Clinical trial NCT03149848
Conditions: Infection, Human Immunodeficiency Virus HIV Infections
Keywords: Tuberculosis Human Immunodeficiency Virus Rifabutin Drug-drug interaction Cabotegravir
Sponsor: ViiV Healthcare
Start date: 2017-06-06; Completion date: 2017-09-07
Enrollment: 15 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
This is a Phase I, single-center, open-label, fixed-sequence, 2-period crossover study in healthy adults to evaluate the effect of oral rifabutin (RBT) 300 milligram (mg) on the pharmacokinetics of oral cabotegravir (CAB) 30 milligram ( mg). This study will evaluate the drug-drug interaction (DDI) potential between CAB and RBT to inform dosing strategies for tuberculosis in subjects receiving CAB for human immunodeficiency virus (HIV) treatment or prevention. In Treatment Period 1 (Treatment A) participants will receive CAB 30 mg once daily for 14 days, followed by Treatment Period 2 (Treatment B) where participants will receive RBT 300 mg once daily with CAB 30 mg once daily for 14 days. The total study duration will be approximately for 10 weeks. Approximately 15 healthy subjects will be enrolled to ensure that 12 subjects complete dosing and critical assessments.

Detailed description:

Arms: arm 1: Participants will be administered a single oral dose of CAB 30 mg after an overnight fast of at least 6 hours for 14 days in Period 1. Dosing of study medication on non-PK days may be with or without food. arm 2: Participants will be administered a single dose of RBT 300 mg and a single dose of CAB 30 mg after an overnight fast of at least 6 hours once daily for 14 days in Period 2. Dosing of study medication on non-PK days may be with or without food.
Interventions: intervention 1: Cabotegravir intervention 2: Rifabutin
Intervention descriptions: intervention 1: It will be available as a white aquarius film coated tablet for oral administration. CAB Tablet is composed of GSK1265744B (micronized) lactose monohydrate, microcrystalline cellulose, hypromellose, sodium starch glycolate, magnesium stearate intervention 2: It will be available as an opaque red-brown hard gelatin capsules containing 150 mg of rifabutin for oral administration. These capsules are composed of rifabutin, microcrystalline cellulose, sodium lauryl sulphate, magnesium stearate, and silica gel

Protocol documents:
Prot_000.pdf: 
2016N269788_02
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The GlaxoSmithKline group of companies
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TITLE PAGE
Division: Worldwide Development
Information Type: Protocol Amendment
Title:
Phase I, single-center, open label, fixed-sequence cross-over 
study to evaluate the effect of rifabutin on the pharmacokinetics
of oral cabotegravir in healthy subjects
Compound Number:
GSK1265744
Development Phase:
I
Effective Date:
29-JUN-2017
Protocol Amendment Number:  2
Author (s):
Director of Clinical Development, ViiV
Director of Clinical Development, ViiV
Quantitative Clinical Development, PAREXEL
Clinical Statistics, PAREXEL
Clinical Pharmacology Team Leader, ViiV
Clinical Pharmacology Science and Study Operations
Copyright 2017 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited.
PPD


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Revision Chronology
GlaxoSmithKline
Document Number
Date
Version
2016N269788_00
2017-FEB-23
Original
2016N269788_01
2017-APR-13
Amendment No. 1
The purpose of this protocol amendment is to update Appendix 12.5.1.” Modified List of 
Highly Effective Methods for Avoiding Pregnancy in Females of Reproductive Potential 
(FRP)” The updates include clarifying true abstinence for this study and the deletion of 
double barrier method: condom and occlusive cap (diaphragm or cervical/vault caps) plus 
spermicidal agent foam/gel/film/cream/suppository) as a highly effective method for 
avoiding pregnancy in females of reproductive potential (FRP) .
2016N269788_02
2017-JUN-29
Amendment No. 2
The purpose of this protocol amendment is to:
Clarify the required days for fasting (Day 14 and Day 28). 
Remove Appendix 12.4.3- Definition of Cardiovascular Events. The collection of 
Cardiovascular Events is not applicable to the 205712 study.


PPD
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MEDICAL MONITOR/SPONSOR INFORMATION PAGE
Medical Monitor/SAE Contact Information: 
Role
Name
Day Time Phone 
Number and 
email address
After-hours 
Phone/Cell/
Pager 
Number
Fax Number
Site Address
Primary 
Medical 
Monitor 
 
DO, MSc
ViiV 
Healthcare
5 Moore Drive,
Research 
Triangle Park, 
NC  27709
Secondary 
Medical 
Monitor
 
MD
ViiV 
Healthcare
5 Moore Drive,
Research 
Triangle Park, 
NC  27709
SAE 
contact  
information
 
DO, MSc
, DO
Sponsor Legal Registered Address:
This study is sponsored by ViiV Healthcare.  GlaxoSmithKline is implementing and 
managing all aspects of this study.
ViiV Registered Address
ViiV Healthcare
980 Great West Road
Brentford
Middlesex, TW8 9GS
UK
GlaxoSmithKline Research & Development Limited
980 Great West Road
Brentford
Middlesex, TW8 9GS
UK
PPD
PPD
PPD
PPD
PPD


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In some countries, the clinical trial sponsor may be the local GlaxoSmithKline Affiliate 
Company (or designee). If applicable, the details of the alternative Sponsor and contact 
person in the territory will be provided to the relevant regulatory authority as part of the 
clinical trial application.   
Regulatory Agency Identifying Number(s): 109,678


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INVESTIGATOR PROTOCOL AGREEMENT PAGE
For protocol number 205712 Amendment 2
I confirm agreement to conduct the study in compliance with the protocol, as amended by 
this protocol amendment.
I acknowledge that I am responsible for overall study conduct. I agree to personally 
conduct or supervise the described study.
I agree to ensure that all associates, colleagues and employees assisting in the conduct of 
the study are informed about their obligations. Mechanisms are in place to ensure that site 
staff receives the appropriate information throughout the study. 
Investigator Name:
Investigator Address:
Investigator Phone Number:
Investigator Signature
Date


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TABLE OF CONTENTS
PAGE
1.
PROTOCOL SYNOPSIS FOR STUDY 205712......................................................10
2.
INTRODUCTION....................................................................................................12
2.1.
Study Rationale ..........................................................................................12
2.2.
Brief Background ........................................................................................12
3.
OBJECTIVES AND ENDPOINTS...........................................................................14
4.
STUDY DESIGN ....................................................................................................14
4.1.
Overall Design ............................................................................................14
4.2.
Treatment Periods and Duration.................................................................15
4.3.
Type and Number of Subjects.....................................................................16
4.4.
Design Justification.....................................................................................16
4.5.
Dose Justification........................................................................................16
4.6.
Benefit: Risk Assessment ...........................................................................17
4.6.1.
Risk Assessment-Cabotegravir....................................................18
4.6.2.
Risk Assessment-Rifabutin ..........................................................20
4.6.3.
Other Clinically Relevant Information...........................................21
4.6.4.
Benefit Assessment.....................................................................22
4.6.5.
Overall Benefit: Risk Conclusion..................................................22
5.
SELECTION OF STUDY POPULATION AND WITHDRAWAL CRITERIA .............22
5.1.
Inclusion Criteria.........................................................................................22
5.2.
Exclusion Criteria........................................................................................24
5.3.
Screening/Baseline/Run-in Failures............................................................26
5.4.
Withdrawal/Stopping Criteria.......................................................................26
5.4.1.
Ocular Stopping Criteria...............................................................27
5.4.2.
Liver Chemistry Stopping Criteria ................................................27
5.4.2.1.
Study Treatment Restart or Rechallenge....................28
5.4.3.
QTc Stopping Criteria ..................................................................28
5.4.4.
Neutropenia Stopping Criteria......................................................29
5.4.5.
Uveitis Stopping Criteria ..............................................................29
5.5.
Subject and Study Completion....................................................................29
6.
STUDY TREATMENT ............................................................................................29
6.1.
Investigational Product and Other Study Treatment....................................29
6.2.
Treatment Assignment................................................................................30
6.3.
Blinding.......................................................................................................30
6.4.
Packaging and Labeling..............................................................................30
6.5.
Preparation/Handling/Storage/Accountability..............................................31
6.6.
Compliance with Study Treatment Administration.......................................31
6.7.
Treatment of Study Treatment Overdose....................................................32
6.8.
Treatment after the End of the Study ..........................................................32
6.9.
Lifestyle and/or Dietary Restrictions............................................................32
6.9.1.
Meals and Dietary Restrictions ....................................................32
6.9.2.
Caffeine, Alcohol, and Tobacco ...................................................32
6.9.3.
Activity .........................................................................................33
6.10.
Concomitant Medications and Non-Drug Therapies....................................33


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6.10.1.
Permitted Medications and Non-Drug Therapies..........................33
6.10.2.
Prohibited Medications and Non-Drug Therapies.........................33
7.
STUDY ASSESSMENTS AND PROCEDURES .....................................................33
7.1.
Time and Events Table...............................................................................35
7.2.
Screening and Critical Baseline Assessments ............................................38
7.3.
Safety .........................................................................................................38
7.3.1.
Adverse Events (AE) and Serious Adverse Events (SAEs)..........38
7.3.1.1.
Time period and Frequency for collecting AE 
and SAE information...................................................38
7.3.1.2.
Method of Detecting AEs and SAEs ...........................39
7.3.1.3.
Follow-up of AEs and SAEs........................................39
7.3.1.4.
Regulatory Reporting Requirements for SAEs............39
7.3.2.
Pregnancy ...................................................................................40
7.3.3.
Physical Exams ...........................................................................40
7.3.4.
Vital Signs....................................................................................40
7.3.5.
Electrocardiogram (ECG).............................................................40
7.3.6.
Clinical Safety Laboratory Assessments ......................................41
7.4.
Pharmacokinetics .......................................................................................42
7.4.1.
Blood Sample Collection..............................................................42
7.4.2.
Sample Analysis ..........................................................................43
7.5.
Genetics .....................................................................................................43
8.
DATA MANAGEMENT ...........................................................................................43
9.
STATISTICAL CONSIDERATIONS AND DATA ANALYSES .................................43
9.1.
Hypotheses.................................................................................................43
9.1.1.
Primary Comparisons of Interests................................................44
9.2.
Sample Size Considerations.......................................................................44
9.2.1.
Sample Size Assumptions ...........................................................44
9.2.2.
Sample Size Sensitivity................................................................44
9.2.3.
Sample Size Re-estimation or Adjustment...................................44
9.3.
Data Analysis Considerations .....................................................................45
9.3.1.
Analysis Populations....................................................................45
9.3.2.
Interim Analysis ...........................................................................45
9.4.
Key Elements of Analysis Plan ...................................................................45
9.4.1.
Primary Analyses.........................................................................46
9.4.2.
Secondary Analyses ....................................................................46
9.4.3.
Other Analyses ............................................................................47
10. STUDY GOVERNANCE CONSIDERATIONS........................................................47
10.1.
Posting of Information on Publicly Available Clinical Trial Registers............47
10.2.
Regulatory and Ethical Considerations, Including the Informed 
Consent Process ........................................................................................47
10.3.
Quality Control (Study Monitoring) ..............................................................48
10.4.
Quality Assurance.......................................................................................48
10.5.
Study and Site Closure ...............................................................................48
10.6.
Records Retention......................................................................................49
10.7.
Provision of Study Results to Investigators, Posting of Information 
on Publically Available Clinical Trials Registers and Publication .................50
11. REFERENCES.......................................................................................................51


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12. APPENDICES........................................................................................................54
12.1.
Appendix 1 – Abbreviations and Trademarks..............................................54
12.2.
Appendix 2: Liver Safety Required Actions and Follow up 
Assessments ..............................................................................................57
12.3.
Appendix 3 - Genetic Research ..................................................................59
12.3.1.
References ..................................................................................61
12.4.
Appendix 4: Definition of and Procedures for Recording, Evaluating, 
Follow-Up and Reporting of Adverse Events...............................................62
12.4.1.
Definition of Adverse Events........................................................62
12.4.2.
Definition of Serious Adverse Events...........................................63
12.4.3.
AEs of Special Interest:................................................................64
12.4.4.
Recording of AEs and SAEs ........................................................65
12.4.5.
Evaluating AEs and SAEs............................................................65
12.4.6.
Reporting of SAEs to GSK...........................................................67
12.5.
Appendix 5: Modified List of Highly Effective Methods for Avoiding 
Pregnancy in FRP and Collection of Pregnancy Information.......................68
12.5.1.
Modified List of Highly Effective Methods for Avoiding 
Pregnancy in Females of Reproductive Potential (FRP) ..............68
12.5.2.
Collection of Pregnancy Information ............................................68
12.5.3.
References ..................................................................................69
12.6.
Appendix 6:  Division Of AIDS Table For Grading The Severity Of 
Adult And Pediatric Adverse Events Version 2.0, November 2014..............71
12.7.
Appendix 7: Toxicity Management ..............................................................90
12.8.
Appendix 8: Protocol Changes....................................................................95
12.8.1.
Protocol Changes for Amendment 01 ..........................................95
12.8.2.
Protocol Changes for Amendment 02 (29-JUN-2017) from 
Amendment 1 (13-Apr-2017) .......................................................96


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1.
PROTOCOL SYNOPSIS FOR STUDY 205712
Rationale
Cabotegravir (CAB) is a 2-metal binding integrase inhibitor being developed for the 
treatment and prevention of HIV-1 infection as both an oral and long acting (LA) 
injectable nanosuspension.  Rifabutin (RBT) is an antimycobacterial agent used for the 
treatment of tuberculosis as well as for both treatment and prevention of Mycobacterium 
avium intracellulare (MAC) in advanced HIV infection in individuals with low CD4 cell 
counts. RBT is chemically related to rifampin (RIF), the latter is a potent inducer of UDP 
(Uridine 5'-diphospho-glucuronosyltransferase) -glucuronosyltransferases (UGTs) and 
Cytochrome P450 3A4 (CYP3A4).  RBT appears to induce P450 enzymes and UGTs as 
well, although not as potently as RIF. CAB is primarily metabolized via UGT1A1 and 
UGT1A9.  Evidence from the human mass balance and related metabolite identification 
studies suggests that the CYP enzyme involvement in the metabolism of CAB is likely to 
be minimal. Given that RBT is considered to be a weak enzyme inducer, it is anticipated 
that RBT will modestly reduce CAB exposures during concomitant administration.  This 
study is being conducted to evaluate the drug-drug interaction (DDI) potential between 
CAB and RBT to inform dosing strategies for tuberculosis in subjects receiving CAB for 
HIV treatment or prevention.
Objectives/Endpoints
Objectives
Endpoints
Primary

To compare steady state CAB exposure 
following 30 mg oral dose once  daily 
with and without RBT 300 mg once 
daily

Plasma CAB AUC(0-), Cmax 
Secondary

To describe the pharmacokinetic (PK) 
of CAB 30 mg oral dose once daily 
administered alone and with RBT

Plasma CAB C, tmax, t1/2, CL/F 

To assess the safety and tolerability of 
CAB 30 mg oral dose alone  and in 
combination with RBT 300 mg oral 
dose once daily

Safety and tolerability parameters, 
including adverse events, 
concurrent medication, clinical 
laboratory screens, 
electrocardiogram (ECG), and vital 
signs assessments.


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AUC(0-t) = area under the plasma concentration time curve from time zero to the last 
quantifiable time point
Cmax = maximum observed concentration
Ct = last quantifiable concentration 
tmax = time of maximum observed concentration
t1/2 = the elimination half-life

CL/F = apparent oral clearance
Overall Design
This is a Phase I, single-center, open-label, fixed-sequence, 2-period crossover study in 
healthy adults to evaluate the effect of RBT on the PK of oral CAB 30 mg.
Study Design
Subjects
Screening Period
Period 1 
Days 1 – 14
Period 2 
Days 15 - 28 
Follow-up
N=15 
Within  30 Days of Day 1
Treatment A: once 
daily  x 14 days
Treatment B: once 
daily  x 14 days
~10-14 days after last 
dose of CAB

Treatment A = CAB 30 mg once daily x 14 days

Treatment B =  RBT 300 mg once daily + CAB 30 mg once daily x 14 days
Treatment Periods and Duration
This study will take place in two treatment periods and a follow-up period.  All subjects 
will undergo a screening visit within 30 days from the first dose of study drug.  The 
overall study duration will be approximately 10 weeks (4 weeks screening, 2 weeks for 
treatment Period 1, 2 weeks for treatment Period 2, and 2 week follow-up period).
Treatment Period 1: Treatment A: CAB 30 mg once daily x 14 days
Treatment Period 2: Treatment B: RBT 300 mg once daily + CAB 30 mg once daily x 14 
days
Type and Number of Subjects

Approximately 15 healthy adult subjects will be enrolled to ensure that 12 subjects 
will complete dosing and critical assessments.  

If subjects prematurely discontinue the study, additional replacement subjects may 
be enrolled and assigned to the same treatment sequence at the discretion of the 
Sponsor in consultation with the investigator.
Analysis
No formal hypothesis will be tested. An estimation approach will be used to evaluate the 
effect of RBT on CAB PK parameters. Point estimates and corresponding 90% 
confidence intervals (CIs) will be constructed for the comparisons of interest 
(test:reference).


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2.
INTRODUCTION
2.1.
Study Rationale
Cabotegravir (CAB) is a 2-metal binding integrase inhibitor being developed for the 
treatment and prevention of Human immunodeficiency virus-1 (HIV-1) infection as both 
an oral and long acting (LA) injectable nanosuspension. 
Tuberculosis (TB)/HIV co-infection is common and both conditions often need to be 
treated simultaneously. RIF is a backbone component of TB treatment regimens and is a 
potent inducer of UDP-glucuronosyltransferases (UGTs) and Cytochrome P450 3A4 
(CYP3A4).  CAB is primarily metabolized via UGT1A1 and UGT1A9. Evidence from 
the human mass balance and related metabolite identification studies suggests that the 
CYP enzyme involvement in the metabolism of CAB is likely to be minimal. A reduction 
in CAB serum concentrations due to drug-drug interaction with RIF could lead to a risk 
of treatment failure and the emergence of HIV drug resistance. RIF increased CAB oral 
clearance 2.4-fold and reduced CAB AUC(0- τ)) and terminal phase t1/2 by 59% and 
57%, respectively. RIF had no effect on CAB Cmax. Therefore, co-administration of RIF 
with oral CAB 30mg once daily is not recommended [Ford, 2016].  
RBT is an alternative anti-mycobacterial agent used for the treatment of tuberculosis.  
RBT is chemically related to RIF and is considered a weaker enzyme inducer of UGTs 
and CYP3A as compared to RIF.  The effect of RBT on the PK of CAB has not been 
studied to date. Raltegravir (RAL) is an integrase inhibitor that is also primarily 
metabolized via UGT1A1.  RAL area under the concentration-time curve over 12 hours
(AUC[0-12]) increased by 19% while minimum observed concentration (Cmin) 
decreased by 20% during concurrent RBT administration [Brainard, 2011].  Dolutegravir 
(DTG), another marketed HIV integrase inhibitor, is primarily metabolized via UGT1A1 
with a minor CYP3A component.  Following co-administration of DTG 50 mg once daily 
with RBT 300 mg once daily, DTG AUC(0-) was unchanged [GMR (90% CI) 0.95 
(0.82, 1.10)], Cmax was increased 15% [GMR (90% CI) 1.15 (0.97 ,1.36)], and Cwas 
decreased 30%  [GMR (90% CI) 0.70 (0.57 ,0.87)], [GlaxoSmithKline Document 
Number RM2008/00856/00 ITZ111839 ; Ford, 2013]. Based on RBT drug-drug 
interaction (DDI) data with RAL and DTG, a significant DDI between CAB and RBT is 
not expected.  Because CAB does not induce or inhibit RBT metabolizing enzymes, the 
impact of CAB on RBT PK will not be evaluated in this study. 
This DDI study will evaluate the impact of RBT on the pharmacokinetics of CAB.  The 
results of this study will inform dosing strategies for the management of tuberculosis in 
patients receiving CAB for HIV treatment or prevention
2.2.
Brief Background
Tuberculosis (TB) is surpassed only by human immunodeficiency virus (HIV) as a cause 
of infectious disease-associated deaths worldwide [Frieden, 2003]. In 2012, 1.1 million 
of an estimated 8.6 million people who developed TB worldwide were HIV-positive 
[World Health Organization, 2014]. Given that the yearly incidence of TB is 10% in 
HIV-infected individuals, concomitant treatment for TB is common [Maartens, 2007].  


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Increasingly, the two diseases will be treated concurrently in co-infected individuals.  
Two recent studies evaluating the optimal timing for initiation of highly active 
antiretroviral therapy (HAART) in subjects requiring treatment for active TB 
demonstrated a survival benefit for treating HIV during TB treatment rather than waiting 
until after TB treatment completion [Abdool, 2010a; Abdool, 2010b].  However, co-
treatment is complex and difficult owing to drug-drug interactions, immune 
reconstitution inflammatory syndrome, and overlapping toxicities [McIlleron, 2007].
Although TB is a global issue, the geographic distribution of cases is drastically 
disproportionate.  The spread of HIV and multidrug resistance has fuelled the TB 
epidemic, and in less-developed countries, TB is the most common cause of death in 
HIV-infected patients [Corbett, 2003].  Ninety-five percent of all TB cases and 98% of all 
TB deaths occur in developing countries.  Only 22 high-burden countries (HBCs) account 
for 80% of the global TB burden, with half of these countries located within Asia.  In 
Africa, 40 countries have an estimated TB prevalence rate greater than 100/100,000 
compared to the estimated prevalence rate of <5/100,000 in the United States [U.S. 
Department of Health and Human Services, 2014].  
Currently, rifamycins serve as the cornerstone of TB therapy because of their unique 
sterilizing activity. RIF (rifampicin), the most commonly-used rifamycin, is a semi-
synthetic rifamycin derivative that is highly active against mycobacteria, most gram-
positive bacteria, and some gram-negative bacteria. It is bactericidal for both 
intracellular and extracellular microorganisms. By inhibiting prokaryotic 
deoxyribonucleic acid (DNA) -dependent ribonucleic acid (RNA) polymerase, it 
suppresses the early elongation of the nucleotide chain in RNA synthesis.  RIF is a potent 
inducer of a number of hepatic enzymes involved in the metabolism of drugs and some 
hormones, including UGTs and CYP450 enzymes [Venkatesan, 1992].  Significant 
enzyme induction from RIF limits concurrent use with many antiretroviral agents, 
therefore RBT may be an alternative due to its weak enzyme induction potential.  Most 
antiretrovirals can be co-administered with RBT without dose adjustment, including the 
integrase inhibitors, raltegravir and dolutegravir, however, enzyme induction or inhibition 
by non-nucleoside reverse transcriptase inhibitors and boosted protease inhibitors, require 
dose modification of RBT in some cases [Yapa, 2016]. 
As of October 18 2016, the efficacy, safety, and PK of CAB have been evaluated in 19 
(15 completed, 2 concluded and 2 ongoing) Phase I/IIa ViiV sponsored clinical trials with 
oral CAB and CAB LA. Subjects have been exposed to single oral doses of CAB 
ranging from 5-150 mg and repeat once daily doses of 30 mg for 10-28 days in duration.
There have been no deaths or drug-related SAEs. There were no clinically significant 
trends in lab events, ECG, or vital sign changes, or QTcF >500 msec or QTcF change 
from baseline >60 msec. Refer to the Investigators Brochure (IB) for additional 
information.


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3.
OBJECTIVES AND ENDPOINTS
Primary

To compare steady state CAB 
exposure following 30 mg oral dose 
once daily with and without RBT 
300 mg once daily.

Plasma CAB AUC(0-), Cmax 
Secondary

To describe the pharmacokinetic
(PK) of CAB 30 mg oral dose once 
daily administered alone and co-
administered with RBT.

Plasma CAB C, tmax, t1/2,  CL/F

To assess the safety and tolerability 
of CAB 30 mg oral dose administered 
alone and in combination with RBT 
300 mg once daily.

Safety and tolerability parameters, 
including adverse events, concurrent 
medication, clinical laboratory 
screens, electrocardiogram (ECG), 
and vital signs assessments.
AUC(0-t) = area under the plasma concentration time curve from time zero to the last 
quantifiable time point
Cmax = maximum observed concentration
Ct = last quantifiable concentration 
tmax = time of maximum observed concentration
t1/2 = the elimination half-life

CL/F = apparent oral clearance
4.
STUDY DESIGN
4.1.
Overall Design
This study is a phase I, single-center, open label, fixed-sequence, 2-period crossover 
study in healthy adults to evaluate the effect of RBT on the PK of oral CAB 30 mg. 
Table 1
Study Design
Subjects
Screening Period
Period 1 
Days 1 – 14
Period 2 
Days 15 - 28 
Follow-up
N=15 
Within  30 Days of Day 1
Treatment A
Treatment B
~10-14 days after last 
dose of CAB

Treatment A = CAB 30 mg once daily x 14 days

Treatment B =  RBT 300 mg once daily + CAB 30 mg once daily x 14 days


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4.2.
Treatment Periods and Duration
Subjects will undergo a screening visit within 30 days of the first dose of study drug, 
followed by two treatment periods and a follow-up period. 
Subjects will undergo clinical safety assessments and serial PK assessments at time-
points specified in Section 7.1, Time and Events table of the protocol. 
Period 1  
Eligible participants will be admitted to the unit on Day -1.  
On Day 1, following completion of the required pre-dose measurements, the investigator 
or authorized study unit personnel will administer a single oral dose of 30 mg CAB to 
each subject in the unit.
Subjects will be dispensed a bottle of CAB to be taken at home on Days 2-12 and 
discharged from the unit. Subjects will be provided with a subject diary to document 
daily recordings of dosing occurring outside of the unit.  Subjects will be re-admitted to 
the unit in the morning on Day 13. Prior to dosing, a CAB PK sample will be obtained, 
and then the subjects will receive a single 30 mg dose of CAB on Day 13 and remain in 
the unit overnight.  On Day 14, following an overnight fast of at least 6 hours, subjects 
will receive a single 30 mg dose of CAB with serial CAB PK samples collected pre-dose 
and through 24 hours after dosing up to Day 15.  There will be no washout between 
Period 1 and Period 2.
Period 2
On Day 15 following the completion of the required Day 14 safety assessments and PK 
collection, subjects will proceed to Period 2, where site staff will administer a single dose 
of RBT 300 mg and a single dose of CAB 30 mg in the unit. Subjects will be discharged 
and dispensed a bottle of RBT and a bottle of CAB to be taken at home on Days 16-20. 
Subjects will be provided with a subject diary to document daily recordings of home 
dosing. In the morning of Day 21, subjects will bring their bottle of RBT and bottle of 
CAB for observed dosing in the unit and safety assessments as an outpatient visit.   
Following these procedures, subjects will be discharged with their supply of CAB and 
RBT and instructed to take their daily doses of study medications at home in the 
mornings of Days 22 through 25. On Day 26, subjects will return to the unit for a pre-
dose PK collection and observed dosing as an outpatient visit and then be discharged 
home. On Day 27, subjects will be re-admitted to the unit for a pre-dose PK collection, 
observed dosing, and safety assessments then remain in the unit overnight. In the 
morning of Day 28 following an overnight fast of at least 6 hours, subjects will receive a 
single dose of RBT and a single dose of CAB in the unit with serial CAB PK samples 
collected pre-dose and through 24 hours after dosing up to Day 29. Subjects will be 
discharged from the unit on Day 29 after the final assessment is completed.  Subjects will 
complete a follow-up visit ~ 10-14 days after the last 30 mg oral dose of CAB.


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At the follow-up visit, laboratory safety assessments (including pregnancy test for 
females of childbearing potential) will be performed, and vital signs together with a 
12-lead ECG will be obtained.
4.3.
Type and Number of Subjects

Approximately 15 healthy adult subjects will be enrolled to ensure that 12 subjects 
will complete dosing and critical assessments.

If subjects prematurely discontinue the study, additional replacement subjects may be 
allocated and assigned to the same treatment sequence (A then B) at the discretion of 
the Sponsor in consultation with the investigator.
4.4.
Design Justification
This open-label, fixed sequence, cross-over design is well-established for evaluation of 
drug-drug interaction potential of a perpetrator drug (e.g., RBT) to affect the 
pharmacokinetics of a victim drug (e.g., CAB).  Conducting the study in a fixed sequence 
with daily administration of CAB 30 mg/day for 14 days and then assessing CAB PK 
over 24 hours after the Day 14 dose of CAB will enable characterization of CAB PK by 
itself.  This will avoid the possibility for any inductive effect caused by RBT dosing prior 
to oral administration of CAB alone, as would be the case if the study treatments were to 
be randomized.  Then, in the second treatment period, oral co-administration of RBT 
300 mg once daily and CAB 30 mg once daily for 14 days with the assessment of CAB 
PK over 24 hours after the Day 28 dosing of CAB and RBT will facilitate assessment of 
CAB PK in the presence of RBT at steady-state to observe the likely maximum inductive 
impact of RBT. 
The study is subject to the appropriate regulatory approval and Ethics Committee 
approval, and will be listed on the website ClinicalTrials.gov.  No blinding or placebo 
control will be used, as these are not necessary for the purposes of this study.
4.5.
Dose Justification
A CAB 30 mg single dose was selected for this study as it is the oral induction dose that 
is currently under investigation in the ongoing Phase 2b treatment studies [Protocols 
GlaxoSmithKline Document Number 2012N134026_01,  GlaxoSmithKline Document 
Number 2013N168152_04, 200056] and is the oral induction dose taken into the Phase 3 
studies (the FLAIR and ATLAS studies).  Additionally, for PrEP studies in healthy, 
uninfected subjects, the 30 mg oral dose has been selected for oral lead-in therapy prior to 
injectable dosing in the completed ECLAIR study [Protocol GlaxoSmithKline Document 
Number 2013N184048_01, 201120 and the DAIDS Document ID: 11964 HPTN 077, 
2014 . In two oral relative bioavailability studies [GlaxoSmithKline Document Number 
2012N136689_00, LAI116585 and GlaxoSmithKline Document Number 
2013N165475_00, LAI117020], CAB AUC(0-) was well-estimated with 168 hrs of 
sampling following single dose CAB 30 mg (sodium salt tablet formulation). For these 
two studies, geometric mean AUC(0-) values were 174g*h/mL and 141g*h/mL, and 
Cmax values were 4.24 g/mL and 3.70 g/mL. Assuming a maximal induction effect by 


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RBT of 70-80% reduction, CAB exposure may approximate that of a 5-10 mg oral dose, 
the PK for which has also been well-characterized following single dose administration. 
RBT 300 mg once daily was selected for this study not only for its role as an alternative 
rifamycin for anti-tuberculosis therapy but also because it is the recommended dose for as 
it is the recommended dose for the prevention of disseminated Mycobacterium avium 
complex (MAC) in patients with advanced HIV infection (CD4+ cell count  <200/mm3 
with an AIDS defining diagnosis, or CD4+ cell count  <100/mm3 without an AIDS 
defining diagnosis). The terminal half-life of RBT is approximately 38 hours. Enzyme 
induction by RBT has been demonstrated to occur within 7 days of therapy and auto-
induction of its own metabolism has been demonstrated to occur within 10 days in 
healthy volunteers [Perruca, 1988].  RBT 300 mg (two 150 mg capsules) once daily will 
be administered for 14 days with CAB 30 mg (one 30 mg tablet) once daily for 14 days in 
Treatment Period 2 to ensure that the maximal inductive effect of RBT is achieved. 
The duration of dosing in this study was chosen partly based on scientific convention 
with similar P1 drug-drug interaction studies and particular to this protocol, because of 
the importance of achieving a steady state concentration of study drug (CAB) before PK 
analyses of CAB are performed during Period 1 of the study. Similarly, in Period 2 of the 
study, a similar rationale for duration of 14 days applies to the combination of CAB and 
RBT as well. Oral CAB has a terminal phase elimination t½ of approximately 40 hours 
and reaches steady state by 10-12 days of once daily administration, supporting 14 days 
of dosing in this study [GlaxoSmithKline Document Number 2012N136689_00, 
LAI116585]. Before obtaining PK assessments, both CAB and RBT need to reach steady 
state and 14 days is sufficient time for that to occur. 
4.6.
Benefit: Risk Assessment
Summaries of findings from both clinical and non-clinical studies conducted with 
GSK1265744 (CAB) can be found in the Investigator’s Brochure. The following section 
outlines the risk assessment and mitigation strategy for this protocol:  


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4.6.1.
Risk Assessment-Cabotegravir
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Investigational Product (IP) Cabotegravir 
Drug Induced Liver Injury (DILI)
A small proportion of participants in the 
CAB program to date (total exposure 
approximately 1289 as of 01 October 2016) 
have developed transaminitis (elevated liver 
transaminases characterised by predominant 
alanine aminotransferase [ALT] elevation).  
In some of these participants, transient 
transaminitis was explained by acute 
hepatitis C infection whilst a small number 
of others did not have alternative 
explanations, suggesting a mild form of 
DILI without hepatic dysfunction which 
resolved upon withdrawal of treatment with 
CAB. 
Of the five participants with possible or 
probable cases of DILI identified in Phase 2 
studies, four participants were receiving oral 
CAB and one participant developed 
probable DILI following CAB LA or 
Placebo LA administration.  
Exclusion criteria as described in 
Section 5.2 will prohibit participants 
with significant liver impairment based 
on prior medical history and screening 
liver chemistry including transaminases 
(ALT and Aspartate aminotransferase
[AST]). 
Liver transaminases (ALT and AST) 
will be closely monitored throughout 
this study (refer to Time & Events 
Table) and the liver chemistry stopping 
criteria will be adopted as described in 
Section 5.4.2 of this protocol. 
All instances of liver transaminase 
elevations of Grade 2 and above will be 
followed to resolution.  Participants 
withdrawn from CAB treatment due to 
meeting liver chemistry stopping criteria 
will be regularly monitored both 
clinically and using liver chemistries to 
determine progress towards resolution of 
the liver event.


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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Investigational Product (IP) Cabotegravir 
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. 
Clinical assessments, laboratory tests 
(including liver transaminases) and vital 
signs will be performed throughout this 
study (refer to Time & Events Table).  
Results from these assessments may aid 
early detection of HSR.
Oral CAB will be withdrawn 
immediately for cases with suspected 
HSR. Any HSR reactions that occur 
would be managed supportively.


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4.6.2.
Risk Assessment-Rifabutin
Adverse reactions identified through post-marketing surveillance by system organ class 
(SOC) include: blood cell disorders (agranulocytosis, lymphopenia, granulocytopenia, 
neutropenia, leukopenia, and thrombocytopenia), immune system disorders 
(hypersensitivity, bronchospasm, rash, and eosinophilia), and gastrointestinal disorders 
(Clostridium difficile colitis/ Clostridium difficile associated diarrhea). Pyrexia, rash and 
other hypersensitivity reactions such as eosinophilia and bronchospasm might occur, as 
has been seen with other anti-bacterials. A limited number of skin discolorations have 
been reported. Hypersensitivity to rifamycins has been reported including flu-like 
symptoms, bronchospasm, hypotension, urticaria, angioedema, conjunctivitis, 
thrombocytopenia or neutropenia. See below for the Rifabutin risk assessment and 
mitigation strategy for this protocol.
Neutropenia: Neutropenia is commonly experienced in patients receiving RBT and 
rapidly resolves with discontinuation of RBT.  Subjects will have frequent hematology 
laboratory monitoring and the neutropenia stopping rule is in place, see Section 5.4.4.
Uveitis: Subjects will be followed for development of ocular AEs since RBT has been 
associated with this complication, although it is rare when administered as 300 mg/day. 
Uveitis can develop from 2 weeks to more than 7 months after initiation of RBT 
treatment [Tseng, 1995]. Discontinuation of RBT or dose reduction generally results in 
resolution of uveitis and complete recovery of visual acuity is typical with drug 
withdrawal and topical treatment. Subjects with evidence of new ocular symptoms 
consistent with uveitis (eye pain, eye redness, light sensitivity, blurriness or change in 
vision, that is not attributed to allergic, infectious (bilateral viral/bacterial conjunctivitis 
or HSV keratitis), acute angle-closure glaucoma, corneal abrasions, scleritis, or secondary 
to trauma including intraocular foreign body will be discontinued from study treatment, 
and referred to ophthalmology for evaluation and appropriate treatment. Refer to Ocular 
stopping criteria, Section 5.4.1
Hypersensitivity Reaction (HSR): Clinical assessments, laboratory tests (including liver 
transaminases) and vital signs assessments will be performed throughout this study (refer 
to Time & Events Table).  Results from these assessments may aid early detection of 
HSR. RBT will be withdrawn immediately for cases with suspected HSR. Any HSRs that 
occur would be managed supportively.
Risk Assessment- Rifabutin 
Potential Risk of 
Clinical 
Significance
Summary of 
Data/Rationale for Risk
Mitigation Strategy
Neutropenia
Neutropenia is commonly 
experienced in patients 
reeiving RBT and rapidly 
resolves with 
discontinuation of RBT

Subjects in protocol 205712 will have frequent 
hematology laboratory monitoring and a 
neutropenia stopping rule is in place, see 
Section 5.4.4


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Potential Risk of 
Clinical 
Significance
Summary of 
Data/Rationale for Risk
Mitigation Strategy
Uveitis
While RBT can cause 
uveitis, the condition occurs 
more often with higher 
doses than what is being 
evaluated in this study 
(300 mg).                               

While the likelihood of uveitis is low with the 
dose used in 205712, patients with a current of 
past history of uveitis will be excluded from this 
study (exclusion criteria #7). Also, a uveitis 
stopping criteria (Section 5.4.1) has been added 
to the protocol and subjects who develop eye 
pain, eye redness, blurry vision or 
photosensitivity not attributed to allergic, 
infectious (bilateral viral/bacterial conjunctivitis 
or HSV keratitis), acute angle-closure glaucoma, 
corneal abrasions, scleritis, or secondary to 
trauma (including intraocular foreign body) will 
be discontinued from study treatment, and 
referred to ophthalmology for evaluation and 
appropriate treatment. Medical monitor will be 
notified if a patient develops any signs or 
symptoms of acute uveitis as noted above.
Hypersensitivity 
Reaction (HSR)
While not commonly 
described, HSR can occur 
with the administration of 
any medicinal product 
including RBT
Clinical assessments, laboratory tests (including liver 
transaminases) and vital signs will be performed 
throughout this study (refer to Time & Events 
Table).  Results from these assessments may aid 
early detection of HSR. RBT will be withdrawn 
immediately for cases with suspected HSR. Any 
HSR reactions that occur would be managed 
supportively.
For risks associated with trade name, please refer to the Summary of Product 
Characteristics (SmPC) [Summary of Product Characteristics for Mycobutin, January 
2016].SmPC will serve as the reference safety information for Mycobutin. 
4.6.3.
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. Please refer to Section 6: ‘Summary of Data 
and Guidance for the Investigator’. 
Adverse Events of Special Interest
Seizure
Three cases of seizures have occurred in the cabotegravir programme cumulatively 
through 01 October 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 
[GlaxoSmithKline Document Number 2013N168152_04, 200056] with circumstantial 
and anecdotal evidence of illicit drug use. Overall, there is not convincing evidence that 


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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 all studies. Subjects with recent history of, or recent 
treatment for seizure will be excluded from study participation.
4.6.4.
Benefit Assessment
Subjects participating in the study will not receive any clinical benefit, but will be 
compensated for their time and participation.
4.6.5.
Overall Benefit: Risk Conclusion
Taking into account the measures taken to minimize risk to subjects participating in this 
study, the potential risks identified in association with CAB and RBT are justified by the 
anticipated benefits that may be afforded to subjects with HIV and to those healthy 
subjects who may benefit from CAB as a preventative agent for acquisition of HIV.
5.
SELECTION OF STUDY POPULATION AND 
WITHDRAWAL CRITERIA
Specific information regarding warnings, precautions, contraindications, adverse events, 
and other pertinent information on the GlaxoSmithKline (GSK) investigational product or 
other study treatment that may impact subject eligibility is provided in the IB for 
cabotegravir (CAB) and the Product Monograph for Mycobutin Capsules (rifabutin 
capsules).
Deviations from inclusion and exclusion criteria are not allowed because they can 
potentially jeopardize the scientific integrity of the study, regulatory acceptability or 
subject safety. Therefore, adherence to the criteria as specified in the protocol is essential.
5.1.
Inclusion Criteria
Specific information regarding warnings, precautions, contraindications, adverse events, 
and other pertinent information on the ViiV Healthcare investigational product or other 
study treatment that may impact subject eligibility is provided in the Investigators 
Brochure (IB). 
A subject will be eligible for inclusion in this study only if all of the following criteria 
apply:


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AGE
1. Males and females between 18 and 65 years of age inclusive, at the time of signing 
the informed consent.
TYPE OF SUBJECT AND DIAGNOSIS INCLUDING DISEASE SEVERITY
2. Healthy as determined by the investigator or medically qualified designee based on a 
medical evaluation including medical history, physical examination, laboratory tests 
and cardiac monitoring.
3. A subject with a clinical abnormality or laboratory parameter(s) which is/are not 
specifically listed in the inclusion or exclusion criteria, outside the reference range for 
the population being studied may be included only if the investigator in consultation 
with the Medical Monitor agree and document that the finding is unlikely to introduce 
additional risk factors and will not interfere with the study procedures. Additionally, 
laboratory assessments that are specifically listed in the inclusion or exclusion criteria 
and are outside of the reference range can be repeated once during the screening 
period. 
WEIGHT
4. Body weight 50 kg and body mass index (BMI) within the range 18.5 – 31.0 kg/m2 
(inclusive). 
SEX
5. Male or female
A female subject is eligible to participate if she is not pregnant (as confirmed by a 
negative serum human chorionic gonadotrophin (hCG) test), not lactating, and at least 
one of the following conditions applies:
a. Non-reproductive potential defined as:

Pre-menopausal with one of the following:

Documented tubal ligation

Documented hysteroscopic tubal occlusion procedure with follow-up 
confirmation of bilateral tubal occlusion 

Hysterectomy

Documented Bilateral Oophorectomy
Postmenopausal defined as 12 months of spontaneous amenorrhea [in 
questionable cases a blood sample with simultaneous follicle stimulating 
hormone (FSH) and estradiol levels consistent with menopause FSH: 
>40 MIU/mL and estradiol <40 pg/mL (<147 pmol/L) is confirmatory].  
b. Reproductive potential and agrees to follow one of the options listed in the 
Modified List of Highly Effective Methods for Avoiding Pregnancy in Females 
of Reproductive Potential (FRP) (see Appendix 5: Modified List of Highly 
Effective Methods for Avoiding Pregnancy in FRP and Collection of Pregnancy 


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Information) from 30 days prior to the first dose of study medication until the 
completion of the follow-up visit.
The investigator is responsible for ensuring that subjects understand how to properly use 
these methods of contraception.
INFORMED CONSENT
6. Capable of giving signed informed consent as described in Section 10.2 which 
includes compliance with the requirements and restrictions listed in the consent form 
and in this protocol.
ACCEPTABLE LIVER CHEMISTRY AND HEMATOLOGY CRITERIA
7. ALT, alkaline phosphatase and bilirubin ≤1xULN (isolated bilirubin >1.5xULN is 
acceptable if bilirubin is fractionated and direct bilirubin <35%).
8. White blood cell count and absolute neutrophil count in the normal range.
5.2.
Exclusion Criteria
A subject will not be eligible for inclusion in this study if any of the following criteria 
apply:
CONCURRENT CONDITIONS/MEDICAL HISTORY (INCLUDES LIVER 
FUNCTION AND QTc INTERVAL) 
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 clinically significant cardiovascular disease including: 
a.
Exclusion criteria for screening ECG (a single repeat is allowed for eligibility 
determination):
Males
Females
Heart rate
<45 and >100 beats per 
minute
<50 and >100 beats per 
minute
QRS duration
>120 msec
QTc interval (F)
>450 msec
b. Evidence of previous myocardial infarction (pathologic Q waves, S-T
segment changes (except early repolarization).
c.
History/evidence of symptomatic arrhythmia, angina/ischemia, coronary 
artery bypass grafting (CABG) surgery or percutaneous transluminal 
coronary angioplasty (PCTA) or any clinically significant cardiac disease.
d. Conduction abnormality (including but not specific to left or right complete 
bundle branch block, AV block [2nd degree (type II) or higher], Wolf 
Parkinson White [WPW] syndrome) which in the opinion of the principal 
Investigator and Viiv Medical Monitor, will interfere with the safety for the 
individual subject.


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e.
Sinus pauses >3 seconds. 
f.
Any significant arrhythmia which, in the opinion of the principal Investigator 
and ViiV Medical Monitor, will interfere with the safety for the individual 
subject. 
g. Non-sustained (3 consecutive ventricular ectopic beats) or sustained 
ventricular tachycardia.
NOTES:

The QTc is the QT interval corrected for heart rate according to Fridericia’s 
formula (QTcF), machine-read or manually over-read.
3. History of inflammatory bowel disease.
4. History of cholecystectomy or other gastrointestinal surgery (except appendectomy 
more than three months prior to study). 
5. History of peptic ulceration or pancreatitis within the preceding 6 months of 
screening.
6. 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. 
7. Current or past history of uveitis.
8. Any other medical condition which, in the judgment of the investigator and medical 
monitor, could jeopardize the safety of the subject or the integrity of the data derived 
from that subject. This includes but is not limited to any pre-existing condition that 
interferes with normal gastrointestinal anatomy or motility that could interfere with 
the absorption, metabolism, and/or excretion of the study drug.
CONCOMITANT MEDICATIONS
9. Unable to refrain from the use of prescription or non-prescription drugs, including 
vitamins, herbal and dietary supplements (including St John’s Wort) within 7 days (or 
14 days if the drug is a potential enzyme inducer) or 5 half-lives (whichever is longer) 
prior to the first dose of study medication, unless in the opinion of the Investigator 
and Viiv Medical Monitor the medication will not interfere with the study procedures 
or compromise subject safety. See Section 6.10.2 for concomitant medications that 
are prohibited for this study.
RELEVANT HABITS
10. History of regular alcohol consumption within 6 months of the study defined as an 
average weekly intake of >14 drinks. One drink is equivalent to 12 g of alcohol, 12 
ounces (360 mL) of beer, 5 ounces (150 mL) of wine or 1.5 ounces (45 mL) of 80 
proof distilled spirits.
11. A history of regular use of tobacco, or nicotine-containing products within 30 days 
prior to screening.


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CONTRAINDICATIONS 
12. History of sensitivity to any of the study medications, or components thereof or a 
history of drug or other allergy that, in the opinion of the investigator or Medical 
Monitor, contraindicates their participation.
DIAGNOSTIC ASSESSMENTS AND OTHER CRITERIA
13. Presence of Hepatitis B surface antigen (HBsAg) positivity at screening or within 3 
months prior to first dose of study treatment.  Positive Hepatitis B core antibody 
(HBcAb) with negative hepatitis B surface antibody should also be excluded. 
14. Positive Hepatitis C antibody test.
15. A positive pre-study drug/alcohol screen.  
16. A positive test for HIV antibody.
17. A positive QuantiFERON Gold test or clinical evidence of tuberculosis (TB) 
infection.
18. Where participation in the study would result in donation of blood or blood products 
in excess of 500 mL within a 56 day period.
19. The subject has participated in a clinical trial and has received an investigational 
product within the following time period prior to the first dosing day in the current 
study: 30 days, 5 half-lives or twice the duration of the biological effect of the 
investigational product (whichever is longer).
20. Exposure to more than four new chemical entities within 12 months prior to the first 
dosing day.
5.3.
Screening/Baseline/Run-in Failures
Screen failures are defined as subjects who consent to participate in the clinical trial but 
are never subsequently randomized. In order to ensure transparent reporting of screen 
failure subjects, meet the Consolidated Standards of Reporting Trials (CONSORT) 
publishing requirements, and respond to queries from Regulatory authorities, a minimal 
set of screen failure information is required including Demography, Screen Failure 
details, Eligibility Criteria, and Serious Adverse Events (see Section 7.3.1.4).  Data for 
screen and baseline failures will be collected in source documentation at the site and will 
be transmitted to GSK.
5.4.
Withdrawal/Stopping Criteria
The following actions must be taken in relation to a subject who fails to attend the clinic 
for a required study visit:

The site must attempt to contact the subject and re-schedule the missed visit as 
soon as possible. 

The site must counsel the subject on the importance of maintaining the 
assigned visit schedule and ascertain whether or not the subject wishes to 
and/or should continue in the study. 


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
In cases where the subject is deemed ‘lost to follow up’, the investigator or 
designee must make every effort to regain contact with the subject (where 
possible, 3 telephone calls and if necessary a certified letter to the subject’s 
last known mailing address or local equivalent methods). These contact 
attempts should be documented in the subject’s medical record. 

Should the subject continue to be unreachable, only then will he/she be 
considered to have withdrawn from the study with a primary reason of “Lost 
to Follow-up”. 
A subject may withdraw from 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, behavioural or 
administrative reasons. If a subject withdraws from the study, he/she may request 
destruction of any samples taken, and the investigator must document this in the site 
study records. 
During the treatment phase, pre-specified reasons for discontinuing a participant from the 
study (or, discontinuing administration of study product and continuing safety 
evaluations) may include:

Pregnancy (please see Section 7.3.2)

Protocol deviation

Non-compliance

Subject withdraws consent

Subject lost to follow-up

Investigator discretion

Sponsor discontinues study
5.4.1.
Ocular Stopping Criteria
Subjects who develop eye pain, eye redness, blurry vision or photosensitivity not 
attributed to allergic or infectious (bilateral viral/bacterial conjunctivitis or HSV keratitis) 
causes, or to, acute angle-closure glaucoma, corneal abrasions, scleritis, or secondary to 
trauma (including intraocular foreign body) will be discontinued from study treatment, 
and referred to ophthalmology for evaluation and appropriate treatment. Medical monitor 
should be notified if a patient develops any signs or symptoms of acute uveitis as noted 
above.
5.4.2.
Liver Chemistry Stopping Criteria
Liver chemistry stopping and increased monitoring criteria have been designed to 
assure subject safety and evaluate liver event etiology (in alignment with the FDA 
premarketing clinical liver safety guidance). See Appendix 2 for details. 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf
Study treatment will be discontinued for a subject if liver chemistry stopping criteria are 
met:


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Figure 1
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 2.
5.4.2.1.
Study Treatment Restart or Rechallenge
Study treatment restart or rechallenge after liver chemistry stopping criteria are met by 
any subject participating in this study is not allowed.
Refer to Appendix 2 for full guidance. 
5.4.3.
QTc Stopping Criteria

Fridericia’s QT correction formula must be used for each individual subject to 
determine eligibility for and discontinuation from the study.  This formula may not 
be changed or substituted once the subject has been enrolled.
Fridericia’s QT correction formula must continue to be used for that subject for all QTc 
data being collected for data analysis.  Safety ECGs and other non-protocol specified 
ECGs are an exception.  

The QTc should be based on single or averaged QTc values of triplicate 
electrocardiograms obtained over a brief (e.g., 5-10 minute) recording period and 
then use the averaged QTc values of the 3 ECGs to determine whether the subject 
should be discontinued from the study.  
A subject that meets either bulleted criterion below will be withdrawn from the study. 

QTcF> 500 msec,

Change from baseline: QTc >60 msec


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5.4.4.
Neutropenia Stopping Criteria
Subjects with an absolute neutrophil count (ANC) less than 1 x10^9/L will be 
discontinued from study treatment. The presence of ANC less than 1 x10^9/L and a 
single measured temperature of >38.3 oC or a sustained temperature of ≥ 38 oC (100.4 oF) 
for more than one hour refers to neutropenic fever and subjects should be referred for 
urgent evaluation and appropriate management.
5.4.5.
Uveitis Stopping Criteria
Subjects who develop eye pain, eye redness, blurry vision or photosensitivity not 
attributed to allergic, infectious (bilateral viral/bacterial conjunctivitis or herpes simplex 
virus [HSV] keratitis), acute angle-closure glaucoma, corneal abrasions, scleritis, or 
secondary to trauma (including intraocular foreign body) will be discontinued from study 
treatment, and referred to ophthalmology for evaluation and appropriate treatment. 
Medical monitor should be notified if a patient develops any signs or symptoms of acute 
uveitis as noted above.
5.5.
Subject and Study Completion
A completed subject is one who has completed all phases of the study including the 
follow-up visit.
The end of the study is defined as the last subject’s last visit.
6.
STUDY TREATMENT
6.1.
Investigational Product and Other Study Treatment
The term ‘study treatment’ is used throughout the protocol to describe any combination 
of products received by the subject as per the protocol design. Study treatment may 
therefore refer to the individual study treatments or the combination of those study
treatments.


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Table 2
Investigational Treatment and Other Study Treatment
Study Treatment
Product name:
Cabotegravir Tablets, 30 mg
MYCOBUTIN Capsules (rifabutin capsules) 
sourced in the United Kingdom (UK)
Formulation 
description:
GSK1265744B (micronized) lactose 
monohydrate, microcrystalline cellulose, 
hypromellose, sodium starch glycolate, 
magnesium stearate, Aquarius film-
coating, white BP18237
Rifabutin, microcrystalline cellulose, sodium 
lauryl sulphate, magnesium stearate, and 
silica gel.
Rifabutin supplied as hard gelatin capsules 
having an opaque red-brown cap and body, 
each containing 150 mg of rifabutin.
Dosage form:
Tablet
Capsule
Unit dose 
strength(s)/Dosage 
level(s):
Tablet strength: 30 mg/Dose level:  30 mg
Capsule strength = 150 mg
Dose level = 300 mg
Route of 
Administration:
Administer orally
Administer orally
Dosing instructions1:
Administer 1 tablet with 240 mL of water 
once daily
Administer 2 capsules with 240 mL of water 
once daily.
Manufacturer/Source 
of Procurement:
GlaxoSmithKline
Pfizer Limited
Ramsgate Road
Sandwich
Kent CT139NJ
United Kingdom
Method of 
individualizing 
dosage:
30 mg = one 30 mg tablet
300 mg = two 150 mg capsules
1 Dosing of study medication on non-PK days may be with or without food, but dosing on serial PK days (Day 14 in 
Period 1 and Day 28 in Period 2) must be after an overnight fast of at least 6 hours, and no food will be allowed for 
4 hours after dosing on these serial PK days.
6.2.
Treatment Assignment
In this study, following the 30 day screening period, subjects will be assigned to a single 
sequence in accordance with the single sequence schedule generated by Clinical 
Statistics, prior to the start of the study, using validated internal software.
Treatment Assignment for 205712

Treatment A = CAB 30 mg once daily x 14 days

Treatment B =  RBT 300 mg once daily + CAB 30 mg once daily x 14 days
6.3.
Blinding
This study is not blinded.
6.4.
Packaging and Labeling
The contents of the label will be in accordance with all applicable regulatory 
requirements.


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6.5.
Preparation/Handling/Storage/Accountability
No special preparation of study treatment is required.

Only subjects 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 labelled 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).

Further guidance and information for final disposition of unused study treatment 
are provided in the Study Reference Manual (SRM).

Under normal conditions of handling and administration, study treatment is not 
expected to pose significant safety risks to site staff.  Take adequate precautions 
to avoid direct eye or skin contact and the generation of aerosols or mists. In the 
case of unintentional occupational exposure notify the monitor, Medical Monitor 
and/or GSK study contact.

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.
6.6.
Compliance with Study Treatment Administration
When the individual dose for a subject is prepared from a bulk supply, the preparation of 
the dose will be confirmed by a second member of the study site staff. 
When subjects 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 subject 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.  
Study site personnel will examine each subject’s mouth to ensure that the study treatment 
was ingested. 
When subjects self-administer study treatment(s) at home, compliance with CAB and  
RBT dosing will be assessed through verifying the diary entries and querying the subject 
during the site visits and documented in the source documents and case report form 
(CRF).  A record of the number of CAB and RBT capsules dispensed to and taken by
each subject must be maintained and reconciled with study treatment and compliance 
records.  Treatment start and stop dates will also be recorded in the CRF.


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6.7.
Treatment of Study Treatment Overdose
For this study, any dose of CAB >30 mg and RBT >300 mg within a 12 hour time period 
will be considered an overdose.
In the event of an overdose of RBT, and depending on the degree of overdose and 
investigator evaluation, gastric lavage and diuretic treatment should be carried out.
Supportive care and symptomatic treatment should be administered [Summary of Product 
Characteristics for Mycobutin, January 2016].
GSK does not recommend specific treatment for an overdose of CAB.  
In the event of an overdose the investigator should:
1. contact the Medical Monitor immediately
2. closely monitor the subject for AEs/ SAEs and laboratory abnormalities until CAB 
and RBT can no longer be detected systemically (at least 14 days for CAB)
3. obtain a plasma sample for pharmacokinetic (PK) analysis within 60 hours 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.
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 subject.
6.8.
Treatment after the End of the Study
Subjects will not receive any additional treatment from GSK after completion of the 
study because only healthy volunteers are eligible for study participation.
6.9.
Lifestyle and/or Dietary Restrictions
6.9.1.
Meals and Dietary Restrictions

Subjects must refrain from consumption of red wine, Seville oranges, grapefruit 
or grapefruit juice and/or pummelos, exotic citrus fruits, grapefruit hybrids or fruit 
juices from 7 days prior to the first dose of study medication until after the final 
PK sample.

Dosing of study medication on non-PK days may be with or without food, but 
dosing on serial PK days (Day 14 in Period 1 and Day 28 in Period 2) must be 
after an overnight fast of at least 6 hours, and no food will be allowed for 4 hours 
after dosing on these serial PK days.
6.9.2.
Caffeine, Alcohol, and Tobacco

During each treatment period, subjects will abstain from ingesting caffeine- or 
xanthine-containing products (e.g., coffee, tea, cola drinks and chocolate) for 


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24 hours prior to the start of dosing until collection of the final PK sample of the 
study. 

During each treatment period, subjects will abstain from alcohol for 24 hours 
prior to the start of dosing until collection of the final PK of the study. 

Use of tobacco products is not allowed from screening until after the final follow-
up visit.
6.9.3.
Activity
Subjects will abstain from strenuous exercise for 48 hours prior to each blood collection 
for clinical laboratory tests.  Subjects may participate in light recreational activities 
studies (e.g., watch television, read).
6.10.
Concomitant Medications and Non-Drug Therapies
6.10.1.
Permitted Medications and Non-Drug Therapies
Acetaminophen /Paracetamol, at doses of ≤2 grams/day is permitted for use any time 
during the study.  Other concomitant medications may be considered on a case by case 
basis by the Investigator in consultation with the Medical Monitor if required.
6.10.2.
Prohibited Medications and Non-Drug Therapies
Subjects must abstain from taking prescription or non-prescription drugs (including 
vitamins and dietary or herbal supplements), within 7 days (or 14 days if the drug is a 
potential enzyme inducer) or 5 half-lives (whichever is longer) prior to the first dose of 
study medication until completion of the follow-up visit, unless in the opinion of the 
Investigator and sponsor the medication will not interfere with the study.
Use of antacids, vitamins and iron supplements are strictly prohibited within 7 days (or 
14 days if the drug is a potential enzyme inducer) or 5 half-lives (whichever is longer) 
prior to the first dose of study medication and for the duration of the trial.
7.
STUDY ASSESSMENTS AND PROCEDURES
Protocol waivers or exemptions are not allowed with the exception of immediate safety 
concerns.  Therefore, adherence to the study design requirements, including those 
specified in the Time and Events Table, are essential and required for study conduct.
This section lists the procedures and parameters of each planned study assessment.  The 
exact timing of each assessment is listed in the Time and Events Table Section 7.1.

If assessments are scheduled for the same nominal time, THEN the assessments 
should occur in the following order:
1. 12-lead ECG
2. vital signs
3. blood draws.  


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
Note: The timing of the assessments should allow the blood draw to occur at the 
exact nominal time.

The timing and number of planned study assessments, including safety, 
pharmacokinetic, pharmacodynamic/biomarker or other assessments may be 
altered during the course of the study based on newly available data (e.g., to 
obtain data closer to the time of peak plasma concentrations) to ensure 
appropriate monitoring. 

The change in timing or addition of time points for any planned study 
assessments must be documented in a Note to File which is approved by the 
relevant GSK study team member and then archived in the study sponsor and 
site study files, but this will not constitute a protocol amendment.

The IRB/IEC will be informed of any safety issues that require alteration of the 
safety monitoring scheme or amendment of the Informed Consent Form.

No more than 500 mL of blood will be collected over the duration of the study, 
including any extra assessments that may be required.


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7.1.
Time and Events Table
Procedure
Screen1
Day
-1
Treatment Period 1
Day
Treatment Period 2
Day
Early 
Withdrawal
/ Follow-up
~10-14 
days
1 2
3
4
5
6
7
8
9
1
0
1
1
1
2
1
3
14
1
5
1
6
1
7
1
8
1
9
2
0
2
12
2
2
2
3
2
4
2
5
2
6
2
2
7
2
8
2
9
Informed consent
X
Inclusion and 
exclusion criteria
X
X
Demography
X
Full physical 
exam3
X
Brief physical 
exam3
X
X
X
X
X4
Medical/medicatio
n/drug/alcohol 
history
X
X
X
X
Pregnancy test 5
X
X
X
X
X
FSH and estradiol 
(if needed)
X
TB, HIV, Hep B, 
Hep C screen
X
Drug/Alcohol 
screen
X
X
X
X
Safety Laboratory 
assessments
X
X
X
X
X
X
12-lead ECG6
X
X
X
X
X
Vital signs 
(Including 
Temperature)6
X
X
X
X
X
X


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Procedure
Screen1
Day
-1
Treatment Period 1
Day
Treatment Period 2
Day
Early 
Withdrawal
/ Follow-up
~10-14 
days
1 2
3
4
5
6
7
8
9
1
0
1
1
1
2
1
3
14
1
5
1
6
1
7
1
8
1
9
2
0
2
12
2
2
2
3
2
4
2
5
2
6
2
2
7
2
8
2
9
Administer CAB 
30 mg once daily7
X X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Administer RBT 
300 mg once 
daily7
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Dispense CAB8
X
Dispense 
CAB9and RBT10
X
Pharmacokinetic 
Sampling11
X
X-----X
X
X
X-----
X
Admit to Unit
X
X
X
Discharge from 
Unit
X
X
X
Outpatient Visit
X
X
X
X
Drug 
accountability
X
X
X
X
Genetic sample12
========================================================================================================
SAE Review
=======================================================================================================================
AE Review
========================================================================================================
========================================================================================================
Concomitant 
medication review


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Procedure
Screen1
Day
-1
Treatment Period 1
Day
Treatment Period 2
Day
Early 
Withdrawal
/ Follow-up
~10-14 
days
1 2
3
4
5
6
7
8
9
1
0
1
1
1
2
1
3
14
1
5
1
6
1
7
1
8
1
9
2
0
2
12
2
2
2
3
2
4
2
5
2
6
2
2
7
2
8
2
9
1.
Screening must be performed within 30 days prior to receiving the dose of CAB on Day 1.
2.
Day 21 and Day 26 is an outpatient visit.
3.
An ocular assessment will be performed only for subjects who experience eye symptoms.
4.
A brief symptom directed physical exam will be completed as needed.
5.
A serum pregnancy test will be performed at the screening visit and a urine pregnancy test at all other time points specified. 
6.
Duplicate ECG, BP, and HR assessments will be conducted pre-dose on Day 1.  Single measurements will be collected at all other time points.
7.
Study medication will be administered with 240 mL of water within the unit on Days 1, 13, 14, 15, 21, 26, 27, and 28.  Dosing on non-PK days may be with or without food, but 
dosing on serial PK days (Day 14 in Period 1 and Day 28 in Period 2) must be after an overnight fast of at least 6 hours, and no food will be allowed for 4 hours after dosing on 
these serial PK days.
8.
Dispense the bottle of CAB tablets to the subject on Day 1 to receive CAB dosing at home on Days 2 to 12 in Period 1 
9.
Dispense the bottle of CAB tablets to the subject on Day 15 to receive CAB dosing at home on Days 16 to 20 and Days 22 to 25 in Period 2; dosing on Day 21, 26, 27, and 28 is in 
the unit. 
10. Dispense the bottle of RBT capsules to the subject on Day 15 to receive RBT dosing at home on Days 16 to 20 and Days 22 to 25 in Period 2; dosing on Day 21, 26, 27, and 28 is 
in the unit. 
11. Plasma PK samples (2 mL of blood per sample) will be collected to measure CAB at the following time points: Period 1: predose (within 15 minutes prior to dose) on Day 13; and 
pre-dose (within 15 minutes prior to dose), 1, 2, 3, 4, 8, 12, and 24 hours after CAB dosing on Day 14.  Period 2:  pre-dose (within 15 minutes prior to dose) on Days 26 and 27 
and pre-dose (within 15 minutes prior to dose) on Day 28 and, 1, 2, 3, 4, 8, 12, and 24 hours after CAB +RBT dosing on Day 28.  
12. It is recommended that the Pharmacogenetic sample be collected on Day 1, but it may be collected at any time following administration of investigational product.


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7.2.
Screening and Critical Baseline Assessments
Cardiovascular medical history/risk factors (as detailed in the CRF) will be assessed at 
screening.
The following demographic parameters will be captured: year of birth, sex, race and 
ethnicity.
Medical/medication/family history will be assessed as related to the inclusion/exclusion 
criteria listed in Section 5.  
7.3.
Safety
Planned time points for all safety assessments are listed in the Time and Events Table 
(Section 7.1).  Additional time points for safety tests (such as vital signs, physical exams 
and laboratory safety tests) may be added during the course of the study based on newly 
available data to ensure appropriate safety monitoring.
7.3.1.
Adverse Events (AE) and Serious Adverse Events (SAEs)
The definitions of an AE or SAE can be found in Appendix 4.
The investigator and their designees are responsible for detecting, documenting and 
reporting events that meet the definition of an AE or SAE. 
For this study, the Sponsor considers seizures as an AE of special interest (see 
Investigator’s Brochure for further information). Where seizures or suspected seizures
occur, the Sponsor would like to better characterize these occurrences to enable 
systematic analyses. Investigators are requested to document and report seizure or 
possible seizure events promptly (within 24 hours of learning of the event) to the Sponsor 
for evaluation and onward reporting.  Data should be documented on the appropriate 
AE/SAE page (see Appendix 4, Section 12.4).
7.3.1.1.
Time period and Frequency for collecting AE and SAE information

Any SAEs assessed as related to study participation (e.g., protocol-mandated 
procedures, invasive tests, or change in existing therapy) or related to a GSK 
product will be recorded from the time a subject consents to participate in the 
study up to and including any follow-up contact. 

AEs will be collected from the start of Study Treatment until the follow-up 
contact. Refer to Section 7.3.1.3.

Medical occurrences that begin prior to the start of study treatment but after 
obtaining informed consent may be recorded on the Medical History/Current 
Medical Conditions section of the CRF.

All SAEs will be recorded and reported to GSK within 24 hours, as indicated in 
Appendix 4.


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
Investigators are not obligated to actively seek AEs or SAEs in former study 
subjects. However, if the investigator learns of any SAE, including a death, at any 
time after a subject has been discharged from the study, and he/she considers the 
event reasonably related to the study treatment or study participation, the 
investigator must promptly notify GSK.
NOTE: The method of recording, evaluating and assessing causality of AEs and SAEs 
plus procedures for completing and transmitting SAE reports to GSK are provided in 
Appendix 4.
7.3.1.2.
Method of Detecting AEs and SAEs
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended 
and non-leading verbal questioning of the subject 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?” 
7.3.1.3.
Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each 
subject at subsequent visits/contacts.  All SAEs will be followed until resolution, until the 
condition stabilizes, until the event is otherwise explained, or until the subject is lost to 
follow-up (as defined in Section 5.4). Further information on follow-up procedures is 
given in Appendix 4.
7.3.1.4.
Regulatory Reporting Requirements for SAEs
Prompt notification by the investigator to GSK of SAEs related to study treatment (even 
for non- interventional post-marketing studies) is essential so that legal obligations and 
ethical responsibilities towards the safety of subjects and the safety of a product under 
clinical investigation are met. 
GSK has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a product under clinical investigation.  GSK will 
comply with country specific regulatory requirements relating to safety reporting to the 
regulatory authority, Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC) and investigators.
Investigator safety reports are prepared for suspected unexpected serious adverse 
reactions according to local regulatory requirements and GSK policy and are forwarded 
to investigators as necessary.
An investigator who receives an investigator safety report describing a SAE(s) or other 
specific safety information (e.g., summary or listing of SAEs) from GSK will file it with 
the IB and will notify the IRB/IEC, if appropriate according to local requirements.


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7.3.2.
Pregnancy

Details of all pregnancies in female subjects will be collected after the start of dosing 
and until the last follow-up assessment.

If a pregnancy is reported then the investigator should inform GSK within 2 weeks 
of learning of the pregnancy and should follow the procedures outlined in Appendix 
5.
7.3.3.
Physical Exams

A complete physical examination will include, at a minimum, assessment of the 
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).
An ocular assessment will be performed only for subjects who experience eye symptoms.

Investigators should pay special attention to clinical signs related to previous serious 
illnesses.
7.3.4.
Vital Signs

Vital signs will be measured in semi-supine position after 10 minutes rest and will 
include systolic and diastolic blood pressure and pulse rate. Temperature will also be 
obtained as part of the Vital Signs assessment. 

Measurements that deviate substantially from previous readings will be repeated 
immediately.

Two (2) blood pressure (BP) and heart rate (HR) measurement will be taken at pre-
dose on Day 1, at least 1 minute apart.  The mean value recorded at pre-dose will be 
classified as baseline.  Single BP and HR will be obtained at all other time points 
during the study. A single Temperature (TT) assessment will be obtained at Pre-dose 
as well as other time points during the study as specified in the Time and Event 
Table Section 7.1. 
7.3.5.
Electrocardiogram (ECG)

Two (2) 12-lead ECGs measurements will be performed with the subject in a semi-
supine position having rested in this position for at least 10 minutes beforehand.

Measurements that deviate substantially from previous readings will be repeated 
immediately.
Two (2) measurements will be taken at pre-dose on Day 1, at least 5 minutes 
apart.  The mean value recorded at pre-dose will be classified as baseline.  Single 
ECG measurements will be performed at all other time points.  12-lead ECGs will be 
obtained during the study using an ECG machine that automatically calculates the 
heart rate and measures mean PR interval, QRS, QT, and QTcF (QT corrected by 
Fridericia’s formula) intervals.


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7.3.6.
Clinical Safety Laboratory Assessments
All protocol required laboratory assessments, as defined in Section 7 must be conducted 
in accordance with the Laboratory Manual, and Protocol Time and Events Schedule.
Laboratory requisition forms must be completed and samples must be clearly labeled 
with the subject number, protocol number, site/centre number, and visit date. Details for 
the preparation and shipment of samples will be provided by the laboratory and are 
detailed in the laboratory manual.  Reference ranges for all safety parameters will be 
provided to the site by the laboratory responsible for the assessments.
If additional non-protocol specified laboratory assessments are performed at the 
institution’s local laboratory and result in a change in subject management or are 
considered clinically significant by the investigator (e.g., SAE or AE or dose 
modification) the results must be recorded in the CRF.
Refer to the laboratory manual for appropriate processing and handling of samples to 
avoid duplicate and/or additional blood draws.
Haematology, clinical chemistry, urinalysis and additional parameters to be tested are 
listed in Table 3. 
Table 3
Protocol Required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Haematology
Platelet Count
RBC Indices:
WBC count with Differential:
RBC Count
MCV
Neutrophils
Hemoglobin
MCH
Lymphocytes
Hematocrit
Monocytes
WBC Count (absolute)
Eosinophils
Reticulocyte Count
Basophils
RDW
Clinical 
Chemistry 1
BUN
Potassium
AST (SGOT)
Total and direct 
bilirubin
Creatinine
Sodium
ALT (SGPT)
Total Protein
Glucose 
Calcium
Alkaline phosphatase
Albumin
Total CO2
GGT
Chloride
CPK
Routine 
Urinalysis

Specific gravity

pH, glucose, protein, blood and ketones by dipstick

Microscopic examination (if blood or protein is abnormal)
Other 
Screening 
Tests

TB Quantiferon Gold

HIV antibody

Hepatitis B surface antigen (HBsAg), Hepatitis B surface antibody 
(HBsAb), Hepatitis B core antibody (HBcAb)

Hepatitis C antibody (Hep C antibody)

FSH and estradiol (as needed in women of non-child bearing 


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Laboratory 
Assessments
Parameters
potential only)

Alcohol and drug screen (to include at minimum: amphetamines, 
barbiturates, cocaine, opiates, cannabinoids and benzodiazepines)

Urine or Serum hCG Pregnancy test (as needed for women of child 
bearing potential) 
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 5.4.2 and 
Appendix 2.
Abbreviations:
RBC- Red blood cells, WBC- White blood cells, MCV- Mean corpuscular volume, MCH- Mean 
corpuscular hemoglobin, RDW- Red cell distribution width, BUN- Blood urea nitrogen, SGOT- Serum 
glutamic-oxaloacetic transaminase, SGPT- Serum glutamic pyruvic transaminase, CO2 – Carbon 
dioxide, GGT- Gamma glutamyltransferase, CPK- Creatine phosphokinase
All laboratory tests with values that are considered clinically significantly abnormal 
during participation in the study or within 14 days after the last dose of study treatment 
should be repeated until the values return to normal or baseline.  If such values do not 
return to normal within a period judged reasonable by the investigator, the etiology 
should be identified and the sponsor notified.
7.4.
Pharmacokinetics
7.4.1.
Blood Sample Collection
Blood samples for pharmacokinetic (PK) analysis of CAB, will be collected at the time 
points indicated in Section 7.1, Time and Events Table.  The actual date and time of each 
blood sample collection will be recorded.  The timing of PK sample collection may be 
altered and/or PK samples may be obtained at additional time points to ensure thorough 
PK monitoring.  
Collect whole blood (2 mL) sample into a properly labeled K3EDTA evacuated blood 
collection tube.  Record the exact date and time of sampling in the CRF, as appropriate. 
Immediately after collection, gently invert (DO NOT SHAKE) the evacuated blood 
collection tube 8-10 times to mix the K3EDTA anticoagulant with the whole blood and 
place the sample(s) on ice. 
Within 1 hour of sample collection, separate the plasma by refrigerated (4 C) 
centrifugation at 1,500 to 2,000 x g for a minimum of 10 minutes.
Immediately after sample processing freeze the plasma storage tubes in the upright 
position in a non-self-defrosting freezer. Store at -20C or lower until transfer to 
bioanalytical facility.
Shipping procedures are provided in the Study Reference Manual (SRM). 


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7.4.2.
Sample Analysis
Plasma analysis will be performed under the control of PTS-BIB/TPR, GlaxoSmithKline. 
The details of the analysis will be included in the Study Reference Manual 
(SRM). Concentrations of CAB will be determined in plasma samples using the currently 
approved bioanalytical methodology.  Raw data will be archived at the bioanalytical site 
(detailed in the SRM).
Once the plasma has been analyzed for parent compounds, any remaining plasma may be 
analyzed for other compound-related metabolites and the results reported under a 
separate Platform Technologies and Science (PTS), GlaxoSmithKline protocol.
7.5.
Genetics
Information regarding pharmacogenetic (PGx) research is included in Appendix 4.  The
IRB/IEC and, where required, the applicable regulatory agency must approve the PGx 
assessments before these can be conducted at the site.  In some cases, approval of the 
PGx assessments can occur after approval is obtained for the rest of the study.  If so, then 
the written approval will clearly indicate approval of the PGx assessments is being 
deferred and in most cases, the study, except for PGx assessments, can be initiated.  
When PGx assessments will not be approved, then the approval for the rest of the study 
will clearly indicate this and therefore, PGx assessments will not be conducted.
8.
DATA MANAGEMENT

For this study, subject data will be entered into GSK defined CRFs, transmitted 
electronically to GSK or designee and combined with data provided from other 
sources in a validated data system.  

Management of clinical data will be performed in accordance with applicable 
GSK standards and data cleaning procedures to ensure the integrity of the data, 
e.g., removing errors and inconsistencies in the data.

Adverse events and concomitant medications terms will be coded using MedDRA 
(Medical Dictionary for Regulatory Activities) and an internal validated 
medication dictionary, GSKDrug.  

CRFs (including queries and audit trails) will be retained by GSK, and copies will 
be sent to the investigator to maintain as the investigator copy.  Subject initials 
will not be collected or transmitted to GSK according to GSK policy.
9.
STATISTICAL CONSIDERATIONS AND DATA 
ANALYSES
9.1.
Hypotheses
This study is designed to estimate the drug-interaction effect of RBT on CAB PK 
parameters.  No formal hypothesis will be tested.  An estimation approach will be used to 
evaluate the effect of RBT on CAB PK.  Point estimates and corresponding 90% 


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confidence intervals (CIs) will be constructed for the comparisons of interest 
(test:reference).
9.1.1.
Primary Comparisons of Interests
The primary comparisons will be made for the repeated dose PK parameters of CAB 
when given alone in Period 1 (reference treatment) and when co-administered with 
steady-state RBT in Period 2 (test treatment).
Primary Treatment Comparisons
PK Parameters
Reference Treatment
Test Treatment
Plasma CAB Cmax, 
AUC(0- τ)
CAB 30 mg once daily X 14 days 
RBT 300 mg once daily X 14 days + CAB 
30 mg once daily X 14 days
The point estimates of the geometric least squares (GLS) mean ratio and the associated 
90% CIs will be provided for the treatment comparisons (test:reference).
9.2.
Sample Size Considerations
9.2.1.
Sample Size Assumptions
The sample size of 15 to obtain 12 evaluable subjects was chosen based on an expected 
withdrawal rate of approximately 20% and the within-subject variability of CAB, to 
address the objectives of the study.
The within-subject variations in PK parameters from previous tablet administration in 
CAB studies [GlaxoSmithKline Document Number RM2008/00856/00, ITZ111839 and 
GlaxoSmithKline Document Number 2011N122099_01, LAI116181] were in the range 
of 6.7-7.8%, and 6.9-11.4%, for the CAB PK parameters AUC(0-τ)/AUC(0-∞) and Cmax 
respectively. 
Based on a within-subject coefficient of variation (CVw) of 11.4% and a sample size of 
12 evaluable subjects, it is estimated that the half width of the 90% confidence interval 
for the treatment difference on log-scale will be within 8.3% of the point estimate for 
AUC(0-τ) and Cmax.  If the point estimate of the ratio of geometric means is 1, then 90% 
confidence interval will be approximately (0.92, 1.09)
9.2.2.
Sample Size Sensitivity
Using sensitivity analysis assuming higher within-subject CVw of 22.8%  and a sample 
size of 12 evaluable subjects, it is estimated that the lower and upper bounds of the 90% 
CI for  the treatment difference on log-scale would be within 16.7% of the point estimate 
for AUC(0-t) and Cmax.
9.2.3.
Sample Size Re-estimation or Adjustment
No sample size re-estimation or adjustment will be performed.


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9.3.
Data Analysis Considerations
9.3.1.
Analysis Populations
Safety Population
All subjects who enroll into the study and receive at least one dose of study drug will be 
included in the Safety Population.  This will be the population for the safety analyses, and 
for summarization of baseline/demographic characteristics.
Pharmacokinetic Concentration Populations
The CAB PK Concentration Population will include all subjects who undergo plasma PK 
sampling and have at least one evaluable PK assay results.  CAB assay results from 
samples collected from a subject with emesis occurring within 4 hours of the dose will 
not be considered as evaluable.  These populations will be used for the concentration 
listing.
Pharmacokinetic Parameter Populations
The CAB PK Parameter Population for this study will include all subjects with CAB PK 
parameters estimated.  These populations will be used for PK parameter listing. PK 
parameter populations will also be used for plotting of the individual concentration-time 
data.
Pharmacokinetic Summary Population
The CAB PK Summary Population for this study will include subjects who have CAB 
PK parameter estimates from both serial PK sampling time periods 1 and 2.  These 
populations will be used for the concentration and PK parameters summary figures and 
tables and for the statistical analysis of PK parameter data.
9.3.2.
Interim Analysis
No interim analysis will be performed.
9.4.
Key Elements of Analysis Plan
Final analysis will be performed after the completion of the study and final datasets 
authorization.
Data will be listed and summarized according to GlaxoSmithKline reporting standards, 
where applicable. Listings will be sorted by subject, period, day, and time, noting 
treatment; summaries will be presented by treatment, day, and time.
Unless stated otherwise, descriptive summaries for continuous variables will include n, 
mean, standard deviation (SD), coefficient of variation for the mean (%CV), median, 
minimum, and maximum, geometric mean with associated 95% confidence interval (CI), 
and the between-subject CV (%CVb) for the geometric mean; whereas, n and percent will 
be used as summary statistics for categorical variables.


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Baseline or pre-dose assessment is the last available assessment prior to time of the first 
dose unless it is specified otherwise. If there are multiple assessments collected on 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.
Version 9.3 or higher of the Statistical Analysis Software (SAS) system will be used to 
analyze the data as well as to generate tables, figures, and listings.
Complete details will be documented in the Reporting and Analysis Plan (RAP).
9.4.1.
Primary Analyses
Pharmacokinetic data will be presented in graphical and/or tabular form and will be 
summarized descriptively. All pharmacokinetic data will be stored in the Archives, 
GlaxoSmithKline Pharmaceuticals, R&D.
Pharmacokinetic Analyses
Pharmacokinetic analyses will be the responsibility of Clinical Pharmacokinetics 
Modeling & Simulation Department, Quantitative Sciences, within GlaxoSmithKline.  
Plasma CAB concentration-time data will be analyzed by non-compartmental methods 
with WinNonlin Professional 5.2 or higher.  Calculations will be based on the actual 
sampling times recorded during the study.  From the plasma concentration-time data, the 
following pharmacokinetic parameters will be determined, as data permit: maximum 
observed plasma concentration (Cmax), time to Cmax (tmax), area under the plasma 
concentration-time curve at the end of the dosing interval (AUC(0-)) and C(plasma 
concentration at the end of the dosing interval).
Statistical Analysis of Pharmacokinetic Data
All of the PK parameters will be log-transferred, except tmax.
Pre-dose concentrations collected between Days 13-14 and Day 26-28 will be used to 
assess for achievement of steady-state of CAB when CAB is given with RBT.  
Analysis of variance (ANOVA), considering treatment as fixed effect, will be performed 
using SAS Mixed Linear Models procedure to evaluate the effect of RBT on CAB PK 
parameters: AUC(0-) and Cmax, The ratios of geometric least square (GLS) means and 
associated 90% CIs will be estimated for the PK parameters AUC(0-) and Cmax.
9.4.2.
Secondary Analyses
Safety data will be presented in tabular and/or graphical format and summarized 
descriptively according to GSK’s Integrated Data Standards Library (IDSL) standards.
The point estimates of the geometric least squares (GLS) mean ratio for the PK 
parameters C, t1/2  and CL/F and the associated 90% CIs will be provided for treatment 
comparisons (test:reference).  The PK parameters will be log-transformed prior to 
analysis and treatment comparisons will be expressed as ratios on the original scale as 


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primary PK parameter. Plasma tmax will only be summarized with the descriptive 
statistics.
9.4.3.
Other Analyses
The relationship between CAB exposure and pharmacodynamic (PD) endpoints (e.g., 
safety parameters) may be explored, if needed.
10.
STUDY GOVERNANCE CONSIDERATIONS
10.1.
Posting of Information on Publicly Available Clinical Trial 
Registers
Study information from this protocol will be posted on publicly available clinical trial 
registers before enrollment of subjects begins.
10.2.
Regulatory and Ethical Considerations, Including the 
Informed Consent Process
Prior to initiation of a site, GSK will obtain favourable opinion/approval from the 
appropriate regulatory agency to conduct the study in accordance with International 
Conference on Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use (ICH) Good Clinical Practice (GCP) and applicable 
country-specific regulatory requirements.
The study will be conducted in accordance with all applicable regulatory requirements, 
and with GSK policy.
The study will also be conducted in accordance with ICH Good Clinical Practice (GCP), 
all applicable subject privacy requirements, and the guiding principles of the current 
version of the Declaration of Helsinki.  This includes, but is not limited to, the following:

IRB/IEC review and favorable opinion/approval of the study protocol and 
amendments as applicable

Obtaining signed informed consent

Investigator reporting requirements (e.g. reporting of AEs/SAEs/protocol 
deviations to IRB/IEC)

GSK will provide full details of the above procedures, either verbally, in writing, 
or both.

Signed informed consent must be obtained for each subject prior to participation 
in the study

The IEC/IRB, and where applicable the regulatory authority, approve the clinical 
protocol and all optional assessments, including genetic research.  

Optional assessments (including those in a separate protocol and/or under separate 
informed consent) and the clinical protocol should be concurrently submitted for 
approval unless regulation requires separate submission.  


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
Approval of the optional assessments may occur after approval is granted for the 
clinical protocol where required by regulatory authorities.  In this situation, 
written approval of the clinical protocol should state that approval of optional 
assessments is being deferred and the study, with the exception of the optional 
assessments, can be initiated.
10.3.
Quality Control (Study Monitoring)

In accordance with applicable regulations including GCP, and GSK procedures, 
GSK monitors will contact the site prior to the start of the study to review with the 
site staff the protocol, study requirements, and their responsibilities to satisfy 
regulatory, ethical, and GSK requirements.  

When reviewing data collection procedures, the discussion will also include 
identification, agreement and documentation of data items for which the CRF will 
serve as the source document.
GSK will monitor the study and site activity to verify that the:

Data are authentic, accurate, and complete.

Safety and rights of subjects are being protected.

Study is conducted in accordance with the currently approved protocol and any 
other study agreements, GCP, and all applicable regulatory requirements.
The investigator and the head of the medical institution (where applicable) agrees to 
allow the monitor direct access to all relevant documents.
10.4.
Quality Assurance

To ensure compliance with GCP and all applicable regulatory requirements, GSK 
may conduct a quality assurance assessment and/or audit of the site records, and 
the regulatory agencies may conduct a regulatory inspection at any time during or 
after completion of the study. 

In the event of an assessment, audit or inspection, the investigator (and institution) 
must agree to grant the advisor(s), auditor(s) and inspector(s) direct access to all 
relevant documents and to allocate their time and the time of their staff to discuss 
the conduct of the study, any findings/relevant issues and to implement any 
corrective and/or preventative actions to address any findings/issues identified.
10.5.
Study and Site Closure

Upon completion or premature discontinuation of the study, the GSK monitor will 
conduct site closure activities with the investigator or site staff, as appropriate, in 
accordance with applicable regulations including GCP, and GSK Standard 
Operating Procedures.

GSK reserves the right to temporarily suspend or prematurely discontinue this 
study at any time for reasons including, but not limited to, safety or ethical issues 
or severe non-compliance. For multicenter studies, this can occur at one or more 
or at all sites.  


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
If GSK determines such action is needed, GSK will discuss the reasons for taking 
such action with the investigator or the head of the medical institution (where 
applicable).  When feasible, GSK will provide advance notification to the 
investigator or the head of the medical institution, where applicable, of the 
impending action.

If the study is suspended or prematurely discontinued for safety reasons, GSK 
will promptly inform all investigators, heads of the medical institutions (where 
applicable) and/or institution(s) conducting the study. GSK will also promptly 
inform the relevant regulatory authorities of the suspension or premature 
discontinuation of the study and the reason(s) for the action.  

If required by applicable regulations, the investigator or the head of the medical 
institution (where applicable) must inform the IRB/IEC promptly and provide the 
reason for the suspension or premature discontinuation.
10.6.
Records Retention

Following closure of the study, the investigator or the head of the medical 
institution (where applicable) must maintain all site study records (except for 
those required by local regulations to be maintained elsewhere), in a safe and 
secure location.  

The records must be maintained to allow easy and timely retrieval, when needed 
(e.g., for a GSK audit or regulatory inspection) and must be available for review 
in conjunction with assessment of the facility, supporting systems, and relevant 
site staff.  Where permitted by local laws/regulations or institutional policy, some 
or all of these records can be maintained in a format other than hard copy (e.g., 
microfiche, scanned, electronic); however, caution needs to be exercised before 
such action is taken.  

The investigator must ensure that all reproductions are legible and are a true and 
accurate copy of the original and meet accessibility and retrieval standards, 
including re-generating a hard copy, if required.  Furthermore, the investigator 
must ensure there is an acceptable back-up of these reproductions and that an 
acceptable quality control process exists for making these reproductions.

GSK will inform the investigator of the time period for retaining these records to 
comply with all applicable regulatory requirements.  The minimum retention time 
will meet the strictest standard applicable to that site for the study, as dictated by 
any institutional requirements or local laws or regulations, GSK 
standards/procedures, and/or institutional requirements.  

The investigator must notify GSK of any changes in the archival arrangements, 
including, but not limited to, archival at an off-site facility or transfer of 
ownership of the records in the event the investigator is no longer associated with 
the site.


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10.7.
Provision of Study Results to Investigators, Posting of 
Information on Publically Available Clinical Trials Registers 
and Publication
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 subjects, as 
appropriate.
GSK will provide the investigator with the randomization codes for their site only after 
completion of the full statistical analysis.
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.
A manuscript will be progressed for publication in the scientific literature if the results 
provide important scientific or medical knowledge.


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11.
REFERENCES
Abdool Karim SS, Naidoo K, Grobler A, Padayatchi C, Nair G, Bamber S, et al. 
Initiating ART during TB treatment significantly increases survival: results of a 
randomized controlled clinical trial in TB/HIV co-infected patients in South Africa; 
CROI, San Fransisco, CA, 2010b, abstract 36a.
Abdool Karim, S. S., K. Naidoo, A. Grobler, N. Padayatchi, C. Baxter, A. Gray, T, et al. 
Abdool Karim. 2010a. Timing of initiation of antiretroviral drugs during tuberculosis 
therapy. N. Engl. J. Med. 362:697-706. doi: 10.1056/NEJMoa0905848.
Brainard D.M., Kassahun K, Wenning L.A., Petry A.S., Liu C., Lunceford, J.,  et al. Lack 
of a clinically meaningful pharmacokinetic effect of rifabutin on raltegravir: in vitro/in 
vivo correlation. J Clin Pharmacol. 2011 Jun;51(6):943-50. doi: 
10.1177/0091270010375959. Epub 2010 Sep 17.
Corbett, E. L.,Watt, C. J, Walker, N. Maher, D.  Williams, B. G.,  Raviglione, M. C., et 
al. 2003. The growing burden of tuberculosis: global trends and interactions with the HIV 
epidemic. Arch. Intern. Med. 163:1009-1021. doi: 10.1001/archinte.163.9.1009 [doi]; 
163/9/1009 [pii].
Ford, S.L., Gould, E., Chen, S., Lou, Y., Dumont, E., Spreen, W.,et al. 2013. Effects of 
etravirine on the pharmacokinetics of the integrase inhibitor S/GSK1265744. Antimicrob. 
Agents Chemother. 57:277-280.
Ford, S.L., Sutton, K., Lou, Y., Zhang, J., Tenorio, A., Trezza, C., et al. Rifampin (RIF) 
Decreases Cabotegravir (CAB) Exposure following Oral Coadministration. The 17th 
International Workshop on Clinical Pharmacology of HIV & Hepatitis Therapy 
Washington, DC  June 8-10, 2016
Frieden, T. R., Sterling, T.R.,  Munsiff, S.S., Watt, C.J., Dye, C. 2003. Tuberculosis. 
Lancet. 362:887-899. doi: S0140673603143334 [pii]. 
GlaxoSmithKline Document Number 2011N122099_01, LAI116181. A Phase 1, Open-
Label, Crossover Study to Evaluate  the Pharmacokinetics and Safety of GSK1265744 
and Rilpivirine and Dolutegravir and Rilpivirine in Healthy Adult Subjects. November 
2011. 
GlaxoSmithKline Document Number 2012N134026_01 LAI116482. A Phase IIb, dose 
ranging study of oral GSK1265744 in combination with nucleoside reverse transcriptase 
inhibitors for induction of HIV-1 virologic suppression followed by an evaluation of 
maintenance of virologic suppression when oral GSK1265744 is combined with oral 
rilpivirine in HIV-1 infected, antiretroviral therapy naive adult subjects. Effective Date 
May 2012.
GlaxoSmithKline Document Number 2012N136689_00, LAI116585 . A single-center, 
randomized, open-label, crossover study to assess the relative bioavailability of new 
formulations of GSK1265744 in healthy adult subjects. March 2012.


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GlaxoSmithKline Document Number 2013N165475_00, LAI117020. Protocol 
Amendment 1 -A two part, single-center, randomized, open-label, crossover study to 
assess the relative bioavailability of new tablet formulations of GSK1265744 in healthy 
adult subjects. March 2014.
GlaxoSmithKline Document Number 2013N168152_04, 200056. Protocol Amend 02: A 
Phase IIb Study Evaluating a Long-Acting Intramuscular Regimen of GSK1265744 plus 
TMC278 For The Maintenance of Virologic Suppression Following an Induction of 
Virologic Suppression on an Oral regimen of  GSK1265744 plus Abacavir/Lamivudine 
in HIV-1 Infected, Antiretroviral Therapy-Naive Adult Subjects. Effective Date 
November 2013.
GlaxoSmithKline Document Number 2013N184048_01, 201120. Protocol Amendment 
1: A Phase IIa Study to Evaluate the Safety, Tolerability and Acceptability of Long 
Acting Injections of the HIV Integrase Inhibitor, GSK1265744, in HIV Uninfected Men 
(ÉCLAIR). January 2016.
GlaxoSmithKline Document Number DAIDS Document ID: 11964 HPTN 077 study. A 
Phase IIa Study to Evaluate the Safety, Tolerability and Pharmacokinetics of the 
Investigational Injectable HIV Integrase Inhibitor, GSK1265744, in HIV-uninfected Men 
and Women. May 2014.
GlaxoSmithKline Document Number RM2008/00856/00 ITZ111839 . A Phase I, open 
label crossover study to evaluate the effect of etravirine on GSK1265744 
pharmacokinetics in healthy adult subjects (ITZ111839). December 2008.
Maartens, G., and R. J. Wilkinson. 2007. Tuberculosis. Lancet. 370:2030-2043. doi: 
10.1016/S0140-6736(07)61262-8.
McIlleron, H.,  Meintjes, G, Burman, W.J. and Maartens, G. 2007. Complications of 
antiretroviral therapy in patients with tuberculosis: drug interactions, toxicity, and 
immune reconstitution inflammatory syndrome. J. Infect. Dis 2007:196: 1:S63-75. doi: 
10.1086/518655. 
Perruca, E., R. Grimaldi, G. M. Frigo, A. Sardi, and E. E. Mo¨nig Ohnhaus. 1988. 
Comparative effects of rifabutin and rifampicin on hepatic microsomal enzyme activity in 
normal subjects. Eur. J. Clin. Pharmacol. 34:595–599.
Summary of Product Characteristics for Mycobutin, January 2016.
Tseng AL, Walmsley SL. Rifabutin-associated uveitis. Ann Pharmacother 29: 1149-55, 
1995.
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 
2.0. [November 2014].


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Venkatesan, K. 1992. Pharmacokinetic drug interactions with rifampicin. Clin. 
Pharmacokinet. 22:47-65.
World Health Organization.  Global tuberculosis report. WHO Report 2014. Available at: 
http://www.who.int/tb/publications/global_report/en/.
Yapa MH, Boffito M, and Pozniak A.  What Dose of Rifabutin Is Recommended With 
Antiretroviral Therapy? J Acquir Immune Defic Syndr 2016;72:138–152.


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12.
APPENDICES
12.1.
Appendix 1 – Abbreviations and Trademarks
Abbreviations
AE
Adverse Event
ALT
Alanine aminotransferase (SGPT)
AMD
Age-related macular degeneration
ANC
Absolute neutrophil count
ANOVA
Analysis of Variance
AST
Aspartate aminotransferase (SGOT)
AUC
Area under concentration-time curve
AUC(0-)
Area under the concentration-time curve over one dosing 
interval
AUC(0-12)
Area under the concentration-time curve over 12 hours
-HCG
Beta-Human Chorionic Gonadotropin
BMI
Body mass index
BP
Blood pressure
BUN
Blood urea nitrogen
CAB
Cabotegravir
CABG
Coronary artery bypass grafting
CI
Confidence Interval
CL/F
Apparent clearance following oral dosing
Cmax
Maximum observed concentration 
Cmin
Minimum observed concentration
CO2
Carbon dioxide
CONSORT
Consolidated Standards of Reporting Trials
CPDS
Clinical Pharmacology Data Sciences
CPK
Creatine phosphokinase
CRF
Case Report Form
CRO
Contract Research Organization
C
Concentration at the end of the dosing interval
%CV
Coefficient of variation for the mean
%CVb
Between-subject CV
CV
Coefficient of variance
CVw
Coefficient of variation
CYP
Cytochrome P450
DDI
Drug-drug interaction
DDS
Drug Development Sciences
DILI
Drug Induced Liver Injury
dL
Deciliter
DNA
Deoxyribonucleic acid
DTG
Dolutegravir
ECG
Electrocardiogram
FDA
Food and Drug Administration


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FRP
Females of Reproductive Potential
FSH
Follicle Stimulating Hormone
GCP
Good Clinical Practice
GGT
Gamma glutamyltransferase
GLS
Geometric Least-Squares
GSK
GlaxoSmithKline
HAART
Highly active antiretroviral therapy
HBCs
High-burden countries
HBcAb
Positive Hepatitis B core antibody
HBsAg
Hepatitis B surface antigen
hCG
Human chorionic gonadotropin
Hep C
Hepatitis C
HIV
Human Immunodeficiency Virus
h/hr
Hour(s)
HR
Heart rate
HSV
Herpes simplex virus
HSR
Hypersensitivity Reactions
IB
Investigator’s Brochure
ICH
International Conference on Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for 
Human Use
IDSL
Integrated Data Standards Library
IEC
Independent Ethics Committee
IgG
Immunoglobulin G
IRB
Institutional Review Board
IUD
Intrauterine device
IUS
Intrauterine system
z
Terminal phase rate constant
L
Liter
LA
Long Acting
MAC
Mycobacterium avium intracellulare
MCH
Mean corpuscular hemoglobin
MCV
Mean corpuscular volume
MedDRA
Medical Dictionary for Regulatory Activities
Mg
Milligrams
mL
Milliliter
MSDS
Material Safety Data Sheet
mm
Millimeter
msec
Milliseconds
PCTA
Percutaneous transluminal coronary angioplasty
PD
Pharmacodynamic
PD
pharmacodynamic
PGx
Pharmacogenetics
PK
Pharmacokinetic
PTS
Platform Technologies and Science
RDW
Red cell distribution width


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QC
Quality control
QTcB
QT duration corrected for heart rate by Bazett’s formula
QTcF
QT duration corrected for heart rate by Fridericia’s formula
RAL
Raltegravir
RAP
Reporting and Analysis Plan
RBC
Red blood cells
RBT
Rifabutin
RIF
Rifampin/ Rifampicin
RNA
Ribonucleic acid
RPV
Rilpivirine
SAE
Serious adverse event(s)
SAS
Statistical Analysis Software
SD
Standard deviation
SGOT
Serum glutamic-oxaloacetic transaminase
SGPT
Serum glutamic pyruvic transaminase
SmPC
Summary of Product Characteristics
SOC
System organ class
SOP
Standard Operating Procedure
SRM
Study Reference Manual
SPM
Study Procedures Manual
SUSAR
Suspected, Unexpected, Serious Adverse drug Reaction
t½
Terminal phase half-life
τ
Dosing interval
TB
Tuberculosis
TEN
Toxic epidermal necrolysis
tmax
Time of occurrence of Cmax
UDP
Uridine 5'-diphospho-glucuronosyltransferase
UGT
UDP glucuronosyltransferase
ULN
Upper limit of normal
UK
United Kingdom
US
United States
WBC
White blood cells
WGS
Whole genome screen
WPW
Wolf Parkinson White syndrome
744
GSK1265744
Trademark Information
Trademarks of ViiV Healthcare
Trademarks not owned by ViiV 
Healthcare
NONE
Chiron RIBA
Mycobutin
SAS
WinNonlin


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12.2.
Appendix 2: Liver Safety Required Actions and Follow up 
Assessments
Phase I Liver chemistry stopping criteria have been designed to assure subject safety and 
to evaluate liver event etiology (in alignment with the food and drug administration
[FDA] premarketing clinical liver safety guidance).
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf.
Liver Chemistry Stopping Criteria – Liver Stopping Event
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 following Liver Stopping Event
Actions
Follow Up Assessments

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 subject until liver chemistries 
resolve, stabilise, 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 subjects twice weekly until liver 
chemistries resolve, stabilise or return to 
within baseline

A specialist or hepatology consultation is 
recommended

Viral hepatitis serology3

Blood sample for pharmacokinetic (PK) 
analysis, obtained within 60 hours of last 
dose4

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, 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 


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Liver Chemistry Stopping Criteria – Liver Stopping Event
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 subjects weekly until liver 
chemistries resolve, stabilize or return to 
within baseline
total immunoglobulin G (IgG or gamma 
globulins).

Serum acetaminophen adduct HPLC assay 
(quantifies potential acetaminophen 
contribution to liver injury in subjects with 
definite or likely acetaminophen use in the 
preceding week [James, 2009]. 

Liver imaging (ultrasound, magnetic 
resonance, or computerised 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 subject 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 subjects receiving anticoagulants
3.
Includes: 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.
PK sample may not be required for subjects known to be receiving placebo or non-GSK comparator treatments.  
Record the date/time of the PK blood sample draw and the date/time of the last dose of study treatment prior to 
blood sample draw on the CRF. If the date or time of the last dose is unclear, provide the subject’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, Davern TJ, Lee 
WM. Pharmacokinetics of Acetaminophen-Adduct in Adults with Acetaminophen 
Overdose and Acute Liver Failure. Drug Metab Dispos 2009; 37:1779-1784.


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12.3.
Appendix 3 - Genetic Research
Genetics – Background
Naturally occurring genetic variation may contribute to inter-individual variability in 
response to medicines, as well as an individual's risk of developing specific diseases. 
Genetic factors associated with disease characteristics may also be associated with 
response to therapy, and could help to explain some clinical study outcomes. For 
example, genetic variants associated with age-related macular degeneration (AMD) are 
reported to account for much of the risk for the condition [Gorin, 2012] with certain 
variants reported to influence treatment response [Chen, 2012]. Thus, knowledge of the 
genetic etiology of disease may better inform understanding of disease and the 
development of medicines. Additionally, genetic variability may impact the 
pharmacokinetics (absorption, distribution, metabolism, and elimination), or 
pharmacodynamics (relationship between concentration and pharmacologic effects or the 
time course of pharmacologic effects) of a specific medicine and/or clinical outcomes 
(efficacy and/or safety) observed in a clinical study.
Genetic Research Objectives and Analyses
The objectives of the genetic research are to investigate the relationship between genetic 
variants and: 

Response to medicine, including any treatment regimens under investigation in this 
study or any concomitant medicines;

HIV susceptibility, severity, and progression and related conditions
Genetic data may be generated while the study is underway or following completion of 
the study.  Genetic evaluations may include focused candidate gene approaches and/or 
examination of a large number of genetic variants throughout the genome (whole genome 
analyses). Genetic analyses will utilize data collected in the study and will be limited to 
understanding the objectives highlighted above.  Analyses may be performed using data 
from multiple clinical studies to investigate these research objectives.
Appropriate descriptive and/or statistical analysis methods will be used. A detailed 
description of any planned analyses will be documented in a Reporting and Analysis Plan 
(RAP) prior to initiation of the analysis. Planned analyses and results of genetic 
investigations will be reported either as part of the clinical RAP and study report, or in a 
separate genetics RAP and report, as appropriate.
Study Population
Any subject who is enrolled in the study can participate in genetic research.  Any subject 
who has received an allogeneic bone marrow transplant must be excluded from the 
genetic research.


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Study Assessments and Procedures
A key component of successful genetic research is the collection of samples during 
clinical studies. Collection of samples, even when no a priori hypothesis has been 
identified, may enable future genetic analyses to be conducted to help understand 
variability in disease and medicine response.  

A 6 mL blood sample will be taken for Deoxyribonucleic acid (DNA) extraction. 
A blood sample is collected at the baseline visit, after the subject has been 
randomized and provided informed consent for genetic research. Instructions for 
collection and shipping of the genetic sample are described in the laboratory 
manual. The DNA from the blood sample may undergo quality control analyses to 
confirm the integrity of the sample. If there are concerns regarding the quality of 
the sample, then the sample may be destroyed. The blood sample is taken on a 
single occasion unless a duplicate sample is required due to an inability to utilize 
the original sample.  
The genetic sample is labelled (or “coded”) with the same study specific number used to 
label other samples and data in the study.   This number can be traced or linked back to 
the subject by the investigator or site staff. Coded samples do not carry personal 
identifiers (such as name or social security number). 
Samples will be stored securely and may be kept for up to 15 years after the last subject 
completes the study, or GSK may destroy the samples sooner.  GSK or those working 
with GSK (for example, other researchers) will only use samples collected from the study 
for the purpose stated in this protocol and in the informed consent form.  Samples may be 
used as part of the development of a companion diagnostic to support the GSK medicinal 
product.
Subjects can request their sample to be destroyed at any time.
Informed Consent
Subjects who do not wish to participate in the genetic research may still participate in the 
study.  Genetic informed consent must be obtained prior to any blood being taken.
Subject Withdrawal from Study
If a subject who has consented to participate in genetic research withdraws from the 
clinical study for any reason other than being lost to follow-up, the subject will be given a 
choice of one of the following options concerning the genetic sample, if already 
collected:

Continue to participate in the genetic research in which case the genetic DNA 
sample is retained

Discontinue participation in the genetic research and destroy the genetic DNA 
sample 


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If a subject withdraws consent for genetic research or requests sample destruction for any 
reason, the investigator must complete the appropriate documentation to request sample 
destruction within the timeframe specified by GSK and maintain the documentation in 
the site study records. 
Genotype data may be generated during the study or after completion of the study and 
may be analyzed during the study or stored for future analysis. 

If a subject withdraws consent for genetic research and genotype data has not been 
analyzed, it will not be analyzed or used for future research.  

Genetic data that has been analyzed at the time of withdrawn consent will continue 
to be stored and used, as appropriate. 
Screen and Baseline Failures
If a sample for genetic research has been collected and it is determined that the subject 
does not meet the entry criteria for participation in the study, then the investigator should 
instruct the subject that their genetic sample will be destroyed. No forms are required to 
complete this process as it will be completed as part of the consent and sample 
reconciliation process.  In this instance a sample destruction form will not be available to 
include in the site files.
Provision of Study Results and Confidentiality of Subject’s Genetic Data
GSK may summarize the genetic research results in the clinical study report, or 
separately and may publish the results in scientific journals. 
GSK may share genetic research data with other scientists to further scientific 
understanding in alignment with the informed consent. GSK does not inform the subject, 
family members, insurers, or employers of individual genotyping results that are not 
known to be relevant to the subject’s medical care at the time of the study, unless 
required by law. This is due to the fact that the information generated from genetic 
studies is generally preliminary in nature, and therefore the significance and scientific 
validity of the results are undetermined.  Further, data generated in a research laboratory 
may not meet regulatory requirements for inclusion in clinical care.
12.3.1.
References
Chen H, Yu KD, Xu GZ. Association between Variant Y402H in Age-Related Macular
Degeneration (AMD) Susceptibility Gene CFH and Treatment Response of AMD: A
Meta-Analysis. PloS ONE 2012; 7: e42464
Gorin MB. Genetic insights into age-related macular degeneration: Controversies
addressing risk, causality, and therapeutics. Mol. Asp. Med. 2012; 33: 467-486.


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12.4.
Appendix 4: Definition of and Procedures for Recording, 
Evaluating, Follow-Up and Reporting of Adverse Events
12.4.1.
Definition of Adverse Events
Adverse Event Definition:

An AE is any untoward medical occurrence in a patient or clinical investigation 
subject, temporally associated with the use of a medicinal product, whether or not 
considered related to the medicinal product.

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 medicinal product.
Events meeting AE definition include:

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (e.g., ECGs, radiological scans, vital signs measurements), 
including those that worsen from baseline, and felt to be clinically significant in the 
medical and scientific judgment of the investigator.

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 prior to the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected 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 this is an intentional overdose taken with possible suicidal/self-
harming intent.  This should be reported regardless of sequelae).
Events NOT meeting definition of an AE include:

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 subject’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 subject’s 
condition.

Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that 


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leads to the procedure is an AE.

Situations where an untoward medical occurrence did not occur (social and/or 
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.
12.4.2.
Definition of Serious Adverse Events
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, etc).
Serious Adverse Event (SAE) is defined as any untoward medical occurrence that, 
at any dose:
a.
Results in death
b.
Is life-threatening
NOTE:
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
subject 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 hospitalization or prolongation of existing hospitalization
NOTE:

In general, hospitalization signifies that the subject 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 out-patient setting.  Complications that occur during hospitalization are AEs.  
If a complication prolongs hospitalization or fulfills 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 disability/incapacity
NOTE:

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 


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significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (e.g. sprained ankle) which may interfere 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 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 subject or may require medical or surgical intervention to prevent one of the other 
outcomes listed in the above definition.  These should also be considered serious.

Examples of such events are invasive or malignant cancers, intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse
g.
Is associated with liver injury and impaired liver function defined as:

ALT 3xULN and total bilirubin* 2xULN (>35% direct), or

ALT 3xULN and INR** > 1.5.
* Serum bilirubin fractionation should be performed if testing is available; if unavailable, 
measure urinary bilirubin via dipstick.  If fractionation is unavailable and ALT 3xULN 
and total bilirubin 2xULN, then the event is still to be reported as an SAE.
** INR testing not required per protocol and the threshold value does not apply to 
subjects receiving anticoagulants.  If INR measurement is obtained, the value is to be 
recorded on the SAE form.
12.4.3.
AEs of Special Interest:
Seizure
Three cases of seizures have occurred in the CAB program cumulatively through
01 October 2016. ViiV Healthcare has reviewed these cases in detail and does not
believe they constitute a reasonable likelihood of causation associated with CAB. This
assessment is supported by the lack of preclinical signal, class effect or known CNS
mechanism, the relatively low frequency of seizures relative to expected rates in both
healthy and HIV positive subjects and clinical confounders in each case.
When seizures or suspected seizures occur, the Sponsor would like to better characterize 
these occurrences to enable systematic analyses. Investigators are requested to document 
and report seizure or possible seizure events promptly (within 24 hours of learning of the 
event) to the Sponsor for evaluation and onward reporting. Data should be documented 
on the appropriate AE/SAE page.


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12.4.4.
Recording of AEs and SAEs
AEs 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) 
relative to the event.

The investigator will then record all relevant information regarding an AE/SAE in the 
CRF

It is not acceptable for the investigator to send photocopies of the subject’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 instance, all subject identifiers, with the exception of the 
subject number, will be blinded on the copies of the medical records prior to 
submission of to GSK.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information.  In such cases, the diagnosis will be 
documented as the AE/SAE and not the individual signs/symptoms.
12.4.5.
Evaluating AEs and SAEs
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and will assign it to one of the following categories:

Mild:  An event that is easily tolerated by the subject, causing minimal discomfort 
and not interfering with everyday activities.

Moderate:  An event that is sufficiently discomforting to interfere with normal 
everyday activities

Severe:  An event that prevents normal everyday activities. - an AE that is assessed as 
severe will not be confused with an SAE. Severity is a category utilized for rating the 
intensity of an event; and both AEs and SAEs can be assessed as severe.

An event is defined as ‘serious’ when it meets at least one of the pre-defined 
outcomes as described in the definition of an SAE.
IMPORTANT – PLEASE NOTE THE FOLLOWING STATEMENT:
For this study the above criteria regarding mild, moderate and severe will be used in
combination with the Modified Division of AIDS Table for Grading Severity of Adult
Adverse Experiences, December 2004 (Appendix 6). In the InForm electronic data
capture system intensity of adverse events will be recorded using the following 
categories:
1 = Mild or Grade 1


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2 = Moderate or Grade 2
3 = Severe or Grade 3
4 = Grade 4

X = Not applicable
Assessment of Causality

The investigator is obligated to assess the relationship between study treatment and 
the occurrence of each AE/SAE.

A "reasonable possibility" is meant to convey that there are facts/evidence or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled 
out.

The investigator will use clinical judgment to determine the relationship.

Alternative causes, such as natural history of the underlying diseases, concomitant 
therapy, other risk factors, and the temporal relationship of the event to the study 
treatment will be considered and investigated.

The investigator will also consult the Investigator Brochure (IB) and/or Product 
Information, for marketed products, in the determination of 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 when 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 
prior to the initial transmission of the SAE data to GSK.

The investigator may change his/her opinion of causality in light of follow-up 
information, amending the SAE data collection tool accordingly.

The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.
Follow-up of AEs and SAEs

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as may be indicated or as requested by GSK to 
elucidate as fully as possible the nature and/or causality of the AE or SAE.

The investigator is obligated to assist.  This may include additional laboratory tests or 
investigations, histopathological examinations or consultation with other health care 
professionals.

If a subject dies during participation in the study or during a recognized follow-up 


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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 the designated 
reporting time frames.
12.4.6.
Reporting of SAEs to GSK
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

Initial notification via the 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 receipt can be found at this beginning of the protocol on the 
Sponsor/Medical Monitor Contact Information page.


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12.5.
Appendix 5: Modified List of Highly Effective Methods for 
Avoiding Pregnancy in FRP and Collection of Pregnancy 
Information
12.5.1.
Modified List of Highly Effective Methods for Avoiding Pregnancy 
in Females of Reproductive Potential (FRP)
The list does not apply to FRP with same sex partners or for subjects who are and will 
continue to be abstinent from penile-vaginal intercourse on a long term and persistent 
basis, when this is in line with their preferred and usual lifestyle (true abstinence). 
Periodic abstinence (e.g. calendar, ovulation, symptothermal, post-ovulation methods), 
declaration of abstinence for the duration of exposure to IMP and withdrawal are not 
acceptable methods of contraception.
1. Intrauterine device (IUD) or intrauterine system (IUS) that meets the <1% failure rate 
as stated in the product label and does not contain a medication.
2. Male partner sterilization with documentation of azoospermia prior to the female 
subject's entry into the study, and this male is the sole partner for that subject 
[Hatcher, 2011]. The documentation on male sterility can come from the site 
personnel’s: review of subject’s medical records, medical examination and/or semen 
analysis, or medical history interview provided by her or her partner.
These allowed methods of contraception are only effective when used consistently, 
correctly and in accordance with the product label. The investigator is responsible for 
ensuring that subjects understand how to properly use these methods of contraception.
12.5.2.
Collection of Pregnancy Information

Investigator will collect pregnancy information on any female subject, who becomes 
pregnant while participating in this study.

Information will be recorded on the appropriate form and submitted to GSK within 2 
weeks of learning of a subject's pregnancy.

Subject will be followed to determine the outcome of the pregnancy. The investigator 
will collect follow up information on mother and infant, which will be forwarded to 
GSK.  Generally, follow-up will not be required for longer than 6 to 8 weeks beyond 
the estimated delivery date. 

Any termination of pregnancy will be reported, regardless of fetal status (presence or 
absence of anomalies) or indication for procedure.

While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy will be reported as an AE or 
SAE.

A spontaneous abortion is always considered to be an SAE and will be reported as 
such.  

Any SAE occurring as a result of a post-study pregnancy which is considered 
reasonably related to the study treatment by the investigator, will be reported to GSK 


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as described in Appendix 5. While the investigator is not obligated to actively seek 
this information in former study participants, he or she may learn of an SAE through 
spontaneous reporting.
Any female subject who becomes pregnant while participating 

Will be withdrawn from the study.

Investigator will attempt to collect pregnancy information on any female partner of a 
male study subject who becomes pregnant while participating in this study.  This 
applies only to subjects who are randomized to receive study medication. 

After obtaining the necessary signed informed consent from the female partner 
directly, the investigator will record pregnancy information on the appropriate form 
and submit it to GSK within 2 weeks of learning of the partner’s pregnancy.

Partner will also be followed to determine the outcome of the pregnancy.  Information 
on the status of the mother and child will be forwarded to GSK. 

Generally, follow-up will be no longer than 6 to 8 weeks following the estimated 
delivery date.  Any termination of the pregnancy will be reported regardless of fetal 
status (presence or absence of anomalies) or indication for procedure.
12.5.3.
References
CHMP, 2005 - EMA - Guideline on Adjuvants in Vaccines for Human Use, 
(CHMP/VEG/134716/2004), January 2005.
Clinical Investigator's Brochure for Cabotegravir Version 06
Cole LA, Khanlian SA, Sutton JM, Davies S, Rayburn WF. Accuracy of home pregnancy 
tests at the time of missed menses. Am J Ob Gyn 2004(190):100-5.
EMA/CHMP/ICH/449035/2009: General principles to address virus and vector shedding. 
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/
WC500002680.pdf Accessed 28 Nov 2014.
EMEA/CHMP/GTWP/125459/2006: Guideline on the Nonclinical Studies Required 
Before First Clinical Use of Gene Therapy Medicinal Products [2008]
FDA CBER Guidance for industry, “Considerations for Developmental Toxicity Studies 
for Preventive and Therapeutic Vaccines for Infectious Disease Indications. U.S. FDA; 
Feb. 2006. 
FDA Medical Devices Safety Alerts and Notices, “Blood human chorionic gonadotropin 
(hCG) assays: What laboratorians should know about false-positive results”, 
http://www.fda.gov/MedicalDevices/Safety/AlertsandNotices/TipsandArticlesonDeviceS
afety/ucm109390.htm, accessed 17 Nov 2014.


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Hatcher RA, Trussell J, Nelson AL, Cates W Jr, Stewart F, Kowal D, Policar MS, 
editors. Contraceptive Technology. 20th edition. Atlanta, Georgia: Ardent Media, Inc., 
2011: 50. Table 3-2.
International Conference on Harmonization of Technical Requirements for Registration 
of Pharmaceuticals For Human Use. ICH Harmonized Tripartite Guideline. Detection of 
Toxicity to Reproduction for Medicinal Products & Toxicity to Male Fertility. Parent 
Guideline dated 24 June 1993 (Addendum dated 9 November 2000 incorporated in 
November 2005. ICH S5 (R2)
International Conference on Harmonization of Technical Requirements for Registration 
of Pharmaceuticals For Human Use.  ICH Harmonized Tripartite Guideline. Nonclinical 
Evaluation for Anticancer Pharmaceuticals. ICH S9. 2009.
International Conference on Harmonization of Technical Requirements for Registration 
of Pharmaceuticals For Human Use. ICH Harmonized Tripartite Guideline. Nonclinical 
Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorization for 
Pharmaceuticals. ICH M3 (R2). 2009.
International Conference on Harmonization of Technical Requirements for Registration 
of Pharmaceuticals For Human Use. ICH Harmonized Tripartite Guideline. Preclinical 
Safety Evaluation of Biotechnology-Derived Pharmaceuticals. ICH S6 and Addendum 
ICH S6 (R1). 2011.
Kronenberg HM, Melmed S, Polonsky KS, Larsen PR, editors. Williams Textbook of 
Endocrinology, 11th edition. Philadelphia: Saunders, 2008.
Strauss JF, Barbieri RL, editors. Yen and Jaffe’s Reproductive Endocrinology. 5th 
edition, Philadelphia, Elsevier/Saunders, 2004.
U.S. Dept of Health and Human Services, FDA, Center For Biologics Evaluation and 
Research: Guidance for Human Somatic Cell Therapy and Gene Therapy [1998]
WHO, 2013 - WHO - Guidelines on the Nonclinical Evaluation of Vaccine Adjuvants 
and Adjuvanted Vaccines, 2013
World Health Organization. WHO/CONRAD Technical Consultation on Nonoxynol-9.
World Health Organization; Department of Reproductive Health and Research; Geneva; 
9-10 October 2001. Summary Report. 2001. WHO/RHR/03.8.


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12.6.
Appendix 6:  Division Of AIDS Table For Grading The 
Severity Of Adult And Pediatric Adverse Events Version 2.0, 
November 2014
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-THREATENING
ESTIMATING SEVERITY GRADE
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 not 
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 OR Medical or 
operative intervention 
indicated to prevent 
permanent impairment, 
persistent disability, or 
death 
CARDIOVASCULAR
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
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 + 5 
mmHg 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 
New symptoms with 
ischemia (stable 
angina) OR New 
testing consistent 
with ischemia 
Unstable angina OR 
Acute myocardial 
infarction 


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72
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-THREATENING
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) 
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) 
DERMATOLOGIC
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) 


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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-THREATENING
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 
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 
ENDOCRINE AND METABOLIC
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 


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75
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-THREATENING
GASTROINTESTINAL
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 
intermittent 
episodes of 
unformed stools 
OR Increase of ≤ 
3 stools over 
baseline per 24-
hour period 
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) 
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) 


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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-THREATENING
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 indicated 
Life-threatening 
consequences 
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
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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77
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 
NEUROLOGIC
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 


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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-THREATENING
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 
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
Fetal Death or 
Stillbirth (report 
using mother’s 
participant ID) 
Report only one 
NA 
NA 
Fetal loss occurring 
at ≥ 20 weeks 
gestation 
NA 
Preterm Delivery7
(report using 
mother’s participant
ID) 
Delivery at 34 to < 
37 weeks 
gestational age 
Delivery at 28 to < 
34 weeks 
gestational age 
Delivery at 24 to < 28 
weeks gestational 
age 
Delivery at < 24 weeks 
gestational age 
Spontaneous 
Abortion or 
Miscarriage8 (report 
using mother’s 
participant ID) 
Report only one 
Chemical 
pregnancy 
Uncomplicated 
spontaneous 
abortion or 
miscarriage 
Complicated 
spontaneous abortion 
or miscarriage 
NA 
PSYCHIATRIC
Insomnia 
Mild difficulty 
falling asleep, 
staying asleep, or 
waking up early 
Moderate difficulty 
falling asleep, 
staying asleep, or 
waking up early 
Severe difficulty 
falling asleep, staying 
asleep, or waking up 
early 
NA 


2016N269788_02
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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-THREATENING
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 
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
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) 
SENSORY
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) 


2016N269788_02
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PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-THREATENING
< 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 
Medicamylasal 
intervention 
indicated 
Posterior or pan-
uveitis OR Operative 
intervention indicated 
Disabling visual loss in 
affected eye(s) 
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
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 


2016N269788_02
CONFIDENTIAL
205712
82
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-THREATENING
Cytokine Release 
Syndrome9
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 
Pain10 (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 Sickness11 
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) 
Underweight12
> 5 to 19 years of 
age 
NA 
WHO BMI z-score < 
-2 to ≤ -3 
WHO BMI z-score < -
3 
WHO BMI z-score < -3 
with life-threatening 
consequences 
2 to 5 years of age 
NA 
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 
NA 
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 


2016N269788_02
CONFIDENTIAL
205712
83
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-THREATENING
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) 
URINARY
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 
SITE REACTIONS TO INJECTIONS AND INFUSIONS
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 
Redness13 
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 
≤ 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 


2016N269788_02
CONFIDENTIAL
205712
84
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-THREATENING
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 
LABORATORY VALUES Chemistries
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 
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 
Bilirubin14, High 
> 28 days of age 
NA 
NA 
> ULN 
> 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 
≥ 5.0 x ULN 
≤ 28 days of age 
Total Bilirubin for 
Term and Preterm 
Neonates 
Total Bilirubin for 
Term and Preterm 
Neonates 
Total Bilirubin for 
Term and Preterm 
Neonates 
Total Bilirubin for Term 
and Preterm Neonates 


2016N269788_02
CONFIDENTIAL
205712
85
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-THREATENING
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 
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 < 10 x ULN 
10 to < 20 x ULN 
≥ 20 x ULN 
Creatinine, High 
1.1 to 1.3 x ULN 
> 1.3 to 1.8 x ULN 
OR Increase of > 
0.3 mg/dL above 
baseline 
> 1.8 to < 3.5 x ULN 
OR Increase of 1.5 to 
< 2.0 x above 
baseline 
≥ 3.5 x ULN OR 
Increase of ≥ 2.0 x 
above baseline 
Creatinine 
Clearance15 or
eGFR, Low 
Report only one 
NA 
< 90 to 60 ml/min or 
ml/min/1.73 m2 OR 
10 to < 30% 
decrease from 
baseline 
< 60 to 30 ml/min or 
ml/min/1.73 m2 OR ≥ 
30 to < 50% 
decrease from 
baseline 
< 30 ml/min or 
ml/min/1.73 m2 OR ≥ 
50% decrease from 
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 
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 


2016N269788_02
CONFIDENTIAL
205712
86
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-THREATENING
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 
Magnesium16, 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 
0.81 to < LLN 
1.4 to < 2.0 
0.65 to < 0.81 
1.0 to < 1.4 
0.32 to < 0.65 
< 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 
< 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 < 135 
121 to < 125 
121 to < 125 
≤ 120 
≤ 120 


2016N269788_02
CONFIDENTIAL
205712
87
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-THREATENING
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 
Hematology
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 
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 109 to < 
0.600 x 109
350 to < 500 
0.350 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 
Hemoglobin17, Low 
(g/dL; mmol/L)18 
≥ 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 


2016N269788_02
CONFIDENTIAL
205712
88
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-THREATENING
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 
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 < 
124,999 100.000 
x 109 to < 124.999 
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
Urinalysis
Glycosuria (random 
collection tested by 
dipstick) 
Trace to 1+ or 
≤ 250 mg 
2+ or ˃  250 to 
≤ 500 mg 
> 2+ or > 500 mg 
NA 


2016N269788_02
CONFIDENTIAL
205712
89
PARAMETER
GRADE 1
MILD
GRADE 2
MODERATE
GRADE 3
SEVERE
GRADE 4
POTENTIALLY
LIFE-THREATENING
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 
a.
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.  
b.
As per Bazett’s formula.  
c.
For pruritus associated with injections or infusions, see the Site Reactions to Injections and Infusions section 
(page 23).  
d.
Definition: A disorder characterized by fat loss in the face, extremities, and buttocks. 
e.
Definition: A disorder characterized by abnormal fat accumulation on the back of the neck, breasts, and abdomen.  
f.
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.  
g.
Definition: A delivery of a live-born neonate occurring at ≥ 20 to < 37 weeks gestational age. 
h.
Definition: A clinically recognized pregnancy occurring at < 20 weeks gestational age.  
i.
Definition: A disorder characterized by nausea, headache, tachycardia, hypotension, rash, and/or shortness of 
breath. 
j.
For pain associated with injections or infusions, see the Site Reactions to Injections and Infusions section (page 
23).
k.
Definition: A disorder characterized by fever, arthralgia, myalgia, skin eruptions, lymphadenopathy, marked 
discomfort, and/or dyspnea.
l.
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.  
m.
Injection Site Erythema or Redness should be evaluated and graded using the greatest single diameter or 
measured surface area. 
n.
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.  
o.
Use the applicable formula (i.e., Cockroft-Gault in mL/min or Schwatrz in mL/min/1.73m2).  
p.
To convert a magnesium value from mg/dL to mmol/L, laboratories should multiply by 0.4114.  
q.
Male and female sex are defined as sex at birth. 
r.
The conversion factor used to convert g/dL to mmol/L is 0.6206 and is the most commonly used conversion factor. 
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 the appropriate conversion factor for the particular laboratory.  


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12.7.
Appendix 7: 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, subjects may continue study 
medication.  If one or more of the additional tests is abnormal or suggestive of hemolytic 
anemia as specified above, subjects will permanently discontinue study medication and 
be withdrawn from the trial.  Subjects 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:
5.
peripheral blood smear
6.
indirect bilirubin
(abnormal if increased >50% from baseline)
7.
haptoglobin
(abnormal if 25 mg/dL)
8.
reticulocyte count
(abnormal if 4%)
If the additional tests are within the normal range, subjects may continue study 
medication.  If one or more of the additional tests is abnormal or suggestive of hemolytic 
anemia as specified above, subjects will permanently discontinue study medication and 
be withdrawn from the trial.  Consultation with a Hematologist should be considered.  
Subjects 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:
9.
peripheral blood smear
10. indirect bilirubin
11. haptoglobin
12. reticulocyte count


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Subjects will permanently discontinue study medication and be withdrawn from the trial.  
Consultation with a Hematologist should be considered.  Subjects 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).  Subjects may continue study medication.  Subjects 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).  Subjects will permanently discontinue study medication 
and be withdrawn from the trial.  Subjects should be followed up until resolution (return 
to baseline) of bilirubin elevation.
AST AND ALT ELEVATION
See Appendix 2.
RASH
Grade 1 rash (Localized macular rash):
Subjects 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:
13. Temperature > 38.5°C
14. Lymphadenopathy
15. Pharyngitis
16. Any indication of internal organ involvement (hepatitis, nephritis)
In the absence of the above signs or symptoms, subjects with Grade 1 rash may continue 
the study drug at the discretion of the Investigator.  The subject 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 subject may be treated 
symptomatically until the rash resolves. Antihistamines, topical corticosteroids or 


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antipruritic agents may be prescribed.  The subject should remain on the study to be 
followed for safety and PK as outlined in Section 7.3 and Section 7.4
Grade 2 rash (Diffuse macular, maculopapular, or morbilliform rash OR Target 
lesions):
Subjects 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:
17. Temperature > 38.5°C
18. Lymphadenopathy
19. Pharyngitis
20. Any indication of internal organ involvement (hepatitis, nephritis)
In the absence of the above signs or symptoms, subjects 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 subject 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 subject may be treated symptomatically until 
the rash resolves. Antihistamines, topical corticosteroids or antipruritic agents may be 
prescribed.  The subject should remain on the study to be followed for safety and PK as 
outlined in Section 7.3 and Section 7.4.
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):
Subjects with a Grade 3 rash will permanently discontinue the study medication.  The 
subject 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 subject 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 subject should remain on the 
study to be followed for safety and PK as outlined in Section 7.3 and Section 7.4.
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)):


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Subjects 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 GSK Medical Monitor should be notified of this serious adverse 
event within 24hr via phone or fax.  The subject should be closely followed every day 
until resolution of the reaction.  The subject should remain on the study to be followed 
for safety and PK as outlined in Section 7.3 and Section 7.4.
ALLERGIC REACTION
Grade 1 allergic reaction (Pruitis without rash):
Subjects 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:
21. Temperature > 38.5°C
22. Eosinophilia
23. Respiratory involvement including bronchospasm, laryngospasm, or 
angioedema
24. Any indication of internal organ involvement (hepatitis, nephritis)
In the absence of the above signs or symptoms, subjects with Grade 1 allergic reaction 
may continue the study drug at the discretion of the Investigator.  The subject 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 subject may 
be treated symptomatically until the rash resolves. Antihistamines, topical corticosteroids 
or antipruritic agents may be prescribed.  The subject should remain on the study to be 
followed for safety and PK as outlined in Section 7.3 and Section 7.4. 
Grade 2 allergic reaction (Localized urticaria):
Subjects 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:
25. Temperature > 38.5°C
26. Eosinophilia
27. Respiratory involvement including bronchospasm, laryngospasm, or 
angioedema
28. Any indication of internal organ involvement (hepatitis, nephritis)
In the absence of the above signs or symptoms, subjects with Grade 2 allergic reaction 
may continue the study drug at the discretion of the Investigator. The subject should be 
advised to contact the Investigator immediately if there is any worsening of the allergic 


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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 subject may 
be treated symptomatically until the rash resolves. Antihistamines, topical corticosteroids 
or antipruritic agents may be prescribed.  The subject should remain on the study to be 
followed for safety and PK as outlined in Section 7.3 and Section 7.4. 
Grade 3 allergic reaction (Generalized urticaria or angioedema):
Subjects will permanently discontinue the study medication and be withdrawn from the 
trial.  Subjects will be treated as clinically appropriate.  Subjects should be followed up 
until resolution of the adverse event and standard management should be undertaken.
Grade 4 allergic reaction (Anaphylaxis):
Subjects will permanently discontinue the study medication and be withdrawn from the 
trial.  Subjects will be treated as clinically appropriate.  Subjects 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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12.8.
Appendix 8: Protocol Changes
12.8.1.
Protocol Changes for Amendment 01
Summary of Changes and Rationale for Amendment No. 1
Section 
Section Title 
Change
Rationale
12.5.1. 
Modified List of Highly 
Effective Methods for 
Avoiding Pregnancy in 
Females of 
Reproductive Potential 
(FRP)
Clarification to abstinence was 
added.
This clarification 
was made to 
clarify that true 
abstinence
established prior 
to the start of this 
study is an 
acceptable method 
of contraception 
when this is in line 
with the subjects 
preferred and 
usual lifestyle.
12.5.1. 
Modified List of Highly 
Effective Methods for 
Avoiding Pregnancy in 
Females of 
Reproductive Potential 
(FRP)
The double barrier method: 
condom and occlusive cap 
(diaphragm or cervical/vault caps) 
plus spermicidal agent 
(foam/gel/film/cream/suppository) 
was removed from the list of 
highly effective methods for 
avoiding pregnancy in FRP.
This method of 
contraception is 
not considered a  
highly effective 
method for 
avoiding 
pregnancy
in females of 
reproductive 
potential (FRP) for 
this protocol.
Modified text incorporated into protocol amendment 01:
12.5.1. Modified List of Highly Effective Methods for Avoiding Pregnancy
in Females of Reproductive Potential (FRP)
The list does not apply to FRP with same sex partners or for subjects who are and will 
continue to be abstinent from penile-vaginal intercourse on a long term and persistent 
basis, when this is in line with their preferred and usual lifestyle (true abstinence).
Periodic abstinence (e.g. calendar, ovulation, symptothermal, post-ovulation methods), 
declaration of abstinence for the duration of exposure to IMP and withdrawal are not 
acceptable methods of contraception.


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1. Intrauterine device (IUD) or intrauterine system (IUS) that meets the <1% failure
rate as stated in the product label and does not contain a medication
2. Male partner sterilization with documentation of azoospermia prior to the female
subject's entry into the study, and this male is the sole partner for that subject
[Hatcher, 2011]. The documentation on male sterility can come from the site
personnel’s: review of subject’s medical records, medical examination and/or semen
analysis, or medical history interview provided by her or her partner.
These allowed methods of contraception are only effective when used consistently, 
correctly and in accordance with the product label. The investigator is responsible for
ensuring that subjects understand how to properly use these methods of contraception.
Original text:
12.5.1. Modified List of Highly Effective Methods for Avoiding Pregnancy
in Females of Reproductive Potential (FRP)
The list does not apply to FRP with same sex partners or for subjects who are and 
will continue to be abstinent from penile-vaginal intercourse on a long term and 
persistent basis, when this is their preferred and usual lifestyle. Periodic abstinence 
(e.g. calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal 
are not acceptable methods of contraception.
1. Intrauterine device (IUD) or intrauterine system (IUS) that meets the <1% failure
rate as stated in the product label and does not contain a medication
2. Male partner sterilization with documentation of azoospermia prior to the female
subject's entry into the study, and this male is the sole partner for that subject
[Hatcher, 2011]. The documentation on male sterility can come from the site
personnel’s: review of subject’s medical records, medical examination and/or semen
analysis, or medical history interview provided by her or her partner.
3. Double barrier method: condom and occlusive cap (diaphragm or cervical/vault
caps) plus spermicidal agent (foam/gel/film/cream/suppository).
These allowed methods of contraception are only effective when used consistently, 
correctly and in accordance with the product label. The investigator is responsible 
for ensuring that subjects understand how to properly use these methods of 
contraception.
12.8.2.
Protocol Changes for Amendment 02 (29-JUN-2017) from 
Amendment 1 (13-Apr-2017)
Where the amendment applies
This protocol amendment is applicable to all sites.


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Current and Previous Protocols:
Summary of Changes and Rationale for Amendment No. 2
Section 
Section Title 
Change
Rationale
4.2
Treatment Periods and 
Duration
The Fasting requirement for Day 
1 and Day 15 was removed.
Subjects are 
required to fast on 
Day 14 and Day 
28 only.
12.4.3
Definition of 
Cardiovascular Events
Appendix 12.4.3- Definition of 
Cardiovascular Events has been 
removed from the Protocol 
Amendment No. 02. 
The collection of 
Cardiovascular 
Events is not 
applicable to the 
205712 study.
List of Specific Changes
Text which has been deleted from the protocol is indicated in Appendix 12 by strike 
through format.
Modified text incorporated into this protocol amendment (Protocol Amendment No. 
2):
Section 4.2: Treatment Periods and Duration
Rationale for change:
Subjects are required to fast on Day 14 and Day 28 only.
REVISED TEXT:
Paragraph 4 Sentence 1


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On Day 1, following completion of the required pre-dose measurements, the investigator 
or authorized study unit personnel will administer a single oral dose of 30 mg CAB to 
each subject under fasting conditions in the unit.
Paragraph 6 Sentence 1
On Day 15 following the completion of the required Day 14 safety assessments and PK 
collection, subjects will proceed to Period 2, where site staff will administer a single dose 
of RBT 300 mg and a single dose of CAB 30 mg after an overnight fast of at least 6 hours
in the unit. Subjects will be discharged and dispensed a bottle of RBT and a bottle of 
CAB to be taken at home on Days 16-20.
Section 12.4.3: Definition of Cardiovascular Events
Rationale for change:
The collection of Cardiovascular Events is not applicable to the 205712 study.
REVISED TEXT:
12.4.3. Definition of Cardiovascular Events
Cardiovascular Events (CV) Definition:
Investigators will be required to fill out the specific CV event page of the CRF for the 
following AEs and SAEs:
•
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

SAP_001.pdf: 
CONFIDENTIAL
The GlaxoSmithKline group of companies
205712
1
Division
:
Worldwide Development
Information Type     
:
Reporting and Analysis Plan (RAP)
Title
:
Phase I, single-center, open label, fixed-sequence cross-over 
study to evaluate the effect of rifabutin on the 
pharmacokinetics of oral cabotegravir in healthy subjects
Compound Number 
:
GSK1265744
Effective Date 
:
08-SEP-2017
Description:

The purpose of this RAP is to describe the planned analyses and output to be
included in the Clinical Pharmacology Study Report for Protocol 205712

This RAP is intended to describe the safety, pharmacokinetics (PK), and tolerability
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.
RAP Author(s):
Approver
Date
Approval 
Method
Associate Director, Clinical Statistics, PAREXEL
07-SEP-2017
email
Director, Clinical Pharmacology Modelling & 
Simulation, GSK
08-SEP-2017
email
Copyright 2017 the GlaxoSmithKline group of companies. All rights reserved.  
Unauthorised copying or use of this information is prohibited.
PPD
PPD


CONFIDENTIAL
The GlaxoSmithKline group of companies
205712
2
RAP Team Approvals:
Approver
Date
Approval 
Method
30-AUG-2017
email
Clinical Program Lead, PCPS CPSSO, GSK
 
31-AUG-2017
email
Director, Clinical Development, ViiV Physicians
 
05-SEP-2017
email
Principal Data Manager (CPSSO Data 
Management GSK)
07-SEP-2017
email
Principal Statistical Programmer (Statistical 
programming, PAREXEL)
30-AUG-2017
email
Director, (ViiV, Clinical Pharmacology)
Clinical Statistics and Clinical Programming Line Approvals:
Approver
Date
Approval 
Method
31-AUG-2017
email
Manager, Statistics (Infection Disease, Clinical 
Statistics GSK)
31-AUG-2017
email
Programming Manager, (ID, Clinical Programming, 
GSK)
PPD
PPD
PPD
PPD
PPD
PPD
PPD


CONFIDENTIAL
205712
3
TABLE OF CONTENTS
PAGE
1.
INTRODUCTION......................................................................................................5
2.
SUMMARY OF KEY PROTOCOL INFORMATION ..................................................6
2.1.
Changes to the Protocol Defined Statistical Analysis Plan............................6
2.2.
Study Objective(s) and Endpoint(s)...............................................................6
2.3.
Study Design ................................................................................................7
2.4.
Statistical Hypotheses...................................................................................8
3.
PLANNED ANALYSIS..............................................................................................8
3.1.
Interim Analyses ...........................................................................................8
3.2.
Final Analyses ..............................................................................................8
4.
ANALYSIS POPULATIONS .....................................................................................9
4.1.
Protocol Deviations.......................................................................................9
5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA HANDLING 
CONVENTIONS.....................................................................................................10
6.
STUDY POPULATION ANALYSES .......................................................................10
6.1.
Overview of Planned Analyses ...................................................................10
7.
PRIMARY STATISTICAL ANALYSES....................................................................11
7.1.
Pharmacokinetic Analyses..........................................................................11
7.1.1.
Overview of Planned Pharmacokinetic Analyses .........................11
7.1.2.
Drug Concentration Measures .....................................................12
7.1.3.
Pharmacokinetic Parameters.......................................................12
7.2.
Statistical Analysis of Pharmacokinetic Parameters....................................13
8.
SECONDARY STATISTICAL ANALYSES .............................................................14
8.1.
Safety Analyses..........................................................................................14
8.1.1.
Overview of Planned Analyses ....................................................14
9.
REFERENCES.......................................................................................................16
10. APPENDICES........................................................................................................17
10.1.
Appendix 1: Protocol Deviation Management .............................................18
10.1.1.
Exclusions from PK Parameter Summary Population ..................18
10.2.
Appendix 2: Data Management...................................................................19
10.2.1.
Data Format and Process............................................................19
10.3.
Appendix 3: Time & Events.........................................................................20
10.3.1.
Protocol Defined Time & Events ..................................................20
10.4.
Appendix 4: Treatment States and Phases.................................................24
10.4.1.
Treatment State and Study Phases .............................................24
10.4.1.1.
Treatment States for AE, SAE and 
Concomitant Medications Data...................................24
10.4.1.2.
Reporting Other Safety Data ......................................25
10.5.
Appendix 5: Data Display Standards & Handling Conventions....................26
10.5.1.
Study Treatment & Sub-group Display Descriptors......................26
10.5.2.
Baseline Definition & Derivations .................................................26


CONFIDENTIAL
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4
10.5.2.1.
Baseline Definitions....................................................26
10.5.2.2.
Derivations and Handling of Missing Baseline 
Data ...........................................................................27
10.5.3.
Reporting Process & Standards...................................................27
10.6.
Appendix 6: Derived and Transformed Data ...............................................30
10.6.1.
General........................................................................................30
10.6.2.
Study Population..........................................................................30
10.6.3.
Safety ..........................................................................................31
10.7.
Appendix 7: Premature Withdrawals & Handling of Missing Data ...............32
10.7.1.
Premature Withdrawals................................................................32
10.7.2.
Handling of Missing Data.............................................................32
10.7.2.1.
Handling of Missing Dates..........................................32
10.7.2.2.
Handling of PK Concentration Data............................33
10.8.
Appendix 8: Values of Potential Clinical Importance ...................................34
10.8.1.
Laboratory Values........................................................................34
10.8.2.
ECG.............................................................................................34
10.8.3.
Vital Signs....................................................................................34
10.9.
Appendix 9: Model Specifications for Statistical Analysis ............................35
10.9.1.
Statistical Analysis Assumptions and Model Specifications..........35
10.10. Appendix 10 - Abbreviations & Trade Marks...............................................36
10.10.1. Abbreviations...............................................................................36
10.10.2. Trademarks .................................................................................37
10.11. Appendix 11: List of Data Displays..............................................................38
10.11.1. Data Display Numbering..............................................................38
10.11.2. Mock Example Referencing .........................................................38
10.11.3. Study Population Tables..............................................................39
10.11.4. Safety Tables...............................................................................40
10.11.5. Pharmacokinetic Tables...............................................................42
10.11.6. Pharmacokinetic Figures .............................................................43
10.11.7. ICH Listings .................................................................................44
10.11.8. Non-ICH Listings..........................................................................46
10.12. Appendix 12: Example Mock Shells for Data Displays ................................47
10.12.1. Data Display Numbering..............................................................47


CONFIDENTIAL
205712
5
1.
INTRODUCTION
The purpose of this reporting and analysis plan (RAP) is to describe the analyses to be 
included in the Clinical Study Report for Protocol 205712:
Revision Chronology:
GSK Document No.: 
2016N269788_00
23-FEB-2017
Original
GSK Document No.: 
2016N269788_01
13-APR-2017
The purpose of this protocol amendment is to 
update Appendix 12.5.1.” Modified List of Highly 
Effective Methods for Avoiding Pregnancy in 
Females of Reproductive Potential(FRP)”.  The 
updates include clarifying true abstinence for this 
study and the deletion of double barrier method: 
condom and occlusive cap (diaphragm or 
cervical/vault caps) plus spermicidal agent 
foam/gel/film/cream/suppository) as a highly 
effective method for avoiding pregnancy in females 
of reproductive potential (FRP)
GSK Document No.: 
2016N269788_02
29-JUN-2017
Clarify the required days for fasting (Day 14 and 
Day 28). 
Remove Appendix 12.4.3- Definition of 
Cardiovascular Events. The collection of 
Cardiovascular Events is not applicable to the 
205712 study.


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6
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 amendment 2 (Dated: 29-Jun-2017).
2.2.
Study Objective(s) and Endpoint(s)
Objectives
Endpoints
Primary Objectives
Primary Endpoints

To compare steady state CAB exposure 
following 30 mg oral dose once daily 
with and without RBT 300 mg once 
daily.

Plasma CAB AUC(0-), Cmax 
Secondary Objectives
Secondary Endpoints

To describe the pharmacokinetic (PK) of 
CAB 30 mg oral dose once daily 
administered alone and co-administered 
with RBT.

Plasma CAB C, tmax, t1/2 and
CL/F

To assess the safety and tolerability of 
CAB 30 mg oral dose administered 
alone and in combination with RBT 
300 mg once daily.

Safety and tolerability parameters, 
including adverse events, concurrent 
medication, clinical laboratory 
screens, electrocardiogram (ECG), 
and vital signs assessments.
AUC(0-t) = area under the plasma concentration time curve from time zero to the last quantifiable 
time point
Cmax = maximum observed concentration
Ct = last quantifiable concentration 
tmax = time of maximum observed concentration
t1/2 = the elimination half-lifeCL/F = apparent oral clearance


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2.3.
Study Design
Overview of Study Design and Key Features
Table 1
Study Design
Subjects
Screening Period
Period 1 
Days 1 – 14
Period 2 
Days 15 - 28 
Follow-up
N=15 
Within 30 Days of Day 1
Treatment A
Treatment B
~10-14 days after 
last dose of CAB

Treatment A = CAB 30 mg once daily x 14 days

Treatment B = RBT 300 mg once daily + CAB 30 mg once daily x 14 days
Design 
Features
This study is a phase I, single-center, open label, fixed-sequence, 2-period 
crossover study in healthy adults.
Dosing
Subjects will undergo a screening visit within 30 days of the first dose of 
study drug, followed by two treatment periods and a follow-up period. 

Approximately 15 healthy adult subjects will be enrolled to ensure 
that 12 subjects will complete dosing and critical assessments.

Period 1: Eligible participants will be admitted to the unit on Day -1.  
Subjects will be dosed for Days 1, 13 and 14 under the fasting 
conditions in the unit and subjects will be dispensed a bottle of CAB 
to be taken at home on Days 2-12 and discharged from the unit. 
Subjects will be provided with a subject diary to document daily 
recordings of dosing occurring outside of the unit.  There will be no 
washout between Period 1 and Period 2. 

Period 2: On Day 15 following the completion of the required Day 14 
safety assessments and PK collection, subjects will proceed to Period 
2, where site staff will administer a single dose of RBT 300 mg and a 
single dose of CAB 30 mg after an overnight fast of at least 6 hours in 
the unit.  Subjects will be discharged and dispensed a bottle of RBT 
and a bottle of CAB to be taken at home on Days 16-20 and 22-25. 
Subjects will be provided with a subject diary to document daily 
recordings of home dosing. In the morning of Days 21, subjects will 
bring their bottle of RBT and bottle of CAB for observed dosing in the 
unit and safety assessments as an outpatient visit.   On Days 26 and 
27, subjects will return to the unit for a pre-dose PK collection and 
observed dosing as an outpatient visit and then be discharged home. In 
the morning of Day 28 following an overnight fast of at least 6 hours, 
subjects will receive a single dose of RBT and a single dose of CAB 
in the unit with serial CAB PK samples collected pre-dose and 
through 24 hours after dosing up to Day 29. 

Subjects will be discharged from the unit on Day 29 after the final 
assessment is completed.  Subjects will complete a follow-up visit ~ 
10-14 days after the last 30 mg oral dose of CAB.


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Overview of Study Design and Key Features
Treatment 
Assignment
Subjects will receive following treatments in a fixed sequence of A/B: 

Treatment A = CAB 30 mg once daily x 14 days

Treatment B = RBT 300 mg once daily + CAB 30 mg once daily x 14 
days
Interim 
Analysis

No interim analysis will be performed.
2.4.
Statistical Hypotheses
No formal hypothesis will be tested.  This study is designed to estimate the drug-
interaction effect of RBT on CAB PK parameters.  An estimation approach will be used 
to evaluate the effect of RBT on CAB PK.  Point estimates and corresponding 90% 
confidence intervals (CIs) will be constructed for the comparisons of interest 
(test:reference).
3.
PLANNED ANALYSIS
3.1.
Interim Analyses

No interim analysis will be performed.
3.2.
Final Analyses
Final analyses will be performed after the completion of the study, following sequential 
steps and final database authorization:
1. All subjects have completed the study 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.
3. All criteria for unblinding the randomisation codes have been met. 
4. Randomisation codes have been distributed according to RandAll NG procedures.


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4.
ANALYSIS POPULATIONS
Population
Definition / Criteria
Analyses Evaluated
Screening 
Population
All subjects who sign the consent form will 
be included in this population.  

Screening population
listing and summary
Safety 
Population
All subjects who enrol in the study and 
receive at least one dose of study drug will 
be included in the Safety Population.  

Study Population

Safety
PK
Concentration
Population
The CAB PK Concentration Population will 
include all subjects who undergo plasma 
PK sampling and have evaluable PK assay 
results.  

PK concentration 
listing, and individual 
concentration plot
PK Parameter 
Population
The PK Parameter Population will include 
all subjects who have evaluable PK 
parameters. Data from subjects who vomit 
within 4 hours of study drug administration 
will not be considered as evaluable. 

PK parameter listing,
and plotting
PK Summary
Population
The CAB PK Summary Population for this 
study will include subjects who have CAB 
PK parameter estimates from both serial PK 
sampling time periods 1 and 2.  These 
populations will be used for the 
concentration and PK parameters summary 
figures and tables and for the statistical 
analysis of PK parameter data

PK concentrations 
and summary table 
and summary figures

PK Parameter 
Summary table

Statistical analysis of 
parameter data 
NOTES : 

Please refer to Appendix 11 which details the population to be used for each display being generated.
4.1.
Protocol Deviations
Important protocol deviations (including deviations related to study inclusion/exclusion 
criteria, conduct of the trial, subject management or subject assessment) will be 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 unblinding and freezing the database to ensure all 
important deviations and deviations which may lead to exclusion from the PK 
analysis 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 2 provides an overview of appendices within the RAP for outlining general 
considerations for data analyses and data handling conventions. 
Table 2
Overview of Appendices
Section
Component
Section 10.1
Appendix 1: Protocol Deviation Management 
Section 10.2
Appendix 2: Data Management
Section 10.3
Appendix 3: Time & Events
Section 10.4
Appendix 4: Treatment States and Phases
Section 10.5
Appendix 5: Data Display Standards & Handling Conventions
Section 10.6
Appendix 6: Derived and Transformed Data
Section 10.7
Appendix 7: Premature Withdrawals & Handling of Missing Data
Section 10.8
Appendix 8: Values of Potential Clinical Importance
Section 10.9
Appendix 9: Model Checking and Diagnostics for Statistical Analyses.
Section 10.10
Appendix 10: Abbreviations and Trade Marks
Section 10.11
Appendix 11: List of Data Displays
Section 10.12
Appendix 12: Example Mock Shells for Data Displays
6.
STUDY POPULATION ANALYSES
6.1.
Overview of Planned Analyses
The study population analyses will be based on the “Safety” population, unless otherwise 
specified.
Table 3 provides an overview of the planned study population analyses, with full details 
of data displays being presented in Appendix 11: List of Data Displays.
Table 3
Overview of Planned Study Population Analyses
Display Type
Data Displays Generated
Figure
Table
Listing
Study Population 
Analysis Population Summary
Y
Subject Disposition
Subject Disposition
Y
Y


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Display Type
Data Displays Generated
Figure
Table
Listing
Protocol Deviations
Y
Y
Inclusion and Exclusion Criteria Deviations
Y
Demography
Demographics Characteristics
Y
Y
Race & Racial Combinations
Y
Y
Age Group Breakdown for Trial
Y
Others
Concomitant Medication
Y1
Y
Genetic sample collection
Y
Random codes
Y
Treatment non-compliance
Y
Screening information
Y2
Y3
NOTES:

Y = Yes display generated.
1.
Conditional display, if data contains more than 10 records.
2.
Screening population.
3.
All screen failures
7.
PRIMARY STATISTICAL ANALYSES
7.1.
Pharmacokinetic Analyses
The reconciliation of the PK Case Report Form (CRF) and SMS2000 data will be 
performed by Data Management, QSci at GlaxoSmithKline. 
The merge of PK concentration data, randomization and CRF data will be performed. 
The analysis PK concentration dataset and WinNonLin files will be created by statistics 
and programming, under the direct auspices of statistics and programming, Quantitative 
Sciences (QSci), GlaxoSmithKline.   
Derivation of pharmacokinetic parameters will be performed under the direct auspices of 
Clinical Pharmacology Modelling & Simulation (CPMS), QSci, GlaxoSmithKline.
Statistical Analysis of pharmacokinetic parameters will be performed by statistics and 
programming under the direct auspices of statistics and programming, QSci, 
GlaxoSmithKline.
7.1.1.
Overview of Planned Pharmacokinetic Analyses
The pharmacokinetic (PK) analyses will be based on the PK Concentration, PK
Parameter, or PK Summary populations where it is specified.


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Table 4 provides an overview of the planned analyses, with full details being presented in 
Appendix 11: List of Data Displays.
Table 4
Overview of Planned Pharmacokinetic Analyses
Endpoints
Untransformed
Loge-Transformed
Summary
Individual
Summary
Individual
F
T
F
L
F
T
F
L
Plasma Drug Concentrations
Y [1] [2]
Y
Y [1]
Y
Y [1] [2]
Y [1]
Derived PK Parameters
Y
Y[3]
Y
Y
Y[3]
Statistical Analysis PK Parameters
Y[ 4]
Y
Y[5]
NOTES :

T = Table, F = Figures, L = Listings, Y = Yes display generated.

Summary = Represents TF related to any summaries (descriptive statistics) of the observed raw data.

Individual = Represents FL related to any displays of individual subject observed raw data.   

Tmax is not log transformed. 
1.
Linear and Semi-Log plots will be created on the same display.
2.
Mean (+SD) and Median plots will be generated.
3.
Comparative Plot of Individual CAB Plasma PK Parameter vs treatments on linear and semi-log scale
4.
Geometric Mean Treatment Ratio and 90% CI of CAB Plasma PK Parameters will be generated.
5.
Supportive SAS Output from Statistical Analysis of Loge-transformed CAB Plasma PK Parameters
7.1.2.
Drug Concentration Measures
Refer to Appendix 5: Data Display Standards & Handling Conventions (Section 10.5.3
Reporting Process & Standards).
7.1.3.
Pharmacokinetic Parameters
PK analyses will be the responsibility of the CPMS department within GSK or their 
designee.  Plasma CAB concentration-time data will be analyzed by non-compartmental 
methods according to current working practices and using Phoenix WinNonlin 6.3 or 
higher.  Calculations will be based on the actual sampling times recorded during the 
study and based on nominal sampling times.  From the plasma concentration-time data, 
the following PK parameters will be determined, as data permit:  Cmax, Tmax, C, t1/2,
AUC(0-) and CL/F.
Statistics and Programming group will calculate the individual ratios for Cmax, Cand 
AUC(0-).
Refer to Appendix 5: Data Display Standards & Handling Conventions (Section 10.5.3
Reporting Process & Standards). 
Non-compartmental analysis will be performed in accordance with GSK PK Guidance 
document GUI_51487.
Refer Appendix 7 Section 10.7.2.2 for handling of PK Concentration data.


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Table 5
Derived Pharmacokinetic Parameters
Parameter
Parameter Description
AUC(0-)
Area under the plasma concentration-time curve at the end of 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.
C
Plasma concentration at the end of the dosing interval
Tmax
Time to reach Cmax, determined directly from the concentration-time data.
t½
Apparent terminal half-life will be calculated as: t½ = ln2 / Lambda_z
(NOTE: Lambda_z is the terminal phase rate constant).
CL/F
The apparent oral clearance (CL/F) will be calculated as CL/F = 
Dose/AUC(0-) 
PK parameters that have mass in the units should be reported in g/mL and hg/mL for 
CAB.  CL/F should be reported in units of L/h.
7.2.
Statistical Analysis of Pharmacokinetic Parameters
All PK data will be stored in the Archives, GlaxoSmithKline R& D.  Statistical analyses 
of the PK parameter data will be the responsibility of Clinical Statistics, 
GlaxoSmithKline or their designee.
For each of the parameters Cmax, C, AUC(0-), t1/2 and CL/F, if data permit, the 
following summary statistics will be calculated and tabulated by treatment : 

Untransformed Data : N, n, arithmetic mean, SD, median, minimum, maximum 
and %CV.

Loge-transformed Data:  Geometric mean, 95% CI for the geometric mean, SD of 
loge-transformed data and %CVb
For Tmax , the summary statistics specified for untransformed data above will be 
generated.
Primary and Secondary Comparisons of Interest
CAB
PK Parameter
Test
Reference
Assessment
Primary
Cmax and AUC(0-)
Treatment B: RBT+CAB
Treatment A: CAB
Interaction
Secondary
C, t1/2 and CL/F
Treatment B: RBT+CAB
Treatment A: CAB
The PK parameters for CAB (except Tmax) will be loge-transformed and separately 
analyzed using a mixed effects model.  Analysis of variance (ANOVA), considering 
treatment as fixed effect and subject will be treated as a random effect in the model, will 


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be performed using SAS Mixed Linear Models procedure to evaluate the effect of RBT 
on CAB PK parameters: AUC(0-) and Cmax.  Similar model will be applied for 
secondary endpoints: C, t1/2 and CL/F.  Point estimates and their associated 90% CIs 
will be constructed for the differences in PK parameter values between RBT+CAB and 
CAB alone for the treatment comparisons. The point estimates and their associated 90% 
CIs will then be back-transformed to provide point estimates and 90% CIs for the ratios 
of PK parameters between test and reference treatments.
Estimates of within-subject variability for Cmax, C, t1/2, AUC(0-) and CL/F will be 
provided, where CVw(%) = SQRT(exp(MSE) – 1)×100 and MSE is the residual mean 
squared error from the model. CVw represents a pooled measure of within-subject 
variability across the treatments CAB and RBT+CAB.
Pre-dose concentrations collected between Days 13-14 and Days 26-28 will be listed with 
PK concentration profiles and summarized by Day/Time.  To assess for achievement of 
steady-state of CAB when CAB is given with RBT, Analysis of variance (ANOVA), 
considering DAY as fixed effect and subject as a random effect in the model, will be 
performed using SAS Mixed Linear Model on the pre-dose concentration between Days. 
The estimated slope and 90% CI will be presented for models included 2 days (Days 13-
14, 27-28) or 3 days (Days 26-28) pre-dose concentrations.
Comparative Plot of Individual subject CAB Plasma PK Parameter Versus Treatment 
will be generated.
Individual and box plots of Pre-dose concentration of Day 13-14 and Days 26-28 will be 
generated. 
Plots will also be provided showing the adjusted geometric mean ratio of test to reference 
treatment for Cmax, C, AUC(0-), t1/2 and CL/F with 90% CIs.
The SAS output from the statistical models will be included in a listing of supportive 
SAS output.
8.
SECONDARY STATISTICAL ANALYSES
8.1.
Safety Analyses
8.1.1.
Overview of Planned Analyses
The safety analyses will be based on the Safety population, unless otherwise specified.
Table 6 provides an overview of the planned analyses, with full details of data displays 
being presented in Appendix 11: List of Data Displays.


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Table 6
Overview of Planned Safety Analyses
Endpoint
Absolute
Change from Baseline
Summary
Individual
Summary
Individual
T
F
F
L
T
F
F
L
Exposure
Exposure
Y
Y
Adverse Events
All AE’s
Y
Y
Serious AE’s
Y
Drug Related AEs
Y
Y1
Withdrawal AE’s
Y
Y
Relationship Between System 
Organ Class and Verbatim Text
    Y
Liver Event
Y
Laboratory Values 
Clinical Chemistry 
Y
Y2
Hematology 
Y
Y2
Clinical Lab Reference Ranges
Y
Treatment Emergent Toxicity 
Grade
Y
Urinalysis
Y
Y
ECG’s
ECG Findings
Y
Y
ECG Values
Y
Y2
Y
Category of QTc Data
Y
Y
ECG Values Outside the PCI 
Range
Y
Vital Signs
Vitals Values
Y
Y2
Y
Vital Signs Measurements 
Outside the PCI Range
Y
NOTES :

T = Table, F = Figures, L = Listings, Y = Yes display generated.

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: Part of all AEs listing
2: Listing will include toxicity grade or flag for H/L if out of normal range 


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9.
REFERENCES
GlaxoSmithKline Document Number 2016N269788_00: Phase I, single-center, open 
label, fixed-sequence cross-over study to evaluate the effect of rifabutin on the 
pharmacokinetics of oral cabotegravir in healthy subjects. Effective Date: 23-FEB-2017
GlaxoSmithKline Document Number 2016N269788_01: Phase I, single-center, open 
label, fixed-sequence cross-over study to evaluate the effect of rifabutin on the 
pharmacokinetics of oral cabotegravir in healthy subjects Effective Date: 13-APR-2107
GlaxoSmithKline Document Number 2016N269788_02: Phase I, single-center, open 
label, fixed-sequence cross-over study to evaluate the effect of rifabutin on the 
pharmacokinetics of oral cabotegravir in healthy subjects Effective Date: 29-Jun-2017


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10.
APPENDICES
Section
Appendix
RAP Section 4: Analysis Populations
Section 10.1
Appendix 1: Protocol Deviation Management 
RAP Section 5 : General Considerations for Data Analyses & Data Handling 
Conventions
Section 10.2
Appendix 2: Data Management
Section 10.3
Appendix 3: Time and Events
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

Pharmacokinetic
Section 10.7
Appendix 7: Premature Withdrawals & Handling of Missing Data

General

Study Population & Safety
Section 10.8
Appendix 8: Values of Potential Clinical Importance

Laboratory Values

ECG

Vital Signs
Section 10.9
Appendix 9: Model Specifications for Statistical Analyses
Other RAP Appendices
Section 10.10
Appendix 10: Abbreviations & Trade Marks
Section 10.11
Appendix 11: List of Data Displays
Section 10.12
Appendix 12: Example Mock Shells for Data Displays


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10.1.
Appendix 1: Protocol Deviation Management
10.1.1.
Exclusions from PK Parameter Summary Population
All protocol deviations will be reviewed, and only the important deviations will be listed 
and summarized. Some subjects may be excluded from analysis due to protocol 
deviations. A subject meeting any of the following criteria will be excluded from the PK 
Parameter Summary Population:
Number
Exclusion Description
01
Failure of any inclusion/exclusion criteria, but subject is still enrolled
02
A subject with emesis occurring within 4 hours of the dose on Day 14 or 
Day 28
03
A subject who does not have evaluable PK parameters from both periods
04
A subject who has not dosed correctly on the days for PK collections


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10.2.
Appendix 2: Data Management
10.2.1.
Data Format and Process
Data Type
Source 
Format of 
Data
Planned Date of 
Final File
Responsibi
lity
Safety
PIMS>SI data
SI>STDM
DBF
Accenture
PK 
Concentration
SMS2000 data 
file
dat file
DBF
BIB/BESM
PK 
Concentration 
(ADPC), 
WNL File
PK concentration 
data (SDTM PC), 
exposure (EX) 
and demography 
(DM) datasets2
ADaM, CSV 
file
DBF + 5 Days1
QSci
PK 
Parameters
WNL file
CSV file
PK 
Concentration, 
WNL file + 10
Days
CPMS
1.
Provided SDTM PC, EX and DM are in time and clean
2.
PK concentration data is released via SMS2000 by Bioanalysis, Immunogenicity and Biomarkers 
(BIB)/Bioanalytical External Study Monitors (BESM) and the SDTM PC contains date/times and 
PK sample ID


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10.3.
Appendix 3: Time & Events
10.3.1.
Protocol Defined Time & Events
Procedure
Screen1
Day
-1
Treatment Period 1
Day
Treatment Period 2
Day
Early 
Withdrawal
/ Follow-up
~10-14 
days
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
212
22
23
24
25
262
27
28
29
Informed consent
X
Inclusion and 
exclusion criteria
X
X
Demography
X
Full physical 
exam3
X
Brief physical 
exam3
X
X
X
X
X4
Medical/medicatio
n/drug/alcohol 
history
X
X
X
X
Pregnancy test 5
X
X
X
X
X
FSH and estradiol 
(if needed)
X
TB, HIV, Hep B, 
Hep C screen
X
Drug/Alcohol 
screen
X
X
X
X


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Procedure
Screen1
Day
-1
Treatment Period 1
Day
Treatment Period 2
Day
Early 
Withdrawal
/ Follow-up
~10-14 
days
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
212
22
23
24
25
262
27
28
29
Safety Laboratory 
assessments
X
X
X
X
X
X
12-lead ECG6
X
X
X
X
X
Vital signs 
(Including 
Temperature)6
X
X
X
X
X
X
Administer CAB 
30 mg once daily7
X X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Administer RBT 
300 mg once 
daily7
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Dispense CAB8
X
Dispense 
CAB9and RBT10
X
Pharmacokinetic 
Sampling11
X
X-----X
X
X
X-----
X
Admit to Unit
X
X
X
Discharge from 
Unit
X
X
X
Outpatient Visit
X
X
X
X


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Procedure
Screen1
Day
-1
Treatment Period 1
Day
Treatment Period 2
Day
Early 
Withdrawal
/ Follow-up
~10-14 
days
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
212
22
23
24
25
262
27
28
29
Drug 
accountability
X
X
X
X
Genetic sample12
========================================================================================================
SAE Review
=======================================================================================================================
AE Review
========================================================================================================
========================================================================================================
Concomitant 
medication review


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1.
Screening must be performed within 30 days prior to receiving the dose of CAB on Day 1.
2.
Day 21 and Day 26 is an outpatient visit.
3.
An ocular assessment will be performed only for subjects who experience eye symptoms.
4.
A brief symptom directed physical exam will be completed as needed.
5.
A serum pregnancy test will be performed at the screening visit and a urine pregnancy test at all other time points specified. 
6.
Duplicate ECG, BP, and HR assessments will be conducted pre-dose on Day 1.  Single measurements will be collected at all other time points.
7.
Study medication will be administered with 240 mL of water within the unit on Days 1, 13, 14, 15, 21, 26, 27, and 28.  Dosing on non-PK days may be with or without food, 
but dosing on serial PK days (Day 14 in Period 1 and Day 28 in Period 2) must be after an overnight fast of at least 6 hours, and no food will be allowed for 4 hours after 
dosing on these serial PK days.
8.
Dispense the bottle of CAB tablets to the subject on Day 1 to receive CAB dosing at home on Days 2 to 12 in Period 1 
9.
Dispense the bottle of CAB tablets to the subject on Day 15 to receive CAB dosing at home on Days 16 to 20 and Days 22 to 25 in Period 2; dosing on Day 21, 26, 27, and
28 is in the unit. 
10. Dispense the bottle of RBT capsules to the subject on Day 15 to receive RBT dosing at home on Days 16 to 20 and Days 22 to 25 in Period 2; dosing on Day 21, 26, 27, 
and 28 is in the unit. 
11. Plasma PK samples (2 mL of blood per sample) will be collected to measure CAB at the following time points: Period 1: predose (within 15 minutes prior to dose) on 
Day 13; and pre-dose (within 15 minutes prior to dose), 1, 2, 3, 4, 8, 12, and 24 hours after CAB dosing on Day 14.  Period 2:  pre-dose (within 15 minutes prior to dose) on 
Days 26 and 27 and pre-dose (within 15 minutes prior to dose) on Day 28 and, 1, 2, 3, 4, 8, 12, and 24 hours after CAB +RBT dosing on Day 28.  
12. It is recommended that the Pharmacogenetic sample be collected on Day 1, but it may be collected at any time following administration of investigational product.


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10.4.
Appendix 4: Treatment States and Phases
10.4.1.
Treatment State and Study Phases
Assessments and events will be classified according to the time of occurrence relative to 
study visit or the start and/or stop date/time of the study treatment.
Treatment 
State
Study Phase
Pre-Treatment 
Screening assessments collected prior to the Day 1 visit
On-Treatment
Period 1 and Period 2
Follow-up
Follow-up Visit
10.4.1.1.
Treatment States for AE, SAE and Concomitant Medications Data
Treatment 
State
Definition
Screening
AE(SAE or conmed) Start Date/Time < Study Treatment Start Date/Time. 
Based on the protocol, these AEs and concomitant medications prior to dosing 
will not be collected in database, and only record in the source document, but 
SAE will be captured on the dataset
Treatment A
If AE (SAE or conmed) onset date/time is on or after Period 1 treatment start 
date/time & before Period 2 treatment date/time
Study Period 1 Treatment Start Date/Time ≤ AE Start Date/Time < Study 
Period 2 Treatment Date/Time]
Treatment B
If AE (SAE or conmed) onset date/time is on or after Period 2 treatment start 
date/time & before Study Conclusion date/time
Study Period 2 Treatment Start Date/Time ≤ AE Start Date/Time < Study 
follow-up visit Date/Time]
Follow-up
All unsolved AEs (SAE or conmed) during the follow-up will be associated 
with the treatment from Period 2, and no AEs (SAE or conmed) will be report 
under the follow-up
Onset Time
Since First 
Dose
(Days)
If Treatment Start Date/Time > AE Onset Date/Time = AE Onset Date -
Treatment Start Date
If Treatment Start Date/Time ≤ AE Onset Date/Time = AE Onset Date -
Treatment Start Date +1
Missing otherwise
Duration 
(Days) 
AE Resolution Date – AE Onset Date + 1
Drug-related
If relationship is marked ‘YES’ on eCRF 
NOTES: 

If the study treatment stop date is missing then the AE will be considered to be On-Treatment.


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10.4.1.2.
Reporting Other Safety Data
All of other safety measurements will be associated and summarized for each visit based 
on the CRF as the following:
Visit
Time Slices Definition
Screening
Screen
Period 1
Day -1, Period 1 Days 1-Day 14
Period 2
Period 2, Days 15-28
Follow-up
Follow-up


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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
RandAll NG 
Data Displays for 
Reporting 
Code
Description and Footnotes for the Displays
Description
A
CAB 30 mg once daily x 14 days
CAB 30mg
B
RBT 300 mg once daily + CAB 30 mg once daily x 14 days
RBT 300mg + CAB 
30mg
10.5.2.
Baseline Definition & Derivations
10.5.2.1.
Baseline Definitions
For all endpoints (except as noted in the table) the baseline value will be the latest pre-
dose assessment. 
Table 7
Baseline Definitions
Parameter
Study Assessments Considered as 
Baseline
Baseline Used in 
Data Display
Screening
Day -1
Day 1 
(Pre-Dose)
Safety
Labs
X
X
Day -1
ECG
X
Day 1 (Pre-Dose)
Vital Signs (blood 
pressure, and pulse rate)
X
X
Day 1 (Pre-Dose)


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10.5.2.2.
Derivations and Handling of Missing Baseline Data
Definition
Reporting Details
Change from Baseline
= Post-Dose Visit Value – Baseline
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 and S-Plus software will be used.
Reporting Area
HARP Server
: US1SALX00259-HARP PROD-US
HARP Area
: \ARPROD\GSK1265744\mid205712\Final
QC Spreadsheet
: \ARWORK\GSK1265744\mid205712\Final\Documents
Analysis Datasets 

Analysis datasets will be created according to Clinical Data Interchange 
Standards Consortium (CDISC) standards (SDTM IG Version 3.1.3 or higher 
vision & Analysis Data Model (ADaM) Implementation Guide (ADaM IG) 
Version 1.1 or higher dataset standards)
Generation of Rich Text Format (RTF) Files

RTF files will be generated for Safety summary displays.


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Reporting Standard
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:
o
Planned time relative to dosing will be used in figures, summaries, statistical 
analyses and calculation of any derived parameters, unless otherwise stated.
o
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: 
o
Planned and actual time relative to study drug dosing will be shown in listings 
(Refer to IDSL Statistical Principle 5.05.1).
o
Unscheduled or unplanned readings will be presented within the subject’s 
listings. 
o
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.


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Reporting Standard
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)
Reporting of Pharmacokinetic Parameters
Descriptive Summary 
Statistics.                      
(Un-Transformed) 
N, n, arithmetic mean, 95% confidence interval (CI) for the 
arithmetic mean, SD, median, minimum, maximum and 
CV(%)

CV(%)=(SD/mean)*100
Descriptive Summary 
Statistics.                     
(Loge Transformed)   
N, n, geometric mean, 95% CI of geometric mean, standard 
deviation (SD) of logged data and between-subject geometric 
coefficient of variation (CVb (%)) will be reported.

Geometric mean = exp (mean on loge scale)

CVb (%) = √ (exp(SD2) - 1) * 100 [NOTE: SD = SD of 
loge transformed data]
Parameters Not 
Being Loge
Transformed  
Tmax
Listings
Include PK Parameters: Cmax, Tmax, C, AUC(0-), t1/2 and 
CL/F.
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

Mean of the measurements will be calculated and used in any derivation of summary 
statistics but if listed, all data will be presented.
Study Day

Calculated as the number of days from Treatment start date :

Ref Date = Missing                       → Study Day = Missing 

Ref Date < Treatment start Date   → Study Day = Ref Date – Treatment start Date   

Ref Data ≥ Treatment start Date   → Study Day = (Ref Date – Treatment start 
Date) + 1    
10.6.2.
Study Population
Demographics
Age

GSK standard IDSL algorithms will be used for calculating age using date of the 
screening visit relative to birth date, where birth date is imputed as:

Any subject with a missing date and month will have this imputed as ‘30th June’.

Birth date will be presented in listings as ‘YYYY’.
Body Mass Index (BMI)

Calculated as Weight (kg) / [Height (m)]2
Extent of Exposure

Number of days of exposure to study drug will be calculated based on the formula:  
Duration of Exposure in Days = Treatment Stop Date – (Treatment Start Date) + 1


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10.6.3.
Safety
ECG Parameters
RR Interval

IF RR interval (msec) is not provided directly, then RR can be derived as :
[1] If QTcB is machine read & QTcF is not provided, then :
RR = [(QT/QTcB)^(2) ]*1000
[2] If QTcF is machine read and QTcB is not provided, then: 
RR = [(QT/QTcF)^(3) ]*1000
Corrected QT Intervals

When not entered directly in the eCRF, corrected QT intervals using Bazett’s (QTcB) 
and Fredericia’s (QTcF) formulas will be calculated, in msec, depending on the 
availability of other measurements.

IF RR interval (msec) is provided then missing QTcB and/or QTcF will be derived as 
: 
Laboratory Parameters

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. 

Example 1: 2 Significant Digits =  ‘< x ‘ becomes x – 0.01

Example 2: 1 Significant Digit   =  ‘> x’ becomes x + 0.1

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
All subjects who withdraw prematurely from the study/study drug will be 
documented, listed with the reason for their withdrawal recorded in the 
final Clinical Pharmacology Study Report (CPSR).  
10.7.2.
Handling of Missing Data
Element
Reporting Detail
General
Missing PK and safety data will not be imputed 
Outliers
Any subjects excluded from the summaries and/or statistical analyses will be 
documented and flagged in the dataset and listing 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
The eCRF allows for the possibility of partial dates (i.e., only month and 
year) to be recorded for AE start and end dates; that is, the day of the month 
may be missing. In such a case, the following conventions will be applied 
for calculating the time to onset and the duration of the event:
o
Missing Start Day: First of the month will be used unless this is 
before the start date of study treatment; in this case the study 
treatment start date will be used and hence the event is considered 
On-treatment as per Appendix 4: Treatment States and Phases.
o
Missing Stop Day: Last day of the month will be used, unless this is 
after the stop date of study treatment; in this case the study treatment 
stop date will be used.
o
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.


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10.7.2.2.
Handling of PK Concentration Data
Element
Reporting Detail
General
If a PK sample in a profile is ‘no result’, ‘no sample received’, or 
‘insufficient sample’, data will be set as missing. No imputation will be 
applied.


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10.8.
Appendix 8: Values of Potential Clinical Importance
10.8.1.
Laboratory Values
Division of AIDS (DAIDS, Version 2.0, November 2014) AE grade 2 and above of lab 
abnormalities will be listed by subject, period/treatment, visit, and actual date and time.
Statistics and Programming group will use this version to add toxicity grades values in 
the ADAM dataset.
10.8.2.
ECG
ECG Values of Potential Clinical Importance (Healthy Volunteers)
ECG Parameter
Potential Clinical Importance Range (PCI)
Unit
Absolute QTc Interval
>450
msec
Increase from baseline QTc
>60 
msec
PR Interval
<110 and >220
msec
QRS Interval
<75 and >110
msec
10.8.3.
Vital Signs
Vital Signs Values of Potential Clinical Importance (Healthy Volunteers)
Parameter
Potential Clinical Importance Range (PCI)
Unit
Systolic Blood Pressure
<85 and >160
mmHg
Diastolic Blood Pressure
<45 and >100
mmHg
Heart Rate
<40 and >110
bpm


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10.9.
Appendix 9: Model Specifications for Statistical Analysis
10.9.1.
Statistical Analysis Assumptions and Model Specifications
Endpoint(s)
Cmax, C, AUC(0-), t1/2 and CL/F, if data permitted
Analysis
Linear Mixed Model
Specifications:

For the Linear Mixed Model, model assumptions will be PK parameter following log-
normal distribution. 

For drug-drug interaction assessment, an example of SAS code is included here.
Proc Mixed;
By parameter;
    
class treatment subject;
    
model logPKpar = treatment/ddfm=kr outpred=pred;  
random subject;  
    
lsmeans treatment; 
     estimate 'B:A’ treatment -1 1/cl alpha=0.1;
         /* (CAB+RTB) vs (CAB alone)*/
    run;

An example of SAS code to assess achievement of steady-state is included here.
Proc Mixed;
    by dose;
    where day in (13,14); 
    class subject;
    model logC0 = day/ddfm=kr cl alpha=0.1 solution;    
    random intercept/subject=subject type=un solution;
    make ‘solutionf’ output=stat;
run;
repeat for Days 26,27,28 and Days 27,28


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10.10.
Appendix 10 - Abbreviations & Trade Marks
10.10.1.
Abbreviations
Abbreviation
Description
ADaM
Analysis Data Model
ADaM IG
Analysis Data Model Implementation Guide
AE
Adverse Event
ANOVA
Analysis of Variance
AUC
Area under concentration-time curve
AUC(0-)
Area under the concentration-time curve over one dosing interval
BESM
Bioanalytical External Study Monitors
BIB
Bioanalysis, Immunogenicity and Biomarkers
CDISC
Clinical Data Interchange Standards Consortium
CI
Confidence Interval
CL/F
The apparent oral clearance
Cmax
Maximum observed concentration 
CP
Clinical Programming
CPMS
Clinical Pharmacology Modelling & Simulation
CPSSO
Clinical Pharmacology Sciences and Study Operations
CRF
Case record form
CS
Clinical Statistics
Ct 
Concentration at the end of the dosing interval
CV
Coefficient of Variation
CVb/CVw
Coefficient of Variation (Between)/Coefficient of Variation (Within)
DAIDS
Division of Acquired Immune Deficiency Syndrome
DBF
Database Freeze
DBR
Database Release
GSK
GlaxoSmithKline
HARP
Harmonized Analysis and  Reporting Process
IDSL
Integrated Data Standards Library
LLQ
Lower limit of quantification
NC
Not Calculable
NQ
Non-quantifiable concentration measured as below LLQ
PK
Pharmacokinetic
QSci
Quantitative Sciences
RAP
Reporting and Analysis Plan
RBT
Rifabutin
RTF
Rich Text Format
SAS
Statistical Analysis System
SD
Standard deviation
SDTM
Study Data Tabulation Model
SRP
Statistics Resourcing and Programming
t½
Terminal phase half-life
Tmax
Time of occurrence of Cmax


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10.10.2.
Trademarks
Trademarks of ViiV Healthcare
Trademarks not owned by ViiV 
Healthcare
NONE
Mycobutin
SAS
WinNonlin


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10.11.
Appendix 11: List of Data Displays
10.11.1.
Data Display Numbering
The following numbering will be applied for RAP generated displays:
Section
Tables
Figures
Study Population
1.1 to 1.n
N/A
Safety
2.1 to 2.n
N/A
Pharmacokinetic
3.1 to 3.n
3.1 to 3.n
Section
Listings
ICH Listings
1 to x
Other Listings
x+1 to y
10.11.2.
Mock Example Referencing
All displays will be provided with an example from previous CAB studies LAI117010 
and LAI117011 or mock examples are provided.


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10.11.3.
Study Population Tables
Study Population Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable
[Priority]
Subject Disposition 
1.1.
Safety
LAI117010/ Table 1.1
Summary of Analysis Populations
by Overall
SAC
1.2.
Safety
LAI117010/ Table 1.2
Summary of End of Study Record by Treatment 
and Overall
By subject and treatment
SAC
1.3.
Safety
LAI117010/ Table 1.3
Listing of End of Study Record
By subject 
SAC
Demographics and Enrolment Information
1.4.
Safety
LAI117010/ Table 1.5
Summary of Demographic characteristics
Include BMI, Race detail
SAC
1.5.
Safety
LAI117010/ Table 1.6
Summary of Race for Safety Population
By treatment and Overall
SAC
1.6.
Safety
LAI117010/ Table 1.7
Listing of Concomitant Medication
By Subject. Change from 
listing to summary if more 
than 3 pages 
SAC
1.7.
Safety 
LAI117010/ Table 1.8
Listing of Genetics Subject Accountability
SAC
1.8.
Safety
LAI117010/ Table 1.9
Listing of Treatment Non-Compliance
SAC
1.9.
Safety 
LAI117010/Table 1.10
Listing of Subjects with Protocol Deviations
SAC
1.10.
Safety
LAI117010/Table 1.11
Summary of Screening Information
SAC
1.11.
Safety
LAI117011/Table 1.11
Age Group Breakdown for the Trial
For Eudra posting


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10.11.4.
Safety Tables
Safety Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Adverse Events
2.1.
Safety
LAI117010/ Table 2.1
Summary of Exposure Data
By subject and treatment 
SAC
2.2.
Safety
LAI117010/ Table 2.2
Relationship of Adverse Event System Organ 
Classes, Preferred Terms, and Verbatim Text
SAC
2.3.
Safety
LAI117010/ Table 2.3
Summary of All Adverse Events by 
Treatment
SAC
2.4.
Safety
LAI117010/ Table 2.4
Summary of Drug-Related Adverse Events 
by Treatment
SAC
2.5.
Safety
LAI117010/ Table 2.5
Listing of Serious Adverse Events
By subject and treatment.
SAC
2.6.
Safety
LAI117010/ Table 2.6
Listing of Adverse Events Leading to 
Permanent Discontinuation of Study Drug or 
Withdrawal from Study
By subject and treatment
SAC
Labs
2.7.
Safety
LAI117010/ Table 2.7
Listing of Reference Ranges for Clinical 
Laboratory Tests
SAC
2.8.
Safety
LAI117010/ Table 2.8
Summary of Clinical Haematology 
Laboratory Data by Treatment and Time
SAC
2.9.
Safety
LAI117010/ Table 2.9
Summary of Clinical Chemistry Laboratory 
Data by Treatment and Time
SAC
2.10.
Safety
LAI117010/ Table 2.10
Summary of Treatment Emergent Grade 2 or 
Higher Lab Abnormalities by Treatment
Summary of Treatment 
Emergent Lab toxicity 
only.
SAC
2.11.
Safety
LAI117010/ Table 2.11
Listing of Treatment Emergent Grade 2 or 
Higher Lab Abnormalities
By subject and treatment 
SAC
2.12.
Safety
CP_LB5
Summary of All Urinalysis Data
SAC


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Safety Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Vital Signs 
2.13.
Safety
LAI117010/ Table 2.13
Summary of Vital Signs by Treatment and 
Time
Include BP and HR only.
SAC
2.14.
Safety
LAI117010/ Table 2.14
Summary of Change from baseline in Vital 
Signs by Treatment and Time
Include BP and HR only.
SAC
2.15.
Safety
LAI117010/ Table 2.15
Listing of Vital Signs for Subjects with 
Abnormalities of Potential Clinical 
Importance
By subject and treatment
SAC
ECGs
2.16.
Safety
LAI117010/ Table 2.16
Summary of ECG Findings
SAC
2.17.
Safety
LAI117010/ Table 2.17
Summary of ECG Values by Treatment and 
Time
SAC
2.18.
Safety
LAI117010/ Table 2.18
Summary of Change from Baseline in ECG 
Values by Treatment and Time
SAC
2.19.
Safety
LAI117010/ Table 2.19
Summary of Category of QTc Data by 
Treatment and Time
SAC
2.20.
Safety
LAI117010/ Table 2.20
Summary of Category of QTc Change from 
Baseline by Treatment and Time
SAC
2.21.
Safety
LAI117010/ Table 2.21
Listing of ECG Values for Subjects with 
Abnormalities of Potential Clinical 
Importance
By subject and treatment
SAC
2.22.
Safety
LAI117010/ Table 2.22
Listing of Clinically Significant ECG 
Abnormalities
List all data for a subject 
with clinically significant 
abnormalities 
SAC
2.23.
Safety
LAI117011/Table 2.17
Summary of Serious Adverse Events by 
Preferred Term Including Drug-related Status 
and Fatal Status
Eudra posting table
SAC
2.24.
Safety
LAI117011/Table 2.18
Summary of Non-Serious Adverse Evens by 
Preferred Term with Occurrences >5%
Eudra posting table
SAC


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Safety Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.25.
Safety
IDSL LIVER5
Listing of Liver Monitoring and stopping 
Event Reporting
IDSL standard for liver 
event 
SAC
10.11.5.
Pharmacokinetic Tables
Pharmacokinetic Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
3.1.
PK Summary
LAI117010/Table 3.1
Summary of CAB Plasma Concentration-time Data 
(unit) by Treatment 
Treatments A, B 
SAC
3.2.
PK Parameter 
LAI117010/Table 3.2
Listing of Derived Plasma CAB PK Parameters 
All parameters with 
units;
SAC
3.3.
PK Summary
LAI117010/Table 3.3
Summary of Derived Plasma CAB PK Parameters 
All parameters with 
units
SAC
3.4.
PK Summary
LAI117010/Table 3.4
Listing of Individual Plasma CAB PK Parameter 
Treatment Ratios 
For Cmax, AUC(0-τ), 
Cτ
SAC
Statistical Analysis Table 
3.5.
PK Summary
LAI117010/Table 3.5
Summary of Statistical Analysis of CAB Plasma PK 
Parameters Comparison 
SAC
3.6.
PK Summary
ITZ112929/Table 11.9
Summary of Stead-State Assessment  
SAC


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10.11.6.
Pharmacokinetic Figures
Pharmacokinetic Figures
No.
Population
IDSL / TST ID / Example 
Shell
Title
Programming 
Notes
Deliverable 
[Priority]
3.1.
PK Plasma 
Concentration
LAI117010/ Figure 3.1
Individual CAB Plasma Concentration-time Plot 
(Linear and Semi-log) by Subject
Paged by Subject
SAC
3.2.
PK Summary
LAI117010/ Figure 3.2
Median Plasma CAB Concentration-Time Plots by 
Treatment (Linear and Semi-Log) 
SAC
3.3.
PK Summary
LAI117010/ Figure 3.3
Mean Plasma CAB Concentration-Time Plots by 
Treatment (Linear and Semi-Log)
SAC
3.4.
PK Summary
LAI117010/ Figure 3.4
Comparative Plot of Plasma CAB PK Parameters 
between Treatments 
PK_F1 mock up
SAC
3.5.
PK Summary
LAI117010/ Figure 3.5
Geometric Mean Treatment Ratios and 90% CIs of 
CAB PK Parameters
PK_F2 mock up
SAC


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10.11.7.
ICH Listings
ICH Listings
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Randomisation
1
Safety
CP_RA1x (XO)
Listing of Randomized and Actual Treatments
Add randomization date
SAC
Subject Disposition
2
Screening 
ES7
Listing of Reasons for Screening Failures
Include Age and Sex. 
Concatenate with Subjid 
SAC
3
Safety
CP_ES10x (XO)
Listing of Reasons for Withdrawal
SAC
4
Safety
IE4 (XO)
Listing of Subjects with Inclusion/Exclusion Criteria 
Deviations
SAC
Demographics
5
Safety
DM4 (XO)
Listing of Demographic Characteristics
SAC
6
Safety
DM10 (XO)
Listing of Race
SAC
Concomitant Medication
7
Safety
CP_CM4
(XO)
Listing of Concomitant Medications by Generic Term
SAC
Exposure
8
Safety
EX4 (XO)
Listing of Exposure Data
SAC


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ICH Listings
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Adverse Events
9
Safety
AE7
Listing of Subject Numbers for Individual Adverse Events
SAC
10
Safety
CP_AE9 (XO)
Listing of All Adverse Events
SAC
LABS
11
Safety
CP_LB6 (xo) 
Listing of Clinical Chemistry 
Include all tests, toxicity 
grades and range flags
SAC
12
Safety
CP_LB6 (xo) 
Listing of Hematology 
Include all tests, toxicity 
grades and range flags
SAC
13
Safety
UR2b
Listing of Urinalysis Data 
SAC
ECGs
14
Safety
CP_EG4 (xo)
Listing of ECG Values of Potential Clinical Importance
SAC
15
Safety
CP_EG4 (xo)
Listing of All ECG Values for Subjects with any Value of 
Potential Clinical Importance
SAC
16
Safety
CP_EG6 (xo)
Listing of Abnormal ECG findings
SAC
Vital Signs
17
Safety
CP_VS5 (XO)
Listing of Vital Signs of Potential Clinical Importance
SAC
18
Safety
CP_VS5 (XO)
Listing of All Vital Signs for Subjects with any Value of 
Potential Clinical Importance
SAC


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10.11.8.
Non-ICH Listings
Non-ICH : Listings
No.
Population
IDSL / TST 
ID / 
Example 
Shell
Title
Programming 
Notes
Deliverable 
[Priority]
PK
19
PK Plasma 
Concentration
pkcl1x
Listing of CAB Plasma Concentration-time Data
SAC
20
PK Summary
N/A
SAS Output from Statistical Analysis of Loge-transformed CAB 
Plasma PK Parameters of Treatment Comparison
SAC


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10.12.
Appendix 12: Example Mock Shells for Data Displays
10.12.1.
Data Display Numbering
The following numbering will be applied for RAP generated displays:
Example 
: PK_T1
                                                                                          
Protocol : 205712                                                                                                                                                                                                                       Page 1 of n
Population
: PK Parameter Summary
Table xx.xx
Summary of Statistical Analysis of Loge-transformed CAB Plasma Pharmacokinetic Parameters based on Actual Sampling Time
Parameter
Comparison
       Adjusted Geometric Mean
  Ratio
90% Confidence
%CVw
Test vs Reference
      n    Test          n    Ref           
(Test/Ref)              Interval for Ratio
-----------------------------------------------------------------------------------------------------------
Cmax(units)          [Test treatment description] vs          x   xx.xx          x  xx.xx
x.xxxx
(x.xxxx, x.xxxx)          
   xx.x
   [Reference treatment description]
AUC(0-τ)(units)      [Test treatment description] vs         x   xx.xx          x  xx.xx
x.xxxx
(x.xxxx, x.xxxx)           
  xx.x
   [Reference treatment description]
Cτ(units)      [Test treatment description] vs                x   xx.xx          x  xx.xx
x.xxxx
(x.xxxx, x.xxxx)             
  xx.x
   [Reference treatment description]


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Example LIVER5
Protocol: XYZ100001                                                                             Page 1 of 1
Population: Intent-to-Treat/Safety/Other study specific                             (Data as of: 30MAY2011)
Listing X
Listing of Liver Monitoring/Stopping Event Reporting
Treatment: Treatment A
Site Id./
Unique Subject 
Id.
Age(YEARS)/
Sex/
Race Detail
Maximum Status 
of the Liver 
Event
Date 
First 
Detected/ 
Study Day
Time  
Since
First 
Dose
(days)
Time 
Since
Last 
Dose
(days)
Restart/Re-
challenge 
After 
Stopping 
Criteria Was 
Met
Resolved?/
Date 
resolved
63/
M/
WHITE -
WHITE/CAUSASIAN/EUROPEAN 
HERITAGE
LIVER MONITORING 
CRITERIA
101
101 
1 
N
Y/
2010-02-19
61/
F/
ASIAN - JAPANESE 
HERITAGE 
LIVER EVENT 
STOPPING 
CRITERIA
68
  68 
1 
Y
Y/
2010-04-10
LIVER EVENT 
STOPPING 
CRITERIA
134
134 
7 
N
N
PPD
PPD
PPD
PPD
PPD


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Example 
: PK_F1
                         Page 1 of n
Protocol
: 205712
Population
: PK Summary
                                                                      Figure xx.xx
                 Box Plot of Plasma Comparative of Geometric Mean (95% CI) with Individual Subjects
                                              CAB Pharmacokinetic Parameters
                                 
Programming note: add footnote for treatment A, B.


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Example 
: PK_F2
                 Page 1 of n
Protocol
: 205712
Population
: PK Parameter Summary
                                                                         Figure xx.xx
           Geometric Mean Treatment Ratio and 90% CI of CAB Plasma Pharmacokinetic Parameters
                                                                                                     A vs B
Note: The reference lines are at ratios of 0.80, 1.25.
Programming note: add footnote for treatment A, B.