Conditions: Severe Aplastic Anemia
Keywords: severe acquired aplastic anemia SAA first line eltrombopag cyclosporine h-ATG severe aplastic anemia aplastic anemia
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 54
Healthy volunteers: no

Brief summary:
The purpose of this study was to evaluate the efficacy and safety of eltrombopag in combination with cyclosporine alone as first-line therapy on overall hematologic response

Detailed description:
This was an interventional phase II, single-arm, multicenter, open-label, study to investigate the efficacy and safety of the combination of eltrombopag and cyclosporine in treatment-naive, adult subjects with severe aplastic anemia (SAA) as first line therapy.

Eligible subjects received eltrombopag and cyclosporine for up to 6 months. Participants who achieved hematologic response any time on or before 6 months were considered as responders; else they were considered as non-responders.

Responders at Month 6 discontinued eltrombopag and started to taper cyclosporine until relapse or Month 24, whichever was early. Responders who relapsed prior to 6 months and non-responders discontinued the treatment at 6 months and were followed-up for 30 days.

Responders who started to taper cyclosporine and relapsed prior to 24 months discontinued cyclosporine and were followed-up for 30 days.

Arms:
arm 1: Participants received eltrombopag (orally, 150 mg once daily for non-Asian participants / 100 mg once daily for participants of Asian ancestry) in combination with cyclosporine (orally, 10.0 mg/kg/day in divided doses every 12 hours) for up to 6 months. Thereafter, responders at Month 6 were treated with cyclosporine until Month 24

Interventions: intervention 1: eltrombopag intervention 2: Cyclosporine
Intervention descriptions: intervention 1: Film-coated tablets (12.5 mg, 25 mg, 50 mg and 75 mg) administered orally, once daily for up to 6 months. East and Southeast Asian participants were treated with 100 mg once daily, to adjust for the lower apparent clearance of eltrombopag. All other participants were treated with 150 mg once daily. intervention 2: Supplied as oral soft gel capsules. The starting dose was based on body weight at 10.0 mg/kg/day (acceptable rounding range was from 9.5 to 10.5 mg/kg/day) in divided doses every 12 hours. After Day 1, dosing was titrated individually according to therapeutic trough level between 200 and 400 μg/L for 6 months. After 6 months (only for responders at Month 6), tapering of cyclosporine was done as follows:

* 6-9 months: at the 6 months visit, the dose was reduced by 25% for 3 months
* 9-12 months: at the 9 months visit, the dose was further reduced by 25% for another 3 months
* 12-24 months: dose was maintained

Protocol document:
Prot_000.pdf: 


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Table of contents 
Table of contents ................................................................................................................. 2 
List of figures ...................................................................................................................... 6 
List of tables ........................................................................................................................ 6 
List of abbreviations ............................................................................................................ 8 
Glossary of terms ............................................................................................................... 11 
Amendment 2: (15-Feb-2019) ........................................................................................... 13 
Amendment 1: (17-May-2017) .......................................................................................... 19 
Protocol summary: ............................................................................................................. 21 
1 
Background ........................................................................................................................ 25 
1.1 
Overview of disease pathogenesis, epidemiology and current treatment .............. 25 
1.2 
Introduction to investigational treatment(s) and other study treatment(s) ............. 28 
1.2.1 
Overview of eltrombopag olamine (Promacta® – Revolade®) .............. 28 
1.2.2 
Overview of Cyclosporine .................................................................... 39 
2 
Rationale ............................................................................................................................ 43 
2.1 
Study rationale and purpose ................................................................................... 43 
2.2 
Rationale for the study design ............................................................................... 43 
 
 44 
2.3 
Rationale for dose and regimen selection .............................................................. 44 
2.4 
Rationale for choice of combination drugs ............................................................ 45 
2.5 
Rationale for choice of comparators drugs ............................................................ 46 
2.6 
Risks and benefits .................................................................................................. 46 
3 
Objectives and endpoints ................................................................................................... 47 
4 
Study design ...................................................................................................................... 51 
4.1 
Description of study design ................................................................................... 51 
4.2 
Timing of interim analyses and design adaptations ............................................... 51 
4.3 
Definition of end of study ...................................................................................... 52 
4.4 
Early study termination .......................................................................................... 52 
5 
Population .......................................................................................................................... 52 
5.1 
Patient population .................................................................................................. 52 
5.2 
Inclusion criteria .................................................................................................... 52 
5.3 
Exclusion criteria ................................................................................................... 53 
6 
Treatment ........................................................................................................................... 54 
6.1 
Study treatment ...................................................................................................... 54 
6.1.1 
Dosing regimen ..................................................................................... 55 


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6.1.2 
Ancillary treatments .............................................................................. 58 
6.1.3 
Rescue medication ................................................................................ 58 
6.1.4 
Guidelines for continuation of treatment .............................................. 58 
6.1.5 
Treatment duration ................................................................................ 58 
6.2 
Dose escalation guidelines ..................................................................................... 58 
6.3 
Dose modifications ................................................................................................ 59 
6.3.1 
Dose modification and dose delay ........................................................ 59 
6.3.2 
Dose adjustments for QTcF prolongation ............................................. 63 
6.3.3 
Follow-up for toxicities ......................................................................... 64 
6.3.4 
Anticipated risks and safety concerns of the study drug ....................... 65 
6.4 
Concomitant medications ...................................................................................... 67 
6.4.1 
Permitted concomitant therapy ............................................................. 67 
6.4.2 
Permitted concomitant therapy requiring caution and/or action ........... 68 
6.4.3 
Prohibited concomitant therapy ............................................................ 70 
6.4.4 
Use of Bisphosphonates (or other concomitant agents) ........................ 70 
6.5 
Patient numbering, treatment assignment or randomization ................................. 70 
6.5.1 
Patient numbering ................................................................................. 70 
6.5.2 
Treatment assignment or randomization ............................................... 71 
6.5.3 
Treatment blinding ................................................................................ 71 
6.6 
Study drug preparation and dispensation ............................................................... 71 
6.6.1 
Study treatment packaging and labeling ............................................... 71 
6.6.2 
Drug supply and storage ........................................................................ 72 
6.6.3 
Study drug compliance and accountability ........................................... 72 
6.6.4 
Disposal and destruction ....................................................................... 72 
7 
Visit schedule and assessments ......................................................................................... 73 
7.1 
Study flow and visit schedule ................................................................................ 73 
7.1.1 
Molecular pre-screening ........................................................................ 82 
7.1.2 
Screening ............................................................................................... 82 
7.1.3 
Run-in period ........................................................................................ 83 
7.1.4 
Treatment period ................................................................................... 83 
7.1.5 
Discontinuation of study treatment ....................................................... 83 
7.1.6 
Withdrawal of consent .......................................................................... 84 
7.1.7 
Follow up for safety evaluations ........................................................... 84 
7.1.8 
Lost to follow-up ................................................................................... 84 
7.2 
Assessment types ................................................................................................... 85 


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7.2.1 
Efficacy assessments ............................................................................. 85 
7.2.2 
Safety and tolerability assessments ....................................................... 85 
7.2.3 
Pharmacokinetics .................................................................................. 92 
 
 93 
7.2.5 
Resource utilization ............................................................................... 95 
7.2.6 
Patient reported outcomes ..................................................................... 95 
8 
Safety monitoring and reporting ........................................................................................ 96 
8.1 
Adverse events ....................................................................................................... 96 
8.1.1 
Definitions and reporting ...................................................................... 96 
8.1.2 
Laboratory test abnormalities ................................................................ 98 
8.1.3 
Adverse events of special interest ......................................................... 98 
8.2 
Serious adverse events ........................................................................................... 98 
8.2.1 
Definitions ............................................................................................. 98 
8.2.2 
Reporting ............................................................................................... 99 
8.3 
Emergency unblinding of treatment assignment ................................................. 100 
8.4 
Pregnancies .......................................................................................................... 100 
8.5 
Warnings and precautions .................................................................................... 100 
8.6 
Data Monitoring Committee ................................................................................ 100 
8.7 
Steering Committee ............................................................................................. 100 
9 
Data collection and management ..................................................................................... 101 
9.1 
Data confidentiality ............................................................................................. 101 
9.2 
Site monitoring .................................................................................................... 101 
9.3 
Data collection ..................................................................................................... 102 
9.4 
Database management and quality control .......................................................... 102 
10 Statistical methods and data analysis .............................................................................. 102 
10.1 
Analysis sets ........................................................................................................ 103 
10.1.1 
Full Analysis Set ................................................................................. 103 
10.1.2 
Safety set ............................................................................................. 103 
10.1.3 
Per-Protocol set ................................................................................... 103 
10.1.4 
Dose-determining analysis set............................................................. 103 
10.1.5 
Pharmacokinetic analysis set ............................................................... 104 
10.1.6 
Other analysis sets ............................................................................... 104 
10.2 
Patient demographics/other baseline characteristics ........................................... 104 
10.3 
Treatments (study treatment, concomitant therapies, compliance) ..................... 104 
10.3.1 
Study Treatment .................................................................................. 104 


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10.3.2 
Concomitant therapies ......................................................................... 104 
10.4 
Primary objective ................................................................................................. 105 
10.4.1 
Variable ............................................................................................... 105 
10.4.2 
Statistical hypothesis, model, and method of analysis ........................ 105 
10.4.3 
Handling of missing values/censoring/discontinuations ..................... 106 
10.4.4 
Supportive and Sensitivity analyses .................................................... 106 
10.5 
Secondary objectives ........................................................................................... 106 
10.5.1 
Key secondary objective(s) ................................................................. 107 
10.5.2 
Other secondary efficacy objectives ................................................... 109 
10.5.3 
Safety objectives ................................................................................. 109 
10.5.4 
Pharmacokinetics ................................................................................ 111 
10.5.5 
Biomarkers .......................................................................................... 112 
10.5.6 
Resource utilization ............................................................................. 112 
10.5.7 
Patient reported outcomes ................................................................... 112 
 
 112 
 
 112 
 
 112 
10.7 
Interim analysis .................................................................................................... 114 
10.8 
Sample size calculation ........................................................................................ 114 
10.8.1 
Bayesian calculus for a binary endpoint ............................................. 115 
10.9 
Power for analysis of key secondary variables .................................................... 116 
11 Ethical considerations and administrative procedures .................................................... 116 
11.1 
Regulatory and ethical compliance ...................................................................... 116 
11.2 
Responsibilities of the investigator and IRB/IEC/REB ....................................... 116 
11.3 
Informed consent procedures ............................................................................... 116 
11.4 
Discontinuation of the study ................................................................................ 117 
11.5 
Publication of study protocol and results............................................................. 117 
11.6 
Study documentation, record keeping and retention of documents ..................... 117 
11.7 
Confidentiality of study documents and patient records ..................................... 118 
11.8 
Audits and inspections ......................................................................................... 118 
11.9 
Financial disclosures ............................................................................................ 118 
12 Protocol adherence .......................................................................................................... 118 
12.1 
Amendments to the protocol ................................................................................ 119 
13 References (available upon request) ................................................................................ 120 
14 Appendices ...................................................................................................................... 124 


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14.1 
Appendix 1 – Cyclosporine taper dose ................................................................ 124 
14.2 
Appendix 2 – Quality of Life questionnaires ...................................................... 125 
 
List of figures 
Figure 1-1 
Pathophysiology of acquired aplastic anemia “Immune-mediated 
destruction of hematopoiesis” ............................................................... 25 
Figure 4-1 
Study design .......................................................................................... 51 
 
List of tables 
Table 1-1 
Overview of clinical experience in severe aplastic anemia 
(Jan2019) ............................................................................................... 30 
Table 2-1 
Dosing according to ethnicity (Asian vs Non-Asian) (Study NIH 
12-H-0150 /ELT116643/CETB115AUS01T) ....................................... 45 
Table 3-1 
Objectives and related endpoints .......................................................... 48 
Table 6-1 
Dosing according to age and ethnicity .................................................. 55 
Table 6-2 
Eltrombopag dose adjustments ............................................................. 56 
Table 6-3 
Eltrombopag Dosages and Available Treatment Formulations ............ 56 
Table 6-4 
Cyclosporine Dosage ............................................................................ 56 
Table 6-5 
Cyclosporine Dose reduction ................................................................ 57 
Table 6-6 
Cyclosporine Dosages and Available Treatment Formulations* .......... 57 
Table 6-7 
Criteria for eltrombopag dose adjustment based on liver enzyme 
and bilirubin levels ................................................................................ 60 
Table 6-8 
Preparation and dispensing ................................................................... 71 
Table 6-9 
Packaging and labeling ......................................................................... 72 
Table 6-10 
Supply and storage of study treatments ................................................ 72 
Table 7-1 
Visit evaluation schedule – First 6 months ........................................... 74 
Table 7-2 
Visit evaluation schedule –Follow-up for duration of response 
(Responders only) ................................................................................. 78 
Table 7-3 
Clinical laboratory parameters collection plan for central lab (first 
6 months) ............................................................................................... 87 
Table 7-4 
Clinical laboratory parameters collection plan for local lab (first 6 
months) .................................................................................................. 88 
Table 7-5 
Clinical laboratory parameters potentially collected as per local 
standard of care during the 18-months follow-up – Responders 
only ........................................................................................................ 88 


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Table 7-6 
Local ECG collection plan .................................................................... 91 
Table 7-7 
Pharmacokinetic blood collection log (eltrombopag) ........................... 92 
 
 94 
Table 10-1 
Non-compartmental pharmacokinetic parameters of eltrombopag ..... 111 
Table 10-2 
Table showing observed response rate and its posterior distribution 
using a Beta-binomial model .............................................................. 115 
Table 10-3 
Operating characteristics of the study design ...................................... 115 
Table 14-1 
Cyclosporine taper dose recommandations ......................................... 124 
 


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List of abbreviations 
AE 
Adverse Event 
ALT 
Alanine aminotransferase/glutamic pyruvic transaminase/GPT 
AML 
acute myeloid leukemia 
ANC 
absolute neutrophil count 
aPTT 
acute partial thromboplastin time  
AST 
Aspartate aminotransferase/glutamic oxaloacetic transaminase/GOT 
ATG 
anti-thymocyte globulin 
AUC 
area under the plasma concentration - time curve 
AUCinf 
area under the plasma concentration - time curve extrapolated to infinite time 
AUCtau 
Area under the plasma concentration - time curve over the dosing interval 
BCRP 
Breast Cancer Resistance Protein 
BID 
bis in diem/twice a day 
BM 
bone marrow 
CI 
confidence interval 
CL/F 
Apparent clearance 
Cmax 
maximal (peak) plasma concentration 
CPK 
creatine phosphokinase 
CR 
complete response 
CRADA 
Cooperative Research and Development Agreement 
CRO 
Contract Research Organization 
CsA 
Cyclosporine 
CSR 
Clinical study report 
CTCAE 
Common Terminology Criteria on Adverse Events 
DILI 
drug-induced liver injury 
CMO&PS  
Chief Medical Office and Patient Safety 
CYP 
Cytochrome P450 
CyTOF 
Mass Cytometry 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report/Record Form 
EOS 
End of study 
EOT 
End of treatment 
EU 
European Union 
ePRO 
Electronic patient reported outcomes 
eSAE 
Electronic Serious Adverse Event 
FAS 
full analysis set 
G-CSF 
granulocyte-colony stimulating factor 
GGT 
gamma glutamyl transferase 
GPI-anchor 
Glycosylphosphatidylinositol -anchor 
GVHD 
graft-versus-host-disease 
h-ATG 
horse anti-thymocyte globulin 
HBsAg 
hepatitis B surface antigen 
HCV 
Hepatitis C virus 
HIV 
human immune deficiency virus 


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HLA 
human leucocyte antigen 
HSA 
human serum albumin 
HSC 
hematopoietic stem cells 
HSCT 
hematopoietic stem cell transplant 
ICF 
informed consent form 
i.v. 
intravenous(ly) 
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology that includes Interactive Voice Response System and 
Interactive Web Response System 
IST 
immunosuppressive therapy  
ITP 
immune thrombocytopenia  
IUD / IUS 
intrauterine device / intrauterine system 
IWRS 
Interactive Web Response System 
LLOQ 
lower limit of quantitation 
MDS 
myelodysplastic syndrome 
MedDRA 
Medical Dictionary for Regulatory Activities 
MGDF 
megakaryocyte growth & development factor 
NHLBI 
National Heart, Lung and Blood Institute 
NIH 
National Institutes of Health 
OATP 
organic anion transporting polypeptide 
od 
omnia die/once a day 
OR 
overall response 
ORR 
overall response rate 
PAS 
Pharmacokinetic analysis set  
PfOS 
Powder for oral suspension 
Pgp 
p-glycoprotein 
po 
per os/by mouth/orally 
PHI 
Protected Health Information 
PI 
Product information 
PK 
Pharmacokinetic(s) 
PLT 
Platelet 
PNH 
paroxysmal nocturnal hemoglobinuria 
PPS 
Per-Protocol set 
PT 
prothrombin time 
 
 
QTcF 
QT interval corrected for heart rate using Fridericia’s method 
RBC 
red blood cells 
r-ATG 
rabbit anti-thymocyte globulin 
REB 
Research Ethics Board 
SAA 
severe aplastic anemia 
SAE 
Serious Adverse Event 


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SAP 
Statistical Analysis Plan (SAP)  
SmPC 
Summary of Product Characteristics 
SOC 
Standard of care 
TdP 
Torsades de Pointes 
TEE 
thromboembolic events 
Tmax 
time to reach the maximal (peak) plasma concentration 
TPO-R 
thrombopoietin-receptor 
UGT 
uridine diphosphate glucuronosyltransferases 
ULN 
upper limit of normal 


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Glossary of terms 
Assessment 
A procedure used to generate data required by the study 
Biologic Samples 
A biological specimen including, for example, blood (plasma, serum), saliva, 
tissue, urine, stool, etc. taken from a study subject or study patient 
Complete response (CR) 
All three of the following parameters meet the following criteria at two 
consecutive, scheduled visit measurements at least 7 days apart during the 
study and no platelet transfusions within 7 days of platelet measurement 
and no RBC transfusion within 14 days of the hemoglobin measurement: 
Absolute neutrophil count ≥ 1000/µL 
Platelet count ≥ 100 000/µL 
Hemogoblin ≥ 10 g/dL 
Dose level 
The dose of drug given to the patient (total daily or weekly etc.)  
Duration of response  
The start date is the first document response of complete or partial response 
(i.e., the start date of the response, not the date when the response was 
confirmed) and the end date is defined as the date of the first documented 
progression or death due to underlying disorder) 
Enrollment 
Point/time of patient entry into the study; the point at which informed 
consent must be obtained (i.e. prior to starting any of the procedures 
described in the protocol) 
Investigational drug 
The study treatment 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.” 
Investigational treatment 
Drug whose properties are being tested in the study as well as their 
associated placebo and active treatment controls (when applicable). This 
also includes approved drugs used outside of their indication/approved 
dosage, or that are tested in a fixed combination. Investigational treatment 
generally does not include other study treatments administered as 
concomitant background therapy required or allowed by the protocol when 
used in within approved indication/dosage 
Medication number 
A unique identifier on the label of each study treatment package which is 
linked to one of the treatment groups of a study 
Other study treatment 
Any drug administered to the patient as part of the required study 
procedures that was not included in the investigational treatment 
Overall response (OR) 
Includes complete response (CR) + partial response (PR).  
Partial response (PR) 
Any two of the parameters meet the following criteria at two consecutive, 
scheduled visit measurements at least 7 days apart during the study and no 
platelet transfusions within 7 days of platelet measurement (can still be a 
responder if ANC and reticulocyte measurements are valid):  
Absolute neutrophil count ≥ 500/µL 
Platelet count ≥ 20 000/µL 
Reticulocyte count ≥ 60 000/µL (automated) 
Patient Number (Patient No. 
NCDS) 
A unique identifying number assigned to each patient who enrolls in the 
study 
Period 
A subdivision of the study timeline; divides stages into smaller functional 
segments such as screening, baseline, titration, washout, etc. 
SAP 
Statistical Analysis Plan (SAP), a regulatory document which provides 
evidence of preplanned statistical analyses 
Stage related to study timeline 
A major subdivision of the study timeline; begins and ends with major study 
milestones such as enrollment, randomization, completion of treatment, etc. 


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Study treatment 
Includes any drug or combination of drugs in any study arm administered to 
the patient (subject) as part of the required study procedures, including 
placebo and active drug run-ins. 
In specific examples, it is important to judge investigational treatment 
component relationship relative to a study treatment combination; study 
treatment in this case refers to the investigational and non-investigational 
treatments in combination. 
Study treatment discontinuation 
Point/time when patient permanently stops taking study treatment for any 
reason 
Supportive treatment 
Refers to any treatment required by the exposure to a study treatment, e.g. 
premedication of vitamin supplementation and corticosteroid for pemetrexed 
disodium. 
Variable 
Identifier used in the data analysis; derived directly or indirectly from data 
collected using specified assessments at specified timepoints 
Withdrawal of consent 
Withdrawal of consent occurs only when a patient does not want to 
participate in the study any longer, and does not want any further visits or 
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Amendment 2: (15-Feb-2019) 
Amendment rationale  
As of 05-Oct-2018, 31 of the planned 50 patients were enrolled in the study.  
Rationale for this amendment is based on findings in the study that identified the need to clarify 
patient selection and dose management.   
The occurrence of 6 fatal cases (four on treatment, one post treatment and one additional death 
in screening) warranted a thorough assessment by Novartis.   
In order to accurately investigate these findings, assess their causalities, identify and implement 
any necessary corrective actions, Novartis voluntarily put the study on a partial/temporary 
clinical hold (hold of recruitment of new patients), effective 05-Oct-2018. Health Authorities 
were notified in all participating countries.  
In summary, none of these fatal cases were suspected to be related to study treatment 
(eltrombopag and cyclosporine) by the Investigators. Novartis and the Steering Committee 
determined that the six fatal cases reported in this study were due to known complications of 
the underlying SAA, compounded by high-risk baseline demographics (notably age, frailty and 
comorbidities), low adherence to study treatment and worse severity of disease. Likewise all 
six deaths were considered by the Investigators to be due to the underlying disease. 
Novartis therefore considers the events that led to the fatal outcomes do not alter the established 
safety profile of eltrombopag and that the benefit-risk profile for eltrombopag remains positive. 
Based on the findings identified, changes have been implemented in this protocol amendment 
to some inclusion, exclusion criteria and dose management sections (details provided below). 
The enrollment will re-start after approval of this amendment by the local HA/ECs. 
Key changes that will be implemented in this amendment are: 
Clarification on patient eligibility 
• Exclusion criterion 9 was amended to exclude patients with a life-expectancy of at least 
3 months instead of 30 days. 
• Exclusion criterion 17 was added to exclude patients with ECOG performance status of 
≥ 2. 
• Exclusion criterion 8 was amended to clarify that patients who are human immune 
deficiency virus (HIV), hepatitis C virus (HCV) or hepatitis B surface antigen (HBsAg) 
positive are excluded from the study. 
• To avoid discrepancies between local and central bone marrow assessments it will now be 
required that central laboratory bone marrow results are available before enrolling patients 
into the study. The screening period will be extended from 14 to 21 days to accommodate 
for the central review turnaround time. 
• Exclusion criterion 2 was modified to have the assessment of evidence of clonal 
hematologic bone marrow disorder on cytogenetics by central review, even for patients 


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with ANC <200/µL. The update of this exclusion criterion will ensure that no further 
patients are discontinued from the study due to discrepant bone marrow results. 
Cyclosporine and eltrombopag dose management 
Since both study medications may lead to hepatotoxic adverse events, a clarification on the dose 
management based on hepatobiliary laboratory values was added.  
• Eltrombopag and cyclosporine dosing and dose modifications were clarified. 
• Eltrombopag dose level for dose management guidance was specified to be “25mg”. 
• Additional guidance on cyclosporine dose management for increased blood pressure and 
nephrotoxicity was added. 
Adjustments to study objectives and study design 
The following changes to the study objectives and the study duration were implemented:  
• Inclusion criterion 2 was changed to only allow enrollment of patients 18 years and older. 
No pediatric patients were included up to date and hence data collection now will only 
focus on adult patients. 
• The study duration was shortened from 60 months to 24 months. As the primary endpoint 
is defined as hematological response by 6 months with a follow-up of up to 24 months, 
this time period is considered as adequate to provide a robust assessment of sustained 
response and safety follow-up. Also this aligns the study with ongoing clinical studies in a 
comparable setting with regards to the study duration (EBMT RACE study, 
NCT02099747). 
• The treatment with eltrombopag and cyclosporine remains unchanged during the first 6 
months. 
• At 6 months, responders will discontinue eltrombopag and start to taper cyclosporine until 
24 months. Responders who relapse prior to 6 months and non-responders will discontinue 
the treatment and study at 6 months and will be followed-up for 30 days.  
Responders who relapse prior to 24 months will discontinue cyclosporine and study, and 
will be followed-up for 30 days. Responders who relapsed and non-responders already in 
the follow-up under the previous protocol version will be discontinued from the study 
within 30 days of the approval of this protocol amendment. 
• Overall survival was removed as only responder patients will be followed-up until 24 
months or relapse whichever is earlier.  
• Any cytogenetic abnormalities will be reported until 6 months for all patients and until 
24 months for responder patients only. Previous studies showed, that the majority of 
clonal evolutions are expected at an earlier time point and only few occurred past 24 
months.  
• Transfusion restriction was added to the primary endpoint definition of PR and CR. 


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Changes to the protocol 
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underline for insertions. 
• List of abbreviations: Updated list of abbreviations. These changes are considered non-
substantial. 
• Glossary of terms: Updated glossary of terms for complete and partial response. These 
changes are considered non-substantial. 
• Protocol summary: Amended entire protocol summary section according to new study 
design and corrected typos. Some of these changes are considered as substantial. 
• Section 1.1: Added clarifications, corrected typos and updated data based on latest 
publication for CETB115AUS01T study. These changes are considered non-substantial. 
• Section 1.2.1: Added clarifications, corrected typos and updated data based on latest 
information. These changes are considered non-substantial. 
• Section 1.2.1.1: Corrected typos. These changes are considered non-substantial. 
• Section 1.2.1.2: Updated clinical experience based on latest publications and data. This 
change is considered non-substantial. 
• Section 1.2.1.3: Corrected typos and replaced East Asian with Asian ancestry. These 
changes are considered non-substantial. 
• Section 1.2.2: Corrected typo in title. This change is considered non-substantial. 
• Section 1.2.2.1 and 1.2.2.2: Added clarifications and corrected typos. These changes are 
considered non-substantial. 
• Section 2.1 and 2.2: Added clarifications and corrected typos. These changes are 
considered non-substantial. 
• Section 2.3: Added clarification on Asian and non-Asian ancestry and study treatment, 
removed pediatric patients. These changes are considered non-substantial. 
• Section 2.4: Updated based on latest publications and corrected typos. These changes are 
considered non-substantial. 
• Section 2.5: Clarification added. This change is considered non-substantial. 
• Section 2.6: Updated based on latest publications and data, and corrected typos. These 
changes are considered non-substantial. 
• Section 3: Updated primary, secondary 
 objectives and endpoints in Table 
3-1. These changes are considered as substantial. 
• Section 4.1: Updated study design based on new study duration, 6 months eltrombopag 
and cyclosporine treatment with an additional 18 months follow-up for cyclosporine 
tapering and duration of response. Removed cyclosporine dosing information as it’s listed 
in section 6.1.1.2 and removed interim analysis/snapshot information as it’s listed in 
sections 4.2 and 10.7. These changes are considered as substantial. 
• Section 4.2: Updated number of database locks and CSRs based on new study duration. 
This change is considered as substantial. 


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• Section 4.3: Updated definition of end of study based on new study duration. This change 
is considered non-substantial. 
• Section 4.4: Corrected typo. This change is considered non-substantial. 
• Section 5.1: Amended patient population from 6 years or older to 18 years or older to 
exclude pediatrics. This change is considered as substantial. 
• Section 5.2: Amended inclusion criteria 1 from 6 years or older to patients 18 years or 
older and inclusion criteria 4 to remove ECG information related to pediatrics. These 
changes are considered as substantial. 
• Section 5.3: Amended exclusion criteria 2 to be more restrictive by requiring evidence of a 
clonal hematologic bone marrow disorder on cytogenetics by central review for all 
patients. Exclusion criteria 8 revised to be more restrictive by adding an additional criteria 
to exclude patients who are human immune deficiency virus (HIV), hepatitis C virus 
(HCV) or hepatitis B surface antigen (HBsAg) positive. HCV-RNA negative patients are 
allowed to be enrolled. Exclusion criteria 9 revised to be more stringent to exclude patient 
with less than 3 months of life-expectancy. Exclusion criteria 17 added to exclude patients 
with ECOG performance status of ≥2. Exclusion criteria 18 added to exclude patients 
under age 40 who are eligible for transplantation. These changes are considered as 
substantial. 
• Section 6.1: Removed cyclosporine oral solution as no pediatric patients will be enrolled. 
This change is considered as non-substantial. 
• Section 6.1.1.1: Updated East-Asian ancestry to Asian ancestry and added the Asian 
ancestries, removed pediatric population, added clarification on eltrombopag dosing and 
in case of early discontinuation of eltrombopag. These changes are considered as non-
substantial. 
• Section 6.1.1.2: Added clarification on cyclosporine dosing, acceptable rounding range for 
cyclosporine and on tapering. Removed pediatric population and oral solution. Added 
clarification in case of early discontinuation of cyclosporine. These changes are 
considered as non-substantial. 
• Section 6.1.2: Clarification added on wording for ancillary treatment. This change is 
considered as non-substantial. 
• Section 6.1.3: Clarification added on wording for rescue medication. This change is 
considered as non-substantial. 
• Section 6.1.4: Clarification added on cyclosporine tapering after 24 months. This change 
is considered as non-substantial. 
• Section 6.1.5: Clarification added on treatment duration. This change is considered as 
substantial. 
• Sections 6.3.1 and 6.3.1.1: Clarification added on wording for eltrombopag dose 
modification and to Table 6-7. It was added to the footnote that “One dose level” defined 
as eltrombopag dose reduction by 25 mg. These changes are considered non-substantial. 
• Section 6.3.1.2: Corrected typos. These changes are considered non-substantial. 


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• Sections 6.3.1.3 and 6.3.1.4: Added these two sections to clarify cyclosporine dose 
modification due to increase in blood pressure and nephrotoxicity. These changes are 
considered non-substantial. 
• Section 6.3.2: Corrected typos. These changes are considered non-substantial. 
• Section 6.3.3: Corrected typos and added clarifications. These changes are considered 
non-substantial. 
• Sections 6.3.3.1 and 6.3.3.2: Added clarifications on wording. These changes are 
considered non-substantial. 
• Section 6.3.4 and 6.3.4.1: Corrected typos and added clarifications on anticipated risks and 
safety concerns of the study drug including drug-induced liver injury. These changes are 
considered non-substantial. 
• Sections 6.4.1 and 6.4.1.1: Added clarifications on permitted concomitant therapy and 
supportive care (transfusion restrictions). These changes are considered non-substantial. 
• Sections 6.4.2.1 and 6.4.2.2: Added clarifications on wording. These changes are 
considered non-substantial. 
• Sections 6.4.3 and 6.4.3.1: Added clarifications on wording. These changes are considered 
non-substantial. 
• Section 6.5.2: Corrected typo. This change is considered non-substantial. 
• Section 6.6: Removed oral solution. This change is considered non-substantial. 
• Section 7.1: Updated based on new study design, added clarifications and corrected typos. 
Table 7-1 updated to extend the screening period from 14 to 21 days, and to remove height 
measurement for pediatrics, Tanner staging, to revise the time points for 
 
prophylactic therapy, ophthalmic and neurologic assessments. Table 7-2 for responders 
amended to remove visits after 24 months and for responders removed. Section numbers 
updated in both tables. These changes are considered as substantial. 
• Section 7.1.2: Screening period extended from 14 to 21 days and paragraph regarding 
bone marrow aspirate and biopsy removed and referenced to section 7.2.2.7. These 
changes are considered non-substantial. 
• Section 7.1.2.3: Clarification added that transfusion history should be collected within 4 
weeks prior to first dosing. This change is considered non-substantial. 
• Section 7.1.4: Updated duration for cyclosporine treatment according to new study 
duration. This change is considered non-substantial. 
• Section 7.1.5: Clarifications added on discontinuation of study treatment. These changes 
are considered non-substantial. 
• Section 7.1.5.1: Replacement policy revised. This change is considered non-substantial.  
• Section 7.1.6: Corrected typo. This change is considered non-substantial. 
• Section 7.1.7: Corrected typos and added clarifications. These changes are considered 
non-substantial. 
• Section 7.2.1: Added clarifications on transfusion restriction. These changes are 
considered non-substantial. 








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Protocol summary: 
Title 
SOAR, Interventional phase II single-arm study to assess efficacy and safety of 
Eltrombopag combined with cyclosporine as first line therapy in adult patients with 
severe acquired aplastic anemia 
Brief title 
SOAR: Eltrombopag combined with cyclosporine as first line therapy in adult patients 
with severe acquired aplastic anemia 
Sponsor and 
Clinical Phase 
Novartis 
With marketed products study in new indication is phase 2 (exploratory) 
Investigation type 
Drug 
Study type 
Interventional 
Purpose and 
rationale 
This interventional Phase II, single-arm, multicenter, open-label study will investigate the 
efficacy and safety of a combination regimen of 6 months eltrombopag and cyclosporine 
treatment in adult patients with severe aplastic anemia (SAA) as first line therapy, with 
an additional 18 months follow-up for cyclosporine tapering and duration of response 
until relapse or 24 months whichever is earlier (responders only who do not relapse prior 
to 6 months). 
This study will address the unmet medical need for first-line treatment of SAA in 
countries where horse-ATG is not available or where patients are not able to tolerate h-
ATG. The usage of eltrombopag and cyclosporine combines two therapies with different 
modes of action. Cyclosporine acts as an immunosuppressant and eltrombopag acts as 
a stimulator of bone marrow progenitor cells. Given that SAA is currently viewed as 
having an autoimmune pathogenesis resulting in bone marrow progenitor cell 
destruction, the combination of eltrombopag and cyclosporine is supported by the 
synergistic mechanism of actions. 
Primary 
Objective(s) and  
To evaluate the efficacy of eltrombopag + cyclosporine as first-line therapy on overall 
hematologic response (partial and complete response) by 6 months 
Secondary 
Objectives 
Objective 1: Evaluate the effect of eltrombopag + cyclosporine on overall hematologic 
response (partial and complete response) by 3 and at 12 months 
The following secondary objectives will be assessed by 6 months (all patients) and 
24 months (responders only) as appropriate and will be reported in a cumulative basis 
Objective 2: To evaluate the duration of hematologic response 
Objective 3: To evaluate the proportion of patients who relapseObjective 4: To evaluate 
the clonal evolution to myelodysplasia, paroxysmal nocturnal hemoglobinuria (PNH), and 
leukemia 
Objective 5: To evaluate red blood cell (RBC) transfusion independence 
Objective 6: To evaluate the platelet transfusion independence 
Objective 7: To evaluate the longest interval without a platelet or RBC transfusion 
Objective 8: To evaluate the effect of eltrombopag and cyclosporine on patient 
symptoms and health related quality of life 
Objective 9: To evaluate the safety and tolerability of eltrombopag + cyclosporine 
Objective 10: To characterize the PK of eltrombopag when combined with cyclosporine 
Study design 
This is an interventional phase II, single-arm, multicenter, open-label, study to investigate 
the efficacy and safety of the combination of eltrombopag and cyclosporine in treatment-
naive, adult patients with SAA as first line therapy administered for 6 months, with an 
additional 18 months follow-up for cyclosporine tapering and duration of response until 
relapse or 24 month whichever is earlier (responders only who do not relapse prior to 6 
months). 
At 6 months, responders will discontinue eltrombopag and start to taper cyclosporine 
until 24 months. Responders who relapse prior to 6 months and non-responders will 
discontinue the treatment and study at 6 months and will be followed-up for 30 days. 
Responders who relapse prior to 24 months will discontinue cyclosporine and study, and 
will be followed-up for 30 days.    


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Responders who relapsed and non-responders already in the follow-up under the 
previous protocol version will be discontinued from the study within 30 days of the 
approval of this protocol amendment.  
Population 
All patients aged 18 years or older with treatment-naïve SAA will be considered for 
enrollment. Patients under the age of 40, who have a suitable matched sibling donor, will 
be referred for consideration of allogeneic bone marrow transplantation. Patients not 
willing or unable to undergo transplantation will be considered for enrollment. For this 
protocol, treatment-naïve is defined as not having received an anti-thymocyte globulin 
(ATG) regimen, cyclosporine, alemtuzumab, or thrombopoietin receptor (TPO-R) 
agonist. 
Inclusion criteria 
1. Patient has signed the Informed Consent (ICF) prior to any screening procedures 
being performed.  
2. Patient is male/female ≥18 years old at the time of informed consent and able to 
swallow a tablet. 
3. Patient has SAA characterized by:  
 
a. Bone marrow cellularity <30% (excluding lymphocytes) and  
 
b. At least two of the following (peripheral blood): 
 
 
● Absolute neutrophil count <500/µL 
 
 
● Platelet count <20 000/µL 
 
 
● Absolute reticulocyte count <60 000/µL (automated) 
4. Normal ECG defined as the following as determined via the mean of a triplicate ECG 
 
● Resting heart rate: 50-90 bpm 
 
● QTcF at screening <450 msec (male patients), 460 msec (female patients) 
Exclusion criteria 
1. Diagnosis of Fanconi anemia. 
2. Evidence of a clonal hematologic bone marrow disorder on cytogenetics by central 
review. 
3. Prior immunosuppressive therapy with cyclosporine, alemtuzumab, rabbit or horse 
ATG and thrombopoietin receptor (TPO-R) agonists. 
4.  a. Hypersensitivity to eltrombopag or cyclosporine or their components. 
 
b. Contraindications to cyclospsorine. 
5. AST or ALT >3 x ULN. 
6. Serum creatinine, total bilirubin, and alkaline phosphatase >1.5 x ULN. 
7. Patient with liver cirrhosis. 
8. a. Infection not adequately controlled with appropriate therapy. 
b. Patients who are human immune deficiency virus (HIV), hepatitis C virus or hepatitis B 
surface antigen (HBsAg) positive. HCV-RNA negative patients are allowed to be 
enrolled.  
9. Moribund status or concurrent hepatic, renal, cardiac, neurologic, pulmonary, 
infectious, or metabolic disease of such severity that it would preclude the patient’s 
ability to consent, be compliant with study procedures, tolerate protocol therapy, or 
patients with less than 3 months of life expectancy. 
10. Patients with cancer who are not considered cure, are on active chemotherapeutic 
treatment or who take drugs with hematological effects. 
11. Administration of an investigational drug within 30 days or 5 half-lives, whichever is 
longer, preceding the first dose of study treatment. 
12. Pregnancy statements and contraception requirements:  
Pregnancy or nursing (lactating) women 
Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant (or female partners of male patients), unless they are using highly 
effective methods of contraception during dosing and for 3 months after stopping 
medication. Highly effective contraception methods include: 
● Total abstinence (when this is in line with the preferred and usual lifestyle of the 
patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation 
methods) and withdrawal are not acceptable methods of contraception 
● Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy), total hysterectomy, or tubal ligation at least six weeks before taking study 
treatment. In case of oophorectomy alone, only when the reproductive status of the 


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woman has been confirmed by follow up hormone level assessment 
 ● Male sterilization (at least 6 months prior to screening). The vasectomized male 
partner should be the sole partner for that patient 
● Use of oral, injected or implanted hormonal methods of contraception or placement of 
an intrauterine device (IUD) or intrauterine system (IUS), or other forms of hormonal 
contraception that have comparable efficacy (failure rate <1%), for example hormone 
vaginal ring or transdermal hormone contraception. 
● Sexually active males unless they use a condom during intercourse while taking the 
drug during treatment and for 3 months after stopping treatment and should not father a 
child in this period. A condom is required to be used also by vasectomized men as well 
as during intercourse with a male partner in order to prevent delivery of the drug via 
semen. 
In case of use of oral contraception women should have been stable on the same 
contraceptive pill for a minimum of 3 months before taking study treatment. 
13. Not able to understand the investigation nature of the study or to give informed 
consent. 
14. Clinically significant ECG abnormality including cardiac arrhythmias (e. g. ventricular 
tachycardia) complete left bundle branch block, high grade atrioventricular block, or 
inability to determine the QTcF interval on the ECG. 
15. Presence of cardiac disease, or family history of idiopathic sudden death or 
congenital long QT syndrome. 
16. Risk factors for Torsades de Pointe including uncorrected hypokalemia or 
hypomagnesemia, or use of concomitant medication(s) with a known risk to prolong the 
QT interval that cannot be discontinued or replaced by safe alternative medication per 
qtdrugs.org. 
17. ECOG performance status of ≥2.18. Patients under the age of 40 must be referred 
for consideration of allogeneic bone marrow transplantation (HSCT) if (human leukocyte 
antigen) HLA matching has been done and a suitable matched sibling donor is available 
and the patient is willing to undergo transplantation (i.e. patients who do not have a HLA 
match or are not medically fit, not willing or unable to undergo transplantation will be 
considered for enrollment). 
Investigational 
and reference 
therapy 
Eltrombopag film coated tablets 
Cyclosporine capsules 
Efficacy 
assessments 
● Neutrophil count 
● Reticulocyte count 
● Platelet count 
● Hemoglobin 
● Use of immunosuppressive therapy 
● Use of platelet transfusions 
● Use of red blood cell transfusions 
● Bone marrow biopsy 
Safety 
assessments 
● Cyclosporine levels 
● Flow cytometry of peripheral blood for GPI-cells 
● Adverse events 
● ECG 
● Bone Marrow for clonal evolution 
Other 
assessments 
● Full PK profile over 8 hours at 2 weeks and trough samples at 1 month, 2 months, 
3 months, and 6 months 
Data analysis 
50 patients will be enrolled in the study.  
Data will be analyzed at two important time points 6 and 24 months:  
● The primary analysis will be done on all the patients enrolled who have completed 
6 months or discontinued prior to 6 months. 
● The final analysis will be done on the responders who have completed 24 months or 


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discontinued the study prior to 24 months on the cumulative data obtained (where 
applicable). 
The primary objective of the study is to evaluate the combination of eltrombopag + 
cyclosporine as first-line therapy as assessed by the overall hematologic response rate 
by 6 months. Bayesian approach will be used for analysis of the primary endpoint. The 
primary analysis will be based on the calculation of observed overall hematologic 
response rate by 6 months and its posterior distribution using a beta-binomial model. 
Combination therapy of eltrombopag + cyclosporine will be declared efficacious if the 
following criteria are met:  
 
a. Observed hematologic ORR ≥ “clinically meaningful” threshold (30%) 
 
b. Probability of true ORR “not being clinically meaningful (response ≤ 20%) is less 
than 10%.  
Criteria a) and b) are based on available historical data. Therefore, a 30% Overall 
Response Rate (ORR) is considered as a clinically meaningful response rate and any 
response rate of ≤ 20% is considered not clinically meaningful. 
Both criteria a) and b) will be fulfilled if at least 15 responders out of 50 treated patients 
are observed.  
The primary endpoint will be estimated using the sample proportion, and a 95% 
confidence interval will be provided using Clopper and Pearson exact method. 
Descriptive statistics (n, mean, standard deviation, median, minimum, and maximum) will 
be used to summarize continuous variables and frequency counts and percentages will 
be provided for categorical variables. 
Time to event endpoints will be analyzed using the Kaplan-Meier method where 
appropriate. 
Key words 
Severe aplastic anemia, eltrombopag, cyclosporine 




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activity on hematopoietic progenitor and stem cells, can induce overexpression of Fas on target 
cells (Young 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 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 (de Latour 2010, Solomou 2006, Solomou 2007, Scheinberg 2013, Kordasti 2012, Kook 
2002, Risitano 2004, Tang 2010, Young 1997). 
Symptoms in SAA derive from low blood counts. Anemia leads to fatigue, weakness, lassitude, 
headaches, and in older patients, dyspnea and chest pain. These manifestations are most 
commonly responsible for the clinical presentation. Thrombocytopenia produces mucosal 
bleeding: petechiae of the skin and mucous membranes, epistaxis, and gum bleeding are 
frequent and early complaints. Bleeding can be a risk in the presence of accompanying physical 
lesions; i.e. gastritis and fungal infections of the lungs. The most feared complication of 
thrombocytopenia is intracranial hemorrhage. Bacterial and fungal infections in the setting of 
neutropenia are a major cause of morbidity and mortality, and are most often the cause of death 
in refractory cytopenias. 
Historically, SAA was almost always a fatal diagnosis due to infection or hemorrhage resulting 
from prolonged pancytopenia. Allogeneic hematopoietic stem cell transplant (HSCT) offers the 
opportunity for cure in 70% of patients, but most patients are not suitable candidates for this 
treatment modality due to advanced age, comorbidities, or lack of a histocompatible donor. 
Additionally, HSCT can only be offered in centers with expertise in this treatment and is costly. 
Alternative donor transplantation (matched unrelated donors) can be effective in select patients 
with SAA (Socie 2013), but there are issues of donor availability, cost, and treatment-related 
morbidity and mortality. To date, outcomes following umbilical cord transplant have been 
extremely poor in patients with bone marrow failure syndromes. Cord and haploidentical 
transplants are not recommended outside of clinical studies (Marsh 2013). 
Despite its often acute presentation, aplastic anemia is now recognized as a chronic disease with 
frequent flares of the immune process and the need for long-term immunosuppression. There is 
evidence that depletion of primitive hematopoietic stem and progenitor cells is profound, 
demonstrating that immune attack against the most primitive stem cells is paramount. Even with 
recovery of blood counts following successful immunosuppressive therapy, a significant 
quantitative stem cell defect persists, suggesting either ongoing immune destruction or 
persistent depletion of stem cells even in the absence of an active immune process. 
Outcomes in patients with SAA have improved dramatically due to definitive treatment with 
either intensive immunosuppressive therapy (IST) with anti-thymocyte globulin and 
cyclosporine (ATG/ cyclosporine), or HSCT. Due to the hematologic responses observed with 
these treatments, 12 months survival rates for patients with SAA improved from 10% to 80- 90% 
at 1-2 years after diagnosis (Rosenfeld 2003, Scheinberg 2011, Valdez 2011). However, 
approximately one-third of patient do not show blood count improvement after 


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ATG/cyclosporine and are considered to have refractory disease. Furthermore, poor blood count 
responses to a single course of ATG (non-robust responders), even when transfusion-
independence is achieved, predicts a markedly worse prognosis compared to those who achieve 
a robust hematologic improvement (Rosenfeld 2003, Young 2006). The standard IST regimen 
is horse antithymocyte globulin (h-ATG) and cyclosporine, which was established 25 years ago 
when h-ATG/ cyclosporine was compared to cyclosporine alone (Frickhofen 1991). 
Most of the experience of rabbit ATG in SAA has been in patients who are refractory to initial 
h-ATG (response of about 30%) and in relapsed SAA (response of about 60%). A randomized 
study comparing horse and rabbit ATG as first line therapy showed inferior outcomes with the 
latter resulting in worst hematologic response rates and survival (Scheinberg 2006, Scheinberg 
2012). A prospective study from EU has comparing h-ATG and r-ATG and the best total 
response rate was 67% versus 60% respectively (Marsh 2012). 
One of the most important advances in SAA treatment in the past few decades has been the 
thrombopoietin receptor agonist eltrombopag, which has shown activity in SAA. Eltrombopag 
was studied in a single-arm, single-centre open-label study in 43 patients with severe aplastic 
anaemia with refractory thrombocytopenia following at least one prior immunosuppressive 
therapy (IST) and who had a platelet count ≤ 30,000/µl. The haematological response rate was 
40% (17/43 patients; 95% CI 25, 56), the majority were unilineage responses (13/17, 76%) 
whilst there were 3 bilineage and 1 trilineage responses at week 12 (Desmond 2014, Olnes 
2012).  
Given its activity in the refractory setting, eltrombopag is being investigated as upfront therapy 
with h-ATG/ cyclosporine in an ongoing non-randomized, single-center, single-arm pilot phase 
I/II study (ETB115AUS01T) in the US (Townsley 2017). This study is investigating the 
standard IST regimen of h-ATG + CsA, in combination with eltrombopag in treatment-naive 
SAA patients and is sponsored by the National Heart, Lung and Blood Institute (NHLBI) 
Division of Intramural Research Program. It is conducted under a Cooperative Research and 
Development Agreement (CRADA) with Novartis. The patients were enrolled sequentially in 
4 consecutive cohorts: Cohort 1, 2, 3, and the Extension Cohort. The cohorts differed only by 
the starting day of eltrombopag, the duration of eltrombopag, and by the addition of a CsA 
maintenance regimen. The results of Cohort 3 and Extension in which treatment regimen has 
eltrombopag from day 1 to 6 months, starting concurrently in combination with h-ATG and 
CsA showed the highest rate of improvement in hematological parameters with CR rate of 
43.7%, which was 27% higher than the complete response rate historically observed with the 
standard IST alone; and the overall response rate of 79.3% (95% CI 69, 87) at 6 months. Based 
on these results, on 16-Nov-2018, the FDA approved eltrombopag in combination with standard 
immunosuppressive therapy for the first-line treatment of adult and pediatric patients 2 years 
and older with SAA. 
Despite significant improvements in standard supportive care treatments (particularly 
antifungal antimicrobials and other antibiotics), approximately 40% of IST-refractory SAA 
patients die of bleeding or infection within 5 years of diagnosis (Valdez 2011). 


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Therefore new therapeutic options are urgently needed for both newly diagnosed patients as 
well as for patients who have an insufficient response to IST or who relapse following IST. 
1.2 
Introduction to investigational treatment(s) and other study 
treatment(s) 
1.2.1 
Overview of eltrombopag olamine (Promacta® – Revolade®) 
Thrombopoietin, also known as Megakaryocyte Growth and Development Factor (MGDF) and 
the ligand for the cellular myeloproliferative leukemia proto-oncogene 9c-mpl) is the principal 
cytokine involved in the regulation of megakaryopoiesis and platelet production. Native TPO 
is a 60-70 kDa heavily glycosylated polypeptide of 332 amino acids produced by the liver 
parenchymal, bone marrow and sinusoidal epithelial kidney cells (Geddis 2002). 
Eltrombopag olamine (ETB115), the bis-monoethanolamine salt form of eltrombopag, is an 
orally bioavailable small molecule TPO-R agonist. Eltrombopag interacts with the 
transmembrane domain of the TPO-R (also known as C-MPL) leading to increased platelet 
production. 
Eltrombopag has been approved for the treatment of adult patients with chronic immune 
thrombocytopenic purpura (ITP) in over 90 countries worldwide. Eltrombopag is also approved 
for pediatric patients aged 1 year and older with chronic ITP with insufficient response to 
corticosteroids or immunoglobulins. This approval was supported by efficacy and safety data 
from two clinical studies (PETIT and PETIT2) investigating efficacy and safety of eltrombopag 
in pediatric patients with previously treated chronic ITP. Both studies were randomized, double-
blind, placebo-controlled studies (Bussel 2013, Grainger 2015, Bussell 2015). 
Eltrombopag is also approved for the treatment of adult patients with hepatitis C virus (HCV)-
related thrombocytopenia in over 45 countries worldwide. 
Recently, eltrombopag has also been approved for the treatment of adult patients with SAA who 
have had insufficient responses to IST. Dose adjustments are based upon the platelet count. 
Hematologic response requires dose titration, generally up to 150 mg daily, and may take up to 
16 weeks after starting treatment (US PI, EU SmPc).  
1.2.1.1 
Non-clinical experience 
1.2.1.1.1 Non-clinical pharmacology 
Eltrombopag interacts with the transmembrane domain of the TPO-R on megakaryocytes and 
human bone marrow progenitor cells (Erickson-Miller 2010, Sun 2012). Eltrombopag increases 
hematopoiesis by inducing proliferation and differentiation of early bone marrow progenitor 
cells in a manner similar to endogenous TPO (Jenkins 2007, Erickson-Miller 2009, Jeong 
2010). 
TPO-R is expressed on the surface of hematopoietic stem cells (HSCs), as well as on cells of 
the megakaryocytic lineages. TPO-R is reported to be essential for the maintenance of normal 
hematopoiesis (Ballmaier 2003); and several preclinical experiments have demonstrated a 


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necessary and positive influence of TPO and the TPO-R on expansion of HSC (Zeigler 1994, 
Alexander 1996, Kimura 1998, Qian 2007). Eltrombopag also induces expansion of the early 
progenitor cells, resulting in an increased number of cells of multiple lineages (Sun 2012). Since 
eltrombopag 
is 
capable 
of 
activating 
parts 
of 
the 
cMpl 
signaling 
pathway 
(growth/differentiation factor), there was a theoretical concerns that it could stimulate the 
proliferation and differentiation of leukemic cells. However, in several preclinical studies of 
cell lines of myelodysplastic syndrome/acute myeloid leukemia, it was demonstrated that 
eltrombopag given at high concentrations inhibited the proliferation of leukemic cells (Kalota 
2010, Erickson-Miller 2009). This mechanism was characterized as a non-TPO-R-dependent 
pathway (Roth 2012). It has also been noted that eltrombopag displays trilineage hematopoietic 
effects and this may offer benefit to patients with complete bone marrow failure (e.g., SAA) 
(Olnes 2012, Desmond 2014). 
The ability of eltrombopag to interact with TPO-R in a non-competitive and additive way with 
TPO (Erickson-Miller 2009) may suggest an additional mechanism for affecting a multi-lineage 
response from HSCs. Eltrombopag has demonstrated such effects on HSC in preclinical 
research (Sun 2012). In aplastic anemia, eltrombopag may exert effects not only on 
megakaryocytes and their precursors, but also on erythroid and granulocyte lineages through 
stimulation of HSCs.  
1.2.1.1.2 Non-clinical pharmacokinetics and metabolism 
Absorption, distribution, metabolism and elimination (ADME) of eltrombopag have been 
investigated in mice, rats and dogs, the species used for the toxicity evaluation of eltrombopag. 
Oral bioavailability of eltrombopag (parent compound) as a solution was low in the rat (26%) 
and high in dog (83%) and in monkey (89%). Eltrombopag is highly bound to plasma proteins 
in mouse, rat, dog, monkey and human (>99.9%). The plasma protein binding of eltrombopag 
to human serum albumin (HSA) was greater than to human alpha-1-acid glycoprotein (AAG). 
Eltrombopag is primarily eliminated in feces as the intact moiety in nonclinical species. Minor 
metabolites derived from glucuronidation or oxidation were also detected in mouse, rat and dog 
bile. The predominant route of elimination of drug-related materials was via feces (73% to 
97%), with urinary excretion representing a minor route of elimination (1.5% to 14%). In vitro, 
eltrombopag was shown to be an inhibitor of cytochrome P450 (CYP)2C8, CYP2C9, of several 
uridine diphosphate glucuronosyltransferases (UGT), of organic anion-transporting polypeptide 
(OATP)1B1 and of breast cancer resistance protein (BCRP). In vitro studies demonstrated that 
eltrombopag was neither an inhibitor nor a substrate of human P-glycoprotein (Pgp). 
Additional details on eltrombopag non-clinical pharmacokinetics (PK) can be found in the 
eltrombopag Investigator’s Brochure (IB). 
1.2.1.1.3 Non-clinical safety data 
Eltrombopag has undergone a comprehensive non-clinical evaluation to support its safe use in 
adult and pediatric patients. This evaluation includes repeat dose toxicity studies of up to 13 
weeks in mice, 28 weeks in rats and 52 weeks in dogs. The toxic potential of eltrombopag was 
also assessed in a battery of in vitro and in vivo genetic toxicology studies, carcinogenicity 


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studies in mice and rats, developmental and reproductive toxicology studies in rats and rabbits 
and immunotoxicity in rats and juvenile toxicity studies (dosing initiated on Day 4 post-partum) 
in rats. The principal non-clinical toxicology findings associated with eltrombopag treatment 
include cataracts (mice and rats), renal tubular toxicity (mice and rats) and hepatotoxicity (mice, 
rats and dogs). At non-tolerated doses, endosteal hyperostosis (femur and tibia) was observed 
in rats and effects on erythroid parameters (bone marrow erythroid hyperplasia in rats and 
decreased reticulocyte counts in rats and dogs) were observed. While eltrombopag was 
phototoxic in vitro, no in vivo phototoxicity was observed following single or repeated dosing 
in rats or mice. 
Additional details of preclinical pharmacology, pharmacokinetics and toxicology can be found 
in the eltrombopag Investigator’s Brochure.  
1.2.1.2 
Clinical experience 
Eltrombopag clinical development program has involved adult patients with SAA, chronic ITP, 
HCV infection, chronic liver disease, myelodysplastic syndrome, acute myeloid leukemia and 
solid tumors. Eltrombopag was also investigated in the pediatric population. Two studies were 
designed for pediatric patients 1 to 17 years of age with chronic immune thrombocytopenia 
(PETIT and PETIT2). Two ongoing studies are investigating eltrombopag in pediatric patients 
with SAA: ETB115E2201ETB11E2201 (patients from 1 to <18 years) and ETB115AUS01T 
(adult and pediatric patients 2 years and above).  
1.2.1.2.1 Overview of efficacy 
The efficacy of eltrombopag in SAA was investigated in several Novartis-sponsored and 
investigator-initiated studies as listed in Table 1-1. 
Table 1-1 
Overview of clinical experience in severe aplastic anemia (Jan2019) 
Study 
Population 
enrolled/ planned 
Study design 
Primary endpoint 
Study 
status 
NIH 09-H-
0154/ GSK 
ELT112523/ 
ETB115AUS2
8T 
Heavily pretreated 
SAA N=44/44 
Phase II, non-
randomized, open-label, 
study in patients with 
SAA who had persistent 
thrombocytopenia after 
IST 
Hematologic response at 3 
months 
Completed 
with final 
CSR 
NIH 13-H-
0133/ GSK 
ELT116826/ 
ETB115AUS1
8T 
Heavily pretreated 
SAA N=40/60 
Phase II study in patients 
with refractory aplastic 
anemia  
Hematologic response at 6 
months 
Ongoing 
NIH 12-H-
0150/ GSK 
ELT116643/E
TB115AUS01
T 
 
First line SAA 
treatment-naïve 
SAA patients 2 
years and 
above  N=154/154 
Eltrombopag added to 
standard 
immunosuppression in 
treatment-naïve SAA 
patients age 2 and above 
Pilot, phase I/II, single-
arm, open-label study 
Complete hematologic 
response at 6 months 
Ongoing  
Primary 
CSR 
completed 


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Study 
Population 
enrolled/ planned 
Study design 
Primary endpoint 
Study 
status 
h-ATG/ cyclosporine + 
eltrombopag 150 mg/day 
ETB115E120
1 (Japanese 
study) 
Refractory 
Moderate or more 
Severe Aplastic 
Anemia (2nd line) 
N=21/20 
Phase II, non-
randomized, open-label 
study to assess the 
safety and efficacy of 
eltrombopag in Japanese 
patients with refractory, 
moderate or more SAA 
 
Eltrombopag 
Dosage: starting dose 
25mg, max 100mg, dose 
escalation based on 
individual platelet counts 
Hematologic response at 6 
months (defined as proportion 
of patients who met any 
criteria of erythroid, platelet or 
neutrophil response) 
Completed 
with final 
CSR 
ETB115E120
2 (Japanese 
study) 
Moderate or Severe 
Aplastic Anemia (1st 
line) 
N=10/10 
Phase II, study  
Eltrombopag in 
combination with rATG / 
CsA in patients with 
moderate or severe 
aplastic anemia who 
have not received prior 
ATG/anti-lymphocyte 
globulin (ALG) treatment 
Overall response rate at 6 
months (CR plus PR) 
Completed 
with final 
CSR 
CETB115E22
01 (Pediatric 
study) 
Relapsed/refractory 
SAA or treatment 
naive SAA or 
recurrent AA 
patients age 1 to 
<18 years 
N=60 
Phase II 
Dosage: 25-150 mg/kg 
Eltrombopag + hATG + 
cyclosporine  
Eltrombopag + 
cyclosporine  
Characterize the PK of 
eltrombopag after oral 
administration in pediatric 
patients with SAA 
Ongoing 
The ETB115AUS28T and ETB115AUS18T studies were the pivotal and supportive studies, 
respectively, that were the basis for the refractory SAA indication which evaluated eltrombopag 
monotherapy in treatment-refractory patients with SAA. 
The phase II study ETB115AUS28T in which eltrombopag was administered to patients with 
SAA that were refractory to IST, demonstrated clinically significant hematologic responses 
with minimal toxic effects (Olnes et al 2012, Desmond et al 2014). Efficacy results for the entire 
cohort of 43 patients (1 patient excluded), demonstrated an overall response rate (ORR) of 40% 
(17 of 43 patients), including tri- and bilineage responses. Of the 14 patients who entered the 
extension, 7 had improvement in more than one lineage following continuation of treatment. 5 
patients had maintained trilineage hematopoiesis since discontinuing eltrombopag treatment 
(median follow-up 20.6 months; range 5.7 to 22.5 months) (Desmond et al 2014). Based on 
these results, in Aug-2014, the FDA granted approval for the use of eltrombopag in patients 
with SAA who had insufficient response to IST. In Aug-2015, the European Medicines Agency 
(EMA) approved the use of eltrombopag in patients with SAA who are refractory to IST or 
heavily pretreated and not suitable for HSC transplant. 


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The ETB115AUS01T study was the pivotal study and the studies ETB115E1201 and 
ETB115E1202 were the supportive studies that were the basis for the first line SAA indication.  
The ETB115AUS01T study is an ongoing non-randomized, single-center, single-arm pilot 
phase I/II (ETB115AUS01T) study in the US, investigating the standard 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 results of this study is described in section 1.1 which 
provided the basis of the FDA approval (on 16-Nov-2018) for eltrombopag in combination with 
standard immunosuppressive therapy for the first-line treatment of adult and pediatric patients 
2 years and older with SAA.Given its activity in the refractory setting, eltrombopag is being 
investigated as upfront therapy with h-ATG/ cyclosporine in an ongoing non-randomized, 
single-center, single-arm pilot phase I/II study (ETB115AUS01T) in the US (Townsley 2017), 
investigating the standard IST regimen of h-ATG + CsA, in combination with eltrombopag as 
experimental therapy in patients  with SAA who have not received prior definitive IST. 
ETB115AUS01T study is sponsored by the National Heart, Lung and Blood Institute (NHLBI) 
Division of Intramural Research Program and conducted under a Cooperative Research and 
Development Agreement (CRADA) with Novartis.  
The patients were enrolled sequentially in 4 consecutive cohorts: Cohort 1, 2, 3, and the 
Extension Cohort. The cohorts differed only by the starting day of eltrombopag, the duration of 
eltrombopag, and by the addition of a CsA maintenance regimen. The results of Cohort 3 and 
Extension in which treatment regimen has eltrombopag from day 1 to 6 months, starting 
concurrently in combination with h-ATG and CsA showed the highest rate of improvement in 
hematological parameters with CR rate of 43.7%, which was 27% higher than the complete 
response rate historically observed with the standard IST alone; and the overall response rate of 
79.3% (95% CI 69, 87) at 6 months. Based on these results, on 16-Nov-2018, the FDA approved 
eltrombopag in combination with standard immunosuppressive therapy for the first-line 
treatment of adult and pediatric patients 2 years and older with SAA (ETB115AUS01T_Safety 
and Efficacy Update; data cut-off 28-Feb-2018). 
The ETB115E1201 study was a non-randomized, open-label, phase II study to assess the 
efficacy and safety of eltrombopag monotherapy in MAA or SAA patients with a platelet count 
<30,000/μL who were refractory to ATG-based IST, who had relapsed after ATG-based IST, 
or who were ineligible for ATG-based IST. Twenty-one patients were enrolled. Eltrombopag 
was administered at a maximum dose of 100 mg per day, adjusted to account for differences of 
exposure in Asian patients (ethnic sensitivity). Ten patients (47.6%; 95%CI, 25.7 – 70.2) have 
met the hematological response criteria at Week 26. Of these 10 patients, 40% (4/10) had uni-
lineage response, 50% (5/10) had bi-lineage response and 10% (1/10) had tri-lineage response. 
No new safety issues were identified. The AEs observed were as expected for this patient 
population and as seen with treatment with eltrombopag (Scheinberg 2018).  
The ETB115E1202 study was a non-randomized, open label, single-arm, phase II study to 
evaluate the efficacy and safety of eltrombopag in combination with r-ATG and CsA in 
Japanese patients with MAA or SAA who had not received prior ATG/ALG-based IST. Ten 
patients were enrolled. Eltrombopag 75 mg/day was started on Day 15 (±3 days) and decreased 
by 25 mg every 2 weeks thereafter according to the platelet count until Week 26 following r-


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ATG/ CsA. The starting dose of 75 mg/day was chosen considering the known pharmacokinetic 
characteristics of eltrombopag in patients of Asian ethnicity. The ORR at Week 26, the primary 
efficacy endpoint, was 70.0% (7 of 10). The ORR at Week 52 was 60.0% (6 of 10). All 
responses in 6 patients were PRs. The median duration of response at Week 52 assessment was 
8.31 months. Of 7 responders who achieved PR before Week 26 assessment, 6 maintained their 
response until Week 52 assessment despite interruption of eltrombopag after entering the 
Extension part according to the dose adjustment criteria. The remaining 1 responder interrupted 
eltrombopag before Week 26 assessment according to the dose adjustment criteria. While the 
dose of eltrombopag was resumed and increased in the Extension part, the patient had a relapse 
on Day 309 and discontinued eltrombopag on Day 355. No new safety issues were identified. 
The AEs observed were as expected for this patient population (ETB115E1202 CSR; data cut-
off 6-Jan-2017). 
1.2.1.2.2 Overview of Safety 
As of September 2018, an estimated 96,357 patient years of eltrombopag treatment has been 
prescribed worldwide since its initial approval in the United States in 2008. Additionally, an 
estimated 4,456 patients have been exposed to eltrombopag in sponsored, ongoing and 
completed interventional studies in patients with ITP, liver diseases, hematology- oncology 
related thrombocytopenia and healthy volunteers. The dose explored in human patients ranged 
from 5 mg to 300 mg /day.Refer to the eltrombopag Investigator’s Brochure for additional 
details.  
Eltrombopag safety in SAA population  
The primary safety database for the refractory SAA population was from the pivotal study 
ETB115AUS28T. Patients received eltrombopag once daily with a starting dose of 50 mg (25 
mg for Asian patients), which was increased by 25 mg daily every 2 weeks based on platelet 
counts to a maximum of 150 mg (75 mg for EA patients) daily in nearly all patients.  
The study reported a favorable toxicity profile of eltrombopag, similar to the ITP studies despite 
higher doses of eltrombopag (150 mg vs. 75 mg). A 6 month course of eltrombopag is reported 
as safe in refractory SAA, a longer course of eltrombopag therapy has not been studied front 
line. Two patients out of 43 who received at least one dose of eltrombopag had reversible 
transaminitis related to drug; both required dose interruption. One patient was maintained on 
75 mg with a sustained response. Liver function abnormalities in the other patient returned to 
baseline after stopping drug for 4 days, and he tolerated reinstitution at 150 mg. No significant 
increase in bone marrow fibrosis was reported after a median follow-up of 13 months (range, 
3-51 months) with biopsies performed every 6 months. No thrombotic events were reported 
during eltrombopag therapy. One patient experienced deep venous thrombosis of lower 
extremity 14 months after eltrombopag had been discontinued, with a platelet count of 60x109/L 
and normal hemoglobin and neutrophil levels (Desmond 2014).  
In the ETB115AUS01T study the most common AEs were febrile neutropenia, known to occur 
in subjects with the underlying disease SAA, ALT and AST increased, known to occur with 
eltrombopag, CsA, and h-ATG, blood bilirubin increased known to occur with CsA and 


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eltrombopag, and serum sickness known to occur with h-ATG. The hepatobiliary events were 
reported more commonly in combined Cohort 3 + Extension Cohort. There were no new 
hepatotoxicity signals from the study. Most of the AEs requiring dose interruption/adjustment 
were increased ALT and AST, however none led to discontinuation. The overall safety profile 
of eltrombopag at doses up to 150 mg daily is consistent with the expected safety profile for 
subjects with SAA and the established safety profile of eltrombopag in the approved chronic 
ITP, HCV and refractory SAAindications. No new or unexpected safety signals were observed 
that were not already listed in the prescribing information for h-ATG, CsA or eltrombopag 
(ETB115AUS01T_Safety and Efficacy Update; data cut-off 28-Feb-2018). 
In the ETB115AUS01T study the most common AEs were febrile neutropenia, known to occur 
in subjects with the underlying disease SAA, ALT and AST increased, known to occur with 
eltrombopag, CsA, and h-ATG, blood bilirubin increased known to occur with CsA and 
eltrombopag, and serum sickness known to occur with h-ATG. The hepatobiliary events were 
reported more commonly in combined Cohort 3 + Extension Cohort. There were no new 
hepatotoxicity signals from the study. Most of the AEs requiring dose interruption/adjustment 
were increased ALT and AST, however none led to discontinuation. The overall safety profile 
of eltrombopag at doses up to 150 mg daily in Study AUS01T is consistent with the expected 
safety profile for subjects with SAA and the established safety profile of eltrombopag in the 
approved chronic ITP, HCV and refractory SAAindications. No new or unexpected safety 
signals were observed that were not already listed in the prescribing information for h-ATG, 
CsA or eltrombopag (ETB115AUS01T_Safety and Efficacy Update; data cut-off 28-Feb-2018 
). 
Eltrombopag safety in pediatric patients  
The safety, tolerability, and PK of eltrombopag in previously treated pediatric patients with 
chronic ITP were investigated (Grainger 2015, Bussel 2015). The most common AEs reported 
in the eltrombopag group (≥10% of patients) were headache, upper respiratory tract infection, 
and nasopharyngitis, with the latter 2 being reported in a higher proportion of patients when 
compared to the placebo group. A higher proportion of patients in the placebo group reported 
SAEs compared with the eltrombopag group. With the exception of epistaxis, reported by 2 
patients in the placebo group, there were no SAEs that were reported by more than 1 patient in 
either treatment group. There were no SAEs common to both treatment groups. There were 2 
patients with SAEs that led to discontinuation of study treatment; 1 patient in the eltrombopag 
group with separate SAEs of AST abnormal and ALT abnormal, and 1 patient in the placebo 
group with hemorrhage. There were no fatal SAEs.  
The use of eltrombopag in pediatric patients with SAA is currently being studied in studies 
ETB115AUS01T and CETB115E2201. 
In the ETB115AUS01T study, the AEs reported in pediatric patients were consistent with those 
reported in adult patients, with the exception of a higher incidence of febrile neutropenia and 
upper respiratory tract infection. None resulted in discontinuation (ETB115AUS01T_Safety 
and Efficacy Update; data cut-off 28-Feb-2018; section 2.5.2.8). 


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1.2.1.2.3 Events of Special Interest in Patients with Severe Aplastic Anemia 
Hepatobiliary Events 
Eltrombopag is metabolized in the liver and liver enzyme elevations have been reported in 
patients receiving eltrombopag. Furthermore, eltrombopag is known to inhibit UGT1A1, the 
enzyme responsible for glucuronidation of bilirubin in humans and OATP1B1, a hepatic 
transporter of bilirubin. Therefore, eltrombopag-mediated inhibition of OATP1B1 may 
contribute to elevation of indirect bilirubin (Campbell 2004, Cui 2001). 
In study ETB115AUS28T, hepatobiliary AEs were reported for 16 patients. Thirteen patients 
had no changes to eltrombopag dosing; 2 patients had treatment interrupted due to elevated liver 
function tests and 1 patient discontinued treatment due abnormal LFT and subsequently 
diagnosed with acute hepatitis B. Eleven of the 16 patients had a maximum laboratory toxicity 
grade of Grade 1 (5 patients) or Grade 2 (6 patients). Four patients had a laboratory toxicity 
grade 3 reported during the study. One additional patient had grade 3 AE of elevated ALT and 
AST reported. Seven of the 13 patients with laboratory toxicity grades 1 or 2 and all 4 patients 
with grade 3 elevation had prior history of transaminase elevations or elevations at baseline. 
Hepatobiliary laboratory parameters were evaluated according to the FDA Guidance for 
Industry entitled “Drug-Induced Liver Injury (DILI): Premarketing Clinical Evaluation (July 
2009)”. Based on this assessment, two patients had ALT or AST >3xULN with concurrent 
elevation in total indirect bilirubin >1.5xULN. Four patients had elevations of ALT >5xULN 
or elevations of both ALT and AST >5xULN. All 4 patients had elevations in ALT and/or AST 
at study entry. One of the 4 patients was diagnosed with acute hepatitis B during the study. Six 
patients had total bilirubin elevation >1.5xULN. In all patients, bilirubin elevations were due to 
indirect bilirubin, with direct fractions ≤25%.  
In study ETB115AUS01T increased aminotransferases (ALT and AST) and increased blood 
bilirubin were reported in 29.3%, 17.4%, and 17.4% of patients, respectively, in the combined 
Cohort 3 +Extension Cohort. Most transaminase increases and one event each of increased 
blood bilirubin and liver injury required dose interruption/ adjustment. None of the 
hepatobiliary events led to therapy discontinuation. No LFTs or hepatobiliary events or met the 
criteria of DILI/Hy’s law. There were no new hepatotoxicity signals from the study 
(ETB115AUS01T_Safety and Efficacy Update; data cut-off 28-Feb-2018).  
In study ETB115E1201, AESIs (hepatobiliary, renal-related, bleeding, and cytogenetic 
abnormalities) were infrequent. One patient with elevated baseline aminotransferases (ALT: 81 
IU/L, AST: 75 IU/L) experienced hepatic function abnormal (grade 3) and eltrombopag was 
discontinued; the patient had ALT levels ≥ 5 × ULN at the time of treatment withdrawal. The 
event of hepatic function abnormal was suspected to be treatment-related.  
In study ETB115E1202, seven patients had hepatobiliary AEs (ALT increased, blood bilirubin 
increased, blood alkaline phosphatase increased, GGT increased, hepatic function abnormal, 
and liver injury; grade 1/2).Two patients had hepatobiliary laboratory abnormalities. None of 
these events were considered related to eltrombopag. 


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Thromboembolic Events  
In study ETB115AUS28T no patient had a thromboembolic event during treatment with 
eltrombopag. One patient had an unrelated serious AE of deep vein thrombosis which occurred 
14 months after discontinuation of treatment with eltrombopag.  
In study ETB115AUS01T, thromboembolic events were rare in all cohorts, not observed in 
Cohort 1 and only seen twice in Cohort 2 and Cohort 3 + Extension. None led to therapy 
discontinuation or to dose interruption/adjustment. Two (3%) patients (1 in Cohort 3 and 1 in 
Extension Cohort) experienced a thromboembolic event: one was a catheter-related thrombosis 
in the basilica vein and the other was a non-occlusive clot in the subclavian vein. 
In study ETB115E1202, one patient had thromboembolic AE of blood creatinine 
phosphokinase increased.  
Renal Events 
In study ETB115AUS28T, increased blood creatinine was reported as an AE for one patient. 
This patient had a history of ‘cyclosporine-induced renal dysfunction’ and hypertension and 
had Grade 2 creatinine (163.5 µmol/L) at the screening visit. No creatinine lab values shifted to 
Grade 3 or 4 during the study. 
In study ETB115AUS01T, renal events (AE of acute kidney injury) were observed in one 
patient in Cohort 2 and one patient in Extension Cohort. None led to therapy discontinuation or 
to dose interruption/adjustment (ETB115AUS01T_Safety and Efficacy Update; data cut-off 28-
Feb-2018). 
Bleeding Events after study drug discontinuation 
In study ETB115AUS28T, bleeding was not recorded as an event of special interest, it was 
rather captured as an adverse event. 
In study ETB115AUS01T, bleeding is a known complication of thrombocytopenia and SAA. 
The treatment emergent AESIs of bleeding were rare events that did not cluster to a specific 
type of bleeding. In Cohort 2, Cohort 3 and Cohort 3 + Extension, these events were observed 
in one patient in each cohort. Two patients had several types of hemorrhage: One patient had 
epistaxis at baseline, as well as gingival bleeding and abdominal pain. During the study, 
this patient had bleeding events of ileal hemorrhage, hematoma and lower gastrointestinal 
hemorrhage that resolved without study drugs adjustment or interruption. Another patient had a 
history of subarachnoid hemorrhage and epistaxis, as well as bruising and gum bleeding at 
baseline. During the study, this patient experienced epistaxis and conjunctival hemorrhage 
that resolved without study drugs adjustment or interruption. None of the bleeding events 
led to therapy discontinuation, dose interruption or dose adjustments (ETB115AUS01T_Safety 
and Efficacy Update; data cut-off 28-Feb-2018). 
In study ETB115E1202, three patients had bleeding AEs (hematuria, hemorrhoidal hemorrhage, 
petechiae, and subcutaneous hematoma). None of these events were considered related to 
eltrombopag.  


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Cytogenetic Abnormalities 
Cytogenetic abnormalities are a known risk in the SAA patient population and a serious 
complication of aplastic anemia is its evolution to clonal hematologic diseases such as 
myelodysplastic syndrome (MDS) and acute 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. Historically, the NIH 
has seen a 5-year evolution rate of 14-20% in SAA patients treated with immunosuppression 
alone (Scheinberg 2014). 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 2002). Clonal evolution involving chromosome 7 abnormalities is frequently 
observed in SAA, mostly in refractory patients. Patients with abnormalities of chromosome 7 
in SAA fared as poorly as in primary MDS, with a high rate of conversion to acute leukemia. 
In study ETB115AUS28T at baseline, 3 (7%) patients had cytogenetic abnormalities present. 
Of the 43 patients refractory to IST, 7 (16.2%) developed clonal cytogenetic abnormalities 
after treatment. For the 7 patients who had a cytogenetic abnormality detected during the 
study, the median time on study to a cytogenetic abnormality was 2.9 months. 
In study ETB115AUS18T with a median time of initial treatment of 10 months (6-68 months), 
of the 40 patients refractory to IST, 6 (18%) patients developed cytogenetic abnormalities 
during eltrombopag administration. The author hypothesized that due to the temporal 
relationship between clonal evolution and drug exposure it suggests that in a subgroup of 
patients, eltrombopag may promote expansion of dormant pre-existing clones with an aberrant 
karyotype (Winkler 2017). 
In study ETB115AUS01T clonal evolution had occurred in 15 of 154 (10%) patients, which is 
within the range that would be expected with immunosuppression treatment alone at 2 years 
after the initiation of treatment (Townsley 2017). It is unclear if these evolutions occurred due 
to the underlying disease, the IST and/or eltrombopag, however, it does not appear that 
eltrombopag is associated with higher frequency or earlier onset of clonal evolution 
(ETB115AUS01T_Safety and Efficacy Update; data cut-off 28-Feb-2018).  
In study ETB115E1202, one patient was detected with a cytogenetic abnormality that was not 
associated with dysplasia or an increase in bone marrow blasts; no progression to MDS was 
reported. This event was not reported as an AE by the Investigator. No AEs of malignancies or 
post-therapy thrombocytopenia was reported. 
In study ETB115E1202, three patients (all with normal karyotype at baseline) had a new 
cytogenetic abnormality detected after treatment, none of which was a hematologic malignancy. 
1.2.1.3 
Clinical Pharmacokinetics 
1.2.1.3.1 Pharmacokinetics of eltrombopag in adults 
Eltrombopag human PK in plasma has been described in healthy volunteers and in patients 
within the targeted disease indications including patients with ITP, hepatitis C virus (HCV), 
and solid tumors. Eltrombopag PK in patients with ITP or solid tumors is generally similar to 


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that observed in healthy subjects. Data in SAA patients is limited to preliminary results in 23 
SAA 
patients 
(3 
of 
them 
being 
) 
from 
study 
NIH 
12-H-0150 
(ELT116643/CETB115AUS01T) normalized to a dose of 150 mg daily. Exposure (AUCtau, 
Cmax) in these patients was 2 to 3 times higher than exposure observed in healthy volunteers 
or ITP patients, and consistent with exposure observed in HCV patients.   
In general, exposure to eltrombopag increased with increasing doses with no major deviation 
from dose-proportionality. Eltrombopag is absorbed with a peak concentration occurring 2 to 6 
hours after oral administration. Based on urinary excretion and biotransformation products 
eliminated in feces, the oral absorption of drug-related material following administration of a 
single 75-mg solution of [14C]-eltrombopag was estimated to be at least 52%. 
A standard high-fat breakfast decreased plasma eltrombopag AUCinf by approximately 59% 
and Cmax by 65% and delayed Tmax by 1 hour. The calcium content of this meal may have 
also contributed to this decrease in exposure by chelation. Co-administration of 75 mg of 
eltrombopag with a polyvalent cation-containing antacid (1.524 mg aluminum hydroxide, 1.425 
mg magnesium carbonate, and sodium alginate) to 26 healthy adult subjects decreased plasma 
eltrombopag AUCinf and Cmax by approximately 70%. 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. 
The predominant route of eltrombopag excretion is via feces (59%), and 31% of the dose is 
found in the urine. Unchanged eltrombopag in feces accounts for approximately 20% of the 
dose. Only metabolites are detected in urine. 
Eltrombopag is primarily metabolized through hydrazine cleavage. Oxidative metabolism is a 
minor pathway (21% of the dose). It is mediated through CYP1A2 and CYP2C8. 
Glucuronidation is also a minor metabolic pathway. It is mediated through UGT1A1 and 
UGT1A3. 
The plasma elimination half-life of eltrombopag is approximately 21 to 32 hours in healthy 
subjects and 26 to 35 hours in ITP patients. 
Ethnic sensitivity pooled analyses in patients with ITP, Chronic liver disease or HCV showed 
that eltrombopag apparent clearance (CL/F) was decreased by 30% to 37% in patients of Asian 
ancestry compared to non-Asian patients. 
The administration of a single dose of eltrombopag 50 mg with 200 mg cyclosporine (a BCRP 
inhibitor) decreased the mean Cmax and the mean AUCinf of eltrombopag by 25% and 18%, 
respectively. The co-administration of 600 mg cyclosporine 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 recommended when eltrombopag is co-administered with cyclosporine. Platelet count should 
be closely monitored when eltrombopag is co-administered with cyclosporine and eltrombopag 
dose may need to be increased based on these platelet counts. Although eltrombopag is unlikely 


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to cause any modification of the exposure to cyclosporine (since its metabolism is mediated by 
CYP3A4), it is recommended to regularly monitor cyclosporine levels as per the cyclosporine 
prescribing information. 
1.2.1.3.2 Pharmacokinetics of eltrombopag in pediatric patients  
The PK of eltrombopag administered once daily has been evaluated in 168 pediatric patients 
with ITP, aged 1 year and older (TRA108062/PETIT and TRA115450/PETIT2). Dose-
normalized eltrombopag exposure (Cmax and AUC) at steady state was similar between 
pediatric patients in the 12-17 years group and adult patients. Exposures in patients in the 1-5 
years and in the 6-11 years groups were similar, while both of these age groups showed higher 
exposures compared to adults. However, these increased exposures in young pediatric patients 
did not translate into any increased incidence of AEs. The overall safety profile of eltrombopag 
in previously treated pediatric patients with chronic ITP was consistent with the known safety 
profile of eltrombopag in the treatment of adult ITP regardless of the higher exposures observed 
in the 1-5 years and 6-11 years groups compared to adults and patients in the 12-17 years group. 
As it was observed in adults, pediatric ITP patients with Asian ancestry (such as Chinese, 
Japanese, Taiwanese, Korean, or Thai) had lower eltrombopag CL/F (30%) than non-Asian 
patients. Despite this difference in exposure, Asian and non-Asian patients were titrated up to 
similar final eltrombopag doses. 
Additional details on eltrombopag pharmacokinetics in pediatrics are provided in the 
eltrombopag Investigator’s Brochure. 
1.2.2 
Overview of Cyclosporine 
Cyclosporine is a cyclic polypeptide consisting of 11 amino acids. It is a potent 
immunosuppressive agent which, in animals, prolongs survival of allogeneic transplants of skin, 
heart, kidney, pancreas, bone marrow, small intestine or lung. Cyclosporine inhibits the 
development of cell-mediated reactions, including allogeneic immunity, delayed cutaneous 
hypersensitivity, experimental allergic encephalomyelitis, Freund’s adjuvant arthritis, GVHD, 
and T-cell dependent antibody production. At the cellular level cyclosporine inhibits production 
and release of lymphokines including IL-2 (T-cell growth factor). Cyclosporine appears to 
block the resting lymphocytes in the G0 or G1 phase of the cell cycle and inhibits the antigen-
triggered release of lymphokines by activated T-cells. 
Cyclosporine acts specifically and reversibly on lymphocytes. It does not depress hemopoiesis 
and has no effect on the function of phagocytic cells. Patients treated with cyclosporine are less 
prone to infection than those receiving other immunosuppressive therapy. 
Cyclosporine is indicated for the prevention of graft rejection following kidney, liver, heart, 
combined heart-lung, lung or pancreas allogeneic transplantations and for the treatment of 
transplant rejection in patients previously receiving other immunosuppressive agents. 
Cyclosporine is also indicated for the prevention of graft rejection following bone marrow 
transplantation and for the prevention of GVHD. Non-transplant indications for cyclosporine 
are treatment of active sight-threatening intermediate or posterior uveitis of non-infectious 


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etiology in patients where conventional therapy fails or causes unacceptable side effects, 
treatment of Behçet uveitis with repeated inflammatory attacks involving the retina, steroid-
dependent and steroid-resistant nephrotic syndrome in adults and children, due to glomerular 
diseases such as minimal change nephropathy, focal and segmental glomerulosclerosis or 
membranous glomerulonephritis, steroid-dependent and steroid-resistant nephrotic syndrome 
in adults and children due to glomerular diseases such as minimal change nephropathy, focal 
and segmental glomerulosclerosis or membranous glomerulonephritis, and to induce and 
maintain remissions in patients with nephrotic syndrome and to maintain steroid-induced 
remission, allowing withdrawal of steroids, treatment of severe active rheumatoid arthritis, 
treatment of severe psoriasis in patients in whom conventional therapy is inappropriate or 
ineffective and in patients with severe atopic dermatitis when systemic therapy is required. 
1.2.2.1 
Non-clinical experience 
Cyclosporine gave no evidence of mutagenic or teratogenic effects in the standard test systems 
with oral applications (rats up to 17 mg/kg and rabbits up to 30 mg/kg per day orally). At toxic 
doses (rats at 30 mg/kg and rabbits at 100 mg/kg per day orally), cyclosporine was embryo- and 
fetotoxic as indicated by increased prenatal and postnatal mortality, and reduced fetal weight 
together with skeletal retardations. 
Rabbits exposed to cyclosporine in utero (10 mg/kg/day subcutaneously) demonstrated reduced 
numbers of nephrons, renal hypertrophy, systemic hypertension, and progressive renal 
insufficiency up to 35 weeks of age. 
Pregnant rats which received 12 mg/kg/day of cyclosporine intravenously (twice the 
recommended human intravenous dose) had fetuses with increased incidence of ventricular 
septal defect. 
These findings have not been demonstrated in other species and their relevance in humans in 
unknown. 
Carcinogenecity studies were carried out in male and female rats and mice. In the 78-week 
mouse study, at doses of 1, 4, and 16 mg/kg per day, evidence of a statistically significant trend 
was found for lymphocytic lymphomas in females and the incidence of hepatocellular 
carcinomas in mid-dose males significantly exceeded the control value. In the 24 month rat 
study conducted at 0.5, 2, and 8 mg/kg/day, pancreatic islet cell adenomas significantly 
exceeded the control rate at the low dose level. The hepatocellular carcinomas and pancreatic 
islet cell adenomas were not dose related. 
No impairment in fertility was demonstrated in studies of male and female rats. 
An increased incidence of malignancy is a recognized complication of immunosuppression in 
recipients of organ transplants. The most common forms of neoplasms are non-Hodgkin’s 
lymphoma and carcinomas of the skin. The risk of malignancies during cyclosporine treatment 
is higher than in the normal, healthy population, but similar to that in patients receiving other 
immunosuppressive therapies. It has been reported that reduction or discontinuance of 
immunosuppression may cause the lesions to regress.  


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1.2.2.2 
Clinical experience 
Cyclosporine has been extensively investigated in clinical studies in solid organ transplantation 
including kidney, liver, heart, combined heart-lung, or pancreas allogeneic transplantation, bone 
marrow transplantation. It has also been studied in clinical studies in the following non-
transplant indications: endogenous uveitis including Behcet’s uveitis, nephrotic syndrome, 
rheumatoid arthritis, psoriasis, and atopic dermatitis.  
Additional information regarding clinical study experience with cyclosporine are provided in 
the local prescribing information.  
1.2.2.2.1 Summary of the Safety Profile 
The principal adverse reactions observed in clinical studies and associated with the 
administration of cyclosporine include renal dysfunction, tremor, hirsutism, hypertension, 
diarrhea, anorexia, nausea, and vomiting.  
Many side effects associated with cyclosporine therapy are dose-dependent and responsive to 
dose reduction. In the various indications, the overall spectrum of side effects is essentially 
similar. There are, however, differences in incidence and severity. As a consequence of the 
higher initial doses and longer maintenance therapy required after transplantation, side effects 
are more frequent and usually more severe in transplant patients than in patients treated for 
other indications. 
Anaphylactoid reactions have been observed following intravenous administration. 
Lymphomas and other malignancies 
Like other immunosuppressants, cyclosporine increases the risk of developing lymphomas and 
other malignancies, particularly those of the skin. The increased risk appears to be related to the 
degree and duration of immunosuppression rather than to the use of specific agents. Hence a 
treatment regimen containing multiple immunosuppressants (including cyclosporine) should be 
used with caution as this could lead to lymphoproliferative disorders and solid organ tumors, 
some with reported fatalities. In view of the potential risk of skin malignancy, patients treated 
with cyclosporine should be warned to avoid excess ultraviolet light. 
Hepatotoxicity and Liver Injury 
Cyclosporine may also cause dose-dependent, reversible increases in serum bilirubin, and in 
liver enzymes. There have been solicited and spontaneous post-marketing reports of 
hepatotoxicity and liver injury including cholestasis, jaundice, hepatitis, and liver failure in 
patients treated with cyclosporine. Most reported included patients with significant co-
morbidities, underlying conditions, and other confounding factors including infectious 
complications and co-medications with hepatotoxic potential. In some cases, mainly in 
transplant patients, fatal outcomes have been reported. Close monitoring of parameters that 
assess hepatic function is required. Abnormal values may necessitate dose reduction. 


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Monitoring cyclosporine levels 
Routine monitoring of cyclosporine blood levels is an important safety measure. For monitoring 
cyclosporine levels in whole blood, a specific monoclonal antibody (measurement of parent 
drug) is preferred. A high performance liquid chromatography method, which also measures 
the parent drug, can be used as well. If plasma or serum is used, a standard separation protocol 
(time and temperature) should be followed. It must be remembered that cyclosporine 
concentration in blood, plasma or serum is only one of many factors contributing to the clinical 
status of the patient. Results should serve only as a guide to dosage in relationship to other 
clinical and laboratory parameters. 
Live-attenuated vaccines 
During treatment with cyclosporine, vaccination may be less effective. The use of live-
attenuated vaccines should be avoided. 
Pregnancy 
Animal studies have shown reproductive toxicity in rats and rabbits. 
Breast-feeding 
Cyclosporine passes into breast milk. The ethanol content of the cyclosporine formulations 
should also be taken into account in women who are breast-feeding.  
Others 
Other potential side effects on cyclosporine included: hypertension, blood lipids increases, 
hyperkalemia, hypomagnesemia, hyperuricemia, infections, acute and chronic nephrotoxicity. 
Refer to the label for additional information regarding the safety profile and potential 
interactions with cyclosporine. 
1.2.2.2.2 Pharmacokinetics  
Cyclosporine is distributed largely outside the blood volume. In the blood, 33% to 47% is 
present in the plasma, 4% to 9% in lymphocytes, 5% to 12% in granulocytes, and 41% to 58% 
in erythrocytes. In plasma, approximately 90% is bound to proteins, mostly lipoproteins. 
Cyclosporine is extensively biotransformed to approximately 15 metabolites. There is no single 
major metabolic pathway. Elimination is primarily biliary, with only 6% of the oral dose 
excreted in the urine; only 0.1% is excreted in the urine as unchanged drug. 
There is high variability in the data reported on the terminal half-life of cyclosporine depending 
on the assay and the target population. The terminal half-life of cyclosporine ranges from 6.3 
in healthy volunteers to 20.4 hours in patients with severe liver disease. 
Refer to the local prescribing information for additional information regarding the PK of 
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2 
Rationale 
2.1 
Study rationale and purpose 
The standard of care for the treatment of severe aplastic anemia patients who are not candidate 
for HSCT was immunosuppressive therapy (IST) for a long time. The standard regimen for IST 
remains ATG (h-ATG or r-ATG) and CsA, with hematological recovery in 50 to 79% of cases 
(Scheinberg 2012).  
Patients treated with IST are not cured of their disease and are at risk for 3 major complications: 
1) no response - 1/3 of patients are refractory to initial h-ATG/Cs; 2) relapse - hematologic 
relapses occur in 35% of responders following initial response to h-ATG/CsA; and 3) clonal 
evolution is still observed in 10-15% of patients (Bacigalupo 2017). In addition, the lack of 
availability of ATG in several countries is leaving a large proportion of patients with SAA with 
limited treatment options and poor outcome. 
In order to address these limitations, efforts to improve initial IST in treatment-naïve patients 
with the addition of mycophenolate mofetil and sirolimus to standard h-ATG/CsA or use of 
lymphocytotoxic agents such as r-ATG/CsA or alemtuzumab have not yielded the expected 
better outcomes when compared to standard h-ATG/CsA (Scheinberg 2006, Scheinberg 2012).  
After initial results in refractory patients (Desmond 2014), eltrombopag has also been used 
together with hATG and CsA as triple combination (Townsley 2017) (see Section 1.1) and is 
now considered as a therapy option for SAA patients in a non-transplantation setting. 
In this context, scientific question that remain to be answered in order to address unmet medical 
need is whether the combination CsA and eltrombopag, two therapies with different modes of 
action, is safe and efficacious therapy for treatment-naïve SAA patients mainly in countries 
where h-ATG is not available or for the patients who are ineligible for h-ATG.  
The purpose of this study is to explore efficacy and safety of combination of CsA and 
eltrombopag in treatment-naive SAA patients.   
2.2 
Rationale for the study design 
In many countries only r-ATG is available. Rabbit ATG as first-line therapy showed inferior 
outcomes to h-ATG indicated by hematologic response rates and survival (Scheinberg 2011). 
This study is designed based on the hypothesis, that an outpatient ATG-free regimen 
(eltrombopag plus CsA) can be a safe and efficacious therapy option for treatment-naive SAA 
patients in countries with no access to h-ATG or for patients who cannot tolerate h-ATG.  
The results of this study will be discussed from the perspective of  historic data with rabbit-
ATG/CsA as first line therapy which shows a response rate of 30-35%. A Brazilian 
retrospective study showed a hematologic response rate of 34.5% (Garanito 2014, Scheinberg 
2014, Atta 2012) with rabbit ATG as the first-line therapy in SAA. The combined Brazilian and 
Argentinian data show nearly an identical response rate of 34%. Therefore, a ≥ 30% ORR of 
eltrombopag and CsA would be considered a clinically meaningful response in this study. 


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2.3 
Rationale for dose and regimen selection 
The eltrombopag doses proposed in this study were adapted from those administered in a 
Phase II NIH study of triple therapy (eltrombopag + h-ATG + cyclosporine) in treatment-naïve 
SAA patients (Townsley 2017, [Study NIH 12-H-0150 /ELT116643/CETB115AUS01T]) (See 
Section 1.2.1.2.1). 
In that NIH study, eltrombopag was administered at 150 mg daily in non-Asian patients >12 
years, and at half that dose (75 mg daily) in patients between 6 to 11 years old. Eltrombopag 
was administered daily for a maximum of 6 months. The same doses will be evaluated in the 
present study in non-Asian patients (refer to Table 2-1). 
The dose in patients of Asian ancestry (i.e. Japanese, Chinese, Taiwanese, Korean, or Thai) will 
be reduced by approximately 1/3 to account for the 30% - 37% lower eltrombopag apparent 
clearance (CL/F) observed in these patients compared to non-Asian ones (refer to Section 
1.2.1.3.1). Therefore, the doses administered in patients of Asian ancestry will be 100 mg daily 
(refer to Table 2-1). 


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Table 2-1 
Dosing according to ethnicity (Asian vs Non-Asian) (Study NIH 12-H-
0150 /ELT116643/CETB115AUS01T) 
Ethnicity 
Daily dose  
Non-Asian 
150 mg 
Asian 
100 mg 
All patients will receive eltrombopag and cyclosporine in the first 6 months of the study. 
Cyclosporine tapering will be done for an additional 18months for responders who do not 
relapse prior to 6 months. Responders who relapse prior to 6 months and non-responders will 
discontinue the treatment and study at 6 months and will be followed-up for 30 days. 
Responders who relapse prior to 24 months will discontinue cyclosporine and study, and will 
be followed-up for 30 days. Responders who relapsed and non-responders already in the follow-
up under the previous protocol version will be discontinued from the study within 30 days of 
the approval of this protocol amendment. 
Co-therapy with trimethoprim-sulfamethoxazole double strength may be administered as 
infectious prophylaxis of Pneumocystis jiroveci at the discretion of the Investigator. 
2.4 
Rationale for choice of combination drugs  
Eltrombopag and cyclosporine combination rationale is given that each agent has a distinct 
mechanism of action whereby the autoimmune pathogenesis with CsA and a deficient marrow 
progenitor compartment with eltrombopag are addressed. 
Eltrombopag has demonstrated activity in combination with h-ATG and cyclosporine in 
treatment-naïve patients with SAA (Townsley 2017). The addition of eltrombopag to h-ATG 
and cyclosporine in patients with treatment naïve SAA demonstrated an ORR of 94% and a CR 
rate of 58% in cohort 3. The results suggested that immediate institution of eltrombopag and 
IST may salvage and expand residual hematopoietic stem cells in patients with SAA, 
accelerating the rate and quality of hematopoietic recovery.  
As noted previously, h-ATG is not widely available globally. Therefore, the co-administration 
of eltrombopag and cyclosporine is attractive since it combines two therapies with different 
modes of action. Cyclosporine acts as an immunosuppressant and eltrombopag acts as a 
stimulator of bone marrow progenitor cells. Given that SAA is viewed as having an autoimmune 
pathogenesis resulting in bone marrow progenitor cell destruction, the combination of the two 
treatments is logical. Preliminary experience with their combined use appears favorable with 
no untoward toxicity observed to date. Thus the combination of eltrombopag and cyclosporine 
is proposed as first-line therapy in SAA. 
No starting dose adjustment is recommended when eltrombopag is co-administered with 
cyclosporine. Platelet count and lab parameters should be closely monitored when eltrombopag 
is co-administered with cyclosporine and eltrombopag dose may need to be adapted based on 
these platelet counts and any toxicity event, refer to Tables 6-2 and 6-7. Although eltrombopag 
is unlikely to cause any modification of the exposure to cyclosporine (since its metabolism is 
mediated by CYP3A4), it is recommended to regularly monitor cyclosporine levels as per the 
cyclosporine prescribing information. 


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2.5 
Rationale for choice of comparators drugs  
This study aims to address an unmet medical need in countries where h-ATG is not available 
or in countries where h-ATG is available and patients are not able to tolerable h-ATG. 
No comparator drug is used in this single-arm study. 
2.6 
Risks and benefits 
SAA is considered a rare disorder, which can be, life threatening if untreated. Without effective 
treatment, patients with SAA have a life expectancy of 1 to 2 years after diagnosis due to fatal 
infections or hemorrhagic complications.  
The current options for effective treatment for SAA are HSCT or IST. However, HSCT is 
available to only a minority of patients, and about half of patients who receive IST as a first line 
therapy fail to achieve hematologic response and experience relapse or clonal evolution 
associated with myelodysplasia and leukemia. 
No new or unexpected safety signals were observed in studies conducted in SAA patients, in 
both refractory and first-line indications.  
The safety profile of eltrombopag up to 150 mg alone or in combination with h-ATG and CsA 
is acceptable and consistent with the prescribing information (for all 3 drugs), in light of the 
underlying population with SAA. No new or unexpected safety signals were observed.The risk 
specific to patients with SAA is the potential for cytogenetic abnormalities. The role of 
eltrombopag in the development of cytogenetic abnormalities remains unknown. The 
development of cytogenetic abnormalities is a known risk for patients with SAA and part of the 
natural history of the underlying disease. The incidence of clonal evolution observed in the 
refractory studies (ETB115AUS18T and ETB115AUS28T) and in the pivotal study 
(ETB115AUS01T) in IST-naive SAA patients is consistent with what has been reported in the 
historical data. A final conclusion about the early onset of cytogenetic abnormalities relative to 
SAA, immunosuppression treatment or eltrombopag cannot be made. Bone marrow 
examination including cytogenetics will be performed as described in Section 7.2.4 and Table 
7-1. Development of new cytogenetic abnormalities will result in permanent discontinuation of 
investigational treatment as described in Section 6.3.1.2. 
The risks to patients in this study may come from adverse events and lack of efficacy (described 
in Section 1.2.1.2.2, Section 1.2.1.2.3, Section 8.1 and Section 8.1.3). 
There may be unforeseen risks with the study treatment which could be serious. These include 
but may not be limited to drug to drug interactions and long-term safety. Close adherence to 
eligibility criteria, study procedures safety monitoring and dose adjustment as described above 
will help to minimize unforeseen risks. Potential for drug-drug interaction and measures to 
minimize undesired drug-drug interactions are described in Section 1.2.1.3.1, Section 1.2.1.3.2, 
Section 1.2 and Section 6.4.2. 
Eltrombopag is not a nephrotoxic drug (please refer to the eltrombopag Investigator’s Brochure), 
no dose adjustment is generally necessary in patients with renal impairment. However, due to 


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administration in combination with cyclosporine (CsA) which is a known nephrotoxic drug, 
close monitoring of renal functions in this protocol was established. 
 
Furthermore, a strict monitoring schedule including that of renal parameters is proposed in the 
protocol in particular in the first 6 months: day 1 to 2 months; weekly, 2 months to 6 months; 
biweekly. 
The risk for patients in this study may be minimized by compliance with the eligibility criteria 
and study procedures, close clinical monitoring, safety and tolerability assessments as described 
in Section 7.2.2 and dose modifications as described in Section 6.3. Appropriate eligibility 
criteria, as well as specific dose modification and stopping rules are included in this protocol. 
Recommended guidelines for prophylactic or supportive treatment for expected toxicities, 
including management of study-drug induced adverse events, i.e., hepatotoxicity, thrombotic 
complications, bone marrow fibrosis and ocular changes are provided in Section 6.3.3 and 
Section 6.3.4. Additional information can be found in the eltrombopag Investigator’s Brochure 
and local prescribing information.  
The results of the pivotal ETB115AUS28T study in which eltrombopag was administered to 
IST-refractory SAA patients, demonstrated clinically significant hematologic responses with 
minimal toxic effects (Olnes et al 2012, Desmond et al 2014). 
In the pivotal ETB115AUS01T study the addition of eltrombopag to standard IST with h-ATG 
and 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 complete hematological response (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 adults 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 2003): a robust hematological response at 3 months, with reticulocyte or platelet 
count > 50x103/μL predicted a survival at 5 years of 90% vs. 42% in patients who had a later 
response or a less robust hematological recovery at 3 months. 
In conclusion, the key benefits of eltrombopag alone or in combination with IST of h-ATG + 
CsA outweigh the risks for its intended use in refractory or first-line treatment, respectively, in 
adult and pediatric (in first line indication) patients with SAA. Eltrombopag meets an important 
unmet medical need in this population, without incurring unacceptable risk. 
3 
Objectives and endpoints 
Objectives and related endpoints are described in Table 3-1 below. 


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Table 3-1 
Objectives and related endpoints 
Objective 
Endpoint 
Analysis 
Primary 
 
Refer to Section 10.4  
To evaluate the efficacy of eltrombopag + cyclosporine as 
first-line therapy on overall hematologic response (partial and 
complete response) by 6 months 
Overall hematologic response (CR + PR)* rate by 6 months (definition of CR 
and PR is given as footnote below) 
 
Secondary 
 
Refer to Section 10.5.1  
1. Evaluate the effect of eltrombopag + cyclosporine on 
overall hematologic response (partial and complete 
response): 
● by 3 months   
● at 12 months 
● at 24 months 
Overall hematologic response (CR + PR)* rate: 
● by 3 months   
● at 12 months 
● at 24 months 
Responders are 
defined in Section 
10.4.2 
The following secondary objectives will be assessed by 6 months and 24 months (responders only) as appropriate and will be reported in a cumulative basis 
2. To evaluate the duration of hematologic response 
Time from the date of the start of first response to the date of first relapse 
(defined as no longer meeting definition of PR (and not CR)  
 
3. To evaluate the proportion of patients who relapse  
Percentage of patients who relapse 
 
4. To evaluate the clonal evolution to myelodysplasia, 
paroxysmal nocturnal hemoglobinuria (PNH), and leukemia 
Percentage of patients with evolution to myelodysplasia, PNH, and acute 
leukemia occurring at any time during the study  
 
5. To evaluate red blood cells (RBC) transfusion 
independence 
Percentage of patients who are RBC transfusion independent at least once 
by 6 months and by 24 months. Independence defined as no RBC 
transfusion for at least 56 days 
 
6. To evaluate platelet transfusion independence 
Percentage of patients who are platelet transfusion independent at least 
once by 6 months and by 24 months. Independence defined as no platelet 
transfusion for at least 28 days. 
 
7. To evaluate the longest interval without  a platelet or RBC 
transfusion 
Duration of longest interval without a platelet transfusion by 6 months and 
by 24 months  
Duration of longest interval without a RBC transfusion by 6 months and by  
24 months  
 
8. To evaluate the effect of Eltrombopag and cyclosporine on 
patient symptoms and health related quality of life 
Change in scores from baseline to 6 months and 24 months on the FACT-
G, FACT-TH18, and FACIT-Fatigue scales 
 


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Objective 
Endpoint 
Analysis 
9. To evaluate the safety and tolerability of eltrombopag + 
cyclosporine 
Safety will be assessed by: 
● Frequency and severity of AEs, serious AEs (SAEs) based on the 
Common Terminology Criteria of Adverse Events (CTCAE version 4. 03), 
and AEs leading to discontinuation, and evaluating changes in laboratory 
values within 6 months and within 24 months (responders only) 
● Incidence of the following adverse events of special interest 
Refer to Section 10.5.3  
10. To characterize the PK of eltrombopag when combined to 
cyclosporine 
Plasma PK parameters of eltrombopag  2 weeks and trough concentrations 
at 1 month 1, 2 months, 3 months, and 6 months 
Refer to Section 10.5.4  


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Objective 
Endpoint 
Analysis 
*Overall hematologic response = patients with complete response (CR) + patients with partial response (PR) 
a. Partial response is defined as any two of the following parameters at two consecutive, scheduled visit measurements at least 7 days apart during the study and no 
platelet transfusions within 7 days of platelet measurement (can still be a responder if ANC and reticulocyte measurements are valid): 
 
● Absolute neutrophil count (ANC) ≥ 500/µL 
 
● Platelet count ≥ 20 000/µL 
 
● Reticulocyte count ≥ 60 000/µL (automated)  
b. Complete response is defined as all three parameters meet the following criteria at two consecutive, scheduled visit measurements at least 7 days apart during the 
study and no platelet transfusions within 7 days of platelet measurement and no RBC transfusion within 14 days of the hemoglobin measurement: 
 
● Absolute neutrophil count (ANC) ≥ 1 000/µL 
 
● Platelet count ≥ 100 000/µL 
 
● Hemoglobin ≥ 10 g/dL 
Example: At the end of 6 months out of 50 patients enrolled, if 13 patients satisfy the criteria for CR and 3 patients satisfy the criteria for PR, the overall hematologic 
response will be 13+3=16 patients. 


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4 
Study design 
4.1 
Description of study design 
This is aninterventional phase II, single-arm, multicenter, open-label, study to investigate the 
efficacy and safety of the combination of eltrombopag and cyclosporine in treatment-naive 
adult patients with SAA as first line therapy administered for 6 months , with an additional 18 
months follow-up for cyclosporine tapering and duration of response until relapse or 24 months 
whichever is earlier (responders only who do not relapse prior to 6 months).After signing the 
informed consent form (ICF) and completing the screening assessments, eligible patients will 
receive eltrombopag and cyclosporine for up to 6 months.  
At 6 months, responders will discontinue eltrombopag and start to taper cyclosporine until 
24 months. Responders who relapse prior to 6 months and non-responders will discontinue the 
treatment and study at 6 months and will be followed-up for 30 days. Responders who relapse 
prior to 24 months will discontinue cyclosporine and study, and will be followed-up for 30 days.  
Responders who relapse and non-responders already in the follow-up under the previous 
protocol version will be discontinued from the study within 30 days of the approval of this 
protocol amendment. 
Figure 4-1 
Study design 
 
The cyclosporine tapering schedule from 6 month to 24 is described in detail in Section 6.1.1.2. 
4.2 
Timing of interim analyses and design adaptations  
No formal interim analysis is planned for this study. One interim lock for the steering committee 
safety review purposes was planned and executed for this study as described in the Steering 
Committee Charter. At the time of the cut-off 31 patients were enrolled (data cut-off date 
15-Nov-2018 and interim database lock date 11-Dec-2018). 
An interim lock before the final lock is planned for the primary analysis at 6 months, no adaptive 
changes are planned. 
During the course of this study, two clinical study reports (CSRs) will be written: 




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3. Patient has SAA characterized by:  
a. Bone marrow cellularity <30% (excluding lymphocytes) and  
b. At least two of the following (peripheral blood): 
• Absolute neutrophil count <500/µL 
• Platelet count <20 000/µL 
• Absolute reticulocyte count <60 000/µL 
4. Normal ECG defined as the following as determined via the mean of a triplicate ECG 
• Resting heart rate 
 50-90 bpm 
• QTcF at screening <450 msec (for male patients), <460 msec (for female patients) 
5.3 
Exclusion criteria 
Patients eligible for this study must not meet any of the following criteria: 
1. Diagnosis of Fanconi anemia. 
2. Evidence of a clonal hematologic bone marrow disorder on cytogenetics by central 
review. 
3. Prior immunosuppressive therapy with cyclosporine, alemtuzumab, rabbit or horse ATG 
and thrombopoietin receptor (TPO-R) agonists. 
4. a. Hypersensitivity to eltrombopag or cyclosporine or their components. 
b. Contraindications to cyclospsorine. 
5. AST or ALT >3 x ULN. 
6. Serum creatinine, total bilirubin, or alkaline phosphatase >1.5 x ULN. 
7. Patient with liver cirrhosis. 
8. a. Infection not adequately controlled with appropriate therapy. 
b. Patients who are human immune deficiency virus (HIV), hepatitis C virus or hepatitis B 
surface antigen (HBsAg) positive. HCV-RNA negative patients are allowed to be 
enrolled. 
9. Moribund status or concurrent hepatic, renal, cardiac, neurologic, pulmonary, infectious, 
or metabolic disease of such severity that it would preclude the patient’s ability to consent, 
be compliant with study procedures, tolerate protocol therapy, or patients with less than 3 
months of life expectancy. 
10. Patients with cancer who are not considered cure, are on active chemotherapeutic 
treatment or who take drugs with hematological effects. 
11. Administration of an investigational drug within 30 days or 5 half-lives, whichever is 
longer, preceding the first dose of study treatment. 
12. Pregnancy statements and contraception requirements:  
Pregnancy or nursing (lactating) women 
Women of child-bearing potential, defined as all women physiologically capable of becoming 
pregnant (or female partners of male patients), unless they are using highly effective methods 
of contraception during dosing and for 3 months after stopping medication. Highly effective 
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• Total abstinence (when this is in line with the preferred and usual lifestyle of the patient. 
Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) 
and withdrawal are not acceptable methods of contraception 
• Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy), total hysterectomy, or tubal ligation at least six weeks before taking study 
treatment. In case of oophorectomy alone, only when the reproductive status of the woman 
has been confirmed by follow up hormone level assessment 
• Male sterilization (at least 6 months prior to screening). The vasectomized male partner 
should be the sole partner for that patient 
• Use of oral, injected or implanted hormonal methods of contraception or placement of an 
intrauterine device (IUD) or intrauterine system (IUS), or other forms of hormonal 
contraception that have comparable efficacy (failure rate <1%), for example hormone 
vaginal ring or transdermal hormone contraception. 
• Sexually active males unless they use a condom during intercourse while taking the drug 
during treatment and for 3 months after stopping treatment and should not father a child in 
this period. A condom is required to be used also by vasectomized men as well as during 
intercourse with a male partner in order to prevent delivery of the drug via semen. 
In case of use of oral contraception women should have been stable on the same contraceptive 
pill for a minimum of 3 months before taking study treatment. 
13. 
Not able to understand the investigation nature of the study or to give informed 
consent. 
14. 
Clinically significant ECG abnormality including cardiac arrhythmias (e. g. ventricular 
tachycardia) complete left bundle branch block, high grade atrioventricular block, or 
inability to determine the QTcF interval on the ECG. 
15. 
Presence of cardiac disease, or family history of idiopathic sudden death or congenital 
long QT syndrome. 
16. 
Risk factors for Torsades de Pointe including uncorrected hypokalemia or 
hypomagnesemia, or use of concomitant medication(s) with a known risk to prolong 
the QT interval that cannot be discontinued or replaced by safe alternative medication 
per qtdrugs.org. 
17. 
ECOG performance status of ≥2. 
18. 
Patients under the age of 40 must be referred for consideration of allogeneic bone 
marrow transplantation (HSCT) if (human leukocyte antigen) HLA matching has been 
done and a suitable matched sibling donor is available and the patient is willing to 
undergo transplantation (i.e. patients who do not have a HLA match or are not 
medically fit, not willing or unable to undergo transplantation will be considered for 
enrollment). 
6 
Treatment 
6.1 
Study treatment 
The investigational/study treatments for this study are eltrombopag (ETB115) and cyclosporine. 


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Eltrombopag will be supplied as film-coated tablets (12.5 mg, 25 mg, 50 mg and 75 mg) 
provided either as commercial packages or clinical packages centrally or site pharmacists, see 
Table 6-3. 
Cyclosporine will be supplied as soft-gelatin capsules. Cyclosporine will be supplied as 
commercial packages either centrally or through site pharmacists. 
6.1.1 
Dosing regimen 
All patients will receive eltrombopag and cyclosporine. 
6.1.1.1 
Eltrombopag 
Eltrombopag must be initiated at Day 1 and continued as a daily therapy for 6 months after 
which the patients will no longer receive eltrombopag irrespective of whether the patient is a 
responder or not. 
The starting dose of eltrombopag for non-Asian patients must be 150 mg once daily and 
eltrombopag continued for a total of 6 months. 
To adjust for the lower eltrombopag apparent clearance observed in adult patients of Asian 
ancestry the starting dose for these patients must be rat 100 mg once daily and eltrombopag 
continued for a total of 6 months. 
Asian ancestries are defined as Japanese, Chinese, Taiwanese, Korean, or Thai. 
The dosing according to ethnicity is described in Table 6-1. 
Table 6-1 
Dosing according to age and ethnicity 
Age groups 
Daily dose 
Non-Asian 
150 
 Asian ancestry 
100 
Eltrombopag must be administered orally, once daily at least 2 hours before or 4 hours after any 
products such as antacids, dairy products, or mineral supplements containing polyvalent cations 
(e.g., aluminum, calcium, iron, magnesium, selenium, and zinc). Eltrombopag may be taken 
with food containing little (<50 mg) or preferable no calcium.  
Patients must be instructed to take eltrombopag daily at the same time each day. 
On days when PK samples are obtained, the patient should take eltrombopag during the clinic 
visit after the pre-dose PK samples and prior to post-dose PK samples, when instructed by the 
study staff. 
If vomiting occurs during the course of treatment, patients should not take the study drug 
(eltrombopag) again before the next scheduled dose. 
Patients will be instructed not to make up missed doses. A missed dose is defined as a case 
when the full dose is not taken within 8 hours of the approximate time of the usual daily dose. 
That day’s dose should be omitted and the patient should continue treatment with the next 
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Eltrombopag dose must be interrupted when clinically indicated at the discretion of the 
investigator. Interruptions will be reported. However, when the interruption is greater than 7 
days or a consequence to an AE or SAE (refer to Table 6-2 and Table 6-7 respectively) the daily 
dose of eltrombopag must be decreased according to the following rules: 
Table 6-2 
Eltrombopag dose adjustments 
Platelet count 
Dose adjustment or response 
>200 000/µL (untransfused) at any time 
on study 
Decrease daily dose by 25 mg every 2 weeks to the lowest dose than 
maintains platelet count ≥50 000/µL 
>400 000/µL (untransfused) at any time 
on study 
Discontinue eltrombopag for one week. If platelet count falls to <200 
000/µL restart eltrombopag at a dosage decrease of 25 mg/day 
A decrease in eltrombopag exposure was observed with co-administration of 200 mg and 
600 mg cyclosporine. This decrease in exposure is not considered clinically meaningful. The 
prescribing information for eltrombopag recommends monitoring platelet count at least weekly 
for 2 to 3 weeks when eltrombopag is co-administered with cyclosporine. Therefore, in this 
study platelet count must be monitored weekly from day 1 to 2 month and every 2 weeks from 
2 to 6 months. 
In case of early discontinuation of eltrombopag, cyclosporine should be continued until 
6 months for all patients and for responders who do not relapse prior to 6 months tapering to 
24 months, following the cyclosporine dosing guidelines. 
Table 6-3 
Eltrombopag Dosages and Available Treatment Formulations 
Study Treatment 
Pharmaceutical Form and 
Route of Administration 
Strength 
Frequency and/or 
Regimen 
ETB115/eltrombopag 
Tablet for oral use 
12.5 mg 
Once daily 
ETB115/eltrombopag 
Tablet for oral use 
25 mg 
Once daily  
ETB115/eltrombopag 
Tablet for oral use 
50 mg 
Once daily 
ETB115/eltrombopag 
Tablet for oral use 
75 mg 
Once daily 
6.1.1.2 
Cyclosporine 
Cyclosporine is a cyclic polypeptide immunosuppressant agent consisting of 11 amino acids. It 
is produced as a metabolite by the fungus species Beauveria nivea. 
The starting daily dose of cyclosporine must be 10.0 mg/kg/day (acceptable rounding range is 
from 9.5 to 10.5 mg/kg/day) orally in divided doses every 12 hours (q12hr) beginning on Day 
1 with eltrombopag. Dosing must be based on actual body weight. Due to considerable inter- 
and intra-individual variations in absorption and elimination and the possibility of PK drug 
interactions, dosing should be titrated individually. After Day 1 cyclosporine dosing must be 
adjusted to obtain a therapeutic cyclosporine trough level between 200 and 400 µg/L. For all 
patients cyclosporine will be initiated orally and administered for 6 months. 
Table 6-4 
Cyclosporine Dosage 
Daily dose 
10.0 mg/kg/day orally divided doses q12hrs (starting dose) 
Cyclosporine dose adjusted to a therapeutic cyclosporine trough level between 200 and 400 µg/L at each visit 


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During the tapering of cyclosporine after 6 months for responders, cyclosporine dose must NOT 
be adjusted to cyclosporine trough level. Tapering must be done according to Table 6-5.  
• 6-9 months: at the 6 months visit, the dose must be reduced by 25% for 3 months 
• 9-12 months: at the 9 months visit, the dose must be further reduced by 25% for another 3 
months  
• 12-24 months: maintain dose 
At 12 months the cyclosporine dose will be maintained at the same level for an additional year. 
In patients still experiencing cyclosporine related toxicities at the 12 month dose, a further 25% 
reduction will be allowed and continued for the duration of the 2nd year. A gradual cyclosporine 
taper will be performed in order to prevent this complication as suggested by a recent report 
where very infrequent relapses were observed while patients were on 5/8 of the full dose of 
cyclosporine. (Scheinberg 2014)  
 Cyclosporine dose taper guidance is provided in Appendix 1. 
Responders who relapse prior to 24 months will discontinue cyclosporine and study, and will 
be followed-up for 30 days. 
Table 6-5 
Cyclosporine Dose reduction 
Time periods 
6-9 months 
9-12 months 
12-24 months 
 
 
Dose reductions 
- 25% 
- 25% 
Maintain the dose 
 
 
For administration of cyclosporine, the local prescribing information on contraindications 
should be considered in accordance with exclusion criterion. 
Cyclosporine oral soft gelatin capsules should be swallowed whole. 
Cyclosporine dose may be interrupted temporarily or discontinued early when clinically 
indicated at the discretion of the investigator or treating physician according to the local 
cyclosporine prescribing information. The parenteral route of administration may be used 
temporarily for cyclosporine administration if indicated. Temporary interruptions for transient 
toxicities or dose adjustments will be reported. In case of early discontinuation of cyclosporine, 
eltrombopag should be continued until 6 months, following the eltrombopag dosing guidelines. 
Table 6-6 
Cyclosporine Dosages and Available Treatment Formulations*  
Study treatments 
Pharmaceutical form and 
route of administration 
Strengths 
Frequency and/or 
Regimen 
Cyclosporine 
Soft gelatin capsule 
10 mg 
Every 12 hours 
Cyclosporine 
Soft gelatin capsule 
25 mg 
Every 12 hours 
Cyclosporine 
Soft gelatin capsule 
50 mg 
Every 12 hours 
Cyclosporine 
Soft gelatin capsule 
100 mg 
Every 12 hours 
*Treatment formulation availabilities depend on countries marketing authorization as a local 
commercial supply is used. 
Cyclosporine dose management can be rounded to the nearest quartile (25 mg increments), e.g. : 
“If a patient weighs 82 kg, the total CsA dose will be 820 mg which would result in 410 mg 
every 12 hours. The q12 dosing can be rounded to 400 mg. Furthermore, if a patient weighs 67 


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kg, the total daily dose will be 670 mg which would result in 335 mg every 12 hours. The q12 
dosing for this patient can be rounded to 325 mg every 12 hours.” 
6.1.2 
Ancillary treatments 
Antibacterial and antifungal prophylaxis will not be included systematically with the 
immunosuppressive regimen, but may be administered at the discretion of the investigator or 
treating physician according to the local standard of care on a case-by-case basis. Infection 
prophylaxis for Pneumocystis jiroveci with trimethoprim/ sulfamethoxazole may be provided 
as trimethoprim/sulfamethoxazole double-strength (160 mg/ 800 mg) orally once per day two 
times per week (Monday-Thursday or Tuesday-Friday) at the discretion of the Investigator. 
Dosing may start two weeks after initiation of cyclosporine and continue for 6 months. After 
the cyclosporine taper is initiated at 6 months, infection prophylactic therapy may be 
discontinued.  In addition, equivalent alternative regimens may be implemented at the discretion 
of the investigator or treating physician to those who are allergic or intolerant to a particular 
prophylaxis drug. Prophylactic therapy may be continued at the discretion of the investigator. 
Supportive care for the patient (e.g., transfusion support with red blood cells, platelet or 
granulocytes, anti-infective care and/or growth factors) will be allowed as clinically indicated.  
6.1.3 
Rescue medication  
Transfusions with platelets and/or red blood cells should be limited during study, however must 
be given, when medically necessary as described in Section 6.4.1.  
Treatment with romiplostim or any ATG is not allowed in the study.  
6.1.4 
Guidelines for continuation of treatment 
Further tapering of cyclosporine will be performed outside of the study after 24 months 
according to the cyclosporine dosing guidelines and standard of care. 
6.1.5 
Treatment duration 
The planned duration of treatment with eltrombopag is 6 months.  
The planned duration of treatment with cyclosporine is 6 months for non-responders and up to 
24 months for responders who do not relapse prior to 6 months. Patients who relapse prior to 
24 months will discontinue cyclosporine and study, and will be followed-up for 30 days.  
For patients who meet any toxicity criteria, the investigator must follow the guideline on dose 
reduction and/or discontinuation presented in Section 6.3. Patients can remain on study 
treatment until toxicity or withdrawal of consent, refer to Sections 7.1.5 and 7.1.6. 
6.2 
Dose escalation guidelines 
Not applicable. 


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6.3 
Dose modifications 
6.3.1 
Dose modification and dose delay 
For patients who do not tolerate the protocol-specified dosing schedule, dose interruptions 
and/or reductions are mandated in order to allow patients to continue the study treatment. 
These dose modifications are summarized in Table 6-7. Deviations to mandatory dose 
interruptions and/or reductions are not allowed. Permanent treatment discontinuation is 
mandatory for specific events indicated as such in Table 6-7 or listed in Section 7.1.5.1. 
These dose changes must be recorded on the Dosage Administration Record – electronic case 
report form (eCRF). 
Common Terminology Criteria for Adverse Events Version 4.03 will be used for this study. 
6.3.1.1 
Dose interruption due to liver signals 
Eltrombopag dose must be interrupted when clinically indicated. The dose modifications for 
isolated ALT or AST elevation are listed in Table 6-7. If the dose modification is based on local 
laboratory, then local laboratory results must be entered in the CRF. 


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Table 6-7 
Criteria for eltrombopag dose adjustment based on liver enzyme and bilirubin levels  
Dose modifications for ETB115 
Worst toxicity 
CTCAEa Grade (value) during the treatment 
 
Investigations (Hepatic)  
Isolated Total Bilirubin elevation 
> ULN – 1.5 x ULN 
Maintain dose level 
> 1.5 - 3.0 x ULN* 
Interrupt dosing and weekly monitor LFTsb, or more frequently if clinically indicated, until resolved to ≤ 1.5 × ULN: 
If resolved in ≤ 14 days, then resume at same dose level If resolved in > 14 days, then decrease one dose level e  
> 3.0 - 10.0 x ULN**  
Mandatory: Interrupt dosing and weekly monitor LFTsb, or more frequently if clinically indicated, until resolved to ≤ 
1.5 × ULN: 
If resolved in ≤ 14 days, then decrease one dose level e 
If resolved in > 14 days, then discontinue patient from study drug treatment. LFTsb will continue to be monitored 
weekly, or more frequently if clinically indicated, until total bilirubin have resolved to baseline or stabilization over 4 
weeks. 
> 10.0 x ULN** 
Mandatory: Discontinue patient from study drug treatment 
The subject should be monitored weekly (including LFTsb), or more frequently if clinically indicated, until total 
bilirubin have resolved to baseline or stabilization over 4 weeks. 
* Note: If total bilirubin > 1.5 - ≤ 3 x ULN is due to the indirect (non-conjugated) component only, no changes to dose are required.** Note: If total bilirubin > 3.0 x 
ULN is due to the indirect (non-conjugated) component only, and hemolysis as the etiology has been ruled out as per institutional guidelines (e.g., review of 
peripheral blood smear and haptoglobin determination), then decrease 1 dose level e and continue treatment at the discretion of the investigator 
Isolated AST or ALT elevation  
> ULN - 3.0 x ULN 
Maintain dose level 
> 3.0 - 5.0 x ULN  
Maintain dose level. 
Repeat LFTsb as soon as possible, preferably within 48-72 hours from awareness of the abnormal results. If 
abnormal lab values are confirmed upon the repeat test, then monitor LFTsb weekly, or more frequently if clinically 
indicated, until resolved to ≤ 3.0 × ULN 
Discontinue patient from the study treatment if elevation is combined with any of the following: 
● Clinical symptoms of liver injury or evidence for hepatic decompensation 
● Progressively increasing LFTsb upon repeat testing● Persistence for ≥4 weeks 
> 5.0 - 10.0 x ULN 
Mandatory: Interrupt dose. 
Repeat LFTsb as soon as possible; preferably within 48-72 hours from awareness of the abnormal results. Monitor 
LFTsb weekly, or more frequently if clinically indicated until resolved to ≤ 3.0 x ULN then: 


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Dose modifications for ETB115 
If resolved in ≤14 days, maintain dose level 
If resolved >14 days, decrease one dose level e 
> 10.0 - 20.0 x ULN  
Mandatory: Interrupt dose.   
Repeat LFTsb as soon as possible, preferably within 48-72 hours from awareness of the abnormal results. Monitor 
LFTsb weekly, or more frequently if clinically indicated until resolved to ≤ baseline.  
Then decrease one dose level e. 
> 20.0 x ULN 
Mandatory: Discontinue patient from study drug treatment. 
Repeat LFTsb as soon as possible, preferably within 48-72 hours from awareness of the abnormal results. Monitor 
LFTsb weekly, or more frequently if clinically indicated until resolved to ≤ baseline or stabilization over 4 weeks.  
Combined c elevations of AST or ALT and total bilirubin 
For patients with normal baseline ALT and 
AST and total bilirubin value, [AST or ALT > 
3.0 × ULN] combined with [total bilirubin > 2.0 
× ULN] without evidence of cholestasisd  
OR  
For patients with elevated baseline AST or 
ALT [AST or ALT > 3 × baseline] OR [AST or 
ALT > 5.0 × ULN], whichever is lower, 
combined with [total bilirubin > 2× baseline 
AND > 2.0 × ULN] 
Mandatory: Permanently discontinue patient from study drug treatment. 
Repeat as soon as possible, preferably within 48 hours from awareness of the abnormal results, then with weekly 
monitoring of LFTsb), or more frequently if clinically indicated, until AST, ALT, or bilirubin have resolved to baseline 
or stabilization over 4 weeks. 
All dose modifications should be based on the worst preceding toxicity. 
a Common Toxicity Criteria for Adverse Events (CTCAE Version 4.03) 
b Core LFTs consist of ALT, AST, GGT, total bilirubin (fractionated [direct and indirect], if total bilirubin > 2.0 x ULN), and alkaline phosphatase (fractionated 
[quantification of isoforms], if alkaline phosphatase > 2.0 x ULN.) 
c “Combined” defined as total bilirubin increase to the defined threshold concurrently with ALT/AST increase to the defined threshold 
If combined elevations of AST or ALT and total bilirubin do not meet the defined thresholds, please follow the instructions for isolated elevation of total bilirubin and 
isolated elevation of AST/ALT, and take a conservative action based on the degree of the elevations (e.g. discontinue treatment at the situation when omit dose is 
needed for one parameter and discontinue treatment is required for another parameter).  After all elevations resolve to the defined thresholds that allow treatment re-
initiation, re-start the treatment either at the same dose or at one dose lower if criterion for dose reduction is met. 
d “Cholestasis” defined as ALP elevation (>2.0 xULN and R value <2) in patients without bone metastasis, or elevation of ALP liver fraction in patients with bone 
metastasis. The R value is calculated by dividing the ALT by the ALP, using multiples of the ULN for both values. It denotes whether the relative pattern of ALT 
and/or ALP elevation is due to cholestatic (R ≤ 2), hepatocellular (R ≥ 5), or mixed (R >2 and < 5) liver injury. 
e “One dose level” defined as eltrombopag dose reduction by 25 mg. 


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Eltrombopag can cause hepatobiliary laboratory abnormalities, severe hepatotoxicity, and 
potentially fatal liver injury. Serum ALT, AST and bilirubin should be measured prior to 
initiation of eltrombopag, every 2 weeks during the dose adjustment phase and monthly after 
establishment of a stable dose. Abnormal serum liver tests should be evaluated with repeat 
testing as described in Table 6-7. If the abnormalities are confirmed, serum liver tests should 
be monitored weekly until the abnormalities resolve, stabilize, or return to baseline levels. 
Both eltrombopag and cyclosporine can cause liver enzyme elevations. In the event that it is 
impossible to separate the effects of eltrombopag from the effects of cyclosporine, in order to 
protect patient safety, both drugs must be adjusted or interrupted until the liver normalizes, 
regardless of which drug may be responsible. 
In the case of clinically significant elevated liver enzymes and/or bilirubin levels, a blood 
sample for the determination of cyclosporine blood concentrations must be collected, as per 
cyclosporine label. Cyclosporine dose must be decreased by 25% to 50% depending on 
cyclosporine blood concentrations and to control adverse events, including clinically significant 
lab abnormalities, in accordance with guidance provided in the cyclosporine label.  
Discontinuation of cyclosporine must be considered if liver enzymes and/or bilirubin levels do 
not normalize within 4 weeks after dose modification or after two sequential dose decreases. 
6.3.1.2 
Dose modification for other reasons 
Study drug dosing must be temporarily discontinued in patients unable to ingest the drug due 
to mucositis or vomiting.  
Early discontinuation of eltrombopag  
Eltrombopag must be permanently discontinued if any of the following events occur or is 
identified at any time during the study:  
• Cytogenetic abnormalities associated with dysplastic bone marrow findings 
a. Monosomy 7 – discontinue eltrombopag  
b. Other cytogenetic abnormalities not associated with worsening blood counts or bone 
marrow dysplastic findings – discontinuation at physician and/or Investigator 
discretion. A more frequent bone marrow aspirate monitoring of cytogenetic 
abnormalities and dysplastic findings may be performed in this patient group. 
• Thromboembolism considered related to drug occurs  
• Development of MDS or AML  
• Patient receives HSCT  
• Positive pregnancy test, at any time during the study  
• Difficulties to continue the study treatment due to AE(s)  
• Patient is found to be significantly non-compliant with the requirements of the protocol 
(including treatment noncompliance)  


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6.3.1.3 
Cyclosporine dose modification due to increase in blood pressure 
Cyclosporine can cause blood pressure increase. After informed consent is obtained follow 
Table 7-1 and Section 7.2.2.2 for regular blood pressure monitoring guidelines.  
If there is an increase in blood pressure, treatment with an appropriate antihypertensive agent 
must be initiated. Preference must be given to an antihypertensive agent that does not interfere 
with the pharmacokinetics of cyclosporine.  
Potassium-sparing drugs must not be used as hyperkalemia can occur. If there is no 
improvement in blood pressure, cyclosporine dose must be decreased by 25% to 50%. 
Cyclosporine must be discontinued if antihypertensive treatment(s) and dose decreases do not 
result in return to baseline blood pressure. 
6.3.1.4 
Cyclosporine dose modification due to nephrotoxicity 
After informed consent is obtained follow Table 7-1 and Section 7.2.2.5 for regular serum 
creatinine and BUN monitoring. Cyclosporine can cause nephrotoxicity.  
The cyclosporine induced nephrotoxicity is usually associated with elevation of serum 
creatinine and blood urea nitrogen (BUN) levels. These changes are usually dependent on the 
cyclosporine dose and initially reversible with a dose reduction. In general, fine-tuning of the 
cyclosporine dose to the lower end of the therapeutic range, adequate hydration, optimization 
of blood pressure control, and avoidance of other nephrotoxic agents, can improve the safety 
and tolerability.  
A peripheral blood smear evaluation is recommended to rule out hemolytic uremic syndrome.  
If the serum creatinine is greater than or equal to 25% above the patient’s pre-treatment level, 
serum creatinine must be repeated within two weeks. In the interim, increase of fluid intake and 
decrease dose of other concomitant nephrotoxic medications (e.g., antibiotics) is recommended. 
If the change in serum creatinine remains greater than or equal to 25% above baseline, 
Cyclosporine may be reduced by 25% to 50%. If at any time the serum creatinine increases by 
greater than or equal to 50% above pretreatment level, the cyclosporine must be reduced by 
25% to 50%. Cyclosporine must be discontinued if reversibility (within 25% of baseline) of 
serum creatinine is not achievable after two dose modifications. 
6.3.2 
Dose adjustments for QTcF prolongation 
In case of QTcF >500 msec, (or QTcF prolongation >60 msec from baseline) 
1. Assess the quality of the ECG recording and the QT value and repeat if needed 
2. Interrupt study treatment 
3. Determine the serum electrolyte levels (in particular hypokalemia, hypomagnesemia). If 
abnormal, correct abnormalities before resuming study drug treatment. 
4. Review concomitant medication associated with QT prolongation, including drugs with a 
“Known”, “Possible”, or “Conditional risk of Torsades de Pointes” (refer to 
www.qtdrugs.org), and drugs with the potential to increase the risk of study drug exposure 
related QT prolongation  
5. Check study drug dosing schedule and treatment compliance 


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6. Consider collecting a time-matched PK sample, and record time and date of last study 
drug intake. 
After confirming ECG reading at site, if QTcF > 500 msec 
• Interrupt study treatment  
• Repeat ECG and confirm ECG diagnosis by a cardiologist or central ECG lab 
• If QTcF confirmed > 500 msec: 
• Correct electrolytes, eliminate culprit concomitant treatments, and identify and 
address clinical conditions that could potentially prolong the QT as per the ECG and 
QTc Clinical Safety Standards Guidelines Section 3.3.1. 
• Consult with a cardiologist (or qualified specialist) 
• Increase cardiac monitoring as indicated, until the QTcF returns to ≤ 480 msec. 
• After resolution to ≤ 480 msec, consider re-introducing treatment at reduced dose, and 
increase ECG monitoring for the next treatment(s): 
• If QTcF remains ≤ 500 msec after dose reduction, continue planned ECG monitoring 
during subsequent treatment 
• If QTcF recurs > 500 msec after dose reduction, discontinue patient from study. 
6.3.3 
Follow-up for toxicities 
Patients whose treatment is interrupted or permanently discontinued due to an adverse event or 
clinically significant laboratory value, must be followed-up at least once a week (or more 
frequently if required by institutional practices, or if clinically indicated) for 4 weeks, and 
subsequently at approximately 4-week intervals, until resolution or stabilization of the event, 
whichever comes first. Appropriate clinical experts should be consulted as deemed necessary. 
All patients must be followed-up for adverse events and serious adverse events for 30 days 
following the last dose date of study treatment (eltrombopag and/or cyclosporine).  
6.3.3.1 
Dose delays, modifications or discontinuation for hematologic side 
effects  
Patients who experience a deep venous thrombosis (other than a line-related upper extremity 
thrombosis) or a pulmonary embolus, a transient ischemic attack or stroke, or a myocardial 
infarction at any time while on eltrombopag mustdiscontinue eltrombopag but may remain on 
cyclosporine. 
6.3.3.2 
Dose delays, modifications or discontinuation for non-hematologic 
side effects  
Infection 
Patients who experience an infection requiring intravenous antibiotics must not discontinue 
eltrombopag or cyclosporine. If the patient experiences infection severe enough to require 
vasopressors or intubation, eltrombopag and cyclosporine  must be interrupted until the patient 
is clinically stable. 


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6.3.4 
Anticipated risks and safety concerns of the study drug 
Thrombotic/Thromboembolic complications  
The risk of thromboembolic events (TEEs) has been found to be increased in patients with 
chronic liver disease treated with 75 mg eltrombopag once daily for two weeks in preparation 
for invasive procedures. Six of 143 (4%) adult patients with chronic liver disease receiving 
eltrombopag experienced TEEs (all of the portal venous system) and two of 145 (1%) patients 
in the placebo group experienced TEEs (one in the portal venous system and one myocardial 
infarction). Five of the 6 patients treated with eltrombopag experienced the thrombotic 
complication at a platelet count >20,000/µL and within 30 days of the last dose of eltrombopag. 
Eltrombopag is not indicated for the treatment of thrombocytopenia in patients with chronic 
liver disease in preparation for invasive procedures.  
In eltrombopag clinical studies in ITP, TEEs were observed at low and normal platelet counts. 
Caution should be used when administering eltrombopag to patients with known risk factors 
for thromboembolism including but not limited to inherited (e.g., Factor V Leiden) or acquired 
risk factors (e.g., ATIII deficiency, antiphospholipid syndrome), patients with prolonged 
periods of immobilization, malignancies, contraceptives and hormone replacement therapy, 
surgery/trauma, obesity and smoking. Platelet counts should be closely monitored and dose 
modifications must be made in accordance with parameters provided in the protocol. The risks 
of thromboembolism and any of the following complications versus the benefit of improved 
platelet counts must be evaluated by the Investigator for each patient with known risks of TEEs.  
Risk of hepatotoxicity  
Eltrombopag administration can cause hepatobiliary laboratory abnormalities, severe 
hepatotoxicity and potentially fatal liver injury. In the controlled clinical studies in chronic ITP 
with eltrombopag, increases in serum ALT, AST and bilirubin were observed. Hepatotoxicity 
should be monitored and eltrombopag must be discontinued if hepatobiliary abnormalities are 
observed as described in Section 6.3.3.2. 
Exercise caution when administering eltrombopag to patients with hepatic disease.  
Ophthalmic changes  
Cataracts were observed in toxicology studies of eltrombopag in rodents (Section 1.2.1.1.3), 
but has not been reported at significant rates over control groups in human studies. In controlled 
studies in thrombocytopenic patients with HCV receiving interferon therapy (n = 1439), 
progression of pre-existing baseline cataract(s) or incident cataracts was reported in 8% of the 
eltrombopag group and 5% of the placebo group. Retinal hemorrhages, mostly Grade 1 or 2, 
have been reported in HCV patients receiving interferon, ribavirin and eltrombopag (2% of the 
eltrombopag group and 2% of the placebo group. Hemorrhages occurred on the surface of the 
retina (preretinal), under the retina (subretinal), or within the retinal tissue. Ophthalmologic 
monitoring defined per protocol should be performed and eltrombopag continuation re-
considered in case of suspected cataract development or worsening or in case of retinal 
hemorrhages. In clinical studies of eltrombopag in SAA cataracts have not been reported. 


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Bone marrow reticulin formation and risk of bone marrow fibrosis  
Eltrombopag may increase the risk for development or progression of reticulin fibers within the 
bone marrow. The relevance of this finding, as with other TPO-R agonists, has not been 
established yet.  
If immature or dysplastic cells not linked to primary disease are observed, peripheral blood 
smears should be examined for new or worsening morphological abnormalities (e.g., teardrop 
and nucleated red blood cells, immature white blood cells) or cytopenia(s). If the patient 
develops new or worsening morphological abnormalities or cytopenia(s) not linked to primary 
disease, treatment with eltrombopag must be discontinued and a bone marrow biopsy 
considered, including staining for fibrosis.  
Progression to existing myelodysplastic syndrome 
TPO-R agonists are growth factors that lead to thrombopoietic progenitor cell expansion, 
differentiation and platelet production. The TPO-R is predominantly expressed on the surface 
of cells of the myeloid lineage. For this class of TPO-R agonists, there is a concern that they 
may stimulate the progression of existing hematopoietic malignancies such as myelodysplastic 
syndrome.  
In clinical studies with a TPO-R agonist, romiplostim and eltrombopag, in patients with MDS, 
cases of transient increases in blast cell counts were observed and cases of MDS disease 
progression to AML were reported.  
In the CETB115AUS01T study, eltrombopag in combination with IST was assessed in patients 
with SAA. Published results indicate that clonal cytogenetic evolution with dysplastic changes 
occurred at a similar frequency compared to NIH historic experience with standard IST (10-
15%) (Townsley 2017). All patients should be monitored regularly for new or worsening 
morphological abnormalities or cytopenia(s), and may require bone marrow evaluation, as 
clinically indicated. 
Eltrombopag must be discontinued in case of suspected myeloproliferation not linked to the 
primary disease or if there is a suspected myeloproliferation due to eltrombopag treatment. 
Bleeding events after study drug discontinuation 
Following discontinuation of eltrombopag, platelet counts return to baseline levels within 2 
weeks in the majority of patients, which increases the bleeding risk and in some cases may lead 
to bleeding. Platelet counts should be monitored as per protocol following discontinuation of 
eltrombopag. 
6.3.4.1 
Follow-up on potential drug-induced liver injury (DILI) cases 
Patients with transaminase increase combined with TBIL increase may be indicative of 
potential DILI, and should be considered as clinically important events. 
The threshold for potential DILI may depend on the patient’s baseline AST/ALT and TBIL 
value; patients meeting any of the following criteria must require further follow-up as outlined 
below: 


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• For patients with normal ALT and AST and TBIL value at baseline: [AST or ALT > 3.0 x 
ULN] combined with [TBIL > 2.0 x ULN] OR [INR > 1.5] without evidence of 
cholestasis (no ALP elevation) 
• For patients with elevated AST or ALT or TBIL value at baseline: [AST or ALT > 2 x 
baseline AND > 3.0 x ULN] OR [AST or ALT > 8.0 x ULN], combined with [TBIL > 2 x 
baseline AND > 2.0 x ULN] 
• For subjects with normal baseline ALT: [ALT ≥ 5.0 x ULN] 
Medical review must to ensure that liver test elevations are not caused by cholestasis, defined 
as ALP elevation > 2.0 x ULN with R value < 2 in patients without bone metastasis, or elevation 
of ALP liver fraction in patients with bone metastasis. 
Note: (The R value is calculated by dividing the ALT by the ALP, using multiples of the ULN 
for both values. It denotes whether the relative pattern of ALT and/or ALP elevation is due to 
cholestatic (R ≤ 2), hepatocellular (R ≥ 5), or mixed (R >2 and < 5) liver injury). 
In the absence of cholestasis, these patients must be immediately discontinued from study drug 
treatment, and repeat LFT testing as soon as possible, preferably within 48 hours from the 
awareness of the abnormal results. The evaluation must include laboratory tests, detailed history, 
physical assessment and the possibility of liver metastasis or new liver lesions, 
obstructions/compressions, etc. 
1. Laboratory tests must include ALT, AST, albumin, creatine kinase, total bilirubin, direct 
and indirect bilirubin, GGT, prothrombin time (PT)/INR and alkaline phosphatase. 
2 .  A detailed history, including relevant information, such as review of ethanol, concomitant 
medications, herbal remedies, supplement consumption, history of any pre-existing liver 
conditions or risk factors, must be collected. 
3. Further testing for acute hepatitis A, B, C or E infection and liver imaging (e.g., biliary 
tract) may be warranted. 
4. Obtain PK sample, as close as possible to last dose of study drug, if PK analysis is 
performed in the study. 
5. Additional testing for other hepatotropic viral infection (CMV, EBV or HSV), 
autoimmune hepatitis or liver biopsy may be considered as clinically indicated or after 
consultation with specialist/hepatologist. 
All cases confirmed on repeat testing meeting the laboratory criteria defined above, with no 
other alternative cause for LFT abnormalities identified must be considered as “medically 
significant”, thus, met the definition of SAE (Section 8.2.1) and reported as SAE using the term 
“potential drug-induced liver injury”. All events must be followed up with the outcome clearly 
documented. 
6.4 
Concomitant medications  
6.4.1 
Permitted concomitant therapy 
The patient must be told to notify the investigational site about any new medications he/she 
takes after the start of the study drug. All medications (other than study drug) and significant 
non-drug therapies (including physical therapy, herbal/natural medications and blood 


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transfusions) administered during the study must be listed on the Concomitant Medications or 
the Procedures and Significant Non-Drug Therapies eCRF. 
6.4.1.1 
Supportive Care 
Transfusions for platelets and/or red blood cells should be limited in this study, however, must 
be givenwhen medically needed.  
Note that patients who have a platelet transfusion within 7 days of a scheduled visit platelet 
measurement and/or a pRBC transfusion within 14 days of a scheduled visit hemoglobin 
measurement will not be considered for PR or CR at that scheduled visit. 
Platelet transfusions are recommended when:  
• Platelet level is <10 000 /µL, or  
• Platelets <20 000/µL and with active bleeding or  
• as medically necessary  
RBC transfusions are recommended when:  
• Hemoglobin is <8 g/dL, or if symptomatic according to local standard of care 
Infection management  
The use of antibiotics, anti-fungals, and granulocyte colony stimulating factor (G-CSF) is 
permitted. The local hospital guidelines for treatment of infections / febrile neutropenia should 
be followed.  
6.4.2 
Permitted concomitant therapy requiring caution and/or action  
6.4.2.1 
Eltrombopag 
HMG-CoA Reductase Inhibitors (statins)  
Patients will be permitted to use HMG-CoA reductase (3-hydroxy-3-methyl-glutaryl-CoA) 
inhibitors during the study, but these drugs should be used with caution and a 50% dose 
reduction of the HMG-CoA reductase inhibitor is recommended, with close monitoring for 
safety, such as liver chemistry and signs and symptoms of myolysis, and efficacy, such as 
cholesterol and triglycerides (refer to individual product information for monitoring 
recommendations). 
Preclinical data showed that eltrombopag is an inhibitor of the transporters OATP1B1 and 
BCRP. Therefore, a clinical drug interaction study to evaluate the impact of eltrombopag on the 
PK of rosuvastatin, an OATP1B1 and BCRP substrate, was conducted in healthy patients. Co-
administration of eltrombopag 75 mg once daily for 5 days with a single 10 mg dose of 
rosuvastatin administered on Day 5 increased plasma rosuvastatin Cmax 2.03-fold and AUCinf 
55%. 
Concomitant administration of eltrombopag and other OATP1B1 or BCRP substrates should 
be used with caution.  


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Polyvalent Cations (Chelation)  
Eltrombopag chelates with polyvalent cations such as aluminum, calcium, iron, magnesium, 
selenium and zinc. Eltrombopag must be taken at least two hours before or four hours after any 
products such as antacids, dairy products, or mineral supplements containing polyvalent cations 
to avoid significant reduction in eltrombopag absorption. 
Food Interaction  
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. To avoid significant 
reduction in eltrombopag absorption, eltrombopag must be taken at least two hours before or 
four hours after food containing >50 mg calcium and at least one hour before or two hours after 
food containing little (<50 mg) (or preferably no) calcium. 
6.4.2.2 
Cyclosporine 
The concomitant use of cyclosporine with the following requires caution according to the local 
prescribing information: 
• 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 cyclosporine; 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 cyclosporine; 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 antagonists (cimetidine, ranitidine), 
methotrexate, tacrolimus 
• Concomitant use with nifedipine may results in increased rate of gingival hyperplasia 
• Cyclosporine 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.  
• Cyclosporine 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 


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toxicity. Co-administration of cyclosporine increases blood/plasma concentrations of 
everolimus, sirolimus, repaglinide, bosetan, aliskiren, dabigatran, and the anthracyclines 
6.4.3 
Prohibited concomitant therapy 
As far as possible avoid co-administering drugs with a “Known”, “Possible”, or “Conditional” 
risk of Torsades de Pointes (per www.qtdrugs.org. or any other drug with the potential to 
increase the risk of drug-related QT prolongation) during the course of the study: 
• If concomitant administration of drugs with a “Known risk of Torsades de Pointes” is 
required and cannot be avoided, both study drugs must be interrupted. If, based on the 
investigator assessment and clinical need, study treatment is resumed, close ECG 
monitoring is advised.  
• If during the course of the study, concomitant administration of a drug with ¨Possible risk¨ 
or ¨Conditional risk of Torsades de Pointes¨ is required, based on the investigator 
assessment and clinical need, study treatment may be continued under close ECG 
monitoring to ensure patient safety. 
A list of drugs associated with QT prolongation and/or TdP is available online at qtdrugs.org 
6.4.3.1 
Eltrombopag 
Patients must abstain from using investigational 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. 
Patients must abstain from taking herbal supplements within 7 days (or 14 days if the drug is a 
potential enzyme inducer) or 5-half-lives (whichever is longer) prior to the first dose of study 
treatment until completion of the 30-day follow-up visit. 
Any other TPO-R agonists are prohibited during this study (e.g., N-plate [romiplostim]). 
6.4.3.2 
Cyclosporine  
During treatment with cyclosporine, vaccination may be less effective and the use of live 
vaccines should be avoided. The local label should be considered in regard to contraindicated 
drugs during cyclosporine administration. 
6.4.4 
Use of Bisphosphonates (or other concomitant agents) 
Not applicable. 
6.5 
Patient numbering, treatment assignment or randomization 
6.5.1 
Patient numbering 
The investigator or designated staff will contact the IRT and provide the requested identifying 
information for the patient to register them into the IRT. Once assigned, the Patient No. must 
not be reused for any other patient and the Patient No. for that individual must not be changed, 


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even if the patient is re-screened. If the patient fails to be randomized or start treatment for any 
reason, the reason will be entered into the Screening Disposition page. 
IRT must be notified within 2 days that the patient was not enrolled. 
6.5.2 
Treatment assignment or randomization 
This is an open-label study. There is no randomization and all patients will receive study drugs 
(eltrombopag and cyclosporine).  
6.5.3 
Treatment blinding 
Not applicable. 
6.6 
Study drug preparation and dispensation 
The investigator or responsible site personnel must instruct the patient or caregiver to take the 
study drugs as per protocol. Study drug(s) will be dispensed to the patient by authorized site 
personnel only. All dosages prescribed to the patient and all dose changes during the study must 
be recorded on the Dosage Administration Record eCRF. 
Table 6-8 
Preparation and dispensing 
Study 
treatments 
Dispensing 
Preparation 
Eltrombopag 
Tablets including instructions for administration are dispensed 
by study personnel on an outpatient basis. 
Patients will be provided with adequate supply of study 
treatment for self-administration at home until at least their next 
scheduled study visit. 
Not applicable  
Cyclosporine 
Capsules including instructions for administration are 
dispensed by study personnel on an outpatient basis.  
Patients will be provided with adequate supply of study 
treatment for self-administration at home until at least their next 
scheduled study visit.  
Refer to local product 
information for 
dispensing instructions 
for cyclosporine oral 
solution 
6.6.1 
Study treatment packaging and labeling 
Study treatment, eltrombopag, will be sourced as local commercial supply (in the locally 
approved formulation and packaging configuration) and labeled in the country or region.  
If needed, clinical supplies will be supplied by global DSM as a back up option.  
Study treatment labels will comply with the legal requirements of each country and will include 
storage conditions, a unique medication number (corresponding to study treatment and strength) 
or randomization number if appropriate. 
If the label has 2-parts (base plus tear-off label), immediately before dispensing the package to 
the patient, site personnel will detach the outer part of the label from the package and affix it to 
the patient’s source document. 


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Table 6-9 
Packaging and labeling 
Study treatments 
Packaging 
Labeling (and dosing frequency) 
Eltrombopag 
Refer to local product information 
Refer to local product information 
Cyclosporine 
Refer to local product information 
Refer to local product information 
6.6.2 
Drug supply and storage 
Study treatments must be received by designated personnel 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, the study treatment should be stored according to 
the instructions specified on the drug labels and in the Investigator’s Brochure. 
Table 6-10 
Supply and storage of study treatments  
Study treatments 
Supply 
Storage 
Eltrombopag 
Locally / Centrally 
Refer to local product information 
Cyclosporine 
Locally / Centrally 
Refer to local product information 
A local commercial supply is used to conduct this study; only formulations available in each 
country will be relabeled and supplied for the study purpose. 
6.6.3 
Study drug compliance and accountability 
6.6.3.1 
Study drug compliance 
Compliance will be assessed by the investigator and/or study personnel at each patient visit and 
information provided by the patient and/or caregiver will be captured in the Drug 
Accountability Form. This information must be captured in the source document at each patient 
visit. 
6.6.3.2 
Study drug accountability 
The investigator or designee must maintain an accurate record of the shipment and dispensing 
of study treatment in a drug accountability log. Drug accountability will be noted by the field 
monitor during site visits and at the completion of the study. Patients will be asked to return all 
unused study treatment and packaging on a regular basis, at the end of the study or at the time 
of study treatment discontinuation. 
At study close-out, and, as appropriate during the course of the study, the investigator will return 
all used and 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. 
6.6.3.3 
Handling of other study treatment 
Not applicable. 
6.6.4 
Disposal and destruction 
The study drug supply can be destroyed at the local Novartis facility, Drug Supply group or 
third party, as appropriate. 


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7 
Visit schedule and assessments 
7.1 
Study flow and visit schedule 
Table 7-1 and Table 7-2 list all of the assessments and indicate with an “X”, the visits when 
they are performed. All data obtained from these assessments must be supported in the patient’s 
source documentation. 
Tests, procedures and visits should occur on Day 1 of the weekly schedule as summarized 
whenever possible but patients may be seen more often by the treating physician as clinically 
indicated:  
• Day 1 to Month 2: study visits should take place weekly 
• Month 2 to Month 6: study visits should take place every 2 weeks 
• Month 6 to Month 9 (responders only): will be evaluated every 2 weeks 
• Month 9 to Month 24 (responders only): will be evaluated every 4 weeks  
As optional, additional local assessments may be collected during regular clinic visit based on 
local standard at the discretion of investigator. Patients may be seen more often by the treating 
physician as clinically indicated.  
The landmark visits will be 3, 6, 12 and 24 months. The laboratory data from these visits will 
form the bases for the reporting on efficacy of the proposed regimen in this study. The following 
tests will be assessed at these landmark visits, if available as per local standard of care (SOC)*: 
• Complete blood count with differential 
• Clinical chemistry 
• Reticulocyte count 
• Peripheral blood cytometry for GPI-cells 
• Bone marrow biopsy and aspiration with cytogenetics (at screening, 6, 12, 24 months) 
However, tests, procedures, and visits that occur within the prescribed allowable windows as 
specified below will not constitute protocol deviations. All visit intervals are calculated from 
the first dose of study treatment which will take place on Day 1. All attempts should be made 
to return to the original schedule of visits if visits are completed out of window. Weekly and 
biweekly visits should be completed ± 1 day. Biweekly visits after 6 months should be 
completed ± 2 days. Monthly visits should be completed ± 3 days. Bimonthly visits should be 
completed ± 1 week.  
When electronic case report form(s) (eCRF[s]) will be used, the eCRF cannot be used as source 
document(s). 


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Table 7-1 
Visit evaluation schedule – First 6 months 
Visit Name 
Category 
Protocol Section 7. 
Screening 
Treatment period 1 (Active treatment period with combination treatment) 
Screening 
(-21 to -1 D) 
Months ]0-2] 
(weekly visits) 
Months ]2-6] 
(bi-weekly visits) 
Baseline Week 1 
(Day 1) 
Week 2 
Weeks 4-8 
Weeks 6 
Weeks 3-5-7 
Week 10 
Week 12 (3M)  
Weeks 16-20-24 
Weeks 14-18-22 
Week 26 (6M) 
EOT (eltrombopag 
&/or Cyclosporine) 
Time windows 
 
 
 
 
+/- 1D 
+/- 1D 
+/- 1D 
+/- 1D 
+/- 1D 
+/- 1D 
+/- 1D 
+/- 1D 
+/- 1D 
Obtain Informed Consent 
D 
7.1.2  
X 
 
 
 
 
 
 
 
 
 
 
IWRS/IRT  
D 
7.1.2.1  
X 
X 
 
 
 
 
 
 
 
 
X 
End of phase disposition 
D 
 
X 
 
 
 
 
 
 
 
 
 
X 
Patient history 
 
Demography 
D 
7.1.2.3  
X 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
D 
5.2 / 5.3  
X 
 
 
 
 
 
 
 
 
 
 
Eligibility checklist 
S 
 
 
X 
 
 
 
 
 
 
 
 
 
Medical history 
D 
7.1.2.3  
X 
 
 
 
 
 
 
 
 
 
 
Transfusion history 
D 
7.1.2.3  
X 
 
 
 
 
 
 
 
 
 
 
Diagnosis and Extent of 
disease 
D 
7.1.2.3  
X 
 
 
 
 
 
 
 
 
 
 
Physical examination 
S 
7.2.2.1  
X 
X 
 
 
 
 
 
 
 
 
X 
Performance status (ECOG) 
D 
7.2.2.4  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Weight 
D 
7.2.2.3  
X 
X 
 
 
 
 
 
 
 
 
X 
Height adult patient 
D 
7.2.2.3  
X 
 
 
 
 
 
 
 
 
 
 
Vital signs 
D 
7.2.2.2  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Prior/concomitant medications 
D 
7.1.2.3  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood component transfusion 
D 
7.1.2.3  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


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Visit Name 
Category 
Protocol Section 7. 
Screening 
Treatment period 1 (Active treatment period with combination treatment) 
Screening 
(-21 to -1 D) 
Months ]0-2] 
(weekly visits) 
Months ]2-6] 
(bi-weekly visits) 
Baseline Week 1 
(Day 1) 
Week 2 
Weeks 4-8 
Weeks 6 
Weeks 3-5-7 
Week 10 
Week 12 (3M)  
Weeks 16-20-24 
Weeks 14-18-22 
Week 26 (6M) 
EOT (eltrombopag 
&/or Cyclosporine) 
Time windows 
 
 
 
 
+/- 1D 
+/- 1D 
+/- 1D 
+/- 1D 
+/- 1D 
+/- 1D 
+/- 1D 
+/- 1D 
+/- 1D 
Laboratory assessments (central lab) 
Hematology 
 
Hematology – CBC with 
differential  
D 
7.2.2.5.1  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Reticulocyte count 
D 
7.2.2.5.1  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood type & screen 
S 
7.2.2.5.1  
X 
 
 
 
 
 
 
 
 
 
 
Coagulation 
D 
7.2.2.5.1  
 
X 
 
 
 
 
 
 
 
 
X 
Flow cytometry (for GPI-
deficient cells) 
D 
7.2.2.5.1  
 
X 
 
 
 
 
 
X 
 
 
X 
Chemistry 
 
HLA typing 
S 
7.2.2.5.2  
 
X 
 
 
 
 
 
 
 
 
 
Chemistry 
D 
7.2.2.5.2  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Folate/B12 
D 
7.2.2.5.2  
 
X 
 
 
 
 
 
 
 
 
X 
Viral serologies 
D 
7.2.2.5.2  
X 
 
 
 
 
 
 
 
 
 
 
Thyroids 
D 
7.2.2.5.1  
 
X 
 
 
 
 
 
 
 
 
X 
Additional tests 
D 
7.2.2.5.1  
 
X 
 
 
 
 
 
 
 
 
X 
Urinalysis 
 
Urinalysis 
D 
7.2.2.5.3  
 
X 
 
 
 
 
 
 
 
 
X 
Pregnancy test  
D 
7.2.2.5.4  
X 
X 
 
X 
 
 
 
X 
X 
 
X 
Bone Marrow assessments 
D 
 


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Visit Name 
Category 
Protocol Section 7. 
Screening 
Treatment period 1 (Active treatment period with combination treatment) 
Screening 
(-21 to -1 D) 
Months ]0-2] 
(weekly visits) 
Months ]2-6] 
(bi-weekly visits) 
Baseline Week 1 
(Day 1) 
Week 2 
Weeks 4-8 
Weeks 6 
Weeks 3-5-7 
Week 10 
Week 12 (3M)  
Weeks 16-20-24 
Weeks 14-18-22 
Week 26 (6M) 
EOT (eltrombopag 
&/or Cyclosporine) 
Time windows 
 
 
 
 
+/- 1D 
+/- 1D 
+/- 1D 
+/- 1D 
+/- 1D 
+/- 1D 
+/- 1D 
+/- 1D 
+/- 1D 
Bone marrow aspirate, bone 
marrow biopsy and 
cytogenetics 
D 
7.2.2.6  
X 
 
 
 
 
 
 
 
 
 
X 
Safety 
D 
 
Adverse events 
D 
8.1  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECG 
D 
7.2.2.8.1  
X 
X 
 
 
 
 
 
 
 
 
X 
Cyclosporine level 
D 
6.1.1.2  
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PRO measures 
 
FACIT-Fatigue 
D 
7.2.6  
 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
FACT-TH18 (included FACT-
G) 
D 
7.2.6  
 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 


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Visit Name 
Category 
Protocol Section 7. 
Screening 
Treatment period 1 (Active treatment period with combination treatment) 
Screening 
(-21 to -1 D) 
Months ]0-2] 
(weekly visits) 
Months ]2-6] 
(bi-weekly visits) 
Baseline Week 1 
(Day 1) 
Week 2 
Weeks 4-8 
Weeks 6 
Weeks 3-5-7 
Week 10 
Week 12 (3M)  
Weeks 16-20-24 
Weeks 14-18-22 
Week 26 (6M) 
EOT (eltrombopag 
&/or Cyclosporine) 
Time windows 
 
 
 
 
+/- 1D 
+/- 1D 
+/- 1D 
+/- 1D 
+/- 1D 
+/- 1D 
+/- 1D 
+/- 1D 
+/- 1D 
Other assessment 
 
Eltrombopag PK sampling 
D 
7.2.3  
 
 
X 
X 
 
 
 
X 
 
 
X 
Ophthalmic exam 
S 
7.2.2.1  
X 
X 
 
 
 
 
 
 
 
 
X 
Neurologic exam 
S 
7.2.2.1  
X 
X 
 
 
 
 
 
 
 
 
X 
Radiological examination 
S 
7.2.2.7 
At the investigator’s discretion 
Study Drug administration  
 
Eltrombopag 
D 
6.1.1.1  
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Cyclosporine 
D 
6.1.1.2  
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Prophylactic therapy 
 
Trimethoprim/sulfame-
thoxazole 
D 
6.1.2  
 
 
At the investigator’s discretion 
D = entered into database, S = remains in source document only 


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Table 7-2 
Visit evaluation schedule –Follow-up for duration of response (Responders only) 
Visit Name 
Category
Protocol Section 7. 
Follow-up (cyclosporine tapering down 
 
Months [6-9] 
(visits q 2 weeks) 
Months [9-24] 
(visits q 1 month) 
Safety 
follow
-up 
Week 28 - 36 
Week 38 (9M) 
Week 42 
Week 46 
Week 50 
Week 53 (1Y) 
Months 13-14-15-16-17 
Month 18 
Months 19-20-21-22-23 
Months 24 (2Y) or EOS 
30 D after study 
treatment stop - early 
discontinuation 
Recommended 
visit for 
analysis 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
Time windows 
 
 
+/- 2D 
+/- 2D 
+/- 3D 
+/- 3D 
+/- 3D 
+/- 3D 
+/- 3D  
+/- 3D  
+/- 3D  
+/- 3D  
IWRS/IRT  
D 7.1.2.1  
 
 
 
 
 
 
 
 
 
X 
 
End of phase 
disposition 
D  
 
 
 
 
 
 
 
 
 
X 
 
Physical 
examination 
S 
7.2.2.1  
 
 
 
 
 
X 
 
X 
 
X 
 
Performance 
status (ECOG) 
D 7.2.2.4  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Weight 
D 7.2.2.3  
 
 
 
 
 
X 
 
X 
 
X 
 
Vital signs 
D 7.2.2.2  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Concomitant 
medications 
D 7.1.2.3  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Blood 
component 
transfusion 
D 7.1.2.3  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 


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Visit Name 
Category
Protocol Section 7. 
Follow-up (cyclosporine tapering down 
 
Months [6-9] 
(visits q 2 weeks) 
Months [9-24] 
(visits q 1 month) 
Safety 
follow
-up 
Week 28 - 36 
Week 38 (9M) 
Week 42 
Week 46 
Week 50 
Week 53 (1Y) 
Months 13-14-15-16-17 
Month 18 
Months 19-20-21-22-23 
Months 24 (2Y) or EOS 
30 D after study 
treatment stop - early 
discontinuation 
Recommended 
visit for 
analysis 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
Time windows 
 
 
+/- 2D 
+/- 2D 
+/- 3D 
+/- 3D 
+/- 3D 
+/- 3D 
+/- 3D  
+/- 3D  
+/- 3D  
+/- 3D  
Local laboratory assessments 
Hematology 
 
Hematology – 
CBC with 
differential  
D 7.2.2.5.1  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Reticulocyte 
count 
D 7.2.2.5.1  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Coagulation 
D 7.2.2.5.1  
 
 
 
 
 
X 
 
X 
 
X 
 
Flow cytometry 
(for GPI-deficient 
cells) 
D 7.2.2.5.1  
 
 
 
 
 
X 
 
 
 
X 
 
Chemistry 
 
Chemistry 
D 7.2.2.5.2  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Folate/B12 panel 
D 7.2.2.5.2  
 
 
 
 
 
X 
 
X 
 
X 
 
Thyroids 
D 7.2.2.5.1  
 
 
 
 
 
 
 
 
 
 
 
Additional tests 
D 7.2.2.5.1  
 
 
 
 
 
 
 
 
 
 
 


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Visit Name 
Category
Protocol Section 7. 
Follow-up (cyclosporine tapering down 
 
Months [6-9] 
(visits q 2 weeks) 
Months [9-24] 
(visits q 1 month) 
Safety 
follow
-up 
Week 28 - 36 
Week 38 (9M) 
Week 42 
Week 46 
Week 50 
Week 53 (1Y) 
Months 13-14-15-16-17 
Month 18 
Months 19-20-21-22-23 
Months 24 (2Y) or EOS 
30 D after study 
treatment stop - early 
discontinuation 
Recommended 
visit for 
analysis 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
Time windows 
 
 
+/- 2D 
+/- 2D 
+/- 3D 
+/- 3D 
+/- 3D 
+/- 3D 
+/- 3D  
+/- 3D  
+/- 3D  
+/- 3D  
Pregnancy test  
D 7.2.2.5.4  
X (on monthly basis or as per local standard, if no visit planned the test can be performed at home with urine pregnancy test 
till 2 months after the cyclosporine stop – only blood test results will be collected in the eCRF) 
 
Bone Marrow assessments 
Bone marrow 
aspirate, bone 
marrow biopsy 
and cytogenetics 
D 7.2.2.6  
 
 
 
 
 
X 
 
 
 
X 
 
Safety 
 
Adverse events 
D 8.1  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECG 
D 7.2.2.8.1  
 
 
 
 
 
X 
 
 
 
X 
 
Cyclosporine 
level 
S 
6.1.1.2  
 
 
 
 
 
X 
 
 
 
X 
 
PRO measures 
 
FACIT-Fatigue 
D 7.2.6  
 
X 
 
 
 
X 
 
 
 
X 
 


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Visit Name 
Category
Protocol Section 7. 
Follow-up (cyclosporine tapering down 
 
Months [6-9] 
(visits q 2 weeks) 
Months [9-24] 
(visits q 1 month) 
Safety 
follow
-up 
Week 28 - 36 
Week 38 (9M) 
Week 42 
Week 46 
Week 50 
Week 53 (1Y) 
Months 13-14-15-16-17 
Month 18 
Months 19-20-21-22-23 
Months 24 (2Y) or EOS 
30 D after study 
treatment stop - early 
discontinuation 
Recommended 
visit for 
analysis 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
Time windows 
 
 
+/- 2D 
+/- 2D 
+/- 3D 
+/- 3D 
+/- 3D 
+/- 3D 
+/- 3D  
+/- 3D  
+/- 3D  
+/- 3D  
FACT-TH18 
(included FACT-
G) 
D 7.2.6  
 
X 
 
 
 
X 
 
 
 
X 
 
Other assessment 
Ophthalmic 
exam 
S 
7.2.2.1  
 
 
 
 
 
 
 
 
 
X 
 
Neurologic exam 
S 
7.2.2.1  
 
 
 
 
 
 
 
 
 
X 
 
Radiological 
examination 
S 
7.2.2.7 
At the investigator discretion 
Study Drug administration  
Cyclosporine  
D 6.1.1.2  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Prophylactic therapy 
Trimethoprim/sul
fame-thoxazole 
D 6.1.2  
At the discretion of the investigator 
 


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7.1.1 
Molecular pre-screening  
Not applicable. 
7.1.2 
Screening 
All patients will be screened for study eligibility. All patients must sign informed consent prior 
to any screening procedures being performed.  
Activities for screening will begin up to 21 days prior to initiation of study treatment with 
eltrombopag and cyclosporine. During this time, all patients will complete a bone marrow 
aspirate and biopsy to confirm current SAA diagnosis. The criteria for diagnosis of SAA are 
found in Section 5.2 Inclusion Criteria. Cytogenetics analysis and all other analysis will be 
completed to verify inclusion and exclusion criteria. 
Transfusion history for platelets and red blood cells within the 4-weeks prior to initiation of 
dosing of eltrombopag and cyclosporine will be recorded (= within 4-weeks before baseline 
visit).  
Information regarding eligibility criteria will be collected on the Inclusion/Exclusion eCRF. 
Patients who do not meet all entry criteria should not be entered into the study.  
A re-screening due to lab abnormalities can be submitted to the sponsor for decision. If the re-
screening is authorized, the same patient ID will be used.  
The bone marrow aspirate and biopsy must be performed according to section 7.2.2.7. 
7.1.2.1 
Eligibility screening  
Following registering in the IRT for screening, patient eligibility will be checked once all 
screening procedures are completed. The eligibility check will be embedded in the IRT system. 
Please refer and comply with detailed guidelines in the IRT manual. 
7.1.2.2 
Information to be collected on screening failures 
Patients who sign an informed consent but fail to be started on treatment for any reason will be 
considered a screen failure. The reason for not being started on treatment will be entered on the 
Screening Phase Disposition Page. The demographic information, informed consent, and 
Inclusion/Exclusion pages must also be completed for Screen Failure patients. No other data 
will be entered into the clinical database for patients who are screen failures, unless the patient 
experienced a Serious Adverse Event during the Screening Phase (see Section 8 for SAE 
reporting details). 
7.1.2.3 
Patient demographics and other baseline characteristics 
The following patient demographics and baseline characteristics will be collected on the eCRF:  
• Demography including year of birth, sex, predominant race and ethnicity (where 
permitted)  
• Height and weight (see Section 7.2.2.3)  


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• Medical history (e.g., important medical, surgical, and allergic conditions from the 
patient’s medical history which could have an impact on the patient’s evaluation) / current 
medical conditions (e.g., all relevant current medical conditions which are present at the 
time of signing informed consent). Ongoing medical conditions, symptoms and diseases 
which are recorded on the Medical History eCRF should include the toxicity grade when 
applicable 
• Prior and concomitant medications 
• Transfusion history (within 4 weeks prior to first dose) 
All assessments to be completed and documented during screening and at baseline are detailed 
in Table 7-1. 
7.1.3 
Run-in period  
Not applicable. 
7.1.4 
Treatment period 
The treatment period will begin with initiation of treatment with eltrombopag and cyclosporine 
on Day 1 and continue until completion of cyclosporine at 24 months. For details of assessments, 
refer to Table 7-1 and Table 7-2. 
Eltrombopag and cyclosporine administration will be followed in dedicated eCRF pages. 
The other medications will be reported as concomitant medications like prophylactic treatment 
or all other treatment administrated during the study conduct. 
PK 
 sampling will be done on all patients enrolled in the study, for details of 
assessments refer to Sections 7.2.3 and 7.2.4. 
7.1.5 
Discontinuation of study treatment 
Patients may voluntarily discontinue from the study treatment (eltrombopag and/or 
cyclosporine) for any reason at any time. If a patient decides to discontinue from the study or 
fail to return, the investigator should make a  reasonable effort (e.g. telephone, e-mail, letter) 
to understand the primary reason for this decision and record this information in the patient’s 
chart and on the appropriate eCRF pages, see section 7.1.8. They may be considered withdrawn 
if they state an intention to withdraw, fail to return for visits, or become lost to follow-up for 
any other reason. 
The investigator may discontinue eltrombopag and/or cyclosporine for a given patient if he/she 
believes that continuation would be detrimental to the patient’s well-being. 
Patients who discontinue eltrombopag before 6 months, should continue cyclosporine treatment 
until 6 months (all patients) and until 24 months (responders only). 
Patients who discontinue cyclosporine before 6 months, should continue eltrombopag treatment 
until 6 months. 
Patients who discontinue both eltrombopag and cyclosporine before 6 months or discontinue 
cyclosporine during the additional 18 months follow-up (responders only) should be scheduled 
for an end of study treatment visit as soon as possible after the last dose of study treatment 


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(eltrombopag and cyclosporine), at which time all the assessments listed in the visit evaluation 
schedule (under EOT) will be performed (Table 7-2). At a minimum, all patients who 
discontinue eltrombopag and/or cyclosporine (premature discontinuation, with patients no 
longer being in the study), including those who refuse to return for a final visit, will be contacted 
for safety evaluations during the 30 days following the last dose of study treatment. 
The investigator must also contact the IRT to register the patient’s discontinuation from 
study treatment. 
7.1.5.1 
Replacement policy  
Patients who discontinue from the study will not be replaced. See section 10.8 for the 
enrollment of additional patients. 
7.1.6 
Withdrawal of consent 
Patients may voluntarily withdraw consent to participate in the study for any reason at any 
time. Withdrawal of consent occurs only when a patient does not want to participate in the 
study any longer, and does not want any further visits or assessments, and does not want any 
further study related contact. 
Novartis will continue to retain and use all research results that have already been collected 
for the study evaluation. All biological samples that have already been collected may be 
retained and analyzed at a later date (or as required by local regulations). 
If a patient withdraws consent, the investigator should make a reasonable effort (e.g. telephone, 
e-mail, letter) to understand the primary reason for this decision and record this information. 
Study treatment must be discontinued and no further assessments conducted. 
Further attempts to contact the patient are not allowed unless safety findings require 
communication or follow-up. 
7.1.7 
Follow up for safety evaluations 
Patients will have safety evaluations and efficacy evaluations for the duration of the study.  
All patients who are responders by 6 months will continue to have safety and efficacy 
evaluations up to 24 months.  
All patients who are non-responders by 6 months must have safety evaluations 30 days after the 
last dose of study treatment and then discontinue from the study 
Data collected should be added to the Adverse Events eCRF and the Concomitant Medications 
eCRF.  
7.1.8 
Lost to follow-up 
For patients whose status is unclear because they fail to appear for study visits without stating 
an intention to withdraw consent, the investigator should show "due diligence" by contacting 
the patient, family or family physician as agreed in the informed consent and by documenting 
in the source documents steps taken to contact the patient, e.g. dates of telephone calls, 
registered letters, etc. A patient should not be considered lost to follow-up until due diligence 


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has been completed. Patients lost to follow up should be recorded as such on the appropriate 
Disposition eCRF. 
7.2 
Assessment types 
7.2.1 
Efficacy assessments 
Efficacy assessments will be performed according to the results of the laboratory assessments. 
The primary efficacy endpoint will be based on hematologic and bone marrow assessments by 
6 months. Secondary efficacy endpoints will be based on hematologic and bone marrow 
assessments at the landmark visits.  
Patients will be evaluated to assess if the criteria for partial response (PR), or complete response 
(CR) were met. Patients will also be assessed for overall response (OR) (CR + PR).  
Partial response (PR) is defined as any two of the parameters meeting the following criteria at 
two consecutive, scheduled visit measurements at least 7 days apart during the study (and not 
meeting CR definition) and no platelet transfusions within 7 days of platelet measurement (can 
still be a PR if ANC and reticulocyte measurements are valid):  
• Absolute neutrophil count ≥ 500/µL 
• Platelet count ≥ 20000/µL 
• Reticulocyte count ≥ >60 000/µL (automated) 
Complete response (CR) is defined as all three parameters meeting the following criteria at two 
consecutive, scheduled visit measurements at least 7 days apart during the study and no platelet 
transfusions within 7 days of platelet measurement and no RBC transfusion within 14 days of 
the hemoglobin measurement:  
• Absolute neutrophil count ≥ 1 000/µL 
• Platelet count ≥ 100000/µL 
• Hemoglobin ≥ 10 g/dL 
7.2.2 
Safety and tolerability assessments 
Safety will be monitored by assessing hematology, blood chemistry, urinalysis, vital signs, 
cardiac 
assessment, 
physical 
examinations, 
neurological 
examinations, 
ophthalmic 
examinations and study drug compliance assessments as well as collecting of the adverse events 
at every visit. For details on AE collection and reporting, refer to Section 8. 
7.2.2.1 
Physical examination 
A complete physical examination will include the examination of general appearance, skin, 
neck (including thyroid), eyes, ears, nose, throat, lungs, heart, abdomen, back, lymph nodes, 
extremities, vascular and neurological. If indicated based on medical history and/or symptoms, 
rectal, external genitalia, breast, and pelvic exams will be performed. All vital signs, as well as 
height and weight will be recorded. Neurological and ophthalmic exams will also be included. 
A complete physical examination should be completed approximately every 6 months as per 
the Visit Schedule (Table 7-1 and Table 7-2).  


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Significant findings that were present prior to the signing of informed consent must be included 
in the Medical History page on the patient’s eCRF. Significant new findings that begin or 
worsen after informed consent must be recorded on the Adverse Event page of the patient’s 
eCRF.  
Neurological examination  
The examination should include the following: level of consciousness, mental status, speech, 
cranial nerves, deep tendon reflexes, motor & sensory systems and gait. Neurologic exams will 
be performed at visits according to Table 7-1 and Table 7-2. Neurological exam should be 
performed either during the screening period or at Baseline (Day 1) prior to first study treatment 
whichever is more convenient for the site. 
Ophthalmic examination  
The ophthalmic exam should include the retina, blood vessels, optic disc/nerve. If the presence 
of a cataract(s) is suspected, a slit lamp examination is required. Ophthalmic exams will be 
performed at visits according to Table 7-1 and Table 7-2. Ophthalmic exam should be 
performed either during the screening period or at Baseline (Day 1) prior to first study treatment 
whichever is more convenient for the site. 
Significant findings that were present prior to the signing of informed consent must be included 
in the Medical History page on the patient’s eCRF. Significant new findings that begin or 
worsen after informed consent must be recorded on the Adverse Event page of the patient’s 
eCRF. 
7.2.2.2 
Vital signs 
Vital signs include body temperature, respiratory rate, blood pressure and pulse measurements. 
Vital signs should be taken before any study medication is given on each assessment day (i.e. 
pre-dose).  
Blood pressure will be taken:  
• After the patient has rested for at least 3 minutes. The appropriate cuff size must be used 
to ensure accurate measurement  
• Measurements will be taken per local practice  
If the blood pressure reading is outside the age appropriate normal ranges, repeat the 
measurement, waiting 1-2 minutes between readings, to verify the initial reading. Repeat 
measurements will be documented in the eCRF. 
7.2.2.3 
Height and weight 
Height in centimeters (cm) will be measured at screening according to Table 7-1.  
Body weight (to the nearest 0.1 kilogram [kg], in indoor clothing, but without shoes) will be 
measured at screening and at subsequent time points as specified in Table 7-1 and Table 7-2. 


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7.2.2.4 
ECOG performance status 
The Eastern Cooperative Oncology Group (ECOG) performance status scale will be used as 
described in the Table 7-1. 
7.2.2.5 
Laboratory evaluations 
Clinical laboratory analyses managed by central laboratory are detailed in the Table 7-3 for the 
first 6 months only. All other analysis required in the VES for first 6 months and analysis done 
during the additional 18 months follow-up (responders only) as per standard of care will be 
managed by local laboratory and are detailed in Table 7-4 and Table 7-5. 
At any time during the study, abnormal laboratory parameters which are clinically significant 
and require an action to be taken with study treatment (e.g., require dose modification and/or 
interruption of study treatment, lead to clinical symptoms or signs, or require therapeutic 
intervention), whether specifically requested in the protocol or not, will be recorded on the AE 
eCRF page.  
A central laboratory will be used for analysis of listed specimens collected in the first 6 months 
of the study. Details on the collections, shipment of samples and reporting of results by the 
central laboratory are provided to investigators in the laboratory manual. 
Table 7-3 
Clinical laboratory parameters collection plan for central lab (first 6 
months) 
Test Category 
Test Name 
Hematology 
Hematocrit, Hemoglobin, MCH, MCHC, MCV, Platelets, Red blood cells, White blood 
cells, RBC Morphology, Differential (absolute and percentages)(Basophils, Eosinophils, 
Lymphocytes, Monocytes, Neutrophils and Other), Reticulocytes, and a Peripheral 
blood smear 
Folate/B12 panel 
Serum folate, Vitamin B12 (cobalamin)  
Viral serologies 
included 
Hepatitis markers 
Hepatitis A, B, C, human immunodeficiency virus (HIV), Herpes simplex virus (HSV), 
Epstein Barr virus (EBV), and cytomegalovirus (CMV) 
HBV-DNA, HbsAg, HbsAb, HbcAb, HCV RNA-PCR (baseline) 
Chemistry 
Albumin, Alkaline phosphatase, ALT , AST , Gamma-glutamyl-transferase (GGT), 
Lactate dehydrogenase (LDH), Bicarbonate, Calcium, Magnesium, Phosphorus, 
Chloride, Sodium, Potassium, Creatinine, Creatine kinase, Direct Bilirubin, Indirect 
Bilirubin, Total Bilirubin, Total Cholesterol, LDL, HDL, Total Protein, Triglycerides, 
Blood Urea Nitrogen (BUN) or Urea, Uric Acid 
Amylase, Lipase, Glucose (fasting) 
Urinalysis 
Microscopic Panel (Red Blood Cells, White Blood Cells, Casts, Crystals, Bacteria, 
Epithelial cells) 
Macroscopic Panel (Color, Bilirubin, Blood, Glucose, Ketones, Leukocytes esterase, 
Nitrite, pH, Protein, Specific Gravity, Urobilinogen) 
Coagulation 
Prothrombin time (PT), International normalized ratio [INR], Activated partial 
thromboplastin time (APTT)  
Thyroid 
T3 [free], T4 [free], TSH 
Flow cytometry 
CD4, CD3, CD8, CD19, CD16+56, CD3+4+8, CD4/CD8 Ratio, CD3/CD19 Ratio, 
peripheral blood GPI-deficient cells (absolute value preferred, %s are acceptable) 
Additional tests 
Urine free cortisol (UFC), Insulin-like growth factor 1 (IGF-1), Alpha fetoprotein (AFP), 
Fractionated Alkaline Phosphatase, Testosterone (total and free), LH, FSH and SHBG 


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Test Category 
Test Name 
Pregnancy Test 
When effective contraception is required pregnancy testing is mandated at screening 
and/or pre-dose and at the end of the study. A serum pregnancy test should be 
performed in part 1, while during the part 2 as per SOC and at the end of study urinary 
pregnancy tests are sufficient. 
Table 7-4 
Clinical laboratory parameters collection plan for local lab (first 6 
months) 
Test Category 
Test Name 
Blood type & screen 
ABO and RhD typing, screening serum for atypical antibodies using 2-3 reagent 
screen cells 
HLA type 
Oligotyping, sequence-based typing (if not already available) 
Cyclosporine 
Cyclosporine through level 
Table 7-5 
Clinical laboratory parameters potentially collected as per local 
standard of care during the 18-months follow-up – Responders only 
Test Category 
Test Name 
Hematology 
Hematocrit, Hemoglobin, MCH, MCHC, MCV, Platelets, Red blood cells, White blood 
cells, RBC Morphology, Differential (Basophils, Eosinophils, Lymphocytes, Monocytes, 
Neutrophils), Bands, Reticulocytes, and a Peripheral blood smear 
Folate/B12 panel 
Serum folate, Vitamin B12 (cobalamin)  
Chemistry 
Albumin, Alkaline phosphatase, ALT , AST , Gamma-glutamyl-transferase (GGT), 
Lactate dehydrogenase (LDH), Bicarbonate, Calcium, Magnesium, Phosphorus, 
Chloride, Sodium, Potassium, Creatinine, Direct Bilirubin, Indirect Bilirubin, Total 
Bilirubin, Total Cholesterol, LDL, HDL, Total Protein, Triglycerides, Blood Urea Nitrogen 
(BUN) or Urea, Uric Acid 
Amylase, Lipase, Glucose (fasting)  
Coagulation 
Prothrombin time (PT), International normalized ratio [INR] 
Thyroid 
T3 [free], T4 [free], TSH 
Cyclosporine 
Cyclosporine through level 
Flow cytometry 
CD4, CD3, CD8, CD19, CD16+56, CD3+4+8, CD4/CD8 Ratio, CD3/CD19 Ratio, 
peripheral blood GPI-deficient cells (absolute value preferred, %s are acceptable) 
Additional tests 
Insulin-like growth factor 1 (IGF-1), Alpha fetoprotein (AFP), Testosterone (total and 
free), LH, FSH and SHBG 
Pregnancy Test 
A pregnancy test should be performed during cyclosporine administration as per local 
standard of care 
7.2.2.5.1 Hematology 
Hematology tests are to be performed by the central laboratory till first six months according to 
the schedule of assessments and collection plan outline, respectively, in Table 7-1, Table 7-2 
and Table 7-3. And then after 6 months (responders only) the hematology tests will be 
performed locally, as a minimum the 4 efficacy parameters (absolute neutrophil count, platelet 
count, reticulocyte count, hemoglobin) must be reported at each scheduled visit. 
Reticulocyte count 
Reticulocyte count is to be performed by the central laboratory till first six months according to 
the schedule of assessments and collection plan outline, respectively, in Table 7-1, Table 7-2 
and Table 7-3. And then after 6 months the reticulocyte count will be performed locally. 


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Blood type & screen 
Blood typing and screening is to be performed by the local laboratory at screening, if results are 
not already available in patient chart according to the schedule of assessments and collection 
plan outline, respectively, in Table 7-1 and Table 7-4. 
Coagulation 
Coagulation tests are to be performed at baseline by the central laboratory according to the 
schedule of assessments and collection plan outlined respectively in Table 7-1, Table 7-3 and 
Table 7-5. 
Peripheral blood cytometry for GPI-deficient cells 
Peripheral blood cytometry for the presence of GPI-deficient cells diagnostic of PNH will be 
performed by the central laboratory at baseline, at 3 months and at 6 months and according to 
the schedule of assessments and collection plan outline, respectively, in Table 7-1, Table 7-2 
and Table 7-3. And then after 6 months (responders only) the peripheral blood cytometry will 
be performed locally at 12 months and at 24 months. 
7.2.2.5.2 Clinical chemistry 
Chemistry testing is to be performed by the central laboratory at every visit till first six months 
according to the schedule of assessments and collection plan outline, respectively, in Table 7-
1, Table 7-2 and Table 7-3. And then after 6 months chemistry testing will be performed locally 
at each proposed visit. 
Folate/B12 panel 
Serum folate and vitamin B12 are to be performed by the central laboratory at baseline and at 
month 6 according to the schedule of assessments and collection plan outline, respectively, in 
Table 7-1, Table 7-2 and Table 7-3.  
HLA typing  
Human leukocyte antigen typing is to be performed by the local laboratory, if results are not 
already available in patient chart, as per standard of care. These results will be collected at 
baseline according to the schedule of assessments and collection plan outline, respectively, in 
Table 7-1. 
Viral serologies 
Viral serology testing is to be performed by the central laboratory at screening according to the 
schedule of assessments and collection plan outline, respectively, in Table 7-1. 


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Thyroid test 
T3 [free], T4 [free], TSH will be measured according to the schedule of assessments and 
collection plan outline, respectively, in Table 7-1 and Table 7-2. 
Additional tests 
Urine free cortisol (UFC), Insulin-like growth factor 1 (IGF-1), Alpha fetoprotein (AFP), 
Fractionated Alkaline Phosphatase, Testosterone (total and free), LH, FSH and SHBG will be 
measured according to the schedule of assessments and collection plan outline, respectively, in 
Table 7-1 and Table 7-2. 
7.2.2.5.3 Urinalysis 
Macroscopic urine panel for specific gravity, protein, glucose and blood will be performed at 
baseline and 6 months according to the schedule of assessments and collection plan outlined 
respectively in Table 7-1 and Table 7-3. Any significant findings on macroscopic urine panel 
will be followed up with a microscopic evaluation. 
7.2.2.5.4 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 schedule in Table 7-1 and Table 7-2.  
Serum pregnancy test is required at screening and monthly until the end of treatment of 
eltrombopag and cyclosporine or the end of the study (depending upon the reason why the 
patient discontinued study medication). During the additional 18 months follow-up (responders 
only) of the study, it is highly recommended to perform the pregnancy test on monthly basis 
but the SOC can be also followed at the discretion of the investigator practice. Urine or serum 
pregnancy testing will be repeated approximately every 4 weeks while receiving study drug 
until study drug discontinuation. A serum pregnancy test may be used to confirm the results of 
a urine pregnancy test. Additional pregnancy tests may be performed at the investigator’s 
discretion during the study. Additional pregnancy tests may be performed at the investigator’s 
discretion during the study. Patients becoming pregnant must be discontinued from study drug.  
Females of child-bearing potential who are or might become sexually active, must be informed 
of the potential teratogenic risk with eltrombopag and cyclosporine and the need for highly 
effective contraception to prevent pregnancy while on eltrombopag and cyclosporine therapy:  
Use of oral, injected or implanted hormonal methods of contraception or placement of an 
intrauterine device (IUD) or intrauterine system (IUS) or other forms of hormonal contraception 
that have comparable efficacy (failure rate < 1%), for example hormone vaginal ring or 
transdermal hormone contraception.  
Contraception must be used during the study and for 3 months 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.  


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Sexually active male patients, if they don’t agree to abstinence, must use agree to use of highly 
effective methods of contraception as outlined in the Inclusion Criteria while taking study drugs 
and for 3 months after stopping treatment, and should not father a child during this period. 
7.2.2.6 
Bone marrow assessments  
Bone marrow aspirate and biopsies, for cellularity and cytogenetics, morphology, degree of 
fibrosis, collagen, dysplasia, 
 will be sampled during Screening, 6 months and 
12 months after start of study treatment according to the schedule of assessments and collection 
plan outlined respectively in Table 7-1, Table 7-2 and Table 7-7.  
The bone marrow aspirate and biopsy must be taken during the first days of the screening period 
 and sent for central review to determine patient’s eligibility for 
enrollment and the results will be used as baseline value.  
If local archival bone marrow biopsy sample within 2 months prior to screening is available, it 
may be sent for central review at screening if stored according to standard bone marrow 
sampling and archival process at site, although new biopsy sample is encouraged. However, 
bone marrow aspirate sample must be taken at screening and sent for central review. 
If central 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 send one more 
bone marrow sample as soon as possible to central laboratory (re-screen the patient).  
Bone marrow findings will be recorded and will be correlated with hematological samples. 
7.2.2.7 
Radiological examinations 
Radiological examinations (computed tomography, chest x-ray) may be performed at screening 
and during the study at the discretion of the Investigator.  
7.2.2.8 
Cardiac assessments  
7.2.2.8.1 Electrocardiogram (ECG) 
A standard 12 lead ECG will be performed as per the assessment plan in Table 7-1, Table 7-2 
and Table 7-6. 
Table 7-6 
Local ECG collection plan 
Visit 
Day 
Time 
ECG Type 
Screening 
1 
Pre-dose 
12 Lead, triplicate 
D1 
1 
Pre-dose 
12 Lead, triplicate 
Week 26 (6M) or EOT eltrombopag 
1 
Pre-dose 
12 Lead, triplicate 
Week 53 (1Y)* 
1 
Pre-dose 
12 Lead, triplicate 
Month 24 (2Y) or EOT cyclosporine* 
1 
Pre-dose 
12 Lead, triplicate 
Unscheduled sample 
Anytime 
12 Lead, triplicate 
*only for responders. 
Interpretation of the tracing must be made by a qualified physician and documented on the ECG 
eCRF page. Each ECG tracing should be labeled with the study number, patient initials (where 


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regulations permit), patient number, date, and kept in the source documents at the study site. 
Clinically significant findings must be discussed with Novartis prior to enrolling the patient in 
the study.  
Triplicate ECG must be performed, the individual ECGs must be recorded approximately 2 
minutes apart. The mean QTcF value for each visit must be calculated from the triplicate ECGs 
for each patient. 
Additional, unscheduled, safety ECGs may be repeated at the discretion of the investigator at 
any time during the study as clinically indicated. Unscheduled ECGs with clinically significant 
findings should be collected in triplicate. Local cardiologist ECG assessment may also be 
performed at any time during the study at the discretion of the investigator. 
Clinically significant ECG abnormalities present at screening should be reported on the Medical 
History eCRF page. New or worsened clinically significant findings occurring after informed 
consent must be recorded on the Adverse Events eCRF page. 
7.2.2.8.2 Cardiac imaging - MRA (magnetic resonance angiography), MUGA (multiple gated 
acquisition) scan or echocardiogram 
Not applicable. 
7.2.2.8.3 Cardiac enzymes 
CK will be assessed at each landmark visits 3, 6, 12* and 24*. 
*Only for responders. 
7.2.2.9 
Tolerability 
Not applicable. 
7.2.3 
Pharmacokinetics 
Blood samples for eltrombopag pharmacokinetic (PK) evaluation will be collected from all 
patients who receive at least one dose of eltrombopag. 
Blood sampling for PK will be performed as indicated in the Visit Evaluation Schedule (Table 
7-1). Sampling time points for the study of eltrombopag PK are detailed in Table 7-7. 
Table 7-7 
Pharmacokinetic blood collection log (eltrombopag) 
PK Sample # 
PK collection # dose 
reference ID (DRID) 
Study week 
Scheduled time point 
(hours post-dose) 
1 
1a/101b 
2 
Pre-dosea, d/0 hr 
2 
1 
2 
2 (± 15 min) 
3 
1 
2 
4 (± 30 min) 
4 
1 
2 
6 (± 30min) 
5 
1 
2 
8 (± 30min) 
7 
2 a/102b 
4 
Pre-dosea/0 hr 
8 
3 a/103b 
8 
Pre-dosea/0 hr 
9 
4 a/104b 
12 
Pre-dosea/0-hr 
10 
5 a/105b 
26 
Pre-dosea/0-hr 




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7.2.5 
Resource utilization 
Not Applicable. 
7.2.6 
Patient reported outcomes 
Patients with SAA often present with significant symptoms that interfere with their health 
related quality of life including, fatigue, difficulty breathing on exertion, easy bruising, epistaxis, 
petechiae and gingival bleeding. The effect of eltrombopag on patient symptoms will be 
measured using several assessment tools including Eastern Cooperative Oncology Group 
(ECOG) performance status, the FACIT-fatigue, the FACT-TH18 (includes FACT-G) 
 
 All questionnaires, except the ECOG performance status, which is completed by 
the treating physician, are electronic patient reported outcomes (ePRO): these questionnaires 
will be completed on a tablet by the patient.  
Instructions for all ePROs will be provided as separate documents: Patients must complete the 
questionnaires before other clinical assessments at any given visit. The ePRO questionnaires 
should be completed in the same order at each visit to ensure that the patient is answering them 
as consistently as possible. The questionnaires should be given in the following order: 
1. FACIT-Fatigue 
2. FACT-TH18 
 
Questionnaires will be collected according to the Visit Schedule outlines in Table 7-1, and Table 
7-2. 
The patient should be given sufficient space and time to complete the ePRO questionnaires. The 
site personnel should check the questionnaires for completeness and ask the patient to complete 
any missing responses. The original questionnaire will be kept with the patient’s file as the 
source document. 
Completed questionnaires and any unsolicited comments provided by the patient should be 
assessed by the investigator which may indicate potential AEs or SAEs before any clinical study 
examination. This assessment should be documented in study source records. If AEs or SAEs 
are confirmed, study investigators should not encourage the patient to change responses 
reported in the completed questionnaires, Study investigators must follow reporting instruction 
outlines in Section 8 (e.g. reference “Adverse Event” section) of the study protocol. 
The FACIT-Fatigue  
The FACIT- Fatigue is a 13-items fatigue subscale that asks the patient to rate their degree of 
tiredness, weakness and fatigue. All items of the FACIT-Fatigue use a 5 point scale ranging 
from 0 to 4 with a 0 rating being “not at all” and a 4 rating being “very much”. 
Total score ranges from 0 to 52. Negatively worded items are reverse scored prior to summing 
so that higher total scores indicate less fatigue. 


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The FACT-TH18 is comprised of the FACT-G and a thrombocytopenia specific questionnaire.  
The FACT-G consists of 27-items divided into four QOL domains:  
• Physical Well-Being 
• Social/Family Well-Being 
• Emotional Well-Being 
• Functional Well-Being  
The FACT-TH18 has 18-items which asks the patient to rate their degree of thrombocytopenia. 
All items of the FACT-TH18 use a 5 point scale ranging from 0 to 4 with a 0 rating being “not 
at all” and a 4 rating being “very much”. 
8 
Safety monitoring and reporting 
8.1 
Adverse events 
8.1.1 
Definitions and reporting 
An adverse event is defined as the appearance of (or worsening of any pre-existing) undesirable 
sign(s), symptom(s), or medical condition(s) that occur after patient’s signed informed consent 
has been obtained. 
Abnormal laboratory values or test results occurring after informed consent constitute adverse 
events only if they induce clinical signs or symptoms, are considered clinically significant, 
require therapy (e.g., hematologic abnormality that requires transfusion or hematological stem 
cell support), or require changes in study medication(s). 
Adverse events that begin or worsen after informed consent should be recorded in the Adverse 
Events eCRF. Conditions that were already present at the time of informed consent should be 
recorded in the Medical History page of the patient’s eCRF. Adverse event monitoring should 
be continued for at least 30 days (or 5 half-lives, whichever is longer) following the last dose 
of study treatment. Adverse events (including lab abnormalities that constitute AEs) should be 
described using a diagnosis whenever possible, rather than individual underlying signs and 
symptoms. When a clear diagnosis cannot be identified, each sign or symptom should be 
reported as a separate adverse event. 


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Adverse events will be assessed and graded according to the Common Terminology Criteria for 
adverse events (CTCAE) version 4.03. Grade 1 to 5 will be used to characterize the severity of 
the adverse event. 
If CTCAE grading does not exist for an adverse event, the severity of mild, moderate, severe, 
and life-threatening, death related to the AE corresponding respectively to Grades 1 - 5, will be 
used. Information about any deaths (related to an adverse event or not) will also be collected 
though a Death form. 
The occurrence of adverse events should be sought by non-directive questioning of the patient 
(subject) during the screening process after signing informed consent and at each visit during 
the study. Adverse events also may be detected when they are volunteered by the patient 
(subject) during the screening process or between visits, or through physical examination, 
laboratory test, or other assessments. As far as possible, each adverse event should be evaluated 
to determine: 
1. The severity grade (CTCAE Grade 1-5) 
2. Its duration (Start and end dates) 
3. Its relationship to the study treatment (Reasonable possibility that AE is related: No, Yes) 
4. Action taken with respect to study treatment (none, dose adjusted, temporarily interrupted, 
permanently discontinued, unknown, not applicable) 
5. Whether medication or therapy was given (no concomitant medication/non-drug therapy, 
concomitant medication/non-drug therapy) 
6. Whether it is serious, where a Serious Adverse Event (SAE) is defined as in Section 8.2.1 
and which seriousness criteria have been met 
7. Outcome 
(not 
recovered/not 
resolved, 
recovered/resolved, 
recovering/resolving, 
recovered/resolved with sequelae, fatal, unknown)  
If the event worsens the event should be reported a second time in the eCRF noting the start 
date when the event worsens in toxicity. For grade 3 and 4 adverse events only, if improvement 
to a lower grade is determined a new entry for this event should be reported in the eCRF noting 
the start date when the event improved from having been Grade 3 or Grade 4.   
All adverse events should be treated appropriately. If a concomitant medication or non-drug 
therapy is given, this action should be recorded on the Adverse Event eCRF. 
Once an adverse event is detected, it should be followed until its resolution or until it is judged 
to be permanent, and assessment should be made at each visit (or more frequently, if necessary) 
of any changes in severity, the suspected relationship to the study treatment, the interventions 
required to treat it, and the outcome. 
Progression of malignancy (including fatal outcomes), if documented by use of appropriate 
method (for example, as per RECIST criteria for solid tumors or as per Cheson's guidelines for 
hematological malignancies), should not be reported as a serious adverse event. 
Adverse events separate from the progression of malignancy (example, deep vein thrombosis 
at the time of progression or hemoptysis concurrent with finding of disease progression) will 


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be reported as per usual guidelines used for such events with proper attribution regarding 
relatedness to the drug. 
8.1.2 
Laboratory test abnormalities 
8.1.2.1 
Definitions and reporting 
Laboratory abnormalities that constitute an adverse event in their own right (are considered 
clinically significant, induce clinical signs or symptoms, require concomitant therapy or require 
changes in study treatment), should be recorded on the Adverse Events eCRF. Whenever 
possible, a diagnosis, rather than a symptom should be provided (e.g. anemia instead of low 
hemoglobin). Laboratory abnormalities that meet the criteria for adverse events should be 
followed until they have returned to normal or an adequate explanation of the abnormality is 
found. When an abnormal laboratory or test result corresponds to a sign/symptom of an already 
reported adverse event, it is not necessary to separately record the lab/test result as an additional 
event. 
Laboratory abnormalities, that do not meet the definition of an adverse event, should not be 
reported as adverse events. A Grade 3 or 4 event (severe) as per CTCAE does not automatically 
indicate a SAE unless it meets the definition of serious as defined below and/or as per 
investigator’s discretion. A dose hold or medication for the lab abnormality may be required by 
the protocol in which case the lab abnormality would still, by definition, be an adverse event 
and must be reported as such. 
8.1.3 
Adverse events of special interest 
Adverse events of special interest (AESI) are defined as events (serious or non-serious) which 
are ones of scientific and medical concern specific to the sponsor’s product or program, for 
which ongoing monitoring and rapid communication by the investigator to the sponsor may be 
appropriate. Such events may require further investigation in order to characterize and 
understand them. 
Adverse events of special interest are defined on the basis of an ongoing review of the safety 
data. AESIs are discussed in detail in the Investigator’s Brochure. 
8.2 
Serious adverse events 
8.2.1 
Definitions 
Serious Adverse Event (SAE) is defined as one of the following: 
• Is fatal or life-threatening 
• Results in persistent or significant disability/incapacity 
• Constitutes a congenital anomaly/birth defect 
• Is medically significant, i.e., defined as an event that jeopardizes the patient or may 
require medical or surgical intervention to prevent one of the outcomes listed above 
• Requires inpatient hospitalization or prolongation of existing hospitalization, 
• Note that hospitalizations for the following reasons should not be reported as serious 
adverse events: 


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• Routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition 
• Elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent 
• Social reasons and respite care in the absence of any deterioration in the patient’s 
general condition 
• Note that treatment on an emergency outpatient basis that does not result in hospital 
admission and involves an event not fulfilling any of the definitions of a SAE given above 
is not a serious adverse event 
8.2.2 
Reporting 
To ensure patient safety, every SAE, regardless of suspected causality, occurring after the 
patient has provided informed consent and until at least 30 days after the patient has stopped 
study treatment must be reported to Novartis within 24 hours of learning of its occurrence. 
Any additional information for the SAE including 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 should be 
reported separately as a new event. 
Any SAEs experienced after the 30 day safety evaluation follow-up period should only be 
reported to Novartis if the investigator suspects a causal relationship to the study treatment. 
Information about all SAEs is collected and recorded on the Serious Adverse Event Report 
Form; all applicable sections of the form must be completed in order to provide a clinically 
thorough report. The investigator must assess and record the relationship of each SAE to each 
specific study treatment (if there is more than one study treatment), complete the SAE Report 
Form in English, and submit the completed form within 24 hours to Novartis. Detailed 
instructions regarding the SAE submission process and requirements for signatures are to be 
found in the investigator folder provided to each site 
Follow-up information is submitted in the same way as the original SAE Report. Each re-
occurrence, complication, or progression of the original event should be reported as a follow-
up to that event regardless of when it occurs. The follow-up information should describe 
whether the event has resolved or continues, if and how it was treated, whether the blind was 
broken or not, and whether the patient continued or withdrew from study participation. 
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 Novartis study treatment, an oncology Novartis 
Chief Medical Office and Patient Safety (CMO&PS) department associate may urgently require 
further information from the investigator for Health Authority reporting. Novartis may need to 
issue an Investigator Notification (IN), to inform all investigators involved in any study with 
the same drug that this SAE has been reported. Suspected Unexpected Serious Adverse 
Reactions (SUSARs) will be collected and reported to the competent authorities and relevant 
ethics committees in accordance with Directive 2001/20/EC or as per national regulatory 
requirements in participating countries. 


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8.3 
Emergency unblinding of treatment assignment 
Not applicable. 
8.4 
Pregnancies 
To ensure patient safety, each pregnancy occurring while the patient is on study treatment must 
be reported to Novartis within 24 hours of learning of its occurrence. The pregnancy should be 
followed up to determine outcome, including spontaneous or voluntary termination, details of 
the birth, and the presence or absence of any birth defects, congenital abnormalities, or maternal 
and/or newborn complications. 
Pregnancy should be recorded on a Clinical Trial Pregnancy Form and reported by the 
investigator to the oncology Novartis Chief Medical Office and Patient Safety (CMO&PS). 
Pregnancy follow-up should be recorded on the same form and should include an assessment 
of the possible relationship to the study treatment any pregnancy outcome. Any SAE 
experienced during pregnancy must be reported on the SAE Report Form. 
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. 
8.5 
Warnings and precautions 
No evidence available at the time of the approval of this study protocol indicated that special 
warnings or precautions were appropriate, other than those noted in the provided Investigator 
Brochure. Additional safety information collected between IB updates will be communicated 
in the form of Investigator Notifications. This information will be included in the patient 
informed consent and should be discussed with the patient during the study as needed. 
8.6 
Data Monitoring Committee  
Not applicable. 
8.7 
Steering Committee  
A steering committee (SC) will be established comprising investigators participating in the 
study, an independent investigator not participating in the study and Novartis representatives 
from the Clinical Trial Team. The SC will ensure transparent management of the study 
according to the protocol through recommending and approving modifications as circumstances 
require. The SC will be responsible to review safety data before the time of primary analysis. 
Efficacy data will not be summarized but may be included in patient listings in order to support 
review of patient safety and study conduct. The SC will review protocol amendments as 
appropriate. Together with the clinical trial team, the SC will also develop recommendations 
for publications of study results including authorship rules. The details of the role of the SC will 
be defined in a SC charter.  


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9 
Data collection and management 
9.1 
Data confidentiality 
Information about study patients will be kept confidential and managed under the applicable 
laws and regulations. Those regulations require a signed patient authorization informing the 
patient of the following: 
• What protected health information (PHI) will be collected from patients in this study 
• Who will have access to that information and why 
• Who will use or disclose that information 
• The rights of a research patient to revoke their authorization for use of their PHI. 
In the event that a patient revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of patient 
authorization. For patients that have revoked authorization to collect or use PHI, attempts 
should be made to obtain permission to collect follow-up safety information (e.g. has the patient 
experienced any new or worsened AEs) at the end of their scheduled study period. 
The data collection system for this study uses built-in security features to encrypt all data for 
transmission in both directions, preventing unauthorized access to confidential participant 
information. Access to the system will be controlled by a sequence of individually assigned 
user identification codes and passwords, made available only to authorized personnel who have 
completed prerequisite training. 
Prior to entering key sensitive personally identifiable information (Patient Initials and exact 
Date of Birth), the system will prompt site to verify that this data is allowed to be collected. If 
the site indicates that country rules or ethics committee standards do not permit collection of 
these items, the system will not solicit Patient Initials. Year of birth will be solicited (in the 
place of exact date of birth) to establish that the patient satisfies protocol age requirements and 
to enable appropriate age-related normal ranges to be used in assessing laboratory test results. 
9.2 
Site monitoring 
Before study initiation, at a site initiation visit or at an investigator’s meeting, Novartis 
personnel (or designated CRO) will review the protocol and eCRFs with the investigators and 
their staff. During the study, the field monitor will visit the site regularly to check the 
completeness of patient records, the accuracy of entries on the eCRFs, the adherence to the 
protocol to Good Clinical Practice, the progress of enrollment, and to ensure that study 
treatment is being stored, dispensed, and accounted for according to specifications. Key study 
personnel must be available to assist the field monitor during these visits. 
The investigator must maintain source documents for each patient in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information recorded on eCRFs must be traceable to source documents in the 
patient's file. The investigator must also keep the original signed informed consent form (a 
signed copy is given to the patient). 


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The investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the eCRF entries. Novartis monitoring standards require full verification for 
the presence of informed consent, adherence to the inclusion/exclusion criteria and 
documentation of SAEs. Additional checks of the consistency of the source data with the eCRFs 
are performed according to the study-specific monitoring plan. 
9.3 
Data collection 
For studies using Electronic Data Capture (EDC), the designated investigator staff will enter 
the data required by the protocol into the Electronic Case Report Forms (eCRF). The eCRFs 
have been built using fully validated secure web-enabled software that conforms to 21 CFR Part 
11 requirements, Investigator site staff will not be given access to the EDC system until they 
have been trained. Automatic validation programs check for data discrepancies in the eCRFs 
and, allow modification or verification of the entered data by the investigator staff. 
The Principal Investigator is responsible for assuring that the data entered into eCRF is complete, 
accurate, and that entry and updates are performed in a timely manner. 
Samples for Central lab, 
 PK and Quality of Life questionnaires should be sent to 
the vendors on timely manner. Please refer to the corresponding section for more information.  
9.4 
Database management and quality control 
For studies using eCRFs, Novartis personnel (or designated CRO) will review the data entered 
by investigational staff for completeness and accuracy. Electronic data queries stating the nature 
of the problem and requesting clarification will be created for discrepancies and missing values 
and sent to the investigational site via the EDC system. Designated investigator site staff are 
required to respond promptly to queries and to make any necessary changes to the data. 
Concomitant treatments and prior medications entered into the database will be coded using the 
WHO Drug Reference List, which employs the Anatomical Therapeutic Chemical classification 
system. Medical history/current medical conditions and adverse events will be coded using the 
Medical dictionary for regulatory activities (MedDRA) terminology. 
Samples and/or data will be processed centrally and the results will be sent electronically to 
Novartis (or a designated CRO). 
For EDC studies, after database lock, the investigator will receive a CD-ROM or paper copies 
of the patient data for archiving at the investigational site. 
10 
Statistical methods and data analysis 
Data will be summarized with respect to demographic and baseline characteristics, efficacy 
observations and measurements, safety observations and measurements, and other assessments. 
Continuous variables will be summarized by number of patients, mean, standard deviation, 
minimum, 25th percentile, median, 75th percentile and maximum. Categorical variables will be 
summarized by absolute and relative frequencies. 
Unless otherwise stated, the “baseline value” is defined as the last available measurement on or 
before the date of first dose of study treatment (eltrombopag or cyclosporine). Whenever an 


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event is required to have a confirmation at a later assessment, time to event will be calculated 
from the date of first dose of study treatment to the initial instance. 
The primary analysis will be based on enrolled patients who have completed 6 months or 
discontinued prior to 6 months. 
The final analysis will be based on the cumulative data obtained after responder patients have 
completed 24 months or discontinued prior to 24 months.   
10.1 
Analysis sets 
10.1.1 
Full Analysis Set 
The Full Analysis Set (FAS) includes all patients who received at least one dose of study 
treatment (eltrombopag or cyclosporine).  
10.1.2 
Safety set 
The Safety Set includes all patients who received at least one dose of study treatment 
(eltrombopag or cyclosporine).  
10.1.3 
Per-Protocol set 
The Per-Protocol Set (PPS) includes the patients in the FAS who had no major protocol 
deviations. 
Oncology standards for protocol deviations potentially leading to exclusion from the PPS are: 
• If the protocol deviation is very likely to confound the scientific analysis of the primary 
efficacy endpoint(s) or if it precludes any meaningful efficacy measurement. 
If it is in direct conflict with the analysis set definition given in the title of the study (i.e. 
patient diagnosis, stage of disease or use of prior treatment dose not correspond to the 
intended patient population to be studied). 
Note that patients who were enrolled and then discontinued from the study based on 
discrepancies between the local and central bone marrow assessment for exclusion 
criterion 2 will be excluded, this will ensure that only patients in the target population are 
included in the PPS analyses 
• If documentation of pre-baseline disease progression is required and is missing. 
• Treatment differs from treatment assigned 
• Patient compliance as defined as patient being evaluated for primary efficacy endpoint at 
least once. Patient who discontinue prior to the first efficacy assessment due to adverse 
events, including death, will be included. 
Protocol deviations leading to exclusion from the PPS will be specified in the study Statistical 
Analysis Plan (SAP) based on codes provided in the DHP.  
10.1.4 
Dose-determining analysis set 
Not applicable. 


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10.1.5 
Pharmacokinetic analysis set 
The Pharmacokinetic Analysis Set (PAS) includes all patients who provide at least one 
evaluable PK concentration. For a concentration to be evaluable, patients are required to: 
• For samples on Week 2: 
• Take the same dose of eltrombopag for all dosing days prior to sampling on Week 2 
• For pre-dose samples, do not vomit within 4 hours after the dosing of eltrombopag 
prior to sampling   
• For post-dose samples, do not vomit within 4 hours after the dosing of eltrombopag 
on the sampling day  
• For all pre-dose samples, have the sample collected before the next dose administration.  
10.1.6 
Other analysis sets  
Not applicable. 
10.2 
Patient demographics/other baseline characteristics 
Demographic and other baseline characteristics (including disease characteristics) will be 
summarized descriptively on the FAS. Categorical data will be presented as frequencies and 
percentages. For continuous data, mean, standard deviation, median, 25th and 75th percentiles, 
minimum and maximum will be presented. 
Relevant medical histories and current medical conditions at baseline will be summarized 
separately for ongoing and historical medical conditions by system organ class and preferred 
term on the FAS.  
10.3 
Treatments (study treatment, concomitant therapies, 
compliance) 
10.3.1 
Study Treatment 
Duration of exposure to study treatment, cumulative dose, average daily dose, actual dose 
intensity and relative dose intensity of each of the components of study treatment will be 
summarized. 
Categorical data will be summarized as frequencies and percentages. For continuous data, 
mean, standard deviation, median, 25th and 75th percentiles, minimum, and maximum will be 
presented. Safety set will be used for the analyses. 
The number of patients with dose changes/interruptions and their reasons corresponding to each 
of the components of study treatment will be summarized on the Safety set and all dosing data 
will be listed.  
10.3.2 
Concomitant therapies 
Concomitant medications or procedures and significant non-drug therapies taken concurrently 
with the study treatment (eltrombopag + cyclosporine) will be listed and summarized by 
Anatomical Therapeutic chemical (ATC) Class, preferred term, by means of frequency counts 


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and percentages. These summaries will include medications starting on or after the start of study 
treatment (defined as Day 1) or medications starting prior to the start of study treatment and 
continuing after the start of study treatment.  
Any prior concomitant medications or significant non-drug therapies starting and ending prior 
to the start of study treatment will be listed. 
The Safety set will be used for all of the above mentioned concomitant medication tables and 
listings. 
10.4 
Primary objective 
The primary objective of this study is to assess efficacy of study treatment (eltrombopag + 
cyclosporine) as first-line therapy as measured by the overall hematologic response rate by 
6 months after all the patients enrolled has completed 6 months of treatment with 
eltrombopag+cyclosporine or discontinued treatment with eltrombopag prior to 6 months. 
10.4.1 
Variable 
Overall hematologic response (OR) is defined as the proportion of patients achieving complete 
response (CR) and partial response (PR) in the following way: 
Partial response (PR) is defined as any two of the following parameters at two consecutive, 
scheduled visit measurements at least 7 days apart during the study (and not meeting CR 
definition) and no platelet transfusions within 7 days of platelet measurement (can still be a PR 
if ANC and reticulocyte measurements are valid): 
• Absolute neutrophil count (ANC) ≥ 500/µL 
• Platelet count ≥ 20 000/µL 
• Reticulocyte count ≥ 60 000/µL (automated) 
Complete response (CR) is defined as all three parameters meet the following criteria at two 
consecutive, scheduled visit measurements at least 7 days apart during the study and no platelet 
transfusions within 7 days of platelet measurement and no RBC transfusion within 14 days of 
the hemoglobin measurement:  
• Absolute neutrophil count (ANC) ≥ 1 000/µL 
• Platelet count ≥ 100 000/µL 
• Hemoglobin ≥ 10 g/dL 
For the primary objective of overall hematologic response, all patients in the FAS will be 
included and the proportion of patients achieving overall hematologic response (i.e., number of 
patients who achieved CR + number of patients who achieved PR/total number of patients in 
the FAS) by 6 months.  
10.4.2 
Statistical hypothesis, model, and method of analysis 
The assessment of primary efficacy of study treatment (eltrombopag + cyclosporine) will be 
based on the calculation of observed overall hematologic response rate (see Section 10.4.1) by 
6 months, obtained from the proportion of patients achieving the overall hematologic response 
any time from start of treatment till 6 months, and its posterior distribution using a Beta-


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binomial model. The FAS will be used for the primary analysis. The PPS will be used as a 
supportive analysis. Combination therapy of eltrombopag + cyclosporine will be declared 
efficacious if the following criteria are met: 
a. Observed overall hematologic response rate ≥ “clinically meaningful” threshold (30%) 
b. Probability of true overall hematologic response rate “not being clinically meaningful 
(response ≤ 20%)” is less than 10%. 
With 50 patients, criteria a and b will be met if the observed hematologic response rate is ≥ 30%, 
i.e., at least 15 responders out of 50 patients treated with the combination of eltrombopag + 
cyclosporine are observed by 6 months which will give a probability of “not being clinically 
meaningful (response ≤ 20%)” of 0.0538. 
The primary analysis will be performed after all the patients have completed 6 months or 
discontinued prior to 6 months. The point estimate of the proportion of patients achieving 
overall hematologic response (based on two consecutive measurements of the required 
parameters at least 7 days apart) along with corresponding exact 95% confidence interval using 
Clopper and Pearson exact method will be presented. 
If any patient achieves hematologic response (either CR or PR) any time on or before 6 months, 
they will be considered as responders, else they are considered as non-responders. 
10.4.3 
Handling of missing values/censoring/discontinuations 
If any patient achieves confirmed overall hematologic response any time before 6 months but 
discontinues prior to 6 months or has missing parameters required for assessing overall 
hematologic response at any point after achieving the first response, they will be considered as 
responders. 
10.4.4 
Supportive and Sensitivity analyses 
The OR by 6 months (primary analysis as described in Section 10.4.2) will also be repeated on 
the PPS.  
A sensitivity analyses using the OR at 6 months will be done in the following ways: 
• The overall hematologic response will be calculated at 6 months (based on assessment at 
6 month visit and the previous visit at least 7 days apart) only based on the evaluable 
patients (i.e., patients for whom data is available for assessing hematologic response at 
6 months).  
The overall hematologic response will be calculated at month 6 for all patients in the FAS and 
also repeated on the PPS. If a patient discontinued early or has missing values for the 
parameters required for assessing the response at month 6, they will be considered as non-
responders. 
10.5 
Secondary objectives 
All secondary efficacy analyses will be performed on the FAS, unless otherwise specified. All 
safety related objectives will be analyzed on the Safety set unless otherwise specified. 
Responders are defined in Section 10.4.2. 


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10.5.1 
Key secondary objective(s) 
Overall hematologic response rate by 3 months 
The overall hematologic response (CR + PR) rate by 3 months will be evaluated using the point 
estimate of the proportion of patients achieving overall hematologic response (based on two 
consecutive, scheduled visit measurements of the required parameters at least 7 days apart and 
respective transfusion restrictions) along with corresponding 95% confidence interval using 
Clopper and Pearson exact method.  
• Hematologic response rate by 3 months (FAS) = Number of patients who achieved 
hematologic response by 3 months/Number of patients in FAS 
• Hematologic response rate by 3 months (PPS) = Number of patients who achieved 
hematologic response by 3 months/Number of patients in PPS 
For missing values and discontinuations, a similar approach will be adopted as for the primary 
objective. If any patient achieves overall hematologic response any time before 3 months but 
discontinues prior to 3 months or has missing parameters required for assessing overall 
hematologic response at any point after achieving the first response, they will be considered as 
responders by 3 months.  
Analyses will be reported in the 6 month CSR and provided again in the 24 months CSR. 
Overall hematologic response rate at 12 and 24 months 
The overall hematologic response (CR + PR) rate at 12 months and 24 months will be evaluated. 
The point estimate of the proportion of patients achieving overall hematologic response (based 
on two consecutive, scheduled visit measurements of the required parameters at least 7 days 
apart and respective transfusion restrictions) along with corresponding exact 95% confidence 
interval using Clopper and Pearson exact method.  
• Hematologic response rate at 12 months (FAS) = Number of patients who achieved 
hematologic response at 12 months/Number of patients in FAS 
• Hematologic response rate at 12 months (PPS) = Number of patients who achieved 
hematologic response at 12 months/Number of patients in PPS 
• Hematologic response rate at 24 months (FAS) = Number of patients who achieved 
hematologic response at 24 months/Number of patients in FAS 
• Hematologic response rate at 24 months (PPS) = Number of patients who achieved 
hematologic response at 24 months/Number of patients in PPS 
If any 6 month responder achieves hematologic response at the 12 month visit, they will be 
considered a 12 month responder, else they are a 12 month non-responder. The 12 month 
visit will be the confirmatory visit of the most recent visit assessment prior to this assessment 
(at least 7 days apart). Similar for a 24 month responder and non-responder. 
Analyses will be reported in the 24 months CSR. 
Duration of response 
The number (%) of by 6 months responder patients who relapsed will be summarized together 
with the corresponding exact 95% confidence interval using Clopper and Pearson exact method. 


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Time from the date of the start of the first hematologic response (either CR or PR whichever 
occurs earlier) to the date of first relapse will be calculated using the Kaplan-Meier method to 
evaluate the duration of hematologic response occurring at any time during the study and will 
be reported by 6 months and 24 months on a cumulative basis.  
Relapse is defined as no longer meeting the definition of PR (and not CR). 
Responders are defined in Section 10.4.2. 
Relapse rate 
To evaluate the relapse rate, the percentage of responders who relapse at any time during the 
study will be reported by 6 months and 25 months on a cumulative basis.  
Clonal evolution 
To evaluate the clonal evolution to myelodysplasia, PNH or leukemia, percentage of patients 
with clonal evolution to myelodysplasia, PNH and acute leukemia occurring at any time during 
the study and will be reported by 6 months and 24months (responders only) on a cumulative 
basis. Clonal evolution to myelodysplasia is defined as a new marrow cytogenic abnormality 
with or without characteristic dysplastic marrow findings. Evolution to leukemia is defined as 
greater than 20% peripheral blood and/or marrow blasts. Evolution to paroxysmal nocturnal 
hemoglobinuria (PNH) is defined as a clone at baseline <10% that rose to greater than 50% on 
study. The percentage will be calculated using point estimate of the proportion of patients along 
with corresponding exact 95% confidence interval using Clopper and Pearson exact method. 
Transfusion independence 
The number (%) of patients with corresponding 95% confidence interval (using Clopper and 
Pearson exact method) will be summarised by 6 months and 24 months (responders only) for 
patients: 
• who received at least one platelet transfusion 
• who received at least one RBC transfusion  
• with platelet transfusion independence 
• with RBC transfusion independence 
Transfusion independency is considered if transfusions are not required in at least a 28 day 
period for platelet transfusions and at least 56 day period for RBC transfusions.  
In addition the duration of the longest interval without a platelet or RBC transfusion by 6 months 
and by 24 months (responders only) will be summarised using Kaplan-Meier analysis. 
The platelet and RBC transfusions will be evaluated separately. 
Quality of life 
FACT-G, FACIT-Fatigue and FACT-TH18 responses will be generated in accordance with the 
respective scoring manual. Descriptive statistics will be used to summarize the raw and absolute 
change from baseline to each assessment visit. Patients with an evaluable baseline score and at 
least one evaluable post baseline score during the treatment period will be included in the 


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change from baseline analyses. Missing items data in a scale will be handled based on each 
instrument manual. All PRO analyses will include data as imputed according to the scoring 
manual. No imputation will be applied if the total or subscale scores are missing at a visit. 
Summaries will be reported by 6 months and 24 months (responders only). 
Additional analyses may be performed if deemed necessary. Such analyses will be defined in 
the SAP. 
All of the above analyses will be done on the FAS. 
10.5.2 
Other secondary efficacy objectives 
Not applicable 
10.5.3 
Safety objectives 
10.5.3.1 Analysis set and grouping for the analyses 
For all safety analyses, the safety set will be used, unless specified otherwise.  
The overall observation period will be divided into three mutually exclusive segments: 
1. pre-treatment period: from day of patient’s informed consent to the day before first dose 
of study medication 
2. on-treatment period: from day of first dose of study medication to 30 days after last dose 
of study medication 
3. post-treatment period: starting at day 30+1 after last dose of study medication.  
The on-treatment period corresponds to the period from day of first dose of study medication 
to 30 days after last dose of study medication (either eltrombopag or eltrombopag + 
cyclosporine or cyclosporine).  
The safety summary tables will include only assessments collected within 30 days after study 
treatment discontinuation and assessments prior to the data cut-off date for ongoing patients, 
unless otherwise specified.  
Summary outputs will be provide for the responder patients where specified. Responders are 
defined in Section 10.4.2. 
All data, regardless of the observation period, will be listed and assessments collected in the 
pretreatment and post-treatment period will be flagged in all the listings.  
10.5.3.2 Adverse events (AEs) 
Summary tables for Adverse Events (AEs) will include only AEs that started or worsened 
during the on-treatment period, the treatment-emergent AEs. 
The incidence of treatment-emergent 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 
Serious adverse events, non-serious AEs and AEs of special interest (AESI) during the on-
treatment period will be tabulated. 




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The number (%) of patients with notable values will be presented 
ECOG performance status 
Shift tables comparing the baseline ECOG performance status with the worst result during post-
baseline will be summarized. 
10.5.3.5 Supportive analyses for secondary objectives  
Not applicable. 
10.5.3.6 Tolerability 
Not applicable. 
10.5.4 
Pharmacokinetics 
The PAS will be used in all PK data analysis and PK summary statistics. 
10.5.4.1 Eltrombopag 
PK parameters for eltrombopag will be determined using non-compartmental methods using 
Phoenix (Pharsight, Mountain View, CA) or other appropriate software. PK parameters listed 
in Table 10-1 will be estimated and reported, when feasible.  
Table 10-1 
Non-compartmental pharmacokinetic parameters of eltrombopag 
Parameter 
Description 
Cmax 
Observed maximum plasma concentration following administration (mass/volume) 
AUClast 
Area under the curve calculated to the last quantifiable concentration point (Tlast) 
(mass*time/volume) 
AUCtau 
Area under the curve calculated to the end of the dosing interval ( tau) (mass*time/volume) 
Ctrough 
Pre-dose plasma concentration (mass/volume) 
Tmax 
The time to reach peak or maximum concentration (time) 
CLss/F 
Apparent systemic (or total body) clearance at steady state from plasma (volume/time) 
The concentrations obtained for the Week 2 pre-dose sample (sample 1) will be duplicated in 
order to also be analyzed as a 24 h post-dose sample (and will be attributed sample number 6). 
All concentrations below the LLOQ or missing data will be labeled as such in the concentration 
data listings. Concentrations below the LLOQ will be treated as zero in summary statistics.  
Descriptive statistics of all PK parameters and PK concentrations will include arithmetic and 
geometric mean, median, SD, and coefficient of variation (CV), geometric CV, minimum and 
maximum. Zero concentrations will not be included in the geometric mean calculation. Since 
Tmax is generally evaluated by a nonparametric method and median values and ranges will be 
given for this parameter. 
Exposure-response analysis will be conducted, if supported by the data to evaluate relationship 
between exposure of eltrombopag and response and specific adverse events of special interests. 
These relationships will be explored by graphical methods. Any apparent relationship may be 
further characterized by a model as appropriate and supported by the data.  


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Population PK may be performed if supported by the data to explore relevant covariates. The 
methods and results of these analyses will be reported separately. 
10.5.4.2 Data handling principles 
Missing concentration values will be reported as is in data listings. Concentration values below 
the LLOQ will be handled as zero in summary statistics, and reported as in data listings. Any 
missing PK parameter data will not be imputed.  
Concentrations from patients having vomited before 4 hours post-administration will be 
excluded from the calculation of PK parameters. 
10.5.5 
Biomarkers 
Not applicable. 
10.5.6 
Resource utilization  
Not applicable. 
10.5.7 
Patient reported outcomes 
See Section 10.1 for FACT-G, FACIT-Fatigue and FACT-TH18 analyses 
 


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10.7 
Interim analysis 
Refer to Section 4.2, since no adaptive changes are planned, no type I error adjustments will be 
done.  
10.8 
Sample size calculation 
50 patients will be enrolled in the study. With 50 patients criteria: 


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a: observed overall hematologic response rate ≥ “clinically meaningful” threshold (30%) and  
b: probability of true overall hematologic response rate “not being clinically meaningful 
(response ≤ 20%)” is less than 10%  
will be met if the observed hematologic ORR is ≥30%, i.e., at least 15 responders out of 
50 patients treated with combination therapy, eltrombopag + cyclosporine are observed by 
6 months. Criteria a and b are based on available historical data as described in Section 2.2. 
Table 10-2 
Table showing observed response rate and its posterior distribution 
using a Beta-binomial model 
Sample size 
No. of responders 
Observed response rate 
(%) 
Probability of ‘not being clinically 
meaningful (response rate ≤20%)” 
N=50 
13 
26 
0.1693 
 
14 
28 
0.0992 
 
15 
30 
0.0538 
 
16 
32 
0.0269 
 
17 
34 
0.0125 
The operating characteristics of the design are presented in the table below. This table shows 
probability for positive conclusion (i.e. success criteria met at the end of the study) under 
different underlying true response rate. When the effect of the combination therapy is not being 
clinically meaningful (true response rate ≤20%), the probability of positive conclusion is <10% 
(false success rate). The probability of success is >94% when the true response rate by 6 months 
is 40%.  
Table 10-3 
Operating characteristics of the study design 
Sample size 
True response rate (%) 
Probability of positive conclusion 
N=50 
10 
0.0001 
 
20 
0.0607 
 
30 
0.5532 
 
40 
0.9460 
 
50 
0.9987 
10.8.1 
Bayesian calculus for a binary endpoint 
For the binary endpoint, overall hematologic response rate (ORR), let Y be the number of 
responders in n patients. The sampling model is binomial 
Y | θ ~ Bin( n, θ ) 
with true response rate θ. The prior distribution is a Beta distribution 
θ ~ Beta( a, b ) 
In this conjugate setting, the posterior distribution is again a Beta distribution 
θ | Y ~ Beta( a+Y, b+n-Y ) 
Here, the parameters a and b are the a priori number of responders and non-responders, 
respectively, and a+b is the prior effective sample size. 


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For this study, the parameters (a, b) of the Beta prior distribution are a = 0.25 and b = 1. This 
prior distribution has mean = a / (a + b) = 0.25 / (0.25 + 1) = 0.2 assuming a low response rate 
a priori. Furthermore, the prior effective sample size is small (a + b = 1.25).  
10.9 
Power for analysis of key secondary variables 
Not Applicable. 
11 
Ethical considerations and administrative procedures 
11.1 
Regulatory and ethical compliance 
This clinical study was designed, shall be implemented and reported in accordance with the 
ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable local 
regulations (including European Directive 2001/20/EC and US Code of Federal Regulations 
Title 21), and with the ethical principles laid down in the Declaration of Helsinki. 
11.2 
Responsibilities of the investigator and IRB/IEC/REB 
The protocol and the proposed informed consent form must be reviewed and approved by a 
properly 
constituted 
Institutional 
Review 
Board/Independent 
Ethics 
Committee/ 
Research Ethics Board (IRB/IEC/REB) before study start. Prior to study start, the investigator 
is required to sign a protocol signature page confirming his/her agreement to conduct the study 
in accordance with these documents and all of the instructions and procedures found in this 
protocol and to give access to all relevant data and records to Novartis monitors, auditors, 
Novartis Clinical Quality Assurance representatives, designated agents of Novartis, 
IRBs/IECs/REBs and regulatory authorities as required. 
11.3 
Informed consent procedures 
Eligible patients may only be included in the study after providing written (witnessed or parents 
for pediatric patient, where required by law or regulation), IRB/IEC/REB-approved informed 
consent 
Informed consent must be obtained before conducting any study-specific procedures (i.e. all of 
the procedures described in the protocol). The process of obtaining informed consent should be 
documented in the patient source documents. The date when a patient’s Informed Consent was 
actually obtained will be captured in their eCRFs. 
Novartis will provide to investigators, in a separate document, a proposed informed consent 
form (ICF) that is considered appropriate for this study and complies with the ICH GCP 
guideline and regulatory requirements. Any changes to this ICF suggested by the investigator 
must be agreed to by Novartis before submission to the IRB/IEC/REB, and a copy of the 
approved version must be provided to the Novartis monitor after IRB/IEC/REB approval. 
Women of child bearing potential should be informed that taking the study medication 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 requirement for the 
duration of the study. If there is any question that the patient will not reliably comply, they 


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should not be entered in the study. Male participants will be requested to provide the 
information for female partner to their partner. 
Additional consent form  
Not applicable 
11.4 
Discontinuation of the study 
Novartis reserves the right to discontinue this study under the conditions specified in the clinical 
study agreement. Specific conditions for terminating the study are outlined in Section 4.4. 
11.5 
Publication of study protocol and results 
Novartis is committed to following high ethical standards for reporting study results for its 
innovative medicine, including the timely communication and publication of clinical study 
results, whatever their outcome. Novartis assures that the key design elements of this protocol 
will be posted on the publicly accessible database, e.g. www.clinicaltrials.gov before study start. 
In addition, results of interventional clinical studies in adult patients are posted on 
www.novartisclinicaltrials.com, a publicly accessible database of clinical study results within 
1 year of study completion (i.e., LPLV), those for interventional clinical studies involving 
pediatric patients within 6 months of study completion. 
Novartis follows the ICMJE authorship guidelines (www.icmje.org) and other specific 
guidelines of the journal or congress to which the publication will be submitted 
Authors will not receive remuneration for their writing of a publication, either directly from 
Novartis or through the professional medical writing agency. Author(s) may be requested to 
present poster or oral presentation at scientific congress; however, there will be no honorarium 
provided for such presentations. 
As part of its commitment to full transparency in publications, Novartis supports the full 
disclosure of all funding sources for the study and publications, as well as any actual and 
potential conflicts of interest of financial and non-financial nature by all authors, including 
medical writing/editorial support, if applicable. 
For the Novartis Guidelines for the Publication of Results from Novartis-sponsored Research, 
please refer to www.novartis.com. 
11.6 
Study documentation, record keeping and retention of 
documents 
Each participating site will maintain appropriate medical and research records for this study, in 
compliance with Section 4.9 of the ICH E6 GCP, and regulatory and institutional requirements 
for the protection of confidentiality of patients. As part of participating in a Novartis-sponsored 
study, each site will permit authorized representatives of the sponsor(s) and regulatory agencies 
to examine (and when required by applicable law, to copy) clinical records for the purposes of 
quality assurance reviews, audits and evaluation of the study safety and progress. 
Source data are all information, original records of clinical findings, observations, or other 
activities in a clinical study necessary for the reconstruction and evaluation of the study. 


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Examples of these original documents and data records include, but are not limited to, hospital 
records, clinical and office charts, laboratory notes, memoranda, patients’ diaries or evaluation 
checklists, pharmacy dispensing records, recorded data from automated instruments, copies or 
transcriptions certified after verification as being accurate and complete, microfiches, 
photographic negatives, microfilm or magnetic media, x-rays, and patient files and records kept 
at the pharmacy, at the laboratories, and medico-technical departments involved in the clinical 
study. 
Data collection is the responsibility of the clinical study staff at the site under the supervision 
of the site Principal Investigator. The electronic study case report form (eCRF) is the primary 
data collection instrument for the study. The investigator should ensure the accuracy, 
completeness, legibility, and timeliness of the data reported in the eCRFs and all other required 
reports. Data reported on the eCRF, that are derived from source documents, should be 
consistent with the source documents or the discrepancies should be explained. All data 
requested on the eCRF must be recorded. Any missing data must be explained. Any change or 
correction to a paper eCRF should be dated, initialed, and explained (if necessary) and should 
not obscure the original entry. For electronic eCRFs an audit trail will be maintained by the 
system. The investigator should retain records of the changes and corrections to paper eCRFs. 
The investigator/institution should maintain the study documents as specified in Essential 
Documents for the Conduct of a Clinical Trial (ICH E6 Section 8) and as required by applicable 
regulations and/or guidelines. The investigator/institution should take measures to prevent 
accidental or premature destruction of these documents. 
Essential documents (written and electronic) should be retained for a period of not less than 
fifteen (15) years from the completion of the slinical study unless Sponsor provides written 
permission to dispose of them or, requires their retention for an additional period of time 
because of applicable laws, regulations and/or guidelines. 
11.7 
Confidentiality of study documents and patient records 
The investigator must ensure anonymity of the patients; patients must not be identified by names 
in any documents submitted to Novartis. Signed informed consent forms and patient enrollment 
log must be kept strictly confidential to enable patient identification at the site. 
11.8 
Audits and inspections 
Source data/documents must be available to inspections by Novartis or designee or Health 
Authorities. 
11.9 
Financial disclosures 
Financial disclosures should be provided by study personnel who are directly involved in the 
treatment or evaluation of patients at the site - prior to study start. 
12 
Protocol adherence 
Investigators ascertain they will apply due diligence to avoid protocol deviations. Under no 
circumstances should the investigator contact Novartis or its agents, if any, monitoring the study 


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to request approval of a protocol deviation, as no authorized deviations are permitted. If the 
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/REB it cannot be implemented. All significant protocol 
deviations will be recorded and reported in the CSR. 
12.1 
Amendments to the protocol 
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/REB. Only 
amendments that are required for patient safety may be implemented prior to IRB/IEC/REB 
approval. Notwithstanding the need for approval of formal protocol amendments, the 
investigator is expected to take any immediate action required for the safety of any patient 
included in this study, even if this action represents a deviation from the protocol. In such cases, 
Novartis should be notified of this action and the IRB/IEC at the study site should be informed 
according to local regulations (e.g. UK requires the notification of urgent safety measures 
within 3 days) but not later than 10 working days. 


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13 
References (available upon request) 
Alexander WS, Roberts AW, Nicola NA, Li R, Metcalf D. Deficiencies in progenitor cells of 
multiple hematopoietic lineages and defective megakaryocytopoiesis in mice lacking the 
thrombopoietic receptor c-mpl. Blood. 1996;87:2162-2170. 
Atta EH, Dias DS, Marra VL, de Azevedo AM. Comparison between horse and rabbit 
antithymocyte globulin as first-line treatment for patients with severe aplastic anemia: a 
single-center retrospective study. Ann Hematol. 2010;89(9):851-859. 
Bacigalupo A. How I treat acquired aplastic anemia. Blood. 2017;129:1428-1436 
Ballmaier M, Germeshausen M, Krukaeeir S, and Welte K. Thrombopoietin is essential for 
the maintenance of normal hematopoiesis in humans:development of aplastic anemia in 
patients with congenital amegakaryotic thrombocytopenia. Ann NY Acad. 2003;996:17-25. 
Bussel JB, Saleh MN, Vasey SY, Mayer B, Arning M, Stone NL. Repeated short-term use of 
eltrombopag in patients with chronic immune thrombocytopenia (ITP). Br J Haematol. 
2013;160(4):538-546. 
Bussel JB, de Miguel PG, Despotovic JM, et al. Eltrombopag for the treatment of children 
with persistent and chronic immune thrombocytopenia (PETIT): randomized, multicenter, 
placebo-controlled study. Lancet Haematol. 2015;2(8):e315-e325.  
Camitta BM, Rappeport JM, Parkman R, and Nathan DG. Selection of patients for bone 
marrow transplantation in severe aplastic anemia. Blood. 1975; 45(3):355-363. 
Campbell SD, de Morais SM, Xu JJ. Inhibition of human organic anion transporting 
polypeptide OATP1B1 as a mechanism of drug-induced hyperbilirubinemia. Chem Biol 
Interact. 2004;150(2):179-187. 
Cui Y, König J, Leier I, Buchholz U, Keppler D. Hepatic uptake of bilirubin and its 
conjugates by the human organic anion transporter SLC21A6. J Biol Chem. 
2001;276(13)_9626-9630. 
De Latour RP, Visconte V, Takaku T, et al. Th17 immune responses contribute to the 
pathophysiology of aplastic anemia. Blood. 2010;116(20):4175-4184 
Desmond R, Townsley DM, Dumitriu B, et al. Eltrombopag restores trilineage hematopoiesis 
in refractory severe aplastic anemia that can be sustained on discontinuation of drug. Blood. 
2014;123(12):1818-1825. 
Erickson-Miller CL, Delorme E, Tian SS, et al. Preclinical activity of eltrombopag (SB-
497115), an oral, nonpeptide thrombopoietin receptor agonist. Stem Cells. 2009;27(2):424-
430. 
Erickson-Miller CL, Kirchnera J, aivado M, Mayc R, Paynec P, Chadderton A. Reduced 
proliferation of non-megakaryocytic acute myelogenous leukemia and other leukemia and 
lymphoma cell lines in response to eltrombopag. Leukemia Research. 2010;34:1224-1231.  
Frickhofen N, Kaltwasser JP, Schrezenmeier H, et al. Treatment of aplastic anemia with 
antilymphocyte globulin and methylprednisolone with or without cyclosporine. The German 
Aplastic Anemia Study Group. N Eng J Med. 1991;324(19):1297-1304. 


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Garanito MP, Carneiro JD, Filho VO, Scheinberg P. Outcome of children with severe 
acquired aplastic anemia treated with rabbit antithymocyte globulin and cyclosporine A. J 
Pediatr (Rio J). 2014;90(5):523-527. 
Geddis AE, Linden HM, Kaushansky K. Thrombopoietin: a pan-hematopoietic cytokine. 
Cytokine Growth Factor Rev. 2002;13(1):61-73. 
Grainger JD, Locatelli F, Chotsampancharoen T, et al. Eltrombopag for children with chronic 
immune thrombocytopenia (PETIT2) :a randomised, multicentre, placebo-controlled trial. 
Lancet. 2015;386(10004):1649-1658. 
Investigator’s Brochure. Eltrombopag. ed 14, 2017. 
Jenkins J, Williams D, Deng Y, et al. Phase 1 clinical study of eltrombopag, an oral 
nonpeptide, thrombopoietin agonist. Blood. 2007;109(11);4739-4741. 
Jeong J-Y, Vanasse KG. Eltrombopag, a nonpeptide thrombopoietin receptor agonist, 
enhances the ex vivo expansión of human hematopoietic stem cells. Cancer Res. 
2010;70(suppl 1):A4267. 
Kalota A, Gerwitz AM. A prototype nonpeptidyl, hydrazone class, thrombopoietin receptor 
agonist, SB-559457, is toxic to primary human myeloid cells. Blood. 2010;115(1):89-93. 
Kimura S, Robert AW, Metcalf D, Alexander WS. Hematopoietic stem cell deficiencies in 
mice lacking c-mpl, the receptor for thrombopoietin. Proc Natl Acad Sci USA. 
1998;95(3):1195-1200. 
Kook H, Risitano A, Zeng W, et al. Changes in T-cell receptor VB repertoire in aplastic 
anemia: effects of different immunosuppressive regimens. Blood. 2002;99(10):3668-3675. 
Kordasti S, Marsh J, Al-Khan S, et al. Functional characterization of CD4+ T cells in aplastic 
anemia. Blood. 2012;119(9):2033-2043. 
Maciejewski JP, Risitano A, Sloand EM, Nunez O, Young NS. Distinct clinical outcomes for 
cytogenetic abnormalities evolving from aplastic anemia. Blood. 2002;99(9):3129-3135. 
Marsh JCW, Ball SE, Cavanaugh J, et al. Guidelines for the diagnosis and management of 
aplastic anemia. Br J Haematol. 2009;147:43-70.  
Marsh JC1, Bacigalupo A, Schrezenmeier H, Tichelli A, Risitano AM, Passweg JR, Killick 
SB, Warren AJ, Foukaneli T, Aljurf M, Al-Zahrani HA, Höchsmann B, Schafhausen P, Roth 
A, Franzke A, Brummendorf TH, Dufour C, Oneto R, Sedgwick P, Barrois A, Kordasti S, 
Elebute MO, Mufti GJ, Socie G; European Blood and Marrow Transplant Group Severe 
Aplastic Anaemia Working Party. Prospective study of rabbit antithymocyte globulin and 
cyclosporine for aplastic anemia from the EBMT Severe Aplastic Anaemia Working Party. 
Blood. 2012 Jun 7;119(23):5391-6. doi: 10.1182/blood-2012-02-407684. Epub 2012 Apr 27 
Marsh JCW and Kulasekararaj AG. Management of the refractory aplastic anemia patient: 
what are the options? Blood. 2013;122:3561-3567. 
Olnes MJ, Scheinberg P, Calvo KR, et al. Eltrombopag and improved hematopoiesis in 
refractory aplastic anemia. N Eng J Med. 2012;367(1):11-19. Erratum: N Eng J Med. 
2012;367(3):284.  
Qian H, Buza-Vidas N, Hyland CD, et al. Critical role of thrombopoietin in maintaining adult 
quiescent hematopoietic stem cells. Cell Stem Cell. 2007;1(6):671-684. 


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Risitano AM, Maciejewski JP, Green S, Plasilova M, Zeng W, Young NS. In-vivo dominant 
immune responses in aplastic anaemia: molecular tracking of putatively pathogenetic T-cell 
clones by TCR beta-CDR3 sequencing. Lancet. 2004;364:355-364. 
Rosenfeld S, Follman D, Nunez O, Young NA. Antithymocyte globulin and cyclosporine for 
severe aplastic anemia: association between hematologic response and long-term outcome. J 
Am Med Assoc. 2003;289(9):1130-1135. 
Roth M1, Will B, Simkin G, Narayanagari S, Barreyro L, Bartholdy B, Tamari R, Mitsiades 
CS, Verma A, Steidl U. Eltrombopag inhibits the proliferation of leukemia cells via reduction 
of intracellular iron and induction of differentiation. Blood. 2012 Jul 12;120(2):386-94. doi: 
10.1182/blood-2011-12-399667. Epub 2012 May 24. 
Scheinberg P, Nunez O, Wu C, Young NS. Treatment of severe aplastic anemia with 
combined immunosuppression: anti-thymocyte globulin, cyclosporine and mycophenolate 
mofetil. Br J Haematol. 2006; 133(6):606-611. 
Scheinberg P, Nunez O, Weinstein B, et al. Horse versus rabbit antithymocyte globulin in 
acquired aplastic anemia. N Eng J Med. 2011;365(5):430-438. 
Scheinberg P, Nunez O, Weinstein B, Scheinberg P, Wu Com Yong NS. Activity of 
alemtuzumab monotherapy in treatment-naive, relapsed, and refractory severe acquire aplastic 
anemia. Blood. 2012;119(2):345-354. 
Scheinberg P, Young NS. How I treat acquired aplastic anemia. Blood. 2012;120(6):1185-
1196. 
Scheinberg P, Chen J. Aplastic anemia: what have we learned from animal models and from 
the clinic. Semin Hematol. 2013;50(2):156-164.  
Scheinberg P, Townsley D, Dumitriu B, et al. Horse antithymocyte globulin as salvage 
therapy after rabbit antithymocyte golubulin for severe aplastic anemia. Am J Hematol 
2014;89(5):467-469. 
Scheinberg P. Activity of eltrombopag in SAA. Hematology. 2018;450-456. 
SmPC Cyclosporine – Oct 2013 
Socie G. Allogeneic BM transplantation for the treatment of aplastic anemia: current results 
and expanding donor possibilities. Aplastic Anemia, American Society of Hematology 
Education Book. 2013:82-86. 
Solomou EE, Keyvanfar K, Young NS. T-bet, a Th1 transcription factor, is upregulated in T-
cells from patients with aplastic anemia. Blood. 2006;107(10):3983-3991. 
Solomou EE, Rezvani K, Mielke S, et al. Deficient CD4+ CD25+ FOXP3+ T regulatory cells 
in acquired aplastic anemia. Blood. 2007;110(5):1603-1606. 
Sun H, Tsai Y, Nowak I, Liesveld J, Chen Y. Eltrombopag, a thrombopoietin receptor 
agonist, enhances human umbilical cord blood hematopoietic stem/primitive progenitor cell 
expansion and promotes multi-lineage hematopoiesis. Stem Cell Research. 2012; 9(2):77-86. 
Tang Y, Desierto MJ, Chen J, Yong NS. The role of Th1 transcription factor T-bet in a mouse 
model of immune-mediate bone marrow failure. Blood. 2010;155(3):541-548. 
Townsley DM, Scheinberg P, Winkler T, et al. Eltrombopag added to standard 
immunosuppression for aplastic anemia. N Engl J Med. 2017;376(16):1540-50 


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Valdez JM, Scheinberg H, Socie G, et al. Decreased infection-related mortality and improved 
survival in severe aplastic anemia in the past two decades. Clin Infect Dis. 2011;52(6):726-
735. 
Winkler T, Cooper JN, Townsley DM, et al. Eltrombopag for Refractory Severe Aplastic 
Anemia: Dosing Regimens, Long-Term Follow-up, Clonal Evolution and Somatic Mutation 
Profiling, 59th Annual meeting and exposition, ASH 2017.Young NS, Maciejewski J. The 
pathophysiology of acquire aplastic anemia. N Eng J Med. 1997;336(19):1365-1372. 
Young NS, Tisdale JF. High-dose cyclophosphamide for treatment of aplastic anemia. Ann 
Intern Med. 2002;137(6):549-550. 
Young NS, Calado RT, Scheinberg P. Current copies in the pathophysiology and treatment of 
aplastic anemia. Blood. 2006;108(8):2509-2519. 
Young NS et al. Curr Opin Hematol 2008;15:162–168 
Young NS and Kaufman DW. The epidemiology of acquired aplastic anemia. Haematologica. 
2008;93:489-492. 
Zeigler FC, de Sauvage F, Widmer HR, et al. In vitro megakaryocytopoietic and 
thrombopoietic activity of c-mpl ligand (TPO) on purified murine hematopoietic stem cells. 
Blood. 1994;84(12):4045-4052.  


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14 
Appendices 
14.1 
Appendix 1 – Cyclosporine taper dose 
Table 14-1 
Cyclosporine taper dose recommandations 
Daily dose 
25% Dose 
reduction 
Taper daily dose 
Taper BID dosing 
Taper BID dosing 
(rouded) 
900 
225 
675 
337.5 
350 
850 
212.5 
637.5 
318.75 
325 
800 
200 
600 
300 
300 
750 
187.5 
562.5 
281.25 
275 
650 
162.5 
487.5 
243.75 
250 
600 
150 
450 
225 
225 
550 
137.5 
412.5 
206.25 
200 
500 
125 
375 
187.5 
175 
450 
112.5 
337.5 
168.75 
175 
400 
100 
300 
150 
150 
350 
87.5 
262.5 
131.25 
125 
300 
75 
225 
112.5 
100 
250 
62.5 
187.5 
93.75 
100 
200 
50 
150 
75 
75 
150 
37.5 
112.5 
56.25 
50 
100 
25 
75 
37.5 
25 
50 
12.5 
37.5 
18.75 
25 mg once a day 
25 
6.25 
18.75 
9.375 
25 mg every other 
day 


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14.2 
Appendix 2 – Quality of Life questionnaires 


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FACT-TH18 
 


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FACT-Fatigue 
 

SAP_001.pdf: 




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Date 
Time 
point 
Reason for 
update 
Outcome for update 
Section and 
title impacted 
(Current) 
transfusion 
information 
and 
relevant AEs.  
Sample 
timing 
for 
primary 
endpoint was clarified. 
Clarification on derivation of 
duration 
of 
 
hematologic 
response. 
Clarification on definition of the 
start and end dates for the 
transfusion independence. 
Updated 
PROs 
text 
with 
including 
information 
on 
boxplots. 
FPFV: First patient first visit 
 


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Table of contents 
Table of contents ................................................................................................................. 4 
List of abbreviations ............................................................................................................ 6 
1 
Introduction ......................................................................................................................... 8 
1.1 
Study design............................................................................................................. 8 
1.2 
Study objectives and endpoints ............................................................................... 9 
2 
Statistical methods ............................................................................................................. 11 
2.1 
Data analysis general information ......................................................................... 11 
2.1.1 
Data included in the analysis................................................................. 11 
2.1.2 
General analysis conventions ................................................................ 12 
2.1.3 
General definitions ................................................................................ 12 
2.2 
Analysis sets .......................................................................................................... 17 
2.2.1 
Full Analysis Set ................................................................................... 17 
2.2.2 
Safety Set .............................................................................................. 17 
2.2.3 
Per-Protocol Set .................................................................................... 17 
2.2.4 
Pharmacokinetic Analysis Set ............................................................... 18 
2.2.5 
Screening failures .................................................................................. 18 
2.2.6 
Subgroups of interest............................................................................. 18 
2.3 
Patient disposition, demographics and other baseline characteristics ................... 19 
2.3.1 
Patient disposition ................................................................................. 19 
2.3.2 
Patient demographics and other baseline characteristics ...................... 19 
2.4 
Treatments (study treatment, concomitant therapies and compliance) ................. 20 
2.4.1 
Study treatment ..................................................................................... 20 
2.4.2 
Prior, concomitant and post therapies ................................................... 20 
2.4.3 
Protocol deviations ................................................................................ 20 
2.4.4 
Handling of missing values ................................................................... 21 
2.5 
Analysis of the primary objective .......................................................................... 21 
2.5.1 
Primary endpoint ................................................................................... 21 
Handling of missing values/discontinuations ........................................................ 22 
2.5.2 
Supportive analyses ............................................................................... 22 
2.6 
Analysis of secondary efficacy objective(s) .......................................................... 22 
2.6.1 
ORR by 3 months, at 12 months and at 24 months ............................... 22 
2.6.2 
Duration of hematologic response ........................................................ 23 
2.6.3 
Relapse rate ........................................................................................... 23 
2.6.4 
Clonal evolution .................................................................................... 23 
2.6.5 
Blood (RBC) and platelet transfusions ................................................. 24 


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2.7 
Safety analyses ....................................................................................................... 24 
2.7.1 
Adverse events (AEs) ............................................................................ 24 
2.7.2 
Deaths .................................................................................................... 26 
2.7.3 
Laboratory data ..................................................................................... 26 
2.7.4 
Other safety data ................................................................................... 27 
2.8 
Pharmacokinetic endpoints .................................................................................... 29 
2.9 
Patient-reported outcomes (PROs) ........................................................................ 30 
2.9.1 
FACIT-Fatigue and FACT-TH18 (includes FACT-G) ......................... 30 
 
 31 
 
 32 
 
 32 
 
 32 
 
 33 
 
 33 
 
 34 
2.11 
Interim analysis ...................................................................................................... 35 
3 
Sample size calculation ..................................................................................................... 35 
3.1.1 
Bayesian calculus for a binary endpoint ............................................... 36 
4 
Changes to protocol specified analyses ............................................................................. 36 
5 
References ......................................................................................................................... 37 
6 
Appendix 1 ........................................................................................................................ 38 
6.1 
Imputation rules ..................................................................................................... 38 
6.1.1 
AE, concomitant medication (CM) and safety assessment date 
imputation ............................................................................................. 38 
6.1.2 
Prior therapies date imputation ............................................................. 39 
6.2 
Laboratory parameters derivations ........................................................................ 39 
6.3 
Statistical models ................................................................................................... 39 
6.3.1 
Primary analysis .................................................................................... 39 
6.3.2 
Key secondary analysis ......................................................................... 40 
6.4 
FACIT-Fatigue scoring guideline .......................................................................... 40 
6.5 
FACT-Th18 and FACT-G scoring guideline ........................................................ 41 


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List of abbreviations 
AE 
adverse event 
AESI 
adverse events of special interest 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
AST 
aspartate aminotransferase 
ATC 
anatomical therapeutic classification 
ATG 
anti-thymocyte globulin 
AUC 
area under the curve 
BM 
bone marrow 
CM 
concomitant medication 
CR 
complete response 
CRS 
case retrieval sheet 
CSR 
clinical study report 
CTCAE 
common terminology criteria for adverse events 
CV 
coefficient of variation 
DHP 
data handling plan 
DI 
dose intensity 
DNA 
deoxyribonucleic acid  
EC/ECG 
electrocardiogram 
ECOG 
eastern cooperative oncology group 
eCRF 
electronic case report form 
EOT 
end of treatment 
FACIT 
functional assessment of chronic illness therapy 
FAS 
full analysis set 
FPFV 
first patient first visit 
GPS 
global programming & statistical environment 
HLGT 
high level group term 
HLT 
high level term 
HR 
heart rate 
IST 
immunosuppressive therapy 
LB 
laboratory 
LLOQ 
lower limit of quantification 
LPLV 
last patient last visit 
MedDRA 
medical dictionary for drug regulatory affairs 
NCDS 
Novartis clinical data standards 
NGS 
next generation sequencing 
NMQ 
Novartis MedDRA queries 
ORR 
overall response rate 
PA 
protocol amendment 
PAS 
pharmacokinetic analysis set 
PDI 
planned dose intensity 
PDS 
programming data specifications 
PK 
pharmacokinetics 
PNH 
paroxysmal nocturnal hemoglobinuria 
PPS 
per-protocol set 


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PR 
partial response 
PRO 
patient-reported outcomes 
PT 
preferred term 
QTcF 
QT correction Fridericia 
RBC 
red blood cells 
RDI 
relative dose intensity 
 
 
RT-PCR 
reverse transcription polymerase chain reaction 
SAA 
severe aplastic anemia 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
sd 
standard deviation 
SI 
international system of units 
SMQs 
standardized MedDRA queries 
SOC 
system organ class 
TBL 
total bilirubin  
TFLs 
tables, figures, listings 
TPO-R 
thrombopoietin receptor 
ULOQ 
upper limit of quantification 
VS 
vital signs 
 
 
 


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1 
Introduction 
This statistical analysis plan (SAP), describes the analyses for the CETB115E2403 study and is 
based on protocol v02, dated 26-Feb-2019.  Enrollment was completed on 11-May-2020 with 
fifty four (54) adult patients. The interim database lock for the primary analysis was on 09-Dec-
2020. 
There are 2 planned reporting events: 
1. The primary analysis, was done after all enrolled patients completed 6 months or 
discontinued prior to 6 months. A primary clinical study report (CSR) was written. 
2. The final analysis will be done after all patients have completed the study or discontinued 
early, for the patients responding at 6 months this will be once they have completed 
24 months in the study or discontinued the study prior to 24 months. A final CSR will be 
written. 
The shells for the in-text tables and figures as well as the post-text tables, figures and 
listings (TFLs) are in the TFL shells document. Programming specifications for datasets, 
including derivation of variables, are given in the programming data specifications (PDS) 
document. 
All data will be analysed by Novartis using Novartis clinical data standards (NCDS). Analysis 
data sets and statistical outputs will be produced using the SAS system Version 9.4 or higher 
(UNIX environment) in the global programming & statistical (GPS) environment 
1.1 
Study design 
The study design is shown in Figure 1-1 and Figure 1-2.  
This is an interventional, phase II, single-arm, multicenter, open-label, study to investigate the 
efficacy and safety of the combination of eltrombopag and cyclosporine in treatment-naive 
adult patients with severe aplastic anemia (SAA) as first line therapy administered for 6 months, 
with an additional 18 months follow-up for responders for cyclosporine tapering and duration 
of response until relapse or 24 months whichever is earlier. 
At 6 months, responders will discontinue eltrombopag and start to taper cyclosporine until 
24 months. Responders who are no longer responding at 6 months and non-responders will 
discontinue the treatment and study at 6 months and will be followed-up for 30 days. 
Responders who relapse prior to 24 months will discontinue cyclosporine and study, and will 
be followed-up for 30 days.  
Responders who relapse and non-responders already in the follow-up under the previous 
protocol version will be discontinued from the study within 30 days of the approval of the 
protocol amendment. 
The lack of availability of anti-thymocyte globulin (ATG) in several countries has left a large 
proportion of patients with SAA with limited treatment options and poor outcome. In this 
context, the combination of cyclosporine and eltrombopag, 2 therapies with different modes of 
action, is an attractive therapeutic option to address this unmet medical need. Cyclosporine acts 
as an immunosuppressant and eltrombopag acts as a stimulator of bone marrow progenitor cells. 
Fifty (50) patients are planned to be enrolled. 


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Figure 1-1 
Study design under protocol amendment 1 
Under protocol amendment (PA) 1 (4 phases: Treatment 1; Treatment 2; Follow-up; post-
treatment follow-up) 
 
Study part 1 
Study part 2 
Figure 1-2 
Study design under protocol amendment 2 
Under PA2 (2 phases: Treatment 1 and Treatment 2) 
 
1.2 
Study objectives and endpoints 
Table 1-1 displays the study objectives and endpoints. 
Table 1-1 
Objectives and related endpoints 
Objective 
Endpoint 
Primary 
 
To evaluate the efficacy of eltrombopag + 
cyclosporine as first-line therapy on overall 
hematologic response (partial and complete 
response) by 6 months 
Overall hematologic response (CR + PR)* rate by 6 months 
(definition of CR and PR is given as footnote below) 


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Objective 
Endpoint 
Secondary 
 
1. Evaluate the effect of eltrombopag + 
cyclosporine on overall hematologic response 
(partial and complete response): 
● by 3 months   
● at 12 months 
● at 24 months 
Overall hematologic response (CR + PR)* rate: 
● by 3 months   
● at 12 months 
● at 24 months 
The following secondary objectives will be assessed by 6 months and 24 months (responders only) as 
appropriate and will be reported in a cumulative basis until the cutoff date (LPLV for final analysis) 
2. To evaluate the duration of hematologic 
response 
Time from the date of the first response to the date of first 
relapse (defined as no longer meeting definition of PR (and 
not CR) 
3. To evaluate the proportion of patients who 
relapse 
Percentage of patients who relapse 
4. To evaluate the clonal evolution to 
myelodysplasia, paroxysmal nocturnal 
hemoglobinuria (PNH), and leukemia 
Percentage of patients with evolution to myelodysplasia, 
PNH, and acute leukemia occurring at any time during the 
study  
5. To evaluate red blood cells (RBC) 
transfusion independence 
Percentage of patients who are RBC transfusion 
independent at least once by 6 months and by 24 months. 
Independence defined as no RBC transfusion for at least 
56 days  
6. To evaluate platelet transfusion 
independence 
Percentage of patients who are platelet transfusion 
independent at least once by 6 months and by 24 months. 
Independence defined as no platelet transfusion for at 
least 28 days  
7. To evaluate the longest interval without a 
platelet and RBC transfusion 
Duration of longest interval without a platelet transfusion 
by 6 months and 24 months 
Duration of longest interval with a RBC transfusion by 
6 months and by 24 months  
8. To evaluate the effect of Eltrombopag and 
cyclosporine on patient symptoms and health 
related quality of life 
Change in scores from baseline to 6 months and 24 
months on the FACT-G, FACT-TH18, and FACIT-Fatigue 
scales 
9. To evaluate the safety and tolerability of 
eltrombopag + cyclosporine 
Safety will be assessed by: 
● Frequency and severity of AEs, serious AEs (SAEs) 
based on the Common Terminology Criteria of Adverse 
Events (CTCAE version 4. 03), and AEs leading to 
discontinuation, and evaluating changes in laboratory 
values within 6 months and within 24 months (responders 
only) 
● Incidence of adverse events of special interest 
10. To characterize the PK of eltrombopag 
when combined to cyclosporine 
Plasma PK parameters of eltrombopag at 2 weeks and 
trough concentrations at 1 month, 2 months, 3 month, and 
6 months 


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Objective 
Endpoint 
*Overall hematologic response = patients with complete response (CR) + patients with partial response (PR) 
a. Partial response is defined as any two of the following parameters at two consecutive, scheduled visit 
measurements at least 7 days apart during the study (and not sufficient for CR) and no platelet transfusions 
within 7 days of platelet measurement (can still be a responder if ANC and reticulocyte measurements are 
valid): 
 
● Absolute neutrophil count (ANC) ≥ 500/µL 
 
● Platelet count ≥ 20 000/µL 
 
● Reticulocyte count ≥ 60 000/µL (automated) 
b. Complete response is defined as all three parameters meet the following criteria at two consecutive, 
scheduled visit measurements at least 7 days apart during the study and no platelet transfusions within 
7 days of platelet measurement and no RBC transfusion with 14 days of the hemoglobin measurements: 
 
● Absolute neutrophil count (ANC) ≥ 1 000/µL 
 
● Platelet count ≥ 100 000/µL 
 
● Hemoglobin ≥ 10g/dL 
Example: At the end of 6 months out of 50 patients enrolled, if 13 patients satisfy the criteria for CR and 
3 patients satisfy the criteria for PR, the overall hematologic response will be 13+3=16 patients. 
2 
Statistical methods 
2.1 
Data analysis general information 
2.1.1 
Data included in the analysis 
Statistical analyses will be performed using all data collected in the database up to the respective 
data cut-off dates (last patient last visit (LPLV) for the final analysis). All data with an 
assessment date or event start date (e.g. vital sign assessment date or start date of an adverse 
event (AE)) 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 or 
missing will be reported as ‘ongoing’. For these events, the end date will show as missing in 
the listings however the earliest of; death date, last contact date or cutoff date will be used in 
derivations of endpoints as appropriate. 


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Withdrawal of Informed Consent 
Any data collected in the clinical database after a patient 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 study consent is recorded in the electronic case report form (eCRF).   
2.1.2 
General analysis conventions 
Data from all study centers will be pooled for analyses. 
Qualitative data (e.g., gender, race, etc.) will be summarised by absolute and relative 
frequencies. A missing category will be included where applicable. Percentages will be 
calculated using the number of patients in the relevant analysis set or subgroup as the 
denominator. 
Quantitative data (e.g., age, body weight, etc.) will be summarised by appropriate descriptive 
statistics (i.e. mean, standard deviation (sd), minimum, 25th percentile, median, 75th percentile 
and maximum). 
2.1.3 
General definitions  
Study drug and study treatment 
Study drugs refer to the individual drugs used in the study, eltrombopag or cyclosporine. 
Study treatment refers to either eltrombopag or cyclosporine or eltrombopag+cyclosporine. 
Date of first administration of study drug 
The date of first administration of study drug is derived as the first date when a nonzero dose 
of study drug is administered. The date of first administration of study drug is also referred to 
as start date of study drug. Start date of study drug is defined for each study drug. For 
cyclosporine it is irrespective of capsule or solution form. 
Date of last administration of study drug 
The date of last administration of study drug is defined as the last date when a nonzero dose of 
study drug is administered. This date is also referred to as last date of study drug. Last date of 
study drug is defined for each study drug. For cyclosporine it is irrespective of capsule or 
solution form. 
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 is administered. 
For example, if the 1st dose of eltrombopag is taken on 08-Feb-2017, and 1st dose of 
cyclosporine, is taken on 07-Feb-2017, then the date of first administration of study treatment 
is 07-Feb-2017. The date of first administration of study treatment is also referred to as start 
date of study treatment. 


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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 is administered.  
For example if the last dose of eltrombopag is taken on 08-Aug-2017, and the last dose of 
cyclosporine is taken on 07-Aug-2017, then the date of last administration of study treatment is 
on 08-Aug-2017. This date is also referred to as last date of study treatment. 
Duration of exposure 
The duration of exposure for the study drugs will be calculated as: 
• Duration of study drug exposure (months) = (last date of study drug) – (first date of study 
drug) + 1.  
The duration of exposure for the study treatment will be calculated as: 
• Duration of study treatment exposure (months) = (last date of study treatment) – (first date 
of study treatment) + 1.   
If the start or end date of a study drug is missing, the duration will be missing. The durations 
will include periods of temporary interruption (planned or actual) for any reason. 
Dose interruption 
An interruption is defined as an actual zero dose on one or more days between two non-zero 
dosing records.  
Note: The last zero dose of a study drug (followed by permanent discontinuation) is not 
considered as a dose interruption. For the purpose of summarizing interruptions and reasons, in 
case multiple entries for interruption are entered on consecutive days with different reasons 
these will be counted as separate interruptions. However, if the reason is the same in these 
multiple entries on consecutive days, then it will be counted as one interruption. 
Dose reduction 
A dose reduction is where the prescribed dose is lower than the previous prescribed dose or 
where the actual dose administered/total daily dose is lower than the prescribed dose. Any dose 
change to correct a dosing error will not be considered a dose reduction, e.g. if due to a dosing 
error, a patient receives higher than protocol planned starting dose and moves down to the 
planned starting dose then this is not counted as a reduction, however if they move directly from 
a higher than planned starting dose down to a lower than protocol planned starting dose, then 
this is counted as a reduction. 
Note: It is assumed that if there is a dose reduction, then the ‘Dose changed’ box was ticked on 
the dose administration eCRF page. 
Cumulative dose 
Cumulative dose of a study treatment is defined as the total dose given during the study 
treatment exposure and will be summarised for each of the study treatment components 
(eltrombopag and cyclosporine), respectively. 


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The planned cumulative dose for a study treatment component refers to the total planned dose 
as per the protocol up to the last date of study drug administration. The planned cumulative 
dose is not summarised/listed. It is used for relative dose intensity calculations. The actual 
cumulative dose refers to the total actual dose administered, over the duration for which the 
patient is on the study treatment as documented in the dose administration eCRF.  
For continuous dosing, the actual cumulative dose is the sum of the non-zero doses recorded 
over the dosing period and the planned cumulative dose is the planned starting dose summed 
over the same dosing period. 
For cyclosporine the cumulative dose will be calculated separately for capsules (mg) and 
solution (mg/ml). 
For patients who did not take any drug, the actual cumulative dose is by definition equal to zero 
for that drug. 
Dose intensity and relative dose intensity 
Dose intensity (DI) for patients with non-zero duration of exposure is defined as follows: 
DI (dosing unit / unit of time) = Actual cumulative dose (dosing unit) / Duration of exposure 
(unit of time). 
e.g. DI (mg/day) = (100 mg/day * 1050 days) / 1080 days = 97.2 mg/day   
For patients who did not take any drug the DI is by definition equal to zero. 
Planned dose intensity (PDI) is the assigned dose by unit of time planned to be given to 
patients as per protocol in the same dose unit and unit of time as that of the DI, i.e.  
PDI (dosing unit / unit of time) = Planned cumulative dose (dosing unit) / Duration of exposure 
(unit of time). 
For Part 2 of the study, note that only cyclosporine is administered and it is with a tapering 
regime. 
For cyclosporine use 10 mg/kg/day as the planned dose for the first record and after that use the 
“prescribed dose x 2” as the planned dose and the “total daily dose” as the actual dose for 
exposure calculations. Summarise results in mg/kg/day. 
For eltrombopag use 150 mg/day (or 100 mg/day for E/SE Asian patients) for planned dose for 
all records and “total daily dose” as the actual dose. Summarise results in mg/day. 
Relative dose intensity (RDI) is defined as follows: 
RDI = DI (dosing unit / unit of time) / PDI (dosing unit / unit of time). 
e.g. RDI = DI (92.7 mg/day) / PDI (100 mg/day) = 0.927 


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Study day 
The study day describes the relative day of the event related to the start date of study treatment. 
The reference start date is designated as Study Day 1. Study Day –1 is the day that precedes 
Day 1. Study Day 0 is not defined.  Study day is not to be used in numerical computations, for 
example in calculating exposure. 
The study day will be calculated as: 
• The date of the event (visit date, onset date of an event, assessment date etc.) - reference 
start date + 1, if event is on or after the reference start date.  
• The date of the event (visit date, onset date of an event, assessment date etc.) - reference 
start date, if event precedes the reference start date.  
The reference start date for all assessments (safety, efficacy, patient reported outcomes (PROs), 
etc.) will be the start date 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 in the listing will be negative. 
Baseline 
Baseline is the result of an investigation describing the “true” uninfluenced state of the patient, 
defined as the period from the date of signing any informed consent document to the start date 
of study treatment. Assessments, specified to be collected post-dose on the first date of study 
treatment are not considered. 
The last non-missing assessment, including unscheduled assessments on or before the date of 
start of study treatment is defined as “baseline value” or “baseline assessment”.   
Where multiple measurements meet the baseline definition, with no further flag or label that 
can identify the chronological order, then values from central assessments should be considered 
as baseline rather than local values.  
For electrocardiogram (ECG) parameters, if there are multiple replicates per time point, the 
average of these measurements would be calculated for baseline (if not already available in the 
database). 
If patients have no value as defined above, the baseline result will be missing.  
Observation periods 
The overall observation period will be divided into three mutually exclusive segments: 
1. Pre-treatment: from day of patient’s informed consent to start date of study treatment 
2. On-treatment: from start date study treatment to last date of study treatment + 30 days 
3. Post-treatment: from last date of study treatment + 31 days 
On-treatment assessments/events 
The definition of on-treatment is given below, depending on the context. 


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For safety summary tables an on-treatment AE is defined as any AE reported in the following 
time interval (including the lower and upper limits):  
• <date of first administration of study treatment; date of last administration of study 
treatment + 30 days> 
This corresponds to the definition of treatment-emergent AEs given in the protocol, i.e. AEs 
which are newly reported or worsening from baseline.  
An on-treatment assessment is defined as any assessment performed after the date of first 
administration of study treatment (except for assessments specified to be collected post-dose on 
that day), i.e. assessments performed in the following time interval (including the lower and 
upper limits):  
• <date of first administration of study treatment + 1; date of last administration of study 
treatment + 30 days> 
For patients whose last date of study treatment is missing, on-treatment assessments/events 
include any assessment/event present in the database occurring after the start date of study 
treatment.  
Listings will contain all data, flagging assessments/events outside of the on-treatment period 
where applicable. 
Definition of Months and Years 
A month will be calculated as (365.25 / 12) = 30.4375 days. If duration is to be reported in 
months, duration in days will be divided by 30.4375.  If duration is to be reported in years, 
duration in days will be divided by 365.25. 
Time since initial SAA diagnosis 
Time since initial SAA diagnosis (days) = First dose date (Epag/CsA) – date of initial diagnosis.  
Time windows 
Time windows for assessments are based on protocol specified windows. Weekly and biweekly 
visits should be completed ± 1 day. Biweekly visits after 6 months should be completed ± 2 
days. Monthly visits should be completed ± 3 days. Bimonthly visits should be completed ± 1 
week. 
Time windows for multiple assessments 
In order to summarise data of assessments collected over time (including any unscheduled 
visits), the assessments will be time slotted. If more than one assessment is done within the 
same time window, the assessment performed closest to the target date will be used. If 2 
assessments within a time window are equidistant from the target date, then the earlier of the 2 
assessments will be used. If multiple assessments on the same date then the worst case will be 
used. The end of treatment assessment will be included if collected within 30 days of the last 
treatment date. Data from all assessments (scheduled and unscheduled), including multiple 
assessments, will be listed. 


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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: 
Table 2-1 
Last contact date data sources  
Source data 
Conditions 
Date of withdrawal of consent  
Withdrawal of study informed consent 
Date of discontinuation/phase completion 
On the last disposition page completed 
Start/End dates from drug administration records  
Both study drugs. Doses of 0 are allowed 
Sample collection dates 
Sample collection marked as ‘done’ e.g. 
laboratory or pharmacokinetics (PK)  
Assessment dates 
At least one non-missing parameter value e.g. 
vital signs weight value, performance status 
available etc. 
Start/End dates of AEs, medications or surgeries  
Non-missing verbatim term 
The cut-off date will not be used for last contact date, unless the patient was last 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. 
The last contact date will be used for censoring of patients in the analysis of duration of 
hematological response. 
2.2 
Analysis sets 
Patients who did not sign an informed consent form will be excluded from all analysis sets. All 
screened patients will be used in selected outputs. 
2.2.1 
Full Analysis Set 
The Full Analysis Set (FAS) includes all patients who received at least one dose of study 
treatment (eltrombopag or cyclosporine).  
2.2.2 
Safety Set 
The Safety Set includes all patients who received at least one dose of study treatment 
(eltrombopag or cyclosporine).  
2.2.3 
Per-Protocol Set 
The Per-Protocol Set (PPS) includes the patients in the FAS who had no major protocol 
deviations. 
The list of protocol deviations in Table 2-2 will lead to exclusion of the patient from the PPS. 


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Table 2-2 
Protocol deviations leading to exclusion of patients from PPS 
PD description 
Protocol deviation ID 
Informed consent not obtained 
INCL01 
SAA characterization not met 
INCL03 
Evidence of clonal hematologic bone marrow disorder on cytogenetics* 
EXCL02 
Prior immunosuppressive therapy with cyclosporine, alemtuzumab, rabbit or 
horse ATG and thrombopoietin receptor (TPO-R) agonists. 
EXCL03 
Hypersensitivity to eltrombopag or its components 
EXCL04 
Administration of an investigational drug within 30 days or 5 half-lives, 
whichever is longer, preceding the first dose of study treatment 
EXCL11 
Eltrombopag starting dose not correct 
TRT01 
Cyclosporine starting dose not correct 
TRT02 
Failure to withdraw eltrombopag despite various reasons 
WTH02 
Patient impacted by COVID19 
OTH02,-03,-04,-06 & 
TRT10,-11 
*In addition the 4 patients who were enrolled and then discontinued from the study based on 
discrepancies between the local and central bone marrow assessment will be excluded – Using 
discontinued study with reason “Technical problems” 
2.2.4 
Pharmacokinetic Analysis Set 
The Pharmacokinetic Analysis Set (PAS) includes all patients who provide at least one 
evaluable pharmacokinetics (PK) concentration. For a concentration to be evaluable, patients 
are required to: 
• For samples on Week 2 
• take the same dose of eltrombopag for all dosing days prior to sampling on Week 2 
• for pre-dose sample, do not vomit within 4 hours after the dosing of eltrombopag 
prior to sampling 
• for post-dose samples, do not vomit within 4 hours after the dosing of eltrombopag on 
the sampling day 
• For all pre-dose samples, have the sample collected before the next dose administration  
2.2.5 
Screening failures 
Patients who sign an informed consent form but fail to start on study treatment for any reason 
will be considered a screen failure. 
2.2.6 
Subgroups of interest 
The following subgroups of interest may be used in analyses: 
• Age (<60, ≥ 60 years) 
• Ethnicity (East/South East (E/SE) Asian vs Other)  
• Responder status (Responder, Non-responder) – see Section 2.5.1 for definition 


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2.3 
Patient disposition, demographics and other baseline 
characteristics 
The Full Analysis Set (FAS) will be used for all baseline and demographic summaries and 
listings unless otherwise specified. 
2.3.1 
Patient disposition 
Disposition data will be summarised descriptively and listed. Summaries will include number 
and percentage (%) of patients who; complete a study phase (screening, treatment period 1, 
treatment period 2, post treatment follow-up and/or treatment discontinuation follow-up), 
patients who continue to the next phase, patients who discontinue a study phase with primary 
reason as reported on the disposition eCRF pages. Number (%) of patients who permanently 
discontinued study treatment with reason, as reported in the dose administration record eCRF 
pages will also be provided. 
Informed consent and inclusion/exclusion criteria data will also be listed. 
Data will be listed for screening failures. 
The denominator will be based on the number of patients who enter the respective study phase 
(4 phases are used under PA1 and 2 phases are used under PA2, see study design figures in 
Section 1.1). 
2.3.2 
Patient demographics and other baseline characteristics 
Demographic and other baseline data (e.g. medical history, transfusion history, diagnosis and 
extent of cancer, and eastern cooperative oncology group (ECOG) performance status etc.) will 
be summarised descriptively and listed. Age by category will also be summarised. 
Demographic data for screen failure patients will be listed. 
Demographic data will also be summarised by age sub-groups, ethnicity and/or responder status. 
Medical history 
Medical histories and current medical conditions at baseline will be summarised separately for 
ongoing and historical medical conditions by primary system organ class (SOC) and preferred 
term (PT). Medical history and current medical conditions will be coded using the latest version 
of the Medical Dictionary for Regulatory Activities (MedDRA) at the time of analysis. Listings 
will be provided of all data. 
Transfusion history 
Transfusion history for platelets and for red blood cells (RBCs) in the 4-weeks prior to initiation 
of dosing of eltrombopag and cyclosporine will be summarised and listed. The number of 
platelet/RBCs transfusions and time since last platelet/RBCs transfusion will be provided.  
Time since last platelet/RBCs transfusion (in days) = Start date of treatment – start date of last 
platelet/RBCs transfusion. 


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Analyses sets 
The number (%) of patients in each analysis set (defined in Section 2.2) will be summarised. 
2.4 
Treatments (study treatment, concomitant therapies and 
compliance) 
Eltrombopag (film-coated tablets) will be administered orally, once daily for 6 months. 
Cyclosporine (soft-gelatin capsules) will be administered orally, twice daily for the first 
6 months and for a further 18 months (tapering regime for responder patients only).   
All patients must have safety evaluations for 30 days, after the last dose of study treatment. 
2.4.1 
Study treatment 
Duration of study drug exposure (months), actual cumulative dose, actual dose intensity (DI) 
and relative dose intensity (RDI) will be summarised separately for each study drug 
(eltrombopag and cyclosporine) for the safety set. 
The number of patients with dose changes, interruptions and permanent discontinuations will 
be presented, along with reasons for the dose change/interruption/permanent discontinuation 
for each study drug. 
Duration of exposure (months) will also be categorized and summarised using the following 
time intervals: 
• Eltrombopag: <1, ≥ 1, ≥ 2, ≥ 3, ≥ 4, ≥ 5, ≥ 6 
• Cyclosporine: <1, ≥ 1, ≥ 2, ≥ 3, ≥ 4, ≥ 5, ≥ 6, ≥ 12, ≥ 18, ≥ 24  
Listings will be provided of all data. 
2.4.2 
Prior, concomitant and post therapies 
Medications and significant non-drug therapies prior to and after the start of the study treatment 
will be coded according to the world health organization (WHO) Drug Reference List and 
summarised by anatomical therapeutic chemical (ATC) classification and preferred term.  
Summary tables for concomitant medications and concomitant non-drug therapies for the safety 
set will be provided. Prior, concomitant and post study treatment medications and non-drug 
therapies will be listed for the safety set. Medications and therapies outside of the on-treatment 
period will be flagged. 
Listings will be provided. 
2.4.3 
Protocol deviations 
The number (%) of patients with protocol deviations will be summarised by deviation category 
(as specified in the latest version of the study data handling plan (DHP) at the time of analysis) 
and overall for the FAS. All protocol deviations will be listed, flagging those leading to the 
exclusion of a patient from an analysis set. Protocol deviations will be listed for screening 
failures (if any). 


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2.4.4 
Handling of missing values 
For analyses prior to the final analysis (at 24 months), if the date of last administration of study 
drug is completely missing and there is no end of treatment eCRF page, the patient is considered 
as on-going  and the earliest of; death date, last contact date or cut-off date, will be used as the 
‘last dosing date’ for calculation/derivation purposes e.g. durations. Last administration date 
should not be missing for the final analyses.  
2.5 
Analysis of the primary objective 
The primary objective of this study is to evaluate the efficacy of eltrombopag+cyclosporine as 
first-line therapy as measured by the overall hematologic response rate by 6 months. That is, 
after all enrolled patients have completed 6 months of study treatment or discontinued study 
treatment or study prior to 6 months. Efficacy analyses and listings are based on the FAS. 
2.5.1 
Primary endpoint 
The overall hematologic response rate (ORR) is defined as the proportion of patients achieving 
complete response (CR) and partial response (PR) defined as follows: 
Partial response (PR) is defined as any two of the following parameters at two consecutive, 
scheduled visit measurements at least 7 days apart during the first 6 months of study (and not 
sufficient for CR) and no platelet transfusions within 7 days of platelet measurement (can still 
be a PR if ANC and reticulocyte measurements are valid): 
• Absolute neutrophil count (ANC) ≥ 500/µL 
• Platelet count ≥ 20 000/µL 
• Reticulocyte count ≥ 60 000/µL (automated) 
Complete response (CR) is defined as all three parameters meet the following criteria at two 
consecutive, scheduled visit measurements at least 7 days apart during the first 6 months of 
study and no platelet transfusions within 7 days of platelet measurement and no RBC 
transfusion with 14 days of the hemoglobin measurements:  
• ANC ≥ 1 000/µL 
• Platelet count ≥ 100 000/µL 
• Hemoglobin ≥ 10 g/dL 
ORR_6 = Number of patients who achieved hematologic response by 6 months/Number of 
patients in the FAS. 
Responder status: If any patient achieves hematologic response (either CR or PR) any time on 
or before the 6 months visit, they will be considered a responder, else they are a non-responder. 
The point estimate along with the corresponding exact 95% confidence interval using Clopper 
and Pearson exact method will be presented for ORR_6. 
Day 10 (plat 8 000) sample at 10:00 and platelet transfusion Day 10 11:00 (plat 60 000)– assume 
transfusion is always after the blood sample Day 10 sample is valid for efficacy. 
Day 11 to Day 16 not valid (Day 11 (50 000), 12 (45 000), 13, 14, 15, 16 (transfusion minimal 
impact by day 7) not valid). Both Day 10 and Day 17 samples are valid for efficacy 


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Handling of missing values/discontinuations 
If any patient achieves overall hematologic response any time before 6 months but discontinues 
prior to 6 months or has missing parameters required for assessing overall hematologic response 
at any point after achieving the first response, they will be considered as responders.  
Due to COVID19 situation some patients may have local instead of central lab results for 
scheduled visits. For all patients, local results (including the visit window period) will be used 
if all 4 results of the efficacy parameters (hemoglobin, neutrophils, reticulocytes, platelets) from 
the central laboratory are not available for a scheduled visit. 
2.5.2 
Supportive analyses 
The ORR by 6 months (primary analysis) will be repeated on the PPS.  
The ORR by 6 months (primary analysis) will also be summarised by age sub-groups and/or 
ethnicity using the FAS and/or PPS. 
The ORR at 6 months will be summarised using the FAS as follows: 
• The overall hematologic response will be calculated at 6 months (based on assessment at 6 
months visit and the previous visit at least 7 days apart) based on the evaluable patients 
(i.e., patients for whom data is available at 6 months). Thus if a patient has missing 
laboratory parameters at 6 months or the prior visit at least 7 days apart required to 
calculate CR or PR, or if the patient discontinued earlier than 6 months, then the patient 
will be considered as a non-responder. 
• ORR_a6 = Number of patients who achieved hematologic response at 6 months/Number 
of patients in the FAS. 
2.6 
Analysis of secondary efficacy objective(s) 
All secondary efficacy analyses will be performed on the FAS, unless otherwise specified. 
Secondary objectives will be summarised in the 6 and 24 months CSRs with data reported 
cumulatively. Listings will be provided. 
2.6.1 
ORR by 3 months, at 12 months and at 24 months 
The ORR by 3 months will be evaluated and summarised as for the ORR by 6 months, i.e. if 
any patient achieves hematologic response any time on or before the month 3 visit, they will be 
considered a 3 month responder, else they are a 3 month non-responder. 
• ORR_3 = Number of patients who achieved hematologic response by 3 months/Number 
of patients in the FAS. 
• The ORR by 3 months will be repeated on the PPS.  
• The ORR by 3 months will also be summarised by age sub-groups and/or ethnicity using 
the FAS and/or PPS. 
The ORR at 12 months and at 24 months will be summarised as for the ORR at 6 months. If 
any 6 month responder achieves hematologic response at 12 months (24 months) visit, they will 
be considered at 12 months (24 months) responder, else they are at 12 month (24 month) non-


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responder. The 12 months (24 months) visit will be the confirmatory visit of the most recent 
visit assessment prior to this assessment (at least 7 days apart). 
• ORR_a12 (ORR_a24) = Number of patients who achieved hematologic response at 
12 months (24 months)/Number of patients in the FAS. 
• The ORR at 12 months (24 months) will be repeated on the PPS.  
• The ORR at 12 months (24 months) will also be summarised by age sub-groups and/or 
ethnicity using the FAS and/or PPS. 
2.6.2 
Duration of hematologic response 
The time from start of the first hematologic response (the initial assessment, not the 
confirmatory assessment, of either CR or PR whichever occurs first by 6 months) to the date of 
first relapse will be derived as:  
• Duration of first hematologic response (days) = End date (Date of first relapse) – start date 
of first hematologic response + 1 
Longest duration will also be presented: 
• Longest duration of hematologic response (days) = End date (Date of relapse) – start date 
of longest hematologic response + 1 
Relapse is defined as no longer meeting the definition of PR (and not CR). 
The duration of hematological response will be estimated using Kaplan-Meier method and the 
median time to relapse will be presented along with 95% confidence interval.If no relapse 
occurs, the patient will be censored at the date of last contact. 
2.6.3 
Relapse rate 
The number (%) of responders who relapse during the study will be reported by 6 and 
24 months on a cumulative basis and will be summarised together with the corresponding exact 
95% confidence interval using Clopper and Pearson exact method. 
2.6.4 
Clonal evolution 
The number (%) of patients along with corresponding exact 95% confidence interval (using 
Clopper and Pearson exact method) with possible clonal evolution to myelodysplasia, 
paroxysmal nocturnal hemoglobinuria (PNH) and/or acute leukemia occurring during the study 
will be summarised by 6 and 24 months. Clonal evolution to each group is defined as: 
• myelodysplasia: a new marrow cytogenic abnormality with complex karyotype marked as 
‘Yes’  
• taken from the ‘Cytogenetics / Other Abnormalities’ eCRF page. 
• PNH: a clone of peripheral blood GPI-deficient (%) having cumulative PNH sub-type of 
type 2 RBC% and type 3 RBC% value of <10% at baseline that rose to >50% on study 
• taken from the ‘Flow cytometry’ eCRF page using the parameter ‘Peripheral blood 
GPI-deficient (%)’ 
• Any rise (local or central) will be considered 
• acute leukemia: >20% peripheral blood and/or marrow blasts post baseline 


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• marrow blasts are taken from the ‘Bone Marrow Aspirate’ or the ‘Bone Marrow 
Biopsy’ eCRF page using the ‘Blast Cells (%)’ parameter 
Programmed listing results will be reviewed by clinical and/or steering committee members and 
confirmed cases of clonal evolution will be discussed in the CSR. 
2.6.5 
Blood (RBC) and platelet transfusions 
The number (%) of patients with corresponding 95% confidence interval (using Clopper and 
Pearson exact method) will be summarised by 6 and 24 months (responders only) for patients: 
• who received at least one platelet transfusion 
• who received at least one RBC transfusion  
• with platelet transfusion independence 
• with RBC transfusion independence 
Transfusion independency is considered if transfusions are not required in at least a 28 day 
period for platelet transfusions and at least 56 day period for RBC transfusions. 
In addition the duration of the longest interval without a platelet or RBC transfusion by 
6 months and by 24 months (responders only) will be summarised using Kaplan-Meier analysis 
and the median longest duration will be presented along with 95% confidence interval. 
• Longest duration of platelet transfusion independence (days) = End date of longest 
interval – start date of longest interval + 1 
• Longest duration of RBC transfusion independence (days) = End date of longest interval – 
start date of longest interval + 1 
Note that: 
• the start date of the longest interval might use the patient’s first dose date or the patient’s 
last transfusion date + 1 
• the end date of the longest interval might use the patient’s first transfusion date – 1 or if no 
end date of longest interval without a platelet or RBC transfusion occurs, the patient will be 
censored at the date of last contact. 
Listings will be provided. 
Transfusions packed red blood cells, platelets and longest duration of transfusion independence 
will be also summarised by age sub-groups  and/or ethnicity. 
2.7 
Safety analyses 
Safety analyses will be based on the safety set unless otherwise specified. The summary tables 
will be presented for ‘Responders’, ‘Non-responders’ and ‘All subjects’ where indicated. 
Listings will be provided.  
2.7.1 
Adverse events (AEs) 
The AEs will be coded using the latest version of MedDRA at the time of the analysis. AEs will 
be graded using the common toxicity criteria for adverse events (CTCAE) Version 4.03 


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AE summaries will only include AEs during the on-treatment period. A column for ‘Grade ≥ 3’ 
may be included in the AE tables. If a patient reported more than one AE with the same preferred 
term (PT), the AE with the greatest severity will be presented. If a patient reported more than 
one AE within the same primary system organ class (SOC), the patient will be counted only 
once with the greatest severity at the SOC level, where applicable. An AE with missing CTCAE 
grade will be included in the ‘All grades’ column of the summary tables. 
In AE summaries, the primary SOC will be presented alphabetically and the PTs will be sorted 
within the primary SOC in descending frequency. 
Summary tables will be provided for: 
• Overview of AEs 
• In-text table 
• All AEs regardless of relationship to study treatment by primary SOC, PT and maximum 
severity and age as well as ethnicity 
• In-text table by SOC and maximum severity 
• In-text table by PT and maximum severity 
• AEs suspected to be related to study treatment by SOC, PT and maximum severity 
• In-text table by PT and maximum severity 
• AEs leading to study treatment discontinuation regardless of relationship to study 
treatment by SOC, PT and maximum severity 
• In-text table by PT and maximum severity 
• AEs leading to study treatment discontinuation suspected to be related to study treatment 
by SOC, PT and maximum severity 
• AEs leading to study treatment adjustment and/or interruption regardless of relationship to 
study treatment by SOC, PT and maximum severity 
• SAEs regardless of relationship to study treatment by SOC, PT and maximum severity 
• In-text table by PT and maximum severity 
• SAEs suspected to be related to study treatment by SOC, PT and maximum severity 
• On-treatment deaths and SAEs suspected to be related to study treatment by SOC and PT 
• Non-SAEs regardless of relationship to study treatment (threshold 0-5%) by SOC and PT 
• On-treatment deaths by SOC and PT and age, ethnicity as well as responder status 
• In-text table by SOC and PT 
• All deaths by SOC and PT and responder status 
All AEs will be listed. AEs outside of the on-treatment period will be flagged. 
Adverse events of special interest / grouping of AEs 
The adverse events of special interest (AESI) are maintained and updated on a regular basis in 
the project case retrieval sheet (CRS) and the latest version at the time of the analyses will be 
used. An in-text and post-text summary table by SOC, PT and maximum severity will be 
provided.  


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An AESI is a grouping of AEs that are of scientific and medical concern specific to 
eltrombopag. These groupings are defined using MedDRA terms, standardized MedDRA 
queries (SMQs), high level group terms (HLGTs), HLT (high level terms) and PTs. Customized 
SMQs called Novartis MedDRA queries (NMQs) 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. For each specified AESI, number (%) 
of patients with at least one event of the AESI occurring during on-treatment period will be 
summarised by responder status and overall. 
A listing of AESIs will be provided and a listing of all grouping levels down to the MedDRA 
preferred terms used to define each AESI will be generated. 
2.7.2 
Deaths 
See Section 2.7.1. A listing will be provided of all deaths, deaths outside of on-treatment period 
will be flagged. This all deaths listing will be for “All screened patients” so that deaths during 
screening are also presented. 
2.7.3 
Laboratory data 
Laboratory values (central and local) are converted to the international system of units (SI). 
CTCAE Grade 0 will be assigned for all non-missing values not graded as 1 or higher. Grade 5 
will not be used. For laboratory tests where grades are not defined by CTCAE version 4.03, 
results will be categorized as low/normal/high based on laboratory normal ranges.  
The following summaries will be generated separately for hematology and for the safety set: 
• Shift tables by CTCAE grade (or low/normal/high classification) to compare baseline to 
the worst on-treatment value: 
• Hematology: Neutrophils (absolute), platelets and hemoglobin 
• Chemistry: Creatinine, total bilirubin (TBL), aspartate aminotransferase (AST), 
alanine aminotransferase (ALT) and alkaline phosphatase (ALP) 
• Summary statistics on platelets for change from baseline for months 3, 6, 12 and 24 will 
be provided. On-treatment platelet values will be used up to Month 24. 
• Box plots showing parameter values over time (baseline and on-treatment time points 3, 6, 
12 and 24 months) will be displayed based on time windows for the following selected 
parameters: Neutrophils (absolute), platelets, reticulocytes, hemoglobin and RBCs. 
Boxplots will display boxes (25th – 75th percentiles) and median (line) as well as joint 
mean (dot) values. Whiskers extend to the 10th – 90th percentiles with any values outside 
the whiskers not being displayed. A footnote will explain that these values are not 
displayed. However, all values are used to calculate mean and percentiles displayed on the 
graph. The number of observations used for this analysis is to be stated at the bottom. 
Listings of laboratory data (hematology and biochemistry) will be provided showing the 
corresponding CTCAE grades, if applicable, and the classifications relative to the laboratory 
normal ranges. Values measured outside of on-treatment period will be flagged. 


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Liver function parameters 
Liver function parameters of interest are TBL, ALT, AST and ALP. 
The number (%) of patients with worst on-treatment values will be summarised: 
• ALT or AST > 3xULN  
• ALT or AST > 5xULN 
• ALT or AST > 8xULN 
• ALT or AST > 10xULN 
• ALT or AST > 20xULN 
• TBL > 2xULN 
• TBL > 3xULN 
• ALT or AST > 3xULN & TBL > 2xULN 
• ALT or AST > 3xULN & TBL > 2xULN & ALP ≥ 2xULN  
• ALT or AST > 3xULN & TBL > 2xULN & ALP < 2xULN (potential Hy’s law) 
Listings of liver event data will be provided. Values measured outside of on-treatment period 
will be flagged. 
2.7.4 
Other safety data 
2.7.4.1 
ECG  
12-lead ECGs, including QTcF (Fridericia’s correction), mean heart rate (HR), PR-, QT- and 
QRS-durations, will be obtained locally for each patient during the study. ECG data will be read 
and interpreted locally. 
Where ECG replicates are provided for an assessment, the average of the ECG parameters at 
that assessment will be used in the analyses. 
The number (%) of patients with notable values will be presented.  
Table 2-3 
Notable criteria for ECG parameters 
Parameter 
 Notable low value  
Notable high value 
QTcF 
 
New value of >450 and ≤ 480 ms 
New value of >480 and ≤ 500 ms 
New value of >500 ms 
Increase from baseline of >30 ms to ≤ 60 ms 
Increase from baseline of >60 ms 
Heart rate 
Decrease >25% from baseline 
and to a value <50 bpm 
Increase >25% from baseline and to a value >100 bpm 
PR 
-- 
Increase >25% from baseline and to a value >200 ms 
New value of >200 ms 
QRS 
-- 
Increase >25% from baseline and to a value >120 ms 
New value of >120 ms 


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A listing of all ECG assessments will be produced. Notable values as well as values measured 
outside of on-treatment period will be flagged in the listings.  
2.7.4.2 
Vital signs 
Vital sign assessments are performed in order to characterise basic body function. The following 
parameters were collected: height (cm, inch), weight (kg, pound), body temperature (°C, 
Fahrenheit), position, pulse (beats/minute), systolic and diastolic blood pressure (mmHg). 
The number (%) of patients with notable values will be presented. 
Table 2-4 
Notable criteria for vital signs  
Vital sign (unit) 
 Notable low value  
Notable high value 
Weight (kg) 
decrease  ≥  10% from baseline 
increase ≥ 10% from baseline 
Body temperature ( o C) 
-- 
≥ 39.1 
Pulse rate (bpm) 
≤ 50 and  
decrease from baseline of >25% 
≥ 100 and  
increase from baseline of >25% 
Systolic blood pressure 
(mmHg) 
≤ 90 and  
decrease from baseline of ≥ 20 
≥ 180 and  
increase from baseline of ≥ 20 
Diastolic blood pressure 
(mmHg) 
≤ 50 and  
decrease from baseline of ≥ 15 
≥ 105 and  
increase from baseline of ≥ 15  
A listing of all vital sign assessments will be produced and notable values will be flagged. 
Assessments collected outside of on-treatment period will be flagged. 
ECOG performance status 
The eastern cooperative oncology group (ECOG) performance status will be used to assess 
physical health of patients, ranging from 0 (most active) to 5 (least active). 
Shift tables comparing the baseline status with the worst post-baseline status will be provided. 
Table 2-5 
ECOG performance scale 
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 house work, 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 bed or chair 
5 
Dead 
A listing of all ECOG performance status assessments will be produced, flagging assessments 
collected outside of the on-treatment period. 


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Ophthalmic and neurologic examinations 
No summaries or listings as only collected as source data. 
2.8 
Pharmacokinetic endpoints   
The PAS will be used for the PK data analysis and the FAS for the listings.  
PK parameters for eltrombopag will be determined using non-compartmental methods using 
Phoenix (Pharsight, Mountain View, CA) or other appropriate software. PK parameters listed 
in the table below will be estimated and reported, when feasible.  
Table 2-6 
Non-compartmental PK parameters of eltrombopag 
Parameter 
Description 
Cmax 
Observed maximum plasma concentration following administration (mass/volume) 
AUClast 
Area under the curve calculated to the last quantifiable concentration point (Tlast) 
(mass*time/volume) 
AUCtau 
Area under the curve calculated to the end of the dosing interval ( tau) (mass*time/volume) 
Ctrough 
Pre-dose plasma concentration (mass/volume) 
Tmax 
The time to reach peak or maximum concentration (time) 
CLss/F 
Apparent systemic (or total body) clearance at steady state from plasma (volume/time) 
The concentrations obtained for the Week 2 pre-dose sample (sample 1) will be duplicated in 
order to also be analysed as a 24 h post-dose sample (and will be attributed sample number 6 
for analysis purposes). 
Descriptive statistics of all PK parameters and PK concentrations will include arithmetic and 
geometric mean, median, sd, and coefficient of variation (CV), geometric CV, minimum and 
maximum. Zero concentrations will not be included in the geometric mean calculation. Since 
Tmax is generally evaluated by a nonparametric method, only n, median values and ranges will 
be given for this parameter.  
PK parameters and PK concentrations will be summarized descriptively by ethnicity subgroups 
(if at least 3 patients with PK parameters and/or concentrations in the subgroup) and overall. 
The PK parameters, Cmax, AUClast, AUCtau, and Ctrough, will be normalized to the protocol 
starting dose i.e. 100 mg for S/SE Asians and 150 mg for Others. 
Individual PK concentrations will be listed. The PK sample/concentrations will be flagged in 
the listing when: 
1- Patient changed or interrupted the dose during 7 days before PK sample collection 
2- Patient changed the dose during the 2 weeks before PK sample collection 
3- Patient vomited within 4 hours after dosing on day of PK assessment for post-dose samples, 
or on the day prior to sampling, for pre-dose samples 
4- PK sample was collected out of time interval for the 24-hour sample, the time window 
considered is 20-28 hours 
These flags will be programmatically set up during the PK merge with the clinical database. 
For the first three PK flags the sample will be excluded from the analysis for PK parameter 
calculation and from the descriptive statistics of concentrations over scheduled sample 


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collection time. For the fourth PK flag the sample will be excluded from the descriptive statistics 
of concentrations over scheduled sample collection time only. 
In addition, during analysis the pharmacokinetics will flag PK samples/concentrations when 
dose, sample collection time and/or concentration value are missing, as well if pre-dose samples 
are collected post-dose. Those PK samples/concentrations will be excluded from the analysis 
for PK parameter calculation and from the descriptive statistics of concentrations over 
scheduled sample collection time. 
All individual PK parameters and PK concentrations will be listed. Those PK concentrations or 
PK parameters not evaluable for statistical analysis will be flagged and the reason for exclusion 
will be given in the listings. 
The following analyses and results may be performed and reported separately from the CSR: 
Exposure-response analysis will be conducted, if supported by the data to evaluate relationship 
between exposure of eltrombopag and response and specific AEs of special interests. These 
relationships will be explored by graphical methods. Any apparent relationship may be further 
characterized by a model as appropriate and supported by the data.  
Population PK may be performed if supported by the data to explore relevant covariates.  
Handling of PK data below LLOQ or missing 
Missing concentration values will be reported as such in data listings. Concentration values 
below the LLOQ will be handled as zero in summary statistics, and reported as such in data 
listings. Any missing PK parameter data will not be imputed. 
2.9 
Patient-reported outcomes (PROs) 
The FAS will be used for analysing PRO data unless otherwise specified. The summary tables 
will be presented for ‘Responders’, ‘Non-responders’ and ‘All subjects’. Listings will be 
provided. Box plots showing parameter values over time will be displayed, as applicable. 
Boxplots will display boxes (25th – 75th percentiles) and median (line) as well as joint mean 
(dot) values. Whiskers extend to the 10th – 90th percentiles with any values outside the whiskers 
not being displayed. 
2.9.1 
FACIT-Fatigue and FACT-TH18 (includes FACT-G) 
Functional assessment of chronic illness therapy (FACIT)-Fatigue, functional assessment of 
cancer therapy-thrombocytopenia 18 (FACT-TH18) and functional assessment of cancer 
therapy-general (FACT-G) responses will be generated in accordance with the respective 
scoring manual. Descriptive statistics will be used to summarise the actual subtotal/total score 
and absolute change from baseline to each visit assessment. Patients with an evaluable baseline 
score and at least one evaluable post baseline subtotal/total score during the on-treatment period 
will be included in the change from baseline analyses.  
Missing responses for items in a scale will be handled based on the respective instrument 
manual. All PRO analyses will include data as imputed according to the scoring manual. No 
imputation will be applied if the total or subscale scores are missing at a visit. 


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FACIT-Fatigue 
There are 13 items. Negatively worded items are reverse scored prior to summing. Add the 
scores together, multiply by 13 and then divide by the number of items answered. A total score 
of <30 indicates severe fatigue. The higher the total score the better the quality of life. Total 
score can vary from 0 to 52. 
In cases some answers are missing, a total score is prorated from the score of the answered 
items, so long as more than 50% of the items (i.e., at least 7 of 13) were answered.  
FAT_N = N(OF HI7 HI12 AN1-AN5 AN7 AN8 AN12 AN14-AN16); 
IF (FAT_N/13 > 0.50) THEN Fatigue = SUM(OF HI7 HI12 AN1-AN5 AN7 AN8 AN12 
AN14-AN16)*13/(FAT_N); 
Further details on the FACIT-Fatigue scoring is provided in Appendix 6.4 and at: 
http://www.facit.org/FACITOrg/Questionnaires  
http://www.physio-pedia.com/Functional_Assessment_of_Chronic_Illness_Therapy 
FACT-TH18 and FACT-G 
There are 27-items divided into 4 domains in the FACT-G part, Physical Well-Being (PWB), 
Social/Family Well-Being (SWB), Emotional Well-Being (EWB), Functional Well-Being 
(FWB). Calculate the total scores for each subscale and overall in a similar way as for the 
FACIT-Fatigue, i.e. after reversing the scoring of negatively worded items (so that a higher 
score always indicated a favorable response), item responses are summed.  
In cases where some answers may be missing, a total score is prorated from the score of the 
answered items, so long as more than 50% of the items were answered. E.g. for PWB, where 
PWB_N = N(OF GP1-GP7) i.e. number of items not missing in GP1 to GP7 
 IF (PWB_N/7 > 0.50) THEN PWB = SUM(OF GP1-GP7)*7/(PWB_N); 
Note that a total score should only be calculated if ALL of the component subscales have valid 
scores. 
Summary of the total scores: 
• FACT-G total score: PWB score + SWB score  + EWB score + FWB score 
• FACT-Th total score: PWB score + SWB score + EWB score + FWB score + ThS score 
i.e. FACT-Th total score = FACT-G total score + Th subscale score 
• FACT-Th Trial Outcome Index (TOI): PWB score + FWB score + ThS score 
Further details on FACT-TH18 and FACT-G scoring is provided in Appendix 6.4 and at: 
https://www.rtog.org/LinkClick.aspx?fileticket=bAZw9mE3jlQ%3D&tabid=118 


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2.11 
Interim analysis 
There are 2 planned reporting events, each with a CSR: 
• Primary analysis (6 months) 
• Final analysis (24 months) 
3 
Sample size calculation 
50 patients will be enrolled in the study. 
With 50 patients criteria 
• a: observed overall hematologic response rate (ORR) ≥ “clinically meaningful” threshold 
(30%) and 
• b: probability of true overall hematologic response rate “not being clinically meaningful 
(response ≤ 20%)” is less than 10%  
will be met if at least 15 responders out of 50 patients treated with combination therapy, 
eltrombopag+cyclosporine are observed by 6 months.  
With 54 patients the criteria will be met if at least 17 responders out of 54 patients are observed.   
Table 3-1 
Table showing observed response rate and its posterior distribution 
using a Beta-binomial model 
Sample size 
No. of responders 
Observed response rate (%) 
Probability of ‘not being clinically 
meaningful (response rate ≤20%)” 
N=50 
13 
26.0 
0.1693 
 
14 
28.0 
0.0992 
 
15 
30.0 
0.0538 
 
16 
32.0 
0.0269 
 
17 
34.0 
0.0125 
N=54 
14 
25.9 
0.1618 
 
15 
27.8 
0.0961 
 
16 
29.6 
0.0530 
 
17 
31.5 
0.0272 
 
18 
33.3 
0.0130 
For example, if 15 responders out of 50 patients are observed, the observed ORR will be 30% 
and the posterior probability that θ ≤ 20% is 0.0538. The latter is found using the posterior 
distribution θ|Y ~ Beta(0.25 + 15, 1 + 50 – 15). In R this would be calculated as pbeta(0.2, 
15.25, 36). 
The operating characteristics of the design are presented in the table below. This table shows 
the probability of a positive conclusion (i.e. success criteria met at the end of the study) under 
different underlying true response rates. When the effect of the combination therapy is not 
clinically meaningful (true response rate ≤ 20%), the probability of a positive conclusion is <10% 
(false success rate). The probability of success is >94% when the true response rate by 6 months 
is 40%.  






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6 
Appendix 1 
6.1 
Imputation rules 
6.1.1 
AE, concomitant medication (CM) and safety assessment date 
imputation 
Table 5-1 
Imputation of start dates (AE, CM) and assessments (LB, EG, VS) 
Missing 
Element 
Rule 
day, month, 
and year 
• No imputation will be done for completely missing dates 
day, month 
• If available year = year of study treatment start date then  
o If stop date contains a full date and stop date is earlier than 
study treatment start date then set start date = 01JanYYYY  
o Else set start date = study treatment start date.  
• If available year > year of study treatment start date then 01JanYYYY 
• If available year < year of study treatment start date then 01JulYYYY 
day 
• If available month and year = month and year of study treatment start 
date then  
o If stop date contains a full date and stop date is earlier than 
study treatment start date then set start date= 01MONYYYY.  
o Else set start date = study treatment start date. 
• If available month and year > month and year of study treatment start 
date then 01MONYYYY   
• If available month and year < month year of study treatment start date 
then 15MONYYYY   
LB: Laboratory, EG: ECG, VS: Vital signs 
Table 5-2 
Imputation of end dates (AE, CM)  
Missing 
Element 
Rule  
(*=last treatment date plus 30 days not > (death date, cut-off date, 
withdrawal of consent date)) 
day, month, 
and year 
• 
Completely missing end dates (incl. ongoing events) will be imputed 
by the end date of the on-treatment period*  
day, month 
• 
If partial end date contains year only, set end date = earliest of 
31DecYYYY or end date of the on-treatment period *  
day 
• 
If partial end date contains month and year, set end date = earliest of 
last day of the month or end date of the on-treatment period* 
Any AEs and CMs with partial/missing dates will be displayed as such in the data listings. Any 
AEs and CMs which are continuing as per data cut-off will be shown as ‘ongoing’ rather than 
the end date provided. 


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6.1.2 
Prior therapies date imputation 
Missing day is defaulted to the 15th of the month and missing month and day is defaulted to 01-
Jan. 
6.2 
Laboratory parameters derivations 
CTCAE 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) 
Further derivation of laboratory parameters might be required for CTCAE grading. For 
instance, corrected calcium can be derived using the reported total calcium value and albumin 
at the same assessment using the following formula: 
Corrected Calcium (mg/dL) = Calcium (mg/dL) – 0.8 [Albumin (g/dL)-4] 
In order to apply the above formula, albumin values in g/L will be converted to g/dL by  
multiplying by 0.1), calcium values in mmol/L will be converted to mg/dL by dividing by 
0.2495. For calculation of laboratory CTCAE grades 0 and 1, the normal range for derived 
corrected calcium is set to the same limits (in mg/dL) as for calcium. 
6.3 
Statistical models 
6.3.1 
Primary analysis 
Calculation of posterior probability  
The efficacy criteria for this study are: 
1. Observed overall hematologic response rate ≥ “clinically meaningful” threshold (30%) 
2. Probability of true overall hematologic response rate “not being clinically meaningful 
(response ≤ 20%)” is less than 10% 
Let p denote the proportion of patients who achieves overall hematologic response by 6 months 
and follow a beta prior distribution Beta [a, b], where a>0, b>0. Let y out of n patients achieve 
overall hematologic response by 6 months. Therefore, the posterior distribution of p is Beta[ a+y, 
b+ n-y] [Spiegelhalter et al. 2004]. 
A minimally informative unimodal Beta prior [Neuenschwander et al. 2008] Beta [0.25, 1] will 
be used.   The parameters were chosen so that the posterior probability of the true response rate 
≤ 20% (considered not clinically meaningful) is equal to 0.0538.  
The efficacy criteria will be assessed based on the actual number of patients enrolled in the 
study. For example, if the total number of patients is 50, the efficacy criteria requires that at 
least 15 patients achieve overall hematologic response by 6 months. In that case, the posterior 


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distribution is Beta[0.25+15, 1+50-15] i.e. Beta[15.25, 36] and the probability of success is >90% 
when the true responder rate is 40%. 
Confidence interval for response rate 
Responses will be summarised in terms of percentage rates with 100(1 − α)% confidence 
interval using exact binomial confidence interval (implemented using SAS procedure FREQ 
with EXACT statement for one-way table [Clopper and Pearson 1934]. 
6.3.2 
Key secondary analysis 
Kaplan-Meier estimates 
An estimate of the survival function (i.e., time to relapse, duration of transfusion 
independence) will be constructed using Kaplan-Meier (product-limit) method as 
implemented in PROC LIFETEST with METHOD=KM option. The PROC LIFETEST 
statement will use the option CONFTYPE=LOGLOG. 
Median survival 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 summarised. The standard error of the Kaplan-Meier estimate will be calculated 
using Greenwood’s formula [Collett 1994]. 
6.4 
FACIT-Fatigue scoring guideline 
FACIT-Fatigue Subscale Scoring Guidelines (Version 4) – Page 1 
Instructions:* 
1. Record answers in "item response" column. If missing, mark with an X 
    
2. Perform reversals as indicated, and sum individual items to obtain a score. 
3. Multiply the sum of the item scores by the number of items in the subscale, then divide by 
the number of items answered.  This produces the subscale score. 
4. The higher the score, the better the QOL. 
 
Subscale 
         Item Code       Reverse item?            Item response         
 Item Score  
FATIGUE 
 
HI7 
      
4 
- 
________ 
 
=________ 
SUBSCALE 
 
HI12 
 
4 
- 
________ 
 
=________ 
    
 
 
An1 
 
4 
- 
________ 
 
=________ 
An2 
 
4 
- 
________ 
 
=________ 
An3 
 
4 
- 
________ 
 
=________ 
An4 
 
4 
- 
________ 
 
=________ 
An5 
 
0 
+ 
________ 
 
=________ 
An7 
 
0 
+ 
________ 
 
=________ 
An8 
 
4 
- 
________ 
 
=________ 
An12 
 
4 
- 
________ 
 
=________ 
An14 
 
4 
- 
________ 
 
=________ 
An15 
 
4 
- 
________ 
 
=________ 
An16 
 
4 
- 
________ 
 
=________ 
 
              Sum individual item scores:________   
Score range: 0-52 


Novartis 
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Page 41 
SAP amendment 4 
 
CETB115E2403 
 
 
 
 
                   Multiply by 13: ________ 
            Divide by number of items answered: ________=Fatigue 
Subscale score 
6.5 
FACT-Th18 and FACT-G scoring guideline 
Scoring Guidelines (Version 4) 
Instructions:* 
1. Record answers in "item response" column. If missing, mark with an X 
    
2. Perform reversals as indicated, and sum individual items to obtain a score. 
3. Multiply the sum of the item scores by the number of items in the subscale, then divide by 
the number of items answered.  This produces the subscale score. 
4. Add subscale scores to derive total FACT-G score.  
5. The higher the score, the better the QOL. 
Subscale 
 
  Item Code    Reverse item?       Item response         
Item Score  
PHYSICAL 
GP1 
4 
- 
________ 
 
=________ 
WELL-BEING 
GP2 
4 
- 
________ 
 
=________ 
   (PWB) 
GP3 
4 
- 
________ 
 
=________ 
       
GP4 
4 
- 
________ 
 
=________ 
       
GP5 
4 
- 
________ 
 
=________ 
       
GP6 
4 
- 
________ 
 
=________ 
       
GP7 
4 
- 
________ 
 
=________ 
 
              Sum individual item scores: ________   
 
 
 
                      Multiply by 7: ________ 
             Divide by number of items answered: ________=PWB subscale 
score 
Subscale 
 
  Item Code    Reverse item?       Item response         
Item Score  
SOCIAL/FAMILY 
GS1 
0 
+ 
________ 
 
=________ 
WELL-BEING 
GS2 
0 
+ 
________ 
 
=________ 
    (SWB) 
GS3 
0 
+ 
________ 
 
=________ 
       
GS4 
0 
+ 
________ 
 
=________ 
       
GS5 
0 
+ 
________ 
 
=________ 
    
GS6 
0 
+ 
________ 
 
=________ 
       
GS7 
0 
+ 
________ 
 
=________ 
 
             Sum individual item scores: ________   
 
 
 
                     Multiply by 7: ________ 
            Divide by number of items answered: ________=SWB subscale 
score 
Subscale 
 
  Item Code    Reverse item?       Item response         
Item Score  
EMOTIONAL 
GE1 
4 
- 
________ 
 
=________ 
WELL-BEING 
GE2 
0 
+ 
________ 
 
=________ 
    (EWB) 
GE3 
4 
- 
________ 
 
=________ 
       
GE4 
4 
- 
________ 
 
=________ 
      
GE5 
4 
- 
________ 
 
=________ 
 
 
 
 
GE6 
4 
- 
________ 
 
=________ 
 
Score range: 0-28 
Score range: 0-28 
Score range: 0-24 


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Page 42 
SAP amendment 4 
 
CETB115E2403 
 
             Sum individual item scores: ________   
 
 
 
                     Multiply by 6: ________ 
            Divide by number of items answered: ________=EWB subscale 
score 
Subscale 
 
  Item Code    Reverse item?       Item response         
Item Score  
FUNCTIONAL   
GF1 
0 
+ 
________ 
 
=________ 
WELL-BEING  
GF2 
0 
+ 
________ 
 
=________ 
     (FWB) 
GF3 
0 
+ 
________ 
 
=________ 
       
GF4 
0 
+ 
________ 
 
=________ 
       
GF5 
0 
+ 
________ 
 
=________ 
       
GF6 
0 
+ 
________ 
 
=________ 
       
GF7 
0 
+ 
________ 
 
=________ 
 
             Sum individual item scores: ________   
 
 
 
                     Multiply by 7: ________ 
            Divide by number of items answered: ________=FWB subscale 
score 
 
Subscale 
         Item Code       Reverse item?            Item response         
 Item Score  
THROMBO- 
 
An5 
 
0 
+ 
________ 
 
=________ 
CYTOPENIA 
 
An7 
 
0 
+ 
________ 
 
=________ 
SUBSCALE 
 
Th1 
 
4 
- 
________ 
 
=________ 
    (ThS)  
 
Th2 
 
4 
- 
________ 
 
=________ 
       
Th3 
 
4 
- 
________ 
 
=________ 
 
Th4 
 
4 
- 
________ 
 
=________ 
      
Th5 
 
4 
- 
________ 
 
=________ 
 
Th6 
 
4 
- 
________ 
 
=________ 
       
Th7 
 
4 
- 
________ 
 
=________ 
       
Th8 
 
4 
- 
________ 
 
=________ 
Th9 
 
4 
- 
________ 
 
=________ 
HI7 
 
4 
- 
________ 
 
=________ 
       
Th10 
 
4 
- 
________ 
 
=________ 
 
Th11 
 
4 
- 
________ 
 
=________ 
       
Th12 
 
4 
- 
________ 
 
=________ 
       
Th13 
 
4 
- 
________ 
 
=________ 
 
Th14 
 
4 
- 
________ 
 
=________ 
 
Th15 
 
4 
- 
________ 
 
=________ 
       
 
              Sum individual item scores:________   
 
 
 
                   Multiply by 18: ________ 
        Divide by number of items answered:     ________=Th Subscale 
score 
 
To derive a FACT-Th Trial Outcome Index (TOI): 
 
  __________ + __________ + __________ =________=FACT-Th TOI 
  (PWB score)   (FWB score)   (ThS score)   
Score range: 0-28 
Score range: 0-128 
Score range: 0-72 


Novartis 
For business use only 
Page 43 
SAP amendment 4 
 
CETB115E2403 
 
 
To Derive a FACT-G total score: 
 
        __________ + __________ + __________ + __________=________=FACT-G Total 
score 
        (PWB score)    (SWB score)   (EWB score)  (FWB score) 
 
To Derive a FACT-Th total score: 
 
 
              _________ + __________ + __________ + __________ + __________ =________=FACT-Th 
Total score 
                            (PWB score)  (SWB score)   (EWB score)  (FWB score)   (ThS score) 
 
*For guidelines on handling missing data and scoring options, please refer to the Administration and Scoring 
Guidelines in the manual or on-line at www facit.org. 
Score range: 0-108 
Score range: 0-180