Analyses........................................................25
8.1.1.
Overview of Planned Secondary Pharmacokinetic 
Analyses......................................................................................25
8.1.2.
Secondary Drug Concentration Measures ...................................25
8.1.3.
Secondary Pharmacokinetic Parameters .....................................25
 
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8.1.3.1.
Deriving Secondary Pharmacokinetic 
Parameters.................................................................25
8.2.
Safety and Tolerability Analyses of Oral CAB .............................................26
8.3.
Acceptability of CAB LA..............................................................................27
8.4.
Concentration-effect Relationships for Safety and Tolerability 
Parameters.................................................................................................28
8.5.
General Safety Analyses ............................................................................28
8.5.1.
Extent of Exposure to CAB ..........................................................28
8.5.2.
Possible suicidality-related Adverse Events.................................29
8.5.3.
Social Harms ...............................................................................29
8.5.4.
ECG.............................................................................................30
8.5.5.
Cardiovascular Events.................................................................30
8.5.6.
Liver Events.................................................................................30
9.
REFERENCES.......................................................................................................32
10. APPENDICES........................................................................................................33
10.1.
Appendix 1: Protocol Deviation Management and Definitions for Per 
Protocol Population.....................................................................................34
10.1.1.
Exclusions from Per Protocol Population .....................................34
10.2.
Appendix 2: Time & Events.........................................................................35
10.2.1.
Protocol Defined Time & Events ..................................................35
10.3.
Appendix 3: Assessment Windows .............................................................39
10.3.1.
Assessment Windows..................................................................39
10.4.
Appendix 4: Study Phase and State............................................................40
10.4.1.
Treatment Phases .......................................................................40
10.4.2.
Treatment States .........................................................................40
10.4.2.1.
Treatment States for AE Data.....................................40
10.5.
Appendix 5: Data Display Standards & Handling Conventions....................41
10.5.1.
Study Treatment & Sub-group Display Descriptors......................41
10.5.2.
Baseline Definition & Derivations .................................................41
10.5.2.1.
Baseline Definitions....................................................41
10.5.2.2.
Derivations and Handling of Missing Baseline 
Data ...........................................................................41
10.5.3.
Reporting Process & Standards...................................................41
10.6.
Appendix 6: Derived and Transformed Data ...............................................44
10.6.1.
General........................................................................................44
10.6.2.
Study Population..........................................................................44
10.6.3.
Safety ..........................................................................................45
10.7.
Appendix 7: Premature Withdrawals & Handling of Missing Data ...............46
10.7.1.
Premature Withdrawals................................................................46
10.7.2.
Handling of Missing Data.............................................................46
10.7.2.1.
Handling of Missing Dates..........................................46
10.7.2.2.
Handling of Partial Dates............................................46
10.7.2.3.
Handling of Missing Data for Statistical 
Analysis......................................................................47
10.8.
Appendix 8: Values of Potential Clinical Importance ...................................48
10.8.1.
Laboratory Values........................................................................48
10.8.2.
ECG.............................................................................................49
10.8.3.
Vital Signs....................................................................................49
10.9.
Appendix 9: Multicenter Studies..................................................................50
 
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10.9.1.
Methods for Handling Centres .....................................................50
10.10. Appendix 10: Examination of Covariates, Subgroups & Other Strata..........51
10.10.1. Handling of Covariates, Subgroups & Other Strata......................51
10.11. Appendix 11: Multiple Comparisons & Multiplicity .......................................52
10.11.1. Handling of Multiple Comparisons & Multiplicity...........................52
10.12. Appendix 12: Model Checking and Diagnostics for Statistical 
Analyses.....................................................................................................53
10.12.1. Statistical Analysis Assumptions..................................................53
10.13. Appendix 13: Abbreviations & Trade Marks ................................................54
10.13.1. Abbreviations...............................................................................54
10.13.2. Trademarks .................................................................................55
10.14. Appendix 14: List of Data Displays..............................................................56
10.14.1. Data Display Numbering..............................................................56
10.14.2. Mock Example Shell Referencing ................................................56
10.14.3. Deliverable [Priority].....................................................................56
10.14.4. Study Population Tables..............................................................57
10.14.5. Safety Tables...............................................................................58
10.14.6. Tolerability Tables........................................................................61
10.14.7. Acceptability Tables.....................................................................61
10.14.8. Pharmacokinetic Tables...............................................................62
10.14.9. Pharmacokinetic Figures .............................................................64
10.14.10.ICH Listings .................................................................................65
10.14.11.Non-ICH Listings..........................................................................70
10.15. Appendix 15: Example Mock Shells for Data Displays ................................71
10.16. Appendix 16: Adverse Events of Special Interest Used for Data 
Summaries .................................................................................................72
 
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1.
REPORTING & ANALYSIS PLAN SYNOPSIS
Overview
Key Elements of the RAP
Purpose

The purpose of this reporting and analysis plan (RAP) is to describe any 
planned analyses and output to be included in the clinical study report for 
Protocol 206898.
Protocol

This RAP is based on the Protocol Amendment 1 (Dated: 06JUN2018) of study 
Protocol 206898 (GSK Document No.: 2016N293702_01] and eCRF Version 
(2.00, Dated: 26SEP2018).
Primary 
Objective

Evaluate the safety and tolerability of the injectable agent, cabotegravir 
(GSK1265744) long acting (CAB LA) injectable (600 mg dose administered 
every 4 weeks for 2 doses followed by every 8 weeks for 3 doses) through 
Week 5-41 in HIV-1 uninfected Chinese men.

Evaluate the plasma pharmacokinetics of CAB following repeat oral 
administration (Day 1 to Week 4) and CAB LA IM injections throughout the 
Injection Phase (Weeks 5-41).
Primary 
Endpoint

Safety and tolerability parameters, including adverse events, clinical laboratory 
tests, study withdrawals due to AEs, vital signs assessments, and evaluation of 
injection site reactions (ISRs), for injection phase (Week 5-41).

Plasma CAB AUC(0-), Cmax, C, tmax, λz, t½, CL/F, and Vz/F following daily 
oral administration of CAB through Day 1 to Week 4.

Plasma CAB AUC(0-), Cmax, C, and tmax following IM injections of CAB LA 
once every 8 weeks through Weeks 5-41.
Secondary 
Objective 

Evaluate the plasma pharmacokinetics of CAB LA throughout the Injection and 
Long-term Follow-up Phases (Week 5 to Week 89).

Evaluate the safety and tolerability of oral CAB in HIV uninfected Chinese men 
during the oral lead-in Phase (Day 1 to Week 4)

Evaluate the acceptability of CAB LA injections through 41 weeks.

Explore concentration-effect relationships for various safety and tolerability 
parameters if relevant.
Secondary 
Endpoint

Plasma CAB AUC(0-), Cmax, C, tmax, λz, t½, CL/F, and Vz/F through Weeks 
5-89.

Safety and tolerability parameters, including adverse events, study withdrawals 
due to AEs, vital signs assessments, and clinical laboratory assessments, for 
oral lead-in phase (Day 1 to Week 4).

Injection discontinuation rate, the number and severity of ISRs and additional 
acceptability measures.

Evaluation of relationships between significant safety and tolerability 
 
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Overview
Key Elements of the RAP
parameters and CAB PK may be explored.
Study 
Design

This will be an open label, non-randomized, single arm study. Participants will 
receive daily oral CAB (30mg tablets) for 4 weeks during the Oral Phase of the 
study and intramuscular (IM) injections of 600 mg of CAB LA at Week 5, Week 
9, Week 17, Week 25 and Week 33.

Starting at 8 weeks post last injection, participants will be seen once every 12 
weeks for 48 weeks during the follow-up phase.

Subjects who volunteer to participate in the intensive PK assessment will have 
serial blood sampling for measurement of plasma CAB concentrations following 
oral administration over a 24 h window starting on Day 27 and ending on Day 
28

PK samples at trough for Oral Phase will be collected for all subjects prior to 
dose within 20 to 28 hours following oral administration the day prior; Intensive 
oral PK samples will be collected from approximately 16 participants.

PK Samples for Injection Phase will be collected prior to CAB LA injections at 
Week 5, 9, 17, 25, and 33 with the exception of 1-week post injection samples 
at Weeks 6, 10, 18, 26, 34, 37 (4-week post injection sample) and Week 41

Long-term follow up PK samples will be collected at Week 53, 65, 77, and 89.
Planned 
Analyses

The primary safety analysis and PK analyses including both oral phase and 
injection phase through Weeks 5 to 41 will be performed after all ongoing 
participants complete the Week 41 visit or withdraw from the study treatment, 
whichever comes first.

The end of study analysis will be performed after all ongoing participants 
complete the Week 89 visit or withdraw from the study treatment, whichever 
comes first.
Analysis 
Populations

The All Subjects Screened Population will include all subjects who consent to 
participate in the clinical study. Subjects in this population will be used for 
disposition summary

The Safety Population will include all subjects who receive at least one dose of 
the study treatment. Subjects in this population will be used for all demographic 
and safety summaries or listings, as well as for the analysis of acceptability of 
CAB LA.

Safety Injection Population will include all subjects received at least one CAB 
LA injection. Subjects in this population will be used to evaluate the safety and 
tolerability of CAB LA injection in primary analysis.

Oral PK Population: subjects in the ‘Safety population’ for whom an intensive 
oral pharmacokinetic sample was obtained and analysed. PK samples that may 
be affected by protocol deviations will be reviewed by the study team to 
determine whether or not the sample will be excluded. This population will be 
used for reporting of Oral PK data.
 
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Overview
Key Elements of the RAP

Injection (Week 41) PK Population: subjects in the ‘Safety population’ for whom 
an injection pharmacokinetic sample was obtained and analysed during Weeks 
5 to 41. PK samples that may be affected by protocol deviations will be 
reviewed by the study team to determine whether or not the sample will be 
excluded. This population will be used for reporting of Injection PK data from 
Weeks 5 to 41.

Injection (Week 89) PK Population: subjects in the ‘Safety population’ for whom 
an injection pharmacokinetic sample was obtained and analysed during Weeks 
5 to 89. PK samples that may be affected by protocol deviations will be 
reviewed by the study team to determine whether or not the sample will be 
excluded. This population will be used for reporting of Injection PK data from 
Weeks 5 to 89.
Hypothesis

No formal statistical hypotheses will be evaluated.
Primary 
Analyses

To assess safety of CAB LA, the number and the percent of participants 
experiencing each safety endpoint will be tabulated including adverse events, 
clinical laboratory tests, study withdrawals due to AEs, and vital signs 
assessments.

To assess tolerability of CAB LA, the proportion 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.

To assess the plasma pharmacokinetics of CAB following repeat oral 
administration (Day 1 to Week 4) and CAB LA IM injections throughout the 
Injection Phase (Week 5 to Week 41).
Secondary 
Analyses

To assess the plasma pharmacokinetics of CAB LA throughout the Injection 
and Long-term Follow-up Phases (Week 5 to Week 89).

To assess the safety and tolerability of oral CAB, each safety and tolerability 
endpoint will be tabulated including adverse events, study withdrawals due to 
AEs, vital signs assessments and clinical laboratory assessments.

To assess the acceptability of the CAB LA, injection discontinuation rate, the 
number and severity of ISRs, and the proportion (with 95% CI for the CAB LA 
arm) of participants who would consider using CAB LA for HIV prevention in the 
future will be tabulated among all enrolled participants (including those who
terminated product use during the trial.

Overall treatment satisfaction score and answers to each individual question on 
HIV-PrevTSQc will be summarized to evaluate tolerability
 
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2.
SUMMARY OF KEY PROTOCOL INFORMATION
2.1.
Changes to the Protocol Defined Statistical Analysis Plan
The current adverse events of special interest (AESIs) included in the protocol are 
seizures and seizure like events, diarrhea, hypertriglyceridemia/hypercholesterolemia, 
decline in renal function, proximal renal tubule dysfunctions and proteinuria.
We are modifying the study AESIs to align them with the rest of the Cabotegravir 
programme, now that the AESIs related to CAB have now been fully developed.
The RAP AESIs will differ from the AESIs defined in the protocol. AESIs of 
hepatoxicity, hypersensitivity reactions, injection site reactions, impact on creatinine, and 
neuropsychiatric events have been added to the list of AESIs for the RAP.
The events of diarrhea, hypertriglyceridemia/hypercholesterolemia, have been removed 
for the list of AESIs in the RAP.
Seizures and seizure like events, Decline in renal function, proximal renal tubule 
dysfunctions, proteinuria, which were defined in the protocol, will be kept as the AESIs 
for the study. 
2.2.
Study Objective(s) and Endpoint(s)
Objectives
Endpoints
Primary Objectives
Primary Endpoints
Evaluate the safety and tolerability of the 
injectable agent, cabotegravir (GSK1265744) 
long acting (CAB LA) injectable (600 mg dose 
administered every 4 weeks for 2 doses 
followed by every 8 weeks for 3 doses) 
through Week 5-41 in HIV-1 uninfected 
Chinese men.
Safety and tolerability parameters, including 
adverse events, clinical laboratory tests, study 
withdrawals due to AEs, vital signs assessments, 
and evaluation of injection site reactions (ISRs).
Evaluate the plasma pharmacokinetics of 
CAB following repeat oral administration (Day 
1 to Week 4) and CAB LA IM injections 
throughout the Injection Phase (Week 5 to 
Week 41).
Plasma CAB AUC(0-), Cmax, C, tmax, λz, t½, 
CL/F, and Vz/F at Week 4 following daily oral 
administration of CAB.
Plasma CAB AUC(0-), Cmax, C, and tmax at 
Week 41 following IM injections of CAB LA.
Secondary Objectives
Secondary Endpoints
Evaluate the plasma pharmacokinetics of 
CAB LA throughout the Injection and Long-
term Follow-up Phases (Week 5 to Week 89)
Plasma CAB AUC(0-), Cmax, C, tmax, λz, t½, 
CL/F, and Vz/F
Evaluate the safety and tolerability of oral 
CAB in HIV uninfected Chinese men during 
the oral lead-in Phase (Day 1 to Week 4)
Safety and tolerability parameters, including 
adverse events, study withdrawals due to AEs, 
vital signs assessments and clinical laboratory 
 
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Objectives
Endpoints
assessments.
Evaluate the acceptability of CAB LA 
injections through 41 weeks.
Injection discontinuation rate, the number and 
severity of ISRs and additional acceptability 
measures.
Explore concentration-effect relationships for 
various safety and tolerability parameters if 
relevant.
Evaluation of relationships between significant 
safety and tolerability parameters and CAB PK 
may be explored.
2.3.
Study Design
Overview of Study Design and Key Features
This study is an open label (OL) Phase 1, multi-site, study to evaluate the PK, safety, tolerability, 
and acceptability of CAB LA in adult male participants. Eligible participants will receive oral CAB 
tablets as well as open label CAB LA.
Design Features
Oral lead-in phase is from Day 1 to week 4; injection phase is 
from week 5 to week 41; and follow-up phase is from week 41 to 
week 89
Dosing
Oral CAB tablet is 30mg and dose level=1 tablet;
CAB Sterile Suspension for Injection Vial is 200mg/mL and dose 
level = 600mg (3mL)
Participants will receive daily oral CAB (30mg tablets) for 4 
weeks during the Oral Phase of the study and IM injections of 
600 mg of CAB LA at Week 5, Week 9, Week 17, Week 25 and 
Week 33.
 
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Overview of Study Design and Key Features
Treatment Assignment
Eligible participants will receive oral CAB tablets in the first four 
weeks, and will received CAB LA injections since Week 5 
following planned schedules.
Interim Analysis
No interim analysis is planned in this study.
2.4.
Statistical Hypotheses
No formal statistical hypotheses will be evaluated. The study is designed to evaluate the 
PK, safety, tolerability, and acceptability of the injectable agent, CAB LA (600 mg dose
administered at 8-week intervals after 2 initial doses 4 weeks apart) in HIV-uninfected
men in China where at least 60% of the men are of a population who have sex with men. 
Where appropriate, an estimation approach will be taken, and point estimates and 
confidence intervals will be constructed.
 
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3.
PLANNED ANALYSES
3.1.
Interim Analyses
No formal interim analysis is planned in the study.
However, two preliminary PK analyses during the study will be performed in an informal 
manner. One will be after all planned participants complete the oral phase, and the other 
one will be after 50% of planned participants complete Week 17 visit. Safety data will be 
provided after all planned participants complete the oral phase as well. Study team will 
review preliminary safety and PK data.
3.2.
Final Analyses
The primary safety analysis and PK analyses including both oral phase and injection 
phase through Weeks 5 to 41 will be performed after all ongoing participants complete 
the Week 41 visit and datasets have been authorized. Other secondary analyses as 
mentioned, where appropriate, will also be performed. The end of study analysis will be 
performed after all ongoing participants complete the Week 89 visit. All planned primary 
and secondary analyses will be included in the second formal analyses.
The planned analyses will be performed after the completion of the following sequential 
steps:
1.
All subjects have completed the specific study visit (i.e. week 41 or week 89) as 
defined in the protocol.
2.
All required database cleaning activities have been completed and final database 
release and database freeze has been declared by Data Management.
 
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4.
ANALYSIS POPULATIONS
Population
Definition / Criteria
Analyses Evaluated
All Subjects 
Screened 

Comprise of all subjects who consent to 
participate in the clinical study. 

Disposition summary
Safety

Comprise of all subjects who receive at 
least one dose of the study treatment.

All demographic

General safety analyses

Safety analysis for the 
oral phase

Analysis of acceptability 
of CAB LA
Safety Injection 
Comprise of all subjects received at 
least one CAB LA injection

Safety and tolerability 
analyses of CAB LA in 
primary and extended 
analyses
Oral 
Pharmacokinetic 
(PK)

Will consist of all subjects in the ‘Safety
population’ for whom an intensive oral 
pharmacokinetic sample was obtained 
and analysed. PK samples that may be 
affected by protocol deviations will be 
reviewed by the study team to 
determine whether or not the sample will 
be excluded.

Oral PK Concentration

Oral PK Parameters
Injection (Week 41) 
Pharmacokinetic 
(PK)

Will consist of all subjects in the ‘Safety
population’ for whom an injection 
pharmacokinetic sample was obtained 
and analysed during Weeks 5 to 41. PK 
samples that may be affected by 
protocol deviations will be reviewed by 
the study team to determine whether or 
not the sample will be excluded.

Injection PK 
Concentration

Injection PK 
Parameters
Injection (Week 89) 
Pharmacokinetic 
(PK) 

Will consist of all subjects in the ‘Safety 
population’ for whom an injection 
pharmacokinetic sample was obtained 
and analysed during Weeks 5 to 89. PK 
samples that may be affected by 
protocol deviations will be reviewed by 
the study team to determine whether or 
not the sample will be excluded.

Injection PK 
Concentration

Injection PK 
Parameters
NOTES:
Please refer to Appendix 14: List of Data Displays which details the population to be used for each display being generated.
 
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4.1.
Protocol Deviations

Important protocol deviations (including deviations related to study 
inclusion/exclusion criteria, conduct of the trial, patient management or patient 
assessment) will be summarised and listed.

Protocol deviations will be tracked by the study team throughout the conduct of the 
study in accordance with the Protocol Deviation Management Plan.
o
Data will be reviewed prior to freezing the database to ensure all important 
deviations are captured and categorised on the protocol deviations dataset. 
o
This dataset will be the basis for the summaries and listings of protocol 
deviations.

A separate summary and listing of all inclusion/exclusion criteria deviations will also 
be provided. This summary will be based on data as recorded on the 
inclusion/exclusion page of the eCRF.
 
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5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA 
HANDLING CONVENTIONS
Table 1 provides an overview of appendices within the RAP for outlining general 
considerations for data analyses and data handling conventions. 
Table 1
Overview of Appendices
Section
Component
10.1
Appendix 1: Protocol Deviation Management and Definitions for Per Protocol 
Population
10.2
Appendix 2: Time & Events
10.3
Appendix 3: Assessment Windows
10.4
Appendix 4: Treatment States and Phases
10.5
Appendix 5: Data Display Standards & Handling Conventions
10.6
Appendix 6: Derived and Transformed Data
10.7
Appendix 7: Premature Withdrawals & Handling of Missing Data
10.8
Appendix 8: Values of Potential Clinical Importance
10.9
Appendix 9: Multicenter Studies
10.10
Appendix 10: Examination of Covariates, Subgroups & Other Strata
10.11
Appendix 11: Multiple Comparisons & Multiplicity
10.12
Appendix 12: Model Checking and Diagnostics for Statistical Analyses.
10.13
Appendix 13: Abbreviations & Trade Marks
10.14
Appendix 14: List of Data Displays
 
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6.
STUDY POPULATION ANALYSES
6.1.
Overview of Planned Analyses
The study population analyses will be based on the safety population, unless otherwise 
specified. All summary data and statistics are calculated from available data, unless 
otherwise specified.
Table 2 provides an overview of the planned study population analyses, with full details 
of data displays being presented in Appendix 14: List of Data Displays.
Table 2
Overview of Planned Study Population Analyses
Display Type
Data Displays Generated
Table
Figure
Listing
Disposition
Retention Rate and Reasons for Withdrawals
Y
Y
Demography and Baseline Characteristics
General Demographics Characteristics
Y
Y
Medical History and Concomitant Medications
Medical History
Y
Y
Prior Medications
Y
Y
Concomitant Medications
Y
Y
Protocol Deviations
Deviation of Inclusion/Exclusion Criteria
Y
Y
Important Protocol Deviations
Y
Y
NOTES:

Y = Yes display generated.
6.1.1.
Disposition
The reasons of screening failure will be summarized based on the screened population. 
The number and percentage of each reason will be tabulated.
A summary of subject disposition by phase will be provided, including the number and 
percentage of subjects entering oral/injection phase, the number and percentage of 
subjects completing oral/injection phase and the number and percentage of subjects 
withdrawing from oral/injection phase.
Subject disposition data will be presented in a listing.
6.1.2.
Demographics
General demographics including age, self-identified gender when entering the study, and 
ethnicity will be summarized.
 
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A subject’s age is calculated using the year part of informed consent form (ICF) – year of 
birth collected in CRF.
6.1.3.
Medical History
Summaries of medical history will be presented by GSK pre-specified body system
categories as collected in the eCRF. Number and percentage of subjects in each category 
will be tabulated.
6.1.4.
Prior and Concomitant Medications
Medications will be coded to therapeutic drug classes and generic drug names using the 
GSKDRUG 1.4 or later. Medications initiated prior to the Day 1 of the study will be 
counted as prior medications. Concomitant medications are defined as medications that 
are taken on or after the Day 1. Medications initiated prior to the Day 1 and continued 
after the Day 1 will be counted as both prior and concomitant medications.
Summaries showing the number and percentage of subjects who take prior or 
concomitant medications will be presented by therapeutic drug class and generic drug 
name.
6.1.5.
Protocol Deviation
Important protocol deviations (PD) will be summarized PD category and subcategory, 
and will also be presented in a listing. A separate summary table and a listing will be 
provided for subjects with deviation of the inclusion/exclusion criteria in the safety 
population 
 
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7.
PRIMARY STATISTICAL ANALYSES
7.1.
Safety Analyses of CAB LA
Four study phases are defined for this study: screening phase, oral phase, injection phase 
and follow-up phase (see Appendix 4 for the definition of each phase).
The primary safety analysis will be conducted after all ongoing participants complete the 
Week 41 visit and datasets have been authorized. All data from injected participants 
collected from Week 5 to Week 41 (i.e., in the injection phase) will be analysed. Analysis 
endpoints will include Grade 2 or higher clinical and laboratory events that occur from 
the initial injection to 8 weeks after the last injection among participants who receive at 
least one injection.
The extended safety analysis will be conducted after all ongoing participants complete 
the Week 89 visit and datasets have been authorized. All data from injected participants 
collected from Week 5 to Week 89 (i.e., in the injection phase and the follow-up phase) 
will be analysed. Analysis endpoints are the same as in the primary safety analysis.
To assess safety, the number and the percent of participants experiencing each safety 
endpoint will be tabulated. Each participant will contribute once in each category (i.e., 
only for the highest severity AE) for the evaluation of safety.
7.1.1.
Injection Site Reaction
The number and percentage of participants experiencing each type of injection site 
reaction sign or symptom will be tabulated by severity from the safety injection 
population. For a given sign or symptom, each participant’s ISR will be counted once 
under the maximum severity for all injection visits. Overall summary of ISR and 
summary of ISR by needle length will both be provided. ISR related details, such as 
cardiovascular activity, strength training exercise, will be listed only.
Table 3 provides an overview of the planned ISR analyses, with full details of data 
displays being presented in Appendix 14: List of Data Displays.
Table 3
Overview of Planned ISR Analyses
Display Type
Data Displays Generated
Stats Analysis
Summary
Individual
T
F
L
T
F
F
L
ISR Analyses 
All ISR Symptoms
Y
Y
NOTES:

T = Table, F = Figure, L = Listing, Y = Yes display generated.

Stats Analysis = Represents TFL related to any formal statistical analyses (i.e. modelling) conducted.

Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data.

Individual = Represents FL related to any displays of individual subject observed raw data.
 
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7.1.2.
Adverse Events
Adverse events will be tabulated using MedDRA (v20.0 or above) system organ class 
(SOC) and preferred terms (PT), or preferred terms alone, by study phase. The number 
and percentage of participants experiencing each specific AEs (Grade 2 or higher, All 
AEs, SAEs, AEs leading to permanent treatment discontinuation or study withdrawal) 
will be tabulated. Number of subjects in the safety population who entered the study 
phase will be used as denominator in the calculation of percentages.
Drug-related AEs, SAEs, and Grade 2-4 AEs will also be tabulated. Any AE is assumed 
to be study treatment-related if relationship is marked ‘YES’ on CRF or value is missing.
In addition, a summary table will be created for AEs by maximum severity by study 
phase. Common AEs are defined as AEs occurring in >=5% subjects during the study 
(based on preferred term). Common AEs, common non-serious AEs, common Grade 2-4 
AEs, and common drug-related Grade 2-4 AEs will be tabulated.
All AE tables will be presented in a decreasing frequency order of SOC or PT unless 
otherwise specified.
Table 4 provides an overview of the planned AE analyses, with full details of data 
displays being presented in Appendix 14: List of Data Displays.
Table 4
Overview of Planned AE Analyses
Display Type
Data Displays Generated
Stats Analysis
Summary
Individual
T
F
L
T
F
F
L
AE Analyses 
All AEs
Y
Y
Grade 2 or higher AEs
Y
Y
SAEs
Y
Y
AE leading to treatment 
discontinuation or study 
withdrawal
Y
Y
Drug-related AEs
Y
Drug-related SAEs
Y
Drug-related Grade 2 or 
higher AEs
Y
Common AEs
Y
Common non-serious AEs
Y
Common Grade 2-4 AEs
Y
Common drug-related 
Grade 2-4 AEs
Y
NOTES:

T = Table, F = Figure, L = Listing, Y = Yes display generated.

Stats Analysis = Represents TFL related to any formal statistical analyses (i.e. modelling) conducted.

Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data.

Individual = Represents FL related to any displays of individual subject observed raw data.
 
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7.1.3.
Clinical Laboratory Tests
All clinical laboratory tests will be graded according to the Appendix 7 from the study
protocol. Grade 2 or higher laboratory events will be tabulated by number and percentage 
of subjects with the event by study phase. 
Change from baseline in hematology, fasting chemistry, fasting lipid profile, and 
coagulation profile will be summarized by visit. For the definition of baseline, refer to 
Section 10.5.2. Urinalysis and urine chemistry results will be summarized by visit as
either categorical values or as continuous values, depending on the type of the parameter. 
For each lab test, shift from baseline table will be provided based on toxicity grade, both 
by visit and for the shift to maximum toxicity grade in each study phase. Data collected at 
unscheduled visits will not be included in the by-visit summary, but will be used in the 
calculation of maximum grade in each study phase. Subjects having both high and low 
values will be counted in both High and Low categories for the summary by study phase.
All lab data, as well as lab data for subjects with Grade 2 or higher abnormalities, will be 
listed. Abnormal data will be listed with an indicator, which is low/high relative to 
normal range. All laboratory results from local labs, if any, will be listed only
Table 5 provides an overview of the planned lab test analyses, with full details of data 
displays being presented in Appendix 14: List of Data Displays.
Table 5
Overview of Planned Lab Test Analyses
Display Type
Absolute
Change from Baseline
Summary
Individual
Summary
Individual
T
F
F
L
T
F
F
L
Laboratory Test Analyses
Grade 2 or high 
laboratory events
Y
Clinical Chemistry 
Y
Y
Hematology
Y
Y
Fasting Lipid Profile
Y
Y
Coagulation Profile
Y
Y
Urinalysis and Urine 
Chemistry
Y
Y
Y
Other lab data 
including local lab
Y

T = Table, F = Figure, L = Listing, Y = Yes display generated.

Stats Analysis = Represents TFL related to any formal statistical analyses (i.e. modelling) conducted.

Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data.

Individual = Represents FL related to any displays of individual subject observed raw data.
7.1.4.
Vital Sign Assessments
Change from baseline in vital signs, including temperature, systolic and diastolic blood 
pressure, and pulse rate andrespiratory rate will be summarized by study visit. For the 
 
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definition of baseline, refer to Section 10.5.2. Shift from baseline table (with respect to 
clinical concern range) will also be provided.
All vital signs, as well as vital signs for subjects with abnormalities of potential clinical 
importance, will be listed with an indicator, which is low/high relative to clinical concern 
range.
Table 6 provides an overview of the planned vital sign analyses, with full details of data 
displays being presented in Appendix 14: List of Data Displays.
Table 6
Overview of Planned Vital Sign Analyses
Display Type
Absolute
Change from Baseline
Summary
Individual
Summary
Individual
T
F
F
L
T
F
F
L
Vital Signs
Vital signs
Y
Y
NOTES:

T = Table, F = Figure, L = Listing, Y = Yes display generated.

Stats Analysis = Represents TFL related to any formal statistical analyses (i.e. modelling) conducted.

Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data.

Individual = Represents FL related to any displays of individual subject observed raw data.
7.1.5.
Death
Both primary and secondary causes, if any, will be listed for each deceased participant.
Table 7 provides an overview of the planned death analyses, with full details of data 
displays being presented in Appendix 14: List of Data Displays.
 
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Table 7
Overview of Planned Death Analyses
Display Type
Data Displays Generated
Stats Analysis
Summary
Individual
T
F
L
T
F
F
L
Death Analysis 
Death
Y
NOTES:

T = Table, F = Figure, L = Listing, Y = Yes display generated.

Stats Analysis = Represents TFL related to any formal statistical analyses (i.e. modelling) conducted.

Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data.

Individual = Represents FL related to any displays of individual subject observed raw data.
7.2.
Tolerability Analyses of CAB LA
The tolerability analyses will be based on the safety injection population, unless 
otherwise specified. All summary data and statistics are calculated from available data, 
unless otherwise specified.
To assess tolerability of CAB LA, the proportion (with 95% confidence interval) 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 will be calculated out of those participants that received at least one injection.
A questionnaire will also be used to assess participant tolerability and satisfaction to the 
treatment. For each question, the responses will be summarized by the proportion of 
participants reporting the response out of all those that answered the question. An overall 
treatment satisfaction score will be calculated for each participant.
Total score is defined as the sum of the scores for individual questions. If less than or 
equal to 50% of the questions for an individual participant are missing, the missing total
scores will be estimated using the average of the existing questions multiplied by twelve; 
if more than 50% of the questions for an individual participant are missing, the total score 
will not be estimated and will be considered as missing. When calculating total scores, 
question
 will be used and question
 
 will be excluded.
Table 8 provides an overview of the planned tolerability analyses, with further details of 
data displays being presented in Appendix 14: List of Data Displays.
 
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Table 8
Overview of Planned Tolerability Analyses
Display Type
Data Displays Generated
Stats Analysis
Summary
Individual
T
F
L
T
F
F
L
CAB LA Discontinuation
Injection 
Discontinuation Rate
Y
Y
Treatment Satisfaction Questionnaire
Each question in the 
questionnaire
Y
Y
Treatment total 
satisfaction score
Y
Y
NOTES:

T = Table, F = Figure, L = Listing, Y = Yes display generated.

Stats Analysis = Represents TFL related to any formal statistical analyses (i.e. modelling) conducted.

Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data.

Individual = Represents FL related to any displays of individual subject observed raw data
7.3.
Primary Pharmacokinetic Analyses
7.3.1.
Overview of Planned Primary Pharmacokinetic Analyses
The primary pharmacokinetic (PK) analyses will be based on the Oral PK and Injection 
(Week 41) PK populations, unless otherwise specified.
Table 9 provides an overview of the planned efficacy analyses, with full details of data 
displays being presented in Appendix 14: List of Data Displays.
Table 9
Overview of Planned Primary Pharmacokinetic Analyses
Display Type
Untransformed
Log-Transformed
Stats Analysis
Summary
Individual
Stats Analysis
Summary
Individual
T
F
L
T
F
F
L
T
F
L
T
F
F
L
Oral/Injection
PK Concentrations
Y
Y [1]
Y [1]
Y
Plasma PK Parameters
Y
Y
Y
Y
Y
NOTES:

T = Table, F = Figure, L = Listings, Y = Display generated.

Stats Analysis = Represents TFL related to any formal statistical analyses (i.e. modelling) conducted.

Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data.

Individual = Represents FL related to any displays of individual subject observed raw data.
[1] Linear and Semi-Logarithmic plots will be created on the same display.
7.3.2.
Primary Drug Concentration Measures
Refer to Appendix 5: Data Display Standards & Handling Conventions (Section 10.5.3
Reporting Process & Standards).
 
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7.3.3.
Primary Pharmacokinetic Parameters
7.3.3.1.
Deriving Primary Pharmacokinetic Parameters

Refer to Appendix 5: Data Display Standards & Handling Conventions
(Section 10.5.3 Reporting Process & Standards).

The pharmacokinetic parameters will be calculated by standard non-compartmental 
analysis according to current working practices and using Phoenix WinNonlin 
Version 6.4 or higher.

All calculations of non-compartmental parameters will be based on actual sampling 
times, and all concentrations will be included in the estimation of PK parameters 
regardless of whether samples are collected within the specified time window or not.

Pharmacokinetic parameters described in Table 10 will be determined from the 
plasma concentration-time data, as data permits.
Table 10
Derived Primary Pharmacokinetic Parameters
Parameter
Parameter Description
AUC(0-)
Area under the concentration-time curve over the dosing interval will be calculated using the 
linear trapezoidal rule for each incremental trapezoid and the log trapezoidal rule for each 
decremental trapezoid.
Cmax
Maximum observed concentration, determined directly from the concentration-time data.
tmax
Time to reach Cmax, determined directly from the concentration-time data.
C
Observed concentration at the end of the dosing interval, determined directly from the 
concentration-time data.
t½
Terminal absorption elimination half-life will be calculated as: 
t½ = ln2 / λz
λz
Terminal absorption elimination rate constant
CL/F
Clearance (adjusted for bioavailability, F) will be calculated as: 
CL/F = Dose / AUC(0-)
Vz/F
Volume of distribution (adjusted for bioavailability, F) will be calculated as: 
Vz/F = CL / λz
NOTES:

Additional parameters may be included as required.

λz, CL/F, Vss and t½ will be determined for the Oral PK population only in the primary analysis; these 
parameters will be further explored for the Injection (Week 89) PK population (Section 8.1.3.1).
 
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7.3.3.2.
Statistical Analysis of Primary Pharmacokinetic Parameters
The following pharmacokinetic statistical analyses will only be performed, if sufficient 
data is available (i.e. if subjects have well defined plasma profiles). 
Pharmacokinetic Statistical Analyses
Endpoint(s)

Plasma primary PK endpoints include C, as data permit
Model Specification
Assessment of Accumulation (Injection Phase only):

To determine accumulation of plasma CAB following treatment with CAB LA, the log-
transformed Cvalues for CAB will be analyzed using a mixed effects model (ANOVA) as 
appropriate to the study design, fitting fixed effect terms for visit and treating subject as a 
random effect. Point estimates and 90% confidence intervals (CIs) for the differences of 
interest (i.e. accumulation of CAB based on AUC(0-): Week 34 / Week 6) will be constructed 
using the residual variance.
Attainment of Steady state (Injection Phase only):

If data permit, a statistical analysis of steady-state trough concentrations (C) will be performed 
after log-transformation of Con Weeks 17, 25, 33, and 41 to evaluate whether steady state 
was achieved using the Helmert transformation approach. A mixed effect model (ANOVA) will 
be fitted by visit (as a categorical covariate) as a fixed effect term and subject as a random 
effect term. The comparison will begin with Week 17 vs. the average of Weeks 25 through 
Week 41. If the p-value for Week 17 vs. the average of Week 25 through Week 41 comparison 
is ≤0.05 (i.e. steady state not achieved at Week 17), then the comparison will continue with 
Week 25 vs. Week 33 through Week 41.
Model Checking & Diagnostics

Refer to Appendix 12: Model Checking and Diagnostics for Statistical Analyses.
Model Results Presentation

Statistical analysis of accumulation of plasma CAB following treatment with CAB LA will be 
presented in tabular format with geometric mean ratios between Week 34 and Week 6, and 
90% CIs for the ratios of Cfor CAB.

In steady-state analysis, the ratio of Geometric LS means and its 95% CI will be presented for 
the comparison(s).
 
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8.
SECONDARY STATISTICAL ANALYSES
8.1.
Secondary Pharmacokinetic Analyses
8.1.1.
Overview of Planned Secondary Pharmacokinetic Analyses
The secondary pharmacokinetic (PK) analyses will be based on the Injection (Week 89) 
PK population, unless otherwise specified.
Table 11 provides an overview of the planned analyses, with full details being presented 
in Appendix 14: List of Data Displays. 
Table 11
Overview of Planned Secondary Pharmacokinetic Analyses
Display Type
Untransformed
Log-Transformed
Stats Analysis
Summary
Individual
Stats Analysis
Summary
Individual
T
F
L
T
F
F
L
T
F
L
T
F
F
L
Oral/Injection
PK Concentrations
Y
Y [1]
Y [1]
Y
Plasma PK Parameters
Y
Y
Y
Y
Y
NOTES:

T = Table, F = Figure, L = Listings, Y = Display generated.

Stats Analysis = Represents TFL related to any formal statistical analyses (i.e. modelling) conducted.

Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data.

Individual = Represents FL related to any displays of individual subject observed raw data.
[1] Linear and Semi-Logarithmic plots will be created on the same display.
8.1.2.
Secondary Drug Concentration Measures
Refer to Appendix 5: Data Display Standards & Handling Conventions (Section 10.5.3
Reporting Process & Standards).
8.1.3.
Secondary Pharmacokinetic Parameters
8.1.3.1.
Deriving Secondary Pharmacokinetic Parameters

Refer to Appendix 5: Data Display Standards & Handling Conventions
(Section 10.5.3 Reporting Process & Standards).

The pharmacokinetic parameters will be calculated by standard non-compartmental 
analysis according to current working practices and using Phoenix WinNonlin 
Version 6.4 or higher.

All calculations of non-compartmental parameters will be based on actual sampling 
times, and all concentrations will be included in the estimation of PK parameters 
regardless of whether samples are collected within the specified time window or not.

Pharmacokinetic parameters described in Table 12 will be determined from the 
plasma concentration-time data, as data permits.
 
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Table 12
Derived Secondary Pharmacokinetic Parameters
Parameter
Parameter Description
AUC(0-)
Area under the concentration-time curve over the dosing interval will be calculated using the 
linear trapezoidal rule for each incremental trapezoid and the log trapezoidal rule for each 
decremental trapezoid.
Cmax
Maximum observed concentration, determined directly from the concentration-time data.
tmax
Time to reach Cmax, determined directly from the concentration-time data.
C
Observed concentration at the end of the dosing interval, determined directly from the 
concentration-time data.
t½
Terminal absorption elimination half-life will be calculated as: 
t½ = ln2 / λz
λz
Terminal absorption elimination rate constant
CL/F
Clearance (adjusted for bioavailability, F) will be calculated as: 
CL/F = Dose / AUC(0-)
Vz/F
Volume of distribution (adjusted for bioavailability, F) will be calculated as: 
Vz/F = CL / λz
NOTES:

Additional parameters may be included as required.
8.2.
Safety and Tolerability Analyses of Oral CAB
The safety and tolerability analyses of oral CAB will include Grade 2 or higher clinical 
and laboratory events occurred during the oral phase. Analysis time frame is from the 
first date of taking oral CAB tablet to the date right before the first CAB LA injection. 
For subjects who withdraw treatment from the oral phase, the analysis will include all 
safety and tolerability assessments from the first date of taking oral CAB tablet up to the 
date of last study visit.
Safety endpoints including adverse events, laboratory test, vital signs, and death will be 
analysed. The same analysis approaches will be conducted as in the primary analysis, but 
with different time frame.
Table 13 provides an overview of the planned analyses, with full details of data displays 
being presented in Appendix 14: List of Data Displays.
 
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Table 13
Overview of Planned AE, LB, VS, and Death Analyses
Display Type
Data Displays Generated
Stats Analysis
Summary
Individual
T
F
L
T
F
F
L
AE Analyses 
All AEs 
Y
Y
Grade 2 or higher AEs
Y
Y
SAEs 
Y
Y
AE leading to 
treatment 
discontinuation or 
study withdrawal
Y
Y
Drug-related AEs
Y
Drug-related SAEs
Y
Drug-related Grade 2 
or higher AEs
Y
Common AEs
Y
Common non-serious 
AEs
Y
Common Grade 2-4 
AEs
Y
Common drug-related 
Grade 2-4 AEs
Y
Laboratory Tests
Grade 2 or higher 
laboratory events
Y
Clinical Chemistry 
Y
Y
Hematology
Y
Y
Fasting Lipid Profile
Y
Y
Urinalysis
Y
Y
Coagulation Profile
Y
Y
Other lab data 
including local lab
Y
Vital Sign Analysis 
Vital Signs
Y
Y
Death Analysis
Death
Y
NOTES:

T = Table, F = Figure, L = Listing, Y = Yes display generated.

Stats Analysis = Represents TFL related to any formal statistical analyses (i.e. modelling) conducted.

Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data.

Individual = Represents FL related to any displays of individual subject observed raw data.
8.3.
Acceptability of CAB LA
The secondary acceptability analyses will be based on safety population, unless otherwise 
specified. All summary data and statistics are calculated from available data, unless 
otherwise specified.
 
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To assess acceptability of the CAB LA, the proportion (with 95% confidence interval) of 
participants who would consider using CAB LA for HIV prevention in the future will be 
calculated among all subjects in the safety population (including those who terminated 
product use during the trial). Participants will be asked if they would consider using CAB 
LA for HIV prevention in the future at their Week 41 visit or at their withdrawal visit, 
whichever occurs first. Patients who are lost to follow up or with missing responses will 
be presented as such in a separate category.
Table 14 provides an overview of the planned acceptability analyses, with further details 
of data displays being presented in Appendix 14: List of Data Displays.
Table 14
Overview of Planned Acceptability Analyses
Display Type
Data Displays Generated
Stats Analysis
Summary
Individual
T
F
L
T
F
F
L
Acceptability of the CAB LA
participants who 
would consider using 
CAB LA
Y
Y
NOTES:

T = Table, F = Figure, L = Listing, Y = Yes display generated.

Stats Analysis = Represents TFL related to any formal statistical analyses (i.e. modelling) conducted.

Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data.

Individual = Represents FL related to any displays of individual subject observed raw data.
8.4.
Concentration-effect Relationships for Safety and 
Tolerability Parameters
Evaluation of relationships between significant safety and tolerability parameters and 
CAB PK may be explored.
8.5.
General Safety Analyses
This section will describe safety analyses that are not mentioned in Section 7.1 or Section 
8.2, but usually are performed as safety assessment.
8.5.1.
Extent of Exposure to CAB
Duration of exposure to CAB and cumulative dose (see Section 10.6.2 for the definition) 
will be summarized for the oral phase and the injection phase separately. Overall 
exposure to the study drug and to the study (for safety evaluation) will also be calculated 
and summarized. Exposure data will also be listed.
Table 15 provides an overview of the planned analyses, with full details of data displays 
being presented in Appendix 14: List of Data Displays.
 
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Table 15
Overview of Planned Analyses for Extent of Exposure
Display Type
Data Displays Generated
Stats Analysis
Summary
Individual
T
F
L
T
F
F
L
Extent of Exposure
Extent of exposure
Y
Y
NOTES:

T = Table, F = Figure, L = Listing, Y = Yes display generated.

Stats Analysis = Represents TFL related to any formal statistical analyses (i.e. modelling) conducted.

Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data.

Individual = Represents FL related to any displays of individual subject observed raw data.
8.5.2.
Possible suicidality-related Adverse Events
Possible suicidality-related will be listed.
Table 16 provides an overview of the planned analyses, with full details of data displays 
being presented in Appendix 14: List of Data Displays.
Table 16
Overview of Analyses for possible suicidality-related AEs
Display Type
Data Displays Generated
Stats Analysis
Summary
Individual
T
F
L
T
F
F
L
AE Analyses 
Possible Suicidality-
Related Adverse Event
Y
NOTES:

T = Table, F = Figure, L = Listing, Y = Yes display generated.

Stats Analysis = Represents TFL related to any formal statistical analyses (i.e. modelling) conducted.

Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data.

Individual = Represents FL related to any displays of individual subject observed raw data.
8.5.3.
Social Harms
Details of social harms collected on the eCRF will be listed for each participant.
Table 17 provides an overview of the planned study population analyses, with full details 
of data displays being presented in Appendix 14: List of Data Displays.
Table 17
Overview of Planned Study Population Analyses
Display Type
Data Displays Generated
Table
Figure
Listing
Social Harms
All Social Harms
Y
NOTES:

Y = Yes display generated.
 
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8.5.4.
ECG
ECG test will be performed at Screening only. Details collected on the eCRF will be 
listed for each subject. Baseline ECG findings (normal, abnormal – not clinically 
significant, or abnormal - clinically significant) will be summarized by number and 
percentage of subjects and presented as part of the ‘Demographic Characteristics’ table.
Table 18 provides an overview of the planned study population analyses, with full details 
of data displays being presented in Appendix 14: List of Data Displays.
Table 18
Overview of Planned Study Population Analyses
Display Type
Data Displays Generated
Table
Figure
Listing
ECG
ECG Parameters and Results
Y
Y
NOTES:

Y = Yes display generated.
8.5.5.
Cardiovascular Events
Any cardiovascular events will be listed only.
Table 19 provides an overview of the planned cardiovascular event analyses, with full
details of data displays being presented in Appendix 14: List of Data Displays.
Table 19
Overview of Planned Cardiovascular Event Analyses
Display Type
Data Displays Generated
Stats Analysis
Summary
Individual
T
F
L
T
F
F
L
CV Event Analyses 
All CV events
Y
NOTES:

T = Table, F = Figure, L = Listing, Y = Yes display generated.

Stats Analysis = Represents TFL related to any formal statistical analyses (i.e. modelling) conducted.

Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data.

Individual = Represents FL related to any displays of individual subject observed raw data.
8.5.6.
Liver Events
Number and percentage of subjects with liver events will be tabulated by study phase. 
Number and percentage of subjects with clinical significant hepatobiliary laboratory 
abnormalities during the study will also be tabulated. Full information of liver events will 
be listed.
Table 20 provides an overview of the planned liver event analyses, with full details of 
data displays being presented in Appendix 14: List of Data Displays.
 
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Table 20
Overview of Planned Liver Event Analyses
Display Type
Data Displays Generated
Stats Analysis
Summary
Individual
T
F
L
T
F
F
L
Liver Event Analyses 
All liver events
Y
Y
Hepatobiliary 
laboratory 
abnormalities
Y
NOTES:

T = Table, F = Figure, L = Listing, Y = Yes display generated.

Stats Analysis = Represents TFL related to any formal statistical analyses (i.e. modelling) conducted.

Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data.

Individual = Represents FL related to any displays of individual subject observed raw data.
 
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9.
REFERENCES
Dube MP, Stein JH, Aberg JA, Fichtenbaum CJ, Gerber JG, Tashima KT et al. 
Guidelines for the evaluation and management of dyslipidemia in human 
immunodeficiency virus (HIV)-infected adults receiving antiretroviral therapy: 
recommendations of the HIV Medical Association of the Infectious Disease Society of
America and the Adult AIDS Clinical Trials Group. Clin Infect Dis 2003; 37(5):613-27.
GlaxoSmithKline Document Number 2016N293702_00 (Original – 20-JUL-2017): An 
Open Label, Phase 1 Study to Evaluate the PK, Safety, Tolerability and Acceptability of 
Long Acting Injections of the HIV Integrase Inhibitor, Cabotegravir (CAB; 
GSK1265744) in HIV Uninfected Chinese Men (20-JUL-2017)
GlaxoSmithKline Document Number 2016N293702_01 (Original – 20-JUL-2017): An 
Open Label, Phase 1 Study to Evaluate the PK, Safety, Tolerability and Acceptability of 
Long Acting Injections of the HIV Integrase Inhibitor, Cabotegravir (CAB; GSK1265744) 
in HIV Uninfected Chinese Men (06-JUN-2018)
Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF, Feldman HI, et.al. A new 
equation to estimate glomerular filtration rate. Ann Int Med. 2009; 150: 604-12.
 
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10.
APPENDICES
Section
Appendix
RAP Section 4 : Analysis Populations
Section 10.1
Appendix 1: Protocol Deviation Management and Definitions for Per Protocol 
Population
RAP Section 5 : General Considerations for Data Analyses & Data Handling Conventions
Section 10.2
Appendix 2: Time and Events
Section 10.3
Appendix 3: Assessment Windows
Section 10.4
Appendix 4: Treatment States & Phases
Section 10.5
Appendix 5: Data Display Standards & Handling Conventions

Study Treatment & Sub-group Display Descriptors

Baseline Definitions & Derivations

Reporting Process & Standards
Section 10.6
Appendix 6: Derived and Transformed Data

General, Study Population & Safety
Section 10.7
Appendix 7: Premature Withdrawals & Handling of Missing Data

Premature Withdrawals

Handling of Missing Data
Section 10.8
Appendix 8: Values of Potential Clinical Importance
Section 10.9
Appendix 9: Multicentre Studies
Section 10.10
Appendix 10: Examination of Covariates and Subgroups & Other Strata
Section 10.11
Appendix 11: Multiple Comparisons and Multiplicity
Section 10.12
Appendix 12: Model Checking and Diagnostics for Statistical Analyses
Other RAP Appendices
Section 10.13
Appendix 13: Abbreviations & Trade Marks
Section 10.14
Appendix 14: List of Data Displays
 
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10.1.
Appendix 1: Protocol Deviation Management and Definitions 
for Per Protocol Population
Protocol waivers or exemptions are not allowed with the exception of immediate safety
concerns that may arise after the oral administration of CAB.
Deviations from inclusion and exclusion criteria are not allowed because they can
potentially jeopardize the scientific integrity of the study, regulatory acceptability or
participant safety. Therefore, adherence to the criteria as specified in the protocol is
essential
10.1.1.
Exclusions from Per Protocol Population
Not applicable. Per protocol population is not defined in this study.
 
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10.2.
Appendix 2: Time & Events
10.2.1.
Protocol Defined Time & Events
Table 21
Schedule of Activitiesq
Clinical Assessments
Screeninga
Oral
Phasem
Injection Phase
Follow-
up 
Phase
& Final
Visit
Day 1
Day 28 (Week 4)
Day 35 (Week 5)
Injection 1
Day 42 (Week 6)
Week 9
Injection 2
Week 10
Week 17
Injection 3
Week 18
Week 25
Injection 4
Week 26
Week 33
Injection 5
Week 34
Week 37
Week 41
Week 53, 65, 77
Week 89
Written informed consent
X
Inclusion/Exclusion criteriab
X
Demographic information
X
Full physical exam/medical 
historyc
X
X
Brief physical exam
X
X
X
X
X
X
X
X
X
X
X
X
X
Height/weight/BMId
X
X
Medication/drug/alcohol history
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
Dispense oral study medication
(with counseling)e
X
Drug accountability (pill counts)
X
X
 
 
 
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Clinical Assessments
Screeninga
Oral
Phasem
Injection Phase
Follow-
up 
Phase
& Final
Visit
Day 1
Day 28 (Week 4)
Day 35 (Week 5)
Injection 1
Day 42 (Week 6)
Week 9
Injection 2
Week 10
Week 17
Injection 3
Week 18
Week 25
Injection 4
Week 26
Week 33
Injection 5
Week 34
Week 37
Week 41
Week 53, 65, 77
Week 89
CAB LA Injection (with
counseling)
X
X
X
X
X
HIV-PrevTSQcf
X
ISR AE Diaryg
X
X
X
X
X
AE
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
SAE review (SAE will be 
collected from the signing ofICF)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant medicationcheck
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Vital signsh
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Qualitative HIV RNA by NAATi
X
HIV PoC testj
X
X
X
X
X
X
X
X
X
X
ECGk
X
HbsAg and HbsAb, HCV 
Antibody
X
Hematology/Chemistry testing
X
X
X
X
X
X
X
X
X
X
X
Urinalysis
X
X
Urine screen for Chlamydiaand
gonorrhea
X
Liver Chemistry Testsl
X
 
 
 
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Clinical Assessments
Screeninga
Oral
Phasem
Injection Phase
Follow-
up 
Phase
& Final
Visit
Day 1
Day 28 (Week 4)
Day 35 (Week 5)
Injection 1
Day 42 (Week 6)
Week 9
Injection 2
Week 10
Week 17
Injection 3
Week 18
Week 25
Injection 4
Week 26
Week 33
Injection 5
Week 34
Week 37
Week 41
Week 53, 65, 77
Week 89
Fasting lipid profile
X
X
Coagulation testing
X
X
TRUST for Syphilis screen
X
Plasma for CAB
concentrationm,n,o
Xm
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Plasma storage samplep
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
AE: Adverse events, BMI: Body mass index, CAB: Cabotegravir, CAB LA: Cabotegravir long-acting, ECG: Electrocardiogram, HbsAg: Hepatitis B surface antigen, HIV: Human
Immunodeficiency Virus, HCV: Hepatitis C Virus, ISR: Injection site reactions, SAE: Serious adverse event, HIV-PrevTSQc: HIV-Prevention Treatment Satisfaction
Questionnaire (change): TRUST: Toluidine Red Unheated Serum Test, RNA: Ribonucleicacid.
a.
Screening (including drug screen) is to be performed within 30 days of the first dose in the Oral Phase of the study. See Appendix 2 from the study protocol
b.
Inclusion/exclusion criteria will be fully assessed at the Screening visit. Changes between the screening visit and the Day 1 visit should be assessed to ensure eligibility,
including additional assessments performed at Day 1.
c.
A full physical exam will be performed at Week 89.
d.
Weight will be collected at Screening and at Week 89. Height and BMI will be collected at Screening only.
e.
Oral phase consists of 28 days with a 7 day washout period between Day 28 (last oral dose) and Day 35 (first injection visit).
f.
HIV-PrevTSQc: HIV-Prevention Treatment Satisfaction Questionnaire (change) will be given at Week 10 only (after 2nd injection).
g.
ISR AE 7 Day Post Injection Diary will be distributed at the injection visit at Week 5, 9, 17, 25 and 33 and returned to the clinic at weeks 6, 10, 18, 26, and 34. For
participants having ISR on the last day of week 5, 9, 17, 25 and 33, additional ISR AE Weeks 2 – 12 Post Injection Diary will be distributed at weeks 6,10, 18, and 26,34. 
Participants will be asked to bring the diary to each clinic visit.
h.
Vital sign measurements will be performed following 5 minutes of rest.
i.
Qualitative HIV Nucleic Acid Amplification Testing (NAAT) will be performed at Screening. See Appendix 9 from the study protocol for the HIV testing algorithm at 
screening, Day 1 and during the course of the study.
 
 
 
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j.
HIV PoC (Point of care) test will be performed at each time point during the course of the study and must be reviewed prior to IM dosing. See Appendix 9 from the 
study protocol for the HIV testing algorithm at screening, Day 1 and during the course of the study.
k.
ECGs will be performed following 5 minutes of rest in a semi-supine position.
l.
Liver Chemistry Tests include Alanine aminotransferase (ALT), Aspartate aminotransferase (AST), Bilirubin total and direct.
m.
Oral Pharmacokinetic (PK) sampling at trough will be collected for all subjects prior to dose within 20 to 28 hours following oral administration the day prior. Intensive
oral PK sampling will be collected from approximately16 participants as shown in Table 20.
n.
PK sampling for Injection phase: All PK samples will be collected prior to CAB LA injections at Week 5, 9, 17, 25, and 33 with the exception of 1-week post injection
samples at Weeks 6, 10, 18, 26, 34, 37 (2-week post injection sample) and Week 41
o.
Long-term follow up PK samples: PK sampling during follow up will occur at, Week 53, 65, 77, and 89.
p.
Additional testing is required for participants who have a reactive or positive HIV test after enrolment. Stored plasma from the visit previous to the positive test should be 
tested for HIV using the 4th generation HIV test to best estimate time of infection. HIV acquisition must be confirmed by either western blot, HIV ½ Multispot or the Geenius
HIV Confirmation ½ Assay, and HIV RNA.
q.
Visit may occur in a window ±3 Day
Table 22
Schedule of Intensive Oral PK (Approximately 16 Participants) a,b
Day 25
Day 26
Day 27
Day 28
Check- in Oral dose
administered
(e.g. 8AM)
Prior to oral
dose (e.g.
7:55AM)
Oral dose
administered
(e.g. 8AM)
1-
hour post 
dose (e.g.
9AM)
2-hour
post dose
(e.g.
10AM)
3-hour
post dose
(e.g.
11AM)
4-hour 
post dose
(e.g.
12AM)
8-
hour
post 
dose
(e.g.
4PM)
24-
hour post 
dose
(e.g.
8AM)
Oral dose
administered
(e.g. after 8 AM)
Plasma for CAB
concentration
X
X
X
X
X
X
X
a.
PK sampling may occur 15min
b.
Central lab tests for the intensive oral PK subjects refer to Table 21.
 
 
 
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10.3.
Appendix 3: Assessment Windows
10.3.1.
Assessment Windows
The nominal visit information collected on CRF will be used in the analysis. Analysis 
visit based on the time window will not be defined in this study.
 
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10.4.
Appendix 4: Study Phase and State
10.4.1.
Treatment Phases
Assessments and events will be classified according to the time of occurrence relative to 
the start date of study treatment.
Treatment Phase
Definition
Screening Phase 
Date < Date of first Oral CAB
Oral Phase
Date of First Oral CAB <= Date <= Date of First CAB LA Injection -1 day; for subjects 
who discontinued before receiving CAB LA Injection, the end date of the oral phase is 
the date of last study visit. 
Injection Phase
Date of First CAB LA Injection <= Date <= 8 weeks after Last CAB LA Injection
Follow-up Phase
Date > 8 weeks after Last CAB LA Injection
10.4.2.
Treatment States
Assessments and events will be classified according to time of occurrence relative to the 
start date of the study treatment.
10.4.2.1.
Treatment States for AE Data
Treatment State
Definition
Screening Phase
AE Start Date < Date of First Oral CAB
On-Oral CAB-
Treatment
Day 1 ≤ AE Start Date ≤Date of First CAB LA Injection – 1; 
for subjects who withdraw from oral CAB treatment, Day 1 ≤ AE Start Date ≤
Withdrawal date + 7 days
On-CAB LA-
treatment
Date of First CAB LA Injection ≤ AE Start Date ≤Date of Week 41 Visit ; 
for subjects who withdraw from CAB LA injection, Date of First CAB LA Injection ≤ AE 
Start Date ≤Date of Last CAB LA Injection + 8 Weeks
Post-Treatment
AE Start Date > Date of Last CAB LA Injection + 8 weeks
Onset Time Since 
1st Dose (Days)
If Date of First Oral CAB (or CAB LA injection) ˃ AE Onset Date, duration = AE Onset 
Date - Treatment Start Date
If Date of First Oral CAB (or CAB LA injection) ≤AE Onset Date, duration = AE Onset 
Date - Treatment Start Date +1
Missing otherwise.
AE Duration 
(Days) 
AE Resolution Date – AE Onset Date + 1
Drug-related
If relationship is marked ‘YES’ on CRF OR value is missing
 
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10.5.
Appendix 5: Data Display Standards & Handling 
Conventions
10.5.1.
Study Treatment & Sub-group Display Descriptors
Treatment Group Descriptions
Study Group
Data Displays for Reporting 
Code
Description
Description
Order [1]
A
CAB PO 30 mg QD
CAB 30 mg
1
B
CAB LA IM 600 mg Q8W
CAB LA 600 mg
2
NOTES:
1.
Order represents treatments being presented in TFL, as appropriate.
10.5.2.
Baseline Definition & Derivations
10.5.2.1.
Baseline Definitions
The baseline or pre-dose assessment is the last available assessment prior to the time of 
the first dose unless it is specified otherwise.
10.5.2.2.
Derivations and Handling of Missing Baseline Data
Definition
Reporting Details
Change from Baseline
= Post-Dose Visit Value – Baseline
% Change from Baseline
= 100 x [(Post-Dose Visit Value – Baseline) / Baseline]
Maximum Change from Baseline
= Calculate the change from baseline at each given timepoint 
and determine the maximum change
NOTES:

Unless otherwise specified, the baseline definitions specified in Section 10.5.2.1 Baseline Definitions will be used 
for derivations for endpoints / parameters and indicated on summaries and listings.

Unless otherwise stated, if baseline data is missing no derivation will be performed and will be set to missing.

The baseline definition will be footnoted on all change from baseline displays.
10.5.3.
Reporting Process & Standards
Reporting Process
Software

The currently supported versions of SAS software 9.2 or higher and Phoenix WinNonlin will be 
used.
Analysis Datasets 
Analysis datasets will be created according to CDISC standards SDTMIG v3.2 & ADaMIG v1.0
For creation of ADaM datasets (ADCM/ADAE), the same version of dictionary datasets will be 
implemented for conversion from SI to SDTM.
 
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Reporting Process
Generation of RTF Files

RTF files will be generated for the TLFs. But only compiled PDF file will be used in the delivery.
Reporting Standards
General

The current GSK Integrated Data Standards Library (IDSL) will be applied for reporting, unless 
otherwise stated:
o
4.03 to 4.23: General Principles
o
5.01 to 5.08: Principles Related to Data Listings
o
6.01 to 6.11: Principles Related to Summary Tables
o
7.01 to 7.13: Principles Related to Graphics 
Formats

All data will be reported according to the actual treatment the subject received unless 
otherwise stated.

GSK IDSL Statistical Principles (5.03 & 6.06.3) for decimal places (DP’s) will be adopted for 
reporting of data based on the raw data collected.

Numeric data will be reported at the precision collected on the eCRF.

The reported precision from non eCRF sources will follow the IDSL statistical principles but 
may be adjusted to a clinically interpretable number of DP’s
Planned and Actual Time

Reporting for tables, figures and formal statistical analyses :

Nominal visits collected on the eCRF will be used in figures, summaries, statistical 
analyses and calculation of any derived parameters, unless otherwise stated.

The impact of any major deviation from the planned assessment times and/or scheduled 
visit days on the analyses and interpretation of the results will be assessed as appropriate.

Reporting for Data Listings: 

Planned and actual time relative to study drug dosing will be shown in Pharmacokinetic
listings (Refer to IDSL Statistical Principle 5.05.1).

Unscheduled or unplanned readings will be presented within the subject’s listings. 

Visits outside the protocol defined time-windows (i.e. recorded as protocol deviations) will 
be included in listings but omitted from figures, summaries and statistical analyses.
Unscheduled Visits

Unscheduled visits will not be included in summary tables.

Unscheduled visits will not be included in figures.

All unscheduled visits will be included in listings.
Descriptive Summary Statistics
Continuous Data
Refer to IDSL Statistical Principle 6.06.1
Categorical Data
N, n, frequency, %
Reporting of Pharmacokinetic Concentration Data
Descriptive 
Summary Statistics
Refer to IDSL Statistical Principle 6.06.1
Assign zero to NQ values (Refer to GUI_51487 for further details)
 
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Reporting Standards
Reporting of Pharmacokinetic Parameters

Reporting for PK tables, figures and listings:

Planned time relative to dosing will be used in mean concentration-time figures and 
summaries, and actual times will be used for individual concentration-time figures.

The impact of any major deviation from the planned assessment times and/or scheduled 
visit days on the analyses and interpretation of the results will be assessed as appropriate.

Visits outside the protocol defined time-windows (i.e. recorded as protocol deviations) will 
be included in all PK figures, summaries and listings.
Descriptive 
Summary Statistics 
(Log Transformed)
N, n, geometric mean, 95% CI of geometric mean, standard deviation (SD) 
of logged data and [between and or within] geometric coefficient of variation 
(CVb (%)) will be reported.
CVb (%) = √ (exp(SD2) - 1) * 100
(SD = SD of log transformed data) 
Parameters Not 
Being Log 
Transformed
tmax, first point, last point, and number of points used in the determination of 
λz.
Summary Tables
The following PK parameters will not be summarised: first point, last point, 
and number of points used in the determination of λz
Listings
Additionally, include the first point, last point and number of points used in 
the determination of lambda_z for listings.
Graphical Displays

Refer to IDSL Statistical Principals 7.01 to 7.13.
 
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10.6.
Appendix 6: Derived and Transformed Data
10.6.1.
General
Multiple Measurements at One Time Point

If there are two values within a time window the value closest to the target day for that window 
will be used. If values are the same distance from the target then the mean will be taken.

Subjects having both High and Low values for Normal Ranges at any post-baseline visits for 
safety parameters will be counted in both the High and Low categories of “Any visit post-
baseline” row of related summary tables. This will also be applicable to relevant Potential 
Clinical Importance summary tables.
Study Day

Calculated as the number of days from Day 1 Visit:

Ref Date = Missing           → Study Day = Missing 

Ref Date < Date of Day 1 Visit   → Study Day = Ref Date –Date of Day 1 Visit

Ref Date ≥Date of Day 1 Visit
→ Study Day = Ref Date –Date of Day 1 Visit + 1
10.6.2.
Study Population
Demographics
Age

As the month and date of birth will not be collected in the study, the age will be calculated as 
Year of ICF – Year of Birth;

Birth date will be presented in listings as ‘YYYY’.
Body Mass Index (BMI)

Calculated as Weight (kg) / [Height (m)2]
Extent of Exposure

Duration of exposure to study drug will be calculated based on the formula:
o
The duration of exposure for oral phase is defined as the number of days starting from the 
first oral dose to the last oral dose. 
o
Duration of exposure for injection phase is defined as the number of injections (1, 2, 3, 4 or 
5)
o
Overall exposure to CAB is defined as number of days from the first oral dose to 8 weeks 
following the participant’s last injection. If a participant does not enter the injection phase, 
the overall CAB exposure for the study will be defined as the number of days from the first 
oral dose to the last oral dose.
o
Overall exposure to the study (for safety evaluation) is defined as number of days from the 
first dose to last visit (including unscheduled visit) in days.

The cumulative dose will be based on the formula:
o
Cumulative dose in oral phase is defined as (number of tablets dispensed – number of 
tablets returned) * 30 mg
 
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Extent of Exposure
o
Cumulative dose in injection phase is defined as number of injections * 600 mg
10.6.3.
Safety
Adverse Events
Adverse Events of Special Interest

Seizures and seizure like events

Decline in Renal Function

Proximal Renal Tubule Dysfunctions

Proteinuria

Hepatoxicity

Hypersensitivity Reactions

Injection Site Reactions

Impact on Creatinine

Neuropsychiatirc Events
The adverse events of special interest that were used for data summaries are provided in Section 
10.16
Laboratory Parameters

HIV-1 RNA: For summaries and analyses which use HIV-1 RNA level as a continuous measure, 
the logarithm to base 10 of the value will be used.

If a laboratory value which is expected to have a numeric value for summary purposes, has a 
non-detectable level reported in the database, where the numeric value is missing, but typically 
a character value starting with ‘<x’ or ‘>x’ (or indicated as less than x or greater than x in the 
comment field) is present, the number of significant digits in the observed values will be used to 
determine how much to add or subtract in order to impute the corresponding numeric value. 
o
Example 1: 2 Significant Digits = ‘< x’ becomes x – 0.01
o
Example 2: 1 Significant Digit = ‘> x’ becomes x + 0.1
o
Example 3: 0 Significant Digits = ‘< x’ becomes x – 1
 
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10.7.
Appendix 7: Premature Withdrawals & Handling of Missing 
Data
10.7.1.
Premature Withdrawals
Element
Reporting Detail
General

Subject study completion (i.e. as specified in the protocol) was defined as 
completing all phases of the study including week 89.

If participants prematurely discontinue the oral phase of the study, additional
replacement participants may be recruited at the discretion of the Sponsor. 
Participants who enterthe injection phase of the study will not be replaced

All available data from subjects who were withdrawn from the study will be listed 
and all available planned data will be included in summary tables and figures, 
unless otherwise specified.
10.7.2.
Handling of Missing Data
Element
Reporting Detail
General

Missing data occurs when any requested data is not provided, leading to blank 
fields on the collection instrument:
o
These data will be indicated using a “blank” in subject listing displays. 
Unless all data for a specific visit are missing in which case the data is 
excluded from the table. 
o
Answers such as “Not applicable” and “Not evaluable” are not considered to 
be missing data and should be displayed as such.

Missing endpoints which are not covered in the following rule will not be imputed, 
unless otherwise specified.
Outliers

Any subjects excluded from the summaries and/or statistical analyses will be 
documented along with the reason for exclusion in the clinical study report.
10.7.2.1.
Handling of Missing Dates
Element
Reporting Detail
General
Partial dates will be displayed as captured in subject listing displays.
Adverse 
Events

Completely missing start or end dates will remain missing, with no imputation 
applied. Consequently, time to onset and duration of such events will be 
missing.

Partial missing start or end dates will be imputed using the convention specified 
in Section 10.7.2.2 Handling of Partial Dates
10.7.2.2.
Handling of Partial Dates
Element
Reporting Detail
Concomitant 
Partial dates for any concomitant medications recorded in the CRF will be 
 
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Element
Reporting Detail
Medications
imputed using the following convention:
o
If the partial date is a start date, a '01' will be used for the day and 'Jan' will 
be used for the month
o
If the partial date is a stop date, a '28/29/30/31' will be used for the day 
(dependent on the month and year) and 'Dec' will be used for the month.

The recorded partial date will be displayed in listings.
Adverse 
Events

Any partial dates for adverse events will be raised to data management. If the 
full date cannot be ascertained, the following assumptions will be made:
o
If the partial date is a start date, a '01' will be used for the day and 'Jan' will 
be used for the month. 
o
However, if these results in a date prior to Week 1 Day 1 and the event 
could possibly have occurred during treatment from the partial information, 
then the Week 1 Day 1 date will be assumed to be the start date. The AE 
will then be considered to start on-treatment (worst case).
o
If the partial date is a stop date, a '28/29/30/31' will be used for the day 
(dependent on the month and year) and 'Dec' will be used for the month, 
unless this is after the stop date of study treatment; in this case the study 
treatment stop date will be used.

The recorded partial date will be displayed in listings.
10.7.2.3.
Handling of Missing Data for Statistical Analysis
Element
Reporting Detail
N/A
No statistical analysis is planned, unless otherwise specified.
 
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10.8.
Appendix 8: Values of Potential Clinical Importance
10.8.1.
Laboratory Values
Haematology
Laboratory Parameter
Units
Category
Clinical Concern Range
Low Flag (< x)
High Flag (>x)
Hematocrit 
Ratio of 1
Male
0.54
Female
0.54
∆from BL
↓0.075
Hemoglobin 
g/L
Male
180
Female
180
∆from BL
↓25
Lymphocytes 
x109/ L
0.8
Neutrophil Count 
x109/ L
1.5
Platelet Count 
x109/ L
100
550
While Blood Cell Count (WBC)
x109/ L
3
20
Clinical Chemistry
Laboratory Parameter
Units
Category
Clinical Concern Range
Low Flag (< x)
High Flag (>x)
Albumin 
g/L
30
Calcium
mmol/L
2
2.75
Creatinine
umol/L
∆from BL
↑ 44.2
Glucose
mmol/L
3
9
Phosphorus
mmol/L
0.8
1.6
Potassium
mmol/L
3
5.5
Sodium
mmol/L
130
150
Total CO2
mmol/L
18
32
Liver Function
Test Analyte
Units
Category
Clinical Concern Range
ALT/SGPT 
U/L
High
2x ULN
AST/SGOT 
U/L
High
2x ULN
AlkPhos 
U/L
High
2x ULN
T Bilirubin 
µmol/L
High
1.5xULN
T. Bilirubin + ALT
µmol/L
High
1.5xULN T. Bilirubin
+
U/L
2x ULN ALT
 
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10.8.2.
ECG
ECG Parameter
Units
Clinical Concern Range
Lower
Upper
Absolute
Absolute QTc Interval
msec
> 450 [1]
> 450 [1]
≤ 479 [1]
≥480 [1]
≤ 499 [1]
≥500 [1]
Absolute PR Interval
msec
< 110 [1]
> 220 [1]
Absolute QRS Interval
msec
< 75 [1]
> 110 [1]
Change from Baseline
Increase from Baseline QTc
msec
> 60 [1]
msec
> 30 [1]
≤ 59 [1]
msec
≥ 60 [1]
NOTES: [Remove footnotes for RAP development]
1.
Represent standard ECG values of PCI for HV studies
2.
Represent further subdivisions of ECG values for analysis whereby the RAP team needs to decide whether these 
need to be generated in addition to standard ECG values being flagged. IF not required, then delete.
10.8.3.
Vital Signs
Vital Sign Parameter
(Absolute)
Units
Clinical Concern Range
Lower
Upper
Systolic Blood Pressure
mmHg
< 85
> 160
Diastolic Blood Pressure
mmHg
< 45
> 100
Heart Rate
bpm
< 40
> 110
Vital Sign Parameter
(Change from Baseline)
Units
Clinical Concern Range
Decrease
Increase
Lower
Upper
Lower
Upper
Systolic Blood Pressure
mmHg
≥20
≥40
≥ 20
≥ 40
Diastolic Blood Pressure
mmHg
≥10
≥20
≥ 10
≥ 20
Heart Rate
bpm
≥15
≥30
≥ 15
≥ 30
NOTES: [Remove footnotes for RAP development]
Represent further subdivisions of BP & HR for analysis whereby the RAP team needs to decide whether these need to 
be generated in addition to standard absolute BP & HR values being flagged. IF not required, then delete.
 
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10.9.
Appendix 9: Multicenter Studies
10.9.1.
Methods for Handling Centres

In this multicentre study, enrolment will be presented by investigative site.
 
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10.10.
Appendix 10: Examination of Covariates, Subgroups & 
Other Strata
10.10.1.
Handling of Covariates, Subgroups & Other Strata

Demographic covariates that may be used in descriptive summaries and statistical
analyses, some of which may also be used for subgroup analyses.

Additional covariates of clinical interest may also be considered. 
 
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10.11.
Appendix 11: Multiple Comparisons & Multiplicity
10.11.1.
Handling of Multiple Comparisons & Multiplicity
Not applicable.
 
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10.12.
Appendix 12: Model Checking and Diagnostics for 
Statistical Analyses
10.12.1.
Statistical Analysis Assumptions
Endpoint(s)

PK endpoint C
Analysis

ANOVA (primary)

Model assumptions will be applied, but appropriate adjustments maybe made based on the 
data.

The Kenward and Roger method for approximating the denominator degrees of freedom and 
correcting for bias in the estimated variance-covariance of the fixed effects will be used.
 
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10.13.
Appendix 13: Abbreviations & Trade Marks
10.13.1.
Abbreviations
Abbreviation
Description
ADaM
Analysis Data Model
AE
Adverse Event
AUC(0-)
Area under the concentration-time curve (AUC) over the dosing interval
C
The observed concentration at the end of the dosing interval
CAB
Cabotegravir
CAB LA
Cabotegravir Long Acting
CDISC
Clinical Data Interchange Standards Consortium
CI
Confidence Interval
CL/F
The apparent clearance (adjusted for bioavailability, F)
Cmax
Maximum observed concentration
CSR
Clinical Study Report
CTMS
Clinical Trial Management System
CVb
Coefficient of Variation (Between)
DOB
Date of Birth
DP
Decimal Places
eCRF
Electronic Case Record Form
GSK
GlaxoSmithKline
HIV
Human Immunodeficiency Virus
ICH
International Conference on Harmonisation
IDSL
Integrated Data Standards Library
IM
Intramuscular
IP
Investigational Product
MedDRA
Medical Dictionary for Regulatory Activities
mg
Milligrams
PCI
Potential Clinical Importance
PK
Pharmacokinetic
PrEP
Pre-exposure prophylaxis
QC
Quality Control
RAP
Reporting & Analysis Plan
SAC
Statistical Analysis Complete
SAS
Statistical Analysis Software
SD
Standard deviation
SDTM
Study Data Tabulation Model
SOP
Standard Operation Procedure
t½
Terminal phase half-life
tmax
Time to first occurrence of Cmax
TFL
Tables, Figures & Listings 
Vz/F
The volume of distribution associated with the terminal phase (adjusted 
for bioavailability, F)
λz
Terminal-phase rate constant
 
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10.13.2.
Trademarks
Trademarks of the GlaxoSmithKline 
Group of Companies
Trademarks not owned by the 
GlaxoSmithKline Group of Companies
NONE
Phoenix WinNonlin
SAS
 
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10.14.
Appendix 14: List of Data Displays
10.14.1.
Data Display Numbering
The following numbering will be applied for RAP generated display according to ICH 
standards:
Section
Tables
Figures
Study Population
1.1 to 1.10
NA
Safety
2.1 to 2.32
NA
Pharmacokinetic
3.1 to 3.11
3.1-3.8
Section
Listings
ICH Listings
1-51
10.14.2.
Mock Example Shell Referencing
Non IDSL specifications will be referenced as indicated and if required an example 
mock-up displays provided in Appendix 15: Example Mock Shells for Data Displays.
Section
Figure
Table
Listing
Study Population
POP_Fn
POP_Tn
POP_Ln
Safety
SAFE_Fn
SAFE_Tn
SAFE_Ln
Pharmacokinetic
PK_Fn
PK_Tn
PK_Ln
NOTES: 

Non-Standard displays are indicated in the ‘IDSL / TST ID / Example Shell’ or ‘Programming Notes’ column as 
‘[Non-Standard] + Reference.’
10.14.3.
Deliverable [Priority]
Delivery [Priority] [1]
Description
W41 SAC [1]
Primary Statistical Analysis Complete at Week 41
SAC [1]
Final Statistical Analysis Complete at Week 89
NOTES: 
1.
Indicates priority (i.e. order) in which displays will be generated for the reporting effort.
 
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10.14.4.
Study Population Tables
Study Population Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable [Priority]
Study Population, Disposition and Demographics
1.1
Screened
SP1
Summary of Study Population
W41 SAC [1], 
SAC [1]
1.2
Screened
ES6
Summary of Screen Status and Reasons for Screen 
Failures
W41 SAC [1], 
SAC [1]
1.3
Screened
ES1
Summary of Subject Disposition for the Subject Conclusion 
Record
W41 SAC [1], SAC [1]
1.4
Safety
SD1
Summary of Treatment Status and Reasons for 
Discontinuation of Study Treatment
W41 SAC [1], SAC [1]
1.5
Safety
DM1
Summary of Demographic Characteristics
W41 SAC [1], SAC [1]
Medical History and Concomitant Medications
1.6
Safety
MH4
Summary of Medical Conditions
.
W41 SAC [1], SAC [1]
1.7
Safety
CM1
Summary of Prior Medications
W41 SAC [1], SAC [1]
1.8
Safety
CM1
Summary of Concomitant Medications
W41 SAC [1], SAC [1]
Protocol Deviations
1.9
Safety
IE1
Summary of Inclusion/Exclusion Criteria Deviations
W41 SAC [1], SAC [1]
1.10
Safety
DV1A
Summary of Important Protocol Deviations
W41 SAC [1], SAC [1]
 
 
 
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10.14.5.
Safety Tables
Safety: Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable [Priority]
Exposure
2.1
Safety 
EX1
Summary of Extent of Exposure
W41 SAC [1], 
SAC [1]
Injection Site Reactions
2.2
Safety 
Injection
Summary of Injection Site Reaction
W41 SAC [1], 
SAC [1]
Adverse Events
2.3
Safety
AE1
Summary of All Adverse Events by System Organ Class
and Preferred Term
W41 SAC [1], SAC [1]
2.4
Safety
AE5B
Summary of All Adverse Events by Maximum Grade by 
System Organ Class and Preferred Term
W41 SAC [1], SAC [1]
2.5
Safety
AE3
Summary of All Grade 2 or Higher Adverse Events by 
Overall Frequency
W41 SAC [1], SAC [1]
2.6
Safety
AE3
Summary of Serious Adverse Events
W41 SAC [1], SAC [1]
2.7
Safety
AE16
Summary of Serious Adverse Events by System Organ 
Class and Preferred Term (Number of Subjects and 
Occurrences)
W41 SAC [1], SAC [1]
2.8
Safety
AE3
Summary of Adverse Events Leading to Permanent 
Discontinuation of Study Drug or Withdrawal from Study
W41 SAC [1], SAC [1]
2.9
Safety
AE1
Summary of Drug-Related Adverse Events
W41 SAC [1], SAC [1]
2.10
Safety
AE1
Summary of Drug-Related Serious Adverse Events
W41 SAC [1], SAC [1]
 
 
 
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Safety: Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable [Priority]
2.11
Safety
AE3
Summary of Drug-related Grade 2 or Higher Adverse 
Events
W41 SAC [1], SAC [1]
2.12
Safety
AE3
Summary of Common (>=5%) Adverse Events by Overall 
Frequency
W41 SAC [1], SAC [1]
2.13
Safety
AE15
Summary of Common (>=5%) Non-Serious Adverse 
Events by System Organ Class and Preferred Term 
(Number of Subjects and Occurrences)
W41 SAC [1], SAC [1]
2.14
Safety
AE3
Summary of Common (>=5%) Grade 2-4 Adverse Events 
by Overall Frequency
W41 SAC [1], SAC [1]
2.15
Safety
AE3
Summary of Common (>=5%) Drug-Related Grade 2-4 
Adverse Events by Overall Frequency
W41 SAC [1], SAC [1]
Laboratory Tests
2.16
Safety
Summary of Grade 2 or Higher Laboratory Tests
W41 SAC [1], SAC [1]
2.17
Safety
ES11
Summary of Characteristics of Adverse Events of Special 
Interest
W41 SAC [1], SAC [1]
2.18
Safety
LB1
Summary of Change from Baseline in Hematology and 
Coagulation Data
W41 SAC [1], SAC [1]
2.19
Safety
LB1
Summary of Change from Baseline in Chemistry Data and 
Fasting Lipid Profile
W41 SAC [1], SAC [1]
2.20
Safety
UR3
Summary of Urinalysis and Urine Chemistry Results
W41 SAC [1], SAC [1]
2.21
Safety
LB18
Summary of Hematology and Coagulation Grade Shifts 
from Baseline Grade
W41 SAC [1], SAC [1]
2.22
Safety
LB18
Summary of Chemistry and Fasting Lipid Profile Grade 
Shifts from Baseline Grade
W41 SAC [1], SAC [1]
 
 
 
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Safety: Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable [Priority]
2.23
Safety
LB18
Summary of Urinalysis Grade Shifts from Baseline Grade
W41 SAC [1], SAC [1]
Vital Signs
2.24
Safety
VS1
Summary of Change from Baseline in Vital Signs
W41 SAC [1], SAC [1]
2.25
Safety
VS8
Summary of Vital Sign Shifts from Baseline with Respect to 
Clinical Concern Range
W41 SAC [1], SAC [1]
Liver Events
2.26
Safety
LIVER1
Summary of Liver Events Reporting
W41 SAC [1], SAC [1]
2.27
Safety
LIVER10
Summary of Hepatobiliary Laboratory Abnormalities
W41 SAC [1], SAC [1]
 
 
 
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10.14.6.
Tolerability Tables
Tolerability: Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Tolerability of CAB Injection
2.28
Safety 
Injection
Summary of HIV-Prevention Treatment Satisfaction Scores
W41 SAC [1], 
SAC [1]
10.14.7.
Acceptability Tables
Acceptability: Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Acceptability of the CAB Injection
2.29
Safety
Summary of Acceptability of the CAB LA
W41 SAC [1],
SAC [1]
 
 
 
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10.14.8.
Pharmacokinetic Tables
Pharmacokinetic : Tables
No.
Population
IDSL / TST ID /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Oral Phase
3.1
Oral PK 
PKCT1
Summary of CAB Plasma Pharmacokinetic Concentration-
Time Data – Oral Phase
SAC [1]
3.2
Oral PK 
PKPT4
Summary of Derived CAB Plasma Pharmacokinetic 
Parameters (Non-Transformed) – Oral Phase
Parameters with units 
SAC [1]
3.3
Oral PK 
PKPT4
Summary of Derived CAB Plasma Pharmacokinetic 
Parameters (Log-Transformed) – Oral Phase
Parameters with units 
SAC [1]
Injection Phase (up to Week 41)
3.4
Injection
(Week 41) PK
PKCT1
Summary of CAB Plasma Pharmacokinetic Concentration-
Time Data – Injection Phase (up to Week 41)
W41 SAC [1], 
SAC [1]
3.5
Injection
(Week 41) PK
PKPT4
Summary of Derived CAB Plasma Pharmacokinetic 
Parameters (Non-Transformed) – Injection Phase (up to 
Week 41)
Parameters with units 
W41 SAC [1],
SAC [1]
3.6
Injection
(Week 41) PK
PKPT4
Summary of Derived CAB Plasma Pharmacokinetic 
Parameters (Log-Transformed) – Injection Phase (up to 
Week 41)
Parameters with units 
W41 SAC [1] 
SAC [1]
3.7
Injection
(Week 41) PK
PKPT3
Statistical Analysis of CAB Plasma Accumulation –
Injection Phase (up to Week 41)
Conly for Injection 
Phase at Week 41.
W41 SAC [1], 
SAC [1]
3.8
Injection
(Week 41) PK
PKPT3
Statistical Analysis of CAB Plasma Steady-state Pre-dose 
Concentrations – Injection Phase (up to Week 41)
Conly for Injection 
Phase at Week 41.
W41 SAC [1], 
SAC [1]
 
 
 
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Pharmacokinetic : Tables
No.
Population
IDSL / TST ID /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Injection Phase (up to Week 89)
3.9
Injection
(Week 89) PK
PKCT1
Summary of CAB Plasma Pharmacokinetic Concentration-
Time Data – Injection Phase (up to Week 89)
SAC [1]
3.10
Injection
(Week 89) PK
PKPT4
Summary of Derived CAB Plasma Pharmacokinetic 
Parameters (Non-Transformed) – Injection Phase (up to 
Week 89)
Parameters with units 
SAC [1]
3.11
Injection
(Week 89) PK
PKPT4
Summary of Derived CAB Plasma Pharmacokinetic 
Parameters (Log-Transformed) – Injection Phase (up to 
Week 89)
Parameters with units 
SAC [1]
 
 
 
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10.14.9.
Pharmacokinetic Figures
Pharmacokinetic : Figures
No.
Population
IDSL / TST ID /
Example Shell
Title
Programming 
Notes
Deliverable 
[Priority]
Oral Phase
3.1
Oral PK 
PKCF1P
Individual CAB Plasma Concentration-Time Plots (Linear and 
Semi-Logarithmic) – Oral Phase
SAC [1]
3.2
Oral PK 
PKCF4
Mean (±SD) CAB Plasma Concentration-Time Plots (Linear and 
Semi-Logarithmic) – Oral Phase
SAC [1]
Injection Phase (up to Week 41)
3.3
Injection
(Week 41) PK
PKCF1P
Individual CAB Plasma Concentration-Time Plots (Linear and 
Semi-Logarithmic) – Injection Phase (up to Week 41)
W41 SAC [1], 
SAC [1]
3.4
Injection
(Week 41) PK
PKCF4
Mean (±SD) CAB Plasma Concentration-Time Plots (Linear and 
Semi-Logarithmic) – Injection Phase (up to Week 41)
W41 SAC [1], 
SAC [1]
3.5
Injection
(Week 41) PK
PK26
Individual CAB Plasma Pre-dose Concentration versus Week (Linear 
and Semi-Logarithmic) – Injection Phase (up to Week 41)
W41 SAC [1], 
SAC [1]
3.6
Injection
(Week 41) PK
PK27
Median (range) CAB Plasma Pre-dose Concentration versus Week
(Linear and Semi log) – Injection Phase (up to Week 41)
W41 SAC [1], 
SAC [1]
Injection Phase (up to Week 89)
3.7
Injection
(Week 89) PK
PKCF1P
Individual CAB Plasma Concentration-Time Plots (Linear and 
Semi-Logarithmic) – Injection Phase (up to Week 89)
SAC [1]
3.8
Injection
(Week 89) PK
PKCF4
Mean (±SD) CAB Plasma Concentration-Time Plots (Linear and 
Semi-Logarithmic) – Injection Phase (up to Week 89)
SAC [1]
 
 
 
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10.14.10. ICH Listings
ICH: Listings
No.
Population
IDSL / TST 
ID / Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Study Population, Disposition and Demographics
1
Screened
SP3
Listing of Subjects Excluded from Any 
Population 
W41 SAC [1], SAC 
[1]
2
Screened
ES7
Listing of Reasons for Screen Failure
W41 SAC [1], SAC 
[1]
3
Safety
ES2
Listing of Reasons for Withdrawal
W41 SAC [1], SAC 
[1]
4
Safety
SD2
Listing of Study Drug Discontinuation 
Record
W41 SAC [1], SAC 
[1]
5
Safety
DM2
Listing of Demographic 
Characteristics
W41 SAC [1], SAC 
[1]
6
Safety
EX3
Listing of Exposure Data – Oral Dose
W41 SAC [1], SAC 
[1]
7
Safety
Listing of Exposure Data – Injection
W41 SAC [1], SAC 
[1]
Medical History and Concomitant Medication
8
Safety
MH2
Listing of Medical Conditions
W41 SAC [1], SAC 
[1]
9
Safety
CM5
Listing of Prior Medications
W41 SAC [1], SAC 
[1]
10
Safety
CM5
Listing of Concomitant Medications
W41 SAC [1], SAC 
[1]
 
 
 
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ICH: Listings
No.
Population
IDSL / TST 
ID / Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Protocol Deviations
11
Safety
IE3
Listing of Subjects with 
Inclusion/Exclusion Criteria Deviations
W41 SAC [1], SAC 
[1]
12
Safety
DV2
Listing of Important Protocol 
Deviations
W41 SAC [1], SAC 
[1]
Injection Site Reaction
13
Safety Injection
Listing of Injection Site Reaction –
Daily Diary Card 1
W41 SAC [1],
SAC [1]
14
Safety Injection
Listing of Injection Site Reaction –
Daily Diary Card 2
W41 SAC [1],
SAC [1]
Adverse Events
15
Safety
AE7
Listing of Subject Numbers for 
Individual Adverse Events
W41 SAC [1],
SAC [1]
16
Safety
AE8
Listing of All Adverse Events
W41 SAC [1], SAC 
[1]
17
Safety
AE8CPA
Listing of Serious Adverse Events 
(Fatal and Non-Fatal) 
W41 SAC [1], SAC 
[1]
18
Safety
AE8
Listing of Grader 2 or Higher Adverse 
Events
W41 SAC [1], SAC 
[1]
19
Safety
AE8
Listing of All Adverse Events Leading 
to Premature Discontinuation of Study 
Drug or Withdrawal from Study
W41 SAC [1], SAC 
[1]
20
Safety
AE8
Listing of Adverse Events of Special 
Interest
W41 SAC [1], SAC
[1]
 
 
 
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ICH: Listings
No.
Population
IDSL / TST 
ID / Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
21
Safety
Listing of Possible Suicidality-Rated 
Adverse Events
W41 SAC [1], SAC 
[1]
22
Safety
AE2
Listing of Relationship Between 
System Organ Classes and Verbatim 
Text
W41 SAC [1], SAC 
[1]
23
Safety
AE14
Listing of Reasons for Considering as
a Serious Adverse Event
W41 SAC [1], SAC 
[1]
Deaths
24
Safety
Listing of Death
W41 SAC [1], SAC 
[1]
Laboratory Tests
25
Safety
LB5
Listing of Chemistry Data and Fasting 
Lipid Profile
W41 SAC [1], SAC 
[1]
26
Safety
LB5
Listing of Hematology and 
Coagulation Data
W41 SAC [1], SAC 
[1]
27
Safety
UR2a
Listing of Urinalysis and Urine 
Chemistry Data
W41 SAC [1], SAC 
[1]
28
Safety
LB5
Listing of Laboratory Data for Subjects 
with Grade 2 or Higher Abnormalities
W41 SAC [1], SAC 
[1]
29
Safety
LB14
Listing of HIV Tests
W41 SAC [1], SAC 
[1]
30
Safety
LB5
Listing of Local Lab Data
W41 SAC [1], SAC 
[1]
 
 
 
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ICH: Listings
No.
Population
IDSL / TST 
ID / Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Vital Sign
31
Safety
VS4
Listing of Vital Signs
W41 SAC [1], SAC 
[1]
32
Safety
VS4
Listing of Vital Signs for Subjects with 
Any Value of Potential Clinical 
Importance
W41 SAC [1], SAC 
[1]
ECG’s
33
Safety
Listing of ECG Results
W41 SAC [1], SAC 
[1]
Social Harm
34
Safety
Listing of Social Harm
W41 SAC [1], SAC 
[1]
Cardiovascular Event
35
Safety
Listing of Cardiovascular Event
W41 SAC [1], SAC
[1]
Liver Event
36
Safety
Listing of Liver Event
W41 SAC [1], SAC 
[1]
Tolerability of CAB Injection
37
Safety Injection 
Listing of HIV-Prevention Treatment 
Satisfaction Questionnaire
W41 SAC [1], SAC 
[1]
 
 
 
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ICH: Listings
No.
Population
IDSL / TST 
ID / Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Acceptability of the CAB Injection
38
Safety 
Listing of Acceptability of the CAB LA
W41 SAC [1],
SAC [1]
Pharmacokinetic
39
Oral PK 
PKCL1P
Listing of CAB Plasma
Pharmacokinetic Concentration-Time 
Data – Oral Phase
Please list all the concentration data including 
unscheduled.
SAC [1]
40
Oral PK 
PKPL1P
Listing of Derived CAB Plasma 
Pharmacokinetic Parameters – Oral 
Phase
SAC [1]
41
Injection
(Week 41) PK
PKCL1P
Listing of CAB Plasma
Pharmacokinetic Concentration-Time 
Data – Injection Phase (up to Week 
41)
Please list all the concentration data including 
unscheduled.
W41 SAC [1], 
SAC [1]
42
Injection
(Week 41) PK
PKPL1P
Listing of Derived CAB Plasma 
Pharmacokinetic Parameters –
Injection Phase (up to Week 41)
W41 SAC [1],
SAC [1]
43
Injection
(Week 89) PK
PKCL1P
Listing of CAB Plasma
Pharmacokinetic Concentration-Time 
Data – Injection Phase (up to Week 
89)
Please list all the concentration data including 
unscheduled.
SAC [1]
44
Injection
(Week 89) PK
PKPL1P
Listing of Derived CAB Plasma 
Pharmacokinetic Parameters –
Injection Phase (up to Week 89)
SAC [1]
 
 
 
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10.14.11. Non-ICH Listings
Non-ICH: Listings
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
 
 
 
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10.15.
Appendix 15: Example Mock Shells for Data Displays
Data Display Specification will be made available on Request
 
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10.16.
Appendix 16: Adverse Events of Special Interest Used for 
Data Summaries
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AESI Item
Product of Interest
PT Selection*
Hepatic Safety Profile: Assessment of risk of 
hepatoxicity 
CAB +RPV 
Sub- SMQ** x2
Hypersensitivity reactions (HSR)
CAB
SMQ (modified) plus  selected 
PTs from HLGT
Severe cutaneous adverse reactions (SCAR) 
RPV
SMQ plus selected PTs from 
HLTs
Prolongation of the corrected QT interval of the ECG 
in supratherapeutic doses
RPV
SMQ plus selected PT from HLT
Neuropsychiatric Events
•Suicidal ideation/behaviour
•Depression
•Bipolar disorder
•Psychosis
•Mood disorders
•Anxiety
•Sleep disorders
Injection Site Reactions (ISR)
CAB +RPV 
Use CRF terms for ISRs
Seizures and seizure-like events
CAB
SMQ plus selected PTs from 
HLTs
Impact on Creatinine/Decline in Renal function
CAB+RPV
SMQ plus selected PTs from HLT
Safety in Pregnancy
CAB
Use AE terms co-reported in 
pregnancy exposures to CAB
Protenuria 
CAB+RPV
SMQ 
Proximal Renal Tubule Dysfunctions
CAB+RPV
SMQ 
* All PTs, SMQs, HLT, HLGTs from MedDRA V21
** All SMQs  use narrow terms unless otherwise
specified
CAB +RPV 
SMQ , Sub- SMQ or HLGT
 
 
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20000013
PT
PT Code
Acquired hepatocerebral degeneration
10080860
Acute hepatic failure
10000804
Acute on chronic liver failure
10077305
Acute yellow liver atrophy
10070815
Ascites
10003445
Asterixis
10003547
Bacterascites
10068547
Biliary cirrhosis
10004659
Biliary fibrosis
10004664
Cholestatic liver injury
10067969
Chronic hepatic failure
10057573
Coma hepatic
10010075
Cryptogenic cirrhosis
10063075
Diabetic hepatopathy
10071265
Drug-induced liver injury
10072268
Duodenal varices
10051010
Gallbladder varices
10072319
Gastric variceal injection
10076237
Gastric variceal ligation
10076238
Gastric varices
10051012
Gastric varices haemorrhage
10057572
Hepatectomy
10061997
Hepatic atrophy
10019637
Hepatic calcification
10065274
Hepatic cirrhosis
10019641
Hepatic encephalopathy
10019660
Hepatic encephalopathy prophylaxis
10066599
Hepatic failure
10019663
Hepatic fibrosis
10019668
Hepatic hydrothorax
10067365
Hepatic infiltration eosinophilic
10064668
Hepatic lesion
10061998
Hepatic necrosis
10019692
Hepatic steato-fibrosis
10077215
Hepatic steatosis
10019708
Hepatitis fulminant
10019772
Hepatobiliary disease
10062000
Hepatocellular foamy cell syndrome
10053244
Hepatocellular injury
10019837
Hepatic failure, fibrosis and cirrhosis and other liver damage-
related conditions (SMQ)
Notes: Medical concept of hepatic failure and hepatitis. Sub- SMQs (1) 'Hepatic failure, fibrosis and 
cirrhosis and other liver damage-related conditions' and  (2) 'Hepatitis, non-infectious', both of parent 
SMQ 'Hepatic Disorders'; only narrow terms selected from sub-SMQs. Some preferred terms e.g PT 
'hepatitis fulminant' are duplicated. 
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PT
PT Code
Hepatopulmonary syndrome
10052274
Hepatorenal failure
10019845
Hepatorenal syndrome
10019846
Hepatotoxicity
10019851
Intestinal varices
10071502
Intestinal varices haemorrhage
10078058
Liver and small intestine transplant
10052280
Liver dialysis
10076640
Liver disorder
10024670
Liver injury
10067125
Liver operation
10062040
Liver transplant
10024714
Lupoid hepatic cirrhosis
10025129
Minimal hepatic encephalopathy
10076204
Mixed liver injury
10066758
Nodular regenerative hyperplasia
10051081
Non-alcoholic fatty liver
10029530
Non-alcoholic steatohepatitis
10053219
Non-cirrhotic portal hypertension
10077259
Oedema due to hepatic disease
10049631
Oesophageal varices haemorrhage
10030210
Peripancreatic varices
10073215
Portal fibrosis
10074726
Portal hypertension
10036200
Portal hypertensive colopathy
10079446
Portal hypertensive enteropathy
10068923
Portal hypertensive gastropathy
10050897
Portal vein cavernous transformation
10073979
Portal vein dilatation
10073209
Portopulmonary hypertension
10067281
Primary biliary cholangitis
10080429
Regenerative siderotic hepatic nodule
10080679
Renal and liver transplant
10052279
Retrograde portal vein flow
10067338
Reye's syndrome
10039012
Reynold's syndrome
10070953
Splenic varices
10067823
Splenic varices haemorrhage
10068662
Steatohepatitis
10076331
Subacute hepatic failure
10056956
Varices oesophageal
10056091
Varicose veins of abdominal wall
10072284
White nipple sign
10078438
 
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20000010
PT
PT Code
Acute graft versus host disease in liver
10066263
Allergic hepatitis
10071198
Alloimmune hepatitis
10080576
Autoimmune hepatitis
10003827
Chronic graft versus host disease in liver
10072160
Chronic hepatitis
10008909
Graft versus host disease in liver
10064676
Hepatitis
10019717
Hepatitis acute
10019727
Hepatitis cholestatic
10019754
Hepatitis chronic active
10019755
Hepatitis chronic persistent
10019759
Hepatitis fulminant
10019772
Hepatitis toxic
10019795
Immune-mediated hepatitis
10078962
Ischaemic hepatitis
10023025
Lupus hepatitis
10067737
Non-alcoholic steatohepatitis
10053219
Radiation hepatitis
10051015
Steatohepatitis
10076331
Hepatitis, non-infectious (SMQ)
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Drug reaction with eosinophilia and systemic symptoms 
syndrome (SMQ) -  
20000225
PT
PT Code
Drug reaction with eosinophilia and systemic symptoms
10073508
Pseudolymphoma
10037127
Drug hypersensitivity
10013700
Hypersensitivity
10020751
Type IV Hypersensitivity reaction
10053613
Eosinophillia
10014950
Eye swelling
10015967
Eyelid oedema
10015993
Lip swelling
10024570
Angioedema
10002424
Circumoral oedema
10052250
Face oedema
10016029
Idiopathic angioedema
10073257
Lip oedema
10024558
Mouth swelling
10075203
Oedema mouth
10030110
Periorbital oedema
10034545
Swelling face
10042682
Notes: Medical concept of hypersensitivity reactions/DRESS. Only narrow terms selected from Category 
A of SMQ 'Drug reaction with eosinophilia and systemic symptoms syndrome'. Algorithmic approach 
for this SMQ  not used due to complexity in applying and poor specificity of remaining categories. 
Category A selected as PTs because more specific for concept (only narrow terms) and a pre-requisite 
for any combination in algorithmic search. Overlap of some preferred terms with SMQ 'Severe 
Cutaneous Adverse Reactions' . Plus  additional preferred terms selected from HGLT 'Allergic 
conditions' under SOC 'Immune system disorders'
PTs (Selective)
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20000020
PT
PT Code
Acute generalised exanthematous pustulosis
10048799
Cutaneous vasculitis
10011686
Dermatitis bullous
10012441
Dermatitis exfoliative
10012455
Dermatitis exfoliative generalised
10012456
Drug reaction with eosinophilia and systemic symptoms
10073508
Epidermal necrosis
10059284
Erythema multiforme
10015218
Exfoliative rash
10064579
Oculomucocutaneous syndrome
10030081
Skin necrosis
10040893
Stevens-Johnson syndrome
10042033
Toxic epidermal necrolysis
10044223
Toxic skin eruption
10057970
Eyelid rash
10074620
Genital rash
10018175
Mucocutaneous rash
10056671
Nodular rash
10075807
Perineal rash
10075364
Rash
10037844
Rash erythematous
10037855
Rash generalised
10037858
Rash macular
10037867
Rash maculo-papular
10037868
Rash maculovesicular
10050004
Rash morbilliform
10037870
Rash papular
10037876
Rash rubelliform
10057984
Rash scarlatiniform
10037890
Rash vesicular
10037898
Rash pruritic
10037884
Rash follicular
10037857
Rash pustular
10037888
Drug eruption
10013687
Notes: Medical concept of severe cutaneous adverse reactions. Only narrow terms from 
SMQ 'Severe cutaneous adverse reactions' selected. Plus  several additional preferred terms 
[only G3 and higher] selected from HLTs 'Rashes, eruptions and exanthems NEC', 'Pruritus 
NEC', 'Pustular conditions', 'Dermatitis ascribed to specific agent' all under SOC 'Skin and 
subcutaneous tissue disorders'
Severe cutaneous adverse reactions (SMQ)
PTs (Selective)G3 and higher
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Torsade de pointes/QT prolongation (SMQ)
20000001
PT
PT Code
Electrocardiogram QT interval abnormal
10063748
Electrocardiogram QT prolonged
10014387
Long QT syndrome
10024803
Long QT syndrome congenital
10057926
Torsade de pointes
10044066
Ventricular tachycardia
10047302
Electrocardiogram repolarisation abnormality
10052464
Notes: Medical concept of QT prolongation and complications. Only narrow terms from SMQ 'Torsade 
de pointes/QT prolongation' selected plus  one additional PT  under HLT  'ECG investigations'.
PTs (Selective)
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Suicide/self-injury (SMQ) 
20000037
PT
PT Code
Assisted suicide
10079105
Columbia suicide severity rating scale abnormal
10075616
Completed suicide
10010144
Depression suicidal
10012397
Intentional overdose
10022523
Intentional self-injury
10022524
Poisoning deliberate
10036000
Self-injurious ideation
10051154
Suicidal behaviour
10065604
Suicidal ideation
10042458
Suicide attempt
10042464
Suicide threat
10077417
Notes: Medical concept of suicidal ideation and behaviour. Sub-SMQ 'Suicide/self-injury' (SMQ) from 
parent SMQ of 'Depression and Suicide/Self Injury'. Only narrow terms from the sub-SMQ selected. 
 
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Depression (excl suicide and self injury) (SMQ) - 
20000167
PT
PT Code
Activation syndrome
10066817
Adjustment disorder with depressed mood
10001297
Adjustment disorder with mixed anxiety and depressed mood
10001299
Agitated depression
10001496
Anhedonia
10002511
Antidepressant therapy
10054976
Childhood depression
10068631
Decreased interest
10011971
Depressed mood
10012374
Depression
10012378
Depression postoperative
10012390
Depressive symptom
10054089
Dysphoria
10013954
Electroconvulsive therapy
10014404
Feeling guilty
10049708
Feeling of despair
10016344
Feelings of worthlessness
10016374
Helplessness
10077169
Major depression
10057840
Menopausal depression
10067371
Mixed anxiety and depressive disorder
10080836
Perinatal depression
10078366
Persistent depressive disorder
10077804
Post stroke depression
10070606
Postictal depression
10071324
Notes: Medical concept of Depression. Sub-SMQ 'Depression (excl suicide and self injury)' (SMQ) from parent 
SMQ of 'Depression and Suicide/Self Injury'.Only narrow terms from the sub-SMQ selected. 
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PT
PT Code
Bipolar I disorder
10004939
Bipolar II disorder
10004940
Bipolar disorder
10057667
Cyclothymic disorder
10011724
Hypomania
10021030
Mania
10026749
HLGT Manic and Bipolar mood disorders and 
disturbances
Notes: Medical concept of bipolar disorder. All preferred terms from HLGT 'Manic and Bipolar mood disorders and 
disturbances' under SOC 'Psychiatric disorders'.
 
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Psychosis and psychotic disorders (SMQ) 20000117
20000117
PT
PT Code
Acute psychosis
10001022
Alcoholic psychosis
10001632
Alice in wonderland syndrome
10001666
Brief psychotic disorder with marked stressors
10048549
Brief psychotic disorder without marked stressors
10056395
Brief psychotic disorder, with postpartum onset
10006362
Charles Bonnet syndrome
10063354
Childhood psychosis
10061040
Clang associations
10009232
Cotard's syndrome
10059591
Delusion
10012239
Delusion of grandeur
10012241
Delusion of reference
10012244
Delusion of replacement
10012245
Delusional disorder, erotomanic type
10012249
Delusional disorder, grandiose type
10012250
Delusional disorder, jealous type
10012251
Delusional disorder, mixed type
10012252
Delusional disorder, persecutory type
10053195
Delusional disorder, somatic type
10012254
Delusional disorder, unspecified type
10012255
Delusional perception
10012258
Dementia of the Alzheimer's type, with delusions
10012295
Depressive delusion
10063033
Derailment
10012411
Epileptic psychosis
10059232
Erotomanic delusion
10015134
Flight of ideas
10016777
Hallucination
10019063
Hallucination, auditory
10019070
Hallucination, gustatory
10019071
Hallucination, olfactory
10019072
Hallucination, synaesthetic
10062824
Hallucination, tactile
10019074
Hallucination, visual
10019075
Hallucinations, mixed
10019079
Hypnagogic hallucination
10020927
Hypnopompic hallucination
10020928
Hysterical psychosis
10062645
Notes: Medical concept of psychosis. Only narrow terms from SMQ 'Psychosis and psychotic disorders' 
selected.
 
 
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PT
PT Code
Ideas of reference
10021212
Illusion
10021403
Jealous delusion
10023164
Loose associations
10024825
Mixed delusion
10076429
Neologism
10028916
Neuroleptic-induced deficit syndrome
10075295
Paranoia
10033864
Paranoid personality disorder
10033869
Parkinson's disease psychosis
10074835
Paroxysmal perceptual alteration
10063117
Persecutory delusion
10034702
Postictal psychosis
10070669
Post-injection delirium sedation syndrome
10072851
Posturing
10036437
Psychosis postoperative
10065617
Psychotic behaviour
10037249
Psychotic disorder
10061920
Psychotic disorder due to a general medical condition
10061921
Reactive psychosis
10053632
Rebound psychosis
10074833
Schizoaffective disorder
10039621
Schizoaffective disorder bipolar type
10068889
Schizoaffective disorder depressive type
10068890
Schizophrenia
10039626
Schizophreniform disorder
10039647
Schizotypal personality disorder
10039651
Senile psychosis
10039987
Shared psychotic disorder
10040535
Somatic delusion
10041317
Somatic hallucination
10062684
Substance-induced psychotic disorder
10072388
Tangentiality
10043114
Thought blocking
10043495
Thought broadcasting
10052214
Thought insertion
10043496
Thought withdrawal
10043497
Transient psychosis
10056326
Waxy flexibility
10047853
 
 
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PT
PT Code
Crying
10011469
Mood swings
10027951
Boredom
10048909
Mood altered
10027940
Apathy
10002942
Affective ambivalence
10077173
Emotional poverty
10014557
Euphoric mood
10015535
Premenstrual dysphoric disorder
10051537
Alexithymia
10077719
Laziness
10051602
Blunted affect
10005885
Constricted affect
10010778
Affect lability
10054196
Anger
10002368
Affective disorder
10001443
Lethargy
10024264
Listless
10024642
Inappropriate affect
10021588
Dysphoria
10013954
Mood disorder due to a general medical con10027944
Morose
10027977
Screaming
10039740
Steroid withdrawal syndrome
10042028
Emotional disorder
10014551
Irritability
10022998
Moaning
10027783
Premenstrual syndrome
10036618
Neuroleptic-induced deficit syndrome
10075295
Substance-induced mood disorder
10072387
Flat affect
10016759
Diencephalic syndrome of infancy
10012774
Emotional distress
10049119
Frustration tolerance decreased
10077753
Seasonal affective disorder
10039775
HLGT Mood disorders and disturbances NEC, Psychiatric 
disorders SOC
Notes: Medical concept of mood disorders. All preferred terms from HLGT 'Mood disorders and
 
disturbances NEC', under SOC 'Psychiatric disorders'. 
 
 
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PT
PT Code
Acrophobia
10000605
Activation syndrome
10066817
Acute stress disorder
10001084
Aerophobia
10080300
Agitation
10001497
Agitation neonatal
10001500
Agitation postoperative
10049989
Agoraphobia
10001502
Akathisia
10001540
Algophobia
10078056
Animal phobia
10002518
Anniversary reaction
10074066
Anticipatory anxiety
10002758
Anxiety
10002855
Anxiety disorder
10057666
Anxiety disorder due to a general medical condition
10002859
Arachnophobia
10051408
Astraphobia
10078372
Autophobia
10071070
Body dysmorphic disorder
10052793
Burnout syndrome
10065369
Claustrophobia
10009244
Compulsions
10010219
Compulsive cheek biting
10076510
Compulsive handwashing
10071263
Compulsive hoarding
10068007
Compulsive lip biting
10066241
Compulsive shopping
10067948
Dermatillomania
10065701
Dysmorphophobia
10049096
Emetophobia
10070637
Fear
10016275
Fear of animals
10016276
Fear of closed spaces
10016277
Fear of crowded places
10050365
Fear of death
10066392
Fear of disease
10016278
Fear of eating
10050366
HLGT Anxiety disorders and symptoms
 
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Notes: Medical concept of anxiety disorders. All preferred terms from HLGT 'Anxiety disorders and 
symptoms', under SOC 'Psychiatric disorders'. 


PT
PT Code
Fear of falling
10048744
Fear of injection
10073753
Fear of open spaces
10016279
Fear of pregnancy
10067035
Fear of weight gain
10016280
Fear-related avoidance of activities
10080136
Generalised anxiety disorder
10018075
Glossophobia
10080077
Haemophobia
10073458
Haphephobia
10067580
Hydrophobia
10053317
Hyperarousal
10080831
Immunisation anxiety related reaction
10075205
Kinesiophobia
10078430
Limited symptom panic attack
10024511
Mysophobia
10078769
Nail picking
10066779
Nervousness
10029216
Neurosis
10029333
Noctiphobia
10057946
Nocturnal fear
10057948
Nosophobia
10063546
Obsessive need for symmetry
10077179
Obsessive rumination
10056264
Obsessive thoughts
10029897
Obsessive-compulsive disorder
10029898
Obsessive-compulsive symptom
10077894
Ochlophobia
10050095
Osmophobia
10060765
Paediatric autoimmune neuropsychiatric disorders assoc 10072147
Panic attack
10033664
Panic disorder
10033666
Panic reaction
10033670
Paruresis
10069024
Performance fear
10034432
Phagophobia
10050096
Pharmacophobia
10069423
Phobia
10034912
Phobia of driving
10056676
Phobia of exams
10034913
Phobic avoidance
10034918
 
 
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PT
PT Code
Phonophobia
10054956
Photaugiaphobia
10064420
Post-traumatic stress disorder
10036316
Postpartum neurosis
10036419
Postpartum stress disorder
10056394
Procedural anxiety
10075204
Pseudoangina
10056610
Selective mutism
10039917
Separation anxiety disorder
10040045
Sitophobia
10080170
Social anxiety disorder
10041242
Social fear
10041247
Stress
10042209
Tension
10043268
Terminal agitation
10077416
Thanatophobia
10064723
Thermophobia
10075147
Trichotemnomania
10072752
Trichotillomania
10044629
 
 
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PT
PT Code
Behavioural insomnia of childhood
10072072
Hyposomnia
10067530
Initial insomnia
10022035
Insomnia
10022437
Middle insomnia
10027590
Terminal insomnia
10068932
Breathing-related sleep disorder
10006344
Dyssomnia
10061827
Hypersomnia
10020765
Periodic limb movement disorder
10064600
Pickwickian syndrome
10035004
Poor quality sleep
10062519
Sleep apnoea syndrome
10040979
Somnolence
10041349
Somnolence neonatal
10041350
Stupor
10042264
Upper airway resistance syndrome
10063968
Cataplexy
10007737
Hypnagogic hallucination
10020927
Hypnopompic hallucination
10020928
Narcolepsy
10028713
Sleep attacks
10040981
Sleep paralysis
10041002
Abnormal dreams
10000125
Abnormal sleep-related event
10061613
Confusional arousal
10067494
Exploding head syndrome
10080684
Loss of dreaming
10065085
Nightmare
10029412
Parasomnia
10061910
Rapid eye movement sleep behaviour disorder
10077299
Rapid eye movements sleep abnormal
10037841
Sleep inertia
10067493
Sleep sex
10067492
Sleep talking
10041009
Sleep terror
10041010
Sleep-related eating disorder
10067315
Somnambulism
10041347
Hypersomnia related to another mental condition
10020767
Hypersomnia-bulimia syndrome
10053712
Insomnia related to another mental condition
10022443
Sleep disorder
10040984
Sleep disorder due to a general medical condition
10063910
Sleep disorder due to general medical condition, hypersomnia type
10040985
Sleep disorder due to general medical condition, insomnia type
10040986
Sleep disorder due to general medical condition, mixed type
10040987
Sleep disorder due to general medical condition, parasomnia type
10040988
HLGT Sleep Disorders and Disturbances 
Notes:  Medical concept of sleep disorders. All preferred terms from (1) HLGT 'Sleep Disorders and 
Disturbances', 'Psychiatric disorders' SOC plus (2)HLGT 'Sleep disturbances (incl subtypes)', 'Nervous 
system' SOC. Numerous duplicated preferred terms e.g. middle insomnia
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PT
PT Code
Sopor
10058709
Advanced sleep phase
10001423
Circadian rhythm sleep disorder
10009191
Delayed sleep phase
10012209
Irregular sleep phase
10022995
Irregular sleep wake rhythm disorder
10080301
Non-24-hour sleep-wake disorder
10078086
Shift work disorder
10078088
PT
PT Code
Abnormal dreams
10000125
Abnormal sleep-related event
10061613
Confusional arousal
10067494
Loss of dreaming
10065085
Sleep inertia
10067493
Sleep paralysis
10041002
Sleep sex
10067492
Sleep talking
10041009
Sleep terror
10041010
Sleep-related eating disorder
10067315
Somnambulism
10041347
Behavioural insomnia of childhood
10072072
Hyposomnia
10067530
Initial insomnia
10022035
Insomnia
10022437
Middle insomnia
10027590
Terminal insomnia
10068932
Advanced sleep phase
10001423
Circadian rhythm sleep disorder
10009191
Delayed sleep phase
10012209
Irregular sleep phase
10022995
Irregular sleep wake rhythm disorder
10080301
Non-24-hour sleep-wake disorder
10078086
Shift work disorder
10078088
Cataplexy
10007737
Hypersomnia
10020765
Narcolepsy
10028713
Central-alveolar hypoventilation
10007982
Sleep apnoea syndrome
10040979
Breathing-related sleep disorder
10006344
Dyssomnia
10061827
Fatal familial insomnia
10072077
Microsleep
10076954
Periodic limb movement disorder
10064600
Pickwickian syndrome
10035004
Poor quality sleep
10062519
Rapid eye movement sleep behaviour disorder
10077299
Rapid eye movements sleep abnormal
10037841
Sleep deficit
10080881
Sudden onset of sleep
10050014
HLGT Sleep disturbances (incl subtypes)
 
 
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PT
PT Code
Upper airway resistance syndrome
10063968
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Convulsions (SMQ)
20000079
PT
PT Code
2-Hydroxyglutaric aciduria
10078971
Acquired epileptic aphasia
10052075
Acute encephalitis with refractory, repetitive partial seizures
10076948
Alcoholic seizure
10056347
Aspartate-glutamate-transporter deficiency
10079140
Atonic seizures
10003628
Atypical benign partial epilepsy
10056699
Automatism epileptic
10003831
Autonomic seizure
10049612
Baltic myoclonic epilepsy
10054895
Benign familial neonatal convulsions
10067866
Benign rolandic epilepsy
10070530
Biotinidase deficiency
10071434
Change in seizure presentation
10075606
Clonic convulsion
10053398
Convulsion in childhood
10052391
Convulsion neonatal
10010911
Convulsions local
10010920
Convulsive threshold lowered
10010927
CSWS syndrome
10078827
Deja vu
10012177
Double cortex syndrome
10073490
Dreamy state
10013634
Drug withdrawal convulsions
10013752
Early infantile epileptic encephalopathy with burst-suppression
10071545
Eclampsia
10014129
Epilepsy
10015037
Epilepsy surgery
10079824
Epileptic aura
10015049
Epileptic psychosis
10059232
Febrile convulsion
10016284
Febrile infection-related epilepsy syndrome
10079438
Focal dyscognitive seizures
10079424
Frontal lobe epilepsy
10049424
Generalised non-convulsive epilepsy
10018090
Generalised tonic-clonic seizure
10018100
Glucose transporter type 1 deficiency syndrome
10078727
Gray matter heterotopia
10080533
Hemimegalencephaly
10078100
Hyperglycaemic seizure
10071394
Notes: Medical concept of seizures. Only narrow terms from SMQ 'Convulsions' selected plus selected 
PTs of possible seizure events from HLT 'Disturbances in consciousness NEC' under SOC 'Nervous 
systems disorders' and HLT 'Confusion and disorientation' under SOC 'Psychiatric disorders'  .
 
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PT
PT Code
Hypocalcaemic seizure
10072456
Hypoglycaemic seizure
10048803
Hyponatraemic seizure
10073183
Idiopathic generalised epilepsy
10071081
Infantile spasms
10021750
Juvenile myoclonic epilepsy
10071082
Lafora's myoclonic epilepsy
10054030
Lennox-Gastaut syndrome
10048816
Migraine-triggered seizure
10076676
Molybdenum cofactor deficiency
10069687
Multiple subpial transection
10079825
Myoclonic epilepsy
10054859
Myoclonic epilepsy and ragged-red fibres
10069825
Partial seizures
10061334
Partial seizures with secondary generalisation
10056209
Petit mal epilepsy
10034759
Polymicrogyria
10073489
Post stroke epilepsy
10076982
Post stroke seizure
10076981
Postictal headache
10052470
Postictal paralysis
10052469
Postictal psychosis
10070669
Postictal state
10048727
Post-traumatic epilepsy
10036312
Schizencephaly
10073487
Seizure
10039906
Seizure anoxic
10039907
Seizure cluster
10071350
Seizure like phenomena
10071048
Severe myoclonic epilepsy of infancy
10073677
Simple partial seizures
10040703
Status epilepticus
10041962
Sudden unexplained death in epilepsy
10063894
Temporal lobe epilepsy
10043209
Tonic clonic movements
10051171
Tonic convulsion
10043994
Tonic posturing
10075125
Topectomy
10073488
Tuberous sclerosis complex
10080584
Uncinate fits
10045476
Confusional state
10010305
PTs (Selective)
 
 
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PT
PT Code
Loss of consciousness
10024855
Syncope
10042772
Sopor
10058709
Stupor
10042264
Altered state of consciousness
10050093
Depressed level of consciousness
10012373
Consciousness fluctuating
10050093
 
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Acute renal failure (SMQ)
20000003
PT
PT Code
Acute kidney injury
10069339
Acute phosphate nephropathy
10069688
Anuria
10002847
Azotaemia
10003885
Continuous haemodiafiltration
10066338
Dialysis
10061105
Foetal renal impairment
10078987
Haemodialysis
10018875
Haemofiltration
10053090
Hyponatriuria
10077515
Neonatal anuria
10049778
Nephropathy toxic
10029155
Oliguria
10030302
Peritoneal dialysis
10034660
Prerenal failure
10072370
Renal failure
10038435
Renal failure neonatal
10038447
Renal impairment
10062237
Renal impairment neonatal
10049776
PT
PT Code
Acute Kidney injury
10069339
Anuria
10002847
Atypical haemolytic uraemic syndrome
10079840
Cardiorenal syndrome
10068230
Chronic kidney disease
10064848
Crush syndrome
10050702
Diabetic end stage renal disease
10012660
End stage renal disease
10077512
Foetal renal impairment
10078987
Haemolytic uraemic syndrome
10018932
Hepatorenal failure
10019845
Hepatorenal syndrome
10019846
Renal Failure and Impairment HLT 
Notes: Medical concept of worsening renal function/renal failure in the context of impact on
 
creatinine. Only narrow terms from SMQ 'Acute renal failure' plus  all PTs from HLT 'Renal failure and 
impairment', under SOC 'Renal and urinary disorders'. Numerous duplicated preferred terms e.g. 
renal failure 
 
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PT
PT Code
Nail-patella syndrome
10063431
Neonatal anuria
10049778
Oliguria
10030302
Pancreatorenal syndrome
10056277
Postoperative renal failure
10056675
Postrenal failure
10059345
Prerenal failure
10072370
Propofol infusion syndrome
10063181
Renal failure
10038435
Renal failure neonatal
10038447
Renal impairment
10062237
Renal impairment neonatal
10049776
Renal injury
10061481
Scleroderma renal crisis
10062553
Traumatic anuria
10044501
 
 
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Tubulointerstitial diseases (SMQ)
20000221 Notes: Medical concept of Proximal Renal Tubule Dysfunction. Only narrow terms from SMQ
 
'Tubulointerstitial diseases'. 
PT
PT Code
Acidosis hyperchloraemic
10000489
Acquired aminoaciduria
10073515
Acute phosphate nephropathy
10069688
Aminoaciduria
10001939
Beta-N-acetyl-D-glucosaminidase increased 10004511
Crystal nephropathy
10071503
Eosinophils urine present
10058363
Fanconi syndrome acquired
10052607
Hyperphosphaturia
10051232
Isosthenuria
10023077
Nephritis allergic
10029120
Nephrogenic diabetes insipidus
10029147
Nephropathy toxic
10029155
Renal glycosuria
10038457
Renal papillary necrosis
10038491
Renal tubular acidosis
10038535
Renal tubular atrophy
10038536
Renal tubular disorder
10038537
Renal tubular dysfunction
10050335
Tubulointerstitial nephritis
10048302
Tubulointerstitial nephritis and uveitis syndro10069034
Urine phosphorus increased
10055030
Urine retinol binding protein increased
10061432
 
 
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Proteinuria (SMQ)
20000220 Notes: Medical concept of Proteinuria. Only narrow terms from narrow SMQ 'Proteinuria' included.
PT
PT Code
Albumin globulin ratio increased
10001567
Albumin urine present
10001582
Albuminuria
10001580
Bence Jones protein urine present
10053112
Bence Jones proteinuria
10004231
Beta 2 microglobulin urine increased
10004501
Globulinuria
10018352
Microalbuminuria
10027525
Myoglobinuria
10028629
Orthostatic proteinuria
10031129
Protein urine
10037018
Protein urine present
10053123
Proteinuria
10037032
Urine albumin/creatinine ratio increased
10053541
Urine protein/creatinine ratio abnormal
10053539
Urine protein/creatinine ratio increased
10053538
 
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CONFIDENTIAL
The GlaxoSmithKline group of companies
206898
1
Division
:
Worldwide Development
Information Type
:
Reporting and Analysis Plan (RAP)
Title
:
Reporting and Analysis Plan for 206898: An Open Label, 
Phase 1 Study to Evaluate the PK, Safety, Tolerability and 
Acceptability of Long Acting Injections of the HIV Integrase 
Inhibitor, Cabotegravir (CAB; GSK1265744) in HIV 
Uninfected Chinese Men
Compound Number
:
GSK1265744
Effective Date 
:
28-SEP-2018
Description:

The purpose of this RAP is to describe the planned analyses and output to be
included in the Clinical Study Report for Protocol 206898.

This RAP is intended to describe the safety, tolerability, and pharmacokinetic (PK)
analyses required for the study.

This RAP will be provided to the study team members to convey the content of the
Statistical Analysis Complete (SAC) deliverable.
Author’s Name and Functional Area: 
11-SEP-2018
Biostatistician II, PPD
11-SEP-2018
Pharmacokineticist (Biostatistics, PPD)
Approved by: 
28-SEP-2018
Statistician, GSK
28-SEP-2018
Manager Statistics
Copyright 2018 the GlaxoSmithKline group of companies. All rights reserved. 
Unauthorised copying or use of this information is prohibited.
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TABLE OF CONTENTS
PAGE
1.
REPORTING & ANALYSIS PLAN SYNOPSIS.........................................................5
2.
SUMMARY OF KEY PROTOCOL INFORMATION ..................................................9
2.1.
Changes to the Protocol Defined Statistical Analysis Plan............................9
2.2.
Study Objective(s) and Endpoint(s)...............................................................9
2.3.
Study Design ..............................................................................................10
2.4.
Statistical Hypotheses.................................................................................10
3.
PLANNED ANALYSES ..........................................................................................12
3.1.
Interim Analyses .........................................................................................12
3.2.
Final Analyses ............................................................................................12
4.
ANALYSIS POPULATIONS ...................................................................................13
4.1.
Protocol Deviations.....................................................................................14
5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA HANDLING
CONVENTIONS.....................................................................................................15
6.
STUDY POPULATION ANALYSES .......................................................................16
6.1.
Overview of Planned Analyses ...................................................................16
6.1.1.
Disposition...................................................................................16
6.1.2.
Demographics .............................................................................16
6.1.3.
Medical History ............................................................................17
6.1.4.
Prior and Concomitant Medications .............................................17
6.1.5.
Protocol Deviation........................................................................17
7.
PRIMARY STATISTICAL ANALYSES....................................................................18
7.1.
Safety Analyses of CAB LA ........................................................................18
7.1.1.
Injection Site Reaction .................................................................18
7.1.2.
Adverse Events............................................................................19
7.1.3.
Clinical Laboratory Tests .............................................................20
7.1.4.
Vital Sign Assessments ...............................................................21
7.1.5.
Death...........................................................................................22
7.2.
Tolerability Analyses of CAB LA .................................................................22
7.3.
Primary Pharmacokinetic Analyses.............................................................23
7.3.1.
Overview of Planned Primary Pharmacokinetic Analyses ............23
7.3.2.
Primary Drug Concentration Measures ........................................24
7.3.3.
Primary Pharmacokinetic Parameters..........................................24
7.3.3.1.
Deriving Primary Pharmacokinetic Parameters...........24
7.3.3.2.
Statistical Analysis of Primary Pharmacokinetic 
Parameters.................................................................25
8.
SECONDARY STATISTICAL ANALYSES .............................................................27
8.1.
Secondary Pharmacokinetic Analyses........................................................27
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8.1.1.
Overview of Planned Secondary Pharmacokinetic 
Analyses......................................................................................27
8.1.2.
Secondary Drug Concentration Measures ...................................27
8.1.3.
Secondary Pharmacokinetic Parameters .....................................27
8.1.3.1.
Deriving Secondary Pharmacokinetic 
Parameters.................................................................27
8.2.
Safety and Tolerability Analyses of Oral CAB .............................................28
8.3.
Acceptability of CAB LA..............................................................................30
8.4.
Concentration-effect Relationships for Safety and Tolerability 
Parameters.................................................................................................30
8.5.
General Safety Analyses ............................................................................30
8.5.1.
Extent of Exposure to CAB ..........................................................31
8.5.2.
Possible suicidality-related Adverse Events.................................32
8.5.3.
Social Harms ...............................................................................32
8.5.4.
ECG.............................................................................................33
8.5.5.
Cardiovascular Events.................................................................33
8.5.6.
Liver Events.................................................................................34
9.
REFERENCES.......................................................................................................35
10. APPENDICES........................................................................................................36
10.1.
Appendix 1: Protocol Deviation Management and Definitions for Per 
Protocol Population.....................................................................................37
10.1.1.
Exclusions from Per Protocol Population .....................................37
10.2.
Appendix 2: Time & Events.........................................................................38
10.2.1.
Protocol Defined Time & Events ..................................................38
10.3.
Appendix 3: Assessment Windows .............................................................42
10.3.1.
Assessment Windows..................................................................42
10.4.
Appendix 4: Study Phase and State............................................................43
10.4.1.
Treatment Phases .......................................................................43
10.4.2.
Treatment States .........................................................................43
10.4.2.1.
Treatment States for AE Data.....................................43
10.5.
Appendix 5: Data Display Standards & Handling Conventions....................44
10.5.1.
Study Treatment & Sub-group Display Descriptors......................44
10.5.2.
Baseline Definition & Derivations .................................................44
10.5.2.1.
Baseline Definitions....................................................44
10.5.2.2.
Derivations and Handling of Missing Baseline 
Data ...........................................................................44
10.5.3.
Reporting Process & Standards...................................................44
10.6.
Appendix 6: Derived and Transformed Data ...............................................47
10.6.1.
General........................................................................................47
10.6.2.
Study Population..........................................................................47
10.6.3.
Safety ..........................................................................................48
10.7.
Appendix 7: Premature Withdrawals & Handling of Missing Data ...............49
10.7.1.
Premature Withdrawals................................................................49
10.7.2.
Handling of Missing Data.............................................................49
10.7.2.1.
Handling of Missing Dates..........................................49
10.7.2.2.
Handling of Partial Dates............................................50
 
 
 
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10.7.2.3.
Handling of Missing Data for Statistical 
Analysis......................................................................50
10.8.
Appendix 8: Values of Potential Clinical Importance ...................................51
10.8.1.
Laboratory Values........................................................................51
10.8.2.
ECG.............................................................................................52
10.8.3.
Vital Signs....................................................................................52
10.9.
Appendix 9: Multicenter Studies..................................................................53
10.9.1.
Methods for Handling Centres .....................................................53
10.10. Appendix 10: Examination of Covariates, Subgroups & Other Strata..........54
10.10.1. Handling of Covariates, Subgroups & Other Strata......................54
10.11. Appendix 11: Multiple Comparisons & Multiplicity .......................................55
10.11.1. Handling of Multiple Comparisons & Multiplicity...........................55
10.12. Appendix 12: Model Checking and Diagnostics for Statistical 
Analyses.....................................................................................................56
10.12.1. Statistical Analysis Assumptions..................................................56
10.13. Appendix 13 – Abbreviations & Trade Marks ..............................................57
10.13.1. Abbreviations...............................................................................57
10.13.2. Trademarks .................................................................................58
10.14. Appendix 14: List of Data Displays..............................................................59
10.14.1. Data Display Numbering..............................................................59
10.14.2. Mock Example Shell Referencing ................................................59
10.14.3. Deliverable [Priority].....................................................................59
10.14.4. Study Population Tables..............................................................60
10.14.5. Safety Tables...............................................................................61
10.14.6. Tolerability Tables........................................................................64
10.14.7. Acceptability Tables.....................................................................65
10.14.8. Pharmacokinetic Tables...............................................................66
10.14.9. Pharmacokinetic Figures .............................................................68
10.14.10.ICH Listings .................................................................................69
10.14.11.Non-ICH Listings..........................................................................74
10.15. Appendix 15: Example Mock Shells for Data Displays ................................75
 
 
 
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1.
REPORTING & ANALYSIS PLAN SYNOPSIS
Overview
Key Elements of the RAP
Purpose

The purpose of this reporting and analysis plan (RAP) is to describe any 
planned analyses and output to be included in the clinical study report for 
Protocol 206898.
Protocol

This RAP is based on the Protocol Amendment 1 (Dated: 06JUN2018) of study 
Protocol 206898 (GSK Document No.: 2016N293702_00] and eCRF Version 
(1.00, Dated: 09MAR2018).
Primary 
Objective

Evaluate the safety and tolerability of the injectable agent, cabotegravir 
(GSK1265744) long acting (CAB LA) injectable (600 mg dose administered 
every 4 weeks for 2 doses followed by every 8 weeks for 3 doses) through 
Week 5-41 in HIV-1 uninfected Chinese men.

Evaluate the plasma pharmacokinetics of CAB following repeat oral 
administration (Day 1 to Week 4) and CAB LA IM injections throughout the 
Injection Phase (Weeks 5-41).
Primary 
Endpoint

Safety and tolerability parameters, including adverse events, clinical laboratory 
tests, study withdrawals due to AEs, vital signs assessments, and evaluation of 
injection site reactions (ISRs), for injection phase (Week 5-41).

Plasma CAB AUC(0-), Cmax, C, tmax, λz, t½, CL/F, and Vz/F following daily 
oral administration of CAB through Day 1 to Week 4.

Plasma CAB AUC(0-), Cmax, C, and tmax following IM injections of CAB LA 
once every 8 weeks through Weeks 5-41.
Secondary 
Objective 

Evaluate the plasma pharmacokinetics of CAB LA throughout the Injection and 
Long-term Follow-up Phases (Week 5 to Week 89).

Evaluate the safety and tolerability of oral CAB in HIV uninfected Chinese men 
during the oral lead-in Phase (Day 1 to Week 4)

Evaluate the acceptability of CAB LA injections through 41 weeks.

Explore concentration-effect relationships for various safety and tolerability 
parameters if relevant.
Secondary 
Endpoint

Plasma CAB AUC(0-), Cmax, C, tmax, λz, t½, CL/F, and Vz/F through Weeks 
5-89.

Safety and tolerability parameters, including adverse events, study withdrawals 
due to AEs, vital signs assessments, and clinical laboratory assessments, for 
oral lead-in phase (Day 1 to Week 4).

Injection discontinuation rate, the number and severity of ISRs and additional 
acceptability measures.
 
 
 
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Overview
Key Elements of the RAP

Evaluation of relationships between significant safety and tolerability 
parameters and CAB PK may be explored.
Study 
Design

This will be an open label, non-randomized, single arm study. Participants will 
receive daily oral CAB (30mg tablets) for 4 weeks during the Oral Phase of the 
study and intramuscular (IM) injections of 600 mg of CAB LA at Week 5, Week 
9, Week 17, Week 25 and Week 33.

Starting at 8 weeks post last injection, participants will be seen once every 12 
weeks for 48 weeks during the follow-up phase.

Subjects who volunteer to participate in the intensive PK assessment will have 
serial blood sampling for measurement of plasma CAB concentrations following 
oral administration over a 24 h window starting on Day 27 and ending on Day 
28

PK samples at trough for Oral Phase will be collected for all subjects prior to 
dose within 20 to 28 hours following oral administration the day prior; Intensive 
oral PK samples will be collected from approximately 16 participants.

PK Samples for Injection Phase will be collected prior to CAB LA injections at 
Week 5, 9, 17, 25, and 33 with the exception of 1-week post injection samples 
at Weeks 6, 10, 18, 26, 34, 37 (4-week post injection sample) and Week 41

Long-term follow up PK samples will be collected at Week 53, 65, 77, and 89.
Planned 
Analyses

The primary safety analysis and PK analyses including both oral phase and 
injection phase through Weeks 5 to 41 will be performed after all ongoing 
participants complete the Week 41 visit or withdraw from the study treatment, 
whichever comes first.

The end of study analysis will be performed after all ongoing participants 
complete the Week 89 visit or withdraw from the study treatment, whichever 
comes first.
Analysis 
Populations

The All Subjects Screened Population will include all subjects who consent to 
participate in the clinical study. Subjects in this population will be used for 
disposition summary

The Safety Population will include all subjects who receive at least one dose of 
the study treatment. Subjects in this population will be used for all demographic 
and safety summaries or listings, as well as for the analysis of acceptability of 
CAB LA.

Safety Injection Population will include all subjects received at least one CAB 
LA injection. Subjects in this population will be used to evaluate the safety and 
tolerability of CAB LA injection in primary analysis.

Oral PK Population: subjects in the ‘Safety population’ for whom an intensive 
oral pharmacokinetic sample was obtained and analysed. PK samples that may 
 
 
 
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Overview
Key Elements of the RAP
be affected by protocol deviations will be reviewed by the study team to 
determine whether or not the sample will be excluded. This population will be 
used for reporting of Oral PK data.

Injection (Week 41) PK Population: subjects in the ‘Safety population’ for whom 
an injection pharmacokinetic sample was obtained and analysed during Weeks 
5 to 41. PK samples that may be affected by protocol deviations will be 
reviewed by the study team to determine whether or not the sample will be 
excluded. This population will be used for reporting of Injection PK data from 
Weeks 5 to 41.

Injection (Week 89) PK Population: subjects in the ‘Safety population’ for whom 
an injection pharmacokinetic sample was obtained and analysed during Weeks 
5 to 89. PK samples that may be affected by protocol deviations will be 
reviewed by the study team to determine whether or not the sample will be 
excluded. This population will be used for reporting of Injection PK data from 
Weeks 5 to 89.
Hypothesis

No formal statistical hypotheses will be evaluated.
Primary 
Analyses

To assess safety of CAB LA, the number and the percent of participants 
experiencing each safety endpoint will be tabulated including adverse events, 
clinical laboratory tests, study withdrawals due to AEs, and vital signs 
assessments.

To assess tolerability of CAB LA, the proportion 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.

To assess the plasma pharmacokinetics of CAB following repeat oral 
administration (Day 1 to Week 4) and CAB LA IM injections throughout the 
Injection Phase (Week 5 to Week 41).
Secondary 
Analyses

To assess the plasma pharmacokinetics of CAB LA throughout the Injection 
and Long-term Follow-up Phases (Week 5 to Week 89).

To assess the safety and tolerability of oral CAB, each safety and tolerability 
endpoint will be tabulated including adverse events, study withdrawals due to 
AEs, vital signs assessments and clinical laboratory assessments.

To assess the acceptability of the CAB LA, injection discontinuation rate, the 
number and severity of ISRs, and the proportion (with 95% CI for the CAB LA 
arm) of participants who would consider using CAB LA for HIV prevention in the 
future will be tabulated among all enrolled participants (including those who
terminated product use during the trial.

Overall treatment satisfaction score and answers to each individual question on 
 
 
 
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Overview
Key Elements of the RAP
HIV-PrevTSQc will be summarized to evaluate tolerability
 
 
 
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2.
SUMMARY OF KEY PROTOCOL INFORMATION
2.1.
Changes to the Protocol Defined Statistical Analysis Plan
There were no changes or deviations to the originally planned statistical analysis 
specified in the protocol (Dated: 06/JUN/2018).
2.2.
Study Objective(s) and Endpoint(s)
Objectives
Endpoints
Primary Objectives
Primary Endpoints
Evaluate the safety and tolerability of the 
injectable agent, cabotegravir (GSK1265744) 
long acting (CAB LA) injectable (600 mg dose 
administered every 4 weeks for 2 doses 
followed by every 8 weeks for 3 doses) 
through Week 5-41 in HIV-1 uninfected 
Chinese men.
Safety and tolerability parameters, including 
adverse events, clinical laboratory tests, study 
withdrawals due to AEs, vital signs assessments, 
and evaluation of injection site reactions (ISRs).
Evaluate the plasma pharmacokinetics of 
CAB following repeat oral administration (Day 
1 to Week 4) and CAB LA IM injections 
throughout the Injection Phase (Week 5 to 
Week 41).
Plasma CAB AUC(0-), Cmax, C, tmax, λz, t½, 
CL/F, and Vz/F at Week 4 following daily oral 
administration of CAB.
Plasma CAB AUC(0-), Cmax, C, and tmax at 
Week 41 following IM injections of CAB LA.
Secondary Objectives
Secondary Endpoints
Evaluate the plasma pharmacokinetics of 
CAB LA throughout the Injection and Long-
term Follow-up Phases (Week 5 to Week 89)
Plasma CAB AUC(0-), Cmax, C, tmax, λz, t½, 
CL/F, and Vz/F
Evaluate the safety and tolerability of oral 
CAB in HIV uninfected Chinese men during 
the oral lead-in Phase (Day 1 to Week 4)
Safety and tolerability parameters, including 
adverse events, study withdrawals due to AEs, 
vital signs assessments and clinical laboratory 
assessments.
Evaluate the acceptability of CAB LA 
injections through 41 weeks.
Injection discontinuation rate, the number and 
severity of ISRs and additional acceptability 
measures.
Explore concentration-effect relationships for 
various safety and tolerability parameters if 
relevant.
Evaluation of relationships between significant 
safety and tolerability parameters and CAB PK 
may be explored.
 
 
 
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2.3.
Study Design
Overview of Study Design and Key Features
This study is an open label (OL) Phase 1, multi-site, study to evaluate the PK, safety, tolerability, 
and acceptability of CAB LA in adult male participants. Eligible participants will receive oral CAB 
tablets as well as open label CAB LA.
Design Features
Oral lead-in phase is from Day 1 to week 4; injection phase 
is from week 5 to week 41; and follow-up phase is from 
week 41 to week 89
Dosing
Oral CAB tablet is 30mg and dose level=1 tablet;
CAB Sterile Suspension for Injection Vial is 200mg/mL and 
dose level = 600mg (3mL)
Participants will receive daily oral CAB (30mg tablets) for 4 
weeks during the Oral Phase of the study and IM injections 
of 600 mg of CAB LA at Week 5, Week 9, Week 17, Week 
25 and Week 33.
Treatment Assignment
Eligible participants will receive oral CAB tablets in the first
four weeks, and will received CAB LA injections since 
Week 5 following planned schedules.
Interim Analysis
No interim analysis is planned in this study.
2.4.
Statistical Hypotheses
No formal statistical hypotheses will be evaluated. The study is designed to evaluate the 
PK, safety, tolerability, and acceptability of the injectable agent, CAB LA (600 mg dose
administered at 8-week intervals after 2 initial doses 4 weeks apart) in HIV-uninfected
men in China where at least 60% of the men are of a population who have sex with men. 
 
 
 
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Where appropriate, an estimation approach will be taken, and point estimates and 
confidence intervals will be constructed.
 
 
 
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3.
PLANNED ANALYSES
3.1.
Interim Analyses
No formal interim analysis is planned in the study.
However, two preliminary PK analyses during the study will be performed in an informal 
manner. One will be after all planned participants complete the oral phase, and the other 
one will be after 50% of planned participants complete Week 17 visit. Study team will 
review preliminary safety and PK data.
3.2.
Final Analyses
The primary safety analysis and PK analyses including both oral phase and injection 
phase through Weeks 5 to 41 will be performed after all ongoing participants complete 
the Week 41 visit and datasets have been authorized. Other secondary analyses as 
mentioned, where appropriate, will also be performed. The end of study analysis will be 
performed after all ongoing participants complete the Week 89 visit. All planned primary 
and secondary analyses will be included in the second formal analyses.
The planned analyses will be performed after the completion of the following sequential 
steps:
a.
All subjects have completed the specific study visit (i.e. week 41 or week 89) as 
defined in the protocol.
b.
All required database cleaning activities have been completed and final database 
release and database freeze has been declared by Data Management.
 
 
 
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4.
ANALYSIS POPULATIONS
Population
Definition / Criteria
Analyses Evaluated
All Subjects 
Screened 

Comprise of all subjects who consent to 
participate in the clinical study. 

Disposition summary
Safety

Comprise of all subjects who receive at 
least one dose of the study treatment.

All demographic

General safety analyses

Safety analysis for the 
oral phase

Analysis of acceptability 
of CAB LA
Safety Injection 
Comprise of all subjects received at 
least one CAB LA injection

Safety and tolerability 
analyses of CAB LA in 
primary and extended 
analyses
Oral 
Pharmacokinetic 
(PK)

Will consist of all subjects in the ‘Safety
population’ for whom an intensive oral 
pharmacokinetic sample was obtained 
and analysed. PK samples that may be 
affected by protocol deviations will be 
reviewed by the study team to 
determine whether or not the sample will 
be excluded.

Oral PK Concentration

Oral PK Parameters
Injection (Week 41) 
Pharmacokinetic 
(PK)

Will consist of all subjects in the ‘Safety
population’ for whom an injection 
pharmacokinetic sample was obtained 
and analysed during Weeks 5 to 41. PK 
samples that may be affected by 
protocol deviations will be reviewed by 
the study team to determine whether or 
not the sample will be excluded.

Injection PK 
Concentration

Injection PK 
Parameters
Injection (Week 89) 
Pharmacokinetic 
(PK) 

Will consist of all subjects in the ‘Safety 
population’ for whom an injection 
pharmacokinetic sample was obtained 
and analysed during Weeks 5 to 89. PK 
samples that may be affected by 
protocol deviations will be reviewed by 
the study team to determine whether or 
not the sample will be excluded.

Injection PK 
Concentration

Injection PK 
Parameters
NOTES:
Please refer to Appendix 14: List of Data Displays which details the population to be used for each display being 
generated.
 
 
 
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4.1.
Protocol Deviations

Important protocol deviations (including deviations related to study 
inclusion/exclusion criteria, conduct of the trial, patient management or patient 
assessment) will be summarised and listed.

Protocol deviations will be tracked by the study team throughout the conduct of the 
study in accordance with the Protocol Deviation Management Plan.
o
Data will be reviewed prior to freezing the database to ensure all important 
deviations are captured and categorised on the protocol deviations dataset. 
o
This dataset will be the basis for the summaries and listings of protocol 
deviations.

A separate summary and listing of all inclusion/exclusion criteria deviations will also 
be provided. This summary will be based on data as recorded on the 
inclusion/exclusion page of the eCRF.
 
 
 
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5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA 
HANDLING CONVENTIONS
Table 1 provides an overview of appendices within the RAP for outlining general 
considerations for data analyses and data handling conventions. 
Table 1
Overview of Appendices
Section
Component
10.1
Appendix 1: Protocol Deviation Management and Definitions for Per Protocol 
Population
10.2
Appendix 2: Time & Events
10.3
Appendix 3: Assessment Windows
10.4
Appendix 4: Treatment States and Phases
10.5
Appendix 5: Data Display Standards & Handling Conventions
10.6
Appendix 6: Derived and Transformed Data
10.7
Appendix 7: Premature Withdrawals & Handling of Missing Data
10.8
Appendix 8: Values of Potential Clinical Importance
10.9
Appendix 9: Multicenter Studies
10.10
Appendix 10: Examination of Covariates, Subgroups & Other Strata
10.11
Appendix 11: Multiple Comparisons & Multiplicity
10.12
Appendix 12: Model Checking and Diagnostics for Statistical Analyses.
10.13
Appendix 13: Abbreviations & Trade Marks
10.14
Appendix 14: List of Data Displays
 
 
 
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6.
STUDY POPULATION ANALYSES
6.1.
Overview of Planned Analyses
The study population analyses will be based on the safety population, unless otherwise 
specified. All summary data and statistics are calculated from available data, unless 
otherwise specified.
Table 2 provides an overview of the planned study population analyses, with full details 
of data displays being presented in Appendix 14: List of Data Displays.
Table 2
Overview of Planned Study Population Analyses
Display Type
Data Displays Generated
Table
Figure
Listing
Disposition
Retention Rate and Reasons for Withdrawals
Y
Y
Demography and Baseline Characteristics
General Demographics Characteristics
Y
Y
Medical History and Concomitant Medications
Medical History
Y
Y
Prior Medications
Y
Y
Concomitant Medications
Y
Y
Protocol Deviations
Deviation of Inclusion/Exclusion Criteria
Y
Y
Important Protocol Deviations
Y
Y
NOTES:

Y = Yes display generated.
6.1.1.
Disposition
The reasons of screening failure will be summarized based on the screened population. 
The number and percentage of each reason will be tabulated.
A summary of subject disposition by phase will be provided, including the number and 
percentage of subjects entering oral/injection phase, the number and percentage of 
subjects completing oral/injection phase and the number and percentage of subjects 
withdrawing from oral/injection phase.
Subject disposition data will be presented in a listing.
6.1.2.
Demographics
General demographics including age, self-identified gender when entering the study, and 
ethnicity will be summarized.
 
 
 
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A subject’s age is calculated using the year part of informed consent form (ICF) – year of 
birth collected in CRF.
6.1.3.
Medical History
Summaries of medical history will be presented by GSK pre-specified body system
categories as collected in the eCRF. Number and percentage of subjects in each category 
will be tabulated.
6.1.4.
Prior and Concomitant Medications
Medications will be coded to therapeutic drug classes and generic drug names using the 
GSKDRUG 1.4 or later. Medications initiated prior to the Day 1 of the study will be 
counted as prior medications. Concomitant medications are defined as medications that 
are taken on or after the Day 1. Medications initiated prior to the Day 1 and continued 
after the Day 1 will be counted as both prior and concomitant medications.
Summaries showing the number and percentage of subjects who take prior or 
concomitant medications will be presented by therapeutic drug class and generic drug 
name.
6.1.5.
Protocol Deviation
Important protocol deviations (PD) will be summarized PD category and subcategory, 
and will also be presented in a listing. A separate summary table and a listing will be 
provided for subjects with deviation of the inclusion/exclusion criteria in the safety 
population 
 
 
 
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7.
PRIMARY STATISTICAL ANALYSES
7.1.
Safety Analyses of CAB LA
Four study phases are defined for this study: screening phase, oral phase, injection phase 
and follow-up phase (see Appendix 4 for the definition of each phase).
The primary safety analysis will be conducted after all ongoing participants complete the 
Week 41 visit and datasets have been authorized. All data from injected participants 
collected from Week 5 to Week 41 (i.e., in the injection phase) will be analysed. Analysis 
endpoints will include Grade 2 or higher clinical and laboratory events that occur from 
the initial injection to 8 weeks after the last injection among participants who receive at 
least one injection.
The extended safety analysis will be conducted after all ongoing participants complete 
the Week 89 visit and datasets have been authorized. All data from injected participants 
collected from Week 5 to Week 89 (i.e., in the injection phase and the follow-up phase) 
will be analysed. Analysis endpoints are the same as in the primary safety analysis.
To assess safety, the number and the percent of participants experiencing each safety 
endpoint will be tabulated. Each participant will contribute once in each category (i.e., 
only for the highest severity AE) for the evaluation of safety.
7.1.1.
Injection Site Reaction
The number and percentage of participants experiencing each type of injection site 
reaction sign or symptom will be tabulated by severity from the safety injection 
population. For a given sign or symptom, each participant’s ISR will be counted once 
under the maximum severity for all injection visits. Overall summary of ISR and 
summary of ISR by needle length will both be provided. ISR related details, such as 
cardiovascular activity, strength training exercise, will be listed only.
Table 3 provides an overview of the planned ISR analyses, with full details of data 
displays being presented in Appendix 14: List of Data Displays.
 
 
 
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Table 3
Overview of Planned ISR Analyses
Display Type
Data Displays Generated
Stats Analysis
Summary
Individual
T
F
L
T
F
F
L
ISR Analyses 
All ISR Symptoms
Y
Y
NOTES:

T = Table, F = Figure, L = Listing, Y = Yes display generated.

Stats Analysis = Represents TFL related to any formal statistical analyses (i.e. modelling) conducted.

Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data.

Individual = Represents FL related to any displays of individual subject observed raw data.
7.1.2.
Adverse Events
Adverse events will be tabulated using MedDRA (v20.0 or above) system organ class 
(SOC) and preferred terms (PT), or preferred terms alone, by study phase. The number 
and percentage of participants experiencing each specific AEs (Grade 2 or higher, All 
AEs, SAEs, AEs leading to permanent treatment discontinuation or study withdrawal) 
will be tabulated. Number of subjects in the safety population who entered the study 
phase will be used as denominator in the calculation of percentages.
Drug-related AEs, SAEs, and Grade 2-4 AEs will also be tabulated. Any AE is assumed 
to be study treatment-related if relationship is marked ‘YES’ on CRF or value is missing.
In addition, a summary table will be created for AEs by maximum severity by study 
phase. Common AEs are defined as AEs occurring in >=5% subjects during the study 
(based on preferred term). Common AEs, common non-serious AEs, common Grade 2-4 
AEs, and common drug-related Grade 2-4 AEs will be tabulated.
All AE tables will be presented in a decreasing frequency order of SOC or PT unless 
otherwise specified.
Table 4 provides an overview of the planned AE analyses, with full details of data 
displays being presented in Appendix 14: List of Data Displays.
Table 4
Overview of Planned AE Analyses
Display Type
Data Displays Generated
Stats Analysis
Summary
Individual
T
F
L
T
F
F
L
AE Analyses 
All AEs
Y
Y
Grade 2 or higher AEs
Y
Y
SAEs
Y
Y
AE leading to 
treatment 
Y
Y
 
 
 
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Display Type
Data Displays Generated
Stats Analysis
Summary
Individual
T
F
L
T
F
F
L
discontinuation or 
study withdrawal
Drug-related AEs
Y
Drug-related SAEs
Y
Drug-related Grade 2 
or higher AEs
Y
Common AEs
Y
Common non-serious 
AEs
Y
Common Grade 2-4 
AEs
Y
Common drug-related 
Grade 2-4 AEs
Y
NOTES:

T = Table, F = Figure, L = Listing, Y = Yes display generated.

Stats Analysis = Represents TFL related to any formal statistical analyses (i.e. modelling) conducted.

Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data.

Individual = Represents FL related to any displays of individual subject observed raw data.
7.1.3.
Clinical Laboratory Tests
All clinical laboratory tests will be graded according to the Appendix 7 from the study
protocol. Grade 2 or higher laboratory events will be tabulated by number and percentage 
of subjects with the event by study phase. 
Change from baseline in hematology, fasting chemistry, fasting lipid profile, and 
coagulation profile will be summarized by visit. For the definition of baseline, refer to 
Section 10.5.2. Urinalysis and urine chemistry results will be summarized by visit as
either categorical values or as continuous values, depending on the type of the parameter. 
For each lab test, shift from baseline table will be provided based on toxicity grade, both 
by visit and for the shift to maximum toxicity grade in each study phase. Data collected at 
unscheduled visits will not be included in the by-visit summary, but will be used in the 
calculation of maximum grade in each study phase. Subjects having both high and low 
values will be counted in both High and Low categories for the summary by study phase.
All lab data, as well as lab data for subjects with Grade 2 or higher abnormalities, will be 
listed. Abnormal data will be listed with an indicator, which is low/high relative to 
normal range. All laboratory results from local labs, if any, will be listed only
Table 4 provides an overview of the planned lab test analyses, with full details of data 
displays being presented in Appendix 14: List of Data Displays.
 
 
 
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Table 5
Overview of Planned Lab Test Analyses
Display Type
Absolute
Change from Baseline
Summary
Individual
Summary
Individual
T
F
F
L
T
F
F
L
Laboratory Test Analyses
Grade 2 or high 
laboratory events
Y
Clinical Chemistry 
Y
Y
Hematology
Y
Y
Fasting Lipid Profile
Y
Y
Coagulation Profile
Y
Y
Urinalysis and Urine 
Chemistry
Y
Y
Y
Other lab data 
including local lab
Y

T = Table, F = Figure, L = Listing, Y = Yes display generated.

Stats Analysis = Represents TFL related to any formal statistical analyses (i.e. modelling) conducted.

Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data.

Individual = Represents FL related to any displays of individual subject observed raw data.
7.1.4.
Vital Sign Assessments
Change from baseline in vital signs, including temperature, systolic and diastolic blood 
pressure, and pulse rate and respiratory rate will be summarized by study visit. For the 
definition of baseline, refer to Section 10.5.2. Shift from baseline table (with respect to 
clinical concern range) will also be provided.
All vital signs, as well as vital signs for subjects with abnormalities of potential clinical 
importance, will be listed with an indicator, which is low/high relative to clinical concern 
range.
Table 6 provides an overview of the planned vital sign analyses, with full details of data 
displays being presented in Appendix 14: List of Data Displays.
Table 6
Overview of Planned Vital Sign Analyses
Display Type
Absolute
Change from Baseline
Summary
Individual
Summary
Individual
T
F
F
L
T
F
F
L
Vital Signs
Vital signs
Y
Y
NOTES:

T = Table, F = Figure, L = Listing, Y = Yes display generated.

Stats Analysis = Represents TFL related to any formal statistical analyses (i.e. modelling) conducted.

Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data.

Individual = Represents FL related to any displays of individual subject observed raw data.
 
 
 
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7.1.5.
Death
Both primary and secondary causes, if any, will be listed for each deceased participant.
Table 7 provides an overview of the planned death analyses, with full details of data 
displays being presented in Appendix 14: List of Data Displays.
Table 7
Overview of Planned Death Analyses
Display Type
Data Displays Generated
Stats Analysis
Summary
Individual
T
F
L
T
F
F
L
Death Analysis 
Death
Y
NOTES:

T = Table, F = Figure, L = Listing, Y = Yes display generated.

Stats Analysis = Represents TFL related to any formal statistical analyses (i.e. modelling) conducted.

Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data.

Individual = Represents FL related to any displays of individual subject observed raw data.
7.2.
Tolerability Analyses of CAB LA
The tolerability analyses will be based on the safety injection population, unless 
otherwise specified. All summary data and statistics are calculated from available data, 
unless otherwise specified.
To assess tolerability of CAB LA, the proportion (with 95% confidence interval) 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 will be calculated out of those participants that received at least one injection.
A questionnaire will also be used to assess participant tolerability and satisfaction to the 
treatment. For each question, the responses will be summarized by the proportion of 
participants reporting the response out of all those that answered the question. An overall 
treatment satisfaction score will be calculated for each participant.
Total score is defined as the sum of the scores for individual questions. If less than or 
equal to 50% of the questions for an individual participant are missing, the missing total 
scores will be estimated using the average of the existing questions multiplied by twelve; 
if more than 50% of the questions for an individual participant are missing, the total score 
will not be estimated and will be considered as missing. When calculating total scores, 
question
 will be used and question
 will be excluded.
 
 
 
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Table 8 provides an overview of the planned tolerability analyses, with further details of 
data displays being presented in Appendix 14: List of Data Displays.
Table 8
Overview of Planned Tolerability Analyses
Display Type
Data Displays Generated
Stats Analysis
Summary
Individual
T
F
L
T
F
F
L
CAB LA Discontinuation
Injection 
Discontinuation Rate
Y
Y
Treatment Satisfaction Questionnaire
Each question in the 
questionnaire
Y
Y
Treatment total 
satisfaction score
Y
Y
NOTES:

T = Table, F = Figure, L = Listing, Y = Yes display generated.

Stats Analysis = Represents TFL related to any formal statistical analyses (i.e. modelling) conducted.

Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data.

Individual = Represents FL related to any displays of individual subject observed raw data
7.3.
Primary Pharmacokinetic Analyses
7.3.1.
Overview of Planned Primary Pharmacokinetic Analyses
The primary pharmacokinetic (PK) analyses will be based on the Oral PK and Injection 
(Week 41) PK populations, unless otherwise specified.
Table 9 provides an overview of the planned efficacy analyses, with full details of data 
displays being presented in Appendix 14: List of Data Displays.
Table 9
Overview of Planned Primary Pharmacokinetic Analyses
Display Type
Untransformed
Log-Transformed
Stats Analysis
Summary
Individual
Stats Analysis
Summary
Individual
T
F
L
T
F
F
L
T
F
L
T
F
F
L
Oral/Injection
PK Concentrations
Y
Y [1]
Y [1]
Y
Plasma PK Parameters
Y
Y
Y
Y
Y
NOTES:

T = Table, F = Figure, L = Listings, Y = Display generated.

Stats Analysis = Represents TFL related to any formal statistical analyses (i.e. modelling) conducted.

Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data.

Individual = Represents FL related to any displays of individual subject observed raw data.
[1] Linear and Semi-Logarithmic plots will be created on the same display.
 
 
 
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7.3.2.
Primary Drug Concentration Measures
Refer to Appendix 5: Data Display Standards & Handling Conventions (Section 10.5.3
Reporting Process & Standards).
7.3.3.
Primary Pharmacokinetic Parameters
7.3.3.1.
Deriving Primary Pharmacokinetic Parameters

Refer to Appendix 5: Data Display Standards & Handling Conventions
(Section 10.5.3 Reporting Process & Standards).

The pharmacokinetic parameters will be calculated by standard non-compartmental 
analysis according to current working practices and using Phoenix WinNonlin 
Version 6.4 or higher.

All calculations of non-compartmental parameters will be based on actual sampling 
times, and all concentrations will be included in the estimation of PK parameters 
regardless of whether samples are collected within the specified time window or not.

Pharmacokinetic parameters described in Table 10 will be determined from the 
plasma concentration-time data, as data permits.
 
 
 
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Table 10
Derived Primary Pharmacokinetic Parameters
Parameter
Parameter Description
AUC(0-)
Area under the concentration-time curve over the dosing interval will be calculated using the
linear trapezoidal rule for each incremental trapezoid and the log trapezoidal rule for each 
decremental trapezoid.
Cmax
Maximum observed concentration, determined directly from the concentration-time data.
tmax
Time to reach Cmax, determined directly from the concentration-time data.
C
Observed concentration at the end of the dosing interval, determined directly from the 
concentration-time data.
t½
Terminal absorption elimination half-life will be calculated as: 
t½ = ln2 / λz
λz
Terminal absorption elimination rate constant
CL/F
Clearance (adjusted for bioavailability, F) will be calculated as: 
CL/F = Dose / AUC(0-)
Vz/F
Volume of distribution (adjusted for bioavailability, F) will be calculated as: 
Vz/F = CL / λz
NOTES:

Additional parameters may be included as required.

λz, CL/F, Vss and t½ will be determined for the Oral PK population only in the primary analysis; these 
parameters will be further explored for the Injection (Week 89) PK population (Section 8.1.3.1).
7.3.3.2.
Statistical Analysis of Primary Pharmacokinetic Parameters
The following pharmacokinetic statistical analyses will only be performed, if sufficient 
data is available (i.e. if subjects have well defined plasma profiles). 
Pharmacokinetic Statistical Analyses
Endpoint(s)

Plasma primary PK endpoints include C, as data permit
Model Specification
Assessment of Accumulation (Injection Phase only):

To determine accumulation of plasma CAB following treatment with CAB LA, the log-
transformed Cvalues for CAB will be analyzed using a mixed effects model (ANOVA) as 
appropriate to the study design, fitting fixed effect terms for visit and treating subject as a 
random effect. Point estimates and 90% confidence intervals (CIs) for the differences of 
interest (i.e. accumulation of CAB based on AUC(0-): Week 34 / Week 6) will be constructed 
using the residual variance.
Attainment of Steady state (Injection Phase only):

If data permit, a statistical analysis of steady-state trough concentrations (C) will be performed 
 
 
 
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Pharmacokinetic Statistical Analyses
after log-transformation of Con Weeks 17, 25, 33, and 41 to evaluate whether steady state 
was achieved using the Helmert transformation approach. A mixed effect model (ANOVA) will 
be fitted by visit (as a categorical covariate) as a fixed effect term and subject as a random 
effect term. The comparison will begin with Week 17 vs. the average of Weeks 25 through 
Week 41. If the p-value for Week 17 vs. the average of Week 25 through Week 41 comparison 
is ≤0.05 (i.e. steady state not achieved at Week 17), then the comparison will continue with 
Week 25 vs. Week 33 through Week 41.
Model Checking & Diagnostics

Refer to Appendix 12: Model Checking and Diagnostics for Statistical Analyses.
Model Results Presentation

Statistical analysis of accumulation of plasma CAB following treatment with CAB LA will be 
presented in tabular format with geometric mean ratios between Week 34 and Week 6, and 
90% CIs for the ratios of Cfor CAB.

In steady-state analysis, the ratio of Geometric LS means and its 95% CI will be presented for 
the comparison(s).
 
 
 
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8.
SECONDARY STATISTICAL ANALYSES
8.1.
Secondary Pharmacokinetic Analyses
8.1.1.
Overview of Planned Secondary Pharmacokinetic Analyses
The secondary pharmacokinetic (PK) analyses will be based on the Injection (Week 89) 
PK population, unless otherwise specified.
Table 11 provides an overview of the planned analyses, with full details being presented 
in Appendix 14: List of Data Displays. 
Table 11
Overview of Planned Secondary Pharmacokinetic Analyses
Display Type
Untransformed
Log-Transformed
Stats Analysis
Summary
Individual
Stats Analysis
Summary
Individual
T
F
L
T
F
F
L
T
F
L
T
F
F
L
Oral/Injection
PK Concentrations
Y
Y [1]
Y [1]
Y
Plasma PK Parameters
Y
Y
Y
Y
Y
NOTES:

T = Table, F = Figure, L = Listings, Y = Display generated.

Stats Analysis = Represents TFL related to any formal statistical analyses (i.e. modelling) conducted.

Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data.

Individual = Represents FL related to any displays of individual subject observed raw data.
[1] Linear and Semi-Logarithmic plots will be created on the same display.
8.1.2.
Secondary Drug Concentration Measures
Refer to Appendix 5: Data Display Standards & Handling Conventions (Section 10.5.3
Reporting Process & Standards).
8.1.3.
Secondary Pharmacokinetic Parameters
8.1.3.1.
Deriving Secondary Pharmacokinetic Parameters

Refer to Appendix 5: Data Display Standards & Handling Conventions
(Section 10.5.3 Reporting Process & Standards).

The pharmacokinetic parameters will be calculated by standard non-compartmental 
analysis according to current working practices and using Phoenix WinNonlin 
Version 6.4 or higher.

All calculations of non-compartmental parameters will be based on actual sampling 
times, and all concentrations will be included in the estimation of PK parameters 
regardless of whether samples are collected within the specified time window or not.
 
 
 
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
Pharmacokinetic parameters described in Table 12 will be determined from the 
plasma concentration-time data, as data permits.
Table 12
Derived Secondary Pharmacokinetic Parameters
Parameter
Parameter Description
AUC(0-)
Area under the concentration-time curve over the dosing interval will be calculated using the 
linear trapezoidal rule for each incremental trapezoid and the log trapezoidal rule for each 
decremental trapezoid.
Cmax
Maximum observed concentration, determined directly from the concentration-time data.
tmax
Time to reach Cmax, determined directly from the concentration-time data.
C
Observed concentration at the end of the dosing interval, determined directly from the 
concentration-time data.
t½
Terminal absorption elimination half-life will be calculated as: 
t½ = ln2 / λz
λz
Terminal absorption elimination rate constant
CL/F
Clearance (adjusted for bioavailability, F) will be calculated as: 
CL/F = Dose / AUC(0-)
Vz/F
Volume of distribution (adjusted for bioavailability, F) will be calculated as: 
Vz/F = CL / λz
NOTES:

Additional parameters may be included as required.
8.2.
Safety and Tolerability Analyses of Oral CAB
The safety and tolerability analyses of oral CAB will include Grade 2 or higher clinical 
and laboratory events occurred during the oral phase. Analysis time frame is from the 
first date of taking oral CAB tablet to the date right before the first CAB LA injection. 
For subjects who withdraw treatment from the oral phase, the analysis will include all 
safety and tolerability assessments from the first date of taking oral CAB tablet up to the 
date of last study visit.
Safety endpoints including adverse events, laboratory test, vital signs, and death will be 
analysed. The same analysis approaches will be conducted as in the primary analysis, but 
with different time frame.
Table 13 provides an overview of the planned analyses, with full details of data displays 
being presented in Appendix 14: List of Data Displays.
 
 
 
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Table 13
Overview of Planned AE, LB, VS, and Death Analyses
Display Type
Data Displays Generated
Stats Analysis
Summary
Individual
T
F
L
T
F
F
L
AE Analyses 
All AEs 
Y
Y
Grade 2 or higher AEs
Y
Y
SAEs 
Y
Y
AE leading to 
treatment 
discontinuation or 
study withdrawal
Y
Y
Drug-related AEs
Y
Drug-related SAEs
Y
Drug-related Grade 2 
or higher AEs
Y
Common AEs
Y
Common non-serious 
AEs
Y
Common Grade 2-4 
AEs
Y
Common drug-related 
Grade 2-4 AEs
Y
Laboratory Tests
Grade 2 or higher 
laboratory events
Y
Clinical Chemistry 
Y
Y
Hematology
Y
Y
Fasting Lipid Profile
Y
Y
Urinalysis
Y
Y
Coagulation Profile
Y
Y
Other lab data 
including local lab
Y
Vital Sign Analysis 
Vital Signs
Y
Y
Death Analysis
Death
Y
NOTES:

T = Table, F = Figure, L = Listing, Y = Yes display generated.

Stats Analysis = Represents TFL related to any formal statistical analyses (i.e. modelling) conducted.

Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data.

Individual = Represents FL related to any displays of individual subject observed raw data.
 
 
 
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8.3.
Acceptability of CAB LA
The secondary acceptability analyses will be based on safety population, unless otherwise 
specified. All summary data and statistics are calculated from available data, unless 
otherwise specified.
To assess acceptability of the CAB LA, the proportion (with 95% confidence interval) of 
participants who would consider using CAB LA for HIV prevention in the future will be 
calculated among all subjects in the safety population (including those who terminated 
product use during the trial). Participants will be asked if they would consider using CAB 
LA for HIV prevention in the future at their Week 41 visit or at their withdrawal visit, 
whichever occurs first. Patients who are lost to follow up or with missing responses will 
be presented as such in a separate category.
Table 14 provides an overview of the planned acceptability analyses, with further details 
of data displays being presented in Appendix 14: List of Data Displays.
Table 14
Overview of Planned Acceptability Analyses
Display Type
Data Displays Generated
Stats Analysis
Summary
Individual
T
F
L
T
F
F
L
Acceptability of the CAB LA
participants who 
would consider using 
CAB LA
Y
Y
NOTES:

T = Table, F = Figure, L = Listing, Y = Yes display generated.

Stats Analysis = Represents TFL related to any formal statistical analyses (i.e. modelling) conducted.

Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data.

Individual = Represents FL related to any displays of individual subject observed raw data.
8.4.
Concentration-effect Relationships for Safety and 
Tolerability Parameters
Evaluation of relationships between significant safety and tolerability parameters and 
CAB PK may be explored.
8.5.
General Safety Analyses
This section will describe safety analyses that are not mentioned in Section 7.1 or Section 
8.2, but usually are performed as safety assessment.
 
 
 
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8.5.1.
Extent of Exposure to CAB
Duration of exposure to CAB and cumulative dose (see Section 10.6.2 for the definition) 
will be summarized for the oral phase and the injection phase separately. Overall 
exposure to the study drug and to the study (for safety evaluation) will also be calculated 
and summarized. Exposure data will also be listed.
Table 15 provides an overview of the planned analyses, with full details of data displays 
being presented in Appendix 14: List of Data Displays.
 
 
 
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Table 15
Overview of Planned Analyses for Extent of Exposure
Display Type
Data Displays Generated
Stats Analysis
Summary
Individual
T
F
L
T
F
F
L
Extent of Exposure
Extent of exposure
Y
Y
NOTES:

T = Table, F = Figure, L = Listing, Y = Yes display generated.

Stats Analysis = Represents TFL related to any formal statistical analyses (i.e. modelling) conducted.

Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data.

Individual = Represents FL related to any displays of individual subject observed raw data.
8.5.2.
Possible suicidality-related Adverse Events
Possible suicidality-related will be listed.
Table 16 provides an overview of the planned analyses, with full details of data displays 
being presented in Appendix 14: List of Data Displays.
Table 16
Overview of Analyses for possible suicidality-related AEs
Display Type
Data Displays Generated
Stats Analysis
Summary
Individual
T
F
L
T
F
F
L
AE Analyses 
Possible Suicidality-
Related Adverse Event
Y
NOTES:

T = Table, F = Figure, L = Listing, Y = Yes display generated.

Stats Analysis = Represents TFL related to any formal statistical analyses (i.e. modelling) conducted.

Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data.

Individual = Represents FL related to any displays of individual subject observed raw data.
8.5.3.
Social Harms
Details of social harms collected on the eCRF will be listed for each participant.
Table 17 provides an overview of the planned study population analyses, with full details 
of data displays being presented in Appendix 14: List of Data Displays.
 
 
 
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Table 17
Overview of Planned Study Population Analyses
Display Type
Data Displays Generated
Table
Figure
Listing
Social Harms
All Social Harms
Y
NOTES:

Y = Yes display generated.
8.5.4.
ECG
ECG test will be performed at Screening only. Details collected on the eCRF will be 
listed for each subject. Baseline ECG findings (normal, abnormal – not clinically 
significant, or abnormal - clinically significant) will be summarized by number and 
percentage of subjects and presented as part of the ‘Demographic Characteristics’ table.
Table 18 provides an overview of the planned study population analyses, with full details 
of data displays being presented in Appendix 14: List of Data Displays.
Table 18
Overview of Planned Study Population Analyses
Display Type
Data Displays Generated
Table
Figure
Listing
ECG
ECG Parameters and Results
Y
Y
NOTES:

Y = Yes display generated.
8.5.5.
Cardiovascular Events
Any cardiovascular events will be listed only.
Table 19 provides an overview of the planned cardiovascular event analyses, with full
details of data displays being presented in Appendix 14: List of Data Displays.
Table 19
Overview of Planned Cardiovascular Event Analyses
Display Type
Data Displays Generated
Stats Analysis
Summary
Individual
T
F
L
T
F
F
L
CV Event Analyses 
All CV events
Y
NOTES:

T = Table, F = Figure, L = Listing, Y = Yes display generated.

Stats Analysis = Represents TFL related to any formal statistical analyses (i.e. modelling) conducted.

Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data.
 
 
 
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Display Type
Data Displays Generated
Stats Analysis
Summary
Individual
T
F
L
T
F
F
L

Individual = Represents FL related to any displays of individual subject observed raw data.
8.5.6.
Liver Events
Number and percentage of subjects with liver events will be tabulated by study phase. 
Number and percentage of subjects with clinical significant hepatobiliary laboratory 
abnormalities during the study will also be tabulated. Full information of liver events will 
be listed.
Table 20 provides an overview of the planned liver event analyses, with full details of 
data displays being presented in Appendix 14: List of Data Displays.
Table 20
Overview of Planned Liver Event Analyses
Display Type
Data Displays Generated
Stats Analysis
Summary
Individual
T
F
L
T
F
F
L
Liver Event Analyses 
All liver events
Y
Y
Hepatobiliary 
laboratory 
abnormalities
Y
NOTES:

T = Table, F = Figure, L = Listing, Y = Yes display generated.

Stats Analysis = Represents TFL related to any formal statistical analyses (i.e. modelling) conducted.

Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data.

Individual = Represents FL related to any displays of individual subject observed raw data.
 
 
 
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9.
REFERENCES
Dube MP, Stein JH, Aberg JA, Fichtenbaum CJ, Gerber JG, Tashima KT et al. 
Guidelines for the evaluation and management of dyslipidemia in human 
immunodeficiency virus (HIV)-infected adults receiving antiretroviral therapy: 
recommendations of the HIV Medical Association of the Infectious Disease Society of
America and the Adult AIDS Clinical Trials Group. Clin Infect Dis 2003; 37(5):613-27.
GlaxoSmithKline Document Number 2016N293702_00 (Original – 20-JUL-2017): An 
Open Label, Phase 1 Study to Evaluate the PK, Safety, Tolerability and Acceptability of 
Long Acting Injections of the HIV Integrase Inhibitor, Cabotegravir (CAB; 
GSK1265744) in HIV Uninfected Chinese Men (20-JUL-2017)
Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF, Feldman HI, et.al. A new 
equation to estimate glomerular filtration rate. Ann Int Med. 2009; 150: 604-12.
 
 
 
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10.
APPENDICES
Section
Appendix
RAP Section 4 : Analysis Populations
Section 10.1
Appendix 1: Protocol Deviation Management and Definitions for Per Protocol 
Population
RAP Section 5 : General Considerations for Data Analyses & Data Handling Conventions
Section 10.2
Appendix 2: Time and Events
Section 10.3
Appendix 3: Assessment Windows
Section 10.4
Appendix 4: Treatment States & Phases
Section 10.5
Appendix 5: Data Display Standards & Handling Conventions

Study Treatment & Sub-group Display Descriptors

Baseline Definitions & Derivations

Reporting Process & Standards
Section 10.6
Appendix 6: Derived and Transformed Data

General, Study Population & Safety
Section 10.7
Appendix 7: Premature Withdrawals & Handling of Missing Data

Premature Withdrawals

Handling of Missing Data
Section 10.8
Appendix 8: Values of Potential Clinical Importance
Section 10.9
Appendix 9: Multicentre Studies
Section 10.10
Appendix 10: Examination of Covariates and Subgroups & Other Strata
Section 10.11
Appendix 11: Multiple Comparisons and Multiplicity
Section 10.12
Appendix 12: Model Checking and Diagnostics for Statistical Analyses
Other RAP Appendices
Section 10.13
Appendix 13: Abbreviations & Trade Marks
Section 10.14
Appendix 14: List of Data Displays
 
 
 
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10.1.
Appendix 1: Protocol Deviation Management and Definitions 
for Per Protocol Population
Protocol waivers or exemptions are not allowed with the exception of immediate safety
concerns that may arise after the oral administration of CAB.
Deviations from inclusion and exclusion criteria are not allowed because they can
potentially jeopardize the scientific integrity of the study, regulatory acceptability or
participant safety. Therefore, adherence to the criteria as specified in the protocol is
essential
10.1.1.
Exclusions from Per Protocol Population
Not applicable. Per protocol population is not defined in this study.
 
 
 
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10.2.
Appendix 2: Time & Events
10.2.1.
Protocol Defined Time & Events
Table 21
Schedule of Activitiesq
Clinical Assessments
Screeninga
Oral Phasem Injection Phase
Follow- up Phase
& Final Visit
Day 1
Day 28 (Week 4)
Day 35 (Week 5)
Injection 1
Day 42 (Week 6)
Week 9
Injection 2
Week 10
Week 17
Injection 3
Week 18
Week 25
Injection 4
Week 26
Week 33
Injection 5
Week 34
Week 37
Week 41
Week 53, 65, 77
Week 89
Written informed consent
X
Inclusion/Exclusion criteriab
X
Demographicinformation
X
Full physical exam/medical historyc
X
X
Brief physical exam
X
X
X
X X
X X
X X
X X
X
X
Height/weight/BMId
X
X
Medication/drug/alcohol history
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
Dispense oral study medication (with counseling)e
X
Drug accountability (pill counts)
X
X
 
 
 
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Clinical Assessments
Screeninga
Oral
Phasem
Injection Phase
Follow- up 
Phase
& Final
Visit
Day 1
Day 28 (Week 4)
Day 35 (Week 5)
Injection 1
Day 42 (Week 6)
Week 9
Injection 2
Week 10
Week 17
Injection 3
Week 18
Week 25
Injection 4
Week 26
Week 33
Injection 5
Week 34
Week 37
Week 41
Week 53, 65, 77
Week 89
CAB LA Injection (with counseling)
X
X
X
X
X
HIV-PrevTSQcf
X
ISR AE Diaryg
X
X
X
X
X
AE
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
SAE review (SAE will be collected from 
the signing ofICF)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant medicationcheck
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Vital signsh
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Qualitative HIV RNA by NAATi
X
HIV PoC testj
X
X
X
X
X
X
X
X
X
X
ECGk
X
HbsAg and HbsAb, HCV Antibody
X
Hematology/Chemistry testing
X
X
X
X
X
X
X
X
X
X
X
Urinalysis
X
X
Urine screen for Chlamydiaand
gonorrhea
X
Liver Chemistry Testsl
X
 
 
 
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Clinical Assessments
Screeninga
Oral
Phasem
Injection Phase
Follow- up 
Phase
& Final
Visit
Day 1
Day 28 (Week 4)
Day 35 (Week 5)
Injection 1
Day 42 (Week 6)
Week 9
Injection 2
Week 10
Week 17
Injection 3
Week 18
Week 25
Injection 4
Week 26
Week 33
Injection 5
Week 34
Week 37
Week 41
Week 53, 65, 77
Week 89
Fasting lipid profile
X
X
Coagulation testing
X
X
TRUST for Syphilis screen
X
Plasma for CAB concentrationm,n,o
Xm
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Plasma storagesamplep
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
AE: Adverse events, BMI: Body mass index, CAB: Cabotegravir, CAB LA: Cabotegravir long-acting, ECG: Electrocardiogram, HbsAg: Hepatitis B surface antigen, HIV: Human
Immunodeficiency Virus, HCV: Hepatitis C Virus, ISR: Injection site reactions, SAE: Serious adverse event, HIV-PrevTSQc: HIV-Prevention Treatment Satisfaction
Questionnaire (change): TRUST: Toluidine Red Unheated Serum Test, RNA: Ribonucleicacid.
a.
Screening (including drug screen) is to be performed within 30 days of the first dose in the Oral Phase of the study. See Appendix 2 from the study protocol
b.
Inclusion/exclusion criteria will be fully assessed at the Screening visit. Changes between the screening visit and the Day 1 visit should be assessed to ensure eligibility,
including additional assessments performed at Day 1.
c.
A full physical exam will be performed at Week 89.
d.
Weight will be collected at Screening and at Week 89. Height and BMI will be collected at Screening only.
e.
Oral phase consists of 28 days with a 7 day washout period between Day 28 (last oral dose) and Day 35 (first injection visit).
f.
HIV-PrevTSQc: HIV-Prevention Treatment Satisfaction Questionnaire (change) will be given at Week 10 only (after 2nd injection).
g.
ISR AE 7 Day Post Injection Diary will be distributed at the injection visit at Week 5, 9, 17, 25 and 33 and returned to the clinic at weeks 6, 10, 18, 26, and 34. For
participants having ISR on the last day of week 5, 9, 17, 25 and 33, additional ISR AE Weeks 2 – 12 Post Injection Diary will be distributed at weeks 6,10, 18, and 26,34. 
Participants will be asked to bring the diary to each clinic visit.
h.
Vital sign measurements will be performed following 5 minutes of rest.
i.
Qualitative HIV Nucleic Acid Amplification Testing (NAAT) will be performed at Screening. See Appendix 9 from the study protocol for the HIV testing algorithm at 
screening, Day 1 and during the course of the study.
 
 
 
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j.
HIV PoC (Point of care) test will be performed at each time point during the course of the study and must be reviewed prior to IM dosing. See Appendix 9 from the 
study protocol for the HIV testing algorithm at screening, Day 1 and during the course of the study.
k.
ECGs will be performed following 5 minutes of rest in a semi-supine position.
l.
Liver Chemistry Tests include Alanine aminotransferase (ALT), Aspartate aminotransferase (AST), Bilirubin total and direct.
m.
Oral Pharmacokinetic (PK) sampling at trough will be collected for all subjects prior to dose within 20 to 28 hours following oral administration the day prior. Intensive
oral PK sampling will be collected from approximately16 participants as shown in Table 20.
n.
PK sampling for Injection phase: All PK samples will be collected prior to CAB LA injections at Week 5, 9, 17, 25, and 33 with the exception of 1-week post injection
samples at Weeks 6, 10, 18, 26, 34, 37 (2-week post injection sample) and Week 41
o.
Long-term follow up PK samples: PK sampling during follow up will occur at, Week 53, 65, 77, and 89.
p.
Additional testing is required for participants who have a reactive or positive HIV test after enrolment. Stored plasma from the visit previous to the positive test should be 
tested for HIV using the 4th generation HIV test to best estimate time of infection. HIV acquisition must be confirmed by either western blot, HIV ½ Multispot or the Geenius
HIV Confirmation ½ Assay, and HIV RNA.
q.
Visit may occur in a window ±3 Day
Table 22
Schedule of Intensive Oral PK (Approximately 16 Participants) a,b
Day 25
Day 26
Day 27
Day 28
Check-
in
Oral dose
administered
(e.g. 8AM)
Prior to oral
dose (e.g.
7:55AM)
Oral dose
administered
(e.g. 8AM)
1-
hour post 
dose (e.g.
9AM)
2-hour
post dose
(e.g.
10AM)
3-hour
post dose
(e.g.
11AM)
4-hour 
post dose
(e.g.
12AM)
8-
hour
post 
dose
(e.g.
4PM)
24-
hour post 
dose (e.g.
8AM)
Oral dose
administered
(e.g. after 8 
AM)
Plasma for
CAB
concentration
X
X
X
X
X
X
X
a.
PK sampling may occur 15min
b.
Central lab tests for the intensive oral PK subjects refer to Table 21.
 
 
 
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10.3.
Appendix 3: Assessment Windows
10.3.1.
Assessment Windows
The nominal visit information collected on CRF will be used in the analysis. Analysis 
visit based on the time window will not be defined in this study.
 
 
 
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10.4.
Appendix 4: Study Phase and State
10.4.1.
Treatment Phases
Assessments and events will be classified according to the time of occurrence relative to 
the start date of study treatment.
Treatment Phase
Definition
Screening Phase 
Date < Date of first Oral CAB
Oral Phase
Date of First Oral CAB <= Date <= Date of First CAB LA Injection -1 day; for subjects 
who discontinued before receiving CAB LA Injection, the end date of the oral phase is 
the date of last study visit. 
Injection Phase
Date of First CAB LA Injection <= Date <= 8 weeks after Last CAB LA Injection
Follow-up Phase
Date > 8 weeks after Last CAB LA Injection
10.4.2.
Treatment States
Assessments and events will be classified according to time of occurrence relative to the 
start date of the study treatment.
10.4.2.1.
Treatment States for AE Data
Treatment State
Definition
Screening Phase
AE Start Date < Date of First Oral CAB
On-Oral CAB-
Treatment
Day 1 ≤ AE Start Date ≤Date of First CAB LA Injection – 1; 
for subjects who withdraw from oral CAB treatment, Day 1 ≤ AE Start Date ≤
Withdrawal date + 7 days
On-CAB LA-
treatment
Date of First CAB LA Injection ≤ AE Start Date ≤Date of Week 41 Visit ; 
for subjects who withdraw from CAB LA injection, Date of First CAB LA Injection ≤ AE 
Start Date ≤Date of Last CAB LA Injection + 8 Weeks
Post-Treatment
AE Start Date > Date of Last CAB LA Injection + 8 weeks
Onset Time Since 
1st Dose (Days)
If Date of First Oral CAB (or CAB LA injection) ˃ AE Onset Date, duration = AE Onset 
Date - Treatment Start Date
If Date of First Oral CAB (or CAB LA injection) ≤AE Onset Date, duration = AE Onset 
Date - Treatment Start Date +1
Missing otherwise.
AE Duration 
(Days) 
AE Resolution Date – AE Onset Date + 1
Drug-related
If relationship is marked ‘YES’ on CRF OR value is missing
 
 
 
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10.5.
Appendix 5: Data Display Standards & Handling 
Conventions
10.5.1.
Study Treatment & Sub-group Display Descriptors
Treatment Group Descriptions
Study Group
Data Displays for Reporting 
Code
Description
Description
Order [1]
A
CAB PO 30 mg QD
CAB 30 mg
1
B
CAB LA IM 600 mg Q8W
CAB LA 600 mg
2
NOTES:
1.
Order represents treatments being presented in TFL, as appropriate.
10.5.2.
Baseline Definition & Derivations
10.5.2.1.
Baseline Definitions
The baseline or pre-dose assessment is the last available assessment prior to the time of 
the first dose unless it is specified otherwise.
10.5.2.2.
Derivations and Handling of Missing Baseline Data
Definition
Reporting Details
Change from Baseline
= Post-Dose Visit Value – Baseline
% Change from Baseline
= 100 x [(Post-Dose Visit Value – Baseline) / Baseline]
Maximum Change from Baseline
= Calculate the change from baseline at each given timepoint 
and determine the maximum change
NOTES:

Unless otherwise specified, the baseline definitions specified in Section 10.5.2.1 Baseline Definitions will be used 
for derivations for endpoints / parameters and indicated on summaries and listings.

Unless otherwise stated, if baseline data is missing no derivation will be performed and will be set to missing.

The baseline definition will be footnoted on all change from baseline displays.
10.5.3.
Reporting Process & Standards
Reporting Process
Software

The currently supported versions of SAS software 9.2 or higher and Phoenix WinNonlin will be 
used.
Analysis Datasets 
Analysis datasets will be created according to CDISC standards SDTMIG v3.2 & ADaMIG v1.0
For creation of ADaM datasets (ADCM/ADAE), the same version of dictionary datasets will be 
implemented for conversion from SI to SDTM.
 
 
 
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Reporting Process
Generation of RTF Files

RTF files will be generated for the TLFs. But only compiled PDF file will be used in the delivery.
Reporting Standards
General

The current GSK Integrated Data Standards Library (IDSL) will be applied for reporting, unless 
otherwise stated:
o
4.03 to 4.23: General Principles
o
5.01 to 5.08: Principles Related to Data Listings
o
6.01 to 6.11: Principles Related to Summary Tables
o
7.01 to 7.13: Principles Related to Graphics 
Formats

All data will be reported according to the actual treatment the subject received unless 
otherwise stated.

GSK IDSL Statistical Principles (5.03 & 6.06.3) for decimal places (DP’s) will be adopted for 
reporting of data based on the raw data collected.

Numeric data will be reported at the precision collected on the eCRF.

The reported precision from non eCRF sources will follow the IDSL statistical principles but 
may be adjusted to a clinically interpretable number of DP’s
Planned and Actual Time

Reporting for tables, figures and formal statistical analyses :

Nominal visits collected on the eCRF will be used in figures, summaries, statistical 
analyses and calculation of any derived parameters, unless otherwise stated.

The impact of any major deviation from the planned assessment times and/or scheduled 
visit days on the analyses and interpretation of the results will be assessed as appropriate.

Reporting for Data Listings: 

Planned and actual time relative to study drug dosing will be shown in Pharmacokinetic
listings (Refer to IDSL Statistical Principle 5.05.1).

Unscheduled or unplanned readings will be presented within the subject’s listings. 

Visits outside the protocol defined time-windows (i.e. recorded as protocol deviations) will 
be included in listings but omitted from figures, summaries and statistical analyses.
Unscheduled Visits

Unscheduled visits will not be included in summary tables.

Unscheduled visits will not be included in figures.

All unscheduled visits will be included in listings.
Descriptive Summary Statistics
Continuous Data
Refer to IDSL Statistical Principle 6.06.1
Categorical Data
N, n, frequency, %
Reporting of Pharmacokinetic Concentration Data
Descriptive 
Summary Statistics
Refer to IDSL Statistical Principle 6.06.1
Assign zero to NQ values (Refer to GUI_51487 for further details)
 
 
 
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Reporting Standards
Reporting of Pharmacokinetic Parameters

Reporting for PK tables, figures and listings:

Planned time relative to dosing will be used in mean concentration-time figures and 
summaries, and actual times will be used for individual concentration-time figures.

The impact of any major deviation from the planned assessment times and/or scheduled 
visit days on the analyses and interpretation of the results will be assessed as appropriate.

Visits outside the protocol defined time-windows (i.e. recorded as protocol deviations) will 
be included in all PK figures, summaries and listings.
Descriptive 
Summary Statistics 
(Log Transformed)
N, n, geometric mean, 95% CI of geometric mean, standard deviation (SD) 
of logged data and [between and or within] geometric coefficient of variation 
(CVb (%)) will be reported.
CVb (%) = √ (exp(SD2) - 1) * 100
(SD = SD of log transformed data) 
Parameters Not 
Being Log 
Transformed
tmax, first point, last point, and number of points used in the determination of 
λz.
Summary Tables
The following PK parameters will not be summarised: first point, last point, 
and number of points used in the determination of λz
Listings
Additionally, include the first point, last point and number of points used in 
the determination of lambda_z for listings.
Graphical Displays

Refer to IDSL Statistical Principals 7.01 to 7.13.
 
 
 
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10.6.
Appendix 6: Derived and Transformed Data
10.6.1.
General
Multiple Measurements at One Time Point

If there are two values within a time window the value closest to the target day for that window 
will be used. If values are the same distance from the target then the mean will be taken.

Subjects having both High and Low values for Normal Ranges at any post-baseline visits for 
safety parameters will be counted in both the High and Low categories of “Any visit post-
baseline” row of related summary tables. This will also be applicable to relevant Potential 
Clinical Importance summary tables.
Study Day

Calculated as the number of days from Day 1 Visit:

Ref Date = Missing           → Study Day = Missing 

Ref Date < Date of Day 1 Visit   → Study Day = Ref Date –Date of Day 1 Visit

Ref Date ≥Date of Day 1 Visit
→ Study Day = Ref Date –Date of Day 1 Visit + 1
10.6.2.
Study Population
Demographics
Age

As the month and date of birth will not be collected in the study, the age will be calculated as 
Year of ICF – Year of Birth;

Birth date will be presented in listings as ‘YYYY’.
Body Mass Index (BMI)

Calculated as Weight (kg) / [Height (m)2]
Extent of Exposure

Duration of exposure to study drug will be calculated based on the formula:
o
The duration of exposure for oral phase is defined as the number of days starting from the 
first oral dose to the last oral dose. 
o
Duration of exposure for injection phase is defined as the number of injections (1, 2, 3, 4 or 
5)
o
Overall exposure to CAB is defined as number of days from the first oral dose to 8 weeks 
following the participant’s last injection. If a participant does not enter the injection phase, 
the overall CAB exposure for the study will be defined as the number of days from the first 
oral dose to the last oral dose.
o
Overall exposure to the study (for safety evaluation) is defined as number of days from the 
first dose to last visit (including unscheduled visit) in days.

The cumulative dose will be based on the formula:
o
Cumulative dose in oral phase is defined as (number of tablets dispensed – number of 
tablets returned) * 30 mg
o
Cumulative dose in injection phase is defined as number of injections * 600 mg
 
 
 
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10.6.3.
Safety
Adverse Events
Adverse Events of Special Interest

Diarrhea

Hypertriglyceridemia/ Hypercholesterolemia

Decline in Renal Function

Proximal Renal Tubule Dysfunctions

Proteinuria
Laboratory Parameters

HIV-1 RNA: For summaries and analyses which use HIV-1 RNA level as a continuous measure, 
the logarithm to base 10 of the value will be used.

If a laboratory value which is expected to have a numeric value for summary purposes, has a 
non-detectable level reported in the database, where the numeric value is missing, but typically 
a character value starting with ‘<x’ or ‘>x’ (or indicated as less than x or greater than x in the 
comment field) is present, the number of significant digits in the observed values will be used to 
determine how much to add or subtract in order to impute the corresponding numeric value. 
o
Example 1: 2 Significant Digits = ‘< x’ becomes x – 0.01
o
Example 2: 1 Significant Digit = ‘> x’ becomes x + 0.1
o
Example 3: 0 Significant Digits = ‘< x’ becomes x – 1
 
 
 
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10.7.
Appendix 7: Premature Withdrawals & Handling of Missing 
Data
10.7.1.
Premature Withdrawals
Element
Reporting Detail
General

Subject study completion (i.e. as specified in the protocol) was defined as 
completing all phases of the study including week 89.

If participants prematurely discontinue the oral phase of the study, additional
replacement participants may be recruited at the discretion of the Sponsor. 
Participants who enterthe injection phase of the study will not be replaced

All available data from subjects who were withdrawn from the study will be listed 
and all available planned data will be included in summary tables and figures, 
unless otherwise specified.
10.7.2.
Handling of Missing Data
Element
Reporting Detail
General

Missing data occurs when any requested data is not provided, leading to blank 
fields on the collection instrument:
o
These data will be indicated using a “blank” in subject listing displays. 
Unless all data for a specific visit are missing in which case the data is 
excluded from the table. 
o
Answers such as “Not applicable” and “Not evaluable” are not considered to 
be missing data and should be displayed as such.

Missing endpoints which are not covered in the following rule will not be imputed, 
unless otherwise specified.
Outliers

Any subjects excluded from the summaries and/or statistical analyses will be 
documented along with the reason for exclusion in the clinical study report.
10.7.2.1.
Handling of Missing Dates
Element
Reporting Detail
General
Partial dates will be displayed as captured in subject listing displays.
Adverse 
Events

Completely missing start or end dates will remain missing, with no imputation 
applied. Consequently, time to onset and duration of such events will be 
missing.

Partial missing start or end dates will be imputed using the convention specified 
in Section 10.7.2.2 Handling of Partial Dates
 
 
 
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10.7.2.2.
Handling of Partial Dates
Element
Reporting Detail
Concomitant 
Medications

Partial dates for any concomitant medications recorded in the CRF will be 
imputed using the following convention:
o
If the partial date is a start date, a '01' will be used for the day and 'Jan' will 
be used for the month
o
If the partial date is a stop date, a '28/29/30/31' will be used for the day 
(dependent on the month and year) and 'Dec' will be used for the month.

The recorded partial date will be displayed in listings.
Adverse 
Events

Any partial dates for adverse events will be raised to data management. If the 
full date cannot be ascertained, the following assumptions will be made:
o
If the partial date is a start date, a '01' will be used for the day and 'Jan' will 
be used for the month. 
o
However, if these results in a date prior to Week 1 Day 1 and the event 
could possibly have occurred during treatment from the partial information, 
then the Week 1 Day 1 date will be assumed to be the start date. The AE 
will then be considered to start on-treatment (worst case).
o
If the partial date is a stop date, a '28/29/30/31' will be used for the day 
(dependent on the month and year) and 'Dec' will be used for the month, 
unless this is after the stop date of study treatment; in this case the study 
treatment stop date will be used.

The recorded partial date will be displayed in listings.
10.7.2.3.
Handling of Missing Data for Statistical Analysis
Element
Reporting Detail
N/A
No statistical analysis is planned, unless otherwise specified.
 
 
 
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10.8.
Appendix 8: Values of Potential Clinical Importance
10.8.1.
Laboratory Values
Haematology
Laboratory Parameter
Units
Category
Clinical Concern Range
Low Flag (< x)
High Flag (>x)
Hematocrit 
Ratio of 1
Male
0.54
Female
0.54
∆from BL
↓0.075
Hemoglobin 
g/L
Male
180
Female
180
∆from BL
↓25
Lymphocytes 
x109/ L
0.8
Neutrophil Count 
x109/ L
1.5
Platelet Count 
x109/ L
100
550
While Blood Cell Count (WBC)
x109/ L
3
20
Clinical Chemistry
Laboratory Parameter
Units
Category
Clinical Concern Range
Low Flag (< x)
High Flag (>x)
Albumin 
g/L
30
Calcium
mmol/L
2
2.75
Creatinine
umol/L
∆from BL
↑ 44.2
Glucose
mmol/L
3
9
Phosphorus
mmol/L
0.8
1.6
Potassium
mmol/L
3
5.5
Sodium
mmol/L
130
150
Total CO2
mmol/L
18
32
Liver Function
Test Analyte
Units
Category
Clinical Concern Range
ALT/SGPT 
U/L
High
2x ULN
AST/SGOT 
U/L
High
2x ULN
AlkPhos 
U/L
High
2x ULN
T Bilirubin 
µmol/L
High
1.5xULN
T. Bilirubin + ALT
µmol/L
High
1.5xULN T. Bilirubin
+
U/L
2x ULN ALT
 
 
 
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10.8.2.
ECG
ECG Parameter
Units
Clinical Concern Range
Lower
Upper
Absolute
Absolute QTc Interval
msec
> 450 [1]
> 450 [1]
≤ 479 [1]
≥480 [1]
≤ 499 [1]
≥500 [1]
Absolute PR Interval
msec
< 110 [1]
> 220 [1]
Absolute QRS Interval
msec
< 75 [1]
> 110 [1]
Change from Baseline
Increase from Baseline QTc
msec
> 60 [1]
msec
> 30 [1]
≤ 59 [1]
msec
≥ 60 [1]
NOTES: [Remove footnotes for RAP development]
1.
Represent standard ECG values of PCI for HV studies
2.
Represent further subdivisions of ECG values for analysis whereby the RAP team needs to decide whether these 
need to be generated in addition to standard ECG values being flagged. IF not required, then delete.
10.8.3.
Vital Signs
Vital Sign Parameter
(Absolute)
Units
Clinical Concern Range
Lower
Upper
Systolic Blood Pressure
mmHg
< 85
> 160
Diastolic Blood Pressure
mmHg
< 45
> 100
Heart Rate
bpm
< 40
> 110
Vital Sign Parameter
(Change from Baseline)
Units
Clinical Concern Range
Decrease
Increase
Lower
Upper
Lower
Upper
Systolic Blood Pressure
mmHg
≥20
≥40
≥ 20
≥ 40
Diastolic Blood Pressure
mmHg
≥10
≥20
≥ 10
≥ 20
Heart Rate
bpm
≥15
≥30
≥ 15
≥ 30
NOTES: [Remove footnotes for RAP development]
Represent further subdivisions of BP & HR for analysis whereby the RAP team needs to decide whether these need to 
be generated in addition to standard absolute BP & HR values being flagged. IF not required, then delete.
 
 
 
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10.9.
Appendix 9: Multicenter Studies
10.9.1.
Methods for Handling Centres

In this multicentre study, enrolment will be presented by investigative site.
 
 
 
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10.10.
Appendix 10: Examination of Covariates, Subgroups & 
Other Strata
10.10.1.
Handling of Covariates, Subgroups & Other Strata

Demographic covariates that may be used in descriptive summaries and statistical
analyses, some of which may also be used for subgroup analyses.

Additional covariates of clinical interest may also be considered. 
 
 
 
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10.11.
Appendix 11: Multiple Comparisons & Multiplicity
10.11.1.
Handling of Multiple Comparisons & Multiplicity
Not applicable.
 
 
 
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10.12.
Appendix 12: Model Checking and Diagnostics for 
Statistical Analyses
10.12.1.
Statistical Analysis Assumptions
Endpoint(s)

PK endpoint C
Analysis

ANOVA (primary)

Model assumptions will be applied, but appropriate adjustments maybe made based on the 
data.

The Kenward and Roger method for approximating the denominator degrees of freedom and 
correcting for bias in the estimated variance-covariance of the fixed effects will be used.
 
 
 
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10.13.
Appendix 13 – Abbreviations & Trade Marks
10.13.1.
Abbreviations
Abbreviation
Description
ADaM
Analysis Data Model
AE
Adverse Event
AUC(0-)
Area under the concentration-time curve (AUC) over the dosing interval
C
The observed concentration at the end of the dosing interval
CAB
Cabotegravir
CAB LA
Cabotegravir Long Acting
CDISC
Clinical Data Interchange Standards Consortium
CI
Confidence Interval
CL/F
The apparent clearance (adjusted for bioavailability, F)
Cmax
Maximum observed concentration
CSR
Clinical Study Report
CTMS
Clinical Trial Management System
CVb
Coefficient of Variation (Between)
DOB
Date of Birth
DP
Decimal Places
eCRF
Electronic Case Record Form
GSK
GlaxoSmithKline
HIV
Human Immunodeficiency Virus
ICH
International Conference on Harmonisation
IDSL
Integrated Data Standards Library
IM
Intramuscular
IP
Investigational Product
MedDRA
Medical Dictionary for Regulatory Activities
mg
Milligrams
PCI
Potential Clinical Importance
PK
Pharmacokinetic
PrEP
Pre-exposure prophylaxis
QC
Quality Control
RAP
Reporting & Analysis Plan
SAC
Statistical Analysis Complete
SAS
Statistical Analysis Software
SD
Standard deviation
SDTM
Study Data Tabulation Model
SOP
Standard Operation Procedure
t½
Terminal phase half-life
tmax
Time to first occurrence of Cmax
TFL
Tables, Figures & Listings 
Vz/F
The volume of distribution associated with the terminal phase (adjusted 
for bioavailability, F)
λz
Terminal-phase rate constant
 
 
 
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10.13.2.
Trademarks
Trademarks of the GlaxoSmithKline 
Group of Companies
Trademarks not owned by the 
GlaxoSmithKline Group of Companies
NONE
SAS
Phoenix WinNonlin
 
 
 
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10.14.
Appendix 14: List of Data Displays
10.14.1.
Data Display Numbering
The following numbering will be applied for RAP generated display according to ICH 
standards:
Section
Tables
Figures
Study Population
1.1 to 1.10
NA
Safety
2.1 to 2.32
NA
Pharmacokinetic
3.1 to 3.11
3.1-3.8
Section
Listings
ICH Listings
1-51
10.14.2.
Mock Example Shell Referencing
Non IDSL specifications will be referenced as indicated and if required an example 
mock-up displays provided in Appendix 15: Example Mock Shells for Data Displays.
Section
Figure
Table
Listing
Study Population
POP_Fn
POP_Tn
POP_Ln
Safety
SAFE_Fn
SAFE_Tn
SAFE_Ln
Pharmacokinetic
PK_Fn
PK_Tn
PK_Ln
NOTES: 

Non-Standard displays are indicated in the ‘IDSL / TST ID / Example Shell’ or ‘Programming Notes’ column as 
‘[Non-Standard] + Reference.’
10.14.3.
Deliverable [Priority]
Delivery [Priority] [1]
Description
W41 SAC [1]
Primary Statistical Analysis Complete at Week 41
SAC [1]
Final Statistical Analysis Complete at Week 89
NOTES: 
1.
Indicates priority (i.e. order) in which displays will be generated for the reporting effort.
 
 
 
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10.14.4.
Study Population Tables
Study Population Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable [Priority]
Study Population, Disposition and Demographics
1.1
Screened
SP1
Summary of Study Population
W41 SAC [1], 
SAC [1]
1.2
Screened
ES6
Summary of Screen Status and Reasons for Screen 
Failures
W41 SAC [1], 
SAC [1]
1.3
Screened
ES1
Summary of Subject Disposition for the Subject Conclusion 
Record
W41 SAC [1], SAC [1]
1.4
Safety
SD1
Summary of Treatment Status and Reasons for 
Discontinuation of Study Treatment
W41 SAC [1], SAC [1]
1.5
Safety
DM1
Summary of Demographic Characteristics
W41 SAC [1], SAC [1]
Medical History and Concomitant Medications
1.6
Safety
MH4
Summary of Medical Conditions
.
W41 SAC [1], SAC [1]
1.7
Safety
CM1
Summary of Prior Medications
W41 SAC [1], SAC [1]
1.8
Safety
CM1
Summary of Concomitant Medications
W41 SAC [1], SAC [1]
Protocol Deviations
1.9
Safety
IE1
Summary of Inclusion/Exclusion Criteria Deviations
W41 SAC [1], SAC [1]
1.10
Safety
DV1A
Summary of Important Protocol Deviations
W41 SAC [1], SAC [1]
 
 
 
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10.14.5.
Safety Tables
Safety: Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable [Priority]
Exposure
2.1
Safety 
EX1
Summary of Extent of Exposure
W41 SAC [1], 
SAC [1]
Injection Site Reactions
2.2
Safety 
Injection
Summary of Injection Site Reaction
W41 SAC [1], 
SAC [1]
Adverse Events
2.3
Safety
AE1
Summary of All Adverse Events by System Organ Class
and Preferred Term
W41 SAC [1], SAC [1]
2.4
Safety
AE5B
Summary of All Adverse Events by Maximum Grade by 
System Organ Class and Preferred Term
W41 SAC [1], SAC [1]
2.5
Safety
AE3
Summary of All Grade 2 or Higher Adverse Events by 
Overall Frequency
W41 SAC [1], SAC [1]
2.6
Safety
AE3
Summary of Serious Adverse Events
W41 SAC [1], SAC [1]
2.7
Safety
AE16
Summary of Serious Adverse Events by System Organ 
Class and Preferred Term (Number of Subjects and 
Occurrences)
W41 SAC [1], SAC [1]
2.8
Safety
AE3
Summary of Adverse Events Leading to Permanent 
Discontinuation of Study Drug or Withdrawal from Study
W41 SAC [1], SAC [1]
2.9
Safety
AE1
Summary of Drug-Related Adverse Events
W41 SAC [1], SAC [1]
2.10
Safety
AE1
Summary of Drug-Related Serious Adverse Events
W41 SAC [1], SAC [1]
 
 
 
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Safety: Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable [Priority]
2.11
Safety
AE3
Summary of Drug-related Grade 2 or Higher Adverse 
Events by Overall Frequency
W41 SAC [1], SAC [1]
2.12
Safety
AE3
Summary of Common (>=5%) Adverse Events by Overall 
Frequency
W41 SAC [1], SAC [1]
2.13
Safety
AE15
Summary of Common (>=5%) Non-Serious Adverse 
Events by System Organ Class and Preferred Term 
(Number of Subjects and Occurrences)
W41 SAC [1], SAC [1]
2.14
Safety
AE3
Summary of Common (>=5%) Grade 2-4 Adverse Events 
by Overall Frequency
W41 SAC [1], SAC [1]
2.15
Safety
AE3
Summary of Common (>=5%) Drug-Related Grade 2-4 
Adverse Events by Overall Frequency
W41 SAC [1], SAC [1]
Laboratory Tests
2.16
Safety
Summary of Grade 2 or Higher Laboratory Tests
W41 SAC [1], SAC [1]
2.17
Safety
ES11
Summary of Characteristics of Adverse Events of Special 
Interest
W41 SAC [1], SAC [1]
2.18
Safety
LB1
Summary of Change from Baseline in Hematology and 
Coagulation Data
W41 SAC [1], SAC [1]
2.19
Safety
LB1
Summary of Change from Baseline in Fasting Chemistry
Data and Lipid Profile
W41 SAC [1], SAC [1]
2.20
Safety
UR3
Summary of Urinalysis and Urine Chemistry Results
W41 SAC [1], SAC [1]
2.21
Safety
LB18
Summary of Hematology and Coagulation Grade Shifts 
from Baseline Grade
W41 SAC [1], SAC [1]
2.22
Safety
LB18
Summary of Fasting Chemistry and Lipid Profile Grade 
Shifts from Baseline Grade
W41 SAC [1], SAC [1]
 
 
 
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Safety: Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable [Priority]
2.23
Safety
LB18
Summary of Urinalysis Grade Shifts from Baseline Grade
W41 SAC [1], SAC [1]
Vital Signs
2.24
Safety
VS1
Summary of Change from Baseline in Vital Signs
W41 SAC [1], SAC [1]
2.25
Safety
VS8
Summary of Vital Sign Shifts from Baseline with Respect to 
Clinical Concern Range
W41 SAC [1], SAC [1]
Liver Events
2.26
Safety
LIVER1
Summary of Liver Events Reporting
W41 SAC [1], SAC [1]
2.27
Safety
LIVER10
Summary of Hepatobiliary Laboratory Abnormalities
W41 SAC [1], SAC [1]
 
 
 
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10.14.6.
Tolerability Tables
Tolerability: Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Tolerability of CAB Injection
2.28
Safety 
Injection
Summary of HIV-Prevention Treatment Satisfaction Scores
W41 SAC [1], 
SAC [1]
 
 
 
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10.14.7.
Acceptability Tables
Acceptability: Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Acceptability of the CAB Injection
2.29
Safety
Summary of Acceptability of the CAB LA
W41 SAC [1],
SAC [1]
 
 
 
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10.14.8.
Pharmacokinetic Tables
Pharmacokinetic : Tables
No.
Population
IDSL / TST ID /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Oral Phase
3.1
Oral PK 
PKCT1
Summary of CAB Plasma Pharmacokinetic Concentration-
Time Data – Oral Phase
SAC [1]
3.2
Oral PK 
PKPT4
Summary of Derived CAB Plasma Pharmacokinetic 
Parameters (Non-Transformed) – Oral Phase
Parameters with units 
SAC [1]
3.3
Oral PK 
PKPT4
Summary of Derived CAB Plasma Pharmacokinetic 
Parameters (Log-Transformed) – Oral Phase
Parameters with units 
SAC [1]
Injection Phase (up to Week 41)
3.4
Injection
(Week 41) PK
PKCT1
Summary of CAB Plasma Pharmacokinetic Concentration-
Time Data – Injection Phase (up to Week 41)
W41 SAC [1], 
SAC [1]
3.5
Injection
(Week 41) PK
PKPT4
Summary of Derived CAB Plasma Pharmacokinetic 
Parameters (Non-Transformed) – Injection Phase (up to 
Week 41)
Parameters with units 
W41 SAC [1],
SAC [1]
3.6
Injection
(Week 41) PK
PKPT4
Summary of Derived CAB Plasma Pharmacokinetic 
Parameters (Log-Transformed) – Injection Phase (up to 
Week 41)
Parameters with units 
W41 SAC [1] 
SAC [1]
3.7
Injection
(Week 41) PK
PKPT3
Statistical Analysis of CAB Plasma Accumulation –
Injection Phase (up to Week 41)
Conly for Injection 
Phase at Week 41.
W41 SAC [1], 
SAC [1]
3.8
Injection
(Week 41) PK
PKPT3
Statistical Analysis of CAB Plasma Steady-state Pre-dose 
Concentrations – Injection Phase (up to Week 41)
Conly for Injection 
Phase at Week 41.
W41 SAC [1], 
SAC [1]
 
 
 
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Pharmacokinetic : Tables
No.
Population
IDSL / TST ID /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Injection Phase (up to Week 89)
3.9
Injection
(Week 89) PK
PKCT1
Summary of CAB Plasma Pharmacokinetic Concentration-
Time Data – Injection Phase (up to Week 89)
SAC [1]
3.10
Injection
(Week 89) PK
PKPT4
Summary of Derived CAB Plasma Pharmacokinetic 
Parameters (Non-Transformed) – Injection Phase (up to 
Week 89)
Parameters with units 
SAC [1]
3.11
Injection
(Week 89) PK
PKPT4
Summary of Derived CAB Plasma Pharmacokinetic 
Parameters (Log-Transformed) – Injection Phase (up to 
Week 89)
Parameters with units 
SAC [1]
 
 
 
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10.14.9.
Pharmacokinetic Figures
Pharmacokinetic : Figures
No.
Population
IDSL / TST ID /
Example Shell
Title
Programming 
Notes
Deliverable 
[Priority]
Oral Phase
3.1
Oral PK 
PKCF1P
Individual CAB Plasma Concentration-Time Plots (Linear and 
Semi-Logarithmic) – Oral Phase
SAC [1]
3.2
Oral PK 
PKCF4
Mean (±SD) CAB Plasma Concentration-Time Plots (Linear and 
Semi-Logarithmic) – Oral Phase
SAC [1]
Injection Phase (up to Week 41)
3.3
Injection
(Week 41) PK
PKCF1P
Individual CAB Plasma Concentration-Time Plots (Linear and 
Semi-Logarithmic) – Injection Phase (up to Week 41)
W41 SAC [1], 
SAC [1]
3.4
Injection
(Week 41) PK
PKCF4
Mean (±SD) CAB Plasma Concentration-Time Plots (Linear and 
Semi-Logarithmic) – Injection Phase (up to Week 41)
W41 SAC [1], 
SAC [1]
3.5
Injection
(Week 41) PK
PK26
Individual CAB Plasma Pre-dose Concentration versus Week (Linear 
and Semi-Logarithmic) – Injection Phase (up to Week 41)
W41 SAC [1], 
SAC [1]
3.6
Injection
(Week 41) PK
PK27
Median (range) CAB Plasma Pre-dose Concentration versus Week
(Linear and Semi log) – Injection Phase (up to Week 41)
W41 SAC [1], 
SAC [1]
Injection Phase (up to Week 89)
3.7
Injection
(Week 89) PK
PKCF1P
Individual CAB Plasma Concentration-Time Plots (Linear and 
Semi-Logarithmic) – Injection Phase (up to Week 89)
SAC [1]
3.8
Injection
(Week 89) PK
PKCF4
Mean (±SD) CAB Plasma Concentration-Time Plots (Linear and 
Semi-Logarithmic) – Injection Phase (up to Week 89)
SAC [1]
 
 
 
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10.14.10. ICH Listings
ICH: Listings
No.
Population
IDSL / TST 
ID / Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Study Population, Disposition and Demographics
1
Screened
SP3
Listing of Subjects Excluded from Any 
Population 
W41 SAC [1], SAC 
[1]
2
Screened
ES7
Listing of Reasons for Screen Failure
W41 SAC [1], SAC 
[1]
3
Safety
ES2
Listing of Reasons for Withdrawal
W41 SAC [1], SAC 
[1]
4
Safety
SD2
Listing of Study Drug Discontinuation 
Record
W41 SAC [1], SAC 
[1]
5
Safety
DM2
Listing of Demographic 
Characteristics
W41 SAC [1], SAC 
[1]
6
Safety
EX3
Listing of Exposure Data – Oral Dose
W41 SAC [1], SAC 
[1]
7
Safety
Listing of Exposure Data – Injection
W41 SAC [1], SAC 
[1]
Medical History and Concomitant Medication
8
Safety
MH2
Listing of Medical Conditions
W41 SAC [1], SAC 
[1]
9
Safety
CM5
Listing of Prior Medications
W41 SAC [1], SAC 
[1]
10
Safety
CM5
Listing of Concomitant Medications
W41 SAC [1], SAC 
[1]
 
 
 
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ICH: Listings
No.
Population
IDSL / TST 
ID / Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Protocol Deviations
11
Safety
IE3
Listing of Subjects with 
Inclusion/Exclusion Criteria Deviations
W41 SAC [1], SAC 
[1]
12
Safety
DV2
Listing of Important Protocol 
Deviations
W41 SAC [1], SAC 
[1]
Injection Site Reaction
13
Safety Injection
Listing of Injection Site Reaction –
Daily Diary Card 1
W41 SAC [1],
SAC [1]
14
Safety Injection
Listing of Injection Site Reaction –
Daily Diary Card 2
W41 SAC [1],
SAC [1]
Adverse Events
15
Safety
AE7
Listing of Subject Numbers for 
Individual Adverse Events
W41 SAC [1],
SAC [1]
16
Safety
AE8
Listing of All Adverse Events
W41 SAC [1], SAC 
[1]
17
Safety
AE8CPA
Listing of Serious Adverse Events 
(Fatal and Non-Fatal) 
W41 SAC [1], SAC 
[1]
18
Safety
AE8
Listing of Grader 2 or Higher Adverse 
Events
W41 SAC [1], SAC 
[1]
19
Safety
AE8
Listing of All Adverse Events Leading 
to Premature Discontinuation of Study 
Drug or Withdrawal from Study
W41 SAC [1], SAC 
[1]
20
Safety
AE8
Listing of Adverse Events of Special 
Interest
W41 SAC [1], SAC
[1]
 
 
 
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ICH: Listings
No.
Population
IDSL / TST 
ID / Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
21
Safety
Listing of Possible Suicidality-Rated 
Adverse Events
W41 SAC [1], SAC 
[1]
22
Safety
AE2
Listing of Relationship Between 
System Organ Classes and Verbatim 
Text
W41 SAC [1], SAC 
[1]
23
Safety
AE14
Listing of Reasons for Considering as 
a Serious Adverse Event
W41 SAC [1], SAC 
[1]
Deaths
24
Safety
Listing of Death
W41 SAC [1], SAC 
[1]
Laboratory Tests
25
Safety
LB5
Listing of Chemistry Data and Fasting 
Lipid Profile
W41 SAC [1], SAC 
[1]
26
Safety
LB5
Listing of Hematology and 
Coagulation Data
W41 SAC [1], SAC 
[1]
27
Safety
UR2a
Listing of Urinalysis and Urine 
Chemistry Data
W41 SAC [1], SAC 
[1]
28
Safety
LB5
Listing of Laboratory Data for Subjects 
with Grade 2 or Higher Abnormalities
W41 SAC [1], SAC 
[1]
29
Safety
LB14
Listing of HIV Tests
W41 SAC [1], SAC 
[1]
30
Safety
LB5
Listing of Local Lab Data
W41 SAC [1], SAC 
[1]
 
 
 
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ICH: Listings
No.
Population
IDSL / TST 
ID / Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Vital Sign
31
Safety
VS4
Listing of Vital Signs
W41 SAC [1], SAC 
[1]
32
Safety
VS4
Listing of Vital Signs for Subjects with 
Any Value of Potential Clinical 
Importance
W41 SAC [1], SAC 
[1]
ECG’s
33
Safety
Listing of ECG Results
W41 SAC [1], SAC 
[1]
Social Harm
34
Safety
Listing of Social Harm
W41 SAC [1], SAC 
[1]
Cardiovascular Event
35
Safety
Listing of Cardiovascular Event
W41 SAC [1], SAC 
[1]
Liver Event
36
Safety
Listing of Liver Event
W41 SAC [1], SAC 
[1]
Tolerability of CAB Injection
37
Safety Injection 
Listing of HIV-Prevention Treatment 
Satisfaction Questionnaire
W41 SAC [1], SAC 
[1]
 
 
 
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ICH: Listings
No.
Population
IDSL / TST 
ID / Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Acceptability of the CAB Injection
38
Safety 
Listing of Acceptability of the CAB LA
W41 SAC [1],
SAC [1]
Pharmacokinetic
39
Oral PK 
PKCL1P
Listing of CAB Plasma
Pharmacokinetic Concentration-Time 
Data – Oral Phase
Please list all the concentration data including 
unscheduled.
SAC [1]
40
Oral PK 
PKPL1P
Listing of Derived CAB Plasma 
Pharmacokinetic Parameters – Oral 
Phase
SAC [1]
41
Injection
(Week 41) PK
PKCL1P
Listing of CAB Plasma
Pharmacokinetic Concentration-Time 
Data – Injection Phase (up to Week 
41)
Please list all the concentration data including 
unscheduled.
W41 SAC [1], 
SAC [1]
42
Injection
(Week 41) PK
PKPL1P
Listing of Derived CAB Plasma 
Pharmacokinetic Parameters –
Injection Phase (up to Week 41)
W41 SAC [1],
SAC [1]
43
Injection
(Week 89) PK
PKCL1P
Listing of CAB Plasma
Pharmacokinetic Concentration-Time 
Data – Injection Phase (up to Week 
89)
Please list all the concentration data including 
unscheduled.
SAC [1]
44
Injection
(Week 89) PK
PKPL1P
Listing of Derived CAB Plasma 
Pharmacokinetic Parameters –
Injection Phase (up to Week 89)
SAC [1]
 
 
 
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10.14.11. Non-ICH Listings
Non-ICH: Listings
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
 
 
 
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10.15.
Appendix 15: Example Mock Shells for Data Displays
Data Display Specification will be made available on Request
 
 
 
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