Clinical trial NCT03524612
Conditions: Immune Thrombocytopenic Purpura (ITP)
Keywords: Thrombocytopenic Immune Platelets Bleeding ITP eltrombopag ETB115 induce sustained response off treatment refractory or relapsed first-line steroids
Sponsor: Novartis Pharmaceuticals
Start date: 2018-11-02; Completion date: 2022-10-03
Enrollment: 105 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this trial was to assess the ability of eltrombopag to induce sustained treatment-free remission in immune thrombocytopenia purpura (ITP) subjects who relapsed or failed to respond to an initial treatment with steroids.

Detailed description:
Protocol Amendment 01 added a follow-up period of 12 months for patients with sustained response off treatment at month 12 to obtain further data on response duration.

The starting dose was eltrombopag 50 mg daily (25 mg daily for Asian patients and 12.5 mg daily for Japanese patients in Japan). The starting dose for this study was consistent with the dosing guidelines approved for eltrombopag use in ITP. An increase of eltrombopag dose up to 75 mg was allowed for patients who did not respond to standard-dosage treatment and to reduce the risk of bleeding. The rationale for this increased dose was to use the minimal efficacious dosage of eltrombopag in order to achieve a platelet count ≥ 100×10\^9/L and maintain it around 100×10\^9/L (no counts below 70×10\^9/L) for 2 months in order to allow patients to start the eltrombopag tapering and withdrawal process.

Patients who reached a platelet count of \>= 100 × 10\^9/L and maintained counts around 100×10\^9/L for 2 months with no platelet count \< 70 × 10\^9/L were eligible for tapering-off and treatment discontinuation, which occurred via 25 mg reduction every 2 weeks up to 25 mg on alternate days for 2 weeks until treatment discontinuation.

Patients who successfully discontinue eltrombopag and maintained platelet count \>= 30 × 10\^9/L in the absence of bleeding or use of rescue therapy were followed to month 12. If a relapse (defined as platelet count \<30 × 10\^9/L) occurred during the 12-month treatment period, they were offered a new course of eltrombopag treatment within this timeframe at the appropriate starting dose. If a patient relapsed in the post 12-month follow-up period, no further attempts for tapering and achieving sustained response off treatment were made.

The taper-off scheme followed recommendations within the current established dosing regimen for when to consider dose adjustment.

Arms: arm 1: Participants were treated with eltrombopag to induce sustained response off treatment to reach a target platelet count of \>=100×10\^9/L (CR), after 1st line steroids had failed.
Interventions: intervention 1: eltrombopag
Intervention descriptions: intervention 1: 12.5, 25, 50 and 75 mg tablets for oral use once daily

Protocol documents:
Prot_000.pdf: 
Novartis Research and Development
ETB115/Eltrombopag/Promacta®/Revolade®
CETB115J2411 / NCT03524612
A phase II, open-label, prospective, single-arm, study to 
assess ability of eltrombopag to induce sustained 
remission in subjects with ITP who are refractory or 
relapsed after first-line steroids (TAPER)
Document type:
Amended Protocol Version
EUDRACT number:
2018-000452-18
Version number:
01 (Clean)
Clinical Trial Phase:
II
Release date:
06-Mar-2019
Property of Novartis
Confidential
May not be used, divulged, published, or otherwise disclosed
without the consent of Novartis
Clinical Trial Protocol Template Version 1.0 (01-Dec-2017)


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Table of contents
Table of contents .................................................................................................................2
List of tables ........................................................................................................................5
List of figures ......................................................................................................................6
List of abbreviations............................................................................................................7
Glossary of terms...............................................................................................................10
Amendment 1 (06-Mar-2019) ...........................................................................................11
Protocol summary..............................................................................................................15
1
Introduction .......................................................................................................................19
1.1
Background............................................................................................................19
1.2
Purpose ..................................................................................................................22
2
Objectives and endpoints...................................................................................................23
3
Study design ......................................................................................................................25
4
Rationale............................................................................................................................27
4.1
Rationale for study design .....................................................................................27
4.2
Rationale for dose/regimen and duration of treatment ..........................................27
4.3
Rationale for choice of control drugs (comparator/placebo) or combination 
drugs ......................................................................................................................28
28
4.5
Purpose and timing of interim analyses/design adaptations..................................29
4.6
Risks and benefits..................................................................................................29
5
Population..........................................................................................................................32
5.1
Inclusion criteria ....................................................................................................32
5.2
Exclusion criteria...................................................................................................33
6
Treatment...........................................................................................................................35
6.1
Study treatment......................................................................................................35
6.1.1
Investigational drug...............................................................................36
6.1.2
Additional study treatments ..................................................................36
6.1.3
Treatment duration................................................................................36
6.2
Other treatment(s)..................................................................................................37
6.2.1
Concomitant therapy.............................................................................37
6.2.2
Prohibited medication ...........................................................................38
6.2.3
Rescue therapy ......................................................................................39
6.3
Patient numbering, treatment assignment, randomization.....................................39
6.3.1
Patient numbering .................................................................................39
6.3.2
Treatment assignment, randomization ..................................................39
6.4
Treatment blinding.................................................................................................39


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6.5
Dose escalation and dose modification..................................................................40
6.5.1
Dose escalation guidelines....................................................................40
6.5.2
Dose modifications................................................................................40
6.5.3
Follow-up for toxicities.........................................................................43
6.6
Additional treatment guidance...............................................................................45
6.6.1
Treatment compliance...........................................................................45
6.7
Preparation and dispensation.................................................................................45
6.7.1
Handling of eltrombopag ......................................................................45
6.7.2
Instruction for prescribing and taking study treatment .........................46
7
Informed consent procedures ............................................................................................46
8
Visit schedule and assessments .........................................................................................47
8.1
Screening ...............................................................................................................55
8.1.1
Information to be collected on screening failures.................................55
8.2
Patient demographics/other baseline characteristics .............................................55
8.3
Efficacy..................................................................................................................56
8.3.1
Efficacy assessment 1 ...........................................................................56
8.3.2
Efficacy assessment 2 ...........................................................................56
8.3.3
Appropriateness of efficacy assessments..............................................56
8.4
Safety.....................................................................................................................56
8.4.1
Ophthalmic examination.......................................................................57
8.4.2
Laboratory evaluations..........................................................................57
8.4.3
Electrocardiogram.................................................................................57
8.4.4
Pregnancy..............................................................................................58
8.4.5
Appropriateness of safety measurements..............................................58
8.5
Additional assessments..........................................................................................58
8.5.1
Clinical Outcome Assessments.............................................................58
60
61
62
9
Study discontinuation and completion ..............................................................................63
9.1
Discontinuation......................................................................................................63
9.1.1
Discontinuation of study treatment .......................................................63
9.1.2
Lost to follow-up...................................................................................64
9.1.3
Early study termination by the sponsor.................................................64
9.2
Study completion and post-study treatment ..........................................................65
9.3
Additional 12 months follow-up period for responders ........................................65


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10 Definition of adverse events and reporting requirements..................................................66
10.1.1
Adverse events ......................................................................................66
10.1.2
Serious adverse events ..........................................................................67
10.1.3
SAE reporting........................................................................................68
10.1.4
Pregnancy reporting ..............................................................................68
10.1.5
Reporting of study treatment errors including misuse/abuse................69
10.2
Additional Safety Monitoring................................................................................69
10.2.1
Liver safety monitoring.........................................................................69
10.2.2
Renal safety monitoring........................................................................70
10.2.3
Steering Committee...............................................................................70
11 Data Collection and Database management......................................................................71
11.1
Data collection.......................................................................................................71
11.2
Database management and quality control............................................................71
11.3
Site monitoring ......................................................................................................72
12 Data analysis and statistical methods ................................................................................72
12.1
Analysis sets ..........................................................................................................73
12.2
Patient demographics and other baseline characteristics.......................................73
12.3
Treatments .............................................................................................................73
12.4
Analysis of the primary endpoint(s) ......................................................................73
12.4.1
Definition of primary endpoint .............................................................74
12.4.2
Statistical model, hypothesis, and method of analysis..........................74
12.4.3
Handling of missing values/censoring/discontinuations.......................74
12.4.4
Supportive analyses...............................................................................74
12.5
Analysis of secondary endpoints ...........................................................................74
12.5.1
Efficacy endpoint(s)..............................................................................74
12.5.2
Safety endpoint(s) .................................................................................76
77
77
79
79
12.7
Interim analyses.....................................................................................................79
12.8
Sample size calculation..........................................................................................79
12.8.1
Primary endpoint...................................................................................79
13 Ethical considerations and administrative procedures ......................................................80
13.1
Regulatory and ethical compliance........................................................................80
13.2
Responsibilities of the investigator and IRB/IEC..................................................80


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13.3
Publication of study protocol and results...............................................................81
13.4
Quality Control and Quality Assurance.................................................................81
14 Protocol adherence ............................................................................................................81
14.1
Protocol Amendments ...........................................................................................82
15 References (available upon request)..................................................................................83
16 Appendices ........................................................................................................................87
16.1
Appendix 1: Examples of OATP and BCRP substrates........................................87
16.2
Appendix 2: Bleeding Scales.................................................................................88
16.3
Appendix 3: HRQoL Questionnaires.....................................................................90
List of tables
Table 1-1
First-line treatment options for patients with ITP.................................21
Table 2-1
Objectives and endpoints ......................................................................23
Table 6-1
Eltrombopag dosing guidance for patients not meeting criteria for 
sustained remission ...............................................................................36
Table 6-2
Investigational drug...............................................................................36
Table 6-3
Eltrombopag Dose Adjustments in ITP ................................................40
Table 6-4
Criteria for dose adjustment based on liver enzyme and bilirubin 
levels .....................................................................................................41
Table 8-1
Assessment schedule.............................................................................48
Table 8-2
Physical assessments.............................................................................57
Table 8-3
Laboratory assessments to be performed locally ..................................57
60
62
Table 10-1
Guidance for capturing the study treatment errors including 
misuse/abuse .........................................................................................69
Table 12-1
Numeric results for testing H0: P = P0 versus H1: P > P0 using 
exact binomial test statistic ...................................................................80
Table 16-1
OATP and BCRP Substrates.................................................................87
Table 16-2
Modified WHO Bleeding Scale ............................................................88
Table 16-3
ITP Bleeding Scale................................................................................89
Table 16-4
FACIT-Fatigue Scale Version 4............................................................90
Table 16-5
SF-36V2................................................................................................91
Table 16-6
FACT-Th6 (Version 4) .........................................................................97


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Table 16-7
FACT-G (Version 4).............................................................................98
Table 16-8
Treatment Satisfaction Questionnaire (TSQM) ....................................99
List of figures
Figure 3-1
CETB115J2411 study design................................................................25
Figure 3-2
Example of a patient with sustained remission by Month 12 ...............26


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List of abbreviations
aCL
Anticardiolipin
AE
Adverse Event
AESI
Adverse Event of Special Interest
ALP
Alkaline Phosphatase
ALT
Alanine Aminotransferase
Anti-D
Immunoglobulin that recognizes and binds specifically to the erythrocyte D 
antigen used to treat ITP
aPTT
Activated Partial Thromboplastin Time
ASH
American Society of Hematology
AST
Aspartate Aminotransferase
β-HCG
β-Human Chorionic Gonadotropin
BPM
Beats per Minute
BUN
Blood Urea Nitrogen
CI
Confidence Interval
cITP
Chronic Immune Thrombocytopenia
CMO&PS
Chief Medical Office and Patient Safety
CMV
Cytomegalovirus
CR
Complete Response
CRF
Case Report/Record Form (paper or electronic)
CRO
Contract Research Organization
CSR
Clinical Study Report
CTCAE
Common Terminology Criteria for Adverse Events
CV
Coefficient of Variation
DILI
Drug-Induced-Liver Disease
EBV
Epstein Barr Virus
ECG
Electrocardiogram
eCRF
Electronic Case Report Forms
ECRS
Electronic Case Retrieval Sheet
EDC
Electronic Data Capture
FACIT
Functional Assessment of Chronic Illness Therapy
FACT
Functional Assessment of Cancer Therapy
FACT-Th6
Functional Assessment of Cancer Therapy – Thrombocytopenia 6-item version
FAS
Full Analysis Set
FDA
Food and Drug Administration
FUP
Follow-Up
GCP
Good Clinical Practice
GGT
Gamma-Glutamyl Transferase
GP5
Bothered by side effects component of the FACT-G assessment
HbsAg
Hepatitis B Surface Antigen
HBV
Hepatitis B Virus
HCV
Hepatitis C Virus
HD-DEX
High Dose Dexamethasone
HIV
Human Immunodeficiency Virus
HRQoL
Health-Related Quality of Life
HSV
Herpes Simplex Virus


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IB
Investigator’s Brochure
ICF
Informed Consent Form
ICH
International Conference on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use
IEC
Independent Ethics Committee
INR
International Normalized Ratio
IRB
Institutional Review Board
IRT
Interactive Response Technology
 
ITP
Immune Thrombocytopenia
IVIG
Intravenous Immunoglobulin
LC-MS/MS
Liquid Chromatography – Tandem Mass Spectroscopy
LFT
Liver Function Test 
LDH
Lactate Dehydrogenase
LLOQ
Lower Limit of Quantification
MCS
Mental Component Score
MedDRA
Medical Dictionary for Regulatory Activities
MR
Minor Response
OR
Overall Response
ORR
Overall Response Rate
PCS
Physical Component Score
PGIC
Patient Global Impression of Change
PGIS
Patient Global Impression of Severity
PR
Partial Response
PK
Pharmacokinetic(s)
PRO
Patient-Reported Outcomes
PT
Prothrombin Time
QD
Daily, Every Day
QoL
Quality of Life
QTcF
QT interval corrected by Fridericia’s formula
R Value
RMP
ALT/ALP x ULN
Risk Management Plan
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SC
Steering Committee
SD
Standard Deviation
SF-36
Short Form 36
SOC
System Organ Class
SUSAR
Suspected Unexpected Serious Adverse Reactions
TBIL
Total Bilirubin


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TEAE
Treatment-Emergent Adverse Event
TPO-RA
Thrombopoietin Receptor Agonists
TSQM-9
Treatment Satisfaction Questionnaire for Medication
ULN
Upper Limit of Normal
WHO
World Health Organization 


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Glossary of terms
Assessment
A procedure used to generate data required by the study
Baseline
Baseline is defined as the last available assessment on or before the 
date of start of eltrombopag
Biologic Samples
A biological specimen including, for example, blood (plasma, serum), 
saliva, tissue, urine, stool, etc. taken from a study patient
Dosage
Dose of the study treatment given to the patient in a time unit (e.g. 50 mg 
per day)
Electronic Data Capture 
(EDC)
Electronic data capture (EDC) is the electronic acquisition of clinical 
study data using data collection systems, such as Web-based 
applications, interactive voice response systems and clinical laboratory 
interfaces. EDC includes the use of Electronic Case Report Forms 
(eCRFs) which are used to capture data transcribed from paper source 
forms used at the point of care.
Investigational 
drug/treatment
The drug whose properties are being tested in the study
Medication number
A unique identifier on the label of medication kits
Patient
An individual with the condition of interest for the study
Screen Failure
A patient who did not meet one or more criteria that were required for 
participation in the study
Source Data/Document
Source data refers to the initial record, document, or primary location 
from where data comes. The data source can be a database, a dataset, a 
spreadsheet or even hard-coded data, such as paper or eSource.
Study treatment
Any single drug or combination of drugs or intervention administered to 
the patient as part of the required study procedures.
Study treatment 
discontinuation
When the patient permanently stops taking study drug prior to the defined 
study treatment completion date (if any) for any reason; may or may not 
also be the point/time of study discontinuation 
Study treatment 
interruption
When the patient temporarily stops taking study drug
Subject
A trial participant (can be a healthy volunteer or a patient)
Patient number
A unique number assigned to each patient upon signing the informed 
consent. This number is the definitive, unique identifier for the patient and 
should be used to identify the patient throughout the study for all data 
collected, sample labels, etc.
Variable
A measured value or assessed response that is determined from specific 
assessments and used in data analysis to evaluate the drug being tested 
in the study
Withdrawal of study 
consent 
Withdrawal of consent is defined as when a patient does not want to 
participate in the study any longer, and does not want any further visits or 
assessments, and does not want any further study related contact, and
does not allow analysis of already collected biologic material.


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Amendment 1 (06-Mar-2019)
Amendment rationale
The primary purposes of this protocol amendment are to:

Update the pregnancy prevention language to align with the Clinical Trials Facilitation 
Group (CTFG) recommendations related to contraception and pregnancy testing in clinical 
trials.
 

Add a follow-up period of 12 months for patients who have sustained remission at month 
12 to obtain further data on response and remission duration.

Add a new secondary objective related to the newly added 12 months follow-up period.

Update the drug induced liver injury (DILI) guidance to align with current Novartis DILI 
guidelines.

Update to align with the current eltrombopag program risk language.
Changes to the protocol:
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underline for insertions.

Protocol summary section updated to match the body of the protocol. 

End of Study (EOS) has been revised to end of treatment. Patients who are still on study 
treatment and not in sustained remission at month 12 will come off trial after completing 
the end of treatment visit. Patients who are still in sustained remission at the end of 
treatment visit will enter the follow-up period.

Section 2 Table 2-1 Objectives and endpoints: Added a new secondary objective related to 
the 12 months follow-up period.

Section 2 Table 2-1 Objectives and endpoints: Updated appropriate objectives/endpoints 
to include the 12 months follow-up period.

Section 3 Figure 3-1: Modified to match the study design.

Section 3 Figure 3-2: Clarified the figure is for patients with sustained remission by month 
12.

Section 3 Study Design: Updated to define patients of Asian ancestry.

Section 4.2 Rationale for dose/regimen and duration of treatment: Clarified the starting 
dose for patients.

Section 4.5 Purpose and timing of interim analyses/design adaptations: Added the analysis 
time points.

Section 4.6 Risks and benefits: Updated to align with the current eltrombopag program 
risk language.

Section 4.6 Risks and benefits: Reference updated.

Section 5.2 Exclusion criteria #7: Updated to include creatinine clearance < 45 mL/min.


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
Section 5.2 Exclusion criteria #11: Clarified that local laboratory results for human 
immune deficiency virus (HIV), hepatitis C virus (HCV) or hepatitis B surface antigen 
(HBsAg) are allowed to confirm eligibility. 

Section 5.2 Exclusion criteria #23: Clarified that a serum pregnancy test is required for 
female patients of child bearing potential at screening.

Section 5.2 Exclusion criteria #24: Updated to state highly effective contraception is 
required. This criteria was updated to align with the Clinical Trials Facilitation Group 
(CTFG) recommendations related to contraception and pregnancy testing in clinical trials.  

Section 6.1 Study treatment: Clarified patients who are dose escalated to 75mg QD are 
eligible for tapering and treatment discontinuation as long as they achieve CR and 
maintain their platelet counts. 

Section 6.1 Study treatment: Updated to define patients of Asian ancestry.

Section 6.1.3 Treatment duration: Updated to include the follow-up period and clarified 
the treatment duration for all patients.

Section 6.2.1.1 Permitted concomitant therapy requiring caution and/or action: Updated to 
include language on CYP and UGT inhibitors and inducers.

Section 6.3.1 Patient Numbering: Updated to include re-screening information. 

Section 6.5.2 Table 6-3 Eltrombopag Dose Adjustments in ITP: Added footnote for 
rationale for dose adjustment for platelet count < 100×109/L following 2 weeks of therapy.

Section 6.5.2 Table 6-3 Eltrombopag Dose Adjustments in ITP: Added a row to clarify 
dose adjustment for platelet counts ≥ 100×109/L to < 200 × 109/L.

Section 6.5.2 Table 6-3 Eltrombopag Dose Adjustments in ITP: Added source for dose 
adjustment for platelet counts (≥200 × 109/L to ≤400 × 109/L and >400 ×109/L).

Section 6.5.2 Table 6.4 Criteria for eltrombopag dose adjustment based on liver enzyme 
and bilirubin levels: Title updated and table aligned with current Novartis guidelines for 
dose reduction/interruption due to Investigations (Hepatic).

Section 6.5.2 Table 6-4 Criteria for eltrombopag dose adjustment based on liver enzyme 
and bilirubin levels:  Clarified footnote for the guidelines for when total bilirubin > 3.0 –
10.0 x ULN is due to the indirect (non-conjugated) component only.

Section 6.5.3.2 Follow up on potential DILI cases: Updated to align with current Novartis 
DILI guidance.

Section 8 Visit Schedule and Assessments: Added visit window for visits during the 
follow-up period.

Section 8, Table 8-1 Assessment schedule: Updated to reflect that PE results and weight
are recorded at every visit and are recorded within the source documents. 

Section 8, Table 8-1 Assessment schedule: Updated to reflect that pregnancy tests should 
be performed monthly until the end of treatment visit and results are recorded within the 
source documents.  If no visit is planned the test can be performed at home with urine 
pregnancy test.
 


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
Section 8, Table 8-1 Assessment schedule: Footnote added to follow-up column to reflect 
that patients who achieved sustained remission at month 12 will be followed-up for an 
additional 12 months in order to obtain further data on response and remission duration.

Section 8, Table 8-1 Assessment schedule: Added table for the 12 months follow-up 
period for responders.

Section 8.4 Safety: Updated to include weekly hematology assessments (including platelet 
counts) for the first four weeks after discontinuing eltrombopag for patients who 
discontinue treatment early for reasons other than per protocol tapering.

Section 8.4.4 Pregnancy: Updated to state a serum pregnancy test must be performed 
within 14 days of the first dose of eltrombopag.  Monthly pregnancy tests (serum or urine) 
are required monthly until the end of treatment visit.  A serum pregnancy test is required 
at the end of treatment visit.

Section 8.5.1 Clinical Outcome Assessments: Clarified that PRO assessments are 
collected during treatment, sustained remission, and the 12 months follow-up period.

Section 9.2 Study Completion and post-study treatment: Updated to clarify study 
completion, the end of treatment visit at Week 53, Day 1, and safety follow-up. 

Section 9.3: Added to describe the 12 months follow-up period for patients who have
achieved sustained remission at month 12.  

Section 10.2.1 Liver safety monitoring: Clarified that liver safety monitoring tests should 
be performed at local laboratories used by the site.

Section 12 Data analysis and statistical methods: Added the following text: The 95%
confidence interval (CI) using the Clopper-Pearson method will be provided for selected 
parameters. Kaplan-Meier method will be used for time to event analyses.

Section 12.5.1 Efficacy endpoint(s): The first efficacy endpoint was updated to include:

Kaplan-Maier analyses for the duration of sustained remission (weeks) counted from 
last dose of eltrombopag to relapse for patients with sustained remission (R) at month 
12 and who enter 12 months follow-up period. The patients who do not relapse/die by 
month 24 will be censored. 

Kaplan-Maier analyses for the duration of sustained remission (weeks) counted from 
last dose of eltrombopag to relapse for all patients. The patients who do not 
relapse/die by month 24 will be right-censored. The duration will be considered as 0 
for patients who do not manage to taper off eltrombopag per protocol i.e. do not reach 
sustained remission.

Section 12.5.1 Efficacy endpoint(s): Endpoint added for new secondary objective  (related 
to the 12 months follow-up period):

To assess the proportion of patients maintaining a sustained remission after treatment 
discontinuation until month 24.

Number (%) of patients who are in sustained remission at months 15, 18, 21, and 24 
will be provided.

Section 12.5.1 Efficacy endpoint(s): Clarified the fourth endpoint will be to assess the 
platelet count from baseline and every 3 months until month 24.


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
Section 12.5.1 Efficacy endpoint(s): Clarified the fifth endpoint will be to assess the 
ability of eltrombopag to maintain a platelet count ≥30×109/L from baseline and every 3 
months until month 24.

Section 12.5.1 Efficacy endpoint(s): Updated to include 12 months as a time point for the 
analysis of impact of side effects of treatment and treatment satisfaction.

Section 15 References: Reference updated.

Other clarifications, administrative changes and corrections as needed.
IRBs/IECs
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation.
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment.


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Protocol summary
Protocol number
CETB115J2411
Full Title
A phase II, open-label, prospective, single-arm, study to assess ability of eltrombopag to 
induce sustained remission in subjects with ITP who are refractory or relapsed after first-
line steroids (TAPER)
Brief title
A study to assess the ability of eltrombopag to induce sustained remission in subjects
with ITP
Sponsor and
Clinical Phase
Novartis
II
Investigation 
type
Drug
Study type
Interventional
Purpose and 
rationale
The purpose of this trial is to assess the ability of eltrombopag to induce sustained 
treatment-free remission in ITP subjects who relapsed or failed to respond to an initial 
treatment with steroids.
There is limited, mainly retrospective evidence that earlier use of eltrombopag after ITP 
diagnosis, will allow a larger proportion of patients to achieve sustained remission after
tapering off drug. Clinically there is a need for a less toxic regimen that will provide 
responses and sustained remission with a shorter treatment interval. This trial is designed 
to assess this.
Primary 
Objective(s) 
To assess ability of eltrombopag to induce sustained remission by month 12 in ITP 
patients who relapsed or failed to respond to first-line steroid treatment
Secondary 
Objectives
1.
To assess the duration of sustained remission after treatment discontinuation, by 
month 12, and by month 24. 
2.
To assess the proportion of patients maintaining a sustained remission after 
treatment discontinuation until month 24
3.
To assess the ability of eltrombopag to induce early response by month 1
4.
To assess the ability of eltrombopag to induce a recovery response, in case of loss of 
response during or after tapering of eltrombopag
5.
To assess the platelet count from baseline and every 3 months until month 24 
6.
To assess the ability of eltrombopag to maintain platelet count ≥30×109/L within 12 
months and every 3 months until month 24
7.
To evaluate patient-health-related outcome measures for health-related quality of life 
by use of Functional Assessment of Chronic Illness (FACIT) & Functional 
Assessment of Cancer Therapy – Thrombocytopenia 6-item Version (FACT-Th6) and 
Short Form (SF-36v2) questionnaires from baseline and every 3 months to month 24 
and end of treatment
8.
To explore the overall impact of side effects on patients’ perception of treatment via 
the GP5 assessment at baseline, month 12, and end of treatment
9.
To explore treatment satisfaction with Treatment Satisfaction Questionnaire for 
Medication (TSQM-9) at baseline, month 12, and end of treatment
10. To evaluate the safety and tolerability of eltrombopag
Study design
This is a phase II, open-label, prospective, single-arm, study to assess ability of 
eltrombopag to induce sustained remission in patients with ITP who are refractory or 
relapsed after first line steroids.
Population
The study is designed to include adult patients with ITP who have failed to respond or 
who relapsed following an initial response to a first-line course of steroid therapy (steroid-
relapsed or steroid-refractory).
The enrollment target is 101 patients.


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Inclusion criteria
1.
Signed informed consent must be obtained prior to participation in the study
2.
Patients ≥ 18 years old
3.
Patients with a confirmed diagnosis of primary ITP, who are not responsive or in 
relapse after a first line of steroid therapy ± intravenous immunoglobulin (IVIG) (used 
as a rescue therapy)
First line of steroid therapy will be defined as: prednisone/prednisolone 0.5 to 1
mg/kg/day for a minimum of 2 weeks, or minimum of 1 course of high-dose 
dexamethasone 20-40 mg/day for consecutive 4 days ±IVIG (used as rescue therapy). 
Maximum exposure to high-dose steroids treatment (steroids tapering time excluded) 
should be limited to: 4 weeks of high dose prednisone/prednisolone or 3 courses of high-
dose dexamethasone. Overall exposure to steroids must not be longer than 3 months, 
including period of dose tapering.
4.
Platelet count < 30×109/L and assessed as needing treatment (per physician’s 
discretion)
Exclusion 
criteria
1.
ITP patients previously treated with any ITP second-line therapies, thrombopoietin 
receptor (TPO-R) agonists for ITP, except steroids / IVIG
2.
Patients who relapsed more than one year after the end of first-line full course of 
steroid therapy
3.
Patients with a diagnosis of secondary thrombocytopenia
4.
Patients who are unable to participate in assessments/biological studies
5.
Patients who have life threatening bleeding complications per investigator discretion
6.
Patients who had a deep vein thrombosis or arterial thrombosis in the 6 months 
preceding enrollment
7.
Presence of moderate to severe impaired renal function as indicated by any or all of 
the following criteria:

Creatinine clearance < 45 mL/min as calculated using Cockcroft-Gault formula

Serum creatinine > 1.5 mg/dL
8.
Total bilirubin > 1.5 × upper limit of normal (ULN)
9.
Aspartate transaminase (AST) > 3.0 × ULN
10. Alanine transaminase (ALT) > 3.0 × ULN
11. Patients who are human immune deficiency virus (HIV), hepatitis C virus (HCV), 
hepatitis B surface antigen (HBsAg) positive
12. Patients with hepatic impairment (Child-Pugh score > 5)
13. Patients who are unable to respect the 4-hour interval between eltrombopag and 
other medications (e.g., antacids), calcium-rich foods (e.g., dairy products and 
calcium fortified juices), or supplements containing polyvalent cations such as iron, 
calcium, aluminum, magnesium, selenium, and zinc
14. Patients who are unable to stop medications that are known to cause a drug-drug 
interaction with eltrombopag
15. Patients who have active malignancy
16. Patients with any serious and/or unstable pre-existing medical, psychiatric disorder 
or other conditions that could interfere with patient’s safety, obtaining informed 
consent or compliance with the study procedures per investigator discretion
17. Patients with a known immediate or delayed hypersensitivity reaction or idiosyncrasy 
to eltrombopag or drugs chemically related to eltrombopag or excipients that 
contraindicate their participation
18. History or current diagnosis of cardiac disease indicating significant risk of safety for 
patients participating in the study such as uncontrolled or significant cardiac disease 
or impaired cardiac function including any of the following:

Corrected QTc > 450 msec (male patients), > 460 msec (female patients) using 
Fredericia correction (QTcF) on the screening ECG

Resting heart rate at screening (physical exam or 12 lead electrocardiogram 
[ECG]) < 50 or > 90 beats per minute (BPM)


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
Recent myocardial infarction (within last 6 months)

Uncontrolled congestive heart failure

Unstable angina (within last 6 months)
19. Patients with known active or uncontrolled infections not responding to appropriate 
therapy
20. Patients with evidence of current alcohol/drug abuse
21. Concurrent participation in an investigational study within 30 days prior to enrollment 
or within 5-half-lives of the investigational product, whichever is longest. Note: 
parallel enrollment in a disease registry is permitted
22. Known thrombophilic risk factors. Exception: Patients for whom the potential benefits 
of participating in the study outweigh the potential risks of thromboembolic events, as 
determined by the investigator
23. Female patients who are nursing or pregnant (positive serum  pregnancy test) at 
screening or pre-dose on Day 1
24. Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, and sexually active males unwilling to use highly effective 
methods of contraception during the study.  See Section 5.2 for additional details on 
highly effective contraception.
Study treatment
Patients will be treated with eltrombopag 50 mg once daily (QD) for 2 weeks to reach a 
target platelet count of ≥ 100×109/L. For those patients who do not achieve the target 
platelet count within 2 weeks, the dose of eltrombopag will be increased to 75 mg QD. 
Those patients who have not reached the target platelet count ≥ 100×109/L after being 
treated with eltrombopag 75 mg/day will continue on eltrombopag until month 12.
Patients will be eligible for taper off and treatment discontinuation if they have a reached 
a complete response (CR), defined as platelet counts ≥ 100×109/L, and maintained
platelet counts around 100×109/L for 2 months (no counts below 70×109/L). The duration 
of tapering will be individualized and depend upon starting dose and response of the 
patient: decreases in dose will be performed by 25 mg reductions every 2 weeks. If 
platelet counts are stable, the next reduction should be carried out within 2 weeks, with 
dosing at 25 mg on alternate days for 2 weeks until treatment is totally discontinued.
A reduced initial dosage of 25 mg QD is recommended for patients of Asian ancestry
(such as Chinese, Japanese, Taiwanese, Korean or Thai).
Efficacy 
assessments
Platelet count will be performed at screening visit 1 to assess the eligibility of the patient. 
Hematology including platelet counts will be assessed at week 1/day 1 and weekly during 
the first 8 weeks of treatment. Based on patient response, hematology will be performed 
biweekly thereafter until the end of treatment. 
Additional assessments of platelet count may be performed more frequently than the 
biweekly schedule if needed in accordance with the clinical judgment of the investigator.
Bleeding events will be assessed at each visit and recorded in the adverse event (AE)
case report forms (CRF). Documentation of the use of any rescue therapy will be 
documented on the appropriate CRF.
Key safety 
assessments

Physical assessments: physical exam, vital signs, height and weight

Ophthalmic examination

Laboratory evaluations

Electrocardiogram

Pregnancy testing
Patients who discontinue treatment early for reasons other than per protocol tapering 
require weekly hematology assessments (including platelet counts) for the first four 
weeks after discontinuing eltrombopag.  


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Other 
assessments 

FACIT-Fatigue

Medical Outcome Trust’s Short-Form 36 Health Survey, Version 2 (SF-36 v2)

FACT-Th6

GP5

TSQM-9
Data analysis
Continuous variables will be summarized by number of patients, mean, standard 
deviation, minimum, median, and maximum. For selected parameters, 25th and 75th
percentiles will also be presented.
Categorical variables will be summarized by frequencies and percentages. The 95% 
confidence interval (CI) using the Clopper-Pearson method will be provided for selected 
parameters.
Kaplan-Meier method will be used for time to event analyses. 
The primary endpoint is the proportion of patients with sustained remission by month 12, 
where sustained remission (R) is defined as:

reach platelet count ≥ 100×109/L (CR) and then maintain platelet counts around 
100×109/L for 2 months (no platelet count below 70×109/L) AND then

taper off the drug until treatment discontinuation while,

maintain platelet count ≥ 30×109 /L in the absence of bleeding (no bleeding AE) or 
use of any rescue therapy until month 12.
The number (%) of patients with sustained remission (R) by month 12 will be summarized 
together with 95% CI using the Clopper-Pearson method. A binomial test for one 
proportion, H0: P=0.15 vs. H1:P>0.15 will be performed to test if the proportion of patients 
with sustained remission is greater than 15%.
Key words
Eltrombopag, immune thrombocytopenia, ITP, corticosteroids


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1
Introduction
1.1
Background
Primary immune thrombocytopenia (ITP) is an acquired, immune-mediated disorder of adults 
and children. It is defined as a platelet count of less than 100×109/L, in the absence of other 
causes or disorders that may be associated with thrombocytopenia.
Incidence estimates for adult-onset ITP are reported to range from 1.6 to 3.9 per 100,000 per 
year. The incidence of ITP follows a multimodal distribution pattern, with peaks in young 
children, young adults and the elderly, with the highest age-specific incidence in individuals 
over 60 years (Terrell 2010). The overall prevalence of ITP in adults has been estimated to be 
9.5 per 100,000, ranging from 4.1 per 100,000 in younger ages (19 to 24 years) to 16 per 
100,000 in older age groups (55 to 64 years). Immune thrombocytopenia is found worldwide 
and has similar epidemiologic patterns across regions (Arnold 2013).
Most commonly, ITP patients have asymptomatic thrombocytopenia, however patients usually 
present at hospital and seek medical help once bleeding symptoms occur. Although some 
patients bleed with platelet counts < 30×109/L, many do not. Bleeding symptoms characteristic 
of ITP (“platelet-type bleeding”) include skin bleeding (i.e., bruises, non-palpable purpura, or 
petechiae), oral hemorrhagic blood blisters (purpura) or oral petechiae, epistaxis, menorrhagia, 
or gastrointestinal bleeding. The most feared life-threatening complication is intracerebral 
hemorrhage, reported in 1.5 to 1.8% of adult patients (Lambert 2017, Hoffman 2013).
The degree of bleeding is largely dependent on the severity of thrombocytopenia, with platelet 
counts < 20 to 30×109/L conferring the greatest risk of clinically significant bleeding 
(George 1996; Guidelines l British Society for Haematology 2003). Mild hemorrhages 
presenting with bruising and petechiae are most common, but severe hemorrhages involving 
the gastrointestinal and genitourinary tract are well known complications of the disease, and 
occur in ~ 10% of adult ITP patients. The frequency of death from hemorrhage in patients with 
platelet counts < 30×109/L is estimated to be between 1.6 and 3.9% per patient year, although 
the frequency is influenced by age, severity and duration of thrombocytopenia (Cohen 2000).
Based on the disease duration from initial confirmed ITP diagnosis, there are 3 categories of 
patients: newly diagnosed (between time of diagnosis and 3 months), persistent ITP (between 
3 and 12 months from diagnosis), and chronic ITP (cITP) (reserved for patients with ITP lasting 
for more than 12 months). This clinical categorization inversely correlates with patients’ chance 
of achieving spontaneous remission of the disease (i.e., the longer the duration of disease, the 
lower the chance for spontaneous remission) (Rodeghiero 2009, Hoffman 2013, Provan 2010).
Chronic ITP has been associated with a risk of death that is up to four times higher than that of
the general population. ITP patients are more likely to die of bleeding, infection, and 
hematologic malignancies. Some deaths are attributable to adverse events (AEs) of treatment 
rather than the disease. Quality of Life (QoL) in patients with ITP is lower than that of the 
general population, which is at least partially a result of high prevalence of fatigue that appears 
to be independent of platelet count levels (Portielje 2001, Hoffman 2013, Stasi 2004, Profit 
2006, George 2006)


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The goal of therapy in ITP is not to normalize the platelet count but to achieve a platelet count 
that confers adequate hemostasis and minimizes the risk of clinically significant bleeding for 
the individual patient, avoiding treatment-related toxicity. Therefore, the choice and the 
management of each treatment must be conducted for each patient on a case-by-case basis. In 
general, treatment is seldom required when platelets are > 20 to 30×109/L. For patients with 
platelets < 20×109/L, treatment is required, but depends on a full assessment of the patient 
lifestyle, occupation, bleeding history, comorbidities, and other factors (Provan 2010, 
Rodeghiero 2009).
Observational data from ITP patient cohorts indicate that risk of clinically significant bleeding 
increases with increasing severity of thrombocytopenia and as such, a platelet threshold of 
< 20 to 30×109/L is typically a trigger for treatment, irrespective of bleeding manifestations. 
Treatment guidelines established by the American Society of Hematology (ASH) and the 
International Working Group (IWG) consensus panel of expert clinicians also indicate that it is 
appropriate to initiate treatment for newly diagnosed ITP patients with platelet counts of <
30×109/L (Neunert 2011, Provan 2010).
Current therapies
First-line treatment has remained unchanged for decades and comprises corticosteroids in 
60 to 70% of patients, intravenous immunoglobulin (IVIG) in approximately 20%, and anti-D
immune globulin (less than 10% in countries where anti-D is available). Corticosteroids are 
inexpensive and raise platelet counts rapidly within 2 to 14 days in approximately 75% of 
patients. Corticosteroids will generally induce a response within the first 2 weeks, but less than 
25 to 30% of patients will sustain responses and will relapse within the first year, most 
commonly during steroid taper or shortly after discontinuation (Table 1-1) (Cooper 2017, Wong 
2017).
Side effects of steroids are common and predictable, and have a significant impact on patients’ 
QoL. The most common steroid-related AEs include weakness, impaired cognition and 
insomnia, mood changes, weight gain, headache, impaired glucose metabolism, as well as 
increased risk of infections due to immunosuppressive effects, and osteoporosis due to the effect 
on bone marrow density. Currently available corticosteroids for ITP include prednisone, 
prednisolone, methylprednisolone and dexamethasone, with prednisone and dexamethasone 
being the most widely used.
Prednisone, rather than dexamethasone, has been used predominantly as first-line treatment, but 
the rate of sustained response with prednisone and dexamethasone seem overall similar. The 
typical dosing regimen for prednisone is 0.5 to 2 mg/kg bodyweight daily for four weeks until 
the maximum dose is achieved, followed by tapering. Approximately two-thirds of patients 
demonstrate an initial response to prednisone, but only a limited fraction of patients experience 
long-term remission. However, despite this, prednisone remains the first-line corticosteroid of 
choice. There are conflicting results, and no clear consensus on whether use of high dose 
dexamethasone (HD-DEX) vs prednisone is preferable, even though there is increasing 
evidence, including data from randomized prospective clinical trials demonstrating that 
HD-DEX provides a more effective and rapid response as the initial treatment regimen for ITP 
in comparison to conventional prednisone (Mithoowani 2016, Mashhadi 2012, Wei 2016,
Nakazaki 2012, Sakamoto 2014).


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Table 1-1
First-line treatment options for patients with ITP
Treatment
Typical dose/regimen
Efficacy
Safety
Prednisone
0.5–2 mg/kg/day,
for 2–4 weeks until a response 
is seen, followed by tapering 
over several weeks
Initial response: 60–80%
Sustained response: 
20–47%
AEs vary with the dose 
and duration, but 
include weight gain, 
anxiety, insomnia, and 
diabetes
Dexamethasone
40 mg/day, for 4 days every 2–4 
weeks, for 1–4 cycles
Initial response: up to 90%
Sustained response: 
40–50%
Repeated cycles may result 
in response rates up to 80%
Weakness, insomnia, 
and impaired cognition
IVIG
0.4 g/kg/d for 5 days or
1 g/kg/d for 1–2 days
Initial response: up to 80%
Platelet count usually 
returns to pretreatment 
levels within 2–4 weeks, 
persists for months in few 
patients
Common: headache, 
hypertension, and 
chills
Rare: hemolysis and 
neutropenia
Anti-D
50–75 μg/kg
Similar to IVIG, dependent 
on dose
Common: hemolysis
Rare: intravascular 
hemolysis, can be fatal
Source: Provan 2010
In general, 60-70% of adults with acute ITP achieve an initial response; even higher response 
rates are reported in children. Rates of sustained response with corticosteroid treatment (usually 
defined as a platelet count ≥50 or ≥100×109/L at 6-12 months, with different timeline and 
platelet count thresholds within different publications) are generally low and vary from 20% to 
47%. With longer follow-up, the risk of relapse increases in adults who experience an initial 
response.
Many of the currently available treatments, in particular, high doses of steroids, are associated 
with significant morbidity. Historical data has shown that mortality from ITP more often results 
from infectious complications of steroid treatment and splenectomy rather than directly from 
bleeding. Thus, there is an important need for a tolerable therapy for patients that do not 
experience early ITP remission with steroid treatment.
Options for salvage therapy include retreatment with corticosteroids, switching from one steroid 
type to another, a combination of first-line agent(s), or treatment with a second-line agent. 
According to current guidelines available modalities for second line treatment options for ITP 
patients have quite different mechanisms of action. They are broadly classified into those that 
are given only once (or for only one course) and are intended to induce long-term remission 
(splenectomy, rituximab) and those that need continued or chronic administration 
(corticosteroids, immunosuppressive agents and Thrombopoietin
Receptor Agonists 
[TPO-RAs]).


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There are limited data about duration of steroid recycling, but such regimens vary from a few 
months up to a few years of repeated steroids use and/or switching from one steroid type to 
another. The incidence of steroid-derived AEs, in general, depends greatly on both the average 
dose and cumulative duration of use, indicating that it is essential to both complete whole 
courses of therapy in as short a period as possible and to reduce the total amount of administered 
corticosteroids.
While corticosteroids remain the standard of care for ITP, high relapse rates and considerable 
toxicity associated with long-term corticosteroid use highlight a significant unmet medical need 
in the management of ITP particularly for those patients who relapse after initial treatment. 
Novel therapeutic approaches are warranted that achieve a sustained response and reduce the 
need for long-term corticosteroid use.
1.2
Purpose
The purpose of this trial is to assess the ability of eltrombopag to induce sustained treatment-
free remission in ITP patients who failed to respond or have relapsed after an initial treatment 
with steroids.
This is supported by medical experts´ experience and limited published evidence indicating that 
a certain proportion of patients are able to achieve a stable response and sustained remission
during treatment with TPO-RA earlier in the course of the disease and are able to discontinue 
treatment (Bussel 2015, Gonzalez-Lopez 2015, Newland 2016). TPO-RA used earlier than 12 
months from disease diagnosis might reduce toxicity from steroid exposure and can provide a 
sustained remission. However, an analysis of data collected prospectively and powered to assess 
whether TPO-RA can behave in this manner is lacking.
There is insufficient evidence to create a treatment sequence recommendation for patients who 
relapsed or who failed to respond after first-line steroid treatment within 3-12 months from 
initial diagnosis. The most appropriate treatment sequence for those ITP patients should 
eliminate an unacceptable level of uncertainty and currently is not addressed in any of the 
guidelines.
We will therefore conduct a prospective trial of eltrombopag in patients with ITP, who are 
refractory to or who relapsed after initial treatment with first-line steroids, to assess the ability 
of eltrombopag to induce treatment-free sustained remission.
This trial will help by closing a gap that exists in the medical community, which is to generate
prospective data within clinical trial setting that will demonstrate that eltrombopag could be the
treatment option considered after first-line steroid treatment. The definition of ‘first round of 
steroids” is not standardized, with different duration of steroids cycles being considered as “first 
round” (Provan 2011, Neunert 2011, Gutierrez-Espindola 2003).


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2
Objectives and endpoints
Table 2-1
Objectives and endpoints
Objective(s)
Endpoint(s)
Primary Objective(s)
Endpoints for primary objective(s)
1.
To assess ability of eltrombopag to induce sustained remission by month 12 
in ITP patients who relapsed or failed to respond to first-line steroid 
treatment.
1.
Proportion of patients with sustained remission (R) by month 12 where 
sustained remission is defined as:

reach platelet count ≥ 100×109/L (complete response [CR]) and then 
maintain platelet counts around 100×109/L for 2 months (no counts below 
70×109/L) AND then

taper off the drug until treatment discontinuation (see Section 9.1) while,

maintain platelet count ≥ 30×109/L in the absence of bleeding (no bleeding 
AEs) or use of any rescue therapy (see Section 6.2.3) until month 12.
Secondary Objective(s)
Endpoints for secondary objective(s)
1.
To assess the duration of sustained remission after treatment 
discontinuation by month 12 and by month 24
1a. Median duration of sustained remission (weeks) counted from last dose of 
eltrombopag to month 12 for patients with sustained remission (R) 
1b. Estimated median duration of sustained remission (weeks) by month 24 for 
patients who are in sustained remission (R) at month 12 and enter 12 months 
follow-up period using Kaplan-Meier method
1c. Estimated median duration of sustained remission (weeks) by month 24 for all 
patients using Kaplan-Meier method.
2.
To assess the proportion of patients maintaining a sustained remission after 
treatment discontinuation until month 24.
2. Proportion of sustained remission (R) patients at months 15, 18, 21, and 24.
3.
To assess the ability of eltrombopag to induce early response by month 1
3.
Number (%) of patients with platelet count ≥50×109/L at least once by month 1 
(first month) without bleeding and no rescue therapy
4.
To assess the ability of eltrombopag to induce a recovery response, in case 
of loss of response during or after tapering of eltrombopag until month 24
4.
Number (%) of patients with at least one platelet count ≥30×109/L after 
eltrombopag is re-introduced, in case of loss of response (< 30×109/L and/or 
bleeding event) without bleeding and no rescue therapy by month 12 and 24
5.
To assess the platelet count from baseline and every 3 months until month 
24 
5.
Absolute and relative change in platelet count from baseline to 3, 6, 9,12, 15, 
18, 21, and 24 months and end of treatment
6.
To assess the ability of eltrombopag to maintain platelet count ≥30×109/L 
within 12 months and every 3 months until month 24
6.
.Number (%) of patients who maintain a platelet count ≥30×109/L from the first 
time of reaching that level to month 3, 6, 9, 12, 15, 18, 21, 24, and end of 
treatment without bleeding and no rescue therapy


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Objective(s)
Endpoint(s)
7.
To evaluate patient-Health Related outcome measures for health-related 
quality of life (fatigue level of the patients through FACIT) & FACT-Th6 and 
SF-36v2 questionnaires from baseline and every 3 months to month 24 and 
end of treatment
7.
The analysis of HRQoL parameters; fatigue level of the patients through FACIT 
& FACT-Th6, SF-36v2 questionnaires. Change in scores from baseline to 
month 3, 6, 9, 12, 15, 18, 21, 24, and end of treatment
8.
To explore the overall impact of side effects on treatment via the GP5 at 
baseline, month 12, and end of treatment
8.
Overall change from baseline to month 12 and end of treatment will be 
assessed
9.
To explore treatment satisfaction with TSQM-9 at baseline, month 12, and
end of treatment
9.
Overall change from baseline to month 12 and end of treatment will be 
assessed
10. To evaluate the safety and tolerability of eltrombopag
10. Number (%) and severity of patients with AEs, serious AEs (SAEs), AEs 
leading to discontinuation, AEs leading to dose adjustments, AEs of special 
interest. Change from baseline in vital signs and clinical laboratory tests
FACIT=Functional Assessment of Chronic Illness Therapy; FACT=Functional Assessment of Cancer Therapy; FACT-Th6=Functional Assessment of Cancer Therapy –
Thrombocytopenia 6-item version; GP5-bothered by symptoms component of the FACT-G assessment; HRQoL=Health Related Quality of Life;
 SF-36=Short Form-36;
 TSQM-9=Treatment Satisfaction Questionnaire for Medication;


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3
Study design
This is a phase II, open-label, prospective, single-arm, study to assess ability of eltrombopag to 
induce sustained remission in adult patients with ITP who are refractory or relapsed after first 
line steroids. The study design is provided in Figure 3-1.
Figure 3-1
CETB115J2411 study design
Patients with confirmed diagnosis of ITP, who have failed to respond or who have relapsed 
following initial response after a first-line of steroid therapy with or without intravenous 
immunoglobulin (IVIG) (if used as a rescue therapy) will be screened, and if eligible, will 
receive eltrombopag. First line of steroid therapy will be defined as: prednisone/prednisolone 
0.5 to 1mg/kg/day for a minimum of 2 weeks, or minimum of 1 course of high-dose 
dexamethasone 20 to 40 mg/day for consecutive 4 days ±IVIG (used as rescue therapy). 
Maximum exposure to high-dose steroids treatment (steroids tapering time excluded) should be 
limited to: 4 weeks of high dose prednisone/prednisolone or 3 courses of high-dose 
dexamethasone. Overall exposure to steroids must not be longer than 3 months, including period 
of dose tapering.
In this study, the starting dose will be 50 mg eltrombopag QD (starting dose for Asian patients
will be 25 mg QD, reduced as per Section 6.1).
This eltrombopag starting dose is consistent with the dosing guidelines that have been approved 
for eltrombopag use in adult patients with chronic ITP.
Taper-off and treatment discontinuation: Patients who reach CR (platelet count 
≥100×109/L) and maintain counts around 100×109/L for 2 months (no platelet count below 
70×109/L) will be eligible for taper-off and treatment discontinuation. Duration of tapering will 
vary depending on the starting dose and the response of the patient: decreases in eltrombopag 


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dose will be performed by a 25 mg reduction every 2 weeks up to 25 mg on alternate days for 
2 weeks until treatment discontinuation.
Patients who successfully taper off, i.e. discontinue eltrombopag and maintain platelet count ≥
30×109/L in the absence of bleeding or use of any rescue therapy will be followed up through 
the duration of the trial (to month 12). In case of relapse, patients will be offered a new course 
of eltrombopag treatment within this timeframe, starting at a dose of 50 mg.
Patients with bleeding, or perceived risk of serious bleeding, will be allowed to receive rescue 
therapy as per physician decision, irrespective of platelet counts.
A schematic depicting an example of a patient with sustained remission is provided in 
Figure 3-2. Individual patient study experience will vary dependent on time to response and 
duration of eltrombopag tapering.
Figure 3-2
Example of a patient with sustained remission by Month 12


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4
Rationale
4.1
Rationale for study design
This is a phase II, open-label, prospective, single-arm study to assess ability of eltrombopag to 
induce sustained remission in patients with ITP who are refractory or relapsed after first line 
steroids.
In this context, historical control for this trial are patients who are treated with first round of 
steroids and do not respond or relapse. Based on medical experience and previous data from the 
literature, it is postulated that approximately 15% of patients in this population would have 
sustained remission after 12 months on steroid recycling (Dubbeld 1991, Caulier 1995, Arruda 
1996, Warner 1997, Demiroglu 1997, Stasi 2000, Gutierrez-Espindola 2007). The definition of 
‘first round of steroids” is not standardized, with different duration of steroids cycles being 
considered as “first round” (Provan 2011, Neunert 2011, Gutierrez-Espindola 2003). Published 
response data is not robust with regards to pattern of steroid treatment, making comparison 
across studies difficult.
Rationale for single arm-design: Placebo controlled trial in patients who failed to respond or 
relapsed after first round of steroids treatment would not be considered ethical. According to 
current treatment guidelines, there is no broadly accepted standard of care in this patient 
population that could be potentially considered as comparator arm. In addition, there is not
sufficient evidence to drive the decision for a comparator arm with one treatment option versus 
the other. Therefore, single arm design is suitable for phase II trial, to obtain initial insight about 
ability of eltrombopag to induce treatment-free sustained remission.
There is limited, mainly retrospective evidence that earlier use of eltrombopag after ITP 
diagnosis, will allow a larger proportion of patients to achieve sustained remission after tapering 
off drug. Clinically there is a need for a less toxic regimen that will provide responses and 
sustained remission with a shorter treatment interval. This trial is designed to assess this.
Clinical expertise suggests there will be clinically meaningful improvement if patients are able 
to be tapered off eltrombopag and have sustained remission by month 12, with an estimated 25% 
of patients expected to reach this goal.
The results of this study will be discussed in the context of current knowledge and existing 
historical data.
4.2
Rationale for dose/regimen and duration of treatment
Eltrombopag dosing requirements must be individualized based on the patient’s platelet counts.
Rationale for eltrombopag starting dose: In this study, the starting dose will be 50 mg 
eltrombopag QD (starting dose for Asian patients will be 25 mg QD, reduced as per Section 
6.1).
This eltrombopag starting dose is consistent with the dosing guidelines that have been approved 
for eltrombopag use in adult patients with chronic ITP.
An increase of eltrombopag dose up to 75 mg is typically allowed for patients who do not 
respond to standard-dosage treatment and to reduce the risk for bleeding. The rationale of this 


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study is to use the minimal efficacious dosage of eltrombopag in order to achieve a platelet 
count ≥100×109/L and maintain it around 100×109/L (no counts below 70×109/L) for 2 months 
in order to allow subjects to start the eltrombopag tapering and withdrawal process.
Rationale for CR duration on eltrombopag and taper off initiation: There are no guidelines 
with clear recommendation about platelet count, nor specified duration of treatment required 
prior to TPO-RA tapering off. No predictive factors for the patients who will be able to taper 
off are identified to date.
Medical experts’ input indicates that patients who achieve CR with a lower dose of TPO-RA 
and maintain it are more prone to have sustained remission after drug discontinuation. Scientific 
explanation is based on eltrombopag immunomodulatory effects and potential to restore 
immune tolerance to platelet antigens (Červinek 2015).
Rationale for taper off scheme: Tapering off scheme is based on known efficacy profile of 
eltrombopag, and clinical need to be done by smaller decrements over several weeks.
4.3
Rationale for choice of control drugs (comparator/placebo) or 
combination drugs
Not applicable


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4.5
Purpose and timing of interim analyses/design adaptations
No formal interim analysis is planned for this study. During the course of this study, two 
analyses will be performed:

Primary analysis will be done after all patients have enrolled and have either discontinued 
early from the study or have completed 12 months on study.  The primary CSR will be 
written at this time point.

Second analysis will be done after all patients in the follow-up period have completed 
month 24. The final CSR will be written at this time point.
See Section 12 for details on data analyses reported in these CSRs.
4.6
Risks and benefits
The risks to patients in this study may come from adverse events, adverse events of special 
interest and lack of efficacy.  The risk to patients in this study may be minimized by compliance 
with the eligibility criteria and study procedures, close clinical monitoring, safety and efficacy
assessments as described in Sections 8.3 and Section 8.4; and dose modifications as described 
in Section 6.5. 
There may be unforeseen risks with the study treatment which could be serious. These include 
but may not be limited to drug to drug interactions and long term safety. Close adherence to 
eligibility criteria, study procedures safety monitoring, and dose adjustment as described above 
will help to minimize unforeseen risks. Potential for drug to drug interaction and measures to 
minimize undesired drug to drug interactions are described in Sections 6.2.1 and Section 6.2.2.
Women of child bearing potential and sexually active males must be informed that taking the 
study treatment may involve unknown risks to the fetus if pregnancy were to occur during the 
study, and agree that in order to participate in the study they must adhere to the highly effective
contraception requirements outlined in the exclusion criteria. If there is any question that the 
patient will not reliably comply, they should not be entered or continue in the study.


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Risks Associated with Eltrombopag Use
Identified risks as defined by the Risk Management Plan (RMP) for eltrombopag for the ITP 
indication include hepatotoxicity, thromboembolic events, and post-therapy reoccurrence of 
thrombocytopenia.
Potential risks as defined by the RMP for eltrombopag for the ITP indication include thrombotic 
microangiopathy with acute renal failure, increased bone marrow reticulin formation, 
hematological malignancies, renal tubular toxicity, phototoxicity, and endosteal hyperostosis.
Appropriate eligibility criteria, as well as specific dose modification and stopping rules are
included in this protocol. Recommended guidelines for prophylactic or supportive treatment for
expected toxicities, including management of study-drug induced adverse events, i.e.,
hepatotoxicity, thrombotic complications, and ocular changes are provided below.
Hepatotoxicity
Eltrombopag administration can cause hepatobiliary laboratory abnormalities, severe 
hepatotoxicity and potentially fatal liver injury. In the controlled clinical studies in chronic ITP
with eltrombopag, increases in serum alanine aminotransferase (ALT), aspartate 
aminotransferase (AST), and bilirubin were observed. Exercise caution when administering 
eltrombopag to patients with hepatic disease.
Hepatotoxicity will be monitored through serum alanine aminotransferase (ALT), aspartate 
aminotransferase (AST), and bilirubin levels as described in Section 8.4.2 and additional
investigations as clinically indicated. In case hepatobiliary abnormalities are observed, follow 
the guidelines in Section 10.2.1.
Thrombotic / Thromboembolic complications
In eltrombopag clinical trials in ITP, thromboembolic events were observed at low and normal
platelet counts. Caution must be used when administering eltrombopag to patients with known
risk factors for thromboembolism including but not limited to inherited (e.g., Factor V Leiden)
or acquired risk factors (e.g., ATIII deficiency, antiphospholipid syndrome), patients with
prolonged periods of immobilization, malignancies, contraceptives and hormone replacement
therapy, surgery/trauma, obesity and smoking. Platelet counts must be closely monitored and
dose modifications must be made in accordance with parameters provided in the protocol. The
risks of thromboembolism and any of the following complications versus the benefit of 
improved platelet counts must be evaluated by the Investigator for each patient with known 
risks of thromboembolic events.
Ophthalmic changes
Cataracts were observed in toxicology studies of eltrombopag in rodents. The data from the 
double-blind and open label ITP and HORT studies, as well as data from the LENS study and 
the Phase II HCV study did not suggest an increased risk of cataract development in patients 
treated with eltrombopag. This conclusion was supported by the blinded, independent ocular 
safety data review from the Clinical Events Committee (CEC). In the pooled data from the 
Phase III HCV studies (ENABLE studies), where patients received up to 57 weeks of 
eltrombopag at doses up to 100mg, there was a numerically higher incidence of cataracts in the 
eltrombopag treatment group compared with the placebo group.


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Ophthalmologic monitoring defined per protocol must be performed and investigational 
treatment (eltrombopag) discontinued in case of suspected cataract development or worsening 
or in case of retinal hemorrhages.
Benefits Associated with Eltrombopag Use
Eltrombopag is an oral TPO-RA indicated for the treatment of chronic ITP. It has a well-
established efficacy and safety profile with evidence of improved QoL responses in addition to 
improvement in platelet counts.
Eltrombopag has been approved in over 100 countries for the treatment of chronic immune 
(idiopathic) thrombocytopenia in patients aged 1 year and above who are refractory to other 
treatments (e.g. corticosteroids, immunoglobulins).
Eltrombopag has been shown to be superior to placebo in raising and maintaining platelet count 
above 50×109/L for 6 months with a significant reduction in bleeding symptoms in previously 
treated chronic ITP patients. Eltrombopag also enabled more patients to reduce/discontinue 
concomitant (corticosteroid) medication use (RAISE Study) (Cheng 2011).
Patients with severe “acute” and persistent ITP showed benefit from eltrombopag therapy 
initiated within 6 months from diagnosis. This was demonstrated in a multicenter, single arm 
open label study of 39 patients (platelet count < 30×109/L despite being dosed with 1 mg/kg 
prednisone for at least 2 weeks from diagnosis or requiring prednisone ≥10 mg QD and/or 
recurrent doses of IVIG to maintain a platelet count of ≥30×109/L within 6 months of diagnosis). 
Patients with platelets < 10×109/L began eltrombopag 75 mg QD while those with a count ≥
10×109/L began treatment with 50 mg QD. The eltrombopag dose was increased by 25 mg 
every 2 weeks to a maximum of 150 mg QD if the platelet count remained ≤30×109/L or there 
was clinically significant bleeding every 2 weeks. The steroid could be decreased to zero over 
the subsequent 6 weeks if clinically appropriate. The primary endpoint was overall response 
rate (ORR) at week 12, defined as the proportion of patients achieving CR (platelet 
count > 100×109/L), partial response (PR) (platelet count > 50×109/L) or minor response (MR) 
(platelet ≥30×109/L with ≥50% reduction in the dose intensity of concomitant ITP therapy 
compared with screening). At week 12, the ORR was 64%; at week 26, the ORR was 54%. Two 
patients had SAEs with two episodes of venous thromboembolism (one deep vein thrombosis 
at platelet count 97×109/L; one pulmonary embolism at platelet count 240×109/L). There were 
no other AEs or deaths (Gonzalez-Lopez et al 2017)).
In addition to the benefits described above, a possible direct immunomodulatory effect of 
eltrombopag has been postulated from small retrospective reviews. TPO-RA have been shown 
to dampen immune responses in cITP by increasing the levels of anti-inflammatory cytokines 
and by reducing the levels of pro-inflammatory cytokines, increasing the suppressive activity 
of regulatory T-cells and reducing phagocytic activity of monocytes and macrophages, via 
modulation of Fcγ receptors towards inhibitory phenotype (Bao 2010, Qu 2017, Liu 2016).
There is also evidence that a proportion of patients go into remission and no longer require 
treatment after a number of months of eltrombopag therapy. This action of eltrombopag on ITP 
may be the result of a direct immunomodulatory effect that could impact other diseases as well.


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In a retrospective review of 260 adult cITP patients treated with eltrombopag, among the 
49 evaluable patients who achieved complete remission with eltrombopag (platelet 
count > 100×109/L), and then discontinued further treatment, 26 patients maintained platelet 
counts > 100×109/L with a median follow up of 9 months (Gonzalez-Lopez 2015). In a small, 
retrospective review of 12 patients with cITP, following successful discontinuation of 
eltrombopag (platelet count of 30×109/L and 20×109/L above initial baseline for at least 
6 months without substituting additional anti-ITP therapy), 10 patients maintained platelet 
counts > 100×109/L, with a median follow up of 7 months (Gonzalez-Lopez 2015). These 
findings are based on retrospective reviews only and need to be evaluated in a prospective 
manner; however, they suggest that a fixed duration of treatment with eltrombopag in ITP 
patients may contribute to sustained platelet responses.
The most recent prospective trial in 206 newly diagnosed ITP patients in China, examined the 
effects of HD-DXM or HD-DXM with recombinant (rh) TPO (Wang 2017). Overall response 
(OR) was defined as a platelet count ≥30×109/L and at least 2-fold increase of the baseline 
platelet count and absence of bleeding, while CR was a platelet count ≥100×109/L. The 
proportion of HD-DXM plus rhTPO patients that reached CR at 2 weeks was 75% compared to 
42% of those treated with HD-DXM. After one year, 46% of patients in HD-DXM plus rhTPO 
group had sustained OR versus 31% in HD-DXM group.
Further investigation is warranted to explore possible treatment strategies for ITP patients who 
failed to respond or have relapsed after initial steroid therapy. This will address an unmet 
medical need that a different treatment approach (introducing eltrombopag earlier) can reduce 
the need for repeated cycles of high dose steroids by reducing time of exposure and provide 
sustained remission after eltrombopag treatment discontinuation.
5
Population
The study is designed to include adult patients with ITP who have failed to respond or who 
relapsed following an initial response to a first-line course of steroid therapy (steroid-relapsed 
or steroid-refractory).
The investigator or designee must ensure that only patients who meet all the following inclusion 
and none of the exclusion criteria are offered treatment in the study.
5.1
Inclusion criteria
Patients eligible for inclusion in this study must meet all of the following criteria:
1. Signed informed consent must be obtained prior to participation in the study.
2. ≥18 years old
3. A confirmed diagnosis of primary ITP, who are not responsive or in relapse after a first 
line steroid therapy ± IVIG (used as a rescue therapy)
First line of steroid therapy will be defined as: prednisone/prednisolone 0.5-1mg/kg/day 
for a minimum of 2 weeks, or minimum of 1 course of high-dose dexamethasone 20-
40 mg/day for consecutive 4 days ±IVIG (used as rescue therapy). Maximum exposure to 
high-dose steroids treatment (steroids tapering time excluded) should be limited to: 4 
weeks of high dose prednisone/prednisolone or 3 courses of high-dose dexamethasone. 


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Overall exposure to steroids must not be longer than 3 months, including period of dose 
tapering.
4. Platelet count < 30×109/L and assessed as needing treatment (per physician’s discretion)
5.2
Exclusion criteria
Patients meeting any of the following criteria are not eligible for inclusion in this study.
1. ITP patients previously treated with any ITP second-line therapies, TPO-RA for ITP,
except steroids / IVIG as described in the inclusion criteria
2. Patients who relapsed more than one year after the end of first-line full course of steroid 
therapy
3. Patients with a diagnosis of secondary thrombocytopenia.
4. Patients who are unable to participate in assessments/biological studies
5. Patients who have life threatening bleeding complications per investigator discretion
6. Patients who had a deep vein thrombosis or arterial thrombosis in the 6 months preceding 
enrollment
7. Presence of moderate to severe impaired renal function as indicated by any or all of the 
following criteria:

Creatinine clearance < 45 mL/min as calculated using Cockcroft-Gault formula

Serum creatinine > 1.5 mg/dL
8. Total bilirubin > 1.5 × upper limit of normal (ULN)
9. Aspartate transaminase (AST) > 3.0 × ULN
10. Alanine transaminase (ALT) > 3.0 × ULN
11. Patients who are human immune deficiency virus (HIV), hepatitis C virus (HCV) or 
hepatitis B surface antigen (HBsAg) positive.  These assessments can be performed using 
the local laboratory used by the site.  Central laboratory testing is available for HIV, HCV, 
and HBsAg should local laboratory testing not be available.
12. Patients with hepatic impairment (Child-Pugh score > 5)
13. Patients who are unable to respect the 4-hour interval between eltrombopag and other 
medications (e.g., antacids), calcium-rich foods (e.g., dairy products and calcium fortified 
juices), or supplements containing polyvalent cations such as iron, calcium, aluminum, 
magnesium, selenium, and zinc
14. Patients who are unable to stop medications that are known to cause a drug-drug 
interaction with eltrombopag
15. Patients who have active malignancy
16. Patients with any serious and/or unstable pre-existing medical, psychiatric disorder or 
other conditions that could interfere with patient’s safety, obtaining informed consent or 
compliance with the study procedures as per investigator discretion
17. Patients with a known immediate or delayed hypersensitivity reaction or idiosyncrasy to 
eltrombopag or drugs chemically related to eltrombopag or excipients that contraindicate 
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18. History or current diagnosis of cardiac disease indicating significant risk of safety for 
patients participating in the study such as uncontrolled or significant cardiac disease or 
impaired cardiac function including any of the following:

Corrected QTc > 450 msec (male patients), > 460 msec (female patients) using 
Fredericia correction (QTcF) on the screening ECG

Resting heart rate at screening (physical exam or 12 lead electrocardiogram [ECG]) 
< 50 or > 90 beats per minute (BPM)

Recent myocardial infarction (within last 6 months)

Uncontrolled congestive heart failure

Unstable angina (within last 6 months)
19. Patients with known active or uncontrolled infections not responding to appropriate therapy
20. Patients with evidence of current alcohol/drug abuse
21. Concurrent participation in an investigational study within 30 days prior to enrollment or 
within 5-half-lives of the investigational product, whichever is longest. Note: parallel 
enrollment in a disease registry is permitted
22. Known thrombophilic risk factors. Exception: Patients for whom the potential benefits of 
participating in the study outweigh the potential risks of thromboembolic events, as 
determined by the investigator
23. Female patients who are nursing or pregnant (positive serum pregnancy test) at screening 
or pre-dose on Day 1
24. Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, (or female partners of male patients) unless they are using highly 
effective methods of contraception while taking study treatment and for 3 months after 
stopping medication.  
Highly effective methods of contraception methods include:

Total abstinence (when this is in line with the preferred and usual lifestyle of the
patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation 
methods) and withdrawal are not acceptable methods of contraception

Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy), total hysterectomy, or tubal ligation at least six weeks before taking 
study treatment. In case of oophorectomy alone, only when the reproductive status of 
the woman has been confirmed by follow up hormone level assessment

Male sterilization (at least 6 months prior to screening). For female patients on the 
study, the vasectomized male partner should be the sole partner for that patient

Use of oral (estrogen and progesterone), injected or implanted hormonal methods of 
contraception or placement of an intrauterine device (IUD) or intrauterine system 
(IUS), or other forms of hormonal contraception that have comparable efficacy 
(failure rate < 1%), for example, hormone vaginal ring or transdermal hormone 
contraception..
In case of use of oral contraception women should have been stable on the same pill for a
minimum of 3 months before taking study treatment.


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Women are considered post-menopausal and not of child bearing potential if they have had 12 
months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age 
appropriate history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with 
or without hysterectomy), total hysterectomy or tubal ligation at least six weeks in advance. In 
the case of oophorectomy alone, only when the reproductive status of the woman has been 
confirmed by follow up hormone level assessment is she considered not of child bearing 
potential.
Sexually active males must be willing to use a condom during intercourse while taking study 
treatment and for 3 months after stopping study treatment. A condom is required for all sexually 
active male participants to prevent them from fathering a child AND to prevent delivery of 
study treatment via seminal fluid to their partner. In addition, male participants must not donate 
sperm for the time period specified above.
If local regulations deviate from the contraception methods listed above to prevent pregnancy, 
local regulations apply and will be described in the informed consent form (ICF).
No additional exclusions may be applied by the investigator, in order to ensure that the study 
population will be representative of all eligible patients.
6
Treatment
6.1
Study treatment
Patients will be treated with eltrombopag 50 mg QD for 2 weeks to reach a target platelet count 
of ≥100×109/L (CR). For those patients who do not achieve the target platelet count within 2 
weeks, the dose of eltrombopag will be increased to 75 mg QD. Treatment with eltrombopag 
will be continued at the minimal dosage necessary to achieve and maintain a platelet count
around 100×109/L for 2 months.
Patients will be eligible for taper off and treatment discontinuation once they reach platelet 
count ≥100×109/L and maintain it around 100×109/L (all assessments of platelet count 
≥70x109/L) for 2 months. The duration of tapering will be individualized and depend upon 
starting dose and response of the patient: decreases in dose will be performed by 25 mg 
reductions every 2 weeks. If platelet counts are stable, the next reduction will be carried out 
within 2 weeks, with dosing of 25 mg on alternate days for 2 weeks until treatment is totally 
discontinued. Patients who are dose escalated to 75mg QD are eligible for taper off and 
treatment discontinuation as long as they achieve CR and maintain a platelet count around 
100×109/L (all assessments of platelet count ≥70x109/L) for 2 months.
Different treatment options and eltrombopag dosage for patients not meeting criteria for 
treatment discontinuation are summarized in Table 6-1.
A reduced starting dosage of 25 mg once daily is recommended for patients of Asian ancestry
(such as Chinese, Japanese, Taiwanese, Korean or Thai). The dose of eltrombopag in patients 
with Asian ancestry will be reduced to account for the lower eltrombopag clearance (CL/F) 
observed in these patients compared to the non-Asian population. Therefore, drug tapering for 
patients with Asian ancestry will be done in 12.5 mg decrements every second week.


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Table 6-1
Eltrombopag dosing guidance for patients not meeting criteria for 
sustained remission
Platelet Level
Dose guidance
Patients on 75 mg/day eltrombopag
and platelet < 100×109/L
Continue on eltrombopag 75 mg/day till month 12
Patients who reach CR (platelets ≥100×109/L) but do 
not maintain platelets around 100×109/L for 2 months 
(i.e. platelets < 70×109/L)
Increase dose to a maximum of 75 mg/day as per 
Section 6.1 until CR is reached again and maintain 
platelets around 100×109/L (no platelets < 70×109/L)
Patients who relapse (< 30×109/L) during eltrombopag 
tapering off stage
Use previous dose level (i.e. one dose level higher)
Patients who relapse (< 30×109/L) after
eltrombopag discontinuation
Re-initiate treatment with starting dose 50 mg/day (25 
mg/day for Asian patients) 
6.1.1
Investigational drug
Eltrombopag study drug will be provided by Novartis. Sourcing of study drug by Novartis can 
be either through clinical supply or local commercial supply. Clinical supply will be provided 
globally though Global Clinical Supply and labeled as per local regulations. Local commercial 
supply will be sourced in the country where appropriate and as per local regulations. If 
eltrombopag is sourced through local commercial supply, drug will be labeled in-country and 
the locally approved form and packaging of eltrombopag will be used.
Eltrombopag will not be dosed by weight or body surface area.
All investigational treatment is to be stored in a secure locked area while under the 
responsibility of the investigator. Receipt and dispensing of investigational treatment must be 
recorded by an authorized person at the investigator’s site.
For detailed safety information refer to the [ETB115 Investigators Brochure, current edition] 
and the approved product labeling. A description of the study treatment, pharmaceutical form 
and method of administration of eltrombopag is provided in Table 6-2.
Table 6-2
Investigational drug
Study treatments
Pharmaceutical form and 
route of administration
Dose
Frequency and/or 
Regimen
Eltrombopag
Tablet for oral use
12.5 mg
Daily 
Eltrombopag
Tablet for oral use
25 mg
Daily
Eltrombopag
Tablet for oral use
50 mg
Daily
Eltrombopag
Tablet for oral use
75 mg
Daily
6.1.2
Additional study treatments
No other treatment beyond investigational drug will be considered as study treatments.
6.1.3
Treatment duration
Patients may participate in the study for up to 24 months depending on their response. Patients 
not in sustained remission at month 12 will only be treated with eltrombopag in the study for 
12 months. 


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Patients in sustained remission at month 12 will enter the follow-up period for an additional 12 
months. Patients who relapse during the follow-up period (between months 12 and 24) will be 
offered retreatment with eltrombopag until the end of month 24. Some of the patients might not 
need retreatment with eltrombopag during the follow-up period.
Patients who receive treatment options other than eltrombopag within the follow-up period will 
discontinue the study at that time (see Section 9.3). 
Patients may be discontinued from treatment earlier due to unacceptable toxicity at the 
discretion of the investigator or the patient. These patients will continue to be followed as per 
study design but will not be considered in having achieved sustained remission for the primary 
endpoint.
6.2
Other treatment(s)
Not applicable
6.2.1
Concomitant therapy
The patient must be told to notify the investigational site about any new medications he/she 
takes after the start of the study treatment. All medications (other than study drug) and 
significant non-drug therapies (including physical therapy and herbal/natural medications) 
administered during the study must be listed on the Concomitant Medications or the Procedures 
and Significant Non-Drug Therapies electronic case report form (eCRF).
All medications, procedures and significant non-drug therapies (including physical therapy and 
blood transfusions) administered after the patient was enrolled into the study must be recorded 
on the appropriate Case Report Forms (CRF).
Each concomitant drug must be individually assessed against all exclusion criteria/prohibited 
medication. If in doubt the investigator should contact the Novartis medical monitor before
enrolling a patient or allowing a new medication to be started. If the patient is already enrolled, 
contact Novartis to determine if the patient should continue participation in the study.
6.2.1.1
Permitted concomitant therapy requiring caution and/or action
HMG-CoA Reductase Inhibitors (statins)
Patients will be permitted to use HMG-CoA reductase (3-hydroxy-3-methyl-glutaryl-CoA) 
inhibitors during the study, but these drugs should be used with caution and a 50% dose 
reduction of the HMG-CoA reductase inhibitor is recommended, with close monitoring 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).
Polyvalent Cations (Chelation)
Eltrombopag chelates with polyvalent cations such as aluminum, calcium, iron, magnesium, 
selenium and zinc. Eltrombopag should be taken at least two hours before or four hours after 


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any products such as antacids, dairy products, or mineral supplements containing polyvalent 
cations to avoid significant reduction in eltrombopag absorption.
Food Interaction
To avoid significant reduction in eltrombopag absorption, eltrombopag should be taken at least 
two hours before or four hours after food containing > 50 mg calcium and at least one hour 
before to two hours after food containing little (< 50 mg) (or preferably no) calcium. The 
administration of a single 50 mg dose of eltrombopag with a standard high-calorie, high-fat 
breakfast that included dairy products led to reduced eltrombopag exposure. Foods low in 
calcium (defined as < 50 mg calcium per serving) including fruit, lean ham, beef and unfortified 
(no added calcium, magnesium, iron) fruit juice, unfortified soy milk, and unfortified grain did 
not significantly impact plasma eltrombopag exposure, regardless of calorie and fat content.
Substrates of OATP1B1 or BCRP
Concomitant administration of eltrombopag and other OATP1B1 or BCRP substrates should 
be undertaken with caution.
Examples of drugs which are OATP1B1 or BCRP substrates are given in Appendix 16.1.
CYP and UGT inhibitors and inducers 
Eltrombopag is metabolised through multiple pathways including CYP1A2, CYP2C8, 
UGT1A1, and UGT1A3. Medicinal products that inhibit or induce a single enzyme are unlikely 
to significantly affect plasma eltrombopag concentrations; whereas medicinal products that 
inhibit or induce multiple enzymes have the potential to increase (e.g. fluvoxamine) or decrease 
(e.g. rifampicin) eltrombopag concentrations.
6.2.2
Prohibited medication
Any ITP directed therapy as per investigator assessment, different from what is specified within 
treatment section of the protocol, should be excluded including, but not limited to, platelet 
transfusion, new ITP-treating medication, or splenectomy. Detailed explanation related to 
exception for use of rescue medication is described in Section 6.2.3.
Use of the treatments detailed below are not allowed after screening.
Patients must abstain from using investigational or not use marketed drugs without a 
well-known safety profile and from using prohibited prescription or nonprescription 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 Exclusion Criteria-Section 5.2).
Patients 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 30-day follow-up visit, unless the Investigator and Sponsor 
agree that the medication will not interfere with the study treatment.
Drugs that affect platelet function (including but not limited to, aspirin, clopidogrel and/or non-
steroidal anti-inflammatory drugs [NSAIDS]) should not be taken during the study unless there 


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is a very clear indication and the Investigator documents the rationale. 
 
Any other TPO-R agonists are prohibited during this study (e.g., romiplostim).
6.2.3
Rescue therapy
Any ITP-directed medication or therapy, other than eltrombopag, given during the trial with the 
aim to increase platelet count for the patients who have clinically significant bleeding will be 
considered a rescue therapy and must be recorded on the appropriate CRF page. A patient who 
receives rescue medication or therapy will not be considered in having achieved sustained 
remission for the primary endpoint, unless the patient uses steroids ± IVIG as described below
in the first 14 days of start of eltrombopag.
Steroids ± IVIG use as rescue medication:
In case of clinical necessities because of very low platelet count (< 10×109/L) and/or significant 
bleeding, treatment with steroids ± IVIG and platelet transfusion is permitted together with 
eltrombopag for the first 14 days, calculated from the first dose day of eltrombopag.
6.3
Patient numbering, treatment assignment, randomization
6.3.1
Patient numbering
Each patient is identified in the study by a Patient Number (Patient No.), that is assigned when 
the patient is first screened and is retained as the primary identifier for the patient throughout 
his/her entire participation in the trial. The Patient No. consists of the Center Number (Center 
No.) (as assigned by Novartis to the investigative site) with a sequential patient number suffixed 
to it, so that each patient is numbered uniquely across the entire database. Upon signing the 
informed consent form, the patient is assigned to the next sequential Patient No. available.
The investigator or designated staff will contact the IRT and provide the requested identifying 
information for the patient to register them into the IRT. Once assigned, the patient ID must not 
be reused for any other patient.
If the patient is re-screened, a new unique number will be assigned to the rescreened patient and 
the original assigned number will be captured in the rescreening page. If the patient fails to start 
treatment for any reason, the reason will be entered into the Disposition page.  IRT must be 
notified within 2 days that the patient was not enrolled in the study.
6.3.2
Treatment assignment, randomization
No randomization will be performed in this study. All eligible patients will receive eltrombopag 
per the treatment schedule.
6.4
Treatment blinding
Not applicable.


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6.5
Dose escalation and dose modification
6.5.1
Dose escalation guidelines
Dose escalation will be allowed from 50 mg QD to 75 mg QD as described in Section 6.1.
Patients will be treated with eltrombopag 50 mg QD for 2 weeks to reach a target platelet count 
of ≥100×109/L (CR). For those patients who do not achieve the target platelet count within 
2 weeks, the dose of eltrombopag will be increased to 75 mg QD.
6.5.1.1
Starting dose
In this study, the starting dose will be 50 mg eltrombopag QD (starting dose for Asian patients
will be 25 mg QD, reduced as per Section 6.1).
This eltrombopag starting dose is consistent with the dosing guidelines that have been approved 
for eltrombopag use in adult patients with chronic ITP.
6.5.2
Dose modifications
For patients who do not tolerate the protocol-specified dosing schedule, dose interruptions 
and/or reductions are either recommended or mandated in order to allow patients to continue 
the study treatment.
These dose modifications are summarized in Table 6-3. Deviations to mandatory dose 
interruptions and/or reductions are not allowed. Permanent treatment discontinuation is 
mandatory for specific events indicated as such in Table 6-4.
Table 6-3
Eltrombopag Dose Adjustments in ITP
Platelet count
Dose adjustment or response
< 100×109/L following 2 weeks of 
therapy
Increase daily dose by 25 mg to a maximum of 75 mg/day a
≥100×109/L to < 200 × 109/L
Use lowest dose of eltrombopag to maintain platelet counts around 
100×109/L for 2 months prior to per protocol tapering a
≥200 × 109/L to ≤400 × 109/L
Decrease daily dose by 25 mg. Wait 2 weeks to assess the effects of 
this and any subsequent dose adjustments b c
> 400 ×109/L 
Stop eltrombopag; increase the frequency of platelet monitoring to 
twice weekly. Once the platelet count is < 150 ×109/L, reinitiate 
therapy at a lower daily dose b c
a. This dose adjustment schedule was chosen for this study to have patients use the minimal efficacious 
dosage of eltrombopag in order to achieve a CR. Patients need to maintain a CR for a minimum of 2 months 
before tapering off can be attempted.
b. For patients taking eltrombopag once daily, consideration should be given to dosing at 12.5 mg once daily or 
alternatively a dose of 25 mg once every other day
c. Source: The latest version of the eltrombopag core data sheet (CDS).
These dose changes must be recorded on the appropriate CRF.
Eltrombopag can cause hepatobiliary laboratory abnormalities, severe hepatotoxicity, and 
potentially fatal liver injury. Serum ALT, AST and bilirubin should be measured prior to
initiation of eltrombopag, every 2 weeks during the dose adjustment phase and monthly after 
establishment of a stable dose. Abnormal serum liver tests should be evaluated with repeat 


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testing within 3 to 5 days. If the abnormalities are confirmed, serum liver tests should be 
monitored weekly until the abnormalities resolve, stabilize, or return to baseline levels.
For the grading of adverse events and laboratory results, the Common Terminology Criteria for 
Adverse Events (CTCAE) Version 4.03 will be used.
Table 6-4
Criteria for dose adjustment based on liver enzyme and bilirubin 
levels
Dose modifications for ETB115
Worst toxicity
CTCAEa Grade
(value) during the 
treatment
Investigations (Hepatic)
Isolated Total Bilirubin Elevation
> ULN – 1.5 x ULN
Maintain dose level
> 1.5 - 3.0 x ULN*
Interrupt dosing and weekly monitor liver function tests (LFTs)b, or more frequently if 
clinically indicated, until resolved to ≤ 1.5 × ULN:
If resolved in ≤ 14 days, then resume at same dose level
If resolved in > 14 days, then decrease one dose levele
> 3.0 - 10.0 x ULN** 
Mandatory: Interrupt dosing and weekly monitor LFTsb, or more frequently if clinically 
indicated, until resolved to ≤ 1.5 × ULN:
If resolved in ≤ 14 days, then decrease one dose levele
If resolved in > 14 days, then discontinue patient from study drug treatment. LFTsb
will continue to be monitored weekly, or more frequently if clinically indicated, until 
total bilirubin have resolved to baseline or stabilization over 4 weeks.
> 10.0 x ULN
Mandatory: Discontinue patient from study drug treatment
The patient should be monitored weekly (including LFTsb) , or more frequently if 
clinically indicated, until total bilirubin have resolved to baseline or stabilization over 4 
weeks.
* Note: If total bilirubin > 1.5 - ≤ 3 x ULN is due to the indirect (non-conjugated) 
component only, no changes to dose are required.
** Note: If total bilirubin > 3.0 – 10.0 x ULN is due to the indirect (non-conjugated) 
component only, and hemolysis as the etiology has been ruled out as per institutional 
guidelines (e.g., review of peripheral blood smear and haptoglobin determination), 
then decrease 1 dose levele and continue treatment at the discretion of the 
investigator
Isolated AST or ALT elevation
> ULN - 3.0 x ULN
> 3.0 - 5.0 x ULN
Maintain dose level
Maintain dose level.
Repeat LFTsb as soon as possible, preferably within 48-72 hours from awareness of 
the abnormal results. If abnormal lab values are confirmed upon the repeat test, then 
monitor LFTsb weekly, or more frequently if clinically indicated, until resolved to ≤ 3.0 
× ULN
Discontinue patient from the study drug treatment if elevation is combined with any of 
the following:
Clinical symptoms of liver injury or evidence for hepatic decompensation


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Dose modifications for ETB115
Worst toxicity
CTCAEa Grade
(value) during the 
treatment
Investigations (Hepatic)
Progressively increasing LFTsb upon repeat testing
Persistence ≥4 weeks
> 5.0 - 10.0 x ULN
Mandatory: Interrupt dose.
Repeat LFTsb as soon as possible; preferably within 48-72 hours from awareness of 
the abnormal results. Monitor LFTsb weekly, or more frequently if clinically indicated 
until resolved to ≤ 3.0 x ULN then:
If resolved in ≤14 days, maintain dose level
If resolved >14 days, decrease one dose levele
> 10.0 - 20.0 x ULN 
Mandatory: Interrupt dose.
Repeat LFTsb as soon as possible, preferably within 48-72 hours from awareness of 
the abnormal results. Monitor LFTsb weekly, or more frequently if clinically indicated 
until resolved to ≤ baseline.
Then decrease one dose level e
> 20.0 x ULN
Mandatory:  Discontinue patient from study drug treatment
Repeat LFTsb as soon as possible, preferably within 48-72 hours from awareness of 
the abnormal results. Monitor LFTsb weekly, or more frequently if clinically indicated 
until resolved to ≤ baseline or stabilization over 4 weeks..
Combined c elevations of AST or ALT and total bilirubin
For patients with 
normal baseline ALT 
and AST and total 
bilirubin value [AST or 
ALT > 3.0 × ULN] 
combined with [total 
bilirubin > 2.0 × ULN] 
without evidence of 
cholestasisd
OR 
For patients with 
elevated baseline AST 
or ALT [AST or ALT > 
3 × baseline] OR [AST 
or ALT > 5.0 × ULN], 
whichever is lower, 
combined with [total 
bilirubin > 2× baseline 
AND > 2.0 × ULN]
Mandatory: Permanently discontinue patients from study drug treatment. 
Repeat as soon as possible, preferably within 48 hours from awareness of the 
abnormal results, then with weekly monitoring of LFTsb), or more frequently if 
clinically indicated, until AST, ALT, or bilirubin have resolved to baseline or 
stabilization over 4 weeks
All dose modifications should be based on the worst preceding toxicity.
a Common Toxicity Criteria for Adverse Events (CTCAE Version 4.03)
b Core LFTs consist of ALT, AST, GGT, total bilirubin (fractionated [direct and indirect], if total bilirubin > 2.0 x 
ULN), and alkaline phosphatase (fractionated [quantification of isoforms], if alkaline phosphatase > 2.0 x ULN.)
c “Combined” defined as total bilirubin increase to the defined threshold concurrently with ALT/AST increase to 
the defined threshold
If combined elevations of AST or ALT and total bilirubin do not meet the defined thresholds, please follow the 
instructions for isolated elevation of total bilirubin and isolated elevation of AST/ALT, and take a conservative 


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Dose modifications for ETB115
Worst toxicity
CTCAEa Grade
(value) during the 
treatment
Investigations (Hepatic)
action based on the degree of the elevations (e.g. discontinue treatment at the situation when omit dose is 
needed for one parameter and discontinue treatment is required for another parameter). After all elevations 
resolve to the defined thresholds that allow treatment re-initiation, re-start the treatment either at the same 
dose or at one dose lower if meeting a criterion for dose reduction
d “Cholestasis” defined as alkaline phosphatase (ALP) elevation (>2.0 x ULN and R value <2 ) in patients
without bone metastasis, or elevation of ALP liver fraction in patients with bone metastasis
The R value is calculated by dividing the ALT by the ALP, using multiples of the ULN for both values. It denotes 
whether the relative pattern of ALT and/or ALP elevation is due to cholestatic (R ≤ 2), hepatocellular ( R ≥ 5), or 
mixed (R >2 and < 5) liver injury.
e “One dose level” defined as eltrombopag dose reduction by 25 mg.
6.5.2.1
Dose modifications for other reasons
Eltrombopag dosing is to be interrupted in patients unable to ingest the drug due to mucositis 
or permanent vomiting.
Early discontinuation of treatment
Eltrombopag must be permanently discontinued if any of the following events occur or is 
identified at any time during the study:

Cytogenetic abnormalities

Monosomy 7 – discontinue eltrombopag

Other abnormalities – discontinuation at physician discretion

Thromboembolism, irrespective of relation to study drug

Development of myelodysplastic syndrome or acute myeloid leukemia

Positive pregnancy test, at any time during the study

Difficulties in continuing eltrombopag due to AE(s)

Patient is found to be significantly non-compliant with the requirements of the protocol 
(including treatment noncompliance)

ALT of AST > 20 x ULN
6.5.3
Follow-up for toxicities
Patients whose treatment is interrupted or permanently discontinued due to an AE or clinically 
significant laboratory value, must be followed up at least once a week (or more frequently if 
required by institutional practices, or if clinically indicated) for 4 weeks, and subsequently at 
approximately at least 4-week intervals (or more frequently if required by institutional practices, 
or if clinically indicated), until resolution or stabilization of the event, whichever comes first. 
Appropriate clinical experts such as ophthalmologist, etc. should be consulted as deemed 
necessary.
Patients who permanently discontinue eltrombopag for an AE or clinically significant 
laboratory value will be discontinued from the study and then undergo a 30-day safety follow-
up.


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6.5.3.1
Dose delays, modifications or discontinuation for hematologic side 
effects
Patients who experience a deep venous thrombosis (other than a line-related upper extremity 
thrombosis) or a pulmonary embolus, a transient ischemic attack or stroke, or a myocardial 
infarction at any time while on eltrombopag will discontinue eltrombopag.
6.5.3.2
Follow up on potential drug-induced liver injury (DILI) cases
Patients with transaminase increase combined with total bilirubin (TBIL) increase may be 
indicative of potential DILI, and should be considered as clinically important events.
The threshold for potential DILI may depend on the patient’s baseline AST/ALT and TBIL 
value; patients meeting any of the following criteria will require further follow-up as outlined 
below:

For patients with normal baseline ALT and AST: AST or ALT > 3.0 × ULN combined 
with TBIL > 2.0 × ULN OR INR > 1.5 without evidence of cholestasis (no ALP elevation)

For patients with elevated AST or ALT or TBIL value at baseline: [AST or ALT > 2 x 
baseline AND > 3.0 x ULN] OR [AST or ALT > 8.0 x ULN], combined with [TBIL > 2 x 
baseline AND > 2.0 x ULN]

For patients with normal baseline ALT: ALT ≥ 5 x Upper Limit of Normal (ULN)
Medical review needs to ensure that liver test elevations are not caused by cholestasis, defined 
as Alkaline Phosphatase (ALP) elevation > 2.0 × ULN with R value < 2 in patients without 
bone metastasis, or elevation of ALP liver fraction in patients with bone metastasis.
Note: (The R value is calculated by dividing the ALT by the ALP, using multiples of the ULN 
for both values. It denotes whether the relative pattern of ALT and/or ALP elevation is due to 
cholestatic (R ≤ 2), hepatocellular (R ≥ 5), or mixed (R >2 and < 5) liver injury).
These patients should be immediately discontinued from eltrombopag, and repeat liver function 
test (LFT) testing as soon as possible, preferably within 48 hours from the awareness of the 
abnormal results, then with weekly monitoring of LFTs), or more frequently if clinically 
indicated, until AST, ALT, or bilirubin have resolved to baseline or stabilization over 4 weeks. 
The evaluation should include laboratory tests, detailed history, physical assessment and the 
possibility of liver metastasis or new liver lesions, obstructions/compressions, etc.
1. Laboratory tests should include ALT, AST, albumin, creatinine kinase, TBIL, direct and 
indirect bilirubin, gamma-glutamyl-transferase (GGT), prothrombin time (PT)/
International Normalized Ratio (INR) and ALP.
2. A detailed history, including relevant information, such as review of ethanol, concomitant 
medications, herbal remedies, nutritional supplement consumption, history of any pre-
existing liver conditions or risk factors, should be collected.
3. Further testing for acute hepatitis A, B, C or E infection and liver imaging (e.g. biliary 
tract) may be warranted.
5. Additional testing for other hepatotropic viral infection (cytomegalovirus [CMV], Epstein 
Barr virus [EBV] or Herpes simplex virus [HSV]), autoimmune hepatitis or liver biopsy 
may be considered as clinically indicated or after consultation with specialist/hepatologist.


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All cases confirmed on repeat testing meeting the laboratory criteria defined above, with no 
other alternative cause for LFT abnormalities identified should be considered as “medically 
significant”, thus, met the definition of SAE and reported as SAE using the term “potential 
drug-induced liver injury”. All events should be followed up with the outcome clearly 
documented.
6.6
Additional treatment guidance
6.6.1
Treatment compliance
The investigator must promote compliance by instructing the patient to take eltrombopag
exactly as prescribed and by stating that compliance is necessary for the patient’s safety and the 
validity of the study. The patient must also be instructed to contact the investigator if he/she is 
unable for any reason to take eltrombopag as prescribed. Compliance will be assessed by the 
investigator and/or study personnel at each visit using pill counts (if applicable) and information 
provided by the patient. This information should be captured in the source document at each 
visit. All eltrombopag dispensed and returned must be recorded in the Drug Accountability Log.
 
6.7
Preparation and dispensation
The investigator or responsible site personnel must instruct the patient or caregiver to take the 
study drugs as per protocol. Eltrombopag will be dispensed to the patient by authorized site 
personnel only. All dosages prescribed to the patient and all dose changes during the study must 
be recorded on the Dosage Administration Record eCRF.
6.7.1
Handling of eltrombopag
Eltrombopag study treatment supplies must be received by a designated person at the study site, 
handled and stored safely and properly and kept in a secured location to which only the 
investigator and designated site personnel have access. Upon receipt, all study treatment must 
be stored according to the instructions specified on the labels and in the Investigator’s Brochure.
Clinical supplies are to be dispensed only in accordance with the protocol. Technical complaints 
are to be reported to the respective Novartis CO Quality Assurance.
Medication labels will be in the local language and comply with the legal requirements of each 
country. They will include storage conditions for the study treatment but no information about 
the patient except for the medication number.
The investigator must maintain an accurate record of the shipment and dispensing of study 
treatment in a drug accountability log. Monitoring of drug accountability will be performed by 
monitors during site visits or remotely and at the completion of the trial. Patients will be asked 
to return all unused study treatment and packaging at the end of the study or at the time of 
discontinuation of study treatment.
At the conclusion of the study, and as appropriate during the course of the study, the investigator 
will return all unused study treatment, packaging, drug labels, and a copy of the completed drug 
accountability log to the Novartis monitor or to the Novartis address provided in the investigator 
folder at each site.


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6.7.2
Instruction for prescribing and taking study treatment
A description of eltrombopag, dose and frequency is provided in Table 6-2.

Patients should take eltrombopag at approximately the same time each day either 1 hour 
before eating or 2 hours after eating.

For 2 hours before taking eltrombopag and 4 hours after taking eltrombopag, patients 
should avoid eating dairy products, and calcium- and magnesium-rich foods

Patients should be instructed not to make up missed doses. Patients who miss a dose of 
eltrombopag should wait and take the next scheduled dose. Patients should not take more 
than one dose of eltrombopag in one day.
7
Informed consent procedures
Eligible patients may only be included in the study after providing (witnessed, where required 
by law or regulation), Institutional Review Board (IRB)/Independent Ethics Committee (IEC)-
approved informed consent.
If applicable, in cases where the patient's representative(s) gives consent (if allowed according 
to local requirements), the patient must be informed about the study to the extent possible given 
his/her understanding. If the patient is capable of doing so, he/she must indicate agreement by 
personally signing and dating the written informed consent document.
Informed consent must be obtained before conducting any study-specific procedures (e.g. all of 
the procedures described in the protocol). The process of obtaining informed consent must be 
documented in the patient source documents.
Novartis will provide to investigators in a separate document a proposed informed consent form 
that complies with the International Council of Harmonisation (ICH) Good Clinical Practices 
(GCP) guidelines and regulatory requirements and is considered appropriate for this study. Any 
changes to the proposed consent form suggested by the investigator must be agreed by Novartis 
before submission to the IRB/IEC.
Novartis will review the investigators/clinical research organization (CRO) proposed informed 
consent form to ensure it complies with the ICHE6 GCP guidelines and regulatory requirements 
and is considered appropriate for this study. Any further changes to the proposed consent form 
suggested by the investigator must be agreed to by Novartis before submission to the IRB/IEC.
Information about common side effects already known about the investigational drug can be 
found in the Investigator's Brochure (IB). This information will be included in the patient
informed consent and should be discussed with the patient during the study as needed. Any new 
information regarding the safety profile of the investigational drug that is identified between IB 
updates will be communicated as appropriate, for example, via an investigator notification or 
an aggregate safety finding. New information might require an update to the informed consent 
and then must be discussed with the patient.
Women of child bearing potential must be informed that taking the study treatment may involve 
unknown risks to the fetus if pregnancy were to occur during the study and agree that in order 
to participate in the study they must adhere to the contraception requirements.


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Male patients must be informed that if a female partner becomes pregnant while he is enrolled 
in the study, contact with the female partner will be attempted to request her consent to collect 
pregnancy outcome information.
A copy of the approved version of all consent forms must be provided to Novartis after IRB/IEC 
approval.
8
Visit schedule and assessments
Assessment schedule lists all of the assessments when they are performed. All data obtained 
from these assessments must be supported in the patient’s source documentation.
Screening assessments can occur within 28 days prior to the enrollment as per Table 8-1.
There is a ± 1 day visit window permitted on assessments to take into account scheduling over 
public holidays, from Week 1 Day 1 to Week 9 Day 1. Also a visit window of ± 3 days is 
allowed from Week 11 Day 1 to end of treatment.
 
 
A visit window of ±7 days is allowed during the follow-up period for responders.
Every effort should be made to follow the schedule outlined in Table 8-1.
Patients should be seen for all visits/assessments as outlined in the assessment schedule or as 
close to the designated day/time as possible. Missed or rescheduled visits should not lead to 
automatic discontinuation. Patients who prematurely discontinue the study for any reason 
should be scheduled for a visit as soon as possible, at which time all of the assessments listed 
for the final visit will be performed. At this final visit, all dispensed eltrombopag study 
treatment supplies should be reconciled, and the adverse event and concomitant medications 
recorded on the CRF.


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Table 8-1
Assessment schedule
Screening to Week 9
Period
Screening
Treatment
Visit Name
Screening
Week 1
Day 1
Week 2
Day 1
Week 3
Day 1
Week 4
Day 1
Week 5
Day 1
Week 6
Day 1
Week 7
Day 1
Week 8
Day 1
Week 9
Day 1
Visit Number
1
110
120
130
140
150
160
170
180
190
Obtain informed consent
X
Patient history
X
Demography
X
Inclusion/exclusion criteria
X
Relevant medical 
history/current medical history
X
Physical Exam
S
S
S
S
S
S
S
S
S
S
Height
X
Weight
S
X
S
S
S
S
S
S
S
S
Vital Signs
X
X
X
X
X
X
Laboratory Assessments
Hematology
X
X
X
X
X
X
X
X
X
X
Chemistry
X
X
X
X
X
X
Coagulation
X
Pregnancy Test **
S
S
S
ECG
X


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Period
Screening
Treatment
Visit Name
Screening
Week 1
Day 1
Week 2
Day 1
Week 3
Day 1
Week 4
Day 1
Week 5
Day 1
Week 6
Day 1
Week 7
Day 1
Week 8
Day 1
Week 9
Day 1
Visit Number
1
110
120
130
140
150
160
170
180
190
Adverse Events
X
X
X
X
X
X
X
X
X
X
Ocular Assessments
X
Prior/concomitant Medications
X
X
X
X
X
X
X
X
X
Bone marrow biopsy (optional)
Per investigator discretion
Patient Reported Outcomes
X
FACIT-Fatigue
X
FACT-Th6
X
SF-36v2
X
GP5
X
TSQM-9
X
Study drug administration
X
X
X
X
X
X
X
X
X


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Period
Screening
Treatment
Visit Name
Screening
Week 1
Day 1
Week 2
Day 1
Week 3
Day 1
Week 4
Day 1
Week 5
Day 1
Week 6
Day 1
Week 7
Day 1
Week 8
Day 1
Week 9
Day 1
Visit Number
1
110
120
130
140
150
160
170
180
190
IRT
IRT registration
X
IRT enrollment
X
X = assessment to be recorded in the clinical database or received electronically from a vendor
S = assessment to be recorded in the source documentation only
a= Should be administered before IP administration
**=  on monthly basis or as per local standard, if no visit planned the test can be performed at home with urine pregnancy test. Only blood test results will be collected 
in the eCRF)


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Weeks 11 to follow-up
Period
Treatment
End of 
Treatment
Safety 
Follow-
up
Visit Name
Week 11 Day 1
Week 13 Day 1
Week 15 Day 1
Week 17 Day 1
Week 19 Day 1
Week 21 Day 1
Week 23 Day 1
Week 25 Day 1
Week 27 Day 1
Week 29 Day 1
Week 31 Day 1
Week 33 Day 1
Week 35 Day 1
Week 37 Day 1
Week 39 Day 1
Week 41 Day 1
Week 43 Day 1
Week 45 Day 1
Week 47 Day 1
Week 49 Day 1
Week 51 Day 1
End of 
Treatment
/ Week 53 
Day 1*
Safety
FUP
Visit Number
200
210
220
230
240
250
260
270
280
290
300
310
320
330
340
350
360
370
380
390
400
1999
SFUP
Physical Exam
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
Weight
X
X
X
X
Vital Signs
X
X
X
X
Laboratory 
Assessments
Hematology
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Chemistry
X
X
X
X
X
X
X
X
X
X
X
Coagulation
X
Pregnancy Test
**
S
S
S
S
S
S
S
S
S
S
S
ECG
X
Adverse Events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Ocular 
Assessments
X
X
Prior/concomita
nt Medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X


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Period
Treatment
End of 
Treatment
Safety 
Follow-
up
Visit Name
Week 11 Day 1
Week 13 Day 1
Week 15 Day 1
Week 17 Day 1
Week 19 Day 1
Week 21 Day 1
Week 23 Day 1
Week 25 Day 1
Week 27 Day 1
Week 29 Day 1
Week 31 Day 1
Week 33 Day 1
Week 35 Day 1
Week 37 Day 1
Week 39 Day 1
Week 41 Day 1
Week 43 Day 1
Week 45 Day 1
Week 47 Day 1
Week 49 Day 1
Week 51 Day 1
End of 
Treatment
/ Week 53 
Day 1*
Safety
FUP
Visit Number
200
210
220
230
240
250
260
270
280
290
300
310
320
330
340
350
360
370
380
390
400
1999
SFUP
Bone marrow 
biopsy 
(optional)
Per investigator discretion
Patient 
Reported 
Outcomes
FACIT-Fatigue
X
X
X
X
FACT-Th6
X
X
X
X
SF-36v2
X
X
X
X
GP5
X
TSQM-9
X
Study drug 
administration
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X


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Period
Treatment
End of 
Treatment
Safety 
Follow-
up
Visit Name
Week 11 Day 1
Week 13 Day 1
Week 15 Day 1
Week 17 Day 1
Week 19 Day 1
Week 21 Day 1
Week 23 Day 1
Week 25 Day 1
Week 27 Day 1
Week 29 Day 1
Week 31 Day 1
Week 33 Day 1
Week 35 Day 1
Week 37 Day 1
Week 39 Day 1
Week 41 Day 1
Week 43 Day 1
Week 45 Day 1
Week 47 Day 1
Week 49 Day 1
Week 51 Day 1
End of 
Treatment
/ Week 53 
Day 1*
Safety
FUP
Visit Number
200
210
220
230
240
250
260
270
280
290
300
310
320
330
340
350
360
370
380
390
400
1999
SFUP
IRT enrollment
X
X = assessment to be recorded in the clinical database or received electronically from a vendor
S = assessment to be recorded in the source documentation only
* Patients who have achieved sustained remission at month 12 will be followed quarterly for an additional 12 months to obtain further data on response and remission 
duration.
** On monthly basis or as per local standard, if no visit planned the test can be performed at home with urine pregnancy. Only blood test results will be collected in the 
eCRF)


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Follow-up Period for Responders
Period
Treatment
Safety
Follow-up
Visit Name
FUP Visit #1
M15
FUP Visit #2
M18
FUP Visit #3
M21
End of FUP
M24 b
Safety
FUP
Visit Number
410
420
430
2999
SFUP
Physical Exam
S
S
S
S
Height
S
S
S
S
Weight
X
X
X
X
Vital Signs
X
X
X
X
Adverse Events
X
X
Prior/concomitant Medications
X
X
Pregnancy Test
S
S
S
S
Laboratory Assessments
Hematology
X
X
X
X
Chemistry
X
X
X
X
Patient Reported Outcomes
FACIT-Fatigue
X
X
X
X
FACT-Th6
X
X
X
X
SF-36v2
X
X
X
X
GP5
X
TSQM-9
X
Study Drug Administration a
X
X
X
X
X = assessment to be recorded in the clinical database or received electronically from a vendor
S = assessment to be recorded in the source documentation only
a = If the patient relapses during the follow-up period, they may begin re-treatment with eltrombopag. If the patient is treated with treatment options other than eltrombopag they 
will discontinue the study at that time.
b = Patients who discontinue prior to month 24 and not at a defined study visit should come into complete the end of follow-up / month 24 visit.


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8.1
Screening
All patients will be screened for study eligibility. All patients must sign informed consent
prior to any screening procedures being performed. Activities for screening will begin up to 
28 days prior to initiation of study treatment with eltrombopag.
Information regarding eligibility criteria will be collected on the Inclusion/Exclusion eCRF. 
Patients who do not meet all entry criteria should not be entered into the study.
A re-screening due to lab abnormalities can be submitted to the sponsor for decision. Re-
screening of patients is only allowed once per patient if the patient was not enrolled in the 
treatment phase before. If patient has been enrolled and treated, re-screening of patient is not 
allowed.
In case rescreening occurs, all evaluations to be re-assessed should meet the eligibility criteria. 
A new informed consent form must be signed only if there is an interruption in the patient’s 
eligibility evaluation and the investigator chooses to re-screen the patient following screen 
failure; the 28 day screen period does not apply to the informed consent process. If a new 
informed consent form is signed, AEs and medical history will be assessed relative to the new 
informed consent date.
Following registering in the Interactive Response Technology (IRT) for screening, patient
eligibility will be checked once all screening procedures are completed. The eligibility check 
will be embedded in the IRT system. Please refer and comply with detailed guidelines in the 
IRT manual.
8.1.1
Information to be collected on screening failures
Patients who sign an informed consent form and subsequently found not to be eligible will be 
considered a screen failure. The reason for screen failure should be entered on the applicable 
CRF. The demographic information, informed consent, and Inclusion/Exclusion pages must 
also be completed for screen failure patients. No other data will be entered into the clinical 
database for patients who are screen failures, unless the patient experienced an SAE event 
during the screening phase (see Section 10.1.3 for reporting details).
Patients who sign an ICF and are considered eligible but fail to be started on treatment for any 
reason will be considered an early terminator. The reason for early termination should be 
captured on the appropriate disposition CRF.
8.2
Patient demographics/other baseline characteristics
Country specific regulations should be considered for the collection of demographic and 
baseline characteristics in alignment with CRF
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
Demography including age, sex, predominant race and ethnicity (where permitted)

Height and weight

Medical history (e.g., important medical, surgical, and allergic conditions from the patient’s 
medical history which could have an impact on the patient’s evaluation)/ current medical 
conditions (e.g., all relevant current medical conditions which are present at the time of 
signing informed consent). Ongoing medical conditions, symptoms and diseases which are 
recorded on the Medical History eCRF should include the toxicity grade when applicable

Prior and concomitant medications
Bone marrow biopsy is optional and recommended for patients who did not respond to steroids
and are considered refractory. It can be performed during treatment at the discretion of the 
investigator.
All assessments to be completed and documented during screening are detailed in Table 8-1.
8.3
Efficacy
The efficacy objective is to assess the ability of eltrombopag to induce sustained remission by 
month 12.
8.3.1
Efficacy assessment 1
Platelet count will be performed at screening visit 1 to assess the eligibility of the patient. 
Hematology including platelet counts will be assessed at week 1 /day 1 and weekly during the 
first 8 weeks of treatment. Based on patient response, hematology will be performed biweekly 
thereafter until the end of treatment.
Additional assessments of platelet count may be performed more frequently than the biweekly 
schedule if needed in accordance with the clinical judgment of the investigator.
8.3.2
Efficacy assessment 2
Bleeding events will be assessed at each visit and recorded in the AE CRF. Documentation of 
the use of any rescue therapy will be documented on the appropriate CRF.
8.3.3
Appropriateness of efficacy assessments
Efficacy assessments are standard, as done in daily clinical practice and driven by relevant 
guidelines - ASH 2011 and ICG ITP Guideline (Provan 2010).
8.4
Safety
Safety assessments are specified below with the assessment schedule detailing when each 
assessment is to be performed.
For details on AE collection and reporting, refer to AE section.


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Table 8-2
Physical assessments
Assessment
Specification
Physical examination
A complete physical examination will include the examination of general appearance, 
skin, neck (including thyroid), eyes, ears, nose, throat, lungs, heart, abdomen, back, 
lymph nodes, extremities, vascular, and neurological. If indicated based on medical 
history and/or symptoms, rectal, external genitalia, breast, and pelvic exams will be 
performed.
Information for all physical examinations must be included in the source 
documentation at the study site. Clinically relevant findings that are present prior to 
signing informed consent must be recorded on the appropriate CRF that captures 
medical history. Significant findings made after first administration of investigational 
drug which meet the definition of an AE must be recorded as an AE.
Vital sign
Vital signs include BP and pulse measurements.
Height and weight
Height in centimeters (cm) and body weight (to the nearest 0.1 kilogram (kg) in indoor 
clothing, but without shoes) will be measured.
Patients who discontinue treatment early for reasons other than per protocol tapering require 
weekly hematology assessments (including platelet counts) for the first four weeks after 
discontinuing eltrombopag.
8.4.1
Ophthalmic examination
The ophthalmic exam should include the retina, blood vessels, optic disc/nerve. If the presence 
of a cataracts(s) is suspected, a slip lamp examination is required. Ophthalmic exams will be 
performed at visits according to Table 8-1.
Significant findings that were present prior to the signing of informed consent must be included 
in the Medical History page of the patient’s eCRF. Significant new findings that begin or worsen 
after informed consent must be recorded on the AE page of the patient’s eCRF.
8.4.2
Laboratory evaluations
Table 8-3
Laboratory assessments to be performed locally
Test Category
Test Name
Hematology
Hematocrit, HgB, mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin 
concentration (MCHC), mean corpuscular volume (MCV), Platelets, Red blood cells,
White blood cells, Differential (Basophils, Eosinophils, Lymphocytes, Monocytes, 
Neutrophils, Other (absolute value preferred, %s are acceptable)
Chemistry
Albumin, ALP, ALT, AST, GGT, lactate dehydrogenase (LDH), Bicarbonate, Calcium, 
Magnesium, Phosphorus, Chloride, Sodium, Potassium, Creatinine, Direct Bilirubin, 
TBIL, Total Protein, Blood Urea Nitrogen (BUN) or Urea, Uric Acid,
Amylase, Lipase, Glucose (fasting), Creatine kinase
Coagulation
PT, INR, Activated partial thromboplastin time (aPTT), Fibrinogen
Pregnancy Test
Serum / Urine pregnancy test 
8.4.3
Electrocardiogram
A standard 12 lead ECG will be performed at the screening visit.
Interpretation of the tracing must be made by a qualified physician and documented on the ECG 
CRF page. Each ECG tracing should be labeled with the study number, patient initials (where 
regulations permit), patient number, date, and kept in the source documents at the study site. 


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Clinically significant abnormalities present at screening should be reported on the Medical 
History CRF page. Clinically significant findings must be discussed with Novartis prior to 
enrolling the patient in the study. New or worsened clinically significant findings occurring 
after informed consent must be recorded on the AE CRF page.
Additional, unscheduled, safety ECGs may be repeated at the discretion of the investigator at 
any time during the study as clinically indicated. Local cardiologist ECG assessment may also 
be performed at any time during the study at the discretion of the investigator.
8.4.4
Pregnancy
All pre-menopausal women who are not surgically sterile will have pregnancy testing. 
Additional pregnancy testing might be performed if requested by local requirements.
At screening (or baseline) a serum pregnancy test should be performed within 14 days of the
first dose of eltrombopag.  Pregnancy testing (serum or urine) must be performed on a monthly 
basis or as per local standard while receiving study drug until study drug discontinuation.  If no 
visit is planned the test can be performed at home with urine pregnancy test. Additional 
pregnancy tests may be performed at the investigator’s discretion during the study.
A serum pregnancy test is required at the end of treatment visit for all patients including those
who discontinue early.  Local pregnancy test and associated results will not be collected on
eCRF.
Assessments of Fertility
Medical documentation of oophorectomy, hysterectomy, or tubal ligation must be retained as 
source documents. Subsequent hormone level assessment to confirm the woman is not of child 
bearing potential must also be available as source documentation in the following cases:

surgical bilateral oophorectomy without a hysterectomy

reported 12 months of natural (spontaneous) amenorrhea with an appropriate clinical 
profile.
In the absence of the above medical documentation, FSH testing is required of any female 
patient, regardless of reported reproductive/menopausal status at screening/baseline.
8.4.5
Appropriateness of safety measurements
The safety assessments selected are standard for this indication/patient population.
8.5
Additional assessments
Bone marrow biopsies can be performed at the discretion of the investigator.
8.5.1
Clinical Outcome Assessments
Patient reported outcomes (PRO)
Immune thrombocytopenia is associated with symptoms of fatigue, bruising, and bleeding, 
which can interfere with daily activities. Consequently, patients with ITP have decreased 


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health-related quality of life (HRQoL) compared with healthy individuals. To assess patient-
reported outcomes (PROs), HRQoL changes over time and association between HRQoL and 
platelet response during treatment or while in sustained remission with eltrombopag will be 
assessed using standard validated instruments in patients with ITP who are refractory to 
treatment or who relapsed after first-line steroids.  
The Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) instrument 
is a 13-item, easy-to-administer, validated tool used to measure an individual’s level of fatigue 
during usual daily activities over the past 7 days (Cella 2002, Webster 2003). FACIT-Fatigue 
is a subscale of the FACIT measurement system, which is a validated collection of HRQoL 
questionnaires targeted to the management of chronic illness that are used to measure HRQoL 
on multiple general and disease-specific domains. FACIT-fatigue is scored using a 4-point 
Likert scale (4=not at all fatigued to 0=very much fatigued) where the total possible score ranges 
from 0-5; higher scores represent better HRQoL (Signorovitch 2011). Patients will be
administered the FACIT-Fatigue at baseline, every 3 months during treatment or while in 
sustained remission, at months 15, 18, 21, 24, and end of treatment. A minimal clinically 
important difference from baseline in FACIT-Fatigue score will be evaluated (Cella 2002). The 
overall total score will be evaluated; 
 
.
The Medical Outcome Trust’s Short-Form 36 Health Survey, Version 2 (SF-36v2), which 
is a validated instrument used to measure general physical and mental health status (Ware 2000), 
will be used to assess the impact of ITP on physical function and ability to conduct day-to-day 
activities. The SF-36v2 is used to measure patients' overall HRQoL via assessment of 8 
domains—Physical Functioning, Role Physical, Bodily Pain, General Health, Vitality, Social 
Functioning, Role Emotional, and Mental Health—over the past 4 weeks or 7 days. The SF-36 
is scored using norm-based scoring procedures and scores ranging from 0-100; higher scores 
represent better HRQoL. Two summary scores, the Physical Component Score (PCS) and the 
Mental Component Summary (MCS), can also be calculated.
The SF-36v2, specifically the Physical Functioning and the Role Physical domains, 
demonstrated good reliability and validity for measuring the proposed constructs in the ITP 
population (Signorovitch 2011). The Physical Functioning domain includes 10 items related to 
limitations in physical functioning and is scored using a 3-level Likert scale (1=yes, limited a 
lot; 2=yes, limited a little; and 3=no, not at all limited); higher scores represent less functional 
limitation. The Role Physical domain is used to measure to what degree physical health 
interferes with work/other daily activities, includes 4 items (reduction in the amount of time 
spent on work/other activities, accomplishing less than one would like, limitations in kind of 
work/other activities, and difficulty performing work/other activities), and is scored using a 5-
level Likert scale (1=all of the time; 5=none of the time); lower scores represent less impact on 
daily activities. Patients will be administered the SF-36v2 at baseline, every 3 months during 
treatment or while in sustained remission, at months 15, 18, 21, 24, and end of treatment, and 
change from baseline will be evaluated. 
 
The Functional Assessment of Cancer Therapy - Thrombocytopenia 6-item version 
(FACT-Th6) instrument is used to measure worry/concern about bleeding and bruising, and 
the impact of this worry/concern on physical and social activity (Cella 2006). FACT-Th6 is a 


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6-item subset of the more detailed FACT-Th, which is an 18-item subscale of the validated 
FACT that specifically measures concerns related to thrombocytopenia in the past 7 days. The 
FACT-Th6 is scored using a 5-level Likert scale (0=not at all to 4=very much) and is calculated 
by summing scores for the 6-items; therefore, scores can range from 0–24, with higher scores 
representing better HRQoL. No minimum clinically important change thresholds have been 
established for FACT-Th6. Tentatively anchor-based methods (e.g., based on Patient Global 
Impression of Change [PGIC] and Patient Global Impression-Severity [PGIS]) and distribution-
based methods will be used to determine meaningful change in scores. FACT-Th6 demonstrated 
good reliability and validity for measuring the proposed constructs in the ITP population. 
Patients will be administered the FACT-Th6 at baseline, every 3 months during treatment or 
while in sustained remission, at months 15, 18, 21, 24, and at end of treatment.
The GP5, which is a single question, is used to assess the overall bothersomeness of treatment 
side effects. The GP5 is scored using a 5-point rating scale (0 = not at all; 1 = a little bit; 2 = 
somewhat; 3 = quite a bit; and 4 = very much), where lower scores reflect less bothersomeness 
from treatment side effects. The GP5 will be evaluated at baseline and end of treatment.
Treatment Satisfaction Questionnaire for Medication (TSQM-9) will be used to assess 
treatment satisfaction with medication. The three scales of the TSQM-9 include the 
effectiveness scale, convenience scale, and global satisfaction scale. TSQM-9 will be evaluated 
at baseline and end of treatment.


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9
Study discontinuation and completion
9.1
Discontinuation
9.1.1
Discontinuation of study treatment
Early discontinuation of study treatment for a patient occurs when study treatment is stopped 
earlier than the protocol planned duration, and can be initiated by either the patient or the 
investigator.
The investigator must discontinue study treatment for a given patient if, he/she believes that 
continuation would negatively impact the patient's well-being.
Study treatment must be discontinued under the following circumstances:

Patient/guardian decision

Pregnancy of the participating patient

Use of prohibited treatment as per recommendations in the prohibited treatment section

Any situation in which study participation might result in a safety risk to the patient

Any laboratory abnormalities that in the judgment of the investigator, taking into 
consideration the patient’s overall status, prevents the patient from continuing 
participation in the study
If early discontinuation of study treatment occurs, the investigator should make a reasonable 
effort to understand the primary reason for the patient’s premature discontinuation of study 
treatment and record this information.
Patients who discontinue study treatment or who decide they do not wish to participate in the 
study further should NOT be considered withdrawn from the study UNLESS they withdraw 
their consent (see withdraw of informed consent section,). Where possible, they should return 
for the assessments indicated in the assessment schedule. If they fail to return for these 
assessments for unknown reasons, every effort (e.g. telephone, e-mail, letter) should be made 
to contact the patient/pre-designated contact as specified in the lost to follow-up section. This 
contact should preferably be done according to the study visit schedule.
If the patient cannot or is unwilling to attend any visit(s), the site staff should maintain regular 
telephone contact with the patient, or with a person pre-designated by the patient. This telephone 
contact should preferably be done according to the study visit schedule.
After early study treatment discontinuation (i.e., not per protocol tapering), at a minimum, in 
follow-up visit (30-days after the last dose of eltrombopag) the following data should be 
collected at clinic visits or via telephone/email contact:

new / concomitant treatments

AE / SAEs
The investigator must also contact the IRT to register the patient’s discontinuation from study 
treatment.


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Withdrawal of informed consent
Patients may voluntarily withdraw consent to participate in the study for any reason at any time. 
Withdrawal of consent occurs only when a patient:

Does not want to participate in the study anymore
and

Does not want any further visits or assessments
and

Does not want any further study related contacts
In this situation, the investigator should make a reasonable effort (e.g. telephone, e-mail, letter) 
to understand the primary reason for the patient’s decision to withdraw his/her consent and 
record this information.
Study treatment must be discontinued and no further assessments conducted, and the data that 
would have been collected at subsequent visits will be considered missing.
Further attempts to contact the patient are not allowed unless safety findings require 
communicating or follow-up.
All efforts should be made to complete the assessments prior to study withdrawal. A final 
evaluation at the time of the patient’s study withdrawal should be made as detailed in the 
assessment table.
Novartis will continue to retain and use all research results (data) that have already been 
collected for the study evaluation.
9.1.2
Lost to follow-up
For patients whose status is unclear because they fail to appear for study visits without stating 
an intention to discontinue or withdraw, the investigator must show "due diligence" by 
documenting in the source documents steps taken to contact the patient, e.g. dates of telephone 
calls, registered letters, etc. A patient should not be considered as lost to follow-up until due 
diligence has been completed or until the end of the study.
9.1.3
Early study termination by the sponsor
The study can be terminated by Novartis at any time for any reason. This may include reasons 
related to the benefit/ risk assessment of participating in the study, practical reasons (including 
slow enrollment), or for regulatory or medical reasons. In taking the decision to terminate, 
Novartis will always consider the patient welfare and safety. Should early termination be 
necessary, patients must be seen as soon as possible (provide instruction for contacting the
patient, when the patient should stop taking drug, when the patient should come for a final visit) 
and treated as a prematurely withdrawn patient. The investigator may be informed of additional 
procedures to be followed in order to ensure that adequate consideration is given to the 
protection of the patient’s interests. The investigator or sponsor depending on the local 
regulation will be responsible for informing IRBs/IECs of the early termination of the trial.


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9.2
Study completion and post-study treatment
Study completion is defined as when the last patient finishes their end of follow-up / month 24 
visit, and any repeat assessments associated with this visit have been documented and followed-
up appropriately by the Investigator, or in the event of an early study termination decision, the 
date of that decision.
All patients who are still on study at month 12 will complete the end of treatment visit at Week 
53, Day 1. Patients who are still on study treatment and not in sustained remission at month 12
will come off trial after completing the end of treatment visit. After discontinuing drug at the 
end of treatment visit, patients will be followed-up for safety for an additional 30 days (safety 
follow-up). The following data should be collected during the safety follow-up: adverse events 
and concomitant medications. This data can be collected via telephone/email contact or at a 
clinic visit (as needed). 
Patients who still have sustained remission (see Table 2-1) at the end of treatment visit will 
enter the follow-up period for responders (see Section 9.3).  The follow-up period begins after 
month 12.
Continuing care to study participants should be provided by the investigator and/or referring 
physician. The treating physician can request access to eltrombopag for patients that are 
continuing to benefit from treatment. Access will be dependent on the local regulatory authority 
approval of the product and current reimbursement options.
9.3
Additional 12 months follow-up period for responders
Patients who still have sustained remission at month 12 will be followed quarterly (every 3 
months) until month 24 in order to obtain further data on response and remission duration.  
Patients will be followed quarterly (every 3 months) for physical exams, adverse events, 
concomitant medications, hematology and chemistry laboratory assessments, and patient 
reported outcomes (see Table 8-1 Follow-up period for responders).  
In case of relapse during the follow-up period, patients will be offered a new course of 
eltrombopag treatment within this timeframe, starting at a dose of 50 mg (starting dose for Asian 
patients will be 25 mg QD, reduced as per Section 6.1).
Only patients receiving retreatment with eltrombopag will be followed until month 24. Patients 
re-treated with eltrombopag will be followed-up for safety for an additional 30 days (safety 
follow-up) after month 24.  The following data should be collected during the safety follow-up: 
adverse events and concomitant medications. This data can be collected via telephone/email 
contact or at a clinic visit (as needed).
Patients who are treated with treatment options other than eltrombopag during the follow-up 
period will discontinue the study at that time. 
Patients who discontinue prior to month 24 and not at a defined study visit (see Table 8-1
Follow-up period for responders) should complete their end of follow-up / Month 24 visit.


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10
Definition of adverse events and reporting requirements
10.1.1
Adverse events
An AE is any untoward medical occurrence (e.g., any unfavorable and unintended sign 
[including abnormal laboratory findings], symptom or disease) in a patient or clinical 
investigation patient after providing written informed consent for participation in the study. 
Therefore, an AE may or may not be temporally or causally associated with the use of a 
medicinal (investigational) product.
The investigator has the responsibility for managing the safety of individual patient and 
identifying AEs.
Novartis qualified medical personnel will be readily available to advise on trial related medical 
questions or problems.
The occurrence of AEs must be sought by non-directive questioning of the patient at each visit 
during the study. Adverse events also may be detected when they are volunteered by the patient
during or between visits or through physical examination findings, laboratory test findings, or 
other assessments.
Adverse events must be recorded under the signs, symptoms or diagnosis associated with them, 
accompanied by the following information (as far as possible) (if the event is serious refer to 
Section 10.1.2):
1. Adverse events will be assessed and graded according to the CTCAE version 4.03
2. its relationship to the study treatment
3. its duration (start and end dates) or if the event is ongoing, an outcome of not 
recovered/not resolved must be reported.
4. whether it constitutes a SAE (see Section 10.1.2 for definition of SAE) and which 
seriousness criteria have been met
5. action taken regarding study treatment.
All adverse events must be treated appropriately. Treatment may include one or more of the 
following:

Dose not changed

Dose reduced/increased

Drug interrupted/withdrawn
6. its outcome i.e., its recovery status or whether it was fatal
Conditions that were already present at the time of informed consent should be recorded in 
medical history of the patient.
Adverse events (including lab abnormalities that constitute AEs) should be described using a 
diagnosis whenever possible, rather than individual underlying signs and symptoms.
Adverse event monitoring should be continued for at least 30 days following the last dose of 
study treatment.
Once an adverse event is detected, it must be followed until its resolution or until it is judged to 
be permanent (e.g. Continuing at the end of the study), and assessment must be made at each 


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visit (or more frequently, if necessary) of any changes in severity, the suspected relationship to 
the interventions required to treat it, and the outcome.
Information about adverse drug reactions for the investigational drug can be found in the IB.
Abnormal laboratory values or test results constitute adverse events only if they fulfill at least 
one of the following criteria:

they induce clinical signs or symptoms

they are considered clinically significant

they require therapy
Clinically significant abnormal laboratory values or test results must be identified through a 
review of values outside of normal ranges, significant changes from baseline or the previous 
visit, or values which are considered to be non-typical in patients with the underlying disease.
10.1.2
Serious adverse events
An SAE is defined as any adverse event [appearance of (or worsening of any pre-existing)] 
undesirable sign(s), symptom(s) or medical conditions(s)) which meets any one of the following 
criteria:

fatal

life-threatening
Life-threatening in the context of a SAE refers to a reaction in which the patient was at risk of 
death at the time of the reaction; it does not refer to a reaction that hypothetically might have 
caused death if it were more severe (please refer to the ICH-E2D Guidelines).

results in persistent or significant disability/incapacity

constitutes a congenital anomaly/birth defect

requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for:

routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition.

elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent

social reasons and respite care in the absence of any deterioration in the patient’s 
general condition

treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission

is medically significant, e.g. defined as an event that jeopardizes the patient or may require 
medical or surgical intervention to prevent one of the outcomes listed above
Medical and scientific judgment should be exercised in deciding whether other situations should 
be considered serious reactions, such as important medical events that might not be immediately 
life threatening or result in death or hospitalization but might jeopardize the patient or might 
require intervention to prevent one of the other outcomes listed above. Such events should be 
considered as “medically significant”. Examples of such events are intensive treatment in an 


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emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions that do 
not result in hospitalization or development of dependency or abuse.
All malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met and the malignant neoplasm is not a disease progression of the 
study indication.
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction.
All reports of intentional misuse and abuse of the product are also considered serious adverse 
event irrespective if a clinical event has occurred.
10.1.3
SAE reporting
To ensure patient safety, every SAE, regardless of causality, occurring after the patient has 
provided informed consent and until 30 days following the last dose of eltrombopag must be 
reported to Novartis Safety within 24 hours of learning of its occurrence. Detailed instructions 
regarding the submission process and requirements are to be found in the investigator folder 
provided to each site.
SAEs occurring after the patient has provided informed consent until the time the patient is 
deemed a Screen Failure must be reported to Novartis.
All follow-up information for the SAE including information on complications, progression of 
the initial SAE and recurrent episodes must be reported as follow-up to the original episode 
within 24 hours of the investigator receiving the follow-up information. An SAE occurring at a 
different time interval or otherwise considered completely unrelated to a previously reported 
one must be reported separately as a new event.
If the SAE is not previously documented in the IB or Package Insert (new occurrence) and is 
thought to be related to the study treatment, a Chief Medical Office and Patient Safety (CMO 
& PS) Department associate may urgently require further information from the investigator for 
health authority reporting. Novartis may need to issue an Investigator Notification (IN) to 
inform all investigators involved in any study with the same study treatment that this SAE has 
been reported.
Suspected Unexpected Serious Adverse Reactions (SUSARs) will be collected and reported to 
the competent authorities and relevant ethics committees in accordance with EU Guidance 
2011/C 172/01 or as per national regulatory requirements in participating countries.
Any SAEs experienced after the 30 day period following the last dose of eltrombopag should 
only be reported to Novartis Safety if the investigator suspects a causal relationship to study 
treatment.
10.1.4
Pregnancy reporting
Pregnancies
To ensure patient safety, each pregnancy occurring after signing the informed consent must be 
reported to Novartis within 24 hours of learning of its occurrence. The pregnancy should be 


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followed up to determine outcome, including spontaneous or voluntary termination, details of 
the birth, and the presence or absence of any birth defects, congenital abnormalities, or maternal 
and/or newborn complications.
Pregnancy should be recorded and reported by the investigator to the Novartis CMO&PS. 
Pregnancy follow-up should be recorded on the same form and should include an assessment 
of the possible relationship to eltrombopag and any pregnancy outcome. Any SAE experienced 
during pregnancy must be reported.
Pregnancy outcomes should be collected for the female partners of any males who took study 
treatment in this study. Consent to report information regarding these pregnancy outcomes 
should be obtained from the mother.
10.1.5
Reporting of study treatment errors including misuse/abuse
Medication errors are unintentional errors in the prescribing, dispensing, administration or 
monitoring of a medicine while under the control of a healthcare professional, patient or 
consumer (European Medicines Agency definition) (Table 10-1).
Misuse refers to situations where the medicinal product is intentionally and inappropriately used 
not in accordance with the protocol.
Abuse corresponds to the persistent or sporadic, intentional excessive use of a medicinal product, 
which is accompanied by harmful physical or psychological effects.
Study treatment errors and uses outside of what is foreseen in the protocol will be recorded on 
the appropriate CRF irrespective of whether or not associated with an AE/SAE and reported to 
Safety only if associated with an SAE. Misuse or abuse will be collected and reported in the 
safety database irrespective of it being associated with an AE/SAE within 24 hours of 
Investigator’s awareness.
Table 10-1
Guidance for capturing the study treatment errors including 
misuse/abuse
Treatment error type
Document in Dosing 
CRF (Yes/No)
Document in AE 
eCRF
Complete SAE form
Unintentional study 
treatment error
Yes
Only if associated 
with an AE
Only if associated with an 
SAE
Misuse/Abuse
Yes
Yes
Yes, even if not associated 
with a SAE
For more information on AE and SAE definition and reporting requirements, please see the, 
respective sections.
10.2
Additional Safety Monitoring
10.2.1
Liver safety monitoring
To ensure patient safety and enhance reliability in determining the hepatotoxic potential of an 
investigational drug, a standardized process for identification, monitoring and evaluation of 
liver events has to be followed.  Liver safety monitoring tests should be performed at local 
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The following two categories of abnormalities / adverse events have to be considered during 
the course of the study (irrespective of whether classified/reported as AE/SAE):

Significant liver laboratory abnormalities, which will require repeated assessments of the 
abnormal laboratory parameter

Liver events, which will require close observation, follow-up monitoring and contributing 
factors are recorded on the appropriate CRFs
Please refer to Table 6-4 for dose modifications/discontinuation for liver laboratory 
abnormalities.
Every clinically significant liver event should be followed up by the investigator or designated 
personnel at the trial site, as summarized below. Repeat liver chemistry tests (ALT, AST, 
TBL, PT/INR, ALP and GGT) to confirm elevation.

These liver chemistry repeats should be performed locally. If a liver event is subsequently 
reported, any local liver chemistry tests previously conducted that are associated with this 
event should have results recorded on the appropriate (CRF). These liver chemistry repeats 
should be performed using the local laboratory used by the site. Repeated laboratory test 
results must be reported as appropriate.

If the initial elevation is confirmed, close observation of the patient will be initiated, 
including consideration of treatment interruption if deemed appropriate.

Discontinuation of the investigational drug (refer to the Discontinuation of study treatment 
section), if appropriate

Hospitalization of the patient if appropriate

Causality assessment of the liver event

Thorough follow-up of the liver event should include

These investigations can include based on investigator’s discretion: serology tests, 
imaging and pathology assessments, hepatologist’s consultancy; obtaining more 
detailed history of symptoms and prior or concurrent diseases, history of concomitant 
drug use, exclusion of underlying liver disease
All follow-up information, and the procedures performed must be recorded as appropriate in 
the CRF.
10.2.2
Renal safety monitoring
Not applicable
10.2.3
Steering Committee
The Steering Committee (SC) will be established comprising investigators participating in the 
trial, i.e., not being Novartis representatives from the Clinical Trial Team.
The Steering Committee will ensure transparent management of the study according to the 
protocol through recommending and approving modifications as circumstances require. The SC 
will review protocol amendments as appropriate. Together with the clinical trial team, the SC 
will also develop recommendations for publications of study results including authorship rules. 
The details of the role of the Steering Committee will be defined in a Steering Committee 
charter.


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11
Data Collection and Database management
11.1
Data collection
Data not requiring a separate written record will be defined in the protocol and the assessment 
schedule and can be recorded directly on the CRFs. All other data captured for this study will 
have an external originating source (either written or electronic) with the CRF not being 
considered as source.
All data should be recorded, handled and stored in a way that allows its accurate reporting, 
interpretation and verification.
Designated investigator staff will enter the data required by the protocol into the eCRF. The 
eCRFs have been built using fully validated secure web-enabled software that conforms to 
21 CFR Part 11 requirements, Investigator site staff will not be given access to the EDC system 
until they have been trained. Automatic validation programs check for data discrepancies in the 
eCRFs, allow modification and/or verification of the entered data by the investigator staff.
The investigator/designee is responsible for assuring that the data (recorded on CRFs) (entered 
into eCRF) is complete, accurate, and that entry and updates are performed in a timely manner. 
The Investigator must certify that the data entered are complete and accurate.
EDC studies, after database lock, the investigator will receive a CD-ROM or paper copies of 
the patient data for archiving at the investigational site.
Remote monitoring of the original electronic source records will take place, however on-site 
monitoring inspections will continue to take place in order to review data entry of source 
documentation directly captured on paper and transcribed into the system, to ensure protocol 
adherence, to assess site operational capabilities, and to perform other monitoring activities that 
cannot be performed remotely.
All data should be recorded, handled and stored in a way that allows its accurate reporting, 
interpretation and verification.
11.2
Database management and quality control
Novartis personnel (or designated CRO) will review the data entered by investigational staff 
for completeness and accuracy. Electronic data queries stating the nature of the problem and 
requesting clarification will be created for discrepancies and missing values and sent to the 
investigational site via the electronic data capture (EDC) system. Designated investigator site 
staff are required to respond promptly to queries and to make any necessary changes to the data.
Concomitant treatments, prior medications and rescue medications entered into the database 
will be coded using the WHO Drug Reference List, which employs the Anatomical Therapeutic 
Chemical classification system. Medical history/current medical conditions and adverse events 
will be coded using the Medical dictionary for regulatory activities (MedDRA) terminology.
Once all the necessary actions have been completed and the database has been declared to be 
complete and accurate, it will be locked. Any changes to the database after that time can only 
be made after written agreement by GMA Novartis management.


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11.3
Site monitoring
Before study initiation, at a site initiation visit or at an investigator’s meeting, a 
Novartis/delegated CRO representative will review the protocol and data capture requirements 
(i.e. eSource DDE or eCRFs) with the investigators and their staff. During the study, Novartis
employs several methods of ensuring protocol and GCP compliance and the quality/integrity of 
the sites’ data. The field monitor will visit the site to check the completeness of patient records, 
the accuracy of data capture / data entry, the adherence to the protocol and to GCP, the progress 
of enrollment, and to ensure that study treatment is being stored, dispensed, and accounted for 
according to specifications. Key study personnel must be available to assist the field monitor 
during these visits. Continuous remote monitoring of each site’s data may be performed by a 
centralized Novartis/delegated CRO/CRA organization. Additionally, a central analytics 
organization may analyze data & identify risks & trends for site operational parameters, and 
provide reports to Novartis clinical teams to assist with trial oversight.
The investigator must maintain source documents for each patient in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information on CRFs must be traceable to these source documents in the 
patient’s file. Data not requiring a separate written record will be defined before study start and 
will be recorded directly on the CRFs. The investigator must also keep the original informed 
consent form signed by the patient (a signed copy is given to the patient).
The investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the data capture and/or data entry. Novartis monitoring standards require full 
verification for the presence of informed consent, adherence to the inclusion/exclusion criteria, 
documentation of SAEs, and of data that will be used for all primary variables. Additional 
checks of the consistency of the source data with the CRFs are performed according to the 
study-specific monitoring plan. No information in source documents about the identity of the 
patients will be disclosed.
12
Data analysis and statistical methods
All analyses will be performed by Novartis or a designated CRO. Any data analysis carried out 
independently by the investigator should be submitted to Novartis before publication or 
presentation.
Continuous variables will be summarized by number of patients, mean, standard deviation, 
minimum, median, and maximum. For selected parameters, 25th and 75th percentiles will also 
be presented.
Categorical variables will be summarized by frequencies and percentages.
The 95% confidence interval (CI) using the Clopper-Pearson method will be provided for 
selected parameters. Kaplan-Meier method will be used for time to event analyses. 
In addition to the statistical methods outlined below, further details and any additional 
exploratory analyses that may be performed will be described in the Statistical Analysis Plan 
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The baseline is the result of an investigation describing the “true” state of the patient before 
start of eltrombopag.
The last available assessment on or before the date of start of eltrombopag is taken as “baseline” 
assessment. In case, assessment is captured pre-dose on first day of eltrombopag (e.g. PROs), 
this assessment is used for baseline.
12.1
Analysis sets
The Full Analysis Set (FAS) includes all patients who received at least one dose of 
eltrombopag.
The Safety Set includes all patients who received at least one dose of eltrombopag.
 
12.2
Patient demographics and other baseline characteristics
Demographic and other baseline data including disease characteristics will be listed and 
summarized descriptively based on the FAS.
Relevant medical histories and current medical conditions at baseline will be summarized by 
system organ class and preferred term.
12.3
Treatments
The Safety set will be used for the analyses below.
The duration of exposure in weeks to eltrombopag, as well as the dose intensity (computed as 
the ratio of actual cumulative dose received and actual duration of exposure) and the relative 
dose intensity (computed as the ratio of dose intensity and planned dose intensity) will be 
summarized by means of descriptive statistics.
The number of patients with dose adjustments (reductions, interruption, or permanent 
discontinuation) and the reasons will be summarized and all dosing data will be listed.
Concomitant medications and significant non-drug therapies prior to and after the start of the 
study treatment, including rescue medication therapy, will be listed and summarized according 
to the Anatomical Therapeutic Chemical (ATC) classification system.
12.4
Analysis of the primary endpoint(s)
The primary objective is to assess ability of eltrombopag to induce sustained remission by 
month 12 in ITP patients who relapsed or failed to respond first-line steroid treatment.
For the primary and supportive analyses the FAS will be used.


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12.4.1
Definition of primary endpoint
The primary endpoint is the proportion of patients with sustained remission (R) by month 12.
Sustained remission (R) is defined as:

reach platelet count ≥100×109/L (CR) and then maintain platelet counts around 
100×109/L for 2 months (no counts below 70×109/L) AND then

taper off the drug until treatment discontinuation (see Section 9.1) while,

maintain platelet count ≥30×109 /L in the absence of bleeding (no bleeding AEs) or use of 
any rescue therapy (see Section 6.2.3) until month 12.
12.4.2
Statistical model, hypothesis, and method of analysis
The number (%) of patients with sustained remission (R) by month 12 will be summarized
together with 95% confidence interval (CI) using the Clopper-Pearson method.
A binomial test for one proportion, H0: P=0.15 vs. H1:P>0.15 will be performed to test if the 
proportion of remission patients is greater than 15%.
12.4.3
Handling of missing values/censoring/discontinuations
If patients’ platelet assessments for evaluating the primary endpoint are missing, they will not 
be considered for sustained remission. No imputation will be used for missing platelet values.
A patient who discontinues early from the study (before month 12 e.g. withdrawal of consent) 
will not be considered for sustained remission.
12.4.4
Supportive analyses
The number (%) of patients:

with CR (reaching platelet count ≥100×109/L)

who maintained platelet counts around 100×109/L for 2 months (no counts < 70×109/L)

who managed to start tapering eltrombopag after maintaining platelet counts around
100×109/L (no counts < 70×109/L) for 2 months

who are able to discontinue eltrombopag after tapering
will be provided together with 95% CI using the Clopper-Pearson method.
In addition bar plot(s) for the percentage of patients in each category may be provided.
12.5
Analysis of secondary endpoints
For all efficacy and PRO analyses, the FAS will be used. For all safety analyses the safety set 
will be used.
12.5.1
Efficacy endpoint(s)
1. To assess the duration of sustained remission after treatment discontinuation
1a) Summary statistics for the duration of sustained remission (weeks) counted from last 
dose of eltrombopag to month 12 for patients with sustained remission (R) will be provided.


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1b) Kaplan-Maier analyses for the duration of sustained remission (weeks) counted from 
last dose of eltrombopag to relapse for patients with sustained remission (R) at month 12 
and who enter 12 months follow-up period. The patients who do not relapse/die by month 
24 will be censored. 
1c) Kaplan-Maier analyses for the duration of sustained remission (weeks) counted from 
last dose of eltrombopag to relapse for all patients. The patients who do not relapse/die by 
month 24 will be right-censored. The duration will be considered as 0 for patients who do 
not manage to taper off eltrombopag per protocol i.e. do not reach sustained remission.   
2. To assess the proportion if patients maintaining a sustained remission after treatment 
discontinuation until month 24.
Number (%) of patients who are in sustained remission at months 15, 18, 21, and 24 will 
be provided.
3. To assess the ability of eltrombopag to induce early response by month 1
Number (%) of patients who reach platelet count ≥50×109/L at least once within the first 
month (month 1) without bleeding events and no rescue therapy will be provided.
4. To assess the ability of eltrombopag to induce a recovery response, in case of loss of 
response during or after tapering of eltrombopag
Number (%) of patients with at least one platelet count ≥30×109/L after eltrombopag is re-
introduced, in case of loss of response (< 30×109/L and/or bleeding event) without bleeding 
events and no rescue therapy will be provided.
5. To assess the platelet count from baseline to 3, 6, 9, 12, 15, 18, 21, 24 months
Absolute and relative change in platelet count from baseline to 3, 6, 9, 12, 15, 18, 21, 24
months and end of treatment will be provided. Box plots for absolute and/or relative change 
in platelet counts from baseline to different time points will also be provided.
6. To assess the ability of eltrombopag to maintain platelet count ≥30×109/L within 12 
months and every 3 months until month 24
Number (%) of patients who maintain a platelet count ≥30×109/L from the first time of 
reaching that level to month 3, 6, 9, 12, 15, 18, 21, 24 and end of treatment, without 
bleeding events and no rescue therapy will be provided.
7. To evaluate patient HRQoL outcome measures for Health-Related Quality of Life
(fatigue level of the patient through FACIT), FACT-Th6 and SF-36v2 questionnaires.
Change in each domain score and total score of HRQoL parameters: (fatigue level of 
patients through FACIT), FACT-Th6 and SF-36v2 questionnaires from baseline to 3, 6, 9,
12, 15, 18, 21, 24 months and end of treatment will be provided. In addition, summary 
statistics for the two main summary scores, the PCS and the MCS for SF36 v2 as per 
sustained remission (R) status (sustained remission versus no sustained remission) will also 
be provided. Listings will be provided.
Scoring for SF-36v2 will be provided by an external vendor.
8. To explore the overall impact of side effects of treatment via the GP5 at baseline, 12 
months, and end of treatment


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Overall change from baseline to end of treatment score will be assessed. A listing will be 
provided.
9. To explore treatment satisfaction with TSQM-9
Overall change from baseline, 12 months, and end of treatment score will be assessed. A 
listing will be provided.
10. To evaluate the safety and tolerability of eltrombopag see Section 12.5.2.
12.5.2
Safety endpoint(s)
Safety summary tables include only data from the on-treatment period with the exception of 
baseline data which will also be summarized where appropriate.
The on-treatment period lasts from the date of first dose of eltrombopag to 30 days after the 
date of the last dose of eltrombopag.
Adverse events
All information obtained on adverse events will be displayed by patient. Summary tables for 
adverse events (AEs) will include only AEs that started or worsened during the on-treatment 
period, the treatment-emergent AEs (TEAEs).
The incidence of TEAEs will be summarized by system organ class (SOC) and or preferred 
term, severity based on the CTCAE grades, type of adverse event and relation to eltrombopag.
Serious adverse events, AEs leading to discontinuation, AEs leading to dose adjustment and 
adverse events of special interest (AESI) which includes bleeding events during the on-
treatment period will be tabulated.
Specific groupings of AESI will be considered and the number of patients with at least one 
event in each grouping will be reported. Such groups consists of AEs for which there is a 
specific clinical interest in connection with eltrombopag treatment or AEs which are similar in 
nature (although not identical). Note that certain AEs may be reported within multiple 
groupings/AESIs.
AESIs are defined by MedDRA terms. Definition for retrieval and maintenance is done in the 
electronic case retrieval sheet (eCRS).
The incidence of AESIs will be summarized by SOC and Preferred Term (PT).
The AESIs as specified in the latest version of the case retrieval sheet (CRS) at the time of 
analysis will be used.
All deaths (on-treatment and post-treatment [starting at day 30+1 after last dose of 
eltrombopag]) will be summarized.
All AEs, deaths and SAEs will be listed and those collected during the pre-treatment (from day 
of patient’s informed consent to the day before first dose of eltrombopag) and post-treatment 
period will be flagged.
A patient with multiple AEs within a primary SOC is only counted once towards the total of the 
primary SOC.


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Clinical laboratory evaluations
Grading of laboratory values will be assigned programmatically as per the CTCAE version 4.03.
The calculation of CTCAE grades will be based on the observed laboratory values only, clinical 
assessments will not be taken into account.
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 generated separately for key hematology and biochemistry 
tests laboratory tests:

Shift tables comparing baseline to the worst on-treatment value. Each patient will be 
counted only once for the worst grade observed post-baseline.

For laboratory tests where grades are not defined shift tables using the low/normal/high/ 
(low and high) classification to compare baseline to the worst on-treatment value will be 
used.
In addition to the above mentioned tables and listings, other exploratory analyses, for example 
figures plotting time course of raw or change in laboratory tests over time or box plots might 
be specified in the statistical analytical plan (SAP) and tables/listings/figures (TLF) shells. 
Listings will be provided for all data.
Other safety evaluations
Data on ECG, vital sign, height, weight, ocular findings will be summarized descriptively, listed 
and flagged as appropriate. Any significant findings will be documented as AEs and reported 
as such.


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12.7
Interim analyses
Not applicable
12.8
Sample size calculation
12.8.1
Primary endpoint
Based on medical experts’ advice, it is postulated that approximately 15% of patients who do 
not respond or relapse after a first round of steroid therapy would have sustained remission by 


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12 months if on steroid recycling. In this study, at least a 10% higher sustained remission rate 
is expected by month 12, i.e., a sustained remission rate of at least 25% by 12 months is expected 
in patients who will receive eltrombopag after failing first-line steroids.
The sample size calculation is based on an exact binomial test for single proportion using a 
target alpha level of 0.05 and power of 80% to compare the null hypothesis H0: P=0.15 against 
the alternative hypothesis H1: P>0.15, where P is proportion of patients with sustained 
remission by Month 12.
A sample size of 101 gives at least 80% power if the true sustained remission rate with
eltrombopag is 25% or more with an actual significance level of 0.043. The null hypothesis will 
be rejected if the number of patients with sustained remission is 22 or more.
Table 12-1 shows the sample size, cut-off, actual alpha, beta and power for different sustained 
remission rates. PASS 11 (version 11.0.10) is used for the sample size calculation.
Table 12-1
Numeric results for testing H0: P = P0 versus H1: P > P0 using exact 
binomial test statistic
Proportion 
given H0 
(P0)
Proportion 
given H1
(P1)
Sample 
size (N)
Cut-off
(Reject H0 if 
R>=This)
Actual
Alpha
Actual
Beta
Actual
Power
0.150
0.250
101
22
0.043
0.196
0.804
0.150
0.300
48
12
0.048
0.181
0.819
0.150
0.350
28
8
0.049
0.182
0.818
0.150
0.400
22
7
0.037
0.158
0.842
0.200
0.300
116
31
0.049
0.193
0.807
0.200
0.350
56
17
0.043
0.194
0.806
0.200
0.400
35
12
0.034
0.195
0.805
At the end of the study, for decision-making purposes, the cut-off will be determined based on 
the final sample size and the target alpha and beta.
13
Ethical considerations and administrative procedures
13.1
Regulatory and ethical compliance
This clinical study was designed and shall be implemented, executed and reported in accordance 
with the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable 
local regulations (including European Directive 2001/20/EC, US CFR 21), and with the ethical 
principles laid down in the Declaration of Helsinki.
13.2
Responsibilities of the investigator and IRB/IEC
Before initiating a trial, the investigator/institution must obtain approval/favorable opinion from 
the IRB/IEC for the trial protocol, written informed consent form, consent form updates, patient
recruitment procedures (e.g., advertisements) and any other written information to be provided 
to patients. Prior to study start, the investigator is required to sign a protocol signature page 
confirming his/her agreement to conduct the study in accordance with these documents and all 
of the instructions and procedures found in this protocol and to give access to all relevant data 


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and records to Novartis monitors, auditors, Novartis Quality Assurance representatives, 
designated agents of Novartis, IRBs/IECs, and regulatory authorities as required. If an 
inspection of the clinical site is requested by a regulatory authority, the investigator must inform 
Novartis immediately that this request has been made.
13.3
Publication of study protocol and results
The protocol will be registered in a publicly accessible database such as clinicaltrials.gov and 
as required in EudraCT. In addition, after study completion (e.g., defined as last patient last 
visit) and finalization of the study report the results of this trial will be submitted for publication 
and posted in a publicly accessible database of clinical trial results, such as the Novartis clinical 
trial results website and all required Health Authority websites (e.g. Clinicaltrials.gov, EudraCT 
etc.).
For details on the Novartis publication policy including authorship criteria, please refer to the 
Novartis publication policy training materials that were provided to you at the trial investigator 
meetings.
13.4
Quality Control and Quality Assurance
Novartis maintains a robust Quality Management System (QMS) that includes all activities 
involved in quality assurance and quality control, to ensure compliance with written Standard 
Operating Procedures as well as applicable global/local GCP regulations and ICH Guidelines.
Audits of investigator sites, vendors, and Novartis systems are performed by auditors, 
independent from those involved in conducting, monitoring or performing quality control of the 
clinical trial. The clinical audit process uses a knowledge/risk based approach.
Audits are conducted to assess GCP compliance with global and local regulatory requirements, 
protocols and internal SOPs, and are performed according to written Novartis processes.
14
Protocol adherence
This protocol defines the study objectives, the study procedures and the data to be collected on 
study participants. Additional assessments required to ensure safety of patients should be 
administered as deemed necessary on a case by case basis. Under no circumstances including 
incidental collection is an investigator allowed to collect additional data or conduct any 
additional procedures for any purpose involving any investigational drugs under the protocol, 
other than the purpose of the study. If despite this interdiction prohibition, data, information, 
observation would be incidentally collected, the investigator shall immediately disclose it to 
Novartis and not use it for any purpose other than the study, except for the appropriate 
monitoring on study participants.
Investigators ascertain they will apply due diligence to avoid protocol deviations. If an 
investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by Novartis
and approved by the IRB/IEC and health authorities, where required, it cannot be implemented.


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14.1
Protocol Amendments
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis/, health authorities where required, and the IRB/IEC prior to 
implementation.
Only amendments that are required for patient safety may be implemented immediately 
provided the health authorities are subsequently notified by protocol amendment and the 
reviewing IRB/IEC is notified.
Notwithstanding the need for approval of formal protocol amendments, the investigator is 
expected to take any immediate action required for the safety of any patient included in this 
study, even if this action represents a deviation from the protocol. In such cases, Novartis should 
be notified of this action and the IRB/IEC at the study site should be informed according to 
local regulations.


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15
References (available upon request)
 
Arnold DM, Zeller MP, Smith JW, et al. (2013) In: Hematology: Basic Principles and Practice 
ebook. Hoffman R, Benz EJ, Silberstein CE, et al. Eds. 6th Edition. 2013. Sanders Elsevier. 
Philadelphia, PA.
Arruda VR, Annichino-Bizzacchi JM. (1996) High-dose dexamethasone therapy in chronic 
idiopathic thrombocytopenic purpura. Ann Hematol. 73:175-177.
Bao, W, Bussel, J, Heck, S, et al. (2010) Improved regulatory T-cell activity in patients with 
chronic immune thrombocytopenia treated with thrombopoietic agents. Blood; (116)22:4639-
4645.
Bussel JB, Mahmud SN, Brigstocke SL, Torenten SM. Tapering eltrombopag in patients with 
chronic ITP: how successful is this and in whom does it work? Blood 2015;126:Abstract 
1054.
Caulier MT et al. (1995) Pulsed high-dose dexamethasone in refractory chronic idiopathic 
thrombocytopenic purpura: a report on 10 cases. Br J Haematol. 91:477-479.
Cella D, Nowinski CJ. (2002) Measuring quality of life in chronic illness: the functional 
assessment of chronic illness therapy measurement system. Arch Phys Med Rehabil.
83(12Suppl):S10-S17.
Cella D, Beaumont JL, Webster KA, et al. (2006) Measuring the concerns of cancer patients 
with low platelet counts: the Functional Assessment of Cancer Therapy - thrombocytopenia 
(FACT-Th) questionnaire. Support Care Cancer. 14(12):1220-1231.
Červinek L, Mayer J, Doubek M. (2015) Sustained remission of chronic immune 
thrombocytopenia after discontinuation of treatment with thrombopoietin-receptor agonist in 
adults. Int J Hematol. 102:7-11.
Cheng G, Saleh N, Marcher C, et al. (2011) Eltrombopag management of chronic immune 
thrombocytopenia (RAISE): a 6-month, randomised, phase 3 study. Lancet. 377(9763):393-
402.
Cohen, Y, Djulbegovic, B, Shamai-Lubovitz, O, et al. (2000) The bleeding risk and natural 
history idiopathic thrombocytopenic purpura with persistent low platelet counts. Arch Intern 
Med. (160)11:1630-1638.
Cooper N. (2017) State of the art - how I manage thrombocytopenia. Br J Haematol. 
177(1):39-54.
Demiroğlu H, Dündar S. (1997) High-dose pulsed dexamethasone for immune 
thrombocytopenia. N Engl J Med. 337:425-427.
Dubbeld P, van der Huel C, Hillen HF. (1991) Effect of high-dose dexamethasone in 
prednisone-resistant autoimmune thrombocytopenic purpura (ITP). Neth J Med. 1991;39:6-10


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George JN. (2006) Management of patients with refractory immune thrombocytopenic 
purpura. J Thromb Haemost. 4:1664-1672.
George JN, Woolf SH, Raskob GE, et al. (1996) Idiopathic thrombocytopenic purpura: a 
practice guideline developed by explicit methods for the American Society of Hematology. 
Blood; 88(1):3-40.
Gonzalez-Lopez, T, Pascual C, Álvarez-Román M, et al. (2015) Successful discontinuation of 
eltrombopag after complete remission in patients with primary immune thrombocytopenia.
Am J Hematol; 90(3):E40-43.
González‑López T, Fernández-Fuertes F, Hernández-Rivas J, et al. (2017) Efficacy and safety 
of eltrombopag in persistent and newly diagnosed ITP in clinical practice. Int J Hematol; 
106:508–516
(2003) Guideline for the investigation and management of idiopathic thrombocytopenic 
purpura in adults, children and in pregnancy. Br J Haematol. 120(4):574-596.
Gutierrez-Espindola GR, et al. (2007) High doses of dexamethasone in adult patients with 
idiopathic thrombocytopenic purpura. Arch Med Res 34:31-34.
Gutierrez-Espindola GR, Morales-Polanco MR, Guerrero-Rivera S, et al. (2003) High doses 
of dexamethasone in adult patients with idiopathic thrombocytopenic purpura. Arch Med Res 
34:31-34.
Hoffman, R, Benz, E, Silberstein, L, et al. eds. (2013) Hematology: Basic Principles and 
Practice. 6th ed. Philadelphia, PA: Elsevier Saunders; Chapter 133.
Kaufman RM, Djulbegovic B, Gernsheimer T, et al. (2015) Platelet transfusion: a clinical 
practice guideline from the AABB. Ann Int Med.162(3):162-205.
 
Lambert M, Gernsheimer M. (2017) Clinical updates in adult immune thrombocytopenia.
Blood. 29:2829-2835
Liu, X, Liu S, Feng Q, et al. (2016) Thrombopoietin receptor agonists shift the balance of 
Fcgamma receptors towards inhibitory receptor IIb on monocytes in ITP. Blood. 6:852-861.
Liu X, Zhong H, Bao W, et al. (2012) Defective regulatory B-cell compartment in patients 
with immune thrombocytopenia. Blood. 120(16):3318-3325.
Mashhadi MA, Kaykhaei MA, Sepehri Z, et al. (2012) Single course of high dose 
dexamethasone is more effective than conventional prednisolone therapy in the treatment of 
primary newly diagnosed immune thrombocytopenia. Daru J Pharmaceut Sci. 20(1):7.
Mithoowani S, Gregory-Miller K, Goy J, et al. (2016) High-dose dexamethasone compared 
with prednisone for previously untreated primary immune thrombocytopenia: a systematic 
review and meta-analysis. Lancet Haematol. 3(10):e489-e496.


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Nakazaki K, Hosoi M, Hangaishi A, et al. (2012) Comparison between pulsed high-dose 
dexamethasone and daily corticosteroid therapy for adult primary immune thrombocytopenia: 
a retrospective study. Intern Med. 51(8):859-863.
Neunert C, Lim W, Crowther M, et al. (2011) The American Society of Hematology 2011 
evidence-based practice guideline for immune thrombocytopenia. Blood. 117:4190-4207.
Newland A, Godeau B, Priego V, et al. Remission and platelet responses with romiplostin in 
primary immune thrombocytopenia: final results from a phase 2 study. Br J Haematol. 
2016;172:262-273.
 
Perera M, Garrido T. (2017) advances in the pathophysiology of primary immune 
thrombocytopenia. Hematol. 22(1):41-53.
Portielje JE, Westendorp RG, Kluin-Nelemans HC, et al. (2001) Morbidity and mortality in 
adults with idiopathic thrombocytopenic purpura. Blood. 97:2549-2554.
Profit L. (2006) Eltrombopag: the emerging evidence of its therapeutic value in 
thrombocytopenia. Core Evid. 1:221-231.
Provan D, Stasi R, Newland AC, et al. (2010) International consensus report on the 
investigation and management of primary immune thrombocytopenia. Blood. 115:168-186.
Qu, M, Liu X, Feng Q, et al. (2017) Cytokine Changes in Response to TPO Receptor Agonist 
Treatment in Primary Immune Thrombocytopenia. Cytokine. 92:110-117.
Rodeghiero F, Stasi R, Gernsheimer T, et al (2009) Standardization of terminology, 
definitions and outcome criteria in immune thrombocytopenic purpura of adults and children; 
report from an international working group. Blood. 113:2386-2393
Sakamoto K, Nakasone H, Tsurmi S, et al. (2014) Prednisone versus high-dose 
dexamethasone for untreated primary immune thrombocytopenia. A retrospective study of the 
Japan Hematology Group & Oncology Clinical Study Group. J Thrombosis & Thrombolysis. 
37(3):279-286.
Signorovitch J, Brainsky A, Grotziner KM (2011) Validation of the FACIT-fatigue subscale, 
selected items from FACT-thrombocytopenia, and the SF-36v2 in patients with chronic 
immune thrombocytopenia. Qual Life Res. 20(10):1737-1744.
Stasi R, Brunetti M, Pagano A, et al. (2000) Pulsed intravenous high-dose dexamethasone in 
adults with chronic idiopathic thrombocytopenic purpura. Blood Cells Mol Dis. 26:582–586.
Stasi R, Provan D (2004) Management of immune thrombocytopenic purpura in adults. Mayo 
Clin Proc. 79(4):504-522.
Terrell DR, Beebe LA, Vesely SK, et al (2010) The incidence of immune thrombocytopenic 
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Wang, M, Qin, P Zhou, H, et al. (2017) Recombinant Human Thrombopoietin (rhTPo) and 
High-Dose Dexamethasone (HD-DXM) Versus High-Dose Dexamethasone Monotherapy as 
Frontline Treatment in Newly Diagnosed Adult Immune Thrombocytopenia (ITP): a 
Prospective, Multicentre, Randomised, Controlled Trial. ASH 59th Annual Meeting, Oral 
Poster.
Ware JE (2000) SF-36 health survey update. Spine. 25:24:3130-3139.
Warner M, Wasi P, Couban S, et al. (1997) Failure of pulse high-dose dexamethasone in 
chronic idiopathic immune thrombocytopenia. Am J Hematol. 54:267-270.
Webster K, Cella D, Yost K. (2003) The Functional Assessment of Chronic Illness Therapy 
(FACIT) Measurement System: properties, applications, and interpretation. Health Qual Life 
Outcomes. 1:79.
Wei Y, Ji XB, Wang YW, et al. (2016) High dose dexamethasone versus prednisone for 
treatment of adult immune thrombocytopenia: a prospective multicenter randomized trial. 
Blood. 127(3):296-302.
Wong RSM, Saleh MN, Khelif A, et al. (2017) Safety and efficacy of long-term treatment of 
chronic/persistent ITP with eltrombopag: final results of the EXTEND Study. Blood. Epub. 
DOI10.1182/blood-2017-04-748707.


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16
Appendices
16.1
Appendix 1: Examples of OATP and BCRP substrates
Table 16-1
OATP and BCRP Substrates
OATP
Substrates
aliskiren, ambrisentan, anacetrapib, atenolol, atrasentan, atorvastatin, bosentan,
bromociptine, caspofungin, cerivastatin, celiprolol, danoprevir, empangliflozin,
ezetimibe, fimasartan, fexofenadine, fluvastatin, glyburide, maraviroc, SN-38,
rosuvastatin, simvastatin acid, pitavastatin, pravastatin, repaglinide, rifampin,
valsartan, olmesartan, telmisartan, montelukast, ticlopidine.
BCRP
Substrates
atorvastatin daunorubicin, doxorubicin, hematoporphyrin, imatinib, methotrexate,
mitoxantrone, pitavastatin, rosuvastatin, SN-38 (irinotecan), ethinyl estradiol,
simvastatin, sulfasalazine, sofosbuvir, topotecan, sulfasalazine
OATP1B1 and OATP1B3 substrates and inhibitors are combined into one list due to the
following reasons, (1) over-lapping substrate and inhibitor specificity and (2) lack of clinical
evidence implicating the sole involvement of either OATP in the observed PK interaction.


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16.2
Appendix 2: Bleeding Scales
Table 16-2
Modified WHO Bleeding Scale
WHO Bleeding 
Grade
Examples
1
Oropharyngeal bleeding ≤30 minutes in 24 hours
Epistaxis ≤30 minutes in previous 24 hours
Petechiae of oral mucosa or skin
Purpura ≤1 inch in diameter
Spontaneous hematoma in soft tissue or muscle
Positive stool occult blood loss
Microscopic hematuria or hemoglobinuria
Abnormal vaginal bleeding (spotting)
2
Epistaxis ≥30 minutes in 24 hours
Purpura >1 inch in diameter
Joint bleeding
Melanotic stool
Hematemesis
Gross/visible hematuria
Abnormal vaginal bleeding (more than spotting)
Hemoptysis
Visible blood in body cavity fluid
Retinal bleeding without visual impairment
Bleeding at invasive sites
3
Bleeding requiring red blood cell transfusion over routine transfusion needs
Bleeding associated with moderate hemodynamic instability
4
Bleeding associated with severe hemodynamic instability
Fatal bleeding
CNS bleeding on imaging study with or without dysfunction
CNS=central nervous system; WHO=World Health Organization
Source: Kaufman 2015


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Table 16-3
ITP Bleeding Scale
Site
Bleeding Grade
0
1
2
Skin (physical 
examination (PE)
None
1-5 bruises and/or scattered 
petechiae
>5 bruises with size >2 cm 
and/or diffuse petechiae
Oral (PE)
None
1 blood blister or >5 
petechiae or gum blood that 
cleans easily with rinsing
Multiple blood blisters and/or 
gum bleeding
Skin (history)
None
1-5 bruises and/or scattered 
petechiae
>5 bruises with size >2 cm 
and/or diffuse petechiae
Oral (history)
None
1 blood blister or >5 
petechiae and/or gum 
bleeding <5 minutes
Multiple blood blisters and/or
gum bleeding > 5 minutes
Epistaxis
None
Blood when blowing nose 
and/or epistaxis < 5 min (per 
episode)
Bleeding > 5 min (per episode)
Gastrointestinal (GI)
None
Occult blood
Gross blood
Urinary (U)
None
Microscopic (+ve dipstick)
Macroscopic
Gynecological (GYN)
None 
(normal 
Period)
Spotting not at the time of 
normal period
Bleeding >spotting not at the 
time period or very heavy 
period
Pulmonary
None
N/A
Yes
Intercranial 
hemorrhage
None
N/A
Yes
Subconjunctival 
hemorrhage
None
Yes
N/A
GI=gastrointestinal; GYN=gynecologic; PE=physical exam; U=urinary
Source: Page 2007


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16.3
Appendix 3: HRQoL Questionnaires
Table 16-4
FACIT-Fatigue Scale Version 4


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Table 16-5
SF-36V2


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Table 16-6
FACT-Th6 (Version 4)


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Table 16-7
FACT-G (Version 4)
Please circle or mark one number per line to indicate your response as it applies to the past 7 days.


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Table 16-8
Treatment Satisfaction Questionnaire (TSQM)


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SAP_001.pdf: 
Clinical Development
ETB115/eltrombopag/Promacta®/Revolade®
ETB115J2411 / NCT03524612
A phase II, open-label, prospective, single-arm, study to     
assess ability of eltrombopag to induce sustained 
remission in subjects with ITP who are refractory or    
relapsed after first-line steroids (TAPER)
Statistical Analysis Plan (SAP) – Addendum 2
Document type:
SAP Documentation
Document status:
Final v1.0
Release date:
07-Sep -2022
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


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CETB115J2411
Document History – Changes compared to previous final version of SAP
Date
Time point
Reason for 
update
Outcome for update
Section
impacted 
(Current)
15-Oct-
2018
Prior to FPFV
N/A-Initial version
N/A
N/A
14-Jan-2018
After FPFV
Incorporate changes 
from protocol 
amendment 1 dated 
6-Mar-2019
Included a follow-up period of 12 
Months after sustained remission, 
until Month 24
Moved reporting events to new 
section
Updated study objectives and 
endpoints
Updated general statistical 
methods applied
Included new definitions for 
duration of exposure, end of 
treatment, end of study, months 
and years, time windows for visits 
and multiple assessments
Patient disposition analysis 
updated
Protocol deviations section added
Listings details for efficacy 
response added
1 and 2
1
1.2
2.1
2.1.1
2.3.1
2.4.3
2.5.2
Updated to use SAF population in 
safety analyses
2.7
Included new analyses for new 
secondary endpoints
CTCAE grades for AEs derivation 
from severity grades as reported in 
CRF
Ocular findings section added
2.7.1
2.8.1
2.8.4.4
30-Nov-
2021
Prior to DBL for 
Primary CSR at 
Month 12
The taper down of 
rescue therapy is 
permitted after day 
Changes to protocol specified 
analyses updated
4


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CETB115J2411
Date
Time point
Reason for 
update
Outcome for update
Section
impacted 
(Current)
14 per clinical 
practice
Bleeding events 
permitted during first 
7 days after 
eltrombopag start as 
per clinical practice
Missing cut-off date 
for Primary Analysis
Missing reported
months
Updated cut-off date for Primary 
CSR
Updated months reported with 
corresponding visits
2.1
2.1
26-Apr-
2022
After iDBL for 
Primary CSR at 
Month 12
Incorporate changes 
from protocol 
amendment 1 dated
06-Mar-2019
Change End of Study (EOS) to 
End of Treatment (EOT). EOS 
removed from the SAP
Throughout
SAP
Terminology 
updating
Change “sustained remission” to
“sustained response off treatment”
Throughout
SAP
Further clarifications 
added
Study design figure updated
1.1
Starting dose for Asian patients 
and Japanese patients in Japan
described
Study objectives and endpoints
updated
1.2
Formula for the duration of 
exposure was clarified
2.1.1
Definition of planned dose
provided
Descriptions of observation 
periods clarified
Sections 2.4.2 Rescue therapy
created
2.4.2
More details for the primary 
endpoint calculation provided
2.5.1
More details for the primary 
endpoint calculation provided
2.5.2
More details of the analysis
provided
2.5.3
The description of deaths reporting 
clarified
2.8.2


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SAP Addendum 2
CETB115J2411
Date
Time point
Reason for 
update
Outcome for update
Section
impacted 
(Current)
Section 2.8.4.4 Bleeding adverse 
events created
2.8.4.4
07-Sep-
2022
Prior to final 
DBL for final 
CSR
Further clarification 
added
Time points updated
1
The names of GPS  folder added
1
Data analysis information updated
2.1
General definitions updated
2.1.1
Analysis updated
Provided details about the sub-
group analysis
2.2.1
Further clarification 
added
Provided details about the data 
presenting
2.5.2
Provided details for Step 3 
achieving
2.5.2
Further clarification 
added
No imputation will be used fro
missing platelet values (deleted 
original sentence to avoid 
confusion)
2.5.3
Analysis updated
Updated the description of the 
analysis
2.7.2
 
 
Title updated
2.8.4.4
 
Missing references
References are provided
6
FPFV: First patient first visit
TEMPLATE VERSION AND DATE: Final 2.0 25-Apr-2016, Effective 03-May-2016


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CETB115J2411
Table of contents
Table of contents .................................................................................................................5
List of abbreviations............................................................................................................7
1
Introduction .........................................................................................................................9
1.1
Study design.............................................................................................................9
1.2
Study objectives and endpoints .............................................................................12
2
Statistical methods.............................................................................................................13
2.1
Data analysis general information .........................................................................13
2.1.1
General definitions................................................................................14
2.2
Analysis sets ..........................................................................................................17
2.2.1
Subgroup of interest ..............................................................................18
2.3
Patient disposition, demographics and other baseline characteristics ...................18
2.3.1
Patient disposition.................................................................................18
2.3.2
Patient demographics and other baseline characteristics ......................18
2.4
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance)............................................................................................................19
2.4.1
Study treatment / compliance................................................................19
2.4.2
Rescue therapy ......................................................................................19
2.4.3
Prior, concomitant and post therapies...................................................20
2.4.4
Protocol deviations................................................................................20
2.5
Analysis of the primary objective..........................................................................21
2.5.1
Primary endpoint...................................................................................21
2.5.2
Statistical hypothesis, model, and method of analysis..........................21
2.5.3
Handling of missing values/censoring/discontinuations.......................22
2.5.4
Supportive analyses...............................................................................22
2.6
Analysis of the key secondary objective ...............................................................22
2.7
Analysis of secondary efficacy objective(s)..........................................................22
2.7.1
Secondary endpoints .............................................................................22
2.7.2
Efficacy endpoint(s)..............................................................................22
2.7.3
Statistical hypothesis, model, and method of analysis..........................24
2.7.4
Handling of missing values/censoring/discontinuations.......................24
2.8
Safety analyses.......................................................................................................25
2.8.1
Adverse events (AEs)............................................................................25
2.8.2
Deaths....................................................................................................27
2.8.3
Laboratory data .....................................................................................27
2.8.4
Other safety data ...................................................................................29
31


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CETB115J2411
2.10
Patient-reported outcomes .....................................................................................32
34
36
2.13
Interim analysis......................................................................................................36
3
Sample size calculation .....................................................................................................36
3.1.1
Primary endpoint...................................................................................36
3.1.2
Responders cut-off update due to final sample size..............................37
4
Changes to protocol specified analyses.............................................................................37
5
Appendix ...........................................................................................................................39
5.1
Imputation rules.....................................................................................................39
5.2
Derivation of Health Outcomes Scores .................................................................40
6
References .........................................................................................................................44


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CETB115J2411
List of abbreviations
AE
Adverse event
AESI
Adverse events of special interest
ALP
Alkaline Phosphatase
ALT
Alanine Aminotransferase
AST
Aspartate Aminotransferase
ATC
Anatomical Therapeutic Chemical 
CI
Confidence Interval
CR
Complete Response
CRF
Case Report Form
CRO
Contact Research Organization
CSR
Clinical Study report
CTC
Common Toxicity Criteria
CTCAE
Common Terminology Criteria for Adverse Events
CV
Coefficient of Variation
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
eCRS
Electronic Case Retrieval Sheet
EOS
End of Study
EOT
End of Treatment
FAS
Full Analysis Set
FACIT
Functional Assessment of Chronic Illness Therapy
FACT
Functional Assessment of Cancer Therapy
FACT-Th6
Functional Assessment of Cancer Therapy – Thrombocytopenia 6-item version
GPS
Global Programming and Statistical environment
HRQoL
Health-Related Quality of Life
ITP
Immune Thrombocytopenia
IVIG
Intravenous Immunoglobulin
LLOQ
Lower Limit of Quantification
LPLV
Last Patient Last Visit
MCS
Mental Component Summary
MedDRA
Medical Dictionary for Drug Regulatory Affairs
PCS
Physical Component Score
PGIC
Patient Global Impression of Change
PGIS
Patient Global Impression-Severity


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PRO
Patient-reported Outcomes
PT
Preferred Term
QD
Qua’que di’e / once a day
SAP
Statistical Analysis Plan
SD
Standard Deviation
SE
Standard Error
SF-36
Short Form 36
SOC
System Organ Class
SRoT
Sustained response off treatment
TBIL
Total Bilrubin
TEAE
Treatment-emergent Adverse Events
TPO-RA
Thrombopoietin Receptor Agonists
TSQM
Treatment Satisfaction Questionnaire for Medication
ULN
Upper Limit of Normal
WBC
White Blood Cells


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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 the preparation of the ETB115J2411 (TAPER) clinical study 
reports (CSRs) and is based on the study protocol amendment 1, dated 06-Mar-2019. All
patients (105) have been enrolled in the trial at the time of Addendum 1 and the primary CSR 
was final at the time of this Addendum 2.
During the course of this study, there are two planned reporting events:

Primary analysis was done after all patients were enrolled and either discontinued early 
from the study or completed 12 months on study. The primary Clinical Study Report 
(CSR) was written at this time point. The data cutoff for primary analysis was 22-Oct-
2021 and the interim database lock (iDBL) was on 29-Apr-2022.

Second analysis will be done after all patients in the follow-up period have completed
month 24. The final CSR will be written at this time point.
The shells for the in-text tables and figures as well as the post-text tables, figures and 
listings (TFLs) are in the TFL shells document. Programming specifications for datasets, 
including derivation of variables, are given in the programming data specifications (PDS) 
document.
All data will be analyzed by Novartis in Novartis global programming & statistical (GPS) 
environment, or by a designated CRO. Analysis data sets and statistical outputs will be produced 
using the SAS system Version 9.3 or higher.  Primary CSR datasets and outputs are in GPS 
folder CSR1 and the final CSR datasets and outputs will be in GPS folder CSR2.
1.1
Study design
This is a phase II, open-label, prospective, single-arm, study to assess ability of eltrombopag to 
induce sustained response off treatment (SRoT) in adult patients with ITP who are refractory or 
relapsed after first line steroids. It is noted that “sustained remission” is used in the protocol, all 
other documents use SRoT due to a change in terminology in the treatment landscape for ITP. 
The study design is provided in Figure 1-1.


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Figure 1-1
CETB115J2411 study design as shown in Protocol Amendment 1
Patients with confirmed diagnosis of ITP, who have failed to respond or who have relapsed 
following initial response after a first-line of steroid therapy with or without intravenous 
immunoglobulin (IVIG) (if used as a rescue therapy) will be screened, and if eligible, will 
receive eltrombopag. First line of steroid therapy will be defined as: prednisone/prednisolone 
0.5 to 1mg/kg/day for a minimum of 2 weeks, or minimum of 1 course of high-dose 
dexamethasone 20 to 40 mg/day for consecutive 4 days ±IVIG (used as rescue therapy). 
Maximum exposure to high-dose steroids treatment (steroids tapering time excluded) should be 
limited to: 4 weeks of high dose prednisone/prednisolone or 3 courses of high-dose 
dexamethasone. Overall exposure to steroids must not be longer than 3 months, including period 
of dose tapering.
Treatment in all patients will be initiated at a dose of 50 mg eltrombopag every day (QD), 
allowing dose escalation up to 75 mg eltrombopag QD, as per Section 6.1.1 of the study 
protocol.
Dosing guidelines for patients of Asian ethnicity are provided in Section 6.1 of the study 
protocol.
Dosing guidelines for Japanese patients in Japan are provided in Section 6.1 of the country 
study protocol.
Taper-off and treatment discontinuation: Patients who reach CR (platelet count ≥100×109/L) 
and maintain counts around 100×109/L for 2 months (no platelet count below 70×109/L) will 
be eligible for taper-off and treatment discontinuation. Duration of tapering will vary depending 
on the starting dose and the response of the patient: decreases in eltrombopag dose will be 
performed by a 25 mg reduction every 2 weeks up to 25 mg on alternate days for 2 weeks until 
treatment discontinuation.
Patients who successfully taper off, i.e. discontinue eltrombopag and maintain platelet count 
≥30×109/L in the absence of bleeding or use of any rescue therapy will be followed up through 
the duration of the trial (to month 24). In case of relapse, patients will be offered a new course 


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of eltrombopag treatment within this timeframe, starting at a dose of 50 mg (25 mg for S/SE 
Asian patients and 12.5 mg for Japanese patients in Japan).
Relapse is defined as platelet count <30×109/L and/or bleeding event and/or use of any rescue 
therapy. 
Patients with bleeding, or perceived risk of serious bleeding, will be allowed to receive rescue 
therapy as per physician decision, irrespective of platelet counts.
A schematic depicting an example of a patient with sustained response off treatment is provided 
in Figure 1-2. Individual patient study experience will vary dependent on time to response and 
duration of eltrombopag tapering.
The enrollment target is 101 patients. As this is an open-label study, there will be no 
randomization.
Figure 1-2
Example of a patient with sustained response off treatment by Month 12


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1.2
Study objectives and endpoints
Table 1-1
Objectives and endpoints
Objective(s)
Endpoint(s)
Primary Objective(s)
Endpoints for primary objective(s)
1. To assess ability of eltrombopag to induce 
sustained response off treatment by month 12 in ITP 
patients who relapsed or failed to respond to first-line 
steroid treatment.
1. Proportion of patients with sustained response off 
treatment by month 12 where sustained response off 
treatment is defined as:
●
reach platelet count ≥100×109/L (complete 
response [CR]) and then maintain platelet counts 
around 100×109/L for 2 months (no counts below 
70×109/L) AND then
●
taper off the drug until treatment 
discontinuation (see Section 9.1 of the study 
protocol) while,
●
maintain platelet count ≥30×109/L in the 
absence of bleeding (no bleeding AEs) or use of 
any rescue therapy (see Section 6.2.3 of the study 
protocol) until month 12.
Secondary Objective(s)
Endpoints for secondary objective(s)
1. To assess the duration of sustained response off 
treatment after treatment discontinuation by month 12 
and month 24
1a. Median duration of sustained response off 
treatment (weeks) counted from last dose of 
eltrombopag to month 12 for patients with sustained 
response off treatment
1b. Estimated median duration of sustained response 
off treatment (weeks) by month 24 for patients who 
are in sustained response off treatment at month 12 
and enter 12 months
follow-up period using Kaplan-Meier method
1c. Estimated median duration of sustained response 
off treatment (weeks) by month 24 for all patients 
using Kaplan-Meier method.
2.  To assess the proportion of patients maintaining a 
sustained response off treatment after treatment 
discontinuation until month 24.
2. Proportion of sustained response off treatment 
patients at months 15, 18, 21, and 24.
3. To assess the ability of eltrombopag to induce 
early response by month 1
3. Number (%) of patients with platelet count 
≥50×109/L at least once by month 1 (first month) 
without bleeding and no rescue therapy
4. To assess the ability of eltrombopag to induce a 
recovery response, in case of loss of response after 
tapering off eltrombopag until month 24.
4. Number (%) of patients with at least one platelet 
count ≥30×109/L after eltrombopag is re-introduced, in 
case of loss of response (<30×109/L and/or bleeding 
event) without bleeding and no rescue therapy by 
month 12 and 24
5. To assess the platelet count from baseline and 
every 3 months until month 24
5. Absolute and relative change in platelet count 
from baseline to 3, 6, 9,12,15, 18, 21, and 24 months
and EOT
6. To assess the ability of eltrombopag to maintain 
platelet count ≥30×109/L within 12 months and every 
3 months until month 24.
6. Number (%) of patients who maintain a platelet 
count ≥30×109/L from the first time of reaching that 
level to month 3, 6, 9, 12, 15, 18, 21, 24 and EOT
without bleeding and no rescue therapy
7. To evaluate patient-Health Related outcome 
measures for health-related quality of life (fatigue 
level of the patients through FACIT) & FACT-Th6 and 
SF-36v2 questionnaires from baseline and every 3 
months to month 24 and EOT
7. The analysis of HRQoL parameters; fatigue level 
of the patients through FACIT & FACT-Th6, SF-36v2 
questionnaires. Change in scores from baseline to 
month 3, 6, 9, 12, 15, 18, 21, 24 and EOT
8. To explore the overall impact of side effects on 
treatment via the GP5 at baseline, month 12 and EOT
8. Overall change from baseline to month 12 and 
EOT will be assessed


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Objective(s)
Endpoint(s)
9. To explore treatment satisfaction with TSQM-9 at 
baseline, month 12 and EOT
9. Overall change from baseline to month 12 and 
EOT will be assessed
10. To evaluate the safety and tolerability of 
eltrombopag
10. Number (%) and severity of patients with AEs, 
serious AEs (SAEs), AEs leading to discontinuation, 
AEs leading to dose adjustments, AEs of special 
interest. Change from baseline in vital signs and 
clinical laboratory tests
EOT=end of treatment; FACIT=Functional Assessment of Chronic Illness Therapy; FACT=Functional 
Assessment of Cancer Therapy; FACT-Th6=Functional Assessment of Cancer Therapy – Thrombocytopenia 
6-item version; GP5-bothered by symptoms component of the FACT-G assessment; HRQoL=Health Related 
Quality of Life;
 SF-36=Short Form-36;
 TSQM-
9=Treatment Satisfaction Questionnaire for Medication;
2
Statistical methods
2.1
Data analysis general information
All analyses will be performed by Novartis or a designated CRO. Any data analysis carried out 
independently by the investigator should be submitted to Novartis before publication or 
presentation.
For the Primary CSR at Month 12 analyses, all data until the cut-off date were included. The 
cut-off day was defined as the Week 53 Day 1 visit date of the last patient (22-Oct-2021).
For the Final CSR at Month 24 analyses, the cut-off date is last patient last visit (LPLV). All 
data in the clinical database will be used for the analyses.
Data listings will include all data collected up to the cut-off date for the 12-month analysis, or 
all data recorded in the database for the 24-month analysis.
Continuous variables will be summarized by number of patients, mean, standard deviation, 
minimum, median, and maximum. For selected parameters, 25th and 75th percentiles will also 
be presented.
Categorical variables will be summarized by frequencies and percentages.


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The 95% confidence interval (CI) using the Clopper-Pearson method will be provided for
selected parameters. Kaplan-Meier method will be used for time to event analyses.
2.1.1
General definitions
Investigational drug and study treatment
Investigational drug, study drug and study treatment refer to eltrombopag.
Date of first/last administration of study drug
The date of first administration of study treatment is derived as the first date when a non-zero 
dose of study treatment was administered as per the Dosage Administration CRF. For the sake 
of simplicity, the date of first administration of study treatment will also be referred as start of 
study treatment.
The date of last administration of study treatment is defined as the last date when a non-zero 
dose of study treatment was administered as per Dose Administration (e)CRF. The date of last 
administration of study treatment is the same as the date of last administration of investigational 
drug or control drug.
 
 
Duration of exposure
The duration of exposure for the study drug will be calculated as:

Duration of study drug exposure (months) = (date of last non-zero dose of study drug) –
(first date of study drug) + 1. 
For the primary CSR, if the end date was missing for an ongoing patient the cutoff date will be 
used. The durations will include periods of temporary interruption (planned or actual) for any 
reason. There will be no ongoing patients for final CSR. Additionally, the duration of exposure 
for study drug will be computed excluding days of zero dose. The duration of exposure for days 
without zero dose will be calculated as the sum of all periods with non-zero doses. For each 
period i without zero dose, exposure will be computed as:

Duration of exposure for period i (months) = (last date of study drug for period i) - (last date 
of study drug for period i) + 1.
Dose interruption
An interruption is defined as an actual zero dose on one or more days when the dose is scheduled 
between two non-zero dosing records.
Note: The last zero dose of a study drug (followed by permanent discontinuation) is not 
considered as a dose interruption. For the purpose of summarizing interruptions and reasons, in 
case multiple entries for interruption are entered on consecutive days with different reasons 
these will be counted as separate interruptions. However, if the reason is the same in these 
multiple entries on consecutive days, then it will be counted as one interruption.


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Dose reduction
A dose reduction is where the prescribed dose is lower than the previous prescribed dose or 
where the actual dose administered/total daily dose is lower than the prescribed dose. Any dose 
change to correct a dosing error will not be considered a dose reduction, e.g. if due to a dosing 
error, a patient receives higher than protocol planned starting dose and moves down to the 
planned starting dose then this is not counted as a reduction, however if they move directly from 
a higher than planned starting dose down to a lower than protocol planned starting dose, then 
this is counted as a reduction.
Note: It is assumed that if there is a dose reduction, then the ‘Dose changed’ box was ticked on 
the dose administration eCRF page.
Cumulative dose
Cumulative dose of a study treatment is defined as the total dose given during the study 
treatment exposure and will be summarized.
The planned cumulative dose for a study treatment refers to the total planned dose as per the 
protocol up to the last date of study drug administration. The planned cumulative dose is not 
summarized/listed. It is used for relative dose intensity calculations. The actual cumulative 
dose refers to the total actual dose administered, over the duration for which the patient is on 
the study treatment as documented in the dose administration eCRF. For the patients with 
sustained response off treatment, the duration will be the time from the start of the treatment to 
the date of last non-zero dose. 
For continuous dosing, the actual cumulative dose is the sum of the non-zero doses recorded 
over the dosing period and the planned cumulative dose is the planned starting dose summed 
over the same dosing period.
For patients who did not take any drug, the actual cumulative dose is by definition equal to zero.
Dose intensity and relative dose intensity
Dose intensity (DI) for patients with non-zero duration of exposure is defined as follows:
DI (dosing unit / unit of time) = Actual cumulative dose (dosing unit) / Duration of exposure 
(unit of time).
e.g. DI (mg/day) = (50 mg/day * 219 days) / 365 days = 30 mg/day  
For patients who did not take any drug the DI is by definition equal to zero.
Planned dose intensity (PDI) is the assigned dose by unit of time planned to be given to 
patients as per protocol in the same dose unit and unit of time as that of the DI, i.e.
PDI (dosing unit / unit of time) = Planned cumulative dose (dosing unit) / Duration of exposure 
(unit of time).
Note that eltrombopag is administered with a tapering regime. Therefore, for some patients, the 
duration of exposure will not include the time after tapering when they are not getting any dose.
The planned dose is the starting dose of treatment which was defined for the patient by protocol.
Relative dose intensity (RDI) is defined as follows:


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RDI = DI (dosing unit / unit of time) / PDI (dosing unit / unit of time).
e.g. RDI = DI (92.7 mg/day) / PDI (100 mg/day) = 0.927
Study day
The study day for efficacy (platelet counts) and safety assessments (e.g. adverse event onset, 
laboratory abnormality occurrence, vital sign measurement, dose interruption etc.) will be 
calculated as the difference between the date of the event (onset date of an event, assessment 
date etc.) and the start of study treatment plus 1. The first day of study treatment is therefore 
study day 1. Example: if start of study treatment is on 05-Jan-2014 and start date of an adverse 
event is on 09-Jan-2014 then the study day of the adverse event onset is 5. For safety 
assessments before start of study treatment, the study day is negative and derived by (date of 
event – start date of study treatment). For example: if start of study treatment is on 05-Jan-2014 
and date of lab measurement is on 02-Jan-2014 then the study day of the laboratory abnormality 
is -3. Note, the day of start of study treatment is day 1, and the day before the date of first study 
treatment is day – 1, not day 0. 
Baseline
The baseline is the result of an investigation describing the “true” state of the patient before 
start of eltrombopag.
The last available assessment on or before the date of start of eltrombopag is taken as “baseline” 
assessment. In case, assessment is captured pre-dose on first day of eltrombopag (e.g. PROs), 
this assessment is used for baseline.
On-treatment assessments and observation periods
The overall observation period will be divided into three mutually exclusive segments: 
1. pre-treatment period: from day of patient’s informed consent to the day before first dose 
of eltrombopag
2. on-treatment period: from date of first dose of eltrombopag to 30 days after the date of 
the last non-zero dose of eltrombopag (including start and stop date) for patients who 
completed or discontinued the study early. For ongoing patients, the on-treatment period 
will be until the cut-off date, as a patient can restart treatment at any time during study. 
3. post-treatment period: starting at day 30+1 after last non-zero dose of eltrombopag for 
patients who completed or discontinued the study early. For ongoing patients, there is 
no post-treatment period.
Safety summaries (tables, figures) include all data considering the on-treatment period 
definition with the exception of baseline data which will also be summarized where appropriate 
(e.g. change from baseline summaries). In addition, a separate summary for death including on 
treatment and post treatment deaths will be provided. In particular, summary tables for adverse 
events (AEs) will summarize only on-treatment events, with a start date during the on-treatment 
period (treatment-emergent AEs).  
However, all safety data (including those from the pre and post-treatment period) will be listed 
and those collected during the post-treatment period will be flagged.


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Additionally, a subgroup analyses on key safety outputs will be provided considering the first 
12 months on study. Hence the 12 month on-treatment period is defined as the last non-zero 
dose + 30 days within the first 12 months on study.
End of Treatment and End of Study
For End of treatment (EOT) derivation, see Section 2.7.3.
Definition of Months and Years
A month will be calculated as (365.25 / 12) = 30.4375 days. If duration is to be reported in 
months, duration in days will be divided by 30.4375. If duration is to be reported in years, 
duration in days will be divided by 365.25.
For reporting purposes, Month 3 is corresponding to scheduled visit at Week 13 Day1, Month 
6 to Week 27 Day 1 visit, Month 9 to Week 39 Day 1, Month 12 to Week 53 Day 1 visit. 
Time windows
Time windows for assessments are based on protocol specified windows.
There is a ± 1 day visit window permitted on assessments to take into account scheduling over 
public holidays, from Week 1 Day 1 to Week 9 Day 1. Also a visit window of ± 3 days is 
allowed from Week 11 Day 1 to end of treatment. 
 
 
A visit window of ±7 days is allowed during the follow-up period for patients with sustained 
response off treatment. 
Time windows for multiple assessments
In order to summarize data of assessments collected over time (including any unscheduled 
visits), the assessments will be time slotted. If more than one assessment is done within the 
same time window, the assessment performed closest to the target date will be used. If 2 
assessments within a time window are equidistant from the target date, then the earlier of the 2 
assessments will be used. If multiple assessments on the same date then the worst case will be 
used. The end of treatment assessment will be included if collected within 30 days of the last 
treatment date. Data from all assessments (scheduled and unscheduled), including multiple
assessments, will be listed.
2.2
Analysis sets
The Full Analysis Set (FAS) includes all patients who received at least one dose of 
eltrombopag.
The Safety Set includes all patients who received at least one dose of eltrombopag.
 


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2.2.1
Subgroup of interest
 
For the final CSR, , selected outputs will be presented by SRoT status, e.g. data will be 
displayed by “SRoT until M12”, “non-SRoT untilM12” and “All patients”. “SRoT untilM12” 
patients are patients who met the primary endpoint definition (all four steps until Month 12).
Additionally, the primary efficacy outputs will be presented by the time since ITP diagnosis.
2.3
Patient disposition, demographics and other baseline 
characteristics
The Full Analysis Set (FAS) will be used for all baseline and demographic summaries and 
listings unless otherwise specified.
2.3.1
Patient disposition
Disposition data will be summarized descriptively and listed. Summaries will include all 
reasons for treatment or study discontinuation as reported on the disposition eCRF pages. 
Number (%) of patients who permanently discontinued study treatment with reason, as reported 
in the dose administration record eCRF pages will also be provided.
Informed consent and inclusion/exclusion criteria data will also be listed.
Data will be listed for screening failures.
2.3.2
Patient demographics and other baseline characteristics
Country specific regulations should be considered for the collection of demographic and 
baseline characteristics in alignment with CRF
The following patient demographics and baseline characteristics will be collected on the eCRF:

Demography including age, sex, predominant race and ethnicity (where permitted)

Height and weight

Medical history (e.g., important medical, surgical, and allergic conditions from the 
patient’s medical history which could have an impact on the patient’s evaluation)/ 
current medical conditions (e.g., all relevant current medical conditions which are 
present at the time of signing informed consent). Ongoing medical conditions, 
symptoms and diseases which are recorded on the Medical History eCRF should include 
the toxicity grade when applicable

Prior and concomitant medications
Bone marrow biopsy is optional and recommended for patients who did not respond to steroids 
and are considered refractory. It can be performed during treatment at the discretion of the 
investigator.


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All assessments to be completed and documented during screening are detailed in Table 8-1 of 
the study protocol.
Demographic and other baseline data including disease characteristics will be listed and 
summarized descriptively based on the FAS. Age will be summarized descriptively and will 
also be categorized in the following intervals: 18-<45 years, 45-<65 years, 65-<75 years, 75-
<85, >=85 years.
Time since initial diagnosis (days) = First dose date-date of initial diagnosis, will be 
summarized descriptively based on the FAS.
Relevant medical histories and current medical conditions at baseline will be summarized by 
system organ class and preferred term.
2.4
Treatments (study treatment, rescue medication, 
concomitant therapies, compliance)
2.4.1
Study treatment / compliance
The number of patients with dose adjustments (reductions, interruption, or permanent 
discontinuation) and the reasons will be summarized and all dosing data will be listed.
The duration of exposure in months to eltrombopag will be summarized descriptively and will 
also be categorized in the following intervals: <3 months, 3-<6 months, 6-<9 months, 9-<12
and >=12 months, and less than 1 Month, at least 1 month, at least 2 months, and so on. The 
duration of exposure excluding days of zero dose will be summarized with the same 
categorization. The dose intensity and the relative dose intensity will be summarized by means 
of descriptive statistics. Mean, SD, median, maximum, minimum, 25th percentile and 75th
percentile will be provided. Relative dose intensity will also be categorized in the following 
intervals: <75%, 75-<=90%, 90-<=110%, >110%.
2.4.2
Rescue therapy
Any ITP-directed medication or therapy, other than eltrombopag, given during the trial with the 
aim to increase platelet count for the patients who have clinically significant bleeding will be 
considered a rescue therapy and must be recorded on the appropriate CRF page (Form: 
Concomitant Medication, the category value at the form: Rescue medication). A patient who 
receives rescue medication or therapy between Step 2 and Step 3 will not eligible for Step 3. A 
patient who receives rescue medication or therapy between Step 3 and Step 4 will not be eligible 
for Step 4. A patient who receives rescue medication or therapy will not be considered in having 
achieved sustained response off treatment for the primary endpoint, unless the patient uses 
steroids ± IVIG as described below in the first 14 days of start of eltrombopag.
Steroids ± IVIG use as rescue medication:
In case of clinical need such as very low platelet count (<10×109/L) and/or significant bleeding, 
treatment with steroids ± IVIG and platelet transfusion is permitted together with eltrombopag 
for the first 14 days, calculated from the first dose day of eltrombopag. Any rescue therapy
started before Day 14 may be used after Day 14 if the dose is considered low dose as per 
protocol definition and is being tapered down (i.e., successively lower doses after day 14).


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Rescue medication will be taken from the SDTM cm.sas7bdat dataset where cmcat=’RESCUE 
MED’ for rescue therapy and exported as an EXCEL file. The clinical team will review the 
records captured in an Excel spreadsheet. Medications which were not considered as rescue 
therapy were flagged as ‘Y’ for the column ‘NOT_RESCUE’. Per protocol, medications prior 
to Day 14 are not considered as rescue medication in the efficacy derivations and will be 
programmatically excluded. Medications that started prior to Day 14 and were still being 
tapered after Day 14 will also be programmatically excluded from efficacy derivations. 
Once the database has locked the data will be rechecked again for any changes or new data that 
needs flagging.
The spreadsheet will contain patient level data with patient number (USUBJID), sequence 
number (CMSEQ), reported
drug name (CMTRT),
standardized medication name 
(CMDECOD), category for medication (CMCAT),
indication (CMINDC), dose per 
administration (CMDOSE), dose units (CMDOSU), dosing frequency per interval
(CMDOSFRQ), start date/time of medication (CMSTDTC), end date/time of medication
(CMENDTC), indication 1(CMINDC1), indication 2 (CMINDC2), reported name of drug trade 
name (CMTRDNAM), not rescue medication flag (NOT_RESCUE).
The spreadsheet will be imported into the programming environment (GPS) and merged with 
the patient data for the analysis. The EXCEL document will be stored in CREDI in the study 
folder ETB115J2411/Administrative Files (study level)/RAP or RAMP Meeting and in GPS in 
the study folder: CETB115J2411\csr_1\util.
Platelet transfusions will be taken from the ADCM and ADPR datasets. The variables category 
for medication (CMCAT), standardized medication name (CMDECOD), reported name of drug, 
medication, or therapy (CMTRT) from the ADCM will be used for the looking for platelets 
transfusions. The CMCAT values should be equal to ‘RESCUE MED’, and CMDECOD and/or
CMTRT should contain the text ‘PLATELET’. The variables contained reported names of 
procedure (PRTRT) and standardized procedure name (PRDECOD) from ADPR will be used 
for the looking for platelets transfusions. The PRDECOD and/or PRTRT should contain the 
text ‘PLATELET’.  
2.4.3
Prior, concomitant and post therapies
Concomitant medications and significant non-drug therapies prior to and after the start of the 
study treatment, including rescue medication therapy, will be listed and summarized according 
to the Anatomical Therapeutic Chemical (ATC) classification system. Surgical and medical 
procedures prior to and after the start of the study treatment will be listed and summarized by 
system organ class and preferred term.
2.4.4
Protocol deviations
The number (%) of patients with protocol deviations will be summarized by deviation category
(as specified in the latest version of the study data handling plan (DHP) at the time of analysis) 
and overall for the FAS. All protocol deviations will be listed, flagging those leading to the 
exclusion of a patient from an analysis set. Protocol deviations will be listed for screening 
failures (if any).


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2.5
Analysis of the primary objective
The primary objective is to assess ability of eltrombopag to induce sustained response off 
treatment by month 12 in ITP patients who relapsed or failed to respond first-line steroid 
treatment.
For the primary and supportive analyses the FAS will be used.
2.5.1
Primary endpoint
The primary endpoint is the proportion of patients with sustained response off treatment by 
month 12.
Sustained response off treatment is defined as:

reach platelet count ≥100×109/L (CR) and then maintain platelet counts around 100×109/L
for 2 months (no counts below 70×109/L) AND then

taper off the drug until treatment discontinuation (see Section 9.1 of the study protocol) 
while maintain platelet count ≥30×109/L in the absence of bleeding (no bleeding AEs) or 
use of any rescue therapy (see Section 6.2.3 of the study protocol),

and maintain platelet count ≥30×109/L in the absence of bleeding (no bleeding AEs) or 
use of any rescue therapy (see Section 6.2.3 of the study protocol) until month 12. 
In the first 12 months, the platelet count values from scheduled visits will be used, in the 
follow-up phase values from all visits (scheduled and unscheduled) will be used for the 
analysis of the platelet counts. See mapping of visits in Section 2.1.1 (Time windows).
2.5.2
Statistical hypothesis, model, and method of analysis
The number (%) of patients with sustained response off treatment by month 12 will be 
summarized together with 95% confidence interval (CI) using the Clopper-Pearson method.
A binomial test for one proportion, H0: P=0.15 vs. H1:P>0.15 will be performed to test if the 
proportion of sustained response off treatment patients is greater than 15% using a target alpha 
level of 0.05.
Listing for hematologic response, with flags for: 
platelets <30x109/L, bleeding events, 
transfusions, and rescue medications will be provided. Steps until sustained response off 
treatment at month 12 and during the follow-up period will be flagged as follows: 
-
Patients who reached platelet count >=100×109/L at least once
-
Patients who maintained stable platelet count for 2 months after reaching 100×109/L (no 
counts below 70×109/L)
-
Patients who were able to be tapered off the drug till treatment discontinuation, while
maintain platelet count ≥30×109/L in the absence of bleeding (no bleeding AEs) or use 
of any rescue therapy
-
Patients with sustained response off treatment until month 12, while maintain platelet 
count ≥30×109/L in the absence of bleeding (no bleeding AEs) or use of any rescue 
therapy
-
Patients with sustained response off treatment from month 12 to month 24, while 
maintain platelet count ≥30×109/L in the absence of bleeding (no bleeding AEs) or use 
of any rescue therapy
The patients can re-attempt Steps 1 to 3.


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The patient cannot be considered as having achieved SRoT (step 4)  in the cases below:
1. If a patient has taken rescue med prior to day 14 and if the  dosage was increased after 
day 14 they are not considered as Step 4 at month 12.
2.
If a patient has taken new rescue med after day 14 they are not considered as Step 4 at 
month 12.
3. If a patient taken platelet transfusion after day14 they are not considered as Step 4 at 
month12.
2.5.3
Handling of missing values/censoring/discontinuations
No imputation will be used for missing platelet values.
After achieving CR, at least two platelet counts should be available (at least 14 days apart) to 
assess maintenance around 100×109/L for two months and to assess sustained response off 
treatment after tapering (if tapering ends prior to month 11).
A patient who discontinues early from the study (before month 12, e.g. withdrawal of consent) 
will not be considered for sustained response off treatment.
See mapping of visits in Section 2.1.1 (Time windows).
2.5.4
Supportive analyses
The number (%) of patients:

with CR (reaching platelet count ≥100×109 /L)

who maintained platelet counts around 100×109 /L for 2 months (no counts <70×109 /L)

who managed to start tapering eltrombopag after maintaining platelet counts around 
100×109 /L (no counts <70×109 /L) for 2 months

who are able to discontinue eltrombopag after tapering
will be provided together with 95% CI using the Clopper-Pearson method.
In addition bar plot(s) for the percentage of patients in each category will be provided.
2.6
Analysis of the key secondary objective
There is no key secondary objective.
2.7
Analysis of secondary efficacy objective(s)
For all efficacy and PRO analyses, the FAS will be used. For all safety analyses the safety set
will be used.
2.7.1
Secondary endpoints
2.7.2
Efficacy endpoint(s)
1. To assess the duration of sustained response off treatment after treatment 
discontinuation
1a) Summary statistics for the duration of sustained response off treatment (weeks) counted 
from last dose of eltrombopag to month 12 for patients with sustained response off treatment


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(SRoT_M12 patients) will be provided. Mean, SD, median, maximum, minimum, 25th
percentile and 75th percentile will be provided.
1b) Kaplan-Maier analysis and corresponding plot for the duration of sustained response off 
treatment for all patients meeting the primary endpoint (SRoT_M12 patients) (weeks) will 
be provided and is counted from last dose of eltrombopag to relapse. The SRoT_M12 
patients who do not relapse/ restart eltrombopag treatment until month 24 will be censored.
•
Event: relapse after achieving SRoT_M12 (platelets <30 Gi/L, bleeding event, rescue 
therapy/platelet transfusion, or restarted eltrombopag treatment)
•
Censoring rules: Patients with SRoT_M12 who enter follow-up and do not relapse by 
cut-off date/Month 24 will be censored at the earliest of discontinuation date/death 
date/M24 platelet assessment date/cutoff date. SRoT_M12 patients who did not enter or do 
not yet have platelet assessments in follow-up phase are censored at their M12 platelet 
assessment date.
1c) Kaplan-Maier analysis and corresponding plot for the duration of sustained response off 
treatment for all patients who achieved Step 3 (S3 patients) (weeks) will be provided and is 
counted from their last dose of eltrombopag on or before this last S3 to relapse. 
The S3 patients who do not relapse/ restart eltrombopag treatment until month 24 will be 
censored.
The event and censoring rules are as in 1b) above.
It is noted that the SRoT_M12 patients are a subset of patients in the group of patients who 
achieved Step 3 (S3 patients).
Duration of SRoT (weeks) for the tapered patients who achieved step 3 will be summarized
by SRoT_M12 status.
2. To assess the proportion of patients maintaining a sustained response off treatment after
treatment discontinuation until month 24. Number (%) of patients who are in sustained 
response off treatment at months 15, 18, 21, and 24 will be provided.
3. To assess the ability of eltrombopag to induce early response by month 1
Number (%) of patients who reach platelet count ≥50×109/L at least once within the first 
month (month 1) without bleeding events and no rescue therapy will be provided.
4. To assess the ability of eltrombopag to induce a recovery response, in case of loss of 
response after tapering of eltrombopag
Number (%) of patients with at least one platelet count ≥30×109/L after eltrombopag is re-
introduced, in case of loss of response (<30×109/L and/or bleeding event) without bleeding 
events and no rescue therapy will be provided.
5. To quantify the platelet count from baseline to 3, 6, 9, 12, 15, 18, 21, 24 months
Absolute and relative change in platelet count from baseline to 3, 6, 9, 12, 15, 18, 21, 24
months and EOT will be provided for all scheduled visits. Box plots for absolute and/or 
relative change in platelet counts from baseline to different time points will also be provided.
Additionally, platelet counts ranges (≥30×109/L, ≥50×109/L, ≥70×109/L and ≥100×109/L) 
will be provided only for patients who reach sustained response off treatment at month 12.


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6. To assess the ability of eltrombopag to maintain platelet count ≥30×109/L within 12 
months and every 3 months until month 24
Number (%) of patients who maintain a platelet count ≥30×109/L from the first time of 
reaching that level to month 3, 6, 9, 12, 15, 18, 21, 24 and EOT, without bleeding events 
and no rescue therapy will be provided.
7. To evaluate patient reported outcomes using measures for Health-Related Quality of Life
with the FACIT-Fatigue, FACT-Th6 and SF-36v2 questionnaires.
Change in each domain score and total score of PRO parameters: FACIT-Fatigue, FACT-
Th6 and SF-36v2 questionnaires from baseline to 3, 6, 9, 12, 15, 18, 21, 24 months and EOT
will be provided by SRoT_M12 status. In addition, summary statistics for the two main 
summary scores, the PCS and the MCS for SF36 v2 as per sustained response off treatment
status (sustained response off treatment versus no sustained response off treatment) will also 
be provided. Listings will be provided.
Scoring for SF-36v2 will be provided by an external vendor.
8. To explore the overall impact of side effects of treatment via the GP5 at baseline, 12 months
and EOT.
Overall change from baseline score will be summarized descriptively. A listing will be 
provided.
9. To explore treatment satisfaction with TSQM-9
Overall change from baseline, 12 months and EOT score will be summarized descriptively. 
A listing will be provided.
10. To evaluate the safety and tolerability of eltrombopag see Section 2.8.
2.7.3
Statistical hypothesis, model, and method of analysis
There are few secondary endpoints for which we are measuring the effect at EOT as 
mentioned in Section 2.7.2. 
Here, EOT is defined as last assessment of a discontinued or completed patient irrespective of 
time point; EOT is defined as the last assessment during the follow-up for patients who started 
the follow-up but didn’t complete the study; EOT is the last assessment before discontinuation
for the patients who discontinued the trial before 12 months; EOT is the last assessment for 
patients that discontinued from study at month 12 but not enter in the follow-up period. The 
change from baseline to EOT is defined as the difference between the EOT and baseline values
i.e. Change from baseline = EOT – baseline.
2.7.4
Handling of missing values/censoring/discontinuations
2.7.4.1 FACIT-Fatigue
There are 13 items. Negatively worded items are reverse scored prior to summing. Add the 
scores together, multiply by 13 and then divide by the number of items answered. A total score 
of <30 indicates severe fatigue. The higher the total score the better the quality of life. Total 
score can vary from 0 to 52.
In cases some answers are missing, a total score is prorated from the score of the answered 
items, so long as more than 50% of the items (i.e., at least 7 of 13) were answered.


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FAT_N = N(OF HI7 HI12 AN1-AN5 AN7 AN8 AN12 AN14-AN16);
IF (FAT_N/13 >0.50) THEN Fatigue = SUM(OF HI7 HI12 AN1-AN5 AN7 AN8 AN12
AN14-AN16)*13/(FAT_N);
Further details on the FACIT-Fatigue scoring is provided at:
http://www.facit.org/FACITOrg/Questionnaires
http://www.physio-pedia.com/Functional_Assessment_of_Chronic_Illness_Therapy
2.7.4.2 FACT-Th6
There are 6 questions in FACT-Th6 questionnaires. The calculation of total score is done by 
multiplying the sum of the item scores by the number of items in the subscale, then divide by 
the number of items answered. This produces the subscale score. FACT-Th6 score will only be 
computed if we have no more than 2 missing responses. 
2.7.4.3 SF-36v2
The details for calculation of the score and handling of missing responses in SF-36 v2 is 
provided in Appendix 2.
2.7.4.4 TSQM-9
The details of scoring and handling of missing values is provided in the appendix. In the three 
domains, each require at least 2 non-missing responses for calculating the score. Otherwise the 
overall response will be considered as missing.
2.7.4.5 GP5
Missing responses for GP5 will not be imputed.
2.8
Safety analyses
Safety summary tables include all data (from the on-treatment period) with the exception of 
baseline data which will also be summarized where appropriate.
The on-treatment period lasts from the date of first dose of eltrombopag to 30 days after the 
date of the last dose of eltrombopag for patients who discontinued the study. For ongoing 
patients (not applicable for final CSR analysis), the on-treatment period lasts from first dose of 
eltrombopag to 30 days after the cut-off date. For all safety analyses the safety set will be used.
2.8.1
Adverse events (AEs)
Coding of AEs
Adverse events will be coded using the latest version of MedDRA at the time of the analysis.
Grading of AEs
AEs will be assessed according to the Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.03.
The CTCAE represents a comprehensive grading system for reporting the acute and late effects 
of cancer treatments. CTCAE grading is by definition a 5-point scale generally corresponding 
to mild (as reported in AE CRF in severity grade variable), moderate (as reported in AE CRF 


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in severity grade variable), severe (as reported in AE CRF in severity grade variable or 
“Hospitalization (initial or prolonged)” or “Disability or permanent damage” or “Congenital 
Anomaly or birth defect” or “Other serious (important medical events)”), life threatening, and 
death. This grading system inherently places a value on the importance of an event, although 
there is not necessarily proportionality among grades (a grade 2 is not necessarily twice as bad
as a grade 1).
AE summaries
AE summaries will include all AEs occurring during on-treatment period. All AEs collected in 
the AE (e)CRF page will be listed along with the information collected on those AEs, e.g. AE 
relationship to study drug, AE outcome etc. AEs starting during the post-treatment period will
be flagged in the listings. All information obtained on adverse events will be displayed by 
patient. Summary tables for adverse events (AEs) will include only AEs that started or worsened 
during the on-treatment period, the treatment-emergent AEs (TEAEs).
TEAEs will be summarized by number and percentage of patients having at least one AE, 
having at least one AE in each primary system organ class (SOC) and for each preferred term 
(PT) using MedDRA coding. A patient with multiple occurrences of an AE will be counted only 
once in the respective AE category. A patient with multiple CTCAE grades for the same 
preferred term will be summarized under the maximum CTCAE grade recorded for the event. 
AE with missing CTCAE grade will be included in the ‘All grades’ column of the summary 
tables.
The incidence of TEAEs will be summarized by system organ class (SOC) and or preferred 
term, severity based on the CTCAE grades, type of adverse event and relation to eltrombopag.
In AE summaries the primary system organ class will be presented alphabetically and the 
preferred terms will be sorted within primary SOC in descending frequency. The sort order for 
the preferred term will be based on their frequency.
The following adverse event summaries will be produced; overview of adverse events and 
deaths, AEs by SOC and PT, summarized by relationship, seriousness (SAEs and non-SAEs), 
leading to treatment discontinuation, leading to dose interruption/adjustment, requiring 
additional therapy and leading to fatal outcome. In addition, a summary of serious and non-
serious adverse events with number of occurrences will be produced (an occurrence is defined 
as >1 day between start and prior end date of record of same preferred term) as per EudraCT 
requirements.
All AEs and SAEs will be listed and those collected during the pre-treatment (from day of 
patient’s informed consent to the day before first dose of eltrombopag) and post-treatment 
period will be flagged.
A patient with multiple AEs within a primary SOC is only counted once towards the total of the 
primary SOC.
Summaries of AEs, SAEs, SAEs with fatal outcome, AEs leading to discontinuation and 
overview of AEs will be provided for the month 12 on-treatment period. 
The overview of AE will be provided by SRoT_M12 status.


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2.8.1.1
Adverse events of special interest / grouping of AEs
Serious adverse events, AEs leading to discontinuation, AEs leading to dose adjustment and 
adverse events of special interest (AESI) which includes bleeding events during the on-
treatment period will be tabulated.
Specific groupings of AESI will be considered and the number of patients with at least one 
event in each grouping will be reported. Such groups consists of AEs for which there is a 
specific clinical interest in connection with eltrombopag treatment or AEs which are similar in 
nature (although not identical). Note that certain AEs may be reported within multiple 
groupings/AESIs.
AESIs are defined by MedDRA terms. Definition for retrieval and maintenance is done in the 
electronic case retrieval sheet (eCRS).
The incidence of AESIs will be summarized by SOC and Preferred Term (PT).
The AESIs as specified in the latest version of the case retrieval sheet (CRS) at the time of 
analysis will be used.
Summaries of AESIs will be provided for the month 12 on-treatment period. 
2.8.2
Deaths
Separate summaries for on-treatment and all deaths (on-treatment and post-treatment [starting 
at day 30+1 after last dose of eltrombopag]) will be produced by system organ class and 
preferred term. 
All deaths will be listed and those collected during the pre-treatment (from day of patient’s 
informed consent to the day before first dose of eltrombopag) and post-treatment period will be 
flagged.
2.8.3
Laboratory data
Grading of laboratory values will be assigned programmatically as per the CTCAE version 4.03.
The calculation of CTCAE grades will be based on the observed laboratory values only, clinical 
assessments will not be taken into account.
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 generated separately for key hematology and biochemistry 
tests laboratory tests:

Shift tables comparing baseline to the worst on-treatment value. Each patient will be 
counted only once for the worst grade observed post-baseline.

For laboratory tests where grades are not defined, shift tables using the low/normal/high/ 
(low and high) classification to compare baseline to the worst on-treatment value will be 
used.
Imputation rules
CTC grading for blood differentials is based on absolute values. However, this data may not 
be reported as absolute counts but rather as percentage of WBC. 


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If laboratory values are provided as ‘<X’ (i.e. below limit of detection) or ‘>X’, prior to 
conversion of laboratory values to SI unit, these numeric values are set to X. 
The following rules will be applied to derive the WBC differential counts when only 
percentages are available for a xxx differential
xxx count = (WBC count) * (xxx %value / 100)
Further derivation of laboratory parameters might be required for CTCAE grading. For instance, 
corrected calcium can be derived using the reported total calcium value and albumin at the same 
assessment using the following formula:
Corrected Calcium (mg/dL) = Calcium (mg/dL) – 0.8 [Albumin (g/dL)-4]
In order to apply the above formula, albumin values in g/L will be converted to g/dL by 
multiplying by 0.1), calcium values in mmol/L will be converted to mg/dL by dividing by 
0.2495. For calculation of laboratory CTC grades 0 and 1, the normal range for derived 
corrected calcium is set to the same limits (in mg/dL) as for calcium.
CTC grades for the derived absolute WBC differential counts (neutrophils, lymphocytes, etc.) 
and corrected calcium will be assigned.
Data analysis
On analyzing laboratory results, data from all sources (central and local laboratories) will be 
combined. The summaries will include all assessments available for the lab parameter collected 
no later than 30 days after the last study treatment administration date.
The following summaries will be produced for hematology and biochemistry laboratory data 
(by laboratory parameter and treatment):

Worst post-baseline CTC grade (regardless of the baseline status). Each patient will be 
counted only for the worst grade observed post-baseline.

Shift tables using CTC grades to compare baseline to the worst on-treatment value

For laboratory tests where CTC grades are not defined, shift tables using the 
low/normal/high (low and high) classification to compare baseline to the worst on-
treatment value.

Trends of lab parameter values over time (baseline and selected on-treatment timepoints) 
should be displayed via boxplots based on time windows and corresponding tables 
displaying the statistics used for the box plots by the selected time points. 

The following listings will be produced for the laboratory data:
Listings of all laboratory data, with CTC grades and classification relative to the 
laboratory normal range. Lab data collected during the post-treatment period will be 
flagged.  
Listing of all CTC grade 3 or 4 laboratory toxicities
Liver function parameters
Liver function parameters of interest are total bilirubin (TBIL), ALT, AST and alkaline 
phosphatase (ALP).
The number (%) of patients with worst post-baseline values will be summarized:

ALT or AST >3xULN 


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
ALT or AST >5xULN

ALT or AST >8xULN

ALT or AST >10xULN

ALT or AST >20xULN

TBL >2xULN

TBL >3xULN

ALT or AST >3xULN & TBL >2xULN

ALT or AST >3xULN & TBL >2xULN & ALP <2xULN  
Potential Hy’s Law events are defined as those patients with concurrent occurrence of AST or 
ALT >3xULN and TBL >2xULN and ALP <2xULN in the same assessment sample during 
the on-treatment period. Further medical review must be conducted to assess potential 
confounding factor such as liver metastasis, liver function at baseline etc.
2.8.4
Other safety data
Data on ECG, vital sign, weight, ocular findings and bleeding events will be summarized
descriptively, listed and flagged as appropriate. Any significant findings will be documented as 
AEs and reported as such.
2.8.4.1
ECG
12-lead ECGs, including QTcF (Fridericia’s correction), mean heart rate (HR), PR-, QT- and
QRS-durations will be presented by number and percentages of patients.
Where ECG replicates are provided for an assessment, the average of the ECG parameters at
that assessment will be used in the analyses.
The number (%) of patients with notable values will be presented.
Table 2-1
Notable criteria for ECG parameters
Parameter
Notable low value
Notable high value
QTcF
New value of >450 and ≤480 ms
New value of >480 and ≤500 ms
New value of >500 ms
Increase from baseline of >30 ms to 
≤60 ms
Increase from baseline of >60 ms
Heart rate
Heart rate Decrease >25% from baseline
and to a value <50 bpm
Increase >25% from baseline and to a 
value >100 bpm


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Parameter
Notable low value
Notable high value
PR
Increase >25% from baseline and to a value 
>200 ms
New value of >200 ms
QRS
Increase >25% from baseline and to a value 
>120 ms
New value of >120 ms
A listing of all ECG assessments will be produced. Notable values as well as values measured 
outside of on-treatment period will be flagged in the listings.
2.8.4.2
Vital signs
Vital sign assessments are performed in order to characterize basic body function. The
following parameters will be collected: height (cm, inch), weight (kg, pound), body temperature
(°C, Fahrenheit), position, pulse (beats/minute), systolic and diastolic blood pressure (mmHg).
The number (%) of patients with notable values will be presented.
Table 2-2
Notable criteria for vital signs
Vital sign (unit)
Notable low value 
Notable high value
Weight (kg)
decrease ≥10% from 
baseline
increase ≥10% from baseline
Body temperature ( o C)
--
≥39.1
Pulse rate (bpm)
≤50 and 
decrease from baseline 
of >25%
≥100 and increase from baseline 
of >25%
Systolic blood pressure 
(mmHg)
≤90 and
decrease from baseline of 
≥20
≥180 and 
increase from baseline of ≥20
Diastolic blood pressure 
(mmHg)
≤50 and 
decrease from baseline of 
≥15
≥105 and 
increase from baseline of ≥15 
A listing of all vital sign assessments will be produced and notable values will be flagged.
Assessments collected outside of on-treatment period will be flagged.
2.8.4.3
Bleeding scales
Safety analysis set will be used reporting WHO and ITP bleeding events. 
 
 
 
 
 
WHO Bleeding Scale
The WHO bleeding scale is a measure of bleeding severity with the following grades: Grade 0: 
no bleeding, Grade 1: mild bleeding, Grade 2: moderate bleeding, Grade 3 gross bleeding and 


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Grade 4: debilitating blood loss. The number and percent of subjects within each grade will be 
summarized at each time point, Grade 0 versus those with Grades 1-4 as well as Grade 0-1 
versus those with Grades 2-4. 
ITP Bleeding Score
The ITP Bleeding Score is an assessment of the bleeding severity in each of the following
anatomical locations: Skin: petechiae, Skin: ecchymosis, Oral, Epistaxis, Ocular,
Gastrointestinal, Genitourinary, Gynecological (Females only), Pulmonary and Intracerebral 
Hemorrhage. Severity is graded using scores 0, 1 and 2. The number and percentage of subjects 
in each grade at each time point will be presented by anatomical location for the ITP bleeding 
score assessments.
2.8.4.4
Bleeding adverse events used in efficacy analyses
All Adverse event (AEs) will be taken from the ae.sas dataset and exported as an Excel file.
The clinical team will review the records captured in an Excel spreadsheet and mark with a ‘Y’ 
in new variable ‘bleed_flag’, those terms which are considered as bleeding AEs. Bleeding 
events on or before Day 7 are not considered in the efficacy derivations and will be 
programmatically excluded.
Once the database has locked the data will be rechecked again for any changes or new data that 
needs flagging.
The spreadsheet will contain three (3) tabs, the first tab is the final tab used in the analysis. The 
second and third tabs are used by the clinical team to flag the bleeding records and provide 
comments.
The first tab contains the following variables: reported term for the adverse event (AETERM), 
dictionary-derived term (AEDECOD), bleeding flag(Bleed_flag), the second tab contain the 
same variables with clinical team comments. Third tab contain additional variables to document 
decision making: unique subject identifier (USUBJID), reported term for the adverse event 
(AETERM), dictionary-derived term (AEDECOD, AEDECOD = ‘Thrombocytopenia’) and 
comments. 
The spreadsheet will be imported into the programming environment (GPS) and merged with
the patient data for the analysis where bleeding events will be filtered by the value ‘Y’ for the 
variable ‘Bleed_flag’ using the first tab. The EXCEL document will be stored in CREDI in the 
study folder ETB115J2411/Administrative Files (study level)/RAP or RAMP Meeting and in 
GPS in the study folder CETB115J\CETB115J2411\csr_1\util for primary CSR and folder 
CETB115J\CETB115J2411\csr_2\util for final CSR.
2.8.4.5
Ocular findings
Descriptors at Baseline, week 25 and EOT will be provided for body system examined and 
findings by eye. Frequencies and percentages will be provided for each time point. Listings will 
be provided.


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2.10
Patient-reported outcomes
Immune thrombocytopenia is associated with symptoms of fatigue, bruising, and bleeding, 
which can interfere with daily activities. Consequently, patients with ITP have decreased 
health-related quality of life (HRQoL) compared with healthy individuals. To assess patient-
reported outcomes (PROs), HRQoL changes over time and association between HRQoL and 
platelet response during treatment with eltrombopag will be assessed using standard validated 
instruments in patients with ITP who are refractory to treatment or who relapsed after first-line 
steroids.
2.10.1 The Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue)
instrument is a 13-item, easy-to-administer, validated tool used to measure an individual’s level 
of fatigue during usual daily activities over the past 7 days (Cella 2002, Webster 2003). FACIT-
Fatigue is a subscale of the FACIT measurement system, which is a validated collection of
HRQoL questionnaires targeted to the management of chronic illness that are used to measure 
HRQoL on multiple general and disease-specific domains. FACIT-fatigue is scored using a 4-
point Likert scale. Items are scored as follows: 4=Not At All; 3=A Little Bit; 2=Somewhat; 
1=Quite A Bit; 0=Very Much, EXCEPT items #7 and #8 which are reversed scored. Score range 
from 0-52. A score of less than 30 indicates severe fatigue. The higher the score, the better the 
quality of life. Patients will be administered the FACIT-Fatigue at baseline, every 3 months 
during treatment, and end of treatment (EOT). A minimal clinically important difference from 
baseline in FACIT-Fatigue score will be evaluated (Cella 2002). The overall total score will be 
evaluated; 
. Mean, SD, 
median, maximum, minimum, 25th and 75th percentile will be provided. Box plots at baseline, 
3, 6, 9, 12, 15, 18, 21, 24 months and EOT will be provided. Descriptive statistics will be used 
to summarize change from baseline at month 3, 6, 9, 12, 15, 18, 21, 24 and EOT.
2.10.2 The Medical Outcome Trust’s Short-Form 36 Health Survey, Version 2 (SF-36v2), 
which is a validated instrument used to measure general physical and mental health status 


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(Ware 2000), will be used to assess the impact of ITP on physical function and ability to conduct 
day-to-day activities. The SF-36v2 is used to measure patients' overall HRQoL via assessment 
of 8 domains—Physical Functioning, Role Physical, Bodily Pain, General Health, Vitality, 
Social Functioning, Role Emotional, and Mental Health. The SF-36 is scored using norm-based 
scoring procedures and scores ranging from 0-100; higher scores represent better HRQoL. Two 
summary scores, the Physical Component Score (PCS) and the Mental Component Summary
(MCS), can also be calculated.
The SF-36v2, specifically the Physical Functioning and the Role Physical domains, 
demonstrated good reliability and validity for measuring the proposed constructs in the ITP 
population (Signorovitch 2011). The Physical Functioning domain includes 10 items related to 
limitations in physical functioning and is scored using a 3-level Likert scale (1=yes, limited a 
lot; 2=yes, limited a little; and 3=no, not at all limited); higher scores represent less functional 
limitation. The Role Physical domain is used to measure to what degree physical health 
interferes with work/other daily activities, includes 4 items (reduction in the amount of time 
spent on work/other activities, accomplishing less than one would like, limitations in kind of 
work/other activities, and difficulty performing work/other activities), and is scored using a 5-
level Likert scale (1=all of the time; 5=none of the time); lower scores represent less impact on 
daily activities. Patients will be administered the SF-36v2 at baseline, every 3 months during 
treatment, and EOT, and change from baseline will be evaluated. 
 
Mean, SD, median, maximum, 
minimum, 25th and 75th percentile will be provided. Box plot at baseline, 3, 6, 9 , 12, 15, 18, 21, 
24 months and EOT will be provided. Descriptive statistics will be used to summarize change 
from baseline at month 3, 6, 9, 12, 15, 18, 21, 24 and EOT.
2.10.3 Functional Assessment of Cancer Therapy - Thrombocytopenia 6-item version 
(FACT-Th6) instrument is used to measure worry/concern about bleeding and bruising, and 
the impact of this worry/concern on physical and social activity (Cella 2006). FACT-Th6 is a 
6-item subset of the more detailed FACT-Th, which is an 18-item subscale of the validated 
FACT that specifically measures concerns related to thrombocytopenia in the past 7 days. The 
FACT-Th6 is scored using a 5-level Likert scale (0=not at all to 4=very much) and is calculated 
by summing scores for the 6-items; therefore, scores can range from 0–24, with higher scores 
representing better HRQoL. No minimum clinically important change thresholds have been 
established for FACT-Th6. Tentatively anchor-based methods (e.g., based on Patient Global 
Impression of Change [PGIC] and Patient Global Impression-Severity [PGIS]) and distribution-
based methods will be used to determine meaningful change in scores. FACT-Th6 demonstrated 
good reliability and validity for measuring the proposed constructs in the ITP population. 
Patients will be administered the FACT-Th6 at baseline, every 3 months during treatment, and 
EOT. Mean, SD, median, maximum, minimum, 25th and 75th percentile will be provided. Box 
plot at baseline, 3, 6, 9, 12, 15, 18, 21, 24 months and EOT will be provided. Descriptive 
statistics will be used to summarize change from baseline at month 3, 6, 9, 12, 15, 18, 21, 24
and EOT.
2.10.4 GP5, which is a single question, is used to assess the overall bothersomeness of treatment 
side effects. The GP5 is scored using a 5-point rating scale (0 = not at all; 1 = a little bit; 2 = 
somewhat; 3 = quite a bit; and 4 = very much), where lower scores reflect less bothersomeness 
from treatment side effects. The GP5 will be evaluated at baseline, 12 months, 24 months and 
EOT. The frequencies and percentages for each of the rating points will be provided.


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Descriptive statistics will be used to summarize change from baseline to >0-3 months, >3-6 
months, >6-9 months >9-12 months, >12 months and EOT. Shift table from baseline to worst 
post-baseline value will also be provided.
2.10.5 Treatment Satisfaction Questionnaire for Medication (TSQM-9) will be used to 
assess treatment satisfaction with medication. The three scales of the TSQM-9 include the 
effectiveness scale, convenience scale, and global satisfaction scale. TSQM-9 will be evaluated 
at baseline, month 12, month 24 and EOT. Mean, SD, median, maximum, minimum, 25th and 
75th percentile will be provided at the time points. Descriptive statistics will be used to 
summarize change from baseline at month 12, month 24 and EOT. Shift table from baseline to 
worst post-baseline value will also be provided.


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2.13
Interim analysis
No formal interim analysis is planned for this study. 
3
Sample size calculation
3.1.1
Primary endpoint
Based on medical experts’ advice, it is postulated that approximately 15% of patients who do 
not respond or relapse after a first round of steroid therapy would have sustained response off 
treatment by 12 months if on steroid recycling. In this study, at least a 10% higher sustained 
response off treatment rate is expected by month 12, i.e., a sustained response off treatment rate 
of at least 25% by 12 months is expected in patients who will receive eltrombopag after failing 
first-line steroids.
The sample size calculation is based on an exact binomial test for single proportion using a 
target alpha level of 0.05 and power of 80% to compare the null hypothesis H0: P=0.15 against 
the alternative hypothesis H1: P>0.15, where P is proportion of patients with sustained response 
off treatment by Month 12.
A sample size of 101 gives at least 80% power if the true sustained response off treatment rate
with eltrombopag is 25% or more with an actual significance level of 0.043. The null hypothesis 
will be rejected if the number of patients with sustained response off treatment is 22 or more.
Table 3-1 shows the sample size, cut-off, actual alpha, beta and power for different sustained 
response off treatment rates. PASS 11 (version 11.0.10) is used for the sample size calculation.


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Table 3-1
Numeric results for testing H0: P = P0 versus H1: P >P0 using exact 
binomial test statistic
Proportion 
given H0 
(P0)
Proportion 
given H1
(P1)
Sample 
size (N)
Cut-off
(Reject H0 if 
R>=This)
Actual
Alpha
Actual
Beta
Actual
Power
0.150
0.250
101
22
0.043
0.196
0.804
0.150
0.300
48
12
0.048
0.181
0.819
0.150
0.350
28
8
0.049
0.182
0.818
0.150
0.400
22
7
0.037
0.158
0.842
0.200
0.300
116
31
0.049
0.193
0.807
0.200
0.350
56
17
0.043
0.194
0.806
0.200
0.400
35
12
0.034
0.195
0.805
At the end of the study, for decision-making purposes, the cut-off will be determined based on 
the final sample size and the target alpha and beta.
3.1.2
Responders cut-off update due to final sample size
For decision-making purposes, responders cut-off will be determined based on the final sample 
size and the target alpha and beta.
A final sample size of 105 gives at least 80% power if the true sustained response rate on 
eltrombopag is 25% or more with an actual significance level of 0.037. The null hypothesis will 
be rejected if the number of responders is 23 or more (instead of 22 for an initial sample size of 
101 patients as stated in Protocol, section 12.8.1). 
Table 3-2 shows the sample size, cut-off, actual alpha, beta and power for different sample sizes. 
Table 3-2
Numeric results for testing H0: P = P0 versus H1: P >P0 using exact 
binomial test statistic, for a sample size of 101 and 105 patients
Sample 
size 
(N)
Proportion 
given H0 
(P0)
Proportion 
given H1 
(P1)
Cut-off
(Reject H0 
if R>=This)
Actual 
Alpha
Actual
Beta
Actual
Power
101
0.150
0.250
22
0.043
0.196
0.804
105
0.150
0.250
23
0.037
0.200
0.800
4
Changes to protocol specified analyses
In Section 6.2.3 of the study protocol there is stated that a patient who receives rescue 
medication or therapy will not be considered in having achieved sustained response off 
treatment for the primary endpoint, unless the patient uses steroids ± IVIG as described below 
in the first 14 days of start of eltrombopag. Steroids may be used after day 14 if the dose is 
considered low dose as per protocol definition and/or tapered down (i.e., successively lower 
doses after day 14). This change applies to the derivation of all efficacy endpoints.
By clinical practice, a patient can have a bleeding event during first 7 days after eltrombopag 
start. Only bleeding events that happen from day 8 onwards after the eltrombopag start will


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exclude a patient to reach an efficacy endpoint. This change applies to the derivation of 
secondary efficacy endpoints 3, 4 and 6. 
In addition to descriptive statistics, box plots will also be provided for FACIT, FACT-Th6 and 
SF-36 questionnaire scores.
 
The end of study (EOS) has been revised to end of treatment (EOT).
“Sustained remission” was changed to “sustained response off treatment”.
Starting dose for Asian patients and Japanese patients in Japan described.
Study objective and endpoints updated in accordance with clarifications of the protocol: 
described above.
Section 2.1.1The formula for the duration of exposure was clarified. Definition of the planned 
dose provided. Descriptions of observation periods clarified.
Section 2.4.2 (Rescue therapy) created.
Sections 2.5.1, 2.5.2, 2.5.3 was updated with descriptions of the primary endpoint calculations: 
using of scheduled/unscheduled visits, possibility of re-attempt steps 1-3, handling of missing 
platelets counts at scheduled visits.
Section 2.8.2 The description of deaths reporting was updated.
Section 2.8.4.4 (bleeding adverse events) was created.
Section 1. Timelines were updated. Section 2.1. Cutoff date is provide. Formula of the duration 
of exposure is updated. Clarified the description of the using cutoff date instead missing the end 
date.
Section 2.2.1. Provided details of the sub-group analysis.
Section 2.5.2. Updated the description of the listings. Provided clarifications of the conditions 
for achieving the Step 3.
Section 2.7.2. The analysis description was updated, added the event description, censoring 
rules.
 
Section 2.8.4.4. Title updated
 
 


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5
Appendix
5.1
Imputation rules
Table 5-1
Imputation of start dates (AE, CM) and assessments (LB, EG, VS, 
PRO)
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  
AE: Adverse Events; CM: Concomitant Medications; LB: Laboratory; EG: ECG; VS: Vital Signs; PRO: 
Patient Report Outcomes
Table 5-2
Imputation of end dates (AE, CM) 
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*
Imputation of start and end dates will be used in analysis sets to derivation purposes. Any event 
with partial/missing dates will be displayed as such in the data listings. Any event which are 
continuing as per LPLV or cut-off date will be shown as ‘ongoing’, rather than an imputed end 
date provided, and duration and outcome will be kept in blank. Any event with missing end date 
will be shown as blank, and duration and outcome will be kept as blank, except for “not 
recovered/not resolved”, “recovering/resolving” and “unknown” outcomes.


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5.2
Derivation of Health Outcomes Scores
SF-36v2 Acute Recall – Calculation of Domain and Summary Index Scores
The 36 questions in the SF-36v2 questionnaire are used to evaluate patients’ perception of 
their general quality of life in 8 areas: physical functioning, role-physical (role limitations 
caused by physical problems), social functioning, bodily pain, mental health, role emotional 
(role limitations caused by emotional problems), vitality and general perception of health. 
The score for each domain is a summation of the numerical responses from a subset of the 36 
questions (as shown in the table below). For questions 1, 2, 6, 7, 8, 9a, 9d, 9e, 9h, 11b and 11d 
low response scores indicate better health status, hence the response to these questions are re-
coded in the reverse order prior to any summations. If in error, two or more responses are 
given for a patient for a particular question then the worst score will be used in calculating the 
domain score. For the questions indicated above this would be for the higher scores, and for 
all other questions it would be the lower scores. Any out of range values will be treated as 
missing.
Domain
Question 
Lowest-
Highest 
possible score
Maximum 
Allowed Missing 
Responses*
Physical Functioning
3a, 3b, 3c, 3d, 3e, 3f, 
3g, 3h, 3i, 3j
10 – 30
5
Role-Physical
4a, 4b, 4c, 4d
4 – 20
2
Bodily Pain
7, 8
2 – 12
1
General Health
1, 11a, 11b, 11c, 11d
5 – 25
2
Vitality
9a, 9e, 9g, 9i
4 – 20
2
Social Functioning
6, 10
2 – 10
1
Role-Emotional
5a, 5b, 5c
3 – 15
1
Mental Health
9b, 9c, 9d, 9f, 9h
5 – 25
2
* If no. missing responses are ≤maximum allowed, the mean of the available responses can be used to substitute 
for the missing values in calculation of domain score. If no. of missing values is >maximum allowed the 
domain score cannot be calculated.
Further details about these eight domains can be found in the manual ‘SF-36 Health Survey -
Manual and Interpretation Guide’.
Each domain score is converted to a 0-100 scale norm-based score (a mean of 50 and a SD of 
10) based on the general U.S. population in 1998 using the following equation:
This transformation converts the domain scores to a value between 0 and 100, scores between 
these values represent the percentage of the total possible score achieved. 


100
range
score
raw
Possible
score
raw
possible
Lowest 
-
score
raw
Actual
score
Domain 








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Re-Scoring Responses
For all scores a linear relationship between the scores and health concept is assumed. The 
following scores are rescored to satisfy this assumption. Further details regarding this can be 
found in the SF36v2 Manual.
Bodily Pain (BP) – Questions 7 and 8
Question 7 Original Value
Question 7 New Value
1
6
2
5.4
3
4.2
4
3.1
5
2.2
6
1
Question 8 Original Value
Question 8 New Value
Q7 missing ,Q8 = 1
6
Q7 missing, Q8 = 2
4.75
Q7 missing, Q8 = 3
3.50
Q7 missing, Q8 = 4
2.25
Q7 missing, Q8 = 5
1.00
Q7 = 1, Q8 = 1
6
Q7 between 2 and 6, Q8 = 1
5
Q7 between 1 and 6, Q8 = 2
4
Q7 between 1 and 6, Q8 = 3
3
Q7 between 1 and 6, Q8 = 4
2
Q7 between 1 and 6, Q8 = 5
1


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General Health Perceptions (GH) – Questions 1 and 11a – 11d
Question 1 Original Value
Question 1 New Value
1
5
2
4.4
3
3.4
4
2
5
1
Question 11b and 11d
Original Value
Question 11b and 11d
New Value
Any
6 – Original Value
Vitality (VT) – Questions 9a, 9e, 9g and 9i
Question 9a and 9e
Original Value
Question 9a and 9e
New Value
Any
6 – Original Value
Social Functioning (SF) – Questions 6 and 10
Question 6 Original Value
Question 6 New Value
Any
6 – Original Value
Mental Health (MH) – Questions 9b – 9d, 9f and 9h
Question 9d and 9h
Original Value
Question 9d and 9h
New Value
Any
6 – Original Value
Calculation of Component Scores
Two component scores are calculated from the 8 domain scores; the physical component 
summary (PCS) and the mental component summary (MCS).
First the 8 domain scores are standardized using a z-score transformation based on scores 
from the general US population. This gives the 8 scores PF_Z, RP_Z, BP_Z, GH_Z, VT_Z, 
SF_Z, RE_Z, MH_Z.
Therefore:
PF_Z = (PF - 82.62455) / 24.43176
RP_Z = (RP – 82.65109) / 26.19282


deviation
Standard
Mean
-
score
Domain 
normalised
score
Domain 



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BP_Z = (BP – 73.86999) / 24.00884
GH_Z = (GH – 70.78372) / 21.28902
VT_Z = (VT – 58.41968) / 20.87823
SF_Z = (SF – 85.11568) / 23.24464
RE_Z = (RE – 87.50009) / 22.01216
MH_Z = (MH – 75.76034) / 18.04746
Each component score is than transformed to a norm based (mean = 50, SD = 10) score, based 
on the general U.S. population in 1998. This is achieved by multiplying each aggregated 
component scale score by 10 and adding the resulting product to 50.
Norm based Domain score = 50 + (Normalised Domain score * 10)
These scores are then aggregated using weights (factor score coefficients) which are specific 
to the physical and mental summary measures. The calculations are as below.
Physical Component Summary (PCS):
AGG_PHYS =  (PF_Z * 0.42402) + (RP_Z * 0.35119) + (BP_Z * 0.31754)
+ (GH_Z * 0.24954) + (VT_Z * 0.02877) + (SF_Z * – 0.00753)
+ (RE_Z * – 0.19206) + (MH_Z * – 0.22069)
Mental Component Summary (MCS):
AGG_MENT =   (PF_Z * – 0.22999) + (RP_Z * – 0.12329) + (BP_Z * – 0.09731)
+ (GH_Z * – 0.01571) + (VT_Z * 0.23534) + (SF_Z * 0.26876)
+ (RE_Z * 0.43407) + (MH_Z * 0.48581)
Functional Assessment of Chronic Illness Therapy-Fatigue
A 13-item FACIT-Fatigue Scale (Version 4)
The FACIT-Fatigue Scale is stand alone subscale consisting of 13 questions. All questions 
within this subscale employ a 5-point response scale ranging from 0 (Not at all) to 4 (Very 
much). All but two of the 13 responses are reversed prior to calculating the fatigue subscale 
score, this reversal is done by subtracting the responses from 4.
If there are missing responses to any questions, the Fatigue subscale score can be pro-rated as 
long as more than 50% of the responses are present (at least 7 questions have been answered).
The Fatigue subscale score is thus calculated by summing the individual item scores, 
multiplying by 13 (the number of items in the subscale) and dividing by the number of items 
actually answered. 
The Fatigue subscale score has values between 1 and 52, with the higher scores indicating 
better quality of life.
Fact-Th6
There are 6 items. The total score is calculated by summing Th3+Th4+ Th10+ Th11 + Th12 
and An7 after reversal. If there are missing responses to any questions, the Fact-Th6 subscale 
score can be pro-rated as long as more than 50% of the responses are present (at least 4 
questions have been answered).
TSQM-9
There are three domains in TSQM-9: Effectiveness, Convenience, and Global Satisfaction. 
Scores for each domain are computed by adding the TSQM items in each domain and then 
transforming the composite score into a value ranging from 0 to 100. A score can be computed for 
a domain only if no more than one item is missing. The calculations specific to each domain are 
presented in detail below.
Global Satisfaction 
([Sum(Item 7 to Item 9) – 3] divided by 14) * 100 
If either Item 7 or 8 is missing 


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([(Sum(the two completed items)) – 2] divided by 10) * 100
If Item 9 is missing 
([(Sum(Item7 and Item8)) – 2] divided by 8) * 100 
Effectiveness 
([(Item 1 + Item 2 + Item 3) – 3] divided by 18) * 100 
If one item is missing 
([(Sum(the two completed items – 2] divided by 12) * 100 
Convenience 
([Sum(Item 4 to Item 6) – 3] divided by 18) * 100 
If one item is missing
([(Sum(the two completed items)) – 2] divided by 12) * 100
6
References
1. Oncology guideline for safety analysis, v1.0, dated 09-Jun-2016
2. Cella D, Nowinski CJ. (2002) Measuring quality of life in chronic illness: the 
functional assessment of chronic illness therapy measurement system. Arch Phys Med 
Rehabil.  83(12Suppl):S10-S17.
3. Cella D, Beaumont JL, Webster KA, et al. (2006) Measuring the concerns of cancer
patients with low platelet counts: the Functional Assessment of Cancer Therapy –
thrombocytopenia (FACT-Th) questionnaire. Support Care Cancer. 14(12):1220-1231.
4. Signorovitch J, Brainsky A, Grotziner KM (2011) Validation of the FACIT-fatigue 
subscale, selected items from FACT-thrombocytopenia, and the SF-36v2 in patients 
with chronic immune thrombocytopenia. Qual Life Res. 20(10):1737-1744.
5. Ware JE (2000) SF-36 health survey update. Spine. 25:24:3130-3139.
6. Webster K, Cella D, Yost K. (2003) The Functional Assessment of Chronic Illness 
Therapy (FACIT) Measurement System: properties, applications, and interpretation. 
Health Qual Life Outcomes. 1:79.