Clinical trial NCT06065735
Conditions: Anxiety Disorders
Keywords: Dose escalation QTc Interval Paroxetine Healthy Adults
Sponsor: GlaxoSmithKline
Start date: 2023-10-02; Completion date: 2024-01-08
Enrollment: 38 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The primary purpose of the study is to evaluate the potential effect of paroxetine on QTc interval following escalating doses in healthy participants. Participants with no history of cardiac abnormalities or mood disorders will be enrolled. During the study, participants will take paroxetine at three incremental dose levels. Participants will attend the clinic at screening, baseline, at the end of each dose level administration week, and a final study exit visit. While on treatment outside of clinic visits, participants will be followed-up via video-call. A concentration-QTc analysis will assess any potential correlation between paroxetine plasma concentration and QTc prolongation. In addition, the occurrence of any side-effects will be compared between on and off treatment.

Detailed description:

Arms: arm 1: None
Interventions: intervention 1: Paroxetine
Intervention descriptions: intervention 1: Paroxetine will be administered

Protocol documents:
Prot_000.pdf: 
Protocol Amendment 1
Study ID:  219882
Official Title of Study: An Open-Label, Single Arm, Dose Escalating 
Concentration-QT Study to Investigate the Cardiac Effects and Safety of 
Paroxetine in Healthy Adult Participants
NCT ID: NCT06065735
Date of Document: 20-September-2023 (This date has been redacted as 
Personal Information on page 4 as it is handwritten)


CONFIDENTIAL 
Protocol and Version 2.0 (Final) 
Date: 15-09-2023 
1 
 
Clinical Study Protocol 
Primary Study 
Intervention(s) 
Paroxetine 
Other Study Intervention(s) 
Not applicable 
Study Identifier 
219882 
Approval Date 
15-September-2023 
Title 
An Open-Label, Single Arm, Dose Escalating 
Concentration-QT Study to Investigate the Cardiac 
Effects and Safety of Paroxetine in Healthy Adult 
Participants  
Compound Number/Name 
Paroxetine (BRL-029060) 
Brief Title 
Concentration-QT Study of Paroxetine in Healthy 
Adults 
Sponsor 
GlaxoSmithKline Research & Development Limited 
980 Great West Road, Brentford, Middlesex, TW8 
9GS, UK 
Sponsor signatory 
Oscar Della Pasqua 
Executive Director Clinical Pharmacology 
Clinical Pharmacology Modelling and Simulation 
(CPMS) 
Medical Monitor name and contact can be found in local study contact 
information document 
©2023 GSK group of companies or its licensor. 


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Protocol and Version 2.0 (Final) 
Date: 15-09-2023 
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 Good Clinical Practise (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 and/or digital 
informed consent of the participant.  
− 
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. 


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Protocol and Version 2.0 (Final) 
Date: 15-09-2023 
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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. 
 


PPD


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Protocol and Version 2.0 (Final) 
Date: 15-09-2023 
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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE 
DOCUMENT HISTORY 
Document 
Date of Issue 
Original Protocol 
01 June 2023 
Amendment 01 
15 September 2023 


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Protocol and Version 2.0 (Final) 
Date: 15-09-2023 
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Summary of Changes 
Initial Content 
Amended Wording or 
Revised Content  
Reason/Justification 
for Change 
Substantiality 
(substantial/ 
nonsubstantial) 
Reason for 
substantial 
categorization 
(if applicable) 
Footer 
Page numbers added 
Per sponsor request 
due to publishing QC 
Nonsubstantial 
 
Styles of all 
tables 
Updated to table styles 
to checklist standards 
Per sponsor request 
due to publishing QC 
Nonsubstantial 
 
Section 1.3, 
SoA COVID-19 
test days 
Added additional days 
for COVID-19 test in 
SoA 
Per sponsor request 
Nonsubstantial  
 
Section 1.3, 
SoA footnotes, 
“ECG review 
will be 
performed by 
cardiologist at 
Screening” 
Removed from SoA 
footnotes 
Due to administrative 
error, was not 
previously omitted 
from Section 1.3 
Nonsubstantial 
 
Section 2.3.1, 
Table cell 
“Study 
Intervention(s) 
[Paroxetine]” 
Cell height adjusted 
Per sponsor request 
due to publishing QC 
Nonsubstantial 
 
Section 2.3.1, 
“5.1” 
Hyperlink added 
Per sponsor request 
due to publishing QC 
Nonsubstantial 
 
Section 2.3.1, 
“5.2” 
Hyperlink added 
Per sponsor request 
due to publishing QC 
Nonsubstantial 
 
Section 5.1, 
Number list 3 
letter list b 
Reworded to, 
“…Appendix 4 for at 
least for 2 months 
before screening, up to 
the final follow up visit, 
to sufficiently minimize 
the risk of pregnancy” 
Per sponsor request 
Nonsubstantial  
 
Section 8.3.4, 
Table 5, Note 1 
Removed, “Details of 
liver chemistry stopping 
criteria and required 
actions and follow-up 
are given in Section 
[5.1.1 Liver Chemistry 
Stopping Criteria]” 
Per sponsor request 
due to publishing QC 
(was left in error) 
Nonsubstantial 
 
Section 8.3.6.1, 
“10.5” 
Revised to, “10.2” 
Per sponsor request 
due to publishing QC 
Nonsubstantial 
 


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Protocol and Version 2.0 (Final) 
Date: 15-09-2023 
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Initial Content 
Amended Wording or 
Revised Content  
Reason/Justification 
for Change 
Substantiality 
(substantial/ 
nonsubstantial) 
Reason for 
substantial 
categorization 
(if applicable) 
Section 10.2, 
Table 8, Note 1 
Removed, “Details of 
liver chemistry stopping 
criteria and required 
actions and follow-up 
are given in Section 
[Error! Reference 
source not found. Liver 
Chemistry Stopping 
Criteria] and Section 
Error! Reference 
source not found.: 
Liver Safety: Suggested 
Actions and Follow-up 
Assessments [and Study 
Intervention 
Rechallenge 
Guidelines]].” 
Per sponsor request 
due to publishing QC 
(was left in error) 
Nonsubstantial 
 
Section 10.4.2, 
paragraph 1 
Added, “Female 
patients must use 
contraception for at 
least 2 months before 
screening, up to the 
final follow up visit” 
Added to specify 
duration of 
contraception 
Nonsubstantial  
 
Section 10.4.2, 
Under “Barrier 
methods of 
contraception” 
Added, “Male patients 
must use barrier method 
during the study until 
final follow up visit” 
Added to specify 
duration of 
contraception 
Nonsubstantial  
 
 


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Protocol and Version 2.0 (Final) 
Date: 15-09-2023 
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TABLE OF CONTENTS 
PAGE 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ........................................ 12 
1. 
PROTOCOL SUMMARY ........................................................................................ 17 
1.1. 
Synopsis ..................................................................................................... 17 
1.2. 
Schema ...................................................................................................... 22 
1.3. 
Schedule of activities (SoA) ........................................................................ 23 
2. 
INTRODUCTION .................................................................................................... 28 
2.1. 
Study rationale ............................................................................................ 28 
2.2. 
Background ................................................................................................ 29 
2.3. 
Benefit/risk assessment .............................................................................. 30 
2.3.1. 
Risk assessment .......................................................................... 30 
2.3.2. 
Benefit assessment ..................................................................... 39 
2.3.3. 
Overall benefit-risk conclusion ..................................................... 39 
3. 
OBJECTIVES, ENDPOINTS AND ESTIMANDS .................................................... 40 
4. 
STUDY DESIGN .................................................................................................... 41 
4.1. 
Overall design ............................................................................................. 41 
4.2. 
Scientific rationale for study design ............................................................. 42 
4.2.1. 
Participant input into design ......................................................... 43 
4.3. 
Justification for dose ................................................................................... 43 
4.4. 
End-of-study definition ................................................................................ 43 
5. 
STUDY POPULATION ........................................................................................... 43 
5.1. 
Inclusion criteria .......................................................................................... 44 
5.2. 
Exclusion criteria ......................................................................................... 45 
5.3. 
Lifestyle considerations ............................................................................... 46 
5.3.1. 
Meals and dietary restrictions ...................................................... 46 
5.3.2. 
Caffeine, alcohol, and tobacco ..................................................... 46 
5.3.3. 
Activity ......................................................................................... 46 
5.4. 
Screen failures ............................................................................................ 47 
5.5. 
Criteria for temporarily delaying enrolment/administration of study 
intervention ................................................................................................. 47 
6. 
STUDY INTERVENTION(S) AND CONCOMITANT THERAPY .............................. 47 
6.1. 
Study intervention(s) administered .............................................................. 47 
6.2. 
Preparation, handling, storage, and accountability ...................................... 48 
6.3. 
Assignment to study intervention ................................................................ 48 
6.4. 
Blinding/Masking ......................................................................................... 49 
6.5. 
Study intervention compliance .................................................................... 49 
6.6. 
Dose modification ....................................................................................... 49 
6.7. 
Continued access to study intervention after the end of the study ............... 50 
6.8. 
Treatment of overdose ................................................................................ 50 
6.9. 
Prior and concomitant therapy .................................................................... 50 
7. 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ..................................................................... 51 
7.1. 
Discontinuation of study intervention ........................................................... 51 


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7.1.1. 
QTc Stopping criteria ................................................................... 52 
7.2. 
Participant discontinuation/withdrawal from the study ................................. 52 
7.3. 
Lost to follow-up.......................................................................................... 54 
8. 
STUDY ASSESSMENTS AND PROCEDURES ..................................................... 54 
8.1. 
Administrative procedures .......................................................................... 55 
8.1.1. 
Collection of demographic data .................................................... 55 
8.1.2. 
Medical History ............................................................................ 55 
8.2. 
Efficacy and/or immunogenicity assessments ............................................. 55 
8.3. 
Safety assessments .................................................................................... 55 
8.3.1. 
Physical examination ................................................................... 55 
8.3.2. 
Vital signs .................................................................................... 56 
8.3.3. 
Electrocardiograms ...................................................................... 56 
8.3.4. 
Clinical Safety laboratory tests ..................................................... 57 
8.3.5. 
Pregnancy testing ........................................................................ 59 
8.3.6. 
Study stopping rules, Safety monitoring committee ...................... 59 
8.4. 
Adverse Events (AEs) serious adverse events (SAEs), and other 
safety reporting ........................................................................................... 60 
8.4.1. 
Time period and frequency for collecting AE, SAE, and 
other safety information ............................................................... 61 
8.4.2. 
Method of detecting AEs and SAEs ............................................. 61 
8.4.3. 
Follow-up of AEs and SAEs ......................................................... 61 
8.4.4. 
Regulatory reporting requirements for SAEs ................................ 61 
8.4.5. 
Pregnancy ................................................................................... 62 
8.4.6. 
Cardiovascular and death events ................................................. 62 
8.4.7. 
Disease-related events and/or disease-related outcomes 
not qualifying as AEs or SAEs ..................................................... 63 
8.4.8. 
Contact information for reporting SAEs, pregnancies and 
study holding rules ....................................................................... 63 
8.4.9. 
Participant Card ........................................................................... 63 
8.5. 
Pharmacokinetics ....................................................................................... 63 
8.6. 
Pharmacodynamics .................................................................................... 64 
8.7. 
Genetics ..................................................................................................... 64 
8.8. 
Biomarkers ................................................................................................. 64 
8.9. 
Immunogenicity assessments ..................................................................... 64 
8.10. 
Health economics or medical resource utilization and health 
economics .................................................................................................. 64 
9. 
STATISTICAL CONSIDERATIONS ........................................................................ 64 
9.1. 
Statistical hypothesis/hypotheses/comparisons .......................................... 64 
9.1.1. 
Multiplicity Adjustment ................................................................. 64 
9.2. 
Analysis sets ............................................................................................... 65 
9.3. 
Statistical analyses ..................................................................................... 65 
9.3.1. 
General considerations/definitions ............................................... 65 
9.3.2. 
Primary endpoint analysis ............................................................ 66 
9.3.3. 
Secondary endpoint(s)/estimand(s) analyses .............................. 67 
9.4. 
Interim analyses .......................................................................................... 68 
9.5. 
Sample size determination .......................................................................... 68 
10. SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ............................................................................................... 69 
10.1. 
Appendix 1: Regulatory, ethical, and study oversight considerations .......... 69 


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10.1.1. 
Regulatory and ethical considerations ......................................... 69 
10.1.2. 
Financial disclosure ..................................................................... 69 
10.1.3. 
Informed consent process ............................................................ 70 
10.1.4. 
Recruitment strategy .................................................................... 70 
10.1.5. 
Data protection ............................................................................ 71 
10.1.6. 
Committees structure ................................................................... 72 
10.1.7. 
Dissemination of Clinical Study Data ........................................... 72 
10.1.8. 
Data quality assurance ................................................................ 72 
10.1.9. 
Source documents ....................................................................... 74 
10.1.10. Study and site start and closure ................................................... 74 
10.1.11. Publication policy ......................................................................... 75 
10.2. 
Appendix 2: Clinical laboratory tests ........................................................... 75 
10.3. 
Appendix 3: AEs and SAEs: Definitions and procedures for 
recording, evaluating, follow-up, and reporting ............................................ 77 
10.3.1. 
Definition of AE ............................................................................ 77 
10.3.2. 
Definition of SAE .......................................................................... 78 
10.3.3. 
Definition of CV events ................................................................ 79 
10.3.4. 
Definition of TEAE ....................................................................... 80 
10.3.5. 
Recording, assessment and follow-up of AE, SAE, and 
pregnancies ................................................................................. 80 
10.4. 
Appendix 4: Contraceptive and barrier guidance ......................................... 84 
10.4.1. 
Definitions .................................................................................... 84 
10.4.2. 
Contraception guidance ............................................................... 85 
10.5. 
Appendix 5: Protocol Elements for Redaction ............................................. 86 
10.5.1. 
Information about Sponsor Signatory and Medical Monitor .......... 86 
10.5.2. 
List of Study Staff ......................................................................... 86 
11. REFERENCES ....................................................................................................... 87 
12. APPENDIX ............................................................................................................. 89 
 
LIST OF TABLES 
PAGE 
Table 1 
Interval between study visits .................................................................. 21 
Table 2 
Schedule of Activities – Overview Across Visit Days .............................. 23 
Table 3 
Schedule of Activities – Details of Paroxetine Concentrations 
/ECG Assessment Visit Day Activities .................................................... 27 
Table 4 
Study intervention administered. ............................................................ 47 
Table 5 
Protocol-required safety laboratory tests ................................................ 58 
Table 6 
Timeframes for submitting SAE, pregnancy and other events 
reports to GSK ....................................................................................... 62 
Table 7 
Contact information for reporting SAEs, pregnancies and study 
holding rules ........................................................................................... 63 


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Protocol and Version 2.0 (Final) 
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Table 8 
Protocol-required safety laboratory tests ................................................ 76 
Table 9 
Exclusion Criteria Allowed for Rescreening ............................................ 89 
Table 10 
Sample Size Sensitivity without dropout ................................................. 91 
Table 11 
Sample Size Sensitivity after drop-out .................................................... 92 
LIST OF FIGURES 
Figure 1 
Study design overview ........................................................................... 22 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
BP 
Blood pressure 
CFR 
Code of Federal Regulation 
CI 
Confidence Interval 
CIOMS 
Council for International Organizations of Medical Sciences 
COVID 
Corona Virus Disease 
CONSORT 
Consolidated Standards of Reporting Trials 
CPMS 
Clinical Pharmacology Modelling and Simulation 
CRF/eCRF 
Case report form/electronic case report form 
CRO 
Contract research organization 
CSR 
Clinical study report 
CTA 
Clinical trials application 
CV 
Cardiovascular 
ECG 
Electrocardiogram 
ED 
Early discontinuation 
EDC 
Electronic data capture 
EoS 
End-of-study 
FAS 
Full analysis set 
FDA 
Food and Drug Administration, United States of America 
FPFV 
First participant first visit 
FSH 
Follicle Stimulating Hormone 


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Protocol and Version 2.0 (Final) 
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Abbreviation 
Definition 
GCP 
Good clinical practices 
GDS 
Global Data Sheet 
HCG 
Human chorionic gonadotropin 
HCV 
Hepatitis C virus 
HbsAg 
Hepatitis B surface antigen 
HIV 
Human Immunodeficiency Virus 
HRT 
Hormone Replacement Therapy 
IB 
Investigator’s brochure 
ICF 
Informed consent form 
ICH 
International Council on Harmonization 
IDFU 
Investigational directions for use 
IDMC 
Independent data monitoring committee 
IEC 
Independent ethics committee 
IMP 
Investigational medicinal product 
INR 
International normalized ratio 
IRB 
Institutional review board 
LMP 
Last menstrual period 
LPLV 
Last Participant Last Visit 
LTFU 
Long-term follow-up 
MACE 
Major adverse cardiovascular events 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
Myocardial infarction 
MDD 
Major depressive disorder 
NIMP 
Non-investigational medicinal product 


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Abbreviation 
Definition 
OCD 
Obsessive compulsive disorder 
PD 
Pharmacodynamic 
PK 
Pharmacokinetic 
PT 
Preferred term 
PTSD 
Post traumatic stress disorder 
q.d 
Once daily 
QTcF 
Corrected QT interval by Fridericia 
RBC 
Red blood cell 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SAR 
Serious adverse reaction 
SmPC 
Summary of product characteristics 
SoA 
Schedule of activities 
SSRI 
Selective serotonin reuptake inhibitors 
TEAE 
Treatment-emergent adverse event 
TOC 
Table of contents 
ULN 
Upper Limit of Normal 
WBC 
White blood cell 
WOCBP 
Woman of childbearing potential 
 
Term 
Definition 
Blinding 
In an open-label study, no blind is used. Both the 
Investigator and the participant know the identity of the 
intervention assigned.  


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Protocol and Version 2.0 (Final) 
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Term 
Definition 
Eligible 
Qualified for enrolment 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 
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. 
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 
NIMP/ AxMP 
A NIMP or AxMP is a medicinal product that is not 
classified as an IMP in a study, but may be taken by 
participants during the study, e.g., concomitant or 
rescue/escape medication used for preventive, 
diagnostic, or therapeutic reasons or medication given to 
ensure that adequate medical care is provided for the 
participant during a study. 
Participant number 
A unique identification number assigned to each 
participant who consents to participate in the study. 
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). 


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Protocol and Version 2.0 (Final) 
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Term 
Definition 
Synonym: subject 
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.  
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). 
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 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 monitor 
An individual assigned by the Sponsor and responsible 
for assuring proper conduct of clinical studies at 1 or 
more investigational sites. 
Telemedicine 
The use of electronic information and 
telecommunications technologies (both video-based and 
audio-only) to facilitate remote health care delivery, 
participant and professional health-related education, 
public health and health administration. 


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Protocol and Version 2.0 (Final) 
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1. 
PROTOCOL SUMMARY 
1.1. 
Synopsis 
Protocol Title:  
An Open-Label, Single Arm, Dose Escalating Concentration-QT Study to Investigate the 
Cardiac Effects and Safety of Paroxetine in Healthy Adult Participants 
Brief Title: 
Concentration-QT Study of Paroxetine in Healthy Adults. 
Rationale:  
Paroxetine (Seroxat) is a selective serotonin reuptake inhibitor indicated for the treatment 
of major depressive disorder (MDD), obsessive compulsive disorder (OCD), panic 
disorder with or without agoraphobia, social and generalised anxiety disorders and post-
traumatic stress disorder (PTSD).  
In vitro studies have shown that paroxetine can block human Ether-à-go-go-Related Gene 
(hERG) channels, which in turn can cause QT prolongation. However, clinical reports 
evaluating an association between paroxetine exposure and corrected QT interval (QTc) 
prolongation are limited and vary in their conclusions. Based on the available data from 
published literature, GSK and EudraVigilance safety databases and clinical studies, it has 
been concluded there is some basis for suspicion of an association of QT prolongation 
with paroxetine, but current evidence does not confirm a causal relationship (GSK 
document 2021N481496). As there was no requirement for the evaluation of the potential 
effects on QT interval at the time of approval, no thorough QT (TQT) study has yet been 
performed with paroxetine. There is, however, some QTc data from automated readings 
from a pharmacokinetic (PK) interaction study between pimozide and paroxetine, where 
paroxetine was dosed up to the maximum recommended dose in the label of 60 mg once 
daily (q.d.). This study showed no difference between QTc at baseline and at the 60 mg 
once daily dose, although the electrocardiograms (ECGs) in this study were read 
automatically and performed at paroxetine trough concentrations corresponding to a 60 
mg once daily dose, instead of at peak concentrations (GSK document 
HM2004/00372/01). 
Following a careful assessment of the suitable approaches to characterise the magnitude 
of a potential QT prolonging effect, a concentration-QT (C-QT) study was determined to 
be appropriate to further investigate the potential risk. This approach is in line with the 
updated International Council on Harmonisation (ICH) guidance, which indicates that a 
C-QT study may be sufficient to address the cardiac effects questions when the risk of 
such effects is considered low. In light of the long history of paroxetine use and the 
limited evidence for QT prolongation from available sources, a C-QT study was deemed 
adequate to address the cardiac effects of paroxetine. In a study by Okayasu et al. 2012, 
risk of QTc prolongation seemed to be lower with paroxetine compared to other SSRIs 


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(Okayasu et al. 2012). A systematic review of literature showed that there was likely no 
effect of paroxetine on QTc (Funk et al. 2013). 
A C-QT study design allows the assessment of cardiac effects of a drug and may be more 
sensitive to detect any correlation between drug exposure and cardiac effects than a 
standard TQT study, as the C-QT study takes into account drug concentrations where a 
TQT study does not.  In contrast, a TQT study is powered to detect a QTc increase 
> 10 millisecond (msec) in comparison against a placebo and uses a positive control. The 
current C-QT study will employ a titration design, with escalating doses in steps of 20 
mg, up to 60 mg paroxetine q.d., which corresponds to the maximum recommended 
therapeutic paroxetine dose (as per GSK Seroxat Summary of product characteristics 
[SmPC] 2022).  
Objectives, Endpoints, and Estimands:  
Objectives 
Endpoints 
Primary 
 
• To evaluate the potential effect of 
paroxetine on QTc interval following 
oral doses of 20, 40, and 60 mg once 
daily in healthy adults  
• Change in QTc from baseline (ΔQTc) 
Secondary 
 
• To assess the safety and tolerability of 
paroxetine doses of 20, 40, and 60 mg 
once daily in healthy adults 
• Changes in vital signs (blood pressure, 
heart rate and oral body temperature) 
from baseline 
• Occurrence of adverse events (AEs), 
serious adverse events (SAEs), 
haematological and clinical laboratory 
tests*, vital signs, and physical 
examination 
* Laboratory tests will include full blood count, INR, PT, PTT, renal (Na+, K+, Cl-, creatinine) and hepatic 
(AST, ALT) markers 
Primary estimand 
The primary question of interest: Is there a clinically relevant cardiac effect of paroxetine 
at the maximum recommended therapeutic dose, as measured by an increase in QTc from 
12-lead electrocardiogram (ECG)? 
The estimand is described by the following attributes: 
• Population: Healthy participants of age 18 to 65 years  
• Treatment condition: Dose up titration of paroxetine doses of 20, 40 and 60 mg 
• Endpoint: Change in QTc from baseline (ΔQTc)  
• Summary measure: The upper limit of the90% confidence interval (CI) of model-
predicted ΔQTc at the geometric mean steady-state Cmax of the 60 mg paroxetine dose 
• Intercurrent events: 


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a) Treatment discontinuation due to any reason - While on-treatment strategy 
will be applied to address this intercurrent event.  
b) Any events affect the drug absorption (1 hour) – Treatment Policy strategy 
will be applied to address this intercurrent event. 
• Rationale for estimand:  
a) Interest lies in establishing the relationship between ΔQTc and paroxetine 
concentrations (Cmax) while the participant is exposed to paroxetine as 
planned, i.e., prior to the discontinuation of the treatment.  
b) Interest lies in the overall relationship between the ΔQTc and paroxetine 
concentrations, not with dose - therefore even though the concentration for a 
dose is affected, the data are still relevant even when there is an inaccuracy in 
dosing. 
If this summary measure is ≥10 msec, additional summary measure may be generated at 
the geometric mean Cmax of the 40 mg dose. Additionally, another estimand might need 
to be evaluated. 
Refer to Section 9.3.2 for more details. 
Secondary estimands 
Secondary estimands address all other safety and tolerability findings. 
The estimand is described by the following attributes: 
• Population: Healthy participants of age 18 to 65 years 
• Treatment condition: Dose up and down titration of paroxetine doses of 20, 40 and 
60 mg 
• Endpoint:    
−  Occurrence of adverse events (AEs) and serious adverse events (SAEs) 
− Changes in vital signs (blood pressure, heart rate and oral body 
temperature) from baseline  
− Changes in haematological and clinical laboratory tests from baseline 
• Summary measure: Proportions for AEs and SAEs and means of the change from 
baselines for vital signs, haematological, and clinical laboratory across all dose levels 
• Intercurrent events: Study intervention discontinuation due to any reason – treatment 
policy strategy will be applied for this intercurrent event. 
• Rationale for Estimand: Safety data will be monitored throughout the study after the 
start of study intervention. There is interest in evaluating and reporting safety events 
regardless of whether participants discontinued study intervention. 
Overall Design:  
This is an open-label, dose-titration, single arm, single centre study of paroxetine 
conducted to investigate the cardiac effects, safety and tolerability of paroxetine in 
healthy adult participants. 


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At least 36 participants and no more than 40 healthy participants with no history of 
cardiac abnormalities or mood disorders will be enrolled. All eligible participants will 
receive paroxetine titrated to a dose of 60 mg once daily at increments of 20 mg per 
week.  
All participants will attend a study site visit at Screening (Visit 1: -28 to -31 days to 31 
days), baseline (pre-dose) assessments and first paroxetine administration of 20 mg once 
daily (Visit 2: Day 1), serial ECG and paroxetine concentration measurements (Visit 3, 
Day 7) and dose escalation to 40 mg once daily (Visit 3: Day 8), serial ECG and 
paroxetine concentration measurements at the 40 mg dose (Visit 4, Day 14) and dose 
escalation to 60 mg once daily (Visit 4, Day 15), serial ECG and paroxetine concentration 
measurements (Visit 5, Day 21), and the Exit visit (Visit 6, up to 14 days after last 20 mg 
dose). Tapering from 60 to 40 mg once daily, 40 to 20 mg once daily, and 20 mg once 
daily to no dose will occur at home. Unplanned visits (if needed) will be scheduled for 
participants who needs to visit to clinic due to AEs during home dosing or required to 
start intermediate tapering dose of 10 mg to be started (for both clinic and home dosing) 
during the treatment period.  
During home dosing participants will be interviewed remotely via video call to confirm 
dosing compliance and have daily follow-ups. Paroxetine plasma concentrations will be 
collected as detailed in SOA. 
Number of Participants: 
The number of participants was selected based on the required variability in paroxetine 
concentrations to assess the cardiac effects. At least 36 participants and no more than 40 
healthy participants, men or non-pregnant women, aged 18 to 65 years will be enrolled. 
This number, in combination with the 3 dose titration steps, is expected to result in a 
sufficiently wide range of paroxetine concentrations to cover those typically observed in 
a real-world clinical setting.  
In addition, a previous pharmacokinetics (PK) drug-drug interaction study of paroxetine 
and pimozide in 40 healthy subjects used a dose titration up to 60 mg once daily in 
intervals of 20 mg per 5 days (GSK document HM2004/00372/01). Of these 40 subjects, 
33 subjects had evaluable QTc data at the 60 mg dose. Although 11 subjects dropped out 
in total by the end of the study, approximately half of those dropouts were in relation to 
the combination of the two investigated compounds which were found to interact. This 
study showed that the 60 mg once daily dose can be achieved, at the expected rate of 
titration, without prohibitive dropout rates. The current titration schedule increases the 
time stayed at the same dose to 7 days to improve participant retention. 
A Monte Carlo simulation analysis was used to determine the probability of the 90% 
upper limit of the CI of the ΔQTC at the geometric mean of the 60 mg dose 
encompassing the 10 msec cut-off value. Based on this simulation approach, it is 
expected that under the assumption of no true effect of paroxetine on QTc at the 60 mg 
dose, the expected probability of incorrectly detecting an effect (90% upper limit of the 
CI ≥10 msec) is <1% (false positive) with the inclusion of 36 participants. In case the true 
effect is 5 msec, the expected probability of a false positive is <2%. When the true effect 


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is 10 msec, the expected probability of correctly determining a QTc prolongating effect is 
approximately 82%. For further details, see Section 9.5. 
The sensitivity of missing data was also assessed. With 20% drop out at the 40 mg dose 
and another 25% drop out at the 60 mg dose (in addition to the drop out at the 40 mg 
dose) the expected probability of incorrectly detecting an effect (90% upper limit of the 
CI 10 msec) for 36 participants is 1% (false positive) when the true effect is null. The 
expected probability of a false positive is 5% if the true effect is 5 msec. The expected 
probability of correctly determining a QTc prolonging effect is approximately 85% when 
the true effect is 10 msec. 
Note: "Enrolled" means a participant, agrees to participate in a clinical study following 
completion of the informed consent process. Potential participants who are screened for 
the purpose of determining eligibility for the study, but do not participate in the study, are 
not considered enrolled, unless otherwise specified by the protocol.  
Table 1 
Interval between study visits 
Interval 
Planned visit interval  
Allowed interval range 
Visit 1→Visit 2 
28 days 
28, 31 
Visit 2→Visit 3 
6 days 
None 
Visit 3→Visit 4 
6 days 
None 
Visit 4→Visit 5 
6 days 
None 
Visit 5→Visit 6 
Up to 14 days after the 
last dose 
9, 14 after the last dose 
Intervention Groups and Duration: 
All participants will receive active treatment with paroxetine tablets once daily with 
titration steps every week over a maximum treatment period of 3 weeks. This is followed 
by tapering over the subsequent period of 10 days:  
• Days 1-7: 20 mg once daily  
• Days 8-14: 40 mg once daily 
• Days 15-21: 60 mg once daily 
• Days 22-26: 40 mg once daily 
• Days 27-31: 20 mg once daily. If participants are not able to withdraw from 
20 mg once daily directly due to withdrawal effects, an additional tapering dose 
step of 10 mg once daily may be given for 5 days. Unplanned visits (if needed) 
will be scheduled for participants who need to visit to clinic due to AEs during 
home dosing or required to start intermediate tapering dose of 10 mg to be started 
(for both clinic and home dosing) during the treatment period. 
• 
Day 32 (or 37) onwards: complete stop of paroxetine 
Data Monitoring/Other Committee:  
An Independent Data Monitoring Committee (IDMC) is not required for this study. 


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1.2. 
Schema 
The study design schema is presented in Figure 1. 
Figure 1 
Study design overview 
 
Abbreviations: ECG = Electrocardiogram 
 


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1.3. 
Schedule of activities (SoA) 
Table 2 
Schedule of Activities – Overview Across Visit Days 
Procedures 
Screening 
Baseline 
Treatment Period and Exit Visit1 
Early 
Discontinuation 
/ Withdrawal 
Visit 
Follow-
up / End 
of Study  
Study Visit 
1 
2 
2 
3 
4 
5 
Discontinue / 
Withdrawal Visit 
 
6 
Study Day 
-28 to -31 
-2 
-1 
1 
 
6 
7 
8 
13 
14 
15 
20 
21 
22 
– 
Up to 14 
days after 
last dose 
Informed consent2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
criteria2 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Demography/childbearing 
status assessment 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical and treatment 
history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Brief physical 
examination including 
height and weight3 
X3 
 
 
X 
 
X 
 
 
X 
 
 
X 
 
X 
X 
Arrive in clinic evening 
before Visit day4 
 
X5 
X 
 
X 
 
 
X 
 
 
X 
 
 
 
 
Dosing in clinic6 
 
 
 
X 
 
X 
X 
 
X 
X 
 
X 
 
 
 
Receive first of next dose 
level in clinic7 
 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
 
AE/SAE assessment8 
 
Concomitant medications 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
Vital signs9, 10 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
ECG10, 11 
X 
 
X12 
 
 
X12 
 
 
X12 
 
 
X12 
 
X12 
X12 


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Procedures 
Screening 
Baseline 
Treatment Period and Exit Visit1 
Early 
Discontinuation 
/ Withdrawal 
Visit 
Follow-
up / End 
of Study  
Study Visit 
1 
2 
2 
3 
4 
5 
Discontinue / 
Withdrawal Visit 
 
6 
Study Day 
-28 to -31 
-2 
-1 
1 
 
6 
7 
8 
13 
14 
15 
20 
21 
22 
– 
Up to 14 
days after 
last dose 
Paroxetine 
concentrations10, 11 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
Haematology with 
differential10 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Clinical and renal/liver 
chemistry10 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Pregnancy test, alcohol 
and drug of abuse tests10, 
13 
X 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
FSH test 14 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
COVID-19 test15 
X 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
Serology (HIV, HBV, and 
HCV) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C-SSRS 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Discharge16 
 
 
 
X 
 
 
X 
 
 
X 
 
X17 
X17 
 
 
Complete eCRF 
(ClinBase) 
 
 
X18 
X18 
 
X18 
 
 
X18 
 
 
X18 
 
X 
X 
Abbreviations: AE, adverse event; C-SSRS, Columbia suicide severity rating scale; ECG, electrocardiogram; eCRF, electronic case report form; SAE, 
serious adverse event. 
 
1. All participants will need to attend a clinic visit at Screening (Visit 1), Baseline (Visit 2, Day-1) and first 20 mg dose (Visit 2, Day 1), 
assessment at 20 mg steady-state dose (Visit 3, Day 7), first 40 mg dose (Visit 3, Day 8), assessment at 40 mg steady-state dose (Visit 4, 
Day 14), first 60 mg dose (Visit 4, Day 15) assessment at 60 mg steady-state dose and exit visit (Visit 5, Day 21) . They will also attend 
the clinic for the final follow-up visit (Visit 6). Participants will receive a follow-up video-call from the unit on all other dosing days outside of 
the clinic and the 3 days after last dose, and will take tablets under supervision of clinical staff over video-call.  


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2. Informed consent and eligibility criteria assessment data will all be captured on site. Informed consent must be obtained prior to starting 
screening procedures. 
3. Height will be measured at Screening only. Complete physical examination will be performed at Screening and final Follow-Up Visit, and 
brief physical examination at all further visits 
4. Participants will arrive at clinic in the evening (~20:00 PM) before the visit day (at Baseline [Day -1], Visit 2 [Day 6], Visit 4 [Day 13], and 
Visit 5 [Day 20]). 
5. Participants need to come in the evening on Day -2 and stay overnight for procedures on Day -1. 
6. On Visit 3 (Day 7), 4 (Day 14) and 5 (Day 21), the current (at that time) dose of paroxetine will be taken by the participant under 
supervision of staff. 
7. For Study Days 1 (Visit 2, 20 mg), Day 8 (Visit 3, 40 mg) and Day 15 (Visit 4, 60 mg), the participant will take the first dose of the next 
dose level (20, 40 and 60 mg respectively) under supervision of staff, remaining under observation for 3 hours post-dose and will be 
discharged afterwards. 
8. SAEs must be collected from signing of informed consent if considered related to study procedures. 
9. Vital sign measurements will include oral body temperature, systolic and diastolic blood pressure (BP), and pulse rate. Triplicate BP 
measurements will be performed in supine position at Screening only. 
10. Vitals, laboratory assessments (coagulation parameters, haematology with differential, clinical and liver chemistry, pregnancy test, and 
paroxetine concentrations samples) and ECG data will all be captured at visits on site. During the treatment period, all laboratory samples 
and vitals (including one paroxetine concentration sample) should be obtained pre-dose. 
11. All ECGs will be performed in triplicate collected within 5 min at each timepoint. ECG triplicates will be performed once at Screening (Visit 
1), and at Follow-Up Visit and at discontinuation or withdrawal visits. At Visits 2 (Day -1), 3 (Day 7), 4 (Day 14), and 5 (Day 21) ECG 
triplicates will be performed 15 min pre-dose (-0.25 h) and post-dose at the following timepoints 1, 2, 3, 4, 4.5, 5, 5.5, 6, 8, 10, 12h. Each 
ECG triplicates will be combined with paroxetine concentration assessment. Paroxetine concentrations at Visits 3 (Day 7), 4 (Day 14), and 
5 (Day 21) will be procured at the following timepoints: -0.25, 1, 2, 3, 4, 4.5, 5, 5.5, 6, 8, 10, 12 h. One sample will be collected for 
paroxetine concentrations on Day -1 at 0.25h (pre-dose). The paroxetine dose should be taken at the same clock time each time, at a time 
approximately between 07:00-010:00 (7to 10 am). When scheduled for the same time, ECGs should be performed before blood sampling 
to avoid impact on ECG parameters. 
. 
12. At Visits 2 (Day -1), 3 (Day 7), 4 (Day 14), and 5 (Day 21), follow-up visit and at discontinuation or withdrawal visits, serial ECG review will 
be performed by Mortara system 


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13. Negative urine pregnancy test result must be confirmed prior to dosing in female participants of reproductive potential. If a urine test 
cannot be confirmed as negative (e.g., an ambiguous result), a serum pregnancy test is required. In such cases, the participant must be 
excluded from participation if the serum pregnancy result is positive.  
14. FSH test be performed for postmenopausal women only 
15. COVID-19 testing will be performed as per site practice 
16. Participants will be discharged from the clinic 3 hours after the morning dose on Study Days 1, 8, and 15 (Visit 2, 3, 4) to subsequently 
take paroxetine doses at home until the next Visits in clinic. 
17. Participants will get discharge on either Day 21 or Day 22 (may stay overnight) as per the convenience. 
18. The date and time of the administration of study intervention will be recorded in the eCRF. N.B. participants will be provided with the 
required tablets for dosing up to the next visit. Participants will take the tablet(s) under supervision when in the clinic, and under video-call 
supervision when outside the clinic. 
 
 


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Table 3 
Schedule of Activities – Details of Paroxetine Concentrations /ECG Assessment Visit Day Activities 
Procedures 
Activities at time (h) in relation to paroxetine dose 
Time (h) in relation to paroxetine dose 
- 0.25 
1 
2 
3 
4 
4.5 
5 
5.5 
6 
8 
10 
12 
27 
(Discharge 
time) 
AE/SAE assessment 
 
Vital signs1,3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECG2,3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Paroxetine concentrations 2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Discharge4 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Abbreviations: AE: adverse event, ECG: electrocardiogram, PK: pharmacokinetic, SAE: serious adverse event. 
1. Vital sign measurements will include oral body temperature, systolic and diastolic blood pressure, and pulse rate. Triplicate BP measurements 
will be performed in supine position at Screening only. 
2.  All ECGs will be performed in triplicate collected within 5 min at each timepoint. ECG triplicates will be performed once at Screening (Visit 1), 
and at Follow-Up Visit and at discontinuation or withdrawal visits. At Visits 2 (Day -1), 3 (Day 7), 4 (Day 14), and 5 (Day 21) ECG triplicates will 
be performed 15 min pre-dose (-0.25 h) and post-dose at the following timepoints 1, 2, 3, 4, 4.5, 5, 5.5, 6, 8, 10, 12h. Each ECG triplicates will 
be combined with paroxetine concentration assessment. Paroxetine concentrations at Visits 3 (Day 7), 4 (Day 14), and 5 (Day 21) will be 
procured at the following timepoints: -0.25, 1, 2, 3, 4, 4.5, 5, 5.5, 6, 8, 10, 12 h. The paroxetine dose should be taken at the same clock time 
each time, at a time between 08:00-09:00 (8 to 9 am). When scheduled for the same time, ECGs should be performed before blood sampling 
to avoid impact on ECG parameters. 
3. Vitals, and ECG data will all be captured at visits on site. During the treatment period, all laboratory samples (including one PK sample) should 
be obtained pre-dose. 
4. For Study Days 1 (Visit 2), Day 8 (Visit 3) and Day 15 (Visit 4), participants will take the 20, 40 and 60 mg dose under supervision in the clinic. 
This is on the day after the paroxetine concentration and ECG assessments. Participants will get discharged in 27 ± 3 hours post dose. 
 
 


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2. 
INTRODUCTION  
2.1. 
Study rationale 
Paroxetine (Seroxat) is a selective serotonin reuptake inhibitor indicated for the treatment 
of major depressive disorder (MDD), obsessive compulsive disorder (OCD), panic 
disorder with or without agoraphobia, social and generalised anxiety disorders and post-
traumatic stress disorder (PTSD).  
In vitro studies have shown that paroxetine can block human Ether-à-go-go-Related Gene 
(hERG) channels, which in turn may cause QT prolongation. However, clinical reports 
evaluating an association between paroxetine exposure and QTc prolongation are limited 
and vary in their conclusions. Based on the available data from published literatures, 
GSK and EudraVigilance safety databases and clinical studies, it has been concluded that 
there is some basis for suspicion of an association of QT prolongation with paroxetine, 
but current evidence does not confirm a causal relationship (GSK document 
2021N481496). As there was no requirement for the evaluation of the potential effects on 
QT interval at the time of approval, no thorough QT (TQT) study has yet been performed 
with paroxetine. There is, however, some QTc data from automated readings from a 
pharmacokinetic (PK) interaction study between pimozide and paroxetine, where 
paroxetine was dosed up to the maximum recommended dose in the label of 60 mg once 
daily (q.d.). This study showed no difference between QTc at baseline and at the 60 mg 
once daily dose, although the electrocardiograms (ECGs) in this study were read 
automatically and performed at paroxetine trough concentrations corresponding to a 60 
mg once daily dose, instead of at peak concentrations (GSK document 
HM2004/00372/01). 
Following a careful assessment of the suitable approaches to characterise the magnitude 
of a potential QT prolonging effect, a concentration-QT (C-QT) study was determined to 
be appropriate to further investigate the potential risk. This approach is in line with the 
updated International Council on Harmonisation (ICH) guidance, which indicates that a 
C-QT study may be sufficient to address the cardiac effects questions when the risk of 
such effects is considered low. In light of the long history of paroxetine use and the 
limited evidence for QT prolongation from available sources, a C-QT study was deemed 
adequate to address the cardiac effects of paroxetine. In a study by Okayasu et al. 2012, 
risk of QTc prolongation seemed to be lower with paroxetine compared to other SSRIs 
(Okayasu et al. 2012). A systematic review of literature showed that there was likely no 
effect of paroxetine on QTc (Funk et al. 2013). 
A C-QT study design allows the assessment of cardiac effects of a drug and may be more 
sensitive to detect any correlation between drug exposure and cardiac effects than a 
standard TQT study, as the C-QT study takes into account drug concentrations where a 
TQT study does not.  In contrast, a TQT study is powered to detect a QTc increase 


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> 10 millisecond (msec) in comparison against a placebo, and uses a positive control. The 
current C-QT study will employ a titration design, with escalating doses in steps of 20 
mg, up to 60 mg paroxetine q.d., which corresponds to the maximum recommended 
therapeutic paroxetine dose (as per GSK Seroxat SmPC 2022). 
2.2. 
Background 
Paroxetine is a selective serotonin (5HT) reuptake inhibitor indicated for the treatment of 
MDD, OCD, panic disorder with or without agoraphobia, social anxiety disorder, 
generalised anxiety disorders and PTSD. Its efficacy and safety as an antidepressant have 
also been demonstrated in a range of co-morbidities associated with conditions such as 
anxiety, and heart disease.   
Paroxetine is extensively distributed beyond the plasma compartment in both animals and 
man. In pigmented rats and mice, trace amounts of drug-related material are taken up 
reversibly by melanin-containing tissues. Studies in humans have demonstrated that the 
systemic availability of paroxetine may be modestly enhanced by hepatic enzyme 
inhibition and reduced by hepatic enzyme induction.  
Paroxetine has been shown to be a potent and highly selective inhibitor of 5-HT uptake 
mechanisms in in vitro, ex vivo pharmacological studies and biochemical test in animals. 
Paroxetine has also demonstrated inhibition of 5-HT uptake into platelets after doses of 
30 mg daily to human but did not affect noradrenaline uptake as assessed by the tyramine 
pressure test. It was well tolerated by the cardiovascular (CV) system and was, 
qualitatively and quantitatively, less cardiotoxic than amitriptyline in animal studies. 
Evaluation of ECGs of 682 participants who received paroxetine in double-blind, 
placebo-controlled studies, however, did not indicate that paroxetine was associated with 
the development of significant ECG abnormalities. In addition, paroxetine produced no 
clinically significant changes in blood pressure or heart rate (GSK Seroxat SmPC 2022). 
The PK profile of paroxetine has been fully characterised in the adult population. 
Paroxetine was well absorbed after oral dosing but, because of a significant first-pass 
effect, not all of the dose reaches the systemic circulation. Paroxetine exhibits non-linear 
PK due primarily to dose-dependent bioavailability, arising from the involvement of the 
saturable, polymorphic cytochrome P450 enzyme CYP2D6 in its metabolism (Latham 
and Morton 1993). In single dose studies, paroxetine plasma concentrations increase 
disproportionately with dose in most participants, but not in all. In poor metabolizers 
(PM) participants (PM who lack CYP2D6), concentrations were the highest initially but 
increase linearly with dose. Similarly, in repeat dose studies, although most participants 
show greater than predicted paroxetine accumulation during the approach to 
steady--state, accumulation in PMs was entirely predictable; non-linearity was confined 
to extensive metabolizers (EMs). Importantly, although non-linearity was also evident 
when increasing the daily dose at steady--state, the deviations from linearity were less 
pronounced because CYP2D6 was already partially saturated. In all of these dosing 


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scenarios (increasing dose level and duration), the between-subject PK variability 
progressively diminishes. These properties indicate that all participants (EMs and PMs) 
have alternative, non--saturable pathways by which paroxetine was cleared from the body 
when CYP2D6 was absent or saturated. These linear pathways predominate at 
steady--state, and therefore the influence of CYP2D6 status as a determinant of PK 
properties during the routine clinical use of paroxetine was much reduced. Also, because 
paroxetine plasma concentrations were not predictive of clinical outcome (efficacy or 
AEs), the same starting doses and titration regimens were suitable for EMs and PMs alike 
(Latham and Morton 1993). 
Paroxetine was first approved in the UK for the treatment of depression in December 
1990 and ‘paroxetine’ 20 mg and 30 mg tablets were launched in February 1991. Since 
the total exposure since launch is estimated to be in excess of 400 million patient 
treatments. 
As there was no suspicion of a QT prolonging effect of paroxetine during its development 
and registration, QT prolongating effects were not investigated in a controlled setting 
(e.g., TQT study). Consideration was given to the potential designs in which a QT 
prolonging effect could be evaluated. While historically TQT studies have been the 
standard for such evaluations, in more recent years the C-QT study has become accepted 
in those settings where the suspicion for a potential QT prolonging effect is considered 
low. A C-QT study design allows the assessment of cardiac effects of a drug and may be 
more sensitive to detect any correlation between drug exposure and cardiac effects than a 
standard TQT study, as the C-QT study takes into account drug concentrations where a 
TQT study does not. In contrast, a TQT study is powered to detect a QTc increase > 10 
msec in comparison against a placebo, and uses a positive control (e.g. moxifloxacin). 
The current C-QT study will employ a titration design, with escalating doses in steps of 
20 mg, up to 60 mg paroxetine q.d., which corresponds to the maximum recommended 
therapeutic paroxetine dose (as per GSK Seroxat SmPC 2022).  
For additional information, see the paroxetine label (GDS). 
2.3. 
Benefit/risk assessment 
More detailed information about the known and expected benefits and risks and 
reasonably expected adverse events (AEs) of paroxetine may be found in the GSK 
Seroxat SmPC 2022. 
2.3.1. 
Risk assessment 
Paroxetine has a well-characterized safety profile supported by over 30 years on the 
market across a number of indications, and a large cumulative post-marketing exposure. 
Information about the known and potential risks and reasonably expected AEs may be 


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found in the GSK Seroxat SmPC 2022. Potential risks of clinical significance for this 
particular study are summarised below. 
 


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Potential Risk of Clinical Significance 
Summary of Data/Rationale for Risk 
Mitigation Strategy 
Study Intervention(s) [Paroxetine] 
Serotonin Syndrome/Neuroleptic malignant syndrome like 
events 
Serotonin syndrome has been reported very rarely in 
patients treated with paroxetine. 
 
Paroxetine belongs to a class of drugs known as SSRIs 
whose antidepressant activity results from their ability to 
selectively increase synaptic levels of serotonin in the 
brain. Overstimulation of the serotonergic system can 
lead to serotonin syndrome. 
 
 Symptoms of serotonin syndrome may include any or all 
of the following (note that other symptoms may be 
exhibited): agitation, confusion, diaphoresis, 
hallucinations, hyperreflexia, myoclonus, shivering, 
tachycardia and tremor. Symptoms may worsen with 
continued therapy and can be life threatening.  
 
Serotonin syndrome may occur at any time during 
treatment with paroxetine. It may be more likely to occur if 
paroxetine is co-administered with other serotonergic 
drugs. Of note, although most likely to occur through the 
combined use of various serotonergic drugs, GSK has 
received rare post-marketing reports of the development 
of serotonin syndrome in patients receiving paroxetine in 
the absence of other serotonergic co-medications 
Participants are forbidden to receive other serotonergic 
medications during the study (see Section 5.2, Exclusion 
criteria) 
 
Participants should be alerted to the potential symptoms 
of serotonin syndrome. 
 
If a participant experiences serotonin 
syndrome/neuroleptic malignant syndrome like symptoms 
during the study, paroxetine should be discontinued and 
the participant withdrawn from the study. 


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Bleeding disorders, predominantly of the skin and mucous 
membranes 
Abnormal bleeding, predominantly of the skin and mucous 
membranes has been reported uncommonly in patients 
receiving paroxetine. Gastrointestinal bleeding is 
estimated to be very rare. Abnormal bleeding may occur 
at any time during treatment with paroxetine. 
 
SSRIs are antagonists of the serotonin transporter system 
which can lead to a lower concentration of serotonin in 
platelets. Serotonin mediates vasoconstriction, platelet 
aggregation and platelet activation following injury, and 
because platelets cannot synthesize serotonin, treatment 
with SSRIs can lead to a reduction of platelet serotonin 
and therefore impair haemostasis. 
 
Symptoms and outcomes of blood loss can vary 
depending on a number of factors such as the volume of 
blood loss, rate of loss and cause of the loss. Symptoms 
of more severe blood loss (indicating hypovolaemic 
shock) may include pale skin, rapid breathing, sweating, 
weakness, no or decreased urine output, confusion, 
clammy skin, unconsciousness and death. Depending on 
the severity of the blood loss immediate medical 
treatment may be required and may necessitate blood 
transfusion in extreme cases. 
 
Patients more at risk from paroxetine induced bleeding 
related adverse events will be those who are 
concomitantly using medications that may increase the 
risk for bleeding such as nonsteroidal anti-inflammatory 
drugs (NSAIDs), anticoagulants, antiplatelet medications 
or corticosteroids. Additionally, those patients with a 
known tendency for bleeding or those with predisposing 
conditions such as previous history of gastrointestinal 
bleeding, elderly patients or those with history of peptic 
As per exclusion criteria (refer to Section 5.2), subjects 
cannot participate in the study if they have a history of/or 
concurrent abnormal coagulation parameters, a bleeding 
disorder or conditions which may pre-dispose the subject 
to bleeding. 
 
Participants are forbidden to receive concomitant 
medications during the study which might increase the 
risk for bleeding events (anticoagulants (e.g. warfarin), 
non-steroidal anti-inflammatory drugs, acetylsalicylic acid 
or Cox 2 inhibitors (refer to section 5.2, Exclusion Criteria) 
 
Participants should be made aware of the symptoms of 
blood loss. 
 
If the participant experience blood loss during the study, 
treatment with paroxetine should be discontinued and the 
participant withdrawn from the study. 


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ulcers, cirrhosis of the liver or liver failure will be at 
increased risk. 


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Akathisia 
Rarely, the use of paroxetine or other SSRIs has been 
associated with the development of akathisia, which is 
characterised by an inner sense of restlessness and 
psychomotor agitation such as an inability to sit or stand 
still usually associated with subjective distress. This is 
most likely to occur within the first few weeks of treatment. 
 
 
The mechanism for akathisia is not completely 
understood but it is postulated to be related to a decrease 
in dopaminergic neurotransmission and it has been 
suggested that SSRIs induce akathisia (and 
parkinsonism) by indirectly stimulating serotonin (5-HT)2A 
receptors, which results in inhibition of dopamine release. 
 
Risk factors for the development of akathisia in patients 
taking paroxetine may include the use of multiple 
medications that can cause akathisia (such as 
neuroleptics, other SSRIs, antiemetics), a recently 
increased or high dose of SSRI, previous development of 
akathisia, previous exposure to akathisia inducing 
medications, baseline psychiatric disorders such as 
anxiety, agitation or panic, brain trauma and female sex. 
There is also suggestion that akathisia can occur 
spontaneously in patients with Parkinson’s Disease 
Study participants must be healthy as determined by a 
responsible physician.  Participants with a previous 
history of depression or other mood disorders will be 
excluded from study participation (refer to sections 5.1 
and 5.2, (Inclusion and Exclusion Criteria respectively). 
 
Participants are prohibited from receiving concomitant 
medications during the study including neuroleptic drugs 
or other SSRIs (refer to section 5.2, Exclusion Criteria) 
 
Dose increases of paroxetine (20 mg increments) will be 
conducted under supervision in the clinic. 
 
Participants should be made aware of the symptoms of 
akathisia. 
 
If a participant experiences symptoms of akathisia during 
the study, discontinuation of paroxetine should be 
considered. 


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Symptoms seen on discontinuation of paroxetine 
In clinical trials in adults, adverse events seen on 
treatment discontinuation occurred in 30% of patients 
treated with paroxetine compared to 20% of patients 
treated with placebo.  
 
Common adverse events which can occur following 
discontinuation of treatment with paroxetine include: 
dizziness, sensory disturbances, sleep disturbances, 
anxiety and headache. Adverse events including 
agitation, nausea, tremor, confusion, sweating and 
diarrhoea have also been reported uncommonly after 
discontinuing paroxetine treatment.  
 
Discontinuation type symptoms are most likely to occur on 
abrupt discontinuation of paroxetine but have also been 
seen during the dose taper phase of treatment. Generally, 
these symptoms are self-limiting and usually resolve 
within 2 weeks, though in some individuals they may be 
prolonged (2-3 months or more).  
 
It is recommended that paroxetine should be gradually 
tapered when discontinuing treatment over a period of 
several weeks or months. 
 
After the study dosing period (up to 60 mg daily) 
participants will be undergoing gradual tapering of their 
paroxetine dose in decrements of 20 mg over a total 
tapering period of ten days. Refer to section 1.2, Schema. 
 
Participants should be made aware of the type of 
symptoms which might occur during the tapering phase. 
 
Withdrawal symptoms generally tend to be self-limiting. 
However, based on PI’s clinical assessment of withdrawal 
symptoms during the tapering phase of 20 mg OD to no 
paroxetine, an additional 5 days of 10 mg OD paroxetine 
may be provided. 
In addition, withdrawal symptoms may be treated, at the 
PI’s discretion, as clinically indicated. 


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Suicidality/suicide ideation 
Young adults, especially those with major depressive 
disorder, may be at increased risk for suicidal behaviour 
during treatment with paroxetine.  
 
An analysis of placebo-controlled trials of adults with 
psychiatric disorders showed a higher frequency of 
suicidal behaviour in young adults (prospectively defined 
as aged 18 to 24 years) treated with paroxetine compared 
with placebo (17/776 [2.19%] versus 5/542 [0.92%]), 
although this difference was not statistically significant. In 
the older age groups (aged 25 to 64 years and ≥65 
years), no such increase was observed.  
 
In adults with MDD (all ages), there was a statistically 
significant increase in the frequency of suicidal behaviour 
in patients treated with paroxetine compared with placebo 
(11/3455 [0.32%] versus 1/1978 [0.05%]; all of the events 
were suicide attempts). However, the majority of these 
attempts for paroxetine (8 of 11) were in younger adults 
aged 18 to 30 years. These major depressive disorder 
data suggest that the higher frequency observed in the 
younger adult population across psychiatric disorders may 
extend beyond the age of 24. 
A Colombia Suicide Severity Rating Scale (C-SSRS) will 
be taken at screening. Participants with a history of 
suicidal attempt/ideation or those having undergone 
previous assessment for suicide ideation will be excluded 
from the study along with participants with a history of 
depression or a pre-diagnosed mood disorder (refer to 
Section 5.2, Exclusion Criteria).  
 
Participants will be monitored for suicidal ideation as part 
of regular AE monitoring either in person (during study 
Visits) or via a video call (when dosing at home). In 
addition to the C-SSRS taken at screening, repeat C-
SSRS may be administered at the PI’s discretion, as 
clinically indicated. 


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Pregnancy Outcomes 
Congenital malformations: Epidemiological studies of 
pregnancy outcomes following maternal exposure to 
antidepressants in the first trimester have reported an 
increase in the risk of congenital malformations, 
particularly cardiovascular (e.g. ventricular and atrial 
septal defects), associated with the use of paroxetine. 
The data suggest that the risk of having an infant with a 
cardiovascular defect following maternal paroxetine 
exposure is approximately 1/50, compared with an 
expected rate for such defects of approximately 1/100 
infants in the general population. 
A female participant is only eligible to participate in the 
study if she is of nonchildbearing potential or of child-
bearing potential but having agreed to use one of the 
accepted methods of contraception as detailed in section 
8.1. 
Pregnant females as determined by positive serum β-
HCG test at screening or serum/ urine β-HCG prior to 
dosing will be excluded from the study. 
If a female participant becomes pregnant during the 
study, paroxetine treatment should be discontinued and 
the participant withdrawn from study participation. (Refer 
to section 8.4.5. Follow-up information on the pregnancy 
will be collected and monitored as per company 
pharmacovigilance procedures. 
 


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2.3.2. 
Benefit assessment 
It is not anticipated that there will be any direct benefit for participants participating in 
this study. An indirect benefit is that the information obtained in this study will support 
the continued understanding of the safety profile of paroxetine and support appropriate 
prescribing in patients with underlying cardiac risks. 
2.3.3. 
Overall benefit-risk conclusion 
Considering the measures taken to minimize the risk to participants participating in this 
study, the potential risks are justified by the potential benefits related to the continued 
understanding of the safety profile of paroxetine.   
 


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3. 
OBJECTIVES, ENDPOINTS AND ESTIMANDS 
Objectives 
Endpoints 
Primary 
 
• To evaluate the potential effect of 
paroxetine on QTc interval following 
oral doses of 20, 40, and 60 mg once 
daily in healthy adults 
• Change in QTc from baseline (ΔQTc). 
Secondary 
 
• To assess the safety and tolerability of 
paroxetine doses of 20, 40, and 60 mg 
once daily in healthy adults 
• Changes in vital signs (blood pressure, 
heart rate and oral body temperature) 
from baseline 
• Occurrence of adverse events (AEs), 
serious adverse events (SAEs), 
haematological and clinical laboratory 
tests*, vital signs, and physical 
examination 
* Laboratory tests will include full blood count, INR, PT, PTT renal (Na+, K+, Cl, creatinine) and hepatic 
(AST, ALT) markers. 
 
Primary estimand 
The primary question of interest is: Is there a clinically significant, and clinically relevant 
cardiac effect of paroxetine at the maximum recommended therapeutic dose, as measured 
by a change in QTc from 12-lead ECG? 
The estimand is described by the following attributes: 
• Population: Healthy participants of age 18 to 65 years 
• Treatment condition: Dose up titration of paroxetine doses of 20, 40 and 60 mg. 
• Variable/endpoint: Change in QTc from baseline (ΔQTc)  
• Summary measure: The upper limit of the 90% confidence interval (CI) of 
model--predicted ΔQTc at the geometric mean steady-state Cmax of the 60 mg 
paroxetine dose. 
• Intercurrent events: 
a. Treatment discontinuation due to any reason - While on-treatment 
strategy will be applied to address this intercurrent event.  
b. Any events affect the drug absorption (1 hour) – Treatment Policy 
strategy will be applied to address this intercurrent event. 
• Rationale for estimand:  
a. 
Interest lies in establishing the relationship between ΔQTc and 
paroxetine concentrations (Cmax) while the participant is exposed to 
paroxetine as planned, i.e., prior to the discontinuation of the treatment.   


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b. 
Interest lies in the overall relationship between the ΔQTc and 
paroxetine concentrations, not with dose - therefore even though the 
concentration for a dose is affected, the data are still relevant.  
If this summary measure is ≥10 msec, additional summary measure may be generated at 
the geometric mean Cmax of the 40 mg dose. Additionally, another estimand might need 
to be evaluated. 
Refer to Section 9.3.2 for more details. 
Secondary estimands 
Secondary estimands address all other safety and tolerability findings.  
The estimand is described by the following attributes: 
• Population: Healthy participants of age 18 to 65 years 
• Treatment condition: Dose up and down titration of paroxetine doses of 20, 40 
and 60 mg 
• Variable/endpoint:  
Occurrence of adverse events (AEs) and serious adverse events (SAEs) 
Changes in vital signs (blood pressure, heart rate and oral body 
temperature) from baseline  
Changes in haematological and clinical laboratory tests from baseline 
• Summary measure: Proportions for AEs and SAEs and means of the change 
from baselines for vital signs, haematological, and clinical laboratory across 
all dose levels. 
• Intercurrent events: Study treatment discontinuation due to any reason – 
treatment policy strategy will be applied for this intercurrent event. 
• Rationale for Estimand: Safety data will be monitored throughout the study 
after the start of treatment. There is interest in evaluating and reporting safety 
events regardless of whether participants discontinued treatment. 
 
4. 
STUDY DESIGN 
4.1. 
Overall design 
This is a an open-label, single arm, dose-escalating concentration QT study to investigate 
the cardiac effects, safety and tolerability of paroxetine in healthy adult participants. 
At least 36 participants with no history of cardiac abnormalities or mood disorders will be 
enrolled. All eligible participants will receive paroxetine titrated to a dose of 60 mg once 
daily at increments of 20 mg per week. 
All participants will attend a study site visit at Screening (Visit 1: -28 to -31 days), 
baseline (pre-dose) assessments and first paroxetine administration of 20 mg once daily 
(Visit 2: Day 1), serial ECG and paroxetine concentration measurements (Visit 3, Day 7) 


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and dose escalation to 40 mg once daily (Visit 3: Day 8), serial ECG and paroxetine 
concentration measurements at the 40 mg dose (Visit 4, Day 14) and dose escalation to 
60 mg once daily (Visit 4: Day 15), serial ECG and paroxetine concentration 
measurements (Visit 5, Day 21) and the Exit visit (Visit 6, up to 14 days after last 20 mg 
dose). Tapering from 60 to 40 mg once daily, 40 to 20 mg once daily, and 20 mg once 
daily to no dose will occur at home. Unplanned visits (if needed) will be scheduled for 
participants who needs to visit to clinic due to AEs during home dosing or required to 
start intermediate tapering dose of 10 mg to be started (for both clinic and home dosing) 
during the treatment period. 
During home dosing participants will be interviewed remotely via video-call to confirm 
dosing compliance and have daily follow-ups. The study design schema is presented in 
Figure 1. The intervals between study visits are presented in Table 2. 
Intervention Groups and Duration: 
All participants will receive active treatment with paroxetine tablets once daily with 
titration steps every week over a maximum treatment period of 3 weeks. This is followed 
by tapering over the subsequent period of 10 days:  
• Days 1 -7: 20 mg once daily  
• Days 8 -14: 40 mg once daily 
• Days 15- 21: 60 mg once daily 
• Days 22-26: 40 mg once daily 
• Days 27-31: 20 mg once daily. If participants are not able to withdraw from 
20 mg once daily directly due to withdrawal effects, an additional tapering dose 
step of 10 mg once daily may be given for 5 days. Unplanned visits (if needed) 
will be scheduled for participants who need to visit to clinic due to AEs during 
home dosing or required to start intermediate tapering dose of 10 mg to be started 
(for both clinic and home dosing) during the treatment period. 
• 
Day 32 (or 37) onwards: complete stop of paroxetine 
4.2. 
Scientific rationale for study design 
This is a single arm, open label, dose escalating concentration QT study to investigate the 
cardiac effects, safety and tolerability of paroxetine in healthy adult participants. 
Participants recruited in this study will not be allowed to take other co-administered 
medication other than paracetamol and will be managed according to routine medical 
care where relevant. In vitro studies have shown that paroxetine can block hERG 
channels, which in turn can cause QT prolongation. However, clinical reports evaluating 
an association between paroxetine exposure and QTc prolongation are limited and vary in 
their conclusions. Based on the available data from published literature, GSK and 
EudraVigilance safety databases and clinical studies, it has been concluded that there is 
some basis for suspicion of an association of QT prolongation with paroxetine, but 
current evidence does not confirm a causal relationship (GSK document 2021N481496). 
Following a careful assessment of the suitable approaches to characterise the magnitude 


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of a potential QT prolonging effect, a concentration-QT study was determined to be 
appropriate to further investigate the potential risk. 
4.2.1. 
Participant input into design 
No participants’ input in the design has been considered for this study. 
4.3. 
Justification for dose 
For adults, it is recommended that paroxetine is administered once daily in the study site 
in the morning with food. The tablets should be swallowed rather than chewed. The 20 
mg tablets have functional break lines to allow for breaking the tablets in half to yield 10 
mg doses if needed. As per the Paroxetine label (GDS, 2023), the recommended 
maintenance dose in adults is 20 mg. The current study will employ a titration design to 
limit the probability of side-effects occurring, with escalating doses up to 60 mg 
paroxetine q.d., which corresponds to the maximum recommended therapeutic paroxetine 
dose. 
In this study, all participants will receive active treatment with paroxetine tablets once 
daily with titration/escalation steps every week over a maximum treatment period of 
3 weeks. This is followed by tapering over the period of 10 days as detailed in 
Section 4.1. If intolerable withdrawal symptoms occur during down titration of 
paroxetine from 20 mg once daily to no dose, then an intermediate tapering step of 10 mg 
once daily for an additional 5 days will be allowed. In this case the final follow-up visit 
will remain up to 14 days after the last 20 mg dose. An unplanned visit (if needed) will be 
scheduled for participants for an intermediate tapering dose of 10 mg to be started (for 
both clinic and home dosing) during the treatment period or for those participants who 
needs to visit to clinical due to AEs after dosing was performed at home. 
4.4. 
End-of-study definition 
A participant is considered to have completed the study if they have completed all phases 
of the study. including the last visit for any protocol-related activity (last participant, last 
visit) as shown in the SoA (Section 1.3) are completed. 
The end of the study is defined as the last visit of the last participants in the study. 
5. 
STUDY POPULATION 
Prospective approval of protocol deviations to recruitment and enrolment criteria, also 
known as protocol waivers or exemptions, are not permitted. 


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5.1. 
Inclusion criteria 
Participants are eligible to be included in the study only if all of the following criteria 
apply: 
1. Male or female 18 to 65 years, at the time of signing the informed consent form. 
2. Healthy as determined by an experienced physician, based on a medical 
evaluation including medical history, physical examination, laboratory tests and 
cardiac monitoring. A participant with a clinical abnormality or laboratory 
parameters outside the reference range for the population being studied may be 
included only if the Investigator believes that the finding is unlikely to introduce 
additional risk factors and will not interfere with the study procedures. 
3. A female participant is eligible to participate if she is of: 
a. Nonchildbearing potential defined as premenopausal females with a 
documented tubal ligation or hysterectomy; or postmenopausal defined as 
12 months of spontaneous amenorrhea [in questionable cases a blood 
sample with simultaneous follicle stimulating hormone (FSH) > 40lU/L 
and oestradiol <40 pg/ml (<147 pmol/L) is confirmatory]. Females on 
hormone replacement therapy (HRT) and whose menopausal status is in 
doubt will be required to use one of the contraception methods (oral 
contraceptives, condom with spermicide, etc.) if they wish to continue 
their HRT during the study. Otherwise, they must discontinue HRT to 
allow confirmation of postmenopausal status prior to study enrolment. For 
most forms of HRT, at least 2-4 weeks will elapse between the cessation 
of therapy and the blood draw; this interval depends on the type and 
dosage of HRT. Following confirmation of their postmenopausal status, 
they can resume use of HRT during the study without use of a 
contraceptive method. 
b. Child-bearing potential and agrees to use one of the contraception methods 
listed in Appendix 4 for at least for 2 months before screening, up to the 
final follow up visit,  to sufficiently minimize the risk of pregnancy. 
4. AST, ALT, alkaline phosphatase and bilirubin ≤ 1.5xULN (isolated bilirubin 
>1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%). 
5. Body weight ≥ 45 kg and BMI within the range 18 to 29.5 kg/m2 (inclusive). 
6. No significant abnormality on 12-lead ECG at Screening in supine position, 
including the following specific requirements: 
a. Heart rate ≥ 40 beats per minute 
b. PR interval ≤ 220msec* 
c. Q waves < 50msec* 
d. QRS interval to be ≥ 60msec and < 120msec* 
e. The waveforms must enable the QT interval to be clearly defined 
f. QTcF interval must be < 450msec (machine or manual reading). 
*For PR, QRS and QTcF interval, and Q wave, the mean of triplicate ECGs 
will be used. 
7. Capable of giving written informed consent and a signed and dated written 
informed consent is obtained, which includes compliance with the requirements 
and restrictions listed in the consent form. 


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8. Non-smokers (never smoked or not smoking for >6 months with <10 pack years 
history (Pack years = (cigarettes per day smoked/20) x number of years smoked) 
or light smokers (less than 5 cigarettes per day). 
5.2. 
Exclusion criteria 
Participants are excluded from the study if any of the following criteria apply: 
1. History or presence of any medically significant disease, or any disorder that 
would introduce additional risk or interfere with the study procedures or outcome. 
In particular, a family history of QT prolongation, of early or sudden cardiac 
death or of early cardiovascular disease. 
2. History of symptomatic arrhythmias. 
3. History of hypersensitivity to paroxetine and excipients 
4. History of abnormal coagulation parameters, bleeding disorders or conditions 
which may predispose to bleeding. 
5. History of, or active suicidal ideation. Includes assessment using the Columbia 
Suicide Severity Rating Scale (C-SSRS) 
6. Must not have a pre-diagnosed mood disorder 
7. Participant is mentally or legally incapacitated. 
8. A supine blood pressure that is persistently higher than 140/90 millimetres of 
mercury (mmHG) at Screening. 
9. A supine heart rate outside the range 50-90 beats per minute (BPM) at Screening. 
10. A positive screening Hepatitis B surface antigen or positive Hepatitis C antibody 
result within 3 months of screening. 
11. Current or chronic history of liver disease, or known hepatic or biliary 
abnormalities (with the exception of Gilbert's syndrome or asymptomatic 
gallstones). 
12. A positive drug/alcohol screen at screening or prior to dosing. 
13. A positive test for HIV antibody at Screening. 
14. History of regular alcohol consumption within 6 months of the study defined as: 
o an average weekly intake of >21 units for males or >14 units for females. 
One unit is equivalent to 8 g of alcohol: a half-pint (~240 ml) of beer, 1 
glass (125ml) of wine or 1 (25 ml) measure of spirits. 
15. The participant has participated in a clinical trial and has received an 
investigational product within the following time period prior to the first dosing 
day in the current study: 3 months, 5 half-lives or twice the duration of the 
biological effect of the investigational product (whichever is longer). 
16. Exposure to more than four new chemical entities within 12 months prior to the 
first dosing day. 
17. Use of the following medications 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 the study medication: monoamine oxidase inhibitors (including linezolid), 
thioridazine, pimozide, serotonergic drugs (including L-tryptophan, triptans, 
tramadol, selective serotonin reuptake inhibitors, lithium and fentanyl, tamoxifen, 
anti-coagulants, clozapine, phenothiazines, tricyclic antidepressants, 
acetylsalicylic acid, non-steroidal anti-inflammatory drugs, Cox-2 inhibitors, 


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antiarrhythmics, quinolone antibiotics, macrolides (including clarithromycin and 
erythromycin), ketoconazole and itraconazole 
18. Use of non-prescription drugs, including vitamins, herbal and dietary supplements 
(including St John’s Wort) within 7 days (or 14 days if the drug is a potential 
enzyme inducer) or 5 half-lives (whichever is longer) prior to the first dose of 
study medication. 
19. No current use of any medication other than paracetamol (doses ≤2 grams/day). 
20. Consumption of Seville oranges, pummelos (members of the grapefruit family) or 
grapefruit juice from 7 days prior to the first dose of study medication. 
21. Where participation in the study would result in donation of blood or blood 
products in excess of 500 mL within a 3-month period. 
22. Pregnant females as determined by positive serum β-HCG test at screening or 
serum/ urine β-HCG prior to dosing. 
23. Lactating females. 
24. Unwillingness or inability to follow the procedures outlined in the protocol. 
25. Participants with unsuitable veins for cannulation and repeat venipuncture.  
5.3. 
Lifestyle considerations 
5.3.1. 
Meals and dietary restrictions 
• Participants must refrain from consumption of red wine, Seville oranges, grapefruit, 
or grapefruit juice, pomelos, exotic citrus fruits, grapefruit hybrids, or fruit juices 
from 7 days before the start of study intervention until after the final dose. 
5.3.2. 
Caffeine, alcohol, and tobacco 
• When on the study site, participants will abstain from ingesting caffeine- or xanthine-
containing products (e.g., coffee, tea, cola drinks, and chocolate) until after collection 
of the final paroxetine concentration and/or PD sample. 
• Participants should abstain from alcohol before the study baseline until collection of 
the final sample. It is advised that the participants should not consume alcohol during 
the dose tapering period (in line with the product GDS). 
• Participants will not be permitted to use tobacco products or nicotine-containing 
products (including nicotine patches) while they are in the clinical unit. 
5.3.3. 
Activity 
• Participants will abstain from strenuous exercise for 72 hours before each blood 
collection for clinical laboratory tests. Participants may participate in light 
recreational activities during studies (e.g., watching television, reading). 


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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/entered in the study. 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, AE and any SAE. 
Participants who have consented but not participated will have to complete screen 
failures form and are considered as screen failures. 
Individuals who do not meet the criteria for participation in this study (screen failure) 
may be rescreened once. A new participant number will be issued to the participant at 
re-screening. Re- screening should also be allowed for logistical reasons, i.e. participant 
was a reserve in a previous cohort, or participants can be out of screening window due do 
long turnover time from GPs or if the cohort is full or, due to any other non-medical 
reasons etc. 
In the case where a safety laboratory assessment at Screening is outside of the range 
specified in the eligibility criteria, the assessment may be repeated once prior to the 
treatment. If the repeat value remains outside of the specified range, the participant must 
be excluded from the study. Criteria for re-screening the participants are provided in 
Appendix 1. 
. 
5.5. 
Criteria for temporarily delaying enrolment/administration of 
study intervention 
 Not applicable.  
6. 
STUDY INTERVENTION(S) AND CONCOMITANT 
THERAPY 
The definition of study intervention is provided in the table of definitions. 
6.1. 
Study intervention(s) administered 
The study intervention administered details are provided in Table 4. 
Table 4 
Study intervention administered. 
Intervention Name 
Paroxetine 


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Intervention Description 
Paroxetine tablets will be titrated to a dose of 
60 mg once daily at increments of 20 mg per 
week and subsequently tapered in steps of 20 mg 
per 5 days until stopped 
Type  
Drug 
Dose Formulation 
Tablet 
Unit Dose Strength(s) 
10 mg and 20 mg 
Dosage Level(s) 
20, 40 and 60 mg once daily and 10 mg tapering 
dose (if needed) 
Route of Administration 
Oral 
Use 
Experimental 
IMP and NIMP/AxMP. 
IMP 
Sourcing 
Provided locally by the study site, subsidiary, or 
designee.  
Packaging and Labelling 
Study intervention will be provided in a 
container with 240mL of water. Each container 
will be labelled as required per country 
requirement. HDPE bottles will be used for 
dosing at clinic and cartons will be used for 
dosing at home 
Store tablets between 15 and 30 C (59 and 86F). 
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 will supply, prepare, or administer study intervention 
• All study supply will be stored in a secure, environmentally controlled, and monitored 
(manual or automated) area in accordance with the labelled storage conditions with 
access limited to the Investigator and authorized site staff. For home dosing the exact 
amount of study drug required for the period will be provided by site to participants 
upon their discharge from the unit. Participants will then validate their dosing 
compliance on home dosing days by calling into the site and administering the study 
drug whilst on the call. 
• The Investigator and designee, is responsible for study intervention accountability, 
reconciliation, and record maintenance (i.e., receipt, reconciliation, and final 
disposition records). 
• During the study, participants will receive paroxetine tablets orally once daily at 
clinic and home. During home dosing, participants will take tablets under supervision 
of clinical staff over video-call. Further guidance and information for the final 
disposition of unused study interventions are provided in the pharmacy manual. 
6.3. 
Assignment to study intervention 
Participants will be allocated a unique enrolment number at the study site. This number 
will be retained regardless of whether the participant subsequently fulfils the eligibility 


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criteria. If a participant withdraws from the study, the enrolment number will not be 
reused, and the participant will not be allowed to re-enter the study.  
Participants may be rescreened once in this study if they do not meet any of the criteria.  
In case of dropouts or 20% of the missing data at 60 mg dose, sensitivity analysis may be 
triggered to have additional enrolment of the participants. The enrolment number will be 
used to identify the patient on the eCRFs. A participant’s eligibility will be established 
before study treatment is dispensed.  
6.4. 
Blinding/Masking 
Not applicable as this is an open-label study. 
6.5. 
Study intervention compliance 
The preparation of any individual dose for a participant is prepared from open-label 
supply will be confirmed by a second member of the study site staff.  
When participants are dosed at the site, they will receive study intervention directly from 
the Investigator or designee, under medical supervision. The date and time of each dose 
administered in the clinic will be recorded in the source documents. Dosing compliance 
while dosing at home will be controlled via video-calls with the participant. During these 
calls, the regular morning dose will be taken via video supervision. Although the oral 
cavity cannot be physically inspected during such a call, this is expected to improve 
dosing compliance. 
A record of the quantity of paroxetine dispensed to and administered by each participant 
will 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. 
6.6. 
Dose modification 
For the dose modification process, refer to Section 4.3. In this study, all participants will 
receive active treatment with paroxetine tablets once daily with titration/escalation steps 
every week over a maximum dosing period of 3 weeks. This is followed by tapering over 
the period of 10 days as detailed in Section 4.1. If intolerable withdrawal symptoms occur 
during down titration of paroxetine from 20 mg once daily to no dose, then an 
intermediate tapering step of 10 mg once daily for an additional 5 days will be allowed. 
In this case the final follow-up visit will remain up to 14 days after the last 20 mg dose. 
In case of a decision of early discontinuation, the Investigator may taper the dose (by 
20 mg every 5 days) or immediately stop dosing, as clinically indicated.  
This will be monitored by the Investigator on a case-by-case basis in consultation with 
the Sponsor’s Medical Monitor.  


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6.7. 
Continued access to study intervention after the end of the 
study 
Not Applicable. 
6.8. 
Treatment of overdose 
Participants have generally recovered without serious sequelae even when doses of up to 
2000 mg have been taken alone. 
Experience of paroxetine in overdose has indicated that, vomiting, dilated pupils, 
headache, agitation, fever, blood pressure changes, involuntary muscle contractions, 
anxiety and tachycardia have been reported. 
Events such as coma or ECG changes have occasionally been reported and, very rarely a 
fatal outcome, but generally when paroxetine was taken in conjunction with other 
psychotropic drugs, with or without alcohol. 
No specific antidote is known. The treatment should consist of those general measures 
employed in the management of overdose with any antidepressant. Supportive care with 
frequent monitoring of vital signs and careful observation is indicated as per site practice.  
In the event of an overdose, the Investigator/treating physician should evaluate the 
participant to determine, in consultation with the GSK Medical Monitor, if possible, 
whether study intervention should be interrupted or whether the dose should be reduced. 
6.9. 
Prior and concomitant therapy 
Any medication or vaccine (including over-the-counter or prescription medicines, 
recreational drugs, vitamins, and/or herbal supplements) or other specific categories of 
interest that the participant is receiving at the time of informed consent form or receives 
during the study must be recorded along with: 
• 
Reason for use 
• 
Dates of administration including start and end dates 
• 
Dosage information including dose and frequency 
The GSK Medical Monitor should be contacted if there are any questions regarding 
concomitant or prior therapy. 
Use of the following medications 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 the study 
medication is prohibited: monoamine oxidase inhibitors (including linezolid), 
thioridazine, pimozide, serotonergic drugs (including L-tryptophan, triptans, tramadol, 
selective serotonin reuptake inhibitors, lithium, fentanyl , tamoxifen, anti-coagulants, 
clozapine, phenothiazines, tricyclic antidepressants, acetylsalicylic acid, non-steroidal 


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anti-inflammatory drugs, Cox-2 inhibitors, antiarrhythmics, quinolone antibiotics, 
macrolides (including clarithromycin and erythromycin), ketoconazole and itraconazole. 
Participants must abstain from taking nonprescription drugs (including vitamins, 
recreational drugs, and dietary or herbal 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) before the start of study intervention. Paracetamol/Acetaminophen, at doses of 
≤ 2 grams/day and HRT, are permitted for use any time during the study, only during the 
screening period, etc. Use of other concomitant medications (prescription or non-
prescription) during the study is prohibited. 
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 some 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 or), 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 (e.g., telephone contact). 
Participants starting a concomitant medication during the study which can potentially 
induce QT prolongation (e.g. quinolone antibiotic) should be withdrawn. 
If a participant fails to take study doses, then the participant will be withdrawn due to 
non-compliance. This is assessed on a case-by-case basis, where the Investigator will 
assess the situation in consultation with the Sponsor’s Medical Monitor.  
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 
 
Lack of efficacy 
Lost to follow-up 
Participant Relocated  
Participant was Incarcerated  
Other, specify 
Unknown 
Participant Reached Protocol-Defined 
Stopping Criteria 
 
Participant who fails to take the protocol specified doses (more 
than 2 daily doses at home dosing) 


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Reasons 
Additional items/Sub-reasons 
Physician Decision 
NA 
Pregnancy 
  
Protocol Deviation 
NA 
Site Terminated by Sponsor 
  
Study Terminated by Sponsor 
  
Withdrawal by Participant 
Burden of Procedure  
Participant Relocated  
Pursue Alternative Treatment  
COVID-19 Pandemic  
Other 
Non-compliance 
NA 
Suicidal ideation 
NA 
Conmeds 
NA 
Other 
NA 
Death 
  
7.1.1. 
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. 
The following normal cut-off values are as follows: 
a. Heart rate 40 to 90 beats per minute 
b. PR interval ≤ 220msec 
c. Q waves < 30msec (up to 50 ms permitted in lead III only) 
d. QRS interval to be ≥ 60msec and < 120msec 
e. The waveforms must enable the QT interval to be clearly defined 
f. QTcF interval must be < 500msec (machine or manual reading) and not be 
increased ≥60msec compared to baseline. 
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, behavioural or compliance reasons. 


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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 early discontinuation (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. 
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/SAE 
severe tolerability issues, abnormal lab/vitals  
Lost to follow-up 
Participant Relocated  
Participant was Incarcerated  
Other, specify 
Unknown 
Participant Reached Protocol-Defined 
Stopping Criteria 
 
Participant who fails to take the protocol specified doses (more 
than 2 daily doses at home dosing) 
Physician Decision 
NA 
Pregnancy 
  
Protocol Deviation 
Specify 
Site Terminated by Sponsor 
  
Study Terminated by Sponsor 
  
Withdrawal by Participant 
Burden of Procedure  
Participant Relocated  
Pursue Alternative Treatment  
COVID-19 Pandemic  
Other 
Other 
Specify 
Death 
  


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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 10.3.5.7). 
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 
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.  
• Site personnel, or an independent third party, will attempt to collect the vital status of 
the participant within legal and ethical boundaries for all participants enrolled, 
including those who did not get study intervention. Public sources may be searched 
for vital status information. If vital status of the participant is determined as deceased, 
this will be documented and the participant will not be considered lost to follow-up. 
Sponsor personnel will not be involved in any attempts to collect vital status 
information. 
8. 
STUDY ASSESSMENTS AND PROCEDURES 
• Study procedures and their timing are summarised in the Schedule of activities (SoA). 
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. Participants 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 


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baseline purposes provided the procedures met the protocol-specified criteria and 
were performed within the timeframe defined in the SoA. 
• In the event of a significant study-continuity issue (e.g., caused by a pandemic), 
alternate strategies for participant visits, assessments, study intervention distribution 
and monitoring may be implemented by the Sponsor or the Investigator, as per local 
health authority/ethics requirements allowed by country regulation/ethics, study 
assessments may be conducted virtually (telemedicine, secure video conferences, 
phone calls, or a web portal and/or mobile application)]; however, on-site visits are 
required as per 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 be 
approximately 500 mL. 
• Repeat or unscheduled samples may be taken for safety reasons, to confirm the initial 
reading or for technical issues with the samples. 
8.1. 
Administrative procedures 
8.1.1. 
Collection of demographic data 
Demographic data such as date of birth, sex, race, and ethnicity will be recorded in the 
participant’s CRF. 
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 
Participant’s medical history will be collected and recorded in participant’s medical 
records. Any pre-existing conditions, signs and/or symptoms present prior to study start 
will be recorded in the eCRF. 
8.2. 
Efficacy and/or immunogenicity assessments 
Not applicable for this study. 
8.3. 
Safety assessments 
Planned timepoints for all safety assessments are provided in the SoA (Table 2). 
8.3.1. 
Physical examination 
Physical examinations will be performed and recorded in the eCRF at the times shown in 
Table 2. 


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• A complete physical examination will include, at a minimum, assessments of the 
(CV, respiratory, gastrointestinal, and neurological) systems. Height (at 
screening) and weight (at screening and discontinuation) 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]). 
• After screening, any clinically significant abnormal findings in physical 
examinations should be reported as AEs. 
8.3.2. 
Vital signs 
Vital signs will be performed and recorded in the eCRF at the times shown in Table 2. 
• Vital signs (pulse rate, systolic and diastolic blood pressure, and oral body 
temperature) will be assessed. Triplicate BP measurements will be performed at 
screening only. Resting supine blood pressure and pulse rate will be measured 
using a semi-automatic blood pressure recording device with an appropriate cuff 
size. The participant should have a minimum resting period in a supine position 
before pulse and blood pressure measurements of 5 minutes. 
8.3.3. 
Electrocardiograms 
Standard 12-lead ECG will be obtained as outlined in the SoA (Table 2) using an ECG 
machine that automatically calculates the heart rate. All ECGs in this study should all be 
recorded using the same make of ECG device (Mortara Surveyor Telemetry Central and 
Mortara telemetry transmitters Model: Surveyor S4), with the exception of Screening 
visit, where CardioSoft® will be used. The Mortara system is validated every 12 months. 
Monitors will also be available to spot check the calibration when on-site. The readings 
generated by Mortara surveyor S4 machine will be validated by the cardiologist with 
their interpretation on whether the findings are significant and related to paroxetine. 
ECGs must be recorded after 10 minutes rest in the supine position to ensure a stable 
Baseline. ECGs will be performed and recorded in the eCRF at the times shown in Table 
2. The preferred sequence of cardiovascular data collection during study visits is ECG 
collection first, followed by vital signs, blood sampling, and any remaining assessments 
for that visit. 
At Screening, participants will be excluded based on ECG measurements if the 
resting QTc is >450msec (mean of three twelve-lead ECG measurements and 
using Fridericia’s correction). The Fridericia QT correction formula (QTcF) must 
be used for clinical decisions, e.g., at Screening to assess eligibility. Further, all 
ECGs will be performed in triplicate collected within 5 min, at least 1 minute in 
between, at each timepoint. 
• Triplicate ECGs will be performed at each timepoint as detailed in SOA (Table 
2). The mean QTc value will be calculated from the triplicate ECGs for each 
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• The ECG extractions will be paired with paroxetine concentration samples but 
will be obtained before the actual paroxetine concentration sampling time to avoid 
changes in autonomic tone associated with the psychological aspects of blood 
collection as well as the reduction in blood volume subsequent to blood 
collection. 
• At visits where an ECG is not scheduled, an ECG can be performed if medically 
indicated. 
• All ECG traces will be measured by a third-party vendor, which includes review 
by a licensed cardiologist. The cardiologist will review the ECGs and provide 
interpretation on whether the findings are normal, abnormal but non-clinically 
significant (unrelated to Paroxetine), or abnormal but clinically significant 
(related to paroxetine). 
• More than one cardiologist from the vendor may be reviewing the ECGs in the 
study. However, to remove bias all ECGs of a particular participant will be 
reviewed by the same cardiologist. The cardiologists will also be blinded to study 
visits/timestamps/paroxetine dose at which the ECGs were performed. A copy 
should be filed in the participant’s medical records. Any clinically significant 
finding observed on the ECG should be recorded as an AE. A copy of ECG traces 
(with participant-identifying details redacted) may be collected by a Sponsor 
appointed representative for additional cardiology review if required. Clinically 
significant abnormalities must be recorded on the eCRF as either medical 
history/current medical conditions or adverse events as appropriate. 
8.3.4. 
Clinical Safety laboratory tests 
• See Section 10.2 for the list of clinical laboratory tests to be performed in accordance 
with laboratory manual 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.  
• Abnormal laboratory findings associated with the underlying disease are not 
considered clinically significant unless judged by the Investigator to be more severe 
than expected for the participant’s condition. 
• All laboratory tests with values considered clinically significantly abnormal during 
participation in the study or 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 Sponsor’s Medical Monitor. 
a. 
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 10.3.2).  
b. If clinically significant/any 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. 


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c. 
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 or dose modification), then the results must be recorded. 
• 
The tests detailed in Table 5 will be performed by the local laboratory and refer to 
Section 10.2 for more details/ 
Table 5 
Protocol-required safety laboratory tests  
Laboratory Tests 
Parameters 
Hematology 
• 
Platelet count 
• 
Red blood cell (RBC) count 
• 
RBC indices 
o 
Mean corpuscular volume (MCV) 
o 
%Reticulocytes 
• 
WBC count with 
differential: 
o 
Neutrophils 
o 
Lymphocytes 
o 
Monocytes 
o 
Eosinophils 
o 
Basophils 
• 
Haemoglobin 
• 
Haematocrit 
Clinical chemistry • 
Potassium 
• 
Creatinine 
• 
Sodium 
• 
Calcium 
o 
Aspartate aminotransferase (AST)/serum glutamic-
oxaloacetic transaminase (SGOT) 
o 
Alanine aminotransferase (ALT)/serum glutamic-
pyruvic transaminase (SGPT) 
o 
ALP 
o 
Bilirubin (total, direct and indirect) 
o 
Creatinine kinase 
Coagulation tests • 
Prothrombin time (PT), activated partial thromboplastin time (aPTT), 
international normalized ration (INR),  
Pregnancy testing • 
Highly sensitive serum at screening and final follow-up visit and urine on 
admission human chorionic gonadotropin (hCG) pregnancy test as 
needed for WOCBP 


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Laboratory Tests 
Parameters 
Other screening 
tests 
• 
Follicle stimulating hormone and oestradiol (as needed in WONCBP 
only) 
• 
Urine alcohol and drug screen to include at minimum: amphetamines, 
barbiturates, cocaine, opiates, cannabinoids and benzodiazepines, urine 
creatinine 
• 
Serology HIV antibody and p24 antigen test, HBsAg, and HCV antibody 
 
NOTES: 
1. All events of ALT [or AST] ≥3 × upper limit of normal (ULN) and total bilirubin ≥2 × ULN 
(> 35% direct bilirubin) or ALT [or AST] ≥3 × ULN and international normalized ratio (INR) 
> 1.5 (if INR measured), which may indicate severe liver injury (possible Hy’s law), must be 
reported to [Sponsor] in 24 hours (excluding studies of hepatic impairment or cirrhosis). 
2. If alkaline phosphatase is elevated, consider fractionating. 
3. Local urine testing at screening will be standard for the protocol unless serum testing at 
screening is required by local regulation or IRB/IEC 
 
8.3.5. 
Pregnancy testing 
• Women of childbearing potential must perform a urine/blood pregnancy test before 
the administration of any dose of study intervention. Pregnancy testing must be done 
even if the participant is menstruating at the time of the study visit. The study 
intervention may only be administered if the pregnancy test is negative. 
• Refer to Section 8.4.5 for the information on study continuation for participants who 
become pregnant during the study. 
8.3.6. 
Study stopping rules, Safety monitoring committee 
8.3.6.1. 
Study Stopping Rules 
Participant safety will be continuously monitored by the Sponsor’s Medical Monitor, and 
designated Safety Lead (or delegate) throughout the study. Pertinent findings and 
conclusions are shared with the product’s safety review team for review of the overall 
benefit-risk profile of the product. 
Dependent on regional guidance, any restart following a temporary hold due to stopping 
rules being met will require prior submission and approval of a substantial Clinical Trial 
Application (CTA) amendment to the competent authorities. 
 Dosing will be placed on temporary hold and must be stopped based on full review of all 
available safety data and discussion with the Investigator if any of the following occur: 
• Two or more participants experiencing any Serious Adverse Reaction (SAR) (i.e. a 
SAE suspected to be at least possibly related to the study treatment(s) 


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• Two or more participants experiencing an AE which was assessed as severe in 
intensity (Grade 3) and is considered as potentially related to the study treatment(s).  
• One or more participants in the cohort experiencing QTcF interval >500 msec (or 
QTcF prolongation >60 msec from Baseline) 
• One or more participants in the cohort developing a liver-related finding that would 
stop treatment based on the liver-related AE rules outlined in Section 10.2 considered 
as drug related  
• The Investigator (or designee) and Sponsor considers that the number and/or severity 
of AEs, abnormal safety monitoring tests or abnormal laboratory findings justify 
putting the study on hold.  
 
The Sponsor unilaterally requests it. 
8.3.6.2. 
Safety monitoring committee 
An Independent Data Monitoring Committee (IDMC) is not required for this study. 
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 [all AEs OR SAEs, 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. 
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. 
All AEs and SAEs will be collected from the first dose of the study until the last visit at 
the time points specified in the SoA. All SARs related to study procedure or GSK product 
will be collected from the moment of giving consent until the last visit. SAE 
reconciliation process will be mentioned in data management plan or in SAE plan 
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 (concomitant) will be recorded from the time a participant consents to participate 
in the study. Time period and frequency for collecting AE, SAE, and other safety 
information. 
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 
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8.4.1. 
Time period and frequency for collecting AE, SAE, and other 
safety information 
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. 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. 
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 concluded 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. 
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 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 (as defined in Section 8.4.3) 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 10.3.5.5. 
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 8.4.4 
for reporting timeframes. 
• For SAE the Investigator must always provide an assessment of causality at the time 
of the initial report, as defined in the Section 10.3.5.6. 
• 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 (IB/ investigational directions for use 
[IDFU]/package insert or state other documents) and will notify the IRB/IEC, if 
appropriate according to local requirements. 


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Table 6 
Timeframes for submitting SAE, pregnancy and other events reports 
to GSK 
Type of event 
Initial reports 
Follow-up of relevant information on a 
previous report 
Timeframe 
Documents 
Timeframe 
Documents 
SAEs 
24 hours* ‡ 
electronic AEs Report 
24 hours* 
electronic AEs Report 
Pregnancies 
24 hours* 
electronic pregnancy report  
24 hours * 
electronic pregnancy 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 must 
document in the medical notes that they have reviewed the SAE and have provided an assessment of causality. 
8.4.5. 
Pregnancy 
Participant must be excluded from participation if the serum pregnancy result is positive.  
• Details of all pregnancies in female participants and, if indicated, female partners 
of male participants will be collected after the start of study intervention and until 
time period for reporting pregnancies should align with the time period for 
postintervention contraception determined in Section 5.1. 
• 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 or female partner of male participant (after obtaining the 
necessary signed informed consent from the female partner) 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, foetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs and will be 
reported as such. 
• The pregnant female partner will be followed to determine the outcome of the 
pregnancy. The Investigator will collect follow-up information on the pregnant 
female partner and the neonate and the information will be forwarded to the 
Sponsor. 
• Any poststudy pregnancy-related SAE considered reasonably related to the study 
intervention by the Investigator will be reported to the Sponsor as described in 
Section 8.4.5. While the Investigator is not obligated to actively seek this 
information in former study participants/pregnant female partner], he or she may 
learn of an SAE through spontaneous reporting. 
• Any female participant who becomes pregnant while participating in the study 
will discontinue study intervention or be withdrawn from the study. 
8.4.6. 
Cardiovascular and death events 
For any CV events detailed in Section 10.3.3and all deaths, whether or not they are 
considered SAEs, specific CV and Death sections of the eCRF will be required to be 
completed. These sections include questions regarding CV (including sudden cardiac 
death) and non-CV death.  


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The CV eCRFs are presented as queries in response to reporting of certain CV MedDRA 
terms. The CV information should be recorded in the specific CV section of the eCRF 
within one week of receipt of a CV Event data query prompting its completion.   
The Death eCRF is provided immediately after the occurrence or outcome of death is 
reported. Initial and follow-up reports regarding death must be completed within one 
week of when the death is reported. 
8.4.7. 
Disease-related events and/or disease-related outcomes not 
qualifying as AEs or SAEs 
Not applicable as this is a healthy volunteer study. 
8.4.8. 
Contact information for reporting SAEs, pregnancies and study 
holding rules 
Table 7 
Contact information for reporting SAEs, pregnancies and study 
holding rules 
Study contact for questions regarding SAEs, pregnancies and SAEs linked 
to device deficiencies 
Contact GSK’s local and/or medical contacts 
For medicines: OAX37649@gsk.com 
OR facsimile number +44-20-8181 4780 
Contacts for reporting SAEs, pregnancies and SAEs linked to device 
deficiencies 
Available 24/24 hours and 7/7 days 
For medicines: OAX37649@gsk.com 
OR facsimile number +44-20-8181 4780 
8.4.9. 
Participant Card 
The Investigator (or designee) must provide the participant with a “participant card” 
containing information about the clinical study. The participants 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 that the 
participant is in a clinical study and that relevant information may be obtained by 
contacting the Investigator or their back up. 
8.5. 
Pharmacokinetics 
Blood samples will be collected for measurement of plasma concentrations of study 
intervention as specified in the SoA (Section 1.3). Blood sample collection, processing 
and shipping details will be outlined in a separate laboratory manual. 


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Instructions for the collection and handling of biological samples will be provided by the 
Sponsor. The actual date and time (24-hour clock time) of each sample will be recorded. 
8.6. 
Pharmacodynamics 
Pharmacodynamics (other than cardiac effects as described elsewhere) are not measured 
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 assessed in this study. 
8.10. 
Health economics or medical resource utilization and health 
economics 
Health economics OR Medical resource utilization and health economics parameters are 
not evaluated in this study. 
9. 
STATISTICAL CONSIDERATIONS 
The SAP will be finalized prior to database lock and it 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. 
9.1. 
Statistical hypothesis/hypotheses/comparisons 
9.1.1. 
Multiplicity Adjustment  
No multiplicity adjustment will be required to test hypotheses endpoints. 


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9.2. 
Analysis sets 
Analysis Set 
Definition / Criteria 
Analyses 
Evaluated 
Screened  
• 
All participants who were screened for eligibility. 
• 
Study 
Population 
Enrolled 
• 
All participants who entered the study (who 
received study intervention 
• 
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 
PK 
• 
All participants in the Safety analysis set who 
had at least 1 non-missing PK assessment (non-
quantifiable values will be considered as non-
missing values). 
• 
Data will be reported according to the actual 
study intervention. 
• 
Primary 
analysis 
PD 
• 
All participants in the Safety analysis set who 
had at least 1 non-missing ECG assessment. 
• 
Data will be reported according to the actual 
study intervention. 
• 
Primary 
analysis 
Safety/Exposed 
• 
All participants who received at least one dose of 
study intervention. 
• 
Data will be reported according to the actual 
study intervention. 
• 
Safety 
9.3. 
Statistical analyses 
9.3.1. 
General considerations/definitions  
All data will be listed and descriptive analysis along with appropriate graphs will be 
provided. Categorical data shall be summarized by means of absolute and relative 
frequencies (counts and percentages) and continuous data by means of the number of 
observations, the arithmetic mean, standard deviation, minimum, median, maximum, CI, 
geometric mean and coefficient of variation as appropriate. 


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9.3.2. 
Primary endpoint analysis 
9.3.2.1. 
Definition of endpoints 
The primary endpoint is Change from baseline in QTc (ΔQTc) where baseline is the pre 
dose collection at Visit 2. 
9.3.2.2. 
Main Analytical Approach 
A random-coefficient mixed-effects model will be fit to all available paroxetine 
concentration - ΔQTc data pairs, as described in a white paper (Garnet, 2017). In this 
model, ΔQTc is the dependent variable and paroxetine concentration and time after dose 
are independent variables, it takes the form of: 
ΔQTc𝑖,𝑘= (θ0 + η0,𝑖) + (θ1 + η1,𝑖) ∗𝐶𝑖,𝑘+ θ2 ∗𝑇𝐼𝑀𝐸𝑖,𝑘+ θ3(𝑄𝑇𝑐𝑖,𝑘=0 −𝑄𝑇𝑐0
̅̅̅̅̅̅̅) + 𝜀𝑖,𝑘 
In this equation ΔQTci,k is the change from baseline in QTc for subject i at time k; θ0 is 
the population mean intercept in the absence of a treatment effect; η0,i is the random 
effect associated with the intercept term θ0; θ1 is the population mean slope of the 
assumed linear association between concentration and ΔQTci,k; η1,i is the random effect 
associated with the slope θ1; Ci,k is the concentration for participant i and time k; θ2 is the 
fixed effect associated with time; and θ3 is the fixed effect associated with the difference 
of each baseline values to the overall mean ( Baseline QTci,k=0, QTc0 is overall mean of 
QTci,k=0, i.e., the mean of all the baseline (= time 0) QTc values). It is assumed the 
random effects are normally distributed with mean [0,0] and an unstructured covariance 
matrix G, whereas the residuals are normally distributed with mean 0 and variance R. The 
ΔQTc and paroxetine concentrations corresponding to all doses (20, 40, and 60mg) will 
be used for the modelling (both drawn from each participant at same time intervals). This 
model includes a linear correlation between paroxetine plasma concentration and ΔQTc. 
This model will be estimated including the precision around the parameter estimates. The 
geometric mean of the individual Cmax values for participants at the 60 mg dose will be 
calculated. Based on the estimated model, and the calculated geometric mean Cmax for 
dose 60 will be used in the fitted model to predict the upper limit of the 90% CI of ΔQTc 
at dose 60 mg  
The summary measure of the study is the geometric mean and 90% CI of the predicted 
ΔQTc at Cmax. If the upper bound of 90% CI for the geometric mean of QTc 
corresponding to the Cmax of paroxetine concentration at dose 60mg of that prediction 
falls below the 10 msec mark, the conclusion of the study is that there is no clinically 
relevant QTc prolongation up to and including the 60 mg dose. In case the upper 90% CI 
limit does not fall below the 10 msec mark, the same evaluation will be performed for the 
ΔQTc at the geometric mean Cmax of the 40 mg once daily dose. Intercurrent events and 
handling of missing data: 
1. The data will be affected by occurrence of the intercurrent event (Treatment 
discontinuation of the study) would be treated as missing at random from the 


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occurrence of the intercurrent event until the end of the study. Participant level 
missing data considered as missing at random, will not be imputed and available 
data will be used in the primary analysis. 
2. The treatment policy strategy for events affecting absorption within 1 hour is used 
for the estimation model as it is based on concentration not dose - therefore even 
though the concentration may be affected, the data is still relevant for quantifying 
the relationship between change in QTc and drug concentration. Hence, we will 
use all the data in the modelling (paroxetine concentration and ΔQTc) irrespective 
of the occurrence of the intercurrent event. However, when the model is used to 
predict the upper 90% CI for 60mg doses an absorption event may artificially 
reduce the prediction, hence the corresponding paroxetine concentration data will 
not be used in the calculation of the Cmax at and in the prediction of the geometric 
mean of predicted ΔQTc and 90% CI. 
Detailed analysis will be described in Statistical Analysis Plan. 
9.3.2.3. 
Sensitivity Analyses 
In case 20% or more (8 participants or more) participants at the 60 mg once daily dose 
have either missing paroxetine concentration data around the Cmax at the 60 mg dose 
level, or an intercurrent event of “any events affecting absorption within 1 hour of the 
dose” at the 60 mg dose, a sensitivity analysis will be performed to ensure that there is no 
bias in the calculated geometric mean of the Cmax at the 60 mg once daily dose. This 
analysis will consist of pharmacokinetic model-fitting of the individual paroxetine 
concentration data without the estimation of population level parameters (post-hoc or 
Bayesian fit). This will allow the prediction of the Cmax at the 60 mg once daily dose for 
those participants with missing data, based on the available paroxetine concentration data 
at the earlier doses. Through this method, a geometric mean of Cmax at the 60 mg dose 
can be calculated that should be less affected by dropout, missing data, or intercurrent 
events. An additional calculation of the upper limit of the 90% CI of ΔQTc will then be 
performed using the Cmax of the 60 mg dose calculated using this method. In case the 
evaluation of ΔQTc finds a ≥10 ms upper 90% CI limit at the 60 mg dose, the same 
model-based prediction of Cmax at the 40 mg dose for dropouts will be performed, where 
required. Details of this analysis will be described in the Statistical Analysis Plan. 
9.3.3. 
Secondary endpoint(s)/estimand(s) analyses 
• 
The summary of the absolute value and its change from baseline in each vital sign 
parameter will be provided across the entire intervention. Frequency counts and 
percentages will be provided for abnormalities. 
• 
Frequency counts and percentages will be provided for all the reported Adverse 
Events (AEs) and Serious Adverse Events (SAEs). 


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9.3.3.1. 
Safety analysis 
Safety parameters such as occurrence of Adverse events (AEs) and Serious adverse 
events (SAEs), clinically significant changes in physical examination findings, vital 
signs, and ECG will be descriptively summarized as appropriate. The change from 
baseline for, vital signs, and ECG will be reported across the intervention period. All 
safety analyses will be performed on the safety population. 
9.4. 
Interim analyses 
No interim analysis is planned for this study. 
9.5. 
Sample size determination 
At least 36 participants, men or non-pregnant women, aged 18 to 65 years will be 
enrolled. This number is expected to result in sufficiently wide range of paroxetine 
concentrations to cover those typically observed in a real-world clinical setting. A Monte 
Carlo simulation analysis was used to determine the probability of the 90% upper limit of 
the CI of the ΔQTC at the geometric mean of the 60 mg dose encompassing the 10 ms 
cut-off value. Based on this simulation approach, it is expected that under the assumption 
of no true effect of paroxetine on QTc at the 60 mg dose, the expected probability of 
incorrectly detecting an effect (90% upper limit of the CI ≥10 ms) is <1% (false positive) 
when inclusion is 36 participants. In case the true effect is 5 ms, the expected probability 
of a false positive is <2%. When the true effect is 10 ms, the expected probability of 
correctly determining a QTc prolongating effect is approximately 82%.  
The sensitivity of missing data was also assessed. With 20% drop out at the 40 mg dose 
and another 25% drop out at the 60 mg dose (in addition to the drop out at the 40 mg 
dose) the expected probability of incorrectly detecting an effect (90% upper limit of the 
CI 10 msec) for 36 participants is 1% (false positive) when the true effect is null. The 
expected probability of a false positive is 5% if the true effect is 5 msec. The expected 
probability of correctly determining a QTc prolonging effect is approximately 85% when 
the true effect is 10 msec. 
Please refer Appendix 2 (sample size determination section) for further details. 


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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 Council for International Organizations of 
Medical Sciences (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 and/or substantial 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 Code of Federal Regulation (CFR), ICH guidelines, the 
IRB/IEC, European regulation 536/2014 for clinical studies (if applicable), 
and all other applicable local regulations 
10.1.2. 
Financial disclosure 
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. 


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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. 
• 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. 
Participants who are rescreened are required to sign a new ICF. 
In case of unexpected pregnancy, participant must be informed that Investigator such as 
date of birth, sex of the baby will be collected as part of safety follow-up.  
If partners of male participants become pregnant during the study, consent will need to be 
obtained or notification given as per local regulation to the partner before collecting their 
PI such as [e.g. last menstrual period, year of birth] or the Investigator such as date of 
birth, sex of their baby as part of safety follow-up. 
10.1.4. 
Recruitment strategy 
Week 1 
Screening Window Opens 
• Initiate FB & Instagram Campaigns 
• Contact volunteers from DB 
• Report generation 
• Assess turn up rate vs consenting. 
Week 2 
• Assess digital platform performance 
• Target platform with highest return  
• New audience target and increase reach if appropriate 
• Optimise FB & Instagram Campaigns 


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• Consider newspaper adverts 
Week 3 & 4 
• 
Continual assessment of campaign performance 
• 
Ascertain GP response status, exclusion & drop outs, mitigation as far as possible  
• 
Target subjects with current GP MQs 
• 
Target subjects who participated in previous studies with similar design 
• 
Target eligible subjects who recently completed wash out on previous studies 
• 
Increase screening slots 
• 
Assign staff specifically to chase GP responses 
• 
Escalation of recruiting challenges (if appropriate) 
• 
Exclusion criteria trend monitoring and communication 
• 
Review competitive studies and consider appropriate action 
• 
Increase payment to GPs for fast turnaround of MQ completion 
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. 
• 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. 


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• 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. 
10.1.6. 
Committees structure 
An Independent Data Monitoring Committee (IDMC) is not required for this study. 
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.   
• GSK will provide the Investigator with the participant 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 participant 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 


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data). The Investigator is responsible for verifying that data entries are accurate and 
correct by physically or electronically signing the CRF. 
• A data management plan will be created and maintained throughout the study. 
• SAE reconciliation process will be mentioned in data management plan or in SAE 
plan 
• 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. 
• 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.  
• All data generated by the site personnel will be captured electronically at each study 
centre using electronic case report form (eCRFs). Data from external sources (such as 
laboratory data) will be imported into the database. Once the eCRF clinical data have 
been submitted to the central server at the independent data centre, corrections to the 
data fields will be captured in an audit trail. The reason for change, the name of the 
person who performed the change, together with the time and date will be logged to 
provide an audit trail. 
• If additional corrections are needed, the responsible monitor or data manager will 
raise a query in the electronic data capture (EDC) application. The appropriate staff at 
the study site will answer queries sent to the Investigator. The name of the staff 
member responding to the query, and time and date stamp will be captured to provide 
an audit trail. Once all source data verification is complete and all queries are closed, 
the monitor will freeze the eCRF page. 
• The specific procedures to be used for data entry and query resolution using the EDC 
system/eCRF will be provided to study sites in a training manual. In addition, site 
personnel will receive training on the EDC system/eCRF. 


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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 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 [e.g. source 
data acknowledgment or monitoring guidelines]. 
• 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 FPFV (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 International Committee of Medical Journal Editors (ICMJE) authorship 
requirements. 
10.2. 
Appendix 2: Clinical laboratory tests 
• The tests detailed in Table 8 will be performed by the local laboratory. 
• Local laboratory results are only required in the event that the central laboratory 
results are not available in time for either study intervention administration and/or 
response evaluation. If a local sample is required, it is important that the sample for 
central analysis is obtained at the same time. Additionally, if the local laboratory 
results are used to make either a study intervention decision or response evaluation, 
the results must be recorded. 
• 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 8 
Protocol-required safety laboratory tests  
Laboratory Tests 
Parameters 
Hematology 
• 
Platelet count 
• 
Red blood cell (RBC) count 
• 
RBC indices 
1. Mean corpuscular volume (MCV) 
2. %Reticulocytes 
• 
WBC count with 
differential: 
1. Neutrophils 
2. Lymphocytes 
3. Monocytes 
4. Eosinophils 
5. Basophils 
• 
Haemoglobin 
• 
Haematocrit 
Clinical chemistry • 
Potassium 
• 
Creatinine 
• 
Sodium 
• 
Calcium 
1. Aspartate aminotransferase (AST)/serum glutamic-
oxaloacetic transaminase (SGOT) 
2. Alanine aminotransferase (ALT)/serum glutamic-
pyruvic transaminase (SGPT) 
3. ALP 
4. Bilirubin (total, direct and indirect) 
5. Creatinine kinase 
Pregnancy testing 
• 
Highly sensitive serum at screening and final follow up visit and urine on 
admission human chorionic gonadotropin (hCG) pregnancy test as needed for 
WOCBP 
Other screening tests • 
Follicle stimulating hormone and oestradiol (as needed in WONCBP only) 
• 
Urine alcohol and drug screen to include at minimum: amphetamines, 
barbiturates, cocaine, opiates, cannabinoids and benzodiazepines 
• 
Serology HIV antibody 4th generation test, HBsAg, and HCV antibody 


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Laboratory Tests 
Parameters 
NOTES: 
1. All events of ALT [or AST] ≥3 × upper limit of normal (ULN) and total bilirubin ≥2 × ULN (> 35% 
direct bilirubin) or ALT [or AST] ≥3 × ULN and international normalized ratio (INR) > 1.5 (if INR 
measured), which may indicate severe liver injury (possible Hy’s law), must be reported to [Sponsor] 
in 24 hours (excluding studies of hepatic impairment or cirrhosis). 
2. If alkaline phosphatase is elevated, consider fractionating. 
3. Local urine testing at screening will be standard for the protocol unless serum testing at screening is 
required by local regulation or IRB/IEC 
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 unfavourable 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. 
• 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. 


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• 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. 
• 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. 
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: 
• 
Results in death 
• 
Is life threatening 
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, 
which hypothetically might have caused death, if it were more severe. 
• 
Requires inparticipant 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 
observation and/or treatment that would not have been appropriate in the 
physician’s office or outparticipant setting. Complications that occur during 
hospitalization are AE. If a complication prolongs hospitalization or fulfils any 
other serious criteria, the event is serious. When in doubt as to whether 
“hospitalization” occurred or was necessary, the AE should be considered serious. 
• Hospitalization for elective treatment of a pre-existing condition that did not 
worsen from baseline is not considered an AE. 
• 
Results in persistent or significant disability/incapacity 
• The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions. 


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• This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhoea, 
influenza, and accidental trauma (e.g., sprained ankle) that may interfere with or 
prevent everyday life functions but do not constitute a substantial disruption. 
• 
Is a congenital anomaly/birth defect in the offspring of a study participant 
• 
Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) 
• 
Is a suspected transmission of any infectious agent via an authorized medicinal 
product 
• 
Other situations: 
• Possible Hy’s Law case: ALT ≥ 3x ULN AND total bilirubin ≥ 2x 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 CV events  
CV definition: 
Investigators will be required to fill out the specific CV event page of the eCRF for the 
following AEs and SAEs: 
• Myocardial infarction/unstable angina 
• Congestive heart failure 
• Arrhythmias 
• Valvulopathy 
• Pulmonary hypertension 
• Cerebrovascular events/stroke and transient ischemic attack 
• Peripheral arterial thromboembolism 
• Deep venous thrombosis/pulmonary embolism 
• Revascularization 


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80 
10.3.4. 
Definition of TEAE 
TEAE Definition: 
• A TEAE is defined as an AE that began after the start of trial medication treatment; 
or if the event was continuous from baseline and was serious, trial medication-
related, or resulted in death, discontinuation, or interruption or reduction of trial 
therapy. 
10.3.5. 
Recording, assessment and follow-up of AE, SAE, and 
pregnancies 
10.3.5.1. 
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. 
• It is not acceptable for the Investigator to send photocopies of the participant’s 
medical records to Sponsor/CRO in lieu of completion of the required form. 
• There may be instances when copies of medical records for certain cases are 
requested by Sponsor/CRO. 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 Sponsor/CRO. 
• 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. 
10.3.5.2. 
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. 


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• Severe:  
A type of AE that interrupts usual activities of daily living, or significantly affects 
clinical status, or may require intensive therapeutic intervention.   
10.3.5.3. 
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 
initial report to Sponsor/CRO. 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 Sponsor/CRO. 
• 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. 
10.3.5.4. 
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). 


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10.3.5.5. 
Follow-up of AEs, SAEs, pregnancies or any other events of interest 
• The Investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by Sponsor 
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 Sponsor within 24 hours of 
receipt of the information. 
After the initial AE/SAE/pregnancy or any other event of interest, the Investigator is 
required to proactively follow each participant at subsequent visits/contacts. All SAEs (as 
defined in the Section Error! Reference source not found.), 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 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. 
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 electronic pregnancy 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 10.3.5.7. 
10.3.5.6. 
Updating of SAE, and pregnancy information after removal of write 
access to the participant’s eCRF 
When additional SAE or pregnancy 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 


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Protocol and Version 2.0 (Final) 
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83 
updated report should be sent to the Study contact for reporting SAEs (refer to Section 
8.4.3). 
10.3.5.7. 
Reporting of SAEs, and pregnancies 
SAE Reporting via an Electronic Data Collection Tool 
• The primary mechanism for reporting an SAE 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 GSK Medical Monitor by telephone. 
• If the site during the course of the study or poststudy becomes aware of any serious, 
nonserious AEs, pregnancy exposure, related to any GSK non-IMP they will report 
these events to GSK or to the concerned competent authority via the national 
spontaneous reporting system.  These will be classified as spontaneous individual 
case safety reports. 
• Contacts for SAE reporting can be found in Section 8.4.8. 
SAE Reporting 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 Sponsor’s Medical Monitor. 
• In rare circumstances and in the absence of email/facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by overnight 
mail or courier service. 
• Initial notification via telephone does not replace the need for the Investigator to 
complete and sign the SAE data collection tool within the designated reporting 
timeframes. 
• Contacts for SAE reporting can be found in Section 8.4.8. 


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10.4. 
Appendix 4: Contraceptive and barrier guidance 
10.4.1. 
Definitions 
10.4.1.1. 
Woman of Childbearing Potential (WOCBP) 
Women in the following categories are considered WOCBP (fertile): 
Adolescents of childbearing potential: Tanner stage ≥2 (post-thelarche) irrespective of the 
occurrence of menarche or following menarche. 
From the time of menarche until becoming postmenopausal unless permanently sterile 
(see below) 
Note: Menarche is the first onset of menses in a young female. Menarche is normally 
preceded by several changes associated with puberty including breast development and 
pubic hair growth.  
10.4.1.2. 
Woman of Nonchildbearing Potential (WONCBP) 
Women in the following categories are considered WONCBP: 
• Premenarchal: Tanner stage 1 (prepubertal) 
Permanently sterile due to one of the following procedures: 
a. 
Documented hysterectomy 
b. Documented bilateral salpingectomy 
c. 
Documented bilateral oophorectomy 
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. 
Postmenopausal female 
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. 
• A high follicle stimulating hormone (FSH) level in the postmenopausal range may be 
used to confirm a postmenopausal state in women not using hormonal contraception 
or hormonal replacement therapy (HRT). However, in the absence of 12 months of 
amenorrhea, confirmation with more than one FSH measurement if required (>40 
IU/L or mIU/mL) or remove to allow for flexibility with different local thresholds for 
defining postmenopausal state is required. 


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• Females on HRT and whose menopausal status is in doubt must discontinue HRT to 
allow confirmation of postmenopausal status before study enrolment. 
10.4.2. 
Contraception guidance 
Patients of childbearing potential and participants with partners of childbearing potential 
must agree to practice highly effective contraception plus one barrier method during their 
participation in the study and after the last dose of paroxetine or longer if determined by 
country requirement.  Female patients must use contraception for at least 2 months before 
screening, up to the final follow up visit.  Patients must refrain from donating sperm 
during their participation in the study and following last dose.   
Highly effective forms of contraception 
Highly effective forms of contraception include one or more of the following:  
o Male partner who is sterile (medically effective vasectomy) prior to the 
female participant’s entry into the study and is the sole sexual partner for 
the female participant 
o Combined (estrogen and progestogen-containing) hormonal contraception 
associated with inhibition of ovulation (oral, intravaginal or transdermal)  
o Progestogen-only hormonal contraception associated with inhibition of 
ovulation (oral, intravaginal or transdermal)  
o An intrauterine device  
o Bilateral tubal occlusion 
Barrier methods of contraception:  
Barrier methods of contraception include:  
o Condom or occlusive cap (diaphragm or cervical/vault caps) with 
spermicidal foam/gel/film/cream/vaginal suppository. 
▪ Male patients must use barrier method during the study until final 
follow up visit. 
Childbearing potential 
Childbearing potential is defined as one of: 
o <50 years of age unless amenorrheic for at least 12 months following the 
cessation of exogenous hormonal treatments, and have serum follicle-
stimulating hormone and luteinizing hormone levels in the 
postmenopausal range for the institution. 
o ≥50 years of age and has had menses within 12 months following 
cessation of all exogenous hormonal treatments. 
o Not irreversibly surgically sterilized by hysterectomy, bilateral 
oophorectomy, or bilateral salpingectomy. 


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Protocol and Version 2.0 (Final) 
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Medical Monitor 
Dr.
Contact number:
Email:
Clinical Laboratory 
The Doctor’s Laboratory 
The Halo Building 
1 Mabledon Place  
London 
Wc1H9AX 
UK 
Tel: +442073077315 
Fax: +442073077403 
Bioanalytical Laboratory 
Drug Development Solutions,  
Newmarket Road, 
Fordham, 
Cambridgeshire, 
CB7 5WW, 
United Kingdom. 
11. 
REFERENCES 
Funk KA, Bostwick JR. A comparison of the risk of QT prolongation among SSRIs. Ann 
Pharmacother. 2013 Oct;47(10):1330-41. 
Garnett C, Bonate PL, Dang Q, Ferber G, Huang D, Liu J, Mehrotra D, Riley S, Sager P, 
Tornoe C, Wang Y. Scientific white paper on concentration-QTc modeling. J 
Pharmacokinet Pharmacodyn. 2018 Jun;45(3):383-397. 
Latham T and Morton N, 29060/086. A controlled, double-blind, randomised, parallel 
group study comparing the effects of paroxetine and maprotiline in the treatment of out-
patients with major and minor depression. 1993. 
Okayasu H, Ozeki Y, Fujii K, Takano Y, Saeki Y, Hori H, Horie M, Higuchi T, Kunugi 
H, Shimoda K. Pharmacotherapeutic determinants for QTc interval prolongation in 
Japanese patients with mood disorder. Pharmacopsychiatry. 2012 Nov;45(7):279-83. 
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Seroxat [SmPC; Summary of Product Characteristics]. Brentford, UK: GSK; 2022. 


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Protocol and Version 2.0 (Final) 
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12. 
APPENDIX 
Appendix 1: Exclusion Criteria Allowed for Rescreening 
Table 9 
Exclusion Criteria Allowed for Rescreening 
Criterion No 
Criteria 
Ok to Rescreen if Screening Failure 
(Yes/No) 
EC#8 
A supine blood pressure that is persistently higher than 140/90 millimetres of 
mercury (mmHG) at screening 
Yes (only if participant >50 years of age) 
EC#9 
A supine heart rate outside the range 50-90 beats per minute (BPM) at screening 
Yes 
EC#15 
The participant has participated in a clinical trial and has received an investigational 
product within the following time period prior to the first dosing day in the current 
study: 3 months, 5 half-lives or twice the duration of the biological effect of the 
investigational product (whichever is longer). 
Yes 
EC#17 
Use of the following medications 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 the 
study medication: monoamine oxidase inhibitors (including linezolid), thioridazine, 
pimozide, serotonergic drugs (including L-tryptophan, triptans, tramadol, selective 
serotonin reuptake inhibitors, lithium, and fentanyl, tamoxifen, anti-coagulants, 
clozapine, phenothiazines, tricyclic antidepressants, acetylsalicylic acid, non-
steroidal anti-inflammatory drugs, Cox-2 inhibitors, antiarrhythmics, quinolone 
antibiotics, macrolides (including clarithromycin and erythromycin), ketoconazole 
and itraconazole 
Yes 
EC#18 
Use of prescription or non-prescription drugs, including vitamins, herbal and dietary 
supplements (including St John’s Wort) within 7 days (or 14 days if the drug is a 
potential enzyme inducer) or 5 half-lives (whichever is longer) prior to the first dose 
of study medication 
Yes 


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Protocol and Version 2.0 (Final) 
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EC#19 
No current use of any medication other than paracetamol (doses ≤2 grams/day) 
Yes 
EC#21 
Where participation in the study would result in donation of blood or blood products 
in excess of 500 mL within a 3-month period. 
Yes 


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Appendix 2: Sample Size Determination Section 
The sensitivity of the probability of correctly determining a QTc prolonging effect is calculated with respect to different sample sizes (20, 
30, 36, 46, 56) and assuming true effect as 0 msec, 5 msec, and 10 msec.  
Table 10 
Sample Size Sensitivity without dropout 
True effect 
0 msec 
5 msec 
10 msec 
N 
Probability of the upper 90% limit of model-predicted ΔQTc being ≥10 msec 
20 
0 
4.3 
80.3 
30 
0 
1.8 
82.8 
36 
0 
0.6 
82.5 
46 
0 
0.4 
84.2 
56 
0 
0.1 
85.3 
 
The sensitivity of the probability of correctly determining a QTc prolonging effect is calculated with respect to different sample sizes (20, 
30, 36, 46, 56) and assuming true effect as 0 msec, 5 msec, and 10 msec. Additionally, it incorporates a 20% drop out at the 40 mg dose 
and another 25% drop out at the 60 mg dose (in addition to the drop out at the 40mg dose). 


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Protocol and Version 2.0 (Final) 
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Table 11 
Sample Size Sensitivity after drop-out 
True effect 
0 msec 
5 msec 
10 msec 
N 
Probability of the upper 90% limit of model-predicted ΔQTc being ≥10 msec 
20 
0.6 
15.3 
80.5 
30 
0 
8.7 
83.3 
36 
0 
4.9 
85.1 
46 
0 
3.6 
86.1 
56 
0 
1.2 
84 
 
 

SAP_001.pdf: 
Statistical Analysis Plan
Study ID:  219882
Official Title of Study: An Open-Label, Single Arm, Dose Escalating 
Concentration-QT Study to Investigate the Cardiac Effects and Safety of 
Paroxetine in Healthy Adult Participants
NCT ID: NCT06065735
Date of Document: 7-December-2023


Parexel International 
GlaxoSmithKline Research & Development Limited 
GSK 219882    
Statistical Analysis Plan 
 
Project Document Version No.: 1.0; Document Effective Date:  Date of Last Signature  
Confidential 
TP-GDO-WW-133-04 
 
 
Effective Date:  28 Jul 22 
Related to:  SOP-GDO-WW-019 
Page 1 of 43 
 
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001 
Parexel International 
 
 
 
GlaxoSmithKline Research & Development Limited 
 
 
 
GSK 219882 
 
 
 
An Open-Label, Single Arm, Dose Escalating Concentration-QT Study to Investigate the Cardiac 
Effects and Safety of Paroxetine in Healthy Adult Participants 
 
 
  
Statistical Analysis Plan 
 
 
 
Version: 1.0 
 
 
 
Parexel Project Number: 275921 
 
 
 
 
 


Parexel International 
GlaxoSmithKline Research & Development Limited 
GSK 219882    
Statistical Analysis Plan 
 
Project Document Version No.: 1.0; Document Effective Date:  Date of Last Signature  
Confidential 
TP-GDO-WW-133-04 
 
 
Effective Date:  28 Jul 22 
Related to:  SOP-GDO-WW-019 
Page 2 of 43 
 
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001 
SPONSOR SIGNATURE PAGE 
 
 
 
Approved by:  
_________________________ 
 
_______________ 
 
Oscar Della Pasqua 
 
 
 
 
Date 
 
Executive Director Clinical Pharmacology 
 
 
Clinical Pharmacology Modelling and Simulations (CPMS), GSK 
 
 
 
Approved by:  
_________________________ 
 
_______________ 
 
Ramiya Ravindranath  
 
 
 
Date 
 
Associate Director Statistics    
 
            GSK 
 
 
 
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Parexel International 
GlaxoSmithKline Research & Development Limited 
GSK 219882    
Statistical Analysis Plan 
 
Project Document Version No.: 1.0; Document Effective Date:  Date of Last Signature  
Confidential 
TP-GDO-WW-133-04 
 
 
Effective Date:  28 Jul 22 
Related to:  SOP-GDO-WW-019 
Page 3 of 43 
 
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001 
Parexel Signature Page 
Signatures below confirm that the Statistical Analysis Plan was developed in accordance with 
SOP-GDO-WW-019 and that it is approved for release. 
 
 
 
 
 
 
 
 
 
 
Signatory 
Author 
 
 
Signature 
Project Role: Biostatistics Lead  
 
 
 
 
Signatory 
Author 
 
 
 
Signature 
Project Role: Pharmacometrician 
Company Name: PhinC development 
 
 
 
 
Signatory 
Author 
 
 
Signature 
Project Role:  Clinical Pharmacology Modeling Simulation 
 
 
 
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Parexel International 
GlaxoSmithKline Research & Development Limited 
GSK 219882    
Statistical Analysis Plan 
 
Project Document Version No.: 1.0; Document Effective Date:  Date of Last Signature  
Confidential 
TP-GDO-WW-133-04 
 
 
Effective Date:  28 Jul 22 
Related to:  SOP-GDO-WW-019 
Page 4 of 43 
 
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001 
 
Signatory 
Reviewer 
 
 
Signature 
Project Role: Biostatistics Reviewer 
 
 
 
PPD
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Parexel International 
GlaxoSmithKline Research & Development Limited 
GSK 219882    
Statistical Analysis Plan 
 
Project Document Version No.: 1.0; Document Effective Date:  Date of Last Signature  
Confidential 
TP-GDO-WW-133-04 
 
 
Effective Date:  28 Jul 22 
Related to:  SOP-GDO-WW-019 
Page 5 of 43 
 
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001 
TABLE OF CONTENTS 
1 
INTRODUCTION .................................................................................................................... 10 
2 
STUDY OBJECTIVES ............................................................................................................ 10 
2.1 
Primary Objective ............................................................................................................ 10 
2.2 
Secondary Objective ........................................................................................................ 11 
2.3 
Exploratory Objective(s) ................................................................................................. 11 
3 
INVESTIGATIONAL PLAN................................................................................................... 11 
3.1 
Overall Study Design and Plan ........................................................................................ 11 
3.2 
Endpoints and Associated Variables ............................................................................... 12 
3.2.1 
Primary Endpoint ........................................................................................................ 12 
3.2.2 
Secondary Endpoint .................................................................................................... 12 
3.2.3 
Pharmacokinetic Variables ......................................................................................... 12 
3.2.4 
Safety Variables .......................................................................................................... 13 
3.2.5 
Exploratory Variables ................................................................................................. 13 
4 
STATISTICAL METHODS..................................................................................................... 13 
4.1 
Data Quality Assurance ................................................................................................... 13 
4.2 
General Presentation Considerations ............................................................................... 13 
4.2.1 
Treatment .................................................................................................................... 14 
4.2.2 
Study Day ................................................................................................................... 14 
4.2.3 
End of Study ............................................................................................................... 14 
4.2.4 
Baseline ....................................................................................................................... 14 
4.2.5 
Controlled, Repeat, Retest, Scheduled and Unscheduled Assessment ....................... 14 
4.2.6 
Summary and Representation of Data ........................................................................ 15 
4.3 
Software 15 
4.4 
Study Participants ............................................................................................................ 15 
4.4.1 
Analysis Sets ............................................................................................................... 15 
4.4.2 
Disposition of Participants .......................................................................................... 16 
4.4.3 
Protocol Deviations ..................................................................................................... 16 
4.4.3.2 Protocol Deviations with PK Implications ................................................................. 16 
4.5 
Demographics and Baseline Characteristics .................................................................... 17 
4.6 
Medical History ............................................................................................................... 17 
4.7 
Prior and Concomitant Medications ................................................................................ 17 
4.8 
Treatment Exposure and Compliance .............................................................................. 17 
4.8.1 
Treatment Exposure .................................................................................................... 17 
4.8.2 
Compliance ................................................................................................................. 18 
4.9 
Analysis Supporting Primary Objective(s) ...................................................................... 18 
4.9.1 
Primary Endpoint(s) .................................................................................................... 18 
4.9.2 
Statistical Hypothesis, Model, and Method of Analysis ............................................. 18 
4.9.2.1 Underlying assumptions ............................................................................................. 19 
4.9.2.2 Model evaluation ........................................................................................................ 20 
4.9.2.3 Summary of measure .................................................................................................. 21 
4.9.3 
Handling of Intercurrent Events ................................................................................. 21 
4.9.4 
Handling of Missing Values not Related to Intercurrent Event .................................. 21 
4.9.5 
Sensitivity analyses ..................................................................................................... 22 
4.9.6 
Supplementary analyses .............................................................................................. 22 
4.10 Analysis Supporting Secondary Objective(s) .................................................................. 22 


Parexel International 
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GSK 219882    
Statistical Analysis Plan 
 
Project Document Version No.: 1.0; Document Effective Date:  Date of Last Signature  
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Effective Date:  28 Jul 22 
Related to:  SOP-GDO-WW-019 
Page 6 of 43 
 
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001 
4.11 Pharmacokinetic Analysis, Concentration, and Parameter TFLs, and Statistical Analysis of 
Pharmacokinetic Parameters for Final Analysis .............................................................. 22 
4.11.1 
Pharmacokinetic Concentrations ................................................................................ 22 
4.11.2 
Pharmacokinetic Parameters ....................................................................................... 24 
4.12 Safety Evaluation ............................................................................................................. 26 
4.12.1 
Adverse Events ........................................................................................................... 27 
4.12.2 
Deaths, Serious Adverse Events, and Other Significant Adverse Events .................. 28 
4.12.3 
Clinical Laboratory Evaluation ................................................................................... 28 
4.12.4 
Vital Signs ................................................................................................................... 29 
4.12.5 
12-lead ECG ............................................................................................................... 29 
4.12.6 
Columbia-Suicide Severity Rating Scale .................................................................... 31 
4.12.7 
Physical Examination ................................................................................................. 31 
4.12.8 
COVID-19 Assessment and COVID-19 AEs ............................................................. 31 
4.12.9 
Other Analysis ............................................................................................................ 31 
4.12.10 Daylight Saving Time (DST): ..................................................................................... 31 
4.12.11 Safety Monitoring (Independent Data Monitoring Committee, Data Monitoring 
Committee, Data and Safety Monitoring Board) ........................................................ 31 
4.13 Handling of Dropouts or Missing Data ........................................................................... 31 
4.14 Subgroup Analysis ........................................................................................................... 31 
4.15 Planned Interim Analyses ................................................................................................ 31 
4.16 Determination of Sample Size ......................................................................................... 32 
4.17 Changes in the Conduct of the Study or Planned Analysis ............................................. 33 
4.17.1 
Change in analysis sets defined in protocol section 9.2  Analysis sets: ................... 33 
5 
REFERENCES ......................................................................................................................... 34 
6 
APPENDICES .......................................................................................................................... 35 
6.1 
Schedule of Activities ...................................................................................................... 35 
6.2 
Imputation Rules for Partial Dates .................................................................................. 39 
6.3 
Laboratory Test Parameters ............................................................................................. 41 
6.4 
ECG Notable Criteria ...................................................................................................... 43 
 
  List of Tables 
Table 4-1  
Pharmacokinetic Parameter and Estimation .............................................................. 25 
Table 6-1 
Schedule of Activities - Overview Across Visit Days ............................................... 35 
 
 
List of Figures 
Figure 1-1Study Design Overview .................................................................................................... 12 
 
 


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GSK 219882    
Statistical Analysis Plan 
 
Project Document Version No.: 1.0; Document Effective Date:  Date of Last Signature  
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Effective Date:  28 Jul 22 
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Page 7 of 43 
 
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001 
REVISION HISTORY 
Version No. 
Effective Date 
Summary of Change(s) 
Final 1.0 
Date of Last Signature 
Final document 
 
 


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Statistical Analysis Plan 
 
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Effective Date:  28 Jul 22 
Related to:  SOP-GDO-WW-019 
Page 8 of 43 
 
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001 
LIST OF ABBREVIATIONS  
Abbreviation/Acronym 
Definition/Expansion 
AE 
Adverse event 
BL 
Biostatistician Lead 
BLQ 
Below the lower limit of quantification 
BMI 
Body mass index 
BP 
Blood pressure 
bpm 
Beats per minute 
CI 
Confidence interval 
Cmax 
Maximum observed concentration 
CPMS 
Clinical Pharmacology, Modeling, and Simulation 
CRF 
Case Report Form 
CS 
Clinically significant 
CV 
Coefficient of variation 
DBP 
Diastolic blood pressure 
DRM 
Data Review Meeting 
ECG 
Electrocardiogram 
ENR 
Enrolled Analysis Set 
EOS 
End of study 
ET 
Early termination 
HR 
Heart rate 
IMP 
Investigational medicinal product 
LLOQ 
Lower limit of quantification 
MedDRA 
Medical Dictionary for Regulatory Activities 
NCS 
Not clinically significant 
PCS 
Potentially clinically significant 
PD 
Pharmacodynamic(s) 
PK 
Pharmacokinetic(s) 
PT 
Preferred Term 
QTc 
corrected QT interval 


Parexel International 
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GSK 219882    
Statistical Analysis Plan 
 
Project Document Version No.: 1.0; Document Effective Date:  Date of Last Signature  
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Effective Date:  28 Jul 22 
Related to:  SOP-GDO-WW-019 
Page 9 of 43 
 
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001 
Abbreviation/Acronym 
Definition/Expansion 
QTcF 
 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SBP 
Systolic blood pressure 
SD 
Standard deviation 
SOC 
System Organ Class 
TEAE 
Treatment-emergent adverse event 
TEMA 
Treatment-emergent markedly abnormal 
WHO-DD 
World Health Organization - Drug Dictionary 
 
 
 


Parexel International 
GlaxoSmithKline Research & Development Limited 
GSK 219882    
Statistical Analysis Plan 
 
Project Document Version No.: 1.0; Document Effective Date:  Date of Last Signature  
Confidential 
TP-GDO-WW-133-04 
 
 
Effective Date:  28 Jul 22 
Related to:  SOP-GDO-WW-019 
Page 10 of 43 
 
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001 
1 
INTRODUCTION 
This Statistical Analysis Plan (SAP) describes all planned analyses for the Clinical Study Report 
(CSR) of Study GSK 219882 (Parexel study number: 275921), An Open-Label, Single Arm, Dose 
Escalating Concentration-QT Study to Investigate the Cardiac Effects and Safety of Paroxetine in 
Healthy Adult Participants.  
The content of this SAP is based on following study documents: 
 Study GSK 219882 protocol Version 2.0 (15 Sep 2023). 
This SAP will be finalized prior to database lock. Any changes after the finalization of this SAP will 
be documented in Statistical Method Modification Form. 
2 
STUDY OBJECTIVES 
The objectives of the study are mentioned below:  
 
2.1 
Primary Objective 
 To evaluate the potential effect of paroxetine on QTc interval following oral doses of 20, 40, 
and 60 mg once daily in healthy adults. 
 
 Primary Estimand: 
The primary question of interest: Is there a clinically relevant cardiac effect of paroxetine at 
the maximum recommended therapeutic dose, as measured by an increase in QTc from 12-
lead electrocardiogram (ECG)?  
 
The estimand is described by the following attributes:  
 Population: Healthy participants of age 18 to 65 years  
 Treatment condition: Dose up titration of paroxetine doses of 20, 40 and 60 mg  
 
 
  Summary measure: The upper limit of the 90% confidence interval (CI) of model-
-state Cmax of the 60 mg paroxetine 
dose  
 Intercurrent events: 
 a) Treatment discontinuation due to any reason - While on-treatment strategy will be 
applied to address this intercurrent event.  
 b) Any events affect the drug absorption (1 hour)  Treatment Policy strategy will be 
applied to address this intercurrent event. 
 Rationale for Estimand:  
concentrations while the participant is exposed to paroxetine as planned, i.e., prior to 
the discontinuation of the treatment.  
concentrations, not with dose - therefore even though the concentration for a dose is 
affected, the data are still relevant even when there is an inaccuracy in dosing.  
 


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GSK 219882    
Statistical Analysis Plan 
 
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Page 11 of 43 
 
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001 
mean Cmax of the 40 mg dose. Additionally, another estimand might need to be evaluated. 
2.2 
Secondary Objective 
 To assess the safety and tolerability of paroxetine doses of 20, 40, and 60 mg once daily in 
healthy adults. 
 
 Secondary Estimand: 
Secondary estimand address all other safety and tolerability findings.  
 
The estimand is described by the following attributes:  
 Population: Healthy participants of age 18 to 65 years  
 Treatment condition: Dose up and down titration of paroxetine doses of 20, 40 and 60 mg  
 Endpoint:  
 Occurrence of adverse events (AEs) and serious adverse events (SAEs)  
 Changes in vital signs (blood pressure, heart rate and oral body temperature) from baseline 
 Changes in hematological and clinical laboratory tests from baseline 
 Summary measure: Proportions for AEs and SAEs and means of the change from baselines 
for vital signs, hematological, and clinical laboratory across all dose levels. 
 Intercurrent events: Study intervention discontinuation due to any reason  treatment policy 
strategy will be applied for this intercurrent event.  
 Rationale for Estimand: Safety data will be monitored throughout the study after the start of 
study intervention. There is interest in evaluating and reporting safety events regardless of 
whether participants discontinued study intervention. 
2.3 
Exploratory Objective(s) 
          Not Applicable 
3 
INVESTIGATIONAL PLAN 
3.1 
Overall Study Design and Plan 
This is a an open-label, single arm, dose-escalating concentration QT study to investigate the cardiac 
effects, safety and tolerability of paroxetine in healthy adult participants.  
At least 36 participants with no history of cardiac abnormalities or mood disorders will be enrolled. All 
eligible participants will receive paroxetine titrated to a dose of 60 mg once daily at increments of 20 mg 
per week.  
All participants will attend a study site visit at Screening (Visit 1: -28 to -31 days), baseline (pre-dose) 
assessments and first paroxetine administration of 20 mg once daily (Visit 2: Day 1), serial ECG and 
paroxetine concentration measurements (Visit 3, Day 7) and dose escalation to 40 mg once daily (Visit 
3: Day 8), serial ECG and paroxetine concentration measurements at the 40 mg dose (Visit 4, Day 
14) and dose escalation to 60 mg once daily (Visit 4: Day 15), serial ECG and paroxetine 
concentration measurements (Visit 5, Day 21) and the Exit visit (Visit 6, up to 14 days after last 20 
mg dose). Tapering from 60 to 40 mg once daily, 40 to 20 mg once daily, and 20 mg once daily to no 
dose will occur at home. Unplanned visits (if needed) will be scheduled for participants who needs to 
visit the clinic due to AEs during home dosing or required to start intermediate tapering dose of 10 
mg to be started  (for both clinic and home dosing) during the tapering period.  


Parexel International 
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GSK 219882    
Statistical Analysis Plan 
 
Project Document Version No.: 1.0; Document Effective Date:  Date of Last Signature  
Confidential 
TP-GDO-WW-133-04 
 
 
Effective Date:  28 Jul 22 
Related to:  SOP-GDO-WW-019 
Page 12 of 43 
 
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001 
During home dosing participants will be interviewed remotely via video-call to confirm dosing 
compliance and have daily follow-ups.  
 
The study design schema is presented in Figure 1-1 
Figure 1-1Study Design Overview 
 
 
3.2 
Endpoints and Associated Variables 
The following list of study endpoints and associated variables will be used to Investigate the Cardiac 
Effects and Safety of Paroxetine in Healthy Adult Participants. 
3.2.1 Primary Endpoint 
 
 
3.2.2 Secondary Endpoint 
 Changes in vital signs (blood pressure, heart rate and oral body temperature) from baseline  
 
 Occurrence of adverse events (AEs), serious adverse events (SAEs), hematological and 
clinical laboratory tests, vital signs, and physical examination 
3.2.3 Pharmacokinetic Variables 
Pharmacokinetic concentration data will be obtained at time point(s) described in the schedule of 
assessment in Section 6.1.  


Parexel International 
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GSK 219882    
Statistical Analysis Plan 
 
Project Document Version No.: 1.0; Document Effective Date:  Date of Last Signature  
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Related to:  SOP-GDO-WW-019 
Page 13 of 43 
 
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001 
Unless otherwise stated, derivation of PK parameters will be the responsibility of CPMS group, 
Parexel.   
The following plasma PK parameters listed in Table 3-1 for paroxetine following repeated dose 
administration will be determined using non-compartmental analysis.  
Table 3-1Plasma Pharmacokinetic Parameters after Multiple Dose Administration after Last 
Dose (on Day 7, 14 and 21) 
Parameter 
WNL  
Name 
CDISC 
Name 
Definition 
Cmax 
Cmax 
CMAX 
Maximum observed concentration in a 
dosing 
interval 
after 
last 
dose 
administration 
tmax 
Tmax 
TMAX 
Time corresponding to occurrence of 
Cmax after last dose administration 
 
3.2.4 Safety Variables 
 Physical examinations 
 Vital signs (Blood Pressure, heart rate and oral body temperature) 
 12-lead electrocardiogram (ECG): Heart rate, PR interval, Q waves, QRS interval, QTcF 
interval  
 Clinical laboratory tests (haematology, clinical chemistry, coagulation, and pregnancy testing, 
other screening tests.) 
 Adverse event (AE)/serious adverse event (SAE) assessments 
 Prior and concomitant medication assessments 
 Pregnancy test 
3.2.5 Exploratory Variables 
Not Applicable. 
 
4 
STATISTICAL METHODS 
4.1 
Data Quality Assurance 
All tables, figures, and data listings to be included in the report will be independently checked for 
consistency, integrity, and in accordance with standard Parexel procedures. 
4.2 
General Presentation Considerations 
This section is not applicable to PK data. 


Parexel International 
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GSK 219882    
Statistical Analysis Plan 
 
Project Document Version No.: 1.0; Document Effective Date:  Date of Last Signature  
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Effective Date:  28 Jul 22 
Related to:  SOP-GDO-WW-019 
Page 14 of 43 
 
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001 
4.2.1 Treatment 
All participants will receive active treatment with paroxetine tablets once daily with titration steps 
every week over a maximum treatment period of 3 weeks. This is followed by tapering over the 
subsequent period of 10 days:  
 Days 1-7: 20 mg once daily  
 Days 8-14: 40 mg once daily  
 Days 15-21: 60 mg once daily  
 Days 22-26: 40 mg once daily  
 Days 27-31: 20 mg once daily. If participants are not able to withdraw from 20 mg once daily 
directly due to withdrawal effects, an additional tapering dose step of 10 mg once daily may 
be given for 5 days. Unplanned visits (if needed) will be scheduled for participants who need 
to visit to clinic due to AEs during home dosing or required to start intermediate tapering dose 
of 10 mg to be started (for both clinic and home dosing) during the tapering period.  
 Day 32 (or 37) onwards: complete stop of paroxetine  
4.2.2 Study Day 
Study days will be numbered relative to the first day of study drug administration. 
 
If the date of event is before the study drug administration, then: 
Study day = (Date of event  Date of study drug administration [i.e. Day 1] ) 
 
If the date of event is on or after the study drug administration, then:  
Study day = (Date of event  Date of study drug administration [i.e., Day 1]) + 1 
 
If the date of event is missing, then study day is also missing. 
4.2.3 End of Study 
A participant is considered to have completed the study if they have completed all phases of the 
study. including the last visit for any protocol-related activity (last participant, last visit) as shown 
in the SoA (Section 6.1) are completed.  
 
The end of the study is defined as the last visit of the last participants in the study. 
4.2.4 Baseline 
Baseline is defined as the mean of Day -1 timepoints recorded before first dose of study treatment 
administration for all types of measurements except for primary analysis. 
The baseline definition will be used for following safety variable: 
 Vital signs 
 Clinical laboratory tests  
4.2.5 Controlled, Repeat, Retest, Scheduled and Unscheduled Assessment  
Repeat, retest, and unscheduled assessment will not be considered for the calculation of summary 
statistics and figures, unless assessment qualifies as baseline. 


Parexel International 
GlaxoSmithKline Research & Development Limited 
GSK 219882    
Statistical Analysis Plan 
 
Project Document Version No.: 1.0; Document Effective Date:  Date of Last Signature  
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Effective Date:  28 Jul 22 
Related to:  SOP-GDO-WW-019 
Page 15 of 43 
 
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001 
Average of controlled and planned (scheduled) assessment will be considered for the calculation of 
summary statistics and figures, if more than one controlled/planned assessment will be performed at 
a specific time point.  
4.2.6 Summary and Representation of Data  
Continuous data will be summarized in terms of mean, standard deviation (SD), median, minimum, 
maximum, and number of observations, unless otherwise stated.  
Categorical data will be summarized in terms of the number of participants providing data at the 
relevant time point (n), frequency counts, and percentages.   
The minimum and maximum will be reported to the same number of decimal places as the raw data 
recorded in the database. The mean and median will be reported to one more decimal place than the 
raw data recorded in the database.  The SD will be reported to two more decimal places than the raw 
data recorded in the database.  In general, the maximum number of decimal places reported shall be 
four for any summary statistics. 
Percentages between 1% and 99%, inclusive, will be rounded to integers. Percentages greater than 
0%, but less than 1%, will be reported as <1%, and percentages greater than 99%, but less than 100%, 
will be reported as >99%. If for any summary table, n is less than three then only n, minimum, and 
maximum should be presented, and other summary statistics will be left blank. 
4.3 
Software 
All report outputs will be produced using SAS® version 9.3 or later in a secure and validated 
environment.  
The PK analyses will be conducted using Phoenix® WinNonlin (WNL) version 8.3 or later in a secure 
and validated environment.  
All report outputs will be provided to the Sponsor in RTF for individual TLFs and PDF for combined 
TLFs format.   
4.4 
Study Participants 
4.4.1 Analysis Sets 
Analysis Set 
Definition / Criteria 
Analyses 
Evaluated 
Screened 
 
All participants who were screened for eligibility 
 
Study 
Population 
Enrolled 
 
All participants who entered the study (who 
successfully passed screening)  
 
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/Exposed 
 
All participants who received at least one dose of 
study intervention.  
 
Safety  


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GSK 219882    
Statistical Analysis Plan 
 
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Effective Date:  28 Jul 22 
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Page 16 of 43 
 
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001 
Analysis Set 
Definition / Criteria 
Analyses 
Evaluated 
 
Data will be reported according to the actual study 
intervention.  
PK 
 
All participants in the Safety analysis set who had 
at least 1 non-missing PK assessment (non-
quantifiable values will be considered as non-
missing values).  
 
 
Data will be reported according to the actual study 
intervention.  
 
 
Used for some displays required by EudraCT. 
Studies with single arm should use the text 
 
 
Primary 
analysis  
PD  
 
 
All participants in the Safety analysis set who had 
at least 1 non-missing ECG assessment.  
 
Data will be reported according to the actual study 
intervention.  
 
Primary 
analysis 
4.4.2 Disposition of Participants 
A clear accounting of the disposition of all participants who enter the study will be provided, from 
screening to study completion. 
A summary of participant study/treatment completion status and reason for study withdrawal will be 
provided for the enrolled set. This display will show the number and percentage of participants who 
withdrew from the study, who have completed the study or have discontinued study treatment 
including primary reasons for study withdrawal and discontinuation of study treatment.   
A by participant listing of study discontinuation will be presented for the enrolled set. The listing will 
include last dose date and reasons for study treatment discontinuation. 
A by participant listing for screen failure will be provided including reason for screen failure for all 
participants. 
4.4.3 Protocol Deviations 
All protocol deviations are predefined in the separate document, Protocol Deviation Assessment Plan. 
4.4.3.1 Protocol Deviations with Non-PK Implications 
The defined protocol deviations will be collected during the study period by site monitor/clinical team 
and programming team. All deviations will be described when relating to:  
 Study inclusion or exclusion criteria  
 Conduct of the study 
 Participant management or participant assessment 
 
 
4.4.3.2 Protocol Deviations with PK Implications 
Protocol deviations that may potentially impact PK parameter derivations include, but are not limited 


Parexel International 
GlaxoSmithKline Research & Development Limited 
GSK 219882    
Statistical Analysis Plan 
 
Project Document Version No.: 1.0; Document Effective Date:  Date of Last Signature  
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TP-GDO-WW-133-04 
 
 
Effective Date:  28 Jul 22 
Related to:  SOP-GDO-WW-019 
Page 17 of 43 
 
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001 
to: 
 Emetic episode within 1 hour afteradministering study drug 
 Missed PK samples that impact estimation of PK parameter(s) 
 Concomitant medications not authorized by protocol. 
 PK samples obtained out of allowance window that may impact the estimation of PK 
parameter(s) 
 Food intake deviations (not completely consumed or consumed outside of time allowed)  
Protocol deviations (mentioned in Sections 4.4.3.1 and 4.4.3.2) and analysis sets will be reviewed in 
the (blinded) data review report meeting to decide inclusion or exclusion of participant(s) from 
analyses sets. Decisions regarding the exclusion of participants and/or participant data from analyses 
will be made prior to database lock and will be documented and approved. 
A by-participant listing of important and non-important protocol deviations will be provided 
including participant identifier; exclusion from specific analysis sets; and protocol deviation 
classification, and protocol deviation description and exclusion from specific analysis sets. 
 
4.5 
Demographics and Baseline Characteristics 
The demographic characteristics (e.g., age, race, ethnicity, sex, height, body weight, body mass index 
[BMI]) will be summarized and listed by participant for the Safety Set and enrolled set. 
Age, height, weight and BMI will be summarized using the mean, SD, minimum, median, and 
maximum. The count and percentage will be computed for sex, race, and ethnicity. The summary 
table will be displayed by treatment for the Safety Set. 
4.6 
Medical History 
Medical and surgical history will be coded using Medical Dictionary for Regulatory Activities 
(MedDRA®), Version 26.0 or higher and assigned to a System Organ Class (SOC) and Preferred Term 
(PT). Summary of Medical history will be provided by SOC and PT for Safety Analysis Set. 
4.7 
Prior and Concomitant Medications 
Prior and Concomitant Medication: 
Prior medications are those that started and stopped before the first dose of IMP. Concomitant 
medications are those taken after first dosing (including medications that started before dosing and 
continued after).  
Prior and concomitant medication will be coded according to the World Health Organization Drug 
Dictionary (WHO-DD) (Version March 1, 2023 or latest) and will be classified by Anatomical 
Therapeutic Chemical (ATC) categories.  
By participant listings of prior and concomitant medications will be provided for the Safety Set and 
will include the following information: reported name, preferred term (PT), the route of 
administration, dose, frequency, start date/time, duration, and indication. 
4.8 
Treatment Exposure and Compliance 
4.8.1 Treatment Exposure  
Summary of treatment exposure will be provided in terms of number of dose administered based on 
Safety population for the IP administration. A by-participant listing of participant exposure to study 


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Statistical Analysis Plan 
 
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Page 18 of 43 
 
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001 
drug will be generated. The listing will include dose, date and time, unit, formulation, route, and 
frequency. 
4.8.2 Compliance  
Dose compliance at site and dosing compliance while dosing at home will be evaluated. Participants 
will take the planned dose under direct supervision while on site, and via video-call while dosing at 
home.  
 Compliance (%) at site will be calculated as 100% * total number of actual taken site doses / 
total number of planned site doses.  
 Compliance (%) at home will be calculated as 100% * total number of actual taken home 
doses/ total number of planned home doses. 
4.9 
Analysis Supporting Primary Objective(s) 
4.9.1 Primary Endpoint(s) 
The primary endpoint is the change from baseline in QTc ( QTc), where baseline is the pre-dose 
collection obtained on visit 2 (Day -1, 0.25h before the planned dosing time of Day 1).  
QTc for primary analysis will be measured at Visits 2 (Day -1), 3 (Day 7), 4 (Day 14) and 5 (Day 21) 
as outlined in the SoA. At each time point where replicate ECG is obtained, then mean of the 
triplicates will be used for deriving baseline and change from baseline.  
4.9.2 Statistical Hypothesis, Model, and Method of Analysis 
A random-coefficient linear mixed-effects model will be fit to all available paroxetine concentration 
- 
per (Garnet C et al., 2018 [3]
the dependent variable and paroxetine concentration and time after dose and baseline are independent 
variables, it takes the form of: 
 
 
 
In this equation: 
 
i,k is the change from baseline in QTc for participant i at time k;  
 
0 is the population mean intercept in the absence of a treatment effect;  
 
0,i 
0;  
 
1 is the population mean slope of the assumed linear association between concentration and 
i,k; 
 
1,i 
1;  
 Ci,k is the concentration for participant i and time k; 
 
2,k is the fixed multilevel categorical effect associated with time factor. If inspection of the 
Day -1 data suggests a time-dependent trend, alternative parameterization for the time 
variable, for example based on (co)sine function such as described in Koch et al 2002, could 
be used if relevant;  
 
3 is the fixed effect associated with the difference of each baseline values to the overall mean 
(Baseline QTci,k=0, QTc0 is overall mean of QTci,k=0, i.e., the mean of all the baseline (= 
time 0) QTc values). 


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Statistical Analysis Plan 
 
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Effective Date:  28 Jul 22 
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Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001 
It is assumed the random effects ( 0,I and 
1,i) are normally distributed with mean [0,0] and an 
unstructured covariance matrix G, whereas the residuals are normally distributed with mean 0 and 
variance R. In case of the unstructured covariance matrix for random effects is not supported by the 
data or results in null estimates, and may result in non-convergence problems, other simplified or 
reduced structures will be investigated (Variance component with 2 random effects,1 for slope and 1 
for intercept, variance component with 1 random effect for intercept or slope). 
The QTc and paroxetine concentrations corresponding to all doses (20, 40, and 60mg) will be used 
for the modelling (Both drawn from each participant at same time intervals). Moreover, 
QTc 
obtained on Visit 2 (Day -1) after baseline will be included in the model with paroxetine 
concentrations set to 0. This model assumes a linear correlation between paroxetine plasma 
concentration and QTc. While it is assumed that such a correlation (if at all) can be considered linear 
at clinically meaningful doses, other parameterizations such as the classical Emax function may be 
explored if the linear approach is found inappropriate. 
The model parameters will be estimated including the precision around the parameter estimates using 
a maximum likelihood approach. 
The following SAS® code will be used for the random-coefficient linear mixed-effects model: 
PROC MIXED DATA=ADEG(WHERE=(XXXX)) NOITPRINT CL NOCLPRINT  METHOD=ML PLOTS=NONE; 
ODS OUTPUT SOLUTIONF=SOLF ESTIMATES=ESTF COVPARMS=COV; 
CLASS USUBJID ATPTN ; 
MODEL CHG=BASEC ATPTN PCSTRESN / DDFM=KR SOLUTION ALPHAP=.05 CL RESIDUAL 
OUTPM=PRED OUTP=IPRED; 
RANDOM INT PCSTRESN /SUB=USUBJID TYPE=UN; 
ESTIMATE "DDQTC_60MG" INT 1  PCSTRESN CMAX60MG /CL ALPHA=.1; 
RUN; 
4.9.2.1 Underlying assumptions 
Effect on HR 
Time course of mean changes in HR will be displayed by dose as detailed in Section 4.12.5. 
Appropriateness of the QT correction off-drug (QTc is independent of HR): 
In healthy participants, Fridericia correction of the QT interval (QTcF) is usually considered 
appropriate for drugs with limited effects on HR. QTcF is computed as QTcF (msec) = 
QT/(RR/1000)1/3. 
The appropriateness of the correction can be assessed by determining if the QTc is independent of 
the HR using drug free data. For that purpose, a scatter plot of QTcF values (y-axis) versus HR values 
(x-axis) obtained at Visit 2 (Day -1) will be provided with linear and non-linear (loess) regression 
lines to assess the lack of relationship between QTcF and HR off-drug. Moreover, similarity of the 
range of HR off- and on-drug, to support the correction in both cases, will be assessed by plotting the 
mean QTcF values calculated by decile of HR for each visit (off-drug on Visit 2 and on-drug on Visit 
3, 4 and 5). Linear mixed effects lines and 95% confidence intervals computed for each visit will be 
plotted on the same graph. 
Appropriateness of the QT correction on-drug: 
In addition, the potential of paroxetine to significantly increase of decrease HR should be evaluated. 
Mean increase or decrease > 10 beats/min are considered sufficient to impact the quality of the 
Fridericia correction and the primary endpoint assessment. The impact of paroxetine on HR will be 


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Page 20 of 43 
 
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001 
assessed from the graphical display of change from baseline in HR ( HR) described in Safety 
Evaluation (Section 4.12.5).  
If these graphical explorations suggest insufficient HR correction of the QT interval, alternative 
corrections, such as Bazett (QTcB (msec) = QT/(RR/1000)1/2), could be evaluated.  
No time delay between drug concentration and effect on QTc (direct effect hypothesis, no 
PK/PD hysteresis): 
The direct temporal relationship between paroxetine concentrations and 
QTcF will be assessed 
graphically by plotting the time course of mean 
QTcF with the time course of paroxetine 
concentrations geometric mean by visit. If for the two highest doses of paroxetine (Visits 4 and 5) a 
delay (hysteresis) between the time to reach the peak concentration and the peak QTc effect is more 
than 1 hour, other modeling strategy may be explored. 
Linear relationship between paroxetine relationship and QTcF  
The linear relationship will be assessed using a scatter plot of QTcF (y-axis) vs. concentrations (x-
axis), with linear and non-linear (loess) trend lines. The trend lines, directly obtained from the SAS® 
graphical procedures, will not reflect the model fit of the data but rather rough fixed regressions 
(without random effects) to detect drug effect and whether there are major violations to the linear 
assumption (in case of drug effect) 
In case of the linearity assumption cannot be accepted, alternative models will be explored. A non-
linear alternative could be, for example, the Emax model for which the linear component 
(
is replaced by a component of the form 
, where 
1,1 is 
0 
1,2 is the concentration at which the effect is half 
1,1,  is the hill coefficient 
1,i 
1,1.  
As such an example for a full nonlinear model could be written as : 
 
The model parameters will be estimated including the precision around the parameter estimates using 
a maximum likelihood approach. Initial values will be determined from the graphical display.  
Categorical description of time effect on QTcF  
The standard model contains a categorical variable to account for time dependent changes in QTc 
(
. This parameterization is agnostic to any trends in such changes, and may be better 
represented by other functions. In particular, it has been reported in literature that (co)sinusoidal 
functions may describe the change in QTc due to diurnal / circadian variation, e.g. Koch & Raschka 
2002 [5]. Inspection of the Day -1 serial QTc data may help to elucidate such trends in change of QTc 
over time and drive the specification of such a time-dependent function. 
4.9.2.2 Model evaluation 
Diagnostic and goodness of fit plots will be presented for the final model and will include: 
- 
Quantile-Quantile plots of residuals; 
- 
Concentrations versus residuals; 
- 
Time and baseline versus residuals; 
- 
 
- 
s (quantile plot) with model 
slope and 90% CI. 


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Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001 
4.9.2.3 Summary of measure 
Individual Cmax values for participants at the 60 mg dose will be used to calculate the Cmax 
geometric mean. Based on the estimated model, the calculated geometric mean Cmax for dose 60 mg 
w
follows (in the case of a linear model): 
 
 
 
Where: 
 
 is the predicted 
 mg;  
 
0 is the estimated fixed intercept term; 
 
1 is the estimated fixed slope for concentrations; 
 t(0.95,DF) is the 95th quantile from the student distribution with DF degrees of freedom; 
 SE is the standard error ; 
 var( 0), var( 1) and cov(
0, 1) are respectively the variance of 0 and 1 and their covariance. 
The summary measure of the study is the geometric mean and 90% 
 mg 
Cmax. If the upper bound of 90% CI for this predicted QTc falls below the 10 msec mark, the 
conclusion of the study is that there is no clinically relevant QTc prolongation up to and including 
the 60 mg dose. In case the upper 90% CI limit does not fall below the 10 msec mark, the same 
 
4.9.3 Handling of Intercurrent Events 
The following intercurrent event will be considered: 
a. Treatment discontinuation due to any reason - While on-treatment strategy will be applied to 
address this intercurrent event.  
The data affected by occurrence of the intercurrent event would be treated as missing at 
random from the occurrence of the intercurrent event until the end of the study. Participant 
level missing data considered as missing at random, will not be imputed and available data 
will be used in the primary analysis. 
b. Any events affect the drug absorption (1 hour)  Treatment Policy strategy will be applied to 
address this intercurrent event for the estimation model as it is based on concentration not 
dose - therefore even though the concentration may be affected, the data is still relevant for 
quantifying the relationship between change in QTc and drug concentration. Hence, we will 
occurrence of the intercurrent event. However, when the model is used to predict the upper 
90% CI for 60mg doses an absorption event may artificially reduce the prediction, hence the 
corresponding paroxetine concentration data will not be used in the calculation of the Cmax 
 
 
4.9.4 Handling of Missing Values not Related to Intercurrent Event 
Missing data not related to intercurrent event will not be imputed and available data will be used in 
the primary analysis. 


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Statistical Analysis Plan 
 
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Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001 
4.9.5 Sensitivity analyses 
A sensitivity analysis will be performed to ensure that there is no bias in the calculated geometric 
mean of the Cmax at the 60 mg once daily dose, in case: 
- 
Twenty percent (20%) or more of the total PK data is missing, or 
- 
Twenty percent (20%) or more of participants (8 participants or more) at the 60 mg once daily 
dose have either missing paroxetine concentration data around the Cmax at the 60 mg dose 
at the 60 mg dose 
 
This analysis will consist of a population pharmacokinetic (PopPK) model-fitting of the individual 
paroxetine concentration data without the estimation of population level parameters (post-hoc or 
Bayesian fit), using a paroxetine popPK model developed internally at GSK. Appropriateness of the 
available paroxetine popPK model will be determined based on goodness-of-fit plots (e.g. population 
and individual prediction [PRED, IPRED] vs observed concentrations [DV], CWRES vs IPRED). A 
descriptionof the popPK model, if used for sensitivity analysis, will be included in the study report.  
The individual PK parameters from the Bayesian model fit will allow the model-based individualised 
prediction of the Cmax at the 60 mg once daily dose for those participants with missing data, based 
on the available paroxetine concentration data at the earlier doses. Through this method, a geometric 
mean of Cmax at the 60 mg dose can be calculated that should be less affected by dropout, missing 
then be performed using the Cmax of the 60 mg dose calculated using this method. In case the 
-based 
prediction of Cmax at the 40 mg dose for dropouts will be performed, where required. If such a 
sensitivity analysis is performed, results from both the regular analysis (without PK model fitting and 
predictions) and the sensitivity analysis will be presented in the study report. 
4.9.6 Supplementary analyses 
Not applicable. 
4.10 Analysis Supporting Secondary Objective(s) 
Analysis Supporting secondary Objective are described in section 4.12. 
 
4.11 Pharmacokinetic Analysis, Concentration, and Parameter TFLs, and Statistical Analysis 
of Pharmacokinetic Parameters for Final Analysis 
4.11.1 Pharmacokinetic Concentrations 
Concentration Listings:  
Pharmacokinetic concentration data for paroxetine will be listed by participant for the Safety analysis 
set. Concentration listings will include nominal PK sampling time, actual sampling times relative to 
dose administration, deviation from nominal time, and percent deviation from nominal time, and 
concentrations.  Plasma concentrations below the lower limit of quantification (LLOQ) will be 
presented as below the lower limit of quantification (BLQ) in the listings and the LLOQ value 
presented as a footnote. Missing PK samples will be reported in the (blinded) data review meeting  
report (see section 4.4.3) and not reportable samples will be reported as NR, in listings and considered 
excluded from PK analysis. 


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Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001 
 
Concentration Summary Tables: 
Source data as reported from the laboratory will be used for calculation of concentration summary 
statistics. Tabular summaries for concentration-time data will report N (number of subjects included 
in the PK population for each dose), n (number of subjects at a given timepoint), and n(BLQ) (the 
number of subjects with BLQ samples). 
Concentration for paroxetine will be summarized by dose, and nominal timepoint for the PKAS. The 
following descriptive statistics will be presented for plasma concentrations obtained at each nominal 
time point: N, n, n(BLQ), arithmetic mean, SD, coefficient of variation (CV%), geometric mean, 
geometric CV% (calculated as: gCV% =SQRT(es²-1)*100; where s is the SD of the log-transformed 
values), 95% CI, median, minimum, and maximum values. 
For summary tables, all BLQs will be replaced with zero except when an individual BLQ falls 
between two quantifiable values, in which case it will be omitted for the calculation of all summary 
statistics. For the calculation geometric mean and geometric CV%, BLQ values will be replaced by 
half the LLOQ value instead of zero. Summary statistics will not be calculated if non-BLQ 
concentrations at a scheduled time point is <3 and will be reported as NC, with the exception of 
min
maximum will be reported as BLQ . 
The rules followed for calculation and presentation of concentration data with regards to the number 
of decimal places/significant digits for the listings of participant level concentrations and summary 
tables of concentration are as follows:  
Concentration Listings and Tables 
Rounding 
Individual concentrations 
n s.f. as supplied by bioanalytical laboratory 
Minimum and Maximum 
n s.f.  as original data 
Mean/Median/Geomean 
3 s.f. 
SD, CI 
4 s.f. 
CV%/gCV% 
1 d.p. 
N/n 
Whole number 
s.f = significant figures, d.p. = decimal place 
 
Concentration Figures: 
For arithmetic or geometric mean linear/linear graphs, the data plotted in the figure should match the 
data presented in the summary table, with the exception of values reported in table as NC prior to 
Cmax which should be set to 0 in the figure (to capture lag-time). For arithmetic or geometric mean 
log/linear graphs, all values reported in table as NC will be set to missing. 
For individual linear/linear and log/linear graphs all BLQ values will be substituted as follows: 
 One or more BLQs at the beginning of a participant profile (i.e., before the first incidence of 
a measurable concentration) will be assigned to zero. When using semilog scale, these 
timepoints will be considered missing. 
 BLQs at the end of a participant profile (i.e., after the last incidence of a measurable 
concentration) will be set to missing. 


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Statistical Analysis Plan 
 
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Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001 
 Single BLQs which fall between two measurable concentrations will be set to missing.  
 More than one consecutive BLQs which fall between measurable concentrations will be set 
to zero,  and the subsequent measurable concentrations will be retained.  
To visualize participant-level concentrations and the comparison between groups for each dose, the 
descriptive PK graphs listed below will be generated. Include LLOQ line in individual and summary 
plots. 
 
Individual participant profiles for paroxetine plasma concentration time data  (linear scale and 
semi-logarithmic scale) (SAF) 
 
Overlaid individual participant profiles for paroxetine Plasma Concentration Time Data  (linear 
scale and semi-logarithmic scale) (SAF)  
 
Mean (± SD) paroxetine plasma concentration time data  (linear scale and semi-logarithmic 
scale) (PKAS)  
 
Median (range) paroxetine plasma concentration time data  (linear scale and semi-logarithmic 
scale) (PKAS)  
Figures will be generated in black and white using unique line style and marker for each plot in the 
graph. For all PK concentration-time plots, a linear scale will be used for the x-axis (e.g., not an 
ordinal scale).  
4.11.2 Pharmacokinetic Parameters 
PK parameters will be provided by Parexel CPMS group. PK parameters will be calculated by NCA 
methods from the concentration-time data using Phoenix® WinNonlin® Version 8.3 or higher 
following these guidelines: 
 
Actual time from dose will be used in the calculation of all derived PK parameters, except when 
parameters are calculated for safety/dose escalation meetings when nominal times may be used 
to calculate PK parameters.  
 
Handling of BLQ samples for derivation of plasma PK parameters after each dose administration 
o BLQs at the beginning of a participant profile (i.e., before the first incidence of a 
measurable concentration) will be assigned to zero. 
o BLQs at the end of a participant profile (i.e., after the last incidence of a measurable 
concentration) will be set to missing. 
o Single BLQs which fall between two measurable concentrations will be set to missing. 
o Consecutive BLQs which fall between measurable concentrations will be set to 
missing. Measurable concentrations after consecutive BLQs will also be set to 
missing. 
Pharmacokinetic parameters will be estimated according to the guidelines presented in Table 4-1. 
 
 


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Statistical Analysis Plan 
 
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Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001 
Table 4-1 
Pharmacokinetic Parameter and Estimation 
Parameter 
Guideline for Derivation 
Cmax, tmax 
Obtained directly from the observed concentration-time data, unless specified 
otherwise (see Section 4.9.1). 
 
 
 


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Statistical Analysis Plan 
 
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Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001 
PK Parameters Listings:  
PK parameters will be listed by participant for the SAF. PK parameters that will be flagged and/or 
excluded from summary tables and statistical analyses of PK parameters will be flagged and footnoted 
with the reason for flagging/exclusion.  
PK 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.   
PK parameters will be summarized by treatment for the PK Set. 
Tabular summaries for PK parameters will report N (number of subjects included in the PK 
population for each dose) and n (number of subjects with a specific parameter). 
Descriptive statistics for calculated PK parameters will include N, n, arithmetic mean, SD, CV%, 
geometric mean, gCV%, 95% CI, median, minimum, and maximum values. For tmax, only N, n, 
median, minimum, and maximum values will be presented. No descriptive statistics will be 
determined when fewer than three individual PK parameters are available. 
The rules followed for presentation of PK parameters data with regards to the number of decimal 
places/significant digits for the listings of participant level PK parameters and summary tables of PK 
parameters are as follows:  
PK Parameter Listings and Tables 
Rounding  
Derived Individual parameters 
3 s.f. 
Directly Derived Individual parameters 
(Cmax,) 
n s.f. as supplied by the analytical laboratory but not 
more than 3 s.f. 
Minimum and Maximum 
3 s.f. 
Mean/Median/Geomean 
4 s.f. 
SD 
5 s.f. 
CV%/gCV% 
1 d.p. 
Comparative estimates (e.g. ratios) 
3 d.p. 
CI and other percentages 
4 s.f.  
p-values 
4 d.p. 
N/n 
Whole number 
Exceptions for PK Tables 
  
tmax individuals and min/max 
2 d.p 
tmax median only 
2 d.p 
s.f = significant figures, d.p. = decimal place 
4.12 Safety Evaluation 
Secondary estimands address all other safety and tolerability findings.  
Treatment policy strategy will be applied for Study treatment discontinuation due to any reason  
intercurrent event - Safety data will be monitored throughout the study after the start of treatment. 
There is interest in evaluating and reporting safety events regardless of whether participants 
discontinued treatment. 


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Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001 
All safety analysis will be performed on the Safety Set. All participants who received treatment of 
study medication will be included in the safety analysis. Categorical data will be summarized using 
counts and percentages, however continuous data will be summarized using descriptive statistics 
(number of observations, mean, standard deviation, median, minimum, and maximum for continuous 
data by dose. 
4.12.1 Adverse Events 
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. 
All outputs for Adverse Events (AEs) will be based on the Safety Set unless specified separately in 
TLF shells.  
Summaries of AEs will include the following: 
 Incidence of AEs - Overview by dose and overall 
 Incidence of AEs by dose, SOC, and PT 
 Incidence of AEs by maximum causality, dose, SOC, and PT) 
 Incidence of AEs by maximum intensity by dose, SOC, and PT) 
 Adverse Events (AEs) Leading to discontinuation of study intervention by dose, SOC and PT 
 Incidence of SAEs - Overview by dose and overall 
 Incidence of SAEs by dose, SOC, and PT 
 
Summary of common (>=5%) non-serious adverse events (not included in the serious of 
adverse event) - Number of subjects and occurrences by SOC & PT 
 Summary of drug related any adverse events  Number and percentage of subjects by SOC & 
PT 
 Summary of fatal adverse events  Number and percentage of subjects by SOC & PT 
 Summary of drug related fatal adverse events  Number and percentage of subjects by SOC 
& PT 
 Summary of drug related non-serious adverse events - Number and percentage of subjects by 
SOC & PT 
All TEAE summaries should provide the number and percentages of subjects reporting at least one 
TEAE and the total number of events reported.  
Summaries of TEAEs will include the following: 
 Incidence of TEAEs - Overview by dose and overall 
 Incidence of TEAEs by dose, SOC,  and PT 
Summary tables will contain counts of participants, percentages of participants in parentheses, and 
the number of events where applicable. A participant who has multiple events in the same SOC and 
PT will be counted only once in the participant counts, but all events will be included. 
A listing will be created for all Adverse Events (AEs), which will include  study day, preferred term 
(PT), system organ class (SOC), AE onset date (and time), AE end date (and time) or ongoing, 


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duration of the AE, causal relationship to IMP, AE outcome, intensity and seriousness, action taken 
with IMP, concomitant medication (if administered), and TEAE indicator flag. 
Adverse event summaries will be ordered in terms of decreasing frequency for SOC, and PT within 
SOC, and then alphabetically for SOC, and PT within SOC.  
Adverse events will be coded using Medical Dictionary for Regulatory Activities (MedDRA®), 
Version 26.0 or higher). 
All Adverse Events (AEs) 
 
Treatment-emergent Adverse Event 
A TEAE is defined as an AE that began after the start of trial medication treatment or if the event was 
continuous from baseline and was serious, trial medication-related, or resulted in death, 
discontinuation, or interruption or reduction of trial therapy, those TEAEs will be analysed for the 
purpose of safety analysis. 
4.12.2 Deaths, Serious Adverse Events, and Other Significant Adverse Events 
The following summary tables will be provided. 
 
Summary of all-cause mortality - Number of subjects and occurrences by SOC & PT 
 
Summary of serious adverse events - Number of subjects and occurrences by SOC & PT 
The following listings will be provided. 
 
A by participant listing of all deaths that occurred during the study 
 
A by participant listing of all SAEs 
 
A by participant listing of all TEAEs leading to discontinuation of study treatment 
4.12.3 Clinical Laboratory Evaluation 
Clinical laboratory test results of haematology, clinical chemistry, coagulation, pregnancy testing and 
other screening tests (FSH and oestradiol as needed in WONCBP only, urine alcohol and drug screen, 
serology) will be provided by subject. A list of current reference ranges of laboratory assessments is 
included in Section 6.3. Since laboratory ranges can be subject to changes over time the reference 
ranges presented in Section 6.3 might differ from the ones used and presented on SDTM. For analysis 
purposes only the ranges present on the SDTM will be used. 
All TLFs will display only the standard international (SI) units after conversion by means of standard 
conversion factors.  
Quantitative clinical laboratory variables, ie, haematology, clinical chemistry, and coagulation will 
be summarized using descriptive statistics (n, mean, SD, minimum, maximum and median) by on/off 
treatment. Additionally, a within-participant change will be calculated as the post-baseline 
measurement minus the baseline measurement and summarized in the same way.   
Baseline definition will be defined in section 4.2.4. 
Each laboratory result will be classified as low (L), normal (N), or high (H) at each time point 
according to the laboratory supplied reference ranges. Tabulations will be presented by treatment 
(on/off treatment). 
Measurements obtained at Screening and EOS will not be included in the shift tables.  


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Frequency tabulations of qualitative clinical laboratory variables will be presented by treatment 
(on/off treatment). 
All laboratory data will be displayed in listings. 
Laboratory abnormalities that are considered clinically significant (CS) are recorded in the database 
as AEs. Therefore, no tabulation of laboratory values meeting any CS criteria will be presented as all 
relevant information will be presented in the AE summaries. 
Results of pregnancy tests (females only), serology, alcohol and drug of abuse tests will be listed only. 
4.12.4 Vital Signs 
A by-participant listing of all vital sign measurements (including weight) and change from baseline 
will be presented.  
Baseline will be defined in section 4.2.4. 
Measured (observed) values including changes from baseline will be summarized by on/off treatment 
and by vital sign parameter (pulse rate, systolic and diastolic blood pressure, and oral body  
temperature).  
Individual clinically significant vital sign values that were considered AEs by the PI will be presented 
in the AE listings. 
4.12.5 12-lead ECG 
Standard 12-lead ECG will be obtained as outlined in the SoA (Table 6-1) using an ECG machine 
that automatically calculates the heart rate. All ECGs in this study should all be recorded using the 
same make of ECG device (Mortara Surveyor Telemetry Central and Mortara telemetry transmitters 
Model: Surveyor S4), with the exception of Screening visit, where CardioSoft® will be used. The 
Mortara system is validated every 12 months. Monitors will also be available to spot check the 
calibration when on-site. The readings generated by Mortara surveyor S4 machine will be validated 
by the cardiologist with their interpretation on whether the findings are significant and related to 
paroxetine. ECGs must be recorded after 10 minutes rest in the supine position to ensure a stable 
Baseline. ECGs will be performed and recorded in the eCRF at the times shown in SoA (Table 6-1). 
The preferred sequence of cardiovascular data collection during study visits is ECG collection first, 
followed by vital signs, blood sampling, and any remaining assessments for that visit. 
At Screening, participants will be excluded based on ECG measurements if the resting QTc is 
>450msec (mean of three twelve-
Fridericia QT correction formula (QTcF) must be used for clinical decisions, e.g., at Screening to 
assess eligibility. Further, all ECGs will be performed in triplicate collected within 5 min, at least 1 
minute in between, at each timepoint. 
 Triplicate ECGs will be performed at each timepoint as detailed in SOA (Table 6-1). The 
mean QTc value will be calculated from the triplicate ECGs for each participant. 
 
 The ECG extractions will be paired with paroxetine concentration samples but will be 
obtained before the actual paroxetine concentration sampling time to avoid changes in 
autonomic tone associated with the psychological aspects of blood collection as well as the 
reduction in blood volume subsequent to blood collection. 
 
  At visits where an ECG is not scheduled, an ECG can be performed if medically indicated.  


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 All ECG traces will be measured by a third-party vendor, which includes review by a licensed 
cardiologist. The cardiologist will review the ECGs and provide interpretation on whether the 
findings are normal, abnormal but non-clinically significant , or abnormal but clinically 
significant.  
 A qualitative interpretation of the ECG will be performed by the cardiologist (according to 
the 
charter 
referenced 
as 
"Charte_Cardiabase_v5.7_2019-02-12_AtriumV7"). 
This 
morphological interpretation will provide a codification of the abnormalities detected on the 
recordings according to a code list grouping the abnormalities such as Q or Qs pattern, T/U 
wave abnormalities, Rhythm, etc. 
 More than one cardiologist from the vendor may be reviewing the ECGs in the study. 
However, to remove bias all ECGs of a particular participant will be reviewed by the same 
cardiologist. The cardiologists will also be blinded to study visits/timestamps/paroxetine dose 
records. Any clinically significant finding observed on the ECG should be recorded as an AE. 
A copy of ECG traces (with participant-identifying details redacted) may be collected by a 
Sponsor appointed representative for additional cardiology review if required. Clinically 
significant abnormalities must be recorded on the eCRF as either medical history/current 
medical conditions or adverse events as appropriate. 
All ECG parameters will be listed by participant including changes from baseline.  
Baseline is defined in section 4.2.4. 
If ECGs measurements are performed in triplicate, then mean of the triplicates will be presented in 
the listing and used for deriving baseline and changes from baseline. 
Descriptive statistics for absolute values and changes from baseline will be presented by visit/ dose 
level and time point. Two-sided 90% confidence interval of the mean will also be calculated on 
changes from baseline. 
Time course of mean changes from baseline with 90% confidence interval of the mean will be 
presented by dose level. 
A summary of the number and percentage of participants per visit/dose level with ECG intervals 
exceeding some predefined limits (eg, >450 msec, >480 msec, >500 msec for measured values as 
well as. >30 msec, >60 msec for changes from baseline for QTc intervals will be displayed in a 
frequency table. All thresholds for the categorical analysis are presented in Section 6.4. Values 
meeting the thresholds for abnormality will be flagged in the individual data listings. 
A summary of the number and percentage of participants per visit/dose level with at least one 
treatment emergent morphological abnormality will be displayed in a frequency table. Treatment-
emergent abnormality will be defined as any abnormality not already reported on any of the baseline 
ECGs. 
The listing of ECG abnormalities will be presented separately. 
The listing of morphological ECG abnormalities will be presented separately. 
If ECGs measurement are performed in triplicate, only the mean of the triplicates will be presented 
in the listing and used for deriving baseline and change from baseline. 


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Statistical Analysis Plan 
 
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Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001 
4.12.6 Columbia-Suicide Severity Rating Scale 
As part of the screening procedures, a Columbia Suicide Severity Rating Scale (C-SSRS) will be 
performed, to assess the risk of suicidal ideation by the prospective participant. Those who show a 
risk of suicidal ideation will not be included in the study. 
The C-SSRS may be repeated during the study at the discretion of the PI. 
4.12.7 Physical Examination 
Physical examinations will be performed as shown in section  6.1. 
A complete physical examination will include, at a minimum, assessments of the (cardiovascular, 
respiratory, gastrointestinal, and neurological) systems. Height (at screening) and weight (at 
screening and discontinuation) will also be measured and recorded. Further, BMI will be calculated 
from height and weight, and recorded. 
A brief physical examination will include, at a minimum, assessments of the skin, lungs, 
cardiovascular system, and abdomen (liver and spleen). 
After screening, any clinically significant abnormal findings in physical examinations should be 
reported as AEs. 
4.12.8 COVID-19 Assessment and COVID-19 AEs 
The overall incidence of AEs and SAEs of COVID-19, COVID-19 AEs leading to study intervention 
discontinuation will be summarized.  
4.12.9 Other Analysis 
Not Applicable. 
4.12.10  Daylight Saving Time (DST): 
All scheduled times in ClinBase will be automatically updated to ensure a consistent and protocol-
compliant period from the scheduling medication to the actual time point. 
4.12.11  Safety Monitoring (Independent Data Monitoring Committee, Data Monitoring 
Committee, Data and Safety Monitoring Board)  
An Independent Data Monitoring Committee (IDMC) is not required for this study. 
4.13 Handling of Dropouts or Missing Data 
No imputation of missing data will be performed except for partial dates imputation mention in 
Section 6.2. 
4.14 Subgroup Analysis 
No subgroup analysis is planned for this study. 
4.15 Planned Interim Analyses 
No interim analysis is planned for this study.  


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Statistical Analysis Plan 
 
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Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001 
4.16 Determination of Sample Size 
At least 36 participants, men or non-pregnant women, aged 18 to 65 years will be enrolled. This 
number is expected to result in sufficiently wide range of paroxetine concentrations to cover those 
typically observed in a real-world clinical setting. A Monte Carlo simulation analysis was used to 
60 mg dose encompassing the 10 ms cut-off value. Based on this simulation approach, it is expected 
that under the assumption of no true effect of paroxetine on QTc at the 60 mg dose, the expected 
positive) when inclusion is 36 participants. In case the true effect is 5 ms, the expected probability of 
a false positive is <2%. When the true effect is 10 ms, the expected probability of  
correctly determining a QTc prolongating effect is approximately 82%.  
 
The sensitivity to missing data was also assessed. With 20% drop out at the 40 mg dose and another 
25% drop out at the 60 mg dose (in addition to the drop out at the 40 mg dose) the expected probability 
of incorrectly detecting an effect (90% upper limit of the CI 10 msec) for 36 participants is 1% (false 
positive) when the true effect is null. The expected probability of a false positive is 5% if the true 
effect is 5 msec. The expected  
probability of correctly determining a QTc prolonging effect is approximately 85% when the true 
effect is 10 msec. 
 
 The sensitivity of the probability of correctly determining a QTc prolonging effect is calculated with 
respect to different sample sizes (20, 30, 36, 46, 56) and assuming true effect as 0 msec, 5 msec, and 
10 msec.  
Sample Size Sensitivity without dropout 
True effect 
0 msec 
5 msec 
10 msec 
N 
Probability of the upper 90% limit of model-
 
20 
0 
4.3 
80.3 
30 
0 
1.8 
82.8 
36 
0 
0.6 
82.5 
46 
0 
0.4 
84.2 
56 
0 
0.1 
85.3 
 
The sensitivity of the probability of correctly determining a QTc prolonging effect is calculated with 
respect to different sample sizes (20, 30, 36, 46, 56) and assuming true effect as 0 msec, 5 msec, and 
10 msec. Additionally, it incorporates a 20% drop out at the 40 mg dose and another 25% drop out at 
the 60 mg dose (in addition to the drop out at the 40mg dose). 
 
 


Parexel International 
GlaxoSmithKline Research & Development Limited 
GSK 219882    
Statistical Analysis Plan 
 
Project Document Version No.: 1.0; Document Effective Date:  Date of Last Signature  
Confidential 
TP-GDO-WW-133-04 
 
 
Effective Date:  28 Jul 22 
Related to:  SOP-GDO-WW-019 
Page 33 of 43 
 
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001 
Sample Size Sensitivity after drop-out 
True effect 
0 msec 
5 msec 
10 msec 
N 
Probability of the upper 90% limit of model-
 
20 
0.6 
15.3 
80.5 
30 
0 
8.7 
83.3 
36 
0 
4.9 
85.1 
46 
0 
3.6 
86.1 
56 
0 
1.2 
84 
 
4.17 Changes in the Conduct of the Study or Planned Analysis 
The following changes are made in this study to the planned analysis in study protocol. 
4.17.1 Change in analysis sets defined in protocol section 9.2  Analysis sets:  
Analysis set defined in protocol 
Analysis set defined in SAP 
Rationale 
Enrolled analysis set - All 
participants who entered the study 
(who received study intervention) 
Enrolled analysis set - All 
participants who entered the 
study (who successfully 
passed screening) 
To collect the data from all 
participants who passed 
Screening 
 
 


Parexel International 
GlaxoSmithKline Research & Development Limited 
GSK 219882    
Statistical Analysis Plan 
 
Project Document Version No.: 1.0; Document Effective Date:  Date of Last Signature  
Confidential 
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Effective Date:  28 Jul 22 
Related to:  SOP-GDO-WW-019 
Page 34 of 43 
 
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001 
5 
REFERENCES 
[1] SAS® Version 9.4 of the SAS System for Personal Computers. Copyright ©2002-2003. SAS 
Institute Inc. SAS and all other SAS Institute Inc. product or service names are registered 
trademarks or trademarks of SAS Institute Inc., Cary, NC, USA. 
[2] Phoenix®WinNonlin®  Software Version 8.3. https://www.certara.com 
[3] Garnett C, Bonate PL, Dang Q, Ferber G, Huang D, Liu J, et al. Scientific white paper on 
concentration-QTc modeling. J Pharmacokinet Pharmacodyn. 2018;45(3):383 97 
 
[4] GSK Non-Compartmental Analysis of Pharmacokinetic Data (VQD-GUI-000722 (6.0)) 
[5] Koch HJ & Raschka C. Ultradian diurnal variations of QTc and relevant cardiovascular 
characteristics should be considered awith regard to risk assessment. European Heart Journal (2002) 
23, 341 342 
 
 


 
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GSK 219882    
              Statistical Analysis Plan 
 
Project Document Version No.: 1.0; Document Effective Date:  Date of Last Signature  
Confidential 
TP-GDO-WW-133-04 
 
 
Effective Date:  28 Jul 22 
Related to:  SOP-GDO-WW-019 
Page 35 of 43 
 
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001 
 
6 
APPENDICES 
6.1 
Schedule of Activities 
Figure 2 
Schedule of Activities - Overview Across Visit Days 
Procedures 
Screening Baseline 
Treatment Period and Exit Visit1 
Early 
Discontinuation 
/ Withdrawal 
Visit 
Follow-
up / End 
of Study 
Study Visit 
1 
2 
2 
3 
4 
5 
Discontinue / 
Withdrawal 
Visit 
 
6 
Study Day 
-28 to -
31 
-2 
-1 
1 
 
6 
7 
8 
13 
14 
15 20 21 
22 
 
Up to 14 
days 
after 
last dose 
Informed consent2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
criteria2 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Demography/childbearing 
status assessment 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical and treatment 
history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Brief physical 
examination including 
height and weight3 
X3 
 
 
X 
 
X 
 
 
X 
 
 
X 
 
X 
X 
Arrive in clinic evening 
before Visit day4 
 
X5 
X 
 
X 
 
 
X 
 
 
X 
 
 
 
 
Dosing in clinic6 
 
 
 
X 
 
X 
X 
 
X 
X 
 
X 
 
 
 


 
Parexel International 
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              Statistical Analysis Plan 
 
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Related to:  SOP-GDO-WW-019 
Page 36 of 43 
 
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001 
 
Procedures 
Screening Baseline 
Treatment Period and Exit Visit1 
Early 
Discontinuation 
/ Withdrawal 
Visit 
Follow-
up / End 
of Study 
Study Visit 
1 
2 
2 
3 
4 
5 
Discontinue / 
Withdrawal 
Visit 
 
6 
Study Day 
-28 to -
31 
-2 
-1 
1 
 
6 
7 
8 
13 
14 
15 20 21 
22 
 
Up to 14 
days 
after 
last dose 
Receive first of next dose 
level in clinic7 
 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
 
AE/SAE assessment8 
 
Concomitant medications 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
Vital signs9, 10 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
ECG10, 11 
X 
 
X12 
 
 
X12 
 
 
X12 
 
 
X12 
 
X12 
X12 
Paroxetine 
concentrations10, 11 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
Haematology with 
differential10 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Clinical and renal/liver 
chemistry10 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Pregnancy test, alcohol 
and drug of abuse tests10, 
13 
X 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
FSH test 14 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
COVID-19 test15 
X 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 


 
Parexel International 
GlaxoSmithKline Research & Development Limited 
GSK 219882    
              Statistical Analysis Plan 
 
Project Document Version No.: 1.0; Document Effective Date:  Date of Last Signature  
Confidential 
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Effective Date:  28 Jul 22 
Related to:  SOP-GDO-WW-019 
Page 37 of 43 
 
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001 
 
Procedures 
Screening Baseline 
Treatment Period and Exit Visit1 
Early 
Discontinuation 
/ Withdrawal 
Visit 
Follow-
up / End 
of Study 
Study Visit 
1 
2 
2 
3 
4 
5 
Discontinue / 
Withdrawal 
Visit 
 
6 
Study Day 
-28 to -
31 
-2 
-1 
1 
 
6 
7 
8 
13 
14 
15 20 21 
22 
 
Up to 14 
days 
after 
last dose 
Serology (HIV, HBV, and 
HCV) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C-SSRS 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Discharge16 
 
 
 
X 
 
 
X 
 
 
X 
 
X17 
X17 
 
 
Complete eCRF 
(ClinBase) 
 
 
X18 
X18 
 
X18 
 
 
X18 
 
 
X18 
 
X 
X 
Abbreviations: AE, adverse event; C-SSRS, Columbia suicide severity rating scale; ECG, electrocardiogram; eCRF, electronic case report form; SAE, serious adverse event. 
1. All participants will need to attend a clinic visit at Screening (Visit 1), Baseline (Visit 2, Day-1) and first 20 mg dose (Visit 2, Day 1), assessment at 20 mg steady-state 
dose (Visit 3, Day 7), first 40 mg dose (Visit 3, Day 8), assessment at 40 mg steady-state dose (Visit 4, Day 14), first 60 mg dose (Visit 4, Day 15) assessment at 60 mg 
steady-state dose and exit visit (Visit 5, Day 21) . They will also attend the clinic for the final follow-up visit (Visit 6). Participants will receive a follow-up video-call 
from the unit on all other dosing days outside of the clinic and the 3 days after last dose, and will take tablets under supervision of clinical staff over video-call.  
2. Informed consent and eligibility criteria assessment data will all be captured on site. Informed consent must be obtained prior to starting screening procedures. 
3. Height will be measured at Screening only. Complete physical examination will be performed at Screening and final Follow-Up Visit, and brief physical examination at 
all further visits. 
4. Participants will arrive at clinic in the evening (~20:00 PM) before the visit day (at Baseline [Day -1], Visit 2 [Day 6], Visit 4 [Day 13], and Visit 5 [Day 20]). 
5. Participants need to come in the evening on Day -2 and stay overnight for procedures on Day -1. 
6. On Visit 3 (Day 7), 4 (Day 14) and 5 (Day 21), the current (at that time) dose of paroxetine will be taken by the participant under supervision of staff. 
7. For Study Days 1 (Visit 2, 20 mg), Day 8 (Visit 3, 40 mg) and Day 15 (Visit 4, 60 mg), the participant will take the first dose of the next dose level (20, 40 and 60 mg 
respectively) under supervision of staff, remaining under observation for 3 hours post-dose and will be discharged afterwards. 
8. SAEs must be collected from signing of informed consent if considered related to study procedures. 


 
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Related to:  SOP-GDO-WW-019 
Page 38 of 43 
 
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001 
 
9. Vital sign measurements will include oral body temperature, systolic and diastolic blood pressure (BP), and pulse rate. Triplicate BP measurements will be performed in 
supine position at Screening only. 
10. Vitals, laboratory assessments (coagulation parameters, haematology with differential, clinical and liver chemistry, pregnancy test, and paroxetine concentrations samples) 
and ECG data will all be captured at visits on site. During the treatment period, all laboratory samples and vitals (including one paroxetine concentration sample) should 
be obtained pre-dose. 
11. All ECGs will be performed in triplicate collected within 5 min at each timepoint. ECG triplicates will be performed once at Screening (Visit 1), and at Follow-Up Visit 
and at discontinuation or withdrawal visits. At Visits 2 (Day -1), 3 (Day 7), 4 (Day 14), and 5 (Day 21) ECG triplicates will be performed 15 min pre-dose (-0.25 h) and 
post-dose at the following timepoints 1, 2, 3, 4, 4.5, 5, 5.5, 6, 8, 10, 12h. Each ECG triplicates will be combined with paroxetine concentration assessment. Paroxetine 
concentrations at Visits 3 (Day 7), 4 (Day 14), and 5 (Day 21) will be procured at the following timepoints: -0.25, 1, 2, 3, 4, 4.5, 5, 5.5, 6, 8, 10, 12 h. One sample will be 
collected for paroxetine concentrations on Day -1 at 0.25h (pre-dose). The paroxetine dose should be taken at the same clock time each time, at a time approximately 
between 07:00-010:00 (7to 10 am). When scheduled for the same time, ECGs should be performed before blood sampling to avoid impact on ECG parameters. 
12. . 
13. At Visits 2 (Day -1), 3 (Day 7), 4 (Day 14), and 5 (Day 21), follow-up visit and at discontinuation or withdrawal visits, serial ECG review will be performed by Mortara 
system. 
14. Negative urine pregnancy test result must be confirmed prior to dosing in female participants of reproductive potential. If a urine test cannot be confirmed as negative 
(e.g., an ambiguous result), a serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive.  
15. FSH test be performed for postmenopausal women only. 
16. COVID-19 testing will be performed as per site practice. 
17. Participants will be discharged from the clinic 3 hours after the morning dose on Study Days 1, 8, and 15 (Visit 2, 3, 4) to subsequently take paroxetine doses at home 
until the next Visits in clinic. 
18. Participants will get discharge on either Day 21 or Day 22 (may stay overnight) as per the convenience. 
The date and time of the administration of study intervention will be recorded in the eCRF. N.B. participants will be provided with the required tablets for dosing up to the next visit. 
Participants will take the tablet(s) under supervision when in the clinic, and under video-call supervision when outside the clinic


Parexel International 
GlaxoSmithKline Research & Development Limited 
GSK 219882    
              Statistical Analysis Plan 
 
Project Document Version No.: 1.0; Document Effective Date:  Date of Last Signature  
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Related to:  SOP-GDO-WW-019 
Page 39 of 43 
 
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001 
 
6.2 
Imputation Rules for Partial Dates 
Imputed dates and time will NOT be presented in the listings.  
Table 6-2 and Table 6-3 present algorithm for age derivation, imputing partial dates for AE, TEAE 
and prior/concomitant medication respectively.   
 
Table 6-2 Age Derivation 
Age Derivation 
Age will be calculated based on the Pre-Screening Visit date (or Screening, if pre-screening not 
performed). Only year of birth is collected on eCRF. Day and Month of birth are imputed as 30 
June. Age is derived using the date of the screening visit. Birth date will be presented in listings as 
 
 
  
Table 6-3 Handling of Partial Dates 
Element 
Reporting Detail 
General 
Partial dates will be displayed as captured in participant listing displays.  
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), or elapsed time 
variables (e.g., time since diagnosis). In addition, imputed dates are not 
used for deriving the last contact date in overall survival analysis dataset. 
Adverse Events 
Partial dates for AE recorded in the CRF will be imputed using the 
following conventions: 
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. 
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). 


Parexel International 
GlaxoSmithKline Research & Development Limited 
GSK 219882    
              Statistical Analysis Plan 
 
Project Document Version No.: 1.0; Document Effective Date:  Date of Last Signature  
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Effective Date:  28 Jul 22 
Related to:  SOP-GDO-WW-019 
Page 40 of 43 
 
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001 
 
Element 
Reporting Detail 
Missing 
end 
day and month 
No Imputation 
Completely 
missing 
start/end date 
No imputation 
 
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. 
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 
 
 
 
 


Parexel International 
GlaxoSmithKline Research & Development Limited 
GSK 219882    
              Statistical Analysis Plan 
 
Project Document Version No.: 1.0; Document Effective Date:  Date of Last Signature  
Confidential 
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Effective Date:  28 Jul 22 
Related to:  SOP-GDO-WW-019 
Page 41 of 43 
 
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001 
 
6.3 
Laboratory Test Parameters 
Laboratory Tests 
Parameters 
Hematology 
 
Platelet count 
 
Red blood cell (RBC) count 
 
RBC indices 
o Mean corpuscular volume (MCV) 
 
o %Reticulocytes 
 
WBC count with
differential: 
o Neutrophils 
 
o Lymphocytes 
 
o Monocytes 
 
o Eosinophils 
 
o Basophils 
 
Haemoglobin 
 
Haematocrit 
Clinical chemistry
 
Potassium 
 
 
Creatinine 
 
 
Sodium 
 
 
Calcium 
o Aspartate aminotransferase (AST)/serum glutamic- 
oxaloacetic transaminase (SGOT) 
 
o Alanine aminotransferase (ALT)/serum glutamic- 
pyruvic transaminase (SGPT) 
 
o ALP 
 
o Bilirubin (total, direct and indirect) 
 
o Creatinine kinase 
Coagulation tests 
 
Prothrombin time (PT), activated partial thromboplastin time (aPTT), 
international normalized ration (INR), 
Pregnancy testing 
 
Highly sensitive serum at screening and final follow-up visit and urine on 
admission human chorionic gonadotropin (hCG) pregnancy test as needed
for WOCBP 
Other screening tests  Follicle stimulating hormone and oestradiol (as needed in WONCBP only)
 Urine alcohol and drug screen to include at minimum: amphetamines, 
barbiturates, cocaine, opiates, cannabinoids and benzodiazepines, urine 
creatinine 


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GlaxoSmithKline Research & Development Limited 
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              Statistical Analysis Plan 
 
Project Document Version No.: 1.0; Document Effective Date:  Date of Last Signature  
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Related to:  SOP-GDO-WW-019 
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Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001 
 
 Serology HIV antibody and p24 antigen test, HBsAg, and HCV antibody. 
1. 
 35% direct 
 1.5 (if INR measured), which 
may indicate severe liver inju
of hepatic impairment or cirrhosis). 
2. If alkaline phosphatase is elevated, consider fractionating. 
3. Local urine testing at screening will be standard for the protocol unless serum testing at screening is required by 
local regulation or IRB/IEC. 
 
 


Parexel International 
GlaxoSmithKline Research & Development Limited 
GSK 219882    
              Statistical Analysis Plan 
 
Project Document Version No.: 1.0; Document Effective Date:  Date of Last Signature  
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Effective Date:  28 Jul 22 
Related to:  SOP-GDO-WW-019 
Page 43 of 43 
 
Developed from TP-BPM-WW-032; related to SOP-BPM-WW-001 
 
6.4 
ECG Notable Criteria  
Parameter 
Definition/threshold 
Flag for listings 
QTcF, QTcB (msec) 
 
B 
 
 
H 
 
QTc value >500 msec 
P 
 
 
I 
 
QTc increase>60 msec 
I+ 
HR (beats/min) 
HR<40 beats/min 
L 
 
HR>120 beats/min 
H 
 
HR relative change >25% 
I 
PR (msec) 
PR>220 msec 
H 
 
PR relative change >25% 
I 
QRS (msec) 
QRS relative change >25% 
I 
 
QRS>120 msec 
H 
Flagging system will be used in listings to identify values meeting thresholds, also not necessarily related to clinically 
significant events, the flags can be interpreted as follows: 
L: Low value - B: Borderline value - H: High value - P: Prolonged value 
I: Noticeable increase from baseline - I+: marked increase from baseline. 
QTc correspond to both QTcF and QTcB 
 
 


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Subject: Complete with DocuSign: GSK 219882 (PXL275921)_Statistical Analysis Plan_28Nov2023_V1.0.docx
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Document Pages: 43
Signatures: 6
Envelope Originator: 
Certificate Pages: 6
Initials: 0
AutoNav: Enabled
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Time Zone: (UTC-08:00) Pacific Time (US & Canada)
8 Federal Street
Billerica, MA  01821
IP Address:
Record Tracking
Status: Original
             12/5/2023 7:20:26 AM
Holder: 
            
Location: DocuSign
Status: Original
             12/5/2023 7:24:16 AM
Holder: Docusign EP London Project Management 
Team Shared 
             Docusign.EPLondonProject-Management@
parexel.com
Location: DocuSign
Signer Events
Signature
Timestamp
Security Level: Email, Account Authentication 
(Required)
Signature Adoption: Pre-selected Style
Signature ID: 
F76AC045-6175-4BAF-A736-C51EA3FBF504
Using IP Address: 
With Signing Authentication via DocuSign password
With Signing Reasons (on each tab): 
   I have reviewed this document
Sent: 12/5/2023 7:24:10 AM
Viewed: 12/6/2023 8:30:44 PM 
Signed: 12/7/2023 3:37:07 AM
Electronic Record and Signature Disclosure: 
      Accepted: 10/2/2023 10:37:09 PM
      ID: e5ed34aa-5196-44e4-b034-67445dda0578
Security Level: Email, Account Authentication 
(Required)
Signature Adoption: Pre-selected Style
Signature ID: 
2B2AA041-BAB0-496E-A323-C64E64D89337
Using IP Address: 
With Signing Authentication via DocuSign password
With Signing Reasons (on each tab): 
   I am the author of this document
Sent: 12/5/2023 7:24:11 AM
Viewed: 12/5/2023 8:42:27 AM 
Signed: 12/5/2023 8:44:46 AM
Electronic Record and Signature Disclosure: 
      Accepted: 12/5/2023 8:42:27 AM
      ID: 2ce350f7-bbab-4683-83b6-3d1ef62c9499
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Signer Events
Signature
Timestamp
Security Level: Email, Account Authentication 
(Required)
Signature Adoption: Pre-selected Style
Signature ID: 
297C0EA0-E4F7-4C02-B9C0-41860131E1B7
Using IP Address: 
With Signing Authentication via DocuSign password
With Signing Reasons (on each tab): 
   I approve this document
Sent: 12/5/2023 7:24:12 AM
Viewed: 12/6/2023 8:06:10 AM 
Signed: 12/6/2023 8:07:15 AM
Electronic Record and Signature Disclosure: 
      Accepted: 12/6/2023 8:06:10 AM
      ID: 8b74d965-08f3-4af0-bd64-dd0b6d2f7a49
Security Level: Email, Account Authentication 
(Required)
Signature Adoption: Pre-selected Style
Signature ID: 
64946B0D-9036-4C14-BEB6-CB97F5547617
Using IP Address: 
With Signing Authentication via DocuSign password
With Signing Reasons (on each tab): 
   I am the author of this document
Sent: 12/5/2023 7:24:12 AM
Viewed: 12/6/2023 2:08:11 AM 
Signed: 12/6/2023 2:08:37 AM
Electronic Record and Signature Disclosure: 
      Accepted: 11/29/2023 12:04:00 AM
      ID: 97b1f128-1d36-4b6b-93a0-b07f99401401
Security Level: Email, Account Authentication 
(Required)
Signature Adoption: Pre-selected Style
Signature ID: 
E66EDFC8-2E4C-437C-85DD-02380EFE5FEE
Using IP Address:
With Signing Authentication via DocuSign password
With Signing Reasons (on each tab): 
   I approve this document
Sent: 12/5/2023 7:24:13 AM
Viewed: 12/5/2023 10:31:52 AM 
Signed: 12/5/2023 10:33:17 AM
Electronic Record and Signature Disclosure: 
      Accepted: 9/13/2023 5:26:27 AM
      ID: 3844bf0d-b5cc-4bca-ab40-3aae8d4b0a1d
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Signer Events
Signature
Timestamp
Security Level: Email, Account Authentication 
(Required)
Signature Adoption: Pre-selected Style
Signature ID: 
AC5F4625-2EF9-4BD0-B1FE-22986B4022DE
Using IP Address: 
With Signing Authentication via DocuSign password
With Signing Reasons (on each tab): 
   I approve this document
Sent: 12/5/2023 7:24:14 AM
Viewed: 12/6/2023 9:16:05 AM 
Signed: 12/7/2023 1:43:46 AM
Electronic Record and Signature Disclosure: 
      Accepted: 12/6/2023 9:16:05 AM
      ID: 05d8ce1f-a531-450c-8cfe-7f28cd5bc5e8
In Person Signer Events
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Editor Delivery Events
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Notary Events
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Envelope Summary Events
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Envelope Sent
Hashed/Encrypted
12/5/2023 7:24:14 AM
Certified Delivered
Security Checked
12/6/2023 9:16:05 AM
Signing Complete
Security Checked
12/7/2023 1:43:46 AM
Completed
Security Checked
12/7/2023 3:37:07 AM
Payment Events
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Electronic Record and Signature Disclosure
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ELECTRONIC RECORD AND SIGNATURE DISCLOSURE 
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Confidentiality 
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Until or unless you notify Parexel as described above, you consent to receive exclusively 
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