Clinical trial NCT06354257
Conditions: Tuberculosis
Keywords: Oral contraceptive GSK3036656 Fixed sequence Ethinyl Estradiol Levonorgestrel Drug interaction
Sponsor: GlaxoSmithKline
Start date: 2024-04-05; Completion date: 2024-07-01
Enrollment: 20 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
The purpose of this study is to provide data showing if there are any effects of GSK3036656 on a combined oral contraceptive containing Ethinyl Estradiol (EE) and Levonorgestrel (LNG), which will help inform future studies on suitable contraceptive measures to be used.

Detailed description:

Arms: arm 1: Participants received a dose of Microgynon \[0.03 mg Ethinyl Estradiol (EE)/0.15 mg Levonorgestrel (LNG)\] on Day 1 of Treatment Period 1. In Treatment Period 2, they received GSK3036656 40 mg on Day 4 followed by GSK3036656 20 mg once daily from Day 5 to Day 14. In Treatment Period 3, participants received Microgynon (EE/LNG) along with GSK3036656 20 mg on Day 15, followed by GSK3036656 20 mg once daily from Day 16 to Day 17.
Interventions: intervention 1: Microgynon intervention 2: GSK3036656
Intervention descriptions: intervention 1: Participants received 1 dose of Microgynon (0.03 mg EE/0.15 mg LNG) on Day 1 of Treatment Period 1 and 1 dose co-administered with GSK3036656 20 mg on Day 15 of Treatment Period 3. intervention 2: Participants received 1 loading dose of 40 mg on Day 4 and a dose of 20 mg on Days 5 to 14 once daily in Treatment Period 2. In Treatment Period 3, participants received one 20 mg dose along with Microgynon (0.03 mg EE/0.15 mg LNG) on Day 15 after which a 20 mg dose on Days 17 and 18 once daily.

Protocol documents:
Prot_000.pdf: 
CONFIDENTIAL 
220104 
Protocol Amendment 1 Final 
23 Apr 2024 
1 
CLINICAL STUDY PROTOCOL 
Primary Study 
Intervention(s) 
GSK3036656 
Other Study Intervention(s) 
Microgynon 
Study Identifier 
220104 
EU CT Number  
2023-507839-38-00 
Approval Date 
23 Apr 2024  
Title 
A Phase 1, open-label, fixed sequence, 1-way drug-
drug interaction study to investigate the 
pharmacokinetics, of GSK3036656 and an oral 
contraceptive containing ethinyl estradiol and 
levonorgestrel when the oral contraceptive is 
administered alone and in combination with 
GSK3036656 in healthy female participants of non-
childbearing potential aged 18-65 years of age. 
Compound Number/Name  
GSK3036656 
Brief Title 
A study to investigate the pharmacokinetics of a 
combined oral contraceptive when given alone and 
in combination with GSK3036656 in female 
participants of non-childbearing potential aged 18 to 
65 years of age.  
Sponsor 
GSK Research & Development Limited 
980 Great West Road, Brentford, Middlesex, TW8 
9GS, UK 
Sponsor signatory 
Amanda Oliver 
Head of Clinical Development, Global Health 
Medicines R&D 
Medical monitor name and contact can be found in local study contact 
information document 
©2024 GSK group of companies or its licensor. 


CONFIDENTIAL 
220104 
Protocol Amendment 1 Final 
23 Apr 2024 
2 
Protocol Investigator Agreement 
I agree: 
• 
To conduct the study in compliance with this protocol, any future protocol 
amendments, with the terms of the clinical trial agreement and with any other 
study conduct procedures and/or study conduct documents provided by GSK. 
• 
To assume responsibility for the proper conduct of the study at this site. 
• 
That I am aware of and will comply with GCP and all applicable regulatory 
requirements.  
• 
That I will comply with the terms of the site agreement. 
• 
To comply with local bio-safety legislation. 
• 
To ensure that all persons assisting me with the study are adequately informed 
about the GSK study intervention and other study-related duties and functions 
as described in the protocol. 
• 
To supervise any individual or party to whom I have delegated study-related 
duties and functions conducted at the study site. 
• 
To ensure that any individual or party to whom I have delegated study-related 
duties and functions conducted at the study site are qualified to perform those 
study-related duties and functions. 
• 
To acquire the reference ranges for laboratory tests performed locally and, if 
required by local regulations, obtain the laboratory’s current certification or 
Quality Assurance procedure manual. 
• 
To ensure that no clinical samples (including serum samples) are retained on-
site or elsewhere without the approval of GSK and the express physical 
informed consent of the participant and/or the participant’s LAR.  
• 
To perform no biological assays on the clinical samples other than those 
described in the protocol or its amendment(s).  
• 
To co-operate with representative(s) of GSK in the monitoring and data 
management processes of the study with respect to data entry and resolution of 
queries about the data. 
• 
To have control of all essential documents and records generated under my 
responsibility before, during, and after the study. 
• 
That I have been informed that certain regulatory authorities require the 
sponsor to obtain and supply, as necessary, details about the investigator(s)’ 
ownership interest in the sponsor or the study intervention(s), and more 
generally about their financial ties with the sponsor. GSK will use and disclose 
the information solely for the purpose of complying with regulatory 
requirements. 


CONFIDENTIAL 
220104 
Protocol Amendment 1 Final 
23 Apr 2024 
3 
Hence, I: 
• 
Agree to supply GSK with any necessary information regarding ownership 
interest and financial ties (including those of my spouse and dependent 
children). 
• 
Agree to promptly update this information if any relevant changes occur during 
the study and for 1 year following completion of the study. 
• 
Agree that GSK may disclose any information about such ownership interests 
and financial ties to regulatory authorities. 
• 
Agree to provide GSK with an updated Curriculum Vitae and all other 
documents required by regulatory agencies for this study. 


CONFIDENTIAL 
220104 
Protocol Amendment 1 Final 
23 Apr 2024 
4 
Study identifier 
220104 
EU CT number 
2023-507839-38-00 
Approval date 
23 Apr 2024 
 
 
Title 
 
Investigator name 
 
 
 
Signature 
 
 
 
Date of signature 
(DD Month YYYY) 
 
 
 


CONFIDENTIAL 
220104 
Protocol Amendment 1 Final 
23 Apr 2024 
5 
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE 
DOCUMENT HISTORY 
 
Document 
Date of Issue 
Amendment 01 
23 Apr 2024 
Original Protocol 
06 November 2023 
Amendment 1  
This amendment is considered to be substantial based on the criteria set forth in Article 
10(a) of Directive 2001/20/EC of the European Parliament and the Council of the 
European Union. 
Overall Rationale for the Amendment:  
This study will only recruit women of non-childbearing potential, with the majority of 
them being postmenopausal. Following an extensive review of the database that includes 
potential participants, it has been recognized that the majority of these women may be 
taking medication for concurrent conditions that are common in postmenopausal women. 
To minimise risk to participants by asking them to stop any medication that they require 
to manage these concurrent conditions, it has been determined that the use of concomitant 
omeprazole or levothyroxine will be permitted during the study. This would not impact 
any of the pharmacokinetic endpoints in the study, providing participants have been on a 
stable dose for at least one month prior to Treatment Period 1, and the dose is maintained 
throughout the study. In addition, minor typographical errors and inconsistencies have 
been corrected. 
LIST OF MAIN CHANGES IN THE PROTOCOL AND THEIR RATIONALE: 
 
Section # and Name 
Description of Change 
Brief Rationale 
Section 1.3, Schedule of 
Assessments 
Note added to clarify that outpatient visits 
would take place on Days 8,10 and 12. 
Added for better 
understanding 
Section 1.3, Schedule of 
Assessments, Physical 
examination 
Added weight to list of assessments 
included as part of full and brief physical 
exam, for consistency with Section 8.3.1 
Added for better 
understanding 
Section 1.3, Schedule of 
Assessments, Serial PK for 
EE/LNG 
Note added to clarify that serial PK 
predose sample for EE/LNG should be 
taken within 30 minutes prior to dose 
administration. Also, for any unscheduled 
visit, a predose EE/LNG PK sample should 
only be collected during Treatment Periods 
1 or 3. 
Added for better 
understanding 
Section 1.3, Schedule of 
Assessments, trough 
GSK3036656 PK 
For any unscheduled visit, predose 
GSK3036656 PK sample should only be 
collected during Treatment Periods 2 or 3. 
Added for better 
understanding 


CONFIDENTIAL 
220104 
Protocol Amendment 1 Final 
23 Apr 2024 
6 
Section # and Name 
Description of Change 
Brief Rationale 
Section 5.1 Inclusion criteria 
#2, Type of participants and 
disease characteristics 
Clarified that participants should be 
healthy and compensated. Added a time 
period of at least 30 days prior to 
Treatment Period 1 for discontinuation of 
any HRT to allow confirmation of 
postmenopausal status before study 
enrollment. Also, clarified that, in women 
with less than 12 months of amenorrhea, 
the FSH measurement should be repeated 
and confirmed within the Screening period. 
To allow 
participants to be 
treated with 
protocol-permitted 
medications if 
required. To 
ensure any prior 
HRT use has 
washed out prior 
to baseline PK 
assessments, and 
to confirm timing 
for any repeat 
FSH 
measurement. 
Section 5.2.3, 
prior/concomitant therapy, 
exclusion criterion #1 
Clarification that levothyroxine and 
omeprazole may also be used during the 
study providing the participant has been 
on a stable dose for at least one month 
prior to the start of Treatment Period 1 and 
they maintain the same dose throughout 
the study. The dose of Microgynon should 
be administered at least one hour after the 
dose of levothyroxine or omeprazole. 
Other concomitant medications may be 
considered on a case-by-case basis by the 
investigator in consultation with the 
medical monitor. 
In WONCBP, the 
majority of this 
population are 
postmenopausal. 
These women are 
healthy but be 
compensated and 
require use of 
concomitant 
medication for 
common 
concurrent 
conditions. Use of 
levothyroxine and 
omeprazole and 
any other 
concomitant 
medications 
approved by the 
medical monitor 
will not impact the 
PK endpoints in 
this study. 
Section 5.2.5, Diagnostic 
Assessments, Exclusion 
criteria #18 
Footnote 1 expanded to confirm that a 
QTcF interval between 450 and 460msec 
can be rechecked by ECG within 30 
minutes to verify eligibility 
To provide 
clarification to the 
investigator on 
when a repeat 
ECG should be 
considered at 
screening 
Section 6.8, Prior and 
Concomitant Therapy 
Clarification that levothyroxine and 
omeprazole may also be used during the 
In WONCBP, the 
majority of this 


CONFIDENTIAL 
220104 
Protocol Amendment 1 Final 
23 Apr 2024 
7 
Section # and Name 
Description of Change 
Brief Rationale 
study providing the participant has been 
on a stable dose for at least one month 
prior to the start of Treatment Period 1 and 
they maintain the same dose throughout 
the study. The dose of Microgynon should 
be administered at least one hour after the 
dose of levothyroxine or omeprazole. 
population are 
postmenopausal. 
These women are 
healthy but be 
compensated and 
require use of 
concomitant 
medication for 
common 
concurrent 
conditions. Use of 
levothyroxine and 
omeprazole and 
any other 
concomitant 
medications 
approved by the 
medical monitor 
will not impact the 
PK endpoints in 
this study. 
Section 7.1.2, QTc stopping 
criteria 
Added reference to Section 8.3.3, 
Electrocardiograms, for clarification on the 
time period over which any repeat ECGs 
should be performed. 
Clarification for 
the investigator 
Section 7.1.3, Haematology 
stopping criteria 
Added clarification that second sample 
should be taken within 24 hours of the first 
sample 
Clarification for 
the investigator 
Section 7.2, Participant 
discontinuation/withdrawal 
from the study  
Deleted the sub-reasons of “Unsolicited 
AE” and “Solicited AE” from Table 2 
These are not 
applicable for this 
study. 
Section 10.4, Appendix 4, 
Liver safety: suggested 
actions and follow-up 
assessments 
Table title corrected to read “Liver safety: 
Required and suggested actions and 
follow-up assessments” and missing table 
footnotes have been added.  
Clarification for 
the investigator. 
Section 8.3.5, Pregnancy 
testing 
Deletion of option to only perform 
pregnancy test in females with doubt about 
reproductive status as protocol requires 
that all participants must perform a highly 
sensitive blood or urine pregnancy test 
before the administration of any dose of 
study intervention 
Correction of 
inconsistency 
between this 
section and the 
schedule of 
asssessments 
Section 6.4, Study 
intervention compliance 
Added text to state that a participant diary 
will be provided to capture dosing 
compliance. 
Additional detail 
for investigator 
Section 6.1, Table 4 
Update NIMP by AxMP 
To reflect a 
change in 


CONFIDENTIAL 
220104 
Protocol Amendment 1 Final 
23 Apr 2024 
8 
Section # and Name 
Description of Change 
Brief Rationale 
nomenclature to 
ensure 
consistency 
across all study 
documentation 


CONFIDENTIAL 
220104 
Protocol Amendment 1 Final 
23 Apr 2024 
9 
TABLE OF CONTENTS 
PAGE 
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE ..................................... 5 
List of main changes in the protocol and their rationale: ........................................... 5 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ........................................ 14 
1. 
PROTOCOL SUMMARY ........................................................................................ 22 
1.1. 
Synopsis ..................................................................................................... 22 
1.2. 
Study Schema ............................................................................................ 22 
1.3. 
Schedule of activities (SoA) ........................................................................ 23 
2. 
INTRODUCTION .................................................................................................... 29 
2.1. 
Study rationale ............................................................................................ 29 
2.2. 
Background ................................................................................................ 30 
2.3. 
Benefit/risk assessment .............................................................................. 31 
2.3.1. 
Risk assessment .......................................................................... 32 
2.3.2. 
Benefit assessment ..................................................................... 42 
2.3.3. 
Overall benefit-risk conclusion ..................................................... 42 
3. 
OBJECTIVES, ENDPOINTS AND ESTIMANDS .................................................... 42 
4. 
STUDY DESIGN .................................................................................................... 47 
4.1. 
Overall design ............................................................................................. 47 
4.2. 
Scientific rationale for study design ............................................................. 48 
4.2.1. 
Participant input into design ......................................................... 48 
4.3. 
Justification for dose ................................................................................... 48 
4.4. 
End-of-study definition ................................................................................ 49 
5. 
STUDY POPULATION ........................................................................................... 49 
5.1. 
Inclusion criteria .......................................................................................... 49 
5.2. 
Exclusion criteria ......................................................................................... 50 
5.2.1. 
Medical History ............................................................................ 50 
5.2.2. 
Laboratory Assessments ............................................................. 50 
5.2.3. 
Prior/Concomitant Therapy .......................................................... 51 
5.2.4. 
Prior/Concurrent Clinical Study Experience ................................. 51 
5.2.5. 
Diagnostic Assessments .............................................................. 52 
5.2.6. 
Other Exclusion Criteria ............................................................... 52 
5.3. 
Lifestyle considerations ............................................................................... 52 
5.3.1. 
Meals and dietary restrictions ...................................................... 52 
5.3.2. 
Caffeine, alcohol, and tobacco ..................................................... 53 
5.3.3. 
Activity ......................................................................................... 53 
5.3.4. 
Other restrictions ......................................................................... 53 
5.4. 
Screen failures ............................................................................................ 53 
5.5. 
Criteria for temporarily delaying enrollment ................................................. 53 
6. 
STUDY INTERVENTION(S) AND CONCOMITANT THERAPY .............................. 53 
6.1. 
Study intervention(s) administered .............................................................. 54 
6.2. 
Preparation, handling, storage, and accountability ...................................... 55 
6.3. 
Assignment to study intervention ................................................................ 55 
6.4. 
Study intervention compliance .................................................................... 55 


CONFIDENTIAL 
220104 
Protocol Amendment 1 Final 
23 Apr 2024 
10 
6.5. 
Dose modification ....................................................................................... 56 
6.6. 
Continued access to study intervention after the end of the study ............... 56 
6.7. 
Treatment of overdose ................................................................................ 56 
6.8. 
Prior and concomitant therapy .................................................................... 57 
7. 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ..................................................................... 57 
7.1. 
Discontinuation of study intervention ........................................................... 57 
7.1.1. 
Liver chemistry stopping criteria ................................................... 58 
7.1.2. 
QTc Stopping criteria ................................................................... 59 
7.1.3. 
Haematology Stopping Criteria .................................................... 59 
7.1.4. 
Study Intervention Restart or Rechallenge After Liver 
Stopping Criteria Are Met ............................................................. 60 
7.2. 
Participant discontinuation/withdrawal from the study ................................. 60 
7.3. 
Lost to follow-up.......................................................................................... 61 
8. 
STUDY ASSESSMENTS AND PROCEDURES ..................................................... 62 
8.1. 
Administrative and baseline procedures ..................................................... 62 
8.1.1. 
Collection of demographic data .................................................... 62 
8.1.2. 
Medical history ............................................................................. 62 
8.2. 
Efficacy assessments ................................................................................. 63 
8.3. 
Safety assessments .................................................................................... 63 
8.3.1. 
Physical examination/history directed physical 
examination ................................................................................. 63 
8.3.2. 
Vital signs .................................................................................... 63 
8.3.3. 
Electrocardiograms ...................................................................... 63 
8.3.4. 
Clinical safety laboratory tests ..................................................... 64 
8.3.5. 
Pregnancy testing ........................................................................ 64 
8.3.6. 
Echocardiogram........................................................................... 64 
8.4. 
Adverse Events (AEs) serious adverse events (SAEs), and other 
safety reporting ........................................................................................... 65 
8.4.1. 
Time period and frequency for collecting AE, SAE, and 
other safety information ............................................................... 65 
8.4.2. 
Method of detecting AEs and SAEs ............................................. 66 
8.4.3. 
Follow-up of AEs and SAEs ......................................................... 66 
8.4.4. 
Regulatory reporting requirements for SAEs ................................ 66 
8.4.5. 
Pregnancy ................................................................................... 66 
8.4.6. 
Contact information for reporting SAEs ........................................ 67 
8.4.7. 
Participant card ............................................................................ 67 
8.5. 
Pharmacokinetics ....................................................................................... 68 
8.6. 
Pharmacodynamics .................................................................................... 68 
8.7. 
Genetics ..................................................................................................... 68 
8.8. 
Biomarkers ................................................................................................. 68 
8.9. 
Immunogenicity assessments ..................................................................... 68 
9. 
STATISTICAL CONSIDERATIONS ........................................................................ 68 
9.1. 
Statistical hypothesis .................................................................................. 69 
9.1.1. 
Multiplicity Adjustment ................................................................. 69 
9.2. 
Analysis sets ............................................................................................... 70 
9.3. 
Statistical analyses ..................................................................................... 71 
9.3.1. 
General considerations/definitions ............................................... 71 
9.3.2. 
Primary endpoint(s)/estimand(s) analysis .................................... 71 


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9.3.2.1. 
Definition of endpoint: Pharmacokinetic 
Analyses ..................................................................... 71 
9.3.2.2. 
Main Analytical Approach ........................................... 71 
9.3.2.3. 
Sensitivity Analysis ..................................................... 72 
9.3.3. 
Secondary endpoint(s)/estimand(s) analyses .............................. 72 
9.3.3.1. 
Pharmacokinetics Endpoints ...................................... 72 
9.3.3.1.1. 
Main Analytical Approach ....................... 72 
9.3.4. 
Safety Endpoints/ Estimand ......................................................... 73 
9.3.4.1. 
Main Analytical Approach ........................................... 73 
9.3.4.1.1. 
Adverse Events (AEs) ............................. 73 
9.3.4.1.2. 
Electrocardiograms (ECGs) .................... 73 
9.3.4.1.3. 
Clinical Laboratory Values ...................... 73 
9.3.4.1.4. 
Vital Signs .............................................. 74 
9.4. 
Interim analyses .......................................................................................... 74 
9.5. 
Sample size determination .......................................................................... 74 
9.5.1. 
Calculation of CVw from CI: ......................................................... 75 
10. SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ............................................................................................... 76 
10.1. 
Appendix 1: Regulatory, ethical, and study oversight considerations .......... 76 
10.1.1. 
Regulatory and ethical considerations ......................................... 76 
10.1.2. 
Financial disclosure ..................................................................... 77 
10.1.3. 
Informed consent process ............................................................ 77 
10.1.4. 
Recruitment strategy .................................................................... 77 
10.1.5. 
Data protection ............................................................................ 77 
10.1.6. 
Committees structure ................................................................... 78 
10.1.7. 
Dissemination of Clinical Study Data ........................................... 78 
10.1.8. 
Data quality assurance ................................................................ 79 
10.1.9. 
Source documents ....................................................................... 80 
10.1.10. Study and site start and closure ................................................... 80 
10.1.11. Publication policy ......................................................................... 81 
10.2. 
Appendix 2: Clinical laboratory tests ........................................................... 81 
10.3. 
Appendix 3: AEs and SAEs: Definitions and procedures for 
recording, evaluating, follow-up, and reporting ............................................ 83 
10.3.1. 
Definition of AE ............................................................................ 83 
10.3.2. 
Definition of SAE .......................................................................... 84 
10.3.3. 
Definition of TEAE ....................................................................... 85 
10.3.4. 
Recording, assessment and follow-up of AE, SAE ....................... 85 
10.3.4.1. AE and SAE recording ................................................ 85 
10.3.4.2. Assessment of intensity .............................................. 86 
10.3.4.3. Assessment of causality ............................................. 86 
10.3.4.4. Assessment of outcomes............................................ 87 
10.3.4.5. Follow-up of AEs and SAEs ........................................ 87 
10.3.4.6. Updating of SAE information after removal of 
write access to the participant’s eCRF ........................ 88 
10.3.4.7. Reporting of SAEs ....................................................... 88 
10.4. 
Appendix 4: Liver safety: required and suggested actions and 
follow-up assessments ................................................................................ 89 
10.5. 
Appendix 5: Protocol Amendment History ................................................... 91 
11. REFERENCES ....................................................................................................... 92 
 


CONFIDENTIAL 
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Protocol Amendment 1 Final 
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12 
LIST OF TABLES 
PAGE 
Table 1 
Schedule of Activities ............................................................................. 23 
Table 2 
Summary of Potential Risks of Clinical Significance ............................... 32 
Table 3 
Objectives and Endpoints ....................................................................... 42 
Table 4 
Study Intervention(s) Administered......................................................... 54 
Table 5 
Timeframes for submitting SAE and pregnancy reports to GSK ............. 66 
Table 6 
Contact information for reporting SAEs .................................................. 67 
Table 7 
Intrasubject Coefficient of Variability (CVw%) for PK Parameters 
of EE and LNG ....................................................................................... 74 
Table 8 
Estimated Power and Sample Size Table............................................... 75 
Table 9 
Sample Size: Estimated Precision for Different Observed Effects .......... 75 
Table 10 
Protocol-required safety laboratory tests ................................................ 82 


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LIST OF FIGURES 
PAGE 
Figure 1 
Study design overview ........................................................................... 22 


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Protocol Amendment 1 Final 
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14 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
AE 
Adverse event 
AIDS 
Acquired Immune Deficiency Syndrome  
AUC 
Area under the Plasma Concentration Time Curve 
CIOMS 
Council for International Organizations of Medical Sciences 
Cmax 
Maximum Observed Plasma Concentration 
COC 
Combined Oral Contreceptive 
CONSORT 
Consolidated Standards of Reporting Trials 
CRF/eCRF 
Case report form/electronic case report form 
CSR 
Clinical study report 
Ct  
Trough Concentration 
CV 
Cardiovascular 
DDI 
Drug Drug Interaction 
ECG 
Electrocardiogram 
ED 
Early discontinuation 
EE 
Ethinyl Estradiol  
EMA 
European Medicines Agency 
EoS 
End-of-study 
FDA 
Food and Drug Administration, United States of America 
FSFV 
First subject first visit 
FSH 
Follicle Stimulating Hormone 
GCP 
Good clinical practices 
HBsAg 
Hepatitis B surface antigen 
HCV 
Hepatitis C virus 


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Abbreviation 
Definition 
HIV 
Human Immunodeficiency Virus 
IB 
Investigator’s brochure 
ICF 
Informed consent form 
ICH 
International Council on Harmonisation 
ICMJE 
International Committee of Medical Journal Editors 
ICSR 
Individual case safety reports 
IEC 
Independent ethics committee 
IMP 
Investigational medicinal product 
INR 
International normalized ratio 
IRB 
Institutional review board 
LNG 
Levonorgestrel 
LSLV 
Last Subject Last Visit 
MedDRA 
Medical Dictionary for Regulatory Activities 
MSDS 
Material Safety Data Sheet 
Mtb 
Mycobacterium tuberculosis 
NIMP 
Non-investigational medicinal product 
NOAEL 
No observed adverse effect level  
NQ 
Non-quantifiable 
OC 
Oral contraceptive 
od 
Once a day 
PCI 
Potential Clinical Importance 
PD 
Pharmacodynamic 
PK 
Pharmacokinetic 
QTc 
Corrected QT Interval 


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Abbreviation 
Definition 
QTL 
Quality tolerance limit 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SERM 
Safety Evaluation and Risk Management 
SHBG 
Sex hormone binding globulin  
SmPC 
Summary of product characteristics 
SoA 
Schedule of activities 
SRT 
Safety Review Team 
TB 
Tuberculosis 
TEAE 
Treatment-emergent adverse event 
Tmax 
Time at which Cmax is Observed 
UNITE4TB 
Academia and Industry United Innovation and Treatment for 
Tuberculosis 
WBC 
White blood cell 
WHO 
World Health Organisation 
WOCBP 
Woman of childbearing potential 
WONCBP 
Woman of nonchildbearing potential 
 


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Term 
Definition 
Adverse Drug Reaction 
(ADR) 
An adverse event where a causal relationship between a 
medicinal product and the adverse event is at least a 
reasonable possibility, i.e., the relationship cannot be 
ruled out. 
a. In the context of a clinical trial, an ADR can be 
serious or non-serious. Serious ADRs may be 
subject to expedited reporting if they are considered 
unexpected (see SUSAR definition). 
b. For marketed products, ADRs are subject to 
expedited reporting within the country where they 
are authorized. 
Auxillary Medicinal 
Product (AxMP) 
 
 
 
 
a. Authorized AxMP 
 
 
 
 
 
 
b. Unauthorized AxMP 
Medicinal products used in the context of a clinical trial 
but not as investigational medicinal products, such as 
medicinal products used for background treatment, 
challenge agents,, rescue medication, or used to assess 
end-points in a clinical trial. Auxillary medicinal 
products should not include concomitant medications, 
that is medicationsunrelated to the clinical trial and not 
relavant for the design of the clinical trial. 
Medicinal product authorized in accordance with 
Regulation (EC) No 726/2004, or in any Member 
State concerned in accordance with Directive 
2001/83/EC, irrespective of changes to the labelling 
of the medicinal product. 
1. Safety reporting with regard to auxiliary 
medicinal products shall be made in accordance 
with Chapter 3 of Title IX of Directive 
2001/83/EC. 
a. Medicinal product not authorized in accordance 
with Regulation (EC) No 726/2004 
1. Safety reporting for unauthorised auxiliary 
medicinal products will follow the same 
processes and procedures as SUSAR safety 
reporting 


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18 
Term 
Definition 
Background treatment  
Type of medicinal product administered to each of the 
clinical trial participant, regardless of randomization 
group, to treat the indication that is the object of the 
study. Background treatment is generally considered to 
be the current standard care for the particular indication. 
In these trials, the IMP is given in addition to the 
background treatment and safety efficacy are assessed. 
The protocol may require that the IMP plus the 
background treatment is compared with an active 
comparator or with placebo plus background treatment 
Blinding: 
A procedure in which 1 or more parties to the study are 
kept unaware of the intervention assignment in order to 
reduce the risk of biased study outcomes. The level of 
blinding is maintained throughout the conduct of the 
study, and only when the data are cleaned to an 
acceptable level of quality will appropriate personnel be 
unblinded or when required in case of a SAE. 
In an open-label study, no blind is used. Both the 
investigator and the participant know the identity of the 
intervention assigned.  
Certified copy 
A copy (irrespective of the type of media used) of the 
original record that has been verified (i.e. by a dated 
signature or by generation through a validated process) 
to have the same information, including data that 
describe the context, content, and structure, as the 
original. 
Challenge agents 
A product given to trial participants to produce a 
physiological response that is necessary before the 
pharmacological action of the IMP can be assessed. 
Co-administered 
(concomitant) products 
A product given to clinical trial participants as required 
in the protocol as part of their standard care for a 
condition which is not the indication for which the IMP 
is being tested and is therefore not part of the objective 
of the study. 
Comparator 
Any product used as a reference (including placebo, 
marketed product, GSK or non-GSK) for an 
investigational product being tested in a clinical trial. 
This is any product that is being used to assess the 
safety, efficacy, or other measurable value against the 
test product (IMP). 


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Term 
Definition 
Eligible 
Qualified for enrollment into the study based upon strict 
adherence to inclusion/exclusion criteria. 
Essential documents 
Documents which individually and collectively permit 
evaluation of the conduct of a study and the quality of 
the data produced 
Intervention number 
A number identifying an intervention to a participant, 
according to intervention allocation. 
Investigational medicinal 
An IMP is a pharmaceutical form of an active substance 
or placebo being tested or used as a reference in a 
clinical study, including products already with a 
marketing authorization but used or assembled 
(formulated or packaged) in a way different from the 
authorized form, or when used for an unauthorized 
indication, or when used to gain further information 
about the authorized form. Medicinal products with a 
marketing authorization are IMPs when they are to be 
used as the test substance, reference substance, or 
comparator in a clinical study, provided the 
requirement(s) in the definition is/are met. 
Investigational Product 
A pharmaceutical form of an active substance or 
placebo being tested or used as a reference in a clinical 
trial, including products already with a marketing 
authorization but used or assembled (formulated or 
packaged) in a way different from the authorized form, 
or when used for an unauthorized indication , or when 
used to gain further infirmation about the authorised 
form. 
Investigator 
A person responsible for the conduct of the clinical 
study at a study site. If a study is conducted by a team of 
individuals at a study site, the investigator is the 
responsible leader of the team and may be called the 
principal investigator.  
The investigator can delegate study-related duties and 
functions conducted at the study site to qualified 
individual or party to perform those study-related duties 
and functions 
Medicinal products used to 
assess end-points 
A product given to the participant in a Clinical Trial as a 
tool to assess a relevant clinical trial endpoint; it is not 
being tested or used as a reference in the clinical trial. 


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Term 
Definition 
Participant 
Term used throughout the protocol to denote an 
individual who has been contacted to participate or who 
participates in the clinical study as a recipient of the 
study intervention (vaccine(s)/product(s)/control). 
Synonym: subject 
Participant number 
A unique identification number assigned to each 
participant who consents to participate in the study. 
Placebo 
An inactive substance or treatment that looks the same 
as, and is given in the same way as, an active drug or 
intervention/treatment being studied. 
Primary Completion Date 
The date on which the last participant in a clinical study 
was examined or received an intervention to collect final 
data for the primary outcome measure. 
Whether the clinical study ended according to 
the protocol or was terminated does not affect this date. 
For clinical studies with more than one primary outcome 
measure with different completion dates, this term refers 
to the date on which data collection is completed for all 
the primary outcome measures.  
Randomization 
Process of random attribution of intervention to 
participants to reduce selection bias. 
Rescue Medication 
Medicines identified in the protocol as those that may be 
administered to the participants when the efficacy of the 
IMP is not satisfactory, or the effect of the IMP is too 
great and is likely to cause a hazard to the patient, or to 
manage an emergency situation. 
Source data 
All information in original records and certified copies 
of original records of clinical findings, observations, or 
other activities in a clinical study necessary for the 
reconstruction and evaluation of the study. Source data 
are contained in source documents (original records or 
certified copies). 


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Term 
Definition 
Standard of Care 
Medicine(s) for a specific indication, or a component of 
the standard care for a particular medical indication, 
based on national and/or international consensus; there 
is no regulatory significance to this term. 
1. Products/regimens considered standard of care 
may differ country to country, depending on 
consensus in individual countries. 
Study completion date 
The date on which the last participant in a clinical study 
was examined or received an intervention/treatment to 
collect final data for the primary outcome 
measures, secondary outcome measures, and AEs (that 
is, the last participant's last visit or LSLV). 
Study intervention 
Term used throughout the clinical study to denote a set 
of investigational product(s) or marketed product(s) or 
placebo intended to be administered to a participant. 
Note: “Study intervention” and “study treatment” are 
used interchangeably unless otherwise specified. 
Study monitor 
An individual assigned by the sponsor and responsible 
for assuring proper conduct of clinical studies at 1 or 
more investigational sites. 
SUSAR 
Suspected Unexpected Serious Adverse Reaction; in a 
clinical trial, a serious adverse reaction that is 
considered unexpected, i.e., the nature or severity of 
which is not consistent with the reference safety 
information (e.g., Investigator's Brochure for an 
unapproved investigational medicinal product). All 
ADRs that are both serious and unexpected are subject 
to expedited reporting. 


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1. 
PROTOCOL SUMMARY 
1.1. 
Synopsis 
Protocol Title: A Phase 1, open-label, fixed sequence, 1-way drug-drug interaction study 
to investigate the pharmacokinetics of GSK3036656 and an oral contraceptive containing 
ethinyl estradiol and levonorgestrel when the oral contraceptive is administered alone and 
in combination with GSK3036656 in healthy female participants of non-childbearing 
potential aged 18-65 years of age. 
Brief Title: A study to investigate the pharmacokinetics of a combined oral contraceptive 
when given alone and in combination with GSK3036656 in female participants of non-
childbearing potential aged 18 to 65 years of age. 
Rationale: Refer to Section 2.1. 
Objectives, Endpoints, and Estimands: Refer to Section 3. 
Overall Design: Refer to Section 4.1. 
Number of Participants: Refer to Section 9.5. 
Data Monitoring/Other Committee: Refer to Section 10.1.6. 
1.2. 
Study Schema 
Figure 1 
Study design overview 
 
 


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1.3. 
Schedule of activities (SoA) 
The Schedules of Activities are presented in the following table.  
Table 1 
Schedule of Activities 
Procedure 
Screening 
Treatment Period 1 
Treatment 
Period 2 
Treatment Period 3 
Early 
Withdrawal 
Unscheduled 
Notes 
 
D 
-14 to -1 
D  
1 
D  
2 
D 
3 
D 
4 
D 
5-14 
D 
15 
D 
16-17 
D 
18 
 
 
 
Outpatient visit◦ 
X 
 
 
 
 
X 
 
 
 
 
 
Outpatient visits would occur on Days 8, 10 
and 12 
Informed consent• 
X 
 
 
 
 
 
 
 
 
 
 
Refer to Section 10.1.3 for details. 
Inclusion and exclusion 
criteria• 
X 
 
 
 
 
 
 
 
 
 
 
Refer to Sections 5.1and 5.2 for Inclusion 
and Exclusion criteria. 
Demography• 
X 
 
 
 
 
 
 
 
 
 
 
Refer to Section 8.1.1 for more information. 
Admit to clinic and 
inpatient stay◦ 
 
X◦◦ 
X 
X 
 
 
X◦◦ 
X 
X 
 
 
 
Discharge from clinic◦ 
 
 
 
 
X* 
 
 
 
X 
 
 
Discharge after 72 hour EE/LNG PK sample 
taken.  
*Participants progress immediately from the 
end of Treatment Period 1 to Treatment 
Period 2, with no washout required in 
between 
Evaluation of 
childbearing potential◦ 
X 
 
 
 
 
 
 
 
 
 
 
Evaluation of childbearing potential includes: 
− 
Menstrual history (to confirm no 
menses) 
− 
Documentation of past surgical 
history 
− 
FSH test to confirm ovarian reserve 
status (for participants who were 
not surgically sterilized) 


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Procedure 
Screening 
Treatment Period 1 
Treatment 
Period 2 
Treatment Period 3 
Early 
Withdrawal 
Unscheduled 
Notes 
 
D 
-14 to -1 
D  
1 
D  
2 
D 
3 
D 
4 
D 
5-14 
D 
15 
D 
16-17 
D 
18 
 
 
 
Pregnancy Test• 
 
X 
 
 
 
 
 
 
X 
X 
X 
A highly sensitive pregnancy test (urine or 
serum) to be performed on Day 1 prior to 
dosing with Microgynon and again on Day 18 
prior to discharge. 
Medication/drug/alcohol 
history◦ 
X 
 
 
 
 
 
 
 
 
 
 
Refer to Section 8.1.2 for more information. 
Past and current 
medical conditions• 
X 
 
 
 
 
 
 
 
 
 
 
 
Drug, alcohol, and 
cotinine screen◦ 
X 
 
 
 
 
 
 
 
 
 
 
See Table 10 for specific tests to be 
performed. 
HIV, hepatitis B and C◦ 
X 
 
 
 
 
 
 
 
 
 
 
 
Sex hormone binding 
globulin (SHBG)◦ 
X 
 
 
 
 
 
 
 
 
 
 
 
Physical examination◦ 
X* 
X 
 
 
X 
 
 
 
X 
X 
 
Full physical exam at Screening* and brief 
physical examination at all other scheduled 
timepoints.  
A full physical examination includes at a 
minimum, weight, assessments of the skin, 
cardiovascular, respiratory, gastrointestinal, 
and neurological systems.  
Brief exam includes, at a minimum, weight, 
assessments of the skin, lungs, 
cardiovascular system, and abdomen (liver 
and spleen). 


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Procedure 
Screening 
Treatment Period 1 
Treatment 
Period 2 
Treatment Period 3 
Early 
Withdrawal 
Unscheduled 
Notes 
 
D 
-14 to -1 
D  
1 
D  
2 
D 
3 
D 
4 
D 
5-14 
D 
15 
D 
16-17 
D 
18 
 
 
 
Vital signs• 
X 
X 
 
 
X 
 
X 
 
X 
X 
X 
To be performed within 4 hours prior to the 
first dosing on Day 1 of Treatment Period 1, 
Day 4 of Treatment Period 2 and Day 15 of 
Treatment Period 3. Where a measurement 
is abnormal or significantly different from 
previous measurements, a further 2 readings 
will be taken. When vital signs are measured 
in triplicate, values should be taken at least 1 
minute but not more than 5 minutes apart 
and recorded in the CRF. 
On days where the following assessments 
are done the order should be vital signs 
before blood draws for PK or safety 
assessments. 
12-Lead ECG• 
T 
X 
 
 
X 
 
X 
 
X 
X 
X 
T = Triplicate 
At Screening, triplicate ECGs are taken. 
Single ECGs will be taken on other 
scheduled days. 
On Day 1, day 4 and day 15 ECG should be 
performed within 15 minutes before dosing 
and recorded in the eCRF. On days where 
the following assessments are done the 
order should be: ECGs before blood draws 
for PK or safety assessments. 
Meals at inpatient 
facility• 
 
X 
X 
X 
X 
 
X 
X 
X 
 
 
Meals will be served during in patient stay 
across days 1 to 4 and 15 to 18. 
Water is permitted as desired. 


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Procedure 
Screening 
Treatment Period 1 
Treatment 
Period 2 
Treatment Period 3 
Early 
Withdrawal 
Unscheduled 
Notes 
 
D 
-14 to -1 
D  
1 
D  
2 
D 
3 
D 
4 
D 
5-14 
D 
15 
D 
16-17 
D 
18 
 
 
 
Laboratory 
assessments 
(haematology, 
chemistry, urinalysis 
tests) • 
X 
X 
 
 
X 
 
X 
 
X 
X 
X 
Laboratory assessments to be performed at 
Screening, and prior to dosing on Day 1 of 
Treatment Period 1, Day 4 of Treatment 
Period 2 and Day 15 of Treatment Period 3. 
See Table 10 for specific tests to be 
performed.  
Echocardiogram 
X 
 
 
 
 
 
 
 
 
 
 
Screening echocardiogram to be performed 
at Screening (day -14 to -1).  
Echo should be repeated on participants with 
changes in clinical status warranting a follow 
up echo in the opinion of the investigator. 
Study treatment: 
Microgynon (0.03 mg 
EE/ 0.15 mg LNG) •  
 
X 
 
 
 
 
X 
 
 
 
 
Single dose of Microgynon on Day 1 of 
Treatment Period 1 and day 15 of Treatment 
Period 3. 
Study treatment: 
GSK3036656 20 mg 
od• 
 
 
 
 
X* 
X 
X 
X 
 
 
 
*Loading dose of GSK3036656 40 mg on 
Day 4 


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Procedure 
Screening 
Treatment Period 1 
Treatment 
Period 2 
Treatment Period 3 
Early 
Withdrawal 
Unscheduled 
Notes 
 
D 
-14 to -1 
D  
1 
D  
2 
D 
3 
D 
4 
D 
5-14 
D 
15 
D 
16-17 
D 
18 
 
 
 
Serial PK sampling: 
EE and LNG•  
 
X 
X 
X 
X 
 
X 
X 
X 
 
X* 
PK samples collected predose and after 
dosing with Microgynon at 0.25, 0.5, 1, 1.5, 
2, 3, 4, 6, 8, 12, and 24, 48 and 72 hours 
relative to Day 1 dosing of Treatment Period 
1 and Day 15 dosing of Treatment period 3. 
The predose sample to be taken within 30 
minutes prior to dose administration. 
 
Blood is drawn for PK analysis at 0.25-4 
hours ±5 minutes after dosing. 
 
Blood is drawn for PK analysis at 6-12 hours 
±20 minutes after dosing. 
 
Blood is drawn for PK analysis at 24-72 
hours ±60 minutes after dosing  
 
The Day 72 h sample must be taken prior to 
GSK3036656 dosing on Day 4. 
*At any unscheduled visit, only collect a 
predose EE/LNG PK sample if it occurs 
during Treatment Periods 1 or 3. 
Trough PK sampling: 
GSK3036656• 
 
 
 
 
 
X 
 
 
 
 
X* 
Samples to be taken 24 hours post the 
previous dose and within 30 minutes prior to 
the next dose of GSK3036656 on Days 8, 10 
and 12. 
* At any unscheduled visit, only collect a 
GSK3036656 PK sample if it occurs during 
Treatment Periods 2 or 3.  


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Procedure 
Screening 
Treatment Period 1 
Treatment 
Period 2 
Treatment Period 3 
Early 
Withdrawal 
Unscheduled 
Notes 
 
D 
-14 to -1 
D  
1 
D  
2 
D 
3 
D 
4 
D 
5-14 
D 
15 
D 
16-17 
D 
18 
 
 
 
Serial PK sampling: 
GSK3036656• 
 
 
 
 
 
 
X 
X 
 
 
 
PK samples collected predose 
(GSK3036656) and after dosing at 0.5, 1, 
1.5, 2, 3, 4, 6, 8, 12, 24 hours relative to 
Day 15 dosing in Treatment Period 3.  
The Day 15 24 h sample must be taken prior 
to GSK3036656 dosing on Day 16. 
 
The predose sample to be taken within 30 
minutes prior to dose administration. 
 
Blood is drawn for PK analysis at 0.5-4 hours 
±5 minutes after dosing. 
 
Blood is drawn for PK analysis at 6-12 hours 
±20 minutes after dosing. 
 
Blood is drawn for PK analysis at 24 hours 
±1 hours after dosing.  
AE review• 
 
=========================================➔ 
 
 
AEs collected from the start of study 
intervention until day 18 of Treatment Period 
3. 
SAE review• 
=====================================================➔  
 
SAEs collected from the signing of the ICF 
until Day 18 of Treatment Period 3. 
Concomitant 
medication review• 
 
==========================================➔ 
 
 
 
AE = adverse event; D = Day; ECG = electrocardiogram; EE = ethinyl estradiol; LNG = levonorgestrel; PK = pharmacokinetic; SAE = serious adverse event. 
Assessments performed predose on Day 4 of Treatment Period 2 were considered baseline for GSK3036656 dosing. 
        ● Is used to indicate a study procedure that requires databasing (either in eCRF, laboratory or other third-party vendor). 
○ Is used to indicate a study procedure that does not require databasing (in source only). 
○○Participants may be admitted the night before Day 1 and Day 14, but study procedures will commence on the morning of Day 1 and morning of Day 15. 


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2. 
INTRODUCTION 
2.1. 
Study rationale 
GSK3036656 is being developed for TB and a Phase 2B/C regimen building and duration 
ranging study conducted under the UNITE4TB consortium is planned to start in 4Q2023. 
GSK3036656 was teratogenic in rats and rabbits. In rats (most sensitive species) the 
NOAEL for embryofetal effects was
mg/kg/day, with an exposure (AUCtlast) at this 
dose level of 
 μg.h/mL which is at parity with the
mg clinical dose. Precautions 
will therefore be required prior to starting WOCBP on GSK3036656. The nature of these 
precautions will be subject to discussion with the external TB community, patient groups 
and regulators at the time of file.  
Of the 10.6 million TB patients diagnosed each year, approximately twenty percent are 
WOCBP. Therefore, there exists the potential for broad use and impact of GSK3036656 
containing regimens regardless of any label restrictions. In addition, several potential 
combination TB drugs carry label restrictions for pregnancy and WOCBP, whilst TB 
itself poses risks in pregnancy to both the mother and the developing foetus. 
Based on the in-vitro data, GSK3036656 does not exhibit any induction or inhibition of 
key cytochrome P450s (CYPs). To minimize any risk due to the teratogenicity observed 
in rats and rabbits, ongoing and planned clinical development studies including 
GSK3036656 currently mandate use of non-user dependent contraception (intrauterine 
contraceptive device, or implantable or depot injectable progesterone) during the study 
for female study participants of childbearing potential, or recruitment of women of non-
childbearing potential. In addition, highly sensitive pregnancy testing must be performed 
prior to dosing and throughout the studies. The recommended population to be enrolled 
into clinical drug interaction studies with combined oral contraceptives are 
postmenopausal and premenopausal females (if studying PD endpoints) [FDA, 2023] 
Taking into account the unknown DDI interaction between GSK3036656 and 
Microgynon, contraception should not be considered as effective, therefore enrollment of 
only WONCBP in this study is a safety pregnancy-specific risk minimization measure 
[EMA, 2022]. 
FDA guidance states that if an investigational drug shows any nonclinical reproductive 
and developmental toxicity, then an OC clinical DDI study waiver would be unlikely to 
be granted by regulators, meaning that an OC DDI study would be required for 
GSK3036656 as part of the marketing authorization submission. In addition, as non-user-
dependent contraceptive measures may not be available or culturally acceptable in some 
of the participating countries in the Phase 2B/C study, there is a risk that recruitment will 
be negatively affected, and WOCBP who need access to TB treatment will not be eligible 
for the study. Hence the opportunity of user dependent contraception with an OC could 
exclude fewer WOCBP with TB by offering more choice.  
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Conducting an OC DDI study in parallel with Phase 2B could be beneficial as this could 
potentially generate data that could allow the use of less restrictive contraceptive 
measures during Phase 2C, which would have a positive impact on recruitment. There are 
other regimens within the study that do not require these stringent contraception 
restrictions and these are only being imposed because of GSK656-containing regimens. 
2.2. 
Background 
TB remains a concerning health problem, with Mycobacterium tuberculosis (Mtb) now 
causing more deaths than HIV/ AIDS. In 2021, 1.6 million people died from TB, making 
it the leading bacterial infectious disease killer in the world [EMA, 2022;FDA, 2023; 
WHO, 2022] The current long-standing first-line antituberculosis agents are relatively 
ineffective in controlling the TB epidemic in high-burden countries. Treatment takes 4-18 
months to complete (depending on drug sensitivities of the isolated strain and availability 
of shorter regimens) and is associated with side effects resulting in poor compliance 
which leads to treatment failure and an increased likelihood of developing drug-
resistance.  
The development of new drug combinations that are effective against drug-resistant 
strains of Mtb, and that have the potential to shorten the duration of TB treatments offers 
the hope of tackling the TB pandemic. A new treatment regimen requires at least three 
different drugs to which no clinical resistance exists. This highlights the need for the 
development of additional new chemical entities that strike an appropriate balance 
between antituberculosis activity and safety profiles, a balance that will enable new 
future drug combinations that make the optimal use of previously developed entities. 
GSK3036656 is a compound with a novel mechanism of action under development for 
the treatment of TB. It suppresses protein synthesis in Mtb by selectively inhibiting the 
enzyme Leucyl t-RNA synthetase. 
 
 
 
 and the drug shows potent activity in animal models, resulting 
in very low predicted efficacious human doses. In vitro data show that the risk of drug-
drug interactions with GSK3036656, either as perpetrator or victim, is low. These factors 
make GSK3036656 an attractive potential candidate for the treatment of tuberculosis. 
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Conducting this OC DDI study will provide data showing if there is any pharmacokinetic 
effects of GSK3036656 on a combined oral contraceptive, which, in conjunction with 
cultural sensitivities in specific regions, will help inform future studies on suitable 
contraceptive measures to be used. 
A description of the chemistry, nonclinical and clinical data generated to date for 
GSK3036656 is provided in the IB. 
2.3. 
Benefit/risk assessment 
Data described in the IB support the safety profile of the selected dose of GSK3036656 in 
patients with newly-diagnosed TB and healthy volunteers. The known potential risks 
associated with GSK3036656 can be appropriately mitigated by the careful selection of 
study participants and the proposed safety monitoring procedures. Routine safety and 
tolerability will be evaluated from reported AEs, scheduled physical examinations, vital 
sign measurements, 12-lead ECGs, and clinical laboratory test results as well as 
observation by clinical staff. The potential risks associated with the administration of 
GSK3036656 are considered to be justified by the potential benefits that may be afforded 
to patients with TB if this and future studies with GSK3036656 are deemed successful for 
the participants from the study treatment. More detailed information about the known and 
expected benefits and risks and reasonably expected AEs of GSK3036656 may be found 
in the IB. 
 


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2.3.1. 
Risk assessment 
The Sponsor’s assessment of known and potential risks of GSK3036656 is summarized in Table 2. 
Table 2 
Summary of Potential Risks of Clinical Significance 
Potential Risk of Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
Study Intervention(s) GSK3036656 
Reduction in red blood cell count 
Non-Clinical 
 
In a 4-week rat study (doses 
 
mg/kg/d) - dose-dependent decline in 
reticulocytes (by up to 52% in males and 62% in 
females) at day 7 followed by normal levels by 
day 14 and increased levels by day 29/30 
compared to controls. Hgb levels decreased by 
10-13% compared to controls on day 14 and 
day 29/30.  
 
In a 4 week dog study (doses 
 
mg/kg/d) - mild dose-dependent decrease in 
Hgb on day 14 (by about 10% compared to 
controls) with recovery by week 4. Reticulocyte 
counts unaffected. Dogs not bled on day 7. 
  
No histopathological changes in bone marrow or 
other relevant histopathology in the 4-week 
studies.  
Standard safety haematology and clinical 
chemistry assessments will be performed and 
both trends and changes outside normal range 
will be monitored as part of laboratory safety 
assessments. 
 
Participants whose haemoglobin drops below 
pre-specified limits will be withdrawn from study 
intervention (Section 7.1.3). 
 
 
Haematology Stopping Criteria have been 
implemented as described in Section 7.1.3:  
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Potential Risk of Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
Clinical 
In the study 201040 (FTIH) a possible trend of 
decreased haemoglobin from baseline to follow-
up was noted in aggregate haematology data. 
The mean change from baseline to follow-up 
was -4.9 g/L in the
mg repeat dose cohort, 
compared to -1.5 g/L in the placebo group. 
None of the values hit PCI criteria, and declines 
were not clinically relevant. 
No clinically significant trends in reticulocyte 
values were observed, and there were no 
values of potential clinical importance reported 
for reticulocytes. 
In the Study 201214 no significant trends in the 
haemoglobin level or reticulocytes count were 
observed.  
Reduction in white blood cell count 
Non-Clinical 
In the 4-week rat study, decrease of up to 37% 
in total leucocyte count on day 29/30 compared 
to controls.  
In the 4-week dog study, no reported effects on 
white blood cells.  
Clinical In the study 201040 (FTIH) - No 
clinically significant trends in leukocyte or 
neutrophil count values were observed. Two 
White blood cell count will be monitored as part 
of laboratory safety assessments. Any clinically 
significant changes will be followed up until 
levels are not clinically significant.  
Participants developing neutrophil counts 
<500/mm3 (0.5x109/L) will be withdrawn from the 
study (Section 7.1.3). 
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Potential Risk of Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
participants showed PCI values. One 
participants had low neutrophil count (normal 
range 1.57-6.81 × 10^9/L) from screening (1.38) 
until follow-up (1.41), and also showed low 
leukocyte count (normal range 3.3-9.8 × 10^9/L) 
on Day 4 (2.5), Day 10 (2.6) and Day 14 (2.9) 
and was within normal range at follow-up. Given 
the low screening values, this observation was 
considered likely related to the subject’s 
 
 A second subject had 
a single low neutrophil count at follow-up (1.48).  
In the Study 201214 – in a 1 subject on
mg 
dose drug-related neutropenia was registered. 
Heart valvular and vascular pathology 
Non-Clinical  
In a 7-day dog dose range finding study – 
minimal focal subendocardial haemorrhage on 
the atrial surface of the left atrioventricular valve 
observed in both animals at the top dose of 
 mg/kg/d.  
In a 10-day dog investigative study at
mg/kg/d – vascular lesions (including minimal 
focal necrosis and inflammatory infiltrate) in 3 
out of 8 dogs.  
In the 4-week dog GLP study - no heart or valve 
changes were observed up to the top dose of 
Valvular pathology can be monitored in humans 
with non-invasive echocardiography, these will 
be performed at screening. 
Vascular pathology is not readily monitorable in 
humans.  
Subjects with history of known cardiac valve 
abnormalities, any significant arrhythmia or ECG 
finding are not eligible for the study. 
To avoid risk to study participants, dosing will be 
limited to doses at which individual exposures 
do not exceed AUC0-24 and Cmax to
μg.h/mL and 
μg/mL, respectively.  
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Potential Risk of Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
mg/kg/day and there was no increase in 
inflammatory markers.  
In the 17-week GLP dog study there were no 
heart or valve changes up to the top dose of 
mg/kg/day.  
In the 17-week rat study there were no changes 
in cardiac pathology up to the top dose of 
mg/kg/day.  
Valvular or vascular pathology were not 
observed in rats. This pathological change is not 
commonly seen in animals, and its mechanism 
and significance to humans are not clear. A 
correlation between the presence of 
hemodynamic changes and the presence of this 
pathology is suspected, but currently unproven.  
Clinical  
Echocardiograms were performed at screening 
and follow up in the 201040 FTIH study in order 
to exclude participants with pre-existing valve or 
other cardiac abnormalities from the study, and 
to detect the presence of abnormalities after 
completion of the study. No abnormalities were 
detected.  
No SAEs, or AEs of cardiovascular nature were 
reported. There was no change from baseline in 
These exposures are 10-fold below the lowest 
NOAEL achieved in the 17-week studies (rat) 
QTc stopping criteria have been implemented as 
described in Section 7.1.2. 
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heart rate observed at any dose. No trends in 
blood pressure change were observed. Cardiac 
telemetry and echocardiogram-related 
interpretations were within normal range. There 
were no clinically significant ECG observations. 
There were no troponin I abnormalities in 
participants after receiving study drug.  
In Study 201214, one subject (dose
mg) had 
drug-related ventricular hypokinesia.  One 
subject (dose
mg) had decreased ejection 
fraction. None of the participants met the QTcF 
stopping criteria. No SAEs of cardiovascular 
nature were reported. 
Hemodynamic changes 
Non-Clinical  
Hemodynamic changes in several studies at 
≥
mg/kg in rats and ≥
mg/kg in dogs - 
increased heart rate (rats and dogs), increased 
(rats) or decreased (dogs) blood pressure.  
Clinical  
Data from the 201040 (FTIH) and 201214 
studies showed no significant changes in vital 
signs assessments during the study, and no 
clinically significant changes in ECG or 
telemetry assessments including QTc and PR 
intervals. 
Vital signs will be monitored throughout the 
study as described in Section 8.3.2. 
ECGs will be monitored throughout the study as 
described in Section 8.3.3. 
QTc stopping criteria have been implemented as 
described in Section 7.1.2 
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GSK3036656 is cleared through the kidneys 
Analysis of the 201040 FTIH study data showed 
the main route of clearance for GSK3036656 is 
renal and there is therefore a risk that 
participants with low creatinine clearance may 
accumulate GSK3036656 and exceed 
predefined exposure limits.  Participants with 
creatinine clearance less than 75 mL/min were 
excluded from the 201214 study. 
Participants with an estimated creatinine 
clearance less than 75 mL/min will be excluded. 
Skin depigmentation 
Non-Clinical 
In a 17-week dog toxicology study (doses
 mg/kg /day): loss of pigmentation on 
the eyelids, nose or muzzle of all animals at 45 
mg/kg/day group 
 
μg.h/mL) and most animals in the
mg/kg/day 
group 
 μg.h/mL). PNL-2 (a 
melanocyte marker) immunohistochemistry 
staining demonstrated moderate cytoplasmic 
positivity in a population of cells in the basal 
region of the epidermis (interpreted to be 
melanocytes). The decreased pigmentation was 
therefore not associated with a loss of 
melanocytes in affected animals on 
immunohistochemistry. Depigmentation was not 
observed in the 
 mg/kg/day group (
 
ug/h/mL). Depigmentation was not observed in 
the two previous 4 week dog toxicology studies 
up to
mg/kg/day 
 
ug.h/mL). 
The duration of dosing in this study (14 days) is 
shorter than that used in the dog toxicology 
study and the maximum exposure (AUC0-24) 
has been capped at
ug.h/mL (10-fold below 
effect level for loss of pigment in the 17-week 
dog study). 
The physical examination of study participants 
will include visual examination of the skin. 
Participants with vitiligo will be excluded from 
the study to avoid confounding skin assessment 
at baseline and follow-up physical examinations. 
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Clinical  
No adverse events were reported in the 201040 
(FTIH) and 201214 studies that would be 
considered consistent with an asset-related 
depigmentation.  
Developmental toxicity  
Non-Clinical 
Embryofetal developmental effects were 
observed in both rat and rabbit. In the rat, 
reduction in fetal viability and malformation, 
including skeletal malformations, ventricular 
septal defects and cleft palate were observed 
from
mg/kg/day. The NOAEL for embryofetal 
effects in the rat is
mg/kg/day, the exposure 
(AUCtlast) at this dose level is
µg.h/mL 
which is at parity with the
mg clinical dose. In 
the rabbit, the only test article-related fetal 
abnormality was an increase in the incidence of 
full thoracolumbar ribs. The NOAEL for effects 
on rabbit embryofetal development was
mg/kg/day, and the AUCtlast at this dose was 
 µg.h/mL. 
Clinical  
Studies 201040 (FTIH) and 201214 excluded 
females. 
For the study, only WONCBP will be eligible: 
• 
Particpants with documented infertility 
(hysterectomy, bilateral 
salpingectomy, bilateral 
oophorectomy, other alternative 
documented) 
• 
Postmenopausal females (no menses 
for 12 months without an alternative 
medical cause + high FSH) 
 
Pregnancy testing has been implemented as 
described in Section8.3.5. 
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Study Procedures 
Blood draws 
Venous access in some participants may be 
problematic and the needles used may cause 
bruising (ecchymosis) around the access site. 
A maximum of approximately 160 mL of whole 
blood will be collected over the course of the 
study. 
 
At visits to collect whole blood samples, one or 
more samples of sufficient volume will be 
collected and divided into suitable portions for 
the various analyses. 
 
Whole blood samples will be collected by site 
personnel experienced in phlebotomy. 
MICROGYNON 30 (Microgynon) 
[Microgynon, 2023]. Summary of Product Characteristics, 2023 
Circulatory disorders: risk of venous 
thromboembolism (VTE) and arterial 
thromboembolism (ATE) 
Epidemiological studies have suggested an 
association between the use of COCs 
containing ethinyloestradiol and an increased 
risk of arterial and venous thrombotic and 
thromboembolic diseases such as myocardial 
infarction, stroke, deep venous thrombosis, and 
pulmonary embolism. These events occur rarely 
in average-risk women. 
The use of any combined hormonal 
contraceptive increases the risk of VTE 
compared with no use. Data from a large, 
prospective 3-armed cohort study (EURAS1 and 
LASS2) suggest that this increased risk is 
mainly present during the first 3 months. VTE 
For the study, eligible 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), non-obese, non-
smokers, which exclude presence of major risk 
factors for both VTE and ATE. 
Eligible subjects > 35 years old will be more 
carefully monitored for clinical symptoms of 
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Potential Risk of Clinical Significance 
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may be life-threatening or may have a fatal 
outcome (in 1-2% of cases). 
Epidemiological studies have associated the 
use of CHCs with an increased risk for arterial 
thromboembolism (e.g. myocardial infarction, 
angina pectoris, stroke or TIA). Arterial 
thromboembolic events may be fatal. 
Echocardiography has been implemented at 
screening as defined in Section 8.3.6. 
Full physical examination with vital signs, ECG 
and laboratory tests have been implemented as 
described in Section 8.3. 
Tumors 
A meta-analysis from 54 epidemiological studies 
reported that there is a slightly increased 
relative risk (RR = 1.24) of having breast cancer 
diagnosed in women who are currently taking 
COCs. These studies do not provide evidence 
for causation. The observed pattern of 
increased risk may be due to an earlier 
diagnosis of breast cancer in COC users, the 
biological effects of COCs or a combination of 
both. 
In rare cases, benign liver tumours, and even 
more rarely, malignant liver tumours have been 
reported in users of COCs. 
Exclusion criteria have been added to exclude 
subject with major health conditions (including 
tumors) as described in Section 5.2. 
Full clinical examination is a part of the standard 
safety monitoring for the study. 
Short duration of dosing by COCs mitigates this 
risk. 
Metabolic problems: lipid and glucose 
abnormalities 
Women with hypertriglyceridaemia, or a family 
history thereof, may be at an increased risk of 
pancreatitis when taking COCs. 
Although COCs may have an effect on 
peripheral insulin resistance and glucose 
tolerance, there is no evidence for a need to 
alter the therapeutic regimen in women with 
Subjects with baseline problems are eligible if 
relevantly compensated. 
Lipid and glucose metabolism safety monitoring 
have been implemented as described in 
Section 10.2 Appendix 2.  


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diabetes taking low dose COCs (containing < 50 
µg ethinylestradiol). However, women with 
diabetes should be carefully observed while 
taking COCs. 
Hypertension 
Small increases in blood pressure have been 
reported in many women taking COCs, clinically 
relevant increases are rare. However, if a 
sustained clinically significant hypertension 
develops during the use of a COC, it is prudent 
for the doctor to withdraw the COC and treat the 
hypertension. Where considered appropriate, 
COC use may be resumed if normotensive 
values can be achieved with antihypertensive 
therapy 
Vital signs monitoring have been implemented 
as described in Section 8.3.2 
Gastrointestinal tract problems 
Nausea, diarrhoea, abdominal pain and 
vomiting were reported in COCs users 
Full clinical examination and vital signs are a 
part of the standard safety monitoring as 
described in Section 8.3. 
Liver problems 
Acute or chronic disturbances of liver function 
may necessitate the discontinuation of COC use 
until markers of liver function return to normal. 
Recurrence of cholestatic jaundice which 
occurred first during pregnancy or previous use 
of sex steroids necessitates the discontinuation 
of COCs 
Exclusion criteria have been added to exclude 
participants with hepatitis B, C, impaired LFTs 
(ALT and Bilirubin >1.5 × ULN) and those with 
the history of regular alcohol consumption within 
6 months. 
LFT is a part of the standard safety monitoring 
as described in Section 10.2 
Liver stopping criteria have been implemented 
as described in Section 7.1.1. 
 


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2.3.2. 
Benefit assessment 
This study is being conducted in healthy female participants of non-childbearing potential 
with no significant medical history. Participants will not receive benefit from this study. 
2.3.3. 
Overall benefit-risk conclusion 
Overall, the available data from non-clinical and clinical studies has not identified 
prohibitive risks associated with GSK3036656 at the exposures planned for this study. 
While there are a number of important potential risks identified for GSK3036656, these 
can be addressed in clinical trials with proper participant selection, close safety 
monitoring, and specific risk characterization and mitigation. 
3. 
OBJECTIVES, ENDPOINTS AND ESTIMANDS 
The study objectives and endpoints are presented in Table 3  
Table 3 
Objectives and Endpoints 
 
Objective(s) 
Endpoint(s) 
Primary 
To assess the effect of steady state exposure 
of GSK3036656 on the single dose PK of EE 
and LNG in healthy female participants of non-
childbearing potential 
Area under the plasma concentration-time 
curve to infinity AUC(0-inf) and maximum 
observed concentration (Cmax), after a single 
dose of EE and LNG (EE AUC(0-inf), EE Cmax, 
LNG AUC(0-inf), LNG Cmax) 
Secondary 
To characterize the steady state PK of 
GSK3036656 in the presence of EE/LNG 
AUC(0-τ), Cmax, Cτ (Day 8, 10, 12, 15 and 16) 
and time of maximum observed concentration 
(Tmax) for GSK3036656 
To characterize the single dose PK of EE/LNG 
alone and in the presence of GSK3036656 
AUC(0-t),Tmax and t1/2 for EE and LNG, in 
Treatment Period 1 and Treatment Period 3. 
To assess the safety and tolerability of 
GSK3036656 and Microgynon when given 
alone or in combination in healthy female 
participants of non-childbearing potential 
• 
Incidence of  SAEs within each treatment 
period. 
• 
Incidence of AEs of grade 3 severity or 
higher within each treatment period. 
• 
Incidence of AEs considered by the 
investigator to be possibly, probably, or 
definitely related to study drug within each 
treatment period (overall and separately 
for relationship to Microgynon and to 
GSK3036656). 
• 
Incidence of participants withdrawn from 
the treatment/study due to adverse events 
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Objective(s) 
Endpoint(s) 
• 
Incidence of ECG values PCI within each 
treatment period. 
• 
Incidence of clinical chemistry laboratory 
values of PCI within each treatment 
period. 
• 
Incidence of hematology laboratory values 
of PCI within each treatment period. 
• 
Incidence of vital signs parameters of 
systolic blood pressure (SBP), diastolic 
blood pressure (DBP) and heart rate (HR) 
of PCI within each treatment period. 
 
PRIMARY ESTIMAND 
The primary clinical question of interest is:  
What is the effect of treatment with GSK3036656, estimated by the point estimate and 
90% confidence interval (CI) for the ratio of the geometric mean of 
Microgynon+GSK3036656 compared to Microgynon (within participant comparison), on 
the exposure (AUC(0-inf) and Cmax) of EE and LNG in healthy female participants who 
are missing no more than one 20 mg dose of GSK3036656 in treatment period 2 and are 
100% compliant with study treatments in treatment periods 1 and 3?  
The estimand is described by the following attributes: 
• 
Population: Healthy female participants of non-childbearing potential aged 18 to 65 
years.  
• 
Endpoints: Plasma PK parameters of EE and LNG: AUC(0-inf) and Cmax.  
• 
Treatments: single dose Microgynon +14 days GSK3036656 (Treatment Period 3) 
Vs single dose Microgynon  alone (Treatment Period 1) 
• 
Strategy for intercurrent event: The intercurrent events of interest are participants  
missing dose of Microgynon in treatment periods 1 and 3, missing dose of 
GSK3036656 in treatment period 3, or missing more than one 20 mg dose of 
GSK3036656 in treatment period 2. The strategy for handling all of these 
intercurrent events will be a Principal Stratum Strategy, where we are only interested 
in the strata of participants who are missing no more than one 20 mg dose of 
GSK3036656 in treatment period 2  and are 100% compliant with study treatments 
in treatment periods 1 and 3.  
• 
Population-level summary: The point estimate and 90% CI for the ratio of the 
geometric mean for each of EE AUC(0-inf) , LNG AUC(0-inf) , EE Cmax and LNG 
Cmax, for Microgynon+GSK3036656 (Treatment Period 3) compared to Microgynon 
alone (Treatment Period 1) (within participant comparison). 


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Rationale for estimand: Interest lies in estimating the effect of GSK3036656 on the 
pharmacokinetics of Microgynon, which cannot be accurately assessed in the situation 
where participants are missing more than one 20 mg dose of GSK3036656 in treatment 
period 2 and are not 100% compliant with study treatments in treatment periods 1 and 3.  
Primary estimands of secondary Pharmacokinetic endpoints 
Steady State PK of GSK3036656   
The clinical question of interest is:  
What are the estimates (mean/ median and variability) of steady state PK parameters 
(AUC(0-τ), Cmax, Cτ and Tmax) of GSK3036656 in the presence of EE/LNG in healthy 
female participants, who are missing no more than one 20 mg dose of GSK3036656 in 
treatment period 2 and are 100% compliant with study treatments in treatment period 3? 
The Primary Estimand is described by the following attributes: 
• 
Population: Healthy female participants of non-childbearing potential aged 18 to 65 
years. 
• 
Endpoints: AUC(0-τ), Cmax, Cτ and Tmax for GSK3036656 
• 
Treatments: single dose Microgynon+14 days GSK3036656 
• 
Strategy for intercurrent event:  The intercurrent events of interest are participants 
missing their dose of Microgynon during treatment period 3, or missing a dose of 
GSK3036656 in treatment period 3, or missing more than one 20 mg dose of 
GSK3036656 in treatment period 2. The strategy for handling all of these 
intercurrent events will be a Principal Stratum Strategy, where we are only interested 
in the strata of participants who are missing no more than one 20 mg dose of 
GSK3036656 in treatment period 2 and are 100% compliant with study treatments in 
treatment period 3.  
• 
Population-level summary:  
o For AUC(0-τ), Cmax, and Cτ of GSK3036656:  Descriptive Statistics (including 
n, Arithmetic means with 95% CI, Geometric means with 95% CI, CV%, SD, 
Median with Min, Max);  
o for Tmax of GSK3036656: Descriptive Statistics (including n, Median with Min, 
Max).  
Rationale for estimand: Interest lies in estimating the pharmacokinetics of GSK3036656 
in the presence of Microgynon, which cannot be accurately assessed in the situation 
where participants are missing more than one 20 mg dose of GSK3036656 in treatment 
period 2 and are not 100% compliant with study treatments in treatment period 3. 


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Pharmacokinetics of EE/LNG 
The clinical question of interest is:  
What are the estimates (mean/ median and variability) of  the PK parameters (AUC(0-τ), 
Tmax and t1/2) of EE and LNG with and without GSK3036656 in healthy female 
participants, who, for the estimates with GSK3036656 are missing no more than one 20 
mg dose of GSK3036656 in treatment period 2 and are 100% compliant with doses of 
GSK3036656 in treatment period 3? For the estimates of PK parameters of EE and LNG 
taken alone, no intercurrent events are defined. 
The Primary Estimand is described by the following attributes: 
• 
Population: Healthy female participants of non-childbearing potential aged 
18 to 65 years. 
• 
Endpoints: AUC(0-t), Tmax, Cmax and t1/2 for EE and LNG 
• 
Treatments: single dose Microgynon+ 14 daysGSK3036656 and single dose 
Microgynon 
Strategy for intercurrent event: The intercurrent events of interest, applicable to estimates 
of PK parameters for EE and LNG with GSK3036656 only, is participants missing one or 
more doses of  GSK3036656 in treatment period 3, or missing more than one 20 mg dose 
of GSK3036656 in treatment period 2. The strategy for handling this intercurrent events 
will be a Principal Stratum Strategy, where we are only interested in the strata of 
participants who are missing no more than one 20 mg GSK3036656 dose in treatment 
period 2 and are 100% compliant with doses of GSK3036656 in treatment period 3. For 
the estimates of PK parameters of EE and LNG taken alone, no intercurrent events are 
defined. 
• 
Population-level summary:  
o For AUC(0-t) and t1/2 (h) of EE and LNG:  Descriptive Statistics (including n, 
Arithmetic means with 95% CI, Geometric means with 95% CI, CV%, SD, 
Median with Min, Max);  
o for Tmax of EE and LNG: Descriptive Statistics (including n,  Median with Min, 
Max). 
Rationale for estimand: Interest lies in estimating the pharmacokinetics of Microgynon, 
with and without GSK3036656. The PK of Microgynon taken with GSK3036656 cannot 
be accurately assessed in the situation where participants are missing more than one 20 
mg dose of GSK3036656 in treatment period 2 or are not compliant with doses of 
GSK3036656 in treatment period 3. 


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Primary estimand of secondary Safety endpoints 
For all secondary safety endpoints the primary clinical question of interest:   
Are GSK3036656 and Microgynon, taken separately or together, safe and well tolerated 
in healthy female participants of non-childbearing potential aged 18 to 65 years, 
regardless of study treatment discontinuation and the level of compliance of either 
treatment? 
The primary estimands for Safety are described by the following attributes: 
Adverse Events/ Serious Adverse Events, Clinical laboratory assessments, ECG, and 
Vital Sign measurements: 
• 
Population: Healthy female participants of non-childbearing potential aged 18 to 65 
years. 
• 
Endpoints:  
o Incidence of serious adverse events within each treatment period. 
o Incidence of adverse events of grade 3 severity or higher within each treatment 
period. 
o Incidence of adverse events considered by the investigator to be possibly, 
probably or definitely related to study drug (overall and separately for 
Microgynon and GSK3036656) within each treatment period. 
o Incidence of participants withdrawn from the treatment/study due to adverse 
events within each treatment period. 
o Incidence of ECG values of PCI within each treatment period. 
o Incidence of clinical chemistry laboratory values of PCI within each treatment 
period. 
o Incidence of haematology laboratory values of PCI within each treatment period. 
o Incidence of vital signs parameters of SBP, DBP and HR of PCI within each 
treatment period.  
• 
Treatments: single dose Microgynon, once daily GSK3036656 and single dose 
Microgynon +once daily GSK3036656  
• 
Strategy for intercurrent event: The intercurrent events of interest are participants 
missing the dose of Microgynon, missing one or more doses of  GSK3036656 or 
discontinuing GSK3036656 early due to any reason. The strategy for handling these 
intercurrent events will be a Treatment Policy Strategy, where all safety data after 
the intercurrent event will be included.  
• 
Population-level summary: Frequency and percentage of participants; with the 
denominator for percentages being the number of participants entering the treatment 
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Rationale for estimand: It is important to document all safety issues that could potentially 
be attributable to the regimen, regardless of treatment non-compliance/discontinuation. 
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, safety, and tolerability of GSK3036656 and an oral contraceptive containing 
EE/LNG (Microgynon) when the oral contraceptive is administered alone and in 
combination with GSK3036656 in healthy female participants of non-childbearing 
potential.  
The study consists of a screening period, check-in to the inpatient facility for a single 
dose treatment period with Microgynon given alone followed by PK assessments for 
72 hours, then discharge. The participant immediately starts a 14-day treatment period 
with GSK3036656 and is readmitted to the clinic on Day 15 where they receive a single 
dose of Microgynon in combination with GSK3036656. The participant is discharged 
from the clinic on Day 18 following completion of the 14-day GSK3036656 treatment 
period and the 72 hour EE/LNG PK assessments. 
Participants will be screened within 14 days before the start of Treatment Period 1. The 
treatments are as follows: 
• 
Treatment Period 1: Microgynon (0.03 mg EE/0.15 mg LNG) single dose on Day 1 
of the treatment period.  
• 
Treatment Period 2: A loading dose of GSK3036656 40 mg on Day 4 then 
GSK3036656 20 mg od  from Day 5 to Day 14 
• 
Treatment Period 3: Microgynon (0.03 mg EE/0.15 mg LNG) single dose 
coadministered with GSK3036656 20 mg on Day 15 of Treatment Period 3, then 
GSK3036656 20 mg od alone  from Day 16 to Day 17.  
Participants will take the single dose of Microgynon in the morning after an overnight 
fasting (at least 8h) at approximately the same time in Treatment Periods 1 and 3. 
Participants should remain fasted until at least 4 hours post dose. 
Time of dose administration for GSK3036656 should be approximately 24 hours apart.  
Blood samples for the analysis of EE, LNG and GSK3036656 will be collected as per 
SoA. 
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 
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Study assessments will be performed as indicated in the  SoA Table 1. Participants will 
check into the clinic on Day 1 of Treatment period 1 and will remain confined until 
discharge on Day 4. Participants will be readmitted on Day 15 of Treatment Period 3 and 
will be discharged 72 hours later on Day 18 of Treatment Period 3. The duration of the 
study, including Screening, Treatment Period 1, Treatment Period 2, Treatment Period 3 
and Discharge, will be approximately 4 weeks. 
A study design schematic is presented in Section 1.2. 
4.2. 
Scientific rationale for study design 
This study was designed in accordance with the US FDA Guidance for Industry, Clinical 
Drug Interaction Studies - Study Design, Data Analysis, and Clinical Implications 
[DHHS, 2017] to assess the PK, safety, and tolerability of GSK3306656 and EE/LNG 
when administered alone and in combination. 
The study will only recruit WONCBP to reduce any risk to the participants and to remove 
the need for any additional contraceptive requirements beyond the COC. This will also 
mean that participants only need to be admitted to the clinic for an inpatient stay during 
the PK assessment periods, thus reducing burden on the participants. 
4.2.1. 
Participant input into design 
As this is a healthy volunteer clinical drug interaction study to assess PK, safety, and 
tolerability, there was no participant involvement in the study design, which had to 
conform to FDA requirements. However, every effort has been made to minimize the 
burden on the participants. 
4.3. 
Justification for dose 
The daily clinical dose of 20 mg of GSK3036656 was selected based on evaluation of the 
final efficacy data from the completed monotherapy early bactericidal activity study with 
GSK3036656. Exposure-Response analysis was utilised to determine the clinical steady-
state exposure associated with >90% of response (change from baseline in logCFU) and 
this was set as the targeted clinical exposure. Furthermore, a probabilistic analysis 
(PTA%) using both inter-subject variability and parameters’ uncertainty was conducted 
to ensure that >90% of patients would achieve the targeted clinical exposure.  
Based on this, a daily repeat dose of 20 mg of GSK3036656 will be used in the current 
study with a loading dose of 40 mg on Day 4 administered to ensure a PK profile that 
closely resembles steady-state by Day 8 of Treatment Period 2, thus allowing one week 
(from Day 8 to Day 15) for a potential enzyme induction to occur, while maintaining a 
14-day cycle of GSK3036656 administration.  


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4.4. 
End-of-study definition 
A participant is considered to have completed the study if the participant has completed 
all periods of the study including the last scheduled procedure shown in the SoA Table 1 
The end of the study is defined as the date of the last visit of the last participant in the 
study. 
5. 
STUDY POPULATION 
Prospective approval of protocol deviations to recruitment and enrollment 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 is 18 to 65 years of age, inclusive, at the time of signing the informed 
consent. 
Type of Participant and Disease Characteristics 
2. Participants who are healthy or compensated 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).  
3. A creatinine clearance ≥75 mL/min (Cockroft-Gault formula). 
4. Normal echocardiogram or echocardiogram with normal left ventricular function with 
at most trace to mild valvular regurgitation is allowed and no valvular stenosis. 
Weight 
5. Body weight ≥45.0 kg (99 lbs) and body mass index within the range 18.5 to 
31.0 kg/m2 (inclusive). 
Sex 
6. Female of Nonchildbearing Potential 
Women in the following categories are considered WONCBP: 
1. Permanently sterile due to one of the following procedures: 
a. 
Documented hysterectomy 
b. Documented bilateral salpingectomy 
c. 
Documented bilateral oophorectomy 


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For permanently sterile individuals due to an alternate medical cause other than 
the above, (e.g., Mullerian agenesis, androgen insensitivity, gonadal 
dysgenesis), investigator discretion should be applied to determining study 
entry. If reproductive status is questionable, additional evaluation should be 
considered. 
Note: Documentation can come from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview. 
2. 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 HRT. 
However, in the absence of 12 months of amenorrhea, confirmation with 
more than one FSH measurement is required, within the Screening period. 
• 
Females on HRT and whose menopausal status is in doubt must discontinue 
HRT at least 30 days prior to the start of Treatment Period 1 to allow 
confirmation of postmenopausal status before study enrollment 
Informed Consent 
7. Participant is capable of giving signed informed consent which includes compliance 
with the requirements and restrictions listed in the ICF and in the protocol. 
5.2. 
Exclusion criteria  
Participants are excluded from the study if any of the following criteria apply: 
5.2.1. 
Medical History 
1. History of known cardiac valve abnormalities 
5.2.2. 
Laboratory Assessments 
2. Presence of hepatitis B surface antigen at Screening or within 3 months prior to 
starting study treatment. 
3. Positive hepatitis C antibody test result at Screening or within 3 months prior to 
starting study treatment AND positive on reflex to hepatitis C RNA. 
4. Positive HIV-1 and -2 antigen/antibody immunoassay at Screening. 
5. Alanine aminotransferase (ALT) >1.5×ULN. A single repeat of ALT is allowed 
within a single screening period to determine eligibility. 
6. Bilirubin >1.5×ULN (isolated bilirubin >1.5×ULN is acceptable if bilirubin was 
fractionated and direct bilirubin <35%). 


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7. Any acute laboratory abnormality at Screening which, in the opinion of the 
investigator, should preclude participation in the study of an investigational 
compound.  
8. Participants with haemoglobin <8.0 g/dL 
9. Any Grade 2 to 4 laboratory abnormality at Screening, with the exception of creatine 
phosphokinase and lipid abnormalities (e.g., total cholesterol, triglycerides, etc), and 
ALT (described above), excludes a participant from the study unless the investigator 
provided 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. 
10. 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 
treatment. 
5.2.3. 
Prior/Concomitant Therapy 
11. Unable to refrain from the use of prescription or non-prescription drugs including 
vitamins, herbal and dietary supplements (including St John’s wort) within 7 days (or 
14 days if the drug is a potential enzyme inducer) or 5 half-lives (whichever is 
longer) prior to the first dose of study treatment 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. Levothyroxine and 
omeprazole may also be used during the study providing the participant has been on 
a stable dose for at least one month prior to the start of Treatment Period 1 and they 
maintain the same dose throughout the study. The dose of Microgynon should be 
administered at least one hour after the dose of levothyroxine or omeprazole). Other 
concomitant medications may be permitted on a case by case basis on the discretion 
of the medical monitor and the GSK ganfeborole team. 
12. Treatment with any vaccine within 30 days prior to receiving study treatment. 
13. Unwillingness to abstain from excessive consumption of any food or drink 
containing caffeine, grapefruit or grapefruit juice, Seville oranges, blood oranges, or 
pomelos or their fruit juices within 7 days prior to the first dose of study treatment(s) 
until the end of the study. 
14. The study will exclude participants who have undergone IVF or other assisted 
reproductive techniques within 9 months prior to screening, or are participating in 
such programs at the time of screening, or who plan to undergo IVF or other assisted 
reproductive techniques during the following year. 
5.2.4. 
Prior/Concurrent Clinical Study Experience 
15. 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 plus 10 days, or twice the duration of the biological effect of the 
investigational product (whichever is longer).  


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16. Where participation in the study results in donation of blood or blood products in 
excess of 500 mL within 56 days. 
5.2.5. 
Diagnostic Assessments 
17. Any significant arrhythmia or ECG finding (e.g., symptomatic bradycardia, non-
sustained or sustained atrial arrhythmias, non-sustained or sustained ventricular 
tachycardia, second-degree atrioventricular block Mobitz Type II, or third-degree 
atrioventricular block) which, in the opinion of the investigator or GSK Medical 
Monitor, would interfere with the safety for the individual participant. 
18. Exclusion criteria for screening ECG (a single repeat was allowed for eligibility 
determination): 
Heart rate1 
<50 or >100 beats per minute 
QTcF interval1,2 (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. A QTcF interval between 450 and 460msec can be rechecked by ECG within 30 minutes to verify 
eligibility. 
2. 
The corrected QT (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 is Fridericia’s formula. 
5.2.6. 
Other Exclusion Criteria 
19. Participants with vitiligo.  
20. Participants with hypertension or Type 2 diabetes that cannot be controlled with diet 
and exercise alone. 
21. 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. 
22. Unable to refrain from tobacco- or nicotine-containing products within 3 months 
prior to Screening. 
23. 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 
• 
Participants should arrive fasted for the Screening Visit and will be allowed to eat 
during the Screening Visit after blood draw for clinical chemistry has been 
completed. Participants should fast overnight(at least 8h) prior to dosing of 
Microgynon in Treatment Periods 1 and 3 and remain fasted until at least 4 hours 
post dose. 


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• 
Participants must refrain from any food or drink containing grapefruit or grapefruit 
juice, Seville oranges, blood oranges, or pomelos or their fruit juices within 7 days 
prior to the first dose of study treatment(s) until the end of the study. 
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 6 hours prior to admittance to the 
inpatient unit in treatment periods 1 and 3, and during each inpatient period. 
• 
Participants will abstain from alcohol for 24 hours prior to admittance to the 
inpatient unit in treatment periods 1 and 3, and during each inpatient period. 
• 
Use of tobacco products will not be allowed from 3 months prior to Screening until 
after the final visit. 
5.3.3. 
Activity 
• 
Participants will abstain from strenuous exercise for 4 hours before each blood 
collection for clinical laboratory tests. Participants may participate in light 
recreational activities during studies (e.g., watching television, reading). 
5.3.4. 
Other restrictions 
• 
Participants will be asked to refrain from donating blood for the duration of their 
study participation. 
5.4. 
Screen failures 
A screen failure occurs when a participant who has consented to participate in the clinical 
study is not subsequently assigned to study intervention. A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure participants to 
meet the CONSORT publishing requirements and to respond to queries from regulatory 
authorities. Minimal information includes demography, screen failure details, eligibility 
criteria, and any SAE. 
Individuals who do not meet the criteria for participation in this study (screen failure) 
may not be rescreened. 
5.5. 
Criteria for temporarily delaying enrollment 
Not applicable. 
6. 
STUDY INTERVENTION(S) AND CONCOMITANT 
THERAPY 
The definition of study intervention is provided in the table of definitions.  


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6.1. 
Study intervention(s) administered 
Study intervention is presented in Table 4 
Table 4 
Study Intervention(s) Administered 
Intervention Name 
GSK3036656 
Microgynon 
Type 
Drug 
Drug 
Dose Formulation 
Capsule 
Tablet 
Unit Dose Strength(s) 
20 mg 
Not Applicable 
Dosage Level(s) 
 
Treatment Period 1: 
Microgynon (0.03 mg EE/0.15 
mg LNG) QD on Day 1 of 
treatment period 1.  
Treatment Period 2 
A loading dose of 
GSK3036656 40 mg on Day 
4 of Treatment Period 2, then 
GSK3036656 20 mg od on 
Days 5-14 of Treatment 
Period 2. 
 
Treatment Period 3 
GSK3036656 20 mg 
coadministered with 
Microgynon on Day 15 of 
Treatment Period 3, then 
GSK3036656 20 mg od 
alone on Days 16-17 
Treatment Period 3 
Microgynon (0.03 mg EE/0.15 
mg LNG) QD coadministered 
with GSK3036656 20 mg on 
Day 15 of the treatment 
period. 
Route of Administration 
Oral 
Oral 
Use 
Experimental 
Background Intervention 
IMP and NIMP 
IMP 
 AxMP 
Sourcing 
Provided centrally by the 
Sponsor 
Commercial material sourced 
locally by the study site. 
Packaging and Labelling 
Study intervention will be 
provided in HDPE bottles. 
Each HDPE bottle Each 
HDPE bottle will be labelled 
as required per country 
requirement 
Microgynon will be labelled as 
per country requirement 
Current/Former Name(s) or 
Alias(es)] 
NA 
NA 
HDPE = high-density polyethylene; IMP = investigational medicinal product; NIMP = non-investigational medicinal 
product. 


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6.2. 
Preparation, handling, storage, and accountability 
• 
The investigator or designee must confirm appropriate conditions (e.g., temperature) 
have been maintained during transit for all study intervention received, and any 
discrepancies are reported and resolved before use of the study intervention. 
• 
Only participants enrolled in the study may receive study intervention, and only 
authorized site staff may supply, prepare, or administer study intervention. 
• 
All study intervention must be stored in a secure, environmentally controlled, and 
monitored (manual or automated) area in accordance with the labeled storage 
conditions with access limited to the investigator and authorized site staff. 
• 
The investigator, or authorized site staff is responsible for study intervention 
accountability, reconciliation, and record maintenance (i.e., receipt, reconciliation, 
and final disposition records). 
• 
Further guidance and information for the final disposition of unused study 
interventions are provided in the [pharmacy manual or other specified location]. 
• 
Under normal conditions of handling and administration, study intervention is not 
expected to pose significant safety risks to site staff.  
• 
A MSDS/equivalent document describing occupational hazards and recommended 
handling precautions either will be provided to the investigator, where this is 
required by local laws, or is available upon request from GSK. 
6.3. 
Assignment to study intervention 
This is an open label study. 
6.4. 
Study intervention compliance 
When participants are dosed at the site during the inpatient stays, 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.  
When participants self-administer study intervention(s) at home, compliance with study 
intervention will be assessed at each visit. Compliance will be assessed by direct 
questioning and counting returned capsules, and documented in the source documents 
and relevant form. A participant diary will be provided to capture dosing compliance. 
Deviation(s) from the prescribed dosage regimen should be recorded. 
A record of the quantity of GSK3036656 and Microgynon dispensed to and administered 
by each participant must be maintained and reconciled with study intervention and 
compliance records. Intervention start and stop dates, including dates for intervention 
delays and/or dose reductions will also be recorded. 


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6.5. 
Dose modification 
Not applicable 
6.6. 
Continued access to study intervention after the end of the 
study 
There is no continued access to study intervention following the end of this study as these 
are healthy volunteers. Participants will not require any additional care after they 
complete or discontinue the study as they are healthy volunteers. 
6.7. 
Treatment of overdose 
For this study, any dose of GSK3036656 greater than 20mg within a 24-hour time period, 
other than the loading dose of 40 mg on Day 4 of Treatment Period 2, will be considered 
an overdose. 
In the event of an overdose, the Investigator/treating physician should: 
1. Evaluate the participant to determine, in consultation with the medical monitor, if 
possible, whether study intervention should be interrupted or whether the dose 
should be reduced. 
2. Closely monitor the participant for any AE/SAE and laboratory abnormalities until 
GSK3036656 can no longer be detected systemically (at least 14 days), as medically 
appropriate. 
3. Obtain a plasma sample for PK analysis within 1-2 hours from the time of the last 
dose of study intervention. Additional samples may be 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 overdose. 
For any GSK3036656 overdose, GSK advises administration of activated charcoal if 
ingestion in the last 6 hours and supportive care. Any deliberate overdose would be 
reported as a grade 3 SAE (CTCAE) and would lead to immediate withdrawal from the 
study and referral to emergency services for charcoal and supportive care as well as 
review by a mental health professional. The GSK medical monitor should be contacted, 
and the participant should be observed as described above. 
For Microgynon, there is no risk of overdose as this will be administered to the 
participant on site as a single dose in Treatment Period 1 and a single dose in Treatment 
Period 3. 


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6.8. 
Prior and concomitant therapy 
Participants must abstain from taking prescription or nonprescription drugs (including 
vitamins, recreational drugs, and dietary or herbal supplements) within 7 days (or 14 days 
if the drug is a potential enzyme inducer) or 5 half-lives (whichever is longer) before the 
start of study intervention until completion of the follow-up visit, unless, in the opinion of 
the investigator and sponsor, the medication will not interfere with the study. 
Paracetamol, at doses of  2 grams/day and hydrocortisone cream 1%, are permitted for 
use any time during the study. Levothyroxine and omeprazole may also be used during 
the study providing the participant has been on a stable dose for at least one month prior 
to the start of Treatment Period 1 and they maintain the same dose throughout the study. 
The dose of Microgynon should be administered at least one hour after the dose of 
levothyroxine or omeprazole. Other concomitant medications may be considered on a 
case-by-case basis by the investigator in consultation with the medical monitor. 
7. 
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL 
7.1. 
Discontinuation of study intervention 
‘Discontinuation’ of study intervention refers to any participant who has not received all 
planned doses of the 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 should, if possible, continue other study 
procedures (e.g., safety) planned in the study protocol at the discretion of the investigator. 
If the participant does not agree to continue in-person visits, a modified follow-up must 
be arranged to ensure the collection of endpoints and safety information (e.g., telephone 
contact). See the SoA for data to be collected at the time of discontinuation of study 
intervention and follow-up and for any further evaluations that need to be completed. 
The primary reason for premature discontinuation of the study intervention will be 
documented in the eCRF based on the list below: 
Reasons 
Additional items/Sub-reasons 
AE 
 
Lost to follow-up 
Subject Relocated  
Subject was Incarcerated  
Other, specify 
Unknown 
Participant Reached Protocol-Defined 
Stopping Criteria 
 
Liver chemistry stopping criteria   
QTc Stopping criteria 
Haemotology stopping criteria   
Physician Decision 
Specify 


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Reasons 
Additional items/Sub-reasons 
Pregnancy 
  
Protocol Deviation 
Specify 
Site Terminated by Sponsor 
  
Study Terminated by Sponsor 
  
Withdrawal by Participant 
Burden of Procedure  
Participant Relocated  
Other 
Other 
Specify 
Death 
  
If the participant does not agree to continue in-person visits, a modified follow-up must 
be arranged to ensure the collection of endpoints and safety information. This could be a 
telephone contact with the participant, a contact with a relative or treating physician, or 
collecting information from medical records. The approach taken should be recorded in 
the medical records. A participant who agrees to modified follow-up is not considered to 
have withdrawn consent or to have withdrawn from the study. 
7.1.1. 
Liver chemistry stopping criteria 
Discontinuation of study intervention for abnormal liver tests is required by the 
investigator when a participant meets one of the conditions outlined in the algorithm or in 
the presence of abnormal liver chemistries not meeting protocol-specified stopping rules 
if the investigator believes that it is in best interest of the participant. 


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Phase 1 Liver Chemistry Stopping Criteria – Liver Stopping Event Algorithm 
 
Abbreviations: ALT = alanine transaminase; INR = international normalized ratio; SAE = serious adverse event; 
ULN = upper limit of normal. 
Refer to Section 10.4 for required Liver Safety Actions and Follow up Assessments. 
7.1.2. 
QTc Stopping criteria 
• 
If a clinically significant finding is identified (including, but not limited to changes 
from baseline in QT interval corrected using Fridericia’s formula [QTcF] after 
enrolment, the investigator or qualified designee will determine if the participant can 
continue the study intervention and if any change in participant management is 
needed. This review of the ECG printed at the time of collection must be 
documented. Any new clinically relevant finding should be reported as an AE. 
A participant that meets either bulleted criterion below based on average QTc values of 
triplicate ECGs over a brief recording period (See Section 8.3.3) will discontinue study 
intervention and will be withdrawn from study intervention. 
• 
QTcF > 500 msec, 
• 
Change from baseline in healthy participants: QTcF >60 msec 
7.1.3. 
Haematology Stopping Criteria 
IP will be discontinued for a participant if the following haematology stopping criteria 
are met (confirmed on two samples taken within 24 hours of each other) or at the 
discretion of the investigator in consultation with the medical monitor) and participants 
should be followed up until values are not clinically significant. 
• A reduction in haemoglobin to below 8.0 g/dL 


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• A reduction in neutrophil count to below 500/mm3 (0.5 × 109/L) 
7.1.4. 
Study Intervention Restart or Rechallenge After Liver Stopping 
Criteria Are Met 
Study intervention restart or rechallenge after liver chemistry stopping criteria are met by 
any participant in this study are not allowed. 
7.2. 
Participant discontinuation/withdrawal from the study 
A participant may withdraw from the study at any time at the participant’s own request 
for any reason (or without providing any reason). 
A participant may be withdrawn at any time at the discretion of the investigator for 
safety, behavioral, compliance or administrative reasons. 
Investigators will attempt to contact participants who do not return for scheduled visits or 
follow-up. 
At the time of discontinuing from the study, if possible, an ED visit should be conducted, 
as shown in the SoA. See SoA for data to be collected at the time of study discontinuation 
and follow-up and for any further evaluations that need to be completed. 
The participant will be permanently discontinued from the study intervention and the 
study at that time. 
All data and samples collected up to and including the date of withdrawal of/last contact 
with the participant will be included in the study analyses. 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, the participant may request destruction of any 
samples taken and not tested, and the investigator must document this in the site study 
records. 


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The primary reason for participant discontinuation/ withdrawal from the study will be 
documented in the eCRF based on the list below: 
Reasons 
Additional items/Sub-reasons 
AE 
 
Lost to follow-up 
Subject Relocated  
Subject was Incarcerated  
Other, specify 
Unknown 
Participant Reached Protocol-Defined 
Stopping Criteria 
 
Liver chemistry stopping criteria   
QTc Stopping criteria 
Haemotology stopping criteria   
Physician Decision 
Specify 
Pregnancy 
  
Protocol Deviation 
Specify 
Site Terminated by Sponsor 
  
Study Terminated by Sponsor 
  
Withdrawal by Participant 
Burden of Procedure  
Participant Relocated  
Other 
Other 
Specify 
Death 
  
Participants who are withdrawn from the study because of AEs/SAEs must be clearly 
distinguished from participants who are withdrawn for other reasons. Investigator will 
follow participants who are withdrawn from the study due to an AE/SAE until the event 
is resolved (see Section 10.3.4.5). 
7.3. 
Lost to follow-up 
A participant will be considered lost to follow-up if the participant repeatedly fails to 
return for scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic for a 
required study visit: 
• The site must attempt to contact the participant and reschedule the missed visit as 
soon as possible, counsel the participant on the importance of maintaining the 
assigned visit schedule and ascertain whether 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 


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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, the participant will be considered 
to have withdrawn from the study.  
8. 
STUDY ASSESSMENTS AND PROCEDURES 
• Study procedures and their timing are summarized in the Schedule of activities (SoA) 
Table 1. Protocol waivers or exemptions are not allowed. 
• 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. Subjects who have signed informed consent 
but are not eligible to proceed should be recorded in the eCRF with a status of ‘screen 
failure’. 
• Procedures conducted as part of the participant’s routine clinical management [(e.g., 
blood count)] and obtained before signing of the ICF may be utilized for screening or 
baseline purposes provided the procedures met the protocol-specified criteria and 
were performed within the timeframe 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 160 mL. 
Repeat or unscheduled samples may be taken for safety reasons or for technical issues 
with the samples. 
8.1. 
Administrative and baseline procedures 
8.1.1. 
Collection of demographic data 
Record demographic data such as date of birth, sex, race, and ethnicity in the 
participant’s eCRF.  
Collection of sex, race and ethnicity data is necessary to assess and monitor the diversity 
of the trial participants, and to determine if the trial participants are truly representative of 
the impacted population. 
8.1.2. 
Medical history 
Obtain the participant’s medical history by interviewing the participant and/or review of 
the participant’s medical records. Record any pre-existing conditions, signs and/or 
symptoms present prior to the first dose of study interventionin the eCRF. 


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8.2. 
Efficacy assessments 
Efficacy assessments are not evaluated in this study. 
8.3. 
Safety assessments 
Planned timepoints for all safety assessments are provided in the SoA. 
8.3.1. 
Physical examination/history directed physical examination 
• 
A complete physical examination will include, at a minimum, assessments of the 
skin, CV, respiratory, gastrointestinal, and neurological systems. Height (at 
Screening) and weight (at all scheduled timepoints) will also be measured and 
recorded. 
• 
A brief physical examination will include, at a minimum, assessments of the skin, 
lungs, CV system, and abdomen [liver and spleen]. 
• 
Investigators should pay special attention to clinical signs related to previous serious 
illnesses. 
8.3.2. 
Vital signs 
• 
Temperature, pulse rate, respiratory rate, and blood pressure will be assessed. 
• 
Blood pressure and pulse measurements will be assessed with a completely 
automated device. Position of the participant should be consistent across readings 
(e.g. semi-supine or supine). Manual techniques will be used only if an automated 
device is not available. 
• 
Blood pressure and pulse measurements must 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 at 
least 1 pulse and 1 blood pressure measurement. Where a measurement is abnormal 
or significantly different from previous measurements, a further 2 readings will be 
taken. When vital signs are measured in triplicate, values should be taken at least 1 
minute but not more than 5 minutes apart and recorded in the CRF. 
8.3.3. 
Electrocardiograms 
• 
Single 12-lead ECG will be obtained as outlined in the SoA (see Section 1.3) using 
an ECG machine that automatically calculates the heart rate and measures PR, QRS, 
uncorrected QT intervals. QTcF will be calculated using heart rate and QT by 
Friderica's formula. Refer to Section 7.1.2 for QTc withdrawal criteria and any 
additional QTc readings that may be necessary. 
• 
At Screening, ECGs will be measured in triplicate. In the event where triplicate ECG 
readings are required, 3 individual ECG tracings should be obtained as closely as 
possible in succession, but no more than 2 minutes apart. The full set of triplicates 


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should be completed in less than 10 minutes and the QTc must be based on the 
average of triplicated ECG readings.  
• 
Stopping criteria are described in Section 7.1.2. 
• 
At all other timepoints, a single ECG measurement should be taken. 
8.3.4. 
Clinical safety laboratory tests 
• 
See Section 10.2 for the list of clinical laboratory tests to be performed and the SoA 
(Section 1.3). 
• 
The investigator must review the laboratory results, document this review, and 
record any clinically significant changes occurring during the study as an AE. The 
laboratory results must be retained with source documents.  
• 
All laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 24 hours after the last dose of study intervention 
should be repeated until the values return to normal or baseline or are no longer 
considered clinically significant by the investigator or medical monitor. Further tests 
will be performed as required. 
o In the absence of a diagnosis, abnormal laboratory findings assessments or other 
abnormal results the investigator considers clinically significant will be recorded 
as an AE or SAE, if they meet the definition of an AE or SAE (refer to Sections 
10.3.1 and Section 10.3.2).  
o If clinically significant 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. 
o If laboratory values from non-protocol-specified laboratory tests performed at the 
institution’s local laboratory require a change in participant management or are 
considered clinically significant by the investigator (e.g, SAE or AE), then the 
results must be recorded. 
8.3.5. 
Pregnancy testing 
• 
All participants must perform a highly sensitive blood or urine pregnancy test before 
the administration of any dose of study intervention. The study intervention may 
only be administered if the pregnancy test is negative.  
• 
Refer to Section 8.4.5for the information on study continuation for participants who 
become pregnant during the study. 
8.3.6. 
Echocardiogram 
Transthoracic echocardiography/echocardiogram will be performed at Screening on all 
participants who have undergone all other screening assessments, have been found 
eligible for the study, and are willing to enrol into the study. The echocardiogram is used 
as a screening tool to assess heart function at baseline and will help assess for valve 
dysfunction. If the test is abnormal, the participant will be referred to a cardiologist and 
will be excluded from the study.  


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8.4. 
Adverse Events (AEs) serious adverse events (SAEs), and 
other safety reporting 
For definitions relating to safety information see Section 10.3 
The investigator and any qualified designees are responsible for detecting, documenting, 
and recording events that meet the definition of an AE or SAE and other safety 
information and remain responsible for following up AEs that are serious, considered 
related to the study intervention or study procedures, or that caused the participant to 
discontinue the study. (see Section 7). This includes events reported by the participant 
(or, when appropriate, by a caregiver, surrogate, or the participant’s legally authorized 
representative). 
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Section 10.3 
and/or Section 10.3.4. 
8.4.1. 
Time period and frequency for collecting AE, SAE, and other 
safety information 
All SAEs will be collected from the signing of the ICF until Day 18 of Treatment Period 
3 at the time points specified in the SoA.  
SAEs assessed as related to study participation (e.g., study intervention, protocol-
mandated procedures, invasive tests, or change in existing therapy) or related to a GSK 
product (non-IMP) will be recorded from the time a participant consents to participate in 
the study. 
All AEs will be collected from the start of study intervention until Day 18 of Treatment 
Period 3 at the timepoints specified in the SoA. 
Medical occurrences that begin before the start of study intervention but after obtaining 
informed consent will be recorded as medical history/current medical conditions, not as 
AEs. 
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 Section 10.3 and/or Section 
10.3.4. The investigator will submit any updated SAE data to the sponsor within 24 hours 
of it being available. 
A poststudy AE/SAE is defined as any event that occurs outside of the AE/SAE reporting 
period defined in Section 8.4.1. 
Investigators are not obligated to actively seek information on AEs or SAEs after 
conclusion of the study participation. However, if the investigator learns of any SAE, 
including a death, after a participant has been discharged from the study, the investigator 
must record it in the medical records. If the investigator considers the event to be 
reasonably related to the study intervention or study participation, the investigator must 
promptly notify the sponsor. 


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8.4.2. 
Method of detecting AEs and SAEs  
Care will be taken not to introduce bias when detecting AEs and SAEs. Open-ended and 
nonleading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences. 
8.4.3. 
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 resolution, 
stabilization, the event is otherwise explained, or the participant is lost to follow-up (as 
defined in Section 7.3). Further information on follow-up procedures is provided in 
Section 10.3.4.5. 
8.4.4. 
Regulatory reporting requirements for SAEs  
• 
Prompt notification by the investigator to the sponsor of an SAE is essential so 
that legal obligations and ethical responsibilities toward the safety of participants and 
the safety of a study intervention under clinical investigation are met. See 
[Section 8.4.1] for reporting timeframes. 
• 
For SAEs, the investigator must always provide an assessment of causality at the 
time of the initial report, as defined in the Section 10.3.4.6 
• 
An investigator who receives an investigator safety report describing an 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 IBand will notify the IRB/IEC, if 
appropriate according to local requirements. 
Table 5 
Timeframes for submitting SAE and pregnancy reports to GSK 
Type of event 
Initial reports 
Follow-up of relevant information on a 
previous report 
Timeframe 
Documents 
Timeframe 
Documents 
SAEs 
24 hours* ‡ 
AEs Report 
24 hours* 
AEs Report 
Pregnancies  
24 hours* 
Pregnancy 
Notification/Report  
24 hours * 
Pregnancy Follow-up Report  
* Timeframe allowed after receipt or awareness of the information by the investigator/site staff. 
‡ Paper AEs Report will be dated and signed by the investigator (or designee).  For each SAE, the 
investigator(s) must document in the medical notes that they have reviewed the SAE and have provided an 
assessment of causality. 
8.4.5. 
Pregnancy  
Female participants who become pregnant after the first study intervention dose must not 
receive subsequent doses of the study intervention but may continue other study 
procedures at the discretion of the investigator. 


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• 
Details of all pregnancies in female participants will be collected after the start of 
study intervention and until 30 days after the last dose of study intervention.  
• 
If a pregnancy is reported, the investigator will record pregnancy information on the 
appropriate form and submit it to the sponsor within 24 hours of learning of the 
female participant pregnancy. 
• 
Any pregnancy complication or elective termination of a pregnancy for medical 
reasons will be reported as an AE or SAE. 
• 
Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs and will be reported 
as such. 
• 
The participant will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow-up information on the participant and the neonate and 
the information will be forwarded to the sponsor. See Table 6 for reporting 
timeframes. 
• 
Any post study pregnancy-related SAE considered reasonably related to the study 
intervention by the investigator will be reported to the sponsor as described in 
Section 8.4.4. 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 in the study will 
be withdrawn from the study. 
8.4.6. 
Contact information for reporting SAEs  
Table 6 
Contact information for reporting SAEs 
Study contact for questions regarding SAEs 
 
Contact GSK’s local and/or medical contacts 
Contacts for reporting SAEs 
Available 24/24 hours and 7/7 days 
uk.gsk-rd-gcsp-ctsm-admin@gsk.com 
8.4.7. 
Participant card 
The investigator (or designee) must provide the participant with a “participant card” 
containing information about the clinical study. The participant must be instructed to 
always keep the participant card in their possession for the duration of the study. In an 
emergency, this card serves to inform the responsible attending physician, family 
member that the participant is in a clinical study and that relevant information may be 
obtained by contacting the investigator(s) or their back up. 
• New or updated information will be recorded on the originally completed form 
with all changes signed and dated by the investigator. 


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8.5. 
Pharmacokinetics 
Plasma samples will be used to evaluate the PK of GSK3036656, EE and LNG. Whole 
blood samples of approximately 2 mL will be collected for measurement of plasma 
concentrations of GSK3036656, EE, and LNG as specified in the SoA (Section 1.3).  
Additional timepoints may be added during the study if warranted and agreed upon 
between the investigator and the sponsor. The timing of sampling 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. 
Instructions for the collection (including the volume to be collected), handling and 
processing of biological samples will be provided by the sponsor in the laboratory 
manual. The actual date and time (24-hour clock time) of each sample will be recorded. 
• 
PK Samples will be analysed using an appropriately validated assay method.   
• 
Each whole blood sample will be processed into plasma and divided into separate 
aliquots and sent to the appropriate laboratory (pending the analysis required). 
Additional details for sample collection and processing are provided in the laboratory 
manual.   
• 
Genetic analyses will not be performed on these whole blood samples unless consent 
for this was included in the informed consent. Participant confidentiality will be 
maintained. 
8.6. 
Pharmacodynamics 
There are no pharmacodynamic endpoints in this study. 
8.7. 
Genetics 
Genetics are not evaluated in this study. 
8.8. 
Biomarkers 
Biomarkers are not evaluated in this study. 
8.9. 
Immunogenicity assessments 
Immunogenicity is not evaluated in this study. 
9. 
STATISTICAL CONSIDERATIONS 
The SAP will include a more technical and detailed description of the statistical analyses 
described in this section. This section is a summary of the planned statistical analyses of 
the most important endpoints including primary and key secondary endpoints. 


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9.1. 
Statistical hypothesis 
The primary objective, as outlined in Section 3, is planned to be addressed using formal 
hypothesis testing. For the primary estimand, the following (confirmatory) two 1-sided 
hypothesis is planned to be tested for Microgynon+GSK3036656 (Treatment Period 3) 
versus Microgynon alone (Treatment Period 1):  
H0: μtest /μref < 0.8 or μtest /μref >1.25 
Ha: 0.8 ≤ μtest /μref ≤1.25 
Where μtest is the geometric least squares (LS) mean for PK parameters (AUC(0-inf) and 
Cmax) of EE/LNG when coadministered with GSK3036656 and μref is the geometric LS 
mean for PK parameters of EE/LNG when administered alone. The hypothesis test will 
be assessed using Schuirmann’s two 1-sided t-test procedure with α=0.05 for each test 
[Shhuirmann, 1987] Each ratio will be compared to 0.8 and 1.25 as described above. 
Lack of effect (i.e. lack of a drug-drug interaction) will be demonstrated if the 90% 
confidence intervals (CIs) for both PK parameters (AUC(0-inf) and Cmax) for both EE 
and LNG are within 0.8 and 1.25 (four parameters in total).  
9.1.1. 
Multiplicity Adjustment  
Not applicable. Although there are four comparisons, the null hypothesis must be rejected 
in all four cases, so no adjustment to the type 1 error is required.   


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9.2. 
Analysis sets 
Analysis Set 
Definition / Criteria 
Analyses 
Evaluated 
Screened  
• 
All participants who signed the ICF and 
were screened for eligibility.  
• 
This population will be used for screen 
failure listing and summary. 
Study Population 
Enrolled 
• 
All participants who entered the study 
(who received study intervention or 
underwent a post screening study 
procedure).  
• 
Note screening failures (who never 
passed screening even if rescreened) and 
participants screened but never enrolled 
into the study (Met eligibility but not 
needed) are excluded from the Enrolled 
analysis set as they did not enter the 
study. 
Study Population 
Safety 
• 
All participants who received at least 1 
dose of study medication.  
• 
Participants will be analyzed according to 
the actual study intervention.  
• 
This population will be used for all 
demographic and safety summaries and 
listings. 
Safety 
PK 
• 
All participants in the Safety analysis set 
who had at least 1 non-missing PK 
assessment (NQ values will be considered 
as non-missing values).   
• 
Data will be reported according to the 
actual study intervention. 
• 
This population will be used for PK 
summary tables, statistical analysis tables, 
figures, and listings. 
PK 
 


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9.3. 
Statistical analyses 
9.3.1. 
General considerations/definitions  
Plasma EE, LNG, and GSK3036656 concentration-time data will be analyzed by the 
Clinical Pharmacology Modelling & Simulation department within GSK, using 
noncompartmental methods with Phoenix WinNonlin Version 8.3 or higher.  
Statistical analysis will be performed by Clinical Statistics, GSK. 
9.3.2. 
Primary endpoint(s)/estimand(s) analysis  
9.3.2.1. 
Definition of endpoint: Pharmacokinetic Analyses 
The primary objective of this study is to assess the effect of steady state exposure of 
GSK3036656 on the single dose PK of EE and LNG in healthy female participants of 
non-childbearing potential aged 18 to 65 years, who are missing no more than one 20 mg 
dose of GSK3036656 in treatment period 2 and are 100% compliant with study 
treatments in treatment periods 1 and 3. For the analyses planned in the following section, 
the potential intercurrent events that will be considered are participants missing a dose of 
Microgynon in treatment periods 1 and 3, or missing dose of GSK3036656 in treatment 
period 3, or missing more than one 20 mg dose of GSK3036656 in treatment period 2.  
Events leading to missing data are: participant withdrawal from study/ loss to follow-up, 
or missing PK assessments. Values below limit of quantification for PK should be 
included and are not considered as missing. 
The primary pharmacokinetic endpoints and attributes of the estimands are detailed in 
Section 3. 
9.3.2.2. 
Main Analytical Approach 
The primary analysis for the primary PK endpoints will be performed for the strata of 
participants able to adhere to treatment as defined in primary estimand framework, and 
included in the PK analysis set. Plasma concentrations of EE and LNG will be subjected 
to PK analyses using noncompartmental methods. 
• 
Based on the individual concentration-time data the following primary plasma 
parameters will be estimated: 
o EE (separately for Microgynon+GSK3036656 and Microgynon alone): AUC(0-
inf) and Cmax 
o LNG (separately for Microgynon+GSK3036656 and Microgynon alone): 
AUC(0-inf) and Cmax 
• 
Analyses will be performed on the natural logarithms of AUC(0-inf) and Cmax 
separately using linear mixed effect models with treatment as a fixed effect and 


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subject as a random effect. Effects will be estimated, and CIs will be constructed for 
the following treatment comparison: 
o Microgynon+GSK3036656 (Treatment Period 3) versus Microgynon alone 
(Treatment Period 1) 
• 
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 (including n, arithmetic mean, geometric mean, median, standard 
deviation, minimum, maximum, and coefficient of variation) for plasma EE and 
LNG PK parameter values will be presented by treatment. 
More details will be included in the SAP. 
9.3.2.3. 
Sensitivity Analysis  
Not applicable 
9.3.3. 
Secondary endpoint(s)/estimand(s) analyses  
9.3.3.1. 
Pharmacokinetics Endpoints  
Secondary PK objectives for this study are to characterize the steady state PK of 
GSK3036656 in the presence of EE/LNG and to characterize the single dose PK of 
EE/LNG alone and in the presence of GSK3036656, in healthy female participants. 
The secondary Pharmacokinetic endpoints and attributes of the estimands are detailed in 
in Section 3 "OBJECTIVES, ENDPOINTS AND ESTIMANDS". 
9.3.3.1.1. Main Analytical Approach 
• 
Plasma concentrations of GSK3036656, EE and LNG will be subjected to PK 
analyses using noncompartmental methods. 
• 
The analysis for the secondary PK endpoints will be performed for the participants 
included in the PK analysis set. 
• 
Based on the individual concentration-actual time data the following secondary 
plasma parameters will be estimated: 
o EE and LNG (separately for Microgynon+GSK3036656 and Microgynon alone): 
AUC(0-t), Tmax and t1/2  
o GSK3036656 (Microgynon+GSK3036656): AUC(0-τ), Cmax, Cτ and Tmax.  
• 
Summary statistics (including n, arithmetic mean, geometric mean, 95% CI, median, 
standard deviation, minimum, maximum, and coefficient of variation as appropriate) 
for plasma EE, LNG, and GSK3036656 PK parameter values will be presented by 
treatment. 
More details will be included in the SAP. 


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9.3.4. 
Safety Endpoints/ Estimand 
A secondary objective of this study is to assess that GSK3036656 and Microgynon taken 
alone or together are safe and well tolerated in healthy female participants of non-
childbearing potential. Safety endpoints assess the incidence of safety events (detailed in 
Table 3) occurring during each treatment period. 
The secondary safety endpoints and attributes of the estimands are detailed in Section 3. 
9.3.4.1. 
Main Analytical Approach 
All safety analyses will be performed on the Safety Population. Safety data will be 
presented in tabular format  by treatment groups (Microgynon, GSK3036656 and 
Microgynon+GSK3036656) and summarized descriptively according to GSK’s 
Integrated Data Standards Library standards. For each treatment group, the denominator 
for percentages (N) will be the number of participants entering the associated treatment 
period. No formal statistical analysis of the safety data will be conducted. The values of 
PCI for laboratory parameters, ECGs and vital signs will be detailed in the SAP. 
9.3.4.1.1. Adverse Events (AEs) 
Adverse events will be coded using the MedDRA (Medical Dictionaries for Regulatory 
Activities) coding system.  
Counting of AEs will be based on the number of participants, not the number of AEs. In 
addition to all adverse events, there will be separate summaries for: 
• 
SAEs 
• 
Severe AEs (AEs with a grade of 3 or higher) 
• 
Drug-related AEs 
o Microgynon 
o GSK3036656 
• 
AEs leading to study withdrawal 
• 
AEs leading to study treatment discontinuation 
9.3.4.1.2. Electrocardiograms (ECGs) 
ECG values relative to PCI criteria, will be summarized by treatment group, ECG 
parameter and category.  
9.3.4.1.3. Clinical Laboratory Values 
Haematology and clinical chemistry laboratory data, relative to PCI criteria, will be 
summarized by treatment group, laboratory test and category.  


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9.3.4.1.4. Vital Signs 
Vital sign data (SBP, DBP and HR), relative to PCI criteria, will be summarized by 
treatment group, vital sign and category.  
The details of the statistical analyses of Safety and tolerability data for adverse 
events/serious adverse events, observed and change from baseline clinical laboratory 
assessments, electrocardiograms, and vital sign measurements will be provided in the 
SAP. 
9.4. 
Interim analyses 
There will be no interim analysis performed. 
9.5. 
Sample size determination 
From the Adjusted gMean ratios and 90% CIs reported in the historical reference [Vonk, 
2022], CVw(%) has been obtained using the CVfromCI function from POWERTOST 
package in R software. The R CVfromCI function uses methodology described in Section 
9.5.1. CVw(%) values of 11.5%, 12.5%, 14.9%, 17.9% for EE AUC(0-inf), EE Cmax, 
LNG AUC(0-inf) and LNG Cmax respectively were calculated (Table 7). The largest 
CVw for the analytes and parameters is 17.9%. 
Table 7 
Intrasubject Coefficient of Variability (CVw%) for PK Parameters of 
EE and LNG 
Historical 
Reference 
Analyte 
Parameter 
n 
Adjusted 
gMean ratio 
(90% CI) 
CVw% 
Madelon C. Vonk, 
et al. 
EE 
AUC(0-inf)  
15 
101.2 
(94.0, 109.1) 
11.5 
Cmax 
15 
116.7 
(107.6, 126.5) 
12.5 
LNG 
AUC(0-inf)   
15 
88.1 
(80.0, 97.0) 
14.9 
Cmax 
15 
100.9 
(89.9, 113.2)  
17.9 
The true ratio of Microgynon+GSK3036646 versus Microgynon alone, is assumed to be 
1.0 for all 4 comparaisons, EE AUC(0-inf), EE Cmax, LNG AUC(0-inf) and LNG Cmax. 
In order to calculate the joint power for the four comparisons, a conservative between 
parameter correlation of 0.6 has been assumed; of note considering correlation of 1.0 
would increase the joint power by less than 1% for the same sample size. Based on these 
assumptions an evaluable sample size of 16 provides 92% (Table 8 ) joint power to 
ensure that the 90% CIs for the geometric mean ratios for all parameters lie within the 
range of 0.8 to 1.25. To account for an expected 20% rate of non-evaluable participants, 
approximately 20 participants will be enrolled to ensure at least 16 participants provide 
evaluable data in both test and reference periods. 


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Table 8 
Estimated Power and Sample Size Table 
Analyte 
Parameter 
n 
CVw% 
Power 
EE 
AUC(0-inf) 
16 
11.5 
99.98 
Cmax 
16 
12.5 
99.87 
LNG 
AUC(0-inf) 
16 
14.9 
98.66 
Cmax 
16 
17.9 
92.73 
Joint Power for all 4 comparisons  
16 
91.91 
Table 9 provides the 90% CIs for a range of possible observed ratios, for each assumed  
CVw%, with 16 estimated participants. 
Table 9 
Sample Size: Estimated Precision for Different Observed Effects 
Analyte 
Parameter 
n 
CVw% 
Observed Ratio Estimated 2-sided 
90% CI 
EE 
AUC(0-inf) 
16 
11.5 
0.90 
(0.84,  0.97) 
1.0 
(0.93,  1.07) 
1.10 
(1.02, 1.18) 
Cmax 
16 
12.5 
0.90 
(0.83,  0.97) 
1.0 
(0.93,  1.08) 
1.10 
(1.02,  1.19) 
LNG 
AUC(0-inf) 
16 
14.9 
0.90 
(0.82,  0.99) 
1.0 
(0.91,  1.10) 
1.10 
(1.00,  1.21) 
Cmax 
16 
17.9 
0.90 
(0.81,  1.01) 
1.0 
(0.90,  1.12) 
1.10 
(0.98,  1.23) 
9.5.1. 
Calculation of CVw from CI: 
The point estimate (PE, adjusted geometric mean) and the confidence interval limits have 
been obtained from historical reference. 
The number of subjects / sequence (example 2×2 cross-over), is obtained as follows: 
• 
If total sample size (N) is an even number, assume n1= n2= ½N 
• 
If N is an odd number, assume n1= ½N+ ½, n2= ½N–½ (not n1= n2 = ½N) 
The difference between the CL and the PE can be calculated as follows on the log-scale 
(using the CL which is given with the highest number of significant digits. 
𝛥𝐶𝐿= ln  (𝐶𝐿ℎ𝑖) −  ln(𝑃𝐸) |𝑜𝑟|  𝛥𝐶𝐿= ln(𝑃𝐸) −ln  (𝐶𝐿𝑙𝑜) 


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The Mean Square Error (MSE) is then calculated as follows: 
𝑀𝑆𝐸= 2
(
 
𝛥𝐶𝐿
√( 1
𝑛1 + 1
𝑛2) × 𝑡(1−2∝,𝑛1+𝑛2−2 )
     
)
 
2
 
And finally, the CVw is calculated from the MSE: 
𝐶𝑉𝑤% = 100 × √(𝑒𝑀𝑆𝐸−1) 
10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
10.1. 
Appendix 1: Regulatory, ethical, and study oversight 
considerations 
10.1.1. 
Regulatory and ethical considerations 
• This study will be conducted in accordance with the protocol and with the following: 
o 
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and CIOMS international ethical guidelines 
o 
Applicable ICH GCP guidelines 
o 
Applicable laws and regulations 
• The protocol, protocol amendments, ICF, IB, 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.  
• Protocols and any substantial amendments to the protocol will require health 
authority approval prior to initiation except for changes necessary to eliminate an 
immediate hazard to study participants. 
• The investigator will be responsible for the following, as applicable: 
o 
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 
o 
Notifying the IRB/IEC of SAEs or other significant safety findings as required 
by IRB/IEC procedures 
o 
Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, European regulation 


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536/2014 for clinical studies (if applicable), and all other applicable local 
regulations 
10.1.2. 
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. 
10.1.3. 
Informed consent process 
• The investigator or the investigator’s representative will explain the nature of the 
study, including the risks and benefits, to the participants and answer all questions 
regarding the study. 
• Potential participants must be informed that their participation is voluntary. They will 
be required to physically or digitally sign a statement of informed consent that meets 
the requirements of 21 CFR 50, local regulations, ICH guidelines, HIPAA 
requirements, privacy and data protection requirements, where applicable, and the 
IRB/IEC or study center. 
• The medical record must include a statement that physical or digital informed consent 
was obtained before the participant was enrolled in the study and the date the physical 
or digital consent was obtained. The authorized person obtaining the informed 
consent must also sign the ICF. 
• Participants must be reconsented to the most current version of the ICF(s) during their 
participation in the study. 
• A physical or digital copy of the ICF(s) must be provided to the participant. 
In case of unexpected pregnancy, participant must be informed that PI such as date of 
birth, sex of the baby will be collected as part of safety follow-up. Consent for the baby 
may be obtained from the participant and/or their partner as per local regulations.  
10.1.4. 
Recruitment strategy 
Participants will be identified for potential recruitment using clinical database and 
IEC/IRB-approved advertisements (e.g., newspaper, social media) prior to consenting to 
take part in this study. 
10.1.5. 
Data protection 
• Participants will be assigned a unique identifier by the investigator. 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. 


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• GSK will ensure protection of the personal data of the investigator and site staff 
which is collected within the framework of and for the purpose of the study. 
• The participant must be informed that their 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, that their data will be used as described in 
the informed consent. 
• The participant must be informed that their 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. 
• The contract between sponsor and study sites specifies responsibilities of the parties 
related data protection, including handling of data security breaches and respective 
communication and cooperation of the parties. 
• Information technology systems used to collect, process, and store study-related data 
are secured by technical and organizational security measures designed to protect 
such data against accidental or unlawful loss, alteration, or unauthorized disclosure or 
access. GSK and/or trusted third parties working on behalf of GSK and/or institutions 
working with GSK for the purposes of this study are contractually bound to protect 
participant coded data. GSK will protect participant coded data and will only share it 
as described in the ICF.n 
10.1.6. 
Committees structure 
A SRT is in place for each GSK product. It comprises of a global cross-functional team 
responsible for the ongoing assessment of benefit-risk for a product. The SRT contribute 
to the continual assessment of incoming new efficacy and safety information.  
10.1.7. 
Dissemination of Clinical Study Data 
• The key design elements of this protocol and results summaries will be posted on 
www.ClinicalTrials.gov and/or GSK Clinical Study Register in compliance with 
applicable regulations/GSK policy. GSK will aim to register protocols summaries 
prior to study start and target results summaries submission within 12 months of 
primary/ study completion date. Where external regulations require earlier disclosure, 
GSK will follow those timelines.  
• Where required by regulation, summaries will also be posted on applicable national 
or regional clinical study registers. 
• Where required by applicable regulatory requirements, an investigator signatory will 
be identified for the approval of the study report, and provided reasonable access to 
statistical tables, figures, and relevant reports. GSK will also provide the investigator 
with the full summary of the study results, including a summary of trial results 
understandable to laypersons. The investigator is encouraged to share the plain 
language summary with the study participants, as appropriate. The full study report 
will be made available upon request, after decision on marketing authorization by 
regulatory authorities. 


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• GSK will provide the investigator with the randomization codes and participant-level 
line listings for their site only after completion of the full statistical analysis. 
• GSK intends to make anonymized participant-level data from this study available to 
external researchers for scientific analyses or to conduct further research that can help 
advance medical science or improve patient care. This helps ensure the data provided 
by study participants are used to maximum effect in the creation of knowledge and 
understanding. 
10.1.8. 
Data quality assurance 
• All participant data relating to the study will be recorded on printed or electronic 
CRFs 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. 
• Guidance on completion of eCRFs will be provided in eCRF completion 
guidelines. 
• The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source documents. 
• QTLs will be predefined in the QTL plan to identify systematic issues that can impact 
participant right, safety and/or reliability of study results. These predefined 
parameters will be monitored during the study, and important deviations from the 
QTLs and remedial actions taken will be summarized in the CSR. 
• Monitoring details describing strategy, including definition of study critical data 
items and processes (e.g., risk-based initiatives in operations and quality such as risk 
management and mitigation strategies and analytical risk-based monitoring, 
involvement of central reading mechanism) 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). 
• 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 CSR/ 
equivalent summary unless local regulations or institutional policies require a 
different 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.  
• When copies of source documents are shared with external third parties contracted by 
GSK for review by a central reader mechanism (e.g., endpoint adjudication 
committee; expert reader), documents are stored by the external body for a minimum 
of 7 years. These documents will be used by the third party solely for the purpose 
indicated within this protocol.   


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10.1.9. 
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 eCRFor entered in the eCRF that are transcribed from source 
documents must be consistent with the source documents or the discrepancies must be 
explained. The investigator may need to request previous medical records or transfer 
records, depending on the study. Also, current medical records must be available. 
• Definition of what constitutes source data and its origin can be found in source data 
acknowledgment. 
• The investigator must maintain accurate documentation (source data) that supports 
the information entered in the eCRF. 
• The sponsor or designee will perform monitoring to confirm that data entered into the 
eCRF 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. 
• Copies of documents are shared with external third parties contracted by GSK for 
review by a central reader mechanism (e.g. endpoint adjudication committee; expert 
reader). The non-exhaustive list of documents shared to inform the central reader may 
include, discharge summaries, imaging reports, ECG reports etc. Participant names or 
any information which would make the participant identifiable or is not essential for 
the central reader mechanism will be redacted by the investigator sites prior to 
transfer.  Details of the list of documents and the redaction procedure are provided in 
the site manual or equivalent. These documents will be used by the third party solely 
for the purpose indicated within this protocol.  
10.1.10. 
Study and site start and closure 
Start of study and first act of recruitment 
The start of study and the first act of recruitment are defined as FSFV (first ICF signature 
date) at a country-level. 
Study/Site Termination 
GSK or designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of GSK. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study 
supplies have been collected and a study-site closure visit has been performed. 
The investigator may initiate study-site closure at any time, provided there is reasonable 
cause and sufficient notice is given in advance of the intended termination. 


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Reasons for the early closure of a study site by the sponsor or investigator may include 
but are not limited to: 
For study termination: 
• Discontinuation of further study intervention development 
For site termination: 
• 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 or no recruitment (evaluated after a reasonable amount of time) of 
participants by the investigator 
• Total number of participants included earlier than expected 
If the study is prematurely terminated or temporarily suspended, the sponsor shall 
promptly inform the investigators, the IECs/IRBs, the regulatory authorities, and any 
contract research organization(s) used in the study of the reason for termination or 
temporary suspension, as specified by the applicable regulatory requirements. The 
investigator shall promptly inform the participant and should assure appropriate 
participant therapy and/or follow-up. 
10.1.11. 
Publication policy 
The results of this study may be published in peer reviewed scientific literature and/or 
presented at scientific meetings. The sponsor will comply with the requirements for 
publication of study results in accordance with standard editorial and ethical practice and 
as per the sponsor’s internal policy. Authorship will be determined by mutual agreement 
and in line with ICMJE authorship requirements. 
10.2. 
Appendix 2: Clinical laboratory tests 
• The tests detailed in Table 10 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. 
• Investigators must document their review of each laboratory safety report. 


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Table 10 
Protocol-required safety laboratory tests 
Laboratory Tests 
Parameters 
Haematology 
Platelet count 
Red blood cell (RBC) count 
RBC indices: 
Mean corpuscular volume (MCV) 
Mean corpuscular hemoglobin (MCH) 
Hemoglobin 
Hematocrit 
%Reticulocytes 
WBC count with differential: 
Neutrophils 
Lymphocytes 
Monocytes 
Eosinophils 
Basophils 
Clinical chemistry1 Aspartate aminotransferase (AST)/serum glutamic-oxaloacetic transaminase 
(SGOT) 
Alanine aminotransferase (ALT)/serum glutamic-pyruvic transaminase 
(SGPT) 
Alkaline phosphatase2 
Total bilirubin 
Direct bilirubin 
Total protein 
Blood urea nitrogen (BUN)/Urea 
Potassium 
Creatinine* 
Sodium 
Calcium 
Glucose [indicate if fasting or nonfasting] 
Creatine phosphokinase (CPK) 
Homocysteine 
Antiphospholipid antibodies 
Sex hormone binding globulin (SHBG) 
Routine urinalysis Specific gravity 
pH, glucose, protein, blood, ketones, [bilirubin, urobilinogen, nitrite, leukocyte 
esterase] by dipstick 
Microscopic examination (if blood or protein is abnormal) 
Epithelial cells  
Red Blood cells  
WBC  
Casts 
Crystals  
Culture (if positive: specify pathogen) 
Pregnancy testing Highly sensitive [serum or urine] human chorionic gonadotropin (hCG) 
pregnancy test (as needed for WOCBP)3 


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Laboratory Tests 
Parameters 
Other screening 
tests 
Follicle stimulating hormone and estradiol (as needed in WONCBP only) 
[Serum or urine] [alcohol and drug screen (to include at minimum: 
amphetamines, barbiturates, cocaine, cotinine, opiates, cannabinoids and 
benzodiazepines)] 
[Serology [(HIV antibody 4th generation test, HBsAg, and HCV antibody)] 
SHBG 
NOTES: 
1. 
Details of liver chemistry stopping criteria and required actions and follow-up are given in Section 7.1.1 :Liver 
Chemistry Stopping Criteria and Section 10.4: Liver Safety: Suggested Actions and Follow-up Assessments [and 
Study Intervention Rechallenge Guidelines]]. All events of ALT [or AST] 3× ULN and total bilirubin 2×ULN 
(> 35% direct bilirubin) or ALT [or AST] 3×ULN and INR >1.5 (if INR measured), which may indicate severe liver 
injury (possible Hy’s law), must be reported to [sponsor] in 24 hours (excluding studies of hepatic impairment or 
cirrhosis). 
2. 
If alkaline phosphatase is elevated, consider fractionating. 
3. 
Local urine testing will be standard for the protocol unless serum testing is required by local regulation or IRB/IEC 
* To assess the kidney function, use the eGFR 2021 calculator 
10.3. 
Appendix 3: AEs and SAEs: Definitions and procedures for 
recording, evaluating, follow-up, and reporting 
10.3.1. 
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 (haematology, clinical chemistry, or 
urinalysis) or other safety assessments (e.g., ECG, radiological scans, vital signs 
measurements), including those that worsen from baseline, considered clinically 
significant in the medical and scientific judgment of the investigator (i.e., not 
related to progression of underlying disease). 
• Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition. 
• New condition 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 intervention- intervention 
interaction. 


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• 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 that occur as a result of protocol-mandated procedures (i.e. invasive 
procedures, modification of participant’s previous therapeutic regimen). 
Events NOT Meeting the AE Definition  
• 
Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments that are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition. 
• 
The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the 
participant’s condition. 
• 
Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that 
leads to the procedure is the AE. 
• 
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital, admission for routine examination.). 
• 
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. Pre-existing 
diseases will be recorded in the medical history section of the eCRF. 
• 
Hospitalization for elective treatment of a pre-existing condition (known or 
diagnosed before signing the informed consent) that did not worsen from baseline. 
• 
The event is, in the investigator’s opinion, of greater intensity, frequency, or 
duration than expected for the individual participant, or 
• 
The investigator considers that there is a reasonable possibility that the event was 
related to the administration of the study intervention 
10.3.2. 
Definition of SAE 
An SAE is defined as any untoward medical occurrence that, at any dose, meets one or 
more of the criteria listed: 
a. 
Results in death 
b. Is life threatening 
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, 
which hypothetically might have caused death, if it were more severe. 
c. 
Requires inpatient hospitalization or prolongation of existing hospitalization 
• 
In general, hospitalization signifies that the participant has been admitted (usually 
involving at least an overnight stay) at the hospital or emergency ward for 


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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. 
d. Results in persistent or significant 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) that may interfere with or 
prevent everyday life functions but do not constitute a substantial disruption. 
e. 
Is a congenital anomaly/birth defect in the offspring of a study participant 
f. 
Other situations: 
• 
Possible Hy’s Law case: ALT 3×ULN AND total bilirubin 2×ULN (>35% 
direct bilirubin) or INR >1.5 must be reported as SAE 
• 
Medical or scientific judgment should be exercised by the investigator in deciding 
whether SAE reporting is appropriate in other situations such as significant 
medical events that 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. 
o 
Examples of such events include invasive or malignant cancers, intensive 
treatment for allergic bronchospasm, blood dyscrasias, convulsions, or 
development of intervention dependency or intervention abuse. 
10.3.3. 
Definition of TEAE 
TEAE Definition: 
• 
A TEAE is an event that emerges during treatment, having been absent pre-
treatment or worsens relative to the pre-treatment state. 
10.3.4. 
Recording, assessment and follow-up of AE, SAE 
10.3.4.1. 
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 reports, and diagnostics 
reports) related to the event. 
• 
The investigator will then record all relevant AE/SAE information. 


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• 
It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to GSK in lieu of completion of the required form. 
• 
There may be instances when copies of medical records for certain cases are 
requested by GSK. In this case, all participant identifiers, with the exception of the 
participant number, will be redacted on the copies of the medical records before 
submission to GSK. 
• 
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not 
the individual signs/symptoms) will be documented as the AE/SAE. 
10.3.4.2. 
Assessment of intensity 
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and assign it to one of the following categories:  
• 
Mild: 
A type of AE that is usually transient and may require only minimal treatment or 
therapeutic intervention. The event does not generally interfere with usual activities 
of daily living. 
• 
Moderate:  
A type of AE that is usually alleviated with additional specific therapeutic 
intervention. The event interferes with usual activities of daily living, causing 
discomfort but poses no significant or permanent risk of harm to the research 
participant. 
• 
Severe:  
A type of AE that interrupts usual activities of daily living, or significantly affects 
clinical status, or may require intensive therapeutic intervention.   
10.3.4.3. 
Assessment of causality 
• 
The investigator is obligated to assess the relationship between study intervention 
and each occurrence of each AE/SAE. The investigator will use clinical judgment to 
determine the relationship. 
• 
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. 
• 
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. 
• 
For causality assessment, the investigator will also consult the IB and/or product 
information, for marketed products. 
• 
The investigator must review and provide an assessment of causality for each 
AE/SAE and document this in the medical notes. There may be situations in which 
an SAE has occurred and the investigator has minimal information to include in the 


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initial report to GSK. However, it is very important that the investigator always make 
an assessment of causality for every event before the initial transmission of the SAE 
data to GSK. 
• 
The investigator may change their opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality 
assessment. 
• 
The causality assessment is one of the criteria used when determining regulatory 
reporting requirements. 
10.3.4.4. 
Assessment of outcomes 
The investigator will assess the outcome of all serious and nonserious unsolicited AEs 
recorded during the study as: 
• 
Recovered/resolved 
• 
Recovering/resolving 
• 
Not recovered/not resolved 
• 
Recovered with sequelae/resolved with sequelae 
• 
Fatal (SAEs only). 
10.3.4.5. 
Follow-up of AEs and SAEs 
• 
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by GSK to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, 
or consultation with other health care professionals. 
• 
New or updated information will be recorded in the originally submitted documents. 
• 
The investigator will submit any updated SAE data to GSK within 24 hours of 
receipt of the information. 
After the initial AE/SAE or any other event of interest, 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. 
Other nonserious AEs must be followed until study completion or until the participant is 
lost to follow-up. 
Follow-up during the study 
AEs documented at a previous visit/contact and defined as not recovered/not resolved or 
recovering/resolving will be reviewed at subsequent visits/contacts until the final 
participant has completed the study. 


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If a participant dies during their participation in the study or during a recognized follow-
up period, GSK will be provided with any available postmortem findings, including 
histopathology. 
Follow-up of pregnancies 
Pregnant participants will be followed to determine the outcome of the pregnancy. At the 
end of the pregnancy, whether full-term or premature, information on the status of the 
mother and child will be forwarded to GSK using the paper pregnancy follow-up report 
and the AE Report if applicable. Generally, the follow-up period does not need to be longer 
than 6 to 8 weeks after the estimated date of delivery. 
Regardless of the reporting period for SAEs in this study, if the pregnancy outcome is an 
SAE, it should always be reported as such. 
Furthermore, the investigator must report any SAE occurring as a result of a poststudy 
pregnancy that is considered by the investigator to be reasonably related to the study 
intervention, to GSK as described in the Section 10.3.4.7 
10.3.4.6. 
Updating of SAE information after removal of write access to the 
participant’s eCRF 
When additional SAE information is received after write access to the participant’s eCRF 
is removed, new or updated information should be recorded on the appropriate paper 
report, with all changes signed and dated by the investigator. The updated report should 
be sent to the Study contact for reporting SAEs (refer to Section 8.4.3). 
10.3.4.7. 
Reporting of SAEs  
SAE Reporting to GSK via an Electronic Data Collection Tool 
• 
The primary mechanism for reporting an SAE to GSK will be the electronic data 
collection tool. 
• 
If the electronic system is unavailable, then the site will use the paper SAE data 
collection tool (see next section) to report the event within 24 hours. 
• 
The site will enter the SAE data into the electronic system as soon as it becomes 
available. 
• 
After the study is completed at a given site, the electronic data collection tool will be 
taken offline 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 offline, then the site can report this information on a paper SAE form (see next 
section) or to the medical monitor by telephone. 
• 
If the site during the course of the study or poststudy becomes aware of any serious, 
nonserious AEs, related to any GSK non-IMP they will report these events to GSK 


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or to the concerned competent authority via the national spontaneous reporting 
system.  These will be classified as spontaneous ICSRs. 
• 
Contacts for SAE reporting can be found in Section 8.4.6. 
SAE Reporting to GSK via Paper Data Collection Tool 
• 
Email/facsimile transmission of the SAE paper data collection tool is the preferred 
method to transmit this information to the medical monitor. 
• 
Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE data collection tool within the designated reporting 
timeframes. 
• 
Contacts for SAE reporting can be found in Section 8.4.6. 
10.4. 
Appendix 4: Liver safety: required and suggested actions 
and follow-up assessments  
Phase 1 Liver chemistry stopping criteria have been designed to assure subject safety and 
to evaluate liver event etiology. 
Phase 1 Liver Chemistry Stopping Criteria and Required Follow Up Assessments 
Liver Chemistry Stopping Criteria  
 
ALT-absolute 
ALT3×ULN 
If ALT3×ULN AND total bilirubin2×ULN (>35% direct bilirubin) or 
international normalized ratio (INR) >1.5, report as an SAE1,2. 
Required Actions, Monitoring and Follow up Assessments  
Actions 
Follow Up Assessments 
• Immediately discontinue study 
intervention 
• Report the event to GSK within 24 hours 
• Complete the liver event form and 
complete an SAE data collection tool if 
the event also meets the criteria for an 
SAE2 
• Perform liver event follow up 
assessments as described in the Follow 
Up Assessment column 
• Do not restart or rechallenge participant 
with study intervention  
• Monitor the participant until liver 
chemistries resolve, stabilize, or return 
• Viral hepatitis serology3 
• 
Obtain INR and recheck with each liver 
chemistry assessment until the 
aminotransferases values show 
downward trend 
• Obtain blood sample for PK analysis, 
as soon as possible after the most 
recent dose4  
• Obtain serum creatine phosphokinase 
(CPK), lactate dehydrogenase (LDH), 
gamma-glutamyl transferase (GGT), 
glutamate dehydrogenase (GLDH) and 
serum albumin 
• Fractionate bilirubin, if total bilirubin 
2×ULN 


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Liver Chemistry Stopping Criteria  
to within baseline (see MONITORING) 
MONITORING: 
If ALT3×ULN AND total bilirubin 2×ULN 
or INR >1.5 
• Repeat liver chemistries (include ALT, 
aspartate transaminase [AST], alkaline 
phosphatase, total 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 total bilirubin <2×ULN 
and INR 1.5: 
• Perform liver chemistries (include ALT, 
AST, alkaline phosphatase, total 
bilirubin and INR) and perform liver 
event follow up assessments within 
24-72 hours 
• Monitor participant weekly until liver 
chemistries resolve, stabilize or return 
to within baseline 
• Obtain complete blood count with 
differential to assess eosinophilia 
• Record the appearance or worsening5 
of clinical symptoms of liver injury, or 
hypersensitivity, on the liver event 
form 
• Record use of concomitant 
medications on the concomitant 
medications report form including 
acetaminophen, herbal remedies, 
recreational drugs, and other over-the-
counter medications 
• Record alcohol use on the liver event 
alcohol intake form 
 
If ALT3×ULN AND total bilirubin 2×ULN 
or INR >1.5 obtain the following in addition 
to the assessments listed above: 
• Anti-nuclear antibody, anti-smooth 
muscle antibody, Type 1 anti-liver 
kidney microsomal antibodies, and 
quantitative total immunoglobulin G 
(IgG) or gamma globulins 
• Serum acetaminophen adduct assay 
should be done (where available) to 
assess potential acetaminophen 
contribution to liver injury unless 
acetaminophen use is very unlikely in 
the preceding week (e.g., where the 
participant has been resident in the 
clinical unit throughout) 
• Liver imaging (ultrasound, magnetic 
resonance, or computed tomography) 
and /or liver biopsy to evaluate liver 
disease; complete Liver Imaging form. 
• Liver biopsy may be considered and 
discussed with local specialists if 
available, for instance: 
o In participants when serology 
raises the possibility of 
autoimmune hepatitis (AIH) 


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Liver Chemistry Stopping Criteria  
o In participants when suspected 
DILI progresses or fails to 
resolve on withdrawal of study 
intervention 
o In participants with acute or 
chronic atypical presentation. 
• If liver biopsy is conducted, then 
complete liver biopsy form 
1. 
Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not 
immediately available, discontinue study treatment for that subject if ALT  3xULN and bilirubin  2xULN.. 
Additionally, if serum bilirubin fractionation testing is unavailable, record presence of detectable urinary 
bilirubin on dipstick, indicating direct bilirubin elevations and suggesting liver injury.  
2. 
All events of ALT  3xULN and bilirubin  2xULN (>35% direct bilirubin) or ALT  3xULN and INR>1.5, if INR 
measured which may indicate severe liver injury (possible ‘Hy’s Law’), must be reported as an SAE (excluding 
studies of hepatic impairment or cirrhosis); INR measurement is not required and the threshold value stated 
will not apply to participants receiving anticoagulants 
3. 
Includes: Hepatitis A IgM antibody; Hepatitis B surface antigen (HbsAg) and Hepatitis B Core Antibody (IgM); 
Hepatitis C RNA; Cytomegalovirus IgM antibody; Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, 
obtain heterophile antibody or monospot testing);  Hepatitis E IgM antibody  
4. 
For PK sampling; record the date/time of the PK blood samples* draw and the date/time of the last dose of study 
treatment prior to PK blood sample draw on the CRF. If the date or time of the last dose is unclear, provide the 
participant’s best approximation. If the date/time of the last dose cannot be approximated OR a PK sample cannot 
be collected in the time period indicated above, do not obtain a PK sample. Instructions for sample handling and 
shipping are in the Lab Study Manual.*The following samples will be needed:a sample for Microgynon PK and a 
sample for both Trough and Serial PK of GSK3036656 
5. 
New or worsening symptoms believed to be related to liver injury (such as fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, or jaundice) or believed to be related to hypersensitivity (such as fever, rash or 
eosinophilia) 
10.5. 
Appendix 5: Protocol Amendment History 
The Protocol Amendment Summary of Changes Table for the current amendment is 
located directly before the Table of Contents (TOC). 


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11. 
REFERENCES 
D. J Shhuirmann. A comparison of the two one-sided tests procedure and the power 
approach for assessing the equivalence of average bioavailability. J Pharmacokinet 
Biopharm 1987 Dec;15(6):657-80. doi: 10.1007/BF01068419. 
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. 
EMA. European Medicines Agency; Guideline on good pharmacovigilance practices 
(GVP) Module XVI; 2022 
FDA. U.S Department of Health and Human Services Food and Drug Administration 
Center for Drug Evaluation and Research. Clinical Drug Interaction Studies With 
Combined Oral Contraceptives Guidance for Industry. June 2023. 
Vonk MC, Guillén-Del-Castillo A, Kreuter M, et al. A Drug-Drug Interaction Study to 
Investigate the Effect of Nintedanib on the Pharmacokinetics of Microgynon 
(Ethinylestradiol and Levonorgestrel) in Female Patients with Systemic Sclerosis-
Associated Interstitial Lung Disease. Eur J Drug Metab Pharmacokinet. 2022 
Jan;47(1):81-89. 
Microgynon. Summary of Product Characteristics, 2023. 
https://www.medicines.org.uk/emc/product/1130/smpc 
WHO (World Health Organization). Global tuberculosis report 2022 
http://www.who.int/tb 


Signature Page for  220104 TMF-19109333 v2.0
Signature Page for TMF-19109333 v2.0
Reason for signing: Approved
Name:
Role: Approver
Date of signature: 23-Apr-2024 11:06:16 GMT+0000
PPD

SAP_001.pdf: 
Statistical Analysis Plan
Study ID:  220104
Official Title of Study: A Phase 1, open-label, fixed sequence, 1-way drug-drug 
interaction study to investigate the pharmacokinetics, of GSK3036656 and an oral 
contraceptive containing ethinyl estradiol and levonorgestrel when the oral 
contraceptive is administered alone and in combination with GSK3036656 in 
healthy female participants of non-childbearing potential aged 18-65 years of age
NCT number: NCT06354257
Date of Document: 28-Mar-2024


CONFIDENTIAL 
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Page 1 of 39 
Information Type: 
Statistical Analysis Plan (SAP) 
TITLE PAGE 
Protocol Title: 
A Phase 1, open-label, fixed sequence, 1-way drug-drug 
interaction study to investigate the pharmacokinetics, of 
GSK3036656 and an oral contraceptive containing ethinyl 
estradiol and levonorgestrel when the oral contraceptive is 
administered alone and in combination with GSK3036656 in 
healthy female participants of non-childbearing potential aged 
18-65 years of age. 
Study Number: 
220104 
Compound Number: GSK3036656 
Abbreviated Title: 
PH1, A study to investigate the pharmacokinetics of a 
combined oral contraceptive when given alone and in 
combination with GSK3036656 in female participants of non-
childbearing potential aged 18 to 65 years of age. 
Sponsor Name: GlaxoSmithKline Research & Development Limited 
Regulatory Agency Identifier Number(s). 
Registry 
ID 
Clintrials.gov 
Not Available  
©2024 GSK group of companies or its licensor. 


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TABLE OF CONTENTS 
PAGE 
TITLE PAGE ................................................................................................................... 1 
VERSION HISTORY ....................................................................................................... 5 
1. 
INTRODUCTION ...................................................................................................... 6 
1.1. 
Objectives, Estimands and Endpoints ........................................................... 6 
1.2. 
Study Design .............................................................................................. 11 
2. 
STATISTICAL HYPOTHESES ............................................................................... 12 
2.1. 
Multiplicity Adjustment ................................................................................ 12 
3. 
ANALYSIS SETS ................................................................................................... 12 
4. 
STATISTICAL ANALYSES ..................................................................................... 13 
4.1. 
General Considerations .............................................................................. 13 
4.1.1. 
General Methodology .................................................................. 13 
4.1.2. 
Baseline Definition ....................................................................... 14 
4.2. 
Primary Endpoint(s) Analyses ..................................................................... 15 
4.2.1. 
Definition of endpoint(s)/estimands .............................................. 15 
4.2.1.1. 
Pharmacokinetic Parameters ...................................... 15 
4.2.2. 
Main analytical approach ............................................................. 18 
4.2.3. 
Sensitivity analyses ..................................................................... 19 
4.2.4. 
Additional estimands .................................................................... 19 
4.3. 
Secondary Endpoint(s) Analyses ................................................................ 19 
4.3.1. 
Secondary Pharmacokinetics Endpoints ...................................... 19 
4.3.1.1. 
Definition of [endpoint(s)/estimands] ........................... 19 
4.3.1.2. 
Main analytical approach (Pharmacokinetic 
analysis) ..................................................................... 20 
4.3.1.2.1. 
Pharmacokinetic Concentrations 
Listings ................................................... 20 
4.3.1.2.2. 
Pharmacokinetic Concentration 
Summary Tables .................................... 20 
4.3.1.2.3. 
Pharmacokinetic Concentration 
Figures ................................................... 21 
4.3.1.2.4. 
Pharmacokinetic Parameter 
Listings ................................................... 21 
4.3.1.2.5. 
Pharmacokinetic Parameter 
Summary Tables: ................................... 22 
4.3.2. 
Secondary Safety endpoint(s) ...................................................... 22 
4.3.2.1. 
Definition of [endpoint(s)/estimands] ........................... 22 
4.3.2.2. 
Main analytical approach ............................................ 22 
4.3.2.2.1. 
Adverse Events (AEs) ............................. 22 
4.3.2.2.2. 
Electrocardiograms (ECGs) .................... 23 
4.3.2.2.3. 
Clinical Laboratory Values ...................... 23 
4.3.2.2.4. 
Vital Signs .............................................. 23 
4.4. 
Other Safety Analyses ................................................................................ 23 
4.4.1. 
Additional Safety Assessments .................................................... 24 
4.4.1.1. 
Laboratory Data .......................................................... 24 
4.4.1.2. 
Vital Signs .................................................................. 24 


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4.4.1.3. 
ECG ........................................................................... 24 
4.5. 
Other Analyses ........................................................................................... 25 
4.5.1. 
Subgroup analyses ...................................................................... 25 
4.5.2. 
Analyses to Support Regional Submission ................................... 25 
4.6. 
Interim Analyses ......................................................................................... 25 
4.7. 
Changes to Protocol Defined Analyses ....................................................... 25 
5. 
SAMPLE SIZE DETERMINATION ......................................................................... 25 
5.1.1. 
Calculation of CVw from CI: ......................................................... 27 
6. 
SUPPORTING DOCUMENTATION ....................................................................... 27 
6.1. 
Appendix 1 Study Population Analyses ....................................................... 27 
6.1.1. 
Participant Disposition ................................................................. 28 
6.1.2. 
Demographic and Baseline Characteristics .................................. 28 
6.1.3. 
Protocol Deviations ...................................................................... 28 
6.1.4. 
Prior and Concomitant Medications ............................................. 28 
6.1.5. 
Study Intervention Compliance .................................................... 29 
6.2. 
Appendix 2 Data Derivations Rule .............................................................. 30 
6.2.1. 
Change from Baseline ................................................................. 30 
6.2.2. 
Pharmacokinetic Parameters ....................................................... 30 
6.2.3. 
Criteria for Potential Clinical Importance ...................................... 30 
6.2.3.1. 
Laboratory Values ...................................................... 31 
6.2.3.2. 
ECG Values................................................................ 32 
6.2.3.3. 
Vital Signs .................................................................. 33 
6.2.4. 
Study Period ................................................................................ 33 
6.2.5. 
Study Day, Reference Dates and Period Day .............................. 33 
6.2.6. 
Assessment Window ................................................................... 34 
6.2.7. 
Multiple measurements at One Analysis Time Point .................... 34 
6.2.8. 
Handling of Partial Dates ............................................................. 34 
6.2.9. 
List of Abbreviations .................................................................... 36 
6.2.10. 
Trademarks ................................................................................. 38 
7. 
REFERENCES ....................................................................................................... 39 
 


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LIST OF TABLES 
PAGE 
Table 1: 
 Objectives, Estimands and Endpoints ..................................................... 6 
Table 2: 
 Baseline Assessment ............................................................................ 14 
Table 3: 
 Pharmacokinetic Parameter and Estimation .......................................... 16 
Table 4: 
Intrasubject Coefficient of Variability (CVw%) for PK Parameters 
of EE and LNG ....................................................................................... 26 
Table 5: 
Estimated Power and Sample Size Table............................................... 26 
Table 6:  
Sample Size: Estimated Precision for Different Observed Effects .......... 26 
 


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VERSION HISTORY 
SAP Version 
Approval Date 
Protocol 
Version 
(Date) on 
which SAP 
is Based 
Change 
Rationale 
SAP 
28 Mar 2024 
Protocol 
Version 1 
(06 
November 
2023) 
Not 
Applicable 
Original version 


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1. 
INTRODUCTION 
• 
The purpose of this SAP is to describe the planned analyses and output to be 
included in the Clinical Study Report for Protocol 220104. 
• 
This SAP is intended to describe the full analyses required for the study. 
• 
This SAP will be provided to the study team members to convey the content of the 
Statistical Analysis Complete (SAC) deliverable. 
1.1. 
Objectives, Estimands and Endpoints 
The study objectives and endpoints are presented in Table 1 
Table 1: 
 Objectives, Estimands and Endpoints 
Objectives 
Endpoints 
Primary 
 
• 
To assess the effect of steady state 
exposure of GSK3036656 on the single 
dose PK of EE and LNG in healthy female 
participants of non-childbearing potential 
• 
Area under the plasma concentration-
time curve to infinity AUC(0-inf) and 
maximum observed concentration (Cmax), 
after a single dose of EE and LNG (EE 
AUC(0-inf), EE Cmax, LNG AUC(0-inf), LNG 
Cmax) 
Secondary 
 
• 
To characterize the steady state PK of 
GSK3036656 in the presence of EE/LNG 
• 
AUC(0-τ), Cmax, Cτ (Day 8, 10, 12, 15 and 
16) and time of maximum observed 
concentration (Tmax) for GSK3036656 
• 
To characterize the single dose PK of 
EE/LNG alone and in the presence of 
GSK3036656 
• 
AUC(0-t), Tmax and t1/2 for EE and LNG, in 
Treatment Period 1 and Treatment 
Period 3. 
• 
To assess the safety and tolerability of 
GSK3036656 and Microgynon when given 
alone or in combination in healthy female 
participants of non-childbearing potential 
• 
Incidence of SAEs within each treatment 
period. 
• 
Incidence of AEs of grade 3 severity or 
higher within each treatment period. 
• 
Incidence of AEs considered by the 
investigator to be possibly, probably, or 
definitely related to study drug within 
each treatment period (overall and 
separately for relationship to Microgynon 
and to GSK3036656). 
• 
Incidence of participants withdrawn from 
the treatment/study due to adverse 
events within each treatment period. 
• 
Incidence of ECG values of PCI within 
each treatment period. 


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Objectives 
Endpoints 
• 
Incidence of clinical chemistry laboratory 
values of PCI within each treatment 
period. 
• 
Incidence of hematology laboratory 
values of PCI within each treatment 
period. 
• 
Incidence of vital signs parameters of 
systolic blood pressure (SBP), diastolic 
blood pressure (DBP) and heart rate 
(HR) of PCI within each treatment period. 
PRIMARY ESTIMAND 
The primary clinical question of interest is:  
What is the effect of treatment with GSK3036656, estimated by the point estimate and 
90% confidence interval (CI) for the ratio of the geometric mean of 
Microgynon+GSK3036656 compared to Microgynon (within participant comparison), on 
the exposure (AUC(0-inf) and Cmax) of EE and LNG in healthy female participants who are 
missing no more than one 20 mg dose of GSK3036656 in treatment period 2 and are 
100% compliant with study treatments in treatment periods 1 and 3?  
The estimand is described by the following attributes: 
• 
Population: Healthy female participants of non-childbearing potential aged 18 to 65 
years.  
• 
Endpoints: Plasma PK parameters of EE and LNG: AUC(0-inf) and Cmax.  
• 
Treatments: single dose Microgynon +14 days GSK3036656 (Treatment Period 3) 
Vs single dose Microgynon alone (Treatment Period 1) 
• 
Strategy for intercurrent event: The intercurrent events of interest are participants 
missing dose of Microgynon in treatment periods 1 and 3, missing dose of 
GSK3036656 in treatment period 3, or missing more than one 20 mg dose of 
GSK3036656 in treatment period 2. The strategy for handling all of these 
intercurrent events will be a Principal Stratum Strategy, where we are only interested 
in the strata of participants who are missing no more than one 20 mg dose of 
GSK3036656 in treatment period 2 and are 100% compliant with study treatments in 
treatment periods 1 and 3.  
• 
Population-level summary: The point estimate and 90% CI for the ratio of the 
geometric mean for each of EE AUC(0-inf), LNG AUC(0-inf), EE Cmax and LNG Cmax, 
for Microgynon+GSK3036656 (Treatment Period 3) compared to Microgynon alone 
(Treatment Period 1) (within participant comparison). 
Rationale for estimand: Interest lies in estimating the effect of GSK3036656 on the 
pharmacokinetics of Microgynon, which cannot be accurately assessed in the situation 
where participants are missing more than one 20 mg dose of GSK3036656 in treatment 
period 2 and are not 100% compliant with study treatments in treatment periods 1 and 3.  


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Primary estimands of secondary Pharmacokinetic endpoints 
Steady State PK of GSK3036656   
The clinical question of interest is:  
What are the estimates (mean/ median and variability) of steady state PK parameters 
(AUC(0-τ), Cmax, Cτ and Tmax) of GSK3036656 in the presence of EE/LNG in healthy 
female participants, who are missing no more than one 20 mg dose of GSK3036656 in 
treatment period 2 and are 100% compliant with study treatments in treatment period 3? 
The Primary Estimand is described by the following attributes: 
• 
Population: Healthy female participants of non-childbearing potential aged 18 to 65 
years. 
• 
Endpoints: AUC(0-τ), Cmax, Cτ and Tmax for GSK3036656 
• 
Treatments: single dose Microgynon+14 days GSK3036656 
• 
Strategy for intercurrent event:  The intercurrent events of interest are participants 
missing their dose of Microgynon during treatment period 3, or missing a dose of 
GSK3036656 in treatment period 3, or missing more than one 20 mg dose of 
GSK3036656 in treatment period 2. The strategy for handling all of these 
intercurrent events will be a Principal Stratum Strategy, where we are only interested 
in the strata of participants who are missing no more than one 20 mg dose of 
GSK3036656 in treatment period 2 and are 100% compliant with study treatments in 
treatment period 3.  
• 
Population-level summary:  
− 
For AUC(0-τ), Cmax, and Cτ  of GSK3036656:  Descriptive Statistics (including n, 
Arithmetic means with 95% CI, Geometric means with 95% CI, CV%, SD, 
Median with Min, Max);  
− 
for Tmax of GSK3036656: Descriptive Statistics (including n, Median with Min, 
Max).  
Rationale for estimand: Interest lies in estimating the pharmacokinetics of GSK3036656 
in the presence of Microgynon, which cannot be accurately assessed in the situation 
where participants are missing more than one 20 mg dose of GSK3036656 in treatment 
period 2 and are not 100% compliant with study treatments in treatment period 3. 


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Pharmacokinetics of EE/LNG 
The clinical question of interest is:  
What are the estimates (mean/ median and variability) of the PK parameters (AUC(0-t), 
Tmax and t1/2) of EE and LNG with and without GSK3036656 in healthy female 
participants, who, for the estimates with GSK3036656 are missing no more than one 20 
mg dose of GSK3036656 in treatment period 2 and are 100% compliant with doses of 
GSK3036656 in treatment period 3? For the estimates of PK parameters of EE and LNG 
taken alone, no intercurrent events are defined. 
The Primary Estimand is described by the following attributes: 
• 
Population: Healthy female participants of non-childbearing potential aged 
18 to 65 years. 
• 
Endpoints: AUC(0-t), Tmax , and t1/2 for EE and LNG 
• 
Treatments: single dose Microgynon+ 14 days GSK3036656 and single dose 
Microgynon 
Strategy for intercurrent event: The intercurrent events of interest, applicable to estimates 
of PK parameters for EE and LNG with GSK3036656 only, is participants missing one or 
more doses of GSK3036656 in treatment period 3, or missing more than one 20 mg dose 
of GSK3036656 in treatment period 2. The strategy for handling this intercurrent events 
will be a Principal Stratum Strategy, where we are only interested in the strata of 
participants who are missing no more than one 20 mg GSK3036656 dose in treatment 
period 2 and are 100% compliant with doses of GSK3036656 in treatment period 3. For 
the estimates of PK parameters of EE and LNG taken alone, no intercurrent events are 
defined. 
• 
Population-level summary:  
− 
For AUC(0-t) and t1/2 (h) of EE and LNG:  Descriptive Statistics (including n, 
Arithmetic means with 95% CI, Geometric means with 95% CI, CV%, SD, 
Median with Min, Max);  
− 
for Tmax of EE and LNG: Descriptive Statistics (including n, Median with Min, 
Max). 
Rationale for estimand: Interest lies in estimating the pharmacokinetics of Microgynon, 
with and without GSK3036656. The PK of Microgynon taken with GSK3036656 cannot 
be accurately assessed in the situation where participants are missing more than one 20 
mg dose of GSK3036656 in treatment period 2 or are not compliant with doses of 
GSK3036656 in treatment period 3. 


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Primary estimand of secondary Safety endpoints 
For all secondary safety endpoints the primary clinical question of interest:   
Are GSK3036656 and Microgynon, taken separately or together, safe and well tolerated 
in healthy female participants of non-childbearing potential aged 18 to 65 years, 
regardless of study treatment discontinuation and the level of compliance of either 
treatment? 
The primary estimands for Safety are described by the following attributes: 
• 
Population: Healthy female participants of non-childbearing potential aged 18 to 65 
years. 
• 
Endpoints:  
− 
Incidence of serious adverse events within each treatment period. 
− 
Incidence of adverse events of grade 3 severity or higher within each treatment 
period. 
− 
Incidence of adverse events considered by the investigator to be possibly, 
probably or definitely related to study drug (overall and separately for 
Microgynon and GSK3036656) within each treatment period. 
− 
Incidence of participants withdrawn from the treatment/study due to adverse 
events within each treatment period. 
− 
Incidence of ECG values of PCI within each treatment period. 
− 
Incidence of clinical chemistry laboratory values of PCI within each treatment 
period. 
− 
Incidence of haematology laboratory values of PCI within each treatment 
period. 
− 
Incidence of vital signs parameters of SBP, DBP and HR of PCI within each 
treatment period.  
• 
Treatments: single dose Microgynon, once daily GSK3036656 and single dose 
Microgynon +once daily GSK3036656  
• 
Strategy for intercurrent event: The intercurrent events of interest are participants 
missing the dose of Microgynon, missing one or more doses of GSK3036656 or 
discontinuing GSK3036656 early due to any reason. The strategy for handling these 
intercurrent events will be a Treatment Policy Strategy, where all safety data after 
the intercurrent event will be included.  
• 
Population-level summary: Frequency and percentage of participants; with the 
denominator for percentages being the number of participants entering the treatment 
period. 
Rationale for estimand: It is important to document all safety issues that could potentially 
be attributable to the regimen, regardless of treatment non-compliance/discontinuation. 


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1.2. 
Study Design 
Overview of Study Design and Key Features 
 
Design 
Features 
• 
A Phase 1, open-label, fixed-sequence, 1-way DDI study. 
• 
Participants will be screened within 14 days before the start of 
Treatment Period 1. The treatment periods are then as follows: 
− 
Treatment Period 1: Microgynon only 
− 
Treatment Period 2: GSK3036656 only 
− 
Treatment Period 3: Microgynon + GSK3036656 
• 
Approximately 20 participants will be enrolled to ensure at least 16 
participants provide evaluable data in both test and reference 
periods. 
Study 
intervention 
• 
Treatment Period 1: Microgynon (0.03 mg EE/0.15 mg LNG) 
single dose on Day 1 of the treatment period.  
• 
Treatment Period 2: A loading dose of GSK3036656 40 mg on 
Day 4 then GSK3036656 20 mg od from Day 5 to Day 14. 
• 
Treatment Period 3: Microgynon (0.03 mg EE/0.15 mg LNG) 
single dose co-administered with GSK3036656 20 mg on Day 15, 
then GSK3036656 20 mg od alone from Day 16 to Day 17. 
Study 
intervention 
Assignment 
• 
This is an open-label study. All eligible participants will receive 
the same treatments.  
Interim 
Analysis 
• 
No interim analysis is planned for this study.  


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2. 
STATISTICAL HYPOTHESES  
The primary objective, as outlined in Section 1.1, is planned to be addressed using formal 
hypothesis testing. For the primary estimand, the following (confirmatory) two 1-sided 
hypothesis is planned to be tested for Microgynon+GSK3036656 (Treatment Period 3) 
versus Microgynon alone (Treatment Period 1):  
H0: µtest /µref < 0.8 or µtest /µref >1.25 
Ha: 0.8 ≤ µtest /µref ≤1.25 
Where µtest is the geometric least squares (LS) mean for PK parameters (AUC(0-inf) and 
Cmax) of EE/LNG when coadministered with GSK3036656 and µref is the geometric LS 
mean for PK parameters of EE/LNG when administered alone. The hypothesis test will 
be assessed using Schuirmann’s two 1-sided t-test procedure with α=0.05 for each test 
[D. J Shhuirmann, 1987]. Each ratio will be compared to 0.8 and 1.25 as described above. 
Lack of effect (i.e. lack of a drug-drug interaction) will be demonstrated if the 90% 
confidence intervals (CIs) for both PK parameters (AUC(0-inf) and Cmax) for both EE and 
LNG are within 0.8 and 1.25 (four parameters in total). 
2.1. 
Multiplicity Adjustment 
Not applicable. Although there are four comparisons, the null hypothesis must be rejected 
in all four cases, so no adjustment to the type 1 error is required.   
3. 
ANALYSIS SETS 
Analysis Set 
Definition / Criteria 
Analyses 
Evaluated 
Screened  
• 
All participants who signed the ICF and were 
screened for eligibility.  
• 
This population will be used for screen failure 
listing and summary. 
Study Population 
Enrolled 
• 
All participants who entered the study (who 
received study intervention or underwent a 
post screening study procedure).  
• 
Note screening failures (who never passed 
screening even if rescreened) and participants 
screened but never enrolled into the study 
(Met eligibility but not needed) are excluded 
from the Enrolled analysis set as they did not 
enter the study. 
Study Population 
Safety 
• 
All participants who received at least 1 dose of 
study medication.  
• 
Participants will be analyzed according to the 
actual study intervention.  
Safety 


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Analysis Set 
Definition / Criteria 
Analyses 
Evaluated 
• 
This population will be used for all 
demographic and safety summaries and 
listings. 
PK 
• 
All participants in the Safety analysis set who 
had at least 1 non-missing PK assessment 
(NQ values will be considered as non-missing 
values).   
• 
Data will be reported according to the actual 
study intervention. 
• 
This population will be used for PK summary 
tables, statistical analysis tables, figures, and 
listings. 
PK 
4. 
STATISTICAL ANALYSES 
4.1. 
General Considerations 
Plasma EE, LNG, and GSK3036656 concentration-time data will be analyzed by the 
Clinical Pharmacology Modelling & Simulation department, Parexel, using 
noncompartmental methods with Phoenix WinNonlin Version 8.3 or higher.  
Statistical analysis will be performed by Clinical Statistics, GSK. 
4.1.1. 
General Methodology 
Participants who prematurely withdrew from study will not be replaced.  
Confidence intervals will use 95% confidence levels unless otherwise specified.  
Unless otherwise specified, endpoints defined in Section 1.1 will be summarized using 
descriptive statistics and graphically presented (where appropriate). In summary tables, 
results will be presented by treatment periods (Microgynon only, GSK3036656 only, and 
Microgynon + GSK3036656).  
Unless otherwise specified, continuous data will be summarized using descriptive 
statistics: N, n, mean, standard deviation (std), median, minimum and maximum; for PK 
concentration data, No. Imputed, between-subject CV (%CVb) and 95% CIs, will also be 
reported along with above mentioned summary statistics; categorical variables will be 
summarized using n and percentage of participants in each category; for Tmax, only N, n, 
median, minimum, and maximum values will be presented; loge-transformed plasma 
concentration and PK parameters will be summarized using geometric mean, 95% CI, SD 
(logs) and the geometric %CVb based on geometric mean.  


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To assess primary endpoint, loge-transformed PK parameters will be statistically analyzed 
separately using Analysis of covariance (ANCOVA) Model to report point estimate for 
the ratio of the geometric means of treatment groups under comparison along with 90% 
CIs. 
Further details of analysis, including the full list of data displays to be produced, will be 
provided in the Output & Programming Specification (OPS). 
4.1.2. 
Baseline Definition 
For all endpoints the baseline value (derived for each period) will be the latest pre-dose 
assessment of respective period with a non-missing value, including those from 
unscheduled visits. If time is not collected, Day 1, Day 4 and Day 15 assessments are 
assumed to be taken prior to first dose of the respective period and will be used as 
baseline. 
Unless otherwise stated, if baseline data is missing no derivation will be performed and 
baseline will be set to missing. 
Table 2: 
 Baseline Assessment  
Parameter  
 
Study Assessments  
 
Baseline Used in Data Display  
 
Screening D  
1 
D 
4 
D 
15 
D 
18 
Treatment 
Period 1 
Treatment 
Period 2  
Treatment 
Period 3 
12-Lead  
ECG# 
T# 
X X X 
X 
D 1  
(Pre-Dose)  
 
D 4  
(Pre-Dose)  
 
D 15 
(Pre-Dose)  
 
Clinical 
chemistry^ 
X 
X X X 
X 
D 1  
(Pre-Dose)  
 
D 4  
(Pre-Dose)  
 
D 15 
(Pre-Dose)  
 
Hematology^ X 
X X X 
X 
D 1  
(Pre-Dose)  
 
D 4  
(Pre-Dose)  
 
D 15 
(Pre-Dose)  
 
Vital signs* 
X 
X X X 
X 
D 1  
(Pre-Dose)  
 
D 4  
(Pre-Dose)  
 
D 15 
(Pre-Dose)  
 
# T = Triplicate At Screening, triplicate ECGs are taken. Single ECGs will be taken on other scheduled days. 


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On Day 1, day 4 and day 15 ECG should be performed within 15 minutes before dosing and recorded in the eCRF. 
^ Laboratory assessments to be performed at Screening, and prior to dosing on Day 1 of Treatment Period 1, Day 4 of 
Treatment Period 2 and Day 15 of Treatment Period 3. 
* To be performed within 4 hours prior to the first dosing on Day 1 of Treatment Period 1, Day 4 of Treatment Period 2 
and Day 15 of Treatment Period 3. Where a measurement is abnormal or significantly different from previous 
measurements, a further 2 readings will be taken. When vital signs are measured in triplicate, values should be 
taken at least 1 minute but not more than 5 minutes apart and recorded in the CRF. 
4.2. 
Primary Endpoint(s) Analyses 
The primary objective of this study is to assess the effect of steady state exposure of 
GSK3036656 on the single dose PK of EE and LNG in healthy female participants of 
non-childbearing potential aged 18 to 65 years, who are missing no more than one 20 mg 
dose of GSK3036656 in treatment period 2 and are 100% compliant with study 
treatments in treatment periods 1 and 3. For the analyses planned in the following section, 
the potential intercurrent events that will be considered are participants missing a dose of 
Microgynon in treatment periods 1 and 3, or missing dose of GSK3036656 in treatment 
period 3, or missing more than one 20 mg dose of GSK3036656 in treatment period 2. 
Events leading to missing data are: participant withdrawal from study/ loss to follow-up, 
or missing PK assessments. 
4.2.1. 
Definition of endpoint(s)/estimands 
The primary pharmacokinetic endpoints and attributes of the estimand are detailed in 
Section 1.1. and Section 4.2.1.1 
4.2.1.1. 
Pharmacokinetic Parameters 
The PK parameters will be provided by CPMS group, Parexel. The PK parameters will be 
calculated by NCA methods from the concentration-time data using Phoenix® 
WinNonlin® Version 8.3 or later following these guidelines:  
• 
Actual time from dose will be used in the calculation of all derived PK parameters. 
• 
There will be no imputation of missing data.   
• 
Handling of NQ samples for derivation of plasma PK parameters after each dose 
administration  
− 
NQs at the beginning of a participant profile (i.e., before the first incidence of a 
measurable concentration) will be assigned to zero.  
− 
NQs at the end of a participant profile (i.e., after the last incidence of a 
measurable concentration) will be set to missing.  
− 
Single NQs which fall between two measurable concentrations will be set to 
missing.  
− 
Consecutive NQs which fall between measurable concentrations will be set to 
missing. Measurable concentrations after consecutive NQs will also be set to 
missing.  


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If a participant experiences emesis, the data for the affected period will be excluded from 
summary statistics and statistical analysis if vomiting occurs at or before 2 times median 
Tmax  
The primary and secondary PK parameters (see Section 1.1 and Section 4.3.1) will be 
estimated according to the guidelines presented in Table 3.  
Table 3: 
 Pharmacokinetic Parameter and Estimation  
Parameter  
Guideline for Derivation  
Analyte 
Cmax, Tmax,  
Cτ,  
Obtained directly from the observed 
concentration-time data.  
• 
Cmax and Tmax: EE and LNG 
(Treatment Periods 1 and 3) and 
GSK3036656 (Treatment period 
3) 
• 
 Cτ: GSK3036656 (at Day 8, 10, 
12, 15 and 16). 
AUC(0-t) 
The AUC from zero time (predose) to 
the time of last quantifiable 
concentration will be calculated by a 
combination of linear and logarithmic 
trapezoidal methods. The linear 
up/log down trapezoidal method will 
be employed.  
AUCl(0-t)=∫𝐶(𝑥)𝑑𝑥
𝑡
0
 
EE and LNG (Treatment Periods 1 
and 3) 
AUC(0-τ)  
The AUC over the dosing interval will 
be determined for multiple dose 
studies using the same trapezoidal 
rule as for AUC(0-t). 
If extrapolation is required for  
AUC(0-τ) calculation and it is not 
possible to derive an acceptable λz 
value, then AUC up to the time of last 
quantifiable concentration (AUC(0-t)) 
will be used as approximate estimate 
of AUC(0-τ). This imputation will be 
considered reliable only if the time of 
last measurable concentration is close 
to the end of the dosing interval. 
GSK3036656 (Treatment Period 3) 
AUC(0-inf)  The area from zero time extrapolated 
to infinite time will be calculated as 
follows:   
AUC(0-inf) = AUC(0-t)+ Clast/λz 
 
where Clast is the last observed 
quantifiable concentration.   
EE and LNG (Treatment Periods 1 
and 3) 


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Parameter  
Guideline for Derivation  
Analyte 
%AUCex  
The percentage of AUC(0-inf) obtained 
by extrapolation will be calculated as 
follows:   
%AUCex = (AUC(0-
inf)  ꟷ AUC(0−t))/AUC(0-inf)x100 
If the %AUCex is greater than 20% the 
value, %AUCex, and all dependent 
parameters will be flagged in listings. 
It is acceptable to include data from 
profiles with >20% extrapolated area 
if at least 80% of the profiles in the 
study have <20% of the AUC(0-inf) as 
extrapolated area. Unless otherwise 
determined by PK scientist’s best 
knowledge and judgement, it is 
unacceptable 
to use AUC(0-inf) data if >40% of the 
AUC has been extrapolated: in this 
case,  %AUCex, and all dependent 
parameters will be flagged in listings 
and might be excluded from summary 
tables and statistical analysis of PK 
parameters. The reason for exclusion 
will be listed/footnoted in parameter 
listings.  
EE and LNG (Treatment Periods 1 
and 3) 
λz and t1/2  The apparent terminal phase rate-
constant (λz) will be estimated by 
linear regression of concentration 
versus time data presented in a log-
linear scale (with uniform weighting).  
Only those data points that are judged 
to describe the terminal log-linear 
decline will be used in the 
regression. Data points may be 
dropped from the linear regression if 
the PK Scientist considers the 
reported values to be anomalous. Any 
data points so designated should 
remain in the listings with a footnote 
and be identified in the study report 
with a rationale for exclusion.  
A minimum number of three data 
points in the terminal phase will be 
used in calculating λz with the line of 
regression starting at any post-Cmax 
data point (Cmax will not be part of the 
EE and LNG (Treatment Periods 1 
and 3) 


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Parameter  
Guideline for Derivation  
Analyte 
regression slope). Based on the PK 
Scientist’s best knowledge and 
judgment, if the adjusted coefficient 
of determination (R2 adjusted) is 
<0.85, then λz and all the λz dependent 
parameters (i.e. t1/2, AUC(0-inf)) will be 
flagged in listings and might be 
excluded accordingly from summary 
tables and statistical analysis of PK 
parameters. The reason for flagging/ 
exclusion will be listed/footnoted in 
parameter listings.  
The interval used to determine λz 
should be equal or greater than 2-fold 
the estimated t1/2, and if less than 2-
fold, λz will be flagged in listings. All 
the derived parameters (i.e. t1/2, 
AUC(0-inf)) will also be flagged in 
listings. The reason for flagging will 
be listed/footnoted in parameter 
listings.  
The t1/2 will be calculated as follows:   
            t1/2 =  ln2/λz = 0.693/ λz  
4.2.2. 
Main analytical approach 
The primary analysis for the primary PK endpoints will be performed for the strata of 
participants able to adhere to treatment as defined in primary estimand framework, and 
included in the PK analysis set. τ 
• 
Based on the individual concentration-time data the following primary plasma 
parameters will be estimated, refer Section 4.2.1.1. Pharmacokinetic Parameters for 
more details: 
− 
EE (separately for Microgynon+GSK3036656 and Microgynon alone): AUC(0-
inf) and Cmax 
− 
LNG (separately for Microgynon+GSK3036656 and Microgynon alone): 
AUC(0-inf) and Cmax 


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• 
Analyses will be performed on the natural logarithms of AUC(0-inf) and Cmax, for EE 
and LNG, separately 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: 
− 
Microgynon+GSK3036656 (Treatment Period 3) versus Microgynon alone 
(Treatment Period 1) 
• 
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 for plasma EE and LNG PK parameter values will be presented by 
treatment, refer to Section 4.1.1 General Methodology and Section 4.3.1.2.5 
Pharmacokinetic Parameter Summary Tables for more details.  
4.2.3. 
Sensitivity analyses 
• 
Not applicable 
4.2.4. 
Additional estimands 
• 
Not applicable 
4.3. 
Secondary Endpoint(s) Analyses 
4.3.1. 
Secondary Pharmacokinetics Endpoints  
Secondary PK objectives for this study are to characterize the steady state PK of 
GSK3036656 in the presence of EE/LNG and to characterize the single dose PK of 
EE/LNG alone and in the presence of GSK3036656, in healthy female participants. 
4.3.1.1. 
Definition of [endpoint(s)/estimands] 
The secondary Pharmacokinetic endpoints and attributes of the estimands are detailed in 
in Section 1.1 
Refer to Section 4.2.1.1 Pharmacokinetic Parameters for more details.  


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4.3.1.2. 
Main analytical approach (Pharmacokinetic analysis) 
• 
The analysis for the secondary PK endpoints will be performed for the participants 
included in the PK analysis set. 
• 
Based on the individual concentration-actual time data the following secondary 
plasma parameters will be estimated, as data permits (refer to Section 4.2.1.1 
Pharmacokinetic Parameters for more details): 
− 
EE and LNG (separately for Microgynon+GSK3036656 and Microgynon 
alone): AUC(0-t), Tmax and t1/2  
− 
GSK3036656 (Microgynon+GSK3036656): AUC(0-τ), Cmax, Tmax, and Cτ (Day 8, 
10, 12, 15 and 16). 
− 
GSK3036656 (GSK3036656 alone): Whilst not defined as a secondary endpoint 
Cτ (Day 8, 10 and 12), will also be analysed to aid in interpretation on 
achievement of steady state. 
o 
Analyses will be performed on the natural logarithms of GSK3036656 Cτ, 
separately using mixed effect models with day (include Day 8, 10, 12, and 
15 pre-dose concentration) as a fixed effect and subject as a random effect.  
o 
The coefficients of the slopes for the day effect on log scale, along with 
corresponding 90% confidence intervals, will be used to determine whether 
steady state was achieved prior to co-administration with EE and LNG. 
Summary statistics for plasma EE, LNG, and GSK3036656 PK parameter values will be 
presented by treatment, refer to Section 4.1.1 General Methodology and Section 4.3.1.2.5 
Pharmacokinetic Parameter Summary Tables for more details. 
4.3.1.2.1. Pharmacokinetic Concentrations Listings 
The PK concentration data will be listed by analyte (EE, LNG and GSK3036656), 
treatment, day, time and subject for the PK analysis set. Concentration listings will 
include nominal PK sampling time, actual sampling times, time deviation, and actual 
relative time, and concentrations. Plasma concentrations below the lower limit of 
quantification (LLOQ), i.e. non-quantifiable (NQ), will be presented as NQ in the listings 
and the LLOQ value presented as a footnote.  
4.3.1.2.2. Pharmacokinetic Concentration Summary Tables  
PK concentration data will be reported according to GSK data standards. 
For summary tables, all NQs will be replaced with zero for the calculation of median and 
mean profile however for geometric mean and geometric CV% NQ values will be 
replaced by half the LLOQ value, refer [GSK, VQD-REF-015788] Non-Compartmental 
Analysis of Clinical Pharmacokinetic Data (Section 7 References) for more details. 
Summary statistics will not be calculated if there are less than 3 participants with 
quantifiable concentrations at a scheduled timepoint. The statistics will be reported as 
NC, with the exception of minimum and maximum; minimum will be reported as “NQ” 
and in case of all NQ values, the maximum will also be reported as NQ.  


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Data in concentration summary tables will be reported as per IDSL reporting standards. 
4.3.1.2.3. Pharmacokinetic Concentration Figures  
Comparative linear and semi-logarithmic plots of the median (range) and mean (±SD) 
concentration-time data for each analyte will be prepared. A reference line indicating 
LLOQ will be included on plots. 
For median and mean profiles, PK concentrations that are NQ will be handled as follows: 
• 
All NQ values will be set to zero except when an individual NQ falls between two 
quantifiable values, in which case it will be omitted from the calculation of mean or 
median profiles. 
• 
Measurable concentrations which follow more than one consecutive mid-profile NQ 
will be set to missing. 
Figures will report mean / median values below the LLOQ of the assay, if obtained. For 
linear plots, zero concentration value(s) will be included in the plot. For log-linear plots, 
zero concentration value(s) will be assigned a missing value. 
Individual concentration-time time will be plotted vs actual sample times, in linear and 
log-linear scale. For individual linear and log-linear figures NQ values will be substituted 
as follows:  
• 
NQs at the beginning of a participant profile (i.e., before the first incidence of a 
measurable concentration) will be assigned to zero. For linear plots, zero 
concentration values at the beginning of a participant profile will be included in the 
plot; when using log-linear scale, zero values will be considered missing.  
• 
NQs at the end of a participant profile (i.e., after the last incidence of a measurable 
concentration) will be set to missing.  
• 
Single NQs which fall between two measurable concentrations will be set to 
missing.   
• 
Consecutive NQs which fall between measurable concentrations will be set to zero 
and for individual subject plots  
• 
Measurable concentrations after consecutive NQs will be retained.  
4.3.1.2.4. Pharmacokinetic Parameter Listings   
The PK parameters will be listed by participant for the PK analysis set. The PK 
parameters that will be flagged and/or excluded from summary tables and statistical 
analyses will be flagged and footnoted in the listing with the reason for 
flagging/exclusion. In case of Cτ concentrations that are NQ, they will be presented as 
NQ in parameter listings.  


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4.3.1.2.5. Pharmacokinetic Parameter Summary Tables:  
Biostatistics group will consider the derived PK parameters as source data and will use 
this data without rounding for calculation of PK parameters summary statistics tables.    
The PK parameters will be summarized by analyte, treatment, and day for the PK 
analysis set; for more details, refer to Section 4.1.1 General Methodology.  
PK parameters that are not determined (ND) because the planned calculation could not be 
adequately performed will be assumed missing in both descriptive and statistical analyses 
and no imputation will be performed. 
In case of Cτ concentrations that are NQ, for PK parameter summary tables they will be 
handled with the same rules described as for concentration summary tables.  
Data in PK parameter summary tables will be reported as per IDSL reporting standards.  
4.3.2. 
Secondary Safety endpoint(s) 
A secondary objective of this study is to assess that GSK3036656 and Microgynon taken 
alone or together are safe and well tolerated in healthy female participants of non-
childbearing potential. Safety endpoints assess the incidence of safety events occurring 
during each treatment period. 
4.3.2.1. 
Definition of [endpoint(s)/estimands] 
The secondary safety endpoints and attributes of the estimands are detailed in Section 1.1 
4.3.2.2. 
Main analytical approach 
All safety analyses will be performed on the Safety Population. Safety data will be 
presented in tabular format by treatment groups (Microgynon, GSK3036656 and 
Microgynon+GSK3036656) and summarized descriptively according to GSK’s 
Integrated Data Standards Library. For each treatment group, the denominator for 
percentages (N) will be the number of participants entering the associated treatment 
period. No formal statistical analysis of the safety data will be conducted. Unless 
otherwise specified, available data will be analyzed as collected regardless of intercurrent 
events that may occur (treatment policy). Missing data will not be imputed. 
4.3.2.2.1. Adverse Events (AEs) 
An adverse event (AE) is considered study intervention emergent if the AE onset date is 
on or after study intervention start date for each treatment period. All AE summaries will 
be based on study intervention emergent events unless otherwise specified. Serious 
Adverse Event (SAE) summaries will be based on all SAEs reported regardless of 
whether they meet the definition of study intervention emergent or not. All AE and SAE 
summaries will be by System Organ Class and Preferred Term (PT) only unless 
otherwise specified. 
Adverse events will be coded using the latest version of the standard Medical Dictionary 
for Regulatory Activities (MedDRA dictionary) and graded by the investigator according 


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to the National Cancer Institute Common Terminology Criteria for Adverse Events [NCI-
CTCAE version 4.03]. 
In addition to the summary of all AEs, including counts and percentages of participants 
with any AE, there will be separate summaries for: 
• 
SAEs 
• 
Severe AEs (AEs with a grade of 3 or higher) 
• 
Drug-related AEs 
− 
Microgynon 
− 
GSK3036656 
• 
AEs leading to study withdrawal 
• 
AEs leading to study treatment discontinuation 
• 
Most Common (>=5%) Adverse Events by Overall frequency 
4.3.2.2.2. Electrocardiograms (ECGs) 
ECG data will include heart rate, PR, QRS, QT, and corrected QT (QTc). The QTc data 
analysis will use the collected values based on Fridericia formula.  
ECG values relative to PCI criteria, will be summarized by treatment group, ECG 
parameter and category.  
4.3.2.2.3. Clinical Laboratory Values 
The haematology and clinical chemistry laboratory data, relative to PCI criteria, will be 
summarized by treatment group, laboratory test and category.  
4.3.2.2.4. Vital Signs 
Vital sign data include temperature, systolic blood pressure (SBP), diastolic blood 
pressure (DBP), heart rate (HR), and respiratory rate.  
Vital sign data (SMP, DBP and HR), relative to PCI criteria, will be summarized by 
treatment group, vital sign and category. Worst-Case Vital Sign Results Relative to 
Normal Range Post-Baseline Relative to Baseline will also be summarized.  
4.4. 
Other Safety Analyses 
The safety analyses will be based on the Safety Analysis Set, unless otherwise specified.  


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4.4.1. 
Additional Safety Assessments  
4.4.1.1. 
Laboratory Data 
In addition to laboratory summaries related to PCI criteria, summaries of worst-case 
grade increase from baseline will be provided for all the lab tests that are gradable by 
CTCAE v4.03. These summaries will display the number and percentage of subjects with 
a maximum post-baseline grade increasing from their baseline grade. Any increase in 
grade from baseline will be summarized along with any increase to a maximum grade of 
3 and any increase to a maximum grade of 4. Missing baseline grade will be assumed as 
grade 0. For laboratory tests that are graded for both low and high values, summaries will 
be done separately and labelled by direction, e.g., sodium will be summarized as 
hyponatremia and hypernatremia separately.  
Change from period baseline values of haematology and chemistry will be summarized 
using descriptive statistics. 
For lab tests that are not gradable by CTCAE v4.03, summaries of worst-case changes 
from baseline with respect to normal range will be generated. Decreases to low, changes 
to normal or no changes from baseline, and increases to high will be summarized for the 
worst-case post-baseline. If a subject has a decrease to low and an increase to high during 
the same time interval, then the subject is counted in both the “Decrease to Low” 
categories and the “Increase to High” categories.  
Separate summary tables for haematology and chemistry laboratory tests will be 
produced. Liver function laboratory tests will be included with chemistry lab tests. 
Protocol-required routine urinalysis tests will also be summarized descriptively. 
An e-DISH plot of maximum post baseline total bilirubin versus maximum post baseline 
ALT will be created. 
4.4.1.2. 
Vital Signs 
In addition to above summaries of PCI criteria, summary statistics for all results and 
changes from period baseline will be provided by day of assessment for each test.  
4.4.1.3. 
ECG 
ECG findings are defined from best to worst as: “normal”, “abnormal - not clinically 
significant”, and “abnormal - clinically significant”. The worst finding will be selected at 
each time point when there is repeat ECG. All ECG findings will be summarized by days.  
The QTc data analysis will use the collected values based on Fridericia formula. 


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The QTc values based on Fridericia formula will be rounded to the integer and the values 
will be categorized into the following CTCAE grade and ranges: Grade 0 (<450 msec), 
Grade 1 (450-480 msec), Grade 2 (481-500 msec), and Grade 3 (≥501 msec). Summaries 
of grade increase will be provided. These summaries will display the number and 
percentage of subjects with any grade increase, increase to grade 2 and increase to grade 
3 for the worst-case post-baseline only. Missing baseline grade will be assumed as grade 
0. 
The changes in QTc values will be categorized into the clinical concern ranges which are 
specific to changes in QTc: 31-60 and >60 msec. A summary of change in QTc value will 
display the number and percentage of subjects with a change within each range for the 
worst-case post-baseline only. Subjects with missing baseline values will be excluded 
from this summary. 
A figure plotting the baseline QTc and the worst-case post-baseline values will be 
produced for each period. The figure will have reference lines at 450, 480 and 500 msec 
for both the x and y axes. There will be diagonal reference lines at equality (i.e. a 45-
degree line), at equality plus 30 msec, and at equality plus 60 msec. 
4.5. 
Other Analyses 
4.5.1. 
Subgroup analyses 
There will be no subgroup analysis planned. 
4.5.2. 
Analyses to Support Regional Submission 
There will be no regional submission planned. 
4.6. 
Interim Analyses 
There will be no interim analysis performed. 
4.7. 
Changes to Protocol Defined Analyses 
There were no changes or deviations to the originally planned statistical analysis 
specified in the original version of protocol (Dated: 06 Nov 2023). 
5. 
SAMPLE SIZE DETERMINATION 
From the Adjusted gMean ratios and 90% CIs reported in the historical reference [Vonk, 
2022], CVw(%) has been obtained using the CVfromCI function from POWERTOST 
package in R software. The R CVfromCI function uses methodology described in Section 
5.1.1. CVw(%) values of 11.5%, 12.5%, 14.9%, 17.9% for EE AUC(0-inf), EE Cmax, LNG 
AUC(0-inf) and LNG Cmax respectively were calculated (Table 4). The largest CVw for the 
analytes and parameters is 17.9%. 


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Table 4: 
Intrasubject Coefficient of Variability (CVw%) for PK Parameters of 
EE and LNG 
Historical 
Reference 
Analyt
e 
Parameter 
n 
Adjusted 
gMean ratio 
(90% CI) 
CVw% 
Madelon C. Vonk, 
et al. 
EE 
AUC(0-inf) 
15 
101.2 
(94.0, 109.1) 
11.5 
Cmax 
15 
116.7 
(107.6, 126.5) 
12.5 
LNG 
AUC(0-inf) 
15 
88.1 
(80.0, 97.0) 
14.9 
Cmax 
15 
100.9 
(89.9, 113.2)  
17.9 
The true ratio of Microgynon+GSK3036646 versus Microgynon alone, is assumed to be 
1.0 for all 4 comparaisons, EE AUC(0-inf), EE Cmax, LNG AUC(0-inf) and LNG Cmax. In 
order to calculate the joint power for the four comparisons, a conservative between 
parameter correlation of 0.6 has been assumed; of note considering correlation of 1.0 
would increase the joint power by less than 1% for the same sample size. Based on these 
assumptions an evaluable sample size of 16 provides 92% (Table 5) joint power to ensure 
that the 90% CIs for the geometric mean ratios for all parameters lie within the range of 
0.8 to 1.25. To account for an expected 20% rate of non-evaluable participants, 
approximately 20 participants will be enrolled to ensure at least 16 participants provide 
evaluable data in both test and reference periods. 
Table 5: 
Estimated Power and Sample Size Table 
Analyte 
Parameter 
n 
CVw% 
Power 
EE 
AUC(0-inf) 
16 
11.5 
99.98 
Cmax 
16 
12.5 
99.87 
LNG 
AUC(0-inf) 
16 
14.9 
98.66 
Cmax 
16 
17.9 
92.73 
Joint Power for all 4 comparisons  
16 
 
91.91 
Table 6: provides the 90% CIs for a range of possible observed ratios, for each assumed 
CVw%, with 16 estimated participants. 
Table 6:  
Sample Size: Estimated Precision for Different Observed Effects 
Analyte 
Parameter 
n 
CVw% 
Observed Ratio Estimated 2-sided 
90% CI 
EE 
AUC(0-inf) 
16 
11.5 
0.90 
(0.84,  0.97) 
1.0 
(0.93,  1.07) 
1.10 
(1.02, 1.18) 
Cmax 
16 
12.5 
0.90 
(0.83,  0.97) 
1.0 
(0.93,  1.08) 
1.10 
(1.02,  1.19) 


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Analyte 
Parameter 
n 
CVw% 
Observed Ratio Estimated 2-sided 
90% CI 
LNG 
AUC(0-inf) 
16 
14.9 
0.90 
(0.82,  0.99) 
1.0 
(0.91,  1.10) 
1.10 
(1.00,  1.21) 
Cmax 
16 
17.9 
0.90 
(0.81,  1.01) 
1.0 
(0.90,  1.12) 
1.10 
(0.98,  1.23) 
5.1.1. 
Calculation of CVw from CI: 
The point estimate (PE, adjusted geometric mean) and the confidence interval limits have 
been obtained from historical reference. 
The number of subjects / sequence (example 2×2 cross-over), is obtained as follows: 
• 
If total sample size (N) is an even number, assume n1= n2= ½N 
• 
If N is an odd number, assume n1= ½N+ ½, n2= ½N–½ (not n1= n2 = ½N) 
The difference between the CL and the PE can be calculated as follows on the log-scale 
(using the CL which is given with the highest number of significant digits. 
𝛥𝐶𝐿= ln  (𝐶𝐿ℎ𝑖) −  ln(𝑃𝐸) |𝑜𝑟|  𝛥𝐶𝐿= ln(𝑃𝐸) −ln  (𝐶𝐿𝑙𝑜) 
The Mean Square Error (MSE) is then calculated as follows: 
𝑀𝑆𝐸= 2
(
 
𝛥𝐶𝐿
√( 1
𝑛1 + 1
𝑛2) × 𝑡(1−2∝,𝑛1+𝑛2−2 )
     
)
 
2
 
And finally, the CVw is calculated from the MSE: 
𝐶𝑉𝑤% = 100 × √(𝑒𝑀𝑆𝐸−1) 
6. 
SUPPORTING DOCUMENTATION 
6.1. 
Appendix 1 Study Population Analyses 
Unless otherwise specified, the study population analyses will be based on the Enrolled 
Analysis Set. A summary of the number of participants in each of the participant level 
analysis set will be provided. 
Screen failure participants will be summarized based on Screened analysis set. 


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6.1.1. 
Participant Disposition 
A summary of the number and percentage of participants who completed the study as 
well as those who prematurely withdrew from the study will be provided. Reasons for 
study withdrawal will be summarized.  
A summary of study intervention status will be provided. This display will show the 
number and percentage of participants who have completed the scheduled study 
intervention, or have discontinued study intervention prematurely, as well as primary 
reasons for discontinuation of study intervention. 
6.1.2. 
Demographic and Baseline Characteristics 
The demographic characteristics including age, gender, ethnicity, height/weight at 
screening and race will be summarized with descriptive statistics based on the Enrolled 
Analysis Set. 
Past medical conditions and current medical conditions as of screening will be 
summarized respectively. Substance use, including smoking history, tobacco use, alcohol 
and drug history will be summarized. 
6.1.3. 
Protocol Deviations 
Important protocol deviations will be summarized. 
Protocol deviations will be tracked by the study team throughout the conduct of the 
study. These protocol deviations will be reviewed to identify those considered as 
important as follows: 
• 
Data will be reviewed prior to freezing the database to ensure all important 
deviations are captured and categorised in the protocol deviations ADaM dataset.  
• 
This dataset will be the basis for the summaries of important protocol deviations. 
6.1.4. 
Prior and Concomitant Medications 
Concomitant medications will be coded using both the GSK Drug and WHO Drug 
dictionaries. However, the summary will be based on GSK Drug dictionary only. The 
summary of concomitant medications will be provided by ingredient, i.e. multi-ingredient 
medications will be summarized for each individual ingredient rather than a combination 
of ingredients. The summary will be created using ingredient base names, i.e. ingredients 
with the same base name but different salt will appear under one base name in the 
summary. Anatomical Therapeutic Chemical (ATC) classifications will not appear in the 
summary. 
For classifying study phase for concomitant medication, use the following definition. 


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Medication 
Classification 
Definition 
Prior 
If medication end date is not missing and is on or prior to the 
date of the screening visit 
Concomitant 
Any medication that is not a prior 
Please refer to Section 6.2.8: for handling of partial end dates for concomitant 
medication.  
6.1.5. 
Study Intervention Compliance 
A summary of treatment compliance of Microgynon and GSK3036656 based on the 
exposure data will be produced. Overall compliance categories will also be summarized 
using descriptive statistics, refer to OPS for more details. 


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6.2. 
Appendix 2 Data Derivations Rule 
6.2.1. 
Change from Baseline 
The change from baseline will be calculated by subtracting the period baseline values 
from the subsequent post-baseline values. If either the baseline or post-baseline value is 
missing, the change from baseline is set to missing as well. 
6.2.2. 
Pharmacokinetic Parameters 
For the purposes of calculating summary statistics and for statistical analysis, all PK 
parameters with the exception of Tmax, t1/2 will be loge transformed. 
Between subject coefficient of variation %CVb will be calculated according to the 
following methods: 
Untransformed Data  : 
𝑆𝐷
𝑚𝑒𝑎𝑛 × 100, 
Transformed Data 
:  √𝑒𝑆2 −1 × 100, 
where S is the SD of the loge transformed data, S2 = variance of loge transformed data. 
6.2.3. 
Criteria for Potential Clinical Importance 
Reference ranges for all laboratory parameters collected throughout the study are 
provided by the laboratory. A laboratory value that is outside the reference range is 
considered either high abnormal (value above the upper limit of the reference range) or 
low abnormal (value below the lower limit of the reference range). Note: a high abnormal 
or low abnormal laboratory value is not necessarily of clinical concern.  
National Cancer Institute Common Terminology Criteria for Adverse Events [NCI-
CTCAE v4.0.3] will be used to assign grades to the relevant laboratory parameters, blood 
pressure and QTc. 
In addition, the following criteria will be used to flag potential clinical importance (for 
laboratory data, ECG parameters and vital signs):  


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6.2.3.1. 
Laboratory Values 
Haematology 
Laboratory Parameter 
 
Units 
Category 
Clinical Concern Range 
Low Flag (< x) 
High Flag (>x) 
Hematocrit  
Ratio of 1 
Male 
 
0.54 
Female 
 
0.54 
Change 
from 
Baseline 
Decrease of 
0.075 
 
Haemoglobin  
g/L 
 
Male 
75 
180 
Female 
75 
180 
Change 
from 
Baseline 
Decrease of 25 
 
Lymphocytes  
x109/ L 
 
0.8 
 
Neutrophil Count  
x109/ L 
 
1.5 
 
Platelet Count  
x109/ L 
 
100 
550 
Red blood cell (RBC) 
count 
million/mcL 
 
4.2 
6.1 
Mean corpuscular volume 
(MCV) 
 
fl. 
 
80 
100 
Mean corpuscular 
hemoglobin (MCH) 
picograms 
(pg) 
 
27.5 
33.2 
%Reticulocytes 
% 
 
0.5 
2 
Monocytes 
% 
 
2 
8 
Eosinophils 
% 
 
1 
4 
Basophils 
% 
 
0.5 
1 
Clinical Chemistry 
Laboratory Parameter 
Units 
Category 
Clinical Concern Range 
Low Flag (< x) 
High Flag (>x) 
Calcium 
mmol/L 
 
2 
2.75 
Creatinine 
% 
Change 
from 
Baseline 
 
Increase of 30% 
Glucose 
mmol/L 
 
3 
11 
Potassium 
mmol/L 
 
3 
5.5 
Sodium 
mmol/L 
 
130 
150 
Direct bilirubin 
mg/dl 
 
<0.3 
<0.3 
Total protein 
g/dl 
 
6 
8.3 
Blood urea nitrogen 
(BUN)/Urea 
mg/dl 
 
5 
20 


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Haematology 
Laboratory Parameter 
 
Units 
Category 
Clinical Concern Range 
Low Flag (< x) 
High Flag (>x) 
Creatine phosphokinase 
(CPK) 
mcg/l 
 
10 
120 
Homocysteine 
μmol/L 
 
4 
14 
Antiphospholipid antibodies 
MPL 
 
0 
39.9 
Sex hormone binding 
globulin (SHBG) 
nmol/L 
 
18 
144 
 
Liver Function 
Test Analyte 
Units 
Category 
Clinical Concern Range 
ALT  
IU/L 
High 
≥ 3x ULN 
AST  
IU/L 
High 
≥ 3x ULN 
T Bilirubin  
µmol/L 
High 
≥ 1.5x ULN 
ULN = Upper Limit of Normal; ALT=Alanine Aminotransferase; AST=Aspartate Aminotransferase;  
T. Bilirubin=Total Bilirubin 
6.2.3.2. 
ECG Values 
ECG Parameter 
Units 
Clinical Concern Range 
Lower 
Upper 
Absolute 
Absolute QTcF Interval 
msec 
 
>450 
Absolute PR Interval 
msec 
< 110 
>220 
Absolute QRS Interval 
msec 
< 75 
>110 
Change from Baseline 
Increase from Baseline 
QTcF 
msec 
 
>60 
QTcF=QT Interval corrected for heart rate (Fridericia); PR=Electrocardiographic PR Interval 


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6.2.3.3. 
Vital Signs 
Vital Sign Parameter 
(Absolute) 
Units 
Clinical Concern Range 
Lower 
Upper 
Systolic Blood Pressure 
mmHg 
< 85 
>160 
Diastolic Blood Pressure 
mmHg 
< 45 
>100 
Heart Rate 
bpm 
< 40 
>110 
Respiratory Rate 
Breaths/min 
10 
28 
Temperature 
Degrees C 
35.0 
37.9 
6.2.4. 
Study Period 
Assessments and events will be classified according to the time of occurrence relative to 
the study intervention period.  
Treatment period 1 ranges from Day 1 dose to Day 4 predose, similarly treatment period 
2 ranges from Day 4 dose to Day 15 predose and treatment period 3 ranges from Day 15 
dose until Day 18. 
6.2.5. 
Study Day, Reference Dates and Period Day  
The reference date is the period 1 Microgynon start date and will be used to calculate 
study day for safety and PK measures. 
The study day is calculated as below: 
• 
Assessment Date = Missing              → Study Day = Missing  
• 
Assessment Date < Reference Date → Study Day = Assessment Date – Reference 
Date 
• 
Assessment Data ≥ Reference Date → Study Day = Assessment Date – Reference 
Date + 1 
Period day is calculated as the number of days from first treatment start date for the 
respective period (Period Treatment Start Date):  
• 
Assessment Date = Missing → Period Day = Missing  
• 
Assessment Date < Period Treatment Start Date → Period Day = Assessment Date – 
Period Treatment Start Date  
• 
Assessment Data ≥ Period Treatment Start Date → Period Day = Assessment Date – 
(Period Treatment Start Date) + 1 


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6.2.6. 
Assessment Window  
• 
Actual times will be used in the derivation of PK parameters and in the individual 
concentration-time plots. Planned times will be used in the descriptive summaries 
and in mean and median plots. 
• 
PK concentration listings shall have both the planned and actual times  
• 
Planned time will be used for all other analysis. 
• 
For data summaries by visit, the nominal visit description will be used. The 
unscheduled assessment will be listed. 
6.2.7. 
Multiple measurements at One Analysis Time Point 
When triplicate ECG assessments and triplicate Vitals Sign assessment are taken, mean 
of the measurement will be calculated first and summary statistics will be based on the 
calculated mean. This will apply to both baseline and post baseline assessments. 
For multiple assessments of the lab tests taken on a study day, the worst case will be 
used. 
6.2.8. 
Handling of Partial Dates 
Element 
Reporting Detail 
General 
• 
Partial dates will be displayed as captured in participant listing displays.   
• 
However, where necessary, display macros may impute dates as temporary 
variables for sorting data in listings only. In addition, partial dates may be 
imputed for ‘slotting’ data to study phases or for specific analysis purposes as 
outlined below. 
• 
Imputed partial dates will not be used to derive study day, time to onset or 
duration (e.g., time to onset or duration of adverse events. 
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.  
Unless available data demonstrate that the AE could not have started during 
treatment period 2, AEs with partial start dates will be assumed to have started in 
treatment period 2. This is due to participants being in-patients within the clinic 
during treatment periods 1 and 3, thus partial AE start dates during these periods 
are highly unlikely.  
The following rules will be followed: 
Let  
• 
SM_P1=start month of period 1 (month of first treatment in period 1) 
• 
SM_P2=start month of period 2 (month of first treatment in period 2) 
• 
SM_P3=start month of period 3 (month of first treatment in period 3) 
• 
EM_P1=end month of period 1 (month of day prior to first treatment in period 
2) 
• 
EM_P2=end month of period 1 (month of day prior to first treatment in period 
3) 
• 
SM_AE=start month of AE 
• 
EM_AE=end month of AE 
• 
If SM_P1>SM_AE THEN AE start date=1st of the month  
• 
If AE end date is complete: 


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Element 
Reporting Detail 
1. 
If EM_P1 ≥ SM_AE ≥ SM_P1 AND 
Period 2 start date > AE end date ≥ Period 1 start date 
THEN AE start date = start date of treatment period 1 
2. 
If EM_P2 ≥ SM_AE ≥ SM_P2 AND 
AE end date ≥ Period 2 start date 
THEN AE start date = start date of treatment period 2  
3. 
If SM_AE ≥ SM_P3 AND  
SM_AE ≠ EM_P2 AND 
AE end date ≥ Period 3 start date 
THEN AE start date = start date of treatment period 3 
• 
If AE end date has the day missing: 
1. 
If EM_P1 ≥ SM_AE ≥ SM_P1 AND 
SM_P2 > EM_AE ≥ SM_P1 
THEN AE start date = start date of treatment period 1 
2. 
If EM_P2 ≥ SM_AE ≥ SM_P2 AND 
EM_AE ≥ SM_P2 
THEN AE start date = start date of treatment period 2  
3. 
If SM_AE ≥ SM_P3 AND  
SM_AE ≠ EM_P2 AND 
EM_AE ≥ SM_P3 
THEN AE start date = start date of treatment period 3 
• 
Missing Stop Day: Last day of the month 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/Medical History 
• 
Partial dates for any concomitant medications recorded in the CRF will be 
imputed using the following convention: 
Missing start day 
If study intervention start date is missing (i.e. participant 
did not start study intervention), then set start date = 1st of 
month. 
Else if study intervention start date is not missing: 
• 
If month and year of start date = month and year of 
study intervention start date, then 
− 
If stop date contains a full date and stop 
date is earlier than study intervention 
start date, then set start date= 1st of 
month. 
− 
Else set start date = study intervention 
start date. 
Else set start date = 1st of month. 
Missing start day 
and month 
If study intervention start date is missing (i.e. participant 
did not start study intervention), then set start date = 
January 1. 
Else if study intervention start date is not missing: 
• 
If year of start date = year of study intervention start 
date, then 
− 
If stop date contains a full date and stop date 
is earlier than study intervention start date, 
then set start date = January 1. 


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Element 
Reporting Detail 
− 
Else set start date = study. intervention start 
date.       
Else set start date = January 1. 
Missing end day 
A '28/29/30/31' will be used for the day (dependent on the 
month and year).  
Missing end day 
and month 
A '31' will be used for the day and 'Dec' will be used for the 
month. 
Completely 
missing start/end 
date 
No imputation 
Age 
• 
Age will be calculated based on the Screening Visit date  
• 
GSK standard IDSL algorithms will be used for calculating age where date of 
birth (DOB) will be imputed as follows: 
− 
Any participant with a missing day will have this imputed as day ‘15’. 
− 
Any participant with a missing day and month will have this imputed as 
‘30th June’. 
− 
Birth date will be presented in listings as ‘YYYY’. 
− 
The Date of Birth will be assumed to be 30 June YYYY and age will be 
calculated at screening visit using this assumed date of birth. 
6.2.9. 
List of Abbreviations  
Abbreviation 
Description 
AE 
Adverse Event 
ATC 
Anatomical Therapeutic Chemical 
AUC 
Area under concentration-time curve 
AUC(0-inf) 
Area under the concentration-time curve from time zero (pre-
dose) extrapolated to infinite time 
BMI 
Body Mass Index 
C 
Complement 
CI 
Confidence Interval 
Cmax 
Maximum Observed Concentration 
CPMS 
Clinical Pharmacology Modelling & Simulation 
CSR 
Clinical Study Report 
Ct  
Trough Concentration 
CV 
Coefficient of Variation 


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Abbreviation 
Description 
DDI 
Drug Drug Interaction 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Record Form 
EE 
Ethinyl Estradiol 
GSK 
GlaxoSmithKline 
ICF 
Informed consent form 
LNG 
Levonorgestrel 
MedDRA 
Medical Dictionary for Regulatory Activities 
n 
Number of participants with available data 
NCA 
Non-compartmental Analysis 
NCI-CTCAE 
National Cancer Institute Common Terminology Criteria for 
Adverse Events 
NONMEM 
Non-linear Mixed-effects Modelling 
NQ 
Non-quantifiable 
OPS 
Output and Programming Specification 
PCI 
Potential Clinical Importance 
PK 
Pharmacokinetic 
PT 
Preferred Term 
QTC 
Corrected QT Interval 
RBC 
Red Blood Cell 
SAE 
Serious Adverse Event 
SAP  
Statistical Analysis Plan  
SD 
Standard Deviation 
SOC 
System Organ Class 


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Abbreviation 
Description 
Tmax 
Time at which Cmax is Observed 
WBC 
While Blood Cell 
WHO 
World Health Organisation 
 
6.2.10. 
Trademarks 
Trademarks of the [GlaxoSmithKline] 
Group of Companies 
 
Trademarks not owned by the 
[GlaxoSmithKline] Group of Companies 
None 
 
NONMEM 
 
 
SAS 
 
 
WinNonlin 


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7. 
REFERENCES 
D. J Shhuirmann. A comparison of the two one-sided tests procedure and the power 
approach for assessing the equivalence of average bioavailability. J Pharmacokinet 
Biopharm 1987 Dec;15(6):657-80. doi: 10.1007/BF01068419. 
Vonk MC, Guillén-Del-Castillo A, Kreuter M, et al. A Drug-Drug Interaction Study to 
Investigate the Effect of Nintedanib on the Pharmacokinetics of Microgynon 
(Ethinylestradiol and Levonorgestrel) in Female Patients with Systemic Sclerosis-
Associated Interstitial Lung Disease. Eur J Drug Metab Pharmacokinet. 2022 
Jan;47(1):81-89. 
U.S. Department of Health and Human Services; Common Terminology Criteria for 
Adverse Events (CTCAE) (cancer.gov) Version 5.0 Published: November 27, 2017 
GSK, VQD-REF-015788, Veeva Vault - Non-Compartmental Analysis of Clinical 
Pharmacokinetic Data; Version 1.0, Effective: 14 Sep 2022: 3-32.