A Phase II, Randomized (1:1) Open Label Study to Assess the Efficacy and Safety of Eltrombopag in Combination With Dexamethasone Compared to Dexamethasone, as First-line Treatment in Adult Patients With Newly Diagnosed Immune Thrombocytopenia
Phase: PHASE2
Conditions: Immune Thrombocytopenia (ITP)
Sponsor: Novartis Pharmaceuticals

Document type:
Amended Protocol Version
EUDRACT number:
2019-002658-21
Version number:
0 3 (Clean)
Clinical trial phase:
II
Release date:
28-Jul-2022
Property of Novartis
Confidential
May not be used, divulged, published, or otherwise disclosed
without the consent of Novartis 
Clinical Trial Protocol Template Version 2.0 (01-Aug-2018)
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Novartis Research and Development
ETB115/Eltrombopag
              Clinical Trial Protocol CETB115JDE01 / NCT04346654
A Phase II, randomized (1:1) open label study to assess the
 
 
efficacy and safety of eltrombopag in combination with
 
 
dexamethasone compared to dexamethasone, as first-line
 
 
treatment in adult patients with newly diagnosed immune
 
 
thrombocytopenia (XPAG-ITP)

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Amended Protocol Version 03 (Clean)
Protocol No. CETB115JDE01
Table of contents
Table of contents..................................................................................................................2
List of tables.........................................................................................................................5
List of figures.......................................................................................................................6
List of abbreviations ............................................................................................................7
Glossary of terms.................................................................................................................9
Amendment 3.....................................................................................................................10
Amendment 2.....................................................................................................................12
Amendment 1.....................................................................................................................14
Protocol summary..............................................................................................................16
1
Introduction........................................................................................................................21
1.1
Background............................................................................................................21
1.1.1
Current therapies and unmet medical needs..........................................21
1.1.2
Overview of disease pathogenesis, epidemiology and current 
treatment................................................................................................22
1.1.3
Overview of eltrombopag......................................................................22
1.2
Purpose...................................................................................................................24
2
Objectives and endpoints...................................................................................................24
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
4.2.1
Rationale for dose/regimen for eltrombopag.........................................27
4.2.2
Rationale for duration of treatment with eltrombopag and taper off 
initiation.................................................................................................28
4.3
Rationale for choice of dexamethasone regimen...................................................28
4.4
Purpose and timing of interim analyses/design adaptations ..................................29
4.5
Risks and benefits ..................................................................................................29
4.5.1
Risk associated with Eltrombopag use..................................................29
4.5.2
Benefits associated with Eltrombopag use............................................30
5
Population..........................................................................................................................31
5.1
Inclusion criteria ....................................................................................................32
5.2
Exclusion criteria ...................................................................................................32
6
Treatment...........................................................................................................................34
6.1
Study treatment ......................................................................................................34
6.1.1
Investigational and control drugs ..........................................................35
6.1.2
Additional study treatments...................................................................36
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Amended Protocol Version 03 (Clean)
Protocol No. CETB115JDE01
6.1.3
Treatment arms/group ...........................................................................36
6.1.4
Treatment duration ................................................................................36
6.2
Other treatment ......................................................................................................36
6.2.1
Concomitant therapy .............................................................................37
6.2.2
Prohibited medication............................................................................38
6.2.3
Rescue medication.................................................................................38
6.3
Patient numbering, treatment assignment, randomization.....................................38
6.3.1
Patient numbering..................................................................................38
6.3.2
Treatment assignment, randomization...................................................39
6.4
Treatment blinding.................................................................................................39
6.5
Dose escalation and dose modification..................................................................39
6.5.1
Dose escalation guidelines ....................................................................39
6.5.2
Dose modifications................................................................................39
6.5.3
Follow-up for toxicities.........................................................................42
6.6
Additional treatment guidance...............................................................................44
6.6.1
Treatment compliance ...........................................................................44
6.6.2
Emergency breaking of assigned treatment code ..................................44
6.7
Preparation and dispensation .................................................................................44
6.7.1
Handling of eltrombopag and dexamethasone ......................................44
6.7.2
Instruction for prescribing and taking study treatment..........................44
7
Informed consent procedures.............................................................................................45
8
Visit schedule and assessments..........................................................................................45
8.1
Screening................................................................................................................51
8.1.1
Information to be collected on screening failures .................................51
8.2
Patient demographics/other baseline characteristics..............................................51
8.3
Efficacy..................................................................................................................52
8.3.1
Efficacy assessment 1............................................................................52
8.3.2
Efficacy assessment 2............................................................................53
8.3.3
Appropriateness of efficacy assessments ..............................................53
8.4
Safety .....................................................................................................................53
8.4.1
Ophthalmic examination .......................................................................53
8.4.2
Laboratory evaluations..........................................................................54
8.4.3
Viral serology........................................................................................55
8.4.4
Electrocardiogram .................................................................................55
8.4.5
Pregnancy and assessments of fertility..................................................56
8.4.6
Appropriateness of safety measurements ..............................................56
8.5
Additional assessments ..........................................................................................56
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Protocol No. CETB115JDE01
8.5.1
Clinical Outcome Assessments (COAs)................................................56
57
8.5.3
Other Assessments.................................................................................58
9
Study discontinuation and completion...............................................................................58
9.1
Discontinuation......................................................................................................58
9.1.1
Discontinuation of study treatment .......................................................58
9.1.2
Withdrawal of informed consent...........................................................59
9.1.3
Lost to follow-up...................................................................................59
9.1.4
Early study termination by the sponsor.................................................59
9.2
Study completion and post-study treatment...........................................................60
10 Safety monitoring and reporting........................................................................................60
10.1
Definition of adverse events and reporting requirements......................................60
10.1.1
Adverse events.......................................................................................60
10.1.2
Serious adverse events...........................................................................62
10.1.3
SAE reporting........................................................................................63
10.1.4
Pregnancy reporting...............................................................................63
10.1.5
Reporting of study treatment errors including misuse/abuse ................64
10.2
Additional Safety Monitoring................................................................................64
10.2.1
Liver safety monitoring.........................................................................64
10.2.2
Steering Committee...............................................................................66
11 Data collection and database management ........................................................................66
11.1
Data collection .......................................................................................................66
11.2
Database management and quality control ............................................................67
11.3
Site monitoring.......................................................................................................67
11.4
Data privacy impact assessment ............................................................................68
11.4.1
Systematic description of the envisaged processing operations and 
the purposes of the processing...............................................................68
11.4.2
Assessment of the necessity and proportionality of the processing 
operations in relation to the purposes....................................................68
11.4.3
Assessment of the risks to the rights and freedoms of data subjects.....68
11.4.4
Measures envisaged to address the risks, including safeguards, 
security measures and mechanisms to ensure the protection of 
personal data and to demonstrate compliance with the GDPR 
taking into account the rights and legitimate interests of data 
subjects and other persons concerned....................................................69
12 Data analysis and statistical methods.................................................................................69
12.1
Analysis sets...........................................................................................................70
12.2
Subject demographics and other baseline characteristics ......................................70
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12.3
Treatments..............................................................................................................70
12.4
Analysis of the primary endpoint...........................................................................71
12.4.1
Definition of primary endpoint..............................................................71
12.4.2
Statistical model, hypothesis, and method of analysis ..........................71
12.4.3
Handling of missing values/censoring/discontinuations .......................72
12.4.4
Sensitivity and Supportive analyses......................................................72
12.5
Analysis of secondary endpoints............................................................................73
12.5.1
Efficacy endpoints.................................................................................73
12.5.2
Safety endpoints ....................................................................................74
76
12.5.4
Patient reported outcomes .....................................................................76
76
12.7
Interim analyses .....................................................................................................77
12.8
Sample size calculation..........................................................................................77
12.8.1
Primary endpoint ...................................................................................77
13 Ethical considerations and administrative procedures.......................................................78
13.1
Regulatory and ethical compliance........................................................................78
13.2
Responsibilities of the investigator and IRB/IEC..................................................78
13.3
Publication of study protocol and results...............................................................78
13.4
Quality Control and Quality Assurance.................................................................78
14 Protocol adherence.............................................................................................................79
14.1
Protocol amendments.............................................................................................79
15 References..........................................................................................................................80
16 Appendices.........................................................................................................................83
16.1
Appendix 1: Examples of OATP and BCRP substrates ........................................83
16.2
Appendix 2: Bleeding Scales.................................................................................84
16.3
Appendix 3: HRQoL Questionnaires.....................................................................85
16.4
Appendix 4: Clinical Trials Privacy Impact Assessment.......................................92
List of tables
Table 2-1
Objectives and related endpoints...........................................................24
Table 6-1
Eltrombopag dosing guidance for patients not meeting criteria for 
sustained response .................................................................................35
Table 6-2
Dexamethasone dosing guidance for patients not meeting criteria 
for sustained remission..........................................................................35
Table 6-3
Investigational and control drug............................................................36
Table 6-4
Eltrombopag Dose Adjustments in ITP.................................................40
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Table 6-5
Criteria for dose adjustment based on liver enzyme and bilirubin 
levels......................................................................................................40
Table 8-1
Assessment Schedule.............................................................................46
Table 8-2
Physical assessments .............................................................................53
Table 8-3
Laboratory Assessments........................................................................54
58
Table 10-1
Guidance for capturing the study treatment errors including 
misuse/abuse..........................................................................................64
Table 16-1
OATP and BCRP Substrates .................................................................83
Table 16-2
Modified WHO Bleeding Scale.............................................................84
Table 16-3
FACIT-Fatigue Scale Version 4............................................................85
Table 16-4
SF-36V2 ................................................................................................86
List of figures
Figure 3-1
Study Design .........................................................................................26
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Protocol No. CETB115JDE01
List of abbreviations
AE
Adverse event
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase
AST
Aspartate aminotransferase
BCRP
Breast cancer resistance protein
CR
Complete response
CRF
Case report form 
CTCAE
Common Terminology Criteria for Adverse Event
ECG
Electrocardiogram
eCRF
Electronic case report form
EDC
Electronic Data Capture
EOS
End of study
FACIT
Functional Assessment of Chronic Illness Therapy
FAS
Full analysis set
GGT
Gamma-glutamyl transferase
HbsAg
Hepatitis B surface antigen
HBV
Hepatitis B virus
HCV
Hepatitis C virus
HDD
High dose dexamethasone
HIV
Human immunodeficiency virus
HMG-CoA
3-hydroxy-3-methylglutaryl coenzyme A
HRQoL
Health-Related Quality of Life
IB
Investigator’s Brochure
ICF
Informed consent form
ICH
International Conference on Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use
IEC
Independent Ethics Committee
INR
International Normalized Ratio
IPF
Immature platelet function
IRB
Institutional Review Board
ITP
Immune thrombocytopenia
IVIg
Intravenous immunoglobulin
LDH
lactate dehydrogenase
LFT
Liver function test 
MCS
Mental Component Summary
MedDRA
Medical dictionary for regulatory activities 
NSAIDs
Nonsteroidal anti-inflammatory drugs
OR
Overall response
ORR
Overall response rate
QD
Once daily
PCS
Physical Component Score
PR
Partial response
PRO
Patient reported outcomes
PT
Prothrombin time
QD
Once daily
QMS
Quality Management System
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QTcF
QT interval corrected by Fridericia’s formula
SAE
Serious adverse event
SAP
Statistical Analysis Plan
SC
Steering Committee
SD
standard deviation
SF36v2
Short Form 36 version 2
TBIL
Total bilirubin
TEE
Thromboembolic event
TPO
Thrombopoietin
TPO-R
Thrombopoietin receptor
TPO-RA
Thrombopoietin receptor agonist
ULN
Upper limit of normal
WHO
World Health Organization 
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Protocol No. CETB115JDE01
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 
study treatment.
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 subject in a time unit (e.g. 100 mg once a day, 
75 mg twice a 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
Premature subject 
withdrawal
Point/time when the patient exits from the study prior to the planned completion of all 
study drug administration and/or assessments; at this time all study drug administration 
is discontinued and no further assessments are planned
Randomization 
number
A unique identifier assigned to each randomized patient
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 any of the study drug(s) 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 
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.
Treatment 
arm/group 
A treatment arm/group defines the dose and regimen or the combination, and may 
consist of 1 or more cohorts.
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
Victim drug 
The drug that is affected by the drug-drug interaction
Withdrawal of study 
consent
Withdrawal of consent from the study occurs only when a patient does not want to 
participate in the study any longer and does not allow any further collection of personal 
data 
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Protocol No. CETB115JDE01
Amendment 3
Amendment rationale from protocol version 02
The primary purposes of this protocol amendment are as follows:
•
Due to slow enrollment the feasibility of this trial has been considered and an 
amendment is necessary. Recruitment was possible as of June 2020. First patient was 
recruited on 09th october 2020 and the intended sample size of 106 patient was planned 
to be recruited within 18 months. So far, only 21 out of the approximately 106 
anticipated patients (20%) were enrolled in the study within 24 months. It is very 
unlikely that the number of patients required to determine the primary endpoint will be 
achieved within a reasonable time. A repeated problematic pattern in the current 
pandemic situation is that study centers report fewer eligible patients than anticipated. 
Study centers with a successful performance in previous studies failed to meet 
enrollment or failed to enroll any subject at all. 
•
The inclusion/exclusion criteria were chosen to result in a population that matches the 
intended general patient population. However, the exclusion criteria 2 (patients with 
diagnosis of secondary thrombocytopenia) accounts to additional concerns in finding 
suitable participants in view of the COVID-19 situation and the COVID-19 vaccination. 
There are two types of ITP: primary and secondary. Secondary ITP is sometimes caused 
by infectious diseases, vaccines, and other drugs. It is impossible to strictly distinguish 
between vaccine-induced secondary ITP and incidental primary ITP that occurred soon 
after COVID-19 vaccination. This complexity poses an additional challenge to timely 
diagnose suitable patients for this trial. 
•
In order to report the study results to support therapeutic advances as quickly as is 
reasonable, we propose the following changes to the protocol:
o
Premature termination of recruitment due to feasibility reasons, resulting in an 
expected sample size of ca. 24 patients at the time of approval by the EC/HA. A 
scenario based on 12 patients per group, assuming the above rates of 30 versus 
65%, would allow for a power of 24% to analyze the primary endpoint. 
Consequently, all analyses will be interpreted in a purely descriptive manner.
o
Reduction of the follow-up for responders after Week 52 (secondary endpoint 
number 3). Assuming that 65% of the patients in the combination arm will be in 
sustained response off treatment at Week 52 and in respect to slow enrollment, 
the sample size for this secondary endpoint would be insufficient to detect a 
meaningful result
o
Based on the proposed changes to reduce the follow-up of the responders it will 
be able to share the study data 6 months earlier to increase the benefits of future 
patients and support recent updates in ITP guidelines to prevent an extended and 
recurrent use of corticosteroids that is associated with substantial toxicity. 
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Amended Protocol Version 03 (Clean)
Protocol No. CETB115JDE01
Changes to the protocol: 
Changes to specific sections of the protocol are shown in track change version.
Changes were made to the following sections:
•
Protocol summary section updated to match the body of the protocol.
•
Section 2 Table 2-1 Objectives and endpoints: Deleted endpoint 3 to reduce follow-up 
of patients. With this change no patient will be followed-up after Week 52. 
•
Section 3.1: Study design: Updated to reflect changed study duration. No follow-up of 
patients after Week 52. 
•
Section 4.2.1 Rationale for dose/regimen for eltrombopag adjusted to correct 
inconsistencies
•
Section 5.2: Exclusion criteria: Changed to restrict thromboembolic events to 6 
months before enrollment.
•
Section 6: Study treatment: Eltrombopag dosing guidelines adjusted to correct 
inconsistencies
•
Section 6 Table 6-1: Changes to reflect the reduction of the follow-up. No follow-up of 
patients beyond Week 52. 
•
Section 6.1.4 Treatment duration: Updated to reflect the changed follow-up of patients 
and to clarify that all patients have to discontinue the study latest at Week 52. 
•
Section 6 Table 6-2: Changes to reflect the reduction of the follow-up. No follow-up of 
patients beyond Week 52. 
•
Section 6.2.3 Rescue Medication: Updated to reflect the changed follow-up of patients 
and to clarify that all patients have to discontinue the study latest at Week 52. 
•
Section 8.2 Patient demographics/other baseline characteristics: Changes to required 
screening assessments to allow use of laboratory exams (hematology except 
thrombocyte counts, coagulation, chemistry and viral serology) performed as per local 
practice or under a local protocol within 14 days before randomization (prior to 
signing the study specific informed consent form and start of screening for the study) 
for the purposes of study inclusion.
•
Section 6 Table 6-4: Eltrombopag dosing adjusted to correct inconsistencies
•
Section 8.3.1 Efficacy Assessment 1: Updated to reflect the changed follow-up of 
patients and to clarify that all patients have to discontinue the study latest at Week 52. 
•
Section 8 Table 8-1 Assessments Schedule: Footnote added to clarify that if laboratory 
assessment (hematology except thrombocyte counts, coagulation, chemistry and viral 
serology) data are already available from exams performed within 14 days before 
randomization as per local practice or under a local protocol (prior to signing the study 
specific informed consent form and start of screening for the study, then these may be 
used for the purposes of study inclusion. No changes to required thrombocyte 
assessments. 
•
Section 8.4.2 Table 8-4 Laboratory Assessments: Deletion of chemistry assessment: 
bicarbonate. Updated coagulation parameters. 
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•
Section 12.5.2 Efficacy endpoints: Updated appropriate endpoints to reflect deleted 
endpoint 3. With this change no patient will be followed-up after Week 52.
•
Section 12.8.1 Primary endpoint: Sample size calculation. As described above, with 
Amendment 3 recruitment will be prematurely discontinued. A final number of ca. 24 
patients is expected to be recruited by the time of approval. The analyses will be 
interpreted in a purely descriptive manner.
•
In addition, minor inconsistencies and typos in the protocol have been corrected
IRB/IEC
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. It is required to update and submit for approval 
a revised Informed Consent that takes into account the changes described in this protocol 
amendment.
Amendment 2
Amendment rationale from protocol version 01
The primary purposes of this protocol amendment are as follows:
•
Due to slow enrollment an amendment is necessary. Recruitment was possible as of 
June 2020 and first patient was recruited on 09th October 2020. 
•
It was decided to relax inclusion criteria to one single assessment of thrombocyte count 
at the time of screening, and omitting the second threshold check at baseline. This was 
due to the fact that for some patients the thrombocyte count was below the pre-specified 
threshold at screening, but above at baseline and after pre-treatment.
•
In addition, if pre-treatment is necessary, platelet count data performed directly before 
pre-treatment (prior to signing the study specific informed consent form and start of 
screening for the study as per local practice or under a local protocol) will be used for 
study inclusion (screening value to be used for inclusion/exclusion check and for 
analysis as a covariate). Treatment-naïve patients will be included based on their platelet 
counts performed at screening. The rationale was that the baseline thrombocyte 
threshold check following pre-treatment was deemed of neglible impact regarding the 
primary outcome of sustained response off treatment at week 52. Thus, it was decided 
to omit the second check.
As a consequence, it was decided to also include the screening instead of baseline 
thrombocyte count as a cofactor into the statistical model for the primary outcome 
analysis, as this was regarded as the more adequate way of taking into account the initial 
value at the time of diagnosis and before pre-treatment for all patients. Additional 
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sensitivity analyses were included to assess the impact of pre-treatment and baseline 
thrombocyte count.
Changes to the protocol: 
Changes to specific sections of the protocol are shown in track change version.
Changes were made to the following sections:
•
Protocol summary section updated to match the body of the protocol.
•
Section 2 Table 2-1 Objectives and endpoints: Updated appropriate endpoints to include 
screening instead of baseline thrombocyte. 
•
Section 3.1: Study design: Changes to allowed dexamethasone treatment in Arm B. In 
case a patient in the treatment Arm B (dexamethasone monotherapy) needs treatment 
cycles at an interval of less than 28 days, the dexamethasone can also be given at 14 to 
28 days intervals according to current ITP guidelines.
•
Section 4.3. Rationale for choice of dexamethasone regimen: Changes to allowed 
dexamethasone treatment in Arm B (see Section 3.1)
•
Section 5.1 Inclusion criteria: Changes to required platelet count assessment data that 
are required for the purposes of study inclusion. If pre-treatment is necessary, platelet 
count data performed directly before pre-treatment (prior to signing the study specific 
informed consent form and start of screening for the study as per local practice or 
under a local protocol) can be used for study inclusion (screening value). Treatment-
naïve patients will be included based on their platelet counts performed at screening.
•
Section 5.1 Exclusion criteria: Changes to pre-treatment duration before randomization 
to optimize recruitment. Patients in need of immediate treatment for thrombocytopenia 
while diagnosis or eligibility are being determined may receive treatment with any ITP-
directed therapy for a maximum of 3 days within 7 days before randomization.
•
Section 6.0 Study treatment: Changes to allowed dexamethasone treatment in Arm B 
(see Section 3.1)
•
Section 8 Table 8-1: Footnote added to clarify that if pre-treatment is necessary, platelet 
count data performed directly before pre-treatment (prior to signing the study specific 
informed consent form and start of screening for the study as per local practice or under 
a local protocol) will be used for study inclusion (screening value). Treatment-naïve 
patients will be included based on their platelet counts performed at screening. In 
addition a footnote was added to reflect that ocular assessment has to be done within 28 
days after study start. If ocular assessment data are already available from exams 
performed within 28 days prior to screening (prior to signing the study specific informed 
consent form and start of screening for the study as per local practice or under a local 
protocol), then these may be used for the purposes of study inclusion.
•
Section 8.4.1 Ophthalmic examination: Changes to required ocular assessment data 
required for the purposes of study inclusion (see previous Section 8 Table 8-1). 
•
Section 12 Data analysis and statistical methods: Updated to clarify that the baseline is 
the result of an investigation describing the state of the patient before start of 
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eltrombopag or dexamethasone study treatment, and after a possible pre-treatment. The 
screening value describes the result at screening, before pre-treatment. Should a patient 
not need pre-treatment, screening and baseline values can be identical. In such cases, as 
only one assessment exists, the baseline value will be taken from screening.
•
Section 12.4.1 Definition of primary endpoint: A note of was added to clarify that in 
case a patient in the treatment Arm B (dexamethasone monotherapy) needs treatment 
cycles at an interval of less than 28 days (at least 14 days), and meets the definition for 
sustained response off treatment, such patient will be counted as a responder for 
statistical analysis.
•
Section 12.4.2 Statistical model, hypothesis, and method of analysis: Updated to 
include the screening instead of baseline thrombocyte count as a cofactor into the 
statistical model for the primary outcome analysis.
•
Section 12.4.4 Sensitivity and Supportive analyses: Additional sensitivity analyses 
were included to assess the impact of pre-treatment and baseline thrombocyte count on 
the primary outcome analysis.
•
Section 12.5.2 Efficacy endpoints: Updated appropriate endpoints to include screening 
instead of baseline thrombocyte. 
•
In addition, minor inconsistencies and typos in the protocol have been corrected
IRB/IEC
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 do not affect the Informed Consent.
Amendment 1
Amendment rationale from protocol version 00
The primary purposes of this protocol amendment are to:
•
Address the requirement of the Ethics committee to include a more detailed information 
on the recruitment procedure in the protocol. Version 00 of this protocol was approved 
by end of March by the German health authority (Bundesamt für Arzneimittel und 
Medizinprodukte, BfArM) and by the Ethics Committee Halle-Wittenberg. As feedback, 
inclusion of recruitment procedures were requested by the Ethics Committee, which is 
covered in this amendment.
•
In addition, other clarifications and administrative changes were included as needed. 
Changes from V00 to the protocol: 
Changes to specific sections of the protocol are shown in track change version.
Changes were made to the following sections:
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•
Section 5.0 Population: Information of recruitment procedure of study participants was 
added. 
•
Section 8 Table 8-1 Assessment schedule: Footnotes were added to clarify assessments 
that are required per protocol at the End of Study visit (EOS) for patients with 
premature study withdrawal before or after week 52 and to clarify when the patients 
should be seen for a Safety follow-up visit. In addition an administrative change was 
included to match the appropriate adverse event monitoring.
•
Section 8.4.2 Lab assessments: Quick-test was added as measurement to evaluate 
coagulation.
•
Section 12.5.1 Clarification to the secondary endpoint 2. Duration of sustained response 
off treatment will be assessed until loss of response and not only until Week 52.
•
Section: 12.5.2 Safety endpoints: Updated information on safety monitoring to align 
with information in Section 10.  
•
In addition, minor inconsistencies and typos in the protocol have been corrected.
IRB/IEC
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 do not affect the Informed Consent.
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Protocol No. CETB115JDE01
Protocol summary
Protocol number
CETB115JDE01
Full Title
A Phase II, randomized (1:1) open label study to assess the efficacy and safety 
of 
eltrombopag 
in 
combination 
with 
dexamethasone 
compared 
to 
dexamethasone, as first-line treatment in adult patients with newly diagnosed 
immune thrombocytopenia (XPAG-ITP)
Brief title
A study to assess efficacy and safety of eltrombopag in combination with a 
short course of high-dose dexamethasone compared to 1-3 cycles of 
dexamethasone alone in patients with newly diagnosed ITP
Sponsor and 
Clinical Phase
Novartis
II
Investigation type
Drug
Study type
Interventional
Purpose and 
rationale
The purpose of this study is to compare the ability of eltrombopag in 
combination with a short course of high-dose dexamethasone to induce 
sustained response off treatment in patients with newly-diagnosed ITP versus 
1-3 cycles of dexamethasone monotherapy. 
The unmet clinical need and the potential for eltrombopag when added to 
steroids to improve the treatment outcome and the potential to induce 
sustained response off treatment serve as the basis for clinical investigation of 
eltrombopag in first-line ITP. One ongoing study is assessing the ability of 
eltrombopag to induce sustained response off treatment in patients with ITP, 
who are early refractory to or who relapsed after initial treatment with first-line 
steroids but not in patients with newly diagnosed ITP who have not received 
any pre-treatment. This trial is designed to assess this.
Primary Objective 
To compare the ability of eltrombopag in combination with a short course of 
dexamethasone to induce a sustained response off treatment at 52 weeks 
versus a defined course of dexamethasone
Secondary 
Objectives
1.
To compare the ability of eltrombopag in combination with a short course 
of dexamethasone to induce overall response (OR) after treatment 
discontinuation at Week 52 versus a defined course of dexamethasone
2.
To assess the duration of sustained response off treatment 
3.
To assess the ability of eltrombopag to induce overall response (OR) by 
Week 4
4.
To assess the ability of eltrombopag to induce complete response (CR) by 
Week 4
5.
To quantify the increase in platelet count from screening to baseline and 
to 1, 2, 4, 12, 26 and 52 weeks
6.
To assess the time to overall and complete response
7.
To assess the duration of overall and complete response
8.
To evaluate patient-oriented outcomes for health-related quality of life
9.
To evaluate the safety and tolerability of eltrombopag + dexamethasone
10. To evaluate the incidence and severity of bleeding events
Study design
This is a Phase II, multicenter, randomized (1:1), open-label study to compare 
the efficacy and safety of eltrombopag in combination with a short course of 
high-dose dexamethasone to 1-3 cycles of high-dose dexamethasone 
monotherapy, as first-line treatment in adult patients with newly diagnosed ITP
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Population
The study is designed to include 106 adult patients with newly diagnosed 
primary ITP with screening platelet count < 30 × 109/L and assessed as 
required treatment (per physician’s discretion). 
According to Amendment 3 for premature discontinuation of recruitment, the 
planned sample size will not be reached, expecting in a total of ca. 24 patients 
by the time of approval of Amendment 3.
Key Inclusion 
criteria
1.
Signed informed consent must be obtained prior to participation in the 
study.
2.
Men and women ≥ 18 years of age
3.
Newly diagnosed with primary ITP (time from diagnosis within 3 months)
Platelet count < 30 × 109/L at screening and a need for treatment (per 
physician’s discretion) 
Note: If pre-treatment is necessary, platelet count data performed directly 
before pre-treatment (prior to signing the study specific informed consent 
form and start of screening for the study as per local practice or under a 
local protocol) will be used for study inclusion (screening value to be used 
for inclusion/exclusion check and for analysis as a covariate). Treatment-
naïve patients will be included based on their platelet counts performed at 
screening
Key Exclusion 
criteria
1.
Previous history of treatment for ITP
Note: Patients in need of immediate treatment for thrombocytopenia while 
diagnosis or eligibility are being determined may receive treatment with 
any ITP-directed therapy for a maximum of 3 days within 7 days before 
randomization. These therapies must be discontinued before the patient 
receives the first dose of study treatment
2.
Patients with diagnosis of secondary thrombocytopenia
3.
Patients who have life threatening bleeding complications per physician´s 
discretion
4.
Patients with a history of thromboembolic events in the 6 months preceding 
enrollment or known risk factors for thromboembolism (e.g. Factor V 
Leiden, ATIII deficiency, antiphospholipid syndrome) are excluded. 
Patients with other risk factors which may pose an increased 
thromboembolic event (TEE) risk (prolonged periods of immobilization, 
malignancies, contraceptives and hormone replacement therapy, 
surgery/trauma, obesity and smoking) would be excluded according to the 
discretion of the investigator
5.
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
6.
Total bilirubin (TBIL) > 1.5 × upper limit of normal (ULN)
7.
Aspartate transaminase (AST) > 3.0 × ULN
8.
Alanine transaminase (ALT) > 3.0 × ULN
9.
Patients who are human immunodeficiency virus (HIV), HCV or hepatitis B 
surface antigen (HBsAg) positive.
10. Patients with hepatic impairment (Child-Pugh score > 5)
11. Patients with known active or uncontrolled infections not responding to 
appropriate therapy
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12. History of current diagnosis of cardiac disease or impaired cardiac function 
denoted by any of the following:
•
Corrected QTc >450 msec using Fridericia correction (QTcF) on 
the screening electrocardiogram (ECG) 
•
History of myocardial infarction and unstable angina within 
6 months prior to starting study treatment
•
Clinically significant cardiac arrhythmias or other clinically 
significant cardiovascular disease (e.g., congestive heart failure, 
uncontrolled hypertension) within the six months prior to starting 
study treatment
13. Patients who have active malignancy
14. Patients with evidence of current alcohol/drug abuse
15. Any serious and/or unstable pre-existing medical (including any advanced 
malignancy other than the disease under study), psychiatric disorder, or 
other conditions that could interfere with subject’s safety, obtaining 
informed consent or compliance with the study procedures. 
16. 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
17. Patients with pre-existing medical conditions that are known precautions 
with corticosteroid use, in whom the potential risks of participating in the 
study outweigh the potential benefits as determined by the investigator
18. Female subjects who are nursing or pregnant (positive serum or urine 
B-human chorionic gonadotrophin (B-hCG) pregnancy test) at screening 
or pre-dose on Day 1
19. Women of child-bearing potential, defined as all women physiologically 
capable of becoming pregnant, unless they are using highly effective 
methods of contraception while taking study treatment and for 7 days after 
stopping medication. Highly effective contraception methods include:
•
combined (estrogen and progestogen containing) hormonal 
contraception associated with inhibition of ovulation1:
•
oral
•
intravaginal
•
transdermal
•
progestogen-only hormonal contraception associated with 
inhibition of ovulation1:
•
oral
•
injectable
•
implantable2
•
intrauterine device (IUD)2 
•
intrauterine hormone-releasing system (IUS)2 
•
bilateral tubal occlusion2 
•
vasectomised partner2,3 
•
sexual abstinence4
 
1Hormonal contraception may be susceptible to interaction with the IMP, which 
may reduce the efficacy of the contraception method (see section 4.3).
2 Contraception methods that in the context of this guidance are considered to 
have low user dependency.
3 Vasectomised partner is a highly effective birth control method provided that 
partner is the sole sexual partner of the WOCBP trial participant and that the 
vasectomised partner has received medical assessment of the surgical success.
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4 In the context of this guidance sexual abstinence is considered a highly effective 
method only if defined as refraining from heterosexual intercourse during the 
entire period of risk associated with the study treatments. The reliability of sexual 
abstinence needs to be evaluated in relation to the duration of the clinical trial 
and the preferred and usual lifestyle of the subject.
Study treatment
Eltrombopag and dexamethasone are both investigational drugs. Patients 
randomized to Arm A will receive eltrombopag in combination with a short 
course of high-dose dexamethasone beginning at Day 1. The dose of 
dexamethasone will be 40 mg QD for 4 consecutive days (dexamethasone 
therapy is limited to 1 cycle). The starting dose of eltrombopag will be 50 mg 
QD and treatment will continue at the same dose for 2 weeks to reach a target 
platelet count of 50 × 109/L as necessary to reduce the risk for bleeding. The 
dose of eltrombopag will be increased by 25 mg increments every 2 weeks to 
a maximum dose of 75 mg QD for all patients who do not achieve the target 
platelet count of ≥ 50 × 109/L. Treatment with eltrombopag will be continued at 
the minimal dosage necessary to maintain a platelet count ≥ 50 × 109/L to 
150 × 109/L for 20 weeks. Asian patients will initially receive half of the dose, 
starting at 25 mg of eltrombopag due to lower clearance of eltrombopag as 
compared with non-asian patients. The dose of eltrombopag will be decreased 
by 25 mg if platelet counts are > 150 × 109/L to ≤ 400 × 109/L by 25 mg and 
the effect will be assessed after 2 weeks.
Patients who reach platelet counts ≥ 30 × 109/L and maintain counts 
≥ 30 × 109/L during the tapering phase will be eligible for treatment 
discontinuation. Duration of tapering before treatment discontinuation at Week 
26 will be 6 weeks. Decrease in dose will be performed by 25 mg reductions 
every 2 weeks to a minimum dose of 25 mg every other day for all patients.
Treatment in Arm B consists of 1-3 cycles of high-dose dexamethasone 
administered orally at a dose of 40 mg QD for 4 consecutive days at 2-4 weeks 
intervals. If the platelet counts are > 150 × 109/L no further course of 
dexamethasone will be given. Patients will be treated up to 12 weeks 
(3 months) during the treatment period with dexamethasone. Patients who 
reach platelet counts ≥ 30 × 109/L and maintain counts ≥ 30 × 109/L after 
1-3 cycles of high-dose dexamethasone treatment will be eligible for treatment 
discontinuation. Patients with platelet counts < 30 × 109/L after 3 cycles of 
dexamethasone treatment will be offered a course of eltrombopag treatment 
within the study and will discontinue the study after completion of treatment 
with eltrombopag at Week 52.
Efficacy 
assessments
Platelet count will be assessed at screening visit to assess the eligibility of the 
subject.  If pre-treatment is necessary, platelet count data performed directly 
before pre-treatment (prior to signing the study specific informed consent form 
and start of screening for the study as per local practice or under a local 
protocol) will be used for study inclusion (screening value to be used for 
inclusion/exclusion check and for analysis as a covariate). Hematology 
including platelet counts will be performed at Week 1/Day 1 (i.e. baseline), and 
weekly during the first 4 weeks of treatment. Based on subject’s response, 
hematology will be performed biweekly thereafter until Week 33 Day 1 and 
every 4 weeks till Week 53 Day 1. 
Additional assessments of platelet count may be performed more frequently 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 Form (CRF) and in addition on an unique CRF for 
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bleeding events. Documentation of the use of any rescue therapy will be 
documented on the appropriate CRF.
Key safety 
assessments
•
Physical assessments: Physical examination, vital signs, height and 
weight
•
Ophthalmic examination
•
Laboratory evaluations
•
Electrocardiogram
•
Pregnancy testing
Other 
assessments 
•
Functional 
Assessment 
of 
Chronic 
Illness 
Therapy-Fatigue 
(FACIT-Fatigue)
•
Medical Outcome Trust’s Short-Form 36 Health Survey, Version 2 (SF-36 
v2)
Data analysis
The primary endpoint is the proportion of patients with sustained response off 
treatment at 52 weeks.
Sustained response off treatment is defined as:
•
reach platelet count ≥ 30×109/L and then maintain platelet counts 
≥ 30 × 109/L after treatment discontinuation AND
•
maintain platelet count ≥ 30 × 109/L in the absence of bleeding events 
≥ Grade 2 and without the use of any rescue therapy at all visits until 
Week 52.
The primary analysis will be performed comparing the treatment groups with 
respect to the primary efficacy outcome, based on the Odds Ratio, in a Logistic 
Regression model with the factor treatment and cofactors ITP-directed 
pre-therapy (during 3 out of 7 days before randomization), screening platelet 
count and age (≤ vs. > 60 years). The odds ratio and its 95% confidence 
interval (CI) and p-value will be given.
As a consequence of Amendment 3, all analyses will be interpreted in a purely 
descriptive manner.
Key words
Eltrombopag, immune thrombocytopenia, ITP, corticosteroids
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1
Introduction
1.1
Background
1.1.1
Current therapies and unmet medical needs
The primary goal of treatment in immune thrombocytopenia (ITP) is to prevent bleeding by 
increasing the platelet count that confers adequate hemostasis and minimizes the risk of 
clinically significant bleeding, avoiding as much as possible treatment-related toxicity. 
Initial management is dependent upon several factors, including severity of thrombocytopenia, 
bleeding risk, patient’s age and comorbidities, and the side effect profiles associated with 
therapy. While there is limited evidence to determine a minimum platelet threshold at which a 
patient with ITP should be treated, there is substantial agreement that treatment is indicated in 
the presence of bleeding symptoms (Cines and Bussel 2005). Observational data of ITP patient 
cohorts indicate that risk of clinically significant bleeding increases with increasing severity of 
thrombocytopenia and as such, a platelet threshold of < 20-30 × 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 et al 2011).
Traditional first-line therapy includes oral corticosteroids, intravenous immunoglobulin (IVIg) 
and anti-D immunoglobulin. With conventional first-line treatment, initial response rates are 
70-80%, however only a small proportion of treated patients will sustain durable platelet 
responses following the initial treatment course (Provan et al 2010). Corticosteroids will 
generally induce a response within the first 2 weeks, but < 30% of initial responders will sustain 
durable responses and will relapse within the first year, most commonly during steroid taper, or 
shortly after discontinuation (Cooper 2017). Currently available corticosteroids for ITP include 
prednisone, prednisolone, dexamethasone, with prednisone and dexamethasone being the most 
widely used. 
Options for salvage therapy include retreatment with corticosteroids, a combination of first-line 
agent(s), or treatment with a second-line agent. Long-term administration of corticosteroids is 
limited by the development of side effects, including peripheral edema, hypertension, 
heartburn/peptic ulcers, anxiety, insomnia, agitation, Cushingoid features, diabetes, cataracts, 
potassium 
loss, 
osteoporosis, 
and 
other 
adverse 
experiences. 
Furthermore, 
corticosteroid-treated patients are at increased risk of infections (Portielje et al 2001, Stasi et al 
1995, Pizzuto and Ambriz, 1984).
While corticosteroids remain the standard of care, high relapse rates and considerable toxicity 
associated with long-term corticosteroid use highlight a significant unmet medical need in 
management of first-line ITP. Novel therapeutic approaches are warranted that achieve durable 
responses and reduce the need for long-term corticosteroid use.
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1.1.2
Overview of disease pathogenesis, epidemiology and current 
treatment
Primary immune thrombocytopenia is an acquired, immune-mediated disorder of adults and 
children. It is defined as a platelet count of < 100 × 109/L, in the absence of other causes or 
disorders that may be associated with thrombocytopenia (Rodeghiero et al 2009, Provan et al 
2010).
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 et al 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 et al 2013).
The clinical manifestations of ITP are characterized by an increased tendency to bleed, 
spontaneously or after a hemostatic challenge. The degree of bleeding is largely dependent on 
the severity of thrombocytopenia, with platelet counts < 20-30 × 109/L conferring the greatest 
risk of clinically significant bleeding (George et al 1996, Guidelines l British Society for 
Haematology 2003). Mucocutaneous bleeding involving the skin, oral cavity and 
gastrointestinal tract is the most common clinical manifestation in ITP. 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 most serious and life-threatening bleeding 
complications are intracranial hemorrhages, reported in 1.5-1.8% of adult patients (Lambert and 
Gernsheimer 2017, Neunert et al 2015, Kühne et al 2001). 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 et al 2000).
Based on the disease duration from initial confirmed ITP diagnosis, there are three categories 
of patients: newly diagnosed (diagnosis ≤ 3 months), persistent ITP (between 3 and 12 months 
from diagnosis), and chronic ITP (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 et al 2009, Provan et al 2010).
1.1.3
Overview of eltrombopag
Thrombopoietin (TPO) is the principal cytokine involved in the regulation of megakarypoiesis 
and platelet production. In addition to megakaryocytic cells, hematopoietic stem cells also 
express the TPO receptor and depend on TPO signaling for their maintenance and expansion 
(Geddis 2010)
Eltrombopag (ETB115) is an oral, small-molecule, non-peptide thrombopoietin receptor 
agonist (TPO-RA) that increases hematopoiesis by inducing proliferation and differentiation of 
early bone marrow progenitor cells leading to increased platelet production (Erickson-Miller et 
al 2010, Sun et al 2012). 
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Eltrombopag has demonstrated efficacy in adult and pediatric patients with chronic ITP and has 
a well-established safety profile. It is approved in over 100 countries for the treatment of 
thrombocytopenia in patients with chronic ITP who have had an insufficient response to 
corticosteroids, immunoglobulins, or splenectomy. Eltrombopag has also been approved for the 
treatment of adult patients with hepatitis C virus (HCV)-related thrombocytopenia in over 
45 countries. 
More recently, eltrombopag has also been approved in both the EU and USA for the treatment 
of adult patients with SAA who have had insufficient responses to immunosuppressive therapy. 
The benefit risk remains favorable in all approved indications,
Rationale for development in first-line ITP: 
The efficacy of eltrombopag for achieving hemostatic platelet counts in previously treated adult 
ITP patients with higher than 6-month disease duration is around 80%. However, not many 
studies to date analyzing safety and efficacy of TPO-RAs in newly diagnosed ITP are published. 
Supporting data on the combination of TPO agonists including eltrombopag in combination 
with steroids in the setting of first-line ITP include results of a study of 12 newly diagnosed ITP 
patients treated with a combination of high-dose dexamethasone (Days 1-4) and eltrombopag 
(Days 1-28), where 6/12 patients exhibited platelet counts > 100 × 109/L at 6 months and 
8/12 patients maintained platelet counts > 30 × 109/L at 12 months (Gomez-Almaguer et al 
2014).
A recent study of 196 ITP patients randomized to receive high-dose dexamethasone in 
combination with subcutaneous recombinant human-TPO or high-dose dexamethasone 
monotherapy, superior 6-month sustained response rates were exhibited with combination 
therapy (overall response (OR): 51% vs 36.5%; complete response (CR): 46.0% vs 32.3%) 
(Wang et al 2017) and supports the idea that a frontline combination therapy with eltrombopag 
and steroids could restore an immune tolerance in a greater proportion of patients compared to 
a steroid-monotherapy.
There is also growing literature that suggest that a proportion of patients may exhibit durable 
platelet responses following discontinuation of eltrombopag.
In a retrospective review of 260 adult primary ITP patients treated with eltrombopag after a 
median time from diagnosis of 24 months, among the 49 evaluable patients who achieved 
complete remission with eltrombopag and discontinued further treatment, 26 patients 
maintained platelet counts > 100 × 109/L with a median follow-up of 9 months. These patients 
had received a median of four previous treatments and were characterized with a median time 
since diagnosis of 46 months. In an additional retrospective review of 12 patients with chronic 
ITP with a median time from diagnosis to eltrombopag initiation of 24 months and a median 
number of 5 prior therapies, sustained responses after discontinuing eltrombopag with platelet 
counts > 100 x 109 were identified in 10/12 patients with a median follow-up of 7 months 
(Gonzalez-Lopez et al 2015a, Gonzalez-Lopez et al 2015b).
Data from a pilot study evaluating whether a 12-week course of eltrombopag plus pulsed 
dexamethasone in newly-diagnosed ITP can increase the proportion of patients with prolonged 
response, showed a prolonged response rate in 19 of 34 evaluable patients (Zhang et al 2018).
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The underlying immune mechanism that restores immune tolerance and give rise to a sustained 
response after discontinuing eltrombopag are unknown. However, there is growing evidence 
from preclinical studies that TPO-RA dampen immune responses in chronic ITP by increasing 
the levels of anti-inflammatory cytokines and 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 et al 2010, Liu et al 2016, Qu et al 2017).
1.2
Purpose
The unmet clinical need and the potential for eltrombopag when added to steroids to improve 
the treatment outcome and the potential to induce sustained response off treatment serve as the 
basis for clinical investigation of eltrombopag in first-line ITP. One ongoing study is assessing 
the ability of eltrombopag to induce sustained response off treatment in patients with ITP, who 
are early refractory to or who relapsed after initial treatment with first-line steroids but not in 
patients with newly diagnosed ITP who have not received any pre-treatment. 
We will therefore conduct a prospective trial of eltrombopag in patients with newly-diagnosed 
ITP to compare the ability of eltrombopag in combination with a short course of high-dose 
dexamethasone to induce a sustained response off treatment versus 1-3 cycles of 
dexamethasone monotherapy.
2
Objectives and endpoints
Table 2-1
Objectives and related endpoints 
Objectives
Endpoints
Primary Objective
Endpoint for primary objective
•
To compare the ability of eltrombopag in 
combination with a short course of 
dexamethasone to induce a sustained response 
off treatment at 52 weeks versus a defined 
course of dexamethasone 
•
Rates of patients achieving a sustained response 
off treatment at 52 weeks, comparing the two 
arms
(sustained response off treatment = maintain 
platelet count  ≥ 30 × 109/L after treatment 
discontinuation in the absence of bleeding events 
≥ Grade II or use of any rescue medication at all 
visits until Week 52)
Secondary Objectives
Endpoints for secondary objectives
1.
To compare the ability of eltrombopag in 
combination with a short course of 
dexamethasone to induce overall response (OR) 
after treatment discontinuation at Week 52 versus 
a defined course of dexamethasone
•
Proportion of patients with platelet count 
≥ 30 × 109/L and ≥ 2-fold increase of screening 
platelets after treatment discontinuation in the 
absence of bleeding events ≥ Grade II and no 
rescue therapy at all visits until Week 52
2.
To assess the duration of sustained response off 
treatment 
•
Median duration of sustained response off 
treatment calculated from the time of treatment 
discontinuation until platelet count < 30 × 109/L or 
bleeding events ≥ Grade II or use of any rescue 
therapy
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Objectives
Endpoints
3.
To assess the ability of eltrombopag to induce 
overall response (OR) by Week 4
•
Proportion of patients with platelet count 
≥ 30 × 109/L and ≥ 2-fold increase of screening 
platelet count and absence of bleeding and no 
rescue therapy at least once by Week 4
4.
To assess the ability of eltrombopag to induce 
complete response (CR) by Week 4
•
Proportion of patients with platelet count 
≥ 100 × 109/L and absence of bleeding and no 
rescue therapy at least once by Week 4
5.
To quantify the increase in platelet count from 
screening to baseline, and to 1, 2, 4, 12, 26, and 
52 weeks
•
Absolute values and relative changes in platelet 
count from screening to baseline, and to 1, 2, 4, 
12, 26, and 52 weeks
6.
To assess the time to overall and complete 
response
•
Time from starting study treatment to time of 
achievement of overall and complete response
7.
To assess the duration of overall and complete 
response
•
Duration of overall and complete response as 
defined above
8.
To evaluate patient-oriented outcomes for 
health-related quality of life
•
The analysis of Health–Related Quality of Life 
(HRQoL) parameters by use of Functional 
Assessment of Chronic Illness Therapy (FACIT) 
and Short Form 36 version 2 (SF36v2) 
questionnaires. Change in scores from baseline 
to 1, 2, 4, 12, 26 and 52 weeks
9.
To evaluate the safety and tolerability of 
eltrombopag + dexamethasone
•
Changes from baseline in physical exam findings, 
clinical monitoring, vital signs, clinical laboratory 
tests, and evaluation of reported adverse events
10. To evaluate the incidence and severity of 
bleeding events
•
Incidence and severity of bleeding assessed by 
the World Health Organization (WHO) Bleeding 
Scale
3
Study design
This is a Phase II, multicenter, randomized (1:1), open-label study to compare the efficacy and 
safety of eltrombopag in combination with a short course of high-dose dexamethasone to 
1-3 cycles of high-dose dexamethasone monotherapy, as first-line treatment in adult patients 
with newly diagnosed ITP. Randomization to treatment will follow a 1:1 ratio.  
•
Arm A: Eltrombopag + a short course of high-dose dexamethasone (dexamethasone 
therapy is limited to 1 cycle)
•
Arm B: 1-3 cycles of high-dose dexamethasone 
Adult patients with newly diagnosed ITP who have platelet counts < 30 × 109/L and require 
treatment will be screened, and if eligible, will be randomized to either Arm A (eltrombopag 
QD oral tablet for 26 weeks + 1 cycle of dexamethasone QD for 4 consecutive days) or Arm B 
(1-3 cycles of dexamethasone QD for 4 consecutive days at 4 weeks intervals; the 
dexamethasone can also be given at 14 to 28 days if needed according to current ITP guidelines; 
if the platelet counts are > 150 × 109/L no further course of dexamethasone will be given). The 
study will be conducted in the following periods:
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•
Screening Period: Patients will be screened based on the inclusion and exclusion criteria 
specified in Section 5.1 and Section 5.2, respectively.
•
Treatment Period: 
Arm A: Patients will be treated for 26 weeks (6 months) during the treatment period. 
Patients who reach platelet counts ≥ 30 × 109/L and maintain counts ≥ 30 × 109/L during 
the tapering phase will be eligible for treatment discontinuation. Duration of tapering 
before treatment discontinuation at Week 26 will be 6 weeks. 
Arm B. Patients will be treated up to 12 weeks (3 months) during the treatment period. 
Patients who reach platelet counts ≥ 30 × 109/L and maintain counts ≥ 30 × 109/L after 1-3 
cycles of dexamethasone treatment will be eligible for treatment discontinuation. Patients 
with platelet counts < 30 × 109/L after 3 cycles of dexamethasone treatment will be 
offered a course of eltrombopag treatment within the study and will discontinue from 
study at Week 52. 
•
Observation period: After completion of treatment period, patients will be observed for 
sustained response off treatment.
Arm A: Patients who successfully taper off, discontinue eltrombopag and maintain platelet 
counts ≥ 30 × 109/L in the absence of bleeding or use of any rescue therapy will be 
observed until Week 52 after study start.  Patients who relapse after eltrombopag 
discontinuation will reinitiate treatment with eltrombopag till Week 52 and will 
discontinue from study at Week 52. Patients with platelet counts < 30 × 109/L after 
26 weeks of treatment with eltrombopag will continue eltrombopag treatment till Week 52 
and discontinue from study at Week 52.
Arm B: Patients who successfully discontinue dexamethasone treatment and maintain 
platelet counts ≥ 30 × 109/L in the absence of bleeding or use of any rescue therapy will be 
observed until Week 52 after study start. Patients who relapse (platelet count < 30 × 
109/L) after dexamethasone discontinuation and need treatment will be treated with 
eltrombopag until Week 52 after study start and discontinue from study at Week 52. 
Patients with platelet count < 30 × 109/L after 3 cycles with dexamethasone will initiate 
treatment with eltrombopag and discontinue the study at Week 52.
The study will consist of a 14-day screening phase (after signing the study informed consent 
form (ICF)), 26 week (6 months) treatment phase, 26 weeks (6 months) observational phase, as 
described in Figure 3-1.
Figure 3-1
Study Design
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4
Rationale
4.1
Rationale for study design
This is a Phase II, multicenter, 1:1 randomized, open-label study to compare the efficacy and 
safety of eltrombopag in combination with a short course of high-dose dexamethasone to 
1-3 cycles of high-dose dexamethasone monotherapy, as first-line treatment in adult patients 
with newly diagnosed ITP.
The randomized, parallel group design was chosen to minimize treatment assignment bias, 
balancing both known and unknown prognostic factors including pre-treatment in the 
assignment of treatments. Due to different treatment durations and regimens in Arm A and Arm 
B an open-label study design was chosen.
4.2
Rationale for dose/regimen and duration of treatment
4.2.1
Rationale for dose/regimen for eltrombopag
The dose selected for first-line treatment of ITP with eltrombopag is based on prior experience 
in chronic ITP and is consistent with the dosing guidelines that have been approved for use in 
adult patients with chronic ITP. 
The starting dose of eltrombopag for patients with ITP is 50 mg QD and the total duration of 
treatment will be 26 weeks including tapering. Asian patients, in whom eltrombopag clearance 
has been shown to be lower than non-Asian patients, will initially receive half of the dose, 
starting at 25 mg of eltrombopag. After initiating eltrombopag, the dose must be adjusted to 
achieve and maintain a platelet count ≥ 50 × 109/L as necessary to reduce the risk for bleeding. 
The standard eltrombopag dose adjustment would be 25 mg once daily. It is necessary to wait 
for at least 2 weeks to see the effect of any dose adjustment on the patient’s platelet response 
prior to considering another dose adjustment. A daily dose of 75 mg must not be exceeded for 
all patients. The dose of eltrombopag will be decreased if platelet counts are > 150 × 109/L to 
≤ 400 × 109/L by 25 mg and the effect will be assessed after 2 weeks. Eltrombopag should be 
interrupted if counts are more than 400 × 109/L and resumed at a lower dose when platelets are 
less than 100 × 109/L. 
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4.2.2
Rationale for duration of treatment with 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. No predictive factors for the subjects who will 
be able to taper off are identified to date. 
Promising data from a recent retrospective study indicate that a median duration of eltrombopag 
treatment of 6 months qualify for a successful sustained remission after treatment 
discontinuation (Gonzalez-Lopez et al 2015). 
The treatment goal of this study is to have a platelet count in a safe hemostatic range (no counts 
below 30 × 109/L) in order to allow treatment discontinuation in as many patients as possible 
and not to normalize the platelet counts to a predefined value.
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 dexamethasone regimen
Corticosteroids have been the standard initial treatment for adults with moderate to severe 
thrombocytopenia since their introduction several decades ago (George et al 1996). Several 
studies have examined whether more intensive dosing of steroids, with high dose 
methylprednisolone or dexamethasone, as initial therapy in ITP, could lead to more durable 
remissions. 
In a trial evaluating the efficacy of high dose dexamethasone (HDD) as initial therapy in ITP, 
192 adults were randomized to HDD for one to two cycles or prednisone 1 mg/kg/day for 
4 weeks. One or two courses of HDD resulted in a higher incidence of overall initial response 
(82.1% vs 67.4%) and CR (50.5% vs 26.8%) and a shorter time to response compared with 
prednisone. Sustained response was achieved by 40.0% of patients in the HDD arm and 41.2% 
in the prednisone arm. Sustained response was defined as a platelet count > 30 x 109/L with an 
absence of bleeding symptoms or no requirement for additional ITP-modifying treatment of 
6 consecutive months following achievement of initial response (Wei et al 2016). 
The results of this randomized, controlled trial suggest that HDD may have some important 
advantages over a longer course of prednisone for the initial treatment of ITP. First, this option 
would likely be preferred by many patients simply on the basis of convenience. For most 
patients, a shorter duration of treatment will be much less burdensome. If the physician and the 
patient value these potential advantages, they can now proceed with HDD knowing that it is at 
least as effective as a prednisone taper for both short- and long-term responses. 
The dose of dexamethasone selected for this study is based on prior experience in newly 
diagnosed patients and on established guidelines. The dexamethasone regimen selected for this 
study consists of one course of high-dose dexamethasone 40 mg/day for 4 consecutive days in 
Arm A. In order to provide a less toxic regimen and to avoid possible adverse reactions of the 
combination therapy the dexamethasone treatment in Arm A is limited to a short exposure of 
4 consecutive days from day 1.
In Arm B the treatment consists of maximum 3 courses of high-dose dexamethasone 40 mg/day 
for 4 consecutive days at 4 weeks intervals (the dexamethasone can also be given at 14 to 28 
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days intervals if needed according to current ITP guidelines). If the platelet counts are 
> 150 × 109/L no further course of dexamethasone will be given. According to current 
guidelines the most common treatment regimen with dexamethasone is defined as 40 mg/day 
for 4 days every 2-4 weeks for 1-4 cycles. According to the most recent trial in 
relapsed/refractory ITP patients with eltrombopag, the treatment with steroids is restricted to a 
maximum of 12 weeks and was confirmed by medical experts. Therefore we have chosen the 
same regimen of maximum 12 weeks of treatment with dexamethasone.
4.4
Purpose and timing of interim analyses/design adaptations
No formal interim analysis is planned for this study. 
4.5
Risks and benefits
4.5.1
Risk associated with Eltrombopag use
The risks to patients in this study may come from adverse events (AEs), adverse events of 
special interest (AESI) 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 Section 8.3 and Section 8.4; and dose 
modifications as described in Section 6.5. 
Eltrombopag is approved in more than 100 countries. The benefit risk profile of eltrombopag 
for the treatment of chronic ITP, HCV associated thrombocytopenia and severe aplastic anemia 
continues to be favorable. Important identified risks for the ITP indication include 
hepatotoxicity, thromboembolic events, post-therapy reoccurrence of thrombocytopenia, and 
cataract. Important potential risks of eltrombopag for the ITP include thrombotic 
microangiopathy with acute renal failure, potential for increased bone marrow reticulin 
formation, hematological malignancies, renal tubular toxicity, phototoxicity, potential for 
hematological changes, and potential for endosteal hyperostosis. The clinical benefit of the 
platelet count improvements by eltrombopag was demonstrated by a decrease in bleeding 
symptoms and a reduction in the proportion of eltrombopag-treated patients who required 
rescue therapy compared with patients in the placebo group. Refer to the [Eltrombopag 
Investigator’s Brochure].
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 contraception 
requirements outlined in the exclusion criteria. If there is any question that the subject will not 
reliably comply, they should not be entered or continue in the study. 
Hepatotoxicity: 
Eltrombopag administration can cause hepatobiliary laboratory abnormalities, severe 
hepatotoxicity, and potentially fatal liver injury. In clinical studies of adult and pediatric patients 
(aged 1 to 17 years) with chronic ITP who received eltrombopag, increases in serum alanine 
aminotransferase (ALT), aspartate aminotransferase (AST) and indirect bilirubin were observed. 
Exercise caution when administering eltrombopag to patients with hepatic disease.
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Thrombotic/thromboembolic complications:
Platelet counts above the normal range present a theoretical risk for thrombotic/thromboembolic 
complications. In eltrombopag clinical trials 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.
Cataracts:
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 subjects 
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 subjects received up to 57 weeks of 
eltrombopag at doses up to 100 mg, there was a numerically higher incidence of cataracts in the 
eltrombopag treatment group compared with the placebo group. Routine monitoring of patients 
for cataracts is recommended. 
Bleeding following discontinuation of eltrombopag
Thrombocytopenia is likely to reoccur in ITP patients upon discontinuation of treatment with 
eltrombopag. Following discontinuation of eltrombopag, platelet counts return to baseline 
levels within 2 weeks in the majority of patients, which increases the bleeding risk and in some 
cases may lead to bleeding. This risk is increased if eltrombopag treatment is discontinued in 
the presence of anticoagulants or anti-platelet agents. 
In HCV clinical studies, a higher incidence of gastrointestinal bleeding, including serious and 
fatal cases, was reported following discontinuation of peginterferon, ribavirin, and eltrombopag. 
Following discontinuation of therapy, patients should be monitored for any signs or symptoms 
of gastrointestinal bleeding.
Bone marrow reticulin formation and risk of bone marrow fibrosis 
Eltrombopag may increase the risk for development or progression of reticulin fibres within the 
bone marrow. The relevance of this finding, as with other thrombopoietin receptor (TPO-R) 
agonists, has not been established yet.
4.5.2
Benefits associated with Eltrombopag use
Eltrombopag is an oral TPO-RA approved in over 100 countries for the treatment of patients 
aged 1 year and above with primary ITP lasting 6 months or longer from diagnosis and who are 
refractory to other treatments. It has a well-established efficacy and safety profile with evidence 
of improved QoL responses in addition to improvement in platelet counts. 
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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 subjects to reduce/discontinue 
concomitant (corticosteroid) medication use (RAISE Study) (Cheng et al 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 serious adverse events (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 (Tran 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 chronic ITP 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 et al 2010, Qu et al 2017, 
Liu et al 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 
(see Section 1.1.3).
5
Population
The study is designed to include 106 adult patients with newly diagnosed primary ITP with 
screening platelet count < 30 × 109/L and assessed as required treatment (per physician’s 
discretion).
ITP patients are detected by routine examinations or in the context of preoperative clarifications. 
If a diagnosis of ITP is confirmed the patients are informed about the trial and the informed 
consent process is initiated (it is very important that the patient take time to address any question 
or doubt with the study physician in line with local law). All study specific information is also 
found in the informed consent form and will be presented to the patient. The informed consent 
is a voluntary agreement to participate in research. It is not merely a form that is signed but is 
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a key process for potential study participants, in which the subject has an understanding of the 
clinical trial and its risk. In case of a consent, the screening activity proceeds, meaning the 
inclusion and exclusion criteria as well as the concomitant medication and the medical history 
are evaluated (Section 5.1 and 5.2).
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. Men and women ≥ 18 years of age
3. Newly diagnosed with primary ITP (time from diagnosis within 3 months)
Platelet count < 30 × 109/L at screening and a need for treatment (per physician’s 
discretion) Note: If pre-treatment is necessary, platelet count data performed directly 
before pre-treatment (prior to signing the study specific informed consent form and start of 
screening for the study as per local practice or under a local protocol) can be used for 
study inclusion (screening value). Treatment-naïve patients will be included based on their 
platelet counts performed at screening.
5.2
Exclusion criteria
Patients meeting any of the following criteria are not eligible for inclusion in this study.
1. Previous history of treatment for ITP
Note: Patients in need of immediate treatment for thrombocytopenia while diagnosis or 
eligibility are being determined may receive treatment with any ITP-directed therapy for a 
maximum of 3 days within 7 days before randomization. These therapies must be 
discontinued before the patient receives the first dose of study treatment
2. Patients with diagnosis of secondary thrombocytopenia
3. Patients who have life threatening bleeding complications per physician´s discretion
4. Patients with a history of thromboembolic events in the 6 months preceding enrollment or 
known risk factors for thromboembolism (e.g. Factor V Leiden, ATIII deficiency, 
antiphospholipid syndrome) are excluded. Patients with other risk factors which may pose 
an increased thromboembolic event (TEE) risk (prolonged periods of immobilization, 
malignancies, contraceptives and hormone replacement therapy, surgery/trauma, obesity 
and smoking) would be excluded according to the discretion of the investigator.
5. 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
6. Total bilirubin (TBIL) > 1.5 × upper limit of normal (ULN)
7. Aspartate transaminase (AST) > 3.0 × ULN
8. Alanine transaminase (ALT) > 3.0 × ULN
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9. Patients who are human immunodeficiency virus (HIV), HCV or hepatitis B surface 
antigen (HBsAg) positive
10. Patients with hepatic impairment (Child-Pugh score > 5)
11. Patients with known active or uncontrolled infections not responding to appropriate 
therapy
12. History of current diagnosis of cardiac disease or impaired cardiac function denoted by 
any of the following:
•
Corrected QTc >450 msec using Fridericia correction (QTcF) on the screening 
electrocardiogram (ECG) 
•
History of myocardial infarction and unstable angina within 6 months prior to starting 
study treatment
•
Clinically significant cardiac arrhythmias or other clinically significant cardiovascular 
disease (e.g., congestive heart failure, uncontrolled hypertension) within the six 
months prior to starting study treatment
13. Patients who have active malignancy
14. Patients with evidence of current alcohol/drug abuse
15. Any serious and/or unstable pre-existing medical (including any advanced malignancy 
other than the disease under study), psychiatric disorder, or other conditions that could 
interfere with subject’s safety, obtaining informed consent or compliance with the study 
procedures. 
16. 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
17. Patients with pre-existing medical conditions that are known precautions with 
corticosteroid use, in whom the potential risks of participating in the study outweigh the 
potential benefits as determined by the investigator
18. Female subjects who are nursing or pregnant (positive serum or urine B-human chorionic 
gonadotrophin (B-hCG) pregnancy test) at screening or pre-dose on Day 1
19. Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using highly effective methods of contraception while 
taking study treatment and for 7 days after stopping medication. Highly effective 
contraception methods include:
•
combined (estrogen and progestogen containing) hormonal contraception associated 
with inhibition of ovulation1:
•
oral
•
intravaginal
•
transdermal
•
progestogen-only hormonal contraception associated with inhibition of ovulation1:
•
oral
•
injectable
•
implantable2
•
intrauterine device (IUD)2 
•
intrauterine hormone-releasing system (IUS)2 
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•
bilateral tubal occlusion2 
•
vasectomised partner2,3 
•
sexual abstinence4
 
1Hormonal contraception may be susceptible to interaction with the IMP, which may reduce the efficacy of 
the contraception method (see section 4.3).
2 Contraception methods that in the context of this guidance are considered to have low user dependency.
3 Vasectomised partner is a highly effective birth control method provided that partner is the sole sexual 
partner of the WOCBP trial participant and that the vasectomised partner has received medical assessment 
of the surgical success.
4 In the context of this guidance sexual abstinence is considered a highly effective method only if defined as 
refraining from heterosexual intercourse during the entire period of risk associated with the study treatments. 
The reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and 
the preferred and usual lifestyle of the subject.
6
Treatment
6.1
Study treatment
Patients randomized to Arm A will receive eltrombopag in combination with a short course of 
high-dose dexamethasone beginning at Day 1. The dose of dexamethasone will be 40 mg QD 
for 4 consecutive days and limited to 1 cycle. The starting dose of eltrombopag will be 50 mg 
QD and treatment will continue at the same dose for 2 weeks to reach a target platelet count of 
50 × 109/L as necessary to reduce the risk for bleeding. The dose of eltrombopag will be 
increased by 25 mg increments every 2 weeks to a maximum dose of 75 mg QD for all patients 
who do not achieve the target platelet count of ≥ 50 × 109/L (Table 6-1). Treatment with 
eltrombopag will be continued at the minimal dosage necessary to maintain a platelet count 
≥ 50 × 109/L to 150 × 109/L for 20 weeks. Asian patients will initially receive half of the dose, 
starting at 25 mg of eltrombopag due to lower clearance of eltrombopag as compared with 
non-asian patients. After initiating eltrombopag, the dose must be adjusted to achieve and 
maintain a platelet count ≥ 50 × 109/L as necessary to reduce the risk for bleeding. The standard 
eltrombopag dose adjustment for Asian patients would be 25 mg once daily as well. It is 
necessary to wait for at least 2 weeks to see the effect of any dose adjustment on the patient’s 
platelet response prior to considering another dose adjustment. A daily dose of 75 mg must not 
be exceeded. The dose of eltrombopag will be decreased by 25 mg if platelet counts are 
> 150 × 109/L to ≤ 400 × 109/L by 25 mg and the effect will be assessed after 2 weeks.
Patients will be eligible for taper off and treatment discontinuation once they reach platelet 
counts ≥ 30 × 109/L. The duration of tapering will be 6 weeks starting at W21D1: decrease in 
dose will be performed by 25 mg reductions every 2 weeks to a minimum dose of 25 mg every 
other day for all patients.
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Table 6-1
Eltrombopag dosing guidance for patients not meeting criteria for 
sustained response 
Platelet Level
Dose Guidance
Patients with platelet < 30×109/L after 4 weeks of 
eltrombopag therapy at 75 mg/day 
Discontinue eltrombopag, initiate second-line therapy, 
follow-up till week 52 and discontinue from study at 
Week 52
Patients who relapse (platelet count < 30×109/L) 
during eltrombopag tapering off stage
Use previous dose level (i.e. one dose level higher) 
and continue treatment till Week 52 and discontinue 
from study at Week 52
Patients who relapse (< 30×109/L) after
eltrombopag discontinuation before Week 52
Re-initiate treatment with eltrombopag with a starting 
dose of 50 mg/day till Week 52 and discontinue from 
study at Week 52
Treatment in the control arm consists of 1-3 cycles of high-dose dexamethasone administered 
orally at a dose of 40 mg QD for 4 consecutive days at 4 weeks intervals (dexamethasone can 
also be given at 14 to 28 days intervals if needed according to current ITP guidelines). If the 
platelet counts are > 150 × 109/L no further course of dexamethasone will be given. Patients 
will be treated up to 12 weeks (3 months) during the treatment period with dexamethasone. 
Patients who reach platelet counts ≥ 30 × 109/L and maintain counts ≥ 30 × 109/L after 1-3 
cycles of high-dose dexamethasone treatment will be eligible for treatment discontinuation. 
Patients with platelet counts < 30 × 109/L after 3 cycles of dexamethasone treatment will be 
offered a course of eltrombopag treatment within the study and will discontinue the study after 
completion of treatment with eltrombopag at Week 52 (Table 6-2). 
Table 6-2
Dexamethasone dosing guidance for patients not meeting criteria for 
sustained remission
Platelet Level
Dose Guidance
Patients with platelet count < 30×109/L after 3 cycles 
with dexamethasone
Initiate treatment with eltrombopag with a starting 
dose of 50 mg/day and continue treatment with 
eltrombopag till Week 52 after study start and 
discontinue from study at Week 52 
Patients who relapse (platelet count < 30×109/L) after
dexamethasone discontinuation before Week 52
Initiate treatment with eltrombopag with a starting 
dose of 50 mg/day till Week 52 after study start and 
discontinue from study at Week 52
6.1.1
Investigational and control drugs
Study medication will be supplied in commercially available packaging labeled with “Zur 
klinischen Prüfung bestimmt”. Eltrombopag and dexamethasone are both investigational drugs. 
Eltrombopag study drug will be provided as film-coated tablets.
Dexamethasone is the Standard of Care treatment and will be supplied as tablets. It will be 
provided through Novartis locally for treatment of patients enrolled in this study.
All investigational treatment is to be stored in a secure locked area while under the 
responsibility of the investigator. Receipt and dispensing of investigational and Standard of 
Care treatment must be recorded by an authorized person at the investigator’s site.
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For detailed safety information refer to the [ETB115 Investigators Brochure, current edition] 
and the approved product labeling. A description of the study treatment, dose, frequency, and 
method of administration of eltrombopag and dexamethasone is provided in Table 6-3.
Table 6-3
Investigational and control drug
Study treatments
Pharmaceutical form and 
route of administration
Dose
Frequency and/or 
Regimen
Eltrombopag
Tablet for oral use
25 mg
Daily
Eltrombopag
Tablet for oral use
50 mg
Daily
Dexamethasone
Tablet for oral use
40 mg
Daily
6.1.2
Additional study treatments
No other treatment beyond investigational drug and control drug are included in this trial.
6.1.3
Treatment arms/group
Patients will be randomized at visit Week 1 Day 1 to one of the following 2 treatment 
arms/groups in a ratio of “1:1”
•
Arm A: Eltrombopag + a short course of high-dose of dexamethasone
•
Arm B: 1-3 cycles of high-dose dexamethasone
For detailed treatment guidance refer to Section 6.1.
6.1.4
Treatment duration
Arm A: The treatment duration for all patients in Arm A (eltrombopag QD for 
26 weeks + high-dose dexamethasone QD for 4 consecutive days starting at day 1 and limited 
to 1 cycle) will be 26 weeks (6 months) including 6 weeks tapering period. All patients who 
discontinue study treatment as per study design with platelet counts ≥ 30 × 109/L in the absence 
of bleeding or use of any rescue therapy will be followed for response assessments till Week 52 
after study start. Patients who relapse after eltrombopag discontinuation before Week 52 will 
reinitiate treatment with eltrombopag till Week 52 and will discontinue from study at Week 52. 
Patients with platelet counts < 30 × 109/L after 26 weeks of treatment with eltrombopag will 
continue treatment as summarized in Table 6-1 and discontinue from study at Week 52. 
Arm B: The maximum duration of treatment with dexamethasone for all patients in Arm B will 
be 12 weeks. All patients who discontinue study treatment as per study design with platelet 
counts ≥ 30 × 109/L in the absence of bleeding or use of any rescue therapy will be followed 
for response assessments till Week 52. Patients who relapse (platelet count < 30 × 109/L) after 
dexamethasone discontinuation before Week 52 will be treated with eltrombopag as 
summarized in Table 6-2 and discontinue the study at Week 52. Patients with platelet count 
< 30×109/L after 3 cycles with dexamethasone will initiate treatment with eltrombopag and 
discontinue the study at Week 52. 
6.2
Other treatment
Not applicable.
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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 after the enrollment of the patient in this study must be listed on the Concomitant 
Medications or the Procedures and Significant Non-Drug Therapies electronic case report form 
(eCRF).
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 
randomizing a subject or allowing a new medication to be started. If the subject is already 
enrolled, contact Novartis/sponsor to determine if the subject 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 2 hours before or 4 hours after 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 breast cancer resistance 
protein (BCRP) substrates should be undertaken with caution.
Examples of drugs which are OATP1B1 or BCRP substrates are given in Appendix 16.1.
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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
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 30 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.
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 
nonsteroidal anti-inflammatory drugs [NSAIDs]) should not be taken during the study unless 
there is a very clear indication and the Investigator documents the rationale. This is due to the 
fact that they may affect the results of the bleeding scale assessments.
Please refer to locally approved SmPC of dexamethasone for information regarding prohibited 
concomitant medication.
6.2.3
Rescue medication
Any ITP-directed medication or therapy, other than randomized treatment, given during the 
treatment phase of the trial with the aim to increase platelet count for the subjects who have 
clinically significant bleeding will be considered a rescue therapy and must be recorded on the 
appropriate eCRF page. A subject who receives rescue medication or therapy will not be 
considered in having achieved sustained response off treatment for the primary endpoint. Any 
ITP-directed medication or therapy given during the follow-up phase after treatment 
discontinuation until week 52 will be considered non-responders for the primary endpoint. 
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 enrolled for screening and is retained as the primary identifier for the subject 
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.
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6.3.2
Treatment assignment, randomization
Patients will be randomized to one of the two treatment arms in a ratio of 1:1.
The randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased. A randomization list will be produced by or under the 
responsibility of the Novartis Nürnberg GCP Officer using a validated system that automates 
the random assignment of treatment arms to randomization numbers in the specified ratio. 
The randomization scheme will be reviewed by a Biostatistics Quality Assurance Group and 
locked by them after approval. 
Prior to dosing, all patients who fulfill all inclusion/exclusion criteria will be randomized to one 
of the treatment arms according to the randomization scheme.
6.4
Treatment blinding
Treatment will be open label to subjects, investigator staff, persons performing the assessments, 
and the clinical trial team.
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 for eltrombopag 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 ≥ 50 × 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.
Patients who will have platelet < 30 × 109/L after 3 cycles with dexamethasone, treatment with 
eltrombopag will be initiated at 50 mg/day till Week 52 with eltrombopag dose adjustments 
summarized in Table 6-4.
All escalations and de-escalations must be recorded on the Dosage Administration Record 
eCRF. 
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 6.1.1).
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 6-4. Deviations to mandatory dose 
interruptions and/or reductions are not allowed. Permanent treatment discontinuation is 
mandatory for specific events indicated as such in Table 6-5.
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Table 6-4
Eltrombopag Dose Adjustments in ITP
Platelet count
Dose adjustment or response
< 50 × 109/L following 2 weeks of 
therapy
Increase daily dose by 25 mg to a maximum of 75 mg/day
> 150 × 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 a
> 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 dose
a. For patients taking 25 mg eltrombopag QD, consideration should be given to dosing at 25 mg once every 
other day.
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 
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 AEs and laboratory results, the Common Terminology Criteria for Adverse 
Events (CTCAE) Version 5.0 will be used.
Please refer to the label for dexamethasone for guidance of dose adjustments. 
Table 6-5
Criteria for dose adjustment based on liver enzyme and bilirubin 
levels
Dose modifications for Eltrombopag
Worst toxicity
CTCAEa Grade 
(value) during the 
treatment
Investigations (Hepatic)
Isolated Total Bilirubin Elevation
> ULN – 1.5 × ULN
Maintain dose level
> 1.5 - 3.0 × 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 × 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.
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Dose modifications for Eltrombopag
Worst toxicity
CTCAEa Grade 
(value) during the 
treatment
Investigations (Hepatic)
> 10.0 × 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 × ULN
> 3.0 - 5.0 × 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
Progressively increasing LFTsb upon repeat testing
Persistence ≥4 weeks
> 5.0 - 10.0 × 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 × 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 × 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
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Dose modifications for Eltrombopag
Worst toxicity
CTCAEa Grade 
(value) during the 
treatment
Investigations (Hepatic)
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 5.0)
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 
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.
6.5.3
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
Follow up on potential drug-induced liver injury (DILI) cases
Patients with transaminase increase combined with 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 international normalized ratio (INR) > 1.5 without evidence 
of cholestasis (no alkaline phosphatase (ALP) elevation)
•
For patients with elevated AST or ALT or TBIL value at baseline: [AST or ALT 
> 2 × baseline AND > 3.0 x ULN] OR [AST or ALT > 8.0 x ULN], combined with [TBIL 
> 2 × baseline AND > 2.0 × ULN]
•
For patients with normal baseline ALT: ALT ≥ 5 × ULN
Medical review needs to ensure that liver test elevations are not caused by cholestasis, defined 
as 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)/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.
4. 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.
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.
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6.6
Additional treatment guidance
6.6.1
Treatment compliance
The investigator must promote compliance by instructing the patient to take eltrombopag and 
dexamethasone 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 or dexamethasone 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 and dexamethasone 
dispensed and returned must be recorded in the Drug Accountability Log.
6.6.2
Emergency breaking of assigned treatment code
Not applicable.
6.7
Preparation and dispensation
Each study site will be supplied with study drug in packaging as described under investigational 
and control drugs section.
6.7.1
Handling of eltrombopag and dexamethasone 
Eltrombopag and dexamethasone study treatment 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.
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. Subjects 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/sponsor monitor or to the Novartis address provided in the 
investigator folder at each site.
6.7.2
Instruction for prescribing and taking study treatment
A description of eltrombopag and dexamethasone, dose and frequency is provided in Table 6-3.
•
Patients should take eltrombopag at approximately the same time each day either 1 hour 
before eating or 2 hours after eating.
•
For 4 hours before taking eltrombopag and 2 hours after taking eltrombopag, patients 
should avoid eating dairy products, and calcium- and magnesium-rich foods
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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 subjects may only be included in the study after providing IRB/IEC-approved informed 
consent.
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 subject source documents.
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 subject 
informed consent and should be discussed with the subject 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 subject.
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.
8
Visit schedule and assessments
Table 8-1 lists all of the assessments and indicates with an “x”, the visits when they are 
performed. All data obtained from these assessments must be supported in the patient’s source 
documentation. 
Patients should be seen for all visits/assessments as outlined in the assessment schedule 
(Table 8-1) or as close to the designated day/time (with an allowed “visit window” of ± 1 day 
for weekly visits and ± 3 days for all other visits) 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 
investigational product should be reconciled, and the AE and concomitant medications recorded 
on the CRF.
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8.1
Screening
Molecular pre-screening
Not applicable.
Screening
All patients will be screened for study eligibility. All patients must sign informed consent prior 
to any screening procedures being performed. All screening assessments will be done within 
1 to 14 days prior to randomization (see Table 8-1 for list of assessments to be performed).
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. 
Rescreening 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 14 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. 
8.1.1
Information to be collected on screening failures
Patients who sign an informed consent form and subsequently found to be ineligible prior to 
randomization will be considered a screen failure. The reason for screen failure should be 
recorded on the appropriate 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 a SAE during the screening phase (see SAE section (Section 10.1.3) for reporting 
details). 
Patients who are randomized and fail to start treatment, e.g. patients randomized in error, will 
be considered an early terminator. The reason for early termination should be recorded on the 
appropriate Case Report Form. 
8.2
Patient demographics/other baseline characteristics
The following patient demographics and baseline characteristics will be collected at screening:
•
Demography including age, sex, and race
•
Primary ITP status (time from diagnosis within 3 months)
•
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 
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time of signing informed consent). Ongoing medical conditions, symptoms and disease 
which are recorded on the Medical History eCRF should include the toxicity grade.
•
Height and weight
•
Prior and concomitant medication
Furthermore the following assessments will be performed:
•
Physical examination
•
Vital signs
•
Laboratory evaluations (hematology, chemistry) with thrombocyte assessment at 
screening and baseline
•
Viral serology
•
Serum pregnancy test 
•
Ocular assessment 
•
Electrocardiogram (ECG)
•
Adverse events
•
WHO bleeding scale
Ocular assessment can be performed within 4 weeks after the first dose of study treatment. If 
ocular assessment data are already available from exams performed within 28 days prior to 
screening (prior to signing the study specific informed consent form and start of screening for 
the study as per local practice or under a local protocol), then these may be used for the purposes 
of study inclusion.
If pre-treatment is necessary, platelet count data performed directly before pre-treatment (prior 
to signing the study specific informed consent form and start of screening for the study as per 
local practice or under a local protocol) will be used for study inclusion (screening value). 
Treatment-naïve patients will be included based on their platelet counts performed at screening
In addition, if laboratory evaluations (hematology except thrombocyte counts, coagulation, 
chemistry and viral serology) available from exams performed 14 days before randomization 
as per local practice or under a local protocol (prior to signing the study specific informed 
consent form and start of screening for the study), then these may be used for the purposes of 
study inclusion.
Bone marrow biopsy 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 compare the ability of eltrombopag in combination with a short 
course of high-dose dexamethasone to a defined course of high-dose dexamethasone to induce 
sustained response off treatment at Week 52.
8.3.1
Efficacy assessment 1
Platelet count will be assessed at screening visit to assess the eligibility of the subject. 
Hematology including platelet counts will be performed at Week 1/Day 1 (baseline) and weekly 
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during the first 4 weeks of treatment. Based on subject´s response, hematology will be 
performed biweekly thereafter until Week 33 Day 1 and every 4 weeks till Week 53 Day 1. 
Additional assessments of platelet count may be performed more frequently if needed in 
accordance with the clinical judgment of the investigator as part of clinical routine.
8.3.2
Efficacy assessment 2
Bleeding events will be assessed at each visit and recorded in the AE CRF and in addition on 
an unique CRF for bleeding events. 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 et al 2010).
8.4
Safety
All the safety assessments will be performed according to the visit schedule as outlined in 
Table 8-1. For details on AE collection and reporting, refer to Section 10.1. Significant findings 
that were present prior to the signing of informed consent must be included in the Medical 
History page on the patient’s CRF. Significant new findings that begin or worsen after informed 
consent must be recorded on the AE page of the patient’s CRF. The list of the physical 
assessments planned for this study are provided in Table 8-2.
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 signing informed consent which 
meet the definition of an Adverse Event must be recorded as an adverse event.
Vital signs
Vital signs include blood pressure (supine position preferred when ECG is 
collected), pulse measurement, and body temperature.
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.
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 slit lamp examination is required. Ophthalmic exams will be 
performed at screening (within 2 weeks after study entry) and at additional visits according to 
Table 8-1. Ocular assessment is not required prior to first dose of study treatment, but must be 
completed within the first 4 weeks of study entry. If ocular assessment data are already available 
from exams performed within 28 days prior to screening (prior to signing the study specific 
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informed consent form and start of screening for the study as per local practice or under a local 
protocol), then these may be used for the purposes of study inclusion.
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
Clinical laboratory analyses (hematology and chemistry) are performed by the local laboratory. 
Novartis must be provided with a copy of the laboratory’s certification (if applicable), and a 
tabulation of the normal ranges and units of each parameter collected in the eCRF. Any changes 
regarding normal ranges and units for laboratory values assessed during the study must be 
reported via an updated tabulation indicating the new effective date. Additionally, if at any time 
a patient has laboratory parameters obtained from a different (outside) laboratory, Novartis must 
be provided with a copy of the certification and a tabulation of the normal ranges and units for 
this laboratory as well. The investigator is responsible for reviewing all laboratory reports for 
patients in the study and evaluating any abnormalities for clinical significance.
At any time during the study, abnormal laboratory parameters which are clinically relevant (as 
decided by the investigator) and require an action to be taken with study treatment (e.g., require 
dose modification and/or interruption of study treatment, lead to clinical symptoms or signs, or 
require therapeutic intervention), whether specifically requested in the protocol or not, will be 
recorded on the AE eCRF page. Laboratory data will be summarized using the CTCAE version 
5.0 or above. Additional analyses are left to the discretion of the investigator.
Table 8-3
Laboratory Assessments
Test Category
Test Name
Hematology
Hematocrit, Hemoglobin, Mean corpuscular hemoglobin (MCH), Mean 
corpuscular hemoglobin concentration (MCHC), Mean corpuscular 
volume (MCV), Platelets, Red blood cells (RBCs), White blood cells 
(WBCs), Differential (Basophils, Eosinophils, Lymphocytes, Monocytes, 
Neutrophils, Other
Chemistry 
Albumin, Alkaline phosphatase, Alanine aminotransferase (ALT), 
Aspartate transaminase (AST), Amylase, , Calcium, Chloride, 
Creatinine, Creatinine kinase, Direct Bilirubin, Total Bilirubin (TBIL), 
Lactate dehydrogenase (LDH), Glucose (fasting), GGT, Lipase, 
Magnesium, Phosphorus, Potassium, Sodium, Total Protein, Blood 
Urea Nitrogen (BUN) or Urea, Uric Acid, Lipase, 
Coagulation 
Prothrombin time or International normalized ratio [INR] or Quick-test 
(Quick-value), Activated partial thromboplastin time (aPTT), Fibrinogen, 
Pregnancy Test
Serum / Urine pregnancy test
8.4.2.1
Hematology
Hematology tests are to be performed according to the visit schedules outlined in Table 8-1. 
For details of the Hematology panel, refer to Table 8-3.
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Hematology should be assessed on the scheduled day, even if study drug is being withheld.
8.4.2.2
Biochemistry
Eltrombopag administration can cause abnormal liver function and severe hepatotoxicity, which 
might be life-threatening. 
Serum ALT, AST and bilirubin should be measured prior to initiation of eltrombopag, every 
2 weeks during the dose adjustment phase and monthly following establishment of a stable dose. 
Abnormal serum liver tests should be evaluated with repeat testing within 3 to 5 days. If the 
abnormalities are confirmed, serum liver tests should be monitored until the abnormalities 
resolve, stabilize, or return to baseline levels. Eltrombopag should be discontinued if ALT levels 
increase (> 3 × ULN in patients with normal liver function, or ≥ 3 × baseline or > 5 × ULN, 
whichever is the lower, in patients with pre-treatment elevations in transaminases) and are:
•
progressive, or
•
persistent for ≥ 4 weeks, or
•
accompanied by increased direct bilirubin, or
•
accompanied by clinical symptoms of liver injury or evidence for hepatic decompensation
Biochemistry tests are to be performed according to the visit schedules outlined in Table 8-1. 
For details of the biochemistry panel refer to Table 8-3.
Biochemistry should be assessed on the scheduled day, even if study drug is being withheld.
Eltrombopag is highly colored and so has the potential to interfere with some laboratory tests. 
Serum discoloration and interference with TBIL and creatinine testing have been reported in 
patients taking Revolade/Promacta. If the laboratory results and clinical observations are 
inconsistent, evaluation of contemporaneous aminotransferase values may help in determining 
the validity of low TBL levels in the presence of clinical jaundice and blood urea should be 
evaluated in the event of an unexpectedly high serum creatinine. Re-testing using another 
method may also help in determining the validity of the result (Choy et al 2016).
8.4.3
Viral serology
In addition to medical history, screening assessments for hepatitis B, hepatitis C and human 
immunodeficiency virus (HIV) will be performed by the local laboratory according to 
Table 8-1.
8.4.4
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.
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.
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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.
8.4.5
Pregnancy and assessments of fertility
All pre-menopausal women who are not surgically sterile will have pregnancy testing. Serum 
or urine pregnancy tests are to be performed according to the Visit Schedules outlined in 
Table 8-1. At screening, a serum pregnancy test should be performed regardless of the age of 
the patients, while, during the study, and at the end of study, urinary pregnancy tests (dipstick) 
are sufficient. Pregnancy testing (serum or urine) must be performed on a monthly basis while 
receiving study drug until study drug discontinuation. A positive pregnancy test requires 
immediate interruption of study treatment until the assessment is confirmed. If positive, the 
patient must be discontinued from the study.
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:
1. Surgical bilateral oophorectomy without a hysterectomy
2. 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 
subject regardless of reported reproductive/menopausal status at screening/baseline.
8.4.6
Appropriateness of safety measurements
The safety assessments selected are standard for this indication/patient population.
8.5
Additional assessments
Bone marrow biopsies is recommended for patients > 60 years or in the presence of 
abnormalities and can be performed at the discretion of the investigator.
8.5.1
Clinical Outcome Assessments (COAs)
Patient reported outcomes (PRO)
Immune thrombocytopenia is associated with symptoms of fatigue, bruising, and bleeding, 
which can interfere with daily activities. Consequently, subjects with ITP have decreased 
HRQoL compared with healthy individuals. To assess patient-reported outcomes (PROs), 
HRQoL changes over time will be assessed using standard validated instruments. 
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 and Nowinski 2002, Webster et al 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 
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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 et al 2011). 
FACIT-Fatigue will be administered before any study drug administrations at the beginning of 
treatment and after 1, 2, 4, 12, 26, and 52 weeks and EOS (for patients with premature study 
withdrawal before W53D1). A minimal clinically important difference from baseline in FACIT-
Fatigue score will be evaluated (Cella and Nowinski 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 et al 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. SF-36v2 will be administered before any study drug administrations at the 
beginning of treatment and after 1, 2, 4, 12, 26, and 52 weeks and EOS (for patients with 
premature study withdrawal before W53D1), and change from baseline will be evaluated. 
 
. 
The site personnel should check the questionnaire for completeness and ask the patient to 
complete any missing responses. The original questionnaire will be kept with the patient’s file 
as the source document.
Completed questionnaire(s) and any unsolicited comments written by the patient should be 
reviewed and assessed by the investigator for responses which may indicate potential AEs or 
SAEs.
8.5.2
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8.5.3
Other Assessments
The modified WHO (Kaufman et al 2015) Bleeding Scale (Page et al 2007) will be administered 
at every visit (refer Section 16.2).
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 subject or the 
investigator.
The investigator must discontinue study treatment for a given subject if, he/she believes that 
continuation would negatively impact the subject's well-being.
Study treatment must be discontinued under the following circumstances:
•
Patient/guardian decision
•
Pregnancy
•
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 subject’s overall status, prevents the subject 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 subject’s premature discontinuation of study 
treatment and record this information.
Subjects 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 
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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 subject/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 subject cannot or is unwilling to attend any visits, the site staff should maintain regular 
telephone contact with the subject, or with a person pre-designated by the subject. This 
telephone contact should preferably be done according to the study visit schedule.
After study treatment discontinuation, at a minimum, in abbreviated visits, the following data 
should be collected at clinic visits or via telephone/email contact:
•
new / concomitant treatments
•
AEs/SAEs
9.1.2
Withdrawal of informed consent
Subjects may voluntarily withdraw consent to participate in the study for any reason at any 
time. Withdrawal of consent occurs only when a subject:
•
Does not want to participate in the study anymore, and
•
Does not allow further collection of personal data
In this situation, the investigator should make a reasonable effort (e.g. telephone, e-mail, letter) 
to understand the primary reason for the subject’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 subject 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 subject’s study withdrawal should be made as detailed in the 
assessment table.
Novartis will continue to keep and use collected study information (including any data resulting 
from the analysis of a subject’s samples until the time of withdrawal) according to applicable 
law.
9.1.3
Lost to follow-up
For subjects 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 subject, e.g. dates of telephone 
calls, registered letters, etc. A subject should not be considered as lost to follow-up until due 
diligence has been completed or until the end of the study.
9.1.4
Early study termination by the sponsor
The study can be terminated by Novartis at any time. 
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Reasons for early termination:
•
Unexpected, significant, or unacceptable safety risk to subjects enrolled in the study
•
Decision based on recommendations from applicable board(s) after review of safety and 
efficacy data 
•
Discontinuation of study drug development
In taking the decision to terminate, Novartis will always consider subject welfare and safety. 
Should early termination be necessary, ongoing subjects must be seen as soon as possible 
(provide instruction for contacting the subject, when the subject should stop taking drug, when 
the subject should come in for a final visit) and treated as a prematurely withdrawn subject. 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 subject’s interests. The investigator or 
sponsor depending on local regulation will be responsible for informing IRBs/IECs of the early 
termination of the trial.
9.2
Study completion and post-study treatment
Study completion is defined as when the last subject finishes their Study Completion 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.
Patients who are still on study treatment at W53D1 will come off trial after completing the 
W53D1/visit.  After discontinuing drug at the W53D1 visit, patients will be followed-up for 
safety for an additional 30 days (safety follow-up). Patients who complete the W79D1visit, or 
who discontinue during the follow-up period between Week 52 and Week 78  due to relapse, 
will be followed up for an additional 30 days (safety follow-up). 
For patients with premature withdrawal for any reason an EOS visit will be performed with all 
of the assessments listed for the EOS. After the EOS visit, patients will be followed-up for 
safety for an additional 30 days. 
Continuing care to study participants should be provided by the investigator and/or referring 
physician.
10
Safety monitoring and reporting
10.1
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 subject or clinical 
investigation subject 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 subject and 
identifying AEs.
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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 subject at each visit 
during the study. Adverse events also may be detected when they are volunteered by the subject 
during or between visits or through physical examination findings, laboratory test findings, or 
other assessments.
Adverse events must be recorded in the appropriate CRF capturing AEs 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 5.0
2. its relationship to the study treatment (eltrombopag and/or dexamethasone)
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 AEs must be treated appropriately. Treatment may include one or more of the following:
•
Dose not changed
•
Dose reduced/increased
•
Drug interrupted/withdrawn
•
Subject hospitalized/subject’s hospitalization prolonged
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 subject.
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 after the patient has stopped 
study participation (defined as last dose of study treatment taken or last visit whichever is later).
Once an AE 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 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 
Investigator’s Brochure (IB).
Abnormal laboratory values or test results constitute AEs 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
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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 subjects with the underlying disease.
10.1.2
Serious adverse events
A SAE is defined as any AE (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 subject 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 subject’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 subject 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 subject 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 
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 SAE irrespective 
if a clinical event has occurred.
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10.1.3
SAE reporting
To ensure subject safety, every SAE, regardless of causality, occurring after the subject has 
provided informed consent and until 30 days after the patient has stopped study participation 
(defined as last dose of study treatment taken or last visit whichever is later) must be reported 
to Novartis Safety within 24 hours of learning of its occurrence. Information about all SAEs is 
collected and recorded on the Serious Adverse Event Report Form. The investigator must assess 
and record the relationship of each SAE to each specific study treatment (if there is more than one 
study treatment), complete the SAE Report Form in English, and send the completed, signed form 
by fax within 24 hours to the oncology Novartis Patient Safety department. Detailed instructions 
regarding the submission process and requirements are to be found in the investigator folder 
provided to each site.
SAEs occurring after the subject has provided informed consent until the time the subject 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 should only be reported to Novartis Safety if the 
investigator suspects a causal relationship to study treatment.
10.1.4
Pregnancy reporting
To ensure subject 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 
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 each specific study treatment (eltrombopag and/or 
dexamethasone) and any pregnancy outcome. Any SAE experienced during pregnancy must be 
reported.
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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, subject 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
10.2
Additional Safety Monitoring
10.2.1
Liver safety monitoring
To ensure subject 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 
laboratories used by the site.  
The following two categories of abnormalities / AEs 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 6-5 for dose modifications/discontinuation for liver laboratory 
abnormalities.
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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 subject 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 subject 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.
Thrombotic/thromboembolic complications
The risk of TEEs has been found to be increased in patients with chronic liver disease treated 
with 75 mg eltrombopag QD for 2 weeks in preparation for invasive procedures. Six of 143 
(4%) adult patients with chronic liver disease receiving eltrombopag experienced TEEs (all of 
the portal venous system) and 2 of 145 (1%) patients in the placebo group experienced TEEs 
(one in the portal venous system and one myocardial infarction). Five of the 6 patients treated 
with eltrombopag experienced the thrombotic complication at a platelet count >200,000/µL and 
within 30 days of the last dose of eltrombopag. Eltrombopag is not indicated for the treatment 
of thrombocytopenia in patients with chronic liver disease in preparation for invasive 
procedures. 
Eltrombopag should not be used in ITP patients with hepatic impairment (Child-Pugh score 
≥ 5) unless the expected benefit outweighs the identified risk of portal venous thrombosis. 
When treatment is considered appropriate, caution is required when administering eltrombopag 
to patients with hepatic impairment.
Bleeding following discontinuation of eltrombopag
Thrombocytopenia is likely to reoccur in ITP patients upon discontinuation of treatment with 
eltrombopag. It is recommended that, if treatment with eltrombopag is discontinued, ITP 
treatment be restarted according to current treatment guidelines. Additional medical 
management may include cessation of anticoagulant and/or anti-platelet therapy, reversal of 
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anticoagulation, or platelet support. Platelet counts must be monitored weekly for 4 weeks 
following discontinuation of eltrombopag.
Bone marrow reticulin formation and risk of bone marrow fibrosis 
Prior to initiation of eltrombopag, the peripheral blood smear should be examined closely to 
establish a baseline level of cellular morphologic abnormalities. Following identification of a 
stable dose of eltrombopag, FBC with WBC count differential should be performed monthly. 
If immature or dysplastic cells are observed, peripheral blood smears should be examined for 
new or worsening morphological abnormalities (e.g. teardrop and nucleated red blood cells, 
immature white blood cells) or cytopenia(s). If the patient develops new or worsening 
morphological abnormalities or cytopenia(s), treatment with eltrombopag should be 
discontinued and a bone marrow biopsy considered, including staining for fibrosis.
10.2.2
Steering Committee
The Steering Committee (SC) will be established comprising investigators participating in the 
trial and one external expert in the field of autoimmune cytopenias 
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. 
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 (Table 8-1) 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.
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 Electronic 
Data Capture (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.
All data should be recorded, handled and stored in a way that allows its accurate reporting, 
interpretation and verification. After database lock, the investigator will receive a CD-ROM or 
paper copies of the subject 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 
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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 
subjects will be disclosed.
11.4
Data privacy impact assessment
11.4.1
Systematic description of the envisaged processing operations and 
the purposes of the processing
The categories of personal data as well as the purposes, scope and duration of the data 
processing procedures conducted by the sponsor in connection with this clinical trial are 
described in the attached Clinical Trials Privacy Impact Assessment (see Appendix 4: Clinical 
Trials Privacy Impact Assessment) which is, inter alia regarding the involved personal data as 
well as the processing purposes, further specified in this clinical trial protocol.
11.4.2
Assessment of the necessity and proportionality of the processing 
operations in relation to the purposes
As set out in this clinical trial protocol the processing of personal data performed by the sponsor 
will only cover personal data being necessary for the performance of the clinical trial. 
Furthermore, the sponsor will only process the patients’ personal data in a pseudonym form. 
On the other hand the performance of the clinical trial may create new scientific knowledge 
which may positively affect the health status and medical treatment of the patients. Therefore, 
the nature and scope of the conducted data processing is necessary, suitable and proportionate 
in relation to the purpose of the clinical trial.
11.4.3
Assessment of the risks to the rights and freedoms of data subjects
The performance of the clinical trial involves comprehensive processing of sensitive personal 
data (e. g. data concerning health). Whereas, any unintended and / or unauthorized disclosure 
of patients data may likely result in a high risk to the rights and freedoms of the patients. Patients 
may in particular be stigmatized by their social environment, may lose or fail in obtaining 
insurance coverage. However, the abovementioned risk is significantly reduced by the fact that 
the sponsor solely obtains and processes pseudonym data which cannot directly be attributed to 
an individual patient. In order to safeguard that the patient’s data stays pseudonym technical 
and organizational measures have been established to prevent the sponsor from receiving 
additional information which allows to link the scientific data to individual patients.
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and baseline values can be identical. In such cases, as only one assessment exists, the baseline 
value will be taken from screening.
The last available assessment on or before the date of start of eltrombopag / dexamethasone 
study treatment is taken as “baseline” assessment. In case, assessment is captured pre-dose on 
first day of study treatment (e.g. PROs), this assessment is used for baseline.
12.1
Analysis sets
The Full Analysis Set (FAS) will consist of all patients to whom study treatment has been 
assigned by randomization. The FAS will serve as the primary analysis set for all efficacy 
analyses. According to the intent to treat principle, subjects will be analyzed according to the 
treatment they have been assigned to during the randomization procedure.
Before database lock, relevant protocol deviations and potential impact on analyses will be 
reviewed and adequately processed / documented.  
The Safety Set (SAF) includes all subjects who received at least one dose of study treatment. 
Subjects in the SAF will be analyzed according to the study treatment actually received. Further 
details will be specified in the SAP.
12.2
Subject demographics and other baseline characteristics
Demographic and other baseline data including disease characteristics will be listed and 
summarized descriptively by treatment group and overall for the FAS.
Relevant medical histories and current medical conditions at baseline will be summarized 
separately by system organ class and preferred term, by treatment group and overall.
12.3
Treatments
The Safety set will be used for the analyses below. 
The duration of exposure in weeks to eltrombopag and dexamethasone 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, and shown separately as well as combined for both drugs) will be summarized 
by means of descriptive statistics using the safety set.
The number of subjects with dose adjustments (reductions, interruption, or permanent 
discontinuation) and the respective reasons will be summarized by treatment group and all 
dosing data will be listed.
Furthermore, subjects using rescue treatments as defined in Section 6.2.3 will be summarized 
by treatment group.
Concomitant medications and significant non-drug therapies prior to and after the start of the 
study treatment will be listed and summarized according to the Anatomical Therapeutic 
Chemical (ATC) classification system, by treatment group.
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12.4
Analysis of the primary endpoint
The primary objective is to compare the ability of eltrombopag in combination with a short 
course of high-dose dexamethasone to induce sustained response off treatment at 52 weeks in 
newly-diagnosed ITP patients versus 1-3 cycles course of high-dose dexamethasone.
For the primary and supportive analyses the FAS will be used.
12.4.1
Definition of primary endpoint 
The primary endpoint is the proportion of patients with sustained response off treatment at 
52 weeks.
Sustained response off treatment is defined as:
•
reach platelet count ≥ 30×109/L and then maintain platelet counts ≥ 30 × 109/L after 
treatment discontinuation AND
•
maintain platelet count ≥ 30 × 109/L in the absence of bleeding events ≥ Grade II and 
without the use of any rescue therapy (see Section 6.2.3) at all visits until week 52.
•
Of note: in case a patient in the treatment Arm B (dexamethasone monotherapy) needs 
treatment cycles at an interval of less than 28 days (at least 14 days), and meets the 
definition for sustained response off treatment as given above, such patient will be 
counted as a responder for statistical analysis.
.
12.4.2
Statistical model, hypothesis, and method of analysis
The analysis of the primary endpoint will be based on the following estimand:
The population will be the Full Analysis Set; 
Variable of interest: The primary endpoint is the response rate in terms of sustained response 
off treatment at 52 weeks, in absence of bleeding or use of rescue therapy as defined above, i.e. 
a composite estimand. 
Intervention effect: effect of eltrombopag in combination with a short course of high-dose 
dexamethasone versus 1-3 cycles of high-dose dexamethasone alone at 52 weeks, regardless of 
adherence to randomized treatment.
Summary measure: odds ratio
The statistical hypothesis to be rejected is that the rates of patients achieving sustained response 
at 52 weeks are equal in both treatment groups. The corresponding alternative hypothesis is that 
the rates are not equal under eltrombopag combined with a short course of high-dose 
dexamethasone, compared to 1-3 cycles of high-dose dexamethasone monotherapy.
Let pA and pB denote the proportions of patients achieving sustained response off treatment for 
the treatment groups:
A = eltrombopag combined with a short course of high-dose dexamethasone
B = 1-3 cycles of high-dose dexamethasone “standard”
The following hypotheses will be tested:
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H0: 
(pB / (1- pB)) / (pA / (1- pA)) = ORB/A = 1 
versus HA: 
(pB / (1- pB)) / (pA / (1- pA)) = ORB/A ≠ 1
In other words: 
H0: The rate of patients achieving a sustained response off treatment at 52 weeks in the 
eltrombopag plus a short course of high-dose dexamethasone arm is equal to the respective rate 
in the 1-3 cycles high-dose dexamethasone monotherapy “standard” arm (corresponding to 
equal odds). 
HA: The rate of patients achieving a sustained response off treatment at 52 weeks in the 
eltrombopag plus a short course of high-dose dexamethasone arm is higher than the respective 
rate in the 1-3 cycles of dexamethasone monotherapy “standard” arm. 
The primary analysis will be performed comparing the treatment groups with respect to the 
primary efficacy outcome, based on the Odds Ratio, in a Logistic Regression model with the 
factor treatment and cofactors ITP-directed pre-therapy (during 3 days within 7 days before 
randomization), screening platelet count and age (≤ vs. > 60 years). The odds ratio and its 95% 
confidence interval (CI) and p-value will be given. The null hypothesis of equal odds will be 
rejected if the 2-sided p-value from the logistic regression model for the factor “treatment” is 
<0.05; however, superiority of eltrombopag in combination with a short course of 
dexamethasone will be claimed only if the direction is correct, i.e. if the odds of response are 
higher under eltrombopag plus a short course of high-dose dexamethasone compared to 1-3 
cycles of dexamethasone monotherapy (ORB / A < 1).
12.4.3
Handling of missing values/censoring/discontinuations
If patient´s platelet assessment for evaluating the primary endpoint are missing, they will not 
be considered for sustained response off treatment. Patients dropping out early will be 
considered as early discontinuation or not evaluable, will be considered in the analysis set as 
non-responders. Thus, missing values are not expected for the primary analysis. Details will be 
specified in the respective SAP.
12.4.4
Sensitivity and Supportive analyses
Sensitivity analyses
Sensitivity analyses and supportive analyses will be conducted in order to provide evidence that 
the results seen from the primary analysis are robust. Furthermore, Bayes analyses may be 
considered in addition (Fisch et al 2015).
The impact of the analysis assumptions on the result of sustained response off treatment will be 
assessed as well by repeating the logistic regression model using different populations and ways 
to handle missing data. 
These may include, but are not limited to:
•
Multiple imputation
•
Using a treatment policy estimand (no matter if intercurrent events such as bleeding, 
treatment discontinuation or reinitiation, or rescue treatment occurred)
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•
Using the baseline thrombocyte count (or threshold exceedance, i.e. early increase of 
thrombocyte count above the screening threshold, instead of or in addition to the 
thrombocyte count at screening),
•
Adding further detail information on pre-treatment to the model (type of medication, 
dosage, duration)
Supportive analyses
Data defining the primary outcome of sustained response off treatment will be further reported 
descriptively to give the full picture. This will include
•
PLT counts at treatment discontinuation
•
Number of patients with PLT ≥ 50  x 109/L or PLT ≥ 100  x 109/L or PLT ≥ 150 x 109/L at 
treatment discontinuation; 
•
Time point of reaching PLT ≥ 150 × 109/L measured from start of study treatment
•
Number of patients who are able to discontinue eltrombopag and dexamethasone with 
PLT ≥ 30 × 109/L
•
Number of patients with loss of response after treatment discontinuation
•
Number of patients with bleeding events after treatment discontinuation
•
Number of patients receiving rescue treatment
The primary analysis will be repeated in the following subgroups:
•
Age (≤ vs. > 60 years).
•
Platelet count: thrombocytopenia at screening and at baseline: platelets < 10 × 109/L 
versus platelets > 10 × 109/L  
•
ITP-directed pre-therapy (yes / no)
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 endpoints
1. To compare the ability of eltrombopag in combination with a short course of high-dose 
dexamethasone to induce overall response (OR) after treatment discontinuation at 
week 52 versus a defined course of dexamethasone
Number (%) of patients with platelet count ≥ 30 × 109/L and a 2-fold increase of screening 
platelet count after treatment discontinuation in the absence of bleeding events ≥ Grade II 
and no rescue therapy at all visits until Week 52 will be provided, analysis will be 
equivalent to the primary endpoint analysis.
2. To assess the duration of sustained response off treatment, median duration of response 
off treatment (weeks) counted from last dose of study treatment (eltrombopag or 
dexamethasone) until loss of response will be calculated using a Kaplan-Meier analysis.
3. . 
4. To assess the ability of eltrombopag to induce overall response (OR) by week 4
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Number (%) of patients with platelet count ≥ 30 × 109/L and a 2-fold increase of screening 
platelet count at least once within the first 4 weeks without bleeding events ≥ Grade II and 
no rescue therapy will be provided, analysis will be equivalent to the primary endpoint 
analysis.
5. To assess the ability of eltrombopag to induce a complete response (CR) by week 4
Number (%) of patients with platelet count ≥ 100 × 109/L at least once within the first 
4 weeks without bleeding events ≥ Grade II and no rescue therapy will be provided, 
analysis will be equivalent to the primary endpoint analysis.
6. To assess the platelet count from screening to baseline and to 1, 2, 4, 12, 26 and 52 
weeks; absolute and relative change in platelet count from screening to baseline and to 1, 
2, 4, 12, 26 and 52 weeks and EOS will be provided. Box plots for absolute and/or relative 
change in platelet counts from screening to baseline and to different time points will also 
be provided. 
7. To assess the time to response for overall and complete response using a Kaplan-Meier 
analysis. 
8. To assess the duration of response for overall and complete response using a 
Kaplan-Meier analysis. 
9. 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 through FACIT and 
SF-36v2 questionnaires from baseline to 1, 2, 4, 12, 26, 52 weeks and EOS (for patients 
with premature study withdrawal before W53D1) will be provided. 
10. To evaluate the safety and tolerability of eltrombopag see Section 12.5.2.
11. To evaluate the incidence and severity of bleeding events
12.5.2
Safety endpoints
Safety summary tables include only data from the period from first treatment until 30 days after 
the patient has stopped study participation (defined as last visit). 
Adverse events
All information obtained on AEs will be displayed by treatment group and subject.
The number (and percentage) of subjects with treatment-emergent AEs (events started after the 
first dose of study medication or events present prior to start of treatment but increased in 
severity based on preferred term) will be summarized in the following ways:
•
by treatment, primary system organ class and preferred term.
•
by treatment, primary system organ class, preferred term and maximum severity.
•
by treatment, Standardized MedDRA Query (SMQ) and preferred term
Separate summaries will be provided for study medication related AEs, death, SAEs, other 
significant AEs leading to discontinuation and adverse events leading to dose adjustment.
The number (and proportion) of subjects with AEs of special interest (i.e. 
thromboembolic/thrombotic complications, hepatobiliary laboratory abnormalities, bleeding, 
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bone marrow reticulin formation and bone marrow fibrosis, and ocular changes) will be 
summarized by treatment.
A subject with multiple AEs within a primary system organ class is only counted once towards 
the total of the primary system organ class.
All information obtained on AEs will be displayed by patient. Summary tables for 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 AE and relation to study treatment.
Serious adverse events, AEs leading to discontinuation, AEs leading to dose adjustment and 
AESI which includes bleeding events during the on-treatment period will be tabulated.
The incidence of AESIs will be summarized by SOC and Preferred Term (PT).
All deaths (until 30 days after the patient has stopped study participation defined as last visit.s) 
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 study treatment) and post-treatment 
period will be flagged (until 30 days after the patient has stopped study participation defined as 
last visit)
A patient with multiple AEs within a primary SOC is only counted once towards the total of the 
primary SOC.
Clinical laboratory evaluations
All laboratory data will be listed by treatment group, subject, and visit/time and if normal ranges 
are available abnormalities will be flagged. Summary statistics will be provided by treatment 
and visit/time. Shift tables using the low/normal/high/ (low and high) (or project specific) 
classification will be used to compare baseline to the worst on-treatment value.
Grading of laboratory values will be assigned programmatically as per NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 5.0. 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 v5.0, results will be categorized 
as low/normal/high based on laboratory normal ranges.
The following summaries will be generated separately for hematology, and biochemistry tests:
•
Listing of all laboratory data with values flagged to show the corresponding CTCAE v5.0 
grades if applicable and the classifications relative to the laboratory normal ranges
For laboratory tests where grades are defined by CTCAE v5.0
•
Worst post-baseline CTCAE grade (regardless of the baseline status). Each subject will be 
counted only once for the worst grade observed post-baseline.
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12.7
Interim analyses
No formal interim analysis will be performed on this trial.
12.8
Sample size calculation
12.8.1
Primary endpoint
This trial is intended to estimate the difference in the rates of patients achieving a sustained 
response off treatment at Week 52.
(sustained response off treatment = maintain platelet ≥ 30 × 109/L after treatment 
discontinuation in the absence of bleeding events ≥ Grade II or use of any rescue medication at 
all visits until Week 52) 
The sample size calculation is based on the following assumptions: 
1. Sustained response off treatment is achieved in 30% of the patients in the dexamethasone 
arm and 65% in the eltrombopag + dexamethasone arm 
2. Randomization is allocated in a 1:1 ratio (eltrombopag + dexamethasone: dexamethasone) 
4. A two-sided 5% level of significance will be applied. 
5. The study will have 90% power under the stated assumptions for the primary endpoint. 
Based on these assumptions, a total of 47 patients in each treatment arm would need to be 
randomized. More conservative scenarios based on lower treatment effects and 50 patients per 
group, assuming rates of 30 versus 60% would lead to a power of 81%, and 30 versus 55% 
would still allow for a power of 64%, whereas the radius of the respective confidence interval 
would be between 0.20 and 0.21 based these scenarios.
To allow for some dropouts / protocol violations, a total of 106 patients is planned to be enrolled. 
Due to feasibility reasons, resulting in a substantial delay in recruitment, as described above, 
with Amendment 3 recruitment will be prematurely discontinued. A final number of ca. 24 
patients is expected to be recruited by the time of approval. 
The patients enrolled by then will be analyzed and reported as described, to allow for adequate 
use of the present data.
Based on the assumptions described, the resulting power will be ca. 24%. As a consequence, 
all analyses will be performed in a purely descriptive manner. 
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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 Institutional Review Board/Independent Ethics Committee (IRB/IEC) for the trial protocol, 
written informed consent form, consent form updates, subject recruitment procedures (e.g., 
advertisements) and any other written information to be provided to subjects. 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 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 (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.
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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 subjects 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.
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 subject 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 subject 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
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e.arm.open.label.study.evaluating.the.efficacy.html?f=m2t1574 (accessed 26 October 2017).
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; 25:24:3130-9.
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.
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Line Therapy for Subjects with Immune Thrombocytopenic Purpura (ITP). Blood; 132:733.
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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 et al 2015
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Appendix 3: HRQoL Questionnaires
Table 16-3
FACIT-Fatigue Scale Version 4
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Table 16-4
SF-36V2
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