Clinical trial NCT03988608
Conditions: Aplastic Anemia
Keywords: Severe Aplastic Anemia Eltrombopag ETB115 Chinese subject Chinese refractory or relapsed SAA subjects refractory severe aplastic anemia relapsed severe aplastic anemia
Sponsor: Novartis Pharmaceuticals
Start date: 2019-12-09; Completion date: 2023-05-17
Enrollment: 20 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This was a non-randomized, open-label, phase II study to assess the efficacy and safety of eltrombopag in Chinese subjects with refractory or relapsed severe aplastic anemia (SAA). Treatment with eltrombopag was started at 25 mg/day and increased by 25 mg/day every 2 weeks according to the platelet count up to 150 mg/day. The hematological response rate was assessed at 3, 6 months and 1 year after starting the study treatment (Week 13, 26 and 52).

Detailed description:
This was a bridging study to support China registration. An estimation strategy rather than a formal hypothesis testing was pursued. Twenty subjects were enrolled into the study.

Treatment with eltrombopag started at 25 mg/day and increased by 25 mg/day every 2 weeks according to the platelet count, up to 150 mg/day. Hematological response rate was assessed at 3, 6 months and 1 year (Week 13, 26 and 52) after starting the study treatment. Subjects in whom the treatment was found to be effective at 6 months continued to receive the treatment. Eltrombopag was discontinued if the treatment was ineffective at 6 months. Subjects discontinued eltrombopag before 6 months if any of the treatment discontinuation criteria was met.

Analysis set for the primary endpoint was Full Analysis Set (FAS) and subjects who discontinue from the study before Week 26 were treated as non-responders in the response analysis. Eltrombopag treatment was provided to subjects who were considered to require continued treatment at Week 26. After Week 26, if all of the hematologic response criteria (i.e., platelet count \> 50×109/L, hemoglobin level \> 100 g/L without transfusion, and neutrophil count \> 1.0×109/L) remained fulfilled for more than 8 weeks, the dose of eltrombopag was decreased by half. If the response continued for further 8 weeks even at the decreased dose, the treatment was discontinued. If a decrease in any of the hematologic values (i.e., platelet count \< 30×109/L, hemoglobin \< 90 g/L, or neutrophil count \< 0.5×109/L) was found after dose reduction, the dose was increased to the previous level. Furthermore, after treatment interruption, the treatment was restarted if any of the hematologic values decreased to the above-mentioned levels. The response assessment and safety evaluation were performed at Week 52.

The Extension part of this study started 1 year (Week 52) after the initiation of study treatment. This part was included in the study with an ethical consideration for subjects who required continued treatment. The continued treatment was provided up to the launch of eltrombopag after approval. Follow-up visit was performed 30 days after the discontinuation of eltrombopag treatment.

To better understand the pharmacokinetics (PK) characteristics of eltrombopag in Chinese severe aplastic anemia (SAA) patient population, intensive PK blood samples were collected only in the initial 12 Chinese subjects receiving 25 mg/day dose after reaching steady-state, to provide evaluable full PK profiles. Steady-state trough concentrations were collected at other dose levels and in other subjects.

Arms: arm 1: Subjects started eltrombopag treatment at 25 mg/day since Day 1.
Interventions: intervention 1: Eltrombopag
Intervention descriptions: intervention 1: Eltrombopag are film-coated tablets containing 25 mg of eltrombopag free acid in each tablet.

Protocol documents:
Prot_000.pdf: 
Novartis Research and Development
ETB115
Clinical Trial Protocol CETB115E2202 / NCT03988608
A non-randomized, open-label, multi-center, phase II study 
to assess the safety and efficacy of eltrombopag in 
Chinese subjects with refractory or relapsed severe 
aplastic anemia
Document type:
Amended Protocol Version
EUDRACT number:
NA
Version number:
02 (Clean)
Clinical Trial Phase:
II
Release date:
02-Sep-2019
Property of Novartis
Confidential
May not be used, divulged, published, or otherwise disclosed
without the consent of Novartis
Clinical Trial Protocol Template version 1.0 dated 01-Dec-2017


Novartis
Confidential
Page 2
Amended Protocol Version 02 (Clean)
Protocol No. CETB115E2202
Table of contents
Table of contents .................................................................................................................2
List of tables ........................................................................................................................5
List of figures ......................................................................................................................6
List of abbreviations............................................................................................................7
Glossary of terms...............................................................................................................11
Amendment 2 ....................................................................................................................12
Amendment 1 ....................................................................................................................14
Protocol summary..............................................................................................................16
1
Introduction .......................................................................................................................21
1.1
Background............................................................................................................21
1.2
Purpose ..................................................................................................................22
1.3
Pharmacokinetics and drug-drug interaction in human.........................................23
2
Objectives and endpoints...................................................................................................24
3
Study design ......................................................................................................................24
4
Rationale............................................................................................................................26
4.1
Rationale for study design .....................................................................................26
4.1.1
Rationale for primary endpoint.............................................................26
4.1.2
Rationale for study design.....................................................................26
4.2
Rationale for dose/regimen and duration of treatment ..........................................27
4.2.1
Rationale for dose/regimen ...................................................................27
4.2.2
Rationale for duration of treatment.......................................................29
4.3
Rationale for choice of control drugs (comparator/placebo) or combination 
drugs ......................................................................................................................29
4.4
Purpose and timing of interim analyses/design adaptations..................................29
4.5
Risks and benefits..................................................................................................29
4.5.1
Risk assessment.....................................................................................29
4.5.2
Benefit Assessment ...............................................................................30
4.5.3
Overall risks and benefits conclusion ...................................................30
5
Population..........................................................................................................................31
5.1
Inclusion criteria ....................................................................................................31
5.2
Exclusion criteria...................................................................................................32
6
Treatment...........................................................................................................................34
6.1
Study treatment......................................................................................................34
6.1.1
Investigational and control drugs..........................................................34
6.1.2
Additional study treatments ..................................................................34


Novartis
Confidential
Page 3
Amended Protocol Version 02 (Clean)
Protocol No. CETB115E2202
6.1.3
Treatment arms/group ...........................................................................34
6.1.4
Guidelines for continuation of treatment ..............................................34
6.1.5
Treatment duration................................................................................34
6.2
Other treatment(s)..................................................................................................35
6.2.1
Concomitant therapy.............................................................................35
6.2.2
Prohibited medication ...........................................................................37
6.2.3
Rescue medication ................................................................................37
6.2.4
Treatment of study treatment overdose.................................................37
6.3
Subject numbering, treatment assignment, randomization....................................37
6.3.1
Subject numbering ................................................................................37
6.3.2
Treatment assignment, randomization ..................................................38
6.4
Treatment blinding.................................................................................................38
6.5
Dose escalation and dose modification..................................................................38
6.5.1
Dose modifications................................................................................38
6.5.2
Follow-up for toxicities.........................................................................41
6.6
Additional treatment guidance...............................................................................42
6.6.1
Treatment compliance...........................................................................42
6.6.2
Emergency breaking of assigned treatment code..................................43
6.7
Preparation and dispensation.................................................................................43
6.7.1
Handling of study treatment and additional treatment..........................43
6.7.2
Instruction for prescribing and taking study treatment .........................44
7
Informed consent procedures ............................................................................................44
8
Visit schedule and assessments .........................................................................................45
8.1
Screening ...............................................................................................................49
8.1.1
Information to be collected on screening failures.................................49
8.2
Subject demographics/other baseline characteristics.............................................49
8.3
Efficacy..................................................................................................................50
8.3.1
Primary endpoint...................................................................................50
8.3.2
Secondary endpoints .............................................................................51
8.3.3
Appropriateness of efficacy assessments..............................................51
8.4
Safety.....................................................................................................................51
8.4.1
Laboratory evaluations..........................................................................52
8.4.2
Electrocardiogram (ECG) .....................................................................53
8.4.3
Pregnancy and assessments of fertility .................................................53
8.4.4
Peripheral blood smear, bone marrow aspiration and bone marrow 
biopsy....................................................................................................54
8.4.5
Ophthalmic Assessments ......................................................................54


Novartis
Confidential
Page 4
Amended Protocol Version 02 (Clean)
Protocol No. CETB115E2202
8.4.6
Evaluation of clonal evolution ..............................................................54
8.5
Additional assessments..........................................................................................54
8.5.1
Pharmacokinetics ..................................................................................54
9
Study discontinuation and completion ..............................................................................56
9.1
Discontinuation......................................................................................................56
9.1.1
Discontinuation of study treatment .......................................................56
9.1.2
Withdrawal of informed consent...........................................................58
9.1.3
Lost to follow-up...................................................................................58
9.1.4
Early study termination by the sponsor.................................................58
9.2
Study completion and post-study treatment ..........................................................59
10 Safety monitoring and reporting........................................................................................59
10.1
Definition of adverse events and reporting requirements......................................59
10.1.1
Adverse events ......................................................................................59
10.1.2
Serious adverse events ..........................................................................61
10.1.3
SAE reporting........................................................................................62
10.1.4
Pregnancy reporting ..............................................................................63
10.1.5
Reporting of study treatment errors including misuse/abuse................64
10.2
Additional Safety Monitoring................................................................................64
11 Data Collection and Database management......................................................................65
11.1
Data collection.......................................................................................................65
11.2
Database management and quality control............................................................65
11.3
Site monitoring ......................................................................................................65
12 Data analysis and statistical methods ................................................................................66
12.1
Analysis sets ..........................................................................................................66
12.2
Subject demographics and other baseline characteristics......................................66
12.3
Treatments .............................................................................................................67
12.4
Analysis of the primary endpoint(s) ......................................................................67
12.4.1
Definition of primary endpoint(s).........................................................67
12.4.2
Statistical model, hypothesis, and method of analysis..........................67
12.4.3
Handling of missing values/censoring/discontinuations.......................67
12.4.4
Sensitivity and Supportive analyses......................................................67
12.5
Analysis of secondary endpoints ...........................................................................68
12.5.1
Efficacy and/or Pharmacodynamic endpoint(s)....................................68
12.5.2
Safety endpoints....................................................................................69
12.5.3
Pharmacokinetics ..................................................................................71
72
12.7
Interim analyses.....................................................................................................72


Novartis
Confidential
Page 5
Amended Protocol Version 02 (Clean)
Protocol No. CETB115E2202
12.8
Sample size calculation..........................................................................................73
12.8.1
Primary endpoint(s)...............................................................................73
13 Ethical considerations and administrative procedures ......................................................73
13.1
Regulatory and ethical compliance........................................................................73
13.2
Responsibilities of the investigator and IRB/IEC..................................................73
13.3
Publication of study protocol and results...............................................................74
13.4
Quality Control and Quality Assurance.................................................................74
14 Protocol adherence ............................................................................................................74
14.1
Protocol Amendments ...........................................................................................74
15 References .........................................................................................................................76
16 Appendices ........................................................................................................................78
16.1
Appendix 1: List of substrates of BCRP and OATP1B1.......................................78
16.2
Appendix 2: Liver event and Laboratory trigger Definitions and Follow-up 
Requirements.........................................................................................................78
List of tables
Table 2-1
Objectives and related endpoints ..........................................................24
Table 6-1
Investigational drug...............................................................................34
Table 6-2
Prohibited medication and therapy........................................................37
Table 6-3
Criteria for dose adjustment of eltrombopag between Week 1 and 
Week 26 ................................................................................................38
Table 6-4
Criteria for dose adjustment of eltrombopag after Week 26.................39
Table 6-5
Dose reduce criteria of eltrombopag after Week 26 .............................39
Table 6-6
Criteria for dose reduction / interruption and re-initiation of 
eltrombopag treatment for adverse drug reactions................................40
Table 8-1
Assessment Schedule ............................................................................46
Table 8-2
IWG criteria for Primary Endpoint .......................................................50
Table 8-3
Assessments & Specifications...............................................................52
Table 8-4
Laboratory Assessments........................................................................52
Table 8-5
Sample log table for the evaluation of eltrombopag 
pharmacokinetics...................................................................................55
Table 10-1
Guidance for capturing the study treatment errors including 
misuse/abuse .........................................................................................64
Table 12-1
Non-compartmental pharmacokinetic parameters ................................72
Table 12-2
90% CIs for various observed response rate.........................................73
Table 16-1
List of substrates of BCRP and OATP1B1...........................................78
Table 16-2
Follow up requirements for liver events and laboratory triggers..........78


Novartis
Confidential
Page 6
Amended Protocol Version 02 (Clean)
Protocol No. CETB115E2202
List of figures
Figure 3-1
Study Design .........................................................................................26


Novartis
Confidential
Page 7
Amended Protocol Version 02 (Clean)
Protocol No. CETB115E2202
List of abbreviations
AA
aplastic anemia
AE
adverse event
AESI
adverse event of special interest
AHSCT
autologous hematopoietic stem cell transplantation
ALG
anti-lymphocyte Immunoglobulin
ALP
alkaline phosphatase
ALT
alanine aminotransferase
AML
acute myeloid leukemia
ANC
absolute neutrophil count 
APS
antiphospholipid antibody syndrome
aPTT
acute partial thromboplastin time
AST
aspartate aminotransferase
ATC
anatomical therapeutic chemical
ATG
anti-thymocyte globulin
AUC
area under the plasma concentration-time curve
AUCinf
area under the plasma concentration-time curve from zero (pre-dose) extrapolated to 
infinite time
AUClast
area under the plasma concentration-time curve from zero (pre-dose) to the last 
quantifiable sample time
AUCtau
area under the plasma concentration-time curve over the dosing interval on multiple 
dosing
BCRP
Breast Cancer Resistance Protein
BM
bone marrow
BMT
bone marrow transplantation
BUN
blood urea nitrogen
CBC
complete blood count
CD
Cluster of Differentiation
CE
clonal evolution
CFR
Code of Federal Regulation
CI
Confidence Interval
CL/F 
apparent clearance of the drug from plasma after oral administration
Cmax
maximum plasma concentration following drug administration
CMO&PS
Chief Medical Office and Patient Safety
CMV
Cytomegalovirus
CO
country organization
CRA
Clinical Research Associate
CRF
Case Report/Record Form (paper or electronic)
CsA
Cyclosporine
CSR
Clinical Study Report
CTC
Common Toxicity Criteria
CTCAE
Common Terminology Criteria for Adverse Events


Novartis
Confidential
Page 8
Amended Protocol Version 02 (Clean)
Protocol No. CETB115E2202
Ctrough
pre-dose (trough) concentration at the end of the dosing interval
CV
coefficient of variation
CYP
cytochrome P450 proteins
DAR
dose administration record
DBP
Diastolic Blood Pressure
DDE
direct data entry
DILI
drug-induced liver injury
DNA
deoxyribonucleic acid
EBV
Epstein-Barr Virus
EC
Ethics committee
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
ECOG PS
Eastern Cooperative Oncology Group performance status
eCRF
Electronic Case Report/Record Form
EDC
Electronic Data Capture
EDD
Expected Delivery Date
EMA
European Medicines Agency
EOT
end of treatment
EU
Europe
FAS
Full Analysis Set
FDA
Food and Drug Administration
FISH
fluorescence in situ hybridization
FSH
Follicle Stimulating Hormone
G-CSF
granulocyte colony stimulating factor
GCP
Good Clinical Practice
GGT
Gamma-glutamyl transferase
GPI
glycosylphosphatidylinositol
h
Hour
hATG
horse ATG
HB
Hepatitis B
HBcAb
Hepatitis B core Antibody
HBsAb
Hepatitis B surface Antibody
HBsAg
Hepatitis B surface Antigen
HCV
hepatitis C virus
HIV
human immunodeficiency virus
HMG-CoA
hydroxy methylglutaryl coenzyme A
HSCT
hematopoietic stem cell transplantation
HSPC
hematopoietic stem and progenitor cells
HSV
herpes simplex virus
IB
Investigator's Brochure
ICF
Informed consent form
ICH
International Conference on Harmonisation of Technical Requirements for Registration 


Novartis
Confidential
Page 9
Amended Protocol Version 02 (Clean)
Protocol No. CETB115E2202
of Pharmaceuticals for Human Use
IEC
Independent Ethics Committee
IN
Investigator Notification
INR
International Normalized Ratio
IRB
Institutional Review Board
IST
immunosuppressive therapy 
ITP
immune thrombocytopenia
IUD
intrauterine device
IUS
intrauterine system
IWG
International Working Group
LC-MS/MS
liquid chromatography – tandem mass spectrometry assay
LDH
lactate dehydrogenase
LFT
Liver function test
LLOQ
lower limit of quantification
MDS
myelodysplastic syndromes
MedDRA
Medical dictionary for regulatory activities
mg
milligram(s)
mL
milliliter(s)
msec
milliseconds
NA
not applicable
NCI
National Cancer Institute
NHLBI/NIH
National Heart , Lung, and Blood Institute /National Institutes of Health
NSAIDs
non-steroidal anti-inflammatory drugs
NYHA
New York Heart Association
OATP
organic anion transporting polypeptide
PAS
Pharmacokinetic analysis set
PD
pharmacodynamic(s)
PK
pharmacokinetic(s)
PNH 
paroxysmal nocturnal hemoglobinuria
PT
prothrombin time
QMS
Quality Management System
QoL
quality of life
QTc
corrected QT interval duration
rATG
rabbit ATG
RBC
red blood cell(s)
SAA
severe aplastic anemia
SAE
serious adverse event
SAP
Statistical Analysis Plan
SBP
Systolic Blood Pressure
SD
standard deviation
SOP
Standard Operating Procedure
SUSAR
Suspected Unexpected Serious Adverse Reaction


Novartis
Confidential
Page 10
Amended Protocol Version 02 (Clean)
Protocol No. CETB115E2202
TBIL
total bilirubin
Tmax
time to peak concentration
TPO
thrombopoietin
TPO-R
thrombopoietin receptor
UGT
uridine diphosphate glucuronosyl transferase
ULN
upper limit of normal
US
United States
WHO
World Health Organization


Novartis
Confidential
Page 11
Amended Protocol Version 02 (Clean)
Protocol No. CETB115E2202
Glossary of terms
Assessment
A procedure used to generate data required by the study
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)
Enrollment
Point/time of subject entry into the study; the point at which informed consent must 
be obtained (i.e. prior to starting any of the procedures described in the protocol).
eSource (DDE)
eSource Direct Data Entry (DDE) refers to the capture of clinical study data 
electronically, at the point of care. eSource Platform/Applications combines source 
documents and case report forms (eCRFs) into one application, allowing for the real 
time collection of clinical trial information to sponsors and other oversight 
authorities, as appropriate.
Investigational 
drug
The study drug whose properties are being tested in the study; this definition is 
consistent with US CFR 21 Section 312.3 and Directive 2001/20/EC and is 
synonymous with “investigational new drug” or “test substance”
Part
A single component of a study which contains different objectives or populations 
within that single study. Common parts within a study are: a single dose part and a 
multiple dose part, or a part in patients with established disease and in those with 
newly-diagnosed disease.
Patient
An individual with the condition of interest
Period
A minor subdivision of the study timeline; divides phases into smaller functional 
segments such as screening, baseline, titration, washout, etc.
Personal data
Subject information collected by the Investigator that is transferred to Novartis for 
the purpose of the clinical trial. This data includes subject identifier information, 
study information and biological samples.
Refractory SAA
SAA with severe cytopenia following at least one treatment course of 
immunosuppression with a regimen consisting of either anti-thymocyte globulin/anti-
lymphocyte Immunoglobulin, alemtuzumab or cyclophosphamide.
Screen Failure
A subject who is screened but is not treated or randomized
Study 
completion
Point/time at which the subject came in for a final evaluation visit or when study 
drug was discontinued whichever is later.
Study 
drug/treatment
Any drug (or combination of drugs) administered to the subject as part of the 
required study procedures; includes investigational drug, active drug run-ins or 
background therapy.
Study treatment
Any drug administered to the study participants as part of the required study 
procedures; includes investigational drug (s), control(s) or non-investigational 
medicinal product(s)
Subject
An individual who has consented to participate in this study. The term Subject may 
be used to describe either a healthy volunteer or a patient.
Subject number
A unique number assigned to each subject upon signing the informed consent. This 
number is the definitive, unique identifier for the subject and should be used to 
identify the subject throughout the study for all data collected, sample labels, etc.
Variable
Information used in the data analysis; derived directly or indirectly from data 
collected using specified assessments at specified timepoints.
Withdrawal of 
consent
Withdrawal of consent from the study occurs only when a subject does not want to 
participate in the study any longer and does not allow any further collection of 
personal data


Novartis
Confidential
Page 12
Amended Protocol Version 02 (Clean)
Protocol No. CETB115E2202
Amendment 2
Amendment rationale
Study status: As of 02Sep2019, no patients are enrolled in the protocol.
The main purpose of this amendment is to clarify the definition of the target population 
including “insufficient response” in this study and to update liver event and laboratory trigger 
definitions and follow-up requirement due to protocol template update. In addition, to ensure 
a proper assessment of the hematological response, the interval from platelet transfusion is 
specified and the interval of RBC transfusion is changed.
In addition, editorial changes and clarifications were made at various places in the protocol.
Changes to the protocol
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions.

Protocol summary: removed ECOG PS from the section of Key safety assessment because 
ECOG PS is not collected in CRF.

Table 2-1: removed "refractory or relapsed" due to clarify the target population of this 
study.

Section 5: added text to clarify patients with insufficient response.

Section 5.1: added the new inclusion criteria about the platelet count at screening to avoid 
enrolling relapsed patients and patients who had achieved PR after the latest course of IST  
with  > 30×109/L.

Section 6.2.2: changed the period of using prohibited prescription or nonprescription drugs 
from within 7 days to within 30 days to align with exclusion criteria 15.

Table 8-1: modified the example weeks of assessing Plasma thrombopoietin because 
patients’ visits occur on even weeks. 

Section 8.2: removed ECOG PS because ECOG PS is not collected in CRF.

Table 8-2: changed the table layout to clarify each criteria, specified the time interval from
platelet transfusion to response assessment to ensure that the response is not confounded 
by the transfusion, and changed the time interval from RBC transfusion to response 
assessment from 4 weeks to 14 days to align with other studies using this study drug.

Section 9.2: removed the text that mentioned the alternative setting to provide study 
treatment with patients after the end of the study because this text is not applicable for this 
study.

Table 16-1: updated the version of source guidance.

Section 16.2 Appendix 2: added the table 16-2 related to liver event and laboratory trigger 
definitions and follow-up requirement due to protocol template update.


Novartis
Confidential
Page 13
Amended Protocol Version 02 (Clean)
Protocol No. CETB115E2202
IRB Section
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. 
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment.


Novartis
Confidential
Page 14
Amended Protocol Version 02 (Clean)
Protocol No. CETB115E2202
Amendment 1
Amendment rationale
Study status: As of 17May2019, no patients are enrolled in the protocol.
The main purpose of this amendment is to be able to conduct this study in multiple 
investigational sites. The visit windows have been set and the visit frequency has also be 
adjusted according to the local practice and feasibility feedback from investigators.
In addition, editorial changes and clarifications were made at various places in the protocol.
Changes to the protocol
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions.

Protocol title: changed from "single center" to "multi-center" to be able to conduct this 
study in multiple investigational sites.

Section 6.5.2.1: removed criterias related to bone metastasis and liver metastasis/lesions as 
not applicable for SAA patients.

Section 6.7: changed the description of the study medication label because a unique 
medication number and a 2-part label are not used in this study.

Section 8: added sentences to allow visit windows.

Table 8-1: change the visit frequency from "every week until stabilization of dose" to 
"every 2 weeks until stabilization of dose" after Week 4 due to the local practice and 
feasibility feedback from investigators.

Table 8-1: removed "X" from Characteristics of SAA and Inclusion/Exclusion criteria at 
Day 1 because these items should be performed at the screening visit.

Table 8-1: changed from "X" to "S" in Ophthalmologic examinations, Pregnancy and 
assessments of fertility, Examination of HBsAg, HBsAb, HBcAb, HCV antibody and HIV 
antibody due to no planned analysis.

Table 8-1: inserted the row of Hematological response assessment.

Table 8-1: removed "S" from PK blood sampling after Week 52 due to typo.

Table 8-1: removed "X" from Disposition at Week 183 to 365 due to typo.

Section 8.1.1: deleted the section "Eligibility screening" because it is not applicable in this 
study.

Section 8.1.2: changed the section number from 8.1.2 to 8.1.1 and clarified what is a 
screening failure.

Section 8.2: removed “severity” and “complications” of aplastic anemia because these 
data is not collected.

Section 8.4.5: clarified that the slit lamp examination should be performed when a cataract 
is suspected.


Novartis
Confidential
Page 15
Amended Protocol Version 02 (Clean)
Protocol No. CETB115E2202
IRB Section
A copy of this amended protocol will be sent to the Institutional Review Board
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. 
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment.


Novartis
Confidential
Page 16
Amended Protocol Version 02 (Clean)
Protocol No. CETB115E2202
Protocol summary
Protocol number
CETB115E2202
Full Title
A non-randomized, open-label, multi-center, phase II study to assess the safety 
and efficacy of eltrombopag in Chinese subjects with refractory or relapsed 
severe aplastic anemia
Brief title
Study to assess the safety and efficacy of eltrombopag in Chinese refractory or 
relapsed SAA subjects
Sponsor and 
Clinical Phase
Novartis
Phase II
Investigation type
Drug
Study type
Interventional 
Purpose and 
rationale
Severe aplastic anemia (SAA) is a life-threatening bone marrow failure disorder 
characterized by pancytopenia and a hypocellular bone marrow. Despite its rare 
incidence in the West, SAA is far more prevalent in densely populated areas in 
China and East Asia for reasons that are not fully understood.
As in the rest of world, immunosuppressive therapy (IST) has significantly 
increased patient outcomes and has been established as a standard of care for 
treatment-naive SAA patients. However, in China there is no established 
standard of care for SAA patients who have an insufficient response to IST and 
who are not a candidate or not have a suitable donor for hematopoietic stem cell 
transplantation (HSCT)(other than supportive transfusions or treatment for 
infections). There is a high unmet need for effective, well-tolerated therapies for 
SAA patients who have an insufficient response to IST.
The most important advancement in refractory or relapsed SAA treatment in the 
past few decades has come from the seminal observation that a thrombopoietin 
(TPO) receptor agonist, eltrombopag, has activity in SAA. This was 
demonstrated in a phase I/II study (Study number: ETB115AUS28T)at the 
United states (US) National Institutes of Health (NIH) where a remarkable 40% 
of patients' refractory to IST showed hematologic response to this single oral 
agent.
Efficacy and safety of eltrombopag in refractory SAA patients of East Asian has 
been confirmed by a non-randomized, open-label, phase II Japanese study 
(Study number: ETB115E1201), showing a similar response in Japanese 
subjects, with 47.6% response rate reported at Week 26 following treatment with 
eltrombopag, with multilineage hematologic responses observed. Safety of 
eltrombopag in Chinese patients has been demonstrated in a randomized phase 
III study comparing the efficacy and safety of eltrombopag with placebo in 
Chinese patients with immune thrombocytopenia, where good tolerability was 
shown, with a similar profile compared to that in western population and no new 
safety signals identified in Chinese patient population.
Given the context of all above, it is expected that a favorable benefit/risk profile 
can be acquired to use eltrombopag in the treatment of Chinese refractory or 
relapsed SAA patients, and to meet this high unmet medical need. Therefore, 
current study is designed to assess eltrombopag in such Chinese population.
Primary 
Objective(s) 
The primary objective of this study is to assess the efficacy of eltrombopag at 6 
months in Chinese subjects with a previous diagnosis of severe aplastic anemia 
and who had insufficient response following at least one treatment course in the 


Novartis
Confidential
Page 17
Amended Protocol Version 02 (Clean)
Protocol No. CETB115E2202
period time of > 6 months of immunosuppression with a regimen containing anti-
thymocyte globulin (ATG), anti-lymphocyte globulin (ALG), and/or 
cyclophosphamide, or alemtuzumab, and who are ineligible for HSCT or a 
suitable donor is not available.
Secondary 
Objectives
Objective 1: To evaluate the efficacy of eltrombopag treatment at 3 months and 
1 year
Objective 2: To evaluate the effect of eltrombopag on individual hematologic 
response (change in neutrophil, platelet, hemoglobin)
Objective 3: To evaluate the time to hematologic response and duration
Objective 4: To evaluate the frequency and volume of transfusion (platelet and 
red blood cell (RBC))
Objective 5: To evaluate the safety and tolerability of eltrombopag
Objective 6: To determine the pharmacokinetics (PK) of eltrombopag
Objective 7: To evaluate cytogenetic abnormalities, clonal evolution (CE) 
to paroxysmal nocturnal hemoglobinuria (PNH), evolution to myelodysplastic 
syndromes (MDS) or acute myeloid leukemia (AML).
Study design
This is a non-randomized, open-label, phase II study to assess the efficacy and 
safety of eltrombopag in Chinese subjects with refractory or relapsed severe 
aplastic anemia. Treatment with eltrombopag will be started at 25 mg/day and 
increased by 25 mg/day every 2 weeks according to the platelet count up to 150 
mg/day. The hematological response rate will be assessed at 3, 6 months and 1 
year after starting the study treatment (Week 13, 26 and 52). The primary 
endpoint is the hematologic response rate at Week 26. Analysis set for the 
primary endpoint is Full Analysis Set (FAS) and subjects who discontinued from 
study before Week 26 will be treated as non-responders in the response 
analysis. Continued treatment will be provided up to the launch of the product 
after approval.
Population
Approximately 20 Chinese subjects aged greater than or equal to 18 years 
old, previously diagnosed with severe aplastic anemia and had insufficient 
response following at least one treatment course in the period time of > 6 
months of immunosuppression with a regimen containing anti-thymocyte 
globulin (ATG), anti-lymphocyte Immunoglobulin (ALG), and/or 
cyclophosphamide, or alemtuzumab, and ineligible for HSCT or a suitable donor 
is not available
Key Inclusion 
criteria

Chinese patients aged greater than or equal to 18 years old.

Subjects with a previous diagnosis of severe aplastic anemia and had 
insufficient response following at least one treatment course in the period 
time of > 6 months of immunosuppression with a regimen containing anti-
thymocyte globulin(ATG), anti-lymphocyte globulin(ALG), and/or 
cyclophosphamide, or alemtuzumab. 

Subject had SAA at diagnosis characterized by: 
a.
BM cellularity < 25%, or 25 – 50% with < 30% residual haemopoietic 
cells and
b.
At least two of the following (peripheral blood):
i.
Absolute neutrophil count < 0.5 × 109/L
ii.
Platelet count < 20 × 109/L
iii.
Absolute reticulocyte count < 20 × 109/L

Platelet count ≤ 30 × 109/L at screening.


Novartis
Confidential
Page 18
Amended Protocol Version 02 (Clean)
Protocol No. CETB115E2202

Subjects must not currently have the option of stem cell transplantation, 
either because they are not a candidate, or because a suitable donor is not 
available.
Key Exclusion 
criteria

Treatment with ATG/ALG, alemtuzumab, or cyclophosphamide in the past 6 
months.
Note: Subjects who are receiving cyclosporine or anabolic steroids (excluding 
danazol) at a stable dose may be enrolled if laboratory values are stable at 
screening.

Congenital aplastic anemia (AA) (e.g. Fanconi anemia, congenital 
dyskeratosis).

AST or ALT ≥3 times the upper limit of normal (ULN).

Creatinine, total bilirubin (TBIL), and alkaline phosphatase (ALP) ≥1.5 ×
local upper limit of normal (ULN) (total bilirubin ≥2.5 × local ULN with 
Gilbert's Syndrome).

Paroxysmal nocturnal hemoglobinuria (PNH) granulocyte clone size 
determined by flow cytometry ≥50%.

Presence of chromosomal aberration (-7/7q- detected by fluorescence in 
situ hybridization (FISH), or other aberrations detected by G-band staining).

Evidence of a clonal hematologic bone marrow disorder on cytogenetics. If a 
clonal disorder is identified, the patient will be excluded.

Past medical history of thromboembolism within 6 months or current use of 
anticoagulants. Patient with antiphospholipid antibody syndrome.

Subject must not have any concomitant malignancies and must be fully 
recovered from treatment for any other malignancy and have been disease-
free for 5 years.

Subject with clinically significant (of such severity that it would preclude the 
patient’s ability to consent, be compliant with study procedures, tolerate 
protocol therapy) bacterial, fungal, mycobacterial, parasitic or viral infection.

Subject with known hepatocellular disease (e.g. active hepatitis or cirrhosis).

Past medical history of immediate or delayed hypersensitivity to compounds 
chemically similar to eltrombopag or their excipients.

Prior treatment with eltrombopag, romiplostim, or any other TPO receptor 
agonist.
Study treatment
Eltrombopag, 25 mg, tablet
Efficacy 
assessments

Hematologic response rate defined as the proportion of all subjects who 
meet any of the International Working Group (IWG) criteria shown in the 
table below:
Assessment 
Item
Baseline 
transfusion 
status
Response Criteria
Platelet count
Platelet 
transfusion 
independent
Transfusion independent and increase 
from baseline by 20×109/L or more
Platelet 
transfusion 
dependent
No platelet transfusion requirement for 8 
weeks
Hemoglobin
RBC transfusion 
independent
When the baseline hemoglobin level is < 
90 g/L: transfusion independent and 


Novartis
Confidential
Page 19
Amended Protocol Version 02 (Clean)
Protocol No. CETB115E2202
increase from baseline by 15 g/L or 
more
RBC transfusion 
dependent
A decrease of at least 4 units in RBC 
transfusions in the post-treatment 8-
week period (1 unit = RBC derived from 
200 mL blood)
Or no RBC transfusion requirement for 8 
weeks (less than 4 units RBC in 8-week 
period at Baseline)
Neutrophil 
count
NA
(In the absence of granulocyte colony 
stimulating factor (G-CSF) taken within 
21 days preceding the blood sample 
collection) Increase from baseline by 
0.5×109/L or more, or (if < 0.5×109/L at 
baseline) increase by 100% or more

During regular hematologic assessment, the exclusion period of 
transfusion and G-CSF are detailed below:
Platelet transfusion: 7 days preceding the assessment of platelet count
RBC transfusion: 14 days preceding the assessment of hemoglobin
G-CSF: 21 days preceding the assessment of neutrophil count

Changes in platelet count, hemoglobin and neutrophil count, time to 
hematologic response and duration, frequency and volume of transfusion 
(platelet and RBC) will also be assessed
Pharmacokinetic 
assessments
Blood samples will be collected for eltrombopag PK assessment. Serial 
intensive PK blood samples will be collected for the initial 25 mg/day dose to 
provide at least 12 patients with evaluable PK profiles. After the purpose of 
getting evaluable full PK profiles in 12 subjects has been fulfilled, the rest of 
subjects will receive sparse PK sampling only. In all remaining subjects, one 
blood sample each will be collected at pre-dose on the 15th day for the initial 25 
mg/day dose and after each new dose has started until the maximal dose is 
reached.
Intensive PK Sampling for 12 subjects:

25 mg/day: Serial PK samples will be collected over a 24 hour period on 
Days 14 to 15. A total of 7 blood samples (2 mL/sample) will be collected at 
the following time points: pre-dose, and 1, 2, 4, 6, 8, and 24 h post-dose

50 mg/day and other doses: Pre-dose on Day 15 (14 days from the start of 
any new dose level)
Sparse PK Sampling for 8 subjects:

25 mg/day: Pre-dose on Day 15 (14 days from the start of dosing)

50 mg/day and other doses: Pre-dose on Day 15 (14 days from the start of 
any new dose level)
Key safety 
assessments
Safety assessment will include AE monitoring, clinical examinations, vital signs, 
peripheral blood smear and bone marrow aspiration, ophthalmic assessments, 
flow cytometry of the peripheral blood for GPI-cells, and any necessary 
radiologic and laboratory measures. The latter includes routine CBC, chemistry, 
coagulation profile, electrocardiogram (ECG) and appropriate monitoring for and 
evaluation of any infections.
Data analysis
The Full Analysis Set (FAS) comprises all subjects who receive at least one 
dose of study treatment (eltrombopag). The FAS will be the primary population 
in the assessment of efficacy.


Novartis
Confidential
Page 20
Amended Protocol Version 02 (Clean)
Protocol No. CETB115E2202
The Safety set is identical as the Full Analysis set in the study. All safety 
analyses will be done using the Safety Set.
The primary analyses will be performed when all the subjects have completed 
the Week 26 visit or discontinued earlier.
The primary endpoint is the hematologic response rate at Week 26, which is 
defined as the proportion of all subjects who meet any of the IWG criteria listed 
above. The proportion of the hematological response will be summarized using 
point estimates and 90% exact (Clopper-Pearson) confidence intervals (CI). The 
distribution function of time to hematologic response will be estimated using the 
Kaplan- Meier method. The median time to hematologic response along with 
90% CIs will be presented. If a subject has no response or withdraw from the 
study before or at the cutoff date, this subject will be treated as censored at the 
maximum follow up of the entire trial.
For the rest of the efficacy and safety endpoints (i.e. AE, vital sign, laboratory 
assessment), summary statistics will be presented using n, mean, standard 
deviation, median, 25th and 75th percentiles, minimum and maximum for 
continuous data and frequencies and percentages for categorical data. Shift and 
abnormality tables will be provided for each laboratory and vital sign 
assessment.
Eltrombopag plasma concentration data will be listed and summarized by dose, 
visit and time point, and listed by subject, visit and time point. Descriptive 
statistics will consist of arithmetic and geometric mean, median, standard 
deviation, arithmetic coefficient of variation (CV), geometric CV, minimum and 
maximum. Zero concentrations will not be included in the geometric mean 
calculation.
Where possible, PK parameters will be determined by applying non-
compartmental method(s) using Phoenix WinNonlin version 6.4 or above 
(Pharsight, Mountain View, CA). Derived PK parameters, including but not
limited to: time to peak concentration (Tmax), maximum plasma concentration 
following drug administration (Cmax), area under the plasma concentration-time 
curve over the dosing interval on multiple dosing (AUCtau), area under the 
plasma concentration-time curve from zero (pre-dose) to the last quantifiable 
sample time (AUClast), will be summarized with the descriptive statistics, 
arithmetic and geometric mean, median, standard deviation, arithmetic CV, 
geometric CV, minimum and maximum. Only median values and ranges will be 
given for Tmax. Missing data will not be imputed.
Key words
eltrombopag, Chinese, SAA, refractory, relapse


Novartis
Confidential
Page 21
Amended Protocol Version 02 (Clean)
Protocol No. CETB115E2202
1
Introduction
1.1
Background
Severe aplastic anemia (SAA) is a rare, life-threatening, acquired bone marrow failure disease 
characterized by tri-lineage marrow hypoplasia and a lack of hematopoietic stem and 
progenitor cells (HSPC) due to an immune-mediated attack on the bone marrow. SAA is a 
diagnosis of exclusion, with hypocellular bone marrow (< 25%) and pancytopenia (with at 
least 2 of the following: absolute neutrophil count (ANC) < 0.5 × 109 /L; platelet counts < 20 
×109/L; reticulocytes < 20 × 109/L [< 60 ×109/L via automated counter]) (Camitta et al 1975; 
Rosenfeld et al 2003; Marsh et al 2009). Aplastic anemia affects approximately 2 out of every 
1 million people in western countries (Young and Kaufman 2008). The incidence of aplastic 
anemia (AA) is higher in Asia where it is found at a rate of 3.9-5/million, approximately 2 to 
3 fold of that in western countries (Young and Kaufman 2008; Yang and Zhang 1991). The 
incidence of AA in China was reported as 3.3-7.2/million, while that of SAA was 1.7/million 
(Wang et al 2011; Zhang et al 1999; Yang and Zhang 1991; Zhang et al 2001).
The standard regimen for treatment-naive SAA (ineligible for HSCT) is immunosuppressive 
therapy with ATG/CsA. Since the establishment of ATG/CsA as a standard treatment for 
SAA, no subsequent improvements in treatment have been identified (Scheinberg et al 2012; 
Marsh and Kulasekararaj 2013). Intensification of primary IST for treatment-naïve patients 
with agents more immunosuppressive than horse ATG (hATG), including rabbit ATG (rATG), 
alemtuzumab, or high dose cyclophosphamide, have not been successful and the addition of 
sirolimus or mycophenolate to hATG/CsA have not improved response 
rates 
(Scheinberg et al 2006; Scheinberg et al 2009; Scheinberg et al 2012; Scheinberg et al 2011; 
Scheinberg and Young 2012). Outcomes remain poor for patients who have an insufficient 
response to IST.
Despite significant improvements in standard supportive care treatments (particularly 
antifungals, antimicrobials and other antibiotics), approximately 40% of SAA patients 
unresponsive to initial IST die from the complications of pancytopenia (infection or bleeding) 
within 5 years of diagnosis (Valdez et al 2011). In China, no established standard of care 
exists for SAA patients with an insufficient response to IST who lack a matched related donor 
for 
HSCT, 
other 
than 
transfusion 
support 
and 
treatment 
of 
infections 
Red Blood Cell Disease (Anemia) 2017. Consequently, such patients have a high unmet 
medical need, and outcomes remain unsatisfactory. There is a high unmet need for effective, 
well-tolerated therapies for SAA patients who have an insufficient response to IST.
Thrombopoietin (TPO) is a major cytokine adjusting megakaryocytopoiesis and production of 
platelet. Eltrombopag olamine, the bis-monoethanolamine salt form of eltrombopag, is an 
orally bioavailable, small molecule Thrombopoietin receptor (TPO-R) agonist.  Eltrombopag 
interacts with the transmembrane domain of the of the TPO-R on megakaryocytes and human 
bone marrow progenitor cells (Erickson-Miller et al 2010; Sun et al 2012).  Eltrombopag 
increases haematopoiesis by inducing proliferation and differentiation of early bone marrow 
progenitor cells. The multilineage effects of eltrombopag in patients with aplastic anaemia 
may be through  stimulation of bone marrow progenitor cells, as suggested by recent 
preclinical research. In this research, eltrombopag treatment resulted in multilineage increases 


Novartis
Confidential
Page 22
Amended Protocol Version 02 (Clean)
Protocol No. CETB115E2202
in human peripheral blood cells and bone marrow in mice transplanted with human cord blood 
CD34+ cells compared to placebo after 4 and 6 weeks of dosing. In addition, a 2-4 fold 
increase in the number of CD34+ cells was observed after culture of cord blood CD34+ with 
eltrombopag for 7 days (Sun et al 2012).
Since 2008, eltrombopag has been approved for the treatment of chronic primary immune 
thrombocytopenia (ITP) and hepatitis C virus (HCV)-related thrombocytopenia by regulatory 
authorities world-wide, including the Food and Drug Administration (FDA) and European 
Medicines Agency (EMA). Eltrombopag is also approved for the treatment of SAA with 
insufficient response to immunosuppressive therapy in the US and other countries as of Aug 
2014. Refer to eltrombopag Investigator's Brochure (IB) for detail information on 
eltrombopag. Eltrombopag has been approved by China health authorities in 2017 for chronic 
immune (idiopathic) thrombocytopenic purpura (ITP) adult patients aged 18 year and above 
who are previously refractory to corticosteroids, immunoglobulins.
1.2
Purpose
The most important advancement in refractory and relapsed SAA treatment in the past few 
decades has come from the seminal observation that a thrombopoietin (TPO) receptor agonist, 
eltrombopag, has activity in SAA. This was demonstrated in a phase I/II study (Study number: 
ETB115AUS28T) at the US National Institutes of Health where a remarkable 40% of patients' 
refractory to IST showed hematologic response to this single oral agent (Desmond et al 2014). 
Thrombopoietin is the principal endogenous regulator of platelet production. In addition, TPO 
also has stimulatory effects on more primitive multilineage progenitors and stem cells in vitro 
and in animal models. Given the mechanism of action of eltrombopag and the presence of the 
cognate receptor (c-mpl) in primitive elements of the bone marrow, it is possible that this drug 
stimulates very early progenitors given, in some cases, the marked improvement of all 3-cell 
lineages in SAA patients. 
Efficacy and safety of eltrombopag in refractory SAA patients of East Asian has been 
confirmed by a non-randomized, open-label, phase II Japanese study (Study number: 
ETB115E1201), showing a similar response in Japanese subjects, with 47.6% response rate 
reported at Week 26 following treatment with eltrombopag, with multilineage hematologic 
responses observed. In this study, eltrombopag up to a dose of 100 mg/day was associated 
with a safety profile generally as expected for treatment with eltrombopag and in this 
Japanese subject population (20 subjects). Safety of eltrombopag in Chinese patients has been 
demonstrated in a randomized phase III study comparing the efficacy and safety of 
eltrombopag with placebo in Chinese patients with immune thrombocytopenia, where good 
tolerability was shown, with a similar profile compared to that in western population and no 
new safety signals identified in Chinese patient population.
Given the context of all above, it is expected that a favorable benefit/risk profile can be 
acquired to use eltrombopag in the treatment of Chinese refractory or relapsed SAA patients, 
and to meet this high unmet medical need. Therefore, current study is designed to assess 
eltrombopag in such Chinese population. This is an open-label, non-randomized, phase II 
study to assess the safety and efficacy of eltrombopag in Chinese subjects with refractory or 
relapsed severe aplastic anemia. And the results of this study will be used to support the 
registration of eltrombopag with refractory and relapsed SAA indication in China.


Novartis
Confidential
Page 23
Amended Protocol Version 02 (Clean)
Protocol No. CETB115E2202
1.3
Pharmacokinetics and drug-drug interaction in human
Eltrombopag is absorbed with Tmax of 2-6 hours after oral administration. Administration of 
eltrombopag concomitantly with antacids and other products containing polyvalent cations 
such as dairy products and mineral supplements significantly reduces eltrombopag exposure. 
Eltrombopag is highly bound to human plasma proteins (> 99.9%), predominantly to albumin. 
Eltrombopag is extensively metabolised, primarily through cleavage (bacteria in the lower 
gastrointestinal tract), oxidation (Cytochrome P450 enzymes CYP1A2 and CYP2C8) and 
conjugation with glucuronic acid (uridine diphosphate glucuronosyl transferase UGT1A1 and 
UGT1A3), glutathione, or cysteine. The predominant route of eltrombopag excretion is via 
faeces (59%) with 31% of the dose found in the urine as metabolites. Unchanged eltrombopag 
excreted in faeces accounts for approximately 20% of the dose. The plasma elimination half-
life of eltrombopag is approximately 21-32 hours.
Eltrombopag showed no in vitro inhibition of the CYP450 enzymes 1A2, 2A6, 2C19, 2D6, 
2E1, 3A4/5, and 4A9/11 and was an inhibitor of CYP2C8 and CYP2C9. Administration of 
eltrombopag 75 mg once daily for 7 days did not inhibit or induce the metabolism of probe 
substrates for 1A2 (caffeine), 2C19 (omeprazole), 2C9 (flurbiprofen), or 3A4 (midazolam) in 
humans.
In vitro studies also demonstrated that eltrombopag is an inhibitor of OATP1B1 and BCRP. 
Administration of eltrombopag 75 mg for 5 days with the OATP1B1 and BCRP substrate 
rosuvastatin increased plasma rosuvastatin Cmax 103% and AUCinf 55%.
Eltrombopag is also a substrate of BCRP by in vitro studies. The administration of a single 
dose of eltrombopag 50 mg with 200 mg cyclosporine A (a BCRP inhibitor) decreased the 
mean Cmax and mean the AUCinf of eltrombopag by 25% and 18%, respectively. The co-
administration of 600 mg cyclosporine A decreased the mean Cmax and the mean AUCinf of 
eltrombopag by 39% and 24%, respectively.
Co-administration of a single dose of eltrombopag 75 mg with a polyvalent cation containing 
antacid (1.524 mg aluminum hydroxide, 1.425 mg magnesium carbonate, and sodium 
alginate) decreased the plasma eltrombopag AUCinf and Cmax by 70% and 70%, respectively. 
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.
Asian ethnicity (such as Chinese, Japanese, Taiwanese, Korean, or Thai) has consistently been 
associated with lower eltrombopag apparent clearance (CL/F) of approximatively 30 to 37%, 
translating into higher plasma eltrombopag exposure across different patient populations. 
Asian patients had approximately 50% to 90% higher plasma eltrombopag exposures than 
non-Asian patients.
Additional information can be found in the Investigator’s Brochure [Eltrombopag IB] 
and summary of product characteristics [Eltrombopag China_NPI].


Novartis
Confidential
Page 24
Amended Protocol Version 02 (Clean)
Protocol No. CETB115E2202
2
Objectives and endpoints
Table 2-1
Objectives and related endpoints
Objective(s)
Endpoint(s)
Primary objective(s)
Endpoint(s) for primary objective(s)

To assess the efficacy of eltrombopag treatment at 6 
months in Chinese subjects with a previous diagnosis 
of severe aplastic anemia and who had insufficient 
response following at least one treatment course in the 
period time of > 6 months of immunosuppression with 
a regimen containing anti-thymocyte globulin (ATG), 
anti-lymphocyte globulin (ALG), and/or 
cyclophosphamide, or alemtuzumab, and who are 
ineligible for HSCT or a suitable donor is not available.

Hematologic response rate at 6 
months (Week 26) after starting the 
study treatment defined as the 
proportion of all subjects who meet 
any of the IWG criteria in 
Section 8.3.1.
Secondary objective(s)
Endpoint(s) for secondary 
objective(s)

To evaluate the efficacy of eltrombopag treatment at 3 
months and 1 year

Hematologic response rate at Week 
13 and Week 52

To evaluate the effect of eltrombopag on individual 
hematologic response (change in neutrophil, platelet, 
hemoglobin)

Changes in platelet count (in the 
absence of platelet transfusion), 
hemoglobin (in the absence of RBC 
transfusion) and neutrophil count (in 
the absence of G-CSF).

To evaluate the time to hematologic response and 
duration

Time to hematologic response and 
duration (any response according to 
the response criteria for the primary 
endpoint)

To evaluate the frequency and volume of transfusion 
(platelet and RBC) 

Frequency and volume of 
transfusion (platelet and RBC)

To evaluate the safety and tolerability of eltrombopag

Frequency/severity of AEs, vital 
signs, ECG and laboratory 
abnormalities.

To determine the pharmacokinetics (PK) of 
eltrombopag

Plasma PK parameters of 
eltrombopag and trough 
concentrations

To evaluate cytogenetic abnormalities, clonal evolution 
to PNH, evolution to MDS or AML.

Rate of clonal evolution including 
clonal evolution to PNH, evolution to 
AML or MDS. 
3
Study design
This is a non-randomized, open-label, multi-center, phase II study to assess the efficacy and 
safety of eltrombopag in Chinese subjects with severe aplastic anemia who had insufficient 


Novartis
Confidential
Page 25
Amended Protocol Version 02 (Clean)
Protocol No. CETB115E2202
response or relapsed following at least one treatment course in the period time of > 6 
months of immunosuppression with a regimen containing anti-thymocyte globulin (ATG), 
anti-lymphocyte globulin(ALG), and/or cyclophosphamide, or alemtuzumab. The study 
design is shown in Figure 3-1.
As this is a bridging study to support China registration, an estimation strategy rather than 
formal hypothesis testing will be pursued. Approximately 20 subjects will be enrolled into the 
study based on feasibility and statistical considerations.
Treatment with eltrombopag will be started at 25 mg/day and increased by 25 mg/day every 2 
weeks 
according 
to 
the 
platelet 
count 
up 
to 
150 
mg/day 
(Refer 
to 
Section 6.5.1). Hematological response rate will be assessed at 3, 6 months and 1 year after 
starting the study treatment (Week 13, 26 and 52). 
The primary endpoint is the hematologic response rate (defined as the proportion of subjects 
who meet any of the IWG response criteria) at Week 26. Subjects in whom the treatment is 
assessed as effective (meet any of the response criteria) at 6 months will continue the study 
treatment.
Eltrombopag should be discontinued if the treatment is assessed as ineffective at 6 months in 
order to avoid continuing treatment aimlessly. Subjects are allowed to discontinue 
eltrombopag before 6 months if any of the treatment discontinuation criteria described 
in Section 9.1.1 is met.
Analysis set for the primary endpoint is Full Analysis Set (FAS) and subjects who 
discontinued from the study before Week 26 will be treated as non-responders in the response 
analysis. Eltrombopag treatment will be provided to subjects who are considered to require 
continued treatment at Week 26. After Week 26, if all of the hematologic response criteria (i.e. 
platelet count > 50×109/L, hemoglobin level > 100 g/L without transfusion, and neutrophil 
count > 1.0×109/L) remain fulfilled for more than 8 weeks, the dose of eltrombopag will be 
decreased by half. If the responses continue for further 8 weeks even at the decreased dose, 
the treatment will be discontinued. If a decrease in any of the hematologic values (i.e. platelet 
count < 30×109/L, hemoglobin < 90 g/L, or neutrophil count < 0.5×109/L) is found after dose 
reduction, the dose will be increased to the previous level. Furthermore, after treatment 
interruption, the treatment will be restarted if any of the hematologic values decreases to the 
above mentioned levels. The response assessment and safety evaluation will be performed at 
Week 52.
Extension part of this study will start 1 year (Week 52) after the initiation of study treatment. 
This part was included in the study with an ethical consideration for subjects who require 
continued treatment. The continued treatment will be provided up to the launch of the product 
after approval.
Follow-up visit will be performed 30 days after the discontinuation of eltrombopag treatment.
Intensive PK blood samples will be collected only in the initial subjects receiving 25 mg/day 
dose after reaching steady-state, to provide evaluable full PK profiles in 12 Chinese subjects. 
Some steady-state trough concentrations will be collected in other occasions especially when 
titrated to a higher dose, to better understand the PK characteristics of eltrombopag in Chinese 
SAA patient population. Please refer to Section 8.5.1 for detailed PK design.


Novartis
Confidential
Page 26
Amended Protocol Version 02 (Clean)
Protocol No. CETB115E2202
Figure 3-1
Study Design
4
Rationale
4.1
Rationale for study design
4.1.1
Rationale for primary endpoint
In the ETB115AUS28T study of eltrombopag in SAA subjects with an insufficient response 
to immunosuppressive therapy, a 40% hematologic response rate was observed. 
Improvements not only in platelets but also in hemoglobin and neutrophils were demonstrated. 
Decreases in platelet and red blood cell transfusions were also observed along with restoration 
of bone marrow cellularity (Desmond et al 2015; Olnes et al 2012). Based on the data from 
this study, eltrombopag was approved in the United States for treatment of SAA patients who 
have had an insufficient response to immunosuppressive therapy. The ETB115AUS28T 
study uses the hematologic response rate, defined as the proportion of subjects showing 
improvement in at least one of the three blood cell lineages or a decrease in blood transfusion 
volume as the primary endpoint.
Improvements in blood counts are known to be associated with the reduction of risk of 
infections 
(neutrophil 
improvements), 
complications 
from 
anemia 
(haemoglobin 
improvement), and risks of bleeding (platelet count improvement), which are all considered 
clinically beneficial. In the Chinese consensus of the diagnosis and treatment for AA, the 
counts of platelets, neutrophils, and hemoglobin and the dependence on transfusion of blood 
products were chosen as the evaluation criteria of the therapeutic effect. This endpoint is also 
consistent with the ETB115AUS28T study. So in this study, the above criteria would be used 
as primary endpoints.
4.1.2
Rationale for study design
This is an open-label, non-randomized, phase II study to assess the safety and efficacy of 
eltrombopag in Chinese subjects with refractory or relapsed SAA. 
The rationale for this study design also includes:

For refractory or relapsed SAA patients, there is no available supportive treatment other 
than platelet transfusion, hence this study could not include any positive control.

Any potential carry-over effect of ATG/ALG, alemtuzumab and cyclophosphamide can be 
eliminated by enrolling only patients who have not received ATG/ALG, alemtuzumab and 
cyclophosphamide in the past 6 months. Such patients are unlikely to experience 


Novartis
Confidential
Page 27
Amended Protocol Version 02 (Clean)
Protocol No. CETB115E2202
spontaneous increases in platelet counts, hemoglobin levels, or neutrophil counts as well 
as decreases in the number of transfusion.

A decision to give a transfusion, which is made taking into account not only laboratory 
values but also individual clinical findings, complications, and other factors, must partly 
include the physician’s subjective judgment. However, it is now the common practice to 
limit the use of transfusion to the minimum necessary for the following reasons: (1) 
preventive platelet transfusion induces transfusion refractoriness, (2) the Reference Guide 
for Treatment of Aplastic Anemia states that it is unnecessary to maintain the platelet 
count at 10×109/L or higher unless the patient has an active hemorrhage or undergoes 
surgical procedures, and (3) frequent RBC transfusion induces iron overload. 

The PK collection design in this study is to better understand eltrombopag 
pharmacokinetics in Chinese SAA patients, and help to bridge the exposure, as well as 
potential the efficacy/safety outcome from Chinese patients with patients outside China. 
Also the PK sampling schedule was similar to that in study of Japanese SAA patients 
(ETB115E1201) to enable PK comparison between Chinese and Japanese SAA patients.

Cytogenetic abnormalities, clonal evolution to PNH, evolution to MDS or AML will be 
evaluated in this study. A serious complication of aplastic anemia is its evolution to clonal 
hematologic diseases such as myelodysplastic syndrome (MDS) and leukemia, which is 
usually associated with the appearance of a cytogenetic abnormality in bone marrow cells. 
The actuarial risk for this complication has been estimated in other studies at around 15% 
at 5 years. Conversion from normal to abnormal karyotype occurred at a constant rate after 
initial diagnosis, with about 50% of cases developing within the first 30 months 
(Maciejewski et al 2002). Clonal evolution involving chromosome 7 abnormalities is 
frequently observed in SAA, mostly in refractory subjects. Subjects with abnormalities of 
chromosome 7 in SAA fared as poorly as in primary MDS, with a high rate of conversion 
to acute leukemia. Approximately in 50-60% of patients with AA is detected PNH-clone, 
and during long-term observation the transformation of AA into classic PNH is likely.
4.2
Rationale for dose/regimen and duration of treatment
4.2.1
Rationale for dose/regimen
Eltrombopag 25 mg once daily has been selected as the starting dose for this study because 
this regimen has been safe and effective in increasing platelet counts in East Asian patients 
with HCV and chronic ITP. The dose can be increased by 25 mg/day every 2 weeks according 
to the platelet count to a maximum dose of 150 mg/day in Chinese SAA patients based on the 
following considerations:

In the ETB115AUS28T study, an IIT conducted by the National Heart, Lung, and Blood 
Institute/National Institutes of Health (NHLBI/NIH), the initial dose is 50 mg daily, to a 
maximum dose of 150 mg daily. Eltrombopag was tolerated well; the majority of subjects 
(40/43) required escalation to the maximum dose of 150 mg. The most common AEs 
observed in this study largely reflect the well-known safety profile of eltrombopag and 
events expected in this patient population. A total of 17 subjects (40%) were determined 
by the investigator as having met the hematologic response criteria in at least 1 lineage at 
the primary response assessment.


Novartis
Confidential
Page 28
Amended Protocol Version 02 (Clean)
Protocol No. CETB115E2202

A clear dose and exposure response was seen for eltrombopag of 10-200 mg for healthy 
subjects and 30-75 mg for ITP and HCV patients respectively. In the above dose range, 
eltrombopag was tolerated well. 

In the ETB115AUS28T study, the eltrombopag could be increased to 150 mg/day to 
achieve the desired platelet count target. Meanwhile, to ensure subject safety, it is allowed 
to discontinue or reduce eltrombopag based on the subjects' tolerance. The current study 
uses a dose escalation scheme in which subjects are exposed to the lowest dose necessary 
to achieve the desired platelet count target.
Modified dosing for subjects of East Asian heritage (i.e. Japanese, Chinese, Taiwanese and 
Korean) has been implemented for the following reasons:

In healthy Japanese subjects, plasma eltrombopag AUCtau was approximately 80% higher 
when compared to non-Japanese healthy subjects who were predominantly Caucasian. 

Similarly, in patients with ITP, plasma eltrombopag exposure was approximately 70% 
higher in East Asian (i.e. Japanese, Chinese, Taiwanese and Korean) subjects as compared 
to non-East Asian subjects who were predominantly Caucasian.

In Japanese patients with AA, plasma eltrombopag exposure is similar to the reported 
values in Japanese ITP patients (ETB115E1201).
Following the response assessment at Week 26, if all of the hematologic response criteria (i.e. 
platelet count > 50×109/L, hemoglobin level > 100 g/L without transfusion, and neutrophil 
count > 1.0×109/L) remain fulfilled for more than 8 weeks, the dose of eltrombopag will be 
decreased by half. If the responses continue for further 8 weeks even at the decreased dose, 
the treatment will be discontinued. If a decrease in any of the hematologic values (i.e. platelet 
count < 30×109/L, hemoglobin < 90 g/L, or neutrophil count < 0.5×109/L) is found after dose 
reduction, the dose may be increased to the previous level. Furthermore, after treatment 
interruption, the treatment may be restarted if any of the hematologic values decreases to the 
above mentioned levels. The rationale for tapering eltrombopag after 6 months treatment and 
permitting dose interruption is listed below:

In the ETB115AUS28T study, subjects who achieved the 'trilineage haematopoiesis' 
criteria (defined as platelet count > 50×109/L, hemoglobin level > 100 g/L without 
transfusion, and neutrophil count > 1.0×109/L for more than 8 weeks) tapered off of 
eltrombopag in 75 mg decrement every 8 weeks provided criteria continued to be met. 
Five subjects were tapered off of eltrombopag treatment after meeting these criteria; none 
of these five subjects have subsequently relapsed, with median follow-up duration of 20.6 
months. These data support the current study dosing guidelines.

In the ETB115AUS28T study, seven subjects have tapered off (n=5; due to 'tri-lineage 
hematopoiesis'), or discontinued (n=1; AE leading to withdrawal; n=1 cytogenetic 
abnormality) treatment with eltrombopag and have maintained their response after 
discontinuation of eltrombopag with no additional treatment for SAA. The subject 
discontinuing due to AE (leading to withdrawal) continued to have improvement in 
platelet, ANC as well as hemoglobin values after eltrombopag discontinuation without any 
additional therapy for SAA. The subject who discontinued treatment due to cytogenetic 
abnormality continued to have improvements in platelet count, haemoglobin and ANC 
values at the last study visit, 9 months after the last dose of eltrombopag.


Novartis
Confidential
Page 29
Amended Protocol Version 02 (Clean)
Protocol No. CETB115E2202
These dosing recommendations limit exposure by utilizing the lowest effective dose, 
discontinuing treatment for non-responding patients and tapering treatment in patients with 
trilineage response.
4.2.2
Rationale for duration of treatment
In patients with refractory cytopenias due to severe aplastic anemia, there is little evidence for 
spontaneous recovery. In the extension period of study ETB115AUS28T, a total of 14 of 17 
responders continued on eltrombopag in the extension arm, with a median time on drug of 12 
months (range, 6-37 months). The majority of patients who remained on eltrombopag 
continued to show hematologic improvement, and 7 subjects eventually achieved trilineage 
responses.
In study ETB115AUS28T, responses only began to be observed beginning at the 3 month 
time point, and with continued exposure to drug, blood counts of all lineages improved 
towards the normal range gradually over time. Bone marrow cellularity began to normalize by 
9-15 months.
Eltrombopag treatment will be continued in patients responding to the drug favorably beyond 
the primary endpoint at Week 26 until they reach blood count normalization sufficient for 
tapering or discontinuation of eltrombopag treatment. Toxicity and efficacy data will continue 
to be collected during that time to help identify the secondary endpoints of efficacy, duration 
of response and toxicities with extended duration of therapy.
4.3
Rationale for choice of control drugs (comparator/placebo) or 
combination drugs
This is an open-label, single arm study, and no control drug or combination drug will be 
provided by sponsor.
4.4
Purpose and timing of interim analyses/design adaptations
The primary analysis will be performed after all patients have completed Week 26 or 
discontinued prior to Week 26. An updated analysis and a final analysis will be performed 
after all patients have completed Week 52 or discontinued prior to Week 52 and at the end of 
the study respectively.
4.5
Risks and benefits
4.5.1
Risk assessment
Side effects can occur when a study medicine is given alone or in combination with other 
medication(s), or can occur during study procedures (e.g. taking blood, bone marrow 
aspiration and bone marrow biopsy).
Eltrombopag is a once daily oral medicine with a well characterized safety profile since its 
initial approval in 2008 for chronic immune idiopathic thrombocytopenia (ITP). In the phaseII 
studies of eltrombopag in severe aplastic anemia, the safety profile was as expected for 
eltrombopag and for the underlying disease. The safety assessments as detailed in this 
protocol reflect the known and anticipated safety profile for using eltrombopag in this setting. 


Novartis
Confidential
Page 30
Amended Protocol Version 02 (Clean)
Protocol No. CETB115E2202
Summaries of finding from both clinical and non-clinical studies conducted with eltrombopag 
can be found in the Investigator's Brochure.
Appropriate eligibility criteria and specific dose-limiting toxicity definitions, as well as 
specific dose modification and stopping rules, are included in this protocol. The risk to 
subjects in this trial may be minimized by compliance with the eligibility criteria and study 
procedures, as well as close clinical monitoring. 
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.
4.5.2
Benefit Assessment
Eltrombopag stimulates haematopoiesis in early haematopoietic progenitor and stem cells thus 
offering a mechanistically new treatment option for patients with SAA who are refractory to 
IST or previously treated with IST or not suitable for bone marrow transplantation (BMT). In 
the context of this high unmet need, eltrombopag provides a well-tolerated, oral treatment 
option with durable, multilineage haematologic responses, reductions in transfusion 
requirements and normalization of bone marrow cellularity in patients with insufficient 
response to immunosuppressive therapy. Dramatic improvements in activities of daily living 
following treatment with eltrombopag, such as the ability to return to work and care of family, 
the ability to travel (e.g. return to home country) and the ability to play sports have been 
reported.
Non-clinical and overseas clinical data of eltrombopag indicated the following potential 
benefits of eltrombopag in SAA patients:

Treatment with eltrombopag will provide improvement (increase) not only in the platelet 
count but also in the hemoglobin level and neutrophil count.

Improvement of thrombocytopenia will lead to reduced frequency of platelet transfusion 
or platelet transfusion independence. Improved hemoglobin levels will lead to reduced 
frequency of red blood cells (RBC) transfusion or RBC transfusion independence. Less 
frequent transfusion or transfusion independence will not only result in improved quality 
of life (QOL) but also resolve or alleviate problems including unknown infections 
associated with transfusion, unresponsiveness to treatment, and iron overload, which may 
increase the risk of rejection after AHSCT.

Treatment with eltrombopag will provide not only hematological improvement but also an 
increase in the bone marrow cell density.

Improvements in platelet counts may decrease the risk of bleeding.

Improvements in neutrophil counts may decrease the risk of severe infection.
4.5.3
Overall risks and benefits conclusion
Eltrombopag treatment represents a significant advance in the treatment paradigm for the 
patients with refractory and relapsed SAA in overseas studies. Given the clear clinical benefit 
provided by eltrombopag, and the lack of effective treatment options, this study will be 


Novartis
Confidential
Page 31
Amended Protocol Version 02 (Clean)
Protocol No. CETB115E2202
conducted to confirm the risks and benefits of eltrombopag in Chinese refractory and relapsed 
SAA subjects. The risk to subjects in this trial may be minimized by compliance with the 
eligibility criteria, study procedures and close clinical monitoring.Specific information 
regarding warnings, precautions, contraindications, adverse events, and other pertinent 
information on eltrombopag or other treatment that may impact subject eligibility is provided 
in the Investigator's Brochure.
5
Population
In this study, 20 adult patients previously diagnosed with SAA who have insufficient response 
following at least one course of IST in the period time of > 6 months from the last course of 
IST will be enrolled (Note: As per local practice, patients who are eligible for HSCT will not 
be recruited into this study). Patients with insufficient response to previous IST include below 
populations: 

Relapsed patients, defined as patients with SAA who had achieved a CR (CR defined 
as transfusion independence, normal hemoglobin concentration, neutrophil count 
> 1.5×109/L, and platelet count > 100×109/L) or PR (PR defined as transfusion 
independence and blood counts that do not meet criteria SAA but are not sufficient 
for a CR) after the last course of IST but have subsequently lost hematologic response 
and become transfusion dependent.

Refractory patients, defined as any patient with SAA who has never achieved a PR or 
better following previous courses of IST or patient who has not achieved a PR or 
better following the initiation of the last course of IST .

Patients with SAA who had achieved PR after the last course of IST with platelet 
count ≤ 30×109/L.
*For relapsed patients, platelet count should ≤ 30×109/L at screening visit.
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
Subjects eligible for inclusion in this study must meet all of the following criteria:
1. Chinese patients aged greater than or equal to 18 years old.
2. Patient with a previous diagnosis of severe aplastic anemia and had insufficient response 
following at least one treatment course in the period time of > 6 months of 
immunosuppression with a regimen containing anti-thymocyte globulin (ATG), anti-
lymphocyte globulin (ALG), and/or cyclophosphamide, or alemtuzumab.
Patient had severe aplastic anemia at diagnosis characterized by 
(Red Blood Cell Disease (Anemia) 2017):
1. Bone marrow cellularity < 25%, or 25–50% with < 30% residual haemopoietic cells 
and
2. At least two of the following (peripheral blood): 
1. Absolute neutrophil count < 0.5×109/L
2. Platelet count < 20×109/L


Novartis
Confidential
Page 32
Amended Protocol Version 02 (Clean)
Protocol No. CETB115E2202
3. Absolute reticulocyte count < 20×109/L
3. Platelet count ≤ 30×109/L at screening.
4. Patient must not currently have the option of stem cell transplantation, either because they 
are not a candidate, or because a suitable donor is not available.
5. Patient has an Eastern Cooperative Oncology Group (ECOG) performance status 0-2.
6. Patient with QTcF at screening <450 msec, or <480 msec with bundle branch block, as 
determined via the mean of a triplicate ECG and assessed at site.
7. Signed informed consent must be obtained prior to participation in the study.
5.2
Exclusion criteria
Subjects meeting any of the following criteria are not eligible for inclusion in this study.
1. Treatment with ATG/ALG, cyclophosphamide or alemtuzumab in the past 6 months.
Note: Patients who are receiving cyclosporine or anabolic steroids (excluding danazol) at 
a stable dose may be enrolled if laboratory values are stable at screening.
2. Congenital aplastic anemia (e.g. Fanconi anemia, congenital dyskeratosis).
3. AST or ALT ≥ 3 times the upper limit of normal.
4. Creatinine, total bilirubin, and alkaline phosphatase (ALP) ≥ 1.5× local ULN (total 
bilirubin ≥ 2.5 × local ULN with Gilbert's Syndrome).
5. Paroxysmal nocturnal hemoglobinuria (PNH) granulocyte clone size determined by flow 
cytometry ≥ 50%.
6. Presence of chromosomal aberration (-7/7q- detected by fluorescence in situ hybridization 
(FISH), or other aberrations detected by G-band staining).
7. Evidence of a clonal hematologic bone marrow disorder on cytogenetics.  If a clonal 
disorder is identified, the patient will be excluded.
8. Past medical history of thromboembolism within 6 months or current use of 
anticoagulants. Patient with antiphospholipid antibody syndrome (APS).
9. Patient must not have any concomitant malignancies and must be fully recovered from 
treatment for any other malignancy and have been disease-free for 5 years.
10. Patient with clinically significant (of such severity that it would preclude the patient's 
ability to consent, be compliant with study procedures, tolerate protocol therapy) bacterial, 
fungal, mycobacterial, parasitic or viral infection (Patient with acute bacterial infections 
requiring antibiotic use should delay Screening/enrollment until the course of antibiotic 
therapy has been completed). 
11. Patient with known hepatocellular disease (e.g. active hepatitis or cirrhosis).
12. Presences of hepatitis B surface antigen (HBsAg), positive hepatitis C antibody test result 
at screening. Laboratory test shows positive serology for Hepatitis B (HB) defined as a 
positive test for HBsAg. In addition, if negative for HBsAg but hepatitis B core antibody 
(HBcAb) positive (regardless of hepatitis B surface antibody (HBsAb) status), a HBV 
DNA test will be performed and if positive the subject will be excluded.
13. Cardiac disorder (patients with congestive heart disease of New York Heart Association 
(NYHA) functional classification Grade II/III/IV should not be enrolled; patients with 
NYHA Grade II due to cardiac disorder should not be enrolled but those with NYHA 


Novartis
Confidential
Page 33
Amended Protocol Version 02 (Clean)
Protocol No. CETB115E2202
Grade II due to AA may be enrolled.), or arrhythmia with a risk of thrombosis (e.g. atrial 
fibrillation).
14. Past medical history of immediate or delayed hypersensitivity to compounds chemically 
similar to eltrombopag or their excipients.
15. Treatment with another investigational product within 30 days or the period 5-fold longer 
than the half-life of the investigational product, whichever longer, prior to the first dose of 
eltrombopag.
16. Prior treatment with eltrombopag, romiplostim, or any other TPO receptor agonist.
17. Use of prohibited concomitant medications (see Section 6.2.2).
18. Patient who is unable to comprehend or is unwilling to sign an informed consent form 
(ICF).
19. Patient with active alcohol or drug addiction that, in the investigator’s expert judgment, 
would interfere with their ability to comply with the study requirements.
20. Patient with any concurrent condition that, in the Investigator's opinion, would jeopardize 
the safety of the patient or compliance with the protocol.
21. Positive result for HIV antibody test.
22. Pregnant or nursing (lactating) woman.
23. Woman of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using highly effective methods of contraception 
during dosing and for 7 days after stopping medication. Highly effective contraception 
methods include:

Total abstinence when this is in line with the preferred and usual lifestyle of the 
subject. Periodic abstinence (e.g. calendar, ovulation, symptothermal, post-ovulation 
methods) and withdrawal are not acceptable methods of contraception

Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy), total hysterectomy, or tubal ligation at least six weeks before taking 
study treatment. In case of oophorectomy alone, only when the reproductive status of 
the woman has been confirmed by follow up hormone level assessment

Male sterilization (at least 6 months prior to screening). The vasectomized male 
partner should be the sole partner for that subject

Use of oral, injected or implanted hormonal methods of contraception or placement of 
an intrauterine device (IUD) or intrauterine system (IUS), or other forms of hormonal 
contraception that have comparable efficacy (failure rate < 1%), for example hormone 
vaginal ring or transdermal hormone contraception.
In case of use of oral contraception woman should have been stable on the same pill for a 
minimum of 3 months before taking study treatment.
Women are considered post-menopausal and not of child bearing potential if they have 
had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile 
(e.g. age appropriate, history of vasomotor symptoms) or have had surgical bilateral 
oophorectomy (with or without hysterectomy), total hysterectomy, or tubal ligation at least 
six weeks ago. In the case of oophorectomy alone, only when the reproductive status of 
the woman has been confirmed by follow up hormone level assessment is she considered 
not of child bearing potential.


Novartis
Confidential
Page 34
Amended Protocol Version 02 (Clean)
Protocol No. CETB115E2202
24. Sexually active males unwilling to use a condom during intercourse while taking study 
treatment and for 16 weeks after stopping study treatment. A condom is required for all
sexually active male participants to prevent them from fathering a child AND to prevent 
delivery of study treatment via seminal fluid to their partner. In addition, male participants 
must not donate sperm for the time period specified above.
6
Treatment
6.1
Study treatment
The investigational/study treatments for this study is eltrombopag (ETB115).
Eltrombopag will be supplied as film-coated tablets (25 mg) provided either as commercial 
packages locally or as clinical packages centrally.
6.1.1
Investigational and control drugs
Table 6-1
Investigational drug
Investigational Drug
(Name and Strength)
Pharmaceutical 
Dosage Form
Route of 
Administration
Supply Type
ETB115 25 mg
Tablet 
Oral use
Open label subject 
packs; blisters or 
bottles
This is an open-label, single arm study, hence, only ETB115 will be provided as 
investigational drug.
6.1.2
Additional study treatments
No additional treatment beyond investigational drug are included in this trial.
6.1.3
Treatment arms/group
All eligible Subjects will start eltrombopag treatment at 25 mg/day since Day 1. And the 
treatment with eltrombopag will be increased by 25 mg/day every 2 weeks according to the 
platelet count up to 150 mg/day (refer to Section 6.5.1).
6.1.4
Guidelines for continuation of treatment
For subjects who meet any toxicity criteria, the investigator will follow the guideline on dose 
reduction and/or discontinuation presented in Section 6.5.1.1 and Section 6.5.1.2. Subjects can 
remain 
on 
study 
treatment 
until 
toxicity 
or 
withdrawal 
of 
consent, 
refer 
to Section 6.5.2 and Section 9.1.2.
6.1.5
Treatment duration
If the subject fails to response after 6 months (26 weeks), he/she will discontinue eltrombopag 
treatment. Responding subjects who are considered to require continued treatment at Week 52 
will be provided with continued treatment up to the launch of the product after approval of the 
investigated indication or until the end of the study. 


Novartis
Confidential
Page 35
Amended Protocol Version 02 (Clean)
Protocol No. CETB115E2202
6.1.5.1
Treatment beyond disease progression
Not applicable for Aplastic Anemia.
6.2
Other treatment(s)
6.2.1
Concomitant therapy
All medications, procedures and significant non-drug therapies (including physical therapy 
and blood transfusions) administered after the subject was enrolled into the study (after 
signing the ICF) must be recorded in the concomitant medications/significant non-drug 
therapies or procedures pages.

All prior treatment for aplastic anemia including IST

Drug for aplastic anemia during study: CsA, anabolic steroids except danazol, and other 
supportive therapy except transfusions: from the screening visit to completion of follow 
up

RBC transfusion: from 8 weeks before the start of administration of the investigational 
product to completion of follow up

Platelet transfusion: from 4 weeks before the start of administration of the investigational 
product to completion of follow up
Each concomitant drug must be individually assessed against all exclusion criteria/prohibited 
medication. If in doubt the investigator should contact the Novartis medical monitor before 
enrolling a subject or allowing a new medication to be started. If the subject is already 
enrolled, contact Novartis to determine if the subject should continue participation in the 
study.
6.2.1.1
Permitted concomitant therapy requiring caution and/or action
Permitted concomitant medications/therapies should be taken/conduct in accordance with the 
individual product information for dose adjustment and monitoring recommendations and 
standard practice.
CsA and anabolic steroids
CsA and anabolic steroids (exclude danazol) can be used concomitantly only if maintenance 
dose is used since the enrolment.
Supportive therapy
Supportive therapy can be used if clinically required.

Transfusion (RBC and platelets) and G-CSF is performed as the following guide:
RBC transfusion: Keep the hemoglobin concentration at over 60 g/L or in the presence of 
clinical symptoms such as dyspnea.
Platelet transfusion: The platelet count is less than 10×109/L or when significant bleeding 
occurs.
G-CSF: The neutrophil count is less than 0.2 × 109/L.


Novartis
Confidential
Page 36
Amended Protocol Version 02 (Clean)
Protocol No. CETB115E2202

Iron chelation therapy: Start of this drug is not allowed until Week 26 efficacy assessment. 
If using before the start of the investigational drug, continued usage is allowed.
Substrates of BCRP and OATP1B1 
Preclinical data showed that eltrombopag is an inhibitor of the transporters OATP1B1 and 
BCRP. In a clinical drug interaction study it showed co-administration of eltrombopag 75 mg 
once daily for 5 days with a single 10 mg dose of the OATP1B1 and BCRP substrate 
rosuvastatin increased plasma rosuvastatin Cmax 103% and AUCinf 55%. Administration of 
the hydroxy methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor (statins) should be 
with caution and a 50% dose reduction of statins is recommended during the study, 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).Concomitant administration of eltrombopag and other 
OATP1B1 or BCRP substrates should be used with caution. A list of substrates of BCRP and 
OATP1B1 is available in Appendix 1 (See Section 16.1).
Polyvalent Cations (Chelation) 
Eltrombopag chelates with polyvalent cations such as aluminum, calcium, iron, magnesium,
selenium and zinc. Eltrombopag should be taken at least two hours before or four hours after 
any products such as antacids, calcium-rich foods (e.g., dairy products and calcium-fortified 
juices), or mineral supplements containing polyvalent cations to avoid significant reduction in 
eltrombopag absorption.
Subjects requiring routine (e.g. daily) acid suppression should be encouraged to take H2 
antagonists or proton pump inhibitors. Subjects requiring occasional acid suppression may 
take liquid or chewable antacids provided study medication is taken at least two hours before 
or four hours after any consumption of polyvalent cation containing antacids.
Food Interaction 
To minimize impact of food in eltrombopag absorption, eltrombopag must be taken at least 
one hour before to two hours after food containing little (< 50 mg) (or preferably no) 
calcium. Administration of a single 50 mg-dose of eltrombopag with a standard high-calorie, 
high-fat breakfast that included dairy products reduced plasma eltrombopag AUCinf by 59% 
(90% CI: 54%, 64%) and Cmax by 65% (90% CI: 59%, 70%). 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.
Drugs affecting coagulation/bleeding
The following drugs have a possibility that affects the assessment of bleeding. And in the 
event their use is clinically indicated, those drugs will be permitted, but the subject (s) will be 
excluded from bleeding analyses during the time period the subject was exposed to the 
medication.

Drugs that affect platelet function (including but not limited to, aspirin, clopidogrel and/or 
non-steroidal anti-inflammatory drugs (NSAIDs))

Anticoagulant (warfarin, heparin, etc.)


Novartis
Confidential
Page 37
Amended Protocol Version 02 (Clean)
Protocol No. CETB115E2202
6.2.2
Prohibited medication
Use of the treatments displayed in the below table are not allowed during the study.
Table 6-2
Prohibited medication and therapy
Medication/Therapy
Prohibition period
Action taken
Any other TPO-R agonists 
(e.g.rhTPO [TeBiAo])
From screening to the end of 
administration of eltrombopag
Discontinue study treatment
ATG/ALG, cyclophosphamide, 
alemtuzumab
From 6 months before the start 
of administration of eltrombopag 
to the end of administration
Discontinue study treatment
Bone marrow transplantation
From screening to the end of 
administration of eltrombopag
Discontinue study treatment
CsA and anabolic steroids (exclude danazol) can be used concomitantly only if maintenance 
dose is used since the enrolment.
Subjects must abstain from using investigational or not 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.
6.2.3
Rescue medication
Transfusions with platelets and/or red blood cells may be given during study participation as 
medically necessary. In general, platelet transfusions should be administered when the platelet 
count < 10 x 109/L or when significant bleeding occurs. Packed RBCs should be administered 
for hemoglobin < 60 g/L, or when subjects are symptomatic. Treatment with rhTPO or any 
ATG is not allowed in the study (for additional information see Table 6-2).
6.2.4
Treatment of study treatment overdose
Overdose is defined as the dose administered at the dose higher than the maximum daily dose 
(150 mg) of eltrombopag specified in the study protocol.
When overdose is suspected, perform symptomatic therapy and supportive therapy as needed. 
At overdose, moreover, administer the antacids containing metallic cation such as calcium, 
aluminum or magnesium to inhibit absorption of eltrombopag. Hemodialysis is not expected 
to enhance the elimination of eltrombopag because eltrombopag is not significantly renally 
excreted and is highly bound to plasma proteins. There is no antidote specific to eltrombopag.
6.3
Subject numbering, treatment assignment, randomization
6.3.1
Subject numbering
Each subject is identified in the study by a Subject Number (Subject No.), that is assigned 
when the subject is first enrolled for screening and is retained as the primary identifier for the 
subject throughout his/her entire participation in the trial. The Subject No. consists of the 
Center Number (Center No.) (as assigned by Novartis to the investigative site) with a 
sequential subject number suffixed to it, so that each subject is numbered uniquely across the 


Novartis
Confidential
Page 38
Amended Protocol Version 02 (Clean)
Protocol No. CETB115E2202
entire database. Upon signing the informed consent form, the subject is assigned to the next 
sequential Subject No. available.
6.3.2
Treatment assignment, randomization
This is a single arm, non-randomized study.
Upon completion of all the required screening assessments, eligible subjects will start 
eltrombopag treatment at Day 1.
6.4
Treatment blinding
This is a single arm, open label study.
6.5
Dose escalation and dose modification
6.5.1
Dose modifications
Eltrombopag treatment will be started at a dose of 25 mg/day, and the dose will be titrated in 
the order of 50 mg, 75 mg, 100 mg, 125 mg and 150 mg/day according to the platelet count of 
each subject. The criteria for dose adjustment and schematic are shown in Table 6-3 and Table 
6-4.
It is allowed to discontinue or reduce eltrombopag based on the discretion of the investigator 
(sub-investigator) regardless of these criteria when they judge that it is needed due to adverse 
event.
Table 6-3
Criteria for dose adjustment of eltrombopag between Week 1 and 
Week 26
Standards of platelet count 
Dose adjustment 
At 2 weeks or more of administration, the platelet 
count is < 50×109/L, or the amount required for 
platelet transfusion does not decrease.
Titrate the dose by 25 mg each every 2 weeks up 
to 150 mg/day.
At 2 weeks or more of administration, the platelet 
count is ≥ 50×109/L, and is ≤ 100×109/L.
Maintain the dose.
The platelet count is > 100×109/L under no blood 
transfusion
Reduce the dose by 25 mg each every 2 weeks 
until the platelet count can be maintained at 
100×109/L or lower.
The platelet count is > 200×109/L under no blood 
transfusion
Interrupt the drug until the platelet count becomes 
< 50×109/L. Thereafter, restart administration at 
the dose 25 mg lower (The restarting dose is 25 
mg/day if the dose at interruption was 25 
mg/day).
If dose has increased to 150 mg/day at Week 12, the subject would maintain the maximum 
dose as 150 mg/day from Week 13 to Week 26. When dose decrease under 25 mg/day is 
needed, eltrombopag treatment should be interrupted until the platelet count becomes less 
than 50×109/L.
The criteria for dose adjustment of this drug after Week 26 are shown in Table 6-4.


Novartis
Confidential
Page 39
Amended Protocol Version 02 (Clean)
Protocol No. CETB115E2202
Table 6-4
Criteria for dose adjustment of eltrombopag after Week 26
Standards of hematological value 
Dose adjustment 
The following values are kept for 8 or more 
weeks:
▪Platelet count of > 50×109/L, and
▪Hemoglobin value of > 100 g/L under no blood 
transfusion, and
▪Neutrophil count of > 1.0×109/L
Reduce the dose to the 50% dose (see Table 6-5)
When the above value is kept at the 50% dose for 
further 8 weeks
Interrupt administration.
When the values decrease to the following ones 
at the 50% dose :
▪Platelet count of < 30×109/L, or
▪Hemoglobin value of < 90 g/L, or
▪Neutrophil count of < 0.5×109/L
The dose can be reinitiated at the previous 
effective level
When lower than the above values after 
administration was interrupted tentatively
Administration can be restarted at a dose of 25 
mg/day
Table 6-5
Dose reduce criteria of eltrombopag after Week 26
Dose before decrease
50% decreased dose
150 mg/day
75 mg/day
125 mg/day
75 mg/day or 50 mg/day*
100 mg/day
50 mg/day
75 mg/day
50 mg/day or 25 mg/day*
50 mg/day
25 mg/day
25 mg/day
25 mg Qod
*When eltrombopag dose need to be reduced by 50% from 125 mg/day or 75 mg/day, the 
investigators will need to select an appropriate dose level (choose either 75 mg or 50 mg daily for 
subjects treated with eltrombopag 125 mg/day, and 50 mg or 25 mg daily for subjects treated with 
eltrombopag 75 mg/day) according to subjects' clinical status.
If subject fails to respond after 26 weeks of treatment, he/she will go off study per 
Section 3 and Section 9.1.1.
For subjects who do not tolerate the protocol-specified dosing schedule, dose interruptions 
and/or reductions are either recommended or mandated in order to allow subjects to continue 
the study treatment.
These dose modifications are summarized in Section 6.5.1.1 and Section 6.5.1.2. Permanent 
treatment discontinuation is mandatory for specific events indicated as such in 
Section 9.1.1 and Section 6.2.2.
These dose changes must be recorded on the Dosage Administration Record (DAR) –
electronic case report form (eCRF).
6.5.1.1
Dose adjustments for QTcF prolongation
In case of QTcF > 500 msec, (or QTcF prolongation > 60 msec from baseline)


Novartis
Confidential
Page 40
Amended Protocol Version 02 (Clean)
Protocol No. CETB115E2202
1. Assess the quality of the ECG recording and the QT value and repeat if needed
2. Interrupt study treatment
3. Determine the serum electrolyte levels (in particular hypokalemia, hypomagnesemia). If 
abnormal, correct abnormalities before resuming study drug treatment.
4. Review concomitant medication associated with QT prolongation, including drugs with a 
“Known”, “Possible”, or “Conditional risk of Torsades de Pointes” (refer to qtdrugs.org), 
and drugs with the potential to increase the risk of study drug exposure related QT 
prolongation
5. Check study drug dosing schedule and treatment compliance
6. Consider collecting a ECG time-matched PK sample as unscheduled PK sample, and 
record time and date of last study drug intake.
After confirming ECG reading at site, if QTcF > 500 msec

Interrupt study treatment

Repeat ECG and confirm ECG diagnosis by a cardiologist or central ECG lab

If QTcF confirmed > 500 msec: 

Correct electrolytes, eliminate culprit concomitant treatments, and identify and 
address clinical conditions that could potentially prolong the QT as per the ECG and 
QTc Clinical Safety Standards Guidelines Section 3.3.1.

Consult with a cardiologist (or qualified specialist)

Increase cardiac monitoring as indicated, until the QTcF returns to ≤ 480 msec.

After resolution to ≤ 480 msec, consider re-introducing treatment at reduced dose, and 
increase ECG monitoring for the next treatment(s): 

If QTcF remains ≤ 500 msec after dose reduction, continue planned ECG monitoring 
during subsequent treatment

If QTcF recurs > 500 msec after dose reduction, discontinue subject from trial.
6.5.1.2
Dose interruption due to liver signals
Eltrombopag dose may be interrupted when clinically indicated at the discretion of the 
investigator. Recommended dose modifications for isolated ALT or AST elevation are listed 
in Table 6-6.
Table 6-6
Criteria for dose reduction / interruption and re-initiation of 
eltrombopag treatment for adverse drug reactions
Dose modifications for ETB115
Investigations (Hepatic) 
Isolated ALT elevation 
> ULN - 3.0 x ULN
Maintain dose level
≥3.0 - 5.0 x ULN 
Maintain dose level. Repeat LFTsa 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 LFTsa weekly, or more frequently if 
clinically indicated, until resolved to ≤ 3.0 × ULN. 


Novartis
Confidential
Page 41
Amended Protocol Version 02 (Clean)
Protocol No. CETB115E2202
Dose modifications for ETB115
Discontinue subject from the study treatment if 
elevation ALT ≥ 3.0 x ULN in patients with normal 
liver function, or ≥ 3.0 x baseline or > 5.0 x ULN, 
(whichever is the lower, in patients with pre-
treatment elevations in transaminases) and are 
combined with any of the following: 

Clinical symptoms of liver injury or evidence 
for hepatic decompensation 

Progressively increasing LFTsa upon repeat 
testing 

Persistence for ≥4 weeks
Combined  elevations of ALT and total bilirubin
For subjects with normal liver function at baseline, 
[ALT ≥3.0 × ULN] combined with increased direct 
bilirubin OR For subjects with elevated baseline 
ALT [ALT ≥3.0 × baseline] OR [ALT > 5.0 × 
ULN], whichever is lower, combined with 
increased direct bilirubin.
Permanently discontinue subject from study drug 
treatment. Repeat as soon as possible, preferably 
within 48 hours from awareness of the abnormal 
results, then with weekly monitoring of LFTsa), 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 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.)
In this study, one dose level is equal to 25 mg eltrombopag. 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.
6.5.2
Follow-up for toxicities
Subjects whose treatment is interrupted or permanently discontinued due to an adverse event 
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 4-week intervals, until resolution or stabilization of the event, 
whichever comes first. Appropriate clinical experts such as ophthalmologist, endocrinologist, 
dermatologist, psychiatrists etc. should be consulted as deemed necessary.
All subjects must be followed up for adverse events and serious adverse events for 30 days 
following the last doses of eltrombopag.
6.5.2.1
Follow up on potential drug-induced liver injury (DILI) cases
Subjects with transaminase increase combined with TBIL increase may be indicative of 
potential severe drug-induced liver injury (DILI), and should be considered as clinically 
important events.


Novartis
Confidential
Page 42
Amended Protocol Version 02 (Clean)
Protocol No. CETB115E2202
The threshold for further work-up for potential severe DILI may depend on the subject’s 
baseline AST/ALT and TBIL value; subjects meeting any of the following criteria will require 
further follow-up as outlined below:

For subjects with normal ALT and AST and TBIL value at baseline: AST or ALT > 3.0 x 
ULN combined with TBIL > 2.0 x ULN

For subjects with elevated AST or ALT or TBIL value at baseline: [AST or ALT > 2 x 
baseline AND > 3.0 x ULN] OR [AST or ALT > 5.0 x ULN], combined with [TBIL > 2 x 
baseline AND > 2.0 x ULN]
Medical review needs to ensure that liver test elevations are not caused by cholestasis, defined 
as ALP elevation > 2.0 x ULN with R value < 2 .
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).
In the absence of cholestasis, these subjects should be immediately discontinued from study 
treatment, and repeat liver function test (LFT) testing as soon as possible, preferably within 48 
hours from the awareness of the abnormal results. The evaluation should include laboratory 
tests, detailed history, physical assessment , obstructions/compressions, etc.
1. Laboratory tests should include ALT, AST, albumin, creatine kinase, total bilirubin, direct 
and indirect bilirubin, GGT, prothrombin time (PT)/ International Normalized Ratio (INR) 
and alkaline phosphatase.
2. A detailed history, including relevant information, such as review of ethanol, concomitant 
medications, herbal remedies, 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. Obtain PK sample, as close as possible to last dose of eltrombopag.
5. Additional testing for other hepatotropic viral infection (cytomegalovirus (CMV), Epstein-
Barr virus (EBV) or herpes simplex virus (HSV)), autoimmune hepatitis or liver biopsy 
may be considered as clinically indicated or after consultation with specialist/hepatologist.
All cases confirmed on repeat testing meeting the laboratory criteria defined above, with no 
other alternative cause for LFT abnormalities identified should be considered as “medically 
significant”, thus, met the definition of SAE and reported as SAE using the term “potential 
drug-induced liver injury”. All events should be followed up with the outcome clearly 
documented.
6.6
Additional treatment guidance
6.6.1
Treatment compliance
The investigator must promote compliance by instructing the subject to take the study 
treatment exactly as prescribed and by stating that compliance is necessary for the subject’s 
safety and the validity of the study. The subject must also be instructed to contact the 
investigator if he/she is unable for any reason to take the study treatment as prescribed. 
Compliance will be assessed by the investigator and/or study personnel at each visit using pill 


Novartis
Confidential
Page 43
Amended Protocol Version 02 (Clean)
Protocol No. CETB115E2202
counts and information provided by the subject. This information should be captured in the 
source document at each visit. All study treatment dispensed and returned must be recorded in 
the Drug Accountability Log. 
6.6.2
Emergency breaking of assigned treatment code
This study is an open-label, single arm study.
6.7
Preparation and dispensation
Each study site will be supplied with study drug in packaging as described under 
investigational and control drugs section.
A unique medication number is printed on the study medication label.
As per the treatment assigned to the subject, investigator staff will select the study treatment 
to dispense to the subject. 
6.7.1
Handling of study treatment and additional treatment
6.7.1.1
Handling of study treatment
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 Country Organization (CO) Quality 
Assurance.
Medication labels will be in the local language and comply with the legal requirements of 
each country. They will include storage conditions for the study treatment but no information 
about the subject except for the medication number.
The investigator must maintain an accurate record of the shipment and dispensing of study
treatment in a drug accountability log. Monitoring of drug accountability will be performed by 
monitors during site visits or remotely and at the completion of the trial. 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 monitor or to the Novartis address provided 
in the investigator folder at each site.
6.7.1.2
Handling of additional treatment
Not applicable. There is no specific handling and storage requirements for non-study 
treatment in this study.


Novartis
Confidential
Page 44
Amended Protocol Version 02 (Clean)
Protocol No. CETB115E2202
6.7.2
Instruction for prescribing and taking study treatment
Eltrombopag will be administered orally, once daily, on an empty stomach (1 hour before or 2 
hours after a meal) and at least 2 hours before or 4 hours after any products containing 
polyvalent cations such as antacids, calcium-rich foods (> 50 mg calcium, e.g., dairy products 
and calcium-fortified juices), or mineral supplements containing polyvalent cations (e.g. 
aluminum, calcium, iron, magnesium, selenium, and zinc).
Subjects will be instructed to take eltrombopag daily at the same time each day.
On days that PK samples are obtained, the subject should take eltrombopag during the clinic 
visit after the pre-dose PK samples and prior to post-dose PK samples, when instructed by the 
study staff.
If vomiting occurs during the course of treatment, subjects should not take the study drug 
(eltrombopag) again before the next scheduled dose.
Subjects will be instructed not to make up missed doses. A missed dose is defined as a case 
when the full dose is not taken within 8 hours of the approximate time of the usual daily dose. 
That day's dose should be omitted and the subject should continue treatment with the next 
scheduled dose.
7
Informed consent procedures
Eligible subjects may only be included in the study after providing (witnessed, where required 
by law or regulation), IRB/IEC-approved informed consent.
If applicable, in cases where the subject's representative(s) gives consent (if allowed 
according to local requirements), the subject must be informed about the study to the extent 
possible given his/her understanding. If the subject is capable of doing so, he/she must 
indicate agreement by personally signing and dating the written informed consent document.
Informed consent must be obtained before conducting any study-specific procedures (e.g. all 
of the procedures described in the protocol). The process of obtaining informed consent must 
be documented in the subject source documents.
Novartis will provide to investigators in a separate document a proposed informed consent 
form that complies with the ICH GCP guidelines and regulatory requirements and is 
considered appropriate for this study. Any changes to the proposed consent form suggested by 
the investigator must be agreed by Novartis before submission to the IRB/IEC.
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 (IN) 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.


Novartis
Confidential
Page 45
Amended Protocol Version 02 (Clean)
Protocol No. CETB115E2202
Male subjects must be informed that if a female partner becomes pregnant while he is enrolled 
in the study, contact with the female partner will be attempted to request her consent to collect 
pregnancy outcome information.
A copy of the approved version of all consent forms must be provided to Novartis after 
IRB/IEC approval.
8
Visit schedule and assessments
The Assessment Schedule lists all of the assessments when they are performed. All data 
obtained from these assessments must be supported in the subject's source documentation.
Subjects should be seen for all visits/assessments as outlined in the assessment schedule or as 
close to the designated day/time as possible. Missed or rescheduled visits should not lead to 
automatic discontinuation. Subjects who prematurely discontinue the study for any reason 
other than withdrawal of consent 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 adverse event and 
concomitant medications recorded on the CRF.
Allowed visit windows are specified as follows:

When dose modification, each visit must be completed ± 3 day until dose stabilization,

Until stabilization of dose, each visit must be completed ± 3 day,

After stabiliztion of dose, each visit must be completed ± 7 day,

The efficacy assessment visit (week 13, 26 and 52) must be completed ± 3 day,

The safety follow-up visit must be completed ± 7 day.


Novartis
Confidential
Page 46
Amended Protocol Version 02 (Clean)
Protocol No. CETB115E2202
Table 8-1
Assessment Schedule
Period Screening
Treatment
End of Study
Visit Name Screening Day 1
Week 
1/2/3
Week 4
Week 5 to 51 (Every 
2 weeks until 
stabilization of dose; 
every 4 weeks, after 
stabilization of dose)1
Week 
13
Week 
26/52
Extension part (Every 2 
weeks until stabilization 
of dose; every 4 weeks 
after stabilization of 
dose)1
End of 
treatment
Follow-up (30 days 
after treatment 
discontinuation)
Days
-30 to -1
1 to 1 8 to 22 29 to 29
36 to 358
92
183 to 365
After Week 52
EOT
after EOT
Informed consent
X
Demography
X
Medical history/current 
medical conditions
X
Characteristics of SAA
X
Inclusion / Exclusion criteria
X
Supportive therapy
X
X
X
X
X
X
X
X
X
X
Concomitant medications
X
X
X
X
X
X
X
X
X
X
Physical Examination
S
S
S
S
S
S
S
S
S
S
Vital Signs
X
X
X
Once a month
X
X
Once a month
X
X
Height
X
Body Weight
X
X
X
Standard 12 lead ECG
X
X
Once in 6 months 
(Example: Weeks 78, 
104...)
X
Adverse Events
X
X
X
X
X
X
X
X
X
X
Peripheral blood smear
X
X
X
X
X
X
X
X
X
X
Bone marrow aspiration 
(iliac crest) and cytogenetic 
analysis
Within 3 months 
of Day 1
X
X
Once in 6 months 
(Example: Weeks 78, 
104...)
Not 
necessary 
if 
conducted 
within 6 
months.


Novartis
Confidential
Page 47
Amended Protocol Version 02 (Clean)
Protocol No. CETB115E2202
Period Screening
Treatment
End of Study
Visit Name Screening Day 1
Week 
1/2/3
Week 4
Week 5 to 51 (Every 
2 weeks until 
stabilization of dose; 
every 4 weeks, after 
stabilization of dose)1
Week 
13
Week 
26/52
Extension part (Every 2 
weeks until stabilization 
of dose; every 4 weeks 
after stabilization of 
dose)1
End of 
treatment
Follow-up (30 days 
after treatment 
discontinuation)
Days
-30 to -1
1 to 1 8 to 22 29 to 29
36 to 358
92
183 to 365
After Week 52
EOT
after EOT
Bone marrow biopsy
Within 3 months 
of Day 1
X
Once a year (Example: 
Weeks 104, 156...)
Not 
necessary 
if 
conducted 
within 1 
year.
Hematology
X
X
X
X
X
X
X
X
X
X
Clinical Chemistry
X
X
X
X
X
X
X
X
X
X
Blood coagulation test 
(PT/INR and aPTT)
X
Perform when thromboembolic event is suspected
Ophthalmologic 
examinations
S
S
Once in 6 months 
(Example: Weeks 78, 
104...)
S
Pregnancy and 
assessments of fertility
S
Pregnancy test (serum or 
urine)
Serum test Urine 
test
Urine 
test
Urine test (once a 
month)
Urine test
Urine test (Once a 
month)
Urine test
Examination of HBsAg, 
HBsAb, HBcAb, HCV 
antibody and HIV antibody
S
Plasma thrombopoietin
X
Once every 3 months 
(Example: Week 38)
X
X
Once every 3 months 
(Example: Weeks 64, 
76, 88...)
X
X
Flow Cytometry of the 
Peripheral Blood for 
glycosylphosphatidylinositol 
(GPI)-cells
X
When clinically indicated.
Hematological response 
X
X
X
X
X
X
X


Novartis
Confidential
Page 48
Amended Protocol Version 02 (Clean)
Protocol No. CETB115E2202
Period Screening
Treatment
End of Study
Visit Name Screening Day 1
Week 
1/2/3
Week 4
Week 5 to 51 (Every 
2 weeks until 
stabilization of dose; 
every 4 weeks, after 
stabilization of dose)1
Week 
13
Week 
26/52
Extension part (Every 2 
weeks until stabilization 
of dose; every 4 weeks 
after stabilization of 
dose)1
End of 
treatment
Follow-up (30 days 
after treatment 
discontinuation)
Days
-30 to -1
1 to 1 8 to 22 29 to 29
36 to 358
92
183 to 365
After Week 52
EOT
after EOT
assessment
Evaluation of clonal 
evolution to AML and MDS
X
When clinically indicated.
PK blood sampling
Intensive PK in 12 subjects (pre-dose, 1, 2, 4, 6, 8, and 24 h post-
dose) on day 14 after initial dose; Sparse PK in all subjects: Pre-
dose on day 15 after initial dose and pre-dose on day 15 after 
each new dose has started (dose escalation only)
Prescription of eltrombopag
Eltrombopag will be distributed every 2 weeks or every 4 weeks after stabilization of dose 
according to Section 6.5
Treatment compliance
S
S
S
S
S
S
S
Disposition
X
X
X
X Assessment to be recorded in the clinical database or received electronically from a vendor
S Assessment to be recorded in the source documentation only
1 ”Until stabilization of dose” means that the dose is not changed for at least 4 weeks. If the dose is changed at visiting every 4 weeks, the subject should visit hospital 
since the next visit until stabilization of dose.


Novartis
Confidential
Page 49
Amended Protocol Version 02 (Clean)
Protocol No. CETB115E2202
8.1
Screening
All subjects will be screened for study eligibility. All subjects must sign informed consent 
prior to any screening procedures being performed.
Activities for screening will begin up to 30 days prior to initiation of study treatment with 
eltrombopag. During this time, all subjects will complete a bone marrow aspirate and biopsy 
to confirm current SAA status. The eligibility criteria is found in Section 5.
Information regarding eligibility criteria will be collected on the Inclusion/Exclusion eCRF. 
Subjects who do not meet all entry criteria should not be entered into the study.
Re-screening is not allowed in this study. In the case where a safety laboratory assessment at 
screening is outside of the range specified in the exclusion criteria, the assessment may be 
repeated once prior to initiation of study treatment . If the repeat value remains outside of the 
specified ranges, the subject must be excluded from the study.
8.1.1
Information to be collected on screening failures
Subjects who sign an informed consent form and subsequently found to be ineligible will be 
considered a screen failure. The reason for screen failure should be entered on the applicable 
Case Report Form. The demographic information, informed consent, and Inclusion/Exclusion 
pages must also be completed for screen failure subjects. No other data will be entered into 
the clinical database for subjects who are screen failures, unless the subject experienced a 
serious adverse event during the screening phase (see SAE section for reporting details). 
Subjects who sign an informed consent and are considered eligible but fail to be started on 
treatment for any reason will be considered an early terminator. The reason for early 
termination should be captured on the appropriate disposition Case Report Form.
8.2
Subject demographics/other baseline characteristics
Subject demographic and baseline characteristic data to be assessed on all subjects include:

Demographic information: Age, gender, height and weight, body temperature, BP and 
pulse measurements

Date of diagnosis, etc. of aplastic anemia

Prior treatment for AA including transfusion history, and concomitant medications (see 
Section 6.2.1)

Laboratory evaluations: ECG, Peripheral blood smear, Bone marrow aspiration (iliac 
crest) and cytogenetic analysis, Bone marrow biopsy, Hematology and Chemistry test, 
Blood coagulation test, Pregnancy test, Hepatitis and HIV Screen, Plasma thrombopoietin, 
and Flow Cytometry of the Peripheral Blood for glycosylphosphatidylinositol (GPI)-cells.

Medical history (all important medical, surgical, and allergic conditions that could have an 
impact on the subject's evaluation) / current medical conditions (e.g. all relevant current 
medical conditions which are present at the time of signing informed consent). Ongoing 
medical conditions, symptoms and diseases which are recorded on the Medical History 
eCRF should include the toxicity grade when applicable.


Novartis
Confidential
Page 50
Amended Protocol Version 02 (Clean)
Protocol No. CETB115E2202
Investigators will have the discretion to record abnormal test findings on the medical history 
CRF whenever in their judgment, the test abnormality occurred prior to the informed consent 
signature.
8.3
Efficacy
8.3.1
Primary endpoint
Primary Endpoint - hematologic response rate at Week 26 (6 months) defined as the 
proportion of all subjects who meet any of the IWG criteria shown in the table below. 
Hematologic response assessment will be performed by investigators.
Table 8-2
IWG criteria for Primary Endpoint
Assessment 
Item
Baseline transfusion
status
Response Criteria
Platelet count
Platelet transfusion 
independent
Transfusion independent and increase from 
baseline by 20×109/L or more
Platelet transfusion 
dependent
No platelet transfusion requirement for 8 weeks
Hemoglobin
RBC transfusion 
independent
When the baseline hemoglobin level is < 90 
g/L: transfusion independent and increase from 
baseline by 15 g/L or more
RBC transfusion dependent
A decrease of at least 4 units in RBC 
transfusions in the post-treatment 8-week 
period (1 unit = RBC derived from 200 mL 
blood)
Or no RBC transfusion requirement for 8 weeks 
(less than 4 units RBC in 8-week period at 
Baseline)
Neutrophil count
NA
(In the absence of G-CSF taken within 21 days 
preceding the blood sample collection) Increase 
from baseline by 0.5×109/L or more, or (if < 
0.5×109/L at baseline) increase by 100% or 
more
During regular hematologic assessment, the exclusion period of transfusion and G-CSF 
are detailed below:
Platelet transfusion: 7 days preceding the assessment of platelet count
RBC transfusion: 14 days preceding the assessment of hemoglobin
G-CSF: 21 days preceding the assessment of neutrophil count
Definition of baseline Platelet Transfusion Independence/Dependence and platelet count
Baseline platelet transfusion independence/dependence and platelet count are defined as:

For platelet transfusion independent subjects that did not receive platelet transfusions in 
the 4 weeks before Day 1: The average of the most recent 2 platelet counts before Day 1.

For transfusion dependent subjects that received one or more platelet transfusions in the 4 
weeks before Day 1: The average of the most recent 2 platelet counts before Day 1 


Novartis
Confidential
Page 51
Amended Protocol Version 02 (Clean)
Protocol No. CETB115E2202
(excluding platelet counts within 6 days * following a platelet transfusion). If all platelet 
counts available are within 6 days* following a platelet transfusion, the lowest platelet 
count prior to initiation of study drug will be used as the baseline platelet count.
*: e.g. When a platelet transfusion was done on December 2nd (Monday), the platelet count 
will become available for on December 9th (Monday).
Definition of 
baseline 
RBC 
Transfusion 
Independence/Dependence 
and 
hemoglobin value
Baseline RBC transfusion independence/dependence and hemoglobin value are defined as:

For RBC transfusion independent subjects that did not receive RBC transfusions in the 8 
weeks before Day 1: The most recent hemoglobin value before Day1.

For RBC transfusion dependent subjects that received one or more RBC transfusions in 
the 8 weeks before Day 1: The last hemoglobin value prior to the most recent RBC 
transfusion. If no values exist prior to a RBC transfusion, the lowest value before Day1 
will be used.
8.3.2
Secondary endpoints
Hematologic response rate at Week 13 and Week 52 will also be assessed according to the 
response critieria for the primary endpoints by investigator.
Changes in platelet count, hemoglobin and neutrophil count will be calculated according to 
the lab test results entered into CRF.
Time to hematologic response and duration will be calculated for any response according to 
the response criteria for the primary endpoint.
Frequency and volume of transfusion of platelet and RBC will be required to recorded into 
CRF.
Clonal cytogenetic evolution will be evaluated during the study, and the rate of the subjects 
who developed any clonal evolution including clonal evolution to PNH, evolution to AML or 
MDS will be calculated..
8.3.3
Appropriateness of efficacy assessments
Since eltrombopag is expected to improve trilineage blood cells and decrease transfusion 
frequency based on the result from an overseas study in patients with SAA 
(ETB115AUS28T), this study uses the hematologic response rate, defined as the proportion of 
subjects showing improvement in at least one of the three blood cell lineages or a decrease in 
blood transfusion volume, as the primary endpoint as was the case in overseas studies.
8.4
Safety
Safety assessments are specified below with the assessment schedule detailing when each 
assessment is to be performed.
For details on AE collection and reporting, refer to AE section.


Novartis
Confidential
Page 52
Amended Protocol Version 02 (Clean)
Protocol No. CETB115E2202
Table 8-3
Assessments & Specifications
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.
A short physical exam will include the examination of general appearance and 
vital signs (blood pressure [systolic blood pressure (SBP) and/or diastolic 
blood pressure (DBP)] and pulse). A short physical exam will be at all visits 
starting from week 1 except where a complete physical examination is 
required (see above).
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 included in the Medical History part 
of the CRF. Significant findings made after signing informed consent which 
meet the definition of an Adverse Event must be recorded on the Adverse 
Event section of the CRF.
ECOG Performance status scale will be used for screening and Day 1.
Vital sign
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
Laboratory evaluations
Clinically significant abnormalities must be recorded as either medical history or adverse 
events as appropriate.
All laboratory tests are performed at the study site or designated lab. Examinations at the 
point of the start of the investigational product must be performed before the starting of 
dosing. The hematology test must be conduct before the supportive therapy (if supportive 
therapy is performed).
Table 8-4
Laboratory Assessments
Test Category
Test Name
Hematology
Hematocrit, Hemoglobin, Platelets, Red blood cells, White blood cells, 
Differential (Basophils, Eosinophils, Lymphocytes, Monocytes, Neutrophils, 
Reticulocyte count, Bands, Other (absolute value preferred , percentages are 
acceptable)
Chemistry
Albumin, Alkaline phosphatase, ALT , AST , Lactate dehydrogenase (LDH), 
Calcium, Magnesium, Phosphorus, Sodium, Potassium, Creatinine, Direct 
Bilirubin, Total Bilirubin, Blood Urea Nitrogen (BUN) or Urea, Uric Acid
Amylase, Lipase, Glucose (fasting)
Coagulation
Prothrombin time (PT) , International normalized ratio (INR), Activated partial 
thromboplastin time (aPTT)
Flow cytometry of 
the Peripheral 
Blood
Glycosylphosphatidylinositol (GPI)-cells
Hepatitis markers
HBsAg, HBsAb, HBcAb, HCV antibody


Novartis
Confidential
Page 53
Amended Protocol Version 02 (Clean)
Protocol No. CETB115E2202
Test Category
Test Name
Additional tests
HIV antibody, plasma thrombopoietin
Pregnancy Test
Serum / Urine pregnancy test (refer to Pregnancy and assessments of fertility 
section)
8.4.2
Electrocardiogram (ECG)
ECGs must be recorded after 10 minutes rest in the supine position to ensure a stable baseline.
The preferred sequence of cardiovascular data collection during study visits is ECG collection 
first, followed by vital signs, and blood sampling. The Fridericia's QT correction formula 
(QTcF) should be used for clinical decisions.
The original ECGs and a certified copy on non-heat sensitive paper, appropriately signed, 
must be collected and archived at the study site. Each ECG tracing should be labeled with the 
study number, subject number, date, and kept in the source documents at the study site. Any 
identifier details must be redacted (e.g subject initials, date of birth). Interpretation of the 
tracing must be made by a qualified physician and documented on the relevant CRF pages.
For any ECGs with subject safety concerns, two additional ECGs must be performed to 
confirm the safety finding. A monitoring or review process should be in place for clinically 
significant ECG findings throughout the study and especially at baseline before administration 
of study treatment.
Clinically significant abnormalities must be recorded on the CRF as either medical history or 
adverse events as appropriate. Clinically significant findings must be discussed with Novartis 
prior to enrolling the subject in the study. New or worsened clinically significant findings 
occurring after informed consent must be recorded as adverse events.
Additional, unscheduled, safety ECGs may be repeated at the discretion of the investigator at 
any time during the study as clinically indicated. Unscheduled ECGs with clinically 
significant findings should be collected in triplicate. The individual ECGs should be recorded 
approximately 2 minutes apart. Local cardiologist ECG assessment may also be performed at 
any time during the study at the discretion of the investigator.
In the event that a QTcF value of > 500 ms is observed or if an unscheduled ECG is 
performed for safety reasons, it is recommended to collect a ECG time-matched PK sample as 
unscheduled PK sample and record the time and date of the last study drug intake to 
determine the drug exposure. Dose adjustments in case of QT prolongation should be 
performed per Section 6.5.1.1.
A standard 12 lead ECG will be performed:

at screening or baseline (Triplicate ECG to be collected to assess QTcF invervals)

at Week 26 and Week 52

at the end of treatment
8.4.3
Pregnancy and assessments of fertility
A condom is required for all sexually active male participants to prevent them from fathering 
a child AND to prevent delivery of study treatment via seminal fluid to their partner. In 


Novartis
Confidential
Page 54
Amended Protocol Version 02 (Clean)
Protocol No. CETB115E2202
addition, male participants should not donate sperm for the time period specified above 
(Section 5.2).
All pre-menopausal women who are not surgically sterile will have pregnancy testing. 
Additional pregnancy testing might be performed if requested by local requirements.
Assessments of Fertility
Medical documentation of oophorectomy, hysterectomy, or tubal ligation must be retained as 
source documents. Subsequent hormone level assessment to confirm the woman is not of 
child bearing potential must also be available as source documentation in the following cases:

surgical bilateral oophorectomy without a hysterectomy

reported 12 months of natural (spontaneous) amenorrhea with an appropriate clinical 
profile
In the absence of the above medical documentation, follicle stimulating hormone (FSH) 
testing is required of any female subject, regardless of reported reproductive/menopausal 
status at screening/baseline.
8.4.4
Peripheral blood smear, bone marrow aspiration and bone marrow 
biopsy
Confirm of morphological examination, proportion of blast cells, chromosome analysis, cell 
density and fibrosis is done. Perform hematological examinations and collection of peripheral 
blood smear on the same day.
8.4.5
Ophthalmic Assessments
In this study, ophthalmic assessment including confirming the history, risk factor of cataract 
will be performed to confirm the existence of cataract at assessment time points. If the 
presence of a cataract is suspected, detailed examinations (ex. slit lamp examination etc.) 
should be performed (see Table 8-1).
8.4.6
Evaluation of clonal evolution
Detection of PNH and measurement of PNH granulocyte clone size measurement by flow 
cytometry will be done at baseline and when clinically indicated.
Clonal evolution to AML and MDS will also be monitored during the study period, and 
relevant examinations will be done at baseline and when clinically indicated.
8.5
Additional assessments
No additional tests will be performed on subjects entered into this study.
8.5.1
Pharmacokinetics
Blood samples will be collected from all subjects to assess the plasma concentrations of 
eltrombopag. The plasma concentrations will be used to determine the PK characteristics of 
eltrombopag. Serial intensive PK blood samples will be collected for the initial 25 mg/day 
dose to provide at least 12 subjects with evaluable PK profiles. Sparse PK blood samples will 
be collected for the other doses and in the rest of the subjects.


Novartis
Confidential
Page 55
Amended Protocol Version 02 (Clean)
Protocol No. CETB115E2202
8.5.1.1
Pharmacokinetic blood collection and handling
At least the first 12 subjects starting with 25 mg/day will receive intensive PK sampling over 
a 24 hour period on Days 14 to 15 after the first dose, to ensure 12 subjects providing 
evaluable full PK profiles. For this intensive PK sampling, a total of 7 blood samples (2 
mL/sample) will be collected at the following time points: pre-dose, and 1, 2, 4, 6, 8, and 24 h 
post-dose. A full evaluable PK profile is defined as at least 6 of 7 planned PK samples are 
collected and the subject has not vomited within 4 hours after dose of both PK sampling day 
and the day before PK sampling day. When these subjects who received intensive PK 
sampling escalate to higher dose levels (e.g. 50, 75, 100, 125 and up to 150 mg/day), they will 
provide one blood sampling at pre-dose on the 15th day after each new dose has started.
After the purpose of getting evaluable full PK profiles in 12 subjects has been fulfilled, the 
rest of subjects will receive sparse PK sampling only. In all remaining subjects, one blood 
sample each will be collected at pre-dose on the 15th day for the initial 25 mg/day dose 
and after each new dose has started until the maximal dose is reached.
If a subject meets the criteria for dose reduction and dose is decreased to a lower level which 
the subject has received previously, no planned PK sample will be collected for new lower 
doses.
A detailed blood sampling log for PK evaluation is indicated in Table 8-4 Pharmacokinetic 
log. The time of blood collection will be recorded on the PK blood collection page in the CRF 
(e.g. the actual date/time of blood samples will be recorded relative to the dose 
administration). Vomiting information after administration will be collected within 4 hours of 
dosing. In case of DILI (see Section 6.5.1.2), an unscheduled eltrombopag PK sample should 
be collected. On the days of PK collection, the subject will be instructed to take study drug 
after the pre-dose blood sample is taken.
It is noted that subjects must have received once daily eltrombopag for at least 7 days prior to 
the planned PK sampling day to regard the PK sample as steady state(i.e. be at PK steady-
state with no recent dose interruptions or missing for at least 7 days). If a subject is not 
currently receiving eltrombopag at the time of the planned PK sampling (because of a dose 
interruption) or eltrombopag has been reinitiated after a dose interruption within the 7 days 
prior to the planned PK sampling day, the planned PK sampling should be omitted and the PK 
sampling should be postponed and performed after re-dosing continues at least for 7 days.
If a subject will discontinue the treatment after Week 13 efficacy assessment, the planned pre-
dose collection on Week 13 Day 1 should be still collected.
Subjects who receive blood transfusions within the 7 days prior to the planned PK sampling 
day , will still have PK samples taken but will be identified as such in the PK analyses.
Refer to the [CETB115E2202 Laboratory Manual] for detailed instructions for the collection, 
handling, and shipment of PK samples.
Table 8-5
Sample log table for the evaluation of eltrombopag pharmacokinetics
Week from the 
first dose
Day from new 
dose started
Scheduled time 
point
Dose reference 
ID
Sample number
2
14
Pre-dose/0 ha
1
1*


Novartis
Confidential
Page 56
Amended Protocol Version 02 (Clean)
Protocol No. CETB115E2202
Week from the 
first dose
Day from new 
dose started
Scheduled time 
point
Dose reference 
ID
Sample number
2
14
1 h (±5 min)
1
2*
2
14
2 h (± 15 min)
1
3*
2
14
4 h (± 30 min)
1
4*
2
14
6 h (± 30min)
1
5*
2
14
8 h (± 30min)
1
6*
3
15
24 h (± 1 h)/0 ha
1/101b
7
Variable
15
24 h (± 1 h)d/0 ha,d
2+e/102+b,e
8+f
Variable
Unscheduledc
NA
1001+ c
*: these samples are only collected for the first at least 12 patients receiving 25 mg/day, to ensure at 
least 12 patients providing evaluable PK profiles.
a: Collect PK sample immediately before drug administration (not more than 1 h prior to dosing);
b: The first dose reference ID is for the last dose the subject received prior to the collection of current 
PK sample, while the second dose reference ID is for dose which is to be given after the collection of 
the PK sample (pre-dose sample);
c: Unscheduled PK blood samples may be collected at any time for measurement of plasma drug 
concentrations if clinically indicated or at the Investigator’s discretion and will be uniquely, sequentially 
numbered 1001, 1002, etc;
d: Collect pre-dose sample on the 15th day after each new dose has started (dose escalation only: 50 
mg, 75 mg, 100 mg, 125 mg and 150 mg);
e: Dose reference ID will be sequentially numbered 2, 3, 4...for the last dose the subject received prior 
to the collection of current PK sample and 102, 103, 104...for dose which is to be given after the 
collection of the PK sample (pre-dose sample);
f: Sample number will be sequentially numbered 8, 9, 10...when the PK sample is taken at pre-dose on 
Day 15 after each new dose started.
8.5.1.2
Analytical method
The plasma samples will be assayed for eltrombopag concentrations using a validated liquid 
chromatography – tandem mass spectrometry assay (LC-MS/MS). The lower limit of 
quantification (LLOQ) will be 100 ng/mL.
Concentration values below the LLOQ will be reported as zero, and missing samples will be 
labeled accordingly. Further refinements of these bioanalytical methods may be conducted 
during the course of the study.
 
All 
relevant information will be provided in the [Laboratory Manual].
9
Study discontinuation and completion
9.1
Discontinuation
9.1.1
Discontinuation of study treatment
Discontinuation of study treatment for a subject occurs when study treatment is stopped 
earlier than the protocol planned duration, and can be initiated by either the subject or the 
investigator.


Novartis
Confidential
Page 57
Amended Protocol Version 02 (Clean)
Protocol No. CETB115E2202
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:
*: Discontinuation should be considered if new cytogenetic abnormalities are observed (if the 
risk/benefit of continuing eltrombopag accessed by the Investigator is considered favorable, 
exceptions could be made in consultation with the Sponsor)

Subject/guardian decision

Pregnancy

Any of the following is observed: a new morphological abnormality*, or progression to 
MDS or AML.

Thromboembolism occurs

Subject meets any of the QTcF stopping criteria (see Section 6.5.1.1)

Subject meets any of the liver chemistry stopping criteria (see Section 6.5.1.2)

Any laboratory abnormalities that in the judgment of the investigator, taking into 
consideration the subject’s overall status, prevents the subject from continuing the study 
treatment

Use of prohibited treatment as per recommendations in the prohibited treatment 
section (see Section 6.2.2)

The subject has an unacceptable adverse event whose causal relationship with the 
investigational product cannot be ruled out.

The subject is found to be significantly non-compliant with the requirements of the 
protocol (including treatment incompliance).

The investigator (or sub-investigator) believes that the subject will not benefit from 
eltrombopag if the treatment continues.

The study is prematurely terminated.
If 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 
their consent (see withdraw of informed consent section,). Where possible, they should return 
for the assessments indicated in the assessment schedule (Discontinuation visit and Follow-up 
visit). 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.
9.1.1.1
Replacement policy
Subject will not be replaced on study.


Novartis
Confidential
Page 58
Amended Protocol Version 02 (Clean)
Protocol No. CETB115E2202
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 the samples until the time of withdrawal) according to 
applicable law.  
All biological samples not yet analyzed at the time of withdrawal will no longer be used, 
unless permitted by applicable law. They will be stored according to applicable legal 
requirements.
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
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 the subject welfare and 
safety. Should early termination be necessary, subjects must be seen as soon as possible 
(provide instruction for contacting the subject, when the subject should stop taking drug, 


Novartis
Confidential
Page 59
Amended Protocol Version 02 (Clean)
Protocol No. CETB115E2202
when the subject should come 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 the 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 a subject finishes her/his 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.
All treated subjects should have a safety follow-up visit conducted 30 days after last 
administration of study treatment. The information collected is kept as source documentation. 
All SAEs reported during this time period must be reported as described in Section 10.1.3. 
Documentation of attempts to contact the subject should be recorded in the source 
documentation.
The primary analysis will be performed after all patients have completed Week 26 or 
discontinued prior to Week 26. The primary analysis data will be summarized in the primary 
clinical study report (CSR).Following the cut-off date for the analysis reported in the primary 
CSR, the study will remain open. Ongoing subjects will continue to receive study treatment 
and be followed as per the schedule of assessments, as long as subjects derive benefit from 
eltrombopag. An updated analysis will be conducted when all ongoing subjects complete 1 
year (52 weeks) treatment. The efficacy and safety data till the cut-off date will be analyzed 
and summarized in the updated CSR.
The end of study defined as the earliest occurrence of one of the following:
1. All subjects have died or discontinued from the study.
2. Another clinical study becomes available that can continue to provide eltrombopag in this 
subject population and all subjects ongoing are eligible to be transferred to that clinical 
study.
3. When eltrombopag for the refractory and relapsed SAA is launched in China and available 
for the subjects.
The final analysis will occur at the end of the study. All available data from all subjects up to 
this cut-off date will be analyzed and summarized in a final CSR.
10
Safety monitoring and reporting
10.1
Definition of adverse events and reporting requirements
10.1.1
Adverse events
An adverse event (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 


Novartis
Confidential
Page 60
Amended Protocol Version 02 (Clean)
Protocol No. CETB115E2202
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 adverse events.
Novartis qualified medical personnel will be readily available to advise on trial related 
medical questions or problems.
The occurrence of adverse events 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 Adverse Events CRF 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. The Common Toxicity Criteria (CTC) AE grade (version 4.03 or higher). Grade 1 to 5 
will be used to characterize the severity of the Adverse Event. All grade 4 or higher value 
on Laboratory/investigational finding will be considered a medically significant event.
2. its relationship to the study treatment. If the event is due to lack of efficacy or progression 
of underlying illness (i.e. progression of the study indication) the assessment of causality 
will usually be ‘Not suspected’. The rationale for this guidance is that the symptoms of a 
lack of efficacy or progression of underlying illness are not caused by the trial drug, they 
happen in spite of its administration and/or both lack of efficacy and progression of 
underlying disease can only be evaluated meaningfully by an analysis of cohorts, not on a 
single subject
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 with study treatment.
All adverse events must be treated appropriately. Treatment may include one or more of the 
following:

Dose not changed

Dose Reduced/increased

Drug interrupted/withdrawn
6. its outcome 
a. not recovered/not resolved;
b. recovered/resolved;
c. recovered/resolved with sequelae;
d. fatal; or unknown.
If the event worsens, the event should be reported a second time in the CRF noting the start 
date when the event worsens in toxicity. For grade 3 and 4 adverse events only, if 


Novartis
Confidential
Page 61
Amended Protocol Version 02 (Clean)
Protocol No. CETB115E2202
improvement to a lower grade is determined a new entry for this event should be reported in 
the CRF noting the start date when the event improved from having been Grade 3 or Grade 4.
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 following the last dose of 
study treatment.
Once an adverse event is detected, it must be followed until its resolution or until it is judged
to be permanent (e.g.Continuing at the end of the study), and assessment must be made at 
each 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 adverse events only if they fulfill at least 
one of the following criteria:

they induce clinical signs or symptoms

they are considered clinically significant

they require therapy
Clinically significant abnormal laboratory values or test results must be identified through a 
review of values outside of normal ranges/clinically notable ranges, significant changes from 
baseline or the previous visit, or values which are considered to be non-typical in subjects 
with the underlying disease.
Adverse events of special interest (AESI) are defined as events (serious or non-serious) which 
are ones of scientific and medical concern specific to the sponsor's product or program, for 
which ongoing monitoring and rapid communication by the investigator to Novartis medical 
lead may be appropriate. Such events may require further investigation in order to 
characterize and understand them.
Adverse events of special interest are defined on the basis of an ongoing review of the safety 
data.
10.1.2
Serious adverse events
An SAE is defined as any adverse event [appearance of (or worsening of any pre-existing)] 
undesirable sign(s), symptom(s) or medical conditions(s)) which meets any one of the 
following criteria:

fatal

life-threatening
Life-threatening in the context of a SAE refers to a reaction in which the 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).


Novartis
Confidential
Page 62
Amended Protocol Version 02 (Clean)
Protocol No. CETB115E2202

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 
(please refer to the ICH-E2D Guidelines)
All malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met and the malignant neoplasm is not a disease progression of the 
study indication.
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction.
All reports of intentional misuse and abuse of the product are also considered serious adverse 
event irrespective if a clinical event has occurred.
10.1.3
SAE reporting
To ensure subject safety, every SAE, regardless of causality, occurring after the subject has 
provided informed consent and until 30 days following the last administration of study 
treatment  must be reported to Novartis within 24 hours of learning of its occurrence. Detailed 
instructions regarding the submission process and requirements are to be found in the 
investigator folder provided to each site. SAEs occurring after the 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 


Novartis
Confidential
Page 63
Amended Protocol Version 02 (Clean)
Protocol No. CETB115E2202
one must be reported separately as a new event. SAEs will be followed until resolution or 
until clinically relevant improvement or stabilization.
If the SAE is not previously documented in the Investigator's Brochure 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 (EC) in accordance with Europe 
(EU) Guidance 2011/C 172/01 or as per national regulatory requirements in participating 
countries.
Any SAEs experienced after the 30 day period following the last administration of study 
treatment 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 study treatment 
must be discontinued once the pregnancy is confirmed. The subject may continue all protocol 
assessment, however, all assessment that are considered as a risk during pregnancy must not 
be performed. 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 Chief Medical 
Office and Patient Safety (CMO&PS). Pregnancy follow-up should be recorded on the same 
form and should include an assessment of the possible relationship to the study treatment. 
Any SAE experienced during pregnancy must be reported.
Pregnancy outcomes should be collected for the female partners of any males who took study 
treatment in this study. Consent to report information regarding these pregnancy outcomes 
should be obtained from the mother.
Follow up of the pregnancy (female subject or female partner of subject) should be according 
to the following schedule:
Tracking of pregnancy cases occurs until after Expected Delivery Date (EDD) for all 
prospective pregnancy cases received from clinical studies (including pregnancies where the 
subject was exposed to placebo or comparator and pregnancies due to the conduct of the 
study).

EDD + 1 month (mandatory for all cases). Requesting the pregnancy outcome and other 
clinically relevant pregnancy data or changes in data.

EDD + 2 month (mandatory if no answer is obtained after request at EDD+1 month). A 
reminder letter for the outcome.


Novartis
Confidential
Page 64
Amended Protocol Version 02 (Clean)
Protocol No. CETB115E2202

The follow-up at EDD + 3 months is mandatory for all cases of live birth. Information on 
the status of the baby 3 months after delivery and information on any development issue 
or abnormality that would not be seen at birth must be collected.

The follow up at EDD + 12 months is mandatory for all cases of live birth. Information on 
the status of the baby 12 months after delivery and information on any development issue 
or abnormality that would not be seen at birth must be collected.
If the pregnancy case is lost to follow-up (e.g., no response after 3 attempts) this information 
must be transferred to the Safety Desk of the Country PS.
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 (EMA definition).
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 collected in 
the dose administration record (DAR) eCRF 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 Dose 
Administration (DAR) 
eCRF (Yes/No)
Document in AE 
eCRF
Complete SAE form
Unintentional study 
treatment error
Yes
Only if associated with 
an AE
Only if associated with 
an SAE
Misuse/Abuse
Yes
Yes
Yes, even if not 
associated with a SAE
For more information on AE and SAE definition and reporting requirements, please see the, 
respective sections.
10.2
Additional Safety Monitoring
Not applicable.


Novartis
Confidential
Page 65
Amended Protocol Version 02 (Clean)
Protocol No. CETB115E2202
11
Data Collection and Database management
11.1
Data collection
Designated investigator staff will enter the data required by the protocol into the Electronic 
Case Report Forms (eCRF). The eCRFs have been built using fully validated secure web-
enabled software that conforms to 21 CFR Part 11 requirements, Investigator site staff will 
not be given access to the EDC system until they have been trained. Automatic validation 
programs check for data discrepancies in the eCRFs, allow modification and/or verification of 
the entered data by the investigator staff.
The investigator/designee is responsible for assuring that the data (recorded on CRFs) 
(entered into eCRF) is complete, accurate, and that entry and updates are performed in a 
timely manner. The Investigator must certify that the data entered are complete and accurate.
After final database lock, the investigator will receive copies of the subject data for archiving 
at the investigational site.
All data should be recorded, handled and stored in a way that allows its accurate reporting, 
interpretation and verification.
11.2
Database management and quality control
Novartis personnel will review the data entered by investigational staff for completeness and 
accuracy. Electronic data queries stating the nature of the problem and requesting clarification 
will be created for discrepancies and missing values and sent to the investigational site via the 
EDC system. Designated investigator site staff are required to respond promptly to queries 
and to make any necessary changes to the data.
Concomitant treatments and prior medications entered into the database will be coded using 
the WHO Drug Reference List, which employs the Anatomical Therapeutic Chemical (ATC) 
classification system. Medical history/current medical conditions and adverse events will be 
coded using the Medical dictionary for regulatory activities (MedDRA) terminology.
Once all the necessary actions have been completed and the database has been declared to be 
complete and accurate, it will be locked. Any changes to the database after that time can only 
be made after written agreement by Novartis development management.
11.3
Site monitoring
Before study initiation, at a site initiation visit or at an investigator’s meeting, a Novartis 
representative will review the protocol and data capture requirements (i.e. eSource direct data 
entry (DDE) or eCRFs) with the investigators and their staff. During the study, Novartis 
employs several methods of ensuring protocol and GCP compliance and the quality/integrity 
of the sites’ data. The field monitor will visit the site to check the completeness of subject 
records, the accuracy of data capture / data entry, the adherence to the protocol and to Good 
Clinical Practice, the progress of enrollment, and to ensure that study treatment is being stored, 
dispensed, and accounted for according to specifications. Key study personnel must be 
available to assist the field monitor during these visits. Continuous remote monitoring of each 
site’s data may be performed by a centralized Novartis clinical research associate (CRA) 


Novartis
Confidential
Page 66
Amended Protocol Version 02 (Clean)
Protocol No. CETB115E2202
organization. Additionally, a central analytics organization may analyze data & identify risks 
& trends for site operational parameters, and provide reports to Novartis clinical teams to 
assist with trial oversight.
The investigator must maintain source documents for each subject in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information on CRFs must be traceable to these source documents in the 
subject’s file. The investigator must also keep the original informed consent form signed by 
the subject (a signed copy is given to the subject).
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.
12
Data analysis and statistical methods
Primary safety and efficacy analysis will be conducted on all subject data at the time all 
subjects who are still receiving study treatment will have completed at least 26 weeks of 
treatment. An updated analysis and a final analysis will be performed after all patients have
completed Week 52 or discontinued prior to Week 52 and at the end of the study respectively.
Any data analysis carried out independently by the investigator should be submitted to 
Novartis before publication or presentation.
12.1
Analysis sets
The Full Analysis Set (FAS) comprises all subjects to whom study treatment has been 
assigned and who received at least one dose of study treatment.
The Safety set is identical as the Full Analysis set in the study. All safety analyses will be 
doneusing the Safety Set.
The Pharmacokinetic analysis set (PAS) includes all subjects who received at least one dose 
of eltrombopag and provide at least one evaluable PK sample. The definition of an evaluable 
PK sample will be further defined in the statistical analysis plan.
12.2
Subject demographics and other baseline characteristics
Demographic and other baseline data including disease characteristics will be listed and 
summarized descriptively for all the subjects for the FAS.
Categorical data will be presented as frequencies and percentages. For continuous data, mean, 
standard deviation, median, minimum, and maximum will be presented. For selected 
parameters, 25th and 75th percentiles will also be presented.


Novartis
Confidential
Page 67
Amended Protocol Version 02 (Clean)
Protocol No. CETB115E2202
Relevant medical histories and current medical conditions at baseline will be summarized by 
system organ class and preferred term for the FAS.
12.3
Treatments
The Safety set will be used for the analyses below. Categorical data will be summarized as 
frequencies and percentages. For continuous data, mean, standard deviation, median, 25th and 
75th percentiles, minimum, and maximum will be presented.
The duration of exposure in weeks to eltrombopag as well as the dose intensity (computed as 
the ratio of actual cumulative dose received and actual duration of exposure) will be 
summarized by means of descriptive statistics using the safety set.
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.
The number of subjects with dose adjustments (reductions, interruption, or permanent 
discontinuation) and the reasons will be summarized for all subjects and all dosing data will 
be listed.
12.4
Analysis of the primary endpoint(s)
The primary objective of the study is to assess the efficacy of eltrombopag treatment at 6 
months in Chinese subjects with a previous diagnosis of severe aplastic anemia and who had 
insufficient response following at least one treatment course in the period time of > 6 
months of immunosuppression with a regimen containing anti-thymocyte globulin (ATG), 
anti-lymphocyte globulin (ALG), and/or cyclophosphamide, or alemtuzumab, and who are 
ineligible for HSCT or a suitable donor is not available.
12.4.1
Definition of primary endpoint(s)
The primary endpoint is the hematologic response rate at Week 26, which is defined as the 
proportion of all subjectswho meet any of the International Working Group (IWG) criteria at 
Week 26.
12.4.2
Statistical model, hypothesis, and method of analysis
The proportion of the hematological response will be summarized using point estimates and 
90% exact (Clopper-Pearson) confidence intervals.
12.4.3
Handling of missing values/censoring/discontinuations
All withdrawals will be included in analyses up to the time of withdrawal. The subjects who 
discontinued from the trial before Week 26 will be treated as non-responders in the primary 
analysis.
12.4.4
Sensitivity and Supportive analyses
The number and percentage will be presented for subjects who respond according to each 
combination of criteria (i.e. Platelets only, Platelet and Red cells, Red cells only, Red cells 
and Neutrophils, Neutrophils only, etc) at the Week 26 visit.


Novartis
Confidential
Page 68
Amended Protocol Version 02 (Clean)
Protocol No. CETB115E2202
The number and percentage of assessment item for the detailed hematological response 
criteria (i.e. Platelet count, Platelet transfusion, hemoglobin level, RBC transfusion and ANC) 
will be presented. In this summary, subjects could be counted as a response according to more 
than one criteria.
In addition, hematological response will be listed.
12.5
Analysis of secondary endpoints
The secondary objectives in this study are:

To evaluate the efficacy of eltrombopag treatment at week 13 and week 52

To evaluate the effect of eltrombopag on individual hematologic response (changes in 
neutrophil, platelet, hemoglobin)

To evaluate the time to hematologic response and duration

To evaluate the frequency and volume of transfusion (platelet and RBC)

To evaluate the safety and tolerability of eltrombopag

To determine the pharmacokinetics (PK) of eltrombopag

To evaluate cytogenetic abnormalities, clonal evolution to PNH, evolution to MDS or 
AML.
12.5.1
Efficacy and/or Pharmacodynamic endpoint(s)
Frequency and amount of transfusion
For subjects receiving platelet transfusion at baseline, the frequency and the amount of 
platelets transfusion in each period (Baseline: 4 weeks before Day 1; Week 13, 26, 52: 4 
weeks before each visit day) will be summarized. The same analysis applies to RBC 
transfusion. The amount of transfusion will be defined as the sum of transfusion multiplied by 
the volume of transfusion. Descriptive statistics including median, 25th and 75th quartiles, 
minimum, and maximum will be summarized for the amount of transfusion.
Hematological Response at Week 13 and Week 52
The number and percentage of subjects who meet the hematological response criteria (at 
Week 13 and Week 52 respectively) will be presented and Exact 90% confidence interval will 
be reported. And the number and percentage of assessment item for the hematological 
response criteria and for the detailed hematological response criteria will be presented.
Changes in platelet count, hemoglobin and neutrophil count
Changes in platelet count (in the absence of platelet transfusion), hemoglobin (in the absence 
of RBC transfusion) and neutrophil count (in the absence of G-CSF) will be summarized at 
each visit. Descriptive statistics including median, 25th and 75th quartiles, minimum, and 
maximum will be summarized for the changes.
Time to hematological response
Time to hematological response is defined as the time from the date of first study drug 
administration to the first hematological response which is defined in Section 12.4.1. All 
subjects in the FAS will be included in the time to hematological response calculations. The 


Novartis
Confidential
Page 69
Amended Protocol Version 02 (Clean)
Protocol No. CETB115E2202
distribution function of time to hematologic response will be estimated using the Kaplan-
Meier method and will be plotted. The median time to hematologic response along with 90% 
CIs will be presented. If a subject does not meet hematological response before or at the 
cutoff date, censoring will be performed using the maximum follow up of the entire trial.
Duration of hematological response
For subjects who responded, duration of hematological response will be defined as the 
number of months from the first date of a response until the first date of a relapse or a death. 
Patient still responding at the cut-off date will be censored at date of last response assessment. 
Only subjects with at least 2 response assessments are included in the duration of response 
assessment. Duration of hematological response will be estimated using Kaplan-Meier 
method and will be plotted.
Cytogenetic abnormalities, clonal evolution to PNH, Clonal evolution to AML or MDS
Frequency tables with the number and percentage of patients that have/do not have 
cytogenetic abnormalities, clonal evolution to PNH, evolution to MDS or AML will be 
summarized at each planned biomarker assessment visit. If sufficient data are available, the 
time to clonal evolution to PNH, AML or MDS until data cutoff may also be estimated using 
Kaplan-Meier method and will be plotted.
Proportion of subjects with transfusion decreasing
The number and percentage of subjects with platelet or RBC transfusion decrease or free at 
any time within the 52 weeks of the study when responders are still treated will be presented 
respectively. This analysis will be performed for the subgroup of subjects with baseline 
transfusion dependent.
Maximum duration of Platelet and RBC transfusion independence
Transfusion independence duration will be defined as the period from the next day of 
transfusion to the day before the next transfusion. Maximum duration of platelet and RBC 
transfusion independence will be summarized separately. The proportion of subjects with 
platelet and/or RBC transfusion independence will be summarized separately.
12.5.2
Safety endpoints
For all safety analyses, the safety set will be used. All listings and tables will be presented by 
for all subjects.
Safety summaries (tables, figures) include only data from the on-treatment period with the 
exception of baseline data which will also be summarized where appropriate (e.g., change 
from baseline summaries). In addition, a separate summary for death including on treatment 
and post treatment deaths will be provided. In particular, summary tables for adverse events 
(AEs) will summarize only on-treatment events, with a start date during the on-treatment 
period (treatment-emergent AEs).
The on-treatment period lasts from the date of first administration of study treatment to 30 
days after the date of the last actual administration of study treatment.
The overall observation period will be divided into three mutually exclusive segments:


Novartis
Confidential
Page 70
Amended Protocol Version 02 (Clean)
Protocol No. CETB115E2202
1. pre-treatment period: from day of subject’s informed consent to the day before first dose 
of study medication
2. on-treatment period: from day of first dose of study medication to 30 days after last dose 
of study medication
3. post-treatment period: starting at day 30+1 after last dose of study medication.
Adverse events
All information obtained on adverse events will be displayed by subject.
The number (and percentage) of subjects with treatment emergent adverse events (events 
started after the first dose of study medication or events present prior to start of the first dose 
of study medication 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.
Separate summaries will be provided for study medication related adverse events, death, 
serious adverse events, other significant adverse events leading to discontinuation and adverse 
events leading to dose adjustment.
The number (and proportion) of subjects with adverse events of special interest will be 
summarized.
A subject with multiple adverse events within a primary system organ class is only counted 
once towards the total of the primary system organ class.
Summary tables for adverse events (AEs) will include only AEs that started or worsened 
during the on-treatment period, the treatment-emergent AEs.
The incidence of treatment-emergent adverse events (new or worsening from baseline) will be 
summarized by system organ class and or preferred term, severity (based on Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.03 grades), type of adverse 
event, relation to study treatment.
Serious adverse events, non-serious adverse events and adverse events of special interest 
(AESI) during the on-treatment period will be tabulated.
All deaths (on-treatment and post-treatment) will be summarized.
All AEs, deaths and serious adverse events (including those from the pre and post-treatment 
periods) will be listed and those collected during the pre-treatment and post-treatment period 
will be flagged.
Vital signs
Number and percentage of subjects with at least 1 post-baseline value (in both directions, i.e. 
from baseline to highest post baseline and from baseline to lowest post baseline value) will be 
summarized. Tables with descriptive statistics at baseline, one or several post-baseline time 
points and change from baseline to this/these post-baseline time points will be presented.
All vital signs data will be listed by subject, and visit/time and if ranges are available, 
abnormalities will be flagged.


Novartis
Confidential
Page 71
Amended Protocol Version 02 (Clean)
Protocol No. CETB115E2202
12-lead ECG
PR, QRS, QT, QTcF and RR intervals will be obtained from 12-lead ECGs for each subject 
during the study.
Shift tables from baseline to worst on-treatment result will be generated. Descriptive statistics 
at baseline, one or several post-baseline time points and change from baseline to this/these 
post-baseline time points will be presented.
ECG evaluations for all subjects with at least 1 abnormality will be listed. All ECG data will 
be listed by subject and visit/time, abnormalities will be flagged.
Clinical laboratory evaluations
All laboratory data will be listed by subject and visit/time and if normal ranges are available 
abnormalities will be flagged. Summary statistics will be provided by visit/time.
Grading of laboratory values will be assigned programmatically as per National Cancer 
Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 or 
the latest version at the time of the analysis. 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, results will be categorized as 
low/normal/high based on laboratory normal ranges.
The following summaries will be generated separately for hematology, and chemistry tests:

Listing of all laboratory data with values flagged to show the corresponding CTCAE 
grades if applicable and the classifications relative to the laboratory normal ranges
For laboratory tests where grades are defined by CTCAE:

Worst post-baseline CTCAE grade (regardless of the baseline status). Each subject will be 
counted only once for the worst grade observed post-baseline.

Shift tables using CTCAE grades to compare baseline to the worst on-treatment value
For laboratory tests where grades are not defined by CTCAE:

Shift tables using the low/normal/high/ (low and high) classification to compare baseline 
to the worst on-treatment value.
In addition, regardless of the transfusion or G-CSF, laboratory tests (Platelet counts, 
Hemoglobin, Neutrophil count) value and change from baseline will be listed and summarized 
in scheduled visits using descriptive statistics (mean, standard deviation, median, interquartile 
range, and range)
12.5.3
Pharmacokinetics
PAS will be used in all pharmacokinetic data analyses and PK summary statistics.
PK analyses for subjects with extensive PK samples
A minimum of 12 subjects will have extensive PK profile for eltrombopag. PK sampling 
details are provided in Section 8.5.1.


Novartis
Confidential
Page 72
Amended Protocol Version 02 (Clean)
Protocol No. CETB115E2202
Eltrombopag plasma concentration data will be listed by subject, and visit/sampling time 
point. Descriptive summary statistics including mean (arithmetic and geometric), SD, CV 
(arithmetic and geometric), median, minimum and maximum will be provided by 
visit/sampling time point, including the frequency (n, %) of concentrations below the LLOQ 
and reported as zero. The geometric mean and arithmetic mean (SD) plots will also be 
graphically presented for concentration-time data. Individual concentration-time profiles will 
be displayed graphically. Concentrations below LLOQ will be treated as zero in summary 
statistics and for PK parameter calculations. 
Pharmacokinetic parameters of eltrombopag (and any relevant metabolites), including but not 
limited to those listed in Table 12-1, will be calculated from the individual concentration-time 
profile obtained following the administration of the study treatment and listed by subject. 
Descriptive summary statistics for these PK parameters will include mean (arithmetic and 
geometric), SD, and CV (arithmetic and geometric), median, minimum and maximum. An 
exception to this is Tmax where median, minimum and maximum will be presented.
Table 12-1
Non-compartmental pharmacokinetic parameters
AUClast
The AUC from time zero to the last measurable concentration sampling time (tlast) 
(mass*time*volume-1)
AUCtau
The AUC calculated to the end of a dosing interval (tau) at steady-state 
(amount*time*volume-1)
Cmax
The maximum (peak) observed plasma drug concentration after single dose 
administration (mass*volume-1)
Tmax
The time to reach maximum (peak) plasma drug concentration after single dose 
administration (time)
Ctrough
Pre-dose concentration at the end of dose interval (mass*volume-1)
PK analyses for subjects with sparse PK samples
PK concentrations of eltrombopag will be summarized by dose, visit and scheduled time point. 
If feasible, these samples may be pooled with other studies to assess the relationship between 
eltrombopag exposure and efficacy and/or safety. These analyses may be defined in a separate 
SAP and the results may be reported separately from the CSR.
12.7
Interim analyses
No formal interim analysis is planned for this trial.


Novartis
Confidential
Page 73
Amended Protocol Version 02 (Clean)
Protocol No. CETB115E2202
12.8
Sample size calculation
As this is a bridging study to support China registration, an estimation strategy rather than 
formal hypothesis testing will be pursued. Approximately 20 subjects will be enrolled into the 
study based on the feasibility rather than statistical considerations. This number of subjects is 
considered appropriate to assess the efficacy and safety of eltrombopag in Chinese patients.
12.8.1
Primary endpoint(s)
The hematologic response rate at Week 24 in the pivotal study of NIH-09-H-0154 was 40%. 
Assuming a same response rate (40%) in Chinese subjects, the 90% confidence interval of the 
hematological response rate with a total of 20 subjects will be (21.7%, 60.6%).
Below table shows the 90% CIs for various observed response rate. The maximum half-width 
of the 90% CIs is 19.8%.
Table 12-2
90% CIs for various observed response rate
Sample size
# of responders
Hematologic 
response rate (%)
90% CI (%)
20
4
20
(7.1, 40.1)
20
6
30
(14.0, 50.8)
20
8
40
(21.7, 60.6)
20
10
50
(30.2, 69.8)
The 12 evaluable subjects for intensive PK sampling was chosen based on feasibility and 
practical considerations to assist in characterizing the PK of eltrombopag in Chinese subjects.
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.


Novartis
Confidential
Page 74
Amended Protocol Version 02 (Clean)
Protocol No. CETB115E2202
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 standard operating procedures (SOP), and are performed according to 
written Novartis processes
14
Protocol adherence
This protocol defines the study objectives, the study procedures and the data to be collected 
on study participants. Additional assessments required to ensure safety of 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.


Novartis
Confidential
Page 75
Amended Protocol Version 02 (Clean)
Protocol No. CETB115E2202
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.


Novartis
Confidential
Page 76
Amended Protocol Version 02 (Clean)
Protocol No. CETB115E2202
15
References
References are available upon request
Red Blood Cell Disease (Anemia) Group (2017) [Chinese expert consensus on the diagnosis 
and treatment of aplastic anemia (2017)]. Zhonghua Xue Ye Xue Za Zhi p. 1-5.
Camitta BM, Rappeport JM, Parkman R, et al (1975) Selection of patients for bone marrow 
transplantation in severe aplastic anemia. Blood p. 355-63.
Desmond R, Townsley DM, Dumitriu B, et al (2014) Eltrombopag restores trilineage 
hematopoiesis in refractory severe aplastic anemia that can be sustained on discontinuation of 
drug. Blood p. 1818-25.
Desmond R, Townsley DM, Dunbar C, et al (2015) Eltrombopag in aplastic anemia. Semin. 
Hematol. p. 31-7.
Erickson-Miller CL, Kirchner J, Aivado M, et al (2010) Reduced proliferation of non-
megakaryocytic acute myelogenous leukemia and other leukemia and lymphoma cell lines in 
response to eltrombopag. Leuk. Res. p. 1224-31.
Maciejewski JP, Risitano A, Sloand EM, et al (2002) Distinct clinical outcomes for 
cytogenetic abnormalities evolving from aplastic anemia. Blood p. 3129-35.
Marsh JC, Kulasekararaj AG (2013) Management of the refractory aplastic anemia patient: 
what are the options? Blood p. 3561-7.
Marsh JC, Ball SE, Cavenagh J, et al (2009) Guidelines for the diagnosis and management of 
aplastic anaemia. Br. J. Haematol. p. 43-70.
Olnes MJ, Scheinberg P, Calvo KR, et al (2012) Eltrombopag and improved hematopoiesis in 
refractory aplastic anemia. N. Engl. J. Med. p. 11-9.
Rosenfeld S, Follmann D, Nunez O, et al (2003) Antithymocyte globulin and cyclosporine for 
severe aplastic anemia: association between hematologic response and long-term outcome. 
JAMA p. 1130-5.
Scheinberg P, Young NS (2012) How I treat acquired aplastic anemia. Blood p. 1185-96.
Scheinberg P, Nunez O, Weinstein B, et al (2011) Horse versus rabbit antithymocyte globulin 
in acquired aplastic anemia. N. Engl. J. Med. p. 430-8.
Scheinberg P, Nunez O, Weinstein B, et al (2012) Activity of alemtuzumab monotherapy in 
treatment-naive, relapsed, and refractory severe acquired aplastic anemia. Blood p. 345-54.
Scheinberg P, Nunez O, Wu C, et al (2006) Treatment of severe aplastic anaemia with 
combined immunosuppression: anti-thymocyte globulin, ciclosporin and mycophenolate 
mofetil. Br. J. Haematol. p. 606-11.
Scheinberg P, Wu CO, Nunez O, et al (2009) Treatment of severe aplastic anemia with a 
combination of horse antithymocyte globulin and cyclosporine, with or without sirolimus: a 
prospective randomized study. Haematologica p. 348-54.


Novartis
Confidential
Page 77
Amended Protocol Version 02 (Clean)
Protocol No. CETB115E2202
Sun H, Tsai Y, Nowak I, et al (2012) Eltrombopag, a thrombopoietin receptor agonist, 
enhances human umbilical cord blood hematopoietic stem/primitive progenitor cell expansion 
and promotes multi-lineage hematopoiesis. Stem Cell Res p. 77-86.
Valdez JM, Scheinberg P, Nunez O, et al (2011) Decreased infection-related mortality and 
improved survival in severe aplastic anemia in the past two decades. Clin. Infect. Dis. p. 726-
35.
Wang W, Wang XQ, Li P, et al (2011) [Incidence of adult aplastic anemia in Shanghai, 
China]. Zhonghua Nei Ke Za Zhi p. 284-6.
Yang C, Zhang X (1991) Incidence survey of aplastic anemia in China. Chin. Med. Sci. J. p. 
203-7.
Young NS, Kaufman DW (2008) The epidemiology of acquired aplastic anemia. 
Haematologica p. 489-92.
Zhang XY, Liu HQ, Zhang DL, et al (2001) Epidemiology of leukaemia and Aplastic Anemia 
in Shengzhen, China p. 22(7): 347-349.
Zhang YP, Xu JH, Zhang XC (1999) Epidemiology of Aplastic Anemia in Ning Xia, China. p. 
20(4):211-211.


Novartis
Confidential
Page 78
Amended Protocol Version 02 (Clean)
Protocol No. CETB115E2202
16
Appendices
16.1
Appendix 1: List of substrates of BCRP and OATP1B1
Table 16-1
List of substrates of BCRP and OATP1B1
Substrate
Drug Name
OATP1B1
aliskiren, ambrisentan, anacetrapib, atenolol, asunaprevir, atorvastatin, bosentan, 
bromocriptine, caspofungin, celiprolol, danoprevir, digoxin, docetaxel, eliglustat, 
empangliflozin, ezetimibe, fimasartan, fexofenadine, fluvastatin, glyburide, maraviroc, 
methotrexate, rosuvastatin, saquinavir, simvastatin, paclitaxel, pirataprevir, 
pitavastatin, pravastatin, repaglinide, rifampicin, valsartan, olmesartan, telmisartan, 
montelukast, ticlopidine, thyroxine
BCRP
atorvastatin, daunorubicin, dolutegravir, doxorubicin, hematoporphyrin, imatinib, 
methotrexate, mitoxantrone, paritaprevir, pitavastatin, rosuvastatin, irinotecan, ethinyl-
estradiol, simvastatin, sofosbuvir, sulfasalazine, tenofovir, topotecan, venetoclax
Source: Adapted from Oncology Clinical Pharmacology Drug-Drug Interaction Database (release date: 
January 2018) which was compiled from the Indiana University School of Medicine’s “Clinically 
Relevant” Table and supplemented with the FDA Draft Guidance for Industry, Drug Interaction Studies 
– Study Design, Data Analysis, and Implications for Dosing and Labeling (October 2017), and the 
University of Washington’s Drug Interaction Database. The lists provided may not be exhaustive.
16.2
Appendix 2: Liver event and Laboratory trigger Definitions and 
Follow-up Requirements
Table 16-2
Follow up requirements for liver events and laboratory triggers
Criteria
Actions required
Follow-up monitoring
Potential Hy’s Law casea
Discontinue the study treatment 
immediately
Hospitalize, if clinically appropriate
Establish causality
Record the AE and contributing 
factors (e.g., conmeds, med hx, 
lab) in the appropriate CRF
ALT, AST, TBL, Alb, PT/INR, ALP 
and GGT until resolutionc
(frequency at investigator 
discretion)
ALT or AST
> 8 × ULN
Discontinue the study treatment 
immediately
Hospitalize if clinically appropriate
Establish causality
Record the AE and contributing 
factors (e.g., conmeds, med hx, 
lab) in the appropriate CRF
ALT, AST, TBL, Alb, PT/INR, ALP 
and GGT until resolutionc
(frequency at investigator 
discretion)
> 3 × ULN and INR > 1.5
Discontinue the study treatment 
immediately
Hospitalize, if clinically appropriate
Establish causality
Record the AE and contributing 
ALT, AST, TBL, Alb, PT/INR, ALP 
and GGT until resolutionc
(frequency at investigator 
discretion)


Novartis
Confidential
Page 79
Amended Protocol Version 02 (Clean)
Protocol No. CETB115E2202
Criteria
Actions required
Follow-up monitoring
factors (e.g., conmeds, med hx, 
lab) in the appropriate CRF
> 5 to ≤ 8 × ULN
Repeat LFT within 48 hours
If elevation persists, continue 
follow-up monitoring
If elevation persists for more than 2 
weeks, discontinue the study drug
Establish causality
Record the AE and contributing 
factors (e.g., conmeds, med hx, 
lab) in the appropriate CRF
ALT, AST, TBL, Alb, PT/INR, ALP 
and GGT until resolutionc
(frequency at investigator 
discretion)
> 3 × ULN accompanied 
by symptomsb
Discontinue the study treatment 
immediately
Hospitalize if clinically appropriate
Establish causality
Record the AE and contributing 
factors (e.g., conmeds, med hx, 
lab) in the appropriate CRF
ALT, AST, TBL, Alb, PT/INR, ALP 
and GGT until resolutionc
(frequency at investigator 
discretion)
> 3 to ≤ 5 × ULN (subject 
is asymptomatic)
Repeat LFT within the next week
If elevation is confirmed, initiate 
close observation of the subject
Investigator discretion
Monitor LFT within 1 to 4 weeks
ALP (isolated)
> 2 × ULN (in the 
absence of known bone 
pathology)
Repeat LFT within 48 hours
If elevation persists, establish 
causality
Record the AE and contributing 
factors (e.g., conmeds, med hx, 
lab) in the appropriate CRF
Investigator discretion
Monitor LFT within 1 to 4 weeks or 
at next visit
TBL (isolated)
> 2 × ULN (in the 
absence of known Gilbert 
syndrome)
Repeat LFT within 48 hours
If elevation persists, discontinue 
the study drug immediately
Hospitalize if clinically appropriate
Establish causality
Record the AE and contributing 
factors (e.g., conmeds, med hx, 
lab) in the appropriate CRF
ALT, AST, TBL, Alb, PT/INR, ALP 
and GGT until resolutionc
(frequency at investigator 
discretion)
Test for hemolysis (e.g.,
reticulocytes, haptoglobin, 
unconjugated [indirect] bilirubin)
> 1.5 to ≤ 2 × ULN 
(subject is asymptomatic)
Repeat LFT within the next week
If elevation is confirmed, initiate 
close observation of the subject
Investigator discretion
Monitor LFT within 1 to 4 weeks or 
at next visit
Jaundice
Discontinue the study treatment 
immediately
Hospitalize the subject
Establish causality
Record the AE and contributing 
factors (e.g., conmeds, med hx, 
ALT, AST, TBL, Alb, PT/INR, ALP 
and GGT until resolutionc
(frequency at investigator 
discretion)


Novartis
Confidential
Page 80
Amended Protocol Version 02 (Clean)
Protocol No. CETB115E2202
Criteria
Actions required
Follow-up monitoring
lab) in the appropriate CRF
Any AE potentially 
indicative of a liver 
toxicity*
Consider study treatment 
interruption or discontinuation
Hospitalization if clinically 
appropriate
Establish causality
Record the AE and contributing 
factors (e.g., conmeds, med hx, 
lab) in the appropriate CRF
Investigator discretion
aElevated ALT/AST > 3 × ULN and TBL > 2 × ULN but without notable increase in ALP to > 2 × ULN 
b(General) malaise, fatigue, abdominal pain, nausea, or vomiting, or rash with eosinophilia cResolution 
is defined as an outcome of one of the following: (1) return to baseline values, (2) stable values at 
three subsequent monitoring visits at least 2 weeks apart, (3) remain at elevated level after a 
maximum of 6 months, (4) liver transplantation, and (5) death.
Based on investigator’s discretion, investigation(s) for contributing factors for the liver event 
can include: 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.

SAP_001.pdf: 
Clinical Development
ETB115/Eltrombopag/Revolade®
CETB115E2202 / NCT03988608
A non-randomized, open-label, multi-center, phase II study 
to assess the safety and efficacy of eltrombopag in 
Chinese subjects with refractory or relapsed severe 
aplastic anemia
Statistical Analysis Plan (SAP)
Final Analysis
Author:
Trial Statistician, 
Document type:
SAP Documentation
Document status:
Final 1.0
Release date:
22-Mar-2023
Number of pages:
36
Property of Novartis           
Confidential


Novartis
Confidential
Page 2
SAP
CETB115E2202
Document History – Changes compared to previous final version of SAP
Date
Time point
Section
Changes
06-Dec-2019
Prior to FPFV
N/A - First version
19-Aug-2021
Prior to DBL of 
Primary analysis
Section 
2.3.1
In light of COVID-19 pandemic, additional analysis of 
protocol deviations related to COVID-19 pandemic were 
added.
Section 
2.5.1
Add a note to clarify ‘No platelet/RBC transfusion 
requirement for 8 weeks’.
Section 
2.5.4
Add supplementary analyses for primary endpoint to 
analyse derived hematologic response programmatically.
Section 
2.7.1
To clarify time to response and duration of response 
should be analyzed and plotted for four assessment 
criteria.
Section 
2.7.1
For duration of response, give a definition for relapse.
Section 
2.7.1
For summary of shift baseline for platelet transfusion 
independence and RBC transfusion independence, give 
definition for Platelet and RBC transfusion independence. 
Section 
2.7.2
Plots of Median and interquartile range were added for 
platelet count, hemoglobin and neutrophil count.
Section 
2.8.4.1
Add normal range for ECG findings. 
 
 
Section 
2.12
Remove analysis for time to clonal evolution due to 
limited events of clonal evolution.
09-Feb-2022
Prior to DBL of 
updated analysis
General
Add some sentence to make it clear for which analysis will 
not be reproduced at updated analysis and final analysis.
Section 
2.3.5
Add a few more categories for patients disposition
Section 
2.7.1
Add a summary analysis for relapse-free probability in 
duration of response.
Add a summary analysis for proportion of subjects with 
50% transfusion reduction.
22-Mar-2023
Prior to DBL of 
final analysis
General
Add some sentence to make it clear for which analysis will 
not be reproduced at final analysis.
Section 
5.3
Clarify the rules to derive Reticulocyte absolute count 
which are missing.


Novartis
Confidential
Page 3
SAP
CETB115E2202
Table of contents
Table of contents .................................................................................................................3
1
Introduction .........................................................................................................................8
1.1
Study design.............................................................................................................8
1.2
Study objectives and endpoints ...............................................................................9
2
Statistical methods.............................................................................................................10
2.1
Data analysis general information .........................................................................10
2.1.1
Data included in the analysis.................................................................10
2.1.2
General analysis conventions................................................................10
2.1.3
General definitions................................................................................11
2.2
Analysis sets ..........................................................................................................12
2.2.1
Subgroup of interest ..............................................................................13
2.3
Patient disposition, demographics and other baseline characteristics ...................14
2.3.1
Basic demographic and baseline characteristics ...................................14
2.3.2
Diagnosis and extent of SAA................................................................14
2.3.3
Medical history......................................................................................15
2.3.4
Other......................................................................................................15
2.3.5
Patient disposition.................................................................................15
2.3.6
Protocol deviations................................................................................15
2.3.7
Analysis sets..........................................................................................16
2.4
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance)............................................................................................................16
2.4.1
Study treatment / compliance................................................................16
2.4.2
Prior, concomitant and post therapies ...................................................17
2.5
Analysis of the primary objective..........................................................................18
2.5.1
Primary endpoint...................................................................................18
2.5.2
Statistical hypothesis, model, and method of analysis..........................19
2.5.3
Handling of missing values/censoring/discontinuations.......................20
2.5.4
Supplementary analyses........................................................................20
2.5.5
Supportive analyses...............................................................................20
2.6
Analysis of the key secondary objective ...............................................................21
2.7
Analysis of secondary efficacy objective(s)..........................................................21
2.7.1
Secondary endpoints .............................................................................21
2.7.2
Statistical hypothesis, model, and method of analysis..........................23
2.7.3
Handling of missing values/censoring/discontinuations.......................24
2.8
Safety analyses.......................................................................................................24


Novartis
Confidential
Page 4
SAP
CETB115E2202
2.8.1
Adverse events (AEs)............................................................................24
2.8.2
Deaths....................................................................................................26
2.8.3
Laboratory data .....................................................................................26
2.8.4
Other safety data ...................................................................................27
2.9
Pharmacokinetic endpoints....................................................................................29
31
2.11
Patient-reported outcomes .....................................................................................31
2.12
Cytogenetic abnormalities and clonal evolution....................................................31
31
2.14
Interim analysis......................................................................................................31
3
Sample size calculation .....................................................................................................31
3.1
Primary analysis.....................................................................................................31
4
Change to protocol specified analyses ..............................................................................32
5
Appendix ...........................................................................................................................32
5.1
Imputation rules.....................................................................................................32
5.1.1
Study drug.............................................................................................32
5.1.2
AE, ConMeds and safety assessment date imputation..........................33
5.2
AEs coding/grading ...............................................................................................34
5.3
Laboratory parameters derivations ........................................................................34
5.4
Statistical models...................................................................................................35
5.4.1
Primary analysis....................................................................................35
5.4.2
Key secondary analysis.........................................................................35
6
Reference...........................................................................................................................36


Novartis
Confidential
Page 5
SAP
CETB115E2202
List of tables
Table 1-1
Objectives and related endpoints ............................................................9
Table 2-1
Time windows for hematological response...........................................12
Table 2-2
IWG criteria for Primary Endpoint .......................................................18
Table 2-3
Clinically notable changes in vital signs...............................................29
Table 2-4
Non-compartmental PK parameters......................................................30
Table 3-1
90% CIs for various observed response rate.........................................31
Table 5-1
Imputation of start dates (AE, CM) and assessments (LB, EG, VS) ....33
Table 5-2
Imputation of end dates (AE, CM)........................................................34
List of figures
Figure 1-1
Study Design ...........................................................................................9


Novartis
Confidential
Page 6
SAP
CETB115E2202
List of abbreviations
AE
adverse event
AESI
adverse event of special interest
ALG
anti-lymphocyte Immunoglobulin
ALP
alkaline phosphatase
ALT
alanine aminotransferase
AML
acute myeloid leukemia
ANC
absolute neutrophil count 
ATC
anatomical therapeutic chemical 
ATG
anti-thymocyte globulin
AUC
area under the plasma concentration-time curve
AUClast
area under the plasma concentration-time curve from zero (pre-dose) to the last
quantifiable sample time
AUCtau
area under the plasma concentration-time curve over the dosing interval on 
multiple dosing
CE
clonal evolution
CI
Confidence Interval
Cmax
maximum plasma concentration following drug administration
CRF
Case Report/Record Form (paper or electronic)
CsA
Cyclosporine
CSR
Clinical Study Report
CTC
Common Toxicity Criteria
CTCAE
Common Terminology Criteria for Adverse Events
Ctrough
Concentration level prior to dosing
CV
coefficient of variation
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic Case Report/Record Form
eCRS
Electronic Case Retrieval Strategy
EOT
end of treatment
FAS
Full Analysis Set
G-CSF
granulocyte colony stimulating factor
GPI
glycosylphosphatidylinositol
h
Hour
IWG
International Working Group 
MDS
myelodysplastic syndromes
MedDRA
Medical dictionary for regulatory activities
mg
milligram(s)
mL
milliliter(s)
msec
milliseconds
NA
not applicable
NCI
National Cancer Institute
PAS
Pharmacokinetic analysis set


Novartis
Confidential
Page 7
SAP
CETB115E2202
PD
pharmacodynamic(s)
PK
pharmacokinetic(s)
PNH 
paroxysmal nocturnal hemoglobinuria
PT
Preferred Term
QTc
corrected QT interval duration
rATG
rabbit ATG
RBC
red blood cell(s)
SAA
severe aplastic anemia
SAE
serious adverse event
SAP
Statistical Analysis Plan
SBP
Systolic Blood Pressure
SD
standard deviation
SMQs
Standardized MedDRA Queries
Tmax
time to peak concentration
ULN
upper limit of normal
WHO
World Health Organization


Novartis
Confidential
Page 8
SAP
CETB115E2202
1
Introduction
This statistical analysis plan (SAP) describes all planned analyses for the clinical study report(s)
(CSR) of study ETB115E2202, a non-randomized, open-label, multi-center, phase II study to 
assess the safety and efficacy of eltrombopag in Chinese subjects with refractory or relapsed 
severe aplastic anemia.
As specified in Section 4.4 of the study protocol (version 02 dated 02-Sep-2019), the primary 
analysis will be performed after all patients have completed Week 26 or discontinued prior to 
Week 26. Furthermore, an updated analysis and a final analysis will be performed after all 
patients have completed Week 52 or discontinued prior to Week 52 and at the end of the study 
respectively. This SAP will also support updated analysis and final analysis.
The content of this SAP is based on protocol ETB115E2202 version 02 (dated 02-Sep-2019). 
All decisions regarding analysis, as defined in the SAP document, should be made prior to 
database lock.
1.1
Study design
This is a non-randomized, open-label, multi-center, phase II study to assess the efficacy and 
safety of eltrombopag in Chinese subjects with severe aplastic anemia who had insufficient 
response or relapsed following at least one treatment course in the period time of > 6 months of 
immunosuppression with a regimen containing anti-thymocyte globulin (ATG), anti-
lymphocyte globulin(ALG), and/or cyclophosphamide, or alemtuzumab. The study design is 
shown in Figure 1-1.
As this is a bridging study to support China registration, an estimation strategy rather than 
formal hypothesis testing will be pursued. Approximately 20 subjects will be enrolled into the 
study based on feasibility and statistical considerations.
The primary endpoint is the hematologic response rate (defined as the proportion of subjects 
who meet any of the IWG response criteria) at Week 26. Subjects in whom the treatment is 
assessed as effective (meet any of the response criteria) at 6 months will continue the study 
treatment.
The primary analysis will be performed after all patients have been followed for at least 6
months or have discontinued study. An updated analysis will be performed after all patients 
have completed Week 52 or discontinued prior to Week 52. A final analysis will be performed 
after all patients have completed or discontinued from extension part of this study, i.e. at the 
end of study. Extension part of this study will start 1 year (Week 52) after the initiation of study 
treatment. This part was included in the study with an ethical consideration for subjects who 
require continued treatment. The continued treatment will be provided up to the launch of the 
product after approval.


Novartis
Confidential
Page 9
SAP
CETB115E2202
Figure 1-1
Study Design
1.2
Study objectives and endpoints
Table 1-2
Objectives and related endpoints
Objective(s)
Endpoint(s)
Primary objective(s)
Endpoint(s) for primary objective(s)

To assess the efficacy of eltrombopag treatment at 6 
months in Chinese subjects with a previous diagnosis 
of severe aplastic anemia and who had insufficient 
response following at least one treatment course in 
the period time of > 6 months of immunosuppression 
with a regimen containing anti-thymocyte globulin 
(ATG), anti-lymphocyte globulin (ALG), and/or 
cyclophosphamide, or alemtuzumab, and who are 
ineligible for HSCT or a suitable donor is not available.

Hematologic response rate at 6 
months (Week 26) after starting 
the study treatment defined as the 
proportion of all subjects who meet 
any of the IWG criteria in 
Section 2.5.1.
Secondary objective(s)
Endpoint(s) for secondary 
objective(s)

To evaluate the efficacy of eltrombopag treatment at 3 
months and 1 year

Hematologic response rate at 
Week 13 and Week 52

To evaluate the effect of eltrombopag on individual 
hematologic response (change in neutrophil, platelet, 
hemoglobin)

Changes in platelet count (in the 
absence of platelet transfusion), 
hemoglobin (in the absence of 
RBC transfusion) and neutrophil 
count (in the absence of G-CSF).

To evaluate the time to hematologic response and 
duration

Time to hematologic response and 
duration (any response according 
to the response criteria for the 
primary endpoint)

To evaluate the frequency and volume of transfusion 
(platelet and RBC) 

Frequency and volume of 
transfusion (platelet and RBC)

To evaluate the safety and tolerability of eltrombopag

Frequency/severity of AEs, vital 
signs, ECG and laboratory 
abnormalities.

To determine the pharmacokinetics (PK) of 
eltrombopag

Plasma PK parameters of 
eltrombopag and trough 
concentrations


Novartis
Confidential
Page 10
SAP
CETB115E2202
Objective(s)
Endpoint(s)

To evaluate cytogenetic abnormalities, clonal 
evolution to PNH, evolution to MDS or AML.

Rate of clonal evolution including 
clonal evolution to PNH, evolution 
to AML or MDS. 
2
Statistical methods
2.1
Data analysis general information
The primary analysis, updated analysis and final analysis will be conducted by Novartis and/or 
a designated CRO. SAS version 9.4 or later software will be used to perform all data analyses 
and to generate tables, figures and listings.
2.1.1
Data included in the analysis
The analysis cut-off date for the primary analysis of study data will be established after all 
enrolled patients have completed 26 weeks of treatment or  have discontinued prior to Week 26. 
All statistical analyses will be performed using all data collected in the database up to the data
cutoff date. All data with an assessment date or event start date (e.g. vital sign assessment date
or start date of an adverse event) prior to or on the cut-off date will be included in the analysis.
Any data collected beyond the cut-off date will not be included in the analysis and will not be 
used for any derivations.
All events with start date before or on the cut-off date and end date after the cut-off date will be 
reported as ‘ongoing. The same rule will be applied to events starting before or on the cut-off 
date and not having documented end date. This approach applies, in particular, to adverse event,
concomitant medication reports and exposure to eltrombopag. For these events, the end date 
will not be imputed and therefore will not appear in the listings.
The analysis cutoff date for the updated analysis and final analysis of study data will be 
established after all patients have completed Week 52 or discontinued prior to Week 52 and at 
the end of the study respectively. 
2.1.2
General analysis conventions
Pooling of centers: Unless specified otherwise, data from all study centers will be pooled for 
the analysis. Due to expected small number of patients enrolled at centers, no center effect will 
be assessed. 
Qualitative data (e.g., gender, race, etc.) will be summarized by means of contingency 
tables; a missing category will be included as applicable. Percentages will be calculated using 
the number of patients in the relevant population or subgroup as the denominator.
Quantitative data (e.g., age, body weight, etc.) will be summarized by appropriate 
descriptive statistics (i.e. mean, standard deviation, median, minimum, and maximum). PK 
parameters except Tmax will be summarized by approriate descriptive statistics (n, arithmetic 


Novartis
Confidential
Page 11
SAP
CETB115E2202
mean, CV% mean, standard deviation (SD), median, geometric mean, CV% geo-mean, 
minimum and maximum).
2.1.3
General definitions
Study drug and Study treatment
The study drug/study treatments for this study is eltrombopag (ETB115).
Eltrombopag will be supplied as film-coated tablets (25 mg) provided either as commercial 
packages locally.
Date of first administration of study treatment 
The date of first administration of study treatment will be derived as the first date when a 
nonzero dose of study treatment is administered and recorded on the appropriate CRF.
Date of last administration of study treatment 
The date of last administration of study treatment will be derived as the last date when a 
nonzero dose of study treatment is administered and recorded on the appropriate CRF. For 
those patients still on treatment at cutoff date, the cutoff date will be imputed as the date of 
last administration of study treatment. 
Study day
The study day, describes the day of the event or assessment date, relative to the reference start 
date. 
The study day is defined as:
The date of the event (visit date, onset date of an event, assessment date etc.) − 
reference start date + 1 if event is on or after the reference start date;

The date of the event (visit date, onset date of an event, assessment date etc.) − 
reference start date if event precedes the reference start date.
The reference date for all assessments (safety, efficacy, pk, etc) is the date of first 
administration of study treatment as defined above. The study day will be displayed in the 
data listings.
Time unit
A year length is defined as 365.25 days. A month length is 30.4375 days (365.25/12). If duration 
is reported in months, duration in days will be divided by 30.4375. If duration is reported in 
years, duration in days will be divided by 365.25.
Baseline
For safety and efficacy evaluations, the last available assessment on or before the date of first 
administration of study treatment is defined as “baseline” assessment. If patients have no value 
as defined above, the baseline result will be missing.


Novartis
Confidential
Page 12
SAP
CETB115E2202
On-treatment assessment/event and observation periods
The overall observation period will be divided into three mutually exclusive segments: 
1. pre-treatment period: from day of patient’s informed consent to the day before first 
administration of study treatment
2. on-treatment period: from date of first administration of study treatment to 30 days after 
date of last actual administration of study treatment (including start and stop date)
3. post-treatment period: starting at day 30+1 after last administration of study treatment.
Safety summaries (tables, figures) include only data from the on-treatment period with the 
exception of baseline data which will also be summarized where appropriate (e.g. change from 
baseline summaries). In addition, a separate summary for death including on treatment and post 
treatment deaths will be provided. In particular, summary tables for adverse events (AEs) will 
summarize only on-treatment events, with a start date during the on-treatment period 
(treatment-emergent AEs).  
However, all safety data (including those from the post-treatment period) will be listed and 
those collected during the pre-treatment and post-treatment period will be flagged.
Windows for multiple assessments 
In order to summarize hematological response collected over time (including unscheduled 
visits), the assessments will be time slotted. The following general rule will be applied in 
creating the assessment windows: If more than one assessment is done within the same time
window, the assessment performed closest to the target date will be used. If 2 assessments
within a time window are equidistant from the target date, then the earlier of the 2  assessments 
will be used. Data from all assessments (scheduled and unscheduled), including multiple 
assessments, will be listed.
Table 2-1
Time windows for hematological response
Assessment
         Target day of assessment
Time Interval
  Baseline
On or before Study Day 1
≤ Day 1
  Week 13
Week 13 ± 3 days
Study Day 77 – 105 (i.e. 11 to 15 weeks)
  Week 26
Week 26 ± 3 days
Study Day 168 – 196 (i.e. 24 to 28 weeks)
  Week 52
Week 52 ± 3 days
Study Day 336 – 392 (i.e. 48 to 56 weeks)
2.2
Analysis sets
Full Analysis Set
The Full Analysis Set (FAS) comprises all patients to whom study treatment has been assigned 
and who received one dose of study treatment. 
Safety Set
The Safety set is identical as the Full Analysis set in the study. All safety analyses will be done
using the Safety Set.


Novartis
Confidential
Page 13
SAP
CETB115E2202
Pharmacokinetic analysis set (PAS)
The Pharmacokinetic analysis set (PAS) includes all subjects who received at least one dose of 
eltrombopag and have at least one evaluable PK sample. However, only evaluable PK samples 
will be included in the PK analysis. A concentration will be flagged as NOT evaluable 
programmatically if any of the following
conditions is satisfied:

The dose received is not the protocol-planned dose in any of the 7 consecutive days 
prior to the current dose. 

Vomiting occurs within 4 hours of the last dose (pre-dose trough sample).

Vomiting occues within 4 hours of the current dose (post-dose samples).
Only PK concentrations/parameters which are not flagged for exclusion programmatically will 
be used for summaries or statistical analysis. Any concentration listings will include all 
concentration values, with flags indicating those excluded from analyses.
2.2.1
Subgroup of interest
The following subgroups will be considered for outputs. Details of the use of these subgroups 
will be found in the sections for the relevant endpoints. 
The subgroup analysis will not be reproduced for final CSR.
Efficacy
The primary efficacy endpoint will be summarized by the following subgroups:

Age group (< 65 years) vs. ( ≥ 65 years)

Gender : Male vs. Female

Relapsed patients, refractory patients and patients who achieved PR after the last course of 
IST with platelet count <30 ×109 /L

Baseline platelet counts: <20 ×109 /L, >=20 ×109 /L 

Prior ATG/ALG Therapies: Yes, No 

Baseline Platelet Transfusion: Independence, Dependence

Baseline RBC Transfusion: Independence, Dependence

Concomitant use of CsA and anabolic steroids at baseline: Yes, No
No formal statistical test of hypotheses will be performed for the subgroups, only point estimate 
of the treatment effect and 90% confidence intervals will be provided if applicable. The 
objective of the efficacy subgroup analysis is to demonstrate homogeneity of treatment effect 
in the above subgroups. 


Novartis
Confidential
Page 14
SAP
CETB115E2202
Safety
Safety subgroup analyses will use the same method as for the analysis in the overall analysis 
set. Key safety analyses (all AEs, AEs with suspected relationship to study treatment, SAEs and 
AESIs) will be repeated on safety set in the following subgroups:

Age group (< 65 years) vs. ( ≥65 years)

Gender : Male vs. Female

Concomitant use of CsA and anabolic steroids at baseline: Yes, No
2.3
Patient disposition, demographics and other baseline 
characteristics
The Full Analysis Set (FAS) will be used for all baseline and demographic summaries and 
listings unless otherwise specified. No inferential statistics will be provided.
The analysis for basic demographic and baseline characteristics, diagnosis and extent of SAA, 
medical history, and analysis sets will not be reproduced for final CSR. Only hematological 
parameter counts at baseline will be reproduced for final CSR since some missing values of 
Reticulocyte absolute count will be derived from Reticulocyte count % * RBC count in SI unit 
(10E12/L) * 10.
2.3.1
Basic demographic and baseline characteristics
All demographic data will be summarized and listed. Categorical data (e.g. gender, age groups: 
18-64 years, ≥ 65 years, others as applicable) will be summarized by frequency counts and 
percentages; the number and percentage of patients with missing data will be provided. 
Continuous data (e.g. age, weight, height) will be summarized by descriptive statistics (N, mean, 
median, standard deviation, minimum and maximum).  
Haematological parameters at the assessment of patients eligibility including platelet count, 
haemoglobin, absolute neutrophils count (ANC) and absolute reticulocytes count (ARC) will 
be summarized by descriptive statistics (N, mean, median, standard deviation, minimum and 
maximum). RBC and Platelet Transfusion (Independence and Dependence), and G-CSF 
injection required (Yes/No) at baseline will be summarized by frequency counts and 
percentages.
The following other baseline characteristics will be summarized by frequency counts and 
percentages:

Relapsed patients, refractory patients and patients who achieved PR after the last course of 
IST with platelet count <30 ×109 /L,

Concomitant use of CsA and anabolic steroids at baseline: Yes, No,

Prior ATG/ALG Therapies: Yes, No.
2.3.2
Diagnosis and extent of SAA
Summary statistics will be tabulated for diagnosis and extent of SAA. This analysis will include
the following if they are available: stage at initial diagnosis, time since initial diagnosis, time 


Novartis
Confidential
Page 15
SAP
CETB115E2202
from initial diagnosis to first recurrence/progression (in months), and time since most recent 
relapse/progression to first dose (in months).
2.3.3
Medical history
Medical history and baseline symptoms (current medical conditions) will be summarized
separately and listed. The summaries will be presented by primary system organ class (SOC), 
preferred term (PT) and treatment arm. Medical history and current medical conditions will be
coded using the Medical Dictionary for Regulatory Activities (MedDRA) terminology. The 
MedDRA version used for reporting will be specified in the CSR and as a footnote in the 
applicable tables/listings.
2.3.4
Other
All other data collected at baseline will be listed.
2.3.5
Patient disposition
The number (%) of treated patients included in the FAS will be presented. The number (%) of 
screened and not-treated patients and the reasons for screening failure will also be displayed. 
The following summaries will be provided (with % based on the total number of FAS patients):

Number (%) of patients who are still on-treatment; 

Number (%) of patients who completed the 26 weeks treatment phase;

Number (%) of patients who discontinued earlier than 26 weeks ;

Primary reason for the 26 weeks treatment phase discontinuation;

Number (%) of patients who have entered the 52 weeks treatment phase;

Number (%) of patients who completed the 52 weeks treatment phase;

Number (%) of patients who discontinued between 26 and 52 weeks;

Primary reason for the 52 weeks treatment phase discontinuation;

Number (%) of patients who have entered the extension treatment phase;

Number (%) of patients who are still on extension treatment phase; 

Number (%) of patients who have completed the study

Number (%) of patients who have discontinued the study

Primary reason for discontinuation of the study
2.3.6
Protocol deviations
The number (%) of patients in the FAS with any protocol deviation will be tabulated by 
deviation category (as specified in the study Data Handling Plan) overall for the FAS. All 
protocol deviations will be listed.
In addition to the pre-defined standard PD terms, Novartis has also defined new protocol 
deviations and the corresponding relationship to the COVID-19 pandemic. The protocol
deviations related to the COVID-19 pandemic will be summarized.


Novartis
Confidential
Page 16
SAP
CETB115E2202
2.3.7
Analysis sets
The number (%) of patients in each analysis set (defined in Section 2.3) will be summarized.
2.4
Treatments (study treatment, rescue medication, concomitant 
therapies, compliance)
2.4.1
Study treatment / compliance
Duration of exposure, actual cumulative dose, dose intensity (DI) and relative dose intensity
(RDI) will be summarized. Duration of exposure will be calculated by two methods, the first 
one is actual duration of exposure which is exclusive of interruption of eltrombopag. The second 
one is duration of exposure which is inclusive of interruption due to good response. Duration 
of exposure will be categorized into time intervals; frequency counts and percentages will be 
presented for the number(%) of subjects in each interval. The number (%) of subjects who have 
dose reductions or interruptions, and the reasons, will be summarized. 
Subject level listings of all doses administered on treatment along with dose change reasons 
will be produced.  
The safety set will be used for all summaries and listings of study treatment. 
Duration of exposure to study treatment
Duration of exposure to study treatment is considered by taking into account the duration of 
exposure to the investigational drug:
Duration of exposure to study treatment (days) = (last date of exposure to study treatment) –
(date of first administration of study treatment) + 1.
The last date of exposure to study treatment is the latest of the last dates of exposure to 
investigational drug. For those patients still on treatment at cutoff date, the cutoff date will be 
imputed as the last date of exposure to study treatment.
Summary of duration of exposure of study treatment will include categorical summaries (i.e. <
13 weeks, 13 weeks to 26 weeks, > 26 weeks to 52 weeks, > 52 weeks) and continuous 
summaries (i.e. mean, standard deviation etc.).
Cumulative dose
Cumulative dose is defined as the total dose given during the study treatment exposure.
The planned cumulative dose for a study treatment component refers to the total planned dose 
as per the protocol up to the last date of investigational drug administration. The planned dose 
in this study equals to prescribed dose in Study Treatment eCRF.
The actual cumulative dose refers to the total actual dose administered, over the duration for 
which the subject is on the study treatment as documented in Study Treatment eCRF.
For patients who did not take any drug the cumulative dose is by definition equal to zero.


Novartis
Confidential
Page 17
SAP
CETB115E2202
Dose intensity and relative dose intensity
Dose intensity (DI) for patients with non-zero duration of exposure is defined as follows: 
DI (mg/day) = Actual Cumulative dose (mg) / Duration of exposure (day)
For patients who did not take any drug the DI is by definition equal to zero. 
Planned dose intensity (PDI) is defined as follows:
PDI (mg/day) = Planned Cumulative dose (mg) / Duration of exposure (day).
Relative dose intensity (RDI) is defined as follows:
RDI = DI (mg/day)  / PDI (mg/day).  
DI and RDI will be summarized by descriptive statistics (N, mean, median, standard 
deviation, minimum and maximum) for the study treatment. DI, RDI and cumulative dose will 
be listed together with the appropriate patient characteristics. RDI will be categorized as 
follows: <=75%, >75 - 90%, >90 – 110%, >110%.
Dose changes and interruptions 
The number of subjects who have dose changes, interruptions, and the reasons will be 
summarized. 
‘Dose changed’ and ‘Dose interrupted’ fields from the Study Treatment CRF pages will be used 
to determine the dose changed and dose interruptions.
The corresponding fields ‘Reason for dose changed/dose interrupted’ will be used to summarize 
the reasons.
A dose change is either ‘change in prescribed dose level’ or ‘dosing error’ where actual dose 
administered is different from the prescribed dose.
For the purpose of summarizing interruptions and reasons, in case multiple entries for 
interruption that are entered on consecutive days with different reasons will be counted as 
separate interruptions. However, if the reason is the same in this mentioned multiple entries on 
consecutive days, then it will be counted as one interruption. 
2.4.2
Prior, concomitant and post therapies
Concomitant therapies will be coded using the WHO Drug Reference List dictionary that 
employs the WHO Anatomical Therapeutic Chemical (ATC) classification system and 
summarized by lowest ATC class and preferred term using frequency counts and percentages. 
These summaries will include therapies starting on or after the start of study treatment but no 
later than 30 days after last dose of study treatment or therapies starting prior to the start of 
study treatment and continuing after the start of study treatment. 
Concomitant medications that have the potential to impact efficacy results (e.g. CsA, anabolic 
steroids and G-CSF) will be identified prior to database lock. Separate summaries of these 
concomitant medications will be produced using the FAS. 


Novartis
Confidential
Page 18
SAP
CETB115E2202
All therapies will be listed. Any therapy starting and ending prior to the start of study treatment 
or starting more than 30 days after the last date of study treatment will be flagged in the listing 
as prior or post therapies respectively. Those starting or continuing on or after the start date of 
study treatment and up to 30 days after the last date of study treatment will be flagged as 
concomitant therapies in the listing. The safety set will be used for all therapies tables.
The analysis for prior medication will not be reproduced at updated analysis and final analysis.
2.5
Analysis of the primary objective
The primary objective of the study is to assess the efficacy of eltrombopag treatment at 6 months 
in Chinese subjects with a previous diagnosis of severe aplastic anemia and who had insufficient 
response following at least one treatment course in the period time of > 6 months  of 
immunosuppression with a regimen containing anti-thymocyte globulin (ATG), anti-
lymphocyte globulin (ALG), and/or cyclophosphamide, or alemtuzumab, and who are ineligible 
for HSCT or a suitable donor is not available.
2.5.1
Primary endpoint
The primary endpoint is the hematologic response rate at Week 26, which is defined as the 
proportion of all subjects who meet any of the International Working Group (IWG) criteria at 
Week 26 shown in the table below. The primary endpoint will be based on the investigator 
assessment of response.
The analysis for primary endpoint as well as related supplementary and supportive analysis will 
not be reproduced for final CSR.
The primary analysis will be based on FAS and will include all data observed up-to the cut-off 
date.
Table 2-2
IWG criteria for Primary Endpoint
Assessment 
Item
Baseline transfusion
status
Response Criteria
Platelet count
Platelet transfusion 
independent
Transfusion independent(1) and increase from 
baseline by 20×109/L or more
Platelet transfusion 
dependent
No platelet transfusion requirement for 8 weeks
Hemoglobin
RBC transfusion 
independent
When the baseline hemoglobin level is < 90 
g/L: transfusion independent and increase from 
baseline by 15 g/L or more
RBC transfusion dependent
A decrease of at least 4 units in RBC 
transfusions in the post-treatment 8-week 
period (1 unit = RBC derived from 200 mL 
blood)
Or no RBC transfusion requirement for 8 weeks 
(less than 4 units RBC in 8-week period at 
Baseline)


Novartis
Confidential
Page 19
SAP
CETB115E2202
Assessment 
Item
Baseline transfusion
status
Response Criteria
Neutrophil count
NA
(In the absence of G-CSF taken within 21 days 
preceding the blood sample collection) Increase 
from baseline by 0.5×109/L or more, or (if < 
0.5×109/L at baseline) increase by 100% or 
more
Note: No platelet/RBC transfusion requirement for 8 weeks means there is no any platelet/RBC transfusion 
received by patients during (Visit date-56 days) until Visit date. This definition also applies to Week 13 and 
Week 52. 
(1) Transfusion indepedent means subjects did not receive platelet transfusion in the 4 weeks before Visit date.
During regular hematologic assessment, the exclusion period of transfusion and G-CSF 
are detailed below:
Platelet transfusion: 7 days preceding the assessment of platelet count
RBC transfusion: 14 days preceding the assessment of hemoglobin
G-CSF: 21 days preceding the assessment of neutrophil count
Definition of baseline Platelet Transfusion Independence/Dependence and platelet count
Baseline platelet transfusion independence/dependence and platelet count are defined as:

For platelet transfusion independent subjects that did not receive platelet transfusions 
in the 4 weeks before Day 1(include Day 1): The average of the most recent 2 platelet 
counts before Day 1(include Day 1).

For transfusion dependent subjects that received one or more platelet transfusions in 
the 4 weeks before Day 1(include Day 1): The average of the most recent 2 platelet 
counts before Day 1 (excluding platelet counts within 6 days * following a platelet 
transfusion). If all platelet counts available are within 6 days* following a platelet 
transfusion, the lowest platelet count prior to initiation of study drug will be used as 
the baseline platelet count.
*: e.g. When a platelet transfusion was done on December 2nd (Monday), the platelet count 
will become usable from December 9th (Monday).
Definition of baseline RBC Transfusion Independence/Dependence and hemoglobin value
Baseline RBC transfusion independence/dependence and hemoglobin value are defined as:

For RBC transfusion independent subjects that did not receive RBC transfusions in the 
8 weeks before Day 1(include Day 1): The most recent hemoglobin value before Day
1(include Day 1).

For RBC transfusion dependent subjects that received one or more RBC transfusions 
in the 8 weeks before Day 1(include Day 1): The last hemoglobin value prior to the 
most recent RBC transfusion. If no values exist prior to a RBC transfusion, the lowest 
value before Day 1(include Day 1) will be used.
2.5.2
Statistical hypothesis, model, and method of analysis
The proportion of the hematological response will be summarized using point estimates and 90% 
exact (Clopper-Pearson) confidence intervals.


Novartis
Confidential
Page 20
SAP
CETB115E2202
2.5.3
Handling of missing values/censoring/discontinuations
All withdrawals will be included in analyses up to the time of withdrawal. The subjects who 
discontinued from the trial before Week 26 will be treated as non-responders in the primary 
analysis.
2.5.4
Supplementary analyses
The hematologic response will also be derived programmatically using laboratory results and 
transfusion records instead of the hematologic response reported by the investigators in the 
response assessment CRF. The derived response at week 26 will be summarized and listed.
2.5.5
Supportive analyses
Subjects can respond according to one or more of three criteria: platelets (platelet counts and/or 
platelet transfusions), red cells (hemoglobin level and/or RBC transfusions), neutrophils (ANC 
counts). This results in 7 possible response combinations:

Platelets

Red Cells

Neutrophils

Platelets/Red Cells

Platelets/Neutrophils

Red Cells/Neutrophils

Platelets/Red Cells/Neutrophils
The number and percentage will be made of the number of subjects who respond according to 
each combination of criteria at the Week 26 visit.
The number and percentage of assessment item for the detailed hematological response criteria 
will be presented as follows. In this summary, subjects could be counted as a response according 
to more than one criteria.

Platelet Counts in platelet transfusion independent subjects

Platelet Transfusion in platelet transfusin dependent subjects

Hemoglobin Level in RBC transfusion independent subjects with baseline hemoglobin 
level < 90 g/L

RBC Transfusion in RBC transfusion dependent subjects

ANC counts
The primary efficacy endpoint will be summarized by the above subgroups listed in section 
2.2.1 for efficacy. The proportion of the hematological response in each subgroup will be 
summarized using point estimates and 90% exact (Clopper-Pearson) confidence intervals if 
applicable.
In addition, hematological responses will be listed.


Novartis
Confidential
Page 21
SAP
CETB115E2202
The analysis for primary efficacy endpoint will not be reproduced at updated analysis and final 
analysis.
2.6
Analysis of the key secondary objective
Not applicable
2.7
Analysis of secondary efficacy objective(s)
The secondary efficacy objectives are to:

To evaluate the efficacy of eltrombopag treatment at week 13 and week 52

To evaluate the effect of eltrombopag on individual hematologic response (changes in 
neutrophil, platelet, hemoglobin)

To evaluate the time to hematologic response and duration

To evaluate the frequency and volume of transfusion (platelet and RBC)
2.7.1
Secondary endpoints
The following analyses Changes in platelet count, hemoglobin and neutrophil 
count, Duration of hematological response, Maximum duration of Platelet and 
RBC transfusion independence will be generated for the final CSR. 
Hematological Response at Week 13 and Week 52
Hematologic response rate at Week 13 and Week 52 will also be assessed by investigator 
according to the International Working Group (IWG) criteria for the primary endpoints shown 
in the Table 2-2 above. 
The analysis for hematologic response rate at Week 13 will only be produced at primary 
analysis, and hematologic response rate at week 52 will only be produced at updated analysis.
Changes in platelet count, hemoglobin and neutrophil count
Value and changes in platelet count (in the absence of platelet transfusion), hemoglobin (in the 
absence of RBC transfusion) and neutrophil count (in the absence of G-CSF) will be calculated 
according to the lab test results entered into CRF.
Time to hematological response
Time to hematological response is defined as the time from the date of first study drug 
administration to the first hematological response which is defined in Section 2.5.1. All subjects 
in the FAS will be included in the time to hematological response calculations. 
These will be analyzed and plotted for four assessment criteria: Hematological Response; 
Platelet/Platelet Transfusion; Hemoglobin/RBC Transfusion; Neutrophils.
The analysis for time to hematological response will only be produced at primary analysis.


Novartis
Confidential
Page 22
SAP
CETB115E2202
Duration of hematological response
For subjects who responded, duration of hematological response will be defined as the number 
of months from the first date of a hematological response which is defined in Section 2.5.1 until 
the first date of a relapse (defined as not meeting the response criteria) or a death. Only subjects 
with at least 2 response assessments are included in the duration of response assessment. Patient 
still responding at the cut-off date will be censored at date of last response assessment. 
These will be analyzed and plotted for four assessment criteria: Hematological Response; 
Platelet/Platelet Transfusion; Hemoglobin/RBC Transfusion; Neutrophils.
Frequency and amount of transfusion
For subjects receiving platelet transfusion at baseline, the frequency and the amount of platelets 
transfusion in each period (Baseline: 4 weeks before Day 1; Week 13, 26, 52: 4 weeks before 
each visit day) will be summarized. The same analysis applies to RBC transfusion(period will 
be extended to 8 weeks). The amount of transfusion will be defined as the sum of transfusion 
multiplied by the volume of transfusion.
The analysis for frequency and amount of transfusion will not be reproduced for final CSR.
Proportion of subjects with transfusion decrease
Subjects with platelet transfusion decrease is defined as subjects with transfusion decrease or 
transfusion free in each period (Week 13, 26, 52: 4 weeks before each visit day) compared to
baseline (Baseline: 4 weeks before Day 1). 50% platelet transfusion reduction is defined as 
subjects with transfusion decrease of amount (units) at least 50% compared to baseline. The 
same analysis applies to RBC transfusion (period will be extended to 8 weeks). This analysis 
will be performed for the subgroup of subjects with baseline transfusion dependent.
The analysis for proportion of subjects with transfusion decrease will not be reproduced for 
final CSR.
Maximum duration of Platelet and RBC transfusion independence
Transfusion independence duration will be defined as the period from the next day of 
transfusion to the day before the next transfusion. Maximum duration of platelet and RBC 
transfusion independence for each subject will be picked for analysis. 
Post-baseline transfusion independence will be achieved if subjects who are transfusion 
dependent at baseline become transfusion free for a period of at least 28 (platelets) or 56 days 
(RBCs). The time period for assessment of transfusion independence will be at any time during 
the treatment period. Baseline platelet and RBC transfusion dependence is defined as subjects 
receiving at least one platelet or RBC transfusion in the 4 weeks and 8 weeks, respectively, 
prior to the first dose of eltrombopag.


Novartis
Confidential
Page 23
SAP
CETB115E2202
2.7.2
Statistical hypothesis, model, and method of analysis
Hematological Response at Week 13 and Week 52
The number and percentage of subjects who meet the hematological response criteria (at Week 
13 and Week 52 respectively) will be presented and exact 90% confidence interval will be 
reported. And the number and percentage of assessment item for the hematological response 
criteria and for the detailed hematological response criteria will be presented.
The derived response by programming at week 13 and Week 52 will also be summarized as 
above.
Changes in platelet count, hemoglobin and neutrophil count
Values and changes in platelet count (in the absence of platelet transfusion), hemoglobin (in the 
absence of RBC transfusion) and neutrophil count (in the absence of G-CSF) will be 
summarized at each visit. Descriptive statistics including mean, SD, median, 25th and 75th
percentiles, minimum, and maximum will be summarized for the changes.
Median and interquartile range will be plotted.
Time to hematological response
The distribution function of time to hematologic response will be estimated using the Kaplan-
Meier method and will be plotted. The median time to hematologic response along with 90% 
CIs will be presented. If a subject does not meet hematological response before or at the cutoff 
date, censoring will be performed using the date of the last assessment.
Duration of hematological response
The distribution function of duration of hematologic response will be estimated using the 
Kaplan-Meier method and will be plotted. If the number of relapses or deaths allows, the median 
time to hematologic response along with 90% CIs will be presented.
Relapse-free probability will be estimated using the Kaplan-Meier method at 3 months, 6 
months, 9 monthes, one year, and yearly after as well. 
Frequency and amount of transfusion
The frequency and the amount of platelets transfusion in each period (Baseline: 4 weeks before 
Day 1; Week 13, 26, 52: 4 weeks before each visit day) will be summarized by descriptive 
statistics including mean, SD, median, 25th and 75th percentiles, minimum, and maximum.
Proportion of subjects with transfusion decrease
The number and percentage of subjects with platelet or RBC transfusion decrease or 
transfusion-free in each period will be presented. 
In addition, the number and percentage of subjects with 50% platelet or RBC transfusion 
reduction in each period will be presented.


Novartis
Confidential
Page 24
SAP
CETB115E2202
Maximum duration of Platelet and RBC transfusion independence
Maximum duration of platelet and RBC transfusion independence will be summarized by 
descriptive statistics including mean, SD, median, 25th and 75th percentiles, minimum, and 
maximum separately. 
The summary of shift baseline for platelet transfusion independence and RBC transfusion 
independence will be presented.
2.7.3
Handling of missing values/censoring/discontinuations
Hematological Response at Week 13 and Week 52
For the analysis of hematological response at Week 52, patients who are still ongoing but 
have not reached the considered timepoint yet will not be included in the analysis of response 
at that timepoint. However, patients with a missing or ‘Non-evaluable’ response for other 
reasons will be treated as non-responders at that timepoint in the calculation of the
hematological response rate.
Time to hematological response
For time to hematological response, if a subject does not meet hematological response before 
or at the cutoff date, censoring will be performed using the date of the last assessment.
Duration of hematological response
For duration of hematological response, patient still responding at the cut-off date will be 
censored at date of last response assessment.
2.8
Safety analyses
All safety analyses will be based on the safety set. 
The safety summary tables will include on-treatment assessments collected no later than 30 
days after last dose of study treatment (see definition in Section 2.1.1).
All safety assessments will be listed by patient and flagged appropriately.
All safety assessments will be generated for the final CSR except for subgroup of interest.
2.8.1
Adverse events (AEs)
Coding and grading
Adverse events will be coded using the Medical dictionary for regulatory activities (MedDRA) 
Terminology and their severity assessed according to the Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.03.
General rules for AE Reporting
AE summaries will include all AEs occurring during on treatment period. All AEs collected in 
the AE (e)CRF page will be listed along with the information collected on those AEs e.g. AE 


Novartis
Confidential
Page 25
SAP
CETB115E2202
relationship to study drug, AE outcome etc. AEs with start date outside of on-treatment period 
will be flagged in the listings. 
AEs will be summarized by number and percentage of subjects having at least one AE, having 
at least one AE in each primary system organ class (SOC) and for each preferred term (PT)
using MedDRA coding. A subject with multiple occurrences of an AE will be counted only 
once in the respective AE category. A subject with multiple CTCAE grades for the same 
preferred term will be summarized under the maximum CTCAE grade recorded for the event.
AE with missing CTCAE grade will be included in the ‘All grades’ column of the summary 
tables.
In AE summaries, the primary system organ class will be presented alphabetically and the 
preferred terms will be sorted within primary SOC in descending frequency. The sort order for 
the preferred term will be based on their frequency.
The following adverse event summaries will be produced for AEs occurring during the on-
treatment period; overview of adverse events and deaths, AEs by SOC and PT, summarized by 
maximum CTCAE grade, summarized by relationship (all AEs and AEs related to study 
treatment), seriousness (SAEs and non-SAEs), leading to treatment discontinuation, leading to 
dose interruption/changes, requiring additional therapy and leading to fatal outcome. 
Furthermore, AE occurring during the on-treatment period will be summarized by subgroup 
defined by age group (<65 years and ≥ 65 years), gender (male and female) and concomitant 
use of CsA and anabolic steroids at baseline (Yes and No) (see Section 2.2.1). These summaries 
include: AEs by SOC and PT, AEs with suspected relationship to study drug by SOC and PT 
and SAEs by SOC and PT. These subgroup analysis will not be reproduced for final CSR.
In addition, on treatment adverse events will be summarized by SOC and PT and by periods
(by <=30 days, >30 to <=90 days, >90 to <=180 days, >180 to <=270 days, >270 to <=360 days, 
and > 360 days). Time of onset of first episode will be used when experiencing the same episode 
in a subject.
2.8.1.1
Adverse events of special interest / grouping of AEs
An adverse event of special interest is a grouping of adverse events that are of scientific and 
medical concern specific to compound eltrombopag. These groupings are defined using 
MedDRA terms, SMQs (standardized MedDRA queries), HGLTs (high level group terms), 
HLT (high level terms) and PTs (preferred terms). Customized SMQs (Novartis MedDRA 
queries, NMQ) may also be used. A NMQ is a customized group of search terms which defines 
a medical concept for which there is no official SMQ available or the available SMQ does not 
completely fit the need. It may include a combination of single terms and/or an existing SMQ, 
narrow or broad.
At the project level, a sas dataset named eCRS contains the exact composition of the adverse 
events groupings will be used to map reported adverse events to the notable adverse events 
groupings. This dataset may be updated (i.e., it is a living document) based on review of 
accumulating trial data, and it is the most up to date version at the time of DB lock that will be 
used. Note that certain adverse events may be reported within multiple groupings.


Novartis
Confidential
Page 26
SAP
CETB115E2202
For each specified AESI, number and percentage of patients with at least one event of the AESI 
occurring during on treatment period will be summarized. Summaries of these AESIs will be 
provided by subgroup (see Section 2.2.1). A listing of all grouping levels down to the MedDRA 
preferred terms used to define each AESI will be generated.
2.8.2
Deaths
The number and percentage of deaths occurring during the on-treatment period and at any time 
during the study will be provided. Deaths occurring during the on-treatment period will be 
further summarized by system organ class and preferred term. All deaths will be listed and 
flagged appropriately.
2.8.3
Laboratory data
On analyzing laboratory data, data from all sources (central and local laboratories) will be 
combined. The summaries will include all assessments available for the lab parameter collected 
no later then 30 days after the last treatment administration date (see Section 2.1.1).
Hematology and clinical chemistry laboratory parameters 
The following summaries will be produced for hematology and clinical chemistry laboratory 
data (by laboratory parameter):

Worst post-baseline CTC grade (regardless of the baseline status). Each subject will be 
counted only for the worst grade observed post-baseline.

Shift tables using CTC grades to compare baseline to the worst on-treatment value

For laboratory tests where CTC grades are not defined, shift tables using the 
low/normal/high/(low and high) classification to compare baseline to the worst on-
treatment value.

Trends of lab parameter values over time (baseline and selected on-treatment 
timepoints) should be displayed via boxplots based on time windows and 
corresponding tables displaying the statistics used for the box plots by the selected 
time points and the selected lab parameters.
The following listings will be produced for the laboratory data:

Listings of all laboratory data, with CTC grades and classification relative to the 
laboratory normal range. Lab data collected during the post-treatment period will be 
flagged.  

Listing of all CTC grade 3 or 4 laboratory toxicities
Coagulation
Coagulation assays data (Prothrombin time/international normal ratio, Activated partial 
thromboplastin time) will be listed.


Novartis
Confidential
Page 27
SAP
CETB115E2202
Liver function parameters 
Liver function parameters of interest are total bilirubin (TBL), ALT, AST and alkaline 
phosphatase (ALP). The number (%) of patients with worst post-baseline values as per Novartis 
Liver Toxicity guidelines will be summarized. 
For summaries based on multiple parameters, the results must be obtained from samples 
collected within maximum 30 days of each other.
The following summaries will be produced:

ALT or AST > 3xULN and TBL > 2xULN and (ALP < 2xULN or missing)

ALT or AST > 3xULN and TBL > 2xULN

ALT or AST > 3xULN and TBL > 1.5xULN

ALT or AST > 20xULN

ALT or AST > 10xULN

ALT or AST > 5xULN

ALT or AST > 3xULN

ALT > 20xULN

ALT > 10xULN

ALT > 5xULN

ALT > 3xULN

AST > 20xULN

AST > 10xULN

AST > 5xULN

AST > 3xULN

TBL > 2xULN

TBL > 1.5xULN

ALP > 1.5xULN
2.8.4
Other safety data
2.8.4.1
ECG
A standard 12 lead ECG will be performed:

at screening or baseline (Triplicate ECG to be collected to assess QTcF invervals)

at Week 26 and Week 52

at the end of treatment


Novartis
Confidential
Page 28
SAP
CETB115E2202
Data handling
In case the study requires ECG replicates at any assessment, the average of the ECG parameters 
at that assessment should be used in the analyses.
Data analysis
The following summaries will be produced for ECG results:

Shift tables using ECG findings to compare baseline to the Week 26, Week 52 and to 
the worst post-baseline results.

Descriptive statistics including mean, SD, median, 25th and 75th percentiles, 
minimum, and maximum will be summarized for ECG values at each visit. 

The number and percentage of subjects with notable ECG values below at each visit
will be presented. 

QT, QTcF, or QTcB
-
New value of > 450 and ≤ 480 ms
-
New value of > 480 and ≤ 500 ms
-
New value of > 500 ms
-
Increase from Baseline of > 30 ms to ≤  60ms
-
Increase from Baseline of > 60 ms

HR
-
Increase from baseline >25% and to a value > 100 bpm
-
Decrease from baseline >25% and to a value < 50 bpm

PR
-
Increase from baseline >25% and  to a value > 200 ms
-
New value of > 200 ms

QRS
-
Increase from baseline >25% and  to a value > 120 ms 
-
New values of QRS > 120 ms
A listing of all ECG assessments will be produced by treatment arm and notable values will be 
flagged. In the listing, the assessments collected during the post-treatment period will be flagged.
2.8.4.2
Vital signs
Vital sign assessments are performed in order to characterize basic body function. The 
following parameters were collected: height (cm), weight (kg), body temperature (°C), pulse 
rate, systolic and diastolic blood pressure (mmHg).
Data handling
Vital signs collected on treatment will be summarized. Values measured outside of on treatment 
period will be flagged in the listings.


Novartis
Confidential
Page 29
SAP
CETB115E2202
Data analysis
For analysis of vital signs the clinically notable vital sign criteria are provided in Table 2-10
below.
Table 2-3
Clinically notable changes in vital signs
Vital sign 
(unit)
Clinically notable criteria
above normal value 
below normal value
Weight (kg)
increase > 10% from Baseline
decrease  > 10% from Baseline
Systolic blood 
pressure 
(mmHg)
>=180 with increase from baseline 
of >=20
<=90 with decrease from baseline 
of >=20
Diastolic blood 
pressure 
(mmHg)
>=105 with increase from baseline 
of >=15
<=50 with decrease from baseline 
of >=15
Pulse rate 
(bpm)
>=100 with increase from baseline 
of >25%
<=50 with decrease from baseline of 
> 25%
Body 
temperature
>= 39.1
-
The number and percentage of subjects with notable vital sign values (high/low) will be 
presented.       
In addition, values and change from baseline of vital signs will be summarized at each visit by 
descriptive statistics including mean, SD, median, 25th and 75th percentiles, minimum, and 
maximum.
A listing of all vital sign assessments will be produced and notable values will be flagged. In 
the listing, the assessments collected outside of on-treatment period will be flagged. 
2.8.4.3
Bone Marrow Examination
Following bone marrow examination data will be listed.

Bone marrow aspiration 

Bone marrow biopsy

Chromosomal test (Karyotype)

Peripheral blood smear test
2.9
Pharmacokinetic endpoints
PAS will be used in all pharmacokinetic data analyses and PK summary statistics. In the case 
of samples taken are not within the time windows around the scheduled time points. These 
samples will exclude from the descriptive statistic which are summarized by time point, but 
will include in the non-compartmental analysis. 
PK summary analyses will not reproduced for final CSR.


Novartis
Confidential
Page 30
SAP
CETB115E2202
PK parameters for subjects with extensive PK samples
The PK parameters that will be determined are shown in Table 2-4. PK parameters of 
eltrombopag, including but not limited to those listed in Table 2-4, will be calculated from the 
individual concentration-time profile obtained following the administration of the study 
treatment and listed by subject.
Table 2-4
Non-compartmental PK parameters 
AUClast
The AUC from time zero to the last measurable concentration sampling time (tlast) 
(mass*time*volume-1)
AUCtau
The AUC calculated to the end of a dosing interval (tau) at steady-state (amount*time*volume-1)
Cmax
The maximum (peak) observed plasma drug concentration after single dose administration 
(mass*volume-1)
Tmax
The time to reach maximum (peak) plasma drug concentration after single dose administration 
(time)
Ctrough
Pre-dose concentration at the end of dose interval (mass*volume-1)
CLss/F
Apparent systemic (or total body) clearance at steady state from plasma (volume/time)
Descriptive statistics (n, arithmetic mean, CV% mean, standard deviation (SD), median, 
geometric mean, CV% geo-mean, minimum and maximum) will be presented for PK analysis 
set for all PK parameters defined above except Tmax, where only n, median, minimum and 
maximum will be presented. 
PK concentrations 
Descriptive statistics including mean (arithmetic and geometric), SD, CV (arithmetic and 
geometric), median, minimum and maximum for PK concentration will be presented by dose, 
visit/sampling time point, including the frequency (n, %) of concentrations below the LLOQ 
and reported as zero. 
The geometric mean and arithmetic mean (SD) concentration-time profiles will also be 
graphically presented. In addition, individual concentration-time profiles will be displayed 
graphically. 
In addition, PK concentrations of eltrombopag for subjects with sparse PK samples will be 
summarized by dose, visit and scheduled time point.
All individual plasma eltrombopag concentration data will be listed by dose, visit and scheduled 
time point.
Handling of PK data below LLOQ or missing
All concentration values below the lower limit of quantitation (LLOQ) are set to zero by the 
Bioanalyst, and will be displayed in the listings as zero and flagged. LLOQ values will be 
treated as zero in any calculations of summary statistics, and treated as missing for the 
calculation of the geometric means and their CV%. The number of non-zero concentrations will 
also be reported in the summary statistics.
Missing values for any PK data will not be imputed and will be treated as missing.


Novartis
Confidential
Page 31
SAP
CETB115E2202
2.11
Patient-reported outcomes
There will be no patient-reported outcome analysis planned in this study.
2.12
Cytogenetic abnormalities and clonal evolution
Clonal cytogenetic evolution will be evaluated during the study, and the rate of the subjects 
who developed any clonal evolution including clonal evolution to PNH, evolution to AML or 
MDS etc. will be calculated. 
2.14
Interim analysis
There will be no formal interim analysis planned in this study.
3
Sample size calculation
As this is a bridging study to support China registration, an estimation strategy rather than 
formal hypothesis testing will be pursued. Approximately 20 subjects will be enrolled into the 
study based on the feasibility rather than statistical considerations. This number of subjects is 
considered appropriate to assess the efficacy and safety of eltrombopag in Chinese patients.
3.1
Primary analysis
The hematologic response rate at Week 24 in the pivotal study of NIH-09-H-0154 was 40%. 
Assuming a same response rate (40%) in Chinese subjects, the 90% confidence interval of the 
hematological response rate with a total of 20 subjects will be (21.7%, 60.6%).
Below table shows the 90% CIs for various observed response rate. The maximum half-width 
of the 90% CIs is 19.8%.
Table 3-1
90% CIs for various observed response rate
Sample size
# of responders
Hematologic 
response rate (%)
90% CI (%)
20
4
20
(7.1, 40.1)
20
6
30
(14.0, 50.8)
20
8
40
(21.7, 60.6)


Novartis
Confidential
Page 32
SAP
CETB115E2202
Sample size
# of responders
Hematologic 
response rate (%)
90% CI (%)
20
10
50
(30.2, 69.8)
The 12 evaluable subjects for intensive PK sampling was chosen based on feasibility and 
practical considerationzs to assist in characterizing the PK of eltrombopag in Chinese subjects.
4
Change to protocol specified analyses
No change from protocol specified analysis was made.
5
Appendix
5.1
Imputation rules
5.1.1
Study drug
The following rule should be used for the imputation of the dose end date for a given study 
treatment component:
Scenario 1: If the dose end date is completely missing and there is no EOT page and no death
date, the patient is considered as on-going:
The patient should be treated as on-going and the cut-off date should be used as the dose end
date. 
Scenario 2: If the dose end date is completely or partially missing and the EOT page is 
available:
Case 1: The dose end date is completely missing, and the EOT completion date is complete, 
then this latter date should be used.  
Case 2: Only Year(yyyy) of the dose end date is available and yyyy < the year of EOT date:  
Use Dec31yyyy
Case 3: Only Year(yyyy) of the dose end date is available and yyyy  = the year of EOT date:
Use EOT date
Case 4: Both Year(yyyy) and Month (mm) are available for dose end date, and yyyy  = the 
year of EOT date and mm < the month of  EOT date: 
Use last day of the Month (mm)
All other cases should be considered as a data issue.
After imputation, compare the imputed date with start date of treatment, if the imputed date is 
< start date of treatment: Use the treatment start date
Patients with missing start dates are to be considered missing for all study treatment component 
related calculations and no imputation will be made. If start date is missing then end-date should 
not be imputed.


Novartis
Confidential
Page 33
SAP
CETB115E2202
5.1.2
AE, ConMeds and safety assessment date imputation
Table 5-1
Imputation of start dates (AE, CM) and assessments (LB, EG, VS)
Missing 
Element
Rule
day, month, 
and year

No imputation will be done for completely missing dates
day, month

If available year = year of study treatment start date then 
o
If stop date contains a full date and stop date is earlier than 
study treatment start date then set start date = 01JanYYYY
o
Else set start date = study treatment start date. 

If available year > year of study treatment start date then 01JanYYYY

If available year < year of study treatment start date then 01JulYYYY
day

If available month and year = month and year of study treatment start 
date then 
o
If stop date contains a full date and stop date is earlier than 
study treatment start date then set start date= 01MONYYYY. 
o
Else set start date = study treatment start date.

If available month and year > month and year of study treatment start 
date then 01MONYYYY  

If available month and year < month year of study treatment start date 
then 15MONYYYY  


Novartis
Confidential
Page 34
SAP
CETB115E2202
Table 5-2
Imputation of end dates (AE, CM) 
Missing 
Element
Rule
(*=last treatment date plus 30 days not > (death date, cut-off date, 
withdrawl of consent date))
day, month, 
and year

Completely missing end dates (incl. ongoing events) will be imputed 
by the end date of the on-treatment period* 
day, month

If partial end date contains year only, set end date = earliest of 
31DecYYYY or end date of the on-treatment period * 
day

If partial end date contains month and year, set end date = earliest of 
last day of the month or end date of the on-treatment period*
Any AEs and ConMeds with partial/missing dates will be displayed as such in the data listings.
Any AEs and ConMeds which are continuing as per data cut-off will be shown as ‘ongoing’ 
rather than the end date provided. 
The above imputations are only used for analyses of time to and duration of AEs and 
concomitant medications.
5.1.2.1
Other imputations
Incomplete date of initial diagnosis of SAA and  date of most recent recurrence 
Missing day is defaulted to the 15th of the month and missing month and day is defaulted to 01-
Jan. 
5.2
AEs coding/grading
Adverse events are coded using the Medical dictionary for regulatory activities (MedDRA) 
terminology.
AEs will be assessed according to the Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.03. 
The CTCAE represents a comprehensive grading system for reporting the acute and late effects 
of cancer treatments. CTCAE grading is by definition a 5-point scale generally corresponding 
to mild, moderate, severe, life threatening, and death. This grading system inherently places a 
value on the importance of an event, although there is not necessarily proportionality among 
grades (a grade 2 is not necessarily twice as bad as a grade 1). 
5.3
Laboratory parameters derivations
Grade categorization of lab values will be assigned programmatically as per NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.03 (specify version used in the 
RAP). The calculation of CTCAE grades will be based on the observed laboratory values only, 
clinical assessments will not be taken into account. The criteria to assign CTCAE grades are 
given in Novartis internal criteria for CTCAE grading of laboratory parameters. The latest 
available version of the document based on the underlying CTCAE version 4.03 at the time of 
analysis will be used. 


Novartis
Confidential
Page 35
SAP
CETB115E2202
For laboratory tests where grades are not defined by CTCAE v4.03, results will be graded by 
the low/normal/high (or other project-specific ranges, if more suitable) classifications based on 
laboratory normal ranges.
A severity grade of 0 will be assigned for all non-missing lab values not graded as 1 or higher. 
Grade 5 will not be used. For laboratory tests that are graded for both low and high values, 
summaries will be done separately and labelled by direction, e.g., sodium will be summarized 
as hyponatremia and hypernatremia.
For Reticulocyte absolute count which are missing, the following rules will be applied to derive 
them:
Reticulocyte (absolute count in 10E9/L) = Reticulocyte count % * RBC count in SI unit 
(10E12/L) * 10.
Imputation Rules  
CTC grading for blood differentials is based on absolute values. However,  this data may not 
be reported as absolute counts but rather as percentage of WBC. 
If laboratory values are provided as ‘<X’ (i.e. below limit of detection) or ‘>X’, prior to 
conversion of laboratory values to SI unit, these numeric values are set to X. 
The following rules will be applied to derive the WBC differential counts when only 
percentages are available for a xxx differential
xxx count = (WBC count) * (xxx %value / 100)
CTCAE grades for the derived absolute WBC differential counts will be assigned as described 
earlier.
5.4
Statistical models
5.4.1
Primary analysis
Responses will be summarized in terms of percentage rates with 90% CIs. An exact binomial 
confidence interval (implemented using SAS procedure FREQ with EXACT statement for one-
way tables) will be calculated (Clopper and Pearson, 1934).
SAS procedure FREQ will be used to estimate the proportion of responders, along with the 
associated 90% (=100 × (1 – two-sided alpha level)) two-sided Pearson-Clopper CI.
5.4.2
Key secondary analysis
Kaplan-Meier estimates
For time to event endpoints (time to response, duration of response etc..), an estimate of the
survival function will be constructed using Kaplan-Meier (product-limit) method as 
implemented in PROC LIFETEST with METHOD=KM option. 
Quartiles of the survival function, if reached, will be obtained along with 90% confidence 
intervals calculated from PROC LIFETEST output using the method of (Brookmeyer and 
Crowley, 1982). Kaplan-Meier estimates of the survival function with 90% confidence


Novartis
Confidential
Page 36
SAP
CETB115E2202
intervals at specific time points will be summarized. The standard error of the Kaplan-
Meier estimate will be calculated using Greenwood’s formula (Collett, 1994).
6
Reference
1. Clopper CJ and Pearson ES (1934).  The use of confidence or fiducial limits illustrated in 
the case of the binomial.  Biometrical, 26, 404-413.
2. Brookmeyer R and Crowley J (1982). A Confidence Interval for the Median Survival 
Time. Biometrics, 38, 29 - 41. 
3. Collet D (1994). Modelling survival data in medical research. London, Chapman & Hall.