Clinical trial NCT04328727
Conditions: Severe Aplastic Anemia (SAA)
Keywords: Treatment naïve severe aplastic anemia SAA eltrombopag ETB115 immunosuppressive therapy rabbit anti-thymocyte globulin r-ATG cyclosporine A CsA East-Asian patients
Sponsor: Novartis Pharmaceuticals
Start date: 2020-11-04; Completion date: 2024-12-06
Enrollment: 36 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This study was designed to evaluate the efficacy and safety of eltrombopag when added to r-ATG and CsA in treatment naive East-Asian adult and pediatric patients with severe aplastic anemia (SAA).

Detailed description:
This was a non-randomized, open label, single arm, multi-center, Phase II study to evaluate the efficacy and safety of eltrombopag in combination with immunosuppressive therapy (IST) regimen of r-ATG + CsA in East-Asian patients with severe aplatsic anemia who had not received prior IST.

Eligible participants were enrolled into the study and received eltrombopag (from Day 1 to Week 26) concomitantly with r-ATG (on Days 1-5) and CsA (from Day 1 to Week 26) in the core treatment part.

Participants who were assessed as responders (meeting complete (CR) or partial (PR) response criteria) at Week 26 were eligible for the extension part of the study and continued treatment with eltrombopag and CsA after Week 26 up to Week 52. During the extension part, eltrombopag treatment was provided up to Week 52. CsA was maintained or tapered at the investigator's discretion according to local practice, with a total duration of at least 2 years (18 months after Week 26). There was a 30 days after end of treatment safety follow-up at the end of the extension part.

All participants were offered to enter the long term follow-up after the discontinuation of eltrombopag, with yearly efficacy and clonal evolution assessments up to Year 3 (Week 156).

Arms: arm 1: Participants received eltrombopag in combination with r-ATG and CsA.

* Eltrombopag was administered orally once daily with initial doses of 75mg/day for ≥ 12 years old and 37.5 mg/day for participants between ≥ 6 and \< 12 years. Doses could be adjusted based on platelet count
* r-ATG was administered intravenously at a dose of 2.5 to 3.5 mg/kg/day on Days 1-5
* CsA was administered orally every 12 h at a starting dose of 3-6 mg/kg/day
Interventions: intervention 1: eltrombopag intervention 2: rabbit anti-thymocyte globulin (r-ATG) intervention 3: cyclosporine A (CsA)
Intervention descriptions: intervention 1: Tablet 25mg and 12.5mg intervention 2: r-ATG 25 mg sterile lyophilized powder in 10 mL vials for IV use intervention 3: CsA 25mg Capsule or CsA 5.0g/50mL solution for oral use

Protocol documents:
Prot_000.pdf: 
Novartis Research and Development 
ETB115 
Clinical Trial Protocol CETB115G2201 / NCT04328727 
A non-randomized, open label, multi-center, Phase II study 
to assess the safety and efficacy of eltrombopag in 
combination with rabbit anti-thymocyte globulin (r-ATG) 
and cyclosporine A (CsA) in East-Asian patients with 
treatment naive severe aplastic anemia (REACTS) 
Document type: 
Amended Protocol Version 
EUDRACT number: 
Not applicable 
Version number: 
03 (Clean)  
Clinical Trial Phase: 
II 
Release date: 
22-Dec-2021
Property of Novartis 
Confidential 
May not be used, divulged, published, or otherwise disclosed 
without the consent of Novartis 
Clinical Trial Protocol Template Version 3.0 (31-Jan-2020) 


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Table of contents 
Table of contents ................................................................................................................. 2 
List of tables ........................................................................................................................ 5 
List of figures ...................................................................................................................... 5 
List of abbreviations ............................................................................................................ 6 
Glossary of terms ............................................................................................................... 10 
Amendment 3 (22-Dec-2021) ............................................................................................ 12 
Amendment 2 (08-DEC-2020) .......................................................................................... 15 
Amendment 1 (16-JUN-2020) ........................................................................................... 16 
Protocol summary .............................................................................................................. 18 
1 
Introduction ....................................................................................................................... 22 
1.1 
Background ............................................................................................................ 22 
1.2 
Purpose .................................................................................................................. 25 
1.3 
Pharmacokinetics and drug-drug interaction in human ......................................... 25 
2 
Objectives and endpoints ................................................................................................... 26 
3 
Study design ...................................................................................................................... 27 
4 
Rationale ............................................................................................................................ 29 
4.1 
Rationale for study design ..................................................................................... 29 
4.2 
Rationale for dose/regimen and duration of treatment .......................................... 30 
4.3 
Rationale for choice of combination drugs ............................................................ 31 
4.4 
Purpose and timing of interim analyses/design adaptations .................................. 31 
4.5 
Risks and benefits .................................................................................................. 31 
4.6 
Rationale for Public Health Emergency mitigation procedures ............................ 34 
5 
Population .......................................................................................................................... 34 
5.1 
Inclusion criteria .................................................................................................... 34 
5.2 
Exclusion criteria ................................................................................................... 35 
6 
Treatment ........................................................................................................................... 37 
6.1 
Study treatment ...................................................................................................... 37 
6.1.1 
Investigational and control drugs .......................................................... 37 
6.1.2 
Additional study treatments .................................................................. 40 
6.1.3 
Treatment arms/group ........................................................................... 41 
6.1.4 
Guidelines for continuation of treatment .............................................. 41 
6.1.5 
Treatment duration ................................................................................ 41 
6.2 
Other treatment(s) .................................................................................................. 42 
6.2.1 
Concomitant therapy ............................................................................. 42 
6.2.2 
Prohibited medication ........................................................................... 45 
6.3 
Participant numbering, treatment assignment, randomization .............................. 46 


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6.3.1 
Participant numbering ........................................................................... 46 
6.3.2 
Treatment assignment, randomization .................................................. 46 
6.4 
Treatment blinding ................................................................................................ 46 
6.5 
Dose escalation and dose modification.................................................................. 47 
6.5.1 
Dose modifications ................................................................................ 47 
6.5.2 
Follow-up for toxicities ......................................................................... 50 
6.6 
Additional treatment guidance ............................................................................... 52 
6.6.1 
Treatment compliance ........................................................................... 52 
6.6.2 
Emergency breaking of assigned treatment code .................................. 52 
6.7 
Preparation and dispensation ................................................................................. 52 
6.7.1 
Handling of study treatment and additional treatment .......................... 53 
6.7.2 
Instruction for prescribing and taking study treatment ......................... 53 
7 
Informed consent procedures ............................................................................................ 55 
8 
Visit schedule and assessments ......................................................................................... 57 
8.1 
Screening ............................................................................................................... 65 
8.1.1 
Eligibility screening .............................................................................. 65 
8.1.2 
Information to be collected on screening failures ................................. 66 
8.2 
Participant demographics/other baseline characteristics ....................................... 66 
8.3 
Efficacy .................................................................................................................. 67 
8.3.1 
Appropriateness of efficacy assessments .............................................. 68 
8.4 
Safety ..................................................................................................................... 69 
8.4.1 
Laboratory evaluations .......................................................................... 69 
8.4.2 
Electrocardiogram (ECG) ..................................................................... 71 
8.4.3 
Bone marrow aspiration and biopsy ...................................................... 72 
8.4.4 
Evaluation of clonal evolution .............................................................. 72 
8.4.5 
Pregnancy and assessments of fertility ................................................. 72 
8.4.6 
Ophthalmic Assessments ...................................................................... 74 
8.4.7 
Other safety evaluations ........................................................................ 74 
8.4.8 
Appropriateness of safety measurements .............................................. 74 
8.5 
Additional assessments .......................................................................................... 75 
8.5.1 
Pharmacokinetics .................................................................................. 75 
9 
Study discontinuation and completion .............................................................................. 77 
9.1 
Discontinuation ...................................................................................................... 77 
9.1.1 
Discontinuation of study treatment ....................................................... 77 
9.1.2 
Withdrawal of informed consent ........................................................... 78 
9.1.3 
Lost to follow-up ................................................................................... 79 
9.1.4 
Early study termination by the sponsor ................................................. 79 


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9.2 
Study completion and post-study treatment .......................................................... 80 
10 Safety monitoring and reporting ........................................................................................ 80 
10.1 
Definition of adverse events and reporting requirements ...................................... 80 
10.1.1 
Adverse events ...................................................................................... 80 
10.1.2 
Serious adverse events .......................................................................... 82 
10.1.3 
SAE reporting........................................................................................ 83 
10.1.4 
Pregnancy reporting .............................................................................. 84 
10.1.5 
Reporting of study treatment errors including misuse/abuse ................ 85 
10.2 
Additional Safety Monitoring ................................................................................ 86 
11 Data Collection and Database management ...................................................................... 86 
11.1 
Data collection ....................................................................................................... 86 
11.2 
Database management and quality control ............................................................ 86 
11.3 
Site monitoring ...................................................................................................... 86 
12 Data analysis and statistical methods ................................................................................ 87 
12.1 
Analysis sets .......................................................................................................... 87 
12.2 
Participants demographics and other baseline characteristics ............................... 88 
12.3 
Treatments ............................................................................................................. 88 
12.4 
Analysis of the primary endpoint(s) ...................................................................... 88 
12.4.1 
Definition of primary endpoint(s) ......................................................... 88 
12.4.2 
Statistical model, hypothesis, and method of analysis .......................... 88 
12.4.3 
Handling of missing values/censoring/discontinuations ....................... 89 
12.4.4 
Sensitivity and Supportive analyses ...................................................... 89 
12.5 
Analysis of secondary endpoints ........................................................................... 89 
12.5.1 
Efficacy and/or Pharmacodynamic endpoint(s) .................................... 89 
12.5.2 
Safety endpoints .................................................................................... 90 
12.5.3 
Pharmacokinetics .................................................................................. 93 
12.6 
Analysis of exploratory endpoints ......................................................................... 94 
12.7 
Interim analyses ..................................................................................................... 94 
12.8 
Sample size calculation.......................................................................................... 94 
12.8.1 
Primary endpoint(s) ............................................................................... 94 
13 Ethical considerations and administrative procedures ...................................................... 94 
13.1 
Regulatory and ethical compliance ........................................................................ 94 
13.2 
Responsibilities of the investigator and IRB/IEC .................................................. 94 
13.3 
Publication of study protocol and results............................................................... 95 
13.4 
Quality Control and Quality Assurance ................................................................. 95 
14 Protocol adherence ............................................................................................................ 95 
14.1 
Protocol amendments............................................................................................. 96 


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15 References ......................................................................................................................... 97 
16 Appendices ...................................................................................................................... 101 
16.1 
Appendix 1: List of substrates of BCRP and OATP1B1 ..................................... 101 
16.2 
ECOG/Lansky Performance Status Scales .......................................................... 101 
16.3 
NYHA and Modified Ross Heart Failure Classification for children ................. 102 
List of tables 
Table 2-1 
Objectives and related endpoints .......................................................... 26 
Table 6-1 
Investigational and combination drugs ................................................. 37 
Table 6-2 
Initial dose of eltrombopag ................................................................... 38 
Table 6-3 
Dose adjustment criteria for eltrombopag ............................................. 38 
Table 6-4 
Dose adjustment criteria in extension part after Week 26 (for 
participants maintaining hematologic response for more than 8 
weeks) ................................................................................................... 39 
Table 6-5 
Dose decrease of eltrombopag after Week 26 ....................................... 39 
Table 6-6 
Prohibited medication and therapy ........................................................ 45 
Table 6-7 
Guidelines for eltrombopag dose modification based on liver 
function abnormalities and thrombosis/embolism ................................ 48 
Table 6-8  
Summary of guidance on specific clinical and diagnostic 
assessments ........................................................................................... 51 
Table 6-9 
Dose and treatment schedule in core treatment part ............................. 55 
Table 8-1 
Assessment Schedule ............................................................................ 59 
Table 8-2 
Assessments & Specifications............................................................... 69 
Table 8-3 
Laboratory assessments ......................................................................... 70 
Table 8-4 
Pharmacokinetic blood collection log (eltrombopag) ........................... 75 
Table 10-1 
Guidance for capturing the study treatment errors including 
misuse/abuse ......................................................................................... 85 
Table 12-1 
Non-compartmental pharmacokinetic parameters ................................ 93 
Table 12-2 
95% CIs for various observed response rate ......................................... 94 
Table 16-1 
ECOG Performance Status .................................................................. 101 
Table 16-2 
Lansky Play Performance Scale (Lansky et al., 1987) ........................ 101 
Table 16-3 
NYHA and Modified Ross Heart Failure Classification for children . 102 
List of figures 
Figure 3-1 
Study design .......................................................................................... 28 


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List of abbreviations 
AA 
Aplastic anemia 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALG 
Antilymphocyte globulin 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
AML 
Acute myeloid leukemia 
ANC 
Absolute neutrophil count 
APS 
Antiphospholipid antibody syndrome 
aPTT 
Activated partial thromboplastin time 
AST 
Aspartate aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
ATG 
Anti-thymocyte globulin 
AUC 
Area under the plasma concentration-time curve 
AUClast 
The area under the plasma concentration-time curve from time zero to the last measurable 
concentration sampling time 
AUCtau 
The area under the plasma concentration-time curve calculated to the end of a dosing interval 
(tau) at steady-state  
BCRP 
Breast cancer resistance protein 
BUN 
Blood urea nitrogen 
CD25 
Cluster of Differentiation 25: interleukin-2 receptor 
CDE 
Center for Drug Evaluation 
CDS 
Core Data Sheet (for marketed drugs) 
CFR 
Code of Federal Regulation 
CL 
Clearance 
CLss 
Systemic (or total body) clearance at steady state from plasma 
Cmax 
Observed maximum plasma concentration following administration  
CMO 
Chief Medical Office 
CMV 
Cytomegalovirus 
CR 
Complete response 
CRF 
Case Report/Record Form (paper or electronic) 
CRO 
Contract Research Organization 
CsA 
Cyclosporine A 
CSR 
Clinical study report 
CT 
Computed tomography 
CTC 
Common Toxicity Criteria 
CTCAE 
Common Terminology Criteria for Adverse Events  
Ctrough 
Pre-dose plasma concentration 
CV 
Coefficient of variation 
CYP 
Cytochrome P450 
DAR 
Dosage administration record 
DBIL 
Direct bilirubin 
DBP 
Diastolic blood pressure 
DILI 
Drug induced liver injury 
DNA 
Deoxyribonucleic acid 


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EBV 
Epstein-Barr virus 
EC 
Ethics committee 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EDC 
Electronic Data Capture 
EDD 
Expected delivery date 
EMA 
European Medicines Agency 
EOT 
End of treatment 
ERCP 
Endoscopic Retrograde Cholangio-Pancreatography 
EU 
European Union 
EudraCT 
European Union Drug Regulating Authorities Clinical Trials Database 
F 
Relative bioavailability 
FAS 
Full analysis set 
FDA 
Food and Drug Administration 
FISH 
Fluorescence in situ hybridization 
FLAER 
Fluorescent aerolysin 
FSH 
Follicle-stimulating hormone 
G-CSF 
Granulocyte colony-stimulating factor 
GCP 
Good Clinical Practice 
GGT 
Gamma-glutamyl transferase 
GI 
Gastrointestinal 
GPI 
Glycosylphosphatidylinositol 
h 
Hour 
h-ATG 
Horse anti-thymocyte globulin 
HB 
Hepatitis B 
HBcAb 
Hepatitis B core antibody 
HBsAb 
Hepatitis B surface antibody 
HBsAg 
Hepatitis B surface antigen 
HBV 
Hepatitis B virus 
HCV 
Hepatitis C virus 
HEV 
Hepatitis E virus 
HIV 
Human immunodeficiency virus 
HMG-CoA 
Hydroxy methylglutaryl coenzyme A 
HSCT 
Hematopoietic stem cell transplantation 
HSV 
Herpes simplex virus  
IB 
Investigator's brochure 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation of Technical Requirements for Pharmaceuticals for 
Human Use 
IEC 
Independent Ethics Committee 
IgG 
Immunoglobulin G 
IgM 
Immunoglobulin M 
IN 
Investigator Notification 
INR 
International normalized ratio 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 


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IST 
Immunosuppressive therapy 
ITP 
Immune thrombocytopenia 
LC-MS/MS 
Liquid chromatography - tandem mass spectrometry assay 
LDH 
Lactate dehydrogenase 
LFT 
Liver function test 
LLOQ 
Lower limit of quantification 
MCH 
Mean corpuscular hemoglobin 
MCHC 
Mean corpuscular hemoglobin concentration 
MCV 
mean corpuscular volume 
MDS 
Myelodysplastic syndrome 
MedDRA 
Medical dictionary for regulatory activities 
MRI 
Magnetic resonance imaging 
mg 
Milligram(s) 
mL 
Milliliter(s) 
MRA 
Magnetic resonance angiography 
MUGA 
Multiple gated acquisition 
NIH 
National Institute of Health 
NR 
No response 
NSAID 
Non-steroidal anti-inflammatory drugs 
NYHA 
New York Heart Association 
o.d. 
Once a day 
OATP1B1 
Organic anion transporting polypeptide 1B1  
OS 
Overall survival 
p.o. 
Oral 
PA 
Posterior to anterior 
PAS 
Pharmacokinetic analysis set 
PgP 
P-glycoprotein 
PK 
Pharmacokinetic(s) 
PMDA 
Pharmaceuticals and medical devices agency 
PNH 
Paroxysmal nocturnal hemoglobinuria 
PR 
Partial response 
PS 
Performance Status 
PT 
Prothrombin time 
QMS 
Quality Management System 
QTcF 
Fridericia's QT correction formula 
r-ATG 
Rabbit anti-thymocyte globulin 
RBC 
Red blood cell(s) 
rh-TPO 
Recombinant humanized thrombopoietin 
RNA 
Ribonucleic acid 
SAA 
Severe aplastic anemia 
SAE 
Serious adverse event 
SBP 
systolic blood pressure 
SD 
Standard deviation 
TEE 
Thromboembolic event 
TIA 
Transient ischemic attack 
TIBC 
Total iron binding capacity 


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Tmax 
The time to reach peak or maximum concentration  
TPO 
Thrombopoietin 
TPO-R 
Thrombopoietin receptor 
TSH 
thyroid-stimulating hormone 
UGT 
Uridine diphosphate glucuronosyl transferase 
ULN 
Upper limit of normal 
VSAA 
Very severe aplastic anemia 
WBC 
White blood cell(s) 
WHO 
World Health Organization 
WoC 
Withdrawal of consent 


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Glossary of terms 
Assessment 
A procedure used to generate data required by the study 
Cohort 
A specific group of participants fulfilling certain criteria 
Dosage 
Dose of the study treatment given to the participant in a time unit (e.g. 100 mg once a 
day, 75 mg twice a day) 
Enrollment 
Point/time of participant entry into the study at which informed consent must be 
obtained (i.e. prior to starting any of the procedures described in the protocol) 
Healthy volunteer 
A person with no known significant health problems who volunteers to be a study 
participant  
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 is synonymous with “investigational 
new drug” or “investigational medicinal product”. 
Investigational 
treatment 
All investigational drug(s) whose properties are being tested in the study as well as 
their associated treatment controls. This includes any placebos, any active controls, 
as well as approved drugs used outside of their indication/approved dosage or tested 
in a fixed combination. Investigational treatment generally does not include other 
treatments administered as concomitant background therapy required or allowed by 
the protocol when used within approved indication/dosage. 
Medication number 
A unique identifier on the label of each study drug package in studies that dispense 
study drug using an IRT system. 
Non-investigational 
medicinal Product 
(NIMP) 
Products which are not the object of investigation (e.g. any background therapy 
administered to each of the clinical trial participants, regardless of randomization 
group, rescue medication, active drug run-ins etc.) 
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 
Pediatric participant 
A participant who is younger than 18 years old 
Period 
A minor subdivision of the study timeline; divides phases into smaller functional 
segments such as screening, baseline, titration, washout, etc. 
Premature participant 
withdrawal 
Point/time when the participant exits from the study prior to the planned completion of 
all study drug administration and assessments; at this time all study drug 
administration is discontinued and no further assessments are planned. 
Randomization 
number 
A unique identifier assigned to each randomized participant, corresponding to a 
specific treatment arm assignment 
Screen Failure 
A participant who is screened but is not treated or randomized 
Stage 
A major subdivision of the study timeline; begins and ends with major study 
milestones such as enrollment, randomization, completion of treatment, etc. 
Study completion 
Point/time at which the participant came in for a final evaluation visit or when study 
drug was discontinued whichever is later. 
Study drug 
discontinuation 
Point/time when participant permanently stops taking study drug for any reason; may 
or may not also be the point/time of premature participant withdrawal. 
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) 
Study treatment 
discontinuation 
When the participant permanently stops taking study treatment prior to the defined 
study treatment completion date 
Participant 
A trial participant (can be a healthy volunteer or a patient) 
Participant number 
A unique number assigned to each participant upon signing the informed consent. 
This number is the definitive, unique identifier for the participant and should be used 
to identify the participant throughout the study for all data collected, sample labels, 
etc. 


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Treatment number 
A unique identifier assigned in non-randomized studies to each dosed participant, 
corresponding to a specific treatment arm  
Variable 
A measured value or assessed response that is determined in specific assessments 
and used in data analysis to evaluate the drug being tested in the study 
Withdrawal of consent 
(WoC)  
Withdrawal of consent from the study is defined as when a participant does not want 
to participate in the study any longer, and does not want any further visits or 
assessments, and does not want any further study related contact, and does not 
allow analysis of already obtained biologic material 


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Amendment 3 (22-Dec-2021) 
Amendment rationale  
Study status: The Last Patient First Visit was achieved 03-Dec-2021, as of 07-Dec-2021, 36 
participants have been enrolled into the study, enrollment is complete.  
The purpose of this amendment is to harmonize and clarify several inconsistencies in the 
protocol and add risk mitigation procedures during public health emergency declared by local 
or regional authorities.  
This amendment addresses the following changes: 
• Harmonize and clarify the protocol regarding the term "study treatment" which was used to 
denote either eltrombopag or eltrombopag plus r-ATG and CsA at different places in the 
protocol. 
• Clarify that participants who initiate treatment prior to availability of FISH results must be 
discontinued from the study treatment if fluorescence in situ hybridization (FISH) result is 
found to be abnormal.  
• Add risk mitigation procedures during the public health emergency declared by local or 
regional authorities as per Novartis guidance.  
• Add guidance on pathological myelofibrosis to avoid study treatment discontinuation 
due to clinically insignificant changes.  
• Make other minor editorial revisions, clarifications and corrections throughout the protocol 
for consistency and/or clarifications.  
The updates were not triggered by any safety issues or new safety data becoming available. 
The assessment of the Benefit/Risk identified no additional risks related to COVID-19 and no 
changes have been made as a result. 
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. Please find 
below the summary of changes in protocol version 03 as compared to version 02:  
• Throughout the protocol: Capital E in Eltrombopag was corrected to small e as in 
eltrombopag to harmonize spelling. 
• Table 2-1, Section 4.5, Section 6.3.2, Table 6-7 and Section 8.4.1: The term “investigational 
treatment” was replaced by the term “study treatment” to harmonize the use of these terms 
throughout the protocol.  
• Section 3: The text was reorganized for easier understanding and replacement of 
investigational treatment with study treatment and eltrombopag and clarification added 
regarding End of treatment (EOT) definition. 
• Section 4.6: Addition of rationale for public health emergency mitigation procedures.  
• Section 6.1: Definition of study treatment was added for more clarity that the study 
treatment consists of the combination of the three drugs eltrombopag, CsA and r-ATG. 


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• Section 6.1.5: The term investigational treatment was replaced with eltrombopag, disease 
progression was added as additional criteria for discontinuation as this was already included 
in section 9.1 but omitted in 6.1.5.  
• Section 6.2.1: Time period for collection of concomitant therapy was clarified and aligned 
with section 8.3: for transfusion, data is collected until the end of eltrombopag treatment for 
participants who discontinue eltrombopag due to non-response at W26, relapse or 
alternative SAA treatment, and until the completion of study for all the other participants; 
for concomitant therapy other than those specifically mentioned: collected up to the 
resolution of the last reported AE.  
• Section 6.2.2: Guideline regarding SARS-CoV-2 vaccination was added as communicated 
to study sites via investigator letter issued Feb 2021.  
• Section 6.5.1.2: It is clarified when the dose modification applies to study treatment, and 
when to eltrombopag.  
• Table 6-7: The term investigational treatment was replaced by eltrombopag. In isolated AST 
or ALT elevation > ULN – 3 x ULN, action taken was clarified to maintain dose level, as 
dose escalation is not applicable in this trial so there is no need to include escalation 
language. 
• Section 6.5.2.1: The term study treatment was replaced with eltrombopag regarding PK 
sample to determine exposure to the drug and its metabolites.  
• Section 6.7: A paragraph for public health emergency mitigation procedures was added to 
allow study treatment to be shipped to patient’s home if site visits are not possible. The term 
investigational drug was replaced with eltrombopag to align the protocol language.  
• Section 6.7.2: Clarified the definition of missed CsA dose and that to omit the missed dose, 
to avoid ambiguity. Per protocol CsA is taken twice daily, it was corrected that in case a 
CsA dose is missed that not the day’s dose should be skipped but only that missed dose.  
• Section 7: A paragraph for public health emergency mitigation procedures was added to 
allow a remote consenting process. As enrollment is already completed this may apply for 
reconsenting only.  
• Section 8: The option to use a central laboratory analysis was added for specialized analysis 
(FISH and flow cytometry) if the local labs do not provide the assessments as per protocol 
requirements. The term study treatment was replaced with eltrombopag to clarify that EOT 
refers to eltrombopag and not study treatment and the term “prematurely discontinue” was 
replaced with “discontinue” with regards to efficacy assessments as those are to be collected 
for all participants. In addition, a paragraph for public health emergency mitigation 
procedures was added to allow remote visits if site visits are not possible. 
• Table 8-1: The superscript "3" was added to clarify that ECG is need at Screening OR Day1. 
The superscript “4” was added to provide clarification regarding pregnancy testing at end 
of treatment visit and safety follow-up visit 30-days later. The table header was extended to 
all pages for easier reading.  
• Section 8.1: Clarification was added that participants who start study treatment prior to 
availability of FISH results must be discontinued from study treatment in case of abnormal 
FISH result.  


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• Section 8.2: ECG was removed from laboratories evaluations and added to cardiovascular 
history and risk factor assessment.  
• Section 8.3: Transfusion data collection was clarified to align with Table 8-1.  
• Section 8.4: The paragraph for public health emergency was added to allow remote visits if 
site visits are not possible.  
• Section 8.4.1. The option to use a central laboratory analysis was added for specialized 
analysis (FISH and flow cytometry). The paragraph for public health emergency was added 
to allow usage of alternative lab collection sites.  
• Section 8.4.5. Clarification was added regarding serum or urine pregnancy tests after 
discontinuation of eltrombopag treatment.  
• Section 8.5.1.1: The sequence within to paragraph was changed for easier understanding 
and information added that sample collection information is collect on requisition forms and 
integrated in the eCRF via data transfer.  
• Table 8-4: The D15 Week 2 was corrected from week 3 to week 2 to align with table 8-1 
and clarification was added that 24h sample needs to be taken pre-dose.  
• Section 9.1.1: The term “investigational treatment” was replaced with eltrombopag to align 
protocol language and clarification was added regarding discontinuation if FISH result is 
abnormal (patient started treatment based on normal karyotyping) and guidance on 
pathological myelofibrosis was added.  
• Section 9.2: The term study treatment was replaced with eltrombopag to align with 
definition for EOT.  
• Section 10.1.1 & 10.1.3: Clarification was added that AE and SAE reporting period refers 
to the period 30 days after last dose of eltrombopag treatment to align with paragraph 6.5.2. 
Information was added that details of AESI are available in Investigator’s Brochure.  
• Section 12.5.1: Clarification was added that for all secondary efficacy endpoints FAS will 
be used.  
• Section 12.5.2: The sentence “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 any study treatment.” was deleted, since it conflicts with subsequent definition of on-
treatment period. Change the definition of on-treatment period since there is no difference 
between core treatment period and extension treatment period.  
IRBs/IECs 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRB)/Independent Ethics Committee (IECs) and Health Authorities. The changes described in 
this amended protocol are non-substantial.  
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment. 


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Amendment 2 (08-DEC-2020)  
Amendment rationale  
Study status: As of 08-DEC-2020, three participants are enrolled in China. 
The primary purpose of this Amendment is to change the level of AST/ ALT from >8 x ULN 
to >5 x ULN and to change the recommended action from "dose interruption" to "treatment 
discontinuation" in the Table 6-7 of protocol, 'Guidelines for eltrombopag dose modification 
based on liver function abnormalities and thrombosis/embolism' in response to concerns raised 
by Korean Health Authority. 
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. Please find 
below the summary of changes in protocol version 02 as compared to version 01: 
• Table 6-7: Changed “interrupt dose” to “Discontinue subject from investigational 
treatment”. 
• Table 6-7: Changed “[AST or ALT>8 x ULN]” to “[AST or ALT>5 x ULN]” 
• Table 6-7: Deleted sentence “If there is no alternative causes, discontinue eltrombopag". 
• Table 6-7: Added sentence in footnote b: “If the bilirubin increase is below the defined 
threshold, guidance for isolated AST or ALT elevation should be followed”. 
• Table 6-7: Added general footnote to define “discontinuation”. 
• Section 6.5.2.1: Changed “[AST or ALT>8 x ULN]” to “[AST or ALT>5 x ULN]”. 
• Section 9.1.1: Added “permanently” after “treatment is” in the sentence: “Discontinuation 
of study treatment for a participant occurs when study treatment is stopped earlier than the 
protocol planned duration and can be initiated by either the participant or the investigator. 
IRBs/IECs 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. 
The changes described in this amended protocol are non-substantial and do not require IRB/IEC 
approval prior to implementation. 


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Amendment 1 (16-JUN-2020)  
Amendment rationale  
Study status: As of 16-JUN-2020, no patients are enrolled in the protocol. 
The main purpose of this amendment is to change the starting dose of eltrombopag for 
participants ≥ 18 years old to 75 mg/day in alignment with the global pivotal study 
CETB115AUS01T, and to clarify the efficacy assessments after premature discontinuation of 
study treatment. 
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. 
• Added study brand name “REACTS” to the protocol title. 
• General wording change: “subject” are modified as “participant” due to the template 
language update.  
• Section 3, 8, 9.1.1: Added the clarification that after discontinuation, participants will 
continue to be followed for efficacy assessments until relapse, no response at Week 26 or 
alternative SAA treatment, whichever comes first.  
• Section 4.2: Removed the rationales for 100 mg/day of adults and merge adult and 
adolescent groups with the same starting dose. 
• Section 5.1: Change the word from “ethnicity” to “ancestry”. 
 
  
• Section 6.1.1.1: Modify the initial dose as 75 mg/day for adult participants and merge the 
age groups (≥18 years old and 12-17 years old) with the same initial dose.  
• Table 6-4: Added clarification on dose adjustment criteria. 
• Section 6.5.1.2: Added bilirubin test assessment interference. Measurement based on direct 
bilirubin. Added text on cause of bilirubin increase. Update table 6.7 accordingly. 
• Section 6.5.2.1: Added clarification on DILI as well as clinical and diagnostic assessments. 
• Section 6.7.2: Modify the initial dose as 75mg/day for adult participants and merge the age 
groups (≥18 years old and 12-17 years old) with the same initial dose.  
• Table 8-1: Updated to reflect modification in section 3 (added footnote). 
• Table 8-3: Removed HCV-RNA to keep consistent within program. 
• Table 8-4: Updated to fit 75 mg/day as initial dose. 
• Section 8.4.1: Added the description about interference of eltrombopag to total bilirubin and 
creatinine testing 
• Section 8.4.2: Modified the wording to clarify when to perform triplet ECG. 
• Section 9.1.2: Added two criteria for definition of withdrawal. 
• Section 10.1.1: Deleted the specification of “regardless of timing and seriousness” and 
“SAE reporting mechanism” of clonal evolution. Updated procedure to collect Clonal 
Evolution event.  
• Section 10.1.3: Removed the specification of clonal evolution.  


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• Section 10.1.4: Added stopping study treatment if pregnant.  
IRBs/IECs 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. 
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation.  
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment. 


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Protocol summary 
Protocol number 
CETB115G2201 
Full Title 
A non-randomized, open label, multi-center, Phase II study to assess the safety and 
efficacy of eltrombopag in combination with rabbit anti-thymocyte globulin (r-ATG) and 
cyclosporine A (CsA) in East-Asian patients with treatment naive severe aplastic anemia 
(SAA) 
Brief title 
Study of efficacy and safety of eltrombopag in combination with rabbit anti-thymocyte 
globulin and cyclosporine A in treatment naive East-Asian patients with severe aplastic 
anemia 
Sponsor and 
Clinical Phase 
Novartis 
Phase II 
Investigation type 
Drug 
Study type 
Interventional 
Purpose and 
rationale 
This study is designed to evaluate the efficacy and safety of eltrombopag when added to 
r-ATG and CsA in treatment naive East-Asian adult and pediatric patients with SAA. 
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 more 
prevalent in densely populated areas in East-Asia. Immunosuppressive therapy (IST) 
comprising r-ATG and CsA is the first-line treatment for SAA patients who are ineligible 
for hematopoietic stem cell transplantation (HSCT) in East-Asian countries. However, 
incomplete responses, relapses, and primary refractoriness limit the success of IST and 
highlights the unmet medical need to improve outcome following first-line IST in East-
Asian patients. Eltrombopag, an oral thrombopoietin receptor (TPO-R) agonist, has been 
reported to improve the hematological response with acceptable safety profile for the 
indication of IST naive SAA patients when administered concurrently with IST of horse 
ATG (h-ATG) and CsA in a phase I/II study (Study number: CETB115AUS01T), and in 
Japanese patients with moderate or more SAA who have not received prior ATG/anti-
lymphocyte globulin (ALG)-based IST in another phase II study (Study number: 
CETB115E1202) where eltrombopag was administered in combination with IST of r-ATG 
and CsA. Therefore, it is expected that a favorable benefit/risk profile can be derived from 
the use of eltrombopag in combination with r-ATG and CsA in the treatment of East-Asian 
treatment naive SAA patients.  
Primary 
Objective(s)  
To evaluate the efficacy of eltrombopag in combination with r-ATG and CsA in terms of 
complete response (CR) rate at week 26 in East-Asian patients with treatment naive 
severe aplastic anemia (SAA)  
Secondary 
Objectives 
Objective 1: To evaluate complete response rate at 3, 12 months and yearly after 
Objective 2: To evaluate overall response rate at 3, 6, 12 months and yearly after  
Objective 3: To evaluate duration of response 
Objective 4: To evaluate overall survival 
Objective 5: To evaluate the need for transfusion (packed red blood cell (RBC) units and 
platelet units)  
Objective 6: To evaluate safety and tolerability of eltrombopag in combination with r-ATG 
and CsA 
Objective 7: To evaluate clonal evolution  
Objective 8: To determine the pharmacokinetics (PK) of eltrombopag in East-Asian 
treatment naive SAA patients 
Study design 
This is a non-randomized, open label, single arm, multi-center, Phase II study to evaluate 
the efficacy and safety of eltrombopag in combination with IST regimen of r-ATG + CsA 
in East-Asian patients with SAA who have not received prior IST. Eligible patients will 
receive eltrombopag concomitantly with immunosuppressive therapy of r-ATG and CsA 
during the first 6 months. Responders at Week 26 are eligible to the extension part in 
which eltrombopag treatment will be provided up to Week 52. All participants will be 
followed up to Year 3 for survival and clonal evolution.  


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Population 
This study population is East-Asian adult and pediatric patients (≥ 6 years old) with SAA 
who have not received prior immunosuppressive therapy. Thirty-six participants will be 
enrolled from China, Japan, Korea or Taiwan. Six pediatric participants will be recruited in 
total, with 3 from China and 3 from Japan. At least one of the 6 pediatric participants in 
each age group (6 to 11 years old, and 12 to 17 years old) will be enrolled. For the 30 
adult participants, at least 12 participants will be recruited from China to fulfill the 
requirements for PK profile.  
Key Inclusion 
criteria 
1. 
Written study informed consent and (where applicable) assent from the participant, 
parent, or guardian must be obtained prior to participation in the study.  
2. 
Participants of East Asian ancestry aged ≥ 6 years old at the time of written informed 
consent and assent form (if applicable). 
3. 
SAA characterized by: 
• 
Bone marrow cellularity < 25%, or 25-50% with < 30% residual hematopoietic 
cells and pancytopenia, with at least two of the following parameters in peripheral 
blood:  
• 
Absolute neutrophil count < 0.5×109/L 
• 
Platelet count < 20×109/L 
• 
Absolute reticulocyte count < 20×109/L  
4. 
HSCT is not suitable or available as a treatment option (determined as per local 
practices or national guidelines), or has been refused by participant. 
Key Exclusion 
criteria 
1. 
Prior IST with any ATG/ALG, alemtuzumab, high dose cyclophosphamide (≥ 45 
mg/kg/day), CsA within 6 months, or prior thrombopoietin receptor agonists. 
2. 
Eastern Cooperative Oncology Group (ECOG) performance status (age ≥ 16 
years) >2, or Lansky performance status (age < 16 years) <50. 
3. 
Prior and/or active medical history of: 
• 
Known underlying congenital/inherited bone marrow failure or aplastic anemia 
(e.g.,such as but not limited to Fanconi anemia, congenital dyskeratosis, 
congenital 
amegakaryocytic 
thrombocytopenia, 
or 
Shwachman-Diamond 
Syndrome) 
• 
Symptomatic paroxysmal nocturnal hemoglobinuria (PNH) and/or PNH clones 
>50% of polymorphonuclear neutrophil (PMN) or RCB at time of enrollment 
• 
Myelodysplastic syndrome (MDS)  
• 
Any cytogenetic abnormalities on karyotyping or FISH within 30 days of study 
enrollment (an evaluable karyotyping with at least 10 metaphases is mandatory 
for eligibility) 
• 
Other known or suspected underlying primary immunodeficiency 
• 
Any concomitant malignancies that have not fully recovered from treatment or 
have not been disease-free for 5 years 
4. 
Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >3 times the 
upper limit of normal (ULN). 
5. 
Creatinine ≥ 2.5×local ULN 
6. 
Past medical history of thromboembolism within 6 months, and/or prior or current 
antiphospholipid antibody syndrome (APS). 
7. 
Presence of clinically active uncontrolled significant (of such severity that it would 
preclude the participant's ability to consent, be compliant with study procedures, 
tolerate protocol therapy) infection, including bacterial, fungal, mycobacterial, 
parasitic or viral infection, or any concurrent condition that, in the Investigator's 
opinion, would jeopardize the safety of the participant or compliance with the 
protocol 
8. 
Any severe and/or uncontrolled medical conditions which could cause unacceptable 
safety risks or compromise compliance with the protocol, such as: 
• 
Known hepatocellular disease (e.g. active hepatitis or cirrhosis) 


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• 
Impairment of gastrointestinal (GI) function or gastrointestinal disease that may 
significantly alter the absorption of study treatment (e.g., ulcerative disease, 
uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome) 
• 
Active skin, mucosa, ocular or GI disorders of Grade > 1 
9. 
Presence of hepatitis B surface antigen (HBsAg) or positive hepatitis C antibody test 
result at screening. A positive serology for Hepatitis B (HB) is considered as a 
positive test for HBsAg. In addition, if serology is negative for HBsAg but hepatitis B 
core antibody (HBcAb) is positive (regardless of hepatitis B surface antibody 
(HBsAb) status), a hepatitis B virus (HBV) DNA test will be performed and if positive 
the patient will be excluded. 
10. Cardiac disorder (participants with congestive heart disease of New York Heart 
Association (NYHA) functional classification Grade II/III/IV (for pediatric participants, 
refer to the Grade II/III/IV of Modified ross heart failure classification for Children) 
should not be enrolled; participants with NYHA Grade II due to cardiac disorder 
should not be enrolled but those with NYHA Grade II due to aplastic anemia (AA) 
may be enrolled.), arrhythmia with a risk of thrombosis (e.g. atrial fibrillation), 
pulmonary hypertension, or uncontrolled hypertension (>180/100 mmHg). 
Study treatment 
Investigational drug: eltrombopag. 
Combination drugs: r-ATG and CsA. 
Efficacy 
assessments 
• 
Absolute neutrophil count 
• 
Reticulocyte count 
• 
Platelet count 
• 
Hemoglobin 
• 
Bone marrow aspiration and biopsy 
• 
Use of platelet and/or RBC transfusions 
• 
Survival 
Key safety 
assessments 
Safety assessment will include adverse event (AE) monitoring, physical examinations, 
vital signs, bone marrow assessments of clonal evolution and fibrosis, flow cytometry of 
the peripheral blood for glycosylphosphatidylinositol (GPI)-cells, electrocardiogram 
(ECG), ophthalmic assessments, and any necessary radiologic and laboratory measures. 
The latter includes routine hematology, chemistry, coagulation profile, peripheral blood 
smear, CsA level, pregnancy test and appropriate monitoring for and evaluation of any 
infections. 
Pharmacokinetic 
assessments  
Full PK profile of eltrombopag over 24 hours (h) at 2 weeks after initial dose in 12 
Chinese adult participants and all Japanese pediatric participants. 
Pre-dose PK sample of eltrombopag at steady state at each dose level for all the 
participants. 
Data analysis 
The Full Analysis Set (FAS) comprises all participants to whom study treatment has been 
assigned and who received at least one dose of study treatment.  
The Safety Set includes all participants who received at least one dose of study 
treatment. All safety analyses will be done using the Safety Set. 
The Pharmacokinetic analysis set (PAS) includes all participants who received at least 
one dose of eltrombopag and provided at least one evaluable PK sample. The definition 
of an evaluable PK sample and PK profile will be further defined in the statistical analysis 
plan. 
The primary analyses will be performed when all the participants have completed the 
Week 26 visit or discontinued earlier. 
The primary efficacy endpoint is CR rate at Week 26, which is defined as the proportion 
of all participants who meet the standard criteria of complete response at Week 26. The 
primary efficacy endpoint will be summarized using point estimates and 2-sided exact 
binomial 95% (Clopper-Pearson) confidence intervals. 


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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 assessment. 
Eltrombopag plasma concentration data will be listed and summarized. Descriptive 
statistics will consist of arithmetic and geometric mean, median, standard deviation (SD), 
arithmetic coefficient of variation (CV), geometric CV, minimum and maximum. 
PK parameters will be summarized with the descriptive statistics, arithmetic and 
geometric mean, median, SD, arithmetic CV, geometric CV, minimum and maximum. 
Only median values and ranges will be given for Tmax.  
Key words 
Treatment naive East-Asian patients with severe aplastic anemia, eltrombopag, 
immunosuppressive therapy, rabbit anti-thymocyte globulin, cyclosporine A 


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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 due to an immune-mediated attack on the bone marrow. The diagnosis of SAA is based 
on the exclusion of other disorders that can cause pancytopenia, with hypocellular bone marrow 
(< 25%, or 25-50% with < 30% hematopoietic cells) 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) (Camitta et al 1975, Rosenfeld et al 2003, Marsh et al 2009). 
Aplastic anemia (AA) affects approximately 2 out of every 1 million people in western countries 
(Young and Kaufman 2008), and has a higher incidence in East-Asian countries (about 4-7 
cases per million people) (Young et al 2006, Young and Kaufman 2008,Yang and Zhang 1991). 
The incidence of AA in China was reported as 3.3-7.4 per million, while that of SAA was 1.4-
1.7 
per 
million 
people 
(Wang et al 2011, 
Zhang et al 1999, 
Yang and Zhang 1991, 
Zhang et al 2001). A recent multicenter prospective study in China presented that among all 
AA patients enrolled, 61.9% were diagnosed as SAA, while 23.6% had very severe aplastic 
anemia (VSAA) (Zhu et al 2019). The incidence of AA in Taiwan is 5.67 per million people, 
with about half of the patients suffering from SAA or VSAA (Li et al 2019). In Japan the 
incidence of AA is 8.2 per million people (Ohta et al 2015).  
Although the exact etiology of SAA remains unknown, clinical experiences and laboratory data 
suggest that the ultimate mechanism leading to development of bone marrow failure is immune 
mediated. Bone marrow suppression in AA is likely secondary to specific populations of 
effector T-cells. Activated cytotoxic T-cells expressing HLA-DR, the interleukin-2 receptor 
(CD25), and interferon-γ are elevated in SAA patients and localize in the bone marrow. 
Hematopoietic progenitor and stem cells are targets of the immune attacks by these cells. The 
effect exerted by cytotoxic T-lymphocytes are due, at least in part, to the Fas ligand-induced 
apoptosis of hematopoietic progenitor cells. Interferon-γ, in addition to its intrinsic inhibitory 
activity on hematopoietic progenitor and stem cells, can induce overexpression of Fas on target 
cells (Young et al 2006). Despite its often acute presentation, SAA is now recognized as an 
autoimmune disease which can become chronic with periodic flares of the immune process and 
the need to long-term immunosuppression in some patients. High resolution VB CDR3 analysis 
in patients with SAA shows significant increased non-random skewing of the Vβ-chain families 
of the T-cell receptor, indicative of disease specific clonal expansion (Risitano et al 2004). 
Furthermore, regulatory T-cell deficiency and TH1/TH17 mediated destruction of marrow 
elements corroborate an autoimmune pathogenesis, which has been reproduced in animal 
models 
(deLatour et al 2010, 
Solomou et al 2006, 
Solomou et al 2007, 
Scheinberg and Chen 2013, 
Kordasti et al 2012, 
Kook et al 2002, 
Risitano et al 2004, 
Tang et al 2010, Young and Maciejewski 1997).  
The first-line treatment of choice is allogeneic hematopoietic stem cell transplantation (HSCT) 
for younger patients who are eligible and have an available donor; it is the preferred option 
when 
feasible 
as 
it 
is 
curative 
(Scheinberg and Young 2012, 
Georges et al 2018, 
Red Blood Cell Disease (Anemia) 2017). Yet less than 30% of patients are suitable candidates 
for optimal HSCT, and it is reported that only 3.98% of newly diagnosed SAA patients 
(including VSAA) in China received HSCT as the initial treatment, possibly because of the lack 


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of a matched sibling donor, the lead time to identify a suitable unrelated donor, age, 
comorbidities, or access to transplantation (Marsh et al 2009, Zhu et al 2019).  
The standard regimen for treatment naive SAA patients who are ineligible for HSCT upfront, 
is immunosuppressive therapy (IST) comprising anti-thymocyte globulin (ATG) with 
Cyclosporin A (CsA). Although hematologic recovery with horse ATG (h-ATG)/CsA was 
observed in 60% to 70% patients, only a minority (about 10% historically) reached complete 
response (CR) (Scheinberg 2018, Scheinberg and Young 2012). One quarter to one third of the 
patients did not respond to h-ATG/CsA, and 30-40% of responders relapse 
(Scheinberg and Young 2012). Outcomes remain poor for patients who have an insufficient 
response to IST (Olnes et al 2012, Scheinberg and Young 2012).  
In most Asian countries, only rabbit ATG (r-ATG) is available on the market, hence, r-
ATG/CsA is recommended first-line treatment for patients with SAA in these countries 
(Red Blood Cell Disease (Anemia) 2017, Kojima et al 2011). 
Scheinberg et al 2011 and 
Marsh et al 2012 have reported that patient outcomes including survival were better with h-
ATG compared with r-ATG, but studies from Asia had indicated similar responses to r-ATG 
and h-ATG in AA patients (Chuncharunee et al 2016, Suzuki et al 2016, Shin et al 2013). 
Recent real world study in China reported that half of the patients treated with IST of r-ATG/ 
CsA achieved overall responses, with 9.4% achieved CRs (Zhu et al 2019), which is 
comparable with the findings from clinical studies in Asia that have demonstrated overall 
response rates of 58–70% (Chuncharunee et al 2016, Mahapatra et al 2015, Ramzan et al 2014). 
Incomplete responses, relapses, and primary refractoriness limit the success of this therapy. 
This highlights the unmet need to improve outcome following first-line IST in Asian patients.  
Since the establishment of ATG/CsA as the initial treatment for SAA, there was a long hiatus 
in subsequent improvements to IST, with the notion that a "ceiling" had been reached in regard 
to exploring more intense immunosuppressive regimens in SAA (Passweg and Tichelli 2009). 
Intensification of primary IST for treatment-naive SAA patients with agents more 
immunosuppressive than h-ATG, including alemtuzumab, or high dose cyclophosphamide, 
have not been successful, and the additions of sirolimus or mycophenolate mofetil to h-
ATG/CsA did not improve the response rates (Scheinberg et al 2006, Scheinberg et al 2009, 
Scheinberg et al 2012, Scheinberg 2018, Marsh and Kulasekararaj 2013). A likely limit to the 
efficacy of immunosuppression is the stem-cell deficit, from which the marrow is unable to 
recover after IST. Unfortunately, efforts to stimulate this primitive compartment, such as 
erythropoietin, granulocyte colony-stimulating factor (G-CSF), stem cell factor, and androgens, 
have been to no marked avail (Scheinberg and Young 2012, Marsh and Kulasekararaj 2013). 
Thus, other regimens are needed to address the limitations of IST for SAA patients ineligible 
for HSCT. 
One of the most promising recent treatments for AA is the oral thrombopoietin (TPO) receptor 
agonist eltrombopag, which reported multilineage effect in refractory AA patients and 
improvement in hematological response when added to upfront IST (Desmond et al 2014, 
Townsley et al 2017). Eltrombopag interacts with the transmembrane domain of the TPO 
receptor (TPO-R) on megakaryocytes and human bone marrow progenitor cells, and increases 
hematopoiesis by inducing proliferation and differentiation of early bone marrow progenitor 
cells (Erickson-Miller et al 2010, Sun et al 2012). The multilineage effects of eltrombopag in 


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patients with AA may be through stimulation of bone marrow progenitor cells, as suggested by 
recent preclinical research (Scheinberg 2018, Sun et al 2012). 
Efficacy and safety of eltrombopag in treatment naive SAA patients has been confirmed by the 
global 
pivotal 
study 
(NIH 
12-H-0150/ELT116643/CETB115AUS01T/NCT01623167, 
hereafter referred to as Study CETB115AUS01T) - a non-randomized, single center, pilot phase 
I/II study investigating the IST regimen of h-ATG + CsA in combination with eltrombopag as 
experimental therapy in patients with SAA who have not received prior definitive IST. The 
study met its pre-specified primary objective. The complete hematological response rate (95% 
CI) at month 6 was 58.1% (39.1%, 75.5%) in Cohort 3 where all 3 drugs started concurrently 
on Day 1: h-ATG on Days 1-4, CsA and eltrombopag from Day 1 to month 6. Responding 
participants received low dose of CsA (maintenance dose) from month 6 to month 24. 
Additionally, in the combined Cohort 3 + Extension Cohort, that used the same dosing regimen, 
43.7% (33.1%, 54.7%) participants who had reached the month 6 visit or withdrew earlier were 
complete responders. The addition of a maintenance dose of CsA from Month 6 to Month 24 
was implemented with protocol amendment 15 in participants who were responders at Month 
6. It started with Participant CETB115AUS01T-046 in Cohort 2 and continued with all 
participants enrolled thereafter. In Cohort 2, responders who used maintenance dose of CsA 
(approximately half of participants enrolled) showed a longer median duration of overall 
response of 35.5 months vs. 26.0 months for participants who did not in this cohort, and a better 
relapse-free probability estimate at 1.5 years (80.0% vs 54.5%). The other cohorts used a 
different dosing schedule, and started eltrombopag on Day 14 with eltrombopag lasting for 6 
months (Cohort 1) or for only 3 months (Cohort 2). They also met the primary endpoint but 
with lower CR rates: 33.3% (17.3%, 52.8%) and 25.8% (11.9%, 44.6%) in Cohort 1 and Cohort 
2, respectively. The treatment regimen schedule where eltrombopag started concurrently with 
IST (h-ATG and CsA) on Day 1, lasted for 6 months with maintenance CsA from month 6 to 
month 24 showed the highest rate of improvement in hematological parameters, demonstrated 
an early, robust and consistent hematological recovery, with acceptable safety profile. 
Moreover, long-term survival for responders has been associated with an early and robust 
hematologic recovery (Rosenfeld et al 2003). In conclusion, the key benefits shown by adding 
eltrombopag to h-ATG/CsA based IST include the marked increase in the rate of complete 
hematological response at 6 months in all cohorts, with a higher CR rate of 43.7% in Cohort 3 
+ Extension Cohort (eltrombopag + h-ATG + CsA started on Day 1) which exceeded the 
historical rate of 10-25%. These data support the conclusion of a strong benefit risk for the 
addition of eltrombopag to h-ATG and CsA. 
The clinical benefits derived from adding eltrombopag to ATG-based IST in this target 
population are independently substantiated by Study CETB115E1202 (also identified under 
GSK study code 201793; NCT02404025; hereafter referred to as Study CETB115E1202), a 
non-randomized, open label, single arm, Phase II study conducted in Japan evaluating the 
efficacy and safety of eltrombopag in combination with r-ATG + CsA in participants with 
moderate or more severe AA who had not received prior ATG/antilymphocyte globulin (ALG)-
based IST. The addition of eltrombopag to r-ATG + CsA demonstrated that this treatment is an 
improvement over IST alone, showing better overall hematological response (57.1%) than the 
historical data with r-ATG + CsA alone in (Scheinberg et al 2011) at 6 months (37%), with 
acceptable safety profile consistent with that expected for participants with SAA and that 


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established of eltrombopag in the approved chronic immune thrombocytopenia (ITP), hepatitis 
C virus (HCV) and refractory SAA indications.  
Eltrombopag in combination with IST (h-ATG/CsA) is approved for the first-line treatment of 
adult and pediatric patients (2 years and older) with SAA in the US (since 16-Nov-2018) and 
several other countries. In Japan, eltrombopag in combination with IST (r-ATG/CsA) is also 
approved for the treatment of AA patients who have not been treated with ATG (since 25-Aug-
2017). In Taiwan and Korea, eltrombopag is already approved for the treatment of SAA patients 
who have had an insufficient response to IST. 
1.2 
Purpose 
Data remain limited for eltrombopag combined to IST (r-ATG+CsA) in the first-line treatment 
of East-Asian patients (adults and pediatric) with SAA. Therefore, this study is designed 
to evaluate the efficacy and safety of eltrombopag when added to r-ATG and CsA in treatment 
naive East-Asian adult and pediatric patients with SAA.  
1.3 
Pharmacokinetics and drug-drug interaction in human 
In general, exposure to eltrombopag increased with increasing doses with no major deviation 
from dose-proportionality. 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 CYP 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 was neither an inhibitor nor a substrate of 
human Pgp. Eltrombopag in vitro was an inhibitor of OATP1B1 and BCRP, and substrate of 
BCRP but not OATP1B1. In a clinical study, administration of eltrombopag 75 mg for 5 days 
with the OATP1B1 and BCRP substrate rosuvastatin increased plasma rosuvastatin Cmax 
103% and AUCinf 55%.The administration of a single dose of eltrombopag 50 mg (BCRP 
substrate) with 200 mg cyclosporine A (CsA) (a BCRP inhibitor) to healthy participants 
decreased the mean Cmax and mean the AUCinf of eltrombopag by 25% and 18%, respectively. 
The co-administration of 600 mg CsA decreased the mean Cmax and the mean AUCinf of 
eltrombopag by 39% and 24%, respectively. Given that the eltrombopag dose adjustment is 
permitted during the course of treatment for achieving the target platelet count, this decrease in 
exposure was not considered clinically meaningful. No starting dose adjustment is 


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recommended when eltrombopag is co-administered with CsA. Platelet count should be closely 
monitored when eltrombopag is co-administered with CsA and eltrombopag dose may need to 
be adjusted based on these platelet counts.  
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. It is 
therefore recommended to take eltrombopag at least 2 hours before or 4 hours after other 
medications (e.g., antacids), calcium-rich foods (e.g., dairy products and calcium-fortified 
juices), or supplements containing polyvalent cations such as iron, calcium, aluminum, 
magnesium, selenium, and zinc. 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. Eltrombopag is recommended to take at least 
one hour before or two hours after food containing little (< 50 mg) (or preferably no) calcium.  
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. SAA patients of East-Asian ethnicity need to decrease the initial dose by 50% relative 
to Caucasian, according to eltrombopag Label approved by US food and drug administration 
(FDA) and the european medicines agency (EMA). The initial doses for Chinese ≥12 year-old 
ITP participants (approved by CDE) and Japanese adult SAA participants (approved by 
pharmaceuticals and medical devices agency (PMDA)), were identical with those for East Asian 
participants in US and EMA label.  
Additional information can be found in the Investigator’s Brochure and summary of product 
characteristics in eltrombopag package insert. 
2 
Objectives and endpoints 
For the definition of response, partial response (PR), CR, transfusion independence, and relapse, 
refer to Section 8.3.  
Table 2-1 
Objectives and related endpoints 
Objective(s) 
Endpoint(s) 
Primary objective(s) 
Endpoint(s) for primary objective(s) 
• 
To evaluate the efficacy of eltrombopag in combination 
with r-ATG and CsA in terms of complete response rate 
at 6 months in East-Asian patients with treatment naive 
severe aplastic anemia (SAA) 
• 
CR rate at Week 26 (6 months) after 
starting the study treatment  
Secondary objective(s) 
Endpoint(s) for secondary objective(s) 
• 
To evaluate complete response rate at 3, 12 months and 
yearly after 
• 
CR rate at Week 13 (3 months), Week 52 
(12 months) and yearly after 
• 
To evaluate overall response rate at 3, 6, 12 months and 
yearly after 
• 
Overall response (CR+PR) rate at Week 
13 (3 months), Week 26 (6 months), Week 
52 (12 months) and yearly after 


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Objective(s) 
Endpoint(s) 
• 
To evaluate duration of response 
• 
Time from the date of the start of 
response to the date of relapse or death, 
whichever occurs first at any time during 
the study 
• 
To evaluate overall survival (OS)  
• 
Time from the date of first dose of study 
treatment to the date of death 
• 
Overall survival rate at Week 26, Week 52 
and yearly after 
• 
To evaluate the need for transfusion (packed RBC units 
and platelet units) 
• 
Time from the most recent transfusion 
to Week 13 and Week 26 
• 
Proportion of participants who 
becomes (platelet/RBC) transfusion 
independent  
• 
To evaluate safety and tolerability of eltrombopag in 
combination with r-ATG and CsA 
• 
Frequency and severity of AEs, severe 
adverse events (SAEs), vital signs, 
electrocardiogram and laboratory 
abnormalities 
• 
To evaluate clonal evolution 
• 
Time from the date of first dose of study 
treatment to the date of first occurrence of 
any of the clonal evolution events 
• 
To determine the pharmacokinetics (PK) of eltrombopag 
in East-Asian treatment naive SAA patients 
• 
Plasma PK parameters and trough 
concentration of eltrombopag at steady 
state 
3 
Study design 
This is a non-randomized, open label, single arm, multi-center, Phase II study to evaluate the 
efficacy and safety of eltrombopag in combination with IST regimen of r-ATG + CsA in East-
Asian patients with SAA who have not received prior IST. At least 36 participants will be 
enrolled from China, Japan, Korea or Taiwan. At least 6 pediatric participants will be recruited 
in total, with 3 participants from China and 3 from Japan respectively. At least one of the 6 
pediatric participants in each age group (6 to 11 years old, and 12 to 17 years old) will be 
enrolled. For the 30 adult participants, at least 12 participants will be recruited from China to 
fulfill the requirements for pharmacokinetic (PK) profile.  


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Figure 3-1 
Study design 
  
Eligible participants will be enrolled into the study and will receive eltrombopag (from Day 1 
to Week 26) concomitantly with r-ATG (on Days 1-5) and CsA (from Day 1 to Week 26) in the 
core treatment part. 
Efficacy assessments will be performed at Week 13 and Week 26 in the core treatment part of 
the study. 
Participants who are assessed as responders (meeting CR or PR criteria) at Week 26 are eligible 
to the extension part of the study and continue treatment with eltrombopag and CsA after Week 
26.  


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Study treatment should be discontinued if the participant is not assessed as a responder at Week 
26.  
During the extension part, eltrombopag treatment will be provided up to Week 52. CsA will be 
maintained or tapered at the investigator's discretion according to local practice, with a total 
duration of at least 2 years (18 months after Week 26, see Section 6.1.5).End of treatment (EOT) 
assessments will be performed after eltrombopag discontinuation at anytime during the study. 
After that, safety follow-up visit will be performed 30 days after the discontinuation of 
eltrombopag, and participants will enter the long-term follow-up part, with yearly efficacy and 
clonal evolution assessments up to Year 3 (Week 156). 
For non-responders at Week 26, and participants who relapse or receive alternative SAA 
treatment, safety follow-up visit will be performed 30 days after the discontinuation of 
eltrombopag, and then clonal evolution and survival will continue to be followed up to Year 3 
(Week 156). 
Participants who prematurely discontinue eltrombopag will have efficacy assessments at 
defined time points (Week 13, Week 26, Week 52 and yearly after), unless or until the 
occurrence of no response at Week 26, relapse or alternative SAA treatment (whichever comes 
first). Survival and clonal evolution data will be collected for all participants up to Year 3 (Week 
156) 
4 
Rationale 
4.1 
Rationale for study design 
This is an open-label, non-randomized, phase II study to evaluate the efficacy and safety of 
eltrombopag in combination with r-ATG and CsA in treatment-naive East-Asian participants 
with SAA. The design is based on the hypothesis that the addition of eltrombopag to r-ATG 
and CsA in treatment-naive SAA patients can improve the quality of the response and the 
response rate with an acceptable safety profile. 
The rationale to combine eltrombopag with IST based on ATG is based on the potential benefit 
to improve the outcome of IST alone by increasing stem cell number. It is reasonable to 
conclude that the addition of a hematopoietic growth factor capable of expanding primitive 
HSCs and progenitors would be useful. TPO, is a potent endogenous cytokine and the principal 
regulator of platelet production, as summarized in Section 1.1. Eltrombopag, the TPO-agonist, 
has been shown to increase platelets in healthy participants, patients with chronic ITP, and 
shown to increase blood counts in patients with hepatitis C associated thrombocytopenia 
(McHutchison et al 2007), in refractory SAA patients as single agent and in treatment-naive 
SAA patients in combination with IST (Olnes et al 2012, Townsley et al 2017). These results 
suggest that eltrombopag is likely to act directly to stimulate the proliferation of small numbers 
of residual stem-progenitor cells in patients with AA and offer real clinical benefits.  
The rationale for this single arm study design is as follows: 
• SAA is a rare disease with high unmet medical needs. The incidence of AA is about 3.9 to 
7.4 cases per million in Asian countries (Young et al 2006, Young and Kaufman 2008), 
which makes it difficult to enroll participants from a perspective of feasibility. There is a 
high unmet medical need to improve the rate and quality of response to current front line 


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treatment due to the incomplete responses, relapses and primary refractoriness are related 
to poor outcomes (Olnes et al 2012, Scheinberg and Young 2012).  
• The efficacy endpoints of response and relapse are objective based on platelet counts, 
hemoglobin levels, reticular cell counts and neutrophil counts. 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 
per 
guidelines 
of 
transfusions 
and 
AA 
(Red Blood Cell Disease (Anemia) 2017, Killick et al 2016). Therefore, the investigator's 
decision to give transfusion seems to have no substantial influence on assessment of the 
efficacy endpoint. Hence placebo effects are nearly absent.  
• The use of eltrombopag in the first line setting has been explored in a global pivotal study 
(Study CETB115AUS01T). Eltrombopag was well-tolerated, with a safety profile 
consistent with events that occur in patients with SAA undergoing immunosuppression with 
hATG/CsA. Efficacy and safety data from Study CETB115E1202 conducted in Japan 
provided an independent substantiation of the results from CETB115AUS01T study. 
CETB115E1202 study confirmed the clinical benefit of eltrombopag with rabbit ATG/CsA 
treatment in patients with moderate or more SAA who had not received prior ATG/ALG-
based IST, with no new safety concerns.  
• Eltrombopag first-line SAA indication has been approved in USA and Japan based on these 
studies.  
The study is composed by 3 parts: 
• A core treatment part set from Day 1 to Week 26, the time for primary endpoint assessment, 
as was the case in Cohort 3 and Extension Cohort in Study CETB115AUS01T showing the 
highest CR rate. 
• An extension part for responsive participants, considering that responders may benefit from 
continued treatment to maintain the response. 
• A long-term follow-up part for all participants enrolled, in order to collect information about 
long-term efficacy, survival and clonal evolution. 
4.2 
Rationale for dose/regimen and duration of treatment 
The investigational drug in this study is eltrombopag (ETB115). The study treatment includes 
eltrombopag, r-ATG and CsA. 
Eltrombopag: 
The eltrombopag doses proposed in this study were set at the same level with Study 
CETB115AUS01T (eltrombopag + h-ATG + CsA) in treatment-naive SAA patients, in which 
eltrombopag was administered at 150 mg daily in non-Asian patients ≥12 years old, and at half 
that dose (75 mg daily) in patients between 6 to 11 years old; East-Asians patients were treated 
with half these doses in the same age group (75 mg/day for patients ≥12 years old, and 37.5 
mg/day for patients between 6 to 11 years old). 
The initial dose in this study is set at the same level with Study CETB115AUS01T (75 mg/day 
for participants ≥12 years old; 37.5 mg/day for participants ≥ and <12 years old). This dosage 


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is in alignment with the dose for East-Asian SAA patients in the US product information. The 
use of different starting doses in different age subgroups in Study CETB115AUS01T resulted 
in similar CR rates at Month 6 observed across the age subgroups (including pediatric, adult 
<65 years and elderly) in the primary analysis. At the updated cutoff date (28-Feb-2018), there 
seems to be an apparent difference in CR rate at Month 6 by subgroup of age, with 28.0% (95% 
CI: 12.1-49.4) for participants of 2 to 17 years old, compared with 50.0% (95% CI: 37.0-63.0) 
for participants aged 18 years and above. This difference is confounded by the imbalance of the 
severity of the disease, with 56.0% of VSAA in participants <18 years old vs. 40.3% VSAA in 
participants aged 18 years and above.  
Eltrombopag will be initiated on Day 1 (concomitantly to r-ATG and CsA) and continued for 6 
months till Week 26. After Week 26, responders will continue eltrombopag and CsA in the 
extension part due to the consideration that the responders may benefit from continued 
treatment to maintain the response, see Section 4.1.  
r-ATG and CsA 
Rabbit-ATG will be administered in accordance with local product label. The dose titration of 
CsA will be in accordance with local practice guidelines for SAA treatment. Based on the data 
showed in CETB115AUS01T that relapse rates were numerically lower in responders who had 
CsA maintained for 2 years compared to responders who did not, CsA will be maintained after 
core treatment part up to Year 2 (Week 104). Therefore, the target duration of CsA will be 2 
years (6 months higher dose, and thereafter tapered or maintained per local standard of care). 
4.3 
Rationale for choice of combination drugs 
For SAA participants who are not suitable candidates for HSCT, IST (ATG and CsA) is the 1st 
line therapy of choice worldwide (Scheinberg and Young 2012, Killick et al 2016). IST with h-
ATG and CsA has demonstrated better outcomes compared with r-ATG and CsA in prospective 
studies (Scheinberg et al 2011, Marsh et al 2012). As h-ATG is not available in China, Taiwan, 
Korea and Japan markets, the current standard IST in these countries/regions for participants 
with SAA is r-ATG + CsA (Red Blood Cell Disease (Anemia) 2017, Kojima et al 2011, 
Bacigalupo et al 2018), which is the selected IST in this study. The addition of eltrombopag to 
r-ATG + CsA in Study CETB115E1202 showed a higher overall response rate than that 
reported in (Scheinberg et al 2011) at 6 months with r-ATG + CsA alone.  
CsA will be administered in accordance with local practice guidelines for SAA treatment 
(Red Blood Cell Disease (Anemia) 2017, Kojima et al 2011, Yoshida and Kojima 2018).  
4.4 
Purpose and timing of interim analyses/design adaptations 
Not applicable.  
4.5 
Risks and benefits 
Eltrombopag is a once daily oral medicine with a well characterized safety profile since its 
initial approval for ITP in 2008. Acceptable safety profile were observed in studies conducted 
in SAA patients, in refractory and first-line indications. 


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The safety profile of eltrombopag in combination with ATG and CsA observed in the studies 
CETB115AUS01T and CETB115E1202 is acceptable and consistent with the prescribing 
information (for all 3 drugs) and the underlying population with SAA. 
The efficacy in the target population of the addition of eltrombopag to IST observed in the 
studies CETB115AUS01T and CETB115E1202, demonstrated clinically meaningful 
improvement in hematological response relative to historically published ATG-based IST 
alone.  
Risk assessment 
Eltrombopag, has an established safety profile based on the safety databases supporting 
marketing approval in chronic ITP, pediatric chronic ITP, HCV, refractory SAA, and first-line 
treatment SAA in Japan and US, as well as post-marketing data since initial approval in the US 
in 2008. The safety profile of eltrombopag in combination with ATG and CsA is acceptable and 
consistent with the prescribing information (for all 3 drugs) as demonstrated in Study 
CETB115AUS01T and Study CETB115E1202, in light of the underlying population with SAA.  
• The risks to participants in this study may come from adverse reactions, adverse events of 
special interest (AESI) that have a potential to became adverse reactions and lack of 
efficacy. The risk to participants in this trial may be minimized by compliance with the 
eligibility criteria and study procedures, as well as close clinical monitoring, stopping 
rules, safety and tolerability assessments, and dose modifications.  
• The risk specific to patients receiving eltrombopag is hematological malignancies and 
increased bone marrow reticulin formation (all indications). They will be monitored by bone 
marrow aspiration and biopsy performed at Week 13, Week 26, Week 52 and yearly after, 
as described in Section 8.4.3 and Table 8-1. 
• The risk specific to patients with SAA receiving eltrombopag is the potential for cytogenetic 
abnormalities. Clonal evolution is almost always an early event occurring within 6 months 
after initiation of eltrombopag in refractory SAA participants (Winkler et al 2019). The 
role of eltrombopag in the development of cytogenetic abnormalities in treatment-naive 
SAA patients remains unknown. In Study CETB115AUS01T, clonal cytogenetic evolution 
occurred in 15/154 (10%) participants. Of the 15 participants who experienced cytogenetic 
abnormalities, 4 participants had chromosomal aberrations of unclear significance. 7 of 
these 15 participants had loss of chromosome 7, either alone or in combination with 
complex cytogenetic abnormalities, and in 6 of them, it occurred within the first 6.1 months. 
In 3 of the 7 participants this was accompanied by morphologic evidence of dysplasia or 
full myeloid malignant transformation. In 3 of 15 participants deletion of chromosome 13 
was reported, considered to be a good prognostic factor in patients with aplastic anemia. 
One participant had a follow-up bone marrow assessment at 5 years which was markedly 
changed compared to prior bone marrow assessment, with features of dysplasia with 
hypercellularity concerning for potential development of myelodysplastic syndrome (MDS). 
It is unclear if these evolutions occurred due to the underlying disease, the IST and/or 
eltrombopag. In Study CETB115E1202, one cytogenetic abnormality was detected and it 
was not associated with dysplasia and increase in bone marrow blasts; no progression to 
MDS was reported. For the proposed protocol, bone marrow examination including 
cytogenetics will be performed at Week 13, Week 26, Week 52 and yearly after, as 


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described in Section 8.4.3 and Table 8-1. Development of new cytogenetic abnormalities 
must be documented and will result in permanent discontinuation of study treatment as 
described in Section 9.1.1. 
• There may be unforeseen risks with the study treatment which could be serious. These 
include but may not be limited to drug to drug interactions and long-term safety. Close 
adherence to eligibility criteria, study procedures safety monitoring and dose adjustment 
will help to minimize unforeseen risks. Potential for drug-drug interaction and measures to 
minimize undesired drug-drug interactions are described in Section 6.2.1 and Section 6.2.2. 
• Appropriate eligibility criteria and specific drug toxicities, as well as specific dose 
modification and stopping rules, are included in this protocol. The risk management plan 
will be in place to ensure the safety of the participants.  
• For pediatric participants, the safety of eltrombopag have been established in patients 1 year 
and older with chronic ITP and in pediatric patients 2 years and older with definitive IST-
naïve SAA (in combination with h-ATG and CsA). In the pediatric subgroup in Study 
CETB115AUS01T, there were 37 participants: 2 participants in 2-5 years; 12 participants 
in 6-11 years and 23 participants in the 12-17 years. The AEs observed were consistent with 
those observed in the overall population included in the study, with the exception of a higher 
incidence of febrile neutropenia and upper respiratory tract infection in pediatric patients vs. 
adults. However, both events are more common in the pediatric population and expected by 
the underlying SAA. Therefore the dosing regimen follows the recommendation for Asian 
patients in the approved US label to ensure the safety of the pediatric patients along with 
the risk management plan.  
• 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 must 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 participant will not reliably comply, they should not be entered or continue in the 
study. 
Benefit assessment 
The expected benefit for treatment-naive SAA patients in this study is based on the clinical data 
from Study CETB115AUS01T and Study CETB115E1202. In Study CETB115AUS01T the 
addition of eltrombopag to h-ATG + CsA led to robust, compelling, and consistent results 
demonstrating a clinically meaningful and statistically significant improvement in 
hematological response relative to IST of h-ATG + CsA alone. The CR in 43.7% of the patients 
in the combined Cohort 3 + Extension Cohort observed at 6 months was compelling compared 
to the historical data (~10-25%) in this severely ill pediatric and adult population who are not 
suitable candidates for HSCT and where available treatment options are limited. Moreover, 
long-term survival for responders has been associated with an early and robust hematologic 
recovery (Rosenfeld et al 2003). The use of eltrombopag in combination with r-ATG-based IST 
in Study CETB115E1202 independently substantiate that clinical benefits were derived from 
the use of eltrombopag in combination with r-ATG-based IST in the target population, with 
57.1 % (4 of 7) participants overall response at Week 26 and 3 participants maintained the 
response at Week 52. 


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The expected potential benefits are as follows:  
• The improvement in response (rate and quality, reflected by overall response rate, CR rate, 
and duration of response) and outcome (OS) to r-ATG/CsA.  
• The decreased need of transfusions (platelet and red blood cells (RBC)) by more rapid and 
robust hematological response. 
Risk and benefit evaluation 
In conclusion, the expected benefits of eltrombopag in combination with ATG-based IST in 
treatment-naive SAA patients (both adult and pediatric) indicated a positive risk:benefit ratio 
that support the conduct of this study as the study assessments are carefully selected to minimize 
the risk to enrolled participants. It is expected that eltrombopag can meet the important unmet 
medical need in this population, without incurring unacceptable risk. 
4.6 
Rationale for Public Health Emergency mitigation procedures 
During a Public Health emergency as declared by Local or Regional authorities i.e. pandemic, 
epidemic or natural disaster, mitigation procedures to ensure participant safety and trial integrity 
are listed in relevant sections. Notification of the Public health emergency should be discussed 
with Novartis prior to implementation of mitigation procedures, and permitted/approved by 
Local or Regional Health Authorities and Ethics Committees as appropriate. 
5 
Population 
This study is designed for East-Asian patients aged 6 years or older with treatment-naive 
SAA who lack a suitable matched sibling marrow donor, or are not allogeneic transplantation 
candidates due to patient choice, advanced age, or infeasibility of transplantation. The diagnosis 
is based on objective hematological counts according to the standard Camitta criteria 
(Camitta et al 1975). It is estimated that at least 36 participants will be enrolled from the study 
sites in China, Japan, Korea or Taiwan. At least 6 pediatric participants will be recruited in total, 
with 3 participants from China and 3 from Japan respectively. At least one of the 6 pediatric 
participants in each age group (6 to 11 years old, and 12 to 17 years old) will be enrolled. For 
the 30 adult participants, at least 12 participants will be recruited from China to fulfill the 
requirements for PK profile. Replacement is not allowed in this study. The investigator or 
designee must ensure that only participants who meet all the following inclusion and none of 
the exclusion criteria are offered treatment in the study. 
5.1 
Inclusion criteria 
Participants eligible for inclusion in this study must meet all of the following criteria: 
1. Written study informed consent and (where applicable) assent from the participant, parent, 
or guardian must be obtained prior to participation in the study. 
2. Participants of East Asian ancestry aged≥ 6 years old at the time of written informed consent 
and assent form (if applicable). 
3. SAA characterized by (Camitta et al 1975, Red Blood Cell Disease (Anemia) 2017): 
• Bone marrow cellularity < 25%, or 25-50% with < 30% residual hematopoietic cells 
and pancytopenia, with at least two of the following parameters in peripheral blood:  


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• Absolute neutrophil count < 0.5×109/L 
• Platelet count < 20×109/L 
• Absolute reticulocyte count < 20×109/L  
4. HSCT is not suitable or available as a treatment option (determined as per local practices or 
national guidelines), or has been refused by participant.  
5.2 
Exclusion criteria 
Participants meeting any of the following criteria are not eligible for inclusion in this study. 
1. Prior IST with any ATG/ALG, alemtuzumab, high dose cyclophosphamide (≥45mg/kg/day), 
CsA within 6 months, or prior thrombopoietin receptor (TPO-R) agonists  
2. Participants have an Eastern Cooperative Oncology Group (ECOG) performance status (age 
≥ 16 years) >2, or Lansky performance status (age < 16 years) <50 
3. Prior and/or active medical history of: 
• Known underlying congenital/inherited bone marrow failure or aplastic anemia (such 
as but not limited to Fanconi anemia, congenital dyskeratosis, congenital 
amegakaryocytic thrombocytopenia, or Shwachman-Diamond Syndrome) 
• Symptomatic paroxysmal nocturnal hemoglobinuria (PNH) and/or PNH clones >50% 
of polymorphonuclear neutrophil or RBC at time of enrollment 
• Myelodysplastic syndrome 
• Any 
cytogenetic 
abnormalities 
on 
karyotyping 
or 
fluorescence 
in 
situ 
hybridization (FISH) within 30 days of study enrollment (an evaluable karyotyping 
with at least 10 metaphases is mandatory for eligibility) 
• Other known or suspected underlying primary immunodeficiency 
• Any concomitant malignancies that have not fully recovered from treatment or have 
not been disease-free for 5 years 
4. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >3 times the upper 
limit of normal (ULN) 
5. Creatinine ≥ 2.5× local ULN 
6. Past medical history of thromboembolism within 6 months and/or prior or current 
antiphospholipid antibody syndrome (APS) 
7. Presence of clinically active uncontrolled significant (of such severity that it would preclude 
the participant's ability to consent, be compliant with study procedures, tolerate protocol 
therapy) infection, including bacterial, fungal, mycobacterial, parasitic or viral infection, or 
any concurrent condition that, in the Investigator's opinion, would jeopardize the safety of 
the participant or compliance with the protocol 
8. Any severe and/or uncontrolled medical conditions which could cause unacceptable safety 
risks or compromise compliance with the protocol, such as: 
• Known hepatocellular disease (e.g. active hepatitis or cirrhosis) 
• Impairment of gastrointestinal (GI) function or gastrointestinal disease that may 
significantly alter the absorption of study treatment (e.g., ulcerative disease, 
uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome) 
• Active skin, mucosa, ocular or GI disorders of Grade > 1 


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9. Presence of hepatitis B surface antigen (HBsAg) or positive hepatitis C antibody test result 
at screening. A positive serology for Hepatitis B (HB) is considered as a positive test for 
HBsAg. In addition, if serology is negative for HBsAg but hepatitis B core antibody 
(HBcAb) is positive (regardless of hepatitis B surface antibody (HBsAb) status), a Hepatitis 
B virus (HBV) DNA test will be performed and if positive (any detectable copy of HBV 
DNA will be identified as "positive") the patient will be excluded 
10. Positive result for human immunodeficiency virus (HIV) antibody test 
11. Cardiac disorder (participants with congestive heart disease of New York Heart Association 
(NYHA) functional classification Grade II/III/IV (for pediatric participants, refer to the 
Grade II/III/IV of Modified ross heart failure classification for Children) should not be 
enrolled; participants with NYHA Grade II due to cardiac disorder should not be enrolled 
but those with NYHA Grade II due to AA may be enrolled.), arrhythmia with a risk of 
thrombosis (e.g. atrial fibrillation), pulmonary hypertension, or uncontrolled hypertension 
(>180/100 mmHg) 
12. Contraindications to r-ATG or CsA, or past medical history of immediate or delayed 
hypersensitivity to compounds chemically similar to eltrombopag, CsA, r-ATG or their 
excipients 
13. Participant who is unable to comprehend or is unwilling to sign an informed consent form 
(ICF) or assent form (if applicable) 
14. Unable or unwilling to swallow tablets as per dosing schedule 
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 
investigational treatment. 
16. Pregnant or nursing (lactating) woman. 
17. Woman of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using highly effective methods of contraception while 
taking study treatment and for 7 days after stopping study treatment. Highly effective 
contraception methods include: 
• Total abstinence (when this is in line with the preferred and usual lifestyle of the 
participant. Periodic abstinence (e.g. calendar, ovulation, symptothermal, post-
ovulation methods) and withdrawal are not acceptable methods of contraception. 
• Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy), total hysterectomy, or tubal ligation at least six weeks before taking 
study treatment. In case of oophorectomy alone, only when the reproductive status of 
the woman has been confirmed by follow up hormone level assessment. 
• Male sterilization (at least 6 months prior to screening). For female participants on the 
study, the vasectomized male partner should be the sole partner for that participant. 
• Use of oral, injected or implanted hormonal methods of contraception or placement of 
an intrauterine device or intrauterine system, 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. 


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Women are considered post-menopausal and not of child bearing potential if they have had 
12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age 
appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy 
(with or without hysterectomy), total hysterectomy, or tubal ligation at least six weeks 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. 
If local regulations deviate from the contraception methods listed above to prevent 
pregnancy, local regulations apply and will be described in the ICF. 
18. 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 drug for this study is eltrombopag (ETB115). The study treatment includes 
eltrombopag, r-ATG and CsA. 
6.1.1 
Investigational and control drugs 
Table 6-1 
Investigational and combination drugs 
Investigational/ 
Combination Drug 
(Name and 
Strength) 
Pharmaceutical 
Dosage Form 
Route of 
Administration 
Supply Type 
Supplied by 
Eltrombopag 
(ETB115) 25mg 
Tablet 
Oral use 
Open label 
participant packs; 
bottles 
Sponsor (global) 
Eltrombopag 
(ETB115) 12.5mg 
Tablet 
Oral use 
Open label 
participant packs; 
bottles 
Sponsor (global) 
r-ATG 25mg 
Sterile lyophilized 
powder in 10 mL 
vials 
Intravenous use 
Open label 
participant packs; 
vials 
Sponsor (local) 
CsA 25mg 
Capsule 
Oral use 
Open label 
participant packs; 
blisters 
Sponsor (local) 
CsA 5.0g/50mL*  
Solution 
Oral use 
Open label 
participant packs; 
bottles 
Sponsor (local) 
r-ATG: rabbit anti-thymocyte globulin; CsA: cyclosporine. 
* The CsA solution from Sandoz is not available in China.  
r-ATG and CsA will be provided locally according to the availability of each drug and dosage 
form.  


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This is an open label, single arm study, hence, no control or comparator drug is needed in this 
study.  
6.1.1.1 
Eltrombopag 
For participants ≥ 12 years old, eltrombopag will be initiated at a dose of 75 mg/day. 
For participants ≥ 6 and < 12 years old, eltrombopag will be initiated at a dose of 37.5 mg/day. 
Eltrombopag will be administered orally, once daily. Participants will be instructed to take 
eltrombopag daily with the initial dose shown in Table 6-2 at the same time each day. 
Table 6-2 
Initial dose of eltrombopag 
Age group 
Initial dose of eltrombopag 
For participants ≥ 12 years old  
75 mg/day 
For participants ≥ 6 years old and < 12 years old 
37.5 mg/day 
For detailed information of food and medicine interaction, refer to Section 6.7.2. 
On days that PK samples are obtained, the participants 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. 
The dose of eltrombopag will be adjusted based on platelet count, according to the criteria 
shown in Table 6-3. The daily dose of eltrombopag will be decreased by 25 mg/day every 2 
weeks (12.5 mg/day, for participants below 12 years old) if the platelet count rises above 
200×109/L, and eltrombopag treatment will be interrupted for one week if the platelet count 
rises above 400 × 109/L. Once the platelet count falls below 200×109/L, eltrombopag should be 
reinitiated at a daily dose reduced by 25 mg (12.5 mg for participants below 12 years old).  
Table 6-3 
Dose adjustment criteria for eltrombopag 
Platelet count 
Dose adjustment or response 
Platelet count > 200 x 109/L without transfusion 
Decrease the dose by 25 mg every 2 weeks (by 12.5 
mg for pediatric participants younger than 12 years 
old) 
Wait 2 weeks before next dose adjustment to assess 
the effect of the dose adjustment 
Platelet count > 400 x 109/L without transfusion 
Eltrombopag will be interrupted for at least one week 
until the platelet count becomes 
< 200 x 109/L*, and restarted at a dose decreased by 
25 mg (by 12.5 mg for pediatric participants younger 
than 12 years old) (12.5 mg/day at the lowest).  
* Platelet count will be assessed in absence of platelet transfusion.  
Eltrombopag dose may be interrupted when clinically indicated at the discretion of the 
investigator. Interruptions will be reported. For participants who meet any toxicity criteria (see 
Section 6.5.1 ) or who do not tolerate the protocol-specified dosing schedule, the investigator 
will follow the guideline on dose modification and/or discontinuation presented in Section 6.5.1. 
Participants in whom the treatment is assessed as effective at Week 26 may continue treatment 
with eltrombopag and CsA after Week 26 (in the extension part of the study). Eltrombopag will 


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be provided for the participants who entered the extension part and are considered to require 
continued treatment up to Week 52.  
If participants have achieved their best hematological response (no increase in ANC, 
hemoglobin or platelet occurs within 8 consecutive weeks) in the extension part and all the 
hematologic criteria (platelet count >50 x109/L, hemoglobin level >100 g/L , and ANC >1.0 
x109/L unaided by transfusions and growth factors) remain fulfilled for at least 8 consecutive 
weeks, the dose of eltrombopag will be tapered according to Table 6-4. Maintenance of the dose 
is permitted if, in the opinion of the investigator, a participant is deemed to be placed at a safety 
risk (such as, but not limited to, bleeding or severe infections) at the decreased dose. 
Table 6-4 
Dose adjustment criteria in extension part after Week 26 (for 
participants maintaining hematologic response for more than 8 
weeks) 
Criteria 
Dose adjustment or response 
a) Achieved the best hematological response* and all 
the hematologic criteria (platelet count> 50 x 109/L, 
hemoglobin level > 100 g/L, and ANC > 1.0 
x109/L ) remain fulfilled. 
Decrease by 50% (see Table 6-5). Continue 
monitoring hematology every 2 weeks. 
b) After 8 weeks at this decreased dose if the 
hematological response is maintained and all the 
hematologic criteria (platelet count> 50 x 109/L, 
hemoglobin level > 100 g/L , and ANC 
> 1.0 x 109/L) remain fulfilled 
Interrupt eltrombopag. Continue monitoring 
hematology every 2 weeks. 
For CR participants: 
While at the decreased dose a) or interruption b), 
blood counts drop to that do not meet CR criteria at 2 
serial blood counts at least one week apart (not 
explained by another clinical process) 
For PR participants: 
While at the decreased dose or interruption, drop to 
platelet counts < 30 x109/L or Hb < 90 g/L or ANC 
< 0.5 x 109/L or need transfusion 
Can increase to the dose before decrease or restart 
at the dose before interruption. 
Continue monitoring hematology every 2 weeks. 
*No increase in ANC, hemoglobin or platelet count occurs within 8 consecutive weeks  
Hematological value will be assessed in the absence of platelet transfusion, RBC transfusion and G-CSF. 
If response has been achieved before Week 26 and maintained, the dose will be decreased no sooner than 
Week 26. 
Table 6-5 
Dose decrease of eltrombopag after Week 26 
Dose before decrease 
50% decreased dose 
75 mg/day 
37.5 mg/day 
50 mg/day 
25 mg/day 
37.5mg/day 
25mg/day or 12.5mg/day* 
25 mg/day 
12.5mg/day 
12.5mg/day 
12.5mg/every other day  
* When eltrombopag dose need to be reduced by 50% from 37.5 mg/day, the investigators will need to select 
an appropriate dose level (choose either 25 mg or 12.5 mg daily for participants treated with eltrombopag 37.5 
mg/day) according to participants' clinical status 


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6.1.1.2 
Rabbit anti-thymocyte globulin (r-ATG) 
Usually, r-ATG (Thymoglobuline®) will be administered at a dose of 2.5 to 3.5 mg/Kg/day on 
Days 1 to 5 as a slow intravenous infusion per local practice. The exact dose of r-ATG should 
be decided at the discretion of the investigator but should be within the above range.  
Premedication with corticosteroids, acetaminophen, and/or an antihistamine 1 hour prior to each 
infusion of r-ATG is recommended and may reduce the incidence and intensity of infusion-
associated reactions (detailed in Section 6.2.1). For the treatment for anaphylaxis and infusion-
associated reactions, local label should be followed.  
6.1.1.3 
Cyclosporine (CsA) 
CsA (Neoral®) will be administered orally every 12 hours from Day 1 at a starting dose of 3-6 
mg/Kg/day. Dosing of CsA should be titrated individually to obtain a therapeutic trough level 
of 150-250 μg/L, recommended to be as close to 200 μg/L as possible in the core treatment part. 
In the extension part, CsA should last for at least 18 months, if well tolerated, and will be 
maintained or tapered based at the discretion of the investigator according to local practice in 
this period. It is recommended that CsA treatment dose will last for at least 3 months after 
achieving the best hematologic response, and after that CsA will be decreased by 0.3 mg/kg 
every month or 1mg/kg every 3 months. 
For administration of CsA, the local label contraindications should be considered in accordance 
with exclusion criterion. Certain other medications can change the level of CsA in the blood. 
Some of these medications are azoles (e.g. ketoconazole, fluconazole, voriconazole), 
methylprednisolone, erythromycin, diltiazem, rifampin, phenytoin and phenobarbital. The 
participant must inform the investigator of any medication taken concomitantly while on the 
study. More frequent CsA serum levels may be obtained as needed to achieve target therapeutic 
levels and avoid toxicity when participants are taking any medications that may change the CsA 
level. In terms of concomitant medications requiring caution and/or dose modification, refer 
to Section 6.2.1.1. Grapefruit and grapefruit juice may increase the effects of CsA by increasing 
the amount of this medicine in the body. Participants will be advised not to eat grapefruit or 
drink grapefruit juice while taking this medicine. For detailed information, see Section 6.7.2.  
CsA dose may be reduced or interrupted temporarily when clinically indicated at the discretion 
of the investigator or treating physician (e.g. AE grade 2 or higher). The parenteral route of 
administration may be used temporarily for CsA administration if indicated. Temporary 
interruptions for transient toxicities grade 2 or higher or dose adjustments will be reported. Per 
protocol interruptions and reductions will not be reported as deviations.  
6.1.2 
Additional study treatments 
The investigational site is responsible for sourcing all additional study treatments.  
Infection prophylaxis 
Prophylactic regimen against infection will be administered at the discretion of the investigator 
or treatment physician following local guidelines. Infection prophylaxis (antibacterial, 
antifungal, anti- Pneumocystis Jirovecii, and antiviral) will not be routinely administered 
systematically with the immunosuppressive regimen but may be administered at the discretion 


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of the investigator or treatment physician on a case by case basis. Prophylactic therapy may be 
continued at the discretion of the investigator.  
Premedications of infusion associated reactions 
Premedication with corticosteroids, acetaminophen, and/or an antihistamine prior to each 
infusion of r-ATG should follow the local label of r-ATG to reduce the incidence and intensity 
of infusion associated reactions.  
Supportive care 
Supportive care for the participant (e.g., transfusion support with RBC, platelet or granulocytes, 
anti-infective care and/or growth factors) will be allowed as clinically indicated, as presented 
in Section 6.2.1. 
6.1.3 
Treatment arms/group 
This is a single arm study.  
6.1.4 
Guidelines for continuation of treatment 
For participants who meet any criteria for dose interruption described in Section 6.1.1.1, the 
investigator will follow the guideline presented in Section 6.1.1.1. For participants who meet 
any toxicity criteria, the investigator will follow the guideline on dose reduction, interruption 
and/or discontinuation presented in Section 6.5.1.1 and Section 6.5.1.2. Participants 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 
The core treatment part of this study is 6 month from the start of eltrombopag treatment (Day 1 
to Week 26). Participants assessed as responders at Week 26 will be eligible to enter the 
extension part and may continue treatment with eltrombopag and CsA after Week 26 until 
Week 52.  
Core treatment part 
The planned duration of eltrombopag treatment is 6 months in the core treatment part. 
Participants may be discontinued from treatment earlier due to unacceptable toxicity, disease 
progression and/or treatment is discontinued at discretion of the investigator or of the participant 
(see Section 9.1.1).  
The administration of r-ATG will be from Day 1 to Day 5.  
For all participants, CsA will be administered at doses that obtain the target trough level range 
for 6 months if well tolerated. CsA dose may be interrupted temporarily when clinically 
indicated at the discretion of the investigator or treating physician. The parenteral route of 
administration may be used temporarily for CsA administration if indicated. Temporary 
interruptions for transient toxicities or dose adjustments will be reported. Per protocol 
interruptions will not be reported as deviations. 


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Extension part 
The participants assessed as responders at Week 26 are eligible to enter the extension 
part. Eltrombopag will be provided up to Week 52 for the participants who enter the extension 
part and are considered to require continued treatment. For the participants who meet the 
discontinuation criteria in Section 9.1.1, the study treatment will be discontinued.  
In extension part, CsA will last for at least 18 months after Week 26 if well tolerated (total 
duration is from Day 1 to at least Year 2). CsA will be maintained or tapered based on the 
discretion of the investigator according to local practice. It is recommended that CsA treatment 
dose last for at least 3 months after achieving the best hematologic response, and after that CsA 
is recommended to be tapered by 0.3 mg/kg every month or 1 mg/kg every 3 months. CsA dose 
may be decreased or interrupted temporarily when clinically indicated at the discretion of the 
investigator or treating physician. Temporary interruptions for transient toxicities or dose 
adjustments will be reported. Per protocol interruptions will not be reported as deviations. After 
Year 2 (Week 104), CsA administration will be at the discretion of the investigator, and will 
not be provided within the trial anymore. 
6.1.5.1 
Treatment beyond disease progression 
Study treatment beyond disease progression is not applicable for this study because the 
participant should discontinue the study treatment once assessed as non-responder at Week 26 
or relapse at any time, due to the discontinuation criteria in Section 9.1.1. Other treatments can 
rely on investigator's discretion or refer to treating physician after disease progression. 
6.2 
Other treatment(s) 
6.2.1 
Concomitant therapy 
All medications (including non-prescription drug and herbal medicines), procedures, and 
significant non-drug therapies (including physical therapy and blood transfusions) administered 
after the participant was enrolled into the study (after signing the ICF) must be recorded in the 
concomitant medications/significant non-drug therapies or procedures pages on the case report 
forms (CRFs): 
• Drug for aplastic anemia other than r-ATG and CsA (G-CSF, iron chelation therapy and 
supportive therapy except transfusions): from 7 days before the start of administration of 
the investigational product (or from the screening visit, whichever is earlier) to completion 
of study; 
• RBC and platelet transfusion: from 60 days before the start of administration of the 
investigational product to the end of eltrombopag treatment for participants who discontinue 
eltrombopag due to non-response at W26, relapse or alternative SAA treatment, and until 
the completion of study for all the other participants; 
• All concomitant therapy other than the above-mentioned: up to the resolution of the last 
reported AE. 
Transfusions with platelets and/or RBC may be given during study participation as medically 
necessary per local practice. In general, platelet transfusions should be administered 
prophylactically when the platelet count <10 x 109/L or when significant bleeding occurs. Prior 


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to administration of r-ATG, a daily threshold of 20 x 109/L should be used for the duration of 
the r-ATG course. In participants judged to have additional risk factors for bleeding, a higher 
prophylactic transfusion threshold of 20 x 109/L is also recommended. Packed RBCs are 
recommended generally to be administered for hemoglobin<60 g/L, and it should be 
individualized according to co-morbidities. Improvement in counts that are dependent upon 
transfusion will not be considered as fulfilling response criteria in the efficacy assessments  
(see Section 8.3).  
The use of antibiotics (except for macrolide antibiotics, which may increase the concentration 
of CsA, mentioned in Section 6.2.1.1), anti-fungals, and granulocyte colony stimulating factor 
(G-CSF) are permitted. The local hospital guidelines for treatment of infections / febrile 
neutropenia should be followed. Cautions should be taken when azole anti-fungals are 
administered, mentioned in Section 6.2.1.1. 
Iron chelation is not allowed during the study until Week 26, unless the participant was taking 
it before the study treatment started.  
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 participant or allowing a new medication to be started. If the participant is already 
enrolled, contact Novartis to determine if the participant 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/conducted in accordance with the 
individual product information for dose adjustment and monitoring recommendations and 
standard practice.  
Eltrombopag 
If concomitant administration of drugs with a “Known risk of Torsades de Pointes” is required 
and cannot be avoided, investigational drug must be interrupted. If, based on the investigator 
assessment and clinical need, study treatment is resumed, close electrocardiogram (ECG) 
monitoring is advised. 
Substrates of BCRP and OATP1B1 
Preclinical data showed that eltrombopag is an inhibitor of the transporters OATP1B1 and 
BCRP, therefore use of concomitant medications that are known substrates for these 
transporters should be avoided. If they cannot be avoided, caution should be used during 
concomitant administration with eltrombopag. 
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 by 2-fold and AUCinf by 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, 


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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. 
Participants requiring routine (e.g. daily) acid suppression should be encouraged to take H2 
antagonists or proton pump inhibitors. Participants requiring occasional acid suppression may 
take liquid or chewable antacids provided eltrombopag 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 or 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 and cannot be avoided under the discretion of investigator, those 
drugs will be permitted, but the participant(s) will be excluded from bleeding analyses during 
the time period the participant 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.) 
R-ATG 
Thymoglobulin can stimulate the production of antibodies that cross-react with other rabbit 
immune globulins, therefore concomitant use of other rabbit immune globulins should be 
avoided. If they cannot be avoided, cautions should be used during concomitant administration 
with r-ATG.  


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CsA 
The concomitant use of CsA with the following requires caution: 
• Potassium or potassium supplements, potassium-sparing diuretics, angiotensin converting 
enzyme inhibitors, angiotensin II receptor antagonists which may result in significant 
increases in serum potassium;  
• Medications which may decrease the concentration of CsA: barbiturates, carbamazepine, 
oxcarbamazepine, phenytoin, nafcillin, sulfadimide, rifampicin, octreotide, probucol, 
orlistat, hypercium perforatum (St. John's wort), ticlopidine, sulfinpurazone, terbinafine, 
bosetan; 
• Medications which may increase the concentration of CsA: macrolide antibiotics 
(erythromycin, azithromycin, clarithromycin), ketoconazole, fluconazole, itraconazole, 
voriconazole, diltiazem, nicardipine, verapamil, metoclopramide, oral contraceptives, 
danazol, methylprednisolone (high dose), allopurinol, amiodarone, cholic acid and 
derivatives, protease inhibitors, imatinib, colchicine, nefazadone; 
• Medications which may exhibit nephrotoxic synergy; aminoglycosides (gentamycin, 
tobramycin), 
amphotericin 
B, 
ciprofloxacin, 
vancomycin, 
trimethoprim  
(+ sulfamethoxazole), non-steroidal anti-inflammatory drugs (including diclofenac, 
naproxen, sulidac), melphalan, histamine, H2-receptor antagnoists (cimetidine, ranitidine), 
methotrexate, tacrolimus; 
• Concomitant use with nifedipine may results in increased rate of gingival hyperplasia; 
• CsA is an inhibitor of CYP3A4 and P-glycoprotein and may increase plasma levels of co-
medications that are substrates of this enzyme and/or transporter. 
• CsA may reduce the clearance of digoxin, prednisolone, HMG-coA reductase inhibitors 
(statins), etoposide, aliskiren, bosetan or dabigatran. If co-administration of is necessary, 
close clinical observation is required in order to enable early detection of toxicity. Co-
administration of CsA increases blood/plasma concentrations of everolimus, sirolimus, 
repaglinide, bosetan, aliskiren, dabigatran, and the anthracyclines.  
6.2.2 
Prohibited medication 
Use of the treatments displayed in the below table are not allowed during the study.  
Table 6-6 
Prohibited medication and therapy 
Medication/Therapy 
Prohibition period 
Action taken 
Any other TPO-R agonists (e.g. 
recombinant humanized 
thrombopoietin (rhTPO) [TeBiAo], 
romiplostim [N-plate], Interleukin-
11 [Neumega])  
During screening, during the 
administration of study treatment, 
and when followed as responders. 
During screening: considered a 
screen failure 
During the administration of study 
treatment: discontinue study 
treatment 
When participants are followed as 
responders off study treatment: 
discontinue from efficacy follow-up. 
Only survival and clonal evolution 
will be followed then. 
ATG/ALG other than the study 
treatment, cyclophosphamide, 
alemtuzumab  
Initiation of additional IST other 
than corticosteroids or CsA  
Anabolic steriods  
HSCT 


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Medication/Therapy 
Prohibition period 
Action taken 
The medications which are 
prohibited in the product label of r-
ATG or CsA  
During the administration of r-ATG 
or CsA 
Discontinue study treatment 
Following IST, any vaccinations, including influenza, should be avoided as there is a theoretical 
risk of disease relapse (Killick et al 2016).  
There is no definite contraindication for the use of an inactivated, viral-vector, or mRNA based 
SARS-CoV-2 vaccine in subjects treated with eltrombopag. Recognizing that multiple vaccines 
may have various mechanisms of action with different associated potential risks, the decision 
of vaccination for SARS-CoV-2 should be done on a case-by-case basis and at the discretion of 
the investigator. The administered vaccine must be recorded as a concomitant medication. 
The local labels should be considered in regard to contraindicated drugs during r-ATG/CsA 
administration.  
Participants must abstain from using herbal supplements, investigational drugs or not marketed 
drugs without a well-known safety profile and from using prohibited prescription or 
nonprescription drugs within 7 days or 5-half-lives (whichever is longer) prior to the first dose 
of study treatment and until completion of follow-up procedures unless, in the opinion of the 
Investigator and Sponsor, the medication will not interfere with the study.  
6.3 
Participant numbering, treatment assignment, randomization 
6.3.1 
Participant numbering 
Each participant is identified in the study by a Participant Number (Participant No.), that is 
assigned when the participant is first enrolled for screening and is retained as the primary 
identifier for the participant throughout his/her entire participation in the trial. The Participant 
No. consists of the Center Number (Center No.) (as assigned by Novartis to the investigative 
site) with a sequential participant number suffixed to it, so that each participant is numbered 
uniquely across the entire database. Upon signing the informed consent form, the participant is 
assigned to the next sequential Participant No. available. 
The investigator or designated site staff will contact the Interactive Response Technology (IRT) 
and provide the requested identifying information for the patient to register them into the IRT. 
Once assigned, the Participant No. must not be reused for any other participant and the 
Participant No. for that individual must not be changed. 
6.3.2 
Treatment assignment, randomization 
This is a single arm, non-randomized study. No randomization will be performed in this study.  
Upon completion of all the required screening assessments, eligible participants will start study 
treatment at Day 1. 
6.4 
Treatment blinding 
This is a single arm, open label study.  


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6.5 
Dose escalation and dose modification 
6.5.1 
Dose modifications 
The eltrombopag dose adjustment based on treatment response are in Section 6.1.1.1. 
For participants who do not tolerate the protocol-specified dosing schedule, dose interruptions, 
and/or reductions are either recommended or mandated in order to allow participants to continue 
the study treatment. Deviations to mandatory dose interruptions and/or reductions are not 
allowed.  
Permanent treatment discontinuation is mandatory for specific events indicated as such 
in Section 9.1.1. 
These dose changes must be recorded on the Dosage Administration Record – 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) 
Confirm readout: 
1. Assess the quality of the ECG recording and the QT value and repeat if needed 
2. Interrupt eltrombopag only if no other cause has been identified and if there are cardiac 
signs and symptoms 
3. Determine the serum electrolyte levels (in particular hypokalemia, hypomagnesemia). If 
abnormal, correct abnormalities before resuming investigational drug treatment 
4. Review concomitant medication associated with QT prolongation, including drugs with a 
“Known”, “Possible”, or “Conditional risk of Torsades de Pointes” (crediblemeds.org), and 
drugs with the potential to increase the risk of investigational drug exposure related QT 
prolongation 
5. Check investigational 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 investigational drug intake 
7. Repeat ECG and confirm ECG diagnosis by a cardiologist 
After confirming ECG reading at site, if QTcF > 500 msec 
• Interrupt eltrombopag 
• Correct electrolytes, eliminate culprit concomitant treatments, and identify and address 
clinical conditions that could potentially prolong the QT  
• Consult with a cardiologist (or qualified specialist) 
• Increase cardiac monitoring as indicated, until the QTcF returns to ≤ 480 msec 
• Dose can be resumed if QTc reduces or an alternate cause has been identified and if there 
are no cardiac signs and symptoms 
If resolved (QTcF ≤ 480 msec), consider re-introducing treatment at reduced dose, and increase 
ECG monitoring for the next treatment(s):  


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• If QTcF remains ≤ 500 msec after dose reduction, continue planned ECG monitoring during 
subsequent treatment 
• If QTcF recurs > 500 msec after dose reduction, discontinue participant from study 
treatment. 
6.5.1.2 
Dose reduction/interruption due to liver function abnormalities and 
thrombosis/embolism 
Eltrombopag dose may be interrupted when clinically indicated at the discretion of the 
investigator. Serum ALT, AST and bilirubin (total, direct and indirect) should be measured 
prior to initiation of eltrombopag, every 2 weeks while adjusting the dose and monthly after 
establishment of a stable dose. Abnormal serum liver function tests (LFTs) should be evaluated 
with repeat testing preferably within 48-72 hours (see Table 6-7 and Section 6.5.2.1). If the 
abnormalities are confirmed, serum liver tests should be monitored weekly until the 
abnormalities resolve, stabilize, or return to baseline levels. Alternative causes of LFT 
elevations, such as hepatitis or concomitant medications (e.g., cyclosporine A) must always be 
investigated. 
NOTE: Eltrombopag is known to cause interference in measurement of total bilirubin, which 
may lead to falsely increased levels of total bilirubin (see Section 8.4.1). Please take dose 
modification decision based on direct (conjugated) bilirubin (DBIL) along with ALT and/or 
AST (see Table 6-7 below). 
Table 6-7 summarizes the recommendations for dose interruption or reduction of eltrombopag 
in the management of liver function abnormalities and thrombosis/embolism events. For 
participants who fulfill the criteria of eltrombopag discontinuation in Table 6-7, refer to 
Section 9.1 for the further action to be taken after discontinuation.  
Table 6-7 
Guidelines for eltrombopag dose modification based on liver function 
abnormalities and thrombosis/embolism 
Criteria 
Action 
Isolated AST or ALT elevation 
> ULN - 3 x ULN 
Maintain dose level. 
> 3 - 5 x ULN 
Maintain dose level. 
Repeat liver function test (LFTs)a 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 x ULN. 
Discontinue participant from eltrombopag if elevation 
is combined with any of the following: 
• Clinical symptoms of liver injury or evidence for 
hepatic decompensation 
• Persistence for ≥ 4 weeks 
> 5 - 10 x ULN 
Interrupt dose. 


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Criteria 
Action 
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, monitor LFTsa weekly, or more frequently if 
clinically indicated, until resolved to ≤ 3.0 x ULN, then: 
If resolved in ≤ 14 days, then resume at same dose 
level; If toxicity recurs at same dose, then follow the 
above guideline and resume dose at a lower dose 
level (decrease by one levelc) 
If resolved > 14 days and ≤ 28 days, then decrease 
one dose levelc 
If not resolved within 28 days, then discontinue 
participant from study treatment  
> 10 - 20 x ULN 
Interrupt dose. 
Repeat LFTsa as soon as possible, preferably within 
48-72 hours from awareness of the abnormal results. 
Monitor LFTsa weekly, or more frequently if clinically 
indicated, until resolved to ≤ 3.0 x ULN. If resolved 
within 28 days, decrease by one dose level. 
If not resolved to ≤ 3.0 x ULN within 28 days, then 
discontinue participant from study treatment. 
> 20 x ULN 
Discontinue participant from study treatment. 
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, monitor LFTsa weekly, or more frequently if 
clinically indicated until resolved to baseline or 
stabilization over 4 weeks. 
Combinedb elevations of AST or ALT and direct bilirubin (DBIL) 
For participants with normal baseline ALT and AST 
and DBIL value, [AST or ALT > 3 x ULN] combined 
with [DBIL > 2 x ULN] without evidence of cholestasis 
OR 
For participants with elevated baseline ALT or AST or 
DBIL, [AST or ALT > 3 x baseline] OR [AST or ALT > 
5 x ULN], whichever is lower, combined with [DBIL > 
2 x baseline AND > 2 x ULN] 
Discontinue participant from study treatment 
Repeat LFTsa as soon as possible, preferably within 
48 hours from awareness of the abnormal results, 
then weekly or more frequently (if clinically indicated) 
monitor LFTsa , or more frequently if clinically 
indicated, until ALT, AST or DBIL have resolved to 
baseline or stabilization over 4 weeks. 
Evaluate the possibility of DILI (Section 6.5.2.1) 
Thrombosis/embolism 
Deep vein thrombosis, pulmonary embolus, transient 
ischemic attack (TIA) or stroke, myocardial infarction 
at any time while on eltrombopag 
Discontinue participant from eltrombopag. 
If the platelet level is > 50 x 109/L at the time of 
thrombosis, treatment with enoxaparin or another 
appropriate anticoagulant is recommended as 
clinically indicated until the platelet count drops < 20 x 
109/L or a standard 3 to 6 month course of 
anticoagulation is completed. 
a Core LFTs consists of ALT, AST, GGT (Gamma-glutamyl transferase), total billirubin (direct and indirect), and 
alkaline phosphatase (ALP) 
b "Combined" is defined DBIL increase to the defined threshold concurrently with ALT/AST increase to the 
defined threshold. If the bilirubin increase is below the defined threshold, guidance for isolated AST or ALT 
elevation should be followed 
c Dose level: for participants ≥ 12 years old, one dose level is 25mg; for participants < 12 years old, one dose 
level is 12.5mg. 


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Definition of discontinuation: study treatment is permanently stopped earlier than the protocol-
planned duration  
An isolated bilirubin elevation is not typical for drug-induced liver injury. Bilirubin can be 
elevated either as part of a “Hy’s law” constellation with a preceding elevation of ALT/AST, 
or as part of a cholestatic reaction with simultaneous elevation of other cholestatic parameters 
(ALP, GGT). Isolated bilirubin elevation can be seen in conjunction with drugs that inhibit 
bilirubin conjugation or excretion, but both scenarios do not typically represent liver injury. 
Alternative causes of bilirubin elevation, including bilirubin interference (see Section 8.4.1) 
should be ruled out before basing dose modification decisions on bilirubin values alone 
6.5.2 
Follow-up for toxicities 
Participants whose treatment is interrupted or permanently discontinued due to an AE or 
clinically significant laboratory value, must be followed up at least once a week (or more 
frequently if required by institutional practices, or if clinically indicated) for 4 weeks, and 
subsequently at approximately 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 participants must be followed up for AEs and serious adverse events (SAEs) for 30 days 
following the last doses of eltrombopag.  
6.5.2.1 
Follow-up on potential drug-induced liver injury (DILI) cases 
Participants with transaminase increase combined with bilirubin increase may be indicative of 
potential severe drug-induced liver injury (DILI), and should be considered as clinically 
important events and assessed appropriately to establish the diagnosis. The required clinical 
information, as detailed below, should be sought to obtain the medical diagnosis of the most 
likely cause of the observed laboratory abnormalities. 
The threshold for further work-up for potential severe DILI may depend on the participant's 
baseline AST/ALT and DBIL value; participants meeting any of the following criteria will 
require further follow-up as outlined below: 
• For participants with normal ALT and AST and DBIL value at baseline: AST or ALT > 3 
x ULN combined with DBIL > 2 x ULN 
• For participants with elevated AST or ALT or DBIL value at baseline: [AST or ALT > 3 x 
baseline] OR [AST or ALT > 5 x ULN], whichever is lower, combined with [DBIL > 2 x 
baseline AND > 2 x ULN] 
As DILI is essentially a diagnosis of exclusion, other causes of abnormal liver tests should be 
considered and their role clarified before DILI is assumed as the cause of liver injury. 
A detailed history, including relevant information such as review of ethanol consumption, 
concomitant medications (including cyclosporine A), herbal remedies, supplement 
consumption, history of any pre-existing liver conditions or risk factors, should be collected. 
Laboratory tests are recommended to include ALT, AST, total bilirubin, direct and indirect 
bilirubin, GGT, glutamate dehydrogenase, prothrombin time (PT)/INR, alkaline phosphatase, 
albumin, and creatine kinase. Evaluate status of liver for tumors or vascular occlusion – e.g. 
using CT, magnetic resonance imaging (MRI), or duplex sonography. Perform relevant 


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examinations (Ultrasound or MRI, Endoscopic Retrograde Cholangio-Pancreatography 
(ERCP)) as appropriate, to rule out an extrahepatic cause of cholestasis. Cholestasis is defined 
as 
an 
ALP 
elevation 
> 
2 
x 
ULN 
with 
R 
value 
< 
2 
in 
participants. 
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. For children, 
there are caveats to calculating the R-ratio as normal levels of ALP are higher than in adults 
with standard ranges varying by developmental age. In clinical situations where it is suspected 
that ALP elevations are from an extrahepatic source, the GGT can be used if available. GGT 
may be less specific than ALP as a marker of cholestatic injury, since GGT can also be elevated 
by enzyme induction or by ethanol consumption. It is more sensitive than ALP for detecting 
bile duct injury (livertox.nih.gov). 
Table 6.8 (below) provides guidance on specific clinical and diagnostic assessments which can 
be performed to rule out possible alternative causes of observed LFT abnormalities. 
Table 6-8  
Summary of guidance on specific clinical and diagnostic assessments 
Disease 
Assessment 
Hepatitis A, B, C, E 
• Immunoglobulin M (IgM) anti hepatitis A virus; HBsAg, IgM & 
immunoglobulin G (IgG) anti-HBc, HBV DNA; anti-HCV, HCV RNA, IgM & 
IgG anti-hepatits E virus (HEV), HEV RNA 
CMV, HSV, EBV infection 
• IgM & IgG anti-CMV, IgM & IgG anti-HSV; IgM & IgG anti-EBV 
Autoimmune hepatitis 
• Antinuclear Antibody & Anti Smooth Muscle Antibody titers, total IgM, IgG, 
immunoglobulin E, immunoglobulin A 
Alcoholic hepatitis 
• Ethanol history, GGT, MCV, CD-transferrin 
Nonalcoholic steatohepatitis 
• Ultrasound or MRI 
Hypoxic/ischemic hepatopathy 
• Medical history: acute or chronic congestive heart failure, hypotension, 
hypoxia, hepatic venous occlusion. Ultrasound or MRI. 
Biliary tract disease 
• Ultrasound or MRI, ERCP as appropriate. 
Wilson disease (if <40 yrs old) 
• Caeruloplasmin 
Hemochromatosis 
• Ferritin, transferrin 
Alpha-1-antitrypsin deficiency 
• Alpha-1-antitrypsin 
Other causes should also be considered based upon participants’ medical history 
(hyperthyroidism / thyrotoxic hepatitis – T3, T4, TSH; cardiovascular disease / ischemic 
hepatitis – ECG, prior hypotensive episodes; type 1 diabetes / glycogenic hepatitis).  
Obtain PK sample to determine exposure to eltrombopag and metabolites.  
Following appropriate causality assessments, as outlined above, the causality of the treatment 
is estimated as “probable” i.e. >50% likely, if it appears greater than all other possible causes 
of liver injury combined. The term “treatment-induced” indicates probably caused by the 
treatment, not by something else, and only such a case can be considered a DILI case and should 
be reported as an SAE.  
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”, and thus, meet the definition of SAE and should be reported as SAE using the term 


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“potential treatment-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 participant to take the study 
treatment exactly as prescribed and by stating that compliance is necessary for the participant's 
safety and the validity of the study. The participant 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 
counts and information provided by the participant. The actual dose and prescribed dose should 
be captured in the source document at each visit and eCRF. All study treatment dispensed and 
returned must be recorded in the Drug Accountability Log. 
PK parameters (measures of treatment exposure) will be determined in all participants treated 
with eltrombopag, as detailed in Section 8.5.1. 
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 eltrombopag in packaging as described in Section 6.1.1. 
A unique medication number is printed on the eltrombopag label. 
As per the treatment assigned to the participant, investigator staff will select the eltrombopag 
treatment to dispense to the participant. The eltrombopag has a 2-part label (base plus tear-off 
label), immediately before dispensing the package to the participant, site personnel will detach 
the outer part of the label from the package and affix it to the participant's source document.  
As per Section 4.6, during a Public Health emergency as declared by Local or Regional 
authorities i.e. pandemic, epidemic or natural disaster, that limits or prevents on-site study visits, 
delivery of study treatment directly to a participant's home may be permitted (if allowed by 
Local or Regional Health Authorities and Ethics Committees as appropriate) in the event the 
Investigator has decided that an on-site visit by the participant is no longer appropriate or 
possible, and that it is in the interest of the participant's health to administer the study treatment 
even without performing an on-site visit. The dispatch of study treatment from the site to the 
participant’s home remains under the accountability of the Investigator. Each 
shipment/provisioning will be for a maximum of 2-week supply during the first 26 weeks and 
for a maximum of 1-month supply after Week 26, to ensure study treatment supply until next 
scheduled visit back on site. In this case, regular phone calls or virtual contacts every 1-2 weeks 
during the first 26 weeks, regular phone calls and every 2-4 weeks after Week 26, or virtual 
contacts will occur between the site and the participant for instructional purposes, safety 
monitoring, investigation of any adverse events, ensuring participants continue to benefit from 
treatment, and discussion of the participant's health status until the participants can resume visits 
at the study site. 


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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/region. They will include storage conditions for the study treatment but no information 
about the participant 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. Participants 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. 
6.7.2 
Instruction for prescribing and taking study treatment 
Eltrombopag 
Eltrombopag (25mg/12.5mg) will be administered from Day 1, concurrently with IST. The 
initial dose and dose adjustment for adult and pediatric participants are defined in 
Section 6.1.1.1. The initial dose should not be exceeded.  
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). Participants will be instructed to 
take eltrombopag daily at the same time each day. Considering the clinically feasibility of PK 
blood collection, the participants were required to take eltrombopag at morning. 
On days that PK samples are obtained, the participant 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. 


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If vomiting occurs during the course of treatment, participants should not take the 
investigational drug (eltrombopag) again before the next scheduled dose.  
Participants will be instructed not to make up for 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 participant should continue treatment with the 
next scheduled dose. 
The dose of eltrombopag will be adjusted based on platelet count and LFTs, according to the 
criteria shown in Table 6-3 and Table 6-7. The daily dose of eltrombopag will be decreased by 
25 mg/day every 2 weeks (12.5 mg/day, for participants below 12 years old) if the platelet count 
rises above 200×109/L, and eltrombopag treatment will be discontinued for one week if the 
platelet count rises above 400 ×109/L. Once the platelet count falls below 200 ×109/L, 
eltrombopag should be reinitiated at a daily dose reduced by 25 mg (12.5 mg for participants 
below 12 years old).  
Eltrombopag dose may be interrupted when clinically indicated at the discretion of the 
investigator. Interruptions will be reported. For participants who meet any toxicity criteria (see 
Section 6.5.1) or who do not tolerate the protocol-specified dosing schedule, the investigator 
will follow the guideline on dose modification and/or discontinuation presented in 
Section 6.5.1.  
Participants in whom the treatment is assessed as effective at Week 26 may continue treatment 
with eltrombopag and CsA after Week 26 (in the extension part of the study). Eltrombopag will 
be provided for the participants who entered the extension part and are considered to require 
continued treatment up to Week 52. The daily dose of eltrombopag in extension part is shown 
in Table 6-3 and Table 6-4.  
R-ATG 
R-ATG will be administered intravenously on Days 1-5. Dosing of r-ATG is defined 
in Section 6.1.1.2. 
Administer r-ATG under strict medical supervision in a hospital setting, and carefully monitor 
participants during the infusion. The infusion time may vary based on the participant and 
circumstances. Administer the first dose of r-ATG over a minimum of 6 hours; administer doses 
on subsequent days over at least 4 hours. 
Premedication with corticosteroids, acetaminophen, and/or an antihistamine 1 hour prior to each 
infusion of r-ATG is recommended and may reduce the incidence and intensity of infusion 
associated reactions. Prior to the administration of r-ATG, a daily threshold (pre-transfusion) 
platelet count of 20 x109/L should be used for the duration of the r-ATG course.  
Instructions for reconstitution, dilution and infusion from the local label should be followed 
strictly. 
CsA 
CsA will be administered orally, every 12 hours. Participants will be instructed to take CsA at 
the same time each day. Dosing of CsA is described in Section 6.1.1.3. 


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CsA will be supplied as soft-gelatin capsules or as an oral solution. Switching from the soft-
gelatin capsules to the oral solution should be performed with caution and under close physician 
supervision. The introduction of the new formulation must be made with monitoring of blood 
levels of CsA to ensure that pre-conversion levels are attained. 
Participants should be instructed to swallow whole capsules and not to chew or open them. CsA 
oral solution should be diluted with, preferably orange or apple juice; however, other drinks 
such as soft drinks can be used according to individual taste. Immediately before taking the oral 
solution, it should be stirred well. Owing to its possible interference with the cytochrome P450-
dependent enzyme system, grapefruit juice should be avoided for dilution. The syringe should 
not come in contact with the diluent. If the syringe is to be cleaned, do not rinse it but wipe the 
outside with a dry tissue. 
If vomiting occurs during the course of treatment, participants should not take the study 
treatment CsA again before the next scheduled dose. Participants should be instructed not to 
make up for missed doses. A missed dose is defined as a case when the full dose is not taken 
within 8 hours after the approximate time of the usually dosing time. That dose should be 
omitted and the participant should continue treatment with the next scheduled dose. 
In extension part, CsA will last for at least 18 months if well tolerated (duration of CsA in total 
is from Day 1 to Year 2). CsA will be maintained or tapered based on the discretion of the 
investigator. It is recommended that the therapeutic CsA treatment last for at least 3 months 
after achieving the best hematologic response, and after that CsA is recommended to be tapered 
by 0.3 mg/kg every month or 1mg/kg every 3 months. 
CsA dose may be reduced or interrupted when clinically indicated at the discretion of the 
investigator or treating physician. The parenteral route of administration may be used 
temporarily for CsA administration if indicated. The site will be responsible for the sourcing of 
parenteral route of CsA administration.  
Table 6-9 
Dose and treatment schedule in core treatment part  
Investigational / Combination 
Drug 
(Name and Strength) 
Starting Dose 
Frequency and/or Regimen 
Eltrombopag 25mg/12.5mg 
≥ 12 years old: 75mg (3 X 25mg) 
≥ 6 and < 12 years old: 37.5mg (1 
X 25mg + 1 X 12.5mg) 
Daily 
r-ATG 25mg 
2.5-3.5mg/kg 
Day 1 to Day 5 
CsA 25mg 
3-6 mg/kg 
Every 12 hours 
Dose adjustment based on test results at visit, visit plan refer to Section 8. 
7 
Informed consent procedures 
Eligible participants may only be included in the study after providing (witnessed, where 
required by law or regulation), Institutional Review Board/Independent Ethics Committee 
(IRB/IEC)-approved informed consent. 
If applicable, in cases where the participant's representative(s) gives consent (if allowed 
according to local requirements), the participant must be informed about the study to the extent 


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possible given his/her understanding. If the participant 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 participant source documents. 
Novartis will provide to investigators in a separate document a proposed informed consent form 
that complies with the International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use and Good Clinical Practice (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. 
Novartis will review the investigators proposed informed consent form to ensure it complies 
with the ICH E6 GCP guidelines and regulatory requirements and is considered appropriate for 
this study. Any further changes to the proposed consent form suggested by the investigator must 
be agreed to by Novartis before submission to the IRB/IEC. 
Information about common side effects already known about the investigational drug can be 
found in the Investigator's Brochure (IB) and/or core data sheet (CDS) for marketed drugs. This 
information will be included in the participant informed consent and should be discussed with 
the participant during the study as needed. Any new information regarding the safety profile of 
the investigational drug that is identified between IB updates will be communicated as 
appropriate, for example, via an investigator notification or an aggregate safety finding. New 
information might require an update to the informed consent and then must be discussed with 
the participant. 
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. 
Male participants 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. 
As per Section 4.6, during a Public Health emergency as declared by Local or Regional 
authorities i.e. pandemic, epidemic or natural disaster, that may challenge the ability to obtain 
a standard written informed consent due to limits that prevent an on-site visit, Investigator may 
conduct the informed consent discussion remotely (e.g. telephone, videoconference) if 
allowable by a local Health Authority. 
During a Public Health emergency as declared by Local or Regional authorities i.e. pandemic, 
epidemic or natural disaster, mitigation procedures to ensure participant safety and trial integrity 
are listed in relevant sections. Notification of the Public health emergency should be discussed 
with Novartis prior to implementation of mitigation procedures, and permitted/approved by 
Local or Regional Health Authorities and Ethics Committees as appropriate. Guidance issued 
by local regulatory bodies on this aspect prevail and must be implemented and appropriately 


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documented (e.g. the presence of an impartial witness, sign/dating separate ICFs by trial 
participant and person obtaining informed consent, etc.). 
8 
Visit schedule and assessments 
Assessment schedule (Table 8-1) lists all of the assessments when they are performed. All data 
obtained from these assessments must be supported in the participant’s source documentation. 
All laboratory assessments will be performed locally except for the PK assessments and for 
flow cytometry for the sites in Japan and FISH assay for the sites in Korea and Taiwan in order 
to perform the assessments as per protocol requirements.  
Participants should be seen for all visits/assessments as outlined in the assessment schedule 
(Table 8-1) or as close to the designated day/time as possible. Missed or rescheduled visits 
should not lead to automatic discontinuation. Participants who prematurely discontinue 
eltrombopag for any reason should be scheduled for an end of treatment (EOT) visit as soon as 
possible, at which time all of the assessments listed for the EOT visit will be performed. At this 
EOT visit, all dispensed investigational product should be reconciled, and the AE and 
concomitant medications recorded on the CRF. After that, the safety follow-up visit will be 
performed 30 days after the last administration of eltrombopag, and then participants should be 
seen for survival follow-up and in visits for efficacy and/or clonal evolution assessments. 
Participants who discontinue from study treatments will have efficacy assessments at defined 
time points (Week 13, Week 26, Week 52 and yearly after), unless or until the occurrence of no 
response at Week 26, relapse or alternative SAA treatment (whichever comes first). Survival 
and clonal evolution data will be collected for all participants up to Year 3 (Week 156). 
Allowed visit windows are specified as follows: 
• Following dose modification, each visit must be completed ± 3 days until dose stabilization, 
• After stabilization of dose, each visit must be completed ± 7 days,  
• The efficacy assessment visits in core treatment part (Week 13 and Week 26) must be 
completed ± 3 days, and Week 52 visit in extension part must be completed ± 7 days. Week 
104 and Week 156 visits in follow-up part must be completed ± 30 days 
• The safety follow-up visit after EOT must be completed ± 7 days. 
Because the dose of eltrombopag and CsA may be adjusted based on platelet count and due to 
safety reasons assessed at any visit, after any dose adjustment or interruption of eltrombopag or 
CsA the participant should visit hospital weekly at least for 2 weeks, and after stabilization of 
dose, the participant should visit every 2 weeks in the core treatment part. In the extension part, 
participants should visit hospital at least every 2 weeks until stabilization of dose; every 4 weeks 
after stabilization of dose. Stabilization of eltrombopag/CsA dose is defined as no dosing 
change for at least 4 weeks. If the dose is changed at visiting every 4 weeks, the participant 
should visit hospital from the next visit until stabilization of dose. 
As per Section 4.6, during a Public Health emergency as declared by Local or Regional 
authorities i.e. pandemic, epidemic or natural disaster that limits or prevents on-site study visits, 
alternative methods of providing continuing care may be implemented by the investigator as 
the situation dictates. If allowable by a local Health Authority and depending on operational 
capabilities, phone calls, virtual contacts (e.g. tele consult) or visits by site staff to the 


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participant´s home, can replace on-site study visits, for the duration of the disruption until it is 
safe for the participant to visit the site again.  














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8.1 
Screening 
All participants will be screened for study eligibility. All participants must sign an 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, r-ATG and CsA. During this time, all participants will complete a bone marrow 
aspirate and biopsy to confirm current SAA diagnosis. The sample of bone marrow aspiration 
and biopsy, and the result of cytogenetic analysis obtained within 30 days prior to Day 1 can be 
used for evaluation, and the results will be used as baseline value. The criteria for diagnosis of 
SAA are found in Section 5.1. Cytogenetic analysis and all other analyses will be completed to 
verify inclusion and exclusion criteria.  
An evaluable karyotyping is mandatory for the eligibility assessment. Eligibility must be based 
on a normal karyotype of at least 10 metaphases. If 10 metaphases are not seen, the bone marrow 
aspirate must be repeated. The participant won't be eligible if the karyotyping fails again by the 
second bone marrow aspiration due to insufficient metaphases.  
In addition to conventional karyotyping, FISH should be performed to detect abnormalities in 
chromosome 3, 5, 7, 8 and those associated with SAA, MDS, acute myeloid leukemia 
(AML) etc. Candidate participant may start with the investigational treatment if a normal 
karyotyping result is shown for eligibility assessment while waiting for the FISH result. In case 
the FISH result comes out to be abnormal indicating cytogenetic abnormalities, the participant 
must be discontinued from the study treatment. 
Information regarding eligibility criteria will be collected on the Inclusion/Exclusion eCRF. 
Participants who do not meet all entry criteria should not be entered into the 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 participant must be 
excluded from the study. For bone marrow aspiration and biopsy, if the site laboratory is unable 
to perform the test (i.e., due to quality/sampling issue with the sample), particularly for 
cellularity and chromosome abnormality, the site may get one more bone marrow sample as 
soon as possible before the initiation of study treatment. If the second sample remains 
unevaluable, the participant must be excluded. 
A participant may only be re-screened once for the study. A new ICF will need to be signed if 
the investigator chooses to re-screen the participant. For re-screened participants, a new 
Participant number should be assigned, and all required screening activities except bone marrow 
aspiration and biopsy must be performed when the participant is re-screened for participation 
in the study. Bone marrow aspiration and biopsy do not need to be repeated if they have been 
performed within 30 days of the re-screening visit date. 
8.1.1 
Eligibility screening 
Following registration in the IRT for screening, participant eligibility will be checked once all 
screening procedures are completed. The eligibility check will be embedded in the IRT system. 
Please refer and comply with detailed guidelines in the IRT manual. 


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8.1.2 
Information to be collected on screening failures 
Participants who sign an informed consent but subsequently found to be ineligible will be 
considered a screen failure. The reason for screen failure should be entered on the applicable 
CRF. The demographic information, informed consent, and Inclusion/Exclusion pages must 
also be completed for screen failure participants. No other data will be entered into the clinical 
database for participants who are screen failures, unless the participant experienced a SAE 
during the screening phase (see Section 10.1.2 for reporting details). Participants 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 CRF.  
8.2 
Participant demographics/other baseline characteristics 
Participant demographic and baseline characteristic data to be collected on all participants 
include: 
• Demographic information: age, gender, predominant race and ethnicity 
• ECOG or Lansky performance status, height (cm) and weight (kg), body temperature (ºC), 
blood pressure (mmHg) and pulse rate (bpm). 
• Date of diagnosis, severity etc. of aplastic anemia. 
• Prior and concomitant medications and transfusion history (Within 60 days prior to Day 1). 
• Clinically significant findings in a complete physical examination (see Table 8-2) during 
the screening period. 
• Laboratory evaluations: peripheral blood smear, bone marrow aspiration and cytogenetic 
analysis, flow cytometry of CD34-positive cells from bone marrow aspiration, bone marrow 
biopsy, FISH, hematology and chemistry test, blood coagulation test, pregnancy test, 
hepatitis and HIV screen, serum folate and vitamin B12, iron panel, thyroid function, and 
flow cytometry of the peripheral blood for glycosylphosphatidylinositol (GPI)-cells. 
• Imaging evaluations: chest X-ray, abdominal sonography, echocardiogram. 
• Cardiovascular medical history and risk factors, ECG  
• Cataract medical history and risk factors 
• Medical history (all important medical, surgical, and allergic conditions that could have an 
impact on the participant's evaluation before signing the informed consent) / 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. 
Procedures conducted as part of the participant's routine clinical management (e.g. blood count) 
and obtained prior to signing of informed consent may be utilized for Screening or baseline 
purposes provided the procedure meets the protocol-defined criteria and has been performed in 
the timeframe of the study. Due to the nature of SAA, blood counts may fluctuate depending 
on transfusions, so the baseline count is defined as follows: 
• The hematology assessed at the time of diagnosis will be used for screening and as baseline 
count. 


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• If the assessment at the time of diagnosis is unavailable, the lowest value available within 
30 days before Day 1 will be used as the baseline count. 
Baseline platelet transfusion independence/dependence are defined as: 
• Platelet transfusion independence: participants who did not receive platelet transfusions in 
the 4 weeks before Day 1. 
• Platelet transfusion dependence: participants who received one or more platelet transfusions 
in the 4 weeks before Day 1. 
Baseline RBC transfusion independence/dependence are defined as: 
• RBC transfusion independence: participants who did not receive RBC transfusions in the 
60 days before Day 1. 
• RBC transfusion dependence: participants who received one or more RBC transfusions in 
the 60 days before Day 1. 
Investigators will have the discretion to record abnormal test findings on the appropriate CRF 
whenever, in their judgment, the test abnormality occurred prior to the informed consent 
signature. 
8.3 
Efficacy 
Efficacy assessments include hematologic results, transfusion data, assessment of relapse and 
survival. 
Hematologic parameters will be assessed at Screening, weekly from Week 1 to Week 8, then 
every 2 weeks to Week 26 (weekly until stabilization of the dose), then every 4 weeks until the 
end of eltrombopag treatment (every 2 weeks until stabilization of the dose) and yearly during 
the post-treatment follow-up (up to Year 3). Hematologic parameters will also be assessed as 
per the investigator decision to assess the maintenance of the response, relapse or for safety 
reasons. 
Transfusion data will be recorded for any transfusion administered during the 60 days prior to 
treatment start and until the end of eltrombopag treatment for all participants who discontinue 
eltrombopag due to non-response at W26, relapse or alternative SAA treatment, and until the 
completion of study follow up for all the other participants. The date and time, content and 
number of units of each transfusion will be recorded. 
Relapse will be determined according to the definition in this section by investigator and will 
be recorded into eCRF.  
All participants will be followed for survival status every 3 months regardless of treatment 
discontinuation reason up to Year 3 until study completion, death, lost to follow-up, or 
withdrawal of consent for survival follow-up. Survival information can be obtained via phone, 
and information will be documented in the source documents and relevant eCRFs. 
Hematologic response assessment will be performed by investigators at Week 13, Week 26, 
Week 52 and yearly after. At Week 13 and Week 26, responses assessment needs to be 
confirmed by two serial blood count measurements performed 1-3 weeks apart.  


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Response is defined as blood counts no longer meeting the standard ("Camitta") 
criteria (Camitta et al 1975) for severe pancytopenia in SAA, equivalent to 2 of the following 
values (Scheinberg et al 2009).  
• Absolute neutrophil count ≥ 0.5 x109/L 
• Platelet count ≥ 20 x109/L 
• Reticulocyte count ≥ 20 x109/L  
A CR will be defined as (all 3 must be met): 
• Absolute neutrophil count > 1.0 x109/L 
• Platelet count > 100 x109/L 
• Hemoglobin > 100 g/L 
A PR will be defined as blood counts that do not meet criteria for SAA but are not sufficient 
for a CR. 
Improvement in counts that are dependent upon exogenously administered growth factors or 
transfusion will not be considered as fulfilling response criteria. 
The exclusion period of these therapies are detailed below: 
• Platelet transfusions: 7 days preceding the assessment of platelet count 
• Packed RBC transfusions: 14 days preceding the assessment of hemoglobin 
• Growth factors: 21 days preceding the assessment of response 
No response (NR) is defined as not fulfilling the response criteria. 
Transfusion independence at each assessment point is defined as follows:  
• Platelet transfusion independence: The participants who are transfusion dependent at 
baseline become transfusion free for a period of at least last 4 weeks. 
• RBC transfusion independence: The participants who are transfusion dependent at baseline 
become transfusion free for a period of at least last 8 weeks. 
Clinical relapse is considered as the occurrence of any of the following event in a participant 
who had achieved a hematological response (CR or PR) but has subsequently lost response (not 
explained by any other independent concomitant medical conditions): 
• meeting again the criteria for SAA 
• requirement for transfusion again for participants who had been transfusion independent 
• decrease in any of the peripheral blood counts to: absolute neutrophil count < 0.5 x109/L or 
platelets < 20 x109/L. 
8.3.1 
Appropriateness of efficacy assessments 
The definition of response followed the NIH criteria (Scheinberg et al 2009). The 
measurements for efficacy will follow the CETB115AUS01T in order to bridge the data gap 
for East-Asian patients treated with r-ATG instead of h-ATG. 
There is another widely practised criteria of CR after IST, defined as normal hemoglobin 
concentration for age and gender, with ANC > 1.5 x109/L and platelet count >150 x109/L 


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(Killick et al 2016). Assessments based on these criteria will be analyzed in the supportive and 
sensitive analysis (see Section 12.4.4).  
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 (Section 10.1). 
As per Section 4.6, during a Public Health emergency as declared by Local or Regional 
authorities i.e. pandemic, epidemic or natural disaster, that limits or prevents on-site study visits, 
regular phone or virtual calls can occur (every 1-2 weeks during the first 26 weeks, and every 
4 weeks thereafter, or more frequently if needed) for safety monitoring and discussion of the 
participant´s health status until it is safe for the participant to visit the site again. 
Table 8-2 
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 system. If 
indicated based on medical history and/or symptoms, rectal, external genitalia, 
breast, and pelvic exams will be performed. A complete physical examination 
should be completed approximately every 6 months.  
A short physical exam will include the examination of general appearance and vital 
signs (blood pressure [systolic blood pressure (SBP) and 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 recorded on the appropriate CRF that captures 
medical history. Significant findings made after signing informed consent which 
meet the definition of an AE must be recorded on the AE section of the CRF. 
ECOG (age ≥ 16 years) or Lansky (age < 16 years) Performance status scale 
(shown in Section 16.2) will be used at Day 1. 
Vital signs 
Vital signs include blood pressure (SBP and DPB, 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/current medical 
conditions or AEs as appropriate. 
All laboratory parameters in Table 8-3 will be performed locally, with exception of flow 
cytometry for sites in Japan and FISH assay for sites in Korea and Taiwan. 
Examinations at the point of the start of the study treatment must be performed before the 
starting of dosing. The hematology test must be conducted before the supportive therapy (if 
supportive therapy is performed). 
During a Public Health emergency as declared by Local or Regional authorities i.e. pandemic, 
epidemic or natural disaster, that limits or prevents on-site study visits, if participants cannot 


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visit the site for protocol specified safety lab assessments, an alternative lab (local) collection 
site may be used. 
Table 8-3 
Laboratory assessments 
Test Category 
Test Name 
Hematology 
Hematocrit, Hemoglobin, mean corpuscular hemoglobin (MCH), mean corpuscular 
hemoglobin concentration (MCHC), mean corpuscular volume (MCV), Platelets, RBC, 
White blood cells (WBC), Differential (Basophils, Eosinophils, Lymphocytes, 
Monocytes, Neutrophils, Other) (absolute value preferred, %s are acceptable), 
Reticulocyte count (absolute value) 
Chemistry 
Albumin, ALP, ALT, AST,GGT, Lactate dehydrogenase (LDH), Calcium, Magnesium, 
Phosphorus, Sodium, Potassium, Creatinine, Direct Bilirubin, Total Bilirubin, Blood 
Urea Nitrogen (BUN) or Urea, Uric Acid, Glucose (fasting) 
Coagulation 
PT, International normalized ratio (INR), Activated partial thromboplastin time (aPTT) 
Folate/B12 
Serum folate, Vitamin B12 (cobalamin) 
Iron panel 
Total iron, Ferritin, Total iron binding capacity (TIBC), Transferrin saturation, 
Unsaturated iron binding capacity  
Thyroid 
T3 [free], T4 [free], TSH 
Flow cytometry of 
peripheral blood  
Flow cytometry for Glycosylphosphatidyl-inositol (GPI)-anchored proteins to detect 
PNH clones, as well as fluorescent aerolysin (FLAER) for WBC 
Hepatitis markers 
HBV-DNA, HBsAg, HBsAb, HBcAb, HCV antibody 
Additional tests 
Peripheral blood smear, HIV antibody, CsA level* 
Pregnancy Test 
Serum / Urine pregnancy test (refer to  Section 8.4.5) 
Bone marrow 
aspiration and biopsy 
Morphology, proportion of blasts, cytogenetics (karyotype analysis with G-banding and 
FISH), and for CD34 positive cells, degree of fibrosis (reticulin stain and collagen 
stain), and dysplasia (refer to Section 8.4.3) 
* CsA blood levels will be monitored every week for the first 8 weeks and then every other week for the 
remained treatment period once levels are stabilized in the therapeutic range in the core treatment part. CsA 
dosage will be adjusted to target this range. More frequent drug serum levels may be obtained as needed to 
achieve target therapeutic levels and avoid toxicity (e.g. when participants are taking azoles or 
methylprednisolone). In the extension part the CsA level monitoring will depend on the investigator's 
discretion.  
Bilirubin and creatinine interference 
Eltrombopag is highly colored and so has the potential to interfere with some laboratory tests. 
Serum discoloration and interference with total bilirubin and creatinine testing have been 
reported in patients taking eltrombopag. If the laboratory results and clinical observations are 
inconsistent, evaluation of contemporaneous aminotransferase values may help in determining 
the validity of low total bilirubin levels in the presence of clinical jaundice and blood urea 
should be evaluated in the event of an unexpectedly high serum creatinine. Retesting using 
another method may also help in determining the validity of the result. All data and information 
obtained from these assessments must be recorded on eCRFs and must be supported in the 
patient’s source documentation. 


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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, participant initials (where regulations permit), participant number, date, and kept in 
the source documents at the study site. Any identifier details must be redacted (e.g participant 
initials, date of birth). Interpretation of the tracing must be made by a qualified physician and 
documented on the relevant CRF pages. 
A standard 12 lead ECG will be performed: 
• at screening or baseline (Triplicate ECG to be collected to assess QTcF intervals) 
• at Week 13, Week 26 and Week 52 (in the extension part ECG is only for the responders) 
• at the end of treatment 
Additional, unscheduled, safety ECGs may be repeated at the discretion of the investigator at 
any time during the study as clinically indicated. For any ECGs with participant safety concerns, 
two additional ECGs must be performed to confirm the safety finding. 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. 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/current medical conditions or AEs as appropriate. Clinically significant findings must 
be discussed with Novartis prior to enrolling the participant in the study. New or worsened 
clinically significant findings occurring after informed consent must be recorded as AEs. 
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 investigational drug intake to determine the 
drug exposure. Dose adjustments in case of QT prolongation should be performed 
per Section 6.5.1.1. 
Paper ECGs should be appropriately labeled and kept in the source documents at the study site. 
If an unscheduled ECG is performed at an external medical facility, a copy of the ECG should 
be obtained and kept in the source documents at the study site. 
8.4.2.1 
Cardiac imaging - echocardiogram 
An echocardiogram scan is required to be completed at screening. Clinically significant 
abnormalities present when the participant signed the informed consent should be reported as 
Medical History on the appropriate eCRF. New or worsened clinically significant findings 
occurring after informed consent must be recorded as an AEs on the eCRF. 


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8.4.2.2 
Cardiac enzymes 
Not applicable. 
8.4.3 
Bone marrow aspiration and biopsy 
Bone marrow aspirate for morphology, proportion of blasts, dysplasia, cytogenetics (karyotype 
analysis with G-banding and FISH), and for CD34 positive cells; bone marrow biopsy for 
cellularity, degree of fibrosis (reticulin stain and collagen stain), and dysplasia will be sampled 
during Screening, Week 13, Week 26, Week 52 and yearly after according to the schedule of 
assessments and collection plan outlined in Table 8-1.  
If the site laboratory is unable to perform the test (i.e., due to quality/sampling issue with the 
sample), particularly for cellularity and chromosome abnormality, the site may get one more 
bone marrow sample as soon as possible. 
Bone marrow findings will be recorded and will be correlated with hematological samples.  
8.4.4 
Evaluation of clonal evolution 
Cytogenetic abnormalities will be assessed during the whole study. For all participants, 
regardless of disposition, the assessments will be monitored at Week 13, Week 26, Week 52 
and yearly after, and when clinically indicated. 
Cytogenetic abnormalities will be assessed by karyotyping (G-banding) and FISH (for example, 
probes targeting abnormalities in chromosome 3, 5, 7, 8 and those associated with SAA, MDS, 
AML etc). 
Detection of PNH and measurement of PNH granulocyte clone size measurement by flow 
cytometry will be done at screening period. If persistently negative, it will be monitored every 
6 months up to Year 2 (Week 104) and then Year 3 (Week 156) unless symptoms or signs 
develop. If the PNH screen is, or becomes positive, it will be tested every 3 months and only 
reduce the frequency if the proportion of the PNH cells has remained stable (Killick et al 2016).  
Clonal evolution to AML and MDS will also be monitored during the study period, and relevant 
examinations will be done when clinically indicated. 
8.4.5 
Pregnancy and assessments of fertility 
Females of child-bearing potential are defined as all females physiologically capable of 
becoming pregnant. This includes female children and adolescents who are post-menarche or 
who experience menarche during the study. Pregnancy test will be performed for all females of 
child-bearing potential at baseline according to the Visit Schedule Table 8-1. 
Females of child-bearing potential who are or might become sexually active, must be informed 
of the potential teratogenic risk with eltrombopag, r-ATG and CsA and the need for highly 
effective contraception to prevent pregnancy while on the investigational treatment: use of oral, 
injected or implanted hormonal methods of contraception or placement of an intrauterine device 
or intrauterine system or other forms of hormonal contraception that have comparable efficacy 
(failure rate < 1%), for example hormone vaginal ring or transdermal hormone contraception. 


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Contraception must be used during the study and for 7 days after stopping treatment. The 
decision on the contraceptive method should be reviewed at least every 3 months to evaluate 
the individual need and compatibility of the method chosen. 
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. 
Contraception must be used during the study and for 16 weeks after stopping treatment. In 
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. Serum 
pregnancy testing is required at screening and at the end of treatment (EOT) visit or at the end 
of the study depending when the participants discontinue eltrombopag  treatment:  
• participants who discontinue eltrombopag prior to week 26 or at week 26 will have serum 
pregnancy test performed at EOT visit and at safety follow-up visit (30 days after EOT) 
• participants who discontinue eltrombopag during extension part of the study (week 28 to 
week 52) or who discontinue at week 52 will have serum pregnancy test at the safety follow-
up visit (30 days after EOT) only (at the EOT visit those patients will have a urine pregnancy 
test).  
During the study, urinary pregnancy testing should be done at monthly intervals until one month 
after the eltrombopag discontinues or CsA provided from this study stops (whichever is later), 
as indicated in Table 8-1. In the follow-up part women of child-bearing potential will perform 
at-home urine pregnancy testing monthly using kits provided. Tests results performed at home 
should be brought to each scheduled visit for the site to review. Information for urine pregnancy 
test must be included in the source documentation at the study site as unique source data. If 
local requirements dictate otherwise, local regulations should be followed. Additional 
pregnancy testing might be performed if requested by local requirements. In case of a positive 
test, the participant must contact the investigator immediately. The positive urine test needs 
to be confirmed with serum test. If positive, the participant must be discontinued from study 
treatment.  
Local pregnancy test and associated results will not be collected on CRF.  
Assessments of Fertility 
Medical documentation of oophorectomy, hysterectomy, or tubal ligation must be retained as 
source documents. Subsequent hormone level assessment to confirm the woman is not of child-
bearing potential must also be available as source documentation in the following cases: 
1. Surgical bilateral oophorectomy without a hysterectomy 
2. Reported 12 months of natural (spontaneous) amenorrhea with an appropriate clinical 
profile. 
In the absence of the above medical documentation, follicle-stimulating hormone (FSH) testing 
is required of any female participant regardless of reported reproductive/menopausal status at 
screening/baseline.  


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8.4.6 
Ophthalmic Assessments 
In this study, ophthalmic assessment including confirming the history, and 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). Because the risk of cataract increases with use of treatment such as 
steroids. SAA patients might be pre-medicated with steroids for ATG, therefore having this 
assessment at baseline would be helpful to assess causality to study treatment. 
8.4.7 
Other safety evaluations 
These tests are being performed to screen for occult infections so that appropriate medical 
management per institutional practice can be started prior to initiation of study treatment. 
Chest X-ray 
Standard chest X-ray (PA view) will be performed at screening except for those who have had 
a CT scan of the chest done within 1 month of Day 1.  
Abdominal sonography 
Standard abdominal ultrasound scan including liver, gallbladder, spleen, pancreas and kidney 
will be performed at screening.  
Clinically significant abnormalities present when the participant signed the informed consent 
should be reported as Medical History on the appropriate eCRF. New or worsened clinically 
significant findings occurring after informed consent must be recorded as an AEs on the eCRF. 
8.4.8 
Appropriateness of safety measurements 
The safety assessments selected are standard for this participant population. 
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 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). In CETB115AUS01T, 
clonal evolution occurred in 9 of 123 (7%) participants, which is within the range that would 
be expected with immunosuppression alone at 2 years after the initiation of treatment 
(Townsley et al 2017), while the estimated probability of being clonal evolution-free was above 
90% up to 2 years. These data have since been updated by Novartis, and at the update cutoff of 
(28-Feb-2018), clonal evolution occurred in 15/154 (10%; vs. 7% at the original cutoff) which 
is consistent with the reported incidences of clonal evolution in SAA participant receiving first 
line treatment with IST alone (without the addition of eltrombopag). In the refractory AA 
patients treated with eltrombopag, evolution to an abnormal karyotype occurred in 16 (19%), 
and it is almost always an early event occurring within 6 months after initiation of eltrombopag 
(Winkler et al 2019). 


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8.5 
Additional assessments 
8.5.1 
Pharmacokinetics 
8.5.1.1 
Pharmacokinetic blood collection and handling 
Blood samples (2 mL/sample) for eltrombopag PK evaluation will be collected from all 
participants who receive at least one dose of eltrombopag. 
 It is noted that participants must have received once daily eltrombopag for at least 7 consecutive 
days prior to the planned PK sampling day to ensure the PK sample drawn at steady state (i.e., 
no dose interruptions or missing for at least 7 consecutive days). If a participant discontinued 
eltrombopag treatment 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 not be collected, 
instead PK sampling should be performed after continuing eltrombopag treatment at least for 7 
days (actual date and time will be recorded).  
The scheduled PK sample collection will be only conducted in core treatment period. PK blood 
sampling will be performed as indicated in the Visit Evaluation Schedule (Table 8-1). The 
details of scheduled sampling time points for eltrombopag PK are shown in Table 8-4. 
Considering the clinical feasibility of blood collection, the patients will be required to take the 
dose at morning. 
Intensive PK sample collection： 
Twelve Chinese adult participants and all Japanese pediatric participants will receive intensive 
PK sampling over a 24 hours period on Days 14 to 15 after the initial dose of eltrombopag, in 
order to provide evaluable full PK profiles. A total of 6 blood samples will be collected at the 
following time points: pre-dose (trough), and 2, 4, 6, 8, and 24 hours post-dose. When these 
participants reduce to the lower dose levels, one trough blood sampling each will be collected 
at pre-dose on the 15th day after each new dose has started. 
Sparse PK sample collection： 
For all remaining participants, one trough blood sample each will be collected at pre-dose on 
the 15th day after the initialization of eltrombopag treatment and at pre-dose on the 15th day 
after each new dose has started until the lowest dose is reached.  
Table 8-4 
Pharmacokinetic blood collection log (eltrombopag) 
Week from the 
first dose 
Day from new 
dose started 
Scheduled time 
point 
Dose reference ID 
Sample number 
2 
14 
0 h (Pre-dose)a 
1b/101c 
1* 
2 
14 
2 h (± 15 min) 
1 
2* 
2 
14 
4 h (± 30 min) 
1 
3* 
2 
14 
6 h (± 30min) 
1 
4* 
2 
14 
8 h (± 30min) 
1 
5* 
2 
15 
24 h (± 1 h)/0 h 
(Pre-dose)a 
1c/102b 
6 
Variable 
15 
24 h (± 1 h)d/0 h 
(Pre-dose)a,d 
2+e/103+f  
7+g 
Unscheduled 
 Unscheduled 
Unscheduledh 
NA 
1001+h 


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Week from the 
first dose 
Day from new 
dose started 
Scheduled time 
point 
Dose reference ID 
Sample number 
*: these samples are only collected for 1) the first 12 Chinese adult participants who signed the informed 
consent to participate in the PK study, receiving 75 mg/day, 2) all Japanese pediatric participants at initial dose. 
a: Collect PK sample immediately before drug administration (not more than 1 h prior to dosing); 
b: Dose administration record after PK sampling ; 
c: Dose administration record before PK sampling; 
d: Collect pre-dose PK blood sample on the 15th day after each new dose has started (dose reduction criteria: 
75, 50 and 25 mg/day for the participants ≥ 12 years old; 37.5, 25 and 12.5 mg/day for participants ≥ 6 and < 
12 years old); 
e: Dose reference ID will be sequentially numbered 2, 3 for the last dose prior to pre-dose PK sampling after 
each new dose started, 
f: Dose reference ID will be sequentially numbered 103,104 for dose after pre-dose PK sampling; 
g: Sample number will be sequentially numbered 7, 8 when the PK blood sample is taken at pre-dose on Day 
15 after each new dose started; 
h: 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 as 1001, 1002, etc. 
In case of DILI, an unscheduled eltrombopag PK sample should be collected. 
On the days of PK sample collection, the participant will be advised to take investigational drug 
after the pre-dose blood sample is taken. 
The sample collection must be captured on appropriate eCRF and requisition form(s). The 
actual date and time of each PK sample collection will be integrated in the eCRF via data 
transfer.  
Additionally, for PK analysis purposes, the following information about the most recent dose 
prior to the visit (or DILI) will be recorded in the eCRF: 
• Date and time of dosing. 
• Whether or not eltrombopag was taken at empty stomach (1 hour before or 2 hours after a 
meal) or at least 2 hours before or 4 hours after polyvalent cations and dairy products. 
• Whether or not the participant vomited after receiving eltrombopag within 4 hours of dosing. 
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 
quantitation (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. 
Plasma samples remaining after completion of the determination eltrombopag concentrations 
may be used for exploratory assessments (e.g., metabolite identification), as appropriate. All 
relevant information will be provided in the [Laboratory Manual]. 


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9 
Study discontinuation and completion 
9.1 
Discontinuation 
9.1.1 
Discontinuation of study treatment 
Discontinuation of study treatment for a participant occurs when study treatment is permanently 
stopped earlier than the protocol planned duration and can be initiated by either the participant 
or the investigator. 
The investigator must discontinue study treatment for a given participant if, he/she believes that 
continuation would negatively impact the participant's well-being. 
Study treatment must be discontinued under the following circumstances: 
• The hematologic response is assessed as NR at Week 26.  
• Diagnosis of relapse. 
• Participant/guardian decision. 
• Pregnancy. 
• Any of the following is observed: a new clinical significant morphological, chromosomal 
or cytogenetic abnormality*, diagnosis of myelofibrosis** or progression to MDS or AML. 
• Participant meets any of the stopping criteria in Section 6.5.1. 
• Any laboratory abnormalities that in the judgment of the investigator, taking into 
consideration the participant's overall status, prevents the participant from continuing the 
study treatment. 
• Use of prohibited treatment as per recommendations in the prohibited treatment 
section (see Section 6.2.2). 
• The participant is withdrawn from the treatment with planned r-ATG or CsA, or the 
participant cannot tolerate the planned study treatment (e.g. Infusion-related r-ATG 
reactions refractory to all appropriate supportive measures; Life threatening acute 
hypersensitivity reactions). 
• The participant has an unacceptable AE whose causal relationship with eltrombopag cannot 
be ruled out. 
• The participant is found to be significantly non-compliant with the requirements of the 
protocol (including treatment non-compliance). 
• The investigator (or sub-investigator) believes that the participant will not benefit from 
eltrombopag or 
• that the participant needs to transfer to other therapy (e.g. HSCT, ATG/ALG). 
• The study is prematurely terminated. 
• Any situation in which study participation might result in a safety risk to the participant.  
*: Discontinuation should be considered if any new chromosomal or cytogenetic abnormality 
is observed, and if considered significant should be discontinued. This also applies for 
participants that started treatment based on normal karyotyping while FISH results were not yet 
available.  


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**: Considering TPO-receptor agonists like eltrombopag might lead to pathological increase in 
reticulin or collagen fibers by chronic stimulation of megakaryocytes. It is highly recommended 
to consider discontinuation of eltrombopag if a pathological myelofibrosis (e.g. staining for 
fibrosis is Grade 3 or higher) is confirmed. 
Participants may voluntarily discontinue from the study treatment (eltrombopag and/or r-ATG 
and/or CsA) for any reason at any time. If discontinuation of study treatment occurs, the 
investigator should make a reasonable effort to understand the primary reason for the 
participant's premature discontinuation of study treatment and record this information. 
Participants 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 Section 9.1.2). Where possible, they should return for the assessments 
indicated in the Assessment Schedule. If they fail to return for these assessments for unknown 
reasons, every effort (e.g. telephone, e-mail, letter) should be made to contact the 
participant/pre-designated contact as specified in the lost to follow-up section  
(see Section 9.1.3). This contact should preferably be done according to the study visit schedule. 
If the participant cannot or is unwilling to attend any visit(s), the site staff should maintain 
regular telephone contact with the participant, or with a person pre-designated by the participant. 
This telephone contact should preferably be done according to the study visit schedule. 
After study treatment discontinuation, at a minimum, in abbreviated visits, the following data 
should be collected at clinic visits or via telephone/email contact: 
• New / concomitant treatments 
• AEs / SAEs 
• Clonal evolution assessments 
The investigator must also contact the IRT to register the participant’s discontinuation from 
study treatment. 
Participants who prematurely discontinue study treatments will have efficacy assessments at 
defined time points (Week 13, Week 26, Week 52 and yearly after), unless or until the 
occurrence of no response at Week 26, relapse or alternative SAA treatment (whichever comes 
first). Survival and clonal evolution data will be collected for all participants up to Year 3  
(Week 156). 
9.1.1.1 
Replacement policy 
Participant will not be replaced on study. 
9.1.2 
Withdrawal of informed consent 
Participants may voluntarily withdraw consent to participate in the study for any reason at any 
time. Withdrawal of consent occurs only when a participant: 
• Does not want to participate in the study anymore,  
and 
• Does not want any further visits or assessments 
and 


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• Does not want any further study related contacts 
In this situation, the investigator should make a reasonable effort (e.g. telephone, e-mail, letter) 
to understand the primary reason for the participant’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 participant 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 participant’s study withdrawal should be made as detailed in the 
assessment table. 
Novartis will continue to keep and use collected study information (including any data resulting 
from the analysis of a participant’s samples until the time of withdrawal) according to applicable 
law. 
For Japan: All biological samples not yet analyzed at the time of withdrawal may still be used 
for further testing/analysis in accordance with the terms of this protocol and of the informed 
consent form. 
For China, Korea and Taiwan: 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 participants 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 participant, e.g. dates of 
telephone calls, registered letters, etc. A participant 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. This may include reasons related to the 
benefit/risk assessment of participating in the study, practical reasons (including slow 
enrollment), or for regulatory or medical reasons.  
Reasons for early termination: 
• Unexpected, significant, or unacceptable safety risk to participants enrolled in the study; 
• Decision based on recommendations from applicable board(s) after review of safety and 
efficacy data; 
• Discontinuation of investigational drug development. 
In taking the decision to terminate, Novartis will always consider the participant welfare and 
safety. Should early termination be necessary, participants must be seen as soon as possible and 
treated as a prematurely withdrawn participant. The investigator may be informed of additional 
procedures to be followed in order to ensure that adequate consideration is given to the 


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protection of the participant’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 the last participant 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 participants should have a safety follow-up visit conducted 30 days after last 
administration of eltrombopag. 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 participant should be recorded in the source 
documentation. 
The primary analysis will be performed after all participants 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 participants will continue to receive study treatment 
and be followed as per the schedule of assessments, as long as participants derive benefit from 
eltrombopag. 
The end of study defined as the earliest occurrence of one of the following: 
1. All participants have died or discontinued from the study or complete the study participation 
per protocol. 
2. Another clinical study becomes available that can continue to provide eltrombopag in this 
participant population and all participants ongoing are eligible to be transferred to that 
clinical study.  
At the end of Year 2 in this study, participants who in the opinion of the Investigator are still 
deriving clinical benefit from further CsA treatment should be directed by the treating physician 
to receive the product through commercial channels locally. The final analysis will occur at the 
end of the study. All available data from all participants 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 participant 
or clinical investigation participant after providing written informed consent for participation 
in the study. Therefore, an AE may or may not be temporally or causally associated with the 
use of a medicinal (investigational) product. 


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The investigator has the responsibility for managing the safety of individual participant and 
identifying AEs. 
Novartis qualified medical personnel will be readily available to advise on trial related medical 
questions or problems. 
The occurrence of AEs must be sought by non-directive questioning of the participant at each 
visit during the study. AEs also may be detected when they are volunteered by the participant 
during or between visits or through physical examination findings, laboratory test findings, or 
other assessments. 
Once the study ICF is signed, all AEs per the descriptions below will be captured in the Adverse 
Event CRF. 
AEs must be recorded under the signs, symptoms, or diagnosis associated with them, 
accompanied by the following information (as far as possible) (if the event is serious refer to 
Section 10.1.2): 
1. The Common Toxicity Criteria (CTC) AE grade (version 4.03). Grade 1 to 5 will be used 
to characterize the severity of the AE. AE will be assessed and graded according to the 
Common Terminology Criteria for Adverse Events (CTCAE) version. All grade 4 or higher 
value on Laboratory/investigational finding will be considered a medically significant event. 
Details of CTCAE Grade 5 and Fatal AEs will be recorded on Death page in eCRF. 
2. its relationship to the investigational drug and other investigational 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 participant 
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 AEs must be treated appropriately. Treatment may include one or more of the following: 
• Dose not changed 
• Dose Reduced/increased 
• Drug interrupted/withdrawn 
• Its outcome  
1. not recovered/not resolved; 
2. recovered/resolved; 
3. recovered/resolved with sequelae; 
4. 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 AEs only, if improvement to a lower 


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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 participant. 
AEs (including lab abnormalities that constitute AEs) should be described using a diagnosis 
whenever possible, rather than individual underlying signs and symptoms. 
AE monitoring should be continued for at least 30 days following the last dose of eltrombopag.  
Once an AE is detected, it must be followed until its resolution or until it is judged to be 
permanent (e.g. continuing at the end of the study), and assessment must be made at each visit 
(or more frequently, if necessary) of any changes in severity, the suspected relationship to the 
interventions required to treat it, and the outcome. 
Information about adverse drug reactions for the investigational drug can be found in the 
eltrombopag Investigator's Brochure. 
Abnormal laboratory values or test results constitute AEs only if they fulfill at least one of the 
following criteria: 
• they induce clinical signs or symptoms 
• they are considered clinically significant 
• they require therapy 
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 participants 
with the underlying disease. 
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. 
AESI are defined on the basis of an ongoing review of the safety data. Details of AESI can be 
found in the eltrombopagInvestigator's Brochure. 
In order to appropriately capture data regarding cytogenetic changes, any new cytogenetic 
abnormality must be recorded as an adverse event, on the CRF. In order to track all evidence of 
clonal evolution, any new serious event (SAE) should be submitted on a SAE form to Novartis 
in addition to entering in eCRF while non-serious events should be entered only in the eCRF. 
10.1.2 
Serious adverse events 
An SAE is defined as any AE [appearance of (or worsening of any pre-existing)] undesirable 
sign(s), symptom(s), or medical conditions(s) which meets any one of the following criteria: 
• fatal 
• life-threatening 


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Life-threatening in the context of a SAE refers to a reaction in which the participant was at risk 
of death at the time of the reaction; it does not refer to a reaction that hypothetically might have 
caused death if it were more severe (please refer to the ICH-E2D Guidelines). 
• results in persistent or significant disability/incapacity 
• constitutes a congenital anomaly/birth defect 
• requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for:  
• routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition 
• elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent 
• social reasons and respite care in the absence of any deterioration in the participant’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 participant 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 participant 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 SAE irrespective 
if a clinical event has occurred. 
10.1.3 
SAE reporting 
To ensure participant safety, every SAE, regardless of causality, occurring after the participant 
has provided informed consent and until 30 days following the last administration of 
eltrombopag 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 participant has provided 
informed consent until the time the participant is deemed a Screen Failure must be reported to 
Novartis. 


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All follow-up information for the SAE including information on complications, progression of 
the initial SAE and recurrent episodes must be reported as follow-up to the original episode 
within 24 hours of the investigator receiving the follow-up information. An SAE occurring at a 
different time interval or otherwise considered completely unrelated to a previously reported 
one must be reported separately as a new event. 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 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 European 
Union Guidance 2011/C 172/01 or as per national regulatory requirements in participating 
countries/regions. 
Any SAEs experienced after the 30 day period following EOT (after eltrombopag 
discontinuation at anytime during the study) should only be reported to Novartis Safety if the 
investigator suspects a causal relationship to study treatment. 
10.1.4 
Pregnancy reporting 
Pregnancies 
If a female trial participant becomes pregnant, the study treatment should be stopped, and the 
trial participant must be asked to read and sign pregnancy consent form to allow the Study 
Doctor ask about her pregnancy. To ensure participant 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 
participant 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 investigational drug 
and the investigational treatment of any pregnancy outcome. Any SAE experienced during 
pregnancy must be reported.  
Pregnancy outcomes should be collected for the female partners of any males who took study 
treatment in this study. Consent to report information regarding these pregnancy outcomes 
should be obtained from the mother. 
Follow up of the pregnancy (female participant or female partner of participant) should be 
according to the following schedule: 


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Tracking of pregnancy cases occurs until after Expected Delivery Date (EDD) for all 
prospective pregnancy cases received from clinical studies (including pregnancies where the 
participant 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. 
• 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 Patient Safety. 
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, participant 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 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 also be collected in DAR and 
reported in the safety database irrespective of it being associated with an AE/SAE within 24 
hours of Investigator’s awareness. 
Table 10-1 
Guidance for capturing the study treatment errors including 
misuse/abuse 
Treatment error type 
Document in Dosing 
CRF (Yes/No) 
Document in AE eCRF 
Complete SAE form 
Unintentional study 
treatment error 
Yes 
Only if associated with an 
AE 
Only if associated with an 
SAE 
Misuse/Abuse 
Yes 
Yes 
Yes, even if not 
associated with a SAE 
For more information on AE and SAE definition and reporting requirements, please see the 
respective sections. 


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10.2 
Additional Safety Monitoring 
Not applicable. 
11 
Data Collection and Database management 
11.1 
Data collection 
Designated investigator staff will enter the data required by the protocol into the eCRF. The 
eCRFs have been built using fully validated secure web-enabled software that conforms to 21 
code of federal regulation (CFR) Part 11 requirements, Investigator site staff will not be given 
access to the electronic data capture (EDC) system until they have been trained. Automatic 
validation programs check for data discrepancies in the eCRFs, allow modification and/or 
verification of the entered data by the investigator staff. 
The investigator/designee is responsible for assuring that the data (recorded on CRFs) (entered 
into eCRF) is complete, accurate, and that entry and updates are performed in a timely manner. 
The Investigator must certify that the data entered are complete and accurate. 
After final database lock, the investigator will receive copies of the participant 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 (or designated contract research organization) 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 
World Health Organization (WHO) Drug Reference List, which employs the Anatomical 
Therapeutic Chemical classification system. Medical history/current medical conditions and 
AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
terminology. 
Data about eltrombopag dispensed to the participant will be tracked using an IRT. The system 
will be supplied by a vendor, who will also manage the database. The data will be sent 
electronically to Novartis at specific timelines. 
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/delegated contract research organization (CRO) representative will review the 


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protocol and data capture requirements (i.e. eCRFs) with the investigators and their staff. 
During the study, Novartis employs several methods of ensuring protocol and Good Clinical 
Practice (GCP) compliance and the quality/integrity of the sites’ data. The field monitor will 
visit the site to check the completeness of participant records, the accuracy of data capture / data 
entry, the adherence to the protocol and to GCP, the progress of enrollment, and to ensure that 
study treatment is being stored, dispensed, and accounted for according to specifications. Key 
study personnel must be available to assist the field monitor during these visits. Continuous 
remote monitoring of each site’s data may be performed by a centralized Novartis/delegated 
CRO/CRA organization. Additionally, a central analytics organization may analyze data & 
identify risks & trends for site operational parameters, and provide reports to Novartis clinical 
teams to assist with trial oversight. 
The investigator must maintain source documents for each participant in the study, consisting 
of case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, ECGs, and the results of any other tests or assessments. All 
information on CRFs must be traceable to these source documents in the participant’s file. The 
investigator must also keep the original informed consent form signed by the participant (a 
signed copy is given to the participant). 
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 
participants will be disclosed. 
12 
Data analysis and statistical methods 
Primary analysis will be conducted on all participants data at the time all participants who have 
completed at least 26 weeks of treatment or discontinued prior to week 26.  
A final analysis will be performed at the end of the study.  
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 participants to whom study treatment has been 
assigned and who received at least one dose of study treatment.  
The Safety Set includes all participants who received at least one dose of study treatment. All 
safety analyses will be done using the Safety Set.  
The Pharmacokinetic analysis set (PAS) includes all participants who received at least one dose 
of eltrombopag and provide at least one evaluable PK sample. The definition of an evaluable 
PK sample and PK profile will be further defined in the statistical analysis plan.  


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12.2 
Participants demographics and other baseline characteristics 
Demographic and other baseline data including disease characteristics will be listed and 
summarized descriptively for the FAS. 
Categorical data will be presented as frequencies and percentages. For continuous data, mean, 
standard deviation (SD), median, minimum, and maximum will be presented. For selected 
parameters, 25th and 75th percentiles will also be presented. 
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, SD, median, 25th and 75th percentiles, 
minimum, and maximum will be presented.  
Please note that the relative dose intensity will not be summarized for CsA. The duration of 
exposure in weeks to eltrombopag as well as the dose intensity (computed as the ratio of actual 
cumulative dose received and actual duration of exposure) and the relative dose intensity 
(computed as the ratio of dose intensity and planned dose intensity) will be summarized by 
means of descriptive statistics using the safety set. The duration of exposure in weeks to CsA, 
as well as the dose intensity will be summarized by means of descriptive statistics using the 
safety set. As the dose of CsA will be adjusted through the study to achieve the CsA therapeutic 
level, the relative dose intensity will not be reported. The duration of exposure in days to r-ATG 
as well as the dose intensity and relative dose intensity will be summarized by means of 
descriptive statistics using the safety set. For all three drugs, the number of participants with 
dose adjustments (reductions, interruption, or permanent discontinuation) and the reasons will 
be summarized and all dosing data will be listed. 
Concomitant medications and significant non-drug therapies prior to and after the start of the 
study treatment will be listed and summarized according to the Anatomical Therapeutic 
Chemical (ATC) classification system. 
12.4 
Analysis of the primary endpoint(s) 
The primary objective of the study is to evaluate the efficacy of eltrombopag in combination 
with r-ATG and CsA in terms of CR rate at Week 26 in the treatment-naive East-Asian patients 
with SAA. 
12.4.1 
Definition of primary endpoint(s) 
The primary efficacy endpoint is CR rate at Week 26 (6 months), which is defined as the 
percentage of all participants who meet the hematological criteria of CR in Section 8.3 at Week 
26. The primary efficacy endpoint will be performed in FAS. 
12.4.2 
Statistical model, hypothesis, and method of analysis 
The CR at Week 26 will be summarized using point estimates and 2-sided exact binomial 95% 
(Clopper-Pearson) confidence intervals. 


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12.4.3 
Handling of missing values/censoring/discontinuations 
Participants who are not evaluable for response at Week 26 for any reason, including missing 
data and withdrawal from the study before Week 26, will be treated as non-responders in the 
primary analysis. 
12.4.4 
Sensitivity and Supportive analyses 
Supportive analyses 
Supportive analyses using the CR at Week 26 will be done in the following way: 
• A more stringent definition of CR meeting all the following criteria on 2 consecutive 
serial blood count measurements at least one week apart:  
• Normal hemoglobin concentration for age and gender 
• ANC >1.5x109/L 
• Platelet count > 150x109/L 
Since this is a more stringent definition of CR, very few CRs will be expected for analysis. 
Subgroup analyses 
In addition, the primary endpoint will be summarized by age group. 
12.5 
Analysis of secondary endpoints 
The secondary objectives in this study are: 
• To evaluate complete response rate at 3, 12 months and yearly after; 
• To evaluate overall response rate at 3, 6, 12 months and yearly after; 
• To evaluate duration of response; 
• To evaluate overall survival; 
• To evaluate the need for transfusion (packed RBC units and platelet units); 
• To evaluate the safety and tolerability of eltrombopag in combination with r-ATG and 
CsA; 
• To evaluate clonal evolution; 
• To determine the PK of eltrombopag in East-Asian treatment naive SAA patients. 
12.5.1 
Efficacy and/or Pharmacodynamic endpoint(s) 
For all secondary efficacy endpoints, the FAS will be used.  
CR rate at Week 13, Week 52 and yearly after 
The number and percentage of participants who meet the hematological CR criteria (at Week 
13, Week 52 and yearly after respectively, see Section 8.3 for definition of response) will be 
presented and 2-sided Exact binomial 95% (Clopper-Pearson) confidence interval will be 
reported. For missing values and discontinuations, a similar approach will be adopted as for the 
primary endpoint.  


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Overall response (CR+PR) rate at Week 13, Week 26, Week 52 and yearly after 
Hematologic overall response rate at specific visit is defined as percentage of participants who 
achieved hematologic response (see Section 8.3) at specific visit in FAS. The number and 
percentage of participants who meet the hematological overall response criteria (at Week 13, 
Week 26, Week 52 and yearly after respectively) will be presented and 2-sided Exact binomial 
95% (Clopper-Pearson) confidence interval will be reported. For missing values and 
discontinuations, a similar approach will be adopted as for the primary endpoint.  
Duration of response 
For participants who responded, duration of response will be defined as the time from the first 
date of a response until the first date of relapse or death, which occurs first. Participant still 
responding at the cut-off date will be censored at date of last response assessment. Only 
participants with at least 2 response assessments are included in the duration of response, unless 
they relapsed or died. Duration of response will be estimated using Kaplan-Meier method and 
will be plotted. 
Transfusion-free interval before Week 13 and Week 26 
For platelet transfusion, transfusion-free interval is defined as the time from most recent platelet 
transfusion to the date of response assessment. Only participants with response assessments at 
specific visits (Week 13 or 26) are included in the transfusion-free interval. Descriptive statistics 
including mean, SD, median, 25th and 75th quartiles, minimum, and maximum will be 
summarized for the transfusion-free interval. The same analysis applies to RBC transfusion. 
The analysis will be presented for participants with CR, PR and NR.  
Proportion of participants who becomes transfusion independent 
The number and percentage of participants with platelet or RBC transfusion independence at 
any time during the study will be presented respectively. This analysis will be performed for 
the subgroup of participants with baseline transfusion dependent. 
Overall survival 
OS is defined as the time from the date of the first dose of study treatment to the date of death 
due to any cause. If a participant is not known to have died, survival will be censored at the date 
of last contact. The distribution function of OS will be estimated using the Kaplan- Meier 
method and will be plotted. OS rate will be estimated at Week 26, Week 52 and yearly after as 
well. 
12.5.2 
Safety endpoints 
For all safety analyses, the safety set will be used. All listings and tables will be presented for 
all participants. 
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 


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treatment deaths will be provided. In particular, summary tables for AEs will summarize only 
on-treatment events, with a start date during the on-treatment period (treatment-emergent AEs). 
The overall observation period will be divided into three mutually exclusive segments: 
1. Pre-treatment period: from day of participant’s informed consent to the day before first dose 
of study treatment. 
2. On-treatment period: from date of first administration of study treatment to 30 days after 
date of last administration of eltrombopag.   
3. Post-treatment period: starting at day 30+1 after last dose of eltrombopag 
Adverse events 
All information obtained on AEs will be displayed by participant. 
The number (and percentage) of participants with treatment emergent AEs (events started after 
the first dose of investigational drug or events present prior to start of study treatment but 
increased in severity based on preferred term) will be summarized in the following ways: 
• by treatment, primary system organ class and preferred term. 
• by treatment, primary system organ class, preferred term and maximum CTCAE severity. 
Separate summaries will be provided for investigational drug (eltrombopag) related AEs, death, 
SAEs, other significant AEs leading to discontinuation, and AEs leading to dose modification. 
The number (and proportion) of participants with AEs of special interest will be summarized. 
A participant with multiple AE within a primary system organ class is only counted once 
towards the total of the primary system organ class. 
AEs which will be counted for a specific treatment period are those which are treatment-
emergent. These events are those with an onset after the start of the treatment period, or which 
were present prior to the start of the treatment period but increased in severity, changed from 
being not suspected to being suspected of investigational drug relationship, or developed into 
SAEs after the start of the treatment period. 
Summary tables for AEs will include only AEs that started or worsened during the on-treatment 
period, the treatment-emergent AEs. 
The incidence of treatment-emergent AEs (new or worsening from baseline) will be 
summarized by system organ class and or preferred term, severity (based on CTCAE grades), 
type of AE, relation to study treatment. 
SAEs, non-serious AEs and AESI during the on-treatment period will be tabulated. 
All deaths (on-treatment and post-treatment) will be summarized. 
All AEs, deaths, and SAEs (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 
All vital signs data will be listed by participant, and visit/time and if ranges are available, 
abnormalities will be flagged. Summary statistics will be provided by treatment and visit/time. 


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12-lead ECG 
PR, QRS, QT, QTcF and RR intervals will be obtained from 12-lead ECGs for each participant 
during the study. 
Shift tables of ECG findings (‘Normal’ or ‘Abnormal’) 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 participants with at least 1 abnormality will be listed. All ECG data will 
be listed by participant and visit/time, abnormalities will be flagged. 
Clinical laboratory evaluations 
All laboratory data will be listed by participant and visit/time and if normal ranges are available, 
abnormalities will be flagged. Summary statistics will be provided by treatment and visit/time. 
Shift tables using CTCAE grades or the low/normal/high/ (low and high) classification will be 
used to compare baseline to the worst on-treatment value. 
Grading of laboratory values will be assigned programmatically as per NCI Common 
Terminology Criteria for Adverse Events (CTCAE), version 4.03. The calculation of CTCAE 
grades will be based on the observed laboratory values only, clinical assessments will not be 
taken into account. 
CTCAE Grade 0 will be assigned for all non-missing values not graded as 1 or higher. Grade 5 
will not be used. 
For laboratory tests where grades are not defined by CTCAE, results will be categorized as 
low/normal/high based on laboratory normal ranges. 
The following summaries will be generated separately for hematology, and biochemistry tests: 
• Listing of all laboratory data with values flagged to show the corresponding CTCAE 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 participant 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, SD, median, interquartile range, and 
range). 


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Cytogenetic abnormalities, clonal evolution to PNH and clonal evolution to 
AML or MDS 
Cytogenetic abnormalities, clonal evolution to PNH, evolution to MDS or AML will be 
summarized at each planned biomarker assessment visit. The number and percentage of 
participants with above clonal evolutions will be presented and exact 95% confidence interval 
will be reported. If sufficient data are available, the time to clonal cytogenetic abnormalities, 
clonal evolution to PNH, AML or MDS until data cutoff may also be estimated using Kaplan-
Meier method and will be plotted. 
12.5.3 
Pharmacokinetics 
PAS will be used in all PK data analyses and PK summary statistics. 
PK analyses for participants with extensive PK samples 
PK sampling details are provided in Section 8.5.1. 
Eltrombopag plasma concentration data will be listed by participant, and visit/sampling time 
point. Descriptive summary statistics including mean (arithmetic and geometric), SD, 
coefficient of variation (CV) (arithmetic and geometric), median, minimum and maximum will 
be provided by age group/dose/visit/sampling time point. 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, and treated as missing 
for the calculation of the geometric means and their CV%. Missing data will not be imputed.  
PK parameters of eltrombopag, 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 participant. 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 
Observed maximum plasma concentration following administration (mass/volume) 
Tmax 
The time to reach peak or maximum concentration (time) 
Ctrough 
Pre-dose plasma concentration (mass/volume) 
CLss/F 
Apparent systemic (or total body) clearance at steady state from plasma (volume/time) 
PK analyses for participants with sparse PK samples 
PK concentrations of eltrombopag will be summarized by dose, age group, 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. 


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12.6 
Analysis of exploratory endpoints 
There is no exploratory endpoints in this trial. 
12.7 
Interim analyses 
No formal interim analysis is planned for this trial. The primary analysis will be performed after 
all participants have completed Week 26 or discontinued prior to Week 26. A final analysis will 
be performed after all participants have completed the study. No formal testing of the primary 
endpoint will be performed in this study. 
12.8 
Sample size calculation 
As this is a bridging study to support registration, an estimation strategy rather than formal 
hypothesis testing will be pursued. Approximately 36 participants will be enrolled into the study 
based on the feasibility rather than statistical considerations. This number of participants is 
considered appropriate to assess the efficacy and safety of eltrombopag in Asian patients. 
12.8.1 
Primary endpoint(s) 
Based on the Day 120 report in the pivotal study of CETB115AUS01T, the complete 
hematological response rate at Month 6 in Cohort 3+Extension is 43.7%. If the CR rate obtained 
in naive Asian patients with SAA treated with eltrombopag is expected to be 44.0%, a total of 
36 participants will result in a 95% CI lower bound of about 28%. 
Below table shows the exact 95% CIs for various observed complete hematological response 
rate. The maximum half-width of the 95% CIs is 17.1%. 
Table 12-2 
95% CIs for various observed response rate 
Total sample size 
# of responders 
Complete hematologic 
response rate (%) 
95% CI (%) 
36 
14 
38.9 
(23.1, 56.5) 
36 
16 
44.4 
(27.9, 61.9) 
36 
18 
50.0 
(32.9, 67.1) 
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 International Council for Harmonisation (ICH) Harmonized Tripartite Guidelines for 
GCP, with applicable local regulations (including European Directive 2001/20/EC, US CFR 
21), and with the ethical principles laid down in the Declaration of Helsinki. 
13.2 
Responsibilities of the investigator and IRB/IEC 
Before initiating a trial, the investigator/institution must obtain approval/favorable opinion from 
the IRB/IEC for the trial protocol, written informed consent form, consent form updates, 
participant recruitment procedures (e.g. advertisements) and any other written information to 
be provided to participants. Prior to study start, the investigator is required to sign a protocol 


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


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14.1 
Protocol amendments 
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, health authorities where required, and the IRB/IEC prior to 
implementation. 
Only amendments that are required for participant 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 participant included in this 
study, even if this action represents a deviation from the protocol. In such cases, Novartis should 
be notified of this action and the IRB/IEC at the study site should be informed according to 
local regulations. 


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15 
References 
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Chuncharunee S, Wong R, Rojnuckarin P, et al (2016) Efficacy of rabbit antithymocyte globulin 
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Hwang YY, Gill H, Chan TSY, et al (2018) Eltrombopag in the management of aplastic 
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adult aplastic anaemia. Br. J. Haematol. p. 187-207. 
Kojima S, Nakao S, Young N, et al (2011) The Third Consensus Conference on the treatment 
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Kook H, Risitano AM, Zeng W, et al (2002) Changes in T-cell receptor VB repertoire in aplastic 
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Kordasti S, Marsh J, Al-Khan S, et al (2012) Functional characterization of CD4+ T cells in 
aplastic anemia. Blood p. 2033-43. 
Li SS, Hsu YT, Chang C, et al (2019) Incidence and treatment outcome of aplastic anemia in 
Taiwan-real-world data from single-institute experience and a nationwide population-based 
database. Ann. Hematol. p. 29-39. 
Maciejewski JP, Risitano A, Sloand EM, et al (2002) Distinct clinical outcomes for cytogenetic 
abnormalities evolving from aplastic anemia. Blood p. 3129-35. 


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Mahapatra M, Singh PK, Agarwal M, et al (2015) Epidemiology, Clinico-Haematological 
Profile and Management of Aplastic Anaemia: AIIMS Experience. J Assoc Physicians India p. 
30-5. 
Marsh JC, Bacigalupo A, Schrezenmeier H, et al (2012) Prospective study of rabbit 
antithymocyte globulin and cyclosporine for aplastic anemia from the EBMT Severe Aplastic 
Anaemia Working Party. Blood p. 5391-6. 
Marsh JC, Ball SE, Cavenagh J, et al (2009) Guidelines for the diagnosis and management of 
aplastic anaemia. Br. J. Haematol. p. 43-70. 
Marsh JC, Kulasekararaj AG (2013) Management of the refractory aplastic anemia patient: 
what are the options? Hematology Am Soc Hematol Educ Program p. 87-94. 
McHutchison JG, Dusheiko G, Shiffman ML, et al (2007) Eltrombopag for thrombocytopenia 
in patients with cirrhosis associated with hepatitis C. N. Engl. J. Med. p. 2227-36. 
Ohta A, Nagai M, Nishima M, et al (2015) Incidence of Aplastic Anemia in Japan: Analysis of 
Data from a Nationwide Registration System. International Journal of Epidemiology vol. 44, 
suppl-1; i178 
Olnes MJ, Scheinberg P, Calvo KR, et al (2012) Eltrombopag and improved hematopoiesis in 
refractory aplastic anemia. N. Engl. J. Med. p. 11-9. 
Passweg JR, Tichelli A (2009) Immunosuppressive treatment for aplastic anemia: are we hitting 
the ceiling? Haematologica p. 310-2. 
Ramzan M, Yadav SP, Zafar MS, et al (2014) Outcome of pediatric acquired aplastic anemia: 
a developing world experience. Pediatr Hematol Oncol p. 29-38. 
Red Blood Cell Disease (Anemia) Group, Chinese Society of Hematology, Chinese Medical 
Association (2017) [Chinese expert consensus on the diagnosis and treatment of aplastic anemia 
(2017)] p. 1-5. 
Risitano AM, Maciejewski JP, Green S, et al In-vivo dominant immune responses in aplastic 
anaemia: molecular tracking of putatively pathogenetic T-cell clones by TCR beta-CDR3 
sequencing. Lancet (2004) p. 355-64. 
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. 
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Scheinberg P (2018) Activity of eltrombopag in severe aplastic anemia. Blood Adv p. 3054-
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Scheinberg P, Chen J (2013) Aplastic anemia: what have we learned from animal models and 
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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. 
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Scheinberg P, Young NS (2012) How I treat acquired aplastic anemia. Blood p. 1185-96. 
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patients with severe aplastic anemia: a single-center retrospective study. Ann. Hematol. p. 817-
24. 
Solomou EE, Keyvanfar K, Young NS (2006) T-bet, a Th1 transcription factor, is up-regulated 
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cells in acquired aplastic anemia. Blood p. 1603-6. 
Sun H, Tsai Y, Nowak I, et al (2012) Eltrombopag, a thrombopoietin receptor agonist, enhances 
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Young NS, Maciejewski J (1997) The pathophysiology of acquired aplastic anemia. N. Engl. J. 
Med. p. 1365-72. 
Zhang XY, Liu HQ, Zhang DL, et al (2001) [Epidemiology of leukaemia and Aplastic Anemia 
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16 
Appendices 
16.1 
Appendix 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 (Oct 2017), and the University of Washington’s Drug 
Interaction Database. The lists provided may not be exhaustive. 
16.2 
ECOG/Lansky Performance Status Scales 
Table 16-1 
ECOG Performance Status 
Score 
Description 
0 
Fully active, able to carry on all pre-disease performance without restriction. 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or 
sedentary nature, e.g., light housework, office work. 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about 
more than 50% of waking hours. 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours. 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to a bed or chair. 
5 
Dead. 
Table 16-2 
Lansky Play Performance Scale (Lansky et al., 1987) 
Score 
Description 
100 
Fully active, normal 
90 
Minor restrictions in physically strenuous activity 
80 
Active, but tires more quickly 
70 
Both greater restriction of, and less time spent in, active play 
60 
Up and around, but minimal active play; keeps busy with quieter activities 
50 
Gets dressed, but lies around much of the day; no active play; able to participate in all quiet play 
and activities 
40 
Mostly in bed; participates in quiet activities 
30 
In bed; needs assistance even for quiet play 
20 
Often sleeping; play is entirely limited to very passive activities 
10 
No play; does not get out of bed 
0 
Unresponsive 


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16.3 
NYHA and Modified Ross Heart Failure Classification for children 
Table 16-3 
NYHA and Modified Ross Heart Failure Classification for children 
  
NYHA 
Ross 
Class I 
No limitations of physical activity 
No limitations or symptoms 
Class II 
May experience fatigue, 
palpitations, dyspnea, or angina 
during moderate exercise but not 
during rest 
Mild to moderate dyspnea on 
exertion 
Class III 
Symptoms with minimal exertion 
that interfere with normal daily 
activity 
Marked dyspnea on exertion 
Class IV 
Unable to carry out any physical 
activity because they typically have 
symptoms of heart failure at rest 
that worsen with any exertion 
Symptoms at rest such as 
tachypnea, retractions, grunting, or 
diaphoresis 
 

SAP_001.pdf: 
Clinical Development 
ETB115/Eltrombopag/Revolade® 
CETB115G2201 / NCT04328727
A non-randomized, open label, multi-center, Phase II study 
to assess the safety and efficacy of eltrombopag in 
combination with rabbit anti-thymocyte globulin (r-ATG) 
and cyclosporine A (CsA) in East-Asian patients with 
treatment naive severe aplastic anemia 
Statistical Analysis Plan (SAP) 
Document type: 
SAP Documentation 
Document status: 
Amendment 1.0 
Release date: 
1-July-2022
Number of pages: 
38 
Property of Novartis 
Confidential 
May not be used, divulged, published or otherwise disclosed 
without the consent of Novartis
Template Version 4.0, Effective from 23-Apr-2021 


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cc 
Document History – Changes compared to previous final version of SAP 
 
Date 
Time 
point 
Changes 
Section and 
title 
impacted 
(Current) 
15-
Sep-
2020 
Prior 
to 
FPFV 
N/A - First version 
NA 
1-Jul-
2022 
Prior 
to 
DBL 
Update the definition of on-treatment period and post-
treatment period according to protocol changes; 
Update the windows for multiple assessments 
Section 
2.1.1 
 
 
Remove the race subgroup analysis in efficacy, safety and 
PK;  
Update the China Mainland/Japan specific subgroup 
analysis 
Section 
2.2.1 
 
 
Update the definition of duration of exposure with 
consideration of using hours as unit time for rATG;  
Add the definition and the corresponding statistical analysis 
of actual duration of exposure 
Section 
2.4.1 
 
 
Add the definition and the corresponding statistical analysis 
of actual dose intensity;  
Remove the planned dose intensity and relative dose 
intensity 
Section 
2.4.1 
 
 
Remove the summary analysis and the corresponding table 
for concomitant medications that have the potential to 
impact efficacy results 
Section 
2.4.2 
 
 
Add the supplementary analysis section to specifically 
describe the CR response  that is derived programmatically 
using laboratory results 
Section 
2.5.1; 
Section 
2.5.4 
 
 
Update the definition of the relapse; 
Add the definition and corresponding statistical analysis for 
below-listed item:  
Time to response;  
Maximum duration of Platelet and RBC transfusion free;  
Section 2.7 


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Date 
Time 
point 
Changes 
Section and 
title 
impacted 
(Current) 
Proportion of subjects with transfusion decrease;  
Changes in platelet count, hemoglobin and neutrophil count 
 
 
Specify that the  CTC grade  >=3 adverse events will be 
summarized for AEs by SOC and PT 
Section 
2.8.1 
 
 
Add the sub-items for ALT and AST 
Section 
2.8.3 
 
 
Remove the percentage summary table and the shifted table 
for ECG Findings 
Section 
2.8.4.1 
 
 
Update PD and PK/PD analyses 
Section 2.10 
 
 
Update the definition of the cytogenetic abnormalities and 
clonal evolution observed during the study;  
Remove the time to clonal evolution 
Section 2.12 
 
 
Add the imputation rule of end dates, when missing 
component is the hour for rATG 
Section 
5.1.2 
 


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Table of contents 
Table of contents ................................................................................................................. 4 
1 
Introduction ......................................................................................................................... 7 
1.1 
Study design ............................................................................................................ 7 
1.2 
Study objectives and endpoints ............................................................................... 9 
2 
Statistical methods ............................................................................................................. 10 
2.1 
Data analysis general information ......................................................................... 10 
2.1.1 
General definitions ................................................................................ 11 
2.2 
Analysis sets .......................................................................................................... 14 
2.2.1 
Subgroup of interest .............................................................................. 14 
2.3 
Patient disposition, demographics and other baseline characteristics ................... 15 
2.3.1 
Patient disposition ................................................................................. 16 
2.4 
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance)............................................................................................................ 17 
2.4.1 
Study treatment / compliance ................................................................ 17 
2.4.2 
Prior, concomitant and post therapies ................................................... 18 
2.5 
Analysis of the primary objective .......................................................................... 19 
2.5.1 
Primary endpoint ................................................................................... 19 
2.5.2 
Statistical hypothesis, model, and method of analysis .......................... 19 
2.5.3 
Handling of missing values/censoring/discontinuations ....................... 19 
2.5.4 
Supplementary analyses ........................................................................ 19 
2.5.5 
Supportive analyses ............................................................................... 20 
2.6 
Key secondary endpoint ........................................................................................ 20 
2.7 
Analysis of secondary efficacy objective(s) .......................................................... 20 
2.7.1 
Secondary efficacy endpoints ............................................................... 20 
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....................................................................................................... 25 
2.8.1 
Adverse events (AEs) ............................................................................ 26 
2.8.2 
Deaths .................................................................................................... 27 
2.8.3 
Laboratory data ..................................................................................... 27 
2.8.4 
Other safety data ................................................................................... 29 
2.9 
Pharmacokinetic endpoints .................................................................................... 31 
2.10 
PD and PK/PD analyses ........................................................................................ 32 
2.11 
Patient-reported outcomes ..................................................................................... 32 
2.12 
Cytogenetic abnormalities and clonal evolution .................................................... 32 


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2.13 
Other Exploratory analyses.................................................................................... 33 
2.14 
Interim analysis ...................................................................................................... 33 
3 
Sample size calculation ..................................................................................................... 33 
3.1 
Primary analysis .................................................................................................... 33 
3.2 
Power for analysis of key secondary variables ...................................................... 33 
4 
Change to protocol specified analyses .............................................................................. 33 
5 
Appendix ........................................................................................................................... 34 
5.1 
Imputation rules ..................................................................................................... 34 
5.1.1 
Study drug ............................................................................................. 34 
5.1.2 
AE, ConMeds and safety assessment date imputation .......................... 34 
5.2 
AEs coding/grading ............................................................................................... 36 
5.3 
Laboratory parameters derivations ........................................................................ 36 
5.4 
Statistical models ................................................................................................... 37 
5.4.1 
Primary analysis .................................................................................... 37 
5.4.2 
Secondary analysis ................................................................................ 37 
6 
Reference ........................................................................................................................... 38 
 
List of tables 
Table 1-1 
Objectives and related endpoints ............................................................ 9 
Table 2-1 
Time windows for hematological response........................................... 13 
Table 2-2 
Clinically notable changes in vital signs ............................................... 30 
Table 2-3 
Non-compartmental PK parameters ...................................................... 31 
Table 3-1 
95% CIs for various observed response rate ......................................... 33 
Table 5-1 
Imputation of start dates (AE, CM) and assessments (LB, EG, VS) .... 34 
Table 5-2 
Imputation of end dates (AE, CM) ........................................................ 36 
 
List of figures 
Figure 1-1 
Study design ............................................................................................ 8 
 
 


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List of abbreviations 
AE 
Adverse event 
AESI 
adverse event of special interest 
AML 
Acute Myeloid Leukemia 
ATC 
Anatomical Therapeutic Classification 
ATG 
anti-thymocyte globulin 
AUC 
Area Under the Curve 
AUClast 
Area under concentration-time curve until the last quantifiable sampling time 
AUCtau 
Area under concentration-time cuve during a dosing interval tau 
Cmax 
Maxiumum (peak) concentration 
CR 
Complete Response 
CRF 
Case Report Form 
CSR 
Clinical Study report 
CsA 
Cyclosporine A 
CTC 
Common Toxicity Criteria 
CTCAE 
Common Terminology Criteria for Adverse Events 
Ctrough 
Concentration level prior to dosing 
FAS 
Full Analysis Set 
r-ATG 
Rabbit Anti-Thymocyte Globulin 
HRQL 
Health-related Quality of Life 
IST 
Immunosuppressive Therapy 
LLOQ 
Lower Limit of Quantitation 
MDS 
Myelodysplastic Syndrome 
MedDRA 
Medical Dictionary for Drug Regulatory Affairs 
NCI 
National Cancer Institute 
NIH 
National Institute of Health 
OR 
Overall Response 
OS 
Overall Survival 
PK 
Pharmacokinetics 
PR 
Partial Response 
PT 
Preferred Term 
RAP 
Report and Analysis Process 
SAA 
Severe Aplastic Anemia 
SAP 
Statistical Analysis Plan 
SOC 
System Organ Class 
TFLs 
Tables, Figures, Listings 
Tmax 
Time to reach maximum (peak) concentration 
WHO 
World Health Organization 
 
 
  


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1 
Introduction 
This statistical analysis plan (SAP) describes all planned analyses for the clinical study report(s) 
(CSR) of study CETB115G2201, a non-randomized, open label, multi-center, Phase II study to 
assess the safety and efficacy of eltrombopag in combination with rabbit anti-thymocyte 
globulin (r-ATG) and cyclosporine A (CsA) in East-Asian patients with treatment naive severe 
aplastic anemia (SAA)  
As specified in Section 12 of the study protocol (version 03 dated 22-Dec-2021), the primary 
analysis will be performed after all patients have completed Week 26 or discontinued prior to 
Week 26. Furthermore, a final analysis will be performed at the end of the study. This SAP will 
also support the final analysis. 
The content of this SAP is based on protocol CETB115G2201 version 03 (dated 22-Dec-2021). 
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, single arm, multi-center, Phase II study to evaluate the 
efficacy and safety of eltrombopag in combination with IST regimen of r-ATG + CsA in East-
Asian patients with SAA who have not received prior IST. At least 36 subjects will be enrolled 
from China, Japan, Korea or Taiwan. At least 6 pediatric subjects will be recruited in total, with 
3 subjects from China and 3 from Japan respectively. At least one of the 6 pediatric subjects in 
each age group (6 to 11 years old, and 12 to 17 years old) will be enrolled. For the 30 adult 
subjects, at least 12 subjects will be recruited from China to fulfill the requirements for 
pharmacokinetic (PK) profile. 


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Figure 1-1 
Study design 
  
Eligible subjects will be enrolled into the study and will receive eltrombopag (from Day 1 to 
Week 26) concomitantly with r-ATG (on Days 1-5) and CsA (from Day 1 to Week 26) in the 
core treatment part. 
Efficacy assessments will be performed at Week 13 and Week 26 in the core treatment part of 
the study. 
Participants who are assessed as responders (meeting CR or PR criteria) at Week 26 are eligible 
to the extension part of the study and continue treatment with eltrombopag and CsA after Week 
26.  


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Study treatment should be discontinued if the participant is not assessed as a responder at Week 
26.  
During the extension part, eltrombopag treatment will be provided up to Week 52.  CsA will be 
maintained or tapered at the investigator's discretion according to local practice, with a total 
duration of at least 2 years (18 months after Week 26). 
End of treatment assessments will be performed after eltrombopag discontinuation anytime 
during the study. After that, safety follow-up visit will be performed 30 days after the 
discontinuation of eltrombopag, and participants will enter the long-term follow-up part, with 
yearly efficacy and clonal evolution assessments up to Year 3 (Week 156). 
For non-responders at Week 26, and participants who relapse or receive alternative SAA 
treatment, safety follow-up visit will be performed 30 days after the discontinuation of 
eltrombopag, and then clonal evolution and survival will continue to be followed up to Year 3 
(Week 156). 
Participants who prematurely discontinue eltrombopag will have efficacy assessments at 
defined time points (Week 13, Week 26, Week 52 and yearly after), unless or until the 
occurrence of no response at Week 26, relapse or alternative SAA treatment (whichever comes 
first). Survival and clonal evolution data will be collected for all participants up to Year 3 (Week 
156).  
1.2 
Study objectives and endpoints 
For the definition of response, partial response (PR), CR, transfusion independence, and relapse, 
refer to Section 2.5 and Section 2.7.  
Table 1-1 
Objectives and related endpoints 
Objective(s) 
Endpoint(s) 
Primary objective(s) 
Endpoint(s) for primary objective(s) 
• 
To evaluate the efficacy of eltrombopag in 
combination with r-ATG and CsA in terms of 
complete response rate at 6 months in East-Asian 
patients with treatment naive severe aplastic 
anemia (SAA) 
• 
CR rate at Week 26 (6 months) after 
starting the study treatment  
Secondary objective(s) 
Endpoint(s) for secondary objective(s) 
• 
To evaluate complete response rate at 3, 12 
months and yearly after 
• 
CR rate at Week 13 (3 months), Week 
52 (12 months) and yearly after 
• 
To evaluate overall response rate at 3, 6, 12 
months and yearly after 
• 
Overall response (CR+PR) rate at 
Week 13 (3 months), Week 26 (6 
months), Week 52 (12 months) and 
yearly after 
• 
To evaluate duration of response 
• 
Time from the date of the start of 
response to the date of relapse or 
death, whichever occurs first at any 
time during the study 
• 
To evaluate overall survival (OS)  
• 
Time from the date of first dose of 
study treatment to the date of death 


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Objective(s) 
Endpoint(s) 
• 
Overall survival rate at Week 26, 
Week 52 and yearly after 
• 
To evaluate the need for transfusion (packed RBC 
units and platelet units) 
• 
Time from the most recent transfusion 
to Week 13 and Week 26 
• 
Proportion of subjects who 
becomes (platelet/RBC) transfusion 
independent  
• 
To evaluate safety and tolerability of 
eltrombopag in combination with r-ATG and CsA 
• 
Frequency and severity of AEs, severe 
adverse events (SAEs), vital signs, 
electrocardiogram and laboratory 
abnormalities 
• 
To evaluate clonal evolution 
• 
Time from the date of first dose of 
study treatment to the date of first 
occurrence of any of the clonal 
evolution events 
• 
To determine the pharmacokinetics (PK) of 
eltrombopag in East-Asian treatment naive SAA 
patients 
• 
Plasma PK parameters and trough 
concentration of eltrombopag at 
steady state 
 
2 
Statistical methods 
2.1 
Data analysis general information 
The primary analysis and final analysis will be conducted by Novartis. SAS version 9.4 or later 
software will be used to perform all data analyses and to generate tables, figures and listings. 
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 withdrawn 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 final analysis of study data will be established at the end of the 
study.   


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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 and first and third 
quartiles when appropriate). PK parameters except Tmax will be summarized by approriate 
descriptive statistics (n, arithmetic mean, CV% mean, standard deviation (SD), median, 
geometric mean, CV% geo-mean, minimum and maximum). 
2.1.1 
General definitions  
Investigational drug  
The investigational drug for this study is eltrombopag (ETB115).  
Study treatment 
Study treatment includes any of the following: r-ATG, CsA, eltrombopag or combination of 
these drugs administered to the patient as part of the required study procedures up to the end of 
Year 2.  
Date of first administration of investigational drug 
The date of first administration of investigational drug is defined as the first date when a non-
zero dose of investigational drug (eltrombopag) is administered and recorded on the Dosage 
Administration Record (DAR) eCRF. The date of first administration of investigational drug 
will also be referred to as start of investigational drug. 
Date of last administration of investigational drug 
The date of last administration of investigational drug is defined as the last date when a nonzero 
dose of investigational drug (eltrombopag) is administered and recorded on the DAR eCRF. 
The date of last administration of investigational drug will also be referred to as end of 
investigational drug. 
Date of first administration of study treatment  
The date of first administration of study treatment is derived as the first date when a nonzero 
dose of any component of study treatment was administered as per the DAR eCRF. (Example: 
if 1st dose of eltrombopag is administered on 05-Jan-2015, and 1st dose of combination partner 
is administered on 03-Jan-2015, then the date of first administration of study treatment is 03-
Jan-2015).  


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Date of last administration of study treatment  
The date of last administration of study treatment is derived as the last date when a nonzero 
dose of any component of study treatment was administered as per the DAR eCRF. (Example: 
if the last eltrombopag dose is administered on 15-Apr-2014, and the last dose of a combination 
partner is administered on 17-Apr-2014, then the date of last administration of study treatment 
is 17-Apr-2014).  
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 start of study 
treatment.  
The study day will be displayed in the data listings. If an event starts before the reference start 
date, the study day displayed on the listing will be negative. 
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 start 
of study treatment is defined as “baseline” assessment.  
For ECG assessment, the average of the triplicate assessment should be used as baseline.  
If patients have no value as defined above, the baseline result will be missing. 
On-treatment assessment/event and observation periods  
For adverse event reporting 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 administration of eltrombopag. 
3. post-treatment period: starting at day 30+1 after last dose of eltrombopag. 


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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, 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 earliest of the 2  assessments will be used. Notice that, if there are scheduled 
and unscheduled assessments in the same time window, the scheduled assessment 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 ± 7 days 
Study Day 336 – 392 (i.e. 48 to 56 weeks) 
 Year 2 
Week 104 ± 30 days 
Study Day 672 – 784 (i.e. 96 to 112 weeks) 
 Year 3 
Week 156 ± 30 days 
Study Day 1036 – 1148 (i.e. 148 to 164 weeks) 
Last contact date  
The last contact date will be derived for patients not known to have died at the analysis cut-off 
date using the latest complete date among the following: 
• All assessment dates (e.g. vital signs assessment, collection of blood sample for 
laboratory testing, ECG, bone marrow biopsy, etc.) 
• Medication dates including study medication and concomitant medications. 
• Adverse events dates 
• Survival follow-up dates 
The last contact date is defined as the latest complete date from the above list on or before the 
data cut-off date . The cut-off date will not be used for last contact date, unless the patient was 
seen or contacted on that date. No date post cut-off date will be used. Completely imputed 
dates (e.g. the analysis cut-off date programmatically imputed to replace the missing end date 


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of a dose administration record) will not be used to derive the last contact date. Partial date 
imputation is allowed for event (death)/censoring if coming from ‘Survival’ eCRF.  
The last contact date will be used for censoring of patients in the analysis of overall survival. 
2.2 
Analysis sets 
Full Analysis Set 
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.  
Safety Set 
The Safety Set includes all subjects who received at least one dose of study treatment. All safety 
analyses will be done using the Safety Set.  
Pharmacokinetic analysis set (PAS) 
The Pharmacokinetic analysis set (PAS) includes all subjects who received at least one dose of 
eltrombopag and provide 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 occurs 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.  
Withdrawal of Informed Consent 
Any data collected in the clinical database after a subject withdraws informed consent from all 
further participation in the trial, will not be included in the analysis. The date on which a patient 
withdraws full consent is recorded in the eCRF.   
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.  
Efficacy 
The primary efficacy endpoint will be summarized by the following subgroups: 
• 
Age : (< 18 years) vs. (18-64 years) vs. (≥ 65 years)  


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The primary efficacy endpoint will be further summarized by subgroups of paediatric patients 
defined as (6-11 years) and (12-17 years). 
No formal statistical test of hypotheses will be performed for the subgroups, only point estimate 
of the treatment effect and 95% confidence intervals will be provided (see Sections 2.5.4 for 
further analysis details).  
Safety 
Key safety analyses (all AEs, AEs with suspected relationship to study treatment and/or 
eltrombopag, SAEs, SAEs with suspected relationship to study treatment and/or eltrombopag 
and AESIs) will be repeated in the following subgroups: 
• 
Age : (< 18 years) vs. (18-64 years) vs. (≥ 65 years)  
The key safety endpoint will be further summarized by subgroups of paediatric patients defined 
as (6-11 years) and (12-17 years).The objective for carrying out these subgroup analyses is 
to identify potential safety issues that may be limited to a subgroup of patients, or safety issues 
that are more commonly observed in a subgroup of patients. 
Pharmacokinetics 
PK parameters summaries will be repeated for the following subgroups: 
• Age : (< 18 years) vs. (18-64 years) vs. (≥ 65 years)  
• Gender : Male vs. Female 
The PK parameters will be further summarized by subgroups of paediatric patients defined as 
(6-11 years) and (12-17 years). 
The objective for carrying out these subgroup analyses is to identify potential differences in 
PK parameters between subgroups of patients. 
China Mainland/Japan specific subgroup analysis 
China Mainland subgroup analysis will be displayed in one separate column as overall 
population in each table.  
Key efficacy, safety, and pharmacokinetics outputs, including demographic and baseline 
characteristics will be repeated for both the subjects enrolled in sites from Japan and whose age 
< 18 years. Both subgroup analysis will support Japan submission.  
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. 
Basic demographic and background data 
All demographic and baseline disease characteristics data will be summarized and listed. 
Categorical data (e.g. gender, age groups: <18, further broken down as 6-11 and 12-17, 18-64, 


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≥ 65 years, race, ECOG or Lansky performance status) will be summarized by frequency counts 
and percentages; the number and percentage of patients with missing data will be provided 
when appropriate. Continuous data (e.g. age, weight, height) will be summarized by descriptive 
statistics (N, mean, median, standard deviation, minimum and maximum).  
Disease history and characteristics at screening including time since initial diagnosis to first 
dose,  platelet count, haemoglobin, absolute neutrophils count (ANC) and absolute reticulocytes 
count (ARC) will be summarized by statistiscs for quantitative variables. RBC and Platelet 
Transfusion (Independence and Dependence) at baseline will be summarized by frequency 
counts and percentages. Severity of aplastic anemia and result of cytogenetic analysis as defined 
below, will be summarized by frequency counts and percentages. 
• Severity of aplastic anemia (severe vs. very severe where the latter is defined as 
absolute neutrophil count < 200/µL). 
Medical history 
Medical history and baseline symptoms (current medical conditions) will be summarized and 
listed. The summaries will be presented by primary system organ class (SOC) and preferred 
term (PT). 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. 
Other 
All data collected at baseline will be listed. 
2.3.1 
Patient disposition 
Enrollment by country and center will be summarized for all screened patients. 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 number (%) 
of patients in the FAS who are still on treatment, who discontinued the study phases and the 
reason for discontinuation will be presented. 
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 core treatment phase;  
• Number (%) of patients who discontinued from core treatment phase ; 
• Primary reason for the premature discontinuation from core treatment phase; 
• Number (%) of patients who have entered extension treatment phase;  
• Number (%) of patients who completed the extension treatment phase;  
• Number (%) of patients who discontinued from extension treatment phase; 
• Primary reason for the premature discontinuation from extension treatment phase; 
• Number (%) of patients who have entered the long term follow-up phase;  
• Number (%) of patients who completed the long term follow-up phase;  
• Number (%) of patients who discontinued from long term follow-up phase; 


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Protocol deviations 
The number (%) of patients in the FAS with any protocol deviation will be tabulated by 
deviation category (as specified in the study Edit Check Specification) 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. 
Analysis sets 
The number (%) of patients in each analysis set (defined in Section 2.2) will be summarized 
and listed. 
2.4 
Treatments (study treatment, rescue medication, concomitant 
therapies, compliance) 
2.4.1 
Study treatment / compliance 
Duration of exposure, actual duration of exposure, cumulative dose, dose intensity (DI) and 
actual dose intensity (ADI) will be summarized separately for each single component of study 
treatment. 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 by 
treatment group.  
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 
The duration of exposure to each component (called drug X below) of the study treatment will 
be derived as follows: 
Exposure to drug X = Last unit (date/time) of administration of X – First unit (date/time) of 
administration of X + (1), 
where periods of drug interruption will not be deducted if there is no permanent treatment 
discontinuation following. If the unit is the date, then plus 1; if the unit is the hour, then transfer 
the exposure duration to days and plus 1 when there are residual hours. 
The actual duration of exposure defines as the sum of periods where the dose exposure is non-
zero. 
Duration of exposure and actual duration of exposure to study treatment will be summarized 
for each of the study treatment components separately, using descriptive statistics (mean, 
standard deviation etc). For eltrombopag, the number and percentage of time on study treatment 
(< 3 months, 3 months to 6 months, > 6 months) will be presented. For CsA, the number and 
percentage of time on study treatment (< 3 months, 3 months to 6 months, > 6 months to 12 


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months, > 12 months to 18 months, > 18 months to 24 months) will be presented. A listing of 
data on subject exposure to study treatment will also be produced. 
Cumulative dose 
Cumulative dose is defined as the total dose given during the study treatment exposure and will 
be summarized for each of the study treatment components separately.  
For patients who did not take any drug the cumulative dose is by definition equal to zero. 
The cumulative dose is the sum of the non-zero doses recorded over the dosing period. 
Dose intensity  
Dose intensity (DI) for patients with non-zero duration of exposure is defined as follows:  
DI of X (dosing unit / unit of time) = Cumulative dose of X (dosing unit) / Duration of exposure 
of X (unit of time). 
Actual dose intensity (ADI) for patients with non-zero actual duration of exposure is defined as 
follows:  
ADI of X (dosing unit / unit of time) = Cumulative assigned dose of X (dosing unit) / Actual 
duration of exposure of X (unit of time). 
For patients who did not take any dose of a given drug the ADI is by definition equal to zero.  
Dose reductions, interruptions or permanent discontinuations 
The number of patients who had dose adjustments, including reductions, increases or  
interruptions, and the reasons, will be summarized separately for each of the study treatment 
components.  
An interruption is defined as 0 mg dose recorded or absence of record for one or more days. A 
reduction (increase) is defined as a decrease (increase) in dose from the protocol planned dose 
or from the previous non-zero dose, even if it has been directly preceded by an interruption. A 
decrease (increase) in frequency of administration which results in a lower (higher) cumulative 
dose is also counted as a reduction (increase).  
The number of dose adjustments per patient and the corresponding reasons will be summarized.  
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.  
Surgical and medical procedures will be coded using MedDRA and summarized by SOC and 
preferred term. 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.  
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 


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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. 
2.5 
Analysis of the primary objective 
The primary objective of the study is to evaluate the efficacy of eltrombopag in combination 
with r-ATG and CsA in terms of CR rate at Week 26 in the treatment-naive East-Asian patients 
with SAA. 
2.5.1 
Primary endpoint 
The primary efficacy endpoint is CR rate at Week 26 (6 months), which is defined as the 
percentage of all subjects who meet the hematological criteria of CR at Week 26. A complete 
response (CR) is defined as meeting all the following 3 criteria on 2 consecutive serial blood 
count measurements at least one week apart but not more than 4 weeks apart.  
A CR will be defined as (all 3 must be met): 
• Absolute neutrophil count > 1.0 x109/L 
• Platelet count > 100 x109/L 
• Hemoglobin > 100 g/L 
The primary endpoint will be based on the investigator assessment of response. However, 
improvement in counts that are dependent upon exogenously administered growth factors or 
transfusion will not be considered as fulfilling response criteria. 
The exclusion period of these therapies are detailed below: 
• Platelets transfusions: 7 days preceding the assessment of platelet count 
• Packed RBC transfusions: 14 days preceding the assessment of hemoglobin 
• Growth factors: 21 days preceding the assessment of response 
The analysis of the primary efficacy endpoint will be based on the FAS. 
2.5.2 
Statistical hypothesis, model, and method of analysis 
The CR at Week 26 will be summarized using point estimate and 2-sided exact binomial 95% 
(Clopper-Pearson) confidence intervals. 
2.5.3 
Handling of missing values/censoring/discontinuations 
Subjects who are not evaluable for response at Week 26 for any reason, including missing data 
and withdrawal from the study before Week 26, will be treated as non-responders in the primary 
analysis.  
2.5.4 
Supplementary analyses 
The CR will also be derived programmatically using laboratory results (criteria details are stated 
in the section 2.5.1 ) instead of those reported by the investigators in the response assessment 
CRF. The response will be derived if two consecutive serial blood count measurements meet 
the defined requirements, where one of the measurements is done at Week 26. The derived 


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response will be listed against investigator assessment of response and discrepancies will be 
identified with justifying comment, when available.  
2.5.5 
Supportive analyses 
Supportive analyses using the CR at Week 26 will be generated per programmatically derived 
in the following way: 
A more stringent definition of CR meeting all the following criteria on 2 consecutive serial 
blood count measurements at least one week apart:  
• Normal hemoglobin concentration for agen and gender 
• PLT >150 × 109/L 
• Absolute neutrophil count (ANC) >1.5 × 109/L 
Since this is a more stringent definition of CR, very few CRs will be expected for analysis. 
Subgroup analyses for the primary endpoint  
The primary efficacy endpoint and supportive analyses (more stringent definition of CR) will 
be summarized by the above subgroups listed in section 2.2.1 for efficacy. The proportion of 
the complete response in each subgroup will be summarized using point estimates and 95% 
exact (Clopper-Pearson) confidence intervals. 
In addition, hematological responses will be listed. 
2.6 
Key secondary endpoint 
Not appliacable 
2.7 
Analysis of secondary efficacy objective(s) 
The secondary objectives in this study are: 
• To evaluate complete response rate at 3, 12 months and yearly after; 
• To evaluate overall response rate at 3, 6, 12 months and yearly after; 
• To evaluate duration of response; 
• To evaluate overall survival; 
• To evaluate the need for transfusion (packed RBC units and platelet units); 
• To evaluate the safety and tolerability of eltrombopag in combination with r-ATG and 
CsA; 
• To evaluate clonal evolution; 
• To determine the PK of eltrombopag in East-Asian treatment naive SAA patients. 
2.7.1 
Secondary efficacy endpoints 
CR rate at Week 13, Week 52 and yearly after 


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CR rate at specific visit is defined as percentage of subjects who meet the hematological CR 
criteria by investigator assessment at Week 13, Week 52 and yearly after respectively in FAS. 
See Section 2.5.1 for definition of CR.   
Overall response (CR+PR) rate at Week 13, Week 26, Week 52 and yearly after 
Hematologic overall response rate at specific visit is defined as percentage of subjects who 
achieved hematologic response by investigator assessment at specific visit in FAS.  
The overall hematological response is defined as either complete or partial response. CR is 
defined in section 2.5.1. 
Partial response (PR) is defined as blood counts no longer meeting the standard criteria for 
severe pancytopenia in SAA, equivalent to at least 2 of the 3 criteria below, but are not 
sufficient for a CR. 
• Absolute neutrophil count ≥ 0.5 x109/L 
• Platelet count ≥ 20 x109/L 
• Reticulocyte count ≥ 20 x109/L  
However, improvement in counts that are dependent upon exogenously administered growth 
factors or transfusion will not be considered as fulfilling response criteria. 
The exclusion period of these therapies are detailed below: 
• Platelets transfusions: 7 days preceding the assessment of platelet count 
• Packed RBC transfusions: 14 days preceding the assessment of hemoglobin 
• Growth factors: 21 days preceding the assessment of response. 
Of note that the criteria for complete and partial responses must be met on 2 consecutive serial 
blood count measurements at least one week apart but not more than 4 weeks apart for the Week 
13 and Week 26 assessments but only on one blood count measurements for the yearly 
assessments thereafter. 
Patients who relapse or withdraw from the study will be counted and reported as relapsed or 
withdrawn for all subsequent reponse assessments. No response (NR) is defined as not fulfilling 
the response criteria. 
Time to response 
Time to response is defined as the time from the date of the start of study treatment until the 
first documented and confirmed response (either CR or PR) per programmatically derived. 
Time to complete response is similarly defined as the time from the date of the start of study 
treatment until the first documented complete response. 
All subjects in the FAS will be included in the time to response/CR calculations. 
Duration of response 
Duration of response will be derived as the time from first documented and confirmed response 
(either CR or PR) until the time of relapse or death whichever occurs first. Both the responses 
and the relapse will be programmatically derived. Patients who are neither complete nor partial 
responders will not be included in the analysis of the duration of response.  


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Duration of complete response will be similarly derived for patients who had a complete 
response. Patients who are not complete responders will not be included in the analysis of the 
duration of complete response. 
Clinical relapse is considered as the occurrence of any of the following event in a subject who 
had achieved a hematological response (CR or PR) but has subsequently lost response (not 
explained by any other independent concomitant medical conditions) in one blood count 
meaurements: 
• meeting again the criteria for SAA, equivalent to patients with at least two of the 
following parameters in peripheral blood. 
• 
Absolute neutrophil count < 0.5×109/L 
• 
Platelet count < 20×109/L 
• 
Absolute reticulocyte count < 20×109/L  
• requirement for transfusion again for subjects who had been transfusion independent 
• decrease in any of the peripheral blood counts to: absolute neutrophil count < 
0.5 x109/L or platelets < 20 x109/L. 
The analysis of duration of response will be based on response assessment which are derived 
programmatically using laboratory results instead of those reported in the response assessment 
CRF. 
Transfusion-free interval before Week 13 and Week 26 
For platelet transfusion, transfusion-free interval is defined as the time from most recent platelet 
transfusion preceding response assessment to the date of response assessment. For RBC 
transfusion, transfusion-free interval is defined as the time from most recent RBC transfusion 
preceding response assessment to the date of response assessment.  
Maximum duration of Platelet and RBC transfusion free 
Transfusion free duration will be defined as the period from the next day after transfusion to 
the day of the next transfusion. Maximum duration of platelet and RBC transfusion free for 
each subject will be picked for analysis. 
Proportion of subjects who become transfusion independent 
The number and percentage of subjects with platelet or RBC transfusion independence  during 
the study will be presented respectively. This analysis will be performed for the subgroup of 
subjects with baseline transfusion dependence. 
Post-baseline transfusion independence is defined as follows:  
• Platelet transfusion independence: The subjects who are transfusion dependent at 
baseline become transfusion free for a period of at least 4 weeks after baseline. 
• RBC transfusion independence: The subjects who are transfusion dependent at 
baseline become transfusion free for a period of at least 8 weeks after baseline. 
Transfusion frequency and amount (units) 
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 and Yearly 


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thereafter: 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 units of transfusion.  
Subjects with platelet transfusion decrease is defined as subjects with transfusion decrease or 
transfusion free in each period (Week 13, 26, 52 and Yearly thereafter: 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). The number and percentage of subjects with platelet or RBC transfusion decrease 
and 50% platelet transfusion reduction in each period will be presented.   
Overall survival 
OS is defined as the time from the date of the first dose of study treatment to the date of death 
due to any cause. 
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. 
2.7.2 
Statistical hypothesis, model, and method of analysis 
CR rate at Week 13, Week 52 and yearly after 
The number and percentage of subjects who meet the hematological CR criteria (at Week 13, 
Week 52 and yearly after respectively) will be presented and 2-sided Exact binomial 95% 
(Clopper-Pearson) confidence interval will be reported.  
Overall response (CR+PR) rate at Week 13, Week 26, Week 52 and yearly after 
The number and percentage of subjects who meet the hematological overall response criteria 
(at Week 13, Week 26, Week 52 and yearly after respectively) will be presented and 2-
sided Exact binomial 95% (Clopper-Pearson) confidence interval will be reported.  
The overall response rate will also be summarized by the above subgroups listed in section 2.2.1 
for efficacy.  
Hematological response endpoints will be listed based on the investigator assessment and the 
programmatic derivation. 
Time to response 
The Kaplan-Meier curve of the time to response and time to complete response will be 
constructed, and the quartiles of the survival function will be provided along with 95% 
confidence interval. Kaplan-Meier estimates with 95% confidence intervals every 3 months will 
be summarized as well. 
Duration of response 


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Kaplan-Meier curve of the duration of response and duration of complete response will be 
constructed, and the quartiles of the survival function will be provided along with 95% 
confidence interval. Kaplan-Meier estimates with 95% confidence intervals every 3 months will 
be summarized as well.  
Transfusion-free interval before Week 13 and Week 26 
Descriptive statistics including mean, SD, median, 25th and 75th percentiles, minimum, and 
maximum will be summarized for the transfusion-free interval. The same analysis applies to 
RBC transfusion.  
Maximum duration of Platelet and RBC transfusion free 
Maximum duration of platelet and RBC transfusion free will be summarized by descriptive 
statistics including mean, SD, median, 25th and 75th percentiles, minimum, and maximum 
separately. 
Proportion of subjects who becomes transfusion independent 
The number and percentage of subjects with platelet or RBC transfusion independence at any 
time during the study will be presented repspectively.  
Transfusion frequency and amount 
The frequency and the amount of platelets and RBC transfusion in each period will be 
summarized by descriptive statistics including mean, SD, median, 25th and 75th percentiles, 
minimum, and maximum.  
The number and percentage of subjects with platelet or RBC transfusion decrease and 50% 
platelet transfusion reduction in each period will be presented.   
Overall survival 
Kaplan-Meier curve of the OS will be constructed, and the quartiles of the survival function 
will be provided along with 95% confidence interval. OS rate will be estimated at Week 26, 
Week 52 and yearly after as well. 
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. 
2.7.3 
Handling of missing values/censoring/discontinuations 
CR rate at Week 13, Week 52 and yearly after 
For the analysis CR, 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. Subjects who 
are not evaluable for response at specific visit for any reason, including missing data and 
withdrawal from the study before specific visit, will be treated as non-responders in the analysis.  


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Overall response (CR+PR) rate at Week 13, Week 26, Week 52 and yearly after 
For the analysis overall response, 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. 
Subjects who are not evaluable for response at specific visit for any reason, including missing 
data and withdrawal from the study before specific visit, will be treated as non-responders in 
the analysis.  
Time to response 
For time to response and time to complete response, if a subject does not meet response/CR 
before or at the cutoff date, censoring will be performed using the date of the last response 
assessment. 
Duration of response 
Patients who are neither complete nor partial responders will not be included in the analysis of 
the duration of response. Complete and partial responders who did not relapse at the data cut-
off date will be censored at the date of the last assessment of response with a known outcome. 
Patients who are not complete responders will not be included in the analysis of the duration of 
complete response. Complete responders who did not change to PR or relapse at the data cut-
off date will be censored at the date of the last assessment of response with a known outcome. 
Transfusion-free interval before Week 13 and Week 26 
For platelet transfusion, only subjects with response assessments at specific visits (Week 13 or 
26) are included in the transfusion-free interval. The same rule applies to RBC transfusion. 
Maximum duration of Platelet and RBC transfusion free 
This analysis will be only performed for the subgroup of subjects with baseline transfusion 
dependent. 
Proportion of subjects who becomes transfusion independent 
This analysis will be only performed for the subgroup of subjects with baseline transfusion 
dependent. 
Transfusion frequency and amount 
The transfusion frequence and amount and the proportion of subjects with transfusion decrease 
will be only performed for the subgroup of subjects with baseline transfusion dependent. 
Overall survival 
Analysis of overall survival will be based on the FAS. If a subject is not known to have died, 
survival will be censored at the date of last contact.  
2.8 
Safety analyses 
For all safety analyses, the safety set will be used. All listings and tables will be presented 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 


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baseline summaries). In addition, a separate summary for death including on treatment and post 
treatment deaths will be provided. In particular, summary tables for 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 eltrombopag. 
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 
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 
eltrombopag/CsA/r-ATG), seriousness (SAEs and non-SAEs), leading to treatment 
discontinuation, leading to dose interruption/changes, requiring additional therapy and leading 
to fatal outcome. Specifically, CTC grade  >=3 adverse events will be summarized for AEs by 
SOC and PT. 
Furthermore, AE occurring during the on-treatment period will be summarized by subgroup 
summarized by the above subgroups listed in section 2.2.1. These summaries include: AEs by 
SOC and PT, AEs with suspected relationship to eltrombopag by SOC and PT and SAEs by 
SOC and PT.  
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 <=360 days). Time of onset of 
first episode will be used when experiencing the same episode in a subject. 


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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. 
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 than 30 days after the last study treatment administration date (see Section 2.1.1). 
Grading of laboratory values will be assigned programmatically as per NCI Common 
Terminology Criteria for Adverse Events (CTCAE), version 4.03. The calculation of CTCAE 
grades will be based on the observed laboratory values only, clinical assessments will not be 
taken into account. 
CTCAE Grade 0 will be assigned for all non-missing values not graded as 1 or higher. Grade 5 
will not be used. 
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  


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• 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 by subject and visit/time, 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 by subject and visit/time 
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, SD, median, interquartile range, and 
range). 
Coagulation 
Coagulation assays data (Prothrombin time, international normal ratio, Activated partial 
thromboplastin time) will be listed. 
Liver function parameters  
Liver function parameters of interest are Total bilirubin (TBIL) and Direct bilirubin (DBIL), 
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 (TBIL or DBIL > 2xULN) and (ALP < 2xULN or 
missing) 
• ALT or AST > 3xULN and (TBIL or DBIL > 2xULN) 
• ALT or AST > 3xULN and (TBIL or DBIL > 1.5xULN) 
• ALT or AST > 20xULN 
• ALT or AST > 10xULN 
• ALT or AST > 5xULN 
• ALT or AST > 3xULN 
 
• ALT > 20xULN 
• ALT > 10xULN 
• ALT > 5xULN 


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• ALT > 3xULN 
 
• AST > 20xULN 
• AST > 10xULN 
• AST > 5xULN 
• AST > 3xULN 
 
• DBIL > 2xULN 
• DBIL > 1.5xULN 
• TBIL > 2xULN 
• TBIL > 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 13, Week 26 and Week 52 (in the extension part ECG is only for the 
responders) 
• at the end of treatment 
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: 
• 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 
- 
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 


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- 
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 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. 
Data analysis 
For analysis of vital signs the clinically notable vital sign criteria are provided in Table 2-2 
below. 
Table 2-2 
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 
(°C) 
>= 39.1  
- 
The number and percentage of subjects with notable vital sign values (high/low) will be 
presented.        


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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 and FISH) 
• 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 PK analysis.  
PK parameters for subjects with intensive PK samples 
The PK parameters that will be determined are shown in Table 2-3. PK parameters of 
eltrombopag, including but not limited to those listed in Table 2-3, will be calculated from the 
individual concentration-time profile obtained following the administration of the study 
treatment and listed by subject. 
Table 2-3 
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 dose administration 
(mass*volume-1) 
Tmax 
The time to reach maximum (peak) plasma drug concentration after 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 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 plasma eltrombopag concentration will be 


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presented by dose, visit/sampling time point, including the frequency (n, %) of concentrations 
below the LLOQ and reported as zero.  
For subjects with intensive PK samples, 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, plasma eltrombopag concentrations 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. 
Subgroup analyses for the pharmacokinetic endpoint  
The pharmacokinetic endpoint will be summarized by the above subgroups listed in section 
2.2.1.  
2.10 
PD and PK/PD analyses 
If data permits, PK/PD and exposure-response analyses may be explored in a separate report. 
2.11 
Patient-reported outcomes 
There will be no patient-reported outcome analysis planned in this study. 
2.12 
Cytogenetic abnormalities and clonal evolution 
Cytogenetic abnormalities and clonal evolution observed during the study 
Cytogenetic abnormalities and clonal evolution will be selected from AE page in eCRF, and 
will be chosen as AE Preferred term = “clonal evolution / cytogenetic abnormality / AML / 
MDS / PNH”. 
Clonal cytogenetic evolution will be evaluated during the study, and the rate of the subjects 
who developed any clonal evolution (e.g., clonal evolution to PNH, evolution to AML or MDS 
etc.) will be calculated in a summary table. Short narratives and relevant information for 
subjects with new cytogenetic abnormalities on study will be listed.  
GPI negative neutrophil level 
Shift tables using GPI negative neutrophil and RBC level (≤ 50% and > 50%) to compare 
baseline to the worst on-treatment will be presented. 


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2.13 
Other Exploratory analyses 
The exploratory analysis is PK/PD relationships, for details, please see section 2.10. 
2.14 
Interim analysis 
No formal interim analysis is planned for this trial. The primary analysis will be performed after 
all subjects have completed Week 26 or discontinued prior to Week 26. A final analysis will be 
performed after all subjects have completed the study. No formal testing of the primary endpoint 
will be performed in this study. 
3 
Sample size calculation 
As this is a bridging study to support registration, an estimation strategy rather than formal 
hypothesis testing will be pursued. Approximately 36 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 Asian patients. 
3.1 
Primary analysis 
Based on the Day 120 report in the pivotal study of CETB115AUS01T, the complete 
hematological response rate at Month 6 in Cohort 3+Extension is 43.7%. If the CR rate obtained 
in naive Asian patients with SAA treated with eltrombopag is expected to be 44.0%, a total of 
36 subjects will result in a 95% CI lower bound of about 28%. 
Below table shows the exact 95% CIs for various observed complete hematological response 
rate. The maximum half-width of the 95% CIs is 17.1%. 
Table 3-1 
95% CIs for various observed response rate 
Total sample size 
# of responders 
Complete 
hematologic 
response rate (%) 
95% CI (%) 
36 
14 
38.9 
(23.1, 56.5) 
36 
16 
44.4 
(27.9, 61.9) 
36 
18 
50.0 
(32.9, 67.1) 
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. 
3.2 
Power for analysis of key secondary variables 
Not Applicable 
4 
Change to protocol specified analyses 
Below-listed endpoints were added to further support efficacy analysis beyond protocol. 
• Time to response 
• Maximum duration of Platelet and RBC transfusion free 


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• Proportion of subjects with transfusion decrease 
• Changes in platelet count, hemoglobin and neutrophil count 
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. 
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  


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Missing 
Element 
Rule 
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   


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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* 
hour 
• 
For rATG end dates only, if partial end time contains no time, then set 
the time to 00:00. 
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  
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 


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available version of the document based on the underlying CTCAE version 4.03 at the time of 
analysis will be used.  
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. 
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 95% 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 95% (=100 × (1 – two-sided alpha level)) two-sided Pearson-Clopper CI. 
5.4.2 
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 95% confidence 
intervals calculated from PROC LIFETEST output using the method of (Brookmeyer and 
Crowley, 1982). Kaplan-Meier estimates of the survival function with 95% confidence 
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). 


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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. 
 


Clinical Development 
ETB115/Eltrombopag/Revolade® 
CETB115G2201 / NCT04328727
A non-randomized, open label, multi-center, Phase II study 
to assess the safety and efficacy of eltrombopag in 
combination with rabbit anti-thymocyte globulin (r-ATG) 
and cyclosporine A (CsA) in East-Asian patients with 
treatment naive severe aplastic anemia 
Statistical Analysis Plan (SAP) 
Final Analysis 
Document type: 
SAP Documentation 
Document status: 
Final 1.0 
Release date: 
11-Nov-2024
Number of pages: 
38 
Property of Novartis 
Confidential 
May not be used, divulged, published or otherwise disclosed 
without the consent of Novartis
Template Version 4.0, Effective from 23-Apr-2021 


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Document History – Changes compared to previous final version of SAP 
 
Date 
Time 
point 
Changes 
Section and 
title 
impacted 
(Current) 
11-
Nov-
2024 
Prior to 
DBL of 
Final 
analysis 
N/A - First version 
NA 
 


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Table of contents 
Table of contents ................................................................................................................. 3 
1 
Introduction ......................................................................................................................... 6 
1.1 
Study design ............................................................................................................ 6 
1.2 
Study objectives and endpoints ............................................................................... 8 
2 
Statistical methods ............................................................................................................... 9 
2.1 
Data analysis general information ........................................................................... 9 
2.1.1 
General definitions ................................................................................ 10 
2.2 
Analysis sets .......................................................................................................... 13 
2.2.1 
Subgroup of interest .............................................................................. 13 
2.3 
Patient disposition, demographics and other baseline characteristics ................... 13 
2.3.1 
Patient disposition ................................................................................. 14 
2.4 
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance)............................................................................................................ 15 
2.4.1 
Study treatment / compliance ................................................................ 15 
2.4.2 
Prior, concomitant and post therapies ................................................... 16 
2.5 
Analysis of the primary objective .......................................................................... 16 
2.5.1 
Primary endpoint ................................................................................... 17 
2.5.2 
Statistical hypothesis, model, and method of analysis .......................... 17 
2.5.3 
Handling of missing values/censoring/discontinuations ....................... 17 
2.5.4 
Supplementary analyses ........................................................................ 17 
2.5.5 
Supportive analyses ............................................................................... 17 
2.6 
Key secondary endpoint ........................................................................................ 18 
2.7 
Analysis of secondary efficacy objective(s) .......................................................... 18 
2.7.1 
Secondary efficacy endpoints ............................................................... 18 
2.7.2 
Statistical hypothesis, model, and method of analysis .......................... 21 
2.7.3 
Handling of missing values/censoring/discontinuations ....................... 22 
2.8 
Safety analyses....................................................................................................... 23 
2.8.1 
Adverse events (AEs) ............................................................................ 24 
2.8.2 
Deaths .................................................................................................... 25 
2.8.3 
Laboratory data ..................................................................................... 25 
2.8.4 
Other safety data ................................................................................... 27 
2.9 
Pharmacokinetic endpoints .................................................................................... 29 
2.10 
PD and PK/PD analyses ........................................................................................ 29 
2.11 
Cytogenetic abnormalities and clonal evolution .................................................... 29 
2.12 
Other Exploratory analyses.................................................................................... 29 


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2.13 
Interim analysis ...................................................................................................... 29 
3 
Sample size calculation ..................................................................................................... 30 
3.1 
Primary analysis .................................................................................................... 30 
3.2 
Power for analysis of key secondary variables ...................................................... 30 
4 
Change to protocol specified analyses .............................................................................. 30 
5 
Appendix ........................................................................................................................... 30 
5.1 
Imputation rules ..................................................................................................... 30 
5.1.1 
Study drug ............................................................................................. 30 
5.1.2 
AE, ConMeds and safety assessment date imputation .......................... 31 
5.2 
AEs coding/grading ............................................................................................... 33 
5.3 
Laboratory parameters derivations ........................................................................ 33 
5.4 
Statistical models ................................................................................................... 34 
5.4.1 
Primary analysis .................................................................................... 34 
5.4.2 
Secondary analysis ................................................................................ 34 
6 
Reference ........................................................................................................................... 35 
 
List of tables 
Table 1-1 
Objectives and related endpoints ............................................................ 8 
Table 2-1 
Time windows for hematological response........................................... 12 
Table 2-2 
Clinically notable changes in vital signs ............................................... 28 
Table 2-3 
Non-compartmental PK parameters ...... Error! Bookmark not defined. 
Table 3-1 
95% CIs for various observed response rate ......................................... 30 
Table 5-1 
Imputation of start dates (AE, CM) and assessments (LB, EG, VS) .... 31 
Table 5-2 
Imputation of end dates (AE, CM) ........................................................ 33 
 
List of figures 
Figure 1-1 
Study design ............................................................................................ 7 
 
 


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List of abbreviations 
AE 
Adverse event 
AESI 
adverse event of special interest 
AML 
Acute Myeloid Leukemia 
ATC 
Anatomical Therapeutic Classification 
ATG 
anti-thymocyte globulin 
AUC 
Area Under the Curve 
AUClast 
Area under concentration-time curve until the last quantifiable sampling time 
AUCtau 
Area under concentration-time cuve during a dosing interval tau 
Cmax 
Maxiumum (peak) concentration 
CR 
Complete Response 
CRF 
Case Report Form 
CSR 
Clinical Study report 
CsA 
Cyclosporine A 
CTC 
Common Toxicity Criteria 
CTCAE 
Common Terminology Criteria for Adverse Events 
Ctrough 
Concentration level prior to dosing 
FAS 
Full Analysis Set 
r-ATG 
Rabbit Anti-Thymocyte Globulin 
HRQL 
Health-related Quality of Life 
IST 
Immunosuppressive Therapy 
LLOQ 
Lower Limit of Quantitation 
MDS 
Myelodysplastic Syndrome 
MedDRA 
Medical Dictionary for Drug Regulatory Affairs 
NCI 
National Cancer Institute 
NIH 
National Institute of Health 
OR 
Overall Response 
OS 
Overall Survival 
PK 
Pharmacokinetics 
PR 
Partial Response 
PT 
Preferred Term 
RAP 
Report and Analysis Process 
SAA 
Severe Aplastic Anemia 
SAP 
Statistical Analysis Plan 
SOC 
System Organ Class 
TFLs 
Tables, Figures, Listings 
Tmax 
Time to reach maximum (peak) concentration 
WHO 
World Health Organization 
 
 
  


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1 
Introduction 
This statistical analysis plan (SAP) describes all planned analyses for the clinical study report(s) 
(CSR) of study CETB115G2201, a non-randomized, open label, multi-center, Phase II study to 
assess the safety and efficacy of eltrombopag in combination with rabbit anti-thymocyte 
globulin (r-ATG) and cyclosporine A (CsA) in East-Asian patients with treatment naive severe 
aplastic anemia (SAA)  
As specified in Section 12 of the study protocol (version 03 dated 22-Dec-2021), the final 
analysis will be performed at the end of the study. This SAP will support the final analysis. 
The content of this SAP is based on protocol CETB115G2201 version 03 (dated 22-Dec-2021). 
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, single arm, multi-center, Phase II study to evaluate the 
efficacy and safety of eltrombopag in combination with IST regimen of r-ATG + CsA in East-
Asian patients with SAA who have not received prior IST. At least 36 subjects will be enrolled 
from China, Japan, Korea or Taiwan. At least 6 pediatric subjects will be recruited in total, with 
3 subjects from China and 3 from Japan respectively. At least one of the 6 pediatric subjects in 
each age group (6 to 11 years old, and 12 to 17 years old) will be enrolled. For the 30 adult 
subjects, at least 12 subjects will be recruited from China to fulfill the requirements for 
pharmacokinetic (PK) profile. 


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Figure 1-1 
Study design 
  
Eligible subjects will be enrolled into the study and will receive eltrombopag (from Day 1 to 
Week 26) concomitantly with r-ATG (on Days 1-5) and CsA (from Day 1 to Week 26) in the 
core treatment part. 
Efficacy assessments will be performed at Week 13 and Week 26 in the core treatment part of 
the study. 
Participants who are assessed as responders (meeting CR or PR criteria) at Week 26 are eligible 
to the extension part of the study and continue treatment with eltrombopag and CsA after Week 
26.  


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Study treatment should be discontinued if the participant is not assessed as a responder at Week 
26.  
During the extension part, eltrombopag treatment will be provided up to Week 52.  CsA will be 
maintained or tapered at the investigator's discretion according to local practice, with a total 
duration of at least 2 years (18 months after Week 26). 
End of treatment assessments will be performed after eltrombopag discontinuation anytime 
during the study. After that, safety follow-up visit will be performed 30 days after the 
discontinuation of eltrombopag, and participants will enter the long-term follow-up part, with 
yearly efficacy and clonal evolution assessments up to Year 3 (Week 156). 
For non-responders at Week 26, and participants who relapse or receive alternative SAA 
treatment, safety follow-up visit will be performed 30 days after the discontinuation of 
eltrombopag, and then clonal evolution and survival will continue to be followed up to Year 3 
(Week 156). 
Participants who prematurely discontinue eltrombopag will have efficacy assessments at 
defined time points (Week 13, Week 26, Week 52 and yearly after), unless or until the 
occurrence of no response at Week 26, relapse or alternative SAA treatment (whichever comes 
first). Survival and clonal evolution data will be collected for all participants up to Year 3 (Week 
156).  
1.2 
Study objectives and endpoints 
For the definition of response, partial response (PR), CR, transfusion independence, and relapse, 
refer to Section 2.5 and Section 2.7.  
Table 1-1 
Objectives and related endpoints 
Objective(s) 
Endpoint(s) 
Primary objective(s) 
Endpoint(s) for primary objective(s) 
• 
To evaluate the efficacy of eltrombopag in 
combination with r-ATG and CsA in terms of 
complete response rate at 6 months in East-Asian 
patients with treatment naive severe aplastic 
anemia (SAA) 
• 
CR rate at Week 26 (6 months) after 
starting the study treatment  
Secondary objective(s) 
Endpoint(s) for secondary objective(s) 
• 
To evaluate complete response rate at 3, 12 
months and yearly after 
• 
CR rate at Week 13 (3 months), Week 
52 (12 months) and yearly after 
• 
To evaluate overall response rate at 3, 6, 12 
months and yearly after 
• 
Overall response (CR+PR) rate at 
Week 13 (3 months), Week 26 (6 
months), Week 52 (12 months) and 
yearly after 
• 
To evaluate duration of response 
• 
Time from the date of the start of 
response to the date of relapse or 
death, whichever occurs first at any 
time during the study 
• 
To evaluate overall survival (OS)  
• 
Time from the date of first dose of 
study treatment to the date of death 


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Objective(s) 
Endpoint(s) 
• 
Overall survival rate at Week 26, 
Week 52 and yearly after 
• 
To evaluate the need for transfusion (packed RBC 
units and platelet units) 
• 
Time from the most recent transfusion 
to Week 13 and Week 26 
• 
Proportion of subjects who 
becomes (platelet/RBC) transfusion 
independent  
• 
To evaluate safety and tolerability of 
eltrombopag in combination with r-ATG and CsA 
• 
Frequency and severity of AEs, severe 
adverse events (SAEs), vital signs, 
electrocardiogram and laboratory 
abnormalities 
• 
To evaluate clonal evolution 
• 
Time from the date of first dose of 
study treatment to the date of first 
occurrence of any of the clonal 
evolution events 
• 
To determine the pharmacokinetics (PK) of 
eltrombopag in East-Asian treatment naive SAA 
patients 
• 
Plasma PK parameters and trough 
concentration of eltrombopag at 
steady state 
 
2 
Statistical methods 
2.1 
Data analysis general information 
The final analysis will be conducted by Novartis. SAS version 9.4 or later software will be used 
to perform all data analyses and to generate tables, figures and listings. 
Data included in the analysis 
The analysis cutoff date for the final analysis of study data will be established at the end of the 
study.   
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. 
 


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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 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 and first and third 
quartiles when appropriate). 
2.1.1 
General definitions  
Investigational drug  
The investigational drug for this study is eltrombopag (ETB115).  
Study treatment 
Study treatment includes any of the following: r-ATG, CsA, eltrombopag or combination of 
these drugs administered to the patient as part of the required study procedures up to the end of 
Year 2.  
Date of first administration of investigational drug 
The date of first administration of investigational drug is defined as the first date when a non-
zero dose of investigational drug (eltrombopag) is administered and recorded on the Dosage 
Administration Record (DAR) eCRF. The date of first administration of investigational drug 
will also be referred to as start of investigational drug. 
Date of last administration of investigational drug 
The date of last administration of investigational drug is defined as the last date when a nonzero 
dose of investigational drug (eltrombopag) is administered and recorded on the DAR eCRF. 
The date of last administration of investigational drug will also be referred to as end of 
investigational drug. 
Date of first administration of study treatment  
The date of first administration of study treatment is derived as the first date when a nonzero 
dose of any component of study treatment was administered as per the DAR eCRF. (Example: 
if 1st dose of eltrombopag is administered on 05-Jan-2015, and 1st dose of combination partner 
is administered on 03-Jan-2015, then the date of first administration of study treatment is 03-
Jan-2015).  


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Date of last administration of study treatment  
The date of last administration of study treatment is derived as the last date when a nonzero 
dose of any component of study treatment was administered as per the DAR eCRF. (Example: 
if the last eltrombopag dose is administered on 15-Apr-2014, and the last dose of a combination 
partner is administered on 17-Apr-2014, then the date of last administration of study treatment 
is 17-Apr-2014).  
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, etc.) is the start of study treatment.  
The study day will be displayed in the data listings. If an event starts before the reference start 
date, the study day displayed on the listing will be negative. 
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 start 
of study treatment is defined as “baseline” assessment.  
For ECG assessment, the average of the triplicate assessment should be used as baseline.  
If patients have no value as defined above, the baseline result will be missing. 
On-treatment assessment/event and observation periods  
For adverse event reporting 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 eltrombopag 
2. on-treatment period: from date of first administration of study treatment to 30 days after 
date of last administration of eltrombopag. 
3. post-treatment period: starting at day 30+1 after last dose of eltrombopag. 
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 


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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, 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 earliest of the 2 assessments will be used. Notice that, if there are scheduled 
and unscheduled assessments in the same time window, the scheduled assessment 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 ± 7 days 
Study Day 336 – 392 (i.e. 48 to 56 weeks) 
 Year 2 
Week 104 ± 30 days 
Study Day 672 – 784 (i.e. 96 to 112 weeks) 
 Year 3 
Week 156 ± 30 days 
Study Day 1036 – 1148 (i.e. 148 to 164 weeks) 
Last contact date  
The last contact date will be derived for patients not known to have died at the analysis cut-off 
date using the latest complete date among the following: 
• All assessment dates (e.g. vital signs assessment, collection of blood sample for 
laboratory testing, ECG, bone marrow biopsy, etc.) 
• Medication dates including study medication and concomitant medications. 
• Adverse events dates 
• Survival follow-up dates 
The last contact date is defined as the latest complete date from the above list on or before the 
data cut-off date. The cut-off date will not be used for last contact date, unless the patient was 
seen or contacted on that date. No date post cut-off date will be used. Completely imputed 
dates (e.g. the analysis cut-off date programmatically imputed to replace the missing end date 
of a dose administration record) will not be used to derive the last contact date. Partial date 
imputation is allowed for event (death)/censoring if coming from ‘Survival’ eCRF.  
The last contact date will be used for censoring of patients in the analysis of overall survival. 


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2.2 
Analysis sets 
Full Analysis Set 
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.  
Safety Set 
The Safety Set includes all subjects who received at least one dose of study treatment. All safety 
analyses will be done using the Safety Set.  
Withdrawal of Informed Consent 
Any data collected in the clinical database after a subject withdraws informed consent from all 
further participation in the trial, will not be included in the analysis. The date on which a patient 
withdraws full consent is recorded in the eCRF.   
2.2.1 
Subgroup of interest 
No subgroup analysis will be performed in final analysis, including subgroup by age, sex and 
China and Japan subgroup analysis.  
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.  
Demographic and other baseline data characteristics and medical history will not be reproduced 
in final analysis if there are no data changes compared to the primary analysis.  
Basic demographic and background data 
All demographic and baseline disease characteristics data will be summarized and listed. 
Categorical data (e.g. gender, age groups: <18, further broken down as 6-11 and 12-17, 18-64, 
≥ 65 years, race, ECOG or Lansky performance status) will be summarized by frequency counts 
and percentages; the number and percentage of patients with missing data will be provided 
when appropriate. Continuous data (e.g. age, weight, height) will be summarized by descriptive 
statistics (N, mean, median, standard deviation, minimum and maximum).  
Disease history and characteristics at screening including time since initial diagnosis to first 
dose,  platelet count, haemoglobin, absolute neutrophils count (ANC) and absolute reticulocytes 
count (ARC) will be summarized by statistiscs for quantitative variables. RBC and Platelet 
Transfusion (Independence and Dependence) at baseline will be summarized by frequency 
counts and percentages. Severity of aplastic anemia and result of cytogenetic analysis as defined 
below, will be summarized by frequency counts and percentages. 
• Severity of aplastic anemia (severe vs. very severe where the latter is defined as 
absolute neutrophil count < 200/µL). 


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Medical history 
Medical history and baseline symptoms (current medical conditions) will be summarized and 
listed. The summaries will be presented by primary system organ class (SOC) and preferred 
term (PT). 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. 
Other 
All data collected at baseline will be listed. 
2.3.1 
Patient disposition 
Enrollment by country and center will be summarized for all screened patients. 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 number (%) 
of patients in the FAS who are still on treatment, who discontinued the study phases and the 
reason for discontinuation will be presented. 
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 core treatment phase;  
• Number (%) of patients who discontinued from core treatment phase ; 
• Primary reason for the premature discontinuation from core treatment phase; 
• Number (%) of patients who have entered extension treatment phase;  
• Number (%) of patients who completed the extension treatment phase;  
• Number (%) of patients who discontinued from extension treatment phase; 
• Primary reason for the premature discontinuation from extension treatment phase; 
• Number (%) of patients who have entered the long term follow-up phase;  
• Number (%) of patients who completed the long term follow-up phase;  
• Number (%) of patients who discontinued from long term follow-up phase; 
Protocol deviations 
The number (%) of patients in the FAS with any protocol deviation will be tabulated by 
deviation category (as specified in the study Edit Check Specification) 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. 
Analysis sets 
The number (%) of patients in each analysis set (defined in Section 2.2) will be summarized 
and listed. 


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2.4 
Treatments (study treatment, rescue medication, concomitant 
therapies, compliance) 
2.4.1 
Study treatment / compliance 
Duration of exposure, actual duration of exposure, cumulative dose, dose intensity (DI) and 
actual dose intensity (ADI) will be summarized separately for each single component of study 
treatment. 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 by 
treatment group.  
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 
The duration of exposure to each component (called drug X below) of the study treatment will 
be derived as follows: 
Exposure to drug X = Last unit (date/time) of administration of X – First unit (date/time) of 
administration of X + (1), 
where periods of drug interruption will not be deducted if there is no permanent treatment 
discontinuation following. If the unit is the date, then plus 1; if the unit is the hour, then transfer 
the exposure duration to days and plus 1 when there are residual hours. 
The actual duration of exposure defines as the sum of periods where the dose exposure is non-
zero. 
Duration of exposure and actual duration of exposure to study treatment will be summarized 
for each of the study treatment components separately, using descriptive statistics (mean, 
standard deviation etc). For eltrombopag, the number and percentage of time on study treatment 
(< 3 months, 3 months to 6 months, > 6 months) will be presented. For CsA, the number and 
percentage of time on study treatment (< 3 months, 3 months to 6 months, > 6 months to 12 
months, > 12 months to 18 months, > 18 months to 24 months) will be presented. A listing of 
data on subject exposure to study treatment will also be produced. 
Cumulative dose 
Cumulative dose is defined as the total dose given during the study treatment exposure and will 
be summarized for each of the study treatment components separately.  
For patients who did not take any drug the cumulative dose is by definition equal to zero. 
The cumulative dose is the sum of the non-zero doses recorded over the dosing period. 
Dose intensity  
Dose intensity (DI) for patients with non-zero duration of exposure is defined as follows:  


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DI of X (dosing unit / unit of time) = Cumulative dose of X (dosing unit) / Duration of exposure 
of X (unit of time). 
Actual dose intensity (ADI) for patients with non-zero actual duration of exposure is defined as 
follows:  
ADI of X (dosing unit / unit of time) = Cumulative assigned dose of X (dosing unit) / Actual 
duration of exposure of X (unit of time). 
For patients who did not take any dose of a given drug the ADI is by definition equal to zero.  
Dose réductions, interruptions or permanent discontinuations 
The number of patients who had dose adjustments, including reductions, increases or 
interruptions, and the reasons, will be summarized separately for each of the study treatment 
components.  
An interruption is defined as 0 mg dose recorded or absence of record for one or more days. A 
reduction (increase) is defined as a decrease (increase) in dose from the protocol planned dose 
or from the previous non-zero dose, even if it has been directly preceded by an interruption. A 
decrease (increase) in frequency of administration which results in a lower (higher) cumulative 
dose is also counted as a reduction (increase).  
The number of dose adjustments per patient and the corresponding reasons will be summarized.  
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.  
Surgical and medical procedures will be coded using MedDRA and summarized by SOC and 
preferred term. 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.  
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. 
2.5 
Analysis of the primary objective 
The primary objective of the study is to evaluate the efficacy of eltrombopag in combination 
with r-ATG and CsA in terms of CR rate at Week 26 in the treatment-naive East-Asian patients 
with SAA. 
All analysis for primary endpoint including supplementary analysis, supportive analysis and 
subgroup analysis will not be reproduced in final analysis.  


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2.5.1 
Primary endpoint 
The primary efficacy endpoint is CR rate at Week 26 (6 months), which is defined as the 
percentage of all subjects who meet the hematological criteria of CR at Week 26. A complete 
response (CR) is defined as meeting all the following 3 criteria on 2 consecutive serial blood 
count measurements at least one week apart but not more than 4 weeks apart.  
A CR will be defined as (all 3 must be met): 
• Absolute neutrophil count > 1.0 x109/L 
• Platelet count > 100 x109/L 
• Hemoglobin > 100 g/L 
The primary endpoint will be based on the investigator assessment of response. However, 
improvement in counts that are dependent upon exogenously administered growth factors or 
transfusion will not be considered as fulfilling response criteria. 
The exclusion period of these therapies are detailed below: 
• Platelets transfusions: 7 days preceding the assessment of platelet count 
• Packed RBC transfusions: 14 days preceding the assessment of hemoglobin 
• Growth factors: 21 days preceding the assessment of response 
The analysis of the primary efficacy endpoint will be based on the FAS. 
2.5.2 
Statistical hypothesis, model, and method of analysis 
The CR at Week 26 will be summarized using point estimate and 2-sided exact binomial 95% 
(Clopper-Pearson) confidence intervals. 
2.5.3 
Handling of missing values/censoring/discontinuations 
Subjects who are not evaluable for response at Week 26 for any reason, including missing data 
and withdrawal from the study before Week 26, will be treated as non-responders in the primary 
analysis.  
2.5.4 
Supplementary analyses 
The CR will also be derived programmatically using laboratory results (criteria details are stated 
in the section 2.5.1 ) instead of those reported by the investigators in the response assessment 
CRF. The response will be derived if two consecutive serial blood count measurements meet 
the defined requirements, where one of the measurements is done at Week 26. The derived 
response will be listed against investigator assessment of response and discrepancies will be 
identified with justifying comment, when available.  
2.5.5 
Supportive analyses 
Supportive analyses using the CR at Week 26 will be generated per programmatically derived 
in the following way: 
A more stringent definition of CR meeting all the following criteria on 2 consecutive serial 
blood count measurements at least one week apart:  


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• Normal hemoglobin concentration for age 
 and gender 
• PLT >150 × 109/L 
• Absolute neutrophil count (ANC) >1.5 × 109/L 
Since this is a more stringent definition of CR, very few CRs will be expected for analysis. 
Subgroup analyses for the primary endpoint  
The primary efficacy endpoint and supportive analyses (more stringent definition of CR) will 
be summarized by the above subgroups listed in section 2.2.1 for efficacy. The proportion of 
the complete response in each subgroup will be summarized using point estimates and 95% 
exact (Clopper-Pearson) confidence intervals. 
In addition, hematological responses will be listed. 
2.6 
Key secondary endpoint 
Not applicable 
2.7 
Analysis of secondary efficacy objective(s) 
The secondary objectives in this study are: 
• To evaluate complete response rate at 3, 12 months and yearly after; 
• To evaluate overall response rate at 3, 6, 12 months and yearly after; 
• To evaluate duration of response; 
• To evaluate overall survival; 
• To evaluate the need for transfusion (packed RBC units and platelet units); 
• To evaluate the safety and tolerability of eltrombopag in combination with r-ATG and 
CsA; 
• To evaluate clonal evolution; 
• To determine the PK of eltrombopag in East-Asian treatment naive SAA patients. 
All analysis will not be reproduced in final analysis for secondary endpoints which are at or 
prior to Week 26. These include CR rate at Week 13, overall response (CR+PR) rate at Week 
13 and Week 26, time to response, transfusion-free interval at Week 13 and Week 26, 
transfusion frequency and amount at Week 13 and Week 26, changes in platelet count, 
hemoglobin and neutrophil count at Week 13 and Week 26. 
2.7.1 
Secondary efficacy endpoints 
CR rate at Week 13, Week 52 and yearly after 
CR rate at specific visit is defined as percentage of subjects who meet the hematological CR 
criteria by investigator assessment at Week 13, Week 52 and yearly after respectively in FAS. 
See Section 2.5.1 for definition of CR.   
Overall response (CR+PR) rate at Week 13, Week 26, Week 52 and yearly after 


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Hematologic overall response rate at specific visit is defined as percentage of subjects who 
achieved hematologic response by investigator assessment at specific visit in FAS.  
The overall hematological response is defined as either complete or partial response. CR is 
defined in section 2.5.1. 
Partial response (PR) is defined as blood counts no longer meeting the standard criteria for 
severe pancytopenia in SAA, equivalent to at least 2 of the 3 criteria below, but are not 
sufficient for a CR. 
• Absolute neutrophil count ≥ 0.5 x109/L 
• Platelet count ≥ 20 x109/L 
• Reticulocyte count ≥ 20 x109/L  
However, improvement in counts that are dependent upon exogenously administered growth 
factors or transfusion will not be considered as fulfilling response criteria. 
The exclusion period of these therapies are detailed below: 
• Platelets transfusions: 7 days preceding the assessment of platelet count 
• Packed RBC transfusions: 14 days preceding the assessment of hemoglobin 
• Growth factors: 21 days preceding the assessment of response. 
Of note that the criteria for complete and partial responses must be met on 2 consecutive serial 
blood count measurements at least one week apart but not more than 4 weeks apart for the Week 
13 and Week 26 assessments but only on one blood count measurements for the yearly 
assessments thereafter. 
Patients who relapse or withdraw from the study will be counted and reported as relapsed or 
withdrawn for all subsequent reponse assessments. No response (NR) is defined as not fulfilling 
the response criteria. 
Time to response 
Time to response is defined as the time from the date of the start of study treatment until the 
first documented and confirmed response (either CR or PR) per programmatically derived. 
Time to complete response is similarly defined as the time from the date of the start of study 
treatment until the first documented complete response. 
All subjects in the FAS will be included in the time to response/CR calculations. 
Duration of response 
Duration of response will be derived as the time from first documented and confirmed response 
(either CR or PR) until the time of relapse or death whichever occurs first. Both the responses 
and the relapse will be programmatically derived. Patients who are neither complete nor partial 
responders will not be included in the analysis of the duration of response.  
Duration of complete response will be similarly derived for patients who had a complete 
response. Patients who are not complete responders will not be included in the analysis of the 
duration of complete response. 
Clinical relapse is considered as the occurrence of any of the following event in a subject who 
had achieved a hematological response (CR or PR) but has subsequently lost response (not 


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explained by any other independent concomitant medical conditions) in one blood count 
meaurements: 
• meeting again the criteria for SAA, equivalent to patients with at least two of the 
following parameters in peripheral blood. 
• 
Absolute neutrophil count < 0.5×109/L 
• 
Platelet count < 20×109/L 
• 
Absolute reticulocyte count < 20×109/L  
• requirement for transfusion again for subjects who had been transfusion independent 
• decrease in any of the peripheral blood counts to: absolute neutrophil count < 
0.5 x109/L or platelets < 20 x109/L. 
The analysis of duration of response will be based on response assessment which are derived 
programmatically using laboratory results instead of those reported in the response assessment 
CRF. 
Transfusion-free interval before Week 13 and Week 26 
For platelet transfusion, transfusion-free interval is defined as the time from most recent platelet 
transfusion preceding response assessment to the date of response assessment. For RBC 
transfusion, transfusion-free interval is defined as the time from most recent RBC transfusion 
preceding response assessment to the date of response assessment.  
Maximum duration of Platelet and RBC transfusion free 
Transfusion free duration will be defined as the period from the next day after transfusion to 
the day of the next transfusion. Maximum duration of platelet and RBC transfusion free for 
each subject will be picked for analysis. 
Proportion of subjects who become transfusion independent 
The number and percentage of subjects with platelet or RBC transfusion independence  during 
the study will be presented respectively. This analysis will be performed for the subgroup of 
subjects with baseline transfusion dependence. 
Post-baseline transfusion independence is defined as follows:  
• Platelet transfusion independence: The subjects who are transfusion dependent at 
baseline become transfusion free for a period of at least 4 weeks after baseline. 
• RBC transfusion independence: The subjects who are transfusion dependent at 
baseline become transfusion free for a period of at least 8 weeks after baseline. 
Transfusion frequency and amount (units) 
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 and Yearly 
thereafter: 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 units of transfusion.  
Subjects with platelet transfusion decrease is defined as subjects with transfusion decrease or 
transfusion free in each period (Week 13, 26, 52 and Yearly thereafter: 4 weeks before each 


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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). The number and percentage of subjects with platelet or RBC transfusion decrease 
and 50% platelet transfusion reduction in each period will be presented.   
Overall survival 
OS is defined as the time from the date of the first dose of study treatment to the date of death 
due to any cause. 
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. 
2.7.2 
Statistical hypothesis, model, and method of analysis 
CR rate at Week 13, Week 52 and yearly after 
The number and percentage of subjects who meet the hematological CR criteria (at Week 13, 
Week 52 and yearly after respectively) will be presented and 2-sided Exact binomial 95% 
(Clopper-Pearson) confidence interval will be reported.  
Overall response (CR+PR) rate at Week 13, Week 26, Week 52 and yearly after 
The number and percentage of subjects who meet the hematological overall response criteria 
(at Week 13, Week 26, Week 52 and yearly after respectively) will be presented and 2-
sided Exact binomial 95% (Clopper-Pearson) confidence interval will be reported.  
The overall response rate will also be summarized by the above subgroups listed in section 2.2.1 
for efficacy.  
Hematological response endpoints will be listed based on the investigator assessment and the 
programmatic derivation. 
Time to response 
The Kaplan-Meier curve of the time to response and time to complete response will be 
constructed, and the quartiles of the survival function will be provided along with 95% 
confidence interval. Kaplan-Meier estimates with 95% confidence intervals every 3 months will 
be summarized as well. 
Duration of response 
Kaplan-Meier curve of the duration of response and duration of complete response will be 
constructed, and the quartiles of the survival function will be provided along with 95% 
confidence interval. Kaplan-Meier estimates with 95% confidence intervals every 3 months will 
be summarized as well.  
Transfusion-free interval before Week 13 and Week 26 


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Descriptive statistics including mean, SD, median, 25th and 75th percentiles, minimum, and 
maximum will be summarized for the transfusion-free interval. The same analysis applies to 
RBC transfusion.  
Maximum duration of Platelet and RBC transfusion free 
Maximum duration of platelet and RBC transfusion free will be summarized by descriptive 
statistics including mean, SD, median, 25th and 75th percentiles, minimum, and maximum 
separately. 
Proportion of subjects who becomes transfusion independent 
The number and percentage of subjects with platelet or RBC transfusion independence at any 
time during the study will be presented repspectively.  
Transfusion frequency and amount 
The frequency and the amount of platelets and RBC transfusion in each period will be 
summarized by descriptive statistics including mean, SD, median, 25th and 75th percentiles, 
minimum, and maximum.  
The number and percentage of subjects with platelet or RBC transfusion decrease and 50% 
platelet transfusion reduction in each period will be presented.   
Overall survival 
Kaplan-Meier curve of the OS will be constructed, and the quartiles of the survival function 
will be provided along with 95% confidence interval. OS rate will be estimated at Week 26, 
Week 52 and yearly after as well. 
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. 
2.7.3 
Handling of missing values/censoring/discontinuations 
CR rate at Week 13, Week 52 and yearly after 
For the analysis CR, 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. Subjects who 
are not evaluable for response at specific visit for any reason, including missing data and 
withdrawal from the study before specific visit, will be treated as non-responders in the analysis.  
Overall response (CR+PR) rate at Week 13, Week 26, Week 52 and yearly after 
For the analysis overall response, 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. 
Subjects who are not evaluable for response at specific visit for any reason, including missing 


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data and withdrawal from the study before specific visit, will be treated as non-responders in 
the analysis.  
Time to response 
For time to response and time to complete response, if a subject does not meet response/CR 
before or at the cutoff date, censoring will be performed using the date of the last response 
assessment. 
Duration of response 
Patients who are neither complete nor partial responders will not be included in the analysis of 
the duration of response. Complete and partial responders who did not relapse at the data cut-
off date will be censored at the date of the last assessment of response with a known outcome. 
Patients who are not complete responders will not be included in the analysis of the duration of 
complete response. Complete responders who did not change to PR or relapse at the data cut-
off date will be censored at the date of the last assessment of response with a known outcome. 
Transfusion-free interval before Week 13 and Week 26 
For platelet transfusion, only subjects with response assessments at specific visits (Week 13 or 
26) are included in the transfusion-free interval. The same rule applies to RBC transfusion. 
Maximum duration of Platelet and RBC transfusion free 
This analysis will be only performed for the subgroup of subjects with baseline transfusion 
dependent. 
Proportion of subjects who becomes transfusion independent 
This analysis will be only performed for the subgroup of subjects with baseline transfusion 
dependent. 
Transfusion frequency and amount 
The transfusion frequence and amount and the proportion of subjects with transfusion decrease 
will be only performed for the subgroup of subjects with baseline transfusion dependent. 
Overall survival 
Analysis of overall survival will be based on the FAS. If a subject is not known to have died, 
survival will be censored at the date of last contact.  
2.8 
Safety analyses 
For all safety analyses, the safety set will be used. All listings and tables will be presented 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 AEs will summarize only 
on-treatment events, with a start date during the on-treatment period (treatment-emergent AEs). 


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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 eltrombopag. 
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 
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 eltrombopag), 
seriousness (SAEs and non-SAEs), leading to treatment discontinuation, leading to dose 
interruption/changes, requiring additional therapy and leading to fatal outcome. Specifically, 
CTC grade  >=3 adverse events will be summarized for AEs by SOC and PT. 
Furthermore, AE occurring during the on-treatment period will be summarized by subgroup 
summarized by the above subgroups listed in section 2.2.1. These summaries include: AEs by 
SOC and PT, AEs with suspected relationship to eltrombopag by SOC and PT and SAEs by 
SOC and PT.  
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 <=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 


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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. 
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 than 30 days after the last study treatment administration date (see Section 2.1.1). 
Grading of laboratory values will be assigned programmatically as per NCI Common 
Terminology Criteria for Adverse Events (CTCAE), version 4.03. The calculation of CTCAE 
grades will be based on the observed laboratory values only, clinical assessments will not be 
taken into account. 
CTCAE Grade 0 will be assigned for all non-missing values not graded as 1 or higher. Grade 5 
will not be used. 
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. 


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• 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 by subject and visit/time, 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 by subject and visit/time 
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, SD, median, interquartile range, and 
range). 
Coagulation 
Coagulation assays data (Prothrombin time, international normal ratio, Activated partial 
thromboplastin time) will be listed. 
Liver function parameters  
Liver function parameters of interest are Total bilirubin (TBIL) and Direct bilirubin (DBIL), 
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 (TBIL or DBIL > 2xULN) and (ALP < 2xULN or 
missing) 
• ALT or AST > 3xULN and (TBIL or DBIL > 2xULN) 
• ALT or AST > 3xULN and (TBIL or DBIL > 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 


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• AST > 10xULN 
• AST > 5xULN 
• AST > 3xULN 
 
• DBIL > 2xULN 
• DBIL > 1.5xULN 
• TBIL > 2xULN 
• TBIL > 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 13, Week 26 and Week 52 (in the extension part ECG is only for the 
responders) 
• at the end of treatment 
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: 
• 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 
- 
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 


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- 
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 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. 
Data analysis 
For analysis of vital signs the clinically notable vital sign criteria are provided in Table 2-2 
below. 
Table 2-2 
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 
(°C) 
>= 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. 


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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 and FISH)
•
Peripheral blood smear test
2.9 
Pharmacokinetic endpoints 
Not applicable for final analysis. 
NA.  
2.10 
PD and PK/PD analyses 
Not applicable for final analysis. 
2.11 
Cytogenetic abnormalities and clonal evolution 
Cytogenetic abnormalities and clonal evolution observed during the study 
Cytogenetic abnormalities and clonal evolution will be selected from AE page in eCRF, and 
will be chosen as AE Preferred term = “clonal evolution / cytogenetic abnormality / AML / 
MDS / PNH”. 
Clonal cytogenetic evolution will be evaluated during the study, and the rate of the subjects 
who developed any clonal evolution (e.g., clonal evolution to PNH, evolution to AML or MDS 
etc.) will be calculated in a summary table. Short narratives and relevant information for 
subjects with new cytogenetic abnormalities on study will be listed.  
GPI negative neutrophil level 
Shift tables using GPI negative neutrophil and RBC level (≤ 50% and > 50%) to compare 
baseline to the worst on-treatment will be presented. 
2.12 
Other Exploratory analyses 
Not Applicable. 
2.13 
Interim analysis 
No formal interim analysis is planned for this trial. The primary analysis will be performed after 
all subjects have completed Week 26 or discontinued prior to Week 26. A final analysis will be 
performed after all subjects have completed the study. No formal testing of the primary endpoint 
will be performed in this study. 


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3 
Sample size calculation 
As this is a bridging study to support registration, an estimation strategy rather than formal 
hypothesis testing will be pursued. Approximately 36 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 Asian patients. 
3.1 
Primary analysis 
Based on the Day 120 report in the pivotal study of CETB115AUS01T, the complete 
hematological response rate at Month 6 in Cohort 3+Extension is 43.7%. If the CR rate obtained 
in naive Asian patients with SAA treated with eltrombopag is expected to be 44.0%, a total of 
36 subjects will result in a 95% CI lower bound of about 28%. 
Below table shows the exact 95% CIs for various observed complete hematological response 
rate. The maximum half-width of the 95% CIs is 17.1%. 
Table 3-1 
95% CIs for various observed response rate 
Total sample size 
# of responders 
Complete 
hematologic 
response rate (%) 
95% CI (%) 
36 
14 
38.9 
(23.1, 56.5) 
36 
16 
44.4 
(27.9, 61.9) 
36 
18 
50.0 
(32.9, 67.1) 
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. 
3.2 
Power for analysis of key secondary variables 
Not Applicable 
4 
Change to protocol specified analyses 
Below-listed endpoints were added to further support efficacy analysis beyond protocol. 
• Maximum duration of Platelet and RBC transfusion free 
• Proportion of subjects with transfusion decrease 
• Changes in platelet count, hemoglobin and neutrophil count 
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: 


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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. 
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 


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Missing 
Element 
Rule 
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   


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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* 
hour 
• 
For rATG end dates only, if partial end time contains no time, then set 
the time to 00:00. 
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  
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 


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available version of the document based on the underlying CTCAE version 4.03 at the time of 
analysis will be used.  
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. 
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 95% 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 95% (=100 × (1 – two-sided alpha level)) two-sided Pearson-Clopper CI. 
5.4.2 
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 95% confidence 
intervals calculated from PROC LIFETEST output using the method of (Brookmeyer and 
Crowley, 1982). Kaplan-Meier estimates of the survival function with 95% confidence 
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). 


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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.