Randomized, Open Label, 2-way Crossover, Single Dose Bioequivalence Study of Paroxetine IR Tablets Manufactured in GSKT and Mississauga Sites in Healthy Chinese Participants Under Fasting and Fed Conditions
Phase: PHASE1
Conditions: Anxiety Disorders
Sponsor: GlaxoSmithKline

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GlaxoSmithKline group of companies
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TITLE PAGE
Protocol Title: Randomized, open label, 2-way crossover, single dose bioequivalence 
study of Paroxetine IR tablets manufactured in GSKT and Mississauga sites in healthy 
Chinese participants under fasting and fed conditions.
Protocol Number: 207652 Amendment 1
Short Title: China Paroxetine IR Phase I Healthy Volunteer Single Dose Bioequivalence 
Study
Compound Number:
BRL29060
Sponsor Name and Legal Registered Address: 
GlaxoSmithKline (China) Investment Co., LTD. 
9/F Tower A, Ocean International Centre
Mid 4thEast Ring Rd, Chaoyang District 
Beijing, 200025, China
Medical Monitor Name and Contact Information: will be provided in separately
Regulatory Agency Identifying Number(s): Not Applicable
Approval Date: 20-JUL-2018
Copyright 2018 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited.
 
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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
DOCUMENT HISTORY
List dates of original protocol and all amendments in reverse chronological order.
Document
Date
DNG Number
Amendment 1
20-Jul-2018
2017N312753_01
Original Protocol
01-Jun-2017
2017N312753_00
Amendment 1 20-JUL-2018
Overall Rationale for the Amendment: Sponsor change.
Section # and Name
Description of Change
Brief Rationale
Title page
Sponsor change
Sponsor change
9.4.2 Vital Signs
Add time window for blood 
pressure and pulse rate 
assessing
To have better instruction 
for procedures
10.3.3 Safety Analyses
Change data standard 
description from IDSL to 
CDISC.
Data collection strategy 
changed
Through out
Minor editorial and 
document formatting 
revision
Minor, to make the protocol 
to be consistent
 
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TABLE OF CONTENTS
PAGE
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE.....................................3
1.
SYNOPSIS...............................................................................................................6
2.
SCHEDULE OF ACTIVITIES (SOA).........................................................................9
3.
INTRODUCTION....................................................................................................11
3.1.
Study Rationale ..........................................................................................11
3.2.
Background ................................................................................................11
3.3.
Benefit/Risk Assessment ............................................................................12
3.3.1.
Risk Assessment .........................................................................13
3.3.2.
Benefit Assessment.....................................................................16
3.3.3.
Overall Benefit: Risk Conclusion..................................................16
4.
OBJECTIVES AND ENDPOINTS...........................................................................16
5.
STUDY DESIGN ....................................................................................................17
5.1.
Overall Design ............................................................................................17
5.2.
Number of Participants ...............................................................................18
5.3.
Scientific Rationale for Study Design ..........................................................18
5.4.
Dose Justification........................................................................................19
6.
STUDY POPULATION...........................................................................................19
6.1.
Inclusion Criteria.........................................................................................19
6.2.
Exclusion Criteria........................................................................................20
6.3.
Lifestyle Restrictions...................................................................................22
6.3.1.
Meals and Dietary Restrictions ....................................................22
6.3.2.
Caffeine, Alcohol, and Tobacco ...................................................22
6.3.3.
Activity .........................................................................................22
6.4.
Screen Failures...........................................................................................22
7.
TREATMENTS.......................................................................................................23
7.1.
Treatments Administered............................................................................23
7.2.
Dose Modification .......................................................................................23
7.3.
Method of Treatment Assignment ...............................................................23
7.4.
Blinding.......................................................................................................23
7.5.
Preparation/Handling/Storage/Accountability..............................................24
7.6.
Treatment Compliance................................................................................24
7.7.
Concomitant Therapy..................................................................................24
7.8.
Treatment after the End of the Study ..........................................................25
8.
DISCONTINUATION CRITERIA.............................................................................25
8.1.
Discontinuation of Study Treatment ............................................................25
8.1.1.
Liver Chemistry Stopping Criteria ................................................25
8.1.2.
QTc Stopping Criteria ..................................................................25
8.2.
Withdrawal from the Study..........................................................................26
8.3.
Lost to Follow Up........................................................................................27
9.
STUDY ASSESSMENTS AND PROCEDURES .....................................................27
 
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9.1.
Efficacy Assessments.................................................................................28
9.2.
Adverse Events...........................................................................................28
9.2.1.
Time Period and Frequency for Collecting AE and SAE 
Information...................................................................................28
9.2.2.
Method of Detecting AEs and SAEs.............................................28
9.2.3.
Follow-up of AEs and SAEs.........................................................29
9.2.4.
Regulatory Reporting Requirements for SAEs .............................29
9.2.5.
Pregnancy ...................................................................................29
9.3.
Treatment of Overdose...............................................................................29
9.4.
Safety Assessments ...................................................................................30
9.4.1.
Physical Examinations.................................................................30
9.4.2.
Vital Signs....................................................................................30
9.4.3.
Electrocardiograms......................................................................31
9.4.4.
Clinical Safety Laboratory Assessments ......................................31
9.4.5.
Suicidal Risk Monitoring...............................................................31
9.5.
Pharmacokinetics .......................................................................................32
10. STATISTICAL CONSIDERATIONS........................................................................33
10.1.
Sample Size Determination ........................................................................33
10.1.1.
Sample Size Assumptions ...........................................................33
10.1.2.
Sample Size Sensitivity................................................................33
10.2.
Populations for Analyses ............................................................................34
10.3.
Statistical Analyses.....................................................................................35
10.3.1.
Efficacy Analyses.........................................................................35
10.3.2.
Pharmacokinetic Analyses...........................................................35
10.3.3.
Safety Analyses...........................................................................35
11. REFERENCES.......................................................................................................37
12. APPENDICES........................................................................................................38
12.1.
Appendix 1: Abbreviations and Trademarks................................................38
12.2.
Appendix 2: Contraceptive Guidance and Collection of Pregnancy 
Information..................................................................................................40
12.3.
Appendix 3: Liver Safety: Required Actions and Follow-up 
Assessments ..............................................................................................44
12.4.
Appendix 4: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting .......................................46
12.5.
Appendix 5: Clinical Laboratory Tests.........................................................51
12.6.
Appendix 6: Summary of Blood Sampling...................................................52
12.7.
Appendix 7: Study Governance Considerations..........................................53
12.8.
Appendix 8: Protocol Amendment History...................................................57
 
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1.
SYNOPSIS
Protocol Title: Randomized, open label, 2-way crossover, single dose bioequivalence 
study of Paroxetine IR tablets manufactured in GSKT and Mississauga sites in healthy 
Chinese participants under fasting and fed conditions.
Short Title: China Paroxetine IR Phase I Healthy Volunteer Single Dose Bioequivalence 
Study
Rationale:
China Food and Drug Administration (CFDA, 2016) has published [Article #106]  on 
May 25,2016--- the Relevant Matters for Facilitating the Opinions of the General Office 
of the State Council on Conducting Consistency Evaluation for the Quality and Efficacy 
of Generic Drugs, with a list of 289 products on Essential Drug List Quality consistency
evaluation to be completed before the end of 2018. Seroxat IR tablet as localized 
originator drugs is included in the list.
Paroxetine, as a selective serotonin reuptake inhibitor (SSRI), is registered for use in 
China since 1995. Paroxetine immediate release (IR) formulation was approved for the 
treatment of Major Depressive Disorder in 1995 based on a randomized, double blind, 
amitriptyline controlled study . In 1998, Paroxetine IR (Seroxat IR) was approved for the 
treatment of three anxiety indications in China: Panic Disorder, Obsessive-Compulsive 
Disorder and Social Anxiety Disorder. Panic Disorder was approved based on a 
randomized, double blind, clomipramine controlled, in-parallel study, while Obsessive-
Compulsive Disorder  was approved based on a randomized, double blind, clomipramine
controlled , in-parallel study. Both studies were conducted in Chinese subjects. Social 
Anxiety Disorder was approved by clinical trial waiver.
The licence of Seroxat IR in China is owned by TSKF(Tianjin SmithKline & French) 
and toll manufacture is GSKT (Glaxo SmithKline Tianjin). To meet the requirement of 
quality consistency evaluation, we approached to claim GSKT product as reference 
standard and waive bioequivalence (BE) study but failed, as GSKT product is WG(wet 
granulation) formulation, while GSK reference product manufactured by Missisauga is
DC(direct compression) formulation. GSKT will do manufacture technical transfer from 
WG to DC. After the technical transfer successfully completed, we will conduct a BE 
study between GSKT investigational DC products and Mississauga reference DC 
products to support the quality consistency evaluation.
Objectives and Endpoints:
Objectives
Endpoints
Primary

To evaluate the bioequivalence of 
paroxetine IR tablets manufactured in 
GSKT and Mississauga sites in healthy 
Chinese participants under fasting and 
fed conditions.

AUC(0-), AUC(0-t) and Cmax of
paroxetine IR tablets
 
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Objectives
Endpoints
Secondary

To assess the safety and tolerability of 
dosing with paroxetine IR tablets in
healthy Chinese participants.

To obtain the pharmacokinetic profile 
of paroxetine IR tablets in healthy 
Chinese participants.

Safety and tolerability as measured by 
adverse events, vital signs, ECG and 
clinical laboratory measurements.

Tmax, λz, and t1/2 of paroxetine IR as 
data permit.
Overall Design:
This is a single dose, open-label, randomized, two-way crossover study to demonstrate
the bioequivalence of paroxetine IR tablets manufactured in GSKT(A)
and 
Mississauga(B) sites in healthy Chinese participants under fasting and fed conditions.
This study includes a screening period (up to 7 days) and an open-label treatment period.
Participants will be followed 7 to14 days after last dosing.
From Day -7 to Day -1
After obtaining the Informed Consent Form signed by the participants, they will be 
verified against the inclusion and exclusion criteria to confirm his/her eligibility to 
participate in the study.
From Day 0 to Day 16
On Day 0, participants will be admitted into the study ward to complete vital signs, 
physical examination; eligibility for enrolment will be confirmed; and the participant’s 
concomitant therapies and adverse reactions will also be collected and recorded.
On Day 1, each enrolled participant will take a single dose of paroxetine IR 40mg A or B
(20mg *2 tablets). Blood samples will be collected at a set of timepoints pre- and post-
dosing from Day1 to Day 5 for determination of single-dose pharmacokinetics of 
paroxetine A or B.
Following a washout from Day 6 to Day 11, participants will be crossed over in Period 2 
to receive the treatment that they did not receive in Period 1.  They will be admitted into 
the study ward to complete physical examination and confirm eligibility again on Day 11. 
Eligible participants will take paroxetine IR 40mg A or B (20mg*2 tablets) once on Day 
12, and blood samples will be collected at a set of timepoints pre and post dosing from 
Day12 to Day 16.
Safety data collection includes physical examinations, laboratory tests, electrocardiogram 
(ECG), vital signs measurements and recording of adverse events. Other clinical 
assessments will also be performed as appropriate.
Participants will complete follow-up 7 to 14 days after last dosing, and complete 
monitoring of any adverse events.
 
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Number of Participants:
A sufficient number of healthy participants (approximately 36 for Fasting group and 44 
for Fed group) will be enrolled so that approximately 32 participants in Fasting group and 
40 participants in Fed group complete the study.  
Treatment Groups and Duration:
The whole study will be divided into two groups, one for fasting condition and another 
for fed condition. For each group, eligible participants will be randomized to either AB or 
BA treatment sequence according to 1:1 ratio. 
Refer to the schematics for the study.
 
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2.
SCHEDULE OF ACTIVITIES (SOA)
Screening
First Period
Wash out
Study day
Up to 7 days
D0
D1
D2
D3
D4
D5
D6-10
Visit
V1
V2
V3
V4
V5
V6
V7
Administration

Standard Meal (fed group)

Sampling
(hour after dosing)
Pre, 0.5, 1, 2,3, 4, 5, 6, 7, 8, 10, 12, 16
24,36
48
72
96
Informed consent

Inclusion/exclusion criteria


Demographics and medical history1

C-SSRS2

Weight/Height


Physical examination


Vital signs3







12-lead ECG

Laboratory tests 5

Pregnancy test (WOCBP)4

Alcohol and drug screen

HIV, Hep B, Hep C, Syphilis

Concomitant medication 
AE
SAE
 
 
 
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Second Period
Early Withdraw
Follow up6
Study day
D11
D12
D13
D14 D15
D16
7-14 days after last dose
Visit
V8
V9
V10
V11 V12
V13
V14
V15
Administration

Standard Meal (fed group)

Sampling
(hour after dosing)
Pre, ,0.5, 1, 2,3, 4, 5, 6, 7, 8, 10, 12, 
16
24,36 48
72
96
Inclusion/exclusion criteria

C-SSRS2


Weight/Height


Physical examination



R
Vital signs3







R
12-lead ECG


R
Laboratory tests 5


R
Pregnancy test (WOCBP)4



Concomitant medication 
AE
SAE
Key: × = Mandatory Assessment; R =Repeated in case of abnormal results from the last visit.
1.
Medical history: Medical and medication history and Alcohol/Smoking history
2.
C-SSRS: Screening visit use ‘baseline’ version. The following visit use ‘since last visit’ version.
3.
Temperature, pulse rate, respiratory rate, and blood pressure will be assessed at screening, when admit to unit (Day 0 and Day 11) and as clinically indicated. Blood pressure and 
pulse rate will be measured  pre-dosing and at 2h post-dosing on Day 1 and Day 12; on the Day 2(24h), 3, 4, 5, 13(24h), 14, 15, 16; or early withdraw.
4.
WOCBP=Woman of Childbearing Potential. Pregnancy test: either urine or serum test is valid.
5.
Clinical laboratory tests including haematology, clinical chemistry and routine urinalysis. Refer to Appendix 5 for more details.
6.
The participant will complete follow-up 7-14 days after last dose of medication. The follow-up can be visited by telephone if the participant does not need to receive any 
examination.
 
 
 
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3.
INTRODUCTION
3.1.
Study Rationale
China Food and Drug Administration (CFDA, 2016) has published [Article #106]  on 
May 25,2016--- the Relevant Matters for Facilitating the Opinions of the General Office 
of the State Council on Conducting Consistency Evaluation for the Quality and Efficacy 
of Generic Drugs (http://www.sfda.gov.cn/WS01/CL0087/154042.html), with a list of 
289 products on Essential Drug List Quality consistency evaluation to be completed 
before the end of 2018. Seroxat IR tablet as localized originator drugs is included in the 
list.
Paroxetine, as a selective serotonin reuptake inhibitor (SSRI), is registered for use in 
China since 1995. Paroxetine immediate release (IR) formulation was approved for the 
treatment of Major Depressive Disorder in 1995 based on a randomized, double blind, 
amitriptyline controlled study [Tian, 1996]. In 1998, Paroxetine IR was approved for the 
treatment of  three anxiety indications in China: Panic Disorder, Obsessive-Compulsive 
Disorder and Social Anxiety Disorder. Panic Disorder was approved based on a 
randomized, double blind, clomipramine controlled, in-parallel study [Zhang, 2000] , 
while Obsessive-Compulsive Disorder  was approved based on a randomized, double 
blind, clomipramine controlled, in-parallel study [Wu, 2004]. Both studies were 
conducted in Chinese subjects. Social Anxiety Disorder was approved by clinical trial 
waiver.
The licence of Seroxat IR in China is owned by TSKF(Tianjin SmithKline & French) and 
toll manufacture is GSKT (Glaxo SmithKline Tianjin). To meet the requirement of 
quality consistency evaluation, we approached to claim GSKT product as reference 
standard and waive bioequivalence (BE) study but failed, as GSKT product is WG(wet 
granulation) formulation, while GSK reference product manufactured by Missisauga is
DC(direct compression) formulation. GSKT will do manufacture technical transfer from 
WG to DC. After the technical transfer successfully completed, we will conduct a BE 
study between GSKT investigational DC products and Mississauga reference DC 
products to support the quality consistency evaluation.
3.2.
Background
Paroxetine, a phenylpiperidine compound, is a potent and SSRI. Paroxetine IR 
formulation has been approved in numerous countries for the treatment of depression, 
panic disorder, social anxiety disorder, obsessive compulsive disorder, generalised 
anxiety disorder and post-traumatic stress disorder. Paroxetine can be used for 
maintaining therapy with once daily dosing, with little accumulation of drug over the 
long-term. Thereby, paroxetine also reduces the maximal duration of unwanted 
pharmacological effects that are observed with all SSRIs.
Paroxetine is administered as the hydrochloride salt. All doses stated are equivalent to the 
concentration of paroxetine free base. Comparing oral versus intravenous administration 
of paroxetine, the terminal phase half-life (t1/2) of paroxetine from intravenous injection 
averaged 13.8 hours (range 6.9-37.1; n = 9). Plasma half-lives were longer after oral 
 
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compared to intravenous injection. This dose-route dependency and pharmacokinetic 
non-linearity precludes an estimate of absolute bioavailability. An early study suggested 
that paroxetine available to the systemic circulation is approximately 50%. The effects of 
food on the bioavailability of paroxetine were studied in participants administered a 
single dose with and without food. AUC was only slightly increased (6%) when drug was 
administered with food but the Cmax was 29% greater, while the time to reach peak 
plasma concentration decreased from 6.4 hours post-dosing to 4.9 hours.
Paroxetine is extensively metabolized after oral administration. The principal metabolites 
are polar and conjugated products of oxidation and methylation, which are readily cleared. 
Conjugates with glucuronic acid and sulfate are found predominate, and major 
metabolites have been isolated and identified. Data indicate that the metabolites have no 
more than 1/50 the potency of the parent compound at inhibiting serotonin uptake. The 
metabolism of paroxetine is accomplished in part by Cytochrome P450 2D6. Saturation 
of this enzyme at clinical doses appears to account for the nonlinearity of paroxetine 
kinetics with increasing dose and increasing duration of treatment. Therefore 
pharmacokinetic parameters of paroxetine are not constant resulting in non-linear kinetics. 
Large inter-individual variability in Cmax, t1/2, and AUC was established in studies. 
However, the non-linearity in kinetics is generally small and is confined to those 
participants who achieve low plasma levels at low doses. 
Although the overall safety of paroxetine IR has been well established in numerous
clinical trials, it can produce side effects which can be a discomfort to the patient and
may result in termination of treatment. Data from paroxetine IR clinical trials in major
depression show that nausea is the most frequently reported adverse event associated with 
discontinuation of therapy. Although usually transient and mild, nausea may ultimately 
compromise the patient's recovery by causing noncompliance or treatment 
discontinuation. 
Trials of patients with major depressive disorder (MDD), panic disorder (PD), social 
anxiety disorder (SAD), and obsessive compulsive disorder (OCD) have shown
paroxetine to be of clinical benefit. Therefore, paroxetine has been shown to be a
valuable agent for the treatment of these disorders. A detailed description of the 
chemistry, pharmacology, efficacy, and safety of paroxetine is provided in the 
Investigator’s Brochure/package insert.
3.3.
Benefit/Risk Assessment
More detailed information about the known and expected benefits and risks and 
reasonably expected adverse events of Paroxetine IR may be found in the Paroxetine IR 
Prescription information, Investigator’s Brochure and Periodic Benefit Risk Evaluation
Report.
 
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3.3.1.
Risk Assessment
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Investigational Product (IP) [BRL 29060]
Serotonin syndrome/Neuroleptic 
malignant syndrome-like events
Overstimulation of the serotonergic system can lead to 
serotonin syndrome. This is most likely to occur
through the combined use of various serotonergic 
drugs.
Source: Spontaneous data and evidence from 
published medical literature provide evidence of 
paroxetine induced serotonin syndrome.
Warning patients to be alert for symptoms,
Warning prescribers of risk in patients in whom 
paroxetine is coadministered with other 
serotonergic drugs and recommending prompt
discontinuation of paroxetine should symptoms 
develop. Paroxetine is contraindicated with 
monoamine oxidase inhibitors (MAOIs) due 
to this risk.
Bone Fracture
Serotonin receptors are found in all major types of 
bone cell (osteoblasts, osteocytes, and osteoclasts), 
indicating an important role of the neuroendocrine 
system in bone.
Source: Epidemiological studies on bone fracture risk 
following exposure to some antidepressants, including 
SSRIs, have reported an association with fractures.
Warning prescribers of risk which is greatest in 
the early stages of therapy.
Hyponatraemia
It has been suggested that SSRI-induced syndrome of 
inappropriate antidiuretic hormone secretion (SIADH)
is multifactorial and there are three potential 
mechanism involving antidiuretic hormone (ADH): an
increase in the secretion of ADH centrally, 
augmentation of the effect of ADH in the renal medulla 
and a resetting of the osmostat that lowers the 
threshold for secretion.
Source: Paroxetine clinical studies, scientific and 
medical literature, spontaneous case reports.
Warning prescribers of risk (in particular elderly 
patients) for the development of SIADH and/or 
hyponatraemia.
 
 
 
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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Bleeding disorders, predominantly of the 
skin and mucous membranes
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.
Source: Clinical study data, medical literature and 
spontaneous case reports provide evidence of 
paroxetine induced bleeding.
The risk of bleeding related adverse events may 
be minimised by observing caution when using 
paroxetine in patients concomitantly using
medications that may increase the risk for 
bleeding and in those patients with a known 
tendency for bleeding or those with predisposing 
conditions.
Glaucoma
The serotonin receptors that have been found to be 
involved in eye functioning are 5-HT1A, 5-HT2A, 5-
HT2C and 5-HT7 and there are a number of potential 
mechanisms, by which paroxetine may induce 
glaucoma in certain patients.
Source: Medical literature and spontaneous data 
provide evidence of paroxetine induced acute 
glaucoma.
Observing caution in patients with narrow angle 
glaucoma.
Interaction with CYP2D6 substrates
As with other antidepressants, including other SSRIs,
paroxetine inhibits the hepatic cytochrome P450 
enzyme CYP2D6.
Source: Clinical pharmacology/pharmacokinetic 
studies / In vitro assays / Literature.
Warning prescribers of risk of taking paroxetine 
with other medications and the need to exercise 
caution when prescribing paroxetine to patients 
already receiving known substrates or vice 
versa.
Akathisia
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-
Warning prescribers of risk, informing patients 
regarding signs/symptoms to be aware of.
 
 
 
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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
HT)2A receptors, which results in inhibition of 
dopamine release.
Source: Medical literature and spontaneous case 
reports provide evidence of SSRI induced akathisia.
Symptoms seen on discontinuation of 
paroxetine
Although there are several hypotheses the exact 
mechanism of antidepressant discontinuation 
syndrome remains unknown.
Source: Clinical studies, medical literature and 
spontaneous case reports provide evidence of 
discontinuation related adverse events.
Informing patients regarding signs / symptoms to 
be aware of. Advice to prescribers to gradually 
taper paroxetine when discontinuing treatment.
 
 
 
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3.3.2.
Benefit Assessment
MAJOR DEPRESSIVE DISORDER
Paroxetine is indicated for MDD, including reactive and severe depression and MDD
accompanied by anxiety. In the treatment of depressive disorders, paroxetine exhibits
comparable efficacy to standard (e.g., tricyclic) antidepressants. Results of studies in 
which patients received paroxetine treatment for up to one year indicate that paroxetine is 
effective in preventing the relapse and also recurrence of depressive symptoms.
OBSESSIVE COMPULSIVE DISORDER
Paroxetine has been shown to be effective in the treatment of OCD. In a placebo-
controlled trial, the efficacy of paroxetine in the treatment of OCD has been maintained 
for at least 1 year. Paroxetine was also effective in preventing the relapse of OCD.
PANIC DISORDER
Paroxetine has been shown to be effective in the treatment of PD with and without 
agoraphobia. The combination of paroxetine and cognitive-behavioural therapy has been 
shown to be significantly more effective than cognitive-behavioural therapy alone in the 
treatment of PD.
In a placebo-controlled trial, the efficacy of paroxetine in the treatment of PD has been 
maintained for up to 1 year. Paroxetine has also been shown to be effective in the 
prevention of relapse of PD.
SOCIAL ANXIETY DISORDER/SOCIAL PHOBIA
Paroxetine has been shown to be effective in the treatment of SAD/Social Phobia. The 
maintained efficacy of paroxetine in the long term treatment of SAD/Social Phobia has 
been demonstrated in a Relapse Prevention Study.
3.3.3.
Overall Benefit: Risk Conclusion
Paroxetine has a well-characterised safety profile supported by over 20 years on the
market globally, across a number of indications, and with a large cumulative post-
marketing exposure.
The benefit/risk profile of paroxetine remains favourable, therefore the Sponsor considers 
that investigation of Paroxetine IR is justified in study 207652.
4.
OBJECTIVES AND ENDPOINTS
Objectives
Endpoints
Primary

To evaluate the bioequivalence of 
paroxetine IR tablets manufactured in 
GSKT and Mississauga sites in healthy 
Chinese participants under fasting and 
fed conditions.

AUC(0-), AUC(0-t) and Cmax of
paroxetine IR tablets
 
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Objectives
Endpoints
Secondary

To assess the safety and tolerability of 
dosing with paroxetine IR tablets in 
healthy Chinese participants.

To obtain the pharmacokinetic profile 
of with paroxetine IR tablets in healthy 
Chinese participants.

Safety and tolerability as measured by 
adverse events, vital signs, ECG and 
clinical laboratory measurements.

Tmax, λz, and t1/2 of paroxetine IR as 
data permit.
5.
STUDY DESIGN
5.1.
Overall Design
This is a single dose, open-label, randomized, two-period crossover study to demonstrate
the bioequivalence of paroxetine IR tablets Manufactured in GSKT (A) and Mississauga
(B) sites in healthy Chinese participants under fasting and fed conditions. This study 
includes a screening period (up to 7 days) and two open-label treatment periods.
Participants will be followed up 7 to 14 days after last dosing.
The whole study will be divided into two groups, one for fasting condition and another 
for fed condition. For each group, eligible participants will be randomized to either AB or 
BA treatment sequence according to 1:1 ratio.
From Day -7 to Day -1
After obtaining the Informed Consent Form signed by the participants, they will be 
verified against the inclusion and exclusion criteria to confirm his/her eligibility to 
participate in the study.
From Day 0 to Day 16
On Day 0, participants will be admitted into the study ward to complete vital signs, 
physical examination; eligibility for enrolment will be confirmed; and the participant’s 
concomitant therapies and adverse reactions will also be collected and recorded.
On Day 1, each enrolled participant will take a single dose of paroxetine IR 40mg 
(20mg*2 tablets) A or B once. Blood samples will be collected at a set of timepoints
(refer to SoA) pre and post dosing from Day1 to Day 5 for determination of single-dose 
pharmacokinetics of paroxetine A or B.
Following a washout from Day 6 to Day 11, participants will be crossed over in Period 2 
to receive the treatment that they did not receive in Period 1.  They will be admitted into 
the study ward to complete physical examination and confirm eligibility again on Day 11. 
Eligible participants will take paroxetine IR 40mg (20mg*2 tablets) A or B once on Day 
12 and blood samples will be collected at a set of timepoints (refer to SoA) pre and post 
dosing from Day12 to Day 16.
 
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Safety data collection includes physical examinations, laboratory tests, electrocardiogram
(ECG), vital signs measurements and recording of adverse events. Other clinical 
assessments will also be performed as appropriate.
Participants will complete follow-up 7 to 14 days after last dosing, and complete 
monitoring of any adverse events.
Figure 1
Study Schematics
5.2.
Number of Participants
A sufficient number of healthy participants (approximately 36 for Fasting group and 44 
for Fed group) will be enrolled so that approximately 32 participants in Fasting group and 
40 participants in Fed group complete the study.  Either gender of evaluable participants
should be no less than one-third of the total evaluable participants. Participant and Study 
Completion
A completed participant is one who has completed all phases of the study including the 
follow-up visit.
The end of the study is defined as the last participant’s last visit.
5.3.
Scientific Rationale for Study Design
This is a single dose, open-label, randomized, two-period crossover study in healthy 
Chinese participants to demonstrate the bioequivalence of 40mg paroxetine IR (20mg *2 
tablets) made by GSKT (investigational drug, DC formulation) and Mississauga 
(reference drug, DC formulation) under fasting and fed conditions. 
Both the investigational and the reference drugs are provided by GlaxoSmithKline
(GSK). A two-period cross-over design was selected for this study so that within 
participant comparisons can be utilized and the number of participants required for the 
study can be reduced. Both fasting and fed BE studies are designed according to the 
China bioequivalence guideline. The Pharmacokinetic (PK) sampling and washout period 
 
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are designed to ensure that PK parameters are well-estimated and pre-dose concentrations 
are completely negligible in Period 2.
Sampling time points were decided based on the pharmacokinetic parameters of DC
formulation in past successful global BE studies under both fasting and fed conditions 
and the CFDA bioequivalence study guideline. The last sampling time point was selected 
as 96 hours considering the elimination half-life of around 16 hours. 
5.4.
Dose Justification
Paroxetine IR has been approved in China for the treatment of MDD, PD, OCD and SAD.
In the clinic, Chinese patients receive flexible Paroxetine IR doses that are the same as 
the doses approved in the US, starting from 10 mg/day up to 50-60 mg/day. Nonlinearity 
of paroxetine kinetics has been observed in the past clinical pharmacology studies. From 
the “Product-Specific Guidances for Generic Drug Development”, bioequivalence study 
at 40 mg dose level (both fasting and fed conditions) was suggested for paroxetine IR, 
(https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Gui
dances/ucm089264.pdf). Since the highest strength of GSK paroxetine IR approved in 
China is 20 mg, in the current study, 2*20 mg paroxetine IR will be compared to evaluate 
the bioequivalence of paroxetine IR manufactured between two sites.
The effects of food on the bioavailability of paroxetine were studied in participants 
administered a single dose with and without food. AUC was only slightly increased (6%) 
when drug was administered with food but the Cmax was 29% greater, while the time to 
reach peak plasma concentration decreased from 6.4 hours post-dosing to 4.9 hours. 
Paroxetine IR should be administered as a single daily dose with or without food under 
the same dose level. Thus the same dose levels are used for fasting and fed cohorts.
6.
STUDY POPULATION
Prospective approval of protocol deviations to recruitment and enrolment criteria, also 
known as protocol waivers or exemptions, is not permitted.
6.1.
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria 
apply:
1.
Able to actively communicate with the investigator and to complete the study-related 
documents; able to understand the contents of the Informed consent form (ICF) and 
to sign a written ICF prior to any study-specific procedures.
2.
Males and females aged between 18 and 45 years inclusive, at the time of signing the 
informed consent.
3.
Non-smoking healthy males and females as assessed by medical history and physical 
examination. Healthy as determined by a responsible and 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 which are not specifically listed in the inclusion or exclusion 
 
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criteria, outside the reference range for the population being studied may be included 
only if the Investigator (in consultation with the GSK Medical Monitor if necessary)
agree and document that the finding is unlikely to introduce additional risk factors 
and will not interfere with the study procedures.
4.
Body weight≥50kg(male) or 45kg(female) and Body mass index (BMI) 19.0 to 26.0 
kg/m2 (inclusive).
5.
A female participant is eligible to participate if she is of:

Child-bearing potential with negative pregnancy test as determined by serum 
or urine human chorionic gonadotropin (hCG) test at screening or prior to 
dosing AND

Agrees to use one of the contraception methods listed in Appendix 2 during 
the study and until follow up contact.
6.
Male participants with female partners of child-bearing potential must agree to use 
one of the contraception methods listed in Appendix 2 during the study and until 
follow up contact.
7.
Alanine aminotransferase (ALT), Alkaline phosphatase (ALP) and total bilirubin 
1.5x upper limit of normal (ULN) (isolated bilirubin >1.5x ULN is acceptable if 
bilirubin is fractionated and direct bilirubin <35%). 
8.
Based on single or averaged QTc values of triplicate ECGs obtained over a brief 
recording period:

QTc < 450 msec; or

QTc < 480 msec in participants with bundlebranch block.
6.2.
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1.
Current or chronic history of liver disease, or known hepatic or biliary abnormalities 
(with the exception of Gilbert's syndrome or asymptomatic gallstones).
2.
Drug or alcohol abuse or dependency within one year prior to enrolment. History of 
regular alcohol consumption within one year of the study defined as: an average 
weekly intake of >14 drinks. One drink is equivalent to 12 g of alcohol: 12 ounces 
(360 ml) of beer, 5 ounces (150 ml) of wine or 1.5 ounces (45 ml) of 80 proof 
distilled spirits.
3.
Unstable disease conditions; any laboratory measurements assessed by the 
investigator as clinically relevant (including ECG, haematology, biochemistry and 
urine analysis, etc.) ；any disorder that might interfere with the absorption, 
distribution, metabolism or excretion of the study drug; or in the investigator’s 
opinion the disease may lead to safety concerns or interfere with the 
pharmacokinetics assessment.
 
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4.
Participants with concurrent or previous neuropsychological disorders, as assessed 
by Columbia Suicide Severity Rating Scale or by the investigator, have suicidal 
tendency, or have committed suicidal behavior/attempt. 
5.
Known history of cerebral trauma, previous cerebral disorders, seizures or eating 
disorder, and other conditions that in the investigator’s opinion may increase the risk 
of seizures.
Prior/Concomitant Therapy
6.
Exposure to more than four new chemical entities within 12 months prior to the first 
dosing day.
7.
Unable to refrain from the use of prescription or non-prescription drugs, including 
vitamins, herbal and dietary supplements (including St John’s Wort) within 14 days 
or 5 half-lives (whichever is longer) prior to the first dose of study medication.
8.
In subjects with concomitant use of MAOIs (including linezolid, an antibiotic which 
is a reversible non-selective MAOIs and methylthioninium chloride (methylene 
blue)) or within two weeks of terminating treatment with MAOIs. 
9.
In participants with concomitant use of thioridazine or pimozide.
Prior/Concurrent Clinical Study Experience
10. The participant has participated in a clinical trial and has received an investigational 
product within 90 days prior to the first dosing day in the current study, or has 
participated in a clinical trial without receiving any investigational product within 30 
days prior to the first dosing day in the current study.
Diagnostic assessments
11. A positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody 
result within 3 months.
12. Serum HIV antibody or Syphilis antibody positive.
13. A positive pre-study drug/alcohol screen.
Other Exclusions
14. Known allergy to paroxetine IR Tablets or any of its components.
15. Blood donation in excess of 400 mL in the 3 months prior to enrolment.
16. Obvious evidence of active haematological diseases, or significant blood loss in the 
last 3 months. History of sensitivity to heparin or heparin-induced thrombocytopenia.
17. Lactating females or women of child bearing potential used oral or implanted 
contraceptives within the 30 days prior to enrolment, or received injections of 
chronically acting contraceptives in the 1 year prior to study initiation.
18. Other conditions which, in the Investigator’s judgment, render participants
unsuitable for the clinical study. 
 
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6.3.
Lifestyle Restrictions
6.3.1.
Meals and Dietary Restrictions

In fasting group, the participants should be on fasting overnight for 10 hours prior to 
Day 1 and Day 12 administration. No food can be taken until 4 hours post dose. 
In fed group, the participants should be on fasting overnight for 10 hours prior to 
Day 1 and Day 12, and eat standard breakfast within 30 minutes on Day 1 and Day 
12. The dose should be administered at 30 minutes after the start of the breakfast.

No liquids other than water for drug intake should be taken in the 1 hour pre-dose 
and the 2 hours post-dose. 

Refrain from consumption of red wine, juice, grape fruit, barbecue or cruciferous 
vegetables (broccoli, cauliflower) from 7 days prior to the first dose of study 
medication until collection of the final pharmacokinetic samples.

Unless permitted by the sponsor, any prescription or over the counter (OTC) is 
prohibited during the study.
6.3.2.
Caffeine, Alcohol, and Tobacco

During each dosing session, participants will abstain from ingesting caffeine- or 
xanthine-containing products (e.g. coffee, tea, cola drinks, and chocolate) for 48
hours prior to the start of dosing until collection of the final pharmacokinetic 
samples. 

During each dosing session, participants will abstain from alcohol for 48 hours prior 
to the start of dosing until collection of the final pharmacokinetic samples. 

Participants are non-smokers and will be instructed that use of nicotine-containing 
products (including nicotine patches) will not be permitted for 48 hours prior to the 
start of dosing until collection of the final pharmacokinetic samples.
6.3.3.
Activity
Participants will abstain from strenuous exercises for 48 hours prior to each blood 
collection occasion for clinical laboratory tests. Participants may participate in light 
recreational activities during studies (e.g., watch television, read). Ultraviolet radiation, 
e.g., sun bath, is prohibited during the study.
Participants will be admitted to the study ward in the nights before PK assessments. The 
participants may leave the study ward, if judged as appropriate by the investigator, after 
certain times for PK sampling, but will need to return to the study ward for other 
scheduled times to complete PK blood sampling and adverse event assessments.
6.4.
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study 
but are not subsequently randomized. A minimal set of screen failure information is 
required to ensure transparent reporting of screen failure participants to meet the 
 
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Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes 
demography, screen failure details, eligibility criteria, and any serious adverse events 
(SAEs).
7.
TREATMENTS
Study treatment is defined as any investigational treatment(s), investigational drug(s), 
reference drug(s), marketed product(s), placebo, or medical device(s) intended to be 
administered to a study participant according to the study protocol.
7.1.
Treatments Administered
Study Drug Name:
Paroxetine IR tablets A
(Investigational drug)
Paroxetine IR tablets B
(Reference drug)
Dosage formulation:
film-coated tablet
film-coated tablet
Unit dose strength:
20mg/tablet
20mg/tablet
Route of 
Administration 
oral
oral
Dosing instructions:
2 tablets once daily
2 tablets once daily
Packaging and 
Labelling
Study Treatment will be 
provided in blister. Each 
container will be labelled as 
required per country 
requirement.
Study Treatment will be provided 
in bottle. Each container will be 
labelled as required per country 
requirement.
Manufacturer
TSKF (toll manufacture GSKT)
Mississauga
7.2.
Dose Modification
Not applicable.
7.3.
Method of Treatment Assignment
Participants will be randomly assigned to either regimen sequence (AB or BA) in a 
balanced manner to ensure similar proportions of participants on each sequence, 
according to a randomization schedule prepared in advance of the study by Statistics, 
GlaxoSmithKline, using internal validated software (i.e. RandAll).
7.4.
Blinding
It is not applicable because this will be an open-label study. 
 
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7.5.
Preparation/Handling/Storage/Accountability
No special preparation of investigational product is required.
Investigational product must be dispensed or administered according to procedures 
described herein. Only participants enrolled in the study may receive study treatment. 
Only authorized site staff may supply or administer study treatment. All investigational 
product must be stored in a secure area with access limited to the investigator and 
authorized site staff. Investigational product is to be stored up to 25C/protected from
moisture and light. Maintenance of a temperature log (manual or automated) is required.
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for investigational product accountability, reconciliation, and record 
maintenance. The investigator or the head of the medical institution (where applicable), 
or designated site staff (e.g., storage manager, where applicable) must maintain 
investigational product accountability records throughout the course of the study.  The 
responsible person(s) will document the amount of investigational product received from 
and returned to GSK and the amount administered to participants.  The required counting 
unit for this study will be tablet.  Discrepancies are to be reconciled or resolved.  
Procedures for final disposition of unused investigational product are listed in the Study 
Reference Manual (SRM).
Investigational product is not expected to pose significant occupational safety risk to site 
staff under normal conditions of use and administration.  A Material Safety Data Sheet 
(MSDS)/equivalent document describing occupational hazards and recommended 
handling precautions either will be provided to the investigator, where this is required by 
local laws, or is available upon request from GSK.
7.6.
Treatment Compliance
When participants are dosed at the site, they will receive study treatment directly from 
the investigator or designee, under medical supervision.  The date and time of each dose 
administered in the clinic will be recorded in the source documents.  The dose of study 
treatment and study participant identification will be confirmed at the time of dosing by a 
member of the study site staff other than the person administering the study treatment.  
7.7.
Concomitant Therapy
Any medication or vaccine (including over-the-counter or prescription medicines, 
vitamins, and/or herbal supplements) that the participant is receiving at the time of 
enrollment or receives during the study must be recorded along with:

reason for use

dates of administration including start and end dates

dosage information including dose and frequency
The Medical Monitor should be contacted if there are any questions regarding 
concomitant or prior therapy.
 
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Participants must abstain from taking prescription or nonprescription drugs (including 
vitamins and dietary or herbal supplements) within 7 days (or 14 days if the drug is a 
potential enzyme inducer) or 5 half-lives (whichever is longer) before the start of study 
treatment until completion of the follow-up visit, unless, in the opinion of the investigator 
and sponsor, the medication will not interfere with the study. 
Concomitant medication may be considered on a case by case basis by the investigator in 
consultation with the GSK Medical Monitor.
7.8.
Treatment after the End of the Study
Participants will not receive any additional treatment from GSK after completion of the 
study because only healthy volunteers are eligible for study participation.
8.
DISCONTINUATION CRITERIA
8.1.
Discontinuation of Study Treatment
8.1.1.
Liver Chemistry Stopping Criteria
Liver chemistry stopping and increased monitoring criteria have been designed to 
assure participant safety and evaluate liver event etiology (in alignment with the Food 
and Drug Administration [FDA] premarketing clinical liver safety guidance). 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf
Study treatment will be stopped for a participant if the following liver chemistry 
stopping criteria is met: 

ALT 3xULN
NOTE: Refer to Appendix 5 for details of the required assessments if a participant meets 
the above criteria.
8.1.2.
QTc Stopping Criteria

The same QT correction formula must be used for each individual participant to 
determine eligibility for and discontinuation from the study.  This formula may not be 
changed or substituted once the participant has been enrolled.

For example, if a participant is eligible for the protocol based on QTcB, then 
QTcB must be used for discontinuation of this individual participant as well.

Once the QT correction formula has been chosen for a participant’s eligibility, the 
same formula must continue to be used for that participant for all QTc data being 
collected for data analysis.  Safety ECGs and other non-protocol specified ECGs 
are an exception.  

The QTc should be based on single or averaged QTc values of triplicate 
electrocardiograms obtained over a brief (e.g., 5-10 minute) recording period.  
 
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
A participant that meets either criterion below will be withdrawn from the study. The 
same QT correction formula (e.g QTcB, QTcF) should be used to determine inclusion 
and discontinuation for any individual participant throughout the study.

[QTc, QTcB, QTcF] > 500 msec,

[Change from baseline: QTc >60 msec]
8.2.
Withdrawal from the Study

A participant may withdraw from the study at any time at his/her own request, or may 
be withdrawn at any time at the discretion of the investigator for safety, behavioral, 
compliance or administrative reasons. Some of the possible reasons for withdrawing 
are:
1. In the investigator’s opinion, the participant has experienced serious adverse 
event or significant changes in laboratory measurements that necessitate 
discontinuation from the study and appropriate treatment measures. In this case 
the sponsor should be immediately informed.
2. The participant or the physician in charge requires or the investigator decides that 
the participant should be discontinued from the study.
3. The investigator or GSK terminate the entire study for any reason, or discontinue 
further participation of the participant in the study.
4. Enrolment error, i.e., the participant fails to fulfil the inclusion/exclusion criteria 
for this study.
5. Any situation meeting the exclusion criteria during study.
6. Use of concomitant medications prohibited in the protocol. If possible, it is 
recommended to contact GSK before withdrawing.
7. The participant is unable to tolerate the assigned doses. (Refer to Section 8.1. for 
participant specific dose adaptation/stopping criteria including Liver Chemistry 
and QTc.).
8. The participant becomes pregnant.

If the participant withdraws consent for disclosure of future information, the sponsor 
may retain and continue to use any data collected before such a withdrawal of 
consent.

If a participant withdraws from the study, he/she may request destruction of any 
samples taken and not tested, and the investigator must document this in the site study 
records.

Refer to the SoA for data to be collected at the time of study discontinuation and 
follow-up and for any further evaluations that need to be completed.
 
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8.3.
Lost to Follow Up
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic for a 
required study visit:

The site must attempt to contact the participant and reschedule the missed visit as 
soon as possible and counsel the participant on the importance of maintaining the 
assigned visit schedule and ascertain whether or not the participant wishes to and/or 
should continue in the study.

Before a participant is deemed lost to follow up, the investigator or designee must 
make every effort to regain contact with the participant (where possible, 3 telephone 
calls and, if necessary, a certified letter to the participant’s last known mailing 
address or local equivalent methods). These contact attempts should be documented 
in the participant’s medical record.

Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up. 
9.
STUDY ASSESSMENTS AND PROCEDURES
Study procedures and their timing are summarized in the SoA. 
Protocol waivers or exemptions are not allowed.
Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue 
study treatment.
Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable. 
Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count) and obtained before signing of ICF may be utilized for screening or baseline 
purposes provided the procedure met the protocol-specified criteria and was performed
within the time frame defined in the SoA.
The timing and number of planned study assessments, including safety, pharmacokinetic, 
assessments may be altered during the course of the study based on newly available data 
(e.g. to obtain data closer to the time of peak plasma concentrations) to ensure 
appropriate monitoring. The change in timing or addition of time points for any planned 
study assessments must be documented in a Note to File which is approved by the 
relevant GSK study team member and then archived in the study sponsor and site study 
files, but this will not constitute a protocol amendment. The IRB/IEC will be informed of 
 
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any safety issues that require alteration of the safety monitoring scheme or amendment of 
the Informed Consent Form. No more than 500 mL of blood will be collected over the 
duration of the study, including any extra assessments that may be required.
9.1.
Efficacy Assessments
No efficacy assessment will be conducted in this Bioequivalence study. 
9.2.
Adverse Events
The definitions of an AE or SAE can be found in Appendix 4.
The investigator and any designees are responsible for detecting, documenting, and 
reporting events that meet the definition of an AE or SAE and remain responsible for 
following up AEs that are serious, considered related to the study treatment or the study, 
or that caused the participant to discontinue the study treatment (see Section 8). 
9.2.1.
Time Period and Frequency for Collecting AE and SAE 
Information

All SAEs will be collected from the signing of the ICF until the follow-up visit at the 
time points specified in the SoA.

All AEs will be collected from the start of treatment until the follow-up visit at the 
time points specified in the SoA.

Medical occurrences that begin before the start of study treatment but after obtaining 
informed consent will be recorded on the Medical History/Current Medical 
Conditions section of the case report form (CRF) not the AE section.

All SAEs will be recorded and reported to the sponsor or designee within 24 hours, 
as indicated in Appendix 4. The investigator will submit any updated SAE data to the 
sponsor within 24 hours of it being available.

Investigators are not obligated to actively seek AEs or SAEs in former study 
participants. However, if the investigator learns of any SAE, including a death, at 
any time after a participant has been discharged from the study, and he/she considers 
the event to be reasonably related to the study treatment or study participation, the 
investigator must promptly notify the sponsor.

The method of recording, evaluating, and assessing causality of AEs and SAEs and 
the procedures for completing and transmitting SAE reports are provided in
Appendix 4.
9.2.2.
Method of Detecting AEs and SAEs
Care will be taken not to introduce bias when detecting AE and/or SAE. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about 
AE occurrence. 
 
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9.2.3.
Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All SAEs will be followed until the event is 
resolved, stabilized, otherwise explained, or the participant is lost to follow-up (as 
defined in Section 8.3.). Further information on follow-up procedures is given in
Appendix 4.
9.2.4.
Regulatory Reporting Requirements for SAEs

Prompt notification by the investigator to the sponsor of a SAE is essential so that 
legal obligations and ethical responsibilities towards the safety of participants and 
the safety of a study treatment under clinical investigation are met. 

The sponsor has a legal responsibility to notify both the local regulatory authority 
and other regulatory agencies about the safety of a study treatment under clinical 
investigation. The sponsor will comply with country-specific regulatory 
requirements relating to safety reporting to the regulatory authority, Institutional 
Review Boards (IRB)/Independent Ethics Committees (IEC), and investigators.

Investigator safety reports must be prepared for suspected unexpected serious 
adverse reactions (SUSAR) according to local regulatory requirements and sponsor 
policy and forwarded to investigators as necessary.

An investigator who receives an investigator safety report describing a SAE or other 
specific safety information eg, summary or listing of SAE) from the sponsor will 
review and then file it along with the Investigator’s Brochure and will notify the 
IRB/IEC, if appropriate according to local requirements.
9.2.5.
Pregnancy

Details of all pregnancies in female participants and female partners of male 
participants will be collected after the start of study treatment and until follow up.

If a pregnancy is reported, the investigator should inform GSK within 24 hours of 
learning of the pregnancy and should follow the procedures outlined in Appendix 2.

Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAE.
9.3.
Treatment of Overdose
For this study, any dose of Paroxetine IR > 40mg/day will be considered an overdose.
GSK does not recommend specific treatment for an overdose. The investigator or 
physician in charge of the participant at the time will use clinical judgment to treat any 
overdose.
In the event of an overdose, the investigator should:
1.
Contact the Medical Monitor immediately.
 
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2.
Closely monitor the participant for AE/SAE and laboratory abnormalities until 
Paroxetine IR can no longer be detected systemically (at least 5 days).
3.
Obtain a plasma sample for PK analysis within 5 days from the date of the last dose 
of study treatment if requested by the Medical Monitor (determined on a case-by-
case basis).
4.
Document the quantity of the excess dose as well as the duration of the overdosing 
in the CRF.
Decisions regarding dose interruptions or modifications will be made by the investigator 
in consultation with the Medical Monitor based on the clinical evaluation of the 
participant.
9.4.
Safety Assessments
Planned time points for all safety assessments are provided in the SoA.
9.4.1.
Physical Examinations

A complete physical examination will include assessments of the head, eyes, ears, 
nose, throat, skin, thyroid, neurological, lungs, cardiovascular, abdomen (liver and 
spleen), lymph nodes and extremities.  A brief physical examination will include 
assessments of the skin, lungs, cardiovascular system, and abdomen (liver and 
spleen).

A complete physical examination should be performed at screening. A brief physical 
examination should be made at the beginning/end of the study (Day 0, Day 11, Day 
16 or early withdraw). Other routine medical assessments may also be performed 
during the study as clinically indicated. 

Height and weight will also be measured and recorded. The body weight and height 
measured at screening and Day 0 will be used for determining the inclusion criteria 
body mass index (BMI). 
9.4.2.
Vital Signs

Temperature, pulse rate, respiratory rate, and blood pressure will be assessed at 
screening, when admitted to unit (Day 0 and Day 11) and as clinically indicated.

Blood pressure and pulse rate will be measured pre-dosing (60 minutes pre-dosing to 
dosing time) and at 2h±60 minutes post-dosing on Day 1 and Day 12; on Days 2
(24h±60 minutes post-dosing), Days 3 (48h±60 minutes post-dosing), Day 4
(72h±60 minutes post-dosing), Days 5 (96h±60 minutes post-dosing), Days 13
(24h±60 minutes post-dosing), Day 14 (48h±60 minutes post-dosing), Days 15
(72h±60 minutes post-dosing), Days 16 (96h±60 minutes post-dosing); or early 
withdraw.

Other vital signs may also be measured during the study as clinically indicated.
 
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9.4.3.
Electrocardiograms

12-lead ECG will be obtained as outlined in the SoA using an ECG machine that 
automatically calculates the heart rate and measures PR, QRS, QT, and QTc intervals. 
Refer to Section 8.1.2.for [QTc] withdrawal criteria and additional QTc readings that 
may be necessary.

If triplicate ECG is required, 3 individual ECG tracings should be obtained as closely 
as possible in succession, but no more than 2 minutes apart. The full set of triplicates 
should be completed in less than 4 minutes.
9.4.4.
Clinical Safety Laboratory Assessments

Refer to Appendix 5 for the list of clinical laboratory tests to be performed and to the 
SoA for the timing and frequency. 

The investigator must review the laboratory report, document this review, and record 
any clinically relevant changes occurring during the study in the AE section of the 
CRF. The laboratory reports must be filed with the source documents. Clinically 
significant abnormal laboratory findings are those which are not associated with the 
underlying disease, unless judged by the investigator to be more severe than 
expected for the participant's condition.

All laboratory tests with values considered clinically significantly abnormal during 
participation in Day 16 or early withdraw should be repeated in follow up visit. 

All protocol-required laboratory assessments, as defined in Appendix 5, must be 
conducted in accordance with the laboratory manual and the SoA.

If laboratory values from non-protocol specified laboratory assessments performed at 
the institution’s local laboratory require a change in participant management or are 
considered clinically significant by the investigator (eg, SAE or AE or dose 
modification), then the results must be recorded in the CRF.
9.4.5.
Suicidal Risk Monitoring
As an antidepressant, Paroxetine may increase the risk of suicidal ideation or behavior in 
some participants. Although there has been no evidence of Paroxetine and other 
antidepressants being associated with increased risk of suicidal ideation or behavior in 
healthy volunteers, GSK considers it as vital to closely monitor these events prior to and 
during the conduct of a clinical study.
The participants should receive appropriate assessments to be closely monitored (suicidal 
ideation/behavior, abnormal behavior changes). Withdrawal of Paroxetine should be 
considered in the occurrence of these conditions.
Columbia Suicide Severity Rating Scale (C-SSRS) will be used in this study for baseline 
assessment and for monitoring during the treamtent course. 
The C-SSRS is a measure of suicidal ideation and behavior, with demonstrated predictive 
validity and reliability. Improved assessments of suicidal ideation and behavior are 
necessary to better understand the relationship between suicidal AEs and medication 
 
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treatment. The US FDA recommends the use of suicidality assessment instruments that 
map to the Columbia Classification Algorithm for Suicide Assessment (C-CASA). One 
such instrument is the C-SSRS. Sections of the C-SSRS include suicidal ideation, 
intensity of ideation, suicidal behavior, and actual suicide attempt(s). The C-SSRS 
assesses lifetime and current suicidal thoughts and behaviors across these categories 
based on an increasing severity of a 1- to 5-rating scale. The semi-structured 
questionnaire is completed by a trained and experienced neurologist, psychiatrist, or 
neuropsychologist, or another trained and experienced person approved by the Sponsor, 
who may be the principal investigator or a sub-investigator for the study. The interview is 
expected to take approximately 20 to 30 minutes to administer to the participant.
For any adverse events assessed by the investigator as related to suicidality, in addition to 
reporting in accordance with the adverse event and serious adverse event reporting 
procedures, the investigator will also need to complete the Possible Suicidality-related 
Adverse Event Form (PSRAE Form).
9.5.
Pharmacokinetics
A vacuum tube pre-filled with ethylenediaminetetraacetic acid (EDTA) will be used to 
collect 3mL of whole blood for measurement of plasma concentrations of paroxetine as 
specified in the SoA. Sampling points are planned to be Immediately before and 0.5, 1, 
2,3, 4, 5, 6, 7, 8, 10, 12, 16, 24, 36, 48, 72, and 96 hour after administration .Instructions 
for the collection and handling of biological samples will bespecified in SRM. The actual 
date and time (24-hour clock time) of each sample collection will be recorded. Refer to 
Appendix 6 for summary of blood sampling.
All plasma samples will be sent to Wuxi AppTec for bioanalysis. Paroxetine plasma
concentrations will be determined using a validated method. The detailed information and 
results from sample analysis will be documented in the final sample analysis report.
Pharmacokinetic (PK) analyses will be the responsibility of the Clinical Pharmacology 
Modeling and Simulation (CPMS) department in China. PK parameters will be 
determined from the paroxetine plasma concentration-time data and calculated by 
standard non-compartmental analysis according to current working practices and using 
WinNonlin 6.3 or higher version.
The main pharmacokinetic parameters include:

AUC0-: Area under the concentration-time curve from time zero extrapolated to 
infinite time.

AUC0-t:  Area under the concentration-time curve from administration 
extrapolated to the last time of quantifiable concentration, calculated as 
logarithm of trapezoid area.

Cmax: The observed maximum serum drug concentration

Tmax: Time to reach Cmax

t1/2: Terminal elimination half-time
 
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
z: Terminal elimination rate constant

CL/F: Oral clearance

Vd/F: Apparent volume of distribution

MRT:  Mean residence time
10.
STATISTICAL CONSIDERATIONS
10.1.
Sample Size Determination
A sufficient number of participants (approximately36 for Fasting group and 44 for Fed 
group) will be enrolled so that approximately 32 participants in Fasting group and 40 
participants in Fed group complete the study.  The sample size was primarily determined 
by calculations as follows.
10.1.1.
Sample Size Assumptions
Sample size calculations were based on within-participant estimates of variability (CVW
%) from two previous clinical pharmacology studies of paroxetine in healthy volunteers 
[data on file: Fasting study 973133 and Fed study 973134].
Fasting group: using the highest of the estimates of variability (21.4% for Cmax) in 
study 973133, it is estimated that a total sample size of 28 will provide at least 90% 
power to demonstrate equivalence of AUC and Cmax for paroxetine assuming a true ratio 
of 1.05. Based on the sample size sensitivity analysis, the sample size is further increased 
to 32 participants, which will provide at least 90% power if the CVW% is 23.5% (which 
indicates an increase of 10% for the variability estimates in the reference study).
Fed group: using the highest of the estimates of variability (24% for AUC) in study 
973134, it is estimated that a total sample size of 34 will provide at least 90% power to 
demonstrate equivalence of AUC and Cmax for paroxetine assuming a true ratio of 1.05.
Based on the sample size sensitivity analysis, the sample size is further increased to 40
participants, which will provide at least 90% power if the CVW% is 26.4% (which 
indicates an increase of 10% for the variability estimates in the reference study). 
Equivalence is considered being demonstrated when the 90% confidence interval for the 
ratio of Test (A): Reference (B) (A= paroxetine IR 20 mg GSKT tablet , B= paroxetine IR 
20 mg Mississauga tablet) of AUC, and of Cmax, each separately, is completely
contained within the range (0.80, 1.25) [Schuirmann, 1987].  This range represents a 
symmetric 20% range on the log-scale.  This calculation was based on a two one-sided 
testing procedure, each with a type I error rate of 5%.
10.1.2.
Sample Size Sensitivity
The sensitivity analyses were conducted based on different scenarios. The power to 
demonstrate equivalence for AUC and Cmax between the test drug (A) and reference 
drug (B) given the final determined sample size (32 participants for fasting group and 40 
 
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participants for fed group) is provided below. This calculation was also based on a two 
one-sided testing procedure, each with a type I error rate of 5%.
True Ratio
Fasting group (32 participants)
Fed group (40 participants)
CVW %
Power
CVW %
Power
1
21.4%
98.67%
24%
98.74%
1.05
21.4%
94.2%
24%
94.38%
1.1
21.4%
76.31%
24%
76.65%
1
23.5% (10% inflated)
96.57%
26.4% (10% inflated)
96.68%
1.05
23.5% (10% inflated)
90.06%
26.4% (10% inflated)
90.25%
1.1
23.5% (10% inflated)
69.5%
26.4% (10% inflated)
69.77%
1
24.6% (15% inflated)
94.91%
27.6% (15% inflated)
95.13%
1.05
24.6% (15% inflated)
87.52%
27.6% (15% inflated)
87.83%
1.1
24.6% (15% inflated)
66.13%
27.6% (15% inflated)
66.52%
1
25.7% (20% inflated)
92.86%
28.8% (20% inflated)
93.22%
1.05
25.7% (20% inflated)
84.78%
28.8% (20% inflated)
85.23%
1.1
25.7% (20% inflated)
62.92%
28.8% (20% inflated)
63.42%
10.2.
Populations for Analyses
For purposes of analysis, the following populations are defined:
Population
Description
All participants
All participants who signed the ICF
PK population
All randomized participants who take at least 1 dose of study 
treatment and provide valid pharmacokinetic data.
Safety
All randomized participants who take at least 1 dose of study 
treatment. Participants will be analyzed according to the treatment 
they actually received.
 
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10.3.
Statistical Analyses
Data will be displayed separately for each group (Fasting or Fed).  
10.3.1.
Efficacy Analyses
No efficacy analysis is planned in this Bioequivalence study. 
10.3.2.
Pharmacokinetic Analyses
Endpoint
Statistical Analysis Methods
Primary
Mixed effect model with period and treatment as fixed effects and participant
as random effect.
Secondary
Will be summarized with descriptive methods
Pharmacokinetic parameter of paroxetine will be analyzed by non-compartmental 
methods with WinNonlin Phoenix [version 6.3 or higher version]. Calculations will be 
based on the actual sampling times recorded during the study.  From the serum
concentration-time data, the pharmacokinetic parameters in Section 9.5. will be 
calculated. 
The focus of the statistical analysis of the pharmacokinetic data is to demonstrate 
bioequivalence of paroxetine IR 20 mg GSKT tablet and paroxetine IR 20 mg 
Mississauga tablet.
After loge-transformation, AUC(0-), AUC(0-t) and Cmax will be analyzed, each separately, 
using mixed effect model. The model will include period and treatment as fixed effects, 
and participant as random effects. Point estimates and their associated adjusted 90% 
confidence interval of difference between A and B will be provided for the above 
mentioned PK parameters in log scale. The point estimates and their associated adjusted 
90% confidence intervals will then be back-transformed to provide point estimates and 
adjusted 90% confidence intervals for the ratios of A : B. If the 90% confidence interval 
of AUC(0-), AUC(0–t) (AUC(0–t) only if AUC(0–) can’t be accurately determined) and Cmax
fall in the range of 0.80-1.25, it can be stated that the two formulations are bioequivalent.
All pharmacokinetic parameters will be presented in graphical and/or tabular form and 
will be summarized descriptively in PK population. Details will be provided in Reporting 
and Analysis Plan (RAP).  
10.3.3.
Safety Analyses
Endpoint
Statistical Analysis Methods
Secondary
Will be summarized with descriptive methods
 
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All safety analyses will be performed on the Safety Population. All the subjects who have 
taken study drug will be included in safety population.
No formal statistical analysis of safety data will be performed.  
Adverse events (AEs) will be coded using Medical Dictionary for Regulatory Activities 
(MedDRA) and grouped by system organ classes (SOCs) and preferred term (PT).  All 
adverse events will be listed. A summary of the number and percentage of participants
reporting each AE at least once will be produced for all AEs and also for drug-related 
AEs.  A listing showing the relationship of AE verbatim text to group terms and body 
systems will also be produced.
Vital signs, ECG and clinical laboratory data will be reviewed and summarized during 
the study to evaluate the safety of subjects.  Any clinically relevant abnormalities or 
values of potential clinical concern will be described.  
Safety data will be presented in tabular and/or graphical format and summarized
descriptively according to the Clinical Data Interchange Standard Consortium (CDISC).
More details will be specified in RAP.
 
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11.
REFERENCES
China Food and Drug Administration (CFDA) has published [Article #106]  on May 
25,2016. (http://www.sfda.gov.cn/WS01/CL0087/154042.html)
Schuirmann DJ. 1987. A comparison of the two one-sided tests procedure and the power 
approach for assessing the equivalence of average bioavailability. J Pharmacokinet and 
Biopharm, 15, 657-680.
Tian YH, Wang ZX, Gu NF, Shi SX, Huang MS, Sun XL, et al. A double blinded, 
controlled study of Paroxetine and Amitriptyline in the treatment of major depressive 
disorder. Chinese Journal of Psychiatry, 1996, 29(2): 123-124.
Wu WY, Zhang HY, Zhang MY, Zhang HY, Shu L, Zhao JP, et al. A multi-centre, 
randomized, double blinded, parallel controlled study of Paroxetine and Amitriptyline in 
the treatment of obsessive compulsive disorder. Chinese Journal of Psychiatry, 2004, 
37(1): 18-21.
Zhang HY, Zhang HY, Zhao JP, Ma C, Li M, Tao M, et al. A randomized, double 
blinded, parallel controlled study of Paroxetine and Clomipramine in the treatment of 
panic disorder. Chinese Mental Health Journal, 2000, 14(6): 410-413.
 
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12.
APPENDICES
12.1.
Appendix 1: Abbreviations and Trademarks
Abbreviations
z
Terminal elimination rate constant
AE
adverse event
ALP
alkaline phosphatase
ALT
alanine aminotransferase
AUC0-
Area under the concentration-time curve from time zero extrapolated 
to infinite time
AUC0-t
Area under the concentration-time curve from administration 
extrapolated to the last time of quantifiable concentration
BE
bioequivalence
BMI
body mass index
CFDA
China Food and Drug Administration 
CL/F
Oral clearance
Cmax
The observed maximum serum drug concentration
CONSORT
Consolidated Standards of Reporting Trials
CPMS
Clinical Pharmacology Modeling and Simulation
CRF
case report form
C-SSRS
Columbia Suicide Severity Rating Scale
DC
direct compression
ECG
Electrocardiogram
GSK
GlaxoSmithKline
GSKT
GlaxoSmithKline Tianjin
hCG
human chorionic gonadotropin
ICF
informed consent form
IDSL
Integral Data Standard Library
IEC
Independent Ethics Committees
IR
immediate release
IRB
Institutional Review Boards
MAOIs
monoamine oxidase  inhibitors
MDD
major depressive disorder
MRT
mean residence time
MSDS
Material Safety Data Sheet
OCD
obsessive compulsive disorder
OTC
over the counter
PD
panic disorder
PK
pharmacokinetic
PSRAE
Possible Suicidality-related Adverse Event
PT
preferred term
QTcB
QT interval corrected for heart rate according to Bazett’s formula
QTcF
QT interval corrected for heart rate according to Fridericia’s formula
RAP
Reporting and Analysis Plan
 
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SAD
social anxiety disorder
SAE
serious adverse event
SIADH
syndrome of inappropriate antidiuretic hormone secretion
SOA
Schedule of Activities
SOC
system organ class
SRM
Study Reference Manual
SSRI
selective serotonin reuptake inhibitor
SUSAR
suspected unexpected serious adverse reactions
t1/2
Terminal elimination half-time
Tmax
Time to reach Cmax
TSKF
Tianjin SmithKline & French
ULN
upper limit of normal
Vd/F
Apparent volume of distribution
WG
wet granulation
Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
RANDALL
WinNonlin
SEROXAT IR
Wuxi AppTec
 
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12.2.
Appendix 2: Contraceptive Guidance and Collection of 
Pregnancy Information
Definitions
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile (see below)
Women in the following categories are not considered WOCBP
1.
Premenarchal
2.
Premenopausal female with ONE of the following:

Documented hysterectomy

Documented bilateral salpingectomy

Documented bilateral oophorectomy
Note:  Documentation can come from the site personnel’s: review of participant’s 
medical records, medical examination, or medical history interview.
3.
Postmenopausal female

A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause. A high 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, a single FSH 
measurement is insufficient. 

Females on HRT and whose menopausal status is in doubt will be required to 
use one of the non-hormonal highly effective contraception methods if they wish 
to continue their HRT during the study. Otherwise, they must discontinue HRT 
to allow confirmation of postmenopausal status before study enrollment.
Contraception Guidance
Male participants

Male participants with female partners of child-bearing potential are eligible to 
participate if they agree to ONE of the following during the study and until follow up 
contact: 

Are abstinent from penile-vaginal intercourse as their usual and preferred 
lifestyle (abstinent on a long term and persistent basis) and agree to remain 
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
Agree to use a male condom plus an additional method of contraception with 
a failure rate of <1% per year as described in following when having penile-
vaginal intercourse with a woman of childbearing potential:
o Oral contraceptive, either combined or progestogen alone
o Injectable progestogen 
o Implants of etonogestrel or levonorgestrel
o Estrogenic vaginal ring
o Percutaneous contraceptive patches
o Intrauterine device (IUD) or intrauterine system (IUS) that meets the <1% 
failure rate as stated in the product label
o Male condom combined with a female diaphragm, either with or without a 
vaginal spermicide (foam, gel, cream or suppository).

Men with a pregnant or breastfeeding partner must agree to remain abstinent from 
penile-vaginal intercourse or use a male condom during each episode of penile 
penetration during the study and until follow up contact

Refrain from donating sperm for duration of study and until follow up.
Female participants
Female participants of childbearing potential are eligible to participate if they agree to 
use a highly effective method of contraception consistently and correctly as described in 
the following Highly Effective Contraceptive Methods:

Sexual abstinence (Sexual abstinence is considered a highly effective method only 
if defined as refraining from heterosexual intercourse during the entire period of 
risk associated with the study drug. The reliability of sexual abstinence needs to 
be evaluated in relation to the duration of the study and the preferred and usual 
lifestyle of the participant.) 

Intrauterine device (IUD)

Bilateral tubal occlusion 

Male condom combined with a female diaphragm, either with or without a 
vaginal spermicide (foam, gel, cream or suppository).

Vasectomized partner (A vasectomized partner is a highly effective contraception 
method provided that the partner is the sole male sexual partner of the WOCBP 
and the absence of sperm has been confirmed. If not, an additional highly 
effective method of contraception should be used.)
NOTE: These allowed methods of contraception are only effective when used 
consistently, correctly and in accordance with the product label. The investigator is 
 
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responsible for ensuring subjects understand how to properly use these methods of 
contraception.
Pregnancy Testing

WOCBP should only be included after a confirmed menstrual period and a negative 
highly sensitive urine or serum pregnancy test 

Pregnancy testing will be performed whenever a menstrual cycle is missed or when 
pregnancy is otherwise suspected 
Collection of Pregnancy Information
Male participants with partners who become pregnant

Investigator will attempt to collect pregnancy information on any male participant’s 
female partner of a male study participant who becomes pregnant while participating 
in this study. This applies only to participants who receive study treatment.

After obtaining the necessary signed informed consent from the pregnant female 
partner directly, the investigator will record pregnancy information on the 
appropriate form and submit it to GSK within 24 hours of learning of the partner’s 
pregnancy. 

Partner will also be followed to determine the outcome of the pregnancy. 
Information on the status of the mother and child will be forwarded to GSK

Generally, follow-up will be no longer than 6 to 8 weeks following the estimated 
delivery date. Any termination of the pregnancy will be reported regardless of fetal 
status (presence or absence of anomalies) or indication for procedure. 
Female Participants who become pregnant

Investigator will collect pregnancy information on any female participant, who 
becomes pregnant while participating in this study. 

Information will be recorded on the appropriate form and submitted to GSK within 
24 hours of learning of a participant's pregnancy. 

Participant will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow up information on participant and neonate, which will 
be forwarded to GSK Generally, follow-up will not be required for longer than 6 to 8 
weeks beyond the estimated delivery date.  

Any termination of pregnancy will be reported, regardless of fetal status (presence or 
absence of anomalies) or indication for procedure. 

While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy will be reported as an AE or 
SAE. 

A spontaneous abortion is always considered to be an SAE and will be reported as 
such.  
 
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
Any SAE occurring as a result of a post-study pregnancy which is considered 
reasonably related to the study treatment by the investigator, will be reported to GSK 
as described in Appendix 4. While the investigator is not obligated to actively seek 
this information in former study participants, he or she may learn of an SAE through 
spontaneous reporting. 
Any female participant who becomes pregnant while participating will discontinue the 
study treatment.
 
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12.3.
Appendix 3: Liver Safety: Required Actions and Follow-up 
Assessments
Phase I liver chemistry stopping criteria and required follow up assessments
Liver Chemistry Stopping Criteria 
ALT-absolute
ALT≥3xULN
If ALT≥3xULN AND bilirubin1,2 2xULN (>35% direct bilirubin) or  INR >1.5, 
Report as an SAE.
See additional Actions and Follow Up Assessments listed below
Required Actions and Follow up Assessments 
Actions
Follow Up Assessments

Immediately discontinue study treatment

Report the event to GSK within 24 hours

Complete the liver event CRF, and complete 
an SAE data collection tool if the event also 
meets the criteria for an SAE2

Perform liver event follow up assessments 

Monitor the subject until liver chemistries 
resolve, stabilise, or return to within baseline 
(see MONITORING below)
MONITORING:
If ALT≥3xULN AND bilirubin 2xULN  or INR 
>1.5

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments within  24 
hrs

Monitor subjects twice weekly until liver 
chemistries resolve, stabilise or return to 
within baseline

A specialist or hepatology consultation is 
recommended
If ALT≥3xULN AND bilirubin < 2xULN  and 
INR ≤1.5:

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 

Viral hepatitis serology3

Obtain INR and recheck with each liver 
chemistry assessment until the 
transaminases values show downward 
trend

Serum creatine phosphokinase (CPK) and 
lactate dehydrogenase (LDH).

Fractionate bilirubin, if total 
bilirubin2xULN

Obtain complete blood count with 
differential to assess eosinophilia

Record the appearance or worsening of 
clinical symptoms of liver injury, or 
hypersensitivity, on the AE report form

Record use of concomitant medications on 
the concomitant medications report form 
including acetaminophen, herbal remedies, 
other over the counter medications.

Record alcohol use on the liver event 
alcohol intake case report form
If ALT≥3xULN AND bilirubin 2xULN  or 
INR >1.5:

Anti-nuclear antibody, anti-smooth muscle 
antibody, Type 1 anti-liver kidney 
microsomal antibodies, and quantitative 
total immunoglobulin G (IgG) or gamma 
 
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liver event follow up assessments within 24-
72 hrs 
• Monitor subjects weekly until liver 
chemistries resolve, stabilize or return to 
within baseline 
globulins.
• Liver imaging (ultrasound, magnetic 
resonance, or computerised tomography) 
and /or liver biopsy to evaluate liver 
disease; complete Liver Imaging and/or 
Liver Biopsy CRF forms. 
1. Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not 
immediately available, discontinue study treatment for that subject if ALT ≥ 3xULN and bilirubin ≥ 2xULN. 
Additionally, if serum bilirubin fractionation testing is unavailable, record presence of detectable urinary bilirubin on 
dipstick, indicating direct bilirubin elevations and suggesting liver injury.  
2. All events of ALT ≥ 3xULN and bilirubin ≥ 2xULN (>35% direct bilirubin) or ALT ≥ 3xULN and INR>1.5, if INR 
measured, which may indicate severe liver injury (possible ‘Hy’s Law’), must be reported as an SAE (excluding 
studies of hepatic impairment or cirrhosis); INR measurement is not required and the threshold value stated will 
not apply to subjects receiving anticoagulants 
3. Includes: Hepatitis A IgM antibody; Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM); Hepatitis C 
RNA; Cytomegalovirus IgM antibody;  Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain 
heterophile antibody or monospot testing);  Hepatitis E IgM antibody  
 
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12.4.
Appendix 4: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting
Definition of AE
AE Definition

An AE is any untoward medical occurrence in a clinical study participant, temporally 
associated with the use of a study treatment, whether or not considered related to the 
study treatment.

NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a study treatment.
Events Meeting the AE Definition 

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the 
medical and scientific judgment of the investigator (ie, not related to progression of 
underlying disease).

Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study treatment administration even 
though it may have been present before the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication. Overdose per se will not be reported as an 
AE/SAE unless it is an intentional overdose taken with possible suicidal/self-
harming intent. Such overdoses should be reported regardless of sequelae.
Events NOT Meeting the AE Definition 

Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition.

The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the 
participant’s condition.

Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that 
leads to the procedure is the AE.
 
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
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen.
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (eg, hospitalization for signs/symptoms of the disease under study, 
death due to progression of disease).
A SAE is defined as any untoward medical occurrence that, at any dose:
a.
Results in death
b.
Is life-threatening
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, 
which hypothetically might have caused death, if it were more severe.
c.
Requires inpatient hospitalization or prolongation of existing hospitalization
In general, hospitalization signifies that the participant has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or 
outpatient setting. Complications that occur during hospitalization are AE. If a 
complication prolongs hospitalization or fulfills any other serious criteria, the event is 
serious. When in doubt as to whether “hospitalization” occurred or was necessary, the AE 
should be considered serious.
Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an AE.
d.
Results in persistent disability/incapacity

The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.

This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (eg, sprained ankle) which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect
f.
Other situations:

Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may 
 
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jeopardize the participant or may require medical or surgical intervention to prevent 
one of the other outcomes listed in the above definition. These events should usually 
be considered serious.
Examples of such events include invasive or malignant cancers, intensive treatment 
in an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse.

All events of ALT ≥3xULN and bilirubin ≥2xULN (>35% direct bilirubin) or ALT ≥
3xULN and INR>1.5, if INR measured, which may indicate severe liver injury 
(possible ‘Hy’s Law’), must be reported as an SAE.
Recording AE and SAE
AE and SAE Recording

When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory, and diagnostics reports) 
related to the event.

The investigator will then record all relevant AE/SAE information in the CRF.

It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to GSK in lieu of completion of the GSK /AE/SAE CRF page.

There may be instances when copies of medical records for certain cases are 
requested by GSK. In this case, all participant identifiers, with the exception of the 
participant number, will be redacted on the copies of the medical records before 
submission to GSK.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not 
the individual signs/symptoms) will be documented as the AE/SAE.
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and assign it to 1 of the following categories: 

Mild: An event that is easily tolerated by the participant, causing minimal discomfort 
and not interfering with everyday activities.

Moderate: An event that causes sufficiently discomfort and interferes with normal 
everyday activities.

Severe: An event that prevents normal everyday activities. An AE that is assessed as 
severe should not be confused with an SAE. Severe is a category utilized for rating 
the intensity of an event; and both AE and SAE can be assessed as severe.
An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes 
as described in the definition of an SAE, NOT when it is rated as severe.
 
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Assessment of Causality

The investigator is obligated to assess the relationship between study treatment and 
each occurrence of each AE/SAE.

A "reasonable possibility" of a relationship conveys that there are facts, evidence, 
and/or arguments to suggest a causal relationship, rather than a relationship cannot 
be ruled out.

The investigator will use clinical judgment to determine the relationship.

Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study treatment 
administration will be considered and investigated.

The investigator will also consult the Investigator’s Brochure (IB) and/or Product 
Information, for marketed products, in his/her assessment.

For each AE/SAE, the investigator must document in the medical notes that he/she 
has reviewed the AE/SAE and has provided an assessment of causality.

There may be situations in which an SAE has occurred and the investigator has 
minimal information to include in the initial report to GSK. However, it is very 
important that the investigator always make an assessment of causality for 
every event before the initial transmission of the SAE data to GSK.

The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality 
assessment.

The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.
Follow-up of AE and SAE

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by GSK to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, 
or consultation with other health care professionals.

If a participant dies during participation in the study or during a recognized follow-
up period, the investigator will provide GSK with a copy of any post-mortem 
findings including histopathology.

New or updated information will be recorded in the originally completed CRF.

The investigator will submit any updated SAE data to GSK within 24 hours of 
receipt of the information.
 
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Reporting of SAE to GSK
SAE Reporting to GSK via Paper CRF

Facsimile transmission of the SAE paper CRF is the preferred method to transmit 
this information to the project contact for SAE receipt.

In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by overnight 
mail or courier service.

Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames.

Contacts for SAE reporting can be found in Sponsor information page.
 
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12.5.
Appendix 5: Clinical Laboratory Tests
Haematology, clinical chemistry, urinalysis and additional parameters will be tested at 
local laboratory.
Additional tests may be performed at any time during the study as determined necessary 
by the investigator or required by local regulations. 
Haematology, clinical chemistry, urinalysis and additional parameters to be tested are 
listed below:
Haematology
Platelet Count
Red Blood Cell (RBC Indice)s:
Automated White Blood Cell 
(WBC) Differential:
RBC Count
Mean corpuscular volume (MCV)
Neutrophils
WBC Count (absolute) 
Mean corpuscular haemoglobin 
(MCH)
Lymphocytes
Hematocrit
Mean corpuscular haemoglobin 
concentration (MCHC)
Monocytes
Hemoglobin
Eosinophils
Basophils
Clinical Chemistry
Blood urea nitrogen (BUN)
Sodium
AST (SGOT)
Total and direct bilirubin
Creatinine
Potassium
ALT (SGPT)
Uric Acid
LDH
Chloride
Alkaline phosphatase
Albumin
Gamma-glutamyl 
transferase (GGT)
Calcium
Total cholesterol
Total Protein
Glucose, fasting
Routine Urinalysis
Specific gravity
pH, glucose, protein, blood and ketones by dipstick
Microscopic examination (if blood or protein is abnormal)
Other screening tests
Pregnancy test
HIV,Syphilis
Hepatitis B (HBsAg)
Hepatitis C (Hep C antibody) 
Alcohol and drug screen (to include at minimum: amphetamines, barbiturates, cocaine, opiates, 
cannabinoids and benzodiazepines).
 
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12.6.
Appendix 6: Summary of Blood Sampling
This table summarizes the estimated number of venipunctures and blood volumes 
required for PK sample collection  during the study. Blood volumes required for 
screening, safety laboratory tests will be determined according to local lab requirement. 
The frequencies of venipuncture and blood sample collection can be increased for safety 
considerations without amending the protocol.
Objectives
Estimated blood 
volume taken for 
each sampling (mL)
Estimated 
number of blood 
samples
Estimated total 
volume of blood 
samples (mL)
Paroxetine assay
3
36
108
Sampling time window
Sampling point
Pre dose-3 h
4-16 h
24-36h
48-96h
Window
± 5 min
± 15 min
± 30 min
± 60 min
 
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12.7.
Appendix 7: Study Governance Considerations
Regulatory and Ethical Considerations

This study will be conducted in accordance with the protocol and with:

Consensus ethical principles derived from international guidelines including 
the Declaration of Helsinki and Council for International Organizations of 
Medical Sciences (CIOMS) International Ethical Guidelines

Applicable ICH Good Clinical Practice (GCP) Guidelines

Applicable laws and regulations

The protocol, protocol amendments, ICF, Investigator Brochure, and other relevant 
documents (eg, advertisements) must be submitted to an IRB/IEC by the investigator 
and reviewed and approved by the IRB/IEC before the study is initiated. 

Any amendments to the protocol will require IEC/IRB approval before 
implementation of changes made to the study design, except for changes necessary to 
eliminate an immediate hazard to study participants. 

The investigator will be responsible for the following:

Providing written summaries of the status of the study to the IRB/IEC annually 
or more frequently in accordance with the requirements, policies, and 
procedures established by the IRB/EC

Notifying the IRB/IEC of SAE or other significant safety findings as required 
by IRB/IEC procedures

Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, European regulation 
536/2014 for clinical studies (if applicable), and all other applicable local 
regulations
Financial Disclosure
Investigators and sub-investigators will provide the sponsor with sufficient, accurate 
financial information as requested to allow the sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate regulatory authorities. 
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study.
Informed Consent Process

The investigator or his/her representative will explain the nature of the study to the 
participant or his/her legally authorized representative and answer all questions 
regarding the study. 

Participants must be informed that their participation is voluntary. Participants or 
their legally authorized representative will be required to sign a statement of 
informed consent that meets the requirements of 21 CFR 50, local regulations, ICH 
 
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guidelines, Health Insurance Portability and Accountability Act (HIPAA) 
requirements, where applicable, and the IRB/IEC or study center. 

The medical record must include a statement that written informed consent was 
obtained before the participant was enrolled in the study and the date the written 
consent was obtained. The authorized person obtaining the informed consent must 
also sign the ICF.

Participants must be re-consented to the most current version of the ICF(s) during 
their participation in the study. 

A copy of the ICF(s) must be provided to the participant or the participant’s legally 
authorized representative. 
Data Protection

Participants will be assigned a unique identifier by the sponsor. Any participant 
records or datasets that are transferred to the sponsor will contain the identifier only; 
participant names or any information which would make the participant identifiable 
will not be transferred. 

The participant must be informed that his/her personal study-related data will be 
used by the sponsor in accordance with local data protection law. The level of 
disclosure must also be explained to the participant. 

The participant must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by the 
sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory 
authorities.
Publication Policy

The results of this study may be published or presented at scientific meetings. If this 
is foreseen, the investigator agrees to submit all manuscripts or abstracts to the 
sponsor before submission. This allows the sponsor to protect proprietary 
information and to provide comments.

The sponsor will comply with the requirements for publication of study results. In
accordance with standard editorial and ethical practice, the sponsor will generally 
support publication of multicenter studies only in their entirety and not as individual 
site data. In this case, a coordinating investigator will be designated by mutual 
agreement.

Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.
Dissemination of Clinical Study Data
Where required by applicable regulatory requirements, an investigator signatory will be 
identified for the approval of the clinical study report. The investigator will be provided 
reasonable access to statistical tables, figures, and relevant reports and will have the 
 
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opportunity to review the complete study results at a GSK site or other mutually-
agreeable location.
GSK will also provide the investigator with the full summary of the study results. The 
investigator is encouraged to share the summary results with the study participants, as 
appropriate.
Data Quality Assurance

All participant data relating to the study will be recorded on printed or electronic 
CRF unless transmitted to the sponsor or designee electronically (eg, laboratory data). 
The investigator is responsible for verifying that data entries are accurate and correct 
by physically or electronically signing the CRF. 

The investigator must maintain accurate documentation (source data) that supports 
the information entered in the CRF. 

The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents. 

The sponsor or designee is responsible for the data management of this study 
including quality checking of the data. 

Study monitors will perform ongoing source data verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and 
verifiable from source documents; that the safety and rights of participants are being 
protected; and that the study is being conducted in accordance with the currently 
approved protocol and any other study agreements, ICH GCP, and all applicable 
regulatory requirements. 

Records and documents, including signed ICF, pertaining to the conduct of this study 
must be retained by the investigator for 25 years from the issue of the final Clinical 
Study Report (CSR)/ equivalent summary unless local regulations or institutional 
policies require a longer retention period. No records may be destroyed during the 
retention period without the written approval of the sponsor. No records may be 
transferred to another location or party without written notification to the sponsor. 
Source Documents

Source documents provide evidence for the existence of the participant and 
substantiate the integrity of the data collected. Source documents are filed at the 
investigator’s site.

Data reported on the CRF or entered in the eCRF that are transcribed from 
source documents must be consistent with the source documents or the 
discrepancies must be explained. The investigator may need to request previous 
medical records or transfer records, depending on the study. Also, current 
medical records must be available.

Definition of what constitutes source data can be found in SDV agreement and 
addendum to SDV agreement.
 
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Study and Site Closure
GSK or its designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of GSK. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study 
supplies have been collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time, provided there is reasonable 
cause and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include 
but are not limited to:

Failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsor's procedures, or GCP guidelines

Inadequate recruitment of participants by the investigator

Discontinuation of further study treatment development
 
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12.8.
Appendix 8: Protocol Amendment History
Amendment 1 20-JUL-2018
Overall Rational for the Amendment
The amendment of this protocol including:
Section # and Name
Description of Change
Brief Rationale
Title page
Sponsor change
Sponsor change
9.4.2 Vital Signs
Add time window for blood 
pressure and pulse rate 
assessing
To have better instruction 
for procedures
10.3.3 Safety Analyses
Change data standard 
description from IDSL to 
CDISC.
Data collection strategy 
changed
Through out
Minor editorial and 
document formatting 
revision
Minor, to make the protocol 
to be consistent
TITLE PAGE
# Change 1:
Reason for change: Sponsor change
From:
Sponsor Name and Legal Registered Address: 
GlaxoSmithKline (China) Research & Development Limited
No. 1 building, 917 Halei Road
Zhangjiang Hi-tech Park, Pudong
Shanghai, 201203, China
To:
Sponsor Name and Legal Registered Address: 
GlaxoSmithKline (China) Investment Co., LTD. 
9/F Tower A, Ocean International Centre
Mid 4thEast Ring Rd, Chaoyang District 
Beijing, 200025, China
 
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9.4.2. Vital Signs
#Change 2:
Reason for change: Add time window for blood pressure and pulse rate to have better 
instruction for procedures.
From:
Blood pressure and pulse rate will be measured pre-dosing and at 2h post-dosing on Day 
1 and Day 12; on Days 2(24h), 3, 4, 5, 13(24h), 14, 15, 16; or early withdraw.
To:
Blood pressure and pulse rate will be measured pre-dosing (60 minutes pre-dosing to 
dosing time) and at 2h ±60 minutes post-dosing on Day 1 and Day 12; on Days 2 
(24h±60 minutes post-dosing), Days 3 (48h±60 minutes post-dosing), Day 4 (72h±60 
minutes post-dosing), Days 5 (96h±60 minutes post-dosing), Days 13 (24h±60 minutes 
post-dosing), Day 14 (48h±60 minutes post-dosing), Days 15 (72h±60 minutes post-
dosing), Days 16 (96h±60 minutes post-dosing); or early withdraw.
10.3.3. Safety Analyses
# Change 3:
Reason for change: Data collection strategy changed.
From: 
Safety data will be presented in tabular and/or graphical format and summarized
descriptively according to GSK Integral Data Standard Library (IDSL).
To:
Safety data will be presented in tabular and/or graphical format and summarized
descriptively according to the Clinical Data Interchange Standard Consortium (CDISC).
Through out
# Change 4:
2. Schedule of activities (SOA)
Reason for change: to make the protocol be consistent as per ‘9.4.2 Vital Signs’, vital 
signs should be assessed at Day 11.
 
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From:
Second Period
Early 
Withdraw
Follow up5
Study day
D11 D12
D13
D14 D15 D16
7-14 days 
after last 
dose
Visit
V8
V9
V10
V11 V12 V13 V14
V15
Administration

Standard Meal (fed 
group)

Sampling
(hour after dosing)
Pre, ,0.5, 1, 2,3, 4, 5, 
6, 7, 8, 10, 12, 16
24,36 48
72
96
Inclusion/exclusion 
criteria

C-SSRS2


Weight/Height


Physical 
examination



R
Vital signs3






R
12-lead ECG


R
Laboratory tests 5


R
Pregnancy test 
(WOCBP)4



Concomitant 
medication 
AE
SAE
Key: × = Mandatory Assessment; R =Repeated in case of abnormal results from the last visit.
7.
Medical history: Medical and medication history and Alcohol/Smoking history
8.
C-SSRS: Screening visit use ‘baseline’ version. The following visit use ‘since last visit’ version.
9.
Temperature, pulse rate, respiratory rate, and blood pressure will be assessed at screening, when admit to unit 
(Day 0 and Day 11) and as clinically indicated. Blood pressure and pulse rate will be measured pre-dosing and at 
2h post-dosing on Day 1 and Day 12; on the Day 2(24h), 3, 4, 5, 13(24h), 14, 15, 16; or early withdraw.
10. WOCBP=Woman of Childbearing Potential. Pregnancy test: either urine or serum test is valid.
11. Clinical laboratory tests including haematology, clinical chemistry and routine urinalysis. Refer to Appendix 5 for 
more details.
12. The participant will complete follow-up 7-14 days after last dose of medication. The follow-up can be visited by 
telephone if the participant does not need to receive any examination.
To:
Second Period
Early 
Withdraw
Follow up5
Study day
D11 D12
D13
D14 D15 D16
7-14 days 
after last 
dose
Visit
V8
V9
V10
V11 V12 V13 V14
V15
Administration

 
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Standard Meal (fed 
group)

Sampling
(hour after dosing)
Pre, ,0.5, 1, 2,3, 4, 5, 
6, 7, 8, 10, 12, 16
24,36 48
72
96
Inclusion/exclusion 
criteria

C-SSRS2


Weight/Height


Physical 
examination



R
Vital signs3







R
12-lead ECG


R
Laboratory tests 5


R
Pregnancy test 
(WOCBP)4



Concomitant 
medication 
AE
SAE
Key: × = Mandatory Assessment; R =Repeated in case of abnormal results from the last visit.
13. Medical history: Medical and medication history and Alcohol/Smoking history
14. C-SSRS: Screening visit use ‘baseline’ version. The following visit use ‘since last visit’ version.
15. Temperature, pulse rate, respiratory rate, and blood pressure will be assessed at screening, when admit to unit 
(Day 0 and Day 11) and as clinically indicated. Blood pressure and pulse rate will be measured pre-dosing and at 
2h post-dosing on Day 1 and Day 12; on the Day 2(24h), 3, 4, 5, 13(24h), 14, 15, 16; or early withdraw.
16. WOCBP=Woman of Childbearing Potential. Pregnancy test: either urine or serum test is valid.
17. Clinical laboratory tests including haematology, clinical chemistry and routine urinalysis. Refer to Appendix 5 for 
more details.
18. The participant will complete follow-up 7-14 days after last dose of medication. The follow-up can be visited by 
telephone if the participant does not need to receive any examination.
# Change 5:
5.2. Number of Participants
Reason for change: to make the protocol be consistent as early withdraw participants 
could be replaced according to Section 5.2.
From:
A sufficient number of healthy participants (approximately 36 for Fasting group and 44 
for Fed group) will be enrolled so that approximately 32 participants in Fasting group and 
40 participants in Fed group complete the study.  Either gender of evaluable participants
should be no less than one-third of the total evaluable participants. The early withdrawn 
participants will not be replaced.
 
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To:
A sufficient number of healthy participants (approximately 36 for Fasting group and 44 
for Fed group) will be enrolled so that approximately 32 participants in Fasting group and 
40 participants in Fed group complete the study.  Either gender of evaluable participants
should be no less than one-third of the total evaluable participants.
# Change 6:
9.4.1 Physical Examination
Reason for change: to make the protocol be consistent as per Section ‘2 Schedule of 
activities (SOA)’, physical examination should be performed at Day 11.
From:
A complete physical examination should be performed at screening. A brief physical 
examination should be made at the beginning/end of the study (Day 0, Day 16 or early 
withdraw). Other routine medical assessments may also be performed during the study as 
clinically indicated. 
To:
A complete physical examination should be performed at screening. A brief physical 
examination should be made at the beginning/end of the study (Day 0, Day 11, Day 16 or 
early withdraw). Other routine medical assessments may also be performed during the 
study as clinically indicated.
DOCUMENT HISTORY
List dates of original protocol and all amendments in reverse chronological order.
Document
Date
DNG Number
Amendment 1
20-Jul-2018
2017N312753_01
Original Protocol
01-Jun-2017
2017N312753_00
 
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