Clinical trial NCT03984825
Conditions: HIV Infections
Keywords: GSK3640254 ethinyl estradiol levonorgestrel oral contraceptive drug-drug interaction
Sponsor: ViiV Healthcare
Start date: 2019-06-13; Completion date: 2019-08-16
Enrollment: 23 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is an open-label, single-sequence, 1-way drug-drug interaction study to investigate the effect of GSK3640254 on the pharmacokinetics of a combination oral contraceptive containing ethinyl estradiol (EE) and levonorgestrel (LNG). Effective contraception for women infected with human immunodeficiency virus (HIV) is important in the prevention of unplanned pregnancies. The study will consist of a screening period of 28 days, check-in (Day -4), a run-in period and a treatment period. During the run-in period, subjects will be administered Portia® (0.03 milligrams \[mg\] EE/0.15 mg LNG) once daily on Days -3 to -1. Subjects will then be administered Portia once daily on Days 1 to 10 of treatment period A followed by administration of Portia once daily along with GSK3640254 200 mg on Days 11 to 21 of treatment period B. The duration of the study is approximately 8 weeks, including Screening and Run-in. Portia is a registered trademark of Teva Pharmaceuticals USA.

Detailed description:

Arms: arm 1: Subjects will be administered Portia (0.03 mg EE/0.15 mg LNG) once daily on Days -3 to -1 during run-in period and on Days 1 to 10 in treatment period A. Subjects will then receive Portia (0.03 mg EE/0.15 mg LNG) co-administered with GSK3640254 200 mg once daily on Days 11 to 21 in treatment period B.
Interventions: intervention 1: GSK3640254 intervention 2: Portia
Intervention descriptions: intervention 1: GSK3640254 will be available as a 100 mg capsule. Subjects will be administered 200 mg GSK3640254 once daily via the oral route on Days 11 to 21. intervention 2: Portia will be available in the form of tablets containing 0.03 mg ethinyl estradiol and 0.15 mg levonorgestrel.

Protocol documents:
Prot_000.pdf: 
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TITLE PAGE
Protocol Title: The Effect of Coadministration of GSK3640254 on the Pharmacokinetics 
of a Combined Oral Contraceptive Containing Ethinyl Estradiol and Levonorgestrel in 
Healthy Female Subjects
Protocol Number: 208135
Compound Number:
GSK3640254
Study Phase: Phase I
Short Title: Effect of GSK3640254 on the Pharmacokinetics of a Combination Oral 
Contraceptive
US IND Sponsor Name and Legal Registered Address:
ViiV Healthcare Company
Five Moore Drive
P.O. 13398
Research Triangle Park, NC 27709-3398, USA
Telephone: 
In some countries, local law requires that the Clinical Trial sponsor is a local 
company legal entity. In these instances, the appropriate company to be identified as 
Sponsor must be agreed with the global ViiV Healthcare clinical team and signed off 
by the Vice President, Global Research and Medical Strategy 
This study is sponsored by ViiV Healthcare. PPD with GlaxoSmithKline are
supporting ViiV Healthcare in the conduct of this study.
Medical Monitor Name and Contact Information: Can be found in the Study 
Reference Manual
Regulatory Agency Identifying Number(s):
IND Number: 139,838
Approval Date: 10-MAY-2019
Copyright 2019 ViiV Healthcare and the GlaxoSmithKline group of companies. All 
rights reserved. Unauthorized copying or use of this information is prohibited.
PPD


PPD
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TABLE OF CONTENTS
PAGE
1.
PROTOCOL SUMMARY..........................................................................................6
1.1.
Synopsis.......................................................................................................6
1.2.
Schema ........................................................................................................8
1.3.
Schedule of Activities (SoA)..........................................................................8
2.
INTRODUCTION....................................................................................................13
2.1.
Study Rationale ..........................................................................................13
2.2.
Background ................................................................................................13
2.2.1.
Background and Key Safety Data with a Prior Maturation 
Inhibitor........................................................................................13
2.2.2.
Preliminary Safety and Pharmacokinetic Data in Study 
207187 ........................................................................................14
2.2.3.
Preliminary Safety and Pharmacokinetic Data in 
Study 208131 ..............................................................................15
2.2.4.
Ethinyl Estradiol and Levonorgestrel............................................16
2.3.
Benefit/Risk Assessment ............................................................................16
2.3.1.
Risk Assessment of GSK3640254 ...............................................18
2.3.2.
Benefit Assessment.....................................................................21
2.3.3.
Overall Benefit: Risk Conclusion..................................................21
3.
OBJECTIVES AND ENDPOINTS...........................................................................21
4.
STUDY DESIGN ....................................................................................................22
4.1.
Overall Design ............................................................................................22
4.2.
Scientific Rationale for Study Design ..........................................................23
4.3.
Justification for Dose ..................................................................................24
4.4.
End of Study Definition ...............................................................................24
5.
STUDY POPULATION...........................................................................................24
5.1.
Inclusion Criteria.........................................................................................24
5.2.
Exclusion Criteria........................................................................................26
5.3.
Lifestyle Considerations..............................................................................29
5.3.1.
Meals and Dietary Restrictions ....................................................29
5.3.2.
Caffeine, Alcohol, and Tobacco ...................................................29
5.3.3.
Activity .........................................................................................30
5.4.
Screen Failures...........................................................................................30
6.
STUDY INTERVENTION........................................................................................30
6.1.
Study Interventions Administered ...............................................................31
6.2.
Preparation/Handling/Storage/Accountability..............................................31
6.3.
Measures to Minimize Bias: Randomization and Blinding ...........................32
6.4.
Study Intervention Compliance ...................................................................32
6.5.
Concomitant Therapy..................................................................................32
6.6.
Dose Modification .......................................................................................32
6.7.
Intervention after the End of the Study........................................................32
7.
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL.....................................................................32
7.1.
Discontinuation of Study Intervention..........................................................32


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7.1.1.
Liver Chemistry Stopping Criteria ................................................33
7.1.1.1.
Study Intervention Restart or Rechallenge after 
liver stopping criteria met............................................33
7.1.2.
QTc Stopping Criteria ..................................................................33
7.1.3.
Columbia Suicide Severity Rating Scale Criteria..........................33
7.1.4.
Individual Participant Laboratory Abnormality and Adverse 
Event Stopping Criteria................................................................34
7.2.
Participant Discontinuation/Withdrawal from the Study ...............................34
7.3.
Lost to Follow Up........................................................................................34
8.
STUDY ASSESSMENTS AND PROCEDURES .....................................................35
8.1.
Efficacy Assessments.................................................................................35
8.2.
Safety Assessments ...................................................................................36
8.2.1.
Physical Examinations.................................................................36
8.2.2.
Vital Signs....................................................................................36
8.2.3.
Electrocardiograms......................................................................36
8.2.4.
Clinical Safety Laboratory Assessments ......................................37
8.2.5.
Suicidal Ideation and Behavior Risk Monitoring ...........................37
8.2.6.
Gastrointestinal Toxicity Evaluation and Monitoring Plan.............38
8.3.
Adverse Events and Serious Adverse Events.............................................40
8.3.1.
Time Period and Frequency for Collecting AE and SAE 
Information...................................................................................40
8.3.2.
Method of Detecting AEs and SAEs.............................................40
8.3.3.
Follow-up of AEs and SAEs.........................................................41
8.3.4.
Regulatory Reporting Requirements for SAEs .............................41
8.3.5.
Pregnancy ...................................................................................41
8.4.
Treatment of Overdose...............................................................................41
8.5.
Pharmacokinetics .......................................................................................42
8.6.
Pharmacodynamics ....................................................................................42
8.7.
Genetics .....................................................................................................43
8.8.
Biomarkers .................................................................................................43
8.9.
Medical Resource Utilization and Health Economics ..................................43
9.
STATISTICAL CONSIDERATIONS........................................................................43
9.1.
Statistical Hypotheses.................................................................................43
9.2.
Sample Size Determination ........................................................................43
9.3.
Populations for Analyses ............................................................................45
9.4.
Statistical Analyses.....................................................................................45
9.4.1.
Pharmacokinetic and Pharmacodynamic Analyses......................45
9.4.2.
Safety Analyses...........................................................................47
9.4.3.
Other Analyses ............................................................................47
9.5.
Interim Analyses .........................................................................................47
9.5.1.
Data Monitoring Committee (DMC)..............................................47
10. SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS...............................................................................................48
10.1.
Appendix 1: Abbreviations and Trademarks................................................48
10.2.
Appendix 2: Clinical Laboratory Tests.........................................................51
10.3.
Appendix 3: Contraceptive Guidance and Collection of Pregnancy 
Information..................................................................................................53
10.3.1.
Definitions:...................................................................................53
10.3.2.
Contraception Guidance: .............................................................54


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10.3.3.
Collection of Pregnancy Information: ...........................................54
10.4.
Appendix 4: Regulatory, Ethical, and Study Oversight 
Considerations............................................................................................56
10.4.1.
Regulatory and Ethical Considerations ........................................56
10.4.2.
Financial Disclosure.....................................................................56
10.4.3.
Informed Consent Process ..........................................................56
10.4.4.
Data Protection............................................................................57
10.4.5.
Dissemination of Clinical Study Data ...........................................57
10.4.6.
Data Quality Assurance ...............................................................58
10.4.7.
Source Documents ......................................................................58
10.4.8.
Study and Site Closure ................................................................59
10.4.9.
Publication Policy.........................................................................59
10.5.
Appendix 5: Liver Safety: Required Actions and Follow-up 
Assessments ..............................................................................................60
10.6.
Appendix 6: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting .......................................62
10.6.1.
Definition of AE............................................................................62
10.6.2.
Definition of SAE..........................................................................63
10.6.3.
Recording and Follow-Up of AE and SAE....................................64
10.6.4.
Reporting of SAE to VH/GSK.......................................................66
10.7.
Appendix 7: Genetics..................................................................................67
11. REFERENCES.......................................................................................................68


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1.
PROTOCOL SUMMARY
1.1.
Synopsis
Protocol Title: The Effect of Coadministration of GSK3640254 on the Pharmacokinetics 
of a Combined Oral Contraceptive Containing Ethinyl Estradiol and Levonorgestrel in 
Healthy Female Subjects
Short Title: Effect of GSK3640254 on the Pharmacokinetics of a Combination Oral 
Contraceptive
Rationale: This is an open-label, single-sequence, 1-way drug-drug interaction (DDI) 
study to investigate the effect GSK3640254 has on the pharmacokinetics (PK) of a 
combination oral contraceptive containing ethinyl estradiol (EE) and levonorgestrel 
(LNG). Effective contraception for women infected with human immunodeficiency virus 
(HIV) is important in the prevention of unplanned pregnancies.
Objectives and Endpoints:
Objectives
Endpoints
Primary

To assess the effect of GSK3640254 on the 
steady state PK of EE and LNG under fed 
conditions in healthy female participants
The primary PK endpoints are: 

AUC(0-), Cmax, and Cfor EE and LNG
Secondary

To assess the effect of GSK3640254 on the 
PD of EE/LNG (suppression of ovulation as 
indicated by endogenous progesterone 
levels)

To assess the effect of GSK3640254 on LH 
and FSH

To characterize the steady state PK of 
GSK3640254 in the presence of EE/LNG

To characterize the steady state PK of 
EE/LNG alone and in the presence of 
GSK3640254

To assess the safety and tolerability of 
GSK3640254 and EE/LNG when given in 
combination in healthy female participants
The secondary endpoints are:

Serum progesterone levels

Serum FSH and LH levels

AUC(0-), Cmax, C, Tmax, and t1/2 for 
GSK3640254

Tmax and t1/2 for EE and LNG

Safety and tolerability parameters for 
AEs/SAEs, observed and change from 
baseline clinical laboratory assessments, 
ECGs, and vital sign measurements
AE = adverse event; AUC(0-) = area under the plasma concentration-time curve from time 0 to the end of the dosing 
interval at steady state; Cmax = maximum observed concentration; C= Plasma concentration at the end of the dosing 
interval; ECG = electrocardiogram; EE = ethinyl estradiol; FSH = follicle-stimulating hormone; LH = luteinizing 
hormone; LNG = levonorgestrel; PD = pharmacodynamic; PK = pharmacokinetic; SAE = serious adverse event; 
t1/2 = apparent terminal phase half-life; Tmax = time of maximum observed concentration.


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Overall Design: This is a Phase 1, open-label, fixed-sequence, 1-way DDI study 
designed to assess the PK, pharmacodynamics (PD), safety, and tolerability of 
GSK3640254 and an oral contraceptive containing EE/LNG (Portia) when administered 
alone and in combination in healthy female participants.
The study will consist of a screening period, check-in, a run-in period, and a treatment 
period with Portia given alone and in combination with GSK3640254. Participants will 
be screened within 28 days before check-in (Day -4). 
Participants should take Portia in the morning at approximately the same time throughout 
study participation. During the treatment period, the participants will fast overnight for at 
least 8 hours prior to GSK3640254 dosing and will receive a moderate fat meal 
30 minutes prior to dosing. Participants will eat this meal in 30 minutes or less. Dose 
administration will occur within 5 minutes of completion of meal consumption.
Blood samples for the analysis of EE and LNG will be collected before dosing on Days 9 
to 10 and 19 to 21, and up to 24 and 72 hours after dosing on Days 10 and 21 of the 
treatment period, respectively. Blood samples for the analysis of GSK3640254 will be 
collected before dosing on Days 19 to 21, and up to 96 hours after dosing on Day 21 of 
the treatment period. 
Blood samples for the analysis of progesterone, follicle-stimulating hormone (FSH), and 
luteinizing hormone (LH) will be collected on Days 1, 10, 11, 21, and 22 of the treatment 
period.
Safety and tolerability will be assessed by monitoring and recording of adverse events, 
clinical laboratory test results, vital sign measurements, 12-lead electrocardiogram (ECG) 
results, and physical examination findings.
Study assessments will be performed as indicated in the Schedule of Activities (SoA). 
Participants will check into the clinic on Day -4 and will remain confined until discharge 
on Day 25.
Disclosure Statement: This is a single group, single arm study that has no masking.
Number of Participants: Approximately 25 participants will be treated to ensure that 
20 evaluable participants complete the study.
Intervention Groups and Duration: The treatments will be as follows:

Run-in Period: Portia (0.03 mg EE/0.15 mg LNG) once daily (QD) Days -3 to -1

Treatment A: Portia (0.03 mg EE/0.15 mg LNG) QD on Days 1 to 10 of the 
treatment period

Treatment B: Portia (0.03 mg EE/0.15 mg LNG) QD coadministered with 
GSK3640254 200 mg on Days 11 to 21 of the treatment period
The duration of the study, including Screening and Run-in, is approximately 8 weeks.
Data Monitoring Committee: No


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1.2.
Schema
A summary of the overall study design is presented in Figure 1. 
Figure 1
Study Design Schematic
1.3.
Schedule of Activities (SoA)

Screening procedures may be done over more than one visit, but must all be 
completed within 28 days prior to check-in. 

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.
Screening Visit
Procedure
Screening (up to 28 days before Day -4)
Outpatient visit
X
Informed consent
X
Inclusion and exclusion criteria
X
Demography
X
Full physical examination including height and weight 1
X
Laboratory assessments (hematology, chemistry, urinalysis)
X
12-lead electrocardiogram (ECG)
X
Vital sign measurements
X
Medication/drug/alcohol history
X
Past and current medical conditions  
X
Columbia Suicide Severity Rating Scale (C-SSRS)
X
Serum pregnancy test
X
Drug, alcohol, and cotinine screen
X
Human immunodeficiency virus (HIV), Hepatitis B and C screening
X
1. A full physical examination will include at a minimum, assessments of the skin, cardiovascular, respiratory, 
gastrointestinal (GI), and neurological systems.


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Time and Events Table
Procedure
Check-in
Run-in
Treatment
Washout
Notes
D
-4
D 
-3
D
-2
D
-1
D
1
D
2-9
D
10 1
D
11
D
12
D
13
D
14-18
D
19
D
20
D
21
D
22
D
23
D
24 2
D
25
Admit to clinic
X
Discharge from clinic
X
Brief physical 
examination
X
X
X
A brief physical 
examination will include, at 
a minimum, assessments 
of the skin, lungs, 
cardiovascular system, 
and abdomen (liver and 
spleen.
Vital signs
X
X
X
X
D15
X
X
Obtained before dosing, 
where applicable. Blood 
pressure and pulse will be 
measured in triplicate
when they occur at the 
same time point as clinical 
laboratory assessments.
12-lead ECG
X
X
X
X
D15
X
X
On Day 11, triplicate 
ECGs will be taken before 
dosing.  On Day 11, single 
ECGs will be taken at 2, 4, 
and 6 hours after dosing.
On Day 15, single ECGs 
will be taken at 2, 4, and 6 
hours after dosing.  Single 
ECGs will be taken on 
other scheduled days.


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Procedure
Check-in
Run-in
Treatment
Washout
Notes
D
-4
D 
-3
D
-2
D
-1
D
1
D
2-9
D
10 1
D
11
D
12
D
13
D
14-18
D
19
D
20
D
21
D
22
D
23
D
24 2
D
25
Drug, alcohol, and 
cotinine screen
X
See Appendix 2 for 
specific tests to be 
performed.
Laboratory assessments 
(hematology, chemistry, 
urinalysis tests)
X
X
X
X
X
See Appendix 2 for 
specific tests to be 
performed. Taken before 
dosing, where applicable.
Pregnancy test 
X
X
X
X
Genetic sample 
(optional)
X
C-SSRS
X
X
Study intervention: 
Portia (0.03 mg EE/ 
0.15 mg LNG)
X
X
X
X
X
X
X
X
X
X
X
X
X
Study intervention: 
GSK3640254 200 mg
X
X
X
X
X
X
X
Trough PK sampling: EE 
and LNG 
D9
X
X
PK sample collected 
before dosing.


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Procedure
Check-in
Run-in
Treatment
Washout
Notes
D
-4
D 
-3
D
-2
D
-1
D
1
D
2-9
D
10 1
D
11
D
12
D
13
D
14-18
D
19
D
20
D
21
D
22
D
23
D
24 2
D
25
Serial PK sampling:
EE and LNG 
X
X
X
X
X
X
PK samples will be 
collected predose and 
after dosing at 15 and 
30 minutes and 1, 1.5, 2, 
3, 4, 7, 12, and 24 hours 
relative to Day 10 dosing. 
The 24-hour post-dose 
sample should be taken 
prior to dosing on Day 11. 
PK samples will be 
collected predose and 
after dosing at 15 and 
30 minutes and 1, 1.5, 2, 
3, 4, 7, 12, 24, 48, and 72 
hours relative to Day 21 
dosing.
Trough PK sampling: 
GSK3640254
X
X
PK sample collected 
before dosing.
Serial PK sampling: 
GSK3640254
X
X
X
X
X
PK samples will be 
collected predose and 
after dosing at 1, 2, 2.5, 3, 
3.5, 4, 4.5, 5, 6, 8, 12, 24, 
48, 72, and 96 hours 
relative to Day 21 dosing.
PD sampling: LH, FSH, 
progesterone
X
X
X
X
X
Samples collected before 
dosing.
AE review
==================================================================================
SAE review
=========================================================================================


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Procedure
Check-in
Run-in
Treatment
Washout
Notes
D
-4
D 
-3
D
-2
D
-1
D
1
D
2-9
D
10 1
D
11
D
12
D
13
D
14-18
D
19
D
20
D
21
D
22
D
23
D
24 2
D
25
Concomitant medication 
review
=========================================================================================
AE = adverse event; D = Day; C-SSRS = Columbia Suicide Severity Rating Scale; ECG = electrocardiogram; EE = ethinyl estradiol; FSH = follicle-stimulating hormone; LH = luteinizing 
hormone; LNG = levonorgestrel; PD = pharmacodynamic; PK = pharmacokinetic; SAE = serious adverse event.
1
Assessments performed on Day 10 will be considered Baseline for GSK3640254 dosing.
2
Evaluations scheduled for Day 24 will also be performed for participants who discontinue early.

The timing and number of planned study assessments, including safety, pharmacokinetic (PK), pharmacodynamic (PD), 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. 

Any changes in the timing or addition of time points for any planned study assessments as the result of emerging PK/PD data
from this study must be documented and approved by the relevant study team member and then archived in the sponsor and site 
study files but will not constitute a protocol amendment. The Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC) will be informed of any safety issues that constitute a substantial amendment and require alteration of the safety 
monitoring scheme or amendment of the informed consent form (ICF).


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2.
INTRODUCTION
2.1.
Study Rationale
This is an open-label, single-sequence, 1-way drug-drug interaction (DDI) study to 
investigate the effect GSK3640254 has on the PK of a combination oral contraceptive 
containing ethinyl estradiol (EE) and levonorgestrel (LNG). Effective contraception for 
women infected with human immunodeficiency virus (HIV) is important in the 
prevention of unplanned pregnancies.
2.2.
Background
GSK3640254 is an HIV maturation inhibitor (MI) which is improved over prior 
developmental MIs in the following ways: (1) it exhibits significantly improved 
pan-genotypic coverage and potency against polymorphic variants; (2) in vitro data 
suggest that GSK3640254 exhibits a higher barrier to emergence of resistant viruses 
(except for A364V); (3) GSK3640254 has improved potency in vitro toward all HIV-1 
subtypes; (4) it has potential for improved gastrointestinal (GI) tolerability; and (5) it has 
a projected lower once-daily human dose. Summaries of the pre-clinical and clinical 
studies are included in the Clinical Investigator's Brochure (CIB) [GSK Document 
Number 2018N379610_00].
2.2.1.
Background and Key Safety Data with a Prior Maturation Inhibitor
Bristol-Myers Squibb (BMS), and later ViiV Healthcare (VH), developed a structurally 
similar HIV-1 MI (BMS-955176/GSK3532795), which was studied through Phase 2b 
studies in both treatment-naïve (AI468038/205891) and experienced (AI468048/205892) 
HIV-1 infected adults. In study AI468038/205891, a greater number of participants who 
received GSK3532795 experienced GI intolerability (most frequently Grade 1 to 2 
diarrhea and abdominal pain). A detailed examination of all GI adverse events (AEs) 
(regardless of grade/relationship) revealed a relationship with dose [GSK Document 
Number 2016N302783_00]. Ultimately, the rate of GI intolerability in the GSK3532795 
dose groups in the Phase 2b study 205891 in part led to VH’s decision to end all trials 
and not progress to Phase 3 studies. Gastrointestinal AEs were also previously observed 
in healthy participants in Phase 1 studies with varying doses, durations, and formulations 
of GSK3532795. In both studies, the most common GI AEs were abdominal pain and 
diarrhea.
Aside from mild to moderate GI intolerability, 2 serious adverse events (SAEs) occurred 
in the Phase I Thorough QT study AI468044/206220 [BMS Document Control 
Number 930109388] at supra-therapeutic doses: 1 healthy participant had an episode of 
acute psychosis and another had suicidal ideation/homicidal ideation as diagnosed 
through an interview by a psychiatrist. The 2 participants received GSK3532795 240 mg 
twice daily and 240 mg once daily (QD) with food, respectively. These events were 
assessed as related to study drug but were not observed in any other clinical study with 
GSK3532795. The most frequent neuropsychiatric AEs in studies with GSK3532795 
were headache, dizziness, and sleep abnormalities (e.g., insomnia, abnormal dreams).


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2.2.2.
Preliminary Safety and Pharmacokinetic Data in Study 207187
The primary objective of the first time in human (FTIH) clinical trial (207187) was to 
investigate the safety and tolerability of GSK3640254 following single and repeated daily 
administration. A total of 78 healthy men were ultimately randomized: 20 in the 
single-ascending dose (SAD, doses ranging from 1 to 700 mg) and 58 in the 
multiple-ascending dose (MAD, 50 to 320 mg QD for 14 days). A comprehensive 
summary of results is described in the CIB [GSK Document Number 2018N379610_00] 
and the Study Synopsis [GSK Document Number 2018N375461_00]. A concise 
summary of the data is presented below.
No deaths or SAEs were reported. There were 4 AEs leading to discontinuation. Only 1 
of these AEs was related to study medication. A subject who received GSK3640254 
200 mg QD developed a maculopapular rash after 8 days of study medication. The rash 
lasted for 6 days and there were no laboratory abnormalities. A dermatology consultant 
concluded this was a drug rash and the subject later received fexofenadine 180 mg QD/a 
topical steroid cream with resolution. The other 3 AEs occurred in SAD portion of the 
study (depression in a subject who received placebo and 2 subjects with viral infection). 
There were 9 subjects with 12 AEs assessed as related to study medication by the 
principal investigator (11 Grade 1; 1 Grade 2). The most clinically notable was a subject 
who developed elevated transaminases while receiving GSK3640254 50 mg QD for 
14 days. Specifically, there was a progressive rise in alanine aminotransferase (ALT) 
during treatment with a peak ALT of 83 IU/L on Day 16. The remaining liver chemistries 
were normal throughout. An ultrasound showed a subcapsular area of heterogenous 
echogenicity within segment 7, measuring approximately 35 × 23 × 36 mm. Follow-up 
magnetic resonance imaging and liver chemistries were normal. This subject also had 
3 unrelated AEs during the course of an isolated increased ALT: musculoskeletal 
stiffness, contact dermatitis, and headache. All other related AEs are described in the CIB 
[GSK Document Number 2018N379610_00] and the Study Synopsis [GSK Document 
Number 2018N375461_00].
In the SAD portion of the study, 17 subjects experienced 60 individual AEs (58 Grade 1; 
2 Grade 2). The 2 Grade 2 AEs were headache and depression (both unrelated). The most 
frequent AEs were headache, contact dermatitis primarily due to electrocardiogram 
(ECG) electrodes, and diarrhea. There was no dose/AE relationship. 
In the MAD portion of the study, 44 subjects experienced 130 individual AEs 
(126 Grade 1; 4 Grade 2). The 3 Grade 2 AEs were headache (1 related and 1 unrelated) 
and back pain (2 unrelated). The most frequent AEs were headache, contact dermatitis, 
dizziness, contusion, fatigue, and back pain.
There were no clinically significant abnormal fluctuations or trends in vital signs in the 
SAD or MAD cohorts. There were no abnormal clinically significant arrhythmias or QT 
prolongations (values >500 ms or increases >60 ms from Baseline) observed for any 
participant in the SAD or MAD. A cardiodynamic evaluation of healthy subjects in the 
MAD portion of Study 207187 (placebo or GSK3640254 dose range 50 to 320 mg daily 
for 14 days) was performed. Serial ECGs were extracted from continuous Holter 
monitors at time-matched baseline on Day -1 and for approximately 24 hours post-dose 


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on Days 1 and 14. In the concentration-QTc analysis, a final model with a treatment 
effect-specific intercept reasonably represented the data. The slope of the 
concentration-QTc relationship was 0.004 ms per ng/mL (90% confidence interval [CI]: 
0.0023 to 0.0048) with a small treatment effect-specific intercept of -0.9 ms (90% CI: 
-4.47 to 2.69). The QT effect (∆ΔQTcF) of GSK3640254 could be predicted to be 
5.38 ms (90% CI: 1.66 to 9.10) and 6.70 ms (90% CI: 2.79 to 10.61) for the 200 mg 
(1779 ng/mL) and 320 mg (2154 ng/mL) doses, respectively, on Day 14. Based on this 
concentration-QTc analysis, a QTcF effect above 10 ms could be excluded up to 
GSK3640254 plasma concentrations of approximately 2000 ng/mL (corresponding to 
doses approximately ≤200 mg QD; note, the dose used in this study is 200 mg QD). 
Finally, there were no laboratory abnormality trends across doses that were clinically 
significant or associated with any symptoms.
Preliminary GSK3640254 PK parameters derived based on nominal sampling times 
following single doses of 1 to 700 mg administered after a moderate calorie and fat 
breakfast showed GSK3640254 was slowly absorbed with a median time of maximum 
observed concentration (Tmax) observed between 3 to 4.5 hours after dosing with a 
moderate fat breakfast and slowly eliminated with a mean half-life ranging from 22 to 
26 hours. In general, exposure (maximum observed concentration [Cmax] and area under 
the concentration-time curve [AUC]) increased in a close-to-dose-proportional manner 
from 1 to 400 mg with no further increase in exposure at 700 mg. 
Repeat dose preliminary PK parameters following administration of GSK3640254 50 to 
320 mg QD for 14 days were determined on Day 1 and Day 14 and showed a median 
Tmax ranging between 3.8 to 4.3 hours. The mean half-life ranged from approximately 
22 to 29 hours. Overall, there was a trend of a slightly less than dose-proportional 
increase in Cmax and AUC from time 0 to 24 hours after dosing (AUC[0-24]) from 50 to 
320 mg. The exposure on Day 14 was, on average, 1.9- to 2.3-fold higher than that of 
Day 1 for Cmax and 2.2- to 2.6-fold higher than Day 1 for AUC(0-24). Detailed 
summary statistics are available in the Study Synopsis [GSK Document 
Number 2018N375461_00].
2.2.3.
Preliminary Safety and Pharmacokinetic Data in Study 208131
The FTIH Study 207187 used a bis-hydrochloride salt capsule formulation of 
GSK3640254, which is not suitable for long term clinical development. 
Study 208131 was a single-center, open-label, 2-period, 2-sequence crossover design, 
conducted in 14 healthy subjects in the United Kingdom. This study was designed to 
assess the relative bioavailability of the formulation planned for Phase 2a (mesylate salt 
in a capsule) to the FTIH formulation (bis-hydrochloride salt in a capsule) administered 
following a moderate calorie and fat meal. All subjects completed dosing and the blinded 
preliminary safety data showed a total of 11 AEs (all Grade 1). Two AEs of headache 
were related to study drug. The most common AE was headache (3 instances). There 
were 3 GI AEs (abdominal pain, bleeding gums, and flatulence). There were no cardiac 
or psychiatric AEs. There were no clinically significant changes in vital signs, ECG 
parameters, or safety laboratory parameters.


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Preliminary PK results from study 208131 showed that in the presence of a moderate fat 
meal, the relative bioavailability of GSK3640254 following 200 mg GSK3640254 
mesylate salt administration relative to 200 mg GSK3640254 bis-hydrochloride salt 
administration was 110% and 116% based on AUC from time zero extrapolated to 
infinity (AUC[0-]) and Cmax, respectively.
2.2.4.
Ethinyl Estradiol and Levonorgestrel
Portia has been marketed in the United States (US) since 2002 as a combination oral 
contraceptive. Portia contains 0.03 EE and 0.15 mg LNG. Each blister card provides 21 
pink active tablets, and 7 white inert tablets. Combination oral contraceptives act by 
suppression of gonadotropins. Although the primary mechanism of this action is 
inhibition of ovulation, other alterations include changes in the cervical mucus (which 
increases the difficulty of sperm entry into the uterus) and endometrium (which reduces 
the likelihood of implantation). When taken correctly, oral contraceptives have a failure 
rate of less than 1% per year [Levonorgestrel and Ethinyl Estradiol, 2012].
Portia is administered orally. Both EE and LNG are widely distributed. Ethinyl estradiol 
is highly protein-bound to albumin and induces an increase in the serum concentrations 
of both sex hormone-binding globulin (SHBG) and corticosteroid binding globulin. 
Levonorgestrel is strongly protein-bound, primarily to albumin and SHBG. Steady state 
is reached in approximately 11 days. Excretion of the oral contraceptive steroids as 
inactive metabolites occurs via the urine and feces. Elimination half-life is approximately 
15 hours for EE and 30 hours for LNG at steady state. It is the prolonged biologic effects 
of the hormones that allows for once-daily administration [Levonorgestrel and Ethinyl 
Estradiol, 2012].
2.3.
Benefit/Risk Assessment
Based upon preclinical and clinical studies, the major risks for GSK3640254 are GI 
intolerability (e.g., abdominal pain and diarrhea) and toxicity, prolongation of the 
corrected QT interval (QTc), and neuropsychiatric safety. Reproduction of preclinical GI 
toxicity findings (e.g., single-cell parietal cell necrosis) would be unlikely during the 
limited dosing of GSK3640254 in this study. One preclinical study showed 1 dog with an 
increased QTc interval when given a single dose of GSK3640254. As described in 
Section 2.2.2, a cardiodynamic analysis of healthy subjects in Study 207187 was 
conducted. A final model from the MAD data showed a QT effect (∆ΔQTcF) of 
GSK3640254 could be predicted to be 5.38 ms (90% CI: 1.66 to 9.10) and 6.70 ms 
(90% CI: 2.79 to 10.61) for the 200 mg (1779 ng/mL) and 320 mg (2154 ng/mL) doses, 
respectively, on Day 14. Based on this concentration-QTc analysis, a QTcF effect above 
10 ms could be excluded up to GSK3640254 plasma concentrations of approximately 
2000 ng/mL (corresponding to doses approximately ≤200 mg QD; note, 200 mg QD is 
the dose used in this study). Importantly, there were no abnormal clinically significant 
arrhythmias or QTc prolongations (values >500 ms or increases >60 ms from Baseline) in 
Study 207187. This study contains specific cardiac exclusion criteria, has ECG 
monitoring (at Tmax once GSK3640254 attains steady state concentration), and has 
QTcF based stopping criteria.


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Finally, the protocol will exclude potential participants with any significant pre-existing 
psychiatric condition or positive (abnormal) response confirmed by the investigator on a 
clinician (or qualified designee) administered Columbia Suicide Severity Rating Scale 
(C-SSRS). The C-SSRS assessment will also be administered by a clinician (or qualified 
designee) during the on-treatment portion of the study.
To ensure the overall safety of participants (including, but not limited to, the risk of GI 
intolerability, QTc prolongation, and neuropsychiatric safety), this clinical study will 
include healthy adults who will receive clinical, ECG, and laboratory evaluations during 
their participation. More detailed information about the known and expected benefits and 
risks and reasonably expected AEs of GSK3640254 may be found in the CIB [GSK 
Document Number 2018N379610_00].
The use of oral contraceptives is associated with increased risks of several serious 
conditions including venous and arterial thrombotic and thromboembolic events (such as 
myocardial infarction, thromboembolism, and stroke), hepatic neoplasia, gallbladder 
disease, and hypertension, although the risk of serious morbidity or mortality is very 
small in healthy women without underlying risk factors. Common side effects include 
headache, vaginal bleeding, nausea/vomiting, acne, dysmenorrhea, increased weight, 
mood changes, anxiety/panic attacks, breast pain, and migraines. More detailed 
information about the known and expected risks and reasonably expected AEs for 
EE/LNG may be found in the package insert [Levonorgestrel and Ethinyl Estradiol, 
2012].


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2.3.1.
Risk Assessment of GSK3640254
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Investigational Product (IP) GSK3640254
Cardiovascular (QT prolongation) 
Preclinically, GSK3640254 inhibited cardiac 
hERG/IKr potassium, cardiac SCN5A sodium and 
L-type calcium channel currents recorded from 
HEK 293 cells stably transfected with 
complementary DNA from the ion channels. In a 
single-dose safety pharmacology study in 
telemeterized dogs, increases in QT interval (up 
to 20 ms) occurred primarily in 1 dog given 
17 mg/kg. Later, there were no GSK3640254-
related effects on electrocardiogram (ECG) 
parameters in dogs given up to 25 mg/kg/day for 
4 weeks.
In the first time in human study 207187, no 
participant exhibited QTc change from baseline 
>60 ms or QTc >500 ms. As described in 
Section 2.3, in the concentration-QTc analysis, a 
QTcF effect above 10 ms could be excluded up to 
GSK3640254 plasma concentrations of 
approximately 2000 ng/mL (corresponding to 
doses approximately ≤200 mg QD).
Screening: Protocol exclusion criteria based on 
screening ECG parameters and cardiac medical 
history.
On-Treatment: Participants will have ECG monitoring 
(at a clinically reasonable frequency) during the 
course of the study (see SoA, Section 1.3) with QTc 
stopping criteria (see Section 7.1.2).


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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Gastrointestinal (GI) intolerability and 
toxicity
Clinical signs indicative of GI intolerability 
(sporadic vomiting and abnormal feces beginning 
on Day 1 and continuing throughout the dosing 
periods) occurred mainly in dogs at 
1 mg/kg/day. Additionally, toxicity findings of 
single-cell necrosis of parietal cells and/or chief 
cells were present in preclinical species. These 
findings were reversible. Finally, GI intolerability 
(predominately abdominal pain and diarrhea) was 
seen with a structurally related compound 
GSK3532795 which was evaluated through 
Phase 2b dosing. 
Screening: Protocol exclusion criterion based on 
pre-existing GI pathology or baseline GI 
signs/symptoms.
On-Treatment: Participants will undergo continuous 
evaluation for AEs during their participation in the 
study; there will be individual clinical stopping criteria 
based upon intensity of treatment-emergent AEs. A GI 
toxicity evaluation and monitoring plan will be 
available to guide investigators should GI AEs emerge 
(See Section 8.2.6).
Neurologic/psychiatric safety
Two psychiatric serious adverse events in 
previous maturation inhibitor GSK3532795 clinical 
program (acute psychosis, homicidal/suicidal 
ideation) were seen at supratherapeutic doses in 
healthy subjects in the thorough QT (TQT) study.
From a neurologic and psychiatric AE summary 
and pharmacokinetic/pharmacodynamic analysis 
for GSK3532795 across all studies mild Grade 1 
headache and Grade 1 sleep abnormalities were 
the predominant AEs, with a trend for increasing 
neurologic and psychiatric AEs with increasing 
dose (based on TQT and Phase 2b studies). No 
exposure-response relationship was seen for 
select neurologic and psychiatric AEs (based on 
TQT and Phase 2b studies). Central nervous 
system penetration data for GSK3532795 and 
GSK3640254 in rats demonstrate a similarly low 
Screening: Protocol exclusion criterion based on any 
pre-existing psychiatric condition (including results of 
psychological assessment) for participants. 
Participants will have a clinician (or qualified 
designee) administered Columbia Suicide Severity 
Rating Scale (C-SSRS) and will be included given no 
positive (abnormal) response.
On-Treatment: Participants will undergo physical 
examinations and laboratory testing. In addition, 
participants will undergo continuous evaluation for 
AEs during their participation in the study; there are 
individual clinical stopping criteria and monitoring 
based upon incidence and intensity of 
treatment-emergent psychiatric AEs (Section 7.1.4
and Section 8.2.5). 
Participants will be housed throughout study conduct 
to ensure rapid diagnosis and management of any 


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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
brain distribution/penetration.
potential event.
The C-SSRS will be administered during and after the 
treatment phase of the study. In the event of a positive 
(abnormal) response confirmed by the investigator, 
the participant will discontinue from the trial and the 
investigator will arrange for urgent specialist 
psychiatric evaluation and management. Guidance for 
the investigator on the management of emergent 
psychiatric symptoms will be available.


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2.3.2.
Benefit Assessment
This is a study in healthy participants; no medical benefit will be derived by volunteers’ 
participation.
2.3.3.
Overall Benefit: Risk Conclusion
Given the preclinical profile of GSK3640254, the clinical profile of a structurally similar 
MI (GSK3532795), the clinical data gathered from Studies 207187 and 208131, and the 
planned clinical procedures and evaluations in this study, the potential risks to 
participants receiving GSK3640254 are low, evaluable, and manageable. Given the years 
of experience with combination contraceptives such as Portia, the potential risks to 
participants receiving Portia are low, evaluable, and manageable. More detailed 
information about the known and expected risks and reasonably expected AEs for 
EE/LNG may be found in the package insert [Levonorgestrel and Ethinyl Estradiol, 
2012].
3.
OBJECTIVES AND ENDPOINTS
Objectives
Endpoints
Primary

To assess the effect of GSK3640254 on the 
steady state PK of EE and LNG under fed 
conditions in healthy female participants
The primary PK endpoints are: 

AUC(0-), Cmax, and Cfor EE and LNG
Secondary

To assess the effect of GSK3640254 on the 
PD of EE/LNG (suppression of ovulation as 
indicated by endogenous progesterone 
levels)

To assess the effect of GSK3640254 on LH 
and FSH

To characterize the steady state PK of 
GSK3640254 in the presence of EE/LNG

To characterize the steady state PK of 
EE/LNG alone and in the presence of 
GSK3640254

To assess the safety and tolerability of 
GSK3640254 and EE/LNG when given in 
combination in healthy female participants
The secondary endpoints are:

Serum progesterone levels

Serum FSH and LH levels

AUC(0-), Cmax, C, Tmax, and t1/2 for 
GSK3640254

Tmax and t1/2 for EE and LNG

Safety and tolerability parameters for 
AEs/SAEs, observed and change from 
baseline clinical laboratory assessments, 
ECGs, and vital sign measurements
AE = adverse event; AUC(0-) = area under the plasma concentration-time curve from time 0 to the end of the dosing 
interval at steady state; Cmax = maximum observed concentration; C= Plasma concentration at the end of the dosing 
interval; ECG = electrocardiogram; EE = ethinyl estradiol; FSH = follicle-stimulating hormone; LH = luteinizing 
hormone; LNG = levonorgestrel; PD = pharmacodynamic; PK = pharmacokinetic; SAE = serious adverse event; 
t1/2 = apparent terminal phase half-life; Tmax = time of maximum observed concentration.


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4.
STUDY DESIGN
4.1.
Overall Design
This is a Phase 1, open-label, fixed-sequence, 1-way DDI study designed to assess the 
PK, PD, safety, and tolerability of GSK3640254 and an oral contraceptive containing 
EE/LNG (Portia) when administered alone and in combination in healthy female 
participants.
The study will consist of a screening period, check-in, a run-in period, and a treatment 
period with Portia given alone and in combination with GSK3640254. Participants will 
be screened within 28 days before check-in (Day -4). The treatments will be as follows:

Run-in Period: Portia (0.03 mg EE/0.15 mg LNG) QD (Days -3 to -1)

Treatment A: Portia (0.03 mg EE/0.15 mg LNG) QD on Days 1 to 10 of the 
treatment period

Treatment B: Portia (0.03 mg EE/0.15 mg LNG) QD coadministered with 
GSK3640254 200 mg on Days 11 to 21 of the treatment period
Participants should take Portia in the morning at approximately the same time throughout 
study participation. 
During the treatment period, participants will fast overnight for at least 8 hours prior to 
dosing with GSK3640254 and will receive a moderate fat meal 30 minutes prior to 
dosing. Participants will eat this meal in 30 minutes or less. Dose administration will 
occur within 5 minutes of completion of meal consumption.
Blood samples for the analysis of EE and LNG will be collected before dosing on Days 9 
to 10 and 19 to 21, and up to 24 and 72 hours after dosing on Days 10 and 21 of the 
treatment period, respectively. Blood samples for the analysis of GSK3640254 will be 
collected before dosing on Days 19 to 21, and up to 96 hours after dosing on Day 21 of 
the treatment period.
Blood samples for the analysis of progesterone, follicle-stimulating hormone (FSH), and 
luteinizing hormone (LH) will be collected on Days 1, 10, 11, 21, and 22 of the treatment 
period.
Safety and tolerability will be assessed by monitoring and recording of AEs, clinical 
laboratory test results, vital sign measurements, 12-lead ECG results, and physical 
examination findings.
Study assessments will be performed as indicated in the Schedule of Activities (SoA)
(Section 1.3). Participants will check into the clinic on Day -4 and will remain confined 
until discharge on Day 25. The duration of the study, including Screening and Run-in, is
approximately 8 weeks.


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4.2.
Scientific Rationale for Study Design
This is an open-label, fixed-sequence, 1-way drug interaction study to investigate the 
effect GSK3640254 has on the PK of a combination oral contraceptive containing EE and 
LNG.
The inhibitory potential (direct and metabolism-dependent inhibition) of GSK3640254 
towards 7 major human hepatic cytochrome P450 (CYP) enzymes was evaluated in 
human liver microsomes [CIB, GSK Document Number 2018N379610_00]. 
GSK3640254 demonstrated minimal direct inhibition of all 7 CYP isoforms tested (half 
maximal inhibitory concentration [IC50] values >13.3 µM). At the maximum projected 
clinical dose of 200 mg, there is a low risk for clinically meaningful CYP-mediated DDIs 
with substrates of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and 
CYP3A4.
GSK3640254 did not demonstrate human pregnane X receptor or vitamin D receptor 
mediated transactivation of CYP3A. Therefore, it is unlikely that GSK3640254 would 
induce CYP3A, or other pregnane X receptor and vitamin D receptor regulated 
enzymes/transporters in humans. In addition, GSK3640254 was tested in a panel of CYP 
induction assays using inducible cryopreserved human primary hepatocytes and showed 
no induction (half maximal effective concentration > 5 µM) of CYP3A4, CYP2B6, and 
CYP1A2.
GSK3640254 is an inhibitor of organic anion-transporting polypeptide (OATP)1B3 and 
multi-drug resistance protein (MRP)2 in vitro and has the potential of generating DDIs 
with substrates of these transporters at the projected human systemic exposures. The 
IC50 values of GSK3640254 against OATP1B3 and MRP2 were 0.55 and 2.2 µM, 
respectively. In addition, GSK3640254 was an inhibitor of uridine diphosphate 
glucuronosyltransferase (UGT)1A1 in vitro (IC50 = 3.9 µM) and clinical DDIs via this 
mechanism could be possible although literature reports have not revealed clinically 
significant DDIs with greater than 2-fold change in exposure, with a few exceptions, due 
to UGT1A1 inhibition [Lin, 2002; Williams, 2004]. A clinically meaningful DDI risk due 
to UGT1A1 inhibition by GSK3640254 is likely minimal.
Sulfate conjugation accounts for approximately 60% of the first-pass metabolism of EE 
and once absorbed, hydroxylation by CYP3A4 and glucuronidation occur. GSK3640254 
has an unknown impact on sulfotransferases. Ethinyl estradiol is an inhibitor of 
CYP2C19, CYP3A4, and UGT. There is a risk that GSK3640254 may impact EE 
exposure due to its effect on UGT and its unknown effect on sulfotransferases.
Levonorgestrel and its Phase I metabolites are excreted primarily as glucuronide 
conjugates. Levonorgestrel is not subject to first pass metabolism and has nearly 100% 
bioavailability, therefore, there is low likelihood of a DDI at the absorption step.
This study is designed in accordance with the US Food and Drug Administration 
Guidance for Industry, Clinical Drug Interaction Studies - Study Design, Data Analysis, 
and Clinical Implications [DHHS, 2017] to assess the PK, safety, and tolerability of 
GSK3640254 and EE/LNG when administered alone and in combination. 


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4.3.
Justification for Dose
The dose of 200 mg GSK3640254 was selected for this study as the maximum projected 
clinically therapeutic dose of GSK3640254 is 200 mg QD. The apparent terminal phase 
half-life (t1/2) of GSK3640254 was approximately 22 hours in the MAD portion of 
Study 207187 at the 200-mg dose, and predicted time to steady state is approximately 
5 days. The doses of 0.03 mg EE/0.15 mg LNG in Portia are standard, effective doses for 
an oral contraceptive.
4.4.
End of Study Definition
A participant is considered to have completed the study if she has completed all phases of 
the study including the final date on which data were or are expected to be collected.
The end of the study is defined as the date of the last visit of the last participant in the 
study or last scheduled procedure shown in the SoA (Section 1.3) for the last participant 
in the study.
5.
STUDY POPULATION
Prospective approval of protocol deviations to recruitment and enrolment criteria, also 
known as protocol waivers or exemptions, is not permitted.
5.1.
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria 
apply:
Age
1. Participant must be 18 to 50 years of age inclusive, at the time of signing the 
informed consent.
Type of Participant and Disease Characteristics
2. Participants who are 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 (history and ECG).
Weight
3. Body weight ≥ 45.0 kg (99 lbs) and body mass index (BMI) within the range 18.5 to 
31.0 kg/m2 (inclusive).
Sex
Contraceptive use should be consistent with local regulations regarding the methods of 
contraception for those participating in clinical studies.


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4. Female
a.
Participant must not be pregnant or breastfeeding.
b. Participant is a woman of childbearing potential (WOCBP) with intact ovarian 
function, as determined by medical history. Participants must use Portia for the 
duration of the run-in and treatment periods.
c.
WOCBP must have been on an acceptable form of contraceptive for at least 
28 days prior to start of study intervention. Acceptable forms of contraception 
prior to study intervention include the following:

Intrauterine device or intrauterine system

Combined estrogen and progestogen oral contraceptive

Contraceptive vaginal ring

Percutaneous contraceptive patches (if used, the patch must be removed 
during study participation)

Bilateral tubal occlusion

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. 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.

Sexual abstinence. Note: Sexual abstinence is considered a highly effective 
method only if defined as refraining from penile-vaginal intercourse on a long 
term and persistent basis when this is their preferred and usual lifestyle. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration 
of the study and the preferred and usual lifestyle of the participant.
d. Participants who have been on a stable regimen of an oral contraceptive for at 
least 3 consecutive months must be without evidence of breakthrough bleeding or 
spotting. 
e.
Participants who have been taking oral contraceptives should continue their 
current regimen until check-in to the clinic for the run-in period. Participants not 
currently taking an oral contraceptive are eligible, provided all other eligibility 
criteria are met.
f.
Participants may proceed to the treatment period provided the toxicity profile 
during the run-in period with Portia is acceptable in the opinion of the 
investigator.
g. Participants must agree to use an additional method of contraception from the list 
of contraceptive methods below for the run-in period, treatment period, and for 
28 days after the last dose of study intervention:

Non hormonal Intrauterine device 

Bilateral tubal occlusion


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
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. 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.

Sexual abstinence. Note: Sexual abstinence is considered a highly effective 
method only if defined as refraining from penile-vaginal intercourse on a long 
term and persistent basis when this is their preferred and usual lifestyle. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration 
of the study and the preferred and usual lifestyle of the participant.

For the 28 days after study exit, women may resume oral contraceptives but 
double barrier methods (a combination of male condom with either cervical 
cap, diaphragm, or sponge with spermicide) must be used in addition.
h. Women of childbearing potential must have a negative highly sensitive serum 
pregnancy test on Day -4 and Day -1.
i.
Additional requirements for pregnancy testing during and after study intervention 
are outlined in Appendix 3.
The investigator is responsible for review of medical history, menstrual history, and 
recent sexual activity to decrease the risk for inclusion of a woman with an early 
undetected pregnancy.
Informed Consent
5. Capable of giving signed informed consent as described in Appendix 4 which
includes compliance with the requirements and restrictions listed in the ICF and in 
this protocol.
5.2.
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical History
1.
History of jaundice associated with taking oral contraceptives or with pregnancy.
2.
History of clinically significant irregular bleeding while taking oral contraceptives.
3.
History of past deep venous thrombosis, pulmonary embolism, stroke, transient 
ischemic attack, phlebitis, or migraine headaches with prolonged aura.
4.
History of cerebrovascular or coronary artery disease.
5.
History of retinal vascular lesions.
6.
History of carcinoma of the breast, endometrium, or other known 
estrogen-dependent neoplasia.
7.
Current or chronic history of liver disease or known hepatic or biliary abnormalities 
(with the exception of Gilbert’s syndrome or asymptomatic gallstones).


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8. A pre-existing condition interfering with normal GI anatomy or motility 
(e.g., gastroesophageal reflux disease, gastric ulcers, gastritis), hepatic and/or renal 
function, that could interfere with the absorption, metabolism, and/or excretion of the 
study drugs or render the participant unable to take oral study intervention.
9. Any history of significant underlying psychiatric disorder, including, but not limited 
to, schizophrenia, bipolar disorder with or without psychotic symptoms, other 
psychotic disorders, or schizotypal (personality) disorder.
10. Any history of major depressive disorder with or without suicidal features, or anxiety 
disorders that required medical intervention (pharmacologic or not) such as 
hospitalization or other inpatient treatment and/or chronic (>6 months) outpatient 
treatment. Participants with other conditions such as adjustment disorder or 
dysthymia that have required shorter term medical therapy (<6 months) without 
inpatient treatment and are currently well-controlled clinically or resolved may be 
considered for entry after discussion and agreement with the VH/GSK Medical 
Monitor.
11. Any pre-existing physical or other psychiatric condition (including alcohol or drug 
abuse), which, in the opinion of the investigator (with or without psychiatric 
evaluation), could interfere with the participant’s ability to comply with the dosing 
schedule and protocol evaluations or which might compromise the safety of the 
participant.
12. Medical history of cardiac arrhythmias, prior myocardial infarction in the past 3 
months, or cardiac disease or a family or personal history of long QT syndrome.
Laboratory Assessments
13. Presence of hepatitis B surface antigen at Screening or within 3 months prior to 
starting study intervention.
14. Positive hepatitis C antibody test result at Screening or within 3 months prior to 
starting study intervention AND positive on reflex to hepatitis C RNA.
15. Positive HIV-1 and -2 antigen/antibody immunoassay at Screening.
16. ALT >1.5 × upper limit of normal (ULN). A single repeat of ALT is allowed within a 
single screening period to determine eligibility.
17. Bilirubin >1.5 × ULN (isolated bilirubin >1.5 × ULN is acceptable if bilirubin is 
fractionated and direct bilirubin <35%).
18. Any acute laboratory abnormality at Screening which, in the opinion of the 
investigator, should preclude participation in the study of an investigational 
compound. 
19. Any Grade 2 to 4 laboratory abnormality at Screening, with the exception of creatine 
phosphokinase (CPK) and lipid abnormalities (e.g., total cholesterol, triglycerides, 
etc), and ALT (described above), will exclude a participant from the study unless the 
investigator can provide a compelling explanation for the laboratory result(s) and has 
the assent of the sponsor. A single repeat of any laboratory abnormality is allowed 
within a single screening period to determine eligibility.


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20. A positive test result for drugs of abuse (including marijuana), alcohol, or cotinine 
(indicating active current smoking) at Screening or before the first dose of study 
intervention.
Prior/Concomitant Therapy
21. Unable to refrain from the use of prescription or nonprescription 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 intervention and for the duration of the study. (Note: 
acetaminophen/paracetamol at doses of 2 grams/day and hydrocortisone cream 1%
are permitted for use any time during the study.)
22. Treatment with any vaccine within 30 days prior to receiving study intervention.
23. Unwillingness to abstain from excessive consumption of any food or drink containing 
grapefruit and grapefruit juice, Seville oranges, blood oranges, or pomelos or their 
fruit juices within 7 days prior to the first dose of study intervention(s) until the end 
of the study.
Prior/Concurrent Clinical Study Experience
24. Participation in another concurrent clinical study or prior clinical study (with the 
exception of imaging trials) 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). 
25. Where participation in the study would result in donation of blood or blood products 
in excess of 500 mL within 56 days.
Diagnostic assessments
26. Any positive (abnormal) response confirmed by the investigator on a screening 
clinician- or qualified designee-administered C-SSRS.
27. Any significant arrhythmia or ECG finding (e.g., symptomatic bradycardia, 
nonsustained or sustained atrial arrhythmias, nonsustained or sustained ventricular 
tachycardia, second-degree atrioventricular block Mobitz Type II, or third-degree 
atrioventricular block) which, in the opinion of the investigator or VH/GSK Medical 
Monitor, will interfere with the safety for the individual participant.
28. Exclusion criteria for screening ECG (a single repeat is allowed for eligibility 
determination):
Heart rate1
<50 or >100 beats per minute
QTcF interval2 (Fridericia’s)
>450 ms
1
A heart rate from 100 to 110 beats per minute can be rechecked by ECG or vital signs within 
30 minutes to verify eligibility.
2
The QTc is the QT interval corrected for heart rate according to Fridericia’s formula (QTcF). It is 
either machine read or manually over-read. The specific formula used to determine eligibility and
discontinuation for an individual participant in this study will be Fridericia’s formula.
Other Exclusions


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29. History of regular alcohol consumption within 6 months of the study defined as: an 
average weekly intake of >14 units. One unit is equivalent to 8 g of alcohol: a 
half-pint (~240 mL) of beer, 1 glass (125 mL) of wine or 1 (25 mL) measure of 
spirits.
30. Unable to refrain from tobacco- or nicotine-containing within 3 months prior to 
screening.
31. 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.
5.3.
Lifestyle Considerations
5.3.1.
Meals and Dietary Restrictions

Refrain from excessive consumption of red wine, grapefruit and grapefruit juice, 
Seville oranges, blood oranges, or pomelos or their fruit juices within 7 days 
prior to the first dose of study intervention(s) until the end of the study.
Excessive consumption is defined as more than one glass of wine or juice or one 
of these fruits per day, in combination.

Unless otherwise indicated, all doses of GSK3640254 in this study will be 
administered in the fed state. The participants will fast overnight for at least 
8 hours prior to dosing and will receive a moderate fat meal 30 minutes prior to 
dosing. Participants will eat this meal in 30 minutes or less. Dose administration 
will occur within 5 minutes of completion of meal consumption. Participants 
will not receive any further food until 4 hours post-dose on serial PK sampling 
days (Days 10 and 21 of the treatment period). The moderate fat meal will 
contain about 600 calories with approximately 30% of the calories coming from 
fat.

No water is allowed from 1 hours prior to dosing until 1 hours after dosing with 
GSK3640254 except for the glass of water needed to administer the study 
intervention (e.g., 240 mL). Water is allowed ad libitum at all other times.

A standard lunch will be provided 4 hours after dosing with GSK3640254. A 
standard dinner will be served approximately 10 hours after dosing. The food 
content of meals must be identical on serial PK sampling days (e.g., Days 10 
and 21 of the treatment period).
5.3.2.
Caffeine, Alcohol, and Tobacco

Participants will abstain from ingesting caffeine- or xanthine-containing
products (e.g., coffee, tea, cola drinks, and chocolate) for 24 hours before the 
start of dosing until after collection of the final PK sample.

Participants will abstain from alcohol for 48 hours before the start of dosing
until after collection of the final PK sample. 

Use of tobacco and nicotine-containing products will not be allowed from 
3 months prior to Screening until after the final visit.


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
Participants must have a negative drug test at Screening and check-in on Day -4
and must abstain from recreational drug use from Screening until after the final 
visit.
5.3.3.
Activity

Participants will abstain from strenuous exercise for 24 hours before each blood
collection for clinical laboratory tests. Participants may participate in light 
recreational activities during studies (e.g., watching television, reading).
5.4.
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study 
but are not subsequently entered in the study. A minimal set of screen failure information 
is required to ensure transparent reporting of screen failure participants to meet the 
Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes 
demography, screen failure details, eligibility criteria, and any SAEs.
Individuals who do not meet the criteria for participation in this study (screen failure) 
may not be rescreened.
6.
STUDY INTERVENTION
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according 
to the study protocol.


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6.1.
Study Interventions Administered
Intervention Name
GSK3640254
Portia
Type 
drug
drug
Dose Formulation
capsule
tablet
Unit Dose 
Strength(s)
100 mg
0.03 mg ethinyl estradiol
0.15 mg levonorgestrel
Dosage Level(s)
200 mg once daily
0.03 mg ethinyl estradiol and
0.15 mg levonorgestrel once daily
Route of 
Administration
oral
oral
IMP and NIMP
IMP
IMP
Sourcing
Provided centrally by the 
Sponsor 
Provided locally by the trial site
Packaging and 
Labeling
Study Intervention will be 
provided in high-density 
polyethylene bottles. Each bottle
will be labeled as required per 
country requirement.
Study Intervention will be provided 
in blister cards. Each blister card
will be labeled as required per 
country requirement.
IMP = investigational medicinal product; NIMP = noninvestigational medicinal product
6.2.
Preparation/Handling/Storage/Accountability
1. The investigator or designee must confirm appropriate temperature conditions have 
been maintained during transit for all study intervention received and any 
discrepancies are reported and resolved before use of the study intervention.
2. Only participants enrolled in the study may receive study intervention and only 
authorized site staff may supply or administer study intervention. All study 
interventions must be stored in a secure, environmentally controlled, and monitored 
(manual or automated) area in accordance with the labeled storage conditions with 
access limited to the investigator and authorized site staff.
3. The investigator, institution, or the head of the medical institution (where applicable) 
is responsible for study intervention accountability, reconciliation, and record 
maintenance (i.e., receipt, reconciliation, and final disposition records).
4. Further guidance and information for the final disposition of unused study 
intervention are provided in the Study Reference Manual (SRM). 
5. Under normal conditions of handling and administration, study intervention is not 
expected to pose significant safety risks to site staff.
6. A Material Safety Data Sheet/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 VH/GSK.


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6.3.
Measures to Minimize Bias: Randomization and Blinding
This is an open-label study. All participants will receive the same treatment.
6.4.
Study Intervention Compliance

When the individual dose for a participant is prepared from a bulk supply, the 
preparation of the dose will be confirmed by a second member of the study site 
staff.

When participants are dosed at the site, they will receive study intervention 
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 intervention and study participant identification 
will be confirmed at the time of dosing by a member of the study site staff other 
than the person administering the study intervention. Study site personnel will 
examine each participant’s mouth to ensure that the study intervention was 
ingested.
6.5.
Concomitant Therapy
Acetaminophen/paracetamol at doses of 2 grams/day and hydrocortisone cream 1% are 
permitted for use any time during the study and their use should be documented in the 
case report form (CRF). Other medications are not permitted without prior discussion 
with the VH/GSK medical monitor.
6.6.
Dose Modification
Not applicable.
6.7.
Intervention after the End of the Study
Participants will not receive any additional treatment from VH/GSK, or with 
GSK3640254, after the completion of the study because only healthy volunteers are 
eligible for study participation.
7.
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL
7.1.
Discontinuation of Study Intervention
In rare instances, it may be necessary for a participant to permanently discontinue study 
intervention. If study intervention is permanently discontinued, the participant will 
remain in the study to be evaluated for safety. See the SoA (Section 1.3) for data to be 
collected at the time of discontinuation of study intervention.


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7.1.1.
Liver Chemistry Stopping Criteria
Liver chemistry stopping and increased monitoring criteria have been designed to assure 
participant safety and evaluate liver event etiology (in alignment with the Food and Drug 
Administration premarketing clinical liver safety guidance: 
https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf).
Discontinuation of study intervention for abnormal liver tests is required when a 
participant has an ALT ≥3 × ULN or if the investigator believes study intervention 
discontinuation is in the best interest of the participant. 
Details of liver safety follow-up procedures are described in Appendix 5.
7.1.1.1.
Study Intervention Restart or Rechallenge after liver stopping criteria 
met
Study intervention restart or rechallenge after liver chemistry stopping criteria are met by 
any participant in this study is not allowed.
7.1.2.
QTc Stopping Criteria
The same Fridericia QT correction formula (QTcF) must be used for each individual 
participant to determine eligibility for and discontinuation from the study. This formula 
may not be changed or substituted once the participant has been enrolled.

The Baseline QTcF should be based on averaged QTcF values of triplicate 
ECGs obtained over a brief (e.g., 5 to 10 minute) recording period from the 
Day -4 ECG.

A randomized participant that develops an on-treatment QTcF >500 ms or an 
increase from baseline QTcF >60 ms should have two repeat unscheduled ECGs 
within 10 minutes. Using these triplicate ECGs, if the average QTcF >500 ms or 
an increase from baseline QTcF >60 ms, the participant will be withdrawn from 
the study. Finally, this participant should have repeated unscheduled ECGs until 
their QTcF measurement returns to their original averaged QTcF value at 
Day -4.
See the SoA (Section 1.3) for data to be collected at the time of intervention 
discontinuation and follow-up and for any further evaluations that need to be completed.
7.1.3.
Columbia Suicide Severity Rating Scale Criteria
Emergence of any positive (abnormal) response confirmed by the investigator on a 
clinician (or qualified designee) administered C-SSRS during the on-treatment phase of 
the study will be cause for discontinuation of study intervention.
Refer to the SoA (Section 1.3) for data to be collected at the time of intervention 
discontinuation and follow-up and for any further evaluations that need to be completed.


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7.1.4.
Individual Participant Laboratory Abnormality and Adverse Event 
Stopping Criteria
Investigators should make every effort to have a discussion with the medical monitor 
before the next dose to help assess if the study intervention should be stopped. 

Any clinically significant AE deemed to require discontinuation of study 
intervention

Any Grade 3 or higher rash or Grade 2 rash with evidence of systemic 
involvement 

Any allergic or hypersensitivity reactions to either or both drugs

Any Grade 3 or higher psychiatric AE

New onset suicidal ideation

Any Grade 3 or higher AE related to study intervention

Any Grade 4 AE or laboratory abnormalities (with the exception of an 
asymptomatic Grade 4 cholesterol, triglyceride, or CPK increase)
7.2.
Participant Discontinuation/Withdrawal from the Study

A participant may withdraw from the study at any time at her own request or 
may be withdrawn at any time at the discretion of the investigator for safety, 
behavioral, compliance, or administrative reasons. This is expected to be 
uncommon.

A participant who is withdrawn from the study for any reason related to safety 
(listed in Section 7.1.4 or otherwise) will be continued to be followed to assess 
the outcome of the safety event that triggered discontinuation of study drug.

At the time of discontinuing from the study, if possible, an early discontinuation 
visit should be conducted, as shown in the SoA. See SoA (Section 1.3) for data 
to be collected at the time of study discontinuation and follow-up and for any 
further evaluations that need to be completed.

The participant will be permanently discontinued both from the study 
intervention and from the study at that time.

If the participant withdraws consent for disclosure of future information, the 
sponsor may retain and continue to use any data collected before such a 
withdrawal of consent.

If a participant withdraws from the study, she may request destruction of any 
samples taken and not tested, and the investigator must document this in the site 
study records.
7.3.
Lost to Follow Up
A participant will be considered lost to follow-up if she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 


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The following actions must be taken if a participant fails to return to the clinic for a 
required study visit:

The site must attempt to contact the participant and reschedule the missed visit 
as soon as possible and counsel the participant on the importance of maintaining 
the assigned visit schedule and ascertain whether or not the participant wishes to 
and/or should continue in the study.

Before a participant is deemed lost to follow up, the investigator or designee 
must make every effort to regain contact with the participant (where possible, 
3 telephone calls and, if necessary, a certified letter to the participant’s last 
known mailing address or local equivalent methods). These contact attempts 
should be documented in the participant’s medical record.

Should the participant continue to be unreachable, she will be considered to 
have withdrawn from the study. 
Discontinuation of specific sites or of the study as a whole are handled as part of
Appendix 4.
8.
STUDY ASSESSMENTS AND PROCEDURES

Study procedures and their timing are summarized in the SoA (Section 1.3). 

Protocol waivers or exemptions are not allowed.

Immediate safety concerns should be discussed with the sponsor immediately 
upon occurrence or awareness to determine if the participant should continue or 
discontinue study intervention.

Adherence to the study design requirements, including those specified in the 
SoA, is essential and required for study conduct.

All screening evaluations must be completed and reviewed to confirm that 
potential participants meet all eligibility criteria. The investigator will maintain a 
screening log to record details of all participants screened and to confirm 
eligibility or record reasons for screening failure, as applicable. 

Procedures conducted as part of the participant’s routine clinical management 
(e.g., blood count) and obtained before signing of ICF may be utilized for 
screening or baseline purposes provided the procedure met the 
protocol-specified criteria and was performed within the time frame defined in 
the SoA.

The maximum amount of blood collected from each participant over the 
duration of the study, including any extra assessments that may be required, will 
not exceed 500 mL.

Repeat or unscheduled samples may be taken for safety reasons or for technical 
issues with the samples.
8.1.
Efficacy Assessments
Not applicable.


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8.2.
Safety Assessments
Planned time points for all safety assessments are provided in the SoA (Section 1.3).
8.2.1.
Physical Examinations

A full physical examination will include, at a minimum, assessments of the skin, 
cardiovascular, respiratory, GI, and neurological systems. Height and weight 
will also be measured and recorded.

A brief physical examination will include, at a minimum, assessments of the 
skin, lungs, cardiovascular system, and abdomen (liver and spleen).

Investigators should pay special attention to clinical signs related to previous 
serious illnesses.
8.2.2.
Vital Signs

Oral temperature, pulse rate, respiratory rate, and blood pressure will be 
assessed.

Blood pressure and pulse measurements will be assessed in the semi-recumbent 
position with a completely automated device. Manual techniques will be used 
only if an automated device is not available.

Blood pressure and pulse measurements should be preceded by at least 
5 minutes of rest for the participant in a quiet setting without distractions 
(e.g., television, cell phones).

Vital signs (to be taken before blood collection for laboratory tests) will consist 
of 3 blood pressure and pulse measurements (3 consecutive blood pressure and 
pulse readings will be recorded at intervals of at least 1 minute). Each 
measurement will be recorded in the CRF. Triplicate vital signs are required 
only when they occur at the same time point as clinical safety laboratory 
assessments. Vital signs will be taken as a single measurement at all other time 
points. 
8.2.3.
Electrocardiograms

On Day -4, triplicate ECGs will be taken. The ECGs should be recorded over a 
brief (e.g., 5 to 10 minute) recording period. Each measurement will be recorded 
in the CRF.

Single 12-lead ECG will be obtained at other time points as outlined in the SoA 
(Section 1.3) using an ECG machine that automatically calculates the heart rate 
and measures PR, QRS, QT, and QTcF intervals. Refer to Section 7.1.2 for 
QTcF withdrawal criteria and additional QTcF readings that may be necessary.

Twelve-lead ECGs will be performed with the participant in a supine or 
semi-supine position after a rest of at least 10 minutes.

At each time point at which triplicate ECG are required, 3 individual ECG 
tracings should be obtained as closely as possible in succession, but no more 


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than 2 minutes apart. The full set of triplicates should be completed over a brief 
(e.g., 5 to 10 minute) recording period.
8.2.4.
Clinical Safety Laboratory Assessments

Refer to Appendix 2 for the list of clinical laboratory tests to be performed and 
to the SoA (Section 1.3) for the timing and frequency. 

The investigator must review the laboratory report, document this review, and 
record any clinically relevant changes occurring during the study in the AE 
section of the CRF. The laboratory reports must be filed with the source 
documents. Clinically significant abnormal laboratory findings are those which 
are not associated with the underlying disease, unless judged by the investigator 
to be more severe than expected for the participant's condition.

All laboratory tests with values considered clinically significantly abnormal 
during participation in the study or within 7 days after the last dose of study 
intervention should be repeated until the values return to normal or Baseline or 
are no longer considered significantly abnormal by the investigator or medical 
monitor. 

If such values do not return to normal/baseline within a period of time judged 
reasonable by the investigator, the etiology should be identified and the sponsor 
notified.

All protocol-required laboratory assessments, as defined in Appendix 2, must be
conducted in accordance with the laboratory manual and the SoA.
8.2.5.
Suicidal Ideation and Behavior Risk Monitoring
GSK3640254 is not a central nervous system active drug nor is it being developed for a 
neurologic or psychiatric condition. However, given the risk of suicidal ideation 
identified with previous MI GSK3532795, all participants will undergo screening using 
the C-SSRS administered by a clinician (or qualified designee); any positive (abnormal) 
response confirmed by the investigator, will exclude them from participating. A repeat 
assessment will be done at Day 11 and at the end of the treatment phase of the study. In 
case of positive (abnormal) response confirmed by the investigator, the participant will 
discontinue from the trial and the investigator will arrange for urgent specialist 
psychiatric evaluation and management.
As described in Section 7.1.4, new onset suicidal ideation at any time will result in 
immediate discontinuation from the trial and the investigator will arrange for urgent 
specialist psychiatric evaluation and management.
The definitions of behavioral suicidal events used in this scale are based on those used in 
the Columbia Suicide History Form [Posner, 2007]. Questions are asked on suicidal 
behavior, suicidal ideation, and intensity of ideation. Screening visit questions will be in 
relation to lifetime experiences and current experiences (within the past 2 months) and all 
subsequent questioning in relation to the last assessment.


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Emergent non-suicidal psychiatric AE Evaluation and Management:

Any Grade 1 or 2 psychiatric AE: A Grade 1 or 2 psychiatric AE may result in 
additional unscheduled visits (in-clinic or at home) as clinically indicated. This 
may include a more in-depth assessment of AE through interview, additional 
unscheduled clinical laboratory samples, and/or imaging. Psychiatric consultation 
may be required at the discretion of the investigator. Any pharmacotherapy should 
be discussed with the medical monitor.

Any Grade 3 or 4 psychiatric AE: As described in Section 7.1.4, a Grade 3 or 4 
psychiatric AE will result in discontinuation from the trial and emergency 
psychiatric evaluation (including potential hospitalization and pharmacotherapy 
as indicated).
8.2.6.
Gastrointestinal Toxicity Evaluation and Monitoring Plan
Preclinical toxicology studies in rats and dogs have suggested a potential for GI-related 
toxicity with GSK3640254. This section provides general guidance to the investigator on 
the evaluation and management of primarily upper GI symptoms (Table 1). The 
investigator may contact the VH/GSK Medical Monitor to discuss evaluation and 
management (including discontinuation of a participant) of any GI symptoms throughout 
the study.
Table 1
Gastrointestinal Toxicity Evaluation and Management
HISTORY
For symptoms of all grades, a thorough history forms the foundation of 
proper evaluation and management. The following are potential 
manifestations of some GI clinical syndromes that may occur (possibly in 
combination) during the clinical study. 
Nausea and Vomiting
The investigator should attempt to identify the etiology of these symptoms (and 
whether it is intraperitoneal, extraperitoneal, medication related, infection related, 
or due to a metabolic disorder [Hasler, 2012]. Medications can cause nausea 
and vomiting acutely. 
Dyspepsia
The investigator should identify the presence of red flags (odynophagia, 
unexplained weight loss, recurrent vomiting, GI bleeding, jaundice, palpable 
mass or adenopathy, or family history of GI malignancy). Symptoms of 
dyspepsia could include early satiety, bloating, or belching. Additionally, atypical 
symptoms of dyspepsia could include: pharyngitis, asthma, bronchitis, 
hoarseness, chest pain, or abdominal pain. 
Other Clinical 
Syndromes
Additional diagnostic criteria for other GI disorders potentially encountered in the 
clinical study are available elsewhere [Rome Foundation, 2018].


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PHYSICAL 
EXAMINATION
Physical examination should complement elements obtained from the 
history [Hasler, 2012]. Acutely, the investigator may assess for signs of 
intravascular volume depletion (e.g., orthostasis) and/or aspiration of 
vomitus as appropriate. Abdominal tenderness and guarding may indicate 
inflammation. The presence of fecal blood can indicate mucosal damage 
(e.g., from an ulcer). Complete evaluation of dyspepsia should include an 
oral examination (poor dentition or pharyngeal erythema) and lungs for 
wheezing. 
DIAGNOSTIC 
EVALUATION AND 
MANAGEMENT
A major goal in the diagnostic evaluation of a participant with upper GI 
symptoms is to quickly arrive at a final diagnosis without exposing the 
participant to unnecessary (invasive) testing; investigators should 
exercise good clinical judgment in this regard [Soll, 2009]. A major goal of 
therapy is directed at correcting the underlying identifiable medical or 
surgical abnormalities. Consultation (e.g., gastroenterologist) is 
recommended as clinically indicated.
Grade 1 symptoms
Participants may be treated symptomatically. If participants develop dyspepsia 
alone, generally only limited and direct diagnostic testing should be performed. If 
the participant has dyspepsia they should limit alcohol, caffeine, chocolate, 
tobacco, and eating directly before bedtime. 
Grade 2 symptoms
Diagnostic testing may include but is not limited to the following (as clinically 
indicated):

Serum chemistries and assessment of hemoglobin if not recently performed 

Testing for Helicobacter pylori

Polymerase chain reaction for viruses (e.g., cytomegalovirus)
For participants who are infected with H. pylori, discontinuation from the study is 
necessary. Management should be targeted at addressing the underlying
pathology.
Grade 3 symptoms 1
Diagnostic testing may include but is not limited to the following (as clinically 
indicated):

The testing outlined above in Grade 2

A barium swallow 

Computed tomography scan to identify GI inflammation 

Upper endoscopy with biopsy as indicated (e.g., mucosal injury or the 
presence of red flags)
Management should be targeted at addressing the underlying pathology.
Grade 4 symptoms 1
Diagnostic testing may include but is not limited to the following (as clinically 
indicated):

The testing outlined above in Grade 2 and Grade 3

An acute abdominal series
Initial management can include correction of hemodynamic and electrolyte 
abnormalities as clinically indicated. After stabilization, management should be 
targeted at addressing the underlying pathology.
GI = gastrointestinal.
1
A Grade 4 or related Grade 3 AE: The Investigator will discontinue the participant from the study and perform an 
evaluation/management plan incorporating elements described above.


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8.3.
Adverse Events and Serious Adverse Events
The definitions of an AE or SAE can be found in Appendix 6. As described in
Appendix 6, intensity of AEs (and laboratory abnormalities) will be graded using the 
most recent version of the Division of AIDS (DAIDS) grading table at the time of the last 
participant last visit. While the study population will consist of HIV-1 seronegative 
healthy volunteers, the DAIDS criteria will be used in later phase clinical studies 
(Phase 2a and beyond); additionally, the DAIDS criteria have a more conservative 
grading scale relative to other scales (eg. CTCAE v 4.0). Thus, participant safety 
evaluation and monitoring will be more conservative.
The investigator and any qualified designees are responsible for detecting, documenting, 
and reporting events that meet the definition of an AE or SAE, and remain responsible for 
following up AEs that are serious, considered related to the study intervention or the 
study, or that caused the participant to discontinue the study (see Section 7).
8.3.1.
Time Period and Frequency for Collecting AE and SAE 
Information

All SAEs will be collected from the signing of the ICF until the end of the study 
at the time points specified in the SoA (Section 1.3).

All AEs will be collected from the start of intervention until the end of the study 
at the time points specified in the SoA (Section 1.3).

Medical occurrences that begin before the start of study intervention but after 
obtaining informed consent will be recorded on the Medical History/Current 
Medical Conditions section of the CRF, not the AE section.

All SAEs will be recorded and reported to the sponsor or designee immediately 
and under no circumstance should this exceed 24 hours, as indicated in 
Appendix 6. The investigator will submit any updated SAE data to the sponsor 
within 24 hours of it being available.

Investigators are not obligated to actively seek AEs or SAEs after the conclusion 
of the study participation. However, if the investigator learns of any SAE, 
including a death, at any time after a participant has been discharged from the 
study, and he/she considers the event to be reasonably related to the study 
intervention or study participation, the investigator must promptly notify the 
sponsor.
8.3.2.
Method of Detecting AEs and SAEs

The methods of recording, evaluating, and assessing causality of AEs and SAEs 
and the procedures for completing and transmitting SAE reports are provided in 
Appendix 6.

Care will be taken not to introduce bias when detecting an AE and/or SAE. 
Open-ended and nonleading verbal questioning of the participant is the preferred 
method to inquire about AE occurrence.


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8.3.3.
Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All SAEs will be followed until the event is 
resolved, stabilized, otherwise explained, or the participant is lost to follow-up (as 
defined in Section 7.3). Further information on follow-up procedures is given in 
Appendix 6.
8.3.4.
Regulatory Reporting Requirements for SAEs

Prompt notification by the investigator to the sponsor of a SAE is essential so 
that legal obligations and ethical responsibilities towards the safety of 
participants and the safety of a study intervention under clinical investigation are 
met. 

The sponsor has a legal responsibility to notify both the local regulatory 
authority and other regulatory agencies about the safety of a study intervention 
under clinical investigation. The sponsor will comply with country-specific 
regulatory requirements relating to safety reporting to the regulatory authority, 
IRB/IEC, and investigators.

Investigator safety reports must be prepared for suspected unexpected serious 
adverse reactions (SUSAR) according to local regulatory requirements and 
sponsor policy and forwarded to investigators as necessary.

An investigator who receives an investigator safety report describing a SAE or 
other specific safety information (e.g., summary or listing of SAEs) from the 
sponsor will review and then file it along with the CIB and will notify the 
IRB/IEC, if appropriate, according to local requirements.
8.3.5.
Pregnancy

Details of all pregnancies in female participants will be collected after the start 
of study intervention through the end of pregnancy (termination or delivery).

The investigator will collect pregnancy information on any female participant, 
who becomes pregnant while participating in this study and up to 38 days 
post-treatment completion. 

If a pregnancy is reported, the investigator should inform VH/GSK within 
24 hours of learning of the pregnancy and should follow the procedures outlined 
in Appendix 3.

Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, 
stillbirth, congenital anomalies, ectopic pregnancy) are considered SAEs.
8.4.
Treatment of Overdose
For this study, any dose of GSK3640254 or Portia greater than the planned dose within a 
24-hour time period (±2 hours) will be considered an overdose.


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VH/GSK does not recommend specific treatment for an overdose. The investigator will 
use clinical judgment to treat an overdose.
In the event of an overdose, the investigator should:
1. Contact the medical monitor immediately.
2. Closely monitor the participant for AE/SAE and laboratory abnormalities until 
GSK3640254 can no longer be detected systemically (at least 5 days).
3. Obtain a plasma sample for PK analysis immediately and through 7 days after the 
date of the last dose of study intervention 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 
participant.
8.5.
Pharmacokinetics

Whole blood samples of approximately 2 mL will be collected for measurement 
of plasma concentrations of GSK3640254 as specified in the SoA (Section 1.3). 

Whole blood samples of approximately 2 mL will be collected for measurement 
of plasma concentrations of EE, and 2 mL will be collected for LNG (i.e., total 
of 4 mL for the 2 analytes) as specified in the SoA (Section 1.3). 

A maximum of 10 samples may be collected at additional time points during the 
study if warranted and agreed upon between the investigator and the sponsor. 
Instructions for the collection and handling of biological samples will be 
provided by the sponsor. The actual date and time (24-hour clock time) of each 
sample will be recorded.

Samples will be used to evaluate the PK of GSK3640254, EE, and LNG. 
Samples collected for analyses of GSK3640254, EE, and LNG plasma 
concentration may also be used to evaluate safety aspects related to concerns 
arising during or after the study.

Once the plasma has been analyzed for GSK3640254, EE, and LNG, any 
remaining plasma may be analyzed for other compound-related metabolites and 
the results reported under a separate protocol.
8.6.
Pharmacodynamics
Venous blood samples of approximately 3.5 mL will be collected for measurement of 
serum progesterone, FSH, and LH at the time points indicated in the SoA (Section 1.3).


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8.7.
Genetics
A 6-mL blood sample for DNA isolation will be collected from participants who have 
consented to participate in the genetics analysis component of the study. Participation is 
optional. Participants who do not wish to participate in the genetic research may still 
participate in the study.
In the event of DNA extraction failure, a replacement genetic blood sample may be 
requested from the participant. Signed informed consent will be required to obtain a 
replacement sample unless it was included in the original consent.
See Appendix 7 for information regarding genetic research. Details on processes for 
collection and shipment and destruction of these samples can be found in the SRM.
8.8.
Biomarkers
Biomarkers are not evaluated in this study.
8.9.
Medical Resource Utilization and Health Economics
Medical Resource Utilization and Health Economics parameters are not evaluated in this 
study.
9.
STATISTICAL CONSIDERATIONS
9.1.
Statistical Hypotheses
The hypothesis tested by this study:
H0: test /ref < 0.8 or test /ref > 1.25
Ha: 0.8 ≤ test /ref ≤ 1.25
Where test is the geometric least-squares mean for PK parameters of EE/LNG when 
coadministered with GSK3640254 and ref is the geometric least-squares mean for PK 
parameters of EE/LNG when administered alone. If the null hypothesis is not rejected, 
then there is sufficient evidence to suggest an effect of GSK3640254 on the PK of 
EE/LNG; however, if the null hypothesis is rejected, then there is no evidence to suggest 
an effect of GSK3640254 on the PK of EE/LNG. The hypothesis test will be assessed 
using Schuirmann’s 2 one-sided t-test procedure with α=0.05 for each test
(Schuirmann, 1987). Each ratio will be compared to 0.8 and 1.25 as described above. 
Lack of effect is to be demonstrated if the 90% CIs for both LNG and EE lie within 0.8 
and 1.25.
9.2.
Sample Size Determination
The historical references used for to calculate the intrasubject coefficient of variability 
(CVw) for PK parameters of EE and LNG are provided in Table 2.


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Table 2
Intrasubject Coefficient of Variability for PK Parameters of EE and 
LNG
Historical Reference
Analyte
Parameter
n
CVw%
Anderson, 2011
EE
AUC(0-τ)
19
9.9
Cmax
19
13.4
Barr Laboratories, 2000
EE
AUC(0-τ)
30
13.2
Cmax
30
13.7
LNG
AUC(0-τ)
30
16.6
Cmax
30
13.5
Butler, 2011
EE
AUC(0-τ)
22
30.2
Cmax
22
19.3
LNG
AUC(0-τ)
22
12.1
Cmax
22
12.4
Sevinsky, 2011
EE
AUC(0-τ)
21
22.1
Cmax
21
21.3
LNG
AUC(0-τ)
6
19.7
Cmax
6
12.3
Trezza, 2017
EE
AUC(0-τ)
17
8.9
Cmax
19
19.3
LNG
AUC(0-τ)
19
8.7
Cmax
19
16.1
Based upon the historical references [Anderson, 2011; Barr Laboratories, 2000; Butler,
2011; Sevinsky, 2011; Trezza, 2017] a weighted average was obtained as 17.1%, 17.2%, 
13.6%, 13.7% for EE AUC(0-τ), EE Cmax, LNG AUC(0-τ), and LNG Cmax, 
respectively. The largest weighted average CVw for the analytes and parameters was 
17.2%.
The power computation was performed using PASS 15.0.7 procedure for “Equivalence 
Tests for the Ratio of Two Means in a 2×2 Cross-Over Design”: a CVw of 17.2%, Type I 
error of 0.05, true ratio for the means of 0.95, and a required statistical power of 90%. 
The number of evaluable participants required is 19 to achieve at least 90% statistical 
power. For ease of implementation, a total of 25 participants will be enrolled to ensure at 
least 20 provide evaluable data in both test and reference periods.


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9.3.
Populations for Analyses
For purposes of analysis, the following populations are defined:
Population
Description
Screened
All participants who sign the ICF.
Safety
All participants who receive at least 1 dose of study 
medication. This population will be used for all demographic 
and safety summaries.
Pharmacokinetic Concentration
The PK Concentration Population will include all participants 
who undergo plasma PK sampling and have evaluable PK 
assay results. This population will be used for the 
concentration listing.
Pharmacokinetic Parameter
The PK Parameter Population will include all participants who 
undergo plasma PK sampling and have evaluable PK 
parameters estimated. This population will be used for PK 
parameter listing, summary tables, and plotting of the 
concentration-time data and PK parameter summary.
Pharmacodynamic Concentration
The PD Concentration Population will include all participants 
who undergo plasma PD sampling and have evaluable PD
assay results. This population will be used for the 
concentration listing.
9.4.
Statistical Analyses
9.4.1.
Pharmacokinetic and Pharmacodynamic Analyses
Plasma EE, LNG, and GSK3640254 concentration-time data will be analyzed by PPD, 
under the oversight of the Clinical Pharmacology Modeling & Simulation department 
within GSK, using noncompartmental methods with Phoenix WinNonlin Version 6.4 or 
higher. Statistical analysis will be performed by PPD, under the oversight of Clinical 
Statistics, GSK. Calculations will be based on the actual sampling times recorded during 
the study.


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Endpoint
Statistical Analysis Methods
Primary

The primary endpoints of this study are PK-related. The analysis for the primary 
PK endpoints will be performed for the PK Parameter Population. Plasma 
concentrations of EE, LNG, and GSK3640254 will be subjected to PK analyses 
using noncompartmental methods.

Based on the individual concentration-time data the following primary plasma 
parameters will be estimated:

EE (Treatments A and B): AUC(0-), Cmax, and C

LNG (Treatments A and B): AUC(0-), Cmax, and C

Analyses will be performed to assess the effect of GSK3640254 on the steady 
state PK of EE and LNG, as appropriate. Analyses will be performed on the 
natural logarithms of AUC(0-), C, and Cmax using linear mixed effect models 
with treatment as a fixed effect and subject as a random effect. Effects will be 
estimated, and CIs will be constructed for the following treatment comparison:

Treatment B versus Treatment A

Point estimates and 90% CIs for treatment differences on the log scale derived 
from the model will be exponentiated to obtain estimates for geometric mean 
ratios and CIs on the original scale.

Summary statistics (arithmetic mean, geometric mean, median, standard 
deviation, minimum, maximum, and coefficient of variation) for plasma EE and 
LNG PK parameter values will be summarized by treatment.
Secondary

Plasma concentrations of GSK3640254 will be subjected to PK analyses using 
noncompartmental methods.

Based on the individual concentration-actual time data the following secondary 
plasma parameters will be estimated:

EE and LNG (Treatment A and B): Tmax and t1/2 (as data permit)

GSK3640254 (Treatment B): AUC(0-), Cmax, C, Tmax, and t1/2 (note: 
GSK3640254 PK parameter values in the presence of Portia from this study 
will be compared with GSK3640254 PK parameter values from previous 
studies)

Summary statistics (arithmetic mean, geometric mean, median, standard 
deviation, minimum, maximum, and coefficient of variation) for plasma EE, 
LNG, and GSK3640254 PK parameter values will be summarized by treatment. 

Additionally, predose (trough) PK plasma concentrations (EE and LNG: Days 9, 
10, 11 [Treatment A], 19 through 21 [Treatment B]; GSK3640254: Days 19 
through 21 and the 24-hour post-Day 21 dose [Treatment B]) will be 
summarized using the PK Concentration Population and used to assess 
achievement of steady state.

Summary statistics (arithmetic mean, median, standard deviation, minimum, 
maximum, and coefficient of variation) for serum progesterone, FSH, and LH 
levels will be summarized by treatment using the PD Concentration Population.
Additional data displays will be described in the reporting and analysis plan.
Exploratory
Will be described in the reporting and analysis plan.


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9.4.2.
Safety Analyses
All safety analyses will be performed on the Safety Population. 
Safety data will be presented in tabular format and summarized descriptively according to 
GSK’s Integrated Data Standards Library standards. No formal statistical analysis of the 
safety data will be conducted.
The details of the statistical analyses of safety and PK data will be provided in the 
reporting and analysis plan.
9.4.3.
Other Analyses
Not applicable.
9.5.
Interim Analyses
There will be no interim analysis performed.
9.5.1.
Data Monitoring Committee (DMC)
Not applicable.


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10.
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS
10.1.
Appendix 1: Abbreviations and Trademarks
AE
Adverse event
ALT
Alanine aminotransferase
AST
Aspartate aminotransferase
AUC
Area under the plasma concentration-time curve
AUC(0-24)
Area under the plasma concentration-time curve from time 0 to 24 hours 
after dosing
AUC(0-)
Area under the concentration-time curve from time zero extrapolated to 
infinity
AUC(0-)
Area under the plasma concentration-time curve from time 0 to the end 
of the dosing interval at steady state
BMS
Bristol-Myers Squibb
CFR
Code of Federal Regulations
CI
Confidence interval
CIB
Clinical Investigator's Brochure 
Cmax
Maximum observed concentration 
CONSORT
Consolidated Standards of Reporting Trials 
CPK
Creatine phosphokinase
CRF
Case report form
C-SSRS
Columbia Suicide Severity Rating Scale
C
Plasma concentration at the end of the dosing interval
CVw
Intra-subject coefficient of variability
CYP
Cytochrome P450
DAIDS
Division of AIDS
DDI
Drug-drug interaction
ECG
Electrocardiogram 
EE
Ethinyl estradiol
FSH
Follicle-stimulating hormone
FTIH
First time in human
GCP
Good Clinical Practice
GI
Gastrointestinal
GSK
GlaxoSmithKline 
HIPAA
Health Insurance Portability and Accountability Act
HIV
Human immunodeficiency virus


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IC50
Half maximal inhibitory concentration
ICF
Informed consent form 
ICH
International Council for Harmonisation
IEC
Independent Ethics Committee 
IgM
Immunoglobulin M
INR
International normalized ratio
IRB
Institutional Review Board 
LH
Luteinizing hormone
LNG
Levonorgestrel
MAD
Multiple-ascending dose
MI
Maturation inhibitor
OATP
Organic anion-transporting polypeptide
PD
Pharmacodynamic(s)
PK
Pharmacokinetic(s)
QD
Once daily
QTc
Corrected QT interval
QTcF
Fridericia QT correction formula
SAD
Single-ascending dose
SAE
Serious adverse event 
SHBG
Sex hormone-binding globulin
SoA
Schedule of activities
SRM
Study Reference Manual 
SUSAR
Suspected unexpected serious adverse reactions
t1/2
Apparent terminal phase half-life
Tmax
Time of maximum observed concentration
TQT
Thorough QT
UGT
Uridine diphosphate glucuronosyltransferase
ULN
Upper limit of normal 
USA
United States of America
VH
ViiV Healthcare
WOCBP
Women of childbearing potential 


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Trademark Information
Trademarks of ViiV Healthcare
Trademarks not owned by the ViiV 
Healthcare
NONE
Phoenix
Portia
WinNonlin


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10.2.
Appendix 2: Clinical Laboratory Tests

The tests detailed in Table 3 will be performed by the local laboratory.

Protocol-specific requirements for inclusion or exclusion of participants are 
detailed in Section 5 of the protocol.

Additional tests may be performed at any time during the study as determined 
necessary by the investigator or required by local regulations.

Pregnancy Testing

Refer to Section 5.1 Inclusion Criteria for screening pregnancy criteria.

Pregnancy testing (urine or serum as required by local regulations) should be 
conducted at the time points indicated in the SoA (Section 1.3).

Additional serum or urine pregnancy tests may be performed, as determined 
necessary by the investigator or required by local regulation, to establish the 
absence of pregnancy at any time during the participant's participation in the 
study.
Table 3
Protocol-Required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet Count
Red Blood Cell Indices:
White blood cell count with 
differential:
Red Blood Cell Count
Mean corpuscular volume
Neutrophils
Hemoglobin
Mean corpuscular hemoglobin 
Lymphocytes
Hematocrit
Monocytes
Eosinophils
Basophils
Clinical Chemistry 1
Blood urea nitrogen
Carbon dioxide
Total protein
Creatinine
Aspartate aminotransferase
Albumin
Glucose (fasting)
Alanine aminotransferase
Globulin
Potassium
Gamma-glutamyl transferase
Anion gap
Sodium
Total and direct bilirubin
Alkaline phosphatase
Calcium
Lactate dehydrogenase
Uric acid
Chloride
Total cholesterol
Creatine phosphokinase
Phosphorus
Triglycerides
Serum lipase
Serum amylase
Routine Urinalysis

Specific gravity

pH, glucose, protein, blood, ketones, bilirubin, urobilinogen, nitrite, and leukocyte 
esterase by dipstick

Microscopic examination (if blood, leukocyte esterase, or protein is abnormal)


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Laboratory 
Assessments
Parameters
Other Screening 
Tests

Serology: HIV-1 and -2 antigen/antibody immunoassay, hepatitis B surface 
antigen, hepatitis C antibody

Alcohol, cotinine, and drug screen (to include at minimum amphetamines, 
barbiturates, cocaine, opiates, cannabinoids, and benzodiazepines)

Pregnancy 2
1.
Details of liver chemistry stopping criteria and required actions and follow-up assessments after liver stopping or 
monitoring event are given in Section 7.1 and Appendix 5. All events of ALT 3 ULN and bilirubin 2 × ULN 
(>35% direct bilirubin) or ALT 3 × ULN and international normalized ratio (INR) >1.5, if INR measured, which 
may indicate severe liver injury (possible Hy’s Law), must be reported as an SAE (excluding studies of hepatic 
impairment or cirrhosis).
2.
Local urine testing will be standard for the protocol unless serum testing is required by local regulation or IRB/IEC.


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10.3.
Appendix 3: Contraceptive Guidance and Collection of 
Pregnancy Information
10.3.1.
Definitions:
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile (see below).
If fertility is unclear (e.g., amenorrhea in adolescents or athletes) and a menstrual cycle 
cannot be confirmed before first dose of study intervention, additional evaluation should 
be considered.
Women in the following categories are not considered WOCBP
1. Premenarchal
2. Premenopausal female with 1 of the following:

Documented hysterectomy

Documented bilateral salpingectomy

Documented bilateral oophorectomy

Documented bilateral tubal ligation
For individuals with permanent infertility due to an alternate medical cause other 
than the above, (e.g., Müllerian agenesis, androgen insensitivity), investigator 
discretion should be applied to determining study entry.
Note: Documentation can come from the site personnel’s review of the 
participant’s medical records, medical examination, or medical history interview.
3. Postmenopausal female

A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause. 

A high FSH level in the postmenopausal range may be used to confirm a 
postmenopausal state in women not using hormonal contraception or 
hormonal replacement therapy. However, in the absence of 12 months of 
amenorrhea, confirmation with more than one FSH measurement 
(>40 IU/L or mIU/mL) is required. 


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10.3.2.
Contraception Guidance:
CONTRACEPTIVES ALLOWED DURING THE STUDY INCLUDE:
1.
Participants who have been taking oral contraceptives prior to study entry should continue their 
current regimen until check-in to the clinic for the run-in period.
2.
Participants must use Portia for the duration of the run-in and treatment periods.
3.
Participants must agree to use an additional method of contraception from the list of 
contraceptive methods below for the run-in period, treatment period, and for 28 days after the 
last dose of study intervention:

Non hormonal Intrauterine device 

Bilateral tubal occlusion

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. 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.

Sexual abstinence. Note: Sexual abstinence is considered a highly effective method only if 
defined as refraining from penile-vaginal intercourse on a long term and persistent basis
when this is their preferred and usual lifestyle. The reliability of sexual abstinence needs to 
be evaluated in relation to the duration of the study and the preferred and usual lifestyle of 
the participant.

For the 28 days after study exit, women may resume oral contraceptives but double 
barrier methods (a combination of male condom with either cervical cap, 
diaphragm, or sponge with spermicide) must be used in addition.
10.3.3.
Collection of Pregnancy Information:
Female Participants who become pregnant

The investigator will collect pregnancy information on any female participant, 
who becomes pregnant while participating in this study. 

Information will be recorded on the appropriate form and submitted to VH/GSK
within 24 hours of learning of a participant's pregnancy. 

Participant will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow up information on participant and neonate, which 
will be forwarded to VH/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. 


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
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 intervention by the investigator, will be reported 
to VH/GSK as described in Appendix 6. 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 participant who becomes pregnant while participating will discontinue study 
intervention or be withdrawn from the study.


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10.4.
Appendix 4: Regulatory, Ethical, and Study Oversight 
Considerations
10.4.1.
Regulatory and Ethical Considerations

This study will be conducted in accordance with the protocol and with:

Consensus ethical principles derived from international guidelines 
including the Declaration of Helsinki and Council for International 
Organizations of Medical Sciences International Ethical Guidelines

Applicable International Council for Harmonisation (ICH) Good Clinical 
Practice (GCP) Guidelines

Applicable laws and regulations

The protocol, protocol amendments, ICF, CIB, and other relevant documents 
(e.g., advertisements) must be submitted to an IRB/IEC by the investigator and 
reviewed and approved by the IRB/IEC before the study is initiated. 

Any amendments to the protocol will require IRB/IEC approval before 
implementation of changes made to the study design, except for changes 
necessary to eliminate an immediate hazard to study participants. 

The investigator will be responsible for the following:

Providing written summaries of the status of the study to the IRB/IEC 
annually or more frequently in accordance with the requirements, policies, 
and procedures established by the IRB/IEC

Notifying the IRB/IEC of SAEs or other significant safety findings as 
required by IRB/IEC procedures

Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 Code of Federal Regulations (CFR), ICH guidelines, 
the IRB/IEC, European regulation 536/2014 for clinical studies (if 
applicable), and all other applicable local regulations
10.4.2.
Financial Disclosure
Investigators and sub-investigators will provide the sponsor with sufficient, accurate 
financial information as requested to allow the sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate regulatory authorities. 
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study.
10.4.3.
Informed Consent Process

The investigator or his/her representative will explain the nature of the study to 
the participant or her legally authorized representative and answer all questions 
regarding the study. 

Participants must be informed that their participation is voluntary. Participants 
or their legally authorized representative will be required to sign a statement of 


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informed consent that meets the requirements of 21 CFR 50, local regulations, 
ICH guidelines, Health Insurance Portability and Accountability Act (HIPAA) 
requirements, where applicable, and the IRB/IEC or study center. 

The medical record must include a statement that written informed consent was 
obtained before the participant was enrolled in the study and the date the written 
consent was obtained. The authorized person obtaining the informed consent 
must also sign the ICF.

Participants must be re-consented to the most current version of the ICF(s) 
during their participation in the study. 

A copy of the ICF(s) must be provided to the participant or the participant’s 
legally authorized representative. 

Participants who are rescreened are required to sign a new ICF.
The ICF may contain a separate section that addresses the use of remaining mandatory 
samples for optional exploratory research in accordance with SOP-GSKF-410. The 
investigator or authorized designee will explain to each participant the objectives of the 
exploratory research. Participants will be told that they are free to refuse to participate 
and may withdraw their consent at any time and for any reason during the storage period. 
A separate signature will be required to document a participant's agreement to allow any 
remaining specimens to be used for exploratory research. Participants who decline to 
participate will not provide this separate signature.
10.4.4.
Data Protection

Participants will be assigned a unique identifier by the sponsor. Any participant 
records or datasets that are transferred to the sponsor will contain the identifier 
only; participant names or any information which would make the participant 
identifiable will not be transferred. 

The participant must be informed that his/her personal study-related data will be 
used by the sponsor in accordance with local data protection law. The level of 
disclosure must also be explained to the participant. 

The participant must be informed that his/her medical records may be examined 
by Clinical Quality Assurance auditors or other authorized personnel appointed 
by the sponsor, by appropriate IRB/IEC members, and by inspectors from 
regulatory authorities.
10.4.5.
Dissemination of Clinical Study Data

Where required by applicable regulatory requirements, an investigator signatory 
will be identified for the approval of the clinical study report. The investigator 
will be provided reasonable access to statistical tables, figures, and relevant 
reports and will have the opportunity to review the complete study results at a
VH/GSK site or other mutually-agreeable location.

VH/GSK will also provide the investigator with the full summary of the study 
results. The investigator is encouraged to share the summary results with the 
study participants, as appropriate.


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
The procedures and timing for public disclosure of the protocol and results 
summary and for development of a manuscript for publication for this study will 
be in accordance with VH/GSK Policy.
10.4.6.
Data Quality Assurance

All participant data relating to the study will be recorded on printed or electronic 
CRF unless transmitted to the sponsor or designee electronically (e.g., 
laboratory data). The investigator is responsible for verifying that data entries 
are accurate and correct by physically or electronically signing the CRF. 

The investigator must maintain accurate documentation (source data) that 
supports the information entered in the CRF. 

The investigator must permit study-related monitoring, audits, IRB/IEC review, 
and regulatory agency inspections and provide direct access to source data 
documents. 

Monitoring details describing strategy (e.g., risk-based initiatives in operations 
and quality such as Risk Management and Mitigation Strategies), methods, 
responsibilities and requirements, including handling of noncompliance issues 
and monitoring techniques (central, remote, or on-site monitoring) are provided 
in the Monitoring Plan.

The sponsor or designee is responsible for the data management of this study 
including quality checking of the data. 

The sponsor assumes accountability for actions delegated to other individuals 
(e.g., contract research organizations).

Study monitors will perform ongoing source data verification to confirm that 
data entered into the CRF by authorized site personnel are accurate, complete, 
and verifiable from source documents; that the safety and rights of participants 
are being protected; and that the study is being conducted in accordance with the 
currently approved protocol and any other study agreements, ICH GCP, and all 
applicable regulatory requirements. 

Records and documents, including signed ICF, pertaining to the conduct of this 
study must be retained by the investigator for 25 years from the issue of the final 
Clinical Study Report/equivalent summary unless local regulations or 
institutional policies require a longer retention period. No records may be 
destroyed during the retention period without the written approval of the 
sponsor. No records may be transferred to another location or party without 
written notification to the sponsor.
10.4.7.
Source Documents

Source documents provide evidence for the existence of the participant and 
substantiate the integrity of the data collected. Source documents are filed at the 
investigator’s site.

Data reported on the CRF or entered in the electronic CRF that are transcribed 
from source documents must be consistent with the source documents or the 


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discrepancies must be explained. The investigator may need to request previous 
medical records or transfer records, depending on the study. Also, current 
medical records must be available.

Definition of what constitutes source data can be found in the SRM.
10.4.8.
Study and Site Closure
VH/GSK or its designee reserves the right to close the study site or terminate the study at 
any time for any reason at the sole discretion of VH/GSK. Study sites will be closed upon 
study completion. A study site is considered closed when all required documents and 
study supplies have been collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time, provided there is reasonable 
cause and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include 
but are not limited to:

Failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsor's procedures, or GCP guidelines

Inadequate recruitment of participants by the investigator

Discontinuation of further study intervention development
10.4.9.
Publication Policy

The results of this study may be published or presented at scientific meetings. If 
this is foreseen, the investigator agrees to submit all manuscripts or abstracts to 
the sponsor before submission. This allows the sponsor to protect proprietary 
information and to provide comments.

The sponsor will comply with the requirements for publication of study results. 
In accordance with standard editorial and ethical practice, the sponsor will 
generally support publication of multicenter studies only in their entirety and not 
as individual site data. In this case, a coordinating investigator will be 
designated by mutual agreement.

Authorship will be determined by mutual agreement and in line with 
International Committee of Medical Journal Editors authorship requirements.


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10.5.
Appendix 5: Liver Safety: Required Actions and Follow-up 
Assessments
Liver Chemistry Stopping Criteria 
ALT-absolute
ALT ≥3 × ULN
If ALT≥3 × ULN AND bilirubin1,2 2 × ULN (>35% direct bilirubin) or 
international normalized ratio (INR) >1.5, Report as an SAE.
See additional Actions and Follow Up Assessments listed below
Required Actions and Follow up Assessments 
Actions
Follow Up Assessments

Immediately discontinue study intervention

Report the event to GSK within 24 hours

Complete the liver event CRF, and complete 
an SAE data collection tool if the event also 
meets the criteria for an SAE2

Perform liver event follow up assessments

Monitor the participant until liver chemistries 
resolve, stabilize, or return to within baseline 
(see MONITORING below)
MONITORING:
If ALT ≥3 × ULN AND bilirubin ≥2 × ULN or 
INR >1.5

Repeat liver chemistries (include ALT, 
aspartate transaminase [AST], alkaline 
phosphatase, bilirubin and INR) and perform 
liver event follow up assessments within 
24 hours

Monitor participant twice weekly until liver 
chemistries resolve, stabilize or return to 
within baseline

A specialist or hepatology consultation is 
recommended
If ALT ≥3 × ULN AND bilirubin <2 × ULN and 
INR ≤1.5:

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin and INR) and 

Viral hepatitis serology3

Obtain INR and recheck with each liver 
chemistry assessment until the 
transaminases values show downward 
trend

Obtain blood sample for PK analysis, 
obtained within 48 hours of last dose4 

Serum CPK and lactate dehydrogenase.

Fractionate bilirubin, if total bilirubin
≥2 × ULN

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 ≥3 × ULN AND bilirubin ≥2 × ULN or 
INR >1.5:

Anti-nuclear antibody, anti-smooth muscle 
antibody, Type 1 anti-liver kidney 


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perform liver event follow up assessments 
within 24-72 hours

Monitor participant weekly until liver 
chemistries resolve, stabilize or return to 
within baseline
microsomal antibodies, and quantitative 
total immunoglobulin G or gamma 
globulins.

Serum acetaminophen adduct high 
performance liquid chromatography assay 
(quantifies potential acetaminophen 
contribution to liver injury in subjects with 
definite or likely acetaminophen use in the 
preceding week [James, 2009]. NOTE: not 
required in China.

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 intervention for that subject if ALT 3 × ULN and bilirubin 2 × ULN. 
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 3 × ULN and bilirubin 2 × ULN (>35% direct bilirubin) or ALT 3 × ULN and INR >1.5, which 
may indicate severe liver injury (possible “Hy’s Law”), must be reported as an SAE (excluding studies of hepatic 
impairment or cirrhosis); the INR threshold value stated will not apply to subjects receiving anticoagulants.
3.
Includes: Hepatitis A immunoglobulin (IgM) antibody, Hepatitis B surface antigen, and Hepatitis B Core Antibody; 
Hepatitis C RNA; Cytomegalovirus IgM antibody; Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, 
obtain heterophile antibody or monospot testing) and Hepatitis E IgM antibody 
4.
PK sample may not be required for participants known to be receiving placebo or non-GSK comparator 
interventions. Record the date/time of the PK blood sample draw and the date/time of the last dose of study 
intervention prior to PK blood sample draw on the CRF. If the date or time of the last dose is unclear, provide the 
participant’s best approximation. If the date/time of the last dose cannot be approximated OR a PK sample cannot 
be collected in the time period indicated above, do not obtain a PK sample. Instructions for sample handling and 
shipping are in the SRM.


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10.6.
Appendix 6: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting
10.6.1.
Definition of AE
AE Definition

An AE is any untoward medical occurrence in a clinical study participant, temporally 
associated with the use of a study intervention, whether or not considered related to 
the study intervention.

NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a study intervention.
Events Meeting the AE Definition

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (e.g., ECG, radiological scans, vital sign measurements), 
including those that worsen from Baseline, considered clinically significant in the 
medical and scientific judgment of the investigator (i.e., not related to progression of 
underlying disease).

Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected DDI.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. Overdose per se will not be reported as an 
AE/SAE unless it is an intentional overdose taken with possible suicidal/self-harming 
intent. Such overdoses should be reported regardless of sequelae.
Events NOT Meeting the AE Definition 

Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition.

The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the 
participant’s condition.

Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that 
leads to the procedure is the AE.


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
Situations in which 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.
10.6.2.
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (e.g., hospitalization for signs/symptoms of the disease under study, 
death due to progression of disease).
An SAE is defined as any untoward medical occurrence that, at any dose:
Results in death
Is life-threatening
The term “life-threatening” in the definition of “serious” refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, 
which hypothetically might have caused death, if it were more severe.
Requires inpatient hospitalization or prolongation of existing hospitalization
In general, hospitalization signifies that the participant has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or 
outpatient setting. Complications that occur during hospitalization are AE. If a 
complication prolongs hospitalization or 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.
Results in persistent disability/incapacity

The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.

This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (e.g., sprained ankle) which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
Is a congenital anomaly/birth defect


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Other situations:

Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the participant or may require medical or surgical intervention to prevent 
one of the other outcomes listed in the above definition. These events should usually 
be considered serious.
Examples of such events include invasive or malignant cancers, intensive treatment 
in an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse.
10.6.3.
Recording and Follow-Up of AE and SAE
AE and SAE Recording

When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g., hospital progress notes, laboratory, and diagnostics reports) 
related to the event.

The investigator will then record all relevant AE/SAE information in the CRF.

It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to VH/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 VH/GSK. In this case, all participant identifiers, with the exception of 
the participant number, will be redacted on the copies of the medical records before 
submission to VH/GSK.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not 
the individual signs/symptoms) will be documented as the AE/SAE.
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study using the DAIDS grading table Version 2.1, July 2017
(https://rsc.niaid.nih.gov/sites/default/files/daidsgradingcorrectedv21.pdf) and assign it to 
1 of the following categories: 

Mild: no or minimal interference with usual social & functional activities 

Moderate: greater than minimal interference with usual social and functional 
activities

Severe: inability to perform usual social and functional activities. An AE that is 
assessed as severe should not be confused with an SAE. Severe is a category utilized 
for rating the intensity of an event; and both AE and SAE can be assessed as severe.


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
Life Threatening: inability to perform basic self-care functions
An event is defined as “serious” when it meets at least 1 of the predefined outcomes 
as described in the definition of an SAE, NOT when it is rated as severe.
Assessment of Causality

The investigator is obligated to assess the relationship between study intervention 
and each occurrence of each AE/SAE.

A “reasonable possibility” of a relationship conveys that there are facts, evidence, 
and/or arguments to suggest a causal relationship, rather than a relationship cannot 
be ruled out.

The investigator will use clinical judgment to determine the relationship.

Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study intervention 
administration will be considered and investigated.

The investigator will also consult the CIB and/or Product Information, for marketed 
products, in his/her assessment.

For each AE/SAE, the investigator must document in the medical notes that he/she 
has reviewed the AE/SAE and has provided an assessment of causality.

There may be situations in which an SAE has occurred, and the investigator has 
minimal information to include in the initial report to VH/GSK. However, it is very 
important that the investigator always make an assessment of causality for 
every event before the initial transmission of the SAE data to GSK.

The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality 
assessment.

The causality assessment is 1 of the criteria used when determining regulatory 
reporting requirements.
Follow-up of AE and SAE

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by VH/GSK 
to elucidate the nature and/or causality of the AE or SAE as fully as possible. This 
may include additional laboratory tests or investigations, histopathological 
examinations, or consultation with other health care professionals.

If a participant dies during participation in the study or during a recognized 
follow-up period, the investigator will provide VH/GSK with a copy of any 
post-mortem findings including histopathology.

New or updated information will be recorded in the originally completed CRF.


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
The investigator will submit any updated SAE data to VH/GSK within 24 hours of 
receipt of the information.
10.6.4.
Reporting of SAE to VH/GSK
SAE Reporting to GSK via Electronic Data Collection Tool

The primary mechanism for reporting an SAE to VH/GSK will be the electronic data 
collection tool.

If the electronic system is unavailable, then the site will use the paper SAE data 
collection tool (see next section) in order to report the event within 24 hours.

The site will enter the SAE data into the electronic system as soon as it becomes 
available.

The investigator or medically-qualified sub-investigator must show evidence within 
the electronic CRF (e.g., check review box, signature, etc.) of review and verification 
of the relationship of each SAE to study intervention/study participation (causality) 
within 72 hours of SAE entry into the electronic CRF.

After the study is completed at a given site, the electronic data collection tool will be 
taken off-line to prevent the entry of new data or changes to existing data.

If a site receives a report of a new SAE from a study participant or receives updated 
data on a previously reported SAE after the electronic data collection tool has been 
taken off-line, then the site can report this information on a paper SAE form (see 
next section) or to the medical monitor by telephone.

Contacts for SAE reporting can be found in the SRM.
SAE Reporting to VH/GSK via Paper CRF

Facsimile transmission of the SAE paper CRF is the preferred method to transmit 
this information to the medical monitor.

In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by overnight 
mail or courier service.

Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames.

Contacts for SAE reporting can be found in SRM.


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10.7.
Appendix 7: Genetics
USE/ANALYSIS OF DNA

Genetic variation may impact a participant’s response to study intervention, 
susceptibility, severity, and progression of disease. Variable response to study 
intervention may be due to genetic determinants that impact drug absorption, 
distribution, metabolism, and excretion; mechanism of action of the drug; 
disease etiology; and/or molecular subtype of the disease being treated. 
Therefore, where local regulations and IRB/IEC allow, a blood sample will be 
collected for DNA analysis.

DNA samples will be used for research related to GSK3640254 or HIV and 
related diseases. They may also be used to develop tests/assays including 
diagnostic tests related to GSK3640254 or HIV MIs and HIV. Genetic research 
may consist of the analysis of 1 or more candidate genes or the analysis of 
genetic markers throughout the genome or analysis of the entire genome (as 
appropriate).

DNA samples will be analyzed if it is hypothesized that this may help further 
understand the clinical data. 

The samples may be analyzed as part of a multi-study assessment of genetic 
factors involved in the response to GSK3640254 or study interventions of this 
class. The results of genetic analyses may be reported in the clinical study report 
or in a separate study summary.

The sponsor will store the DNA samples in a secure storage space with adequate 
measures to protect confidentiality. 

The samples will be retained while research on GSK3640254 (or study 
interventions of this class) or HIV continues but no longer than 15 years after 
the last participant’s last visit or other period as per local requirements.


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11.
REFERENCES
Anderson MS, Hanley WD, Moreau AR, et al. Effect of raltegravir on estradiol and 
norgestimate plasma pharmacokinetics following oral contraceptive administration in 
healthy women. Br J Clin Pharmacol. 2011; 71(4):616-20.
Barr Laboratories ANDA 75-803. Center for Drug Evaluation and Research 
Bioequivalency Review(s). Levonorgestrel/Ethinyl Estradiol Tablets, USP 
0.10 mg/0.02 mg. Available from: 
https://www.accessdata.fda.gov/drugsatfda_docs/anda/2002/75803_Levonorgestrel%20A
nd%20Ethinyl%20Estradiol_Bioeqr.pdf. Accessed 11 Dec 2018.
Bristol-Myers Squibb Company Document Control Number 930109388. A randomized, 
double-blind, double-dummy, positive-controlled, crossover study to determine 
electrocardiographic effects of BMS-955176 in healthy subjects. Report Date: 
January 13, 2017.
Butler K and Teng R. Effect of ticagrelor on the pharmacokinetics of ethinyl oestradiol 
and levonorgestrel in healthy volunteers; Curr Med Res and Opin. 2011; 27(8):1585-93.
Department of Health and Human Services (DHHS), Food and Drug Administration, 
Center for Drug Evaluation and Research, Center for Biologics Evaluation and Research 
(US). Guidance for Industry: Clinical Drug Interaction Studies—Study Design, Data 
Analysis, and Clinical Implications. October 2017 [32 screens]. Available from: 
https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM292362.pdf.
GlaxoSmithKline Document Number 2016N302783_00. Clinical Study Report: A Phase 
2b Randomized, Active-Controlled, Double-Blind Trial to Investigate Safety, Efficacy 
and Dose-response of BMS-955176/GSK3532795, Given on a Backbone of 
Tenofovir/Emtricitabine, in Treatment-Naive HIV-1 Infected Adults – Week 24 Interim 
Analysis, 21-Jun-2017.
GlaxoSmithKline Document Number 2018N375461_00. Clinical Pharmacology 
Synopsis. A Double-Blind (Sponsor Unblinded), Randomized, Placebo- Controlled, 
Single and Repeated Dose Escalation Study to Investigate the Safety, Tolerability and 
Pharmacokinetics of GSK3640254 in Healthy Participants. September 2018.
GlaxoSmithKline Document Number 2018N379610_00. GSK3640254 Investigator’s 
Brochure, Version 01. Effective Date: 04 Oct 2018.
Hasler WL. Nausea, Vomiting, and Indigestion: Introduction. Chapter 39. Harrisons 
Principles of Internal Medicine 18th edition. 2012. McGraw Hill.
James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, et al. 
Pharmacokinetics of acetaminophen - protein adducts in adults with acetaminophen 
overdose and acute liver failure. Drug Metab Disp. 2009; 37(8):1779-84.
Levonorgestrel and Ethinyl Estradiol Prescribing Information, January 2012.


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Lin JH and Wong BK. Complexities of glucuronidation affecting in vitro and in vivo 
extrapolation. Curr Drug Metab. 2002; 3(6):623-46.
Posner K, Oquendo MA, Gould M, Stanley B, Davies M. Columbia Classification 
Algorithm of Suicide Assessment (C-CASA): classification of suicidal events in the 
FDA’s pediatric suicidal risk analysis of antidepressants. Am J Psychiatry. 
2007;164(7):1035-43.
Rome Foundation. Rome III Diagnostic Criteria for Functional Gastrointestinal 
Disorders. Available: 
http://www.theromefoundation.org/assets/pdf/19_RomeIII_apA_885-898.pdf. Accessed 
12 Oct 2018.
Schuirmann DJ. A comparison of the two one-sided tests procedure and the power 
approach for assessing the equivalence of average bioavailability. J Pharmacokinetics 
Biopharm. 1987; 15(6): 657-80.
Sevinsky H, Eley T, Persson A, et al. The effect of efavirenz on the pharmacokinetics of 
an oral contraceptive containing ethinyl estradiol and norgestimate in healthy 
HIV-negative women. Antivir Ther. 2011; 16(2):149-56.
Soll AH and Graham DY. Peptic Ulcer Disease. Chapter 40. Textbook of 
Gastroenterology. 5th edition. 2009. Blackwell Publishing.
Trezza C, Ford SL, Gould E, et al. Lack of effect of oral cabotegravir on the 
pharmacokinetics of a levonorgestrel/ethinyl oestradiol-containing oral contraceptive in 
healthy adult women. Br J Clin Pharmacol. 2017; 83(7):1499-1505.
Williams JA, Hyland R, Jones BC, Smith DA, Hurst S, Goosen TC et al. Drug-drug 
interactions for UDP-glucuronosyltransferase substrates: a pharmacokinetic explanation 
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Disposition. 2004; 32(11):1201-8.

SAP_001.pdf: 
CONFIDENTIAL
ViiV Healthcare group of companies
208135
1
Division
:
Worldwide Development
Information Type
:
Reporting and Analysis Plan (RAP)
Title
:
Reporting and Analysis Plan for The Effect of 
Coadministration of GSK3640254 on the Pharmacokinetics 
of a Combined Oral Contraceptive Containing Ethinyl 
Estradiol and Levonorgestrel in Healthy Female Subjects
Compound Number :
GSK3640254
Effective Date 
:
19-JAN-2020
Description:

The purpose of this RAP is to describe the planned analyses and output to be 
included in the Clinical Study Report for Protocol 208135.

This RAP is intended to describe the full 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.
Copyright 2020 ViiV Healthcare group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited


CONFIDENTIAL
ViiV Healthcare group of companies
208135
2
RAP Team Approvals:
Approver
Date
Approval 
Method
17-JAN-2020
Wet Ink Signature 
Page
Principal Statistician, GSK Biostatistics
17-JAN-2020
Wet Ink Signature 
Page
Programmer/Analyst, GSK Biostatics
17-JAN-2020
Wet Ink Signature 
Page
Statistics Leader, GSK Biostatistics
19-JAN-2020
Wet Ink Signature 
Page
Programming Director, GSK Biostatistics
PPD
PPD
PPD
PPD


CONFIDENTIAL
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TABLE OF CONTENTS
PAGE
1.
INTRODUCTION......................................................................................................5
1.1.
RAP Amendments ........................................................................................5
2.
SUMMARY OF KEY PROTOCOL INFORMATION ..................................................5
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...................................................................................7
3.
PLANNED ANALYSES ............................................................................................9
3.1.
Final Analyses ..............................................................................................9
4.
ANALYSIS POPULATIONS .....................................................................................9
4.1.
Protocol Deviations.......................................................................................9
5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA HANDLING 
CONVENTIONS.....................................................................................................11
5.1.
Study Treatment & Sub-group Display Descriptors.....................................11
5.2.
Baseline Definitions ....................................................................................11
5.3.
Other Considerations for Data Analyses and Data Handling 
Conventions................................................................................................12
6.
STUDY POPULATION ANALYSES .......................................................................13
6.1.
Overview of Planned Study Population Analyses........................................13
7.
PHARMACOKINETIC ANALYSES.........................................................................14
7.1.
Primary Pharmacokinetic Analyses.............................................................14
7.1.1.
Endpoint / Variables.....................................................................14
7.1.1.1.
Drug Concentration Measures....................................14
7.1.1.2.
Derived Pharmacokinetic Parameters.........................14
7.1.2.
Summary Measure ......................................................................14
7.1.3.
Population of Interest...................................................................14
7.1.4.
Statistical Analyses / Methods .....................................................14
7.1.4.1.
Statistical Methodology Specification..........................15
7.2.
Secondary Pharmacokinetic Analyses........................................................16
7.2.1.
Endpoint / Variables.....................................................................16
7.2.1.1.
Drug Concentration Measures....................................16
7.2.1.2.
Derived Pharmacokinetic Parameters.........................16
7.2.2.
Summary Measure ......................................................................16
7.2.3.
Population of Interest...................................................................16
7.2.4.
Statistical Analyses / Methods .....................................................17
8.
PHARMACODYNAMIC ANALYSES.......................................................................18
8.1.
Endpoint / Variables....................................................................................18
8.2.
Summary Measures....................................................................................18
8.3.
Population of Interest..................................................................................18
8.4.
Statistical Analysis / Methods......................................................................18
9.
SAFETY ANALYSES .............................................................................................19


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9.1.
Adverse Events Analyses ...........................................................................19
9.2.
Clinical Laboratory Analyses.......................................................................19
9.3.
Other Safety Analyses ................................................................................19
10. REFERENCES.......................................................................................................20
11. APPENDICES........................................................................................................21
11.1.
Appendix 1: Schedule of Activities ..............................................................21
11.1.1.
Protocol Defined Schedule of Events...........................................21
11.2.
Appendix 2: Study Phases and Treatment Emergent Adverse 
Events ........................................................................................................26
11.2.1.
Study Phases ..............................................................................26
11.2.1.1.
Study Phases for Concomitant Medication .................26
11.2.2.
Treatment Emergent Flag for Adverse Events .............................27
11.3.
Appendix 3: Data Display Standards & Handling Conventions....................28
11.3.1.
Reporting Process .......................................................................28
11.3.2.
Reporting Standards....................................................................28
11.3.3.
Reporting Standards for Pharmacokinetics..................................29
11.4.
Appendix 4: Derived and Transformed Data ...............................................31
11.4.1.
General........................................................................................31
11.4.2.
Study Population..........................................................................31
11.4.3.
Safety ..........................................................................................32
11.5.
Appendix 5: Reporting Standards for Missing Data.....................................33
11.5.1.
Premature Withdrawals................................................................33
11.5.2.
Handling of Missing Data.............................................................33
11.5.2.1.
Handling of Missing and Partial Dates ........................33
11.6.
Appendix 6: Division of AIDS (DAIDS) Table for Grading the 
Severity of Adult and Pediatric Adverse Events ..........................................34
11.6.1.
Laboratory Values........................................................................34
11.7.
Appendix 7: Values of Potential Clinical Importance ...................................37
11.7.1.
ECG.............................................................................................37
11.7.2.
Vital Signs....................................................................................37
11.8.
Appendix 8: Abbreviations & Trade Marks ..................................................38
11.8.1.
Abbreviations...............................................................................38
11.8.2.
Trademarks .................................................................................39
11.9.
Appendix 9: List of Data Displays ...............................................................40
11.9.1.
Data Display Numbering..............................................................40
11.9.2.
Mock Example Shell Referencing ................................................40
11.9.3.
Deliverables.................................................................................40
11.9.4.
Study Population Tables..............................................................41
11.9.5.
Safety Tables...............................................................................42
11.9.6.
Safety Figures .............................................................................45
11.9.7.
Pharmacokinetic Tables...............................................................46
11.9.8.
Pharmacokinetic Figures .............................................................49
11.9.9.
Pharmacodynamic Table .............................................................53
11.9.10. Pharmacodynamic Figure............................................................53
11.9.11. ICH Listings .................................................................................54
11.9.12. Non-ICH Listings..........................................................................57


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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: 208135
1.1.
RAP Amendments
Revision chronology:
RAP Section
Amendment Details
Reporting and Analysis Plan_Study208135_Final_V1 [16-JUL-2019]
Reporting and Analysis Plan_Study208135_Amendment_Final_V1 [19-JAN-2020]
7.1.4 and 7.2.4

Add boxplots for pharmacokinetic (PK) parameters overlaid with 
subjects categorized by elevated alanine aminotransferase (ALT) level 
and categorized by progesterone level
9.1

Add adverse events of special interests
9.2

Add plots of ALT, aspartate aminotransferase, alkaline phosphatase, 
total bilirubin, and gamma-glutamyl transferase by time
9.3

Add liver events
11.4.3

Add adverse events of special interest
11.9.4

Add additional summary of treatment status and reasons for 
discontinuation from treatment
11.9.5

Add summary of adverse events of special interests

Add summaries of actual values for clinical chemistry, hematology, 
urine concentration, electrocardiograms (ECGs), and vital signs

Add summaries for liver events
11.9.6

Add figures of ALT, aspartate aminotransferase, alkaline phosphatase, 
total bilirubin, and gamma-glutamyl transferase by time
11.9.8

Add boxplots of ethinyl estradiol (EE), levonorgestrel (LNG), and 
GSK3640254 PK parameters against ALT

Add boxplots of EE, LNG, and GSK3640254 PK parameters against 
progesterone
11.9.11

Add listings of adverse events of special interests, vital results for 
subjects with liver stopping events, and subjects with liver 
monitoring/stopping event reporting
2.
SUMMARY OF KEY PROTOCOL INFORMATION
This is an open-label, single-sequence, one-way drug-drug interaction study to investigate 
the effect GSK3640254 has on the PK of a combination oral contraceptive containing EE 
and LNG. Effective contraception for women infected with human immunodeficiency
virus (HIV) is important in the prevention of unplanned pregnancies. 


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2.1.
Changes to the Protocol Defined Statistical Analysis Plan
Changes from the originally planned statistical analysis specified in the protocol are 
outlined in Table 1.
Table 1
Changes to Protocol Defined Analysis Plan
Protocol
Reporting & Analysis Plan
Statistical Analysis Plan
Statistical Analysis Plan
Rationale for Changes

Pharmacokinetic concentration 
population will be used for 
concentration listing.

Pharmacokinetic 
concentration population 
will be used for the PK 
concentration listings, 
summary tables, and 
plotting of concentration-
time data.

Align with reporting and 
analysis plan (RAP) 209712 
and RAP 208134.

Pharmacokinetic parameter 
population will be used for PK
parameter listing, summary 
tables, and plotting of the
concentration-time data and PK 
parameter summary

Pharmacokinetic parameter 
population will be used for 
PK parameter listings, 
summary tables, and 
statistical analysis tables.

Align with reporting and 
analysis plan (RAP) 209712 
and RAP 208134.
2.2.
Study Objective(s) and Endpoint(s)
Objectives
Endpoints
Primary Objectives
Primary Endpoints

To assess the effect of GSK3640254 
on the steady state PK of EE and 
LNG under fed conditions in healthy 
female participants

AUC(0-), Cmax, and Cfor EE and LNG
Secondary Objectives
Secondary Endpoints

To assess the effect of GSK3640254 
on the PD of EE/LNG (suppression of 
ovulation as indicated by endogenous 
progesterone levels)

Serum progesterone levels

To assess the effect of GSK3640254 
on LH and FSH

Serum FSH and LH levels

To characterize the steady state PK of 
GSK3640254 in the presence of 
EE/LNG

AUC(0-), Cmax, C, Tmax, and t1/2 for GSK3640254

To Characterize the steady state PK 
of EE/LNG alone and in the presence 
of GSK3640254

Tmax and t1/2 for EE and LNG

To assess the safety and tolerability of 
GSK3640254 and EE/LNG when 
given in combination in healthy female 
participants

Safety and tolerability parameters for AEs/SAEs, 
observed and change from baseline clinical laboratory 
assessments, ECGs, and vital sign measurements
AE = adverse event; AUC(0-) = area under the plasma concentration-time curve from time 0 to the end of the dosing 
interval at steady state; Cmax = maximum observed concentration; C= Plasma concentration at the end of the dosing 


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Objectives
Endpoints
interval; ECG = electrocardiogram; EE = ethinyl estradiol; FSH = follicle-stimulating hormone; LH = luteinizing 
hormone; LNG = levonorgestrel; PD = pharmacodynamic; PK = pharmacokinetic; SAE = serious adverse event; 
t1/2 = apparent terminal phase half-life; Tmax = time of maximum observed concentration.
2.3.
Study Design
Overview of Study Design and Key Features
Figure 1
Study Design Schematic
Design
Features

A phase 1, open-label, fixed-sequence, one-way drug-drug interaction study.

The study will consist of a screening period, check-in, a run-in period, a treatment 
period, and a follow-up period.
o
Screening Period: up to 28 days before Day -4
o
Check-in: Day -4
o
Run-in Period: Portia (0.3 mg EE/0.15 mg LNG) once daily (QD) 
(Days -3 to -1)
o
Treatment Period: Portia (0.03 mg EE/0.15 mg LNG) QD on Days 1 to 
10 (Treatment A), followed by Portia (0.03 mg EE/0.15 mg LNG) QD 
coadministered with GSK3640254 200 mg on Days 11 to 21 
(Treatment B)
o
Follow-up Period[1]: 4 days 

Approximately 25 participants will be treated to ensure that 20 evaluable 
participants complete the study.
Dosing

Run-in Portia: Portia (0.03 mg EE/0.15 mg LNG) QD Days -3 to -1

Treatment A: Portia (0.03 mg EE/0.15 mg LNG) QD on Days 1 to 10

Treatment B: Portia (0.03 mg EE/0.15 mg LNG) QD coadministered with 
GSK3640254 200 mg on Days 11 to 21
Time & 
Events

Refer to Appendix 1: Schedule of Activities
Treatment 
Assignment

This is an open-label study. All eligible participants will receive the same treatment.
Interim 
Analysis

No interim analysis is planned for this study
[1] The “Washout” period of this study should be called “Follow Up” as there is only one treatment period. See 208135 
Protocol Clarification dated 10-June-2019
2.4.
Statistical Hypotheses
The hypothesis tested by this study:


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H0: test /ref < 0.8 or test /ref > 1.25
Ha: 0.8 ≤ test /ref ≤ 1.25
Where test is the geometric least-squares mean for PK parameters of EE/LNG when 
coadministered with GSK3640254 and ref is the geometric least-squares mean for PK 
parameters of EE/LNG when administered alone. If the null hypothesis is not rejected, 
then there is sufficient evidence to suggest an effect of GSK3640254 on the PK of 
EE/LNG; however, if the null hypothesis is rejected, then there is no evidence to suggest 
an effect of GSK3640254 on the PK of EE/LNG. The hypothesis test will be assessed 
using Schuirmann’s 2 one-sided t-test procedure with α=0.05 for each test
(Schuirmann, 1987). Each ratio will be compared to 0.8 and 1.25 as described above. 
Lack of effect is to be demonstrated if the 90% CIs for both LNG and EE lie within 0.8 
and 1.25.


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3.
PLANNED ANALYSES
3.1.
Final Analyses
The final planned primary analyses will be performed after the completion of the 
following sequential steps:
1.
All participants have completed the study as defined in the protocol.
2.
All required database cleaning activities have been completed and final database 
release (DBR) and database freeze (DBF) have been declared by Data Management.
4.
ANALYSIS POPULATIONS
Population
Definition / Criteria
Analyses Evaluated
Screened 

All participants who signed the informed consent form

This population will be used for screen failure listing 
and summary

Study Population
Safety

All participants who received at least 1 dose of study 
medication.

This population will be used for all demographic, 
disposition (exclude screen failure), and safety listings, 
summaries, and figure

Study Population

Safety
Pharmacokinetic 
Concentration

All participants who underwent plasma PK sampling 
and had evaluable PK assay results.

This population will be used for the PK concentration 
listings, summary tables, and plotting of concentration-
time data.

PK Concentration
Pharmacokinetic 
Parameter

All participants who underwent plasma PK sampling 
and had evaluable PK parameters estimated.

This population will be used for PK parameter listings, 
summary tables, and statistical analysis tables.

PK Parameter

PK statistical 
analysis
Pharmacodynamic 
Concentration

All participants who underwent plasma PD sampling 
and had evaluable PD assay results.

This population will be used for the PD concentration 
listings, summary tables, and figures.

PD Concentration
Refer to Appendix 9: List of Data Displays which details the population used for each display.
4.1.
Protocol Deviations
Important protocol deviations (including deviations related to study inclusion/exclusion 
criteria, conduct of the trial, participant management or participant assessment) will be 
summarized and listed.
Protocol deviations will be tracked by the study team throughout the conduct of the study 
in accordance with the Protocol Deviation Management Plan. The “significant” protocol 
deviation in the Protocol Deviation Management Plan is equivalent to “important” 
protocol deviations.


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o Data will be reviewed prior to freezing the database to ensure all significant
deviations and deviations which may lead to exclusion from the 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 listing of all inclusion/exclusion criteria deviations will also be provided. This 
listing will be based on data as recorded on the inclusion/exclusion page of the electronic 
case record form (eCRF).


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5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA
HANDLING CONVENTIONS
5.1.
Study Treatment & Sub-group Display Descriptors
Treatment Group Descriptions
Data Displays for Reporting 
Description
Code
Order in TLF 
Portia (0.03 mg EE/0.15 mg LNG) QD on Days -3 to -1
Run-in Portia
1
Portia (0.03 mg EE/0.15 mg LNG) QD on Days 1 to 10
Treatment A
2
Portia (0.03 mg EE/0.15 mg LNG) QD coadministered with 
GSK3640254 200 mg on Days 11 to 21
Treatment B
3
5.2.
Baseline Definitions
For all endpoints (except as noted in baseline definitions), baseline for treatment A is 
defined as the latest pre-dose assessment with a non-missing value, including those from 
unscheduled visits, before the dose of Portia on Day 1; baseline for treatment B is defined 
as the latest pre-dose assessment with a non-missing value, including those from 
unscheduled visits, before the first dose on Day 11. If time is not collected, Day 1 or 
Day 11 assessments are assumed to be taken prior to the dose and used as baseline.
Parameter
Study Assessments Considered as Baseline
Baseline Used in Data 
Display
Screening
Day -
4
Day 1 
(Pre-
Dose)
Day 10
Day 11 
(Pre-
Dose)
Treatment A
Treatment B
Safety
Vital Sign
X
X
X
X
X
Day 1 (Pre-
Dose)[1]
Day 11 (Pre-
Dose)[1]
12-Lead 
ECG
X
X
X
X
X
Day 1 (Pre-
Dose)
Day 11 (Pre-
Dose)[1]
Hematology
X
X
X
X
Day 1 (Pre-
Dose)
Day 10
Clinical 
Chemistry
X
X
X
X
Day 1 (Pre-
Dose)
Day 10
Urinalysis
X
X
X
X
Day 1 (Pre-
Dose)
Day 10
[1] The average (for quantitative assessments) or the worst case (for interpretation) of the predose triplicate 
assessments will be used as the baseline.
Unless otherwise stated, if baseline data is missing no derivation will be performed and 
baseline will be set to missing.


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5.3.
Other Considerations for Data Analyses and Data Handling 
Conventions
Other considerations for data analyses and data handling conventions are outlined in the 
appendices:
Section
Component
11.1
Appendix 1: Schedule of Activities
11.2
Appendix 2: Study Phases and Treatment Emergent Adverse Events
11.3
Appendix 3: Data Display Standards & Handling Conventions
11.4
Appendix 4: Derived and Transformed Data
11.5
Appendix 5: Reporting Standards for Missing Data
11.6
Appendix 6: Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric 
Adverse Events
11.7
Appendix 7: Values of Potential Clinical Importance


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6.
STUDY POPULATION ANALYSES
6.1.
Overview of Planned Study Population Analyses
The study population analyses will be based on the “Safety” or “Screened” population, 
unless otherwise specified.
Study population analyses including analyses of participant’s disposition, protocol 
deviations (including inclusion/exclusion criteria deviations), demographic and baseline 
characteristics, prior and concomitant medications, and exposure will be based on GSK 
Core Data Standards. Details of the planned displays are presented in Appendix 9: List of 
Data Displays.


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7.
PHARMACOKINETIC ANALYSES
7.1.
Primary Pharmacokinetic Analyses
7.1.1.
Endpoint / Variables
7.1.1.1.
Drug Concentration Measures
Refer to Appendix 3: Data Display Standards & Handling Conventions (Section 11.3.3
Reporting Standards for Pharmacokinetics). Plasma concentrations of EE, LNG, and 
GSK3640254 will be measured and reported.
7.1.1.2.
Derived Pharmacokinetic Parameters
Pharmacokinetic parameters will be calculated by standard non-compartmental analysis 
according to current working practices and using the currently supported version of 
WinNonlin (8.0 or higher). All calculations of non-compartmental parameters will be 
based on actual sampling times. Pharmacokinetic parameters listed will be determined 
from the plasma concentration-time data, as data permits.
Parameter
Parameter Description
Cmax
Maximum observed concentration, determined directly from the concentration-time data.
Cτ
Plasma concentration at the end of the dosing interval
AUC(0-τ)
Area under the plasma concentration-time curve from time 0 to the end of the dosing 
interval at steady state, to be calculated using the linear trapezoidal rule for each 
incremental trapezoid and the log trapezoidal rule for each decremental trapezoid.
NOTES:

Additional parameters may be included as required.
7.1.2.
Summary Measure
AUC(0-τ), Cτ and Cmax at steady state following doses of 0.03 mg EE/0.15 mg LNG 
QD Days 1 through 10 in Treatment A and 0.03 mg EE/0.15 mg LNG QD 
coadministered with GSK3640254 200 mg QD on Days 11 through 21 in Treatment B in 
healthy female subjects.
7.1.3.
Population of Interest 
The primary PK analyses will be based on the PK concentration population for plasma 
PK concentrations and the PK parameter population for plasma PK parameters and 
statistical analysis.
7.1.4.
Statistical Analyses / Methods
Details of the planned displays are provided in Appendix 9: List of Data Displays and 
will be based on GSK Data Standards and statistical principles.
Unless otherwise specified, endpoints / variables defined in Section 7.1.1 will be 
summarized using descriptive statistics, graphically presented (where appropriate) and 
listed.


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Primary plasma PK parameters (AUC(0-τ), Cτ, and Cmax) will be estimated for EE and 
LNG (Treatments A and B). Summary statistics (arithmetic mean, geometric mean, 
median, standard deviation (SD), minimum, maximum, and coefficient of variation) for 
plasma EE and LNG PK parameter values will be summarized by treatment.
Boxplots with overlaid individual values of primary plasma PK parameters for EE and 
LNG will be produced for subjects categorized by ALT (ALT level within normal range, 
ALT value is greater than upper limit of normal [ULN] but less than or equal to 3 times 
the ULN, and ALT level is greater than 3 times the ULN) and whether subjects met liver 
stopping criteria. Similarly, boxplots with overlaid individual values of primary plasma 
PK parameters will be produced by treatment with data presented according to subject’s 
progesterone level (progesterone level is less than or equal to 6.36 nmol/L and 
progesterone level is greater than to 6.36 nmol/L) and whether subjects met liver stopping 
criteria.
7.1.4.1.
Statistical Methodology Specification
The following PK statistical analyses will only be performed if sufficient data are
available (i.e. if participants have well defined plasma profiles).
Endpoint / Variables

Plasma primary PK endpoints include AUC(0-τ), Cτ, and Cmax for EE and LNG (Treatments 
A and B), as data permit
Model Specification

Analyses will be performed on the natural logarithms of AUC(0-τ), Cτ and Cmax using linear 
mixed-effect models with treatment as a fixed effect, participants as random effect, and 
measurements within participant as repeated measures. 

Effects will be estimated, and confidence intervals (CIs) will be constructed for the following 
treatment comparisons:
Treatment B versus Treatment A 

Point estimates and 90% CIs for treatment differences on the log scale derived from the 
model will be exponentiated to obtain estimates for geometric mean ratios and CIs on the 
original scale.
Model Checking & Diagnostics

Model assumptions will be applied, but appropriate adjustments may be made based on the 
data.
Model Results Presentation

Statistical analysis by analysis of variance (ANOVA) will be presented in tabular format with 
geometric mean ratios for:
Treatment B versus Treatment A 


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7.2.
Secondary Pharmacokinetic Analyses
7.2.1.
Endpoint / Variables
7.2.1.1.
Drug Concentration Measures 
Refer to Appendix 3: Data Display Standards & Handling Conventions (Section 11.3.3
Reporting Standards for Pharmacokinetic).  
7.2.1.2.
Derived Pharmacokinetic Parameters
Pharmacokinetic parameters will be calculated by standard non-compartmental analysis 
according to current working practices and using the currently supported version of 
WinNonlin (8.0 or higher). All calculations of non-compartmental parameters will be 
based on actual sampling times.
Plasma pharmacokinetic parameters listed below will be determined from the total 
plasma concentration-time data, as data permits.
Parameter
Parameter Description
Cmax
Maximum observed concentration, determined directly from the concentration-time data. 
(GSK3640254 only)
Cτ
Plasma concentration at the end of the dosing interval (GSK3640254 only)
AUC(0-τ)
Area under the plasma concentration-time curve from time 0 to the end of the dosing 
interval at steady state, to be calculated using the linear trapezoidal rule for each 
incremental trapezoid and the log trapezoidal rule for each decremental trapezoid. 
(GSK3640254 only)
Tmax
Time of maximum observed concentration
t1/2
Apparent terminal phase half-life
NOTES:

Additional parameters may be included as required.
7.2.2.
Summary Measure
Ethinyl estradiol and LNG Tmax, and t1/2 at steady state following doses of 0.03 mg 
EE/0.15 mg LNG QD Days 1 through 10 in Treatment A and 0.03 mg EE/0.15 mg LNG 
QD coadministered with GSK3640254 200 mg QD on Days 11 through 21 in 
Treatment B in healthy female subjects.
GSK3640254 AUC(0-τ), Cτ, Cmax, Tmax, and t1/2 at steady state following doses of 
0.03 mg EE/0.15 mg LNG QD coadministered with GSK3640254 200 mg QD on 
Days 11 through 21 in Treatment B in healthy female subjects.
7.2.3.
Population of Interest 
The secondary PK analyses will be based on the PK concentration population for plasma 
PK concentrations, and the PK parameter population for plasma and statistical analysis, 
unless otherwise specified.


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7.2.4.
Statistical Analyses / Methods
Details of the planned displays are provided in Appendix 9: List of Data Displays and 
statistical principles.
Unless otherwise specified, endpoints/variables defined in Section 7.2.1 will be 
summarized using descriptive statistics, graphically presented (where appropriate), and 
listed.
Secondary plasma PK parameters (Tmax and t1/2) will be estimated for EE and LNG 
(Treatments A and B) and secondary plasma PK parameters AUC(0- τ), Cτ, Cmax, 
Tmax, and t1/2 will be estimated for GSK3640254 (Treatment B). Summary statistics 
(arithmetic mean, geometric mean, median, SD, minimum, maximum, and coefficient of 
variation) for secondary plasma PK parameters of GSK3640254 and EE and LNG will be 
summarized by treatment.
Predose (trough) PK plasma concentrations (EE and LNG: Days 9, 10, 11 [Treatment A], 
19 through 21 and the 24-hour post-Day 21 dose [Treatment B]; GSK3640254: Days 19 
through 21 and the 24-hour post-Day 21 dose [Treatment B]) will be summarized using 
the PK Concentration Population and used to assess achievement of steady state.
Boxplots with overlaid individual values of primary plasma PK parameters for 
GSK3640254 will be produced for subjects categorized by ALT (ALT level within 
normal range, ALT value is greater than upper limit of normal [ULN] but less than or 
equal to 3 times the ULN, and ALT level is greater than 3 times the ULN) and whether 
subjects met liver stopping criteria. Similarly, boxplots with overlaid individual values of 
primary plasma PK parameters will be produced by treatment with data presented 
according to subject’s progesterone level (progesterone level is less than or equal to 6.36 
nmol/L and progesterone level is greater than to 6.36 nmol/L) and whether subjects met 
liver stopping criteria.


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8.
PHARMACODYNAMIC ANALYSES
8.1.
Endpoint / Variables
Serum LH, FSH, and progesterone levels when EE/LNG is administered alone and in 
combination with GSK3640254. 
8.2.
Summary Measures
Serum LH, FSH, and progesterone levels. 
8.3.
Population of Interest
The PD analyses will be based on the “Pharmacodynamic Concentration” population, 
unless otherwise specified.
8.4.
Statistical Analysis / Methods
Details of the planned displays are provided in Appendix 9: List of Data Displays and 
will be based on GSK Data Standards and statistical principles.
Individual concentration-time profiles will be created for LH, FSH and progesterone. For 
each parameter, the profiles for both treatments will be overlaid on the same plot.
Actual values for serum LH, FSH, and progesterone levels will be listed and summarized 
by treatment using descriptive statistics; in addition, the mean value with the SD will be 
presented in a figure. The maximum LH and FSH concentration of each treatment period 
will be identified for each subject and listed with treatment and day and summarized by 
treatment.
For each parameter (LH, FSH, and progesterone), the concentrations will be plotted by 
treatment and timepoint using box-plots displaying the median, range, 25th and 75th
percentiles. Maximum LH and FSH will be plotted within the same figure.


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9.
SAFETY ANALYSES
The safety analyses will be based on the “Safety” population unless otherwise specified.
9.1.
Adverse Events Analyses
Adverse events analyses including the analysis of AEs, SAEs, AEs of special interest, 
and other significant AEs will be based on GSK Core Data Standards. The details of the 
planned displays are provided in Appendix 9: List of Data Displays.
9.2.
Clinical Laboratory Analyses
Laboratory evaluations including the analyses of chemistry laboratory tests, hematology 
laboratory tests, urinalysis, liver function tests, and pregnancy test will be based on GSK 
Core Data Standards and will be graded using the Division of AIDS (DAIDS) Table for 
Grading the Severity of Adult and Pediatric Adverse Events (Version 2.1, July 2017). 
Alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, total 
bilirubin, and gamma-glutamyl transferase will be plotted versus time. The details of the 
planned displays are in Appendix 9: List of Data Displays.
9.3.
Other Safety Analyses
The analyses of non-laboratory safety test results including ECGs, vital signs, liver 
events, and Columbia Suicide Severity Rating Scale (C-SSRS) will be based on GSK 
Core Data Standards, unless otherwise specified. A figure of mean change from baseline 
in QTcF interval along with the 2-sided 95% CI using Student’s t distribution will be 
presented by treatment and visit. The details of the planned displays are presented in 
Appendix 9: List of Data Displays.


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10.
REFERENCES
Schuirmann DJ. A comparison of the two one-sided tests procedure and the power 
approach for assessing the equivalence of average bioavailability. J Pharmacokinetics 
Biopharm. 1987; 15(6): 657-80.
ViiV Healthcare group of companies Document Number 2018N383291_00
(10-MAY-2019): The Effect of Coadministration of GSK3640254 on the 
Pharmacokinetics of a Combined Oral Contraceptive Containing Ethiny Estradiol and 
Levonorgestrel in Healthy Female Subjects.208135 Protocol Clarification (10-JUN-
2019).


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11.
APPENDICES
11.1.
Appendix 1: Schedule of Activities
11.1.1.
Protocol Defined Schedule of Events
Screening Visit
Procedure
Screening (up to 28 days before Day -4)
Outpatient visit
X
Informed consent
X
Inclusion and exclusion criteria
X
Demography
X
Full physical examination including height and weight 1
X
Laboratory assessments (hematology, chemistry, urinalysis)
X
12-lead electrocardiogram (ECG)
X
Vital sign measurements
X
Medication/drug/alcohol history
X
Past and current medical conditions  
X
Columbia Suicide Severity Rating Scale (C-SSRS)
X
Serum pregnancy test
X
Drug, alcohol, and cotinine screen
X
Human immunodeficiency virus (HIV), Hepatitis B and C screening
X
1. A full physical examination will include at a minimum, assessments of the skin, cardiovascular, respiratory, 
gastrointestinal (GI), and neurological systems.


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Table 2
Time and Events Table
Procedure
Check-in
Run-in
Treatment
Washout 1
Notes
D
-4
D 
-3
D
-2
D
-1
D
1
D
2-9
D
10 2
D
11
D
12
D
13
D
14-18
D
19
D
20
D
21
D
22
D
23
D
24 3
D
25
Admit to clinic
X
Discharge from clinic
X
Brief physical 
examination
X
X
X
A brief physical 
examination will include, 
at a minimum, 
assessments of the skin, 
lungs, cardiovascular 
system, and abdomen 
(liver and spleen.
Vital signs
X
X
X
X
D15
X
X
Obtained before dosing, 
where applicable. Blood 
pressure and pulse will be 
measured in triplicate 
when they occur at the 
same time point as clinical 
laboratory assessments.
12-lead ECG
X
X
X
X
D15
X
X
On Day 11, triplicate 
ECGs will be taken before 
dosing. On Day 11, single 
ECGs will be taken at 2, 4, 
and 6 hours after dosing. 
On Day 15, single ECGs 
will be taken at 2, 4, and 6 
hours after dosing. Single 
ECGs will be taken on 
other scheduled days.


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Procedure
Check-in
Run-in
Treatment
Washout 1
Notes
D
-4
D 
-3
D
-2
D
-1
D
1
D
2-9
D
10 2
D
11
D
12
D
13
D
14-18
D
19
D
20
D
21
D
22
D
23
D
24 3
D
25
Drug, alcohol, and 
cotinine screen
X
See Protocol Appendix 2
for specific tests to be 
performed.
Laboratory 
assessments 
(hematology, chemistry, 
urinalysis tests)
X
X
X
X
X
See Protocol Appendix 2 
for specific tests to be 
performed. Taken before 
dosing, where applicable.
Pregnancy test 
X
X
X
X
Genetic sample 
(optional)
X
C-SSRS
X
X
Study intervention: 
Portia (0.03 mg EE/ 
0.15 mg LNG)
X
X
X
X
X
X
X
X
X
X
X
X
X
Study intervention: 
GSK3640254 200 mg
X
X
X
X
X
X
X
Trough PK sampling: 
EE and LNG 
D9
X
X
PK sample collected 
before dosing.


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Procedure
Check-in
Run-in
Treatment
Washout 1
Notes
D
-4
D 
-3
D
-2
D
-1
D
1
D
2-9
D
10 2
D
11
D
12
D
13
D
14-18
D
19
D
20
D
21
D
22
D
23
D
24 3
D
25
Serial PK sampling:
EE and LNG 
X
X
X
X
X
X
PK samples will be 
collected predose and 
after dosing at 15 and 
30 minutes and 1, 1.5, 2, 
3, 4, 7, 12, and 24 hours 
relative to Day 10 dosing. 
The 24-hour post-dose 
sample should be taken 
prior to dosing on Day 11. 
PK samples will be 
collected predose and 
after dosing at 15 and 
30 minutes and 1, 1.5, 2, 
3, 4, 7, 12, 24, 48, and 72 
hours relative to Day 21 
dosing.
Trough PK sampling: 
GSK3640254
X
X
PK sample collected 
before dosing.
Serial PK sampling: 
GSK3640254
X
X
X
X
X
PK samples will be 
collected predose and 
after dosing at 1, 2, 2.5, 3, 
3.5, 4, 4.5, 5, 6, 8, 12, 24, 
48, 72, and 96 hours 
relative to Day 21 dosing.
PD sampling: LH, FSH, 
progesterone
X
X
X
X
X
Samples collected before 
dosing.
AE review
==================================================================================

SAE review
=========================================================================================


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Procedure
Check-in
Run-in
Treatment
Washout 1
Notes
D
-4
D 
-3
D
-2
D
-1
D
1
D
2-9
D
10 2
D
11
D
12
D
13
D
14-18
D
19
D
20
D
21
D
22
D
23
D
24 3
D
25
Concomitant medication 
review
=========================================================================================
AE = adverse event; D = Day; C-SSRS = Columbia Suicide Severity Rating Scale; ECG = electrocardiogram; EE = ethinyl estradiol; FSH = follicle-stimulating hormone; LH = luteinizing 
hormone; LNG = levonorgestrel; PD = pharmacodynamic; PK = pharmacokinetic; SAE = serious adverse event.
1
Washout period refers to follow-up period. See 208135 Protocol Clarification dated 10-Jun-2019.
2
Assessments performed on Day 10 will be considered Baseline for GSK3640254 dosing.
3
Evaluations scheduled for Day 24 will also be performed for participants who discontinue early.


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11.2.
Appendix 2: Study Phases and Treatment Emergent 
Adverse Events
11.2.1.
Study Phases
Assessments and events will be classified according to the time of occurrence relative to 
study treatment start date(/time) and stop date(/time).
Study Phase
Definition
Pre-Treatment 
Date and Time ≤ Study Treatment Start Date and Time
On-Treatment
Study Treatment Start Date and Time < Date and Time ≤ Study Treatment Stop Date
and Time + 5 days
Post-Treatment
Date and Time > Study Treatment Stop Date and Time + 5 days
11.2.1.1.
Study Phases for Concomitant Medication
Study Phase
Definition
Prior
If medication end date is not missing and is before Day -4
Concomitant
Any medication that is not a prior
NOTES: 

Please refer to Appendix 5: Reporting Standards for Missing Data for handling of missing and partial dates for 
concomitant medication. Use the rules in this table if concomitant medication date is completely missing.


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11.2.2.
Treatment Emergent Flag for Adverse Events
Flag
Definition
Treatment 
Emergent

If AE onset date and time is on or after treatment start date and time & on or 
before treatment stop date and time + 5 days. 

Study Treatment Start Date and Time ≤ AE Start Date and Time ≤ Study 
Treatment Stop Date and Time + 5 days.

If the AE onset date is completely missing, the AE is considered as treatment 
emergent.
NOTES: 

If the study treatment stop date is missing, then the AE will be considered to be On-Treatment.

Please refer to Appendix 5: Reporting Standards for Missing Data for handling of missing and partial dates for 
adverse events. Use the rules in this table if the adverse event onset date is completely missing.


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11.3.
Appendix 3: Data Display Standards & Handling 
Conventions
11.3.1.
Reporting Process
Software

The currently supported versions of SAS software (9.4) will be used.
Reporting Area
HARP Server
\\us1salx00259.corpnet2.com
HARP Compound
\gsk3640254\mid208135\final_01
Analysis Datasets 

Analysis datasets will be created according to CDISC standards (SDTM IG Version 3.2 & ADaM IG 
Version 1.1).

For creation of ADaM datasets (ADC1/ADCM/ADAE), the same version of dictionary datasets will be 
implemented for conversion from SI to SDTM.
Generation of RTF Files

RTF files will be generated for all reporting efforts described in the RAP.
11.3.2.
Reporting Standards
General

The current GSK Integrated Data Standards Library (IDSL) will be applied for reporting, unless 
otherwise stated (IDSL Standards Location: 
https://spope.gsk.com/sites/IDSLLibrary/SitePages/Home.aspx):

4.03 to 4.23: General Principles

5.01 to 5.08: Principles Related to Data Listings

6.01 to 6.11: Principles Related to Summary Tables

7.01 to 7.13: Principles Related to Graphics 

Do not include participant level listings in the main body of the GSK Clinical Study Report. All 
participant level listings should be located in the modular appendices as ICH or non-ICH listings.
Formats

All data will be reported according to the actual treatment the participant 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, unless otherwise stated.

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:

Planned time relative to dosing will be used in figures, summaries, statistical analyses and 
calculation of any derived parameters, unless otherwise stated.

The impact of any major deviation from the planned assessment times and/or scheduled visit 
days on the analyses and interpretation of the results will be assessed as appropriate.

Reporting for Data Listings: 

Planned and actual time relative to study drug dosing will be shown in listings (Refer to IDSL 
Statistical Principle 5.05.1).


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
Unscheduled or unplanned readings will be presented within the participant’s listings. 

Visits outside the protocol defined time-windows (i.e. recorded as protocol deviations) will be 
included in listings but omitted from figures (mean figures only for PK concentrations), 
summaries, and statistical analyses (excluding statistical analyses of PK parameters).
Unscheduled Visits

Unscheduled visits will not be included in summary tables except for determining the worst-case 
values.

Unscheduled visits will not be included in figures.

All unscheduled visits will be included in listings.
Descriptive Summary Statistics
Continuous Data
Refer to IDSL Statistical Principle 6.06.1
Categorical Data
N, n, frequency, %
Graphical Displays

Refer to IDSL Statistical Principals 7.01 to 7.13.
11.3.3.
Reporting Standards for Pharmacokinetics
Pharmacokinetic Concentration Data
Descriptive Summary 
Statistics, Graphical 
Displays and Listings
Refer to IDSL PK Display Standards.
Refer to IDSL Statistical Principle 6.06.1.
For continuous data:

NQs at the beginning of a participant profile (i.e. before the first incidence of a 
measurable concentration) are deemed to be zero as it is assumed that in this 
circumstance no drug is yet measurable in the blood.

For NQs at the end of the participant profile (i.e. after the last incidence of a 
measurable concentration);

for individual plots and pharmacokinetic analyses these are dropped (set 
to missing) as they do not provide any useful information (and can 
erroneously indicate that absolutely no drug is present)

for summary statistics, these are set to 0 (to avoid skewing of the 
summary statistics)

Individual NQs which fall between two measurable concentrations are set to 
missing (individual values of this nature are assumed to be an anomaly)
If two or more NQ values occur in succession between measurable concentrations, 
the profile will be deemed to have terminated at the last measurable concentration 
prior to these NQs. For the purpose of individual participant plots, these NQs will be 
set to 0, and the subsequent measurable concentrations will be retained. For the 
derivation of pharmacokinetic parameters, these NQs and any subsequent 
measurable concentrations will be omitted (set to missing).
Note: Concentration values will be imputed as per GUI_51487 for descriptive 
summary statistics/analysis and summarized graphical displays only.
Pharmacokinetic Parameter Data
Descriptive Summary 
Statistics, Graphical 
Displays and Listings
N, n, arithmetic mean, 90% CI of arithmetic mean, geometric mean, 95% CI of 
geometric mean, SD, SD of logged data CV (%), and between-subject geometric 
coefficient of variation (CVb (%)) will be reported.
CVb (%) = √ (exp(SD2) - 1) * 100
(SD = SD of Ln-Transformed data)


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Parameters Not 
Being Ln-
Transformed
Tmax, λz, λz lower, λz upper, and λz no. of points.
Parameters Not 
Being Summarized
λz, λz lower, λz upper, and λz no. of points.
Listings
Include the first point, last point and number of points used in the determination of 
λz and Rsq_adjusted for listings.


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11.4.
Appendix 4: Derived and Transformed Data
11.4.1.
General
Multiple Measurements at One Analysis 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.

The worst finding/interpretation associated with multiple measurements as the finding/interpretation 
for that time point.

Participants having both High and Low values for Normal Ranges at any post-baseline visit for safety 
parameters will be counted in both the High and Low categories of “Any visit post-baseline” row of 
related summary tables. This will also be applicable to relevant Potential Clinical Importance 
summary tables.
Study Day

Calculated as the number of days from Dose Date on Day 1:

Assessment Date = Missing 
  → Study Day = Missing 

Assessment Date < Dose Date on Day 1 
  → Study Day = Assessment Date –Dose Date on Day 1

Assessment Date >= Dose Date on Day 1
  → Study Day = Assessment Date – Dose Date on Day 1 + 1
Period Day

Calculated as the number of days from First Dose Date for the respective period:

Assessment Date = Missing 
  → Period Day = Missing 

Assessment Date < Dose Date on Day -3
  → Period Day = Assessment Date – Dose Date on Day -3

Dose Day on Day -3 <= Assessment Date < Dose Date on Day 1
  → Period Day = Assessment Date – Dose Date on Day -3 + 1

Dose Date on Day 1 <= Assessment Date < First Dose Date on Day 11 
  →Period Day = Assessment Date – Dose Date on Day 1 + 1

Assessment Date >= First Dose Date on Day 11 
  →Period Day = Assessment Date – First Dose Date on Day 11 + 1
11.4.2.
Study Population
Age

GSK standard IDSL algorithms will be used for calculating age where birth date will be imputed as 
follows:
o
Any participant with a missing day will have this imputed as day ‘15’.
o
Any participant with a missing day 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]


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11.4.3.
Safety
Adverse Events
AEs of Special Interest

Adverse events of special interest include all AEs classified in the cardiovascular (per MedDRA) 
system organ class, seizure, and syncope.
12-Lead Electrocardiograms
QTcF Interval

QTcF interval will be collected on the eCRF. If QTcF interval is missing on the eCRF, the value 
in msec will be calculated using QT interval (msec) and heart rate (bpm as
QTCF =
	
60/ 

QTcB Interval

QTcB interval in msec will be calculated using QT interval (msec) and heart rate (bpm) as
	
 =
	
60/ 


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11.5.
Appendix 5: Reporting Standards for Missing Data
11.5.1.
Premature Withdrawals
Element
Reporting Detail
General

Participant study completion (i.e. as specified in the protocol) was defined as the 
participant had completed all phases of the study including the final date on which data 
were or are expected to be collected. 

Withdrawn participants were not replaced in the study.

All available data from participants who were withdrawn from the study will be listed 
and all available planned data will be included in summary tables and figures, unless 
otherwise specified.
11.5.2.
Handling of Missing Data
Element
Reporting Detail
General

Missing data occurs when any requested data is not provided, leading to blank fields 
on the collection instrument:
o
These data will be indicated by the use of a “blank” in participant listing displays. 
Unless all data for a specific visit are missing in which case the data is excluded 
from the table. 
o
Answers such as “Not applicable” and “Not evaluable” are not considered to be 
missing data and should be displayed as such.
Outliers

Any participants excluded from the summaries and/or statistical analyses will be 
documented along with the reason for exclusion in the clinical study report.
11.5.2.1.
Handling of Missing and Partial Dates
Element
Reporting Detail
General

Partial dates will be displayed as captured in participant 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 2: Study Phases 
and Treatment Emergent Adverse Events.
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.

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.
Concomitant 
Medications

Partial dates for any concomitant medications recorded in the eCRF will be imputed 
using the following convention:
o
If the partial date is a start date, a '01' will be used for the day and 'Jan' will be 
used for the month
o
If the partial date is a stop date, a '28/29/30/31' will be used for the day (dependent 
on the month and year) and 'Dec' will be used for the month.

The recorded partial date will be displayed in listings.


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11.6.
Appendix 6: Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric 
Adverse Events
11.6.1.
Laboratory Values
Laboratory abnormalities will be graded according to the DAIDS grading table Version 2.1, July 2017. Laboratory results are converted to 
use SI units; only the numeric part of the criteria will be used. If for a laboratory parameter there are multiple grades sharing the same 
criteria, the maximum grade will be used.
HEMATOLOGY
Grade 1
Grade 2
Grade 3
Grade 4
Absolute Lymphocyte Count, Low 
(cell/mm3; cells/L)
> 5 years of age (not HIV infected)
600 to < 650
0.600 × 109 to < 0.650 × 
109
500 to < 600
0.500 × 109 to < 0.600 × 
109
350 to < 500
0.350 × 109 to < 0.500 × 109
< 350
< 0.350 × 109
Absolute Neutrophil Count, Low 
(cells/mm3; cells/L)
> 7 days of age
800 to 1,000
0.800 × 109 to 1.000 × 109
600 to 799
0.600 × 109 to 0.799 × 
109
400 to 599
0.400 × 109 to 0.599 × 109
< 400
< 0.400 × 109
Hemoglobin, Low (g/dL; mmol/L)
≥ 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
Hemoglobin, Low (g/dL; mmol/L)
≥ 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
Platelets, Decreased (cells/mm3; cells/L)
100,000 to < 125,000
100.000 × 109 to < 125.000 
× 109
50,000 to < 100,000
50.000 × 109 to < 
100.000 × 109
25,000 to < 50,000
25.000 × 109 to < 50.000 × 
109
< 25,000
< 25.000 × 109
White Blood Cell, Decreased (cells/mm3; 
cells/L)
> 7 days of age
2,000 to 2,499
2.000 × 109 to 2.499 × 109
1,500 to 1,999
1.500 × 109 to 1.999 × 
109
1,000 to 1,499
1.000 × 109 to 1.499 × 109
< 1,000
< 1.000 × 109


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Clinical Chemistry
Grade 1
Grade 2
Grade 3
Grade 4
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 × ULN
2.5 to < 5.0 × ULN
5.0 to < 10.0 × ULN
≥10.0 × ULN
Alanine Aminotransferase, High
1.25 to < 2.5 × ULN
2.5 to < 5.0 × ULN
5.0 to < 10.0 × ULN
≥ 10.0 ULN
Amylase (Total), High
1.1 to < 1.5 × ULN
1.5 to < 3.0 × ULN
3.0 to < 5.0 × ULN
≥ 5.0 × ULN
Aspartate Aminotransferase, High
1.25 to < 2.5 × ULN
2.5 to < 5.0 × ULN
5.0 to < 10.0 × ULN
≥ 10.0 × 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 < 110.
< 8.0
< 8.0
Direct Bilirubin, High
> 28 days of age
NA
NA
> ULN with other signs and 
symptoms of hepatotoxicity
> ULN with life-threatening consequences 
(e.g., signs and symptoms of liver failure)
Total Bilirubin, High
> 28 days of age
1.1 to < 1.6 × ULN
1.6 to < 2.6 × ULN
2.6 to < 5.0 × ULN
≥ 5.0 × ULN
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
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
Creatine Kinase, High
3 to < 6 × ULN
6 to < 10 × ULN
10 to < 20 × ULN
≥ 20 × ULN
Creatinine, High
Choose the method that selects for the 
higher grade
1.1 to 1.3 × ULN
> 1.3 to 1.8 × ULN OR 
Increase to 1.3 to < 1.5 
× participant’s baseline
> 1.8 to < 3.5 ULN OR 
Increase to 1.5 to < 2.0 × 
participant’s baseline
≥ 3.5 × ULN OR Increase of ≥ 2.0 × 
participant’s baseline
Glucose Fasting, High (mg/dL; mmol/L)
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
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
Lipase, High
1.1 to < 1.5 × ULN
1.5 to < 3.0 × ULN
3.0 to < 5.0 × ULN
≥ 5.0 × ULN
Cholesterol, Fasting, High (mg/dL; 
mmol/L)
≥ 18 years of age
200 to < 240
5.18 to < 6.19
240 to < 300
6.19 to < 7.77
≥ 300
≥ 7.77
NA
Triglycerides, Fasting, High (mg/dL; 
mmol/L)
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
Phosphate, Low (mg/dL; mmol/L)
> 14 years of age
2.0 to < LLN
0.65 to < LLN
1.4 to < 2.0
0.45 to < 0.65
1.0 to < 1.4
0.32 to < 0.45
< 1.0
< 0.32


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Clinical Chemistry
Grade 1
Grade 2
Grade 3
Grade 4
Potassium, High (mEq/L; mmol/L)
5.6 to < 6.0
5.6 to < 6.0
6.0 to < 6.5
6.0 to < 6.5
6.5 to < 7.0
6.5 to < 7.0
≥ 7.0
≥ 7.0
Potassium, Low (mEq/L; mmol/L)
3.0 to < 3.4
3.0 to < 3.4
2.5 to < 3.0
2.5 to < 3.0
2.0 to < 2.5
2.0 to < 2.5
< 2.0
< 2.0
Sodium, High (mEq/L; mmol/L)
146 to < 150
146 to < 150
150 to < 154
150 to < 154
154 to < 160
154 to < 160
≥ 160
≥ 160
Sodium, Low (mEq/L; mmol/L)
130 to < 135
130 to < 135
125 to < 130
125 to < 130
121 to < 125
121 to < 125
≤ 120
≤ 120
Uric Acid, High (mEq/L; 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
NA=not applicable; LLN = lower limit of normal; ULN=upper limit of normal.
Urinalysis
Grade 1
Grade 2
Grade 3
Grade 4
Glucose/Glycosuria (random collection 
tested by dipstick)
Trace to 1+ or ≤ 250 mg
2+ or > 250 to ≤ 500 mg
> 2+ or > 500 mg
NA
Protein/Proteinuria (random collection 
tested by dipstick)
1+
2+
3+ or higher
NA
Red Blood Cells (RBCs)/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
NA=not applicable


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11.7.
Appendix 7: Values of Potential Clinical Importance
11.7.1.
ECG
ECG Parameter
Units
Potential Clinically Important Range
Lower
Upper
Absolute
Absolute QTc Interval
msec
<320
>450
Absolute PR Interval
msec
< 120
> 200
Absolute QRS Interval
msec
< 60
> 120
Change from Baseline
Increase from Baseline QTc
msec
> 60
11.7.2.
Vital Signs
Vital Sign Parameter
(Absolute)
Units
Potential Clinically Important Range
Lower
Upper
Systolic Blood Pressure
mmHg
< 85
> 140
Diastolic Blood Pressure
mmHg
< 45
> 90
Heart Rate
bpm
< 40
> 100


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11.8.
Appendix 8: Abbreviations & Trade Marks
11.8.1.
Abbreviations
Abbreviation
Description
ADaM
Analysis Data Model
AE
Adverse Event
ALT
Alanine Aminotransferase
AUC
Area under the Plasma Concentration-Time Curve
AUC(0-)
AUC from Time 0 to the End of the Dosing Interval at Steady State
CDISC
Clinical Data Interchange Standards Consortium
CI
Confidence Interval
Cmax
Maximum Observed Concentration
C-SSRS
Columbia Suicide Severity Rating Scale
C
Plasma Concentration at the End of the Dosing Interval
CVb
Coefficient of Variation (Between)
DBF
Database Freeze
DBR
Database Release
DP
Decimal Places
ECG
Electrocardiogram
eCRF
Electronic Case Record Form
EE
Ethinyl Estradiol
FSH
Follicle-Stimulating Hormone
GSK
GlaxoSmithKline
HIV
human immunodeficiency virus
ICH
International Conference on Harmonization
IDSL
Integrated Data Standards Library
LH
Luteinizing Hormone
LLN
Lower Limit of Normal
LNG
Levonorgestrel
PD
Pharmacodynamic
PK
Pharmacokinetic
QD
Once Daily
RAP
Reporting & Analysis Plan
SAC
Statistical Analysis Complete
SAE
Serious Adverse Event
SD
Standard Deviation
SDTM
Study Data Tabulation Model
Tmax
Time of Maximum Observed Concentration
ULN
Upper Limit of Normal


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11.8.2.
Trademarks
Trademarks of the ViiV Group of 
Companies
Trademarks not owned by the ViiV
Group of Companies
NONE
SAS 
WinNonlin


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11.9.
Appendix 9: List of Data Displays
11.9.1.
Data Display Numbering
The following numbering will be applied for RAP generated displays:
Section
Tables
Figures
Study Population
1.1 to 1.9
Safety
2.1 to 2.27
2.1 to 2.6
Pharmacokinetic
3.1 to 3.14
3.1 to 3.21
Pharmacodynamic
4.1 to 4.2
4.1 to 4.3
Section
Listings
ICH Listings
1 to 32
Other Listings
33 to 40
11.9.2.
Mock Example Shell Referencing
Non-IDSL specifications will be referenced as indicated and if required example 
mock-up displays provided in the Table/Listing/Figure Shells.
Section
Figure
Table
Listing
Study Population
POP_Fn
POP_Tn
POP_Ln
Safety
SAFE_Fn
SAFE_Tn
SAFE_Ln
Pharmacokinetic
PK_Fn
PK_Tn
PK_Ln
Pharmacodynamic
PD_Fn
PD_Tn
PD_Ln
NOTES: 

Non-Standard displays are indicated in the ‘IDSL / Example Shell’ or ‘Programming Notes’ column as ‘[Non-
Standard] + Reference.’
11.9.3.
Deliverables
Delivery 
Description
SAC
Final Statistical Analysis Complete


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11.9.4.
Study Population Tables
Study Population Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Subject Disposition
1.1.
Safety
NS1
Summary of Number of Subjects Enrolled by Country and Site 
ID
SAC
1.2.
Safety
ES1
Summary of Subject Disposition for the Subject Conclusion 
Record
SAC
1.3.
Safety
SD1
Summary of Treatment Status and Reasons for Discontinuation 
of Study Treatment
SAC
1.4.
Screened
SD1
Summary of Screening Status and Reasons for Screen Failures
SAC
Protocol Deviation
1.5.
Safety
DV1
Summary of Important Protocol Deviations
SAC
Demographic and Baseline Characteristics
1.6.
Safety
DM1
Summary of Demographic Characteristics
SAC
1.7.
Safety
DM5
Summary of Race and Racial Combinations
SAC
1.8.
Safety
DM11
Summary of Age Ranges
SAC
Exposure
1.9.
Safety
EX1
Summary of Exposure to Study Treatment
SAC


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11.9.5.
Safety Tables
Safety: Tables
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Adverse Events (AEs)
2.1.
Safety
AE1CP
Summary of Adverse Events by System Organ Class and 
Preferred Term
SAC
2.2.
Safety
AE1CP
Summary of Drug-Related Adverse Events by System Organ 
Class and Preferred Term
SAC
2.3.
Safety
AE3
Summary of Common (>=5%) Adverse Events by Overall 
Frequency
SAC
2.4.
Safety
AE15
Summary of Common (>=5%) Non-serious Adverse Events by 
System Organ Class and Preferred Term
(Number of Subjects and Occurrences)
SAC
2.5.
Safety
AE16
Summary of Serious Adverse Events by System Organ Class 
and Preferred Term
(Number of Subjects and Occurrences)
SAC
2.6.
Safety
AE5A
Summary of Adverse Events by System Organ Class and 
Preferred Term and Maximum Intensity
SAC
2.20.
Safety
AE1CP
Summary of Adverse Events of Special Interest
SAC
Laboratory: Chemistry 
2.7.
Safety
LB1
Summary of Clinical Chemistry Changes from Baseline
SAC
2.21.
Safety
LB1
Summary of Clinical Chemistry Values
SAC
2.8.
Safety
LB16
Summary of Clinical Chemistry Results by Maximum Grade 
Increase Post-Baseline Relative to Baseline
SAC
Laboratory: Hematology
2.9.
Safety
LB1
Summary of Hematology Changes from Baseline
SAC


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Safety: Tables
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.22.
Safety
LB1
Summary of Hematology Values
SAC
2.10.
Safety
LB16
Summary of Hematology Results by Maximum Grade Increase 
Post-Baseline Relative to Baseline
SAC
Laboratory: Urinalysis
2.11.
Safety
UR3
Summary of Urinalysis Dipstick Results
SAC
2.12.
Safety
LB1
Summary of Urine Concentration Changes from Baseline
SAC
2.23.
Safety
LB1
Summary of Urine Concentration Values
SAC
2.13.
Safety
LB16
Summary of Urinalysis by Maximum Grade Increase Post-
Baseline Relative to Baseline
SAC
ECG
2.14.
Safety
SAFE_T1
Summary of ECG Findings 
SAC
2.15.
Safety
EG2
Summary of ECG Changes from Baseline
SAC
2.24
Safety
EG2
Summary of ECG Values
SAC
2.16.
Safety
EG10
Summary of Maximum QTc Values Post-Baseline Relative to 
Baseline by Category
SAC
2.17.
Safety
EG11
Summary of Maximum Increase in QTc Values Post-Baseline 
Relative to Baseline by Category
SAC
Vital Signs
2.18.
Safety
VS1
Summary of Vital Sign Changes from Baseline
SAC
2.25.
Safety
VS1
Summary of Vital Sign Values
SAC


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Safety: Tables
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
C-SSRS
2.19.
Safety
CSSRS4
Listing of C-SSRS Suicidal Ideation and Behavior Data
Only include participants who have 
suicidal ideation or behavior
SAC
Liver Event
2.26.
Safety
LIVER1
Summary of Liver Monitoring/Stopping Event Reporting
SAC
2.27.
Safety
LIVER10
Summary of Hepatobiliary Laboratory Abnormalities
SAC


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11.9.6.
Safety Figures
Safety: Figures
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
ECG
2.1.
Safety
EG9
Mean (95% CI) Change from Baseline in QTcF Interval by 
Timepoint and Treatment
SAC
Laboratory
2.2.
Safety
LB11
Alanine Aminotransferase by Time
SAC
2.3.
Safety
LB11
Aspartate Aminotransferase by Time
SAC
2.4.
Safety
LB11
Alkaline Phosphatase by Time
SAC
2.5.
Safety
LB11
Total Bilirubin by Time
SAC
2.6.
Safety
LB11
Gamma-Glutamyl Transferase by Time
SAC


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11.9.7.
Pharmacokinetic Tables


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47
Pharmacokinetic: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
PK Concentration Data
3.1.
PK 
Concentration
PKCT1
Summary of Ethinyl Estradiol (EE) Plasma Pharmacokinetic 
Concentration-Time Data (units) by Treatment
SAC
3.2.
PK 
Concentration
PKCT1
Summary of Levonorgestrel (LNG) Plasma Pharmacokinetic 
Concentration-Time Data (units) by Treatment
SAC
3.3.
PK 
Concentration
PKCT1
Summary of GSK3640254 Plasma Pharmacokinetic 
Concentration-Time Data (units) by Treatment
SAC
3.4.
PK 
Concentration
PKCT1
Summary of Predose (trough) Ethinyl Estradiol (EE) Plasma 
Concentration Data (units) by Treatment
SAC
3.5.
PK 
Concentration
PKCT1
Summary of Predose (trough) Levonorgestrel (LNG) Plasma 
Concentration Data (units) by Treatment
SAC
3.6.
PK 
Concentration
PKCT1
Summary of Predose (trough) GSK3640254 Plasma 
Concentration Data (units) by Treatment
SAC
PK Derived Parameters
3.7.
PK 
Parameter
PKPT4
Summary Statistics of Derived Ethinyl Estradiol (EE) 
Plasma Pharmacokinetic Parameters (Non-Transformed) 
Based on Actual Time by Treatment
Parameters with units 
SAC
3.8.
PK 
Parameter
PKPT4
Summary Statistics of Derived Ethinyl Estradiol (EE) 
Plasma Pharmacokinetic Parameters (Ln-Transformed) 
Based on Actual Time by Treatment
Parameters with units 
SAC
3.9.
PK 
Parameter
PKPT4
Summary Statistics of Derived Levonorgestrel (LNG) 
Plasma Pharmacokinetic Parameters (Non-Transformed) 
Based on Actual Time by Treatment
Parameters with units 
SAC
3.10.
PK 
Parameter
PKPT4
Summary Statistics of Derived Levonorgestrel (LNG) 
Plasma Pharmacokinetic Parameters (Ln-Transformed) 
Based on Actual Time by Treatment
Parameters with units 
SAC


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Pharmacokinetic: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
3.11.
PK 
Parameter
PKPT4
Summary Statistics of Derived GSK3640254 Plasma 
Pharmacokinetic Parameters (Non-Transformed) Based 
on Actual Time by Treatment
Parameters with units 
SAC
3.12.
PK 
Parameter
PKPT4
Summary Statistics of Derived GSK3640254 Plasma 
Pharmacokinetic Parameters (Ln-Transformed) Based on 
Actual Time by Treatment
Parameters with units
SAC
PK Analysis Tables
3.13.
PK 
Parameter
PKPT3
Statistical Analysis of Ethinyl Estradiol (EE) Plasma 
Pharmacokinetic Parameters: Analysis of Variance (ANOVA)
AUC(0-τ), Cτ, and Cmax
SAC
3.14.
PK 
Parameter
PKPT3
Statistical Analysis of Levonorgestrel (LNG) Plasma 
Pharmacokinetic Parameters: Analysis of Variance (ANOVA)
AUC(0-τ), Cτ, and Cmax
SAC


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11.9.8.
Pharmacokinetic Figures


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50
Pharmacokinetic: Figures
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
Individual Concentration Plots
3.1.
PK 
Concentration
PKCF1P
Individual Ethinyl Estradiol (EE) Plasma Concentration-Time 
Plots by Participant (Linear and Semi-Logarithmic)
Paginate by Participant
Dashed line represents the LLQ
Treatments Overlaid
SAC
3.2.
PK 
Concentration
PKCF1P
Individual Levonorgestrel (LNG) Plasma Concentration-Time 
Plots by Participant (Linear and Semi-Logarithmic)
Paginate by Participant
Dashed line represents the LLQ
Treatments Overlaid
SAC
3.3.
PK 
Concentration
PKCF1P
Individual GSK3640254 Plasma Concentration-Time Plots by 
Participant (Linear and Semi-Logarithmic)
Paginate by Participant
Dashed line represents the LLQ
SAC
3.4.
PK 
Concentration
PKCF1P
Individual Ethinyl Estradiol (EE) Plasma Concentration-Time 
Plots by Treatment (Linear and Semi-Logarithmic)
Paginate by Treatment
Dashed line represents the LLQ
Individual Overlaid
SAC
3.5.
PK 
Concentration
PKCF1P
Individual Levonorgestrel (LNG) Plasma Concentration-Time 
Plots by Treatment (Linear and Semi-Logarithmic)
Paginate by Treatment
Dashed line represents the LLQ
Individual Overlaid
SAC
3.6.
PK 
Concentration
PKCF1P
Individual GSK3640254 Plasma Concentration-Time Plots by 
Treatment (Linear and Semi-Logarithmic)
Dashed line represents the LLQ
Individual Overlaid
SAC
Mean / Median Concentration Plots
3.7.
PK 
Concentration
PKCF2
Mean (± Standard Deviation) Ethinyl Estradiol (EE) Plasma 
Concentration-Time Plots by Treatment (Linear and Semi-
Logarithmic)
Treatments Overlaid
SAC
3.8.
PK 
Concentration
PKCF2
Mean (± Standard Deviation) Levonorgestrel (LNG) Plasma 
Concentration-Time Plots by Treatment (Linear and Semi-
Logarithmic)
Treatments Overlaid
SAC


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Pharmacokinetic: Figures
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
3.9.
PK 
Concentration
PKCF2
Mean (± Standard Deviation) GSK3640254 Plasma 
Concentration-Time Plots by Treatment (Linear and Semi-
Logarithmic)
SAC
3.10.
PK 
Concentration
PKCF3
Median (Range) Ethinyl Estradiol (EE) Plasma Concentration-
Time Plots by Treatment (Linear and Semi-Logarithmic)
Treatments Overlaid
SAC
3.11.
PK 
Concentration
PKCF3
Median (Range) Levonorgestrel (LNG) Plasma Concentration-
Time Plots by Treatment (Linear and Semi-Logarithmic)
Treatments Overlaid
SAC
3.12.
PK 
Concentration
PKCF3
Median (Range) GSK3640254 Plasma Concentration-Time 
Plots by Treatment (Linear and Semi-Logarithmic)
SAC
3.13.
PK 
Concentration
PKCF2
Mean (± Standard Deviation) Predose (Trough) Ethinyl 
Estradiol (EE) Plasma Concentration Plots by Treatment 
(Linear and Semi-Logarithmic)
Paginate by Treatment
SAC
3.14.
PK 
Concentration
PKCF2
Mean (± Standard Deviation) Predose (Trough) Levonorgestrel 
(LNG) Plasma Concentration Plots by Treatment (Linear and 
Semi-Logarithmic)
Paginate by Treatment
SAC
3.15.
PK 
Concentration
PKCF2
Mean (± Standard Deviation) Predose (Trough) GSK3640254 
Plasma Concentration Plots by Treatment (Linear and Semi-
Logarithmic)
SAC
3.16.
PK Parameter
PK_F1
Boxplot of Ethinyl Estradiol (EE) Pharmacokinetic Parameters 
Categorized by Alanine Aminotransferase
SAC
3.17.
PK Parameter
PK_F1
Boxplot of Levonogrestrel (LNG) Pharmacokinetic Parameters 
Categorized by Alanine Aminotransferase
SAC
3.18.
PK Parameter
PK_F1
Boxplot of GSK3640254 Pharmacokinetic Parameters 
Categorized by Alanine Aminotransferase
SAC
3.19.
PK Parameter 
PK_F2
Boxplot of Ethinyl Estradiol (EE) Pharmacokinetic Parameters 
Categorized by Progesterone
SAC
3.20.
PK Parameter
PK_F2
Boxplot of Levonogrestrel (LNG) Pharmacokinetic Parameters 
Categorized by Progesterone
SAC


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Pharmacokinetic: Figures
No.
Population
IDSL / 
Example 
Shell
Title
Programming Notes
Deliverable 
[Priority]
3.21.
PK Parameter
PK_F3
Boxplot of GSK3640254 Pharmacokinetic Parameters 
Categorized by Progesterone
SAC


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11.9.9.
Pharmacodynamic Table
Pharmacodynamic: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
4.1
PD 
Concentration
PD_T1
Summary of Serum Luteinizing Hormone, Follicle-Stimulating 
Hormone, and Progesterone Concentration
SAC
4.2
PD 
Concentration
PD_T1
Summary of Maximum Serum Luteinizing Hormone and 
Follicle-Stimulating Hormone Concentration
SAC
11.9.10.
Pharmacodynamic Figure
Pharmacodynamic: Figures
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
4.1
PD 
Concentration
PD_F1
Individual Serum Luteinizing Hormone, Follicle-Stimulating 
Hormone, and Progesterone Concentration by Participant
SAC
4.2
PD 
Concentration
PD_F2
Mean (± Standard Deviation) Serum Luteinizing Hormone, 
Follicle-Stimulating Hormone, and Progesterone Concentration 
by Visit and Treatment
SAC
4.3
PD 
Concentration
PD_F3
Boxplot of Serum Luteinizing Hormone, Follicle-Stimulating 
Hormone, and Progesterone Concentration
SAC


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11.9.11.
ICH Listings
ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable
[Priority]
Subject Disposition
1.
Safety
ES3
Listing of Reasons for Study Withdrawal
SAC
2.
Safety
SD2
Listing of Reasons for Study Treatment Discontinuation
SAC
3.
Screened
ES7
Listing of Reasons for Screen Failure
SAC
Protocol Deviations
4.
Safety
DV2
Listing of Important Protocol Deviations
SAC
5.
Safety
IE3
Listing of Subjects with Inclusion/Exclusion Criteria Deviations
SAC
Populations Analyzed
6.
Safety
SP3A
Listing of Subjects Excluded from Any Population
SAC
Demographic and Baseline Characteristics
7.
Safety
DM2
Listing of Demographic Characteristics
SAC
8.
Safety
DM9
Listing of Race
SAC
Prior and Concomitant Medications
9.
Safety
CM5
Listing of Concomitant Medications 
Based on GSK Drug Dictionary
SAC
Exposure and Treatment Compliance
10.
Safety
EX4
Listing of Exposure Data
SAC
11.
Safety
POP_L1
Listing of Meal Data
SAC
Adverse Events
12.
Safety
AE2
Listing of Relationship Between System Organ Class and 
Verbatim Text
SAC
13.
Safety
AE7
Listing of Subject Numbers for Individual Adverse Events
SAC


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ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable
[Priority]
14.
Safety
AE9CP
Listing of All Adverse Events
SAC
42.
Safety
AE9CP
Listing of Adverse Events of Special Interest
SAC
Serious and Other Significant Adverse Events
15.
Safety
AE9CP
Listing of Study Drug Related Adverse Events
SAC
16.
Safety
AE9CP
Listing of Serious Adverse Events (Fatal & Non-Fatal)
SAC
17.
Safety
AE14
Listing of Reasons for Considering as a Serious Adverse Event
SAC
18.
Safety
AE9CP
Listing of Adverse Events Leading to Withdrawal from Study
SAC
19.
Safety
PREG1b
Listing of Subjects Who Became Pregnant During the Study
SAC
Hepatobiliary (Liver)
20.
Safety
MH2
Listing of Medical Conditions for Subjects with Liver Stopping 
Events
SAC
21.
Safety
SU2
Listing of Substance Use for Subjects with Liver Stopping 
Events
SAC
43
Safety
VS5
Listing of Vital Results for Subjects with Liver Stopping Events
SAC
44
Safety
LIVER5
Listing of Subjects with Liver Monitoring/Stopping Event 
Reporting
SAC
All Laboratory
22.
Safety
LB5A
Listing of Clinical Chemistry with any Toxicities 
SAC
23.
Safety
LB5A
Listing of All Clinical Chemistry Data for Subjects with any
Toxicities 
SAC
24.
Safety
LB5A
Listing of Hematology with any Toxicities 
SAC
25.
Safety
LB5A
Listing of All Hematology Data for Subjects with any Toxicities 
SAC
26.
Safety
LB5A
Listing of Urinalysis with any Toxicities 
SAC


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ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable
[Priority]
27.
Safety
LB5A
Listing of All Urinalysis Data for Subjects with any Toxicities 
SAC
28.
Safety
LB5A
Listing of Pregnancy Test Results
SAC
ECG
29.
Safety
EG6
Listing of All ECG Findings
SAC
30.
Safety
EG6
Listing of All Abnormal ECG Findings
SAC
31.
Safety
EG4
Listing of All ECG Values
SAC
Vital Signs
32.
Safety
VS5
Listing of All Vital Signs of Potential Clinical Importance
SAC
33.
Safety
VS5
Listing of All Vital Signs for Subjects with any Value of Potential 
Clinical Importance
SAC


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11.9.12.
Non-ICH Listings
Non-ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Pharmacokinetics
34.
PK 
Concentration
PKCL1P
Listing of Ethinyl Estradiol (EE) Plasma Concentration-Time 
Data by Treatment
SAC
35.
PK 
Concentration
PKCL1P
Listing of Levonorgestrel (LNG) Plasma Concentration-Time 
Data by Treatment
SAC
36.
PK 
Concentration
PKCL1P
Listing of GSK3640254 Plasma Concentration-Time Data by 
Treatment
SAC
37.
PK 
Parameter
PKPL1P
Listing of Ethinyl Estradiol (EE) Plasma Pharmacokinetic 
Parameters Based on Actual Time by Treatment
SAC
38.
PK 
Parameter
PKPL1P
Listing of Levonorgestrel (LNG) Plasma Pharmacokinetic 
Parameters Based on Actual Time by Treatment
SAC
39.
PK 
Parameter
PKPL1P
Listing of GSK3640254 Plasma Pharmacokinetic Parameters 
Based on Actual Time by Treatment
SAC
Pharmacodynamics
40.
PD 
Concentration
PD_L1
Listing of Serum Luteinizing Hormone, Follicle-Stimulating 
Hormone, and Progesterone Concentration
SAC
41.
PD 
Concentration
PD_L1
Listing of Maximum Serum Luteinizing Hormone and Follicle-
Stimulating Hormone Concentration by Treatment
SAC