Conditions: Purpura, Thrombocytopenic, Idiopathic
Keywords: Chronic immune thrombocytopenic purpura, ITP, eltrombopag olamine, thrombopoietin receptor agonist, pediatrics
Enrollment: 9
Healthy volunteers: no

Brief summary:
This was an open-label Phase III extension study to evaluate the long-term safety of eltrombopag in pediatric patients with chronic ITP who previously participated in study TRA115450. This study allowed dosing of eltrombopag at an individualized dose for each subject based upon platelet count. The starting dose was based on the subject's dose at the end of the TRA115450 study. The maximum dose was 75 mg daily.

Detailed description:

Arms:
arm 1: Eligible subject will be allocated to 1 of 3 age-defined cohorts. Cohort 1: between 12 and 17 years old, Cohort 2: between 6 and 11 years old, and Cohort 3: between 1 and 5 years old. For Cohorts 1 and 2, eltrombopag tablets will be administered, however, subjects in Cohort 2 may use eltrombopag powder for oral suspension (Eltrombopag PfOS) if they have difficulty swallowing tablets and are receiving a dose of eltrombopag of \< 40 mg. For Cohort 3, either eltrombopag tablets or PfOS will be administered.

Interventions: intervention 1: Eltrombopag Tablets intervention 2: Eltrombopag PfOS
Intervention descriptions: intervention 1: Eltrombopag tablets will be white, round film coated tablets containing eltrombopag olamine equivalent to 12.5 mg, 25 mg, 50 mg and 75 mg of eltrombopag. The 12.5 mg tablet will be smaller than the 25 mg, 50 mg and 75 mg tablets. Subjects will receive maximum dose of 75 mg once daily (QD). intervention 2: Eltrombopag PfOS is a reddish-brown to yellow powder contained inside an elongated sachet. Each sachet will contain eltrombopag olamine equivalent to 20 mg of eltrombopag per gram of powder. Subjects will receive maximum dose of 75 mg once daily (QD)

Protocol document:
Prot_001.pdf: 
2012N154431_01
CONFIDENTIAL
The GlaxoSmithKline group of companies
TRA117366 / NCT02201290 
1
TITLE PAGE
Division: Worldwide Development
Information Type: Protocol Amendment
Title:
An extension study of eltrombopag in pediatric patients with 
chronic immune (idiopathic) thrombocytopenia purpura (ITP)
Compound Number:
Development Phase:
III
Effective Date:
08-JUL-2013
Protocol Amendment Number:  01
Description: A Phase III Extension study of eltrombopag in Pediatric patients with 
chronic ITP
Subject: Chronic immune thrombocytopenic pupura, ITP, eltrombopag olamine, 
thrombopoietin receptor agonist, pediatrics
Author:
 
Revision Chronology:
2012N154431_00
2013-APR-12
Original
2012N154431_01
2013-JUL-08
Amendment No. 01: Streamlining of 
laboratory and ocular assessments 
within the text and T&E Tables and the 
Data Analysis and Statistics section.  
Clarification of study objective.
  




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SPONSOR INFORMATION PAGE


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INVESTIGATOR AGREEMENT PAGE


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TABLE OF CONTENTS
PAGE
LIST OF ABBREVIATIONS.............................................................................................8
PROTOCOL SUMMARY...............................................................................................10
1.
INTRODUCTION....................................................................................................11
1.1.
Background ................................................................................................11
1.2.
Study Rationale ..........................................................................................13
2.
OBJECTIVE(S) AND ENDPOINTS.........................................................................14
3.
STUDY DESIGN ....................................................................................................14
4.
SUBJECT SELECTION AND DISCONTINUATION/ COMPLETION 
CRITERIA ..............................................................................................................15
4.1.
Subject Selection Criteria............................................................................15
4.1.1.
Number of Subjects .....................................................................15
4.1.2.
Inclusion Criteria..........................................................................15
4.1.3.
Exclusion Criteria.........................................................................16
4.2.
Permanent Discontinuation from Study Treatment and Subject 
Completion Criteria.....................................................................................16
4.2.1.
Permanent Discontinuation from Study Treatment.......................16
4.2.2.
Subject Completion......................................................................17
5.
STUDY TREATMENTS..........................................................................................18
5.1.
Eltrombopag GSK Investigational Product ..................................................18
5.1.1.
Eltrombopag Dosage and Administration.....................................18
5.1.2.
Study Treatment Starting Dose....................................................19
5.1.3.
Dose Adjustment .........................................................................20
5.1.3.1.
General Dose Adjustment Considerations..................20
5.1.3.2.
Dose Adjustment Guidelines for subjects 
receiving the tablet formulation...................................21
5.1.3.3.
Dose Adjustment Guidelines for subjects 
receiving the suspension formulation..........................22
5.2.
Preparation of Study Treatment..................................................................24
5.3.
Handling and Storage of Study Treatment ..................................................24
5.4.
Treatment Assignment................................................................................24
5.5.
Blinding.......................................................................................................25
5.6.
Product Accountability ................................................................................25
5.7.
Treatment Compliance................................................................................25
5.8.
Monitoring, Interruption and Stopping Criteria for Hepatobiliary 
Events ........................................................................................................25
5.8.1.
Liver chemistry stopping criteria...................................................25
5.8.1.1.
Liver Event Follow Up Assessments...........................27
5.8.1.2.
Liver Chemistry Monitoring Criteria.............................28
6.
CONCOMITANT MEDICATIONS AND NON-DRUG THERAPIES .........................28
6.1.
Permitted Medications and Non-Drug Therapies.........................................28
6.1.1.
Antacids and Vitamin/Mineral Supplements.................................29


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6.1.1.1.
Antacids .....................................................................29
6.1.1.2.
Calcium and Vitamin/Mineral Supplements ................29
6.1.2.
HMG-CoA Reductase Inhibitors (statins) .....................................30
6.1.3.
Concomitant  ITP Therapy ...........................................................30
6.2.
Prohibited Medications and Non-Drug Therapies........................................30
6.3.
Treatment after Discontinuation of Study Treatment or Withdrawal 
from/Completion of Study ...........................................................................31
6.4.
Treatment of Eltrombopag Overdose..........................................................31
7.
STUDY ASSESSMENTS AND PROCEDURES .....................................................31
7.1.
Screening and Baseline Assessments........................................................35
7.2.
Safety .........................................................................................................35
7.2.1.
Safety Endpoints..........................................................................35
7.2.1.1.
General Considerations..............................................35
7.2.1.2.
Physical Exam and Vital Signs ...................................35
7.2.1.3.
Clinical Laboratory Assessments................................36
7.2.1.4.
Cataract Assessment .................................................36
7.2.1.4.1.
Ocular Changes of Clinical 
Concern..................................................36
7.2.2.
Adverse Events............................................................................36
7.2.2.1.
Definition of an AE......................................................36
7.2.2.2.
Definition of a SAE .....................................................37
7.2.2.3.
Laboratory and Other Safety Assessment 
Abnormalities Reported as AEs and SAEs .................38
7.2.2.4.
Disease-Related Events and/or Disease-
Related Outcomes Not Qualifying as SAEs ................39
7.2.2.5.
Time Period and Frequency of Detecting AEs 
and SAEs ...................................................................39
7.2.2.6.
Prompt Reporting of SAEs and Other Events to 
GSK ...........................................................................39
7.2.2.7.
Regulatory reporting requirements for SAEs ..............40
7.2.3.
Pregnancy, Testing, Prevention and Reporting............................41
7.2.3.1.
Pregnancy Testing and Prevention.............................41
7.2.3.2.
Pregnancy Reporting..................................................42
7.2.4.
Laboratory Assessments .............................................................43
7.2.5.
Meals and Dietary Restrictions ....................................................43
8.
DATA MANAGEMENT ...........................................................................................43
9.
DATA ANALYSIS AND STATISTICAL CONSIDERATIONS...................................44
9.1.
Hypotheses.................................................................................................44
9.2.
Study Design Considerations......................................................................44
9.2.1.
Sample Size Assumptions ...........................................................44
9.2.2.
Sample Size Sensitivity................................................................44
9.2.3.
Sample Size Re-estimation..........................................................44
9.3.
Data Analysis Considerations .....................................................................44
9.3.1.
Analysis Populations....................................................................44
9.3.2.
Analysis Data Sets.......................................................................44
9.3.3.
Treatment Comparisons ..............................................................44
9.3.3.1.
Primary Comparisons of Interest ................................44
9.3.3.2.
Other Comparisons of Interest....................................45
9.3.4.
Interim Analysis ...........................................................................45


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9.3.5.
Key Elements of Analysis Plan ....................................................45
9.3.5.1.
Safety Analyses..........................................................45
9.3.5.1.1.
Extent of Exposure .................................45
9.3.5.1.2.
Adverse Events ......................................45
9.3.5.1.3.
Clinical Laboratory Evaluations...............46
10. STUDY CONDUCT CONSIDERATIONS ...............................................................46
10.1.
Posting of Information on Publicly Available Clinical Trial Registers............46
10.2.
Regulatory and Ethical Considerations, Including the Informed 
Consent Process ........................................................................................46
10.3.
Quality Control (Study Monitoring) ..............................................................47
10.4.
Quality Assurance.......................................................................................47
10.5.
Study and Site Closure ...............................................................................47
10.6.
Records Retention......................................................................................48
10.7.
Provision of Study Results to Investigators, Posting of Information 
on Publicly Available Clinical Trials Registers and Publication....................49
11. REFERENCES.......................................................................................................50
12. APPENDICES........................................................................................................52
12.1.
Appendix 1:  Liver Chemistry Monitoring, Interruption Stopping and 
Follow-up Criteria........................................................................................52
12.2.
Appendix 2: Protocol Changes....................................................................53


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LIST OF ABBREVIATIONS
AE
Adverse Event
ALT
Alanine aminotransferase 
AST
Aspartate aminotransferase 
ATS
All Treated Subjects
AUC(0-)
Area under the concentration-time curve over the dosing 
interval
-hCG
Beta-human chorionic gonadotropin
BMI
Body mass index
CBC
Complete blood count
CL/F
Apparent clearance following oral dosing
Cmax
Maximum observed concentration 
Cτ
Concentration at the end of the dosing interval
CPK
Creatine phosphokinase
CRF
Case Report Form
CTCAE
Common Terminology Criteria for Adverse Events
DSMB
Data Safety Monitoring Board
ECG
Electrocardiogram
EW
Early Withdrawal
FDA
Food and Drug Administration
FU
Follow-Up
GCP
Good Clinical Practice
GCSP
Global Clinical Safety and Pharmacovigilance
GSK
GlaxoSmithKline
HIV
Human Immunodeficiency Virus
h/hr
Hour(s)
IB
Investigator’s Brochure
ICH
International Conference on Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for 
Human Use
IEC
Independent Ethics Committee
IND
Investigational New Drug
IRB
Institutional Review Board
ITP
Immune (idiopathic) thrombocytopenic purpura
IU
International Unit
IV
Intravenous
Kg
Kilogram
L
Liter
Ln
Naperian (natural) logarithm
µg
Microgram
µL
Microliter
M
Month
MedDRA
Medical Dictionary for Regulatory Activities
Mg
Milligrams


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mL
Milliliter
MSDS
Material Safety Data Sheet
PfOS
Powder for Oral Suspension
PGx
Pharmacogenetics
PK
Pharmacokinetic
QC
Quality control
RBC
Red blood cells
RNA
Ribonucleic Acid
SAE
Serious adverse event(s)
SOC
System Organ Class
SPM
Study Procedures Manual
tmax
Time of occurrence of Cmax
ULN
Upper limit of normal
WBC
White blood cells
WHO
World Health Organization
W (or) WK
Week


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PROTOCOL SUMMARY
Rationale
Study TRA117366 is an extension study for pediatric chronic ITP patients who have 
previously been enrolled in the TRA115450/PETIT2 study and obtain clinical benefit 
from treatment with eltrombopag.
Objective(s)

To provide continued treatment to patients who have completed the TRA115450 
study and to describe the safety and tolerability of eltrombopag when administered to 
pediatric subjects with previously treated chronic ITP.
Study Design
This is an open-label Phase III extension study to evaluate the long-term safety of 
eltrombopag in pediatric patients with chronic ITP who previously participated in study
TRA115450.  This study will allow dosing of eltrombopag at an individualized dose for 
each subject based upon platelet count.  The starting dose will be based on the subject’s 
dose at the end of the TRA115450 study, unless a dose adjustment is warranted due to 
platelet count.  The maximum dose will be 75 mg daily.  
Maximum twelve (n = 12) patients will be enrolled into the study. Subjects may remain 
on treatment in this study until at least one of the following criteria is met: the subject 
reaches 18 years of age or eltrombopag receives local regulatory approval for the 
treatment of pediatric chronic ITP.
Study Assessments
The primary endpoint is the assessment of long-term safety.  Safety assessments will 
include clinical laboratory tests, ocular examinations, and adverse event reporting. 


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1.
INTRODUCTION
1.1.
Background


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1.2.
Study Rationale
Study TRA117366 will be conducted to evaluate the long-term safety of eltrombopag in 
pediatric chronic ITP population. This study will allow dosing of eltrombopag at an 
individualized dose for each subject based upon platelet counts.  


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2.
OBJECTIVE(S) AND ENDPOINTS
Objective
Endpoint
To provide continued treatment to patients who have 
completed the TRA115450 study and to describe 
the safety and tolerability of eltrombopag when 
administered to pediatric subjects with previously 
treated chronic ITP.
Safety parameters include clinical laboratory 
assessments,  and frequency of all adverse 
events, categorized using Common 
Terminology Criteria for Adverse Events 
(CTCAE) toxicity grades. 
3.
STUDY DESIGN
This is a Phase III study in which a screening period will be followed by a single arm 
treatment period and a follow-up period:

A screening period of up to 28 days prior to Day 1 of treatment in this study

Open-label, single arm, dose-adjustment, long-term treatment period, in which
subjects may continue treatment until at least one of the following criteria are met:

Subject reaches 18 years of age: Subject will be considered to have completed
the study, and will be discontinued from study treatment within 3 months of
his/her 18th birthday.

Eltrombopag receives local regulatory approval for pediatric chronic ITP.

Follow-up period. All subjects must complete the 4-week follow-up period, as
described below, as part of their participation in this study:

Subjects who elect not to continue treatment with eltrombopag (i.e., non-study
treatment) after completion of the study treatment period, will have weekly
follow-up visits for 4 weeks after the last dose of study treatment.

Subjects who continue treatment with eltrombopag (i.e., non-study treatment)
after completion of the study treatment periods will have a follow-up visit 4
weeks after the last dose of study treatment.
Maximum twelve (n = 12) subjects will be enrolled in the study.  
The term ‘study treatment’ is used throughout the protocol to describe the product under 
evaluation in this protocol.  
Protocol waivers or exemptions are not allowed with the exception of immediate safety 
concerns. Therefore, adherence to the study design requirements, including those 
specified in the Time and Events Table, are essential and required for study conduct
Supplementary study conduct information not mandated to be present in this protocol is 
provided in the accompanying Study Procedures Manual (SPM). The SPM will provide 
the site personnel with administrative and detailed technical information that does not 
impact subject safety.


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4.
SUBJECT SELECTION AND DISCONTINUATION/
COMPLETION CRITERIA
4.1.
Subject Selection Criteria
4.1.1.
Number of Subjects
Up to twelve (n = 12) subjects will be enrolled.  
4.1.2.
Inclusion Criteria
Specific information regarding warnings, precautions, contraindications, adverse events, 
and other pertinent information on the GSK investigational product that may impact 
subject eligibility is provided in the IB 
 
Deviations from inclusion criteria are not allowed because they can potentially jeopardize 
the scientific integrity of the study, regulatory acceptability or subject safety.  Therefore, 
adherence to the criteria as specified in the protocol is essential.
Subjects eligible for enrolment in the study must meet all of the following criteria:
1.
Written informed consent must be obtained from the subject’s guardian and
accompanying informed assent from the subject (for children over 6 years old).
2.
Subjects must be between 1 year and <18 years of age at Day 1.
3.
Subjects must have enrolled in TRA115450/PETIT2 study.
4.
Subjects must have completed Part 1 and Part 2 of TRA115450/PETIT2 study.
5.
Female subjects of child-bearing potential (after menarche) must:

have a negative pregnancy test within 24 hours of first dose of study treatment,

agree and be able to provide a blood or urine specimen for pregnancy testing
during the study,

agree to use effective contraception, as defined in Section 7.2.3, during the study
and for 28 days following the last dose of study treatment, and

not be lactating.
6.
Male subjects with a female partner of childbearing potential must agree to use
effective contraception as described in Section 7.2.3 from 2 weeks prior to
administration of the first dose of study treatment until 3 months after the last dose of
study treatment.


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4.1.3.
Exclusion Criteria
Deviations from exclusion criteria are not allowed because they can potentially 
jeopardize the scientific integrity of the study, regulatory acceptability or subject safety.  
Therefore, adherence to the criteria as specified in the protocol is essential.
Subjects meeting any of the following criteria must not be enrolled in the study:
1.
Subjects with any clinically relevant abnormality, other than ITP, identified on the
screening examination or any other medical condition or circumstance, which in the
opinion of the investigator makes the subject unsuitable for participation in the study
or suggests another primary diagnosis (e.g. Thrombocytopenia is secondary to
another disease).
2.
Any subject considered to be a child in care, defined as one who has been placed
under the control or protection of an agency, organization, institution or entity by the
courts, the government or a government body, acting in accordance with powers
conferred on them by law or regulation. This can include a child cared for by foster
parents or living in a care home or institution, provided that the arrangement falls
within the definition above. The definition of a child in care does not include a child
who is adopted or who has an appointed legal guardian.
3.
Subjects who have a known immediate or delayed hypersensitivity reaction or
idiosyncrasy to drugs chemically related to eltrombopag or excipients that
contraindicates their participation.
4.
Any serious and/or unstable pre-existing medical, psychiatric disorder, or other
conditions that could interfere with the subject’s safety or compliance to the study
procedures.
4.2.
Permanent Discontinuation from Study Treatment and 
Subject Completion Criteria
4.2.1.
Permanent Discontinuation from Study Treatment
Study treatment must be permanently discontinued for any of the following reasons:

The subject is pregnant.

The subject is significantly non-compliant with the requirements of the protocol.

The subject has an adverse experience that would, in the investigator’s
judgment, make continued participation in the study an unacceptable risk.

The subject has a thrombotic event, unless in the opinion of the investigator
interruption of eltrombopag would lead to a risk of bleeding that would
outweigh the risk of thrombosis.

The subject meets stopping criteria for liver chemistry defined in Section 5.8.1.

At the request of the subject or proxy


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In addition study treatment may be permanently discontinued for any of the following 
reasons:

Due to deviation(s) from the protocol

At the investigator’s discretion

The subject is lost to follow-up

The study is closed or terminated.
Study treatment will be discontinued within 3 months for the following reasons, and 
subject will be considered to have completed the study per Section 4.2.2:

The subject reaches 18 years of age.

The subject is in treatment phase when local regulatory approval is received for
eltrombopag for the treatment of pediatric chronic ITP.
The primary reason study treatment was permanently discontinued must be documented 
in the subject’s medical records and CRF. 
If the subject (or guardian) withdrawals consent, the Investigator must document the 
reason for withdrawal of consent in the CRF if specified by the subject or guardian.
If the subject voluntarily discontinues from treatment due to toxicity, ‘adverse event’ will 
be recorded as the primary reason for permanently discontinuation on the CRF rather 
than subject decision.   
Once a subject has been permanently discontinued from study treatment, retreatment with 
study treatment will not be allowed. 
All subjects who discontinue from study treatment will have safety assessments at the 
time of discontinuation and will have follow-up visits at 1, 2, 3, and 4 weeks after the 
final dose of study treatment, as specified in Time and Events Table, Table 3.
4.2.2.
Subject Completion
A subject will be considered to have completed the study if the subject meets at least one 
of the following conditions:

Subject reaches 18 years of age while in the treatment phase of the study.
Study treatment should be discontinued within 3 months after the 18th birthday.

Subject is in the treatment phase of the study at the time of local regulatory
approval of eltrombopag for pediatric chronic ITP.  Study treatment should be
discontinued within 3 months after regulatory approval is received.


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5.
STUDY TREATMENTS
The term ‘study treatment’ is used throughout the protocol to describe the product under 
evaluation in this protocol. 
5.1.
Eltrombopag GSK Investigational Product
 
 
 
 
 
 
Eltrombopag Tablets
Eltrombopag tablets will be white, round film coated tablets containing eltrombopag 
olamine equivalent to 12.5 mg, 25 mg, 50 mg and 75 mg of eltrombopag. The 12.5 mg 
tablet will be smaller than the 25 mg, 50 mg and 75 mg tablets. 
Tablets will be packaged in white 45cc HDPE bottles with white plastic, induction-seal 
child-resistant caps. Each bottle will contain 35 tablets.
Eltrombopag Powder for Oral Suspension
Eltrombopag powder for oral suspension (Eltrombopag PfOS) is a reddish-brown to 
yellow powder contained inside an elongated sachet.  Each sachet will contain 
eltrombopag olamine equivalent to 20 mg of eltrombopag per gram of powder.  
PfOS sachets will be packaged in a carton.  Each carton pack will hold 35 sachets along 
with a plastic reconstitution container and a syringe-adapt cap. The pack will also contain 
an extra syringe-adapt cap as a spare.  The clinical site will provide a 10cc syringe with 
each carton.
Refer to Section 5.2 for the required preparation of the sachets, which is to be performed 
by the subject/parent/guardian prior to dosing.
5.1.1.
Eltrombopag Dosage and Administration
For subjects between the ages of 6 to 17 years old, eltrombopag tablets will be 
administered, however, subjects between the ages of 6 to 11 years old may use PfOS if 
they have difficulty swallowing tablets and are receiving a dose of eltrombopag of < 40 


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mg.  For subjects between the ages of 1 to 5 years old, either eltrombopag tablets or 
PfOS will be administered.
Any change between PfOS and tablet formulations should take into account the 
differences in bioavailability between formulations. In a relative bioavailability study 
conducted under fasted conditions in healthy adult subjects, the eltrombopag PfOS 
formulation delivered 22% higher plasma eltrombopag AUC(0-) and 30% higher Cmax 
compared to the tablet formulation. When switching from PfOS to tablets, the nearest 
tablet strength rounding up should be used.
The maximum dose allowed will be 75 mg once daily. 
Site personnel will instruct the subjects (and their parents/guardians) on how to take their 
medication. Every effort should be made to encourage subject compliance with the 
dosage regimen as per protocol.  
Study treatment will be dispensed in either bottles containing 35 tablets each, or packs 
containing 35 unit-dose sachets each, which will be given to each subject’s 
parents/guardians starting on Day 1.  
For subjects who receive tablets, new study treatment containers (bottles) will be 
dispensed at each change in dose or dose frequency, and study treatment compliance will 
be assessed as described in Section 5.7. For subjects who receive PfOS, study treatment 
compliance will be assessed at each visit as described in Section 5.7, and additional packs 
of sachets will be dispensed when the site personnel determine the current supply will not 
be sufficient until the next study visit.  All subjects/parents/guardians should be 
instructed to bring all bottles or sachets with any unused drug to each visit with the 
investigator.
5.1.2.
Study Treatment Starting Dose
After completion of treatment in TRA115450, subjects will continue on the same dose 
during this study unless adjustments are warranted according to the dosing guidelines. 
For children between the ages of 1 to 11 years old, a change in formulation (between 
PfOS and tablets) may also be considered based upon guidelines in Section 5.1.1.


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5.1.3.
Dose Adjustment
Each subject’s dose of study treatment will be adjusted as needed following the provided 
dosing guidelines and based upon their individual platelet response. The Investigators are 
allowed to use their clinical judgment in determining dose adjustments. In this study, the 
target platelet count range is between 50 Gi/L and 200 Gi/L.  As previously stated, the 
goal is to have a platelet count in a safe haemostatic range, not necessarily in the normal 
range.
5.1.3.1.
General Dose Adjustment Considerations
Investigators are expected to use their clinical judgment and knowledge about each 
subject’s individual disease characteristics (including platelet count fluctuation and 
response to prior doses) for any dose adjustment.
The following considerations should be taken into account when modifying the dose of 
study treatment.  These considerations should be used in conjunction with the specific 
guidelines for the tablet formulation (Refer to Section 5.1.3.2), and with the specific 
guidelines for the suspension formulation (Refer to Section 5.1.3.3).
1.
Changes in concomitant ITP medications that could affect the platelet count.  
2.
Other clinical situations which, in the opinion of the investigator, may affect the 
platelet count, for example, among others:

Subject received systemic corticosteroids for a different condition

A viral infection that may decrease OR increase the platelet count
3.
Subject’s response to eltrombopag during prior study participation (TRA115450).  If 
a subject has a platelet count that would require changing the dose to a dose that was 
previously proven to achieve platelet counts outside of the desired range (<50 or > 
200 Gi/L), alternating doses of different strength tablets or changes in frequency may 
be considered. For example:

If a subject taking 50 mg daily has a platelet count >200 Gi/L and hence requires 
a dose reduction, but 37.5 daily has proven to result in a platelet count below 
50 Gi/L, the subject may require 50 mg and 37.5 mg doses on alternate days.

If a subject taking 12.5 mg daily has a platelet count <50 Gi/L and hence 
requires a dose increase, but 25 mg has proven to result in a platelet count 
> 200 Gi/L, the subject may require 12.5 mg and 25 mg on alternate days.

If a subject is on a 12.5 mg daily dose and has a platelet count >200 Gi/L, a dose 
of 12.5 mg every other day may be required (changing the frequency of dosing).
After a dose adjustment, investigators must wait at least 2 weeks before making any other 
adjustment, with the exception of reducing eltrombopag if the platelet count rises above 
200 Gi/L and interrupting eltrombopag if the platelet count rises above 400 Gi/L.


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If a subject’s platelet count increases significantly and if the investigator thinks a dose 
reduction is medically appropriate, the dose can be decreased even if the platelet count is 
below 200 Gi/L or a dose modification was done less than 2 weeks before.  
If after an interruption the subject’s platelet count decreases drastically and if the 
investigator thinks re-initiation is medically appropriate, the dose can be reinitiated at the 
next lower dose level even if the platelet count has not yet decreased to below 150 Gi/L. 
(Refer to Dose Decrease guidelines in Section 5.1.3.2, below.)
If a subject’s platelet count decreases drastically and the investigator thinks a dose 
increase is medically appropriate, the dose can be increased even if the platelet count is 
more than 50 Gi/L.
5.1.3.2.
Dose Adjustment Guidelines for subjects receiving the tablet 
formulation
Dose adjustment guidelines for the tablet formulation are provided in the below sections 
and in Table 1.
Dose Increase 
Dose increases can be made every 2 weeks until the target platelet count or the maximum 
allowed dose of 75 mg daily is achieved. 
If a subject has a platelet count < 50 Gi/L and requires a dose increase, and the next 
higher dose (increase of 12.5 mg) has already proven to be associated with platelet counts 
> 200 Gi/L, then alternating doses may be used (e.g., 25 mg and 37.5 mg on alternating 
days).
Dose Decrease 
If platelets rise above 200 Gi/L, subjects will reduce their dose by 12.5 mg at 2 week 
intervals until the platelet count is below 200 Gi/L. If platelets rise above 400 Gi/L, 
subjects will interrupt eltrombopag and platelet counts will be monitored within 1 week 
and every 3-4 days thereafter; once platelets are below 150 Gi/L, eltrombopag will be re-
started at the next available lower dose level.
If a subject requires a dose lower than the available tablet strengths or between 2 
available tablet strengths, alternate dosing regimens that modify the frequency of 
administration may be implemented as described in Section 5.1.3.1. Such alternate 
regimens must be documented in the CRF.


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Table 1
Dose Adjustment Guidelines - Tablet formulation
Platelet count
Dose
Dose adjustment
<50 Gi/L3
12.5 mg
Increase to 25 mg 
25 mg
Increase to 37.5 mg
37.5 mg
Increase to 50 mg
50 mg
Increase to 62.5 mg
62.5 mg
Increase to 75 mg
75 mg
Maintain 75 mg dose1
50 – 200 Gi/L
Maintain current dose
200 – 400 Gi/L2,3
12.5 mg
Decrease to 12.5 mg every other day
25 mg
Decrease to 12.5 mg
37.5 mg
Decrease to 25 mg
50 mg
Decrease to 37.5 mg  
62.5 mg
Decrease to 50 mg  
75 mg
Decrease to 62.5 mg  
>400 Gi/L 
Interrupt study treatment until 
platelets < 150 Gi/L4
12.5 mg
After interruption reinitiate at a reduced 
frequency, 12.5 mg every other day
25 mg
After interruption, reinitiate at 12.5 mg
37.5 mg
After interruption, reinitiate at 25 mg
50 mg
After interruption, reinitiate at 37.5 mg
62.5 mg
After interruption, reinitiate at 50 mg
75 mg
After interruption, reinitiate at 62.5 mg
1.
If a subject has reached the maximum allowed dose and has platelet counts < 50 Gi/L, the investigator (or 
designee) may choose to have the subject continue in the trial if clinical benefit is documented in terms of 
improved platelet counts OR reduced bleeding symptoms. 
2.
If a subject requires a dose adjustment, and the next available dose (adjusting by 12.5 mg) has already proven to 
be associated with platelet counts outside of the target range (i.e., <50 Gi/L or >200 Gi/L), then alternating doses 
may be used, as described in Section 5.1.3.1.
3.
The Investigator may consider keeping the current dose if a drop in platelet counts would be expected by reducing 
the dose. 
4.
If the platelet count is still above 150 Gi/L within one week after study treatment interruption, the platelet count 
needs to be monitored 3-4 days later, and twice a week thereafter. Once the subject's platelet count is ≤150 Gi/L, 
study treatment should be started at the next lower dose or frequency.
5.1.3.3.
Dose Adjustment Guidelines for subjects receiving the suspension 
formulation
The starting dose of eltrombopag for subjects receiving the PfOS formulation will be the 
subject’s last dose in TRA115450 unless an adjustment is required based on the platelet 
count.
The dose of eltrombopag will be increased or decreased according to platelet counts as 
outlined in Section 5.1.3.1.  These modifications will initially be in strength intervals of 
30% (rounded up) as shown in Table 2, but intermediate dosing levels may be used if the 
platelet response warrants it.  Subsequent dose adjustments should be made based upon 
the current dose of eltrombopag. The starting dose and each adjusted dose will be 
documented in the CRF.


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For a calculated dose of 18 to 24 mg, subjects should receive one sachet, which is 
equivalent to a 20 mg dose.  A subsequent dose adjustment would be based upon the 
actual dose of 20 mg, i.e., a 30% increase in dose would be an increase of 6 mg for a total 
of 26 mg.  For calculated doses of 38 to 44 mg, subjects should receive a 40 mg dose 
(two sachets); subsequent dose adjustment would be based on the actual dose received, 
i.e., 40 mg.
Table 2
Dose Adjustment Guidelines – suspension formulation
Weight (kg)
Initial Dose (mg)
Initial Dose
(ml)
Adjust dose by1
(mg)
Adjust dose by 
(ml)
8
10
5
3
1.5
9
11
5.5
4
2
10
12
6
4
2
11
13
6.5
4
2
12
14
7
5
2.5
13
16
8
5
2.5
14
17
8.5
6
3
15
20 2
10
6
3
16
20 2
10
6
3
17
20 2
10
6
3
18
20 2
10
6
3
19
20 2
10
6
3
20
20 2
10
6
3
21
25
12.5
8
4
22
26
13
8
4
23
28
14
9
4.5
24
29
14.5
9
4.5
25
30
15
9
4.5
26
32
16
10
5
27
33
16.5
10
5
28
34
17
11
5.5
29
35
17.5
11
5.5
30
36
18
11
5.5
31
38
19
12
6
32
39
19.5
12
6
33
40
20
12
6
34
41
20.5
13
6.5
35
42
21
13
6.5
36
44
22
14
7
37
45
22.5
14
7
38
46
23
14
7
39
47
23.5
15
7.5
40
48
24
15
7.5
1.
This table illustrates the doses based upon a subject’s weight and the corresponding 30% dose adjustment.
Subsequent dose adjustments would be calculated based upon the current dose (and not the starting dose).
2.
For a calculated dose of 18 to 24 mg, subjects should receive one sachet, which is equivalent to a 20 mg dose.  A


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Weight (kg)
Initial Dose (mg)
Initial Dose
(ml)
Adjust dose by1
(mg)
Adjust dose by 
(ml)
subsequent dose adjustment would be based upon the actual dose of 20 mg, i.e., a 30% increase in dose would 
be an increase of 6 mg for a total of 26 mg.
5.2.
Preparation of Study Treatment
Eltrombopag Tablets
Tablets will be provided to the site and no specific preparation of study treatment is 
required prior to administration.
Eltrombopag Powder for Oral Suspension
The powder for oral suspension PfOS is presented as a reddish brown to yellow powder, 
which when reconstituted with water forms a reddish-brown suspension. The sachet 
should not be opened until ready to use. Add 9.5 mL of water drawn using a 10cc syringe 
into the provided plastic container.  Cut open the sachet and add the entire content of the 
sachet into the container with water.  The container is capped and shaken for 10-20 
seconds.  The resulting suspension contains 2 mg/mL of eltrombopag dose.  The 
prescribed volume (dose) is drawn through the syringe port on the cap with a syringe.  
Upon dosing, the rest of the remaining suspension in the container is discarded.  The 
container and the syringe are rinsed with water and dried.
If the prescribed dose is > 24 mg, which will require that part or all of a second sachet be 
used, then the suspension can be prepared by adding the contents of the two sachets to 
19.0 mL of water, and then following the steps outlined above.  The water has to be 
drawn by using the 10cc syringe twice, and similarly dosing has to occur by using the 
same 10cc syringe twice.
A fresh dose is prepared everyday just prior to the dosing and no storage of the 
reconstituted suspension is allowed.
5.3.
Handling and Storage of Study Treatment
Eltrombopag tablets and PfOS sachets must be stored in a secure area under the 
appropriate physical conditions for the product according to the requirements listed on 
the label. Access to and administration of the study treatment will be limited to the 
investigator and authorized site staff. Study treatment must be dispensed or administered 
only to subjects enrolled in the study and in accordance with the protocol.
Eltrombopag tablets and PfOS sachets will be stored at a controlled room temperature of 
20-25°C (68-77°F); excursions between 15-30°C (59-86°F) are permissible.
5.4.
Treatment Assignment
Subjects will be identified by a unique subject number that will remain consistent for the 
duration of the study.


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Upon completion of all the required screening assessments, eligible subjects will be 
registered into the trial by the investigator or authorized site staff.  All enrolled subjects 
will receive eltrombopag (tablets or PfOS). 
5.5.
Blinding
This is an open-labeled study.
5.6.
Product Accountability
In accordance with local regulatory requirements, the investigator, designated site staff, 
or head of the medical institution (where applicable) must document the amount of 
investigational product dispensed and/or administered to study subjects, the amount 
returned by study subjects, and the amount received from and returned to GSK, when 
applicable.  Product accountability records must be maintained throughout the course of 
the study.  Refer to the SPM for further detailed instructions on product accountability.
5.7.
Treatment Compliance
At each visit, an evaluation of subject compliance with taken medication will be 
performed.    
Compliance with eltrombopag will be assessed through querying the subject during the 
site visits and documented in the source documents and IP dispensing log. 
A record of the number of eltrombopag tablets or sachets dispensed to and taken by each 
subject must be maintained and reconciled with study treatment and compliance records.  
Treatment start and stop dates, including dates for treatment delays and/or dose 
reductions will also be recorded in the IP dispensing log.
The investigator will make every effort to bring non-compliant subjects into compliance. 
If in the opinion of the investigator, there are any significant irregularities in compliance, 
and the subject cannot be brought back into compliance, then the subject should be 
withdrawn from the study.
5.8.
Monitoring, Interruption and Stopping Criteria for 
Hepatobiliary Events
5.8.1.
Liver chemistry stopping criteria
Liver chemistry stopping criteria and follow up requirements have been designed to 
assure subject safety and evaluate liver event etiology in alignment with the FDA 
Guidance for Industry – Drug-Induced Liver Injury: Premarketing Clinical Evaluation 
(July 2009, www.fda.gov).


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Liver chemistry stopping criteria 1-5 are defined as follows:
1.
ALT 3x ULN and bilirubin 2x ULN (>35% direct bilirubin) (or ALT 3x ULN 
and INR > 1.5, if INR measured)
NOTE: If serum bilirubin fractionation is not immediately available, study drug 
should be discontinued if ALT 3x ULN and bilirubin 2x ULN. Serum bilirubin 
fractionation should be performed if testing is available.  If testing is unavailable, 
record presence of detectable urinary bilirubin on dipstick, indicating direct 
bilirubin elevations and suggesting liver injury.
2.
ALT ≥ 5x ULN
3.
ALT ≥ 3x ULN if associated with symptoms (new or worsening) believed to be 
related to hepatitis (such as fatigue, nausea, vomiting, right upper quadrant pain or 
tenderness, or jaundice) or believed to be related to hypersensitivity (such as fever, 
rash or eosinophilia).
4.
ALT ≥ 3x ULN persists for ≥ 4 weeks
5.
ALT ≥ 3x ULN and cannot be monitored weekly for 4 weeks
When any of the liver chemistry stopping criteria 1 - 5 is met, do the following:

Immediately discontinue study treatment

Report the event to GSK within 24 hours of learning its occurrence

Complete the liver event CRF and SAE data collection tool if the event also meets 
the criteria for an SAE  

All events of ALT 3x ULN and bilirubin 2x ULN (>35% direct bilirubin) 
(or ALT 3x ULN and INR > 1.5, if INR measured; INR measurement is not 
required and the threshold value stated will not apply to subjects receiving 
anticoagulants), termed ‘Hy’s Law’, must be reported as an SAE (excluding 
studies of hepatic impairment or cirrhosis).

NOTE: if serum bilirubin fractionation is not immediately available, study 
treatment should be discontinued if ALT 3x ULN and bilirubin 2x ULN. 
Serum bilirubin fractionation should be performed if testing is available. If 
testing is unavailable, record presence of detectable urinary bilirubin on 
dipstick, indicating direct bilirubin elevations and suggesting liver injury.

Complete the liver imaging and/or liver biopsy CRFs if these tests are performed

Perform liver event follow up assessments, and monitor the subject until liver 
chemistries resolve, stabilize, or return to baseline values as described below

Do not rechallenge with investigational product.


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In addition, for subjects meeting liver stopping criterion 1: 

Make every reasonable attempt to have subjects return to clinic within 24 hours for 
repeat liver chemistries, liver event follow up assessments (refer to Section 5.8.1.1), 
and close monitoring

A specialist or hepatology consultation is recommended

Monitor subjects twice weekly until liver chemistries (ALT, AST, alkaline 
phosphatase, bilirubin) resolve, stabilize or return to within baseline values.
For subjects meeting any of the criteria 2 – 5:

Make every reasonable attempt to have subjects return to clinic within 24-72 hrs for 
repeat liver chemistries and liver event follow up assessments (refer to 
Section 5.8.1.1)

Monitor subjects weekly until liver chemistries (ALT, AST, alkaline phosphatase, 
bilirubin) resolve, stabilize or return to within baseline values; 

subjects meeting criterion 5 should be monitored as frequently as possible.
5.8.1.1.
Liver Event Follow Up Assessments
For subjects meeting any of the liver chemistry stopping criteria 1 – 5, make every 
attempt to carry out the liver event follow up assessments described below:

Viral hepatitis serology including:

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 

Serum creatine phosphokinase (CPK) and lactate dehydrogenase (LDH).

Fractionate bilirubin, if total bilirubin 2x ULN.

Obtain complete blood count with differential to assess eosinophilia.

Record the appearance or worsening of clinical symptoms of hepatitis, or 
hypersensitivity, such as fatigue, nausea, vomiting, right upper quadrant pain or 
tenderness, fever, rash or eosinophilia as relevant on the AE form.

Record use of concomitant medications, acetaminophen, herbal remedies, other over 
the counter medications, or putative hepatotoxins, on the concomitant medications 
form.


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
Record alcohol use on the liver event alcohol intake form.
The following assessments are required for subjects with ALT 3x ULN and bilirubin 
2x ULN (>35% direct) but are optional for other abnormal liver chemistries:

Anti-nuclear antibody, anti-smooth muscle antibody, and Type 1 anti-liver kidney 
microsomal antibodies

Liver imaging (ultrasound, magnetic resonance, or computerized tomography) to 
evaluate liver disease.
5.8.1.2.
Liver Chemistry Monitoring Criteria
For subjects with ALT 3x ULN but <5x ULN and bilirubin <2x ULN, without hepatitis 
symptoms or rash, and who can be monitored weekly for 4 weeks, the following actions 
should be taken:

Notify the GSK Medical Monitor within 24 hours of learning of the abnormality to 
discuss subject safety

Can continue study treatment 

Must return weekly for repeat liver chemistries (ALT, AST, alkaline phosphatase, 
bilirubin) until they resolve, stabilize or return to within baseline values 

If at any time the subject meets any of the liver chemistry stopping criteria 1 – 5, 
proceed as described above

If, after 4 weeks of monitoring, ALT <3x ULN and bilirubin <2x ULN, monitor 
subjects twice monthly until liver chemistries normalize or return to within baseline 
values. 
Refer to Appendix 1 for algorithm of liver chemistry monitoring, stopping and follow up 
criteria.
6.
CONCOMITANT MEDICATIONS AND NON-DRUG 
THERAPIES
6.1.
Permitted Medications and Non-Drug Therapies
Any medication taken within 7 days of study medication administration must be recorded 
in the CRF .
All concomitant medications taken during the study will be recorded in the CRF with 
indication, dose information, as well as start and stop dates of administration.
If any medication is required at any time within 7 days before study treatment 
administration until completion of the 4-week follow-up visit, subjects should consult the 
investigator and details should be recorded in the CRF.  


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6.1.1.
Antacids and Vitamin/Mineral Supplements
Ingestion of polyvalent cation-containing antacids, and vitamin/mineral supplements 
(aluminum, calcium, iron, magnesium, selenium, strontium among others) with study 
treatment may result in a decrease in exposure of eltrombopag. Therefore, every effort 
must be made to educate subjects on how to take study treatment with these medications. 
Details of these and all concomitant medications should be recorded in the CRF.
Administration of eltrombopag, as the tablet or the PfOS formulation, with polyvalent 
metal cation-containing antacids or with high-calcium (425mg calcium) meals reduced 
plasma eltrombopag AUC(0-) and Cmax 60 to 80%.  Administration of eltrombopag 
PfOS  2 hours after a high-calcium (425mg calcium) meal reduced plasma eltrombopag 
AUC(0-) and Cmax approximately 50%.  Administration of eltrombopag PfOS 2 hours 
before a high-calcium (425mg calcium) meal attenuated the effect, resulting in plasma 
eltrombopag AUC(0-) and Cmax values 15 to 20% lower compared to fasting.  
Administration of eltrombopag with low-calcium (<50mg calcium) meals did not 
significantly alter plasma eltrombopag exposure.  Given these data, the recommendations 
in the following sections (Section 6.1.1.1 and Section 6.1.1.2) for administration of 
eltrombopag relative to polyvalent metal cation-containing products such as some 
antacids, vitamin/mineral supplements, and dairy products should be followed.
6.1.1.1.
Antacids
Subjects requiring routine (e.g. daily) acid suppression should be encouraged to take H2 
antagonists like ZANTAC™, Famox, Pepzan, Pepcidine, Axid or proton pump inhibitors 
like Losec, Nexium, Zoton, Protium.
Subjects requiring occasional acid suppression may take liquid or chewable antacids 
(TUMS™, Maalox, Mylanta, Amphogel, Milk of Magnesia) provided study medication 
is taken at least 2 hours before or 4 hours after consumption of polyvalent cation 
containing antacids.
6.1.1.2.
Calcium and Vitamin/Mineral Supplements
Calcium and/or vitamin/mineral supplements as described above are permitted during the 
study but study treatment must be taken at least 2 hours before or 4 hours after 
consumption of these products.  


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6.1.2.
HMG-CoA Reductase Inhibitors (statins)
Subjects receiving HMG-CoA reductase (3-hydroxy-3-methyl-glutaryl-coenzyme A) 
inhibitors during the study should be closely monitored for safety, such as liver chemistry 
and signs and symptoms of myolysis, and efficacy, such as cholesterol and triglycerides 
(refer to individual product information for monitoring recommendations).  
Preclinical data showed that eltrombopag is an inhibitor of the transporters OATP1B1 
and BCRP.  Therefore, a clinical drug interaction study to evaluate the impact of 
eltrombopag on the PK of rosuvastatin, an OATP1B1 and BCRP substrate, was 
conducted in healthy subjects.  Co-administration of eltrombopag 75 mg once daily for 
5 days with a single 10 mg dose of rosuvastatin administered on Day 5 increased plasma 
rosuvastatin Cmax 2.03-fold and AUC(0-) 55%. When co-administered with 
eltrombopag, a 50% dose reduction of the HMG-CoA reductase inhibitor is 
recommended.
Concomitant administration of eltrombopag and other OATP1B1 or BCRP substrates 
should be used with caution.
6.1.3.
Concomitant  ITP Therapy
Subjects will be permitted to use stable maintenance ITP therapy (including, but not 
limited to: corticosteroids, azathioprine, danazol, cyclosporine A, mycophenolate 
mofetil), as per local ITP treatment protocols.  
Use of rescue ITP medication is allowed at any time the investigator deems it is 
indicated. Rescue medication is defined as the addition of new therapies intended to raise 
the platelet count, including medications, platelet transfusions, splenectomy or the 
increase of the dose of any concomitant ITP medications taken at baseline. 
Concomitant ITP medications may be reduced at the discretion of the investigator 
according to the platelet count and provided the dose of eltrombopag has been stable for 
3 consecutive weeks.
Investigators may use accepted local protocols or guidelines for reduction of concomitant 
ITP medications; however, the dose of eltrombopag should not be reduced while tapering 
concomitant ITP medications unless clinically indicated. Investigators must carefully 
document all concurrent medications received for treatment of ITP and any changes in 
dosage strength or frequency in the CRF.
6.2.
Prohibited Medications and Non-Drug Therapies
Subjects must abstain from using investigational and prohibited prescription or non-
prescription drugs within 7 days or 5 half-lives (whichever is longer) prior to the first 
dose of study treatment and until completion of follow-up procedures unless in the 
opinion of the Investigator and sponsor the medication will not interfere with the study 
(see Section 4.1 Subject Selection Criteria).


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Drugs that affect platelet function (including but not limited to, aspirin, clopidogrel 
and/or NSAIDS) should not be taken during the study unless there is a very clear 
indication and the Investigator documents the rationale. This is due to the fact that they 
may affect the results of the bleeding scale assessments.
Any other TPO-R agonists are prohibited during the study.
Subjects must abstain from taking herbal supplements within 7 days (or 14 days if the 
drug is a potential enzyme inducer) or 5 half-lives (whichever is longer) prior to the first 
dose of study treatment until completion of the 4-week follow-up visit, unless the 
Investigator and medical monitor agree that the medication will not interfere with the 
study treatment.
6.3.
Treatment after Discontinuation of Study Treatment or 
Withdrawal from/Completion of Study
The investigator is responsible for ensuring that consideration has been given for the 
post-study care of the patient’s medical condition whether or not GSK is providing 
specific post-study treatment.
6.4.
Treatment of Eltrombopag Overdose
Treatment of any suspected or confirmed overdose with eltrombopag should be 
symptomatic, and supportive care is recommended in cases where overdose is suspected, 
as per the IB for eltrombopag 
 
No specific antidote is known.  A hematologist will be consulted and appropriate 
treatments will be determined.
For the purposes of this study, an overdose of eltrombopag is defined as any dose greater 
than the highest daily dose included in the protocol.
7.
STUDY ASSESSMENTS AND PROCEDURES
A signed, written informed consent form must be obtained from the subject’s guardian 
prior to any screening or study-specific procedures or assessments. Subjects over 6 years 
old will be asked to sign an assent form. 
Subjects must be screened to ensure they meet the eligibility criteria specified in 
Section 4.1, Subject Selection Criteria.  All screening and baseline evaluations must be 
completed prior to initiating treatment with study treatment. 
Refer to the Time and Events Table for the timing of all assessments (Table 3).  Details 
on safety assessments are presented in Section 7.2, respectively.  Further details of study 
procedures and assessments can be found in the study procedures manual (SPM).


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Weekly visits will take place within 3 days of the nominal visit date, in reference to 
Day 1.  Monthly visits will take place within 7 days of the nominal visit date, in 
reference to Day 1. Every effort should be made to keep to the nominal schedule. 
Procedures conducted as part of the subject’s routine clinical management (e.g., blood 
count) and obtained prior to signing of informed consent may be used for screening or 
baseline purposes provided the procedure meets the protocol-defined requirements and 
has been performed in the timeframe required for the study.
Investigators may be requested to perform additional safety tests during the course of the 
study based on newly available data to ensure appropriate safety monitoring.  
Appropriate local regulatory and ethical approvals should be obtained before any 
additional testing is performed.


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Table 3
Time and Events Table
TRA117366
Screening1
Open-Label Treatment Period
Follow-up Period
Study Day
Day 1 Weekly
Every 4 
weeks
Every 6 
weeks
End of 
Treatment2
1W 
FU3
2W 
FU3
3W 
FU3
4W 
FU
Informed consent
X
Medical history and evaluation of 
eligibility
X
Physical exam4
X
Concurrent medication review
X
X
X
X
X
X
X
X
X
Pregnancy test (urine)5
X5
At least every 8 weeks
X
CBC 6
X
X
X
X
X
X
X
X
X
Peripheral blood smear7
X
X
X
X
X
Clinical chemistry8
X
X
X
X
X
X
X9
X9
X9
AE questioning
X
X
X
X
X
X
X
X
X
Cataract assessment10
Every 12 months


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Table 3
Time and Events Table (Continued)
W: week; FU: follow-up; M: month
Note: If the subject continues on a stable dose of eltrombopag for 3 consecutive weeks, also if at the day 1 patient received stable dose  in 
TRA115450 for at least 3 consecutive weeks  (without changes in concomitant ITP therapy), assessments may be scheduled every 4 weeks (7 
days of nominal visit day) rather than weekly. If the subject continues on a stable dose of eltrombopag for 3 consecutive monthly visits (without 
changes in concomitant ITP therapy), including any consecutive monthly visits in TRA115450 prior to coming into this study, assessments frequency 
may be further reduced and may be scheduled every 6 weeks (7 days of nominal visit day). If the dose of eltrombopag is not stable, weekly visits 
(3 days of nominal visit day) will be required.  
1.
Screening visit may occur on the same day as the Day 1 visit.
2.
All subjects will attend the End of Treatment visit on the day of or within 3 days after the last dose of study treatment.  
3.
Subjects who continue on treatment with eltrombopag (i.e., non-study treatment) will not be required to attend the Week 1, 2 and 3 Follow-up 
visits.
4.
Physical Exam to be performed at screening.
5.
For female subjects of child-bearing potential, a negative pregnancy test (urine or blood sample) MUST be obtained within 24 hours prior to the 
first dose. Tests to confirm that female subjects of childbearing potential are not pregnant will be conducted at least once every 8 weeks while 
receiving study treatment and after 4 weeks following completion or discontinuation of study treatment.
6.
CBC parameters: platelet count, hemoglobin, and WBC, .
7.
Peripheral blood smear to be performed on Day 1 and at least once every 6 weeks, regardless of the visit schedule (weekly, 4-weekly or 6-
weekly).
8.
Clinical Chemistry:  Alkaline phosphatase, AST, ALT, total bilirubin, and direct bilirubin.  
9.
If clinical chemistry at follow-up week 1 is normal, no clinical chemistry will be measured at follow-up weeks 2, 3 and 4.
10. An age-appropriate  standard of care exam will be performed to assess the presence of cataracts every 12 months while in the study treatment 
period.  


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7.1.
Screening and Baseline Assessments
A signed, written informed consent form must be obtained from the subject’s guardian 
prior to any screening or study-specific procedures or assessments. Subjects over 6 years 
old will be asked to sign an assent form. 
Subjects must be screened to ensure they meet the eligibility criteria specified in 
Section 4.1, Subject Selection Criteria.  Screening assessments will be performed within 
4 weeks (28 days) prior to the first dose of study treatment.  All screening and baseline 
evaluations must be completed prior to initiating study treatment.  The following baseline 
results must be reviewed prior to initiating study treatment, including:

Urine or serum pregnancy test, for females of childbearing potential, within 
24 hours of first dose of study treatment.
The required screening assessments are outlined in Table 3, Time and Events Table.
If a subject is not eligible for the study per the Inclusion and Exclusion Criteria at the 
initial attempt, and in the investigator’s opinion the subject may become eligible at a later 
date during the enrolment period, the investigator is allowed to re-screen the subject.
7.2.
Safety
7.2.1.
Safety Endpoints
Safety and tolerability endpoints include clinical laboratory assessments and frequency of 
all adverse events, categorized using Common Terminology Criteria for Adverse Events 
(CTCAE) toxicity grades.  Refer to the SPM for current version.
7.2.1.1.
General Considerations
Once the dose of eltrombopag and other ITP medications has been stable for 3 
consecutive weeks, which may include the prior 3 weeks in the TRA115450 study, 
monthly visits will be acceptable unless in the investigator’s opinion there is a specific 
medical reason for more frequent evaluations. If the dose is not stable, weekly visits will 
be required. 
Planned time points and more detailed information for all safety assessments are listed in 
the Time and Events Tables (Section 7 Table 3).  
7.2.1.2.
Physical Exam and Vital Signs
Physical Exam
A physical examination will be done at Day 1 per the investigator’s usual practice and 
any abnormal findings will be recorded on the appropriate form in the CRF, e.g, Medical 
History or AE/SAE form. 


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7.2.1.3.
Clinical Laboratory Assessments
Hematology and clinical chemistry parameters to be tested are listed in Section 7.2.4; 
Table 4 lists the parameters to be tested locally.  The amount of blood drawn for all 
routine clinical laboratory assessments for this study is anticipated to be approximately
15-20 mL per study visit. Every effort will be done to reduce this to a minimum 
according to each local lab’s requirements.
7.2.1.4.
Cataract Assessment
Ophthalmic safety, with focus on cataracts, will be assessed in all subjects following 
procedures used in standard practice at the times listed in the Time and Events Table. 
Ocular examinations will be performed by an ophthalmologist or an optometrist under the 
guidance of an ophthalmologist.  Assessments should be performed, whenever possible, 
by the same examiner.
Any abnormal findings will be recorded in the appropriate CRF form, e.g., Medical 
History or AE/SAE form.
7.2.1.4.1.
Ocular Changes of Clinical Concern
Ophthalmic events of clinical concern as defined by the examiner, include, but are not 
limited to:

Decreased vision due to cataractous changes; 

Progressive lens changes:  Worsening cataractous changes observed on slit lamp 
examination; and

Need for cataract surgery.
7.2.2.
Adverse Events
The investigator or site staff will be responsible for detecting, documenting and reporting 
events that meet the definition of an AE or SAE as outlined in Section 7.2.2.1 and 
Section 7.2.2.2.
7.2.2.1.
Definition of an AE
An AE is any untoward medical occurrence in a subject or clinical investigation subject, 
temporally associated with the use of a medicinal product, whether or not considered 
related to the medicinal product.
Note: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a medicinal product.  For marketed medicinal products, this 
also includes failure to produce expected benefits, abuse, or misuse. 


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Examples of events meeting the definition of an AE include:

Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or grade of the condition

New conditions detected or diagnosed after study treatment administration even 
though it may have been present prior to the start of the study

Signs, symptoms, or the clinical sequelae of a suspected interaction

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication (overdose per se will not be reported as an 
AE/SAE unless this is an intentional overdose taken with possible suicidal/self-
harming intent.  This should be reported regardless of sequelae). 

“Lack of efficacy” or “failure of expected pharmacological action” per se is not to 
be reported as an AE or SAE.  However, any signs and symptoms and/or clinical 
sequelae resulting from “lack of efficacy” will be reported as an AE or SAE, if they 
fulfill the definition of an AE or SAE. 
Events that do not meet the definition of an AE include:

Medical or surgical procedure (e.g., endoscopy, appendectomy); the condition that 
leads to the procedure is an AE.

Situations where an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen.

The disease/disorder being studied, or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the subject’s 
condition. 
7.2.2.2.
Definition of a SAE
A serious adverse event is any untoward medical occurrence that, at any dose:
a.
Results in death
b.
Is life-threatening
NOTE:  The term 'life-threatening' in the definition of 'serious' refers to an event in 
which the subject was at risk of death at the time of the event.  It does not refer to an 
event, which hypothetically might have caused death, if it were more severe.
c.
Requires hospitalization or prolongation of existing hospitalization
NOTE:  In general, hospitalization signifies that the subject has been detained 
(usually involving at least an overnight stay) at the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the physician’s 
office or out-subject setting. Complications that occur during hospitalization are 
AEs. If a complication prolongs hospitalization or fulfils any other serious criteria, 


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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 SAE.
d.
Results in disability/incapacity, or
NOTE:  The term disability means a substantial disruption of a person’s ability to 
conduct normal life functions.  This definition is not intended to include experiences 
of relatively minor medical significance such as uncomplicated headache, nausea, 
vomiting, diarrhea, influenza, and accidental trauma (e.g. sprained ankle) which may 
interfere or prevent everyday life functions but do not constitute a substantial 
disruption.
e.
Is a congenital anomaly/birth defect. 
f.
Medical or scientific judgement should be exercised in deciding whether reporting is
appropriate in other situations, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize 
the subject or may require medical or surgical intervention to prevent one of the 
other outcomes listed in the above definition. These should also be considered 
serious. Examples of such events are invasive or malignant cancers, intensive 
treatment in an emergency room or at home for allergic bronchospasm, blood 
dyscrasias or convulsions that do not result in hospitalization, or development of 
drug dependency or drug abuse.
g.
Protocol-Specific SAEs

All events of possible drug-induced liver injury with hyperbilirubinaemia 
defined as ALT 3xULN and bilirubin 2xULN (>35% direct) (or ALT 
3xULN and INR>1.5, if INR measured) or termed ‘Hy’s Law’ events (INR 
measurement is not required and the threshold value stated will not apply to 
patients receiving anticoagulants).
NOTE: bilirubin fractionation is performed if testing is available. If testing is 
unavailable, record presence of detectable urinary bilirubin on dipstick indicating 
direct bilirubin elevations and suggesting liver injury. If testing is unavailable and a 
subject meets the criterion of total bilirubin 2xULN, then the event is still reported 
as an SAE. If INR is obtained, include values on the SAE form. INR elevations >1.5 
suggest severe liver injury 

All Grade 4 laboratory abnormalities assessed using the National Cancer 
Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) 
(see The Study Procedures Manual for: Common Terminology Criteria for 
Adverse Events), except Grade 4 thrombocytopenia. 

An ocular event of clinical concern as defined in Section 7.2.1.4.1 Ocular 
Changes of Clinical Concern.
7.2.2.3.
Laboratory and Other Safety Assessment Abnormalities Reported as 
AEs and SAEs


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Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis), or 
other safety assessments (e.g., ECGs, radiological scans, vital signs measurements) 
including those that worsen from baseline, and events  felt to be clinically significant in 
the medical and scientific judgment of the investigator are to be recorded as an AE or 
SAE, in accordance with the definitions provided.  
In addition, an associated AE or SAE is to be recorded for any laboratory test result or 
other safety assessment that led to an intervention, including permanent discontinuation 
of study treatment, dose reduction, and/or dose interruption/delay.  
However, any clinically significant safety assessments that are associated with the 
underlying disease, unless judged by the investigator to be more severe than expected for 
the subject's condition, are not to be reported as AEs or SAEs.  
Bleeding events should be reported as an AE or SAE as appropriate according to the 
Investigator’s judgment.
7.2.2.4.
Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as SAEs
Thrombocytopenia that results in the administration of rescue medication is to be 
considered treatment failure rather than an AE or SAE.
7.2.2.5.
Time Period and Frequency of Detecting AEs and SAEs
The investigator or site staff is responsible for detecting, documenting and reporting 
events that meet the definition of an AE or SAE. 
AEs will be collected from the time the first dose of study treatment is administered until 
the 4-week follow-up visit. 
SAEs will be collected over the same time period as stated above for AEs.  In addition, 
any SAE assessed as related to study participation (e.g., protocol-mandated procedures, 
invasive tests, or change in existing therapy) or study treatment must be recorded from 
the time a subject consents to participate in the study up to and including the 4-week 
follow-up period. All SAEs will be reported to GSK within 24 hours, as indicated in 
Section 7.2.2.6.   
After discontinuation of study treatment, the investigator will monitor all AEs/SAEs that 
are ongoing until resolution or stabilization of the event or until the subject is lost to 
follow-up.  At any time after the 4-week follow-up visit the investigator may report any 
adverse event that they believe possibly related to study treatment.      
7.2.2.6.
Prompt Reporting of SAEs and Other Events to GSK
SAEs, pregnancies, and liver function abnormalities meeting pre-defined criteria will be 
reported promptly by the investigator to GSK as described in the following table once the 
investigator determines the event meets the protocol definition for that event.


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Initial Reports
Follow-up Information on a Previous 
Report
Type of Event
Time Frame
Documents
Time Frame
Documents
All SAEs
24 hours
SAE data collection 
tool
24 hours
Updated SAE data 
collection tool 
Pregnancy
2 Weeks
Pregnancy 
Notification Form
2 Weeks
Pregnancy Follow 
up Form
Liver chemistry abnormalities:
ALT3xULN and 
bilirubin1.5xULN 
(>35% direct) (or 
ALT3xULN and 
INR>1.5, if INR 
measured) 3
24 hours1 
SAE data collection 
tool.
Liver Event Case 
Report Form (CRF) 
and liver imaging 
and/or biopsy CRFs 
if applicable2
24 hours
Updated SAE data 
collection tool. 
Updated Liver Event 
CRF2
ALT5xULN; 
ALT3xULN with 
hepatitis or rash or ALT 
≥3xULN and <5xULN 
that persists ≥4 weeks
24 hours1
Liver Event CRF2
24 hours
Updated Liver Event 
CRF2
ALT3xULN and 
<5xULN and biliribin 
<1.5xULN
24 hours1
Liver Event CRF 
does not need 
completing unless 
elevations persist  
for 4 weeks or 
subject cannot be 
monitored weekly 
for 4 weeks2
1.
GSK to be notified at onset of liver chemistry elevations to discuss subject safety.
2.
Liver event documents should be completed as soon as possible
3.
INR measurement is not required; if measured, the threshold value stated will not apply to subjects receiving 
anticoagulants.
Methods for detecting, recording, evaluating, and following up on AEs and SAEs plus 
procedures for completing and transmitting SAE reports to GSK are provided in the 
SPM. Procedures for post-study AEs/SAEs are provided in the SPM.
7.2.2.7.
Regulatory reporting requirements for SAEs
Prompt notification of SAEs by the investigator to GSK is essential so that legal 
obligations and ethical responsibilities towards the safety of subjects are met.


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GSK has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a product under clinical investigation.  GSK will 
comply with country specific regulatory requirements relating to safety reporting to the 
regulatory authority, Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC) and investigators.
Investigator safety reports are prepared for suspected unexpected serious adverse 
reactions according to local regulatory requirements and GSK policy and are forwarded 
to investigators as necessary.
An investigator who receives an investigator safety report describing a SAE(s) or other 
specific safety information (e.g., summary or listing of SAEs) from GSK will file it with 
the IB and will notify the IRB/IEC, if appropriate according to local requirements.
7.2.3.
Pregnancy, Testing, Prevention and Reporting
In the event that a pregnancy does occur, the subject will be immediately withdrawn from 
the study.  The subject will receive counseling from the investigator or his/her designee, 
regarding the nature of the study treatment and the potential risk on fetal development.
7.2.3.1.
Pregnancy Testing and Prevention
A screening pregnancy test is mandatory for all female subjects of childbearing potential, 
as defined below, but in no event longer than 24 hours prior to the first administration of 
study treatment.  Unless a serum pregnancy test is required by the medical institution, a 
urine pregnancy test is sufficient.  If the screening pregnancy test cannot be performed 
within 24 hours prior to the first administration of study treatment, a urine pregnancy test 
must be performed and results must be negative on Day 1 prior to dosing with 
eltrombopag.  The results of this test must be negative.  Thereafter, the pregnancy test 
will be repeated at least once every 8 weeks while receiving study treatment or more 
frequently if clinically indicated or required per local regulation (refer to Table 3 Time 
and Events Table).
The need for a screening pregnancy test depends on whether a female subject is of 
childbearing potential or non-childbearing potential.
A female of non-childbearing potential (i.e., physiologically incapable of becoming 
pregnant) is defined as a pre-menarche female or any female (after menarche) who has 
had a hysterectomy, bilateral oophorectomy (ovariectomy) or bilateral tubal ligation, or is 
post-menopausal. 
A female of child-bearing potential is defined as any female who does not meet the 
criteria of non-childbearing potential as described in the previous paragraph. 
If a female subject is of childbearing potential, she must have a urine or serum -hCG 
pregnancy test performed within 24 hours prior to the first dose of study treatment. 
Female subjects with positive pregnancy test result must be excluded from the study. 
Subjects with negative pregnancy test result must agree to use an effective contraception 
method as described below during the study until 28 days following the last dose of study 
treatment.


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Male subjects with a female partner of childbearing potential must agree to use one of 
GSK acceptable effective contraception during the study until 28 days following the 
last dose of study
GSK acceptable contraceptive methods, when used consistently and in accordance with 
both the product label and the instructions of the physician, are as follow:

An intrauterine device with a documented failure rate of less than 1% per year.

Vasectomized partner who is sterile prior to the female subject’s entry and is the sole 
sexual partner for that female.

Complete abstinence from sexual intercourse for 14 days prior to first dose of study 
treatment, through the dosing period, and for at least 28 days after the last dose of 
study treatment.

Double-barrier contraception: condom and occlusive cap (diaphragm or 
cervical/vault caps) with a vaginal spermicidal agent (foam/gel/cream/suppository).

Implants of levonorgestrel where not contraindicated for this patient population or 
per local practice.

Injectable progesterone where not contraindicated for this patient population or per 
local practice. 

Oral contraceptives (either combined or progesterone only) where not 
contraindicated for this patient population or per local practice. 
Female subjects who are lactating must discontinue nursing prior to the first dose of study 
treatment and must refrain from nursing throughout the treatment period and for 28 days 
following the last dose of study treatment.
7.2.3.2.
Pregnancy Reporting
Any pregnancy that occurs during study participation (including treatment and follow-up 
periods) must be reported using a clinical trial pregnancy form.  To ensure subject safety, 
each pregnancy must be reported to GSK within 2 weeks of learning of its occurrence.  
The pregnancy must be followed up to determine outcome (including premature 
termination) and status of mother and child.  Pregnancy complications and elective 
terminations for medical reasons must be reported as an AE or SAE.  Spontaneous 
abortions must be reported as an SAE.
Any SAE occurring in association with a pregnancy brought to the investigator’s 
attention after the subject has completed the study and considered by the investigator as 
possibly related to the study treatment, must be promptly reported to GSK.
In addition, the investigator must attempt to collect pregnancy information on any female 
partners of male study subjects who become pregnant while the subject is enrolled in the 
study.  Pregnancy information must be reported to GSK as described above.


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7.2.4.
Laboratory Assessments
All protocol required laboratory assessments listed in Table 4 will be performed by a 
local laboratory, in accordance with Table 3, Time and Events Table, and recorded in the 
CRF, unless otherwise specified.      
If any additional local laboratory assessments are undertaken during the course of the 
trial and they result in a change in patient management (for example SAE or AE or dose 
modification) the assessment data must be recorded in the patients CRF. 
Table 4
Local Laboratory Assessments
Peripheral Blood Smear
Chemistry
AST
Hematology
ALT
Platelet Count
Total bilirubin
Hemoglobin
Direct bilirubin
WBC count (absolute count)  
Alkaline phosphatase
Urine Pregnancy1
1.
Refer to Section 7.2.3.1. For further details on pregnancy testing.  Results are not captured in CRF, but any 
pregnancy would be reported as specified in Section 7.2.3.
7.2.5.
Meals and Dietary Restrictions
Eltrombopag may be taken with food containing little (<50 mg) or preferably no calcium. 
(See Section 6.1, Permitted Medications and Non-Drug Therapies).
Allow at least a 4 hour interval between eltrombopag and other medications or products 
containing polyvalent cations (e.g. calcium, magnesium, aluminium, zinc, selenium or 
iron) such as antacids, dairy products (milk, yogurt, cheese, ice cream, etc), and mineral 
supplements to avoid significant (70-75%) reduction in eltrombopag absorption due to 
chelation.
8.
DATA MANAGEMENT
For this study subject data will be collected using GSK defined case report forms (CRFs) 
and data entered in a validated system.
Management of clinical data will be performed in accordance with applicable GSK 
standards and data cleaning procedures to ensure the integrity of the data, e.g., removing 
errors and inconsistencies in the data.  Adverse events and concomitant medications 
terms will be coded using MedDRA and an internal validated medication dictionary, 
GSKDrug.  In all cases, subject initials will not be collected or transmitted to GSK 
according to GSK policy.
Original CRFs will be retained by GSK, while the investigator will retain a copy.


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9.
DATA ANALYSIS AND STATISTICAL CONSIDERATIONS
9.1.
Hypotheses
Subjects are being assessed to investigate the safety of eltrombopag.
Since this is an open-label study there are no formal statistical hypothesis tests planned.
9.2.
Study Design Considerations
9.2.1.
Sample Size Assumptions
As this is an extension study for pediatric chronic ITP patients who have previously been 
enrolled in the TRA115450/PETIT2 study the sample size will be based on the number of 
patients previously enrolled in the PETIT2 study and to be included in this study (n = 12).
9.2.2.
Sample Size Sensitivity
Since participation in this study is dependent on enrolment in previous studies (e.g., 
TRA115450) it was not considered necessary to carry out any sample size sensitivity.
9.2.3.
Sample Size Re-estimation
No sample size re-estimation is planned for this study.
9.3.
Data Analysis Considerations
9.3.1.
Analysis Populations
All subjects who receive at least one dose of study medication will be evaluable for 
safety and will comprise the All Treated Subjects (ATS) population.
9.3.2.
Analysis Data Sets
No data sets are planned for this study.
9.3.3.
Treatment Comparisons
9.3.3.1.
Primary Comparisons of Interest
As this is a single arm study, there are no treatment comparisons. The endpoints will be 
summarized utilizing the ATS population. 


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9.3.3.2.
Other Comparisons of Interest
As this is a single arm study, there are no other comparisons of interest..
9.3.4.
Interim Analysis
No interim statistical analyses are planned for this study.
9.3.5.
Key Elements of Analysis Plan
Data will be displayed according to the GSK reporting standards, where applicable.  
All data up to the time of study completion/withdrawal from study will be included in the 
displays, regardless of duration of treatment.  
As the duration of treatment for a given subject will depend on efficacy and tolerability, 
the duration of follow-up will vary between subjects.  Consequently there will be no 
imputation for missing data. 
Demographic and baseline data will be displayed.
9.3.5.1.
Safety Analyses
Safety displays will present safety and tolerability endpoints that include , clinical 
laboratory assessments and frequency of all adverse events, categorized using Common 
Terminology Criteria for Adverse Events (CTCAE) toxicity grades.
“All Treated Subjects” (ATS) population will be used for the presentation of safety data. 
9.3.5.1.1.
Extent of Exposure
Exposure data will be presented according to the duration of the subject’s therapy.
9.3.5.1.2.
Adverse Events
Adverse events (AEs) will be coded using the standard GlaxoSmithKline Medical 
Dictionary for Regulatory Activities (MedDRA) and grouped by system organ class.  
AEs will be graded by the investigator according to the -CTCAE.  
System organ class and preferred term of adverse eventswill be presented. Drug-related 
AEs, serious AEs and AEs leading to discontinuation of study medication will also be 
displayed.
If the AE is listed in the NCI CTCAE table, the maximum grade will be utilized where 
applicable.
The incidence of deaths and the primary cause of death will be presented.


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9.3.5.1.3.
Clinical Laboratory Evaluations
Hematology and clinical chemistry data will be displayed at each scheduled assessment 
according to NCI CTCAE grade .  Unscheduled data will be included in “overall” and 
“any post-screening” displays which will capture a worst case across all scheduled and 
unscheduled visits post first dose of study medication.  
10.
STUDY CONDUCT CONSIDERATIONS
10.1.
Posting of Information on Publicly Available Clinical Trial 
Registers
Study information from this protocol will be posted on publicly available clinical trial 
registers before enrolment of subjects begins
10.2.
Regulatory and Ethical Considerations, Including the 
Informed Consent Process
Prior to initiation of a study site, GSK will obtain favourable opinion/approval from the 
appropriate regulatory agency to conduct the study in accordance with ICH Good Clinical 
Practice (GCP) and applicable country-specific regulatory requirements.
The study will be conducted in accordance with all applicable regulatory requirements.
The study will be conducted in accordance with ICH Good Clinical Practice (GCP), all 
applicable subject privacy requirements, and the ethical principles that are outlined in the 
Declaration of Helsinki 2008, including, but not limited to:

Institutional Review Board (IRB)/Independent Ethics Committee (IEC) review and 
favourable opinion/approval of study protocol and any subsequent amendments.

Subject informed consent.

Investigator reporting requirements.
GSK will provide full details of the above procedures, either verbally, in writing, or both.
Written informed consent must be obtained from each subject prior to participation in the 
study.


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In approving the clinical protocol the IEC/IRB and, where required, the applicable 
regulatory agency are also approving the optional assessments, unless otherwise 
indicated.  Where permitted by regulatory authorities, approval of the optional 
assessments can occur after approval is obtained for the rest of the study.  If so, then the 
written approval will clearly indicate approval of the optional assessments is being 
deferred and the study, except for the optional assessments, can be initiated.  When the 
optional assessments are not approved, then the approval for the rest of the study will 
clearly indicate this and therefore, the optional assessments will not be conducted.
10.3.
Quality Control (Study Monitoring)
In accordance with applicable regulations, GCP, and GSK procedures, the site will be 
contacted prior to the start of the study to review with the site staff the protocol, study 
requirements, and their responsibilities to satisfy regulatory, ethical, and GSK 
requirements.  When reviewing data collection procedures, the discussion will include 
identification, agreement and documentation of data items for which the CRF will serve 
as the source document.
The investigator and the head of the medical institution (where applicable) agrees to 
allow the monitor direct access to all relevant documents and to allocate their time and 
the time to their staff to monitor and discuss findings and any issues.
GSK will monitor the study to ensure that the:

Data are authentic, accurate, and complete.

Safety and rights of subjects are being protected.

Study is conducted in accordance with the currently approved protocol and any other 
study agreements, ICH GCP, and all applicable regulatory requirements.
10.4.
Quality Assurance
To ensure compliance with ICH GCP and all applicable regulatory requirements, GSK 
may conduct quality assurance assessment and/or audit of the site.  Regulatory agencies 
may conduct a regulatory inspection at any time during or after completion of the study.  
In the event of an assessment,audit or inspection, the investigator (and institution) must 
agree to grant the advisor(s), auditor(s) and inspector(s) direct access to all relevant 
documents and to allocate their time and the time of their staff to discuss the conduct of 
the study, any findings/relevant issues and to implement any corrective and/or 
preventative actions to address any findings/issues identified.
10.5.
Study and Site Closure
Upon completion or termination of the study, the monitor will conduct site closure 
activities with the investigator or site staff (as appropriate), in accordance with applicable 
regulations, ICH GCP, and GSK Standard Operating Procedures.


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GSK reserves the right to temporarily suspend or terminate the study at any time for 
reasons including (but not limited to) safety issues, ethical issues, or severe 
noncompliance.  If GSK determines that such action is required, GSK will discuss the 
reasons for taking such action with the investigator or head of the medical institution 
(where applicable).  When feasible, GSK will provide advance notice to the investigator 
or head of the medical institution of the impending action.
If a study is suspended or terminated for safety reasons, GSK will promptly inform all 
investigators, heads of the medical institutions (where applicable),and/or institutions 
conducting the study.  GSK will also promptly inform the relevant regulatory authorities 
of the suspension/termination along with the reasons for such action.  Where required by 
applicable regulations, the investigator or head of the medical institution must inform the 
IRB/IEC promptly and provide the reason(s) for the suspension/termination.
10.6.
Records Retention
Following closure of the study, the investigator or head of the medical institution (where 
applicable) must maintain all site study records (except for those required by local 
regulations to be maintained elsewhere) in a safe and secure location.  The records must 
be easily accessible when needed (e.g., for a GSK audit or regulatory inspection) and 
must be available for review in conjunction with assessment of the facility, supporting 
systems, and relevant site staff.
Where permitted by local laws/regulations or institutional policy, some or all of the 
records may be maintained in a format other than hard copy (e.g., microfiche, scanned, 
electronic); however, caution must be exercised before such action is taken.  The 
investigator must ensure that all reproductions are legible and are a true and accurate 
copy of the original.  In addition, they must meet accessibility and retrieval standards, 
including regeneration of a hard copy, if required.  The investigator must also ensure that 
an acceptable back-up of the reproductions exists and that there is an acceptable quality 
control procedure in place for creating the reproductions.
GSK will inform the investigator of the time period for retaining the site records in order 
to comply with all applicable regulatory requirements.  The minimum retention time will 
meet the strictest standard applicable to a particular site, as dictated by local 
laws/regulations, GSK standard operating procedures, and/or institutional requirements.
The investigator must notify GSK of any changes in the archival arrangements, including, 
but not limited to archival of records at an off-site facility or transfer of ownership of the 
records in the event that the investigator is no longer associated with the site. 


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10.7.
Provision of Study Results to Investigators, Posting of 
Information on Publicly Available Clinical Trials Registers 
and Publication
Where required by applicable regulatory requirements, an investigator signatory will be 
identified for the approval of the clinical study report.  The investigator will be provided 
reasonable access to statistical tables, figures, and relevant reports and will have the 
opportunity to review the complete study results at a GSK site or other mutually-
agreeable location.
GSK will also provide the investigator with the full summary of the study results.  The 
investigator is encouraged to share the summary results with the study subjects, as 
appropriate.
When manuscript publication in a peer-reviewed journal is not feasible, further study 
information will be posted to the GSK Clinical Study Register to supplement the results 
summary. 


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11.
REFERENCES


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12.
APPENDICES
12.1.
Appendix 1:  Liver Chemistry Monitoring, Interruption 
Stopping and Follow-up Criteria
Phase II Liver Safety Algorithm
•Instruct subject to stop investigational product (IP)
•Notify GSK and arrange clinical followupwithin 24h
•Perform liver chemistries and liver event follow up 
assessments (serology, PK sample etc as in protocol) 
•Report as an SAE (excl. hepatic impairment or cirrhosis 
studies) and complete liver event CRF, SAE data 
collection tool, and liver imaging and/or biopsy CRFs if 
tests performed.
•Obtain twice weekly liver chemistries until resolved, 
stabilised or returned to baseline values
•Consultation with hepatologist/specialist recommended
•Withdraw subject from study after monitoring 
complete or from study treatment for protocols with 
survival follow up unless protocol has an option to 
restart drug 
ALT>3xULN
plus Bilirubin>2xULN 
(>35% direct) (or plus
INR>1.5, if measured)*
No
Yes
Yes
•Instruct subject to stop investigational product (IP)
•Notify GSK within 24h and arrange clinical followup
within 24-72h
•Perform liver chemistries  and liver event follow up 
assessments (serology, PK sample etc as in protocol) 
•Complete liver event CRF, SAE data collection tool if 
appropriate, and liver imaging and/or biopsy CRFs if 
these tests performed.
•Obtain weekly liver chemistries [**as far as possible for 
these subjects] until resolved, stabilisedor returned to 
baseline 
•Withdraw subject from study after monitoring 
complete or from study treatment for protocols with 
survival follow up unless protocol has an option to 
restart drug
ALT>5xULN
Hepatitis 
symptoms
or rash?
No
Able to monitor 
weekly  for 4 wks?                      
No
Notify GSK within 24h to discuss 
subject safety; continue IP;
check liver chemistry weekly for 4 
weeks
No
No**
Yes
Yes
Continue IP
Obtain twice monthly liver 
chemistries until normalised
or back to baseline values
Yes
Yes
ALT>3xULN or bilrubin >2xULN?
Yes
*INR value not applicable to subjects on anticoagulants


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12.2.
Appendix 2: Protocol Changes
AMENDMENT 01 CHANGES
Changes to Protocol Amendment 01, dated 08-JUL-2013, are outlined below, 
sequentially by Protocol Section number.
Sponsor Medical Monitor Contact Information
Secondary Medical Monitor has been updated.
List of Abbreviations
PROTOCOL SUMMARY Rationale and Study Assessments
Description and reason for change:  Changes were made to clarify the rationale of the 
study and simplify study assessments.
Original Text:
Rationale
Study TRA117366 is an extension study for pediatric chronic ITP patients who have 
previously been enrolled in the TRA115450/PETIT2 study. 
Amended Text:
Rationale
Study TRA117366 is an extension study for pediatric chronic ITP patients who have 
previously been enrolled in the TRA115450/PETIT2 study and obtain clinical benefit 
from treatment with eltrombopag.
Section 2 Objective(s) and Endpoints
Description and reason for change:  The objective has been clarified to and endpoints 
streamlined.
Original Text:
Objective
Endpoint
To describe the safety and tolerability of 
eltrombopag when administered to pediatric 
subjects with previously treated chronic ITP.
Safety parameters include clinical laboratory 
assessments, ophthalmic examinations, and 
frequency of all adverse events, categorized 
using Common Terminology Criteria for 
Adverse Events (CTCAE) toxicity grades. 


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Revised Text:
Objective
Endpoint
To provide continued treatment to patients who have 
completed the TRA115450 study and to describe 
the safety and tolerability of eltrombopag when 
administered to pediatric subjects with previously 
treated chronic ITP.
Safety parameters include clinical laboratory 
assessments and frequency of all adverse 
events, categorized using Common 
Terminology Criteria for Adverse Events 
(CTCAE) toxicity grades. 
Section 5 Study Treatments
Description and reason for change: Clarification of the term ‘study treatment’.
Original Text:
The term ‘stud treatment’ is used throughout the protocol to describe any combination of 
products received by the subject as per the protocol design.
Amended Text:
The term ‘study treatment’ is used throughout the protocol to describe the product under 
evaluation in this protocol.
Section 5.1.1. Eltrombopag Dosage and Administration
Description and reason for change: Clarification of dosing by age rather than cohort.  
Additional guidance has been included for those subjects who switch formulation during 
the study.
Original Text:
For eltrombopag dosage and administration purposes each eligible subject will be 
allocated to one of 3 age defined cohorts following the same cohort definition as 
described in TRA115450.  Cohort 1 will describe subjects between 12 and 17 years old, 
Cohort 2 will describe subjects between 6 and 11 years old, and Cohort 3 will describe 
subjects between 1 and 5 years old.
For Cohorts 1 and 2, eltrombopag tablets will be administered, however, subjects in 
Cohort 2 may use PfOS if they have difficulty swallowing tablets and are receiving a 
dose of eltrombopag of < 40 mg.  For Cohort 3, either eltrombopag tablets or PfOS will 
be administered.
Amended Text:
For subjects between the ages of 6 to 17 years old, eltrombopag tablets will be 
administered, however, subjects between the ages of 6 to 11 years old may use PfOS if 


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they have difficulty swallowing tablets and are receiving a dose of eltrombopag of < 40 
mg.  For subjects between the ages of 1 to 5 years old, either eltrombopag tablets or PfOS 
will be administered.
Any change between PfOS and tablet formulations should take into account the 
differences in bioavailability between formulations. In a relative bioavailability study 
conducted under fasted conditions in healthy adult subjects, the eltrombopag PfOS 
formulation delivered 22% higher plasma eltrombopag AUC(0-) and 30% higher Cmax 
compared to the tablet formulation. When switching from PfOS to tablets, the nearest 
tablet strength rounding up should be used.
Section 6.1. Permitted Medications and Non-Drug Therapies
Description and reason for change:  Clarification around the time period to record prior 
medications.
Original Text: 
All prior ITP treatments that the subject received prior to Day 1 will be recorded in the
CRF. A reasonable effort will be made to document any other medications the subject
received within 30 days prior to Day 1. Any medication taken within 7 days of study
medication administration must be recorded in the CRF as a prior medication.
Revised Text:
Any medication taken within 7 days of study medication administration must be recorded 
in the CRF .
Section 6.1.1. and 6.1.2.


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Section 7 Study Assessments and Procedures, Table 3
Description and reason for change:  Correction of study number within table as well as clarification of assessments.
Original Text:
Table 3
Time and Events Table
TRA115450
Screening1
Open-Label Treatment Period
Follow-up Period
Study Day
Day 1
Weekly
Every 4 
weeks
Every 6 
weeks
End of 
Treatment2
1W 
FU3
2W 
FU3
3W 
FU3
4W 
FU
24W 
FU
Informed consent
X
Medical history and 
evaluation of eligibility
X
Physical exam4
X
Vital signs4
X
X
X
X
X
X
X
X
X
Concurrent medication 
review
X
X
X
X
X
X
X
X
X
Pregnancy test (urine)5
X5
At least every 8 weeks
X
CBC (incl. platelet count)6
X
X
X
X
X
X
X
X
X
Peripheral blood smear7
X
X
X
X
X
Clinical chemistry8
X
X
X
X
X
X
X9
X9
X9
Coagulation assays 
(INR/aPTT)
X
AE questioning
X
X
X
X
X
X
X
X
X
Ophthalmic assessments10
Every 6 months
X10
X
Additional renal 
assessment11
If indicated11


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Table 3
Time and Events Table (Continued)
W: week; FU: follow-up; M: month
Note: If the subject continues on a stable dose of eltrombopag for 3 consecutive weeks, also if at the day 1 patient received stable dose  in TRA115450 for at least 3 consecutive 
weeks  (without changes in concomitant ITP therapy), assessments may be scheduled every 4 weeks (7 days of nominal visit day) rather than weekly. If the subject continues on a 
stable dose of eltrombopag for 3 consecutive monthly visits (without changes in concomitant ITP therapy), including any consecutive monthly visits in TRA115450 prior to coming into 
this study, assessments frequency may be further reduced and may be scheduled every 6 weeks (7 days of nominal visit day). If the dose of eltrombopag is not stable, weekly visits 
(3 days of nominal visit day) will be required.  
1.
Screening visit may occur on the same day as the Day 1 visit.
2.
All subjects will attend the End of Treatment visit on the day of or within 3 days after the last dose of study treatment.  
3.
Subjects who continue on treatment with eltrombopag (i.e., non-study treatment) will not be required to attend the Week 1, 2 and 3 Follow-up visits.
4.
Physical Exam, including meadusrement and recording of the height and weight, to be performed at on Day 1.  Vital signs to be performed at each visit and to include: heart rate 
and blood pressure.
5.
For female subjects of child-bearing potential, a negative pregnancy test (urine or blood sample) MUST be obtained within 24 hours prior to the first dose. Tests to confirm that 
female subjects of childbearing potential are not pregnant will be conducted at least once every 8 weeks while receiving study treatment and after 4 weeks following completion or 
discontinuation of study treatment.
6.
CBC parameters: to include platelet count, hemoglobin, hematocrit, RBC, WBC, WBC differential (absolute numbers).  Reticulocytes will be measured if haemoglobin <10g/dl.
7.
Peripheral blood smear to be performed on Day 1 and at least once every 6 weeks, regardless of the visit schedule (weekly or monthly).
8.
Clinical Chemistry:  Creatinine, alkaline phosphatase, AST, ALT, total bilirubin, direct bilirubin and albumin at each visit.  
9.
If clinical chemistry at follow-up week 1 is normal, no clinical chemistry will be measured at follow-up weeks 2, 3 and 4.
10. The last full ophthalmologic assessment conducted in the TRA115450 study will be used as the baseline ophthalmic assessment for this study.  An age-appropriate full 
ophthalmologic assessment is required once standard of care exam will be performed to assess the presence of cataracts every 6 months while in the study treatment period, at 
the End of Treatment visit if not conducted within the prior 12 weeks, and at the 24 week follow-up visit.  
11. The ‘Additional renal assessments’ will be done any time there is a creatinine increase considered clinically significant by the ininvestigator.  Additional Renal assessments: urine 
dipstick, microscopic urinalysis, creatinine clearance, urine protein/creatinine ratio.  If the urine protein/creatinine ration is > ULN, then a Urine Protein Electrophoresis should be 
performed,  


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Revised Text:
Refer to revised Time and Events table in Section 7, Table 3. 
Section 7.2.1 Safety Endpoints
Description and reason for change: Clarification of endpoints.
Original Text:
Safety and tolerability endpoints include blood pressure, heart rate, ocular examinations, 
clinical laboratory assessments and frequency of all adverse events, categorized using 
Common Terminology Criteria for Adverse Events (CTCAE) v4.03 toxicity grades.
Revised Text:
Safety and tolerability endpoints include clinical laboratory assessments and frequency of 
all adverse events, categorized using Common Terminology Criteria for Adverse Events 
(CTCAE) toxicity grades.  Refer to the SPM for current version.
Section 7.2.1.1 General Considerations
Description and reason for change: Clarification to be consistent with revised 
assessments and match Time and Events Table.
Original Text:
Subjects will initially be evaluated on Day 1 with clinical assessments, vital signs, 
hematology, albumin, serum creatinine, platelet count and liver enzymes.  Once the dose 
of eltrombopag and other ITP medications has been stable for 3 consecutive weeks, 
which may include the prior 3 weeks in the TRA115450 study, monthly visits will be 
acceptable unless in the investigator’s opinion there is a specific medical reason for more 
frequent evaluations. If the dose is not stable, weekly visits will be required.
Revised Text:
Once the dose of eltrombopag and other ITP medications has been stable for 3 
consecutive weeks, which may include the prior 3 weeks in the TRA115450 study, 
monthly visits will be acceptable unless in the investigator’s opinion there is a specific 
medical reason for more frequent evaluations. If the dose is not stable, weekly visits will 
be required.
Section 7.2.1.2. Physical Exam
Description and reason for change: Clarification and the removal of vital signs.
Original Text:
Physical Exam


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A physical examination will be done at Day 1 per the investigator’s usual practice and 
any abnormal findings will be recorded on the appropriate form in the CRF, e.g, Medical 
History or AE/SAE form. 
Revised Text:
Physical Exam
A physical examination will be done at the Day 1 per the investigator’s usual practice, 
including measurement and recording of height and weight. 
Vital Signs
Vital sign measurements, done at each visit, will include systolic and diastolic blood 
pressure and heart rate.  Vital sign measurements should be performed before any blood 
draws are performed.
Section 7.2.1.4 Renal Monitoring
Description and reason for change: Renal assessments have been removed.
Deleted Text:
Serum creatinine will be measured at each study visit and will serve as the main tool to 
check for global renal function. 
‘Additional renal assessments’ will be performed at any time there is a creatinine increase 
deemed clinically significant by the investigator. No creatinine threshold value is pre-
specified, as the study will cover the whole pediatric age-range and creatinine values 
differ among the different age groups. When a subject requires the ‘additional renal 
assessments’, a visit should be scheduled within a week and the assessments repeated. 
The monitoring should be done weekly until abnormal renal values return to the normal 
range or baseline values.  
‘Additional renal assessments’ will be assessed as follows:

The urine protein/creatinine ratio (UP/CR) will be determined. If the UP/CR is above 
the upper limit of normal, then a urine protein electrophoresis (UPEP) will be 
performed.  

A microscopic urine analysis will be performed. 

A urine dipstick will be performed to look for pH, glucose, protein, blood and 
ketones. Urine dipstick will be performed locally using the dipsticks supplied by the 
central lab.
The glomerular filtration rate (GFR) will be estimated (creatinine clearance).    


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Section 7.5.1.5 Ophthalmic Assessments
Description and reason for change: Title has been changed to reflect more streamlined 
assessment and focus on cataract assessment.  Subsections 7.2.1.5.1. Baseline Ocular 
History and Risk Factors, 7.2.1.5.2 Ophthalmic Examinations and 7.2.1.5.4 Additional 
Ocular Follow-up have been removed.
Original Text:
Ophthalmic safety will be assessed in all subjects using the procedures listed below at the 
times listed in the Time and Events Table. 
Ocular examinations will be performed by an ophthalmologist or an optometrist under the 
guidance of an ophthalmologist.  Baseline and subsequent ocular assessments should be 
performed, whenever possible, by the same examiner.
Revised Text:
Ophthalmic safety, with focus on cataracts, will be assessed in all subjects following 
procedures used in standard practice at the times listed in the Time and Events Table. 
Ocular examinations will be performed by an ophthalmologist or an optometrist under the 
guidance of an ophthalmologist.  Assessments should be performed, whenever possible, 
by the same examiner.
Any abnormal findings will be recorded in the appropriate CRF form, e.g., Medical 
History or AE/SAE form.
Section 7.2.4 Laboratory Assessments
Description and reason for change: Laboratory assessments were streamlined.  Table 4 
has been amended to reflect this change.
Original Text:
All protocol required laboratory assessments listed in Table 4 will be performed by a 
local laboratory, in accordance with Table 3, Time and Events Table.      
If any additional local laboratory assessments are undertaken during the course of the 
trial and they result in a change in patient management (for example SAE or AE or dose 
modification) the assessment data must be recorded in the patients CRF. 


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Table 4
Local Laboratory Assessments
Coagulation Assays
Chemistry
International normalized ration (INR)
Serum creatinine
Activated partial thromboplastin time (aPTT)
AST
ALT
Peripheral Blood Smear
Total bilirubin
Direct bilirubin
Hematology 
Alkaline phosphatase
Platelet Count
Albumin
Red blood cell (RBC) count
Reticulocytes if haemoglobin < 10g/dL
Urine Pregnancy1
Hemoglobin
Hematocrit
Urinalysis, if indicated
WBC count (absolute count) with automated
   Urine Dipstick:
differntial to include:
pH
Total neutrophils (absolute count)
Glucose
Lymphocytes (absolute count)
Protein
Monocytes (absolute count)
Blood
Eosinophils (absolute count)
Ketones
Basophils (absolute count)
Microscopic analysis
Urine protein/creatinine ratio (UP/CR)
Urine protein electrophoresis (UPEP), if 
indicated
Glomerular filtration rate (GFR) (estimated 
using creatinine clrearance)
2.
Refer to Section 7.2.3.1. For further details on pregnancy testing.  
Revised Text:
All protocol required laboratory assessments listed in Table 4 will be performed by a 
local laboratory, in accordance with Table 3, Time and Events Table, and recorded in the 
CRF, unless otherwise specified.      
If any additional local laboratory assessments are undertaken during the course of the 
trial and they result in a change in patient management (for example SAE or AE or dose 
modification) the assessment data must be recorded in the patients CRF. 


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Table 4
Local Laboratory Assessments
Chemistry
AST
ALT
Peripheral Blood Smear
Total bilirubin
Direct bilirubin
Hematology 
Alkaline phosphatase
Platelet Count
Urine Pregnancy1
Hemoglobin
WBC count (absolute count)  
3.
Refer to Section 7.2.3.1. For further details on pregnancy testing.  Results are not captured in CRF, but any 
pregnancy would be reported as specified in Section 7.2.3.
Section 7.2.5. Meals and Dietary Restrictions
Description and reason for change: Clarification around administration of eltrombopag.
Original Text:
Eltrombopag may be taken on an empty stomach (1 hour before or 2 hours after a meal) 
or with food containing little (<50 mg) or preferably no calcium or dairy products. (See 
Section 6.1, Permitted Medications and Non-Drug Therapies).
Revised Text:
Eltrombopag may be taken with food containing little (<50 mg) or preferably no calcium. 
(See Section 6.1, Permitted Medications and Non-Drug Therapies).
Section 8 Data Management
Description and reason for change: Clarification to data process and removal of 
repeated text.


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Original Text:
For this study CRF Subject data will be collected using GSK defined case report forms 
and combined with data provided from other sources in a validated data.
Management of clinical data will be performed in accordance with applicable GSK 
standards and data cleaning procedures to ensure the integrity of the data, e.g., removing 
errors and inconsistencies in the data.  Adverse events and concomitant medications 
terms will be coded using MedDRA and an internal validated medication dictionary, 
GSKDrug.  In all cases, subject initials will not be collected or transmitted to GSK 
according to GSK policy.
Original CRFs will be retained by GSK, while the investigator will retain a copy.
Revised Text:
For this study subject data will be collected using GSK defined case report forms (CRFs) 
and data entered in a validated system.
Management of clinical data will be performed in accordance with applicable GSK 
standards and data cleaning procedures to ensure the integrity of the data, e.g., removing 
errors and inconsistencies in the data.  Adverse events and concomitant medications 
terms will be coded using MedDRA and an internal validated medication dictionary, 
GSKDrug.  In all cases, subject initials will not be collected or transmitted to GSK 
according to GSK policy.
Original CRFs will be retained by GSK, while the investigator will retain a copy.
Section 9.3.5. Key Elements of Analysis Plan
Description and reason for change: The Reporting and Analysis Plan has been 
removed.  This section and each sub-section within have been changes for the 
modification of analysis and data collection.  Changes for each section are highlighted 
below.
Original Text:
Data will be listed and summarized according to the GSK reporting standards, where 
applicable.  Complete details will be documented in the RAP.  And deviations from, or 
additions to, the original analysis plan described in this protocol will be documented in 
the RAP and final study report.
As it is anticipated that accrual will be spread thinly across centers and summaries of data 
by center would be unlikely to be informative, data from all participating centers will be 
pooled prior to analysis.
  
All data up to the time of study completion/withdrawal from study will be included in the 
analysis, regardless of duration of treatment.  


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As the duration of treatment for a given subject will depend on efficacy and tolerability, 
the duration of follow-up will vary between subjects.  Consequently there will be no 
imputation for missing data. 
Demographic and baseline characteristics will be summarized.
Revised Text:
Data will be displayed according to the GSK reporting standards, where applicable.  
All data up to the time of study completion/withdrawal from study will be included in the 
displays, regardless of duration of treatment.  
As the duration of treatment for a given subject will depend on efficacy and tolerability, 
the duration of follow-up will vary between subjects.  Consequently there will be no 
imputation for missing data. 
Demographic and baseline data will be displayed.
Section 9.3.5.1. Safety Analysis
Original Text:
Safety analyses will be performed based on primary safety and tolerability endpoints that 
include blood pressure, heart rate, ocular examinations, clinical laboratory assessments 
and frequency of all adverse events, categorized using Common Terminology Criteria for 
Adverse Events (CTCAE) v4.03 toxicity grades.
The safety will be evaluated using descriptive statistics.
The SAFETY population defined as “All Treated Subjects” (ATS) population will be 
used for the analysis of safety data. Complete details of the safety analyses will be 
provided in the RAP.
Revised Text:
Safety displays will present safety and tolerability endpoints that include , clinical 
laboratory assessments and frequency of all adverse events, categorized using Common 
Terminology Criteria for Adverse Events (CTCAE) toxicity grades.
“All Treated Subjects” (ATS) population will be used for the presentation of safety data.
Section 9.3.5.1.1. Extent of Exposure
Original Text:
The number of subjects administered study medication will be summarized according to 
the duration of therapy.
Revised Test:


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Exposure data will be presented according to the duration of the subject’s therapy.
9.3.5.1.2. Adverse Events
Original Text:
Adverse events (AEs) will be coded using the standard GlaxoSmithKline Medical 
Dictionary for Regulatory Activities (MedDRA) and grouped by system organ class.  
AEs will be graded by the investigator according to the –CTCAE (version 4.03).  
Events will be summarized by frequency and proportion of total subjects, by system 
organ class and preferred term.  Separate summaries will be fiven for all AEs, drug-
related AEs, serious AEs and AEs leading to discontinuation of study medication.
If the AE is listed in the NCI CTCAE(version 4.03) table, the maximum grade will be 
summarized.
The incidence of deaths and the primary cause of death will be summarized.
Revised Text:
Adverse events (AEs) will be coded using the standard GlaxoSmithKline Medical 
Dictionary for Regulatory Activities (MedDRA) and grouped by system organ class.  
AEs will be graded by the investigator according to the -CTCAE.  
System organ class and preferred term of adverse events will be presented. Drug-related 
AEs, serious AEs and AEs leading to discontinuation of study medication will also be 
displayed.
If the AE is listed in the NCI CTCAE table, the maximum grade will be utilized where 
applicable.
The incidence of deaths and the primary cause of death will be presented.
Section 9.3.5.1.3. Clinical Laboratory Evaluations
Original Text:
Hematology and clinical chemistry data will be summarized at each scheduled 
assessment according to NCI CTCAE grade (version 4.03).  The proportion of values 
lying outside the reference range will be presented for laboratory tests that are not graded 
because there are no associated NCI CTCAE criteria.  Summaries will include date from 
scheduled assessments only, and all data will be reported according to the nominal visit 
date for which it was recorded (i.e. no visit windows will be applied).  Unscheduled data 
will be included in “overall” and “any post-screening” summaries which will capture a 
worst case across all scheduled and unscheduled visits post first dose of study 
medication.  Further details will be provided in the RAP.
Revised Text:


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Hematology and clinical chemistry data will be displayed at each scheduled assessment 
according to NCI CTCAE grade .  Unscheduled data will be included in “overall” and 
“any post-screening” displays which will capture a worst case across all scheduled and 
unscheduled visits post first dose of study medication.  
Section 9.3.5.1.4. Other Safety Measures
Original Text:
The results of scheduled assessments of body weight, vital signs, will be summarized.  
Summaries will include data from scheduled assessments only.  All data will be reported 
according to the nominal visit date for which  it was recorded (i.e. no visit windows will 
be applied).  All data will be listed.  Further details will be provided in the RAP.

SAP_000.pdf: 
Clinical Development
ETB115/eltrombopag/Promacta®/Revolade®
ETB115BRU01 / NCT02201290
An extension study of eltrombopag in pediatric patients 
with chronic immune (idiopathic) thrombocytopenia 
purpura (ITP)
Statistical Analysis Plan (SAP) and TFLs - Addendum 1
Author:
Document type:
SAP Documentation
Document status:
Final v1.0
Release date:
28-Nov-2017
Number of pages:
44
Property of Novartis
For business use only
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis


Novartis
For business use only
Page 2
SAP and TFLs
CETB115BRU01/Eltrombopag
Document History – Changes compared to previous final version of SAP
Date
Time 
point
Reason for 
update
Outcome for update
Section and title 
impacted 
(Current)
25-Aug-2017
Prior 
to DBL
N/A – Initial 
version
N/A
N/A
28-Nov-2017
After 
DBL
Additional 
outputs needed
Updated Table 1-1 to align with 
protocol amendment 1. Added
table shells for laboratory 
assessments and listing shells
for treatment compliance, 
laboratory, ocular, liver events, 
vital signs, medical history and 
concomitant medications data
1, 2, 9, 10
DBL: Data base lock
TEMPLATE VERSION AND DATE: Final 2.0 25-Apr-2016, Effective 03-May-2016


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SAP and TFLs
CETB115BRU01/Eltrombopag
Table of contents
Table of contents .................................................................................................................3
List of abbreviations............................................................................................................5
1
Introduction .........................................................................................................................6
1.1
Study design.............................................................................................................6
1.2
Study objectives and endpoints ...............................................................................6
2
Statistical methods...............................................................................................................7
2.1
Data analysis general information ...........................................................................7
2.1.1
General definitions..................................................................................7
2.2
Analysis set..............................................................................................................9
2.3
Patient disposition, demographics and other baseline characteristics .....................9
2.3.1
Patient disposition...................................................................................9
2.3.2
Patient demographics and other baseline characteristics ........................9
2.4
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance)..............................................................................................................9
2.4.1
Study treatment .......................................................................................9
2.4.2
Concomitant medications........................................................................9
2.5
Analysis of the primary objective............................................................................9
2.5.1
Primary endpoint.....................................................................................9
2.6
Safety analyses.........................................................................................................9
2.6.1
Adverse events (AEs)..............................................................................9
2.6.2
Deaths....................................................................................................11
2.6.3
Laboratory data .....................................................................................11
2.6.4
Other safety data ...................................................................................11
2.7
Pharmacokinetic endpoints....................................................................................12
2.8
Other Exploratory analyses....................................................................................12
2.9
Interim analysis......................................................................................................12
3
Sample size calculation .....................................................................................................12
4
Change to protocol specified analyses ..............................................................................12
12
6
Appendix ...........................................................................................................................13
6.1
Imputation rules.....................................................................................................13
14
14
14
14


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List of abbreviations
AE
adverse event
CRF
case report form
CSR
clinical study report
CTCAE
common terminology criteria for adverse events
GPS
global programming & statistical environment
ITP
immune (idiopathic) thrombocytopenic purpura
LPLV
last patient last visit
MedDRA
medical dictionary for drug regulatory affairs
PDS
programming data specifications
PT
preferred term
SAE
serious adverse event
SAP
statistical analysis plan
sd
standard deviation
SOC
system organ class


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1
Introduction
This statistical analysis plan (SAP) provides detailed statistical methodology for the analyses 
of data which will be used for preparation of the ETB115BRU01 (TRA117366) clinical study 
report (CSR) and is based on the study protocol amendment 01, dated 08-Jul-2013.
The output shells information is in Section 7, the in-text table shells are in Section 8, the post-
text tables and listings are in Section 9 and Section 10 respectively. Programming 
specifications for datasets, including derivation of variables, are given in the programming 
data specifications (PDS) document.
All data will be analyzed by 
and then 
imported to the Novartis global programming & statistical (GPS) environment. Analysis data 
sets and statistical outputs will be produced using the SAS system Version 9.3 or higher.
1.1
Study design
This is an open-label, phase III, extension study to evaluate the long-term safety of
eltrombopag in pediatric patients with chronic immune (idiopathic) thrombocytopenic 
purpura (ITP) who previously participated in study TRA115450/PETIT2. This study will 
allow dosing of eltrombopag at an individualized dose for each patient based upon platelet 
count. The starting dose will be based on the patient’s dose at the end of the TRA115450 
study, unless a dose adjustment is warranted due to platelet count. The maximum dose will be 
75 mg daily.
Maximum twelve (n = 12) patients will be enrolled into the study. 
Patients may remain on treatment in this study until at least one of the following criteria is 
met: the patient reaches 18 years of age or eltrombopag receives local regulatory approval for
the treatment of pediatric chronic ITP.
1.2
Study objectives and endpoints
Table 1-1
Study objectives and endpoints
Objective
Endpoints
To provide continued treatment to patients who have completed 
the TRA115450/PETIT2 study and to describe the safety and 
tolerability of eltrombopag when administered to pediatric 
patients with previously treated chronic ITP.
Primary objective
The primary endpoint is the assessment of long-term safety.
Safety parameters include clinical 
laboratory assessments and 
frequency of all adverse 
events (AEs).
Primary endpoint
The frequency of all AEs.


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2
Statistical methods
2.1
Data analysis general information
Categorical data will be presented as frequencies and percentages. For continuous data, n, 
mean, standard deviation, median, minimum, and maximum will be presented.
The analysis will be performed after database lock has occurred (after last patient last visit 
(LPLV)).  
2.1.1
General definitions
Study day
The study day describes the day of the event related to the start date of eltrombopag.
The reference start date is designated as Study Day 1. Study Day –1 is the day that precedes 
Day 1. Study Day 0 is not defined.  Study day is not to be used in numerical computations, for 
example in calculating exposure.
The study day will be calculated as:

The date of the event (visit date, onset date of an event, assessment date etc.) - reference 
start date + 1, if event is on or after the reference start date. 

The date of the event (visit date, onset date of an event, assessment date etc.) - reference 
start date, if event precedes the reference start date.
The reference start date for all assessments (laboratory, ocular etc.) will be the start date of 
eltrombopag.
The study day will be displayed in the data listings. If an event starts before the reference start 
date, the study day displayed in the listing will be negative.
Pre-, on- and post-treatment periods
The overall observation period is divided into the following mutually exclusive periods:
1. Pre-treatment: prior to first dose of eltrombopag
2. On-treatment: from start date of eltrombopag to last date of study treatment + 30 days
It is noted that if patient withdraws study informed consent or dies before then, then it is 
till the withdrawal/death date
3. Post-treatment: from last date of study treatment + 31 days to end of study
On-treatment assessments/events
The definition of on-treatment is given below, depending on the context.
For safety summary tables an on-treatment adverse event (AE) is defined as any AE reported 
in the following time interval (including the lower and upper limits): 

<date of first administration of study treatment; date of last administration of study 
treatment + 30 days>


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This corresponds to the definition of treatment-emergent AEs given in the protocol, i.e. AEs 
which are newly reported or worsening from baseline.
An on-treatment assessment is defined as any assessment performed after the date of first 
administration of study treatment (except for assessments specified to be collected post-dose 
on that day), i.e. assessments performed in the following time interval (including the lower 
and upper limits): 

<date of first administration of study treatment + 1; date of last administration of study 
treatment + 30 days>
For patients whose last date of study treatment is missing, on-treatment assessments/events 
include any assessment/event present in the database occurring after the start date of study 
treatment. 
Listings will contain all data, flagging assessments/events outside of the on-treatment period 
where applicable.
Study treatment
Study treatment refers to eltrombopag.
Date of first administration of study treatment
The date of first administration of eltrombopag is derived as the first date when a nonzero 
dose eltrombopag is administered. This date is also referred to as start date of study treatment.
Date of last administration of study treatment
The date of last administration of eltrombopag is derived as the last date when a nonzero dose 
of eltrombopag is administered. This date is also referred to as last date of study treatment.
Duration of exposure
The duration of exposure is calculated as:

Duration of eltrombopag exposure (months) =[ (last date of study treatment) – (first date 
of study treatment) + 1]/ 30.4375. 
If the start or end date of eltrombopag is missing, the duration will be missing. The duration 
includes periods of temporary interruption (planned or actual) for any reason.
Definition of Months and Years
A month will be calculated as (365.25 / 12) = 30.4375 days. Where duration is to be reported 
in months, duration in days will be divided by 30.4375.  Where duration is to be reported in 
years, duration in days will be divided by 365.25.
Time windows
Time windows for assessments are based on protocol specified windows.


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2.2
Analysis set
The all treated subjects (ATS) analysis set includes all patients who receive at least one dose 
of eltrombopag.
2.3
Patient disposition, demographics and other baseline 
characteristics
The ATS will be used for disposition, demographic and other baseline summaries and listings.
2.3.1
Patient disposition
Disposition data will be summarized descriptively.
2.3.2
Patient demographics and other baseline characteristics
Demographic and other baseline data will be summarized descriptively.
Medical histories and current medical conditions at baseline will be listed.
2.4
Treatments (study treatment, rescue medication, concomitant 
therapies, compliance)
2.4.1
Study treatment 
Duration of eltrombopag exposure (months) will be summarized descriptively and listed for 
the ATS.
Duration of eltrombopag exposure (months) will also be categorized and summarized using 
the following time intervals: <1, ≥ 1, ≥ 3, ≥6, ≥ 12, ≥ 24, ≥36, ≥ 48, ≥60.
A listing will also be provided of study treatment compliance (tablets/sachets dispensed and 
returned).
2.4.2
Concomitant medications
Concomitant medications will be listed.
2.5
Analysis of the primary objective
2.5.1
Primary endpoint
The analyses of the primary endpoint (AEs) are described in Section 2.6.
2.6
Safety analyses
The ATS will be used for safety summaries and listings.
2.6.1
Adverse events (AEs)
The AEs will be re-coded using the latest version of the medical dictionary for regulatory 
activities (MedDRA) at the time of the analysis.


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AEs will be graded using the common toxicity criteria for adverse events (CTCAE) 
Version 4.03. If a patient reported more than one AE with the same preferred term (PT), the 
AE with the greatest severity will be presented. If a patient reported more than one AE within 
the same primary system organ class (SOC), the patient will be counted only once with the 
greatest severity at the SOC level, where applicable. An AE with missing CTCAE grade will 
be included in the ‘All grades’ column of the summary tables.
In AE summaries, the primary SOC will be presented alphabetically and the PTs will be 
sorted within the primary SOC in descending frequency.
Summary tables will be provided for:

All AEs regardless of relationship to study treatment by primary system organ class (SOC), 
preferred term (PT) and maximum severity

In-text table by SOC and maximum severity

In-text table by PT and maximum severity

AEs suspected to be related to study treatment by SOC, PT and maximum severity

In-text table by PT and maximum severity

AEs leading to treatment discontinuation regardless of relationship to study treatment by 
SOC, PT and maximum severity

In-text table by PT and maximum severity

Serious AEs (SAEs) regardless of relationship to study treatment by SOC, PT and 
maximum severity

In-text table by PT and maximum severity

On-treatment deaths by SOC and PT

In-text table by PT

All deaths by SOC and PT

*Non-SAEs regardless of relationship to study treatment (threshold=0%) by SOC and PT

*On treatment deaths and SAEs by SOC and PT
*For the legal requirements of EudraCT, two required tables on <on-treatment/treatment 
emergent> AEs which are not SAEs with an incidence greater than x% and on <on-
treatment/treatment emergent> SAEs and SAE suspected to be related to study treatment will 
be provided by SOC and PT on the ATS.
If for a same patient, several consecutive AEs (irrespective of study treatment causality, 
seriousness and severity) occurred with the same SOC and PT:

a single occurrence will be counted if there is ≤ 1 day gap between the end date of the 
preceding AE and the start date of the consecutive AE

more than one occurrence will be counted if there is > 1 day gap between the end date of 
the preceding AE and the start date of the consecutive AE
For occurrence, the presence of at least one SAE/SAE suspected to be related to study 
treatment/non SAE has to be checked in a block e.g., among AEs in a ≤ 1 day gap block, if at 
least one SAE is occurring, then one occurrence is calculated for that SAE.


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The number of deaths resulting from SAEs suspected to be related to study treatment and 
SAEs irrespective of study treatment relationship will be provided by SOC and PT.
A listing will be provided for all AEs. Records outside of on-treatment period will be flagged.
2.6.2
Deaths
See Section 2.6.1. A listing will be provided of all deaths, deaths outside of on-treatment 
period will be flagged.
2.6.3
Laboratory data
Laboratory values will be converted to the international system of units (SI). CTCAE Grade 0 
will be assigned for all non-missing values not graded as 1 or higher. Grade 5 will not be used. 
For laboratory tests where grades are not defined by CTCAE version 4.03, results will be 
categorized as low/normal/high based on laboratory normal ranges. 
The following summaries will be provided. Note that except for baseline value only on-
treatment values will be used in summaries.

Shift tables using CTCAE grades to compare baseline to the worst on-treatment value for 
platelets, hemoglobin and white blood cells (WBCs). 

Figure for median platelet counts over time (baseline and every 8 weeks post-baseline). 
Horizontal reference lines to be added at 30, 50 and 100 Gi/L. Interquartile range (IQR) to 
be added as vertical lines.
Listings of all laboratory data (hematology, biochemistry, urinalysis, coagulation, pregnancy 
test etc.) will be provided showing the corresponding CTCAE grades, if applicable, and the 
classifications relative to the laboratory normal ranges. Values measured outside of on-
treatment period will be flagged.
Liver function parameters
Liver function parameters of interest are total bilirubin (TBL), alanine aminotransferase 
(ALT), aspartate aminotransferase (AST) and alkaline phosphatase (ALP).
The number (%) of patients with worst on-treatment values will be summarized. For single 
lab parameter lines (e.g. AST >3xULN) the worst value post-baseline is considered. For 
combination of various parameters (e.g. ALT or AST > 3xULN & TBL > 2xULN & 
ALP < 2xULN) the lab values need to be from the same assessment (concurrent 
measurements). 
Listings of all liver event data will be provided. Values measured outside of on-treatment 
period will be flagged.
2.6.4
Other safety data
2.6.4.1
Liver events, ocular and other safety data
Data will be listed.


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2.6.4.2
Vital signs
Data will be listed.
2.7
Pharmacokinetic endpoints
Not applicable..
2.8
Other Exploratory analyses
Not applicable.
2.9
Interim analysis
Not applicable.
3
Sample size calculation
Approximately 12 patients were planned to be enrolled. As this is an extension study for 
pediatric chronic ITP patients the sample size was based on the number of patients previously 
enrolled in the TRA115450/PETIT2 study.
4
Change to protocol specified analyses
Data will be displayed according to Novartis (not GlaxoSmithKline (GSK)) reporting 
standards.
Primary endpoint clarified as the frequency of all AEs.


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6
Appendix
6.1
Imputation rules
Table 6-1
Imputation of start dates (AE) 
Missing 
Element
Rule
day, month, 
and year

No imputation will be done for completely missing dates
day, month

If available year = year of study treatment start date then 
o
If stop date contains a full date and stop date is earlier than study 
treatment start date then set start date = 01JanYYYY
o
Else set start date = study treatment start date. 

If available year > year of study treatment start date then 01JanYYYY

If available year < year of study treatment start date then 01JulYYYY
day

If available month and year = month and year of study treatment start 
date then 
o
If stop date contains a full date and stop date is earlier than study 
treatment start date then set start date= 01MONYYYY. 
o
Else set start date = study treatment start date.

If available month and year > month and year of study treatment start 
date then 01MONYYYY  

If available month and year < month year of study treatment start date 
then 15MONYYYY  
Table 6-2
Imputation of end dates (AE) 
Missing 
Element
Rule
(*=last treatment date plus 30 days not > (death date, cut-off date, 
withdrawal of consent date))
day, month, 
and year

Completely missing end dates (incl. ongoing events) will be imputed by 
the end date of the on-treatment period* 
day, month

If partial end date contains year only, set end date = earliest of 
31DecYYYY or end date of the on-treatment period * 
day

If partial end date contains month and year, set end date = earliest of last 
day of the month or end date of the on-treatment period*
Any AEs with partial/missing dates will be displayed as such in the data listings. Any AEs 
which are continuing as per LPLV will be shown as ‘ongoing’ rather than an imputed end date 
provided.
Calculation of age: If AGE is missing in DMG then Age is calculated using the Date of Birth 
from DMG. 


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Age (years) = truncate((Screening date – Birth date + 1)/365.25) e.g. if age =8.7 then age =8.

If DD is blank, age is calculated as for ’01..’

If MON is blank, age is calculated as for ‘01JAN..’
Invalid Date of Birth generates a missing value for age, i.e. when YYYY component is not 4 
digits long.


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