Conditions: Thrombocytopaenia
Keywords: myelodysplastic syndromes thrombocytopenia acute myeloid leukemia idiopathic thrombocytopenic purpura Eltrombopag pediatrics
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 22
Healthy volunteers: no

Brief summary:
The objective of this study was to provide continued treatment with eltrombopag for subjects who were participating in a Novartis-sponsored investigational study with eltrombopag (parent studies 114968/ASPIRE (NCT01440374), PMA112509 (NCT00903422), and TRA105325/EXTEND (NCT00351468), receiving clinical benefit without unacceptable toxicity and to collect long-term safety data.

Detailed description:
This Phase IV, multicenter, non-randomized, open-label, uncontrolled, rollover study was designed to provide continued access to eltrombopag to eligible subjects. As this study was a rollover study, the subjects were enrolled into this study from the parent studies.

There were 3 cohorts in this study:

Cohort A: Adult subjects who have completed study treatment with eltrombopag during their participation in a parent study for MDS/AML (i.e., 114968/ASPIRE and PMA112509).

Cohort B: Adult subjects who have completed study treatment with eltrombopag during their participation in a parent study for ITP (i.e., TRA105325/EXTEND).

Cohort C: Pediatric subjects who have completed study treatment with eltrombopag during their participation in a parent study for ITP. Once a subject turned 18 years of age, they might remain in the study and follow the Cohort B procedures. No pediatric subjects were enrolled in this cohort/study.

The study consisted of a transition visit, study treatment visits, and a follow-up visit. Subjects in Cohort A and Cohort B completed the Transition visit assessments and then returned for their next schedule visit as per the Visit schedule. In the study treatment visit, subjects received a starting dose of eltrombopag at the same dose and administration that they were receiving at the time of their last study treatment visit in the parent study.

Safety was evaluated through physical examinations, clinical laboratory tests, and monitoring of adverse events. Additional safety assessments were done as per standard of care and/or when medically indicated.

Assessment of clinical benefit was performed throughout the study using local standard of care as determined by the Investigator to determine continued study participation and treatment with eltrombopag. Only subjects considered by the Investigator to be receiving clinical benefit without unacceptable toxicity may continue on study treatment. Once treatment with eltrombopag was permanently discontinued, the subject would attend the follow-up visit.

Arms:
arm 1: All subjects in this cohort received eltrombopag (ELT) at the dose that they were receiving at the time of the transition visit, except in the case where the subject required a dose modification. The range of doses of ELT that were used in this cohort were from 50 to 300 mg once daily (OD) for subjects of non-East Asian heritage. The dose ranges for subjects of East Asian heritage (i.e., Japanese, Chinese, Taiwanese, Thai and Korean) were 25 to 150 mg. Dose adjustments (if required) were done depending on each subject's platelet counts. arm 2: All subjects in this cohort received ELT at the dose that they were receiving at the time of the transition visit, except in the case where the subject required a dose modification. The range of doses of ELT that were used in this cohort were from 12.5 to 75 mg. Dose adjustments (if required) were done depending on each subject's platelet counts. arm 3: All subjects in this cohort received ELT at the dose that they were receiving at the time of the transition visit, except in the case where the subject required a dose modification. The range of doses of ELT that were used in this cohort were from 12.5 to 75 mg. Dose adjustments (if required) were done depending on each subject's platelet counts.

Interventions: intervention 1: Eltrombopag (ELT)
Intervention descriptions: intervention 1: Subjects were dosed with ELT tablets or powder for oral suspension (PfOS) based on the dosage form used in the parent study. ELT tablets were white, round film coated tablets containing ELT olamine equivalent to 12.5 mg, 25 mg, 50 mg, 75 mg and 100 mg of ELT. ELT PfOS was a reddish-brown to yellow powder contained inside an elongated sachet. Each sachet contained ELT olamine equivalent to 20 mg of ELT per gram of powder.

Protocol document:
Prot_000.pdf: 


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Protocol No. 200170 
Amendment 01  
Amendment rationale  
Subsequent to the acquisition of GlaxoSmithKline (GSK) compound SB-497115, the 
purpose of this protocol Amendment 01 is to: 
- 
Delete or replace references to GSK or its staff with that of Novartis and its 
authorized agents to align with the change of sponsorship; 
- 
Make administrative changes to align with Novartis processes and procedures; 
As of 05-APR-16: 
21 patients have received study treatment in 11 countries;  
07 patients have completed or discontinued study treatment. 
The changes described in this amended protocol require Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) approval prior to implementation.  
A copy of this amended protocol will be sent to the IRB/IEC and Health Authorities 
(HAs). 
The changes herein affect the Informed Consent and all sites are required to update and 
submit for approval, a revised Informed Consent that takes into account the change of 
study sponsorship described in the protocol amendment. 
Upon approval of this amendment, patients who have already been enrolled in the study 
will sign a new informed consent form indicating Novartis is the new study sponsor and 
continue the appropriate visit schedule. 
 
 
 






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INVESTIGATOR PROTOCOL AGREEMENT PAGE 
 
I confirm agreement to conduct the study in compliance with the protocol. 
 
I acknowledge that I am responsible for overall study conduct. I agree to 
personally conduct or supervise the described clinical study. 
 
I agree to ensure that all associates, colleagues and employees assisting in the 
conduct of the study are informed about their obligations. Mechanisms are in 
place to ensure that site staff receives the appropriate information throughout the 
study. 
 
Investigator Name:  _____________________________ 
 
 
 
 
Investigator Signature 
 
Date 
 


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TABLE OF CONTENTS 
PAGE 
LIST OF ABBREVIATIONS ............................................................................................. 12 
PROTOCOL SUMMARY ................................................................................................. 14 
1. 
INTRODUCTION ..................................................................................................... 16 
1.1. 
Background .................................................................................................. 16 
1.1.1. 
Chronic Idiopathic Thrombocytopenic Purpura Clinical 
Studies .......................................................................................... 16 
1.1.2. 
Hepatitis C-Associated Thrombocytopenia Clinical Studies ......... 17 
1.1.3. 
Hematology/Oncology Related Thrombocytopenia (HORT) 
Clinical Studies ............................................................................. 17 
1.2. 
Study Rationale ............................................................................................ 18 
1.3. 
Benefit:Risk Assessment .............................................................................. 19 
1.3.1. 
Chronic Idiopathic Thrombocytopenic Purpura ............................. 19 
1.3.2. 
Hepatitis C virus-related thrombocytopenia .................................. 19 
1.3.3. 
Hematology/Oncology Related Thrombocytopenia (HORT) 
Clinical Studies ............................................................................. 20 
1.3.4. 
Post Marketing .............................................................................. 20 
1.3.5. 
Risk Management ......................................................................... 20 
1.3.5.1. 
Pharmacovigilance Activities ....................................... 20 
1.3.5.2. 
Risk Minimization ........................................................ 21 
1.3.6. 
Conclusion .................................................................................... 21 
2. 
OBJECTIVE ............................................................................................................. 22 
3. 
STUDY DESIGN ...................................................................................................... 22 
3.1. 
Discussion of Design .................................................................................... 23 
3.2. 
Cohorts ......................................................................................................... 24 
3.2.1. 
Cohort A (MDS/AML Adult Subjects) ............................................ 24 
3.2.2. 
Cohort B (ITP Adult Subjects) ....................................................... 24 
3.2.3. 
Cohort C (ITP Pediatric Subjects) ................................................. 24 
3.2.4. 
Visit Schedule for Cohort A, Cohort B, and Cohort C ................... 24 
4. 
SUBJECT SELECTION AND DISCONTINUATION/ COMPLETION 
CRITERIA ................................................................................................................ 25 
4.1. 
Subject Selection Criteria ............................................................................. 25 
4.1.1. 
Number of Subjects ...................................................................... 25 
4.1.2. 
Inclusion Criteria ........................................................................... 25 
4.1.3. 
Exclusion Criteria .......................................................................... 26 
4.2. 
Permanent Discontinuation from Study Treatment and Subject 
Completion Criteria....................................................................................... 27 
4.2.1. 
Permanent Discontinuation from Study Treatment ....................... 27 
4.2.2. 
Subject Completion ....................................................................... 28 
5. 
STUDY TREATMENTS ........................................................................................... 28 
5.1. 
Eltrombopag (SB-497115) Novartis Investigational Product ........................ 28 
5.2. 
Eltrombopag Dosage and Administration ..................................................... 29 
5.2.1. 
Dietary Restrictions ....................................................................... 30 


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5.3. 
Eltrombopag Starting Dose .......................................................................... 30 
5.4. 
Dose Adjustments ........................................................................................ 30 
5.4.1. 
Cohort A (MDS/AML Adult Subjects) ............................................ 30 
5.4.1.1. 
Dose Escalation .......................................................... 31 
5.4.1.2. 
Dose Reduction ........................................................... 31 
5.4.1.3. 
Dose Interruption ......................................................... 31 
5.4.2. 
Cohort B and Cohort C (ITP Adults and Pediatric 
Subjects) ....................................................................................... 33 
5.4.2.1. 
Dose Escalation .......................................................... 33 
5.4.2.2. 
Dose Reduction ........................................................... 34 
5.4.2.3. 
Dose Interruption ......................................................... 34 
5.4.2.4. 
Dose Adjustment Guidelines for Tablet 
Formulation ................................................................. 35 
5.4.2.5. 
Dose Adjustment Guidelines for Suspension 
Formulation ................................................................. 36 
5.5. 
Handling and Storage of Study Treatment ................................................... 38 
5.6. 
Treatment Assignment ................................................................................. 38 
5.7. 
Blinding ........................................................................................................ 38 
5.8. 
Product Accountability .................................................................................. 38 
5.9. 
Treatment Compliance ................................................................................. 38 
5.10. 
Monitoring, Interruption and Stopping Criteria for Hepatobiliary 
Events .......................................................................................................... 39 
5.10.1. 
Liver Chemistry Stopping Criteria ................................................. 39 
5.10.1.1.  Liver Event Follow Up Assessments ........................... 40 
5.10.2. 
Liver Chemistry Monitoring Criteria ............................................... 42 
6. 
LIFESTYLE RESTRICTIONS .................................................................................. 42 
6.1. 
Male Subjects ............................................................................................... 42 
7. 
CONCOMITANT MEDICATIONS AND NON-DRUG THERAPIES .......................... 42 
7.1. 
Permitted Medications and Non-Drug Therapies ......................................... 43 
7.1.1. 
Antacids, Cations and Vitamin/Mineral Supplements ................... 43 
7.1.2. 
HMG-CoA Reductase Inhibitors (statins) ...................................... 43 
7.1.3. 
Platelet Transfusions .................................................................... 44 
7.1.4. 
Concomitant Therapy for Cohort A (MDS/AML Adult 
Subjects) ....................................................................................... 44 
7.1.5. 
Concomitant Therapy for Cohort B and Cohort C (ITP 
Adult and Pediatric Subjects) ........................................................ 44 
7.2. 
Prohibited Medications and Non-Drug Therapies ........................................ 44 
7.3. 
Treatment after Discontinuation of Study Treatment or withdrawal 
from/Completion of Study ............................................................................. 45 
7.4. 
Treatment of Study Treatment Overdose ..................................................... 45 
8. 
STUDY ASSESSMENTS AND PROCEDURES ...................................................... 46 
8.1. 
Transition Visit .............................................................................................. 46 
8.2. 
Continuous Dosing Treatment Period .......................................................... 47 
8.3. 
Final Study Visit............................................................................................ 47 
8.4. 
Safety ........................................................................................................... 47 
8.4.1. 
Physical Examination .................................................................... 48 
8.4.2. 
Bone Marrow Examinations .......................................................... 48 
8.4.3. 
Laboratory Assessments .............................................................. 48 
8.4.4. 
Adverse Events ............................................................................. 48 


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8.4.4.1. 
Definition of an AE ....................................................... 49 
8.4.4.2. 
Definition of a SAE ...................................................... 50 
8.4.4.3. 
Laboratory and Other Safety Assessment 
Abnormalities Reported as AEs and SAEs ................. 51 
8.4.4.4. 
Cardiovascular Events ................................................ 49 
8.4.4.5. 
Death Events ............................................................... 50 
8.4.4.6. 
Disease-Related Events and/or Disease-
Related Outcomes Not Qualifying as SAEs ................ 50 
8.4.4.6.1. 
Cohort A (MDS/AML Adult 
Subjects) ................................................. 50 
8.4.4.6.2. 
Cohort B and Cohort C (ITP Adult 
and Pediatric Subjects) ........................... 50 
8.4.5. 
Time Period and Frequency of Detecting AEs and SAEs ............. 50 
8.4.6. 
Method of Detecting AEs and SAEs ............................................. 51 
8.4.7. 
Prompt Reporting of SAEs and Other Events to Novartis ............. 51 
8.4.8. 
Pregnancy, Testing, Prevention and Reporting ............................ 53 
8.4.8.1. 
Pregnancy Testing and Prevention ............................. 53 
8.4.8.2. 
Pregnancy Reporting ................................................... 54 
9. 
DATA MANAGEMENT ............................................................................................. 55 
10.  DATA ANALYSIS AND STATISTICAL CONSIDERATIONS ................................... 55 
10.1. 
Hypotheses .................................................................................................. 55 
10.2. 
Study Design Considerations ....................................................................... 55 
10.2.1. 
Sample Size Considerations ......................................................... 55 
10.2.2. 
Sample Size Re-estimation ........................................................... 55 
10.3. 
Data Analysis Considerations ...................................................................... 55 
10.3.1. 
Analysis Populations ..................................................................... 55 
10.3.2. 
Analysis Data Sets ........................................................................ 55 
10.3.3. 
Interim Analysis ............................................................................. 56 
10.3.4. 
Key Elements of Analysis Plan ..................................................... 56 
10.3.4.1.  Safety Analyses ........................................................... 56 
10.3.4.1.1.  Adverse Events ....................................... 56 
10.3.4.1.2.  Clinical Laboratory Evaluations ............... 57 
11.  STUDY CONDUCT CONSIDERATIONS ................................................................. 57 
11.1. 
Posting of Information on Publicly Available Clinical Trial Registers ............ 57 
11.2. 
Regulatory and Ethical Considerations, Including the Informed 
Consent Process .......................................................................................... 57 
11.3. 
Quality Control (Study Monitoring) ............................................................... 58 
11.4. 
Quality Assurance ........................................................................................ 58 
11.5. 
Study and Site Closure................................................................................. 58 
11.6. 
Records Retention........................................................................................ 59 
11.7. 
Provision of Study Results to Investigators, Posting of Information 
on Publicly Available Clinical Trials Registers and Publication .................... 59 
12.  REFERENCES ........................................................................................................ 61 
13.  APPENDICES .......................................................................................................... 62 
13.1. 
Appendix 1 Time and Events Table ............................................................. 62 
13.2. 
Appendix 2 Liver Chemistry Monitoring, Interruption, Stopping and 
Follow-up Criteria ......................................................................................... 64 


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13.3. 
Appendix 3 Protocol Changes ...................................................................... 65 
LIST OF TABLES 
Table 1 
Dose Adjustment Guidelines for Adult MDS/AML Patients a .................... 30 
Table 2 
Dose Adjustment Guidelines for Adult ITP Patients ................................ 33 
Table 3 
Dose Adjustment Guidelines for Pediatric ITP Patients receiving 
tablets ...................................................................................................... 34 
Table 4 
Dose Adjustment Guidelines – suspension formulation .......................... 35 
Table 5 
Laboratory Assessments ......................................................................... 46 
 
 
 


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LIST OF ABBREVIATIONS 
β-hCG 
Beta-human chorionic gonadotropin 
AE 
Adverse Event 
AI 
Adriamycin (doxorubicin) and ifosfamide 
ALT 
Alanine aminotransferase 
AML 
Acute myeloid leukemia 
AST 
Aspartate aminotransferase 
ATS 
All Treated Subjects 
AUC(0-) 
Area under the plasma concentration-time curve from zero 
(pre-dose) extrapolated to infinite time 
BCRP 
Breast cancer resistance protein 
C 
Degrees Celsius 
CIT 
Chemotherapy-induced thrombocytopenia 
CLD 
Chronic liver disease 
Cmax 
Maximum plasma concentration 
CPK 
Creatine phosphokinase 
CRO 
Clinical Research Organization 
CTCAE 
Common terminology criteria for adverse events 
CV 
Cardiovascular 
eCRF 
Electronic case report form 
EU 
European Union 
F 
Degrees Fahrenheit 
FDA 
Food and Drug Administration 
FSH 
Follicle-stimulating hormone 
GCP 
Good clinical practice 
Gi/L 
Giga units per liter 
GSK 
GlaxoSmithKline 
HCV 
Hepatitis C virus 
HDPE 
High density polyethylene 
HMG-CoA 
3-hydroxy-3-methyl-glutaryl-CoA reductase 
HORT 
Hematology/oncology related thrombocytopenia 
HPLC 
High performance liquid chromatography 
HRT 
Hormone replacement therapy 
IB 
Investigators brochure 
ICH 
International conference on harmonisation 
IDSL 
Integrated data standards library 
IEC 
Independent ethics committee 
INR 
International normalised ratio 
IRB 
Institutional review board 
ITP 
Idiopathic thrombocytopenic purpura 
IVRS 
Interactive voice response system 
LDH 
Lactate dehydrogenase 
LSLV 
Last subject’s last visit 
MDS 
Myelodysplastic syndrome 
MedDRA 
Medical dictionary for regulatory authorities 


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MSDS 
Material safety data sheet 
NCI 
National institutes of health 
OATP1B1 
Organic anion transporting polypeptide 
OS 
Overall Survival 
PBO 
Placebo 
PCR 
Polymerase chain reaction 
PfOS 
Powder for oral suspension 
PK 
Pharmacokinetic 
RAP 
Reporting and analysis plan 
RMP 
Risk management plan 
RNA 
Ribonucleic acid 
SAE 
Serious adverse event 
SOC 
Standard of care 
SOP 
Standard operating procedure 
SPM 
Study procedures manual 
SVR 
Sustained virological response 
TPO 
Thrombopoietin 
TPO-R 
Thrombopoietin receptor 
TRALI 
Transfusion-related acute lung injury 
ULN 
Upper limit of normal 
US 
United States 


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PROTOCOL SUMMARY 
Rationale 
Eltrombopag is an orally bioavailable, small molecule, thrombopoietin receptor TPO-R 
agonist that stimulates platelet production by a mechanism similar, but not identical to 
endogenous thrombopoietin (TPO).  Eltrombopag has been approved in more than 90 
countries including the United States (US) and the European Union (EU) for the 
treatment of chronic idiopathic thrombocytopenic purpura (ITP) and in November 2012 
was approved in the US for the treatment of thrombocytopenia in patients with chronic 
hepatitis C.  This Phase IV, multicenter, non-randomized, open-label rollover study will 
provide continued access to eltrombopag to subjects who are currently participating in a 
Novartis sponsored investigational study with eltrombopag (i.e. parent study such as 
TRC114968/ASPIRE or TRA105325/EXTEND), and are receiving clinical benefit 
without unacceptable toxicity.   
Objective 
The objective of this study is to provide continuing treatment with eltrombopag for 
subjects who are currently participating in a Novartis sponsored investigational study of 
eltrombopag (parent study) and to collect long term safety data. 
Study Design 
This Phase IV, multicenter, non-randomized, open-label, uncontrolled, rollover study is 
designed to provide continued access to eltrombopag to subjects who are currently 
participating in a Novartis sponsored investigational study of eltrombopag  (parent 
study), and are receiving clinical benefit without unacceptable toxicity. Subjects will be 
enrolled into the appropriate cohort based upon the disease under study in their parent 
study (e.g. myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), idiopathic 
thrombocytopenic purpura (ITP) etc).  Enrollment into this study will be dependent upon 
the investigator’s agreement to participate in this study. It is estimated that approximately 
100 subjects will be enrolled. Instructions for the dose and dose adjustments throughout 
the duration of the study are described in Section 5.3 and Section 5.4 respectively. 
Subjects may continue treatment in this rollover study until they are no longer receiving 
clinical benefit, develop an unacceptable toxicity, withdraw consent, enroll into another 
interventional study, or until another mechanism is available for the subject to receive 
eltrombopag such as compassionate use, named patient program, commercially available 
for the appropriate indication, etc. Subjects participating in Investigator Sponsored 
Studies will not eligible to participate in this study. 
Study Assessments 
Safety will be evaluated through physical exams, clinical laboratory tests, and monitoring 
of adverse events as described in the Time and Events table. Additional safety 
assessments may be done as per standard of care (SOC) and/or when medically indicated. 


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Assessment of clinical benefit will be performed throughout the study using local SOC as 
determined by the investigator.  Only subjects considered by the investigator to be 
receiving clinical benefit and without unacceptable toxicity may continue on study 
treatment. 


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1. 
INTRODUCTION 
1.1. 
Background 
Eltrombopag is an orally bioavailable, small molecule, thrombopoietin receptor (TPO-R) 
agonist.  Eltrombopag functions in a similar manner to endogenous thrombopoietin 
(TPO), inducing proliferation and differentiation of megakaryocytes from bone marrow 
progenitors cells.  Administration of eltrombopag in healthy adult subjects and in 
thrombocytopenic humans has resulted in a dose-dependent increase in platelet counts.  
Therefore, eltrombopag may be beneficial in medical disorders associated with 
thrombocytopenia.  
The clinical consequences of thrombocytopenia include petechiae, bruising, and mucosal 
bleeding.  Severe thrombocytopenia may be associated with morbidity and mortality due 
to bleeding, the most severe of which is intracerebral hemorrhage.  Thrombocytopenia is 
a frequent finding in several medical disorders, including chronic idiopathic 
thrombocytopenic purpura (ITP), chronic liver disease (CLD), cancer and/or its 
treatments. 
As of May 3013, Eltrombopag has been approved in more than 90 countries including the 
United States (US) and the European Union (EU) for the treatment of chronic ITP.  The 
use of eltrombopag for the treatment of hepatitis C virus (HCV)-related 
thrombocytopenia has been recently approved in the United States (November 2012). 
Eltrombopag is being developed for the treatment of a variety of additional medical 
disorders associated with thrombocytopenia, including myelodysplastic syndromes 
(MDS) and acute myeloid leukemia (AML) [GlaxoSmithKline Document Number 
UM2005/00217/08]. 
The safety profile of eltrombopag has been evaluated in 24 completed, concluded or 
ongoing Novartis-sponsored clinical studies: eleven studies of subjects with ITP, 
including 2 in pediatric subjects, 7 studies of subjects with CLD related 
thrombocytopenia (including 5 studies in HCV related thrombocytopenia), 5 studies for 
MDS/AML and 1 observational study for evaluation of ocular safety.  
Please refer to the current version of the Investigator’s Brochure (IB) for further 
information regarding pre-clinical and clinical studies [GlaxoSmithKline Document 
Number UM2005/00217/08]. 
1.1.1. 
Chronic Idiopathic Thrombocytopenic Purpura Clinical Studies 
The eltrombopag adult ITP clinical program consists of a total of 9 studies.  Eltrombopag 
has a well-defined safety profile with consistent findings across all ITP studies 
irrespective of treatment duration. Eltrombopag was well-tolerated across the ITP 
program.  In placebo-controlled studies conducted globally, similar overall incidences of 
adverse events (AE), serious adverse events (SAE), and AEs leading to discontinuation 
from study medication were seen in the placebo (PBO) arms versus eltrombopag arms.   


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The ITP clinical studies have consistently demonstrated that eltrombopag raises platelet 
counts rapidly (within 1-2 weeks) and maintains platelet count elevations during therapy, 
regardless of splenectomy status, use of baseline concomitant ITP medication or baseline 
platelet counts.  Bleeding symptoms were significantly reduced compared to placebo and 
during long-term treatment with eltrombopag; subjects were also able to reduce the use of 
concomitant ITP medications (predominantly corticosteroids) and required less rescue 
medication compared to placebo-treated subjects. 
Eltrombopag is also being evaluated in pediatric patients with chronic ITP in 2 ongoing, 
double-blind placebo-controlled studies.  Refer to Investigator’s Brochure for 
Eltrombopag for available data from the pediatric studies [GlaxoSmithKline Document 
Number UM2005/00217/08]. 
1.1.2. 
Hepatitis C-Associated Thrombocytopenia Clinical Studies 
The pooled data from two Phase III studies (TPL103922/ENABLE 1 and 
TPL108390/ENABLE 2) in subjects with HCV-related thrombocytopenia demonstrates 
that eltrombopag treatment increased platelet counts in thrombocytopenic subjects with 
HCV infection to a level sufficient to allow initiation and maintenance of antiviral 
therapy for subjects who would otherwise be ineligible or poor candidates for 
peginterferon-based antiviral therapy.  Therapy with peginterferon and ribavirin plus 
eltrombopag enabled 21% of patients to achieve sustained virological response (SVR); 
13% of subjects in the control arm (which also included eltrombopag during the open 
label phase of the study) achieved an SVR.  The results were statistically significant 
[GlaxoSmithKline Document Number UM2005/00217/08]. 
The AE profile of the eltrombopag treatment arm was consistent with a cirrhotic HCV 
patient population undergoing interferon-based antiviral therapy.  Thromboembolic 
events and events suggestive of hepatic decompensation occurred more frequently in the 
eltrombopag arm.  Hepatic decompensation is a known complication of interferon based 
antiviral therapy in patients with advanced fibrosis and cirrhosis.   
Please refer to the current version of the Investigator’s Brochure (IB) for further 
information regarding pre-clinical and clinical studies [GlaxoSmithKline Document 
Number UM2005/00217/08]. 
1.1.3. 
Hematology/Oncology Related Thrombocytopenia (HORT) 
Clinical Studies 
The HORT clinical program is investigating eltrombopag to treat thrombcocytopenia 
associated with cancer and/or its treatments and includes chemotherapy-induced 
thrombocytopenia (CIT) and thrombocytopenia associated with hematologic 
malignancies. Thrombocytopenia is a significant problem for patients with malignancies 
and can be life-threatening.  The etiology of thrombocytopenia depends on the specific 
type and location of the malignancy, and may encompass an autoimmune component, the 
presence of splenomegaly and/or prior and current treatments [GlaxoSmithKline 
Document Number UM2005/00217/08]. 


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In the completed Phase II study, SB-497115/003, treatment with eltrombopag at 3 
different dose levels after carboplatin/paclitaxel did not increase the severity of clinically 
meaningful side effects compared to treatment with placebo in subjects with cancer.  The 
reported toxicities were consistent with the reported side effect profile of eltrombopag in 
other studies or the known toxicities of the carboplatin/paclitaxel combination.  
Eltrombopag 50 mg, 75 mg, and 100 mg, when given for 10 days after chemotherapy, 
failed to meet the study-defined primary endpoint of change in platelet count in Cycle 2 
(measured by the difference in the platelet count from Day 1 in Cycle 2 to platelet nadir 
in Cycle 2), compared with placebo.  However, mean platelet counts in the eltrombopag 
groups began to rise starting between Day 8 and Day 11, and continued to rise through 
Day 18 (post-nadir period).  This same platelet count rise was not observed in the 
subjects receiving placebo.  These results suggest that the tested schedule of 
administration (and possibly dose) in this study were likely not optimal for this subject 
population and chemotherapy regimen [GlaxoSmithKline Document Number 
UM2005/00217/08]. 
A completed Phase I (TRC105499) study in subjects receiving adriamycin (doxorubicin) 
and ifosfamide (AI) treatment for locally advanced soft tissue sarcoma, reported toxicities 
were consistent with the reported side effect profile of eltrombopag in other studies or the 
known toxicities of the AI combination [GlaxoSmithKline Document Number 
UM2005/00217/08].   
In a completed Phase I/II study (PMA112509) in subjects with advanced MDS/AML 
reported AEs were consistent with those expected for the disease under study and with 
those expected during treatment with eltrombopag.  No significant differences in post-
baseline bone marrow blast percentages were observed for eltrombopag compared to 
placebo-treated subjects [GlaxoSmithKline Document Number UM2005/00217/08]. 
Platelet transfusion independence for ≥8 weeks was reported for 38% of eltrombopag and 
21% of placebo subjects. Grade 3 or greater hemorrhages were reported in 16% of 
eltrombopag subjects compared to 26% of placebo subjects. More eltrombopag subjects 
started antileukemic/palliative treatment during the study (41%) compared to placebo 
subjects (32%).  Median overall survival OS was 27 weeks for eltrombopag versus 15.7 
weeks for PBO (hazard ratio=0.71, P=0.1931).   
TRC114968/ASPIRE study is a three-part (Part 1: open-label, Part 2: randomized, 
double-blind, Part 3: open-label extension), multi-center study to evaluate the effect of 
eltrombopag in subjects with MDS or AML who have thrombocytopenia due to bone 
marrow insufficiency from their underlying disease or prior chemotherapy.  The starting 
dose was 100 mg (50 mg for East Asians), with a maximum dose of 300 mg (150 mg for 
East Asians).  Subject who enrolled in Part 1 received open-label eltrombopag while 
those who enrolled in Part 2 received either eltrombopag or matching placebo. After 
completing Part 1 or 2, subjects could receive open-label eltrombopag in Part 3 (open-
label extension).  The planned number of subjects for this study is 150.   
 
1.2. 
Study Rationale 
This study will provide continued access of eltrombopag to subjects who are currently 
participating in a Novartis sponsored investigational study with eltrombopag (parent 


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study such as TRC114968/ASPIRE or TRA105325/EXTEND), and are receiving clinical 
benefit without unacceptable toxicity. 
1.3. 
Benefit:Risk Assessment 
In chronic ITP, HCV associated thrombocytopenia, and hematology/oncology related 
thrombocytopenia studies so far, eltrombopag has been able to increase platelet counts 
with an acceptable safety profile. In the setting of procedures for liver disease (HCV 
studies), an imbalance in thromboembolic events was observed. Therefore, with the 
exception of procedures for liver disease, the benefit:risk of eltrombopag in the other 
studied disease areas so far remain positive. Summaries of findings from both clinical and 
non-clinical studies conducted with SB-497115 can be found in the GlaxoSmithKline IB 
and product label.  The following sections outline the risk assessment and mitigation 
strategy for this protocol. 
1.3.1. 
Chronic Idiopathic Thrombocytopenic Purpura 
The safety profile of eltrombopag has been well documented in the approved indication 
of chronic idiopathic thrombocytopenic purpura (ITP) to increase platelet counts and 
reduce or prevent bleeding.  Eltrombopag has a well-defined safety profile with 
consistent findings across all ITP studies irrespective of treatment duration.  Eltrombopag 
was well-tolerated across the ITP program.  In placebo-controlled studies conducted 
globally, similar overall incidences of AEs, SAEs, and AEs leading to discontinuation 
from study medication were seen in the placebo (PBO) arms versus eltrombopag arms.   
The ITP clinical studies have consistently demonstrated that eltrombopag raises platelet 
counts rapidly (within 1-2 weeks) and maintains platelet count elevations during therapy, 
regardless of splenectomy status, use of baseline concomitant ITP medication or baseline 
platelet counts. 
1.3.2. 
Hepatitis C virus-related thrombocytopenia 
The use of eltrombopag for the treatment of hepatitis C virus (HCV) related 
thrombocytopenia has been recently approved in the United States (November 2012), and 
is still under regulatory review in the European Union.  
The pooled data from two Phase III studies (TPL103922/ENABLE 1 and 
TPL108390/ENABLE 2) in subjects with HCV-related thrombocytopenia demonstrates 
that eltrombopag treatment increased platelet counts in thrombocytopenic subjects with 
HCV infection to a level sufficient to allow initiation and maintenance of antiviral 
therapy for subjects who would otherwise be ineligible or poor candidates for 
peginterferon-based antiviral therapy. 
The AE profile of the eltrombopag-containing treatment arm was consistent with a 
cirrhotic HCV patient population undergoing interferon-based antiviral therapy.  
Thromboembolic events and events suggestive of hepatic decompensation occurred more 
frequently in the eltrombopag arm.  Hepatic decompensation is a known complication of 
interferon based antiviral therapy in subjects with advanced fibrosis and cirrhosis. 


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1.3.3. 
Hematology/Oncology Related Thrombocytopenia (HORT) 
Clinical Studies 
In the HORT clinical program, eltrombopag continues to be developed as a treatment of 
thrombocytopenia associated with cancer and/or its treatments, including chemotherapy-
induced thrombocytopenia (CIT) and thrombocytopenia associated with hematologic 
malignancies.  The studies are ongoing and eltrombopag has been well tolerated in the 
HORT indication to date. 
1.3.4. 
Post Marketing 
Eltrombopag was first approved for marketing in the US on 20 November 2008 for the 
treatment of thrombocytopenia in patients with chronic immune (idiopathic) 
thrombocytopenic purpura and is currently available in 90 countries. 
The data reported in the post marketing setting are consistent with the known safety 
profile of eltrombopag.  Overall, there was no change in the nature, seriousness or 
frequency of reported events, based on the post marketing data.  The benefit risk profile 
of eltrombopag for the treatment of chronic ITP continues to be favorable in the post 
marketing setting. 
1.3.5. 
Risk Management 
Risk management strategies for eltrombopag are in place for patient safety. 
Novartis has a robust risk management plan (RMP) for eltrombopag where the 
presentation and management of risks are conveyed.  Safety data continue to be collected 
and analyzed for eltrombopag since the initial approval of PROMACTA™ (eltrombopag) 
in the United States in 2008 and the subsequent approval of REVOLADE™ 
(eltrombopag) in the EU in 2010. 
A comprehensive Risk Management Plan (RMP) is in place for eltrombopag. Identified 
risks described in the RMP include hepatobiliary laboratory abnormalities, 
thromboembolic events, post therapy reoccurrence of thrombocytopenia, and hepatic 
decompensation in patients with hepatitis C.  Potential risks in the RMP include increased 
bone marrow reticulin formation, cataract, renal tubular toxicity, and photosensitivity.  
1.3.5.1. 
Pharmacovigilance Activities 
Pharmacovigilance measures are in place and include adverse event collection from 
spontaneous, study, and literature sources, review of individual and aggregate reports, 
and ongoing signal management including signal detection and evaluation.  Additional 
pharmacovigilance activities include targeted follow-up questionnaires for specific risks.  
In addition, the safety data from any ongoing and completed study will be reviewed.  Any 
new safety findings discovered from any of these sources will be communicated in a 
timely fashion. 


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1.3.5.2. 
Risk Minimization 
Risk minimization activities are based on the communication of benefit risk information 
to physicians and patients, with the prescribing information as the main tool.  
Additionally, there are targeted educational materials for physicians with an emphasis on 
the benefits and risks associated with the use of eltrombopag.  The educational materials 
are updated as necessary to communicate the benefits and risks.   
1.3.6. 
Conclusion 
Eltrombopag has been generally well tolerated in chronic ITP and HCV associated 
thrombocytopenia, in clinical studies for other indications under development, and in the 
post marketing setting. 
The benefit risk profile of eltrombopag for the treatment of patients with chronic ITP and 
HCV associated thrombocytopenia to increase platelet counts and reduce or prevent 
bleeding or help achieve sustained viral response continues to be favorable.  Additionally 
the benefit risk profile of eltrombopag for treatment in other indications under 
development, and in the post marketing setting continues to be favorable. 
 


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2. 
OBJECTIVE 
The objective of this study is to provide continuing treatment with eltrombopag for 
subjects who are currently participating in a Novartis sponsored investigational study of 
eltrombopag (parent study) and to collect long term safety data. 
3. 
STUDY DESIGN 
This Phase IV, multicenter, non-randomized, open-label, uncontrolled, rollover study is 
designed to provide continued access to eltrombopag to eligible subjects.  Enrollment 
into this study will be dependent upon the mutual agreement between Novartis and a site 
to participate in this study. 
Subjects must provide written informed consent prior to any study-related assessment or 
procedure being performed or treatment with eltrombopag for this study.  After informed 
consent is obtained, subjects must meet the eligibility criteria for this study in order to 
participate. 
Protocol waivers or exemptions are not allowed with the exception of immediate safety 
concerns. Therefore, adherence to the study design requirements, including those 
specified in each Cohort section and the Time and Events Table [Appendix 1] are 
essential and required for study conduct.  
The study will consist of a Transition Visit, Study Treatment Visits, and a Follow-Up 
Visit. 
Safety will be evaluated through physical exams, clinical laboratory tests, and monitoring 
of adverse events as described in the Time and Events Table [Appendix 1] Additional 
safety assessments may be done as per standard of care (SOC) and or when medically 
indicated. 
Assessment of clinical benefit will be performed throughout the study using local SOC as 
determined by the investigator to determine continued study participation and treatment 
with eltrombopag. Only subjects considered by the investigator to be receiving clinical 
benefit without unacceptable toxicity may continue on study treatment. 
Subjects will receive a starting dose of eltrombopag at the same dose and administration 
that they were receiving at the time of their last study treatment visit in the parent study. 
Instructions for dose adjustments can be found in Section 5.4.  Subjects may continue 
treatment in this rollover study until they are no longer receiving clinical benefit, develop 
an unacceptable toxicity, withdraw consent, enroll into another interventional study, or 
until another mechanism is available for the subject to receive eltrombopag such as 
compassionate use, named patient program, commercially available for the appropriate 
indication, etc.  The duration of the study will be dependent on the length of time the 
subjects do not meet the protocol stopping criteria, but the study will end in 2023.  
Refer to the Time and Events Table [Appendix 1] for timing of all assessments. 


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Supplementary study conduct information not mandated to be present in this protocol is 
provided in the accompanying Study Procedures Manual (SPM). The SPM will provide 
the site personnel with administrative and detailed technical information that does not 
impact subject safety. 
3.1. 
Discussion of Design 
The purpose of this study is to allow for continued treatment with eltrombopag in 
subjects who have participated in a Novartis sponsored investigational study with 
eltrombopag and met the protocol requirements for transitioning to the rollover study. 
Subjects participating in Investigator Sponsored Studies will not eligible to participate in 
this study. Subjects will be closely monitored for stopping criteria. Subjects will be 
follow the appropriate cohort (Section 3.2) based upon the indication and population of 
the parent study.  The schedule of assessments and procedures to be performed during 
this study is provided in the Time and Events Table (Appendix 1).  Subjects will continue 
to receive SOC therapies unless otherwise stated in the protocol.   
The end of study is defined as the last subject, last visit. 
The eltrombopag dose allowed in this study will be individualized based upon the 
dose/regimen received in the parent study at the time of transition to the rollover study.  
Optimal dosing of eltrombopag is based on platelet count in individual subjects. 
Treatment with eltrombopag may enable subjects to initiate and maintain the dose and 
schedule of disease-modifying therapy.  Disease modifying treatments (e.g. 
chemotherapy, azacitidine, decitabine and lenalidomide) will be allowed.  Supportive 
SOC will be allowed as indicated by local practice throughout the study. 
All subjects will receive eltrombopag at the dose that they were receiving at the time of 
the Transition Visit, except in the case where the subject required a dose modification in 
the parent study.  If the dose was modified at the last study visit in the parent study, the 
subject will enter the rollover study and continue treatment on the modified dose, and the 
visit schedule at entry into the rollover study may be weekly to enable proper monitoring 
following the adjusted dose (Figure 1 ).  However, if during the rollover study the 
investigator considers it appropriate to modify the dose of eltrombopag, the dose may be 
modified as needed based on guidelines in Section 5.4.  Dosage must never exceed the 
maximum dose allowed by the parent study. 
Each subject’s visit schedule may begin at any point of the visit schedule in Figure 1 
depending on the stability of their dose.  Any time a change in dose is required, the 
subjects must return for weekly visits and progress through the visit schedule as detailed 
below. 
 
 


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3.2. 
Cohorts 
3.2.1. 
Cohort A (MDS/AML Adult Subjects) 
Cohort A will consist of adult subjects who have completed study treatment with 
eltrombopag during their participation in a parent study for MDS/AML (i.e. 
TRC114968/ASPIRE). 
3.2.2. 
Cohort B (ITP Adult Subjects) 
Cohort B will consist of adult subjects who have completed study treatment with 
eltrombopag during their participation in a parent study for ITP (i.e. 
TRA105325/EXTEND). 
3.2.3. 
Cohort C (ITP Pediatric Subjects) 
Cohort C will consist of pediatric subjects who have completed study treatment with 
eltrombopag during their participation in a parent study for ITP.  Once a subject turns 18 
years of age, they may remain in the study and follow the Cohort B guidelines. 
3.2.4. 
Visit Schedule for Cohort A, Cohort B, and Cohort C 
Figure 1 
Visit Schedule 
 
 
1. For Cohort B and Cohort C, more frequent visits may be required (Section  5.4.2.3.)  
 
Subjects in Cohort A, Cohort B and Cohort C will complete the Transition Visit 
assessments (Section 8.1.) and then return for their next scheduled visit in 2 weeks, or 


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sooner if the visit schedule in the parent study had been more frequent than every two 
weeks (e.g. weekly schedule). Subjects who have been on a stable dose of eltrombopag 
for the previous 2 every two week visits may decrease the frequency of visits to once 
monthly visits.  Subjects who are stable on a monthly dose for the previous 3 monthly 
visits may decrease the frequency of visits to once every 2 months.  If any change in the 
study treatment dose is required, the schedule of visits must begin again with weekly 
visits for at least 4 weeks, followed by biweekly, then monthly and then bimonthly visits 
(See schematic in Figure 1). 
Once treatment with eltrombopag is permanently discontinued, the subject will attend the 
follow up visit as per Appendix 1. If there are any uncertainties about the dose(s) of study 
treatment(s) to be administered or the visit schedule, the Novartis Medical Lead should 
be consulted. 
4. 
SUBJECT SELECTION AND DISCONTINUATION/ 
COMPLETION CRITERIA 
4.1. 
Subject Selection Criteria 
4.1.1. 
Number of Subjects 
Approximately 100 subjects will be transitioned to this study from other eltrombopag 
studies.   
4.1.2. 
Inclusion Criteria 
Specific information regarding warnings, precautions, contraindications, adverse events, 
and other pertinent information on eltrombopag or other approved agent(s) that may 
impact subject eligibility is provided in the Investigators Brochure (IB) for eltrombopag 
[GlaxoSmithKline Document Number UM2005/00217/08]. 
Deviations from inclusion criteria are not allowed because they can potentially jeopardize 
the scientific integrity of the study, regulatory acceptability or subject safety.  Therefore, 
adherence to the criteria as specified in the protocol is essential. 
Subjects eligible for enrolment in the study must meet all of the following criteria: 
1. Written informed consent has been obtained from the subject (or subject’s legally 
acceptable representative) prior to performance of any study-specific procedure. 
2. The subject is participating in a Novartis sponsored investigational study of 
eltrombopag (parent study) within the past 28 days and is receiving clinical benefit 
without unacceptable toxicity as determined by the investigator. 
3. Subjects with a QTc <450msec or <480msec for subjects with bundle branch block 
 
The QTc is the QT interval corrected for heart rate according to either Bazett’s 
formula (QTcB), Fridericia’s formula (QTcF) or another method, machine or manual 
overread. 
 


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For subject eligibility and withdrawal QTcF will be used.   
 
For purposes of data analysis, QTcF will be used. 
 
The QTc should be based on single or averaged QTc values of triplicate 
electrocardiograms (ECGs) obtained over a brief recording period. 
4. Women must be either of non-child bearing potential (see Section 8.4.8.1, for 
definition) or women with child-bearing potential and men with reproductive 
potential must be willing to practice acceptable methods of birth control during the 
study (See Section 8.4.8.1 for acceptable methods of birth control).   
5. Women of childbearing potential must have a negative serum pregnancy test within 
14 days of the first dose of study treatment and agree to use effective contraception, 
as defined in Section 8.4.8.1 during the study and for 4 weeks following the last dose 
of study treatment. 
6. Men with a female partner of childbearing potential must have either had a prior 
vasectomy or agree to use effective contraception as described in Section 6.1 from 
time of first dose until 16 weeks after the last dose of study treatment. 
7. In France, a subject will be eligible for inclusion in this study only if either affiliated 
to, or a beneficiary of, a social security category. 
4.1.3. 
Exclusion Criteria 
Deviations from exclusion criteria are not allowed because they can potentially 
jeopardize the scientific integrity of the study, regulatory acceptability or subject safety.  
Therefore, adherence to the criteria as specified in the protocol is essential. 
Subjects meeting any of the following criteria must not be enrolled in the study: 
1. Permanent discontinuation of eltrombopag in the parent study based upon the study 
treatment discontinuation or study withdrawal criteria from the parent study. 
Subjects who permanently discontinued treatment because they completed all study 
related treatments remain eligible. 
2. The subject is pregnant or a lactating female. 
3. Any serious and/or unstable pre-existing medical, psychiatric disorder or other 
conditions at the time of transition to this study that could interfere with subject’s 
safety, obtaining informed consent or compliance with the study procedures, in the 
opinion of the investigator or Novartis Medical Lead. 
4. French subjects: the French subject has participated in any study using an 
investigational drug during the previous 30 days, with the exception of eltrombopag, 
in the parent study. 


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4.2. 
Permanent Discontinuation from Study Treatment and 
Subject Completion Criteria 
4.2.1. 
Permanent Discontinuation from Study Treatment 
Subjects will receive study treatment until no longer receiving clinical benefit as 
determined by the investigator, death, or unacceptable adverse event, including 
meeting stopping criteria for liver chemistry defined in Section 5.10.1. In addition, study 
treatment must be permanently discontinued for any of the following reasons: 
 
Subject has taken or plans to take any other investigational product(s) during the 
study  
 
Subject becomes pregnant 
 
Significant deviation from the protocol 
 
Investigator’s discretion 
 
Request of the subject or proxy (withdrawal of consent by the subject) 
 
Subject has an adverse experience that would, in the investigator’s or Sponsor’s 
judgment, make continued participation in the study an unacceptable risk  
 
Subject meets any of the liver chemistry threshold criteria (Section 5.10.2.) 
 
Another mechanism is available for the patient to receive eltrombopag such as 
eltrombopag receives regulatory approval and is commercially available and a 
reimbursement decision has been made in the patient’s country, compassionate 
use, or a named patient program 
 
Subject is lost to follow-up 
 
Study is closed or terminated 
 
Subject has a QTc ≥500 msec (if baseline <450 msec), or QTc >530 msec (if 
baseline QTc 450-480 msec) or uncorrected QT >600 msec  
 
The primary reason study treatment was permanently discontinued must be documented 
in the subject’s medical records and electronic case report form (eCRF).  
If the subject voluntarily discontinues from treatment due to toxicity, ‘adverse event’ will 
be recorded as the primary reason for permanently discontinuation on the CRF.  
Once a subject has permanently discontinued from study treatment, the subject will not 
be allowed to be retreated.  
Investigators will make an attempt to contact those patients who do not return for 
scheduled visits (e.g.by phone contact or certified letters). 
All subjects who discontinue from study treatment will have safety assessments at the 
time of discontinuation and during post study treatment follow-up as specified in Time  
and Events Table [Appendix 1] and Section 8.3.   


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4.2.2. 
Subject Completion 
A subject will be considered to have completed the study when the subject has completed 
all study related procedures or dies or withdraws consent.  Subjects will continue to be 
enrolled in this study and receive study treatment until the subject qualifies for Permanent 
Discontinuation for Study Treatment (See Section 4.2.1). 
The cause of death must be documented in the eCRF. A subject will be considered to 
have withdrawn from the study if the subject has not died and is lost to follow-up, has 
withdrawn consent, or if the study is closed/terminated.  
5. 
STUDY TREATMENTS 
The term ‘study treatment’ is used throughout the protocol to describe any combination 
of products received by the subject as per the protocol design. Study treatment may 
therefore refer to the individual study treatments or the combination of those study 
treatments. However, for the purpose of this study investigational product will only refer 
to eltrombopag. 
5.1. 
Eltrombopag (SB-497115) Novartis Investigational Product 
Eltrombopag will be provided to sites by Novartis. 
Based upon the supply of eltrombopag used in the parent study, subjects may be dosed 
with eltrombopag tablets or powder for oral suspension (PfOS). Subjects who had 
received eltrombopag powder for oral suspension in the parent study may switch to 
tablets in the rollover study if relevant criteria are met based upon the parent study (e.g., 
are age-appropriate to receive tablets). If there is a switch from oral suspension to tablets, 
the doses should take into account the differences in bioavailability between 
formulations. In a relative bioavailability study conducted under fasted conditions in 
healthy adult subjects, the eltrombopag PfOS formulation delivered 22% higher plasma 
eltrombopag AUC(0-) and 30% higher Cmax compared to the tablet formulation. 
Eltrombopag Tablets 
Eltrombopag tablets will be white, round film coated tablets containing eltrombopag 
olamine equivalent to 12.5 mg, 25 mg, 50 mg, 75 mg and 100 mg of eltrombopag. The 
12.5 mg tablet will be smaller than the 25 mg, 50 mg, 75 mg and 100 mg tablets.  
Tablets will be packaged in white high density polyethylene (HDPE) bottles with white 
plastic, induction-seal child-resistant caps. Each bottle will contain 35 tablets. The 
contents of the label will be in accordance with all applicable regulatory requirements. 
Eltrombopag Powder for Oral Suspension 
Eltrombopag powder for oral suspension (Eltrombopag PfOS) is a reddish-brown to 
yellow powder contained inside an elongated sachet.  Each sachet will contain 
eltrombopag olamine equivalent to 20 mg of eltrombopag per gram of powder.   


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PfOS sachets will be packaged in a carton.  Each carton pack will hold 35 sachets along 
with a plastic reconstitution container and a syringe-adapt cap. The pack will also contain 
an extra syringe-adapt cap as a spare.  The clinical site will provide a 10cc syringe with 
each carton. 
The sachet should not be opened until ready to use. Add 9.5 mL of water drawn using a 
10cc syringe into the provided plastic container.  Cut open the sachet and add the entire 
content of the sachet into the container with water.  The container is capped and shaken 
for 10-20 seconds.  The resulting suspension contains 2 mg/mL of eltrombopag dose.  
The prescribed volume (dose) is drawn through the syringe port on the cap with a 
syringe.  Upon dosing, the rest of the remaining suspension in the container is discarded.  
The container and the syringe are rinsed with water and dried. 
If the prescribed dose is > 24 mg, which will require that part or all of a second sachet be 
used, then the suspension can be prepared by adding the contents of the two sachets to 
19.0 mL of water, and then following the steps outlined above.  The water has to be 
drawn by using the 10cc syringe twice, and similarly dosing has to occur by using the 
same 10cc syringe twice. 
A fresh dose is prepared everyday just prior to the dosing and no storage of the 
reconstituted suspension is allowed. Eltrombopag will be provided to sites by Novartis. 
The contents of the label will be in accordance with all applicable regulatory 
requirements. 
Under normal conditions of handling and administration, investigational product is not 
expected to pose significant safety risks to site staff.. A Material Safety Data Sheet 
(MSDS) describing the occupational hazards and recommended handling precautions will 
be provided to site staff if required by local laws or will otherwise be available from 
Novartis upon request. 
5.2. 
Eltrombopag Dosage and Administration 
Site personnel will instruct the subjects (and their parents/guardians if applicable) on how 
to take their medication. Every effort should be made to encourage subject compliance 
with the dosage regimen as per protocol.  
Study treatment will be dispensed in either bottles containing 35 tablets each, or packs 
containing 35 unit-dose sachets each. Additional tablets or packs of sachets will be 
dispensed when the site personnel determine the current supply will not be sufficient until 
the next study visit. 
Study treatment compliance will be assessed as described in Section 5.9. For subjects 
who receive PfOS, study treatment compliance will be assessed at each visit as described 
in Section 5.9. All subjects/parents/guardians should be instructed to bring all bottles or 
sachets with any unused drug to each visit with the investigator. 


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5.2.1. 
Dietary Restrictions 
Eltrombopag should be taken at least four hours before or after any products such as 
antacids, dairy products, or mineral supplements containing polyvalent cations (e.g. 
aluminium, calcium (see below), iron, magnesium, selenium and zinc). 
 
Eltrombopag may be taken either on an empty stomach (1 hour before or 2 hours after a 
meal) or with food containing little (< 50 mg) or preferably no calcium or dairy products 
 
Administration of eltrombopag with a polyvalent cation-containing antacid decreased 
plasma eltrombopag exposure by 70%, and a similar reduction was observed when 
eltrombopag was administered with a high-calcium meal [GlaxoSmithKline Document 
Number UM2005/00217/08]. Therefore, every effort must be made to educate subjects 
on how to take study medication with medications or foods containing these polyvalent 
cations. Details of these and all concomitant medications should be recorded in the 
eCRF. 
5.3. 
Eltrombopag Starting Dose 
All subjects will receive eltrombopag at the dose that they were receiving at the time of 
the Transition Visit, except in the case where the subject required a dose modification in 
the parent study or unless adjustments are warranted according to the dosing guidelines. 
5.4. 
Dose Adjustments 
Each subject’s dose of study treatment will be adjusted as needed following the provided 
dosing guidelines and based upon their individual platelet response.  
The investigator may also make dose adjustments based on safety assessments (e.g. for 
adverse event or other safety assessments, provided the discontinuation criteria are not 
met (see Section 5.4.1). Dosage must never exceed the maximum dose allowed by the 
parent study. 
Instructions for dose adjustments throughout the duration of the study are described in 
Table 1, Table 2, Table 3, and Table 4. 
5.4.1. 
Cohort A (MDS/AML Adult Subjects) 
The range of doses of eltrombopag that will be used in this cohort are 50 mg to 300 mg 
once daily for subjects of non- East Asian heritage.  The dose ranges for subjects of East 
Asian heritage (i.e. Japanese, Chinese, Taiwanese, Thai and Korean) will be 25 mg to 
150 mg. 
The dose of eltrombopag can be increased every 2 weeks by 100 mg (50 mg for subjects 
of East Asian heritage) until maximum 300 mg per day (150 mg for subjects of East 
Asian heritage). Dose adjustments will be dependent on each subject’s platelet counts; 
adjusted to maintain platelet counts ≥100 Gi/L, and dose reduced for platelet counts 
>400 Gi/L.  


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If dose increases or decreases are required based upon the dose adjustment guidelines in 
Table 1, subjects must return the previous bottle(s) and may be dispensed new bottles 
containing 35 tablets each.  Site personnel will instruct subjects on any modified dosing 
instructions (i.e. take 2 or 3 tablets per day based on required dose) based upon dose 
adjustment guidelines below. 
The maximum dose will be 300 mg once daily (150 mg daily for subjects of East Asian 
heritage) and must never exceed the maximum dose allowed by the parent study. 
Subsequent dose adjustments will be based upon platelet counts and safety.  If dose 
increases or decreases are required based upon platelet counts, site personnel will instruct 
subjects on modified dosing instructions based upon the guidelines in Table 1.  
5.4.1.1. 
Dose Escalation 
Intra-individual dose adjustments will be made in a stepwise fashion, by sequentially 
increasing from 50 mg to the 100 mg to the 200 mg and 300 mg eltrombopag dose levels 
as needed depending upon platelet counts (dose levels will be reduced by 50% for 
subjects of East Asian heritage i.e., 25 mg, 50 mg, 100 mg and 150 mg, respectively). 
Subsequent dose adjustments will be based upon platelet counts and safety (Table 1).  If 
dose increases or decreases are required based upon platelet counts, site personnel will 
instruct subjects on modified dosing instructions based upon the guidelines in Section 
5.4.1. 
5.4.1.2. 
Dose Reduction 
Subjects whose platelet count exceeds 400 Gi/L at any point during the treatment period 
must decrease the dosage of study medication.  Temporary dose reduction of study 
medication may also be made by the investigator (i.e. to allow for recovery of AEs) as 
per Table 1 and Section 5.4.1.3. 
If a subject’s platelet count increases significantly and if the investigator thinks a dose 
reduction is medically appropriate, the dose can be decreased even if the platelet count is 
below 200 Gi/L or a dose modification was done less than 2 weeks before. 
5.4.1.3. 
Dose Interruption 
Temporary interruptions of study medication may be made by the investigator (e.g. to 
allow for recovery of AEs).   
Refer to Section 4.2.1 for criteria for permanent discontinuation of study medication.   
 


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Table 1 
Dose Adjustment Guidelines for Adult MDS/AML Patients a 
Platelet counts 
<100 Gi/L 
. 
Increase daily dose to the next dose level.b 
Wait for 2 weeks to see the effect of the dose increase on platelet counts before another dose increase is considered. 
Platelet counts 
100-400 Gi/L 
 
Maintain dose. 
 
Platelet counts 
>400 Gi/L 
 
Decrease daily dose.b   
If platelet counts remain >400 Gi/L, wait for 2 weeks to see the effect of the dose decrease on platelet counts before another dose decrease is 
considered. 
Subjects who have disease progression and also experience clinical benefit will be allowed to continue treatment with study medication, provided that in the investigator 
judgement the benefit-risk ratio of continuing treatment with study medication is favorable.  Given that blasts can be leukemic or benign, blasts counts alone must not be 
the sole indicator of disease progression: rather, the totality of the available data must be considered when determining whether subjects are receiving clinical benefit or 
not.  
a. 
After any dose adjustment, monitor platelet counts at least weekly for 4 weeks. The investigator may also make dose adjustments based on safety assessments (e.g. for 
adverse event or other safety assessments, provided the discontinuation criteria are not met [see Section 4.2]).  Use the dose levels outlined in Section 5.4.1.1. and in 
Section 5.4.1.2. for dose adjustments.  Investigators may use their clinical judgment in modifying the schedule of eltrombopag if used as monotherapy or in combination 
with chemotherapy or disease modifying therapies to treat underlying MDS or AML. 
b. 
See Section 5.4.1. for dose escalation or reduction for further details. 
 
 
 
 


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5.4.2. 
Cohort B and Cohort C (ITP Adults and Pediatric Subjects) 
Dose adjustments will be made as needed following the provided dosing guidelines for 
tablet formulation (Table 2 or Table 3) or suspension formulation (Table 4) and based 
upon each subject’s individual platelet response. The target platelet count range for ITP 
patients is between 50 Gi/L and 200 Gi/L.   
Investigators are expected to use their clinical judgment and knowledge about each 
subject’s individual disease characteristics (including platelet count fluctuation and 
response to prior doses) for any dose adjustment. 
The investigator should take into account any changes in concomitant ITP medications 
that could affect the platelet count when modifying the dose of eltrombopag. 
If a subject has a platelet count that would require changing the dose to a dose that was 
previously proven to achieve platelet counts outside of the target range (<50 Gi/L or 
>200 Gi/L), alternating doses of different strength tablets or changes in frequency may be 
considered. 
If a subject’s platelet count increases significantly and if the investigator thinks a dose 
reduction is medically appropriate, the dose can be decreased even if the platelet count is 
below 200 Gi/L or a dose modification was done less than 2 weeks before.   
If after an interruption the subject’s platelet count decreases drastically and if the 
investigator thinks re-initiation is medically appropriate, the dose can be reinitiated at the 
next lower dose level even if the platelet count has not yet decreased to below 150 Gi/L.  
If a subject’s platelet count decreases drastically and the investigator thinks a dose 
increase is medically appropriate, the dose can be increased even if the platelet count is 
more than 50 Gi/L. 
If dose increases or decreases are required based upon platelet counts, site personnel will 
instruct subjects on modified dosing instructions based upon the guidelines in Table 2 or 
Table 3. If dose adjustments are required based upon the dose adjustment guidelines, 
subjects must return the previous bottle(s) and may be dispensed new bottles containing 
35 tablets each, or new cartons containing 35 sachets each.   
The maximum dose for ITP subjects will be 75 mg once daily and must never exceed the 
maximum dose allowed by the parent study. 
5.4.2.1. 
Dose Escalation 
The dose of eltrombopag will be increased in a stepwise fashion, by sequentially 
increasing to the next dose level, until the target platelet count or the maximum allowed 
dose is achieved (Table 2, Table 3 or Table 4).  After increasing the dose of eltrombopag, 
investigators must wait at least 2 weeks before increasing the dose again. 


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If a subject has a platelet count <50 Gi/L and requires a dose increase, and the next higher 
dose has already proven to be associated with platelet counts >200 Gi/L, then 
intermediate or alternating doses may be used. 
5.4.2.2. 
Dose Reduction 
If the platelet count exceeds 200 Gi/L, the dose of eltrombopag will be decreased as 
outlined in Table 2, Table 3 or Table 4.    
If a subject requires a dose lower than the available tablet strengths or between 2 
available tablet strengths, alternate dosing regimens that modify the frequency of 
administration may be used. 
5.4.2.3. 
Dose Interruption 
If the platelet count exceeds 400 Gi/L, the dose of eltrombopag will be interrupted until 
the platelet count < 150 Gi/L. At that point, eltrombopag will be reinitiated at the next 
lower dose or frequency. 
If the platelet count is still above 150 Gi/L within one week after study treatment 
interruption, the platelet count needs to be monitored 3-4 days later, and twice a week 
until the platelet count is ≤150 Gi/L. Once the subject's platelet count is ≤150 Gi/L, study 
treatment should be started at the next lower dose or frequency. 


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5.4.2.4. 
Dose Adjustment Guidelines for Tablet Formulation 
Table 2 
Dose Adjustment Guidelines for Adult ITP Patients 
Platelet count 
Dose 
Dose adjustment 
<50 Gi/L 2 
12.5 mg 
Increase to 25 mg  
25 mg 
Increase to 50 mg 
50 mg 
Increase to 75 mg 
75 mg 
Maintain 75 mg dose 1 
50 – 200 Gi/L 
Maintain current dose 
200 – 400 Gi/L 2,3 
12.5 mg 
Decrease to 12.5 mg every other day 
25 mg 
Decrease to 12.5 mg 
50 mg 
Decrease to 25 mg   
75 mg 
Decrease to 50 mg   
>400 Gi/L  
 Interrupt study treatment until 
platelets < 150 Gi/L 2,4 
12.5 mg 
After interruption reinitiate at a reduced 
frequency, 12.5 mg every other day 
25 mg 
After interruption, reinitiate at 12.5 mg 
50 mg 
After interruption, reinitiate at 25 mg 
75 mg 
After interruption, reinitiate at 50 mg 
1. If a subject has reached the maximum allowed dose and has platelet counts < 50 Gi/L, the investigator (or 
designee) may choose to have the subject continue in the trial if clinical benefit is documented in terms of 
improved platelet counts OR reduced bleeding symptoms.  
2. If a subject requires a dose adjustment, and the next available dose has already proven to be associated with 
platelet counts outside of the target range (i.e., <50 Gi/L or >200 Gi/L), then alternating doses may be used. 
3. The Investigator may consider keeping the current dose if a drop in platelet counts would be expected by reducing 
the dose.  
4. If the platelet count is still above 150 Gi/L within one week after study treatment interruption, the platelet count 
needs to be monitored 3-4 days later, and twice a week thereafter until the platelet count is ≤150 Gi/L. Once the 
subject's platelet count is ≤150 Gi/L, study treatment should be started at the next lower dose or frequency. 
 


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Table 3 
Dose Adjustment Guidelines for Pediatric ITP Patients receiving 
tablets 
Platelet count 
Dose 
Dose adjustment 
<50 Gi/L3 
12.5 mg 
Increase to 25 mg  
25 mg 
Increase to 50 mg1   
37.5 mg 
Increase to 50 mg 
50 mg 
Increase to 75 mg1 
62.5 mg 
Increase to 75 mg 
75 mg 
Maintain 75 mg dose2 
50 – 200 Gi/L 
Maintain current dose 
200 – 400 Gi/L3,4 
12.5 mg 
Decrease to 12.5 mg every other day 
25 mg 
Decrease to 12.5 mg 
37.5 mg 
Decrease to 25 mg 
50 mg 
Decrease to 37.5 mg   
62.5 mg 
Decrease to 50 mg   
75 mg 
Decrease to 62.5 mg   
>400 Gi/L  
 Interrupt study treatment until 
platelets < 150 Gi/L5 
12.5 mg 
After interruption reinitiate at a reduced 
frequency, 12.5 mg every other day 
25 mg 
After interruption, reinitiate at 12.5 mg 
37.5 mg 
After interruption, reinitiate at 25 mg 
50 mg 
After interruption, reinitiate at 37.5 mg 
62.5 mg 
After interruption, reinitiate at 50 mg 
75 mg 
After interruption, reinitiate at 62.5 mg 
1. For a subject who has returned to the 25 mg or 50 mg dose because 50 mg or 75 mg, respectively, led to a 
response of >200 Gi/L, the dose should be increased to 37.5 mg or 62.5 mg, respectively.  
2. If a subject has reached the maximum allowed dose and has platelet counts < 50 Gi/L, the investigator (or 
designee) may choose to have the subject continue in the trial if clinical benefit is documented in terms of 
improved platelet counts OR reduced bleeding symptoms.  
3. If a subject requires a dose adjustment, and the next available dose (adjusting by 12.5 mg) has already proven to 
be associated with platelet counts outside of the target range (i.e., <50 Gi/L or >200 Gi/L), then alternating doses 
may be used. 
4. The Investigator may consider keeping the current dose if a drop in platelet counts would be expected by reducing 
the dose.  
5. If the platelet count is still above 150 Gi/L within one week after study treatment interruption, the platelet count 
needs to be monitored 3-4 days later, and twice a week thereafter until the platelet count is ≤150 Gi/L. Once the 
subject's platelet count is ≤150 Gi/L, study treatment should be started at the next lower dose or frequency. 
5.4.2.5. 
Dose Adjustment Guidelines for Suspension Formulation 
The dose of eltrombopag will be increased or decreased according to platelet counts as 
outlined in Section 5.4.2.  These modifications will initially be in strength intervals of 
30% (rounded up) as shown in Table 4, but intermediate dosing levels may be used if the 
platelet response warrants it.  Subsequent dose adjustments should be made based upon 
the current dose of eltrombopag.  
For a calculated dose of 18 to 24 mg, subjects should receive one sachet, which is 
equivalent to a 20 mg dose.  A subsequent dose adjustment would be based upon the 
actual dose of 20 mg, i.e., a 30% increase in dose would be an increase of 6 mg for a total 


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of 26 mg.  For calculated doses of 38 to 44 mg, subjects should receive a 40 mg dose 
(two sachets); subsequent dose adjustment would be based on the actual dose received, 
i.e. 40 mg. 
Table 4 
Dose Adjustment Guidelines – suspension formulation 
Initial Dose 
(mg) 
Initial Dose 
(ml) 
Adjust dose by1 
(mg) 
Adjust dose by 
(ml) 
10 
5 
3 
1.5 
11 
5.5 
4 
2 
12 
6 
4 
2 
13 
6.5 
4 
2 
14 
7 
5 
2.5 
16 
8 
5 
2.5 
17 
8.5 
6 
3 
20 2 
10 
6 
3 
25 
12.5 
8 
4 
26 
13 
8 
4 
28 
14 
9 
4.5 
29 
14.5 
9 
4.5 
30 
15 
9 
4.5 
1. This table illustrates the initial dose and the corresponding 30% dose adjustment.  
Subsequent dose adjustments would be calculated based upon the current dose. 
2. For a calculated dose of 18 to 24 mg, subjects should receive one sachet, which is 
equivalent to a 20 mg dose.  A subsequent dose adjustment would be based upon the 
actual dose of 20 mg, i.e., a 30% increase in dose would be an increase of 6 mg for a 
total of 26 mg. 
 


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5.5. 
Handling and Storage of Study Treatment 
Eltrombopag tablets and PfOS sachets must be stored in a secure area under the 
appropriate physical conditions for the product according to the requirements listed on 
the label. Access to and administration of the study treatment will be limited to the 
investigator and authorized site staff. Eltrombopag must be dispensed or administered 
only to subjects enrolled in the study and in accordance with the protocol.  
The recommended storage condition is stated on the product label and, where required, 
the label also includes the expiry date. 
For US sites, any unused study medication will be returned by the monitor to Novartis for 
destruction. For non-US sites, any unused study medication will be destroyed locally 
according to local standard operating procedures (SOP). 
5.6. 
Treatment Assignment 
Subjects will be identified by a unique subject number that will remain consistent for the 
duration of the study. 
Subject/treatment numbers originally assigned to subjects during their participation in the 
parent study will be recorded in the eCRF, but will not be used to identify subjects in the 
rollover study. 
Upon completion of all the required screening assessments, eligible subjects will be 
registered into an interactive voice response system (IVRS) by the investigator or 
authorized site staff.   
5.7. 
Blinding 
This is an open-labeled study. 
5.8. 
Product Accountability 
In accordance with local regulatory requirements, the investigator, designated site staff, 
or head of the medical institution (where applicable) must document the amount of 
investigational product dispensed and/or administered to study subjects, the amount 
returned by study subjects, and the amount received from and returned to Novartis, when 
applicable.  Product accountability records must be maintained throughout the course of 
the study.  Refer to the SPM for further detailed instructions on product accountability. 
5.9. 
Treatment Compliance 
At each visit, an evaluation of subject compliance with taken medication will be 
performed to confirm whether the patient has taken their medication exactly as 
prescribed.  The investigator should discuss any tablet discrepancies with the patient, 
document any reasons for the non compliance and make every effort to bring the patient 
back into compliance.  If dose modifications are required, subjects will be instructed to 
take the appropriate number of tablets from each bottle daily. 


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All subjects should be instructed to bring all bottles at each visit, with any unused drug, 
to the investigator.   
Compliance with eltrombopag will be assessed through querying the subject during the 
site visits and documented in the source documents and eCRF.  
A record of the number of eltrombopag tablets dispensed and the number of tablets 
returned, assessing the amount of tablets that should have been taken by each subject 
must be maintained and reconciled with study treatment and compliance records.  
Treatment start and stop dates, including dates for treatment delays and/or dose 
reductions will also be recorded in the eCRF. 
5.10. 
Monitoring, Interruption and Stopping Criteria for 
Hepatobiliary Events 
5.10.1. 
Liver Chemistry Stopping Criteria 
Novartis liver chemistry stopping and follow up criteria have been designed to assure 
subject safety and evaluate liver event etiology in alignment with the FDA premarketing 
clinical liver safety guidance.  
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf 
Phase II liver chemistry stopping criteria 1-5 are defined below and are presented as 
a Figure in Appendix 2: 
1. ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) (or ALT 3xULN and 
INR >1.5, if INR measured). 
NOTE: if serum bilirubin fractionation is not immediately available, study treatment 
should be discontinued if ALT 3xULN and bilirubin 2xULN. Serum bilirubin 
fractionation should be performed if testing is available. If testing is unavailable, 
record presence of detectable urinary bilirubin on dipstick, indicating direct 
bilirubin elevations and suggesting liver injury. 
2. ALT 5xULN. 
3. ALT 3xULN if associated with symptoms (new or worsening) believed to be 
related to hepatitis (such as fatigue, nausea, vomiting, right upper quadrant pain or 
tenderness, or jaundice) or believed to be related to hypersensitivity (such as fever, 
rash or eosinophilia). 
4. ALT 3xULN persists for 4 weeks 
5. ALT 3xULN and cannot be monitored weekly for  weeks 
When any of the liver chemistry stopping criteria 1-5 is met, do the following: 
 
Immediately discontinue subject from study treatment 
 
Promptly report the event to Novartis within 24 hours of learning its occurrence 


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 
Complete the liver event CRF and SAE data collection tool if the event also meets 
the criteria for an SAE.  
 
All events of ALT  3xULN and bilirubin 2xULN (>35% direct bilirubin) (or 
ALT 3xULN and INR >1.5, if INR measured; INR measurement is not 
required and the threshold value stated will not apply to subjects receiving 
anticoagulants), termed ‘Hy’s Law’, must be reported as an SAE (excluding 
studies of hepatic impairment or cirrhosis).  
 
NOTE: if serum bilirubin fractionation is not immediately available, stop study 
treatment for that subject if ALT 3xULN and bilirubin 2xULN. Serum 
bilirubin fractionation should be performed if testing is available. If testing is 
unavailable, record presence of detectable urinary bilirubin on dipstick, 
indicating direct bilirubin elevations and suggesting liver injury. 
 
Complete the liver imaging and/or liver biopsy CRFs if these tests are performed. 
 
Perform liver event follow up assessments, and monitor the subject until liver 
chemistries resolve, stabilize, or return to baseline values as described below.  
 
Withdraw the subject from the study treatment after completion of the liver 
chemistry monitoring as described below (unless further safety follow up is 
required For studies where survival is an endpoint, follow-up for overall survival 
is required following discontinuation from study treatment. 
In addition, for subjects meeting liver stopping criterion 1:  
 
Make every reasonable attempt to have subjects return to clinic within 24 hours for 
repeat liver chemistries, liver event follow up assessments (Section 5.10.1.1), and 
close monitoring. 
 
A specialist or hepatology consultation is recommended. 
 
Monitor subjects twice weekly until liver chemistries (ALT, AST, alkaline 
phosphatase, bilirubin) resolve, stabilize or return to within baseline values. 
For subjects meeting any of the criteria 2, 3, 4 and 5: 
 
Make every reasonable attempt to have subjects return to clinic within 24-72 hrs for 
repeat liver chemistries and liver event follow up assessments (Section 5.10.1.1). 
 
Monitor subjects weekly until liver chemistries (ALT, AST, alkaline phosphatase, 
bilirubin) resolve, stabilize or return to within baseline values;  
 
Subjects meeting criterion 5 should be monitored as frequently as possible. 
5.10.1.1. 
Liver Event Follow Up Assessments 
For subjects meeting any of the liver chemistry stopping criteria 1-5, make every attempt 
to carry out the liver event follow up assessments described below: 
 
Viral hepatitis serology including: 
 
Hepatitis A IgM antibody; 


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 
Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM);  
 
Hepatitis C RNA;  
 
Cytomegalovirus IgM antibody; 
 
Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain 
heterophile antibody or monospot testing);   
 
Hepatitis E IgM antibody  
 
Blood sample for pharmacokinetic (PK) analysis, obtained within 24 hours of last 
dose.  Record the date/time of the PK blood sample draw and the date/time of the last 
dose of study treatment prior to blood sample draw on the CRF. If the date or time of 
the last dose is unclear, provide the subject’s best approximation. If the date/time of 
the last dose cannot be approximated OR a PK sample cannot be collected in the 
time period indicated above, do not obtain a PK sample. Instructions for sample 
handling and shipping are in the SPM.  
 
Serum creatine phosphokinase (CPK) and lactate dehydrogenase (LDH). 
 
Fractionate bilirubin, if total bilirubin 2xULN 
 
Obtain complete blood count with differential to assess eosinophilia 
 
Record the appearance or worsening of clinical symptoms of hepatitis, or 
hypersensitivity, such as fatigue, nausea, vomiting, right upper quadrant pain or 
tenderness, fever rash or eosinophilia as relevant on the AE report form 
 
Record use of concomitant medications, acetaminophen, herbal remedies, other over 
the counter medications, or putative hepatotoxins, on the concomitant medications 
report form. 
 
Record alcohol use on the liver event alcohol intake case report form 
The following are required for subjects with ALT 3xULN and bilirubin 2xULN 
(>35% direct) but are optional for other abnormal liver chemistries: 
 
Anti-nuclear antibody, anti-smooth muscle antibody, Type 1 anti-liver kidney 
microsomal antibodies, and quantitative total immunoglobulin G (IgG or gamma 
globulins). 
 
Serum acetaminophen adduct high performance liquid chromatography(HPLC) assay 
(quantifies potential acetaminophen contribution to liver injury in subjects with 
definite or likely acetaminophen use in the preceding week [James, 2009]).  
 
Only in those with underlying chronic hepatitis B at study entry (identified by 
positive hepatitis B surface antigen): quantitative hepatitis B DNA and hepatitis delta 
antibody. NOTE:  if hepatitis delta antibody assay cannot be performed, it can be 
replaced with a polymerase chain reaction (PCR) of hepatitis D RNA virus (where 
needed [Le Gal, 2005]. 
 
Liver imaging (ultrasound, magnetic resonance, or computerized tomography) to 
evaluate liver disease. 


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5.10.2. 
Liver Chemistry Monitoring Criteria 
For subjects with ALT 3xULN but <5xULN and bilirubin <2xULN, without hepatitis 
symptoms or rash, and who can be monitored weekly for 4 weeks, the following actions 
should be taken 
 
Notify the Novartis Medical Lead within 24 hours of learning of the abnormality to 
discuss subject safety.  
 
Continue study treatment 
 
Must return weekly for repeat liver chemistries (ALT, AST, alkaline phosphatase, 
bilirubin) until they resolve, stabilize or return to within baseline values 
 
If at any time these subjects meet the liver chemistry stopping criteria 1 - 5, proceed 
as described above 
 
If, after 4 weeks of monitoring, ALT <3xULN and bilirubin <2xULN, monitor 
subjects twice monthly until liver chemistries normalize or return to within baseline 
values.  
Refer to Appendix 2 Liver Chemistry Monitoring, Interruption, Stopping and Follow-up 
Criteria for algorithm of liver chemistry monitoring, stopping and follow up criteria 
6. 
LIFESTYLE RESTRICTIONS 
6.1. 
Male Subjects 
Male subjects with a female partner of child bearing potential must agree to use adequate 
contraception during the study and for a total of 16 weeks following the last dose of study 
drug (based upon the lifecycle of sperm).  Novartis acceptable contraceptive methods for 
males, when used consistently and in accordance with both the product label and the 
instructions of the physician, are as follows: 
 
Vasectomized male who is sterile prior to participation in the study  
 
Complete abstinence from sexual intercourse for 14 days prior to first dose of study 
drug, through the dosing period, and for at least 16 weeks after the last dose of study 
drug. 
 
Double-barrier contraception: condom and occlusive cap (diaphragm or 
cervical/vault caps) with a vaginal spermicidal agent (foam/gel/cream/suppository). 
7. 
CONCOMITANT MEDICATIONS AND NON-DRUG 
THERAPIES 
Subjects will be instructed to inform the investigator prior to starting any new 
medications from the time of the Transition Visit until the end of the study (Final Study 
Visit).  Any concomitant medication(s) taken during the study will be recorded in the 
eCRF.   


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If future changes are made to the list of permitted/prohibited medications, formal 
documentation will be provided by Novartis and stored in the study file.  Any such 
changes will be communicated to the investigative sites in the form of a letter. 
7.1. 
Permitted Medications and Non-Drug Therapies 
All concomitant medications taken during the study will be recorded in the eCRF with 
information regarding reason for use, route of administration and dates of administration. 
The following will be recorded on the concomitant medications eCRF page: 
 
A complete list of prescription and over-the-counter medications (including 
herbal remedies) that have been taken within 7 days prior to the first dose of 
study treatment(s) should be listed as a prior or ongoing medication. 
 
All concomitant medications taken during the study. 
Subjects should receive full supportive care during the study, including transfusion of 
blood and blood products, and treatment with antibiotics, antiemetics, antidiarrheals, and 
analgesics, as appropriate. 
7.1.1. 
Antacids, Cations and Vitamin/Mineral Supplements 
Antacids 
Subjects requiring routine (e.g. daily) acid suppression should be encouraged to take H2 
antagonists like ranitidine, famotidine or nizatidine, or proton pump inhibitors like 
omeprazole, esomeprazole or lansoprazole. 
Subjects requiring occasional acid suppression may take liquid or chewable antacids 
(calcium carbonate, aluminum hydroxide or magnesium hydroxide), provided 
investigational product is taken at least 4 hours before or 4 hours after consumption of 
cation-containing antacids. 
Mineral Supplements and Dairy Products 
Mineral supplements (such as calcium, magnesium, aluminium, zinc, selenium or iron) 
are permitted during the study but study medication must be taken at least 4 hours before 
or 4 hours after consumption of these supplements.  Similarly, eltrombopag must be 
taken at least 4 hours before or 4 hours after consumption of dairy products (such as milk, 
yogurt, and cheese). 
7.1.2. 
HMG-CoA Reductase Inhibitors (statins) 
Subjects receiving HMG-CoA reductase (3-hydroxy-3-methyl-glutaryl-coenzyme A) 
inhibitors during the study should be closely monitored 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 Organic 
Anion Transporting Polypeptide (OATP1B1) and Breast Cancer Resistance Protein 
(BCRP).  Therefore, a clinical drug interaction study to evaluate the impact of 


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eltrombopag on the PK of rosuvastatin, an OATP1B1 and BCRP substrate, was 
conducted in healthy subjects.  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 AUC(0-) 55%. When co-administered with 
eltrombopag, a 50% dose reduction of the HMG-CoA reductase inhibitor is 
recommended [GlaxoSmithKline Document Number UM2005/00217/08]. 
Concomitant administration of eltrombopag and other OATP1B1 or BCRP substrates 
should be used with caution. 
7.1.3. 
Platelet Transfusions 
In this study, platelet transfusions are permitted based on SOC and at the investigator’s 
discretion. Investigators will be required to document blood and blood supportive care 
products in the eCRF.  
Any platelet-transfusion related complication (e.g. mild fever, shivering, skin rash, 
bronchospasm, Transfusion-Related Acute Lung Injury [TRALI], etc.) and any treatment 
administered to treat or prevent these (e.g. antagonists, pethidine, paracetamol, 
corticosteroids, oxygen, etc.) will be documented in the eCRF. 
7.1.4. 
Concomitant Therapy for Cohort A (MDS/AML Adult Subjects) 
Supportive SOC or disease modifying agents will be allowed as indicated by local 
practice throughout the study.   
Investigators must carefully document all concurrent medications received for treatment 
of MDS/AML and any changes in dosage strength or frequency in the eCRF. 
7.1.5. 
Concomitant Therapy for Cohort B and Cohort C (ITP Adult and 
Pediatric Subjects) 
Concomitant ITP therapy use is permitted based on clinical judgment of investigator. 
Subjects will be permitted to use stable maintenance ITP therapy as per local ITP 
treatment protocols.   
The dose of eltrombopag should not be reduced while tapering concomitant ITP 
medications unless clinically indicated. Investigators must carefully document all 
concurrent medications received for treatment of ITP and any changes in dosage strength 
or frequency in the eCRF. 
7.2. 
Prohibited Medications and Non-Drug Therapies 
Subjects must abstain from using investigational and prohibited prescription or non-
prescription drugs within 7 days or 5 half-lives (whichever is longer) prior to the first 
dose of study treatment and until completion of follow-up procedures unless in the 
opinion of the investigator and sponsor the medication will not interfere with the study 
(Section 4.1. Subject Selection Criteria). 


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The following medications are prohibited or permitted only with restricted use (as 
outlined below) during the study: 
 
Any other TPO-R agonists, without exception. 
 
Deferasirox shares some aspects of the safety profile of eltrombopag (e.g., hepatic 
abnormalities, renal tubular toxicity in mice and rats, cataract development in young 
rodents, and inhibition/metabolism of the enzymes CYP2C8, CYP1A2, UGT1A1 
and UGT1A3).  Therefore, use of this medication is permitted, if a subject is already 
taking deferasirox at the time of study entry.  No new treatment with deferasirox 
should be initiated while on study medication.  Continuation of deferasirox is 
permitted only if any potential deferasirox-related safety events have clearly been 
documented, and the continuation of deferasirox is deemed clinically important by 
the investigator.  These measures should allow for a better identification of potential 
eltrombopag-related events without confounding by deferasirox.  According to 
published treatment guidelines, iron chelation therapy with deferasirox should not be 
considered in patients with advanced MDS and AML [Bennett, 2008]. 
7.3. 
Treatment after Discontinuation of Study Treatment or 
withdrawal from/Completion of Study 
The investigator is responsible for ensuring that consideration has been given for the 
post-study care of the subject’s medical condition whether or not Novartis is providing 
specific post-study treatment. 
Post-study treatment will not be provided as part of the protocol.  Upon discontinuation 
from study treatment, subjects may receive additional (non-protocol) therapy at the 
discretion of the treating physician.  New therapy should be documented in the eCRF. 
Every effort should be made to complete the required post-treatment follow-up 
evaluations prior to initiating further anti-cancer therapy or dosing of an investigational 
agent (see Appendix 1) for Final Study Visit assessments and procedures. 
7.4. 
Treatment of Study Treatment Overdose 
For the purposes of this study, an overdose of eltrombopag is defined as any dose greater 
than the highest daily dose allowed in the parent study. 
In cases of suspected or confirmed overdose with eltrombopag, consider oral 
administration of a metal cation-containing preparation, such as calcium, aluminum, or 
magnesium preparations to chelate eltrombopag and thus limit absorption.  Closely 
monitor platelet counts.  Hemodialysis is not expected to enhance the elimination of 
eltrombopag because eltrombopag is not significantly renally excreted and is highly 
bound to plasma proteins.  
No specific antidote is known.  A hematologist will be consulted and appropriate 
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8. 
STUDY ASSESSMENTS AND PROCEDURES 
A signed, written informed consent form must be obtained from the subject (or subject’s 
legally acceptable representative) prior to any study-specific procedures or assessments. 
Refer to the Time and Events Table (Appendix 1) for the timing of all study specific 
assessments and procedures.  Further details of study procedures and assessments can be 
found in the study procedures manual (SPM). 
Investigators may be requested to perform additional safety tests during the course of the 
study based on newly available data to ensure appropriate safety monitoring.  
Appropriate local regulatory and ethical approvals should be obtained before any 
additional testing is performed. 
Cardiovascular medical history/risk factors will be assessed at baseline. 
8.1. 
Transition Visit 
For this study, the Transition Visit must occur within 28 days of the last day of study 
treatment of the parent study and may be on the same day as the last study treatment visit 
of the parent study.  The results of any specified study assessments performed on the day 
of the Transition Visit will serve as the baseline value for the said assessment. 
At the Transition Visit, the following assessments will be performed once a signed, 
written consent form for the study 200170 has been obtained from the subject or the 
subject’s legally acceptable representative (prior to any study specific procedures or 
assessments). Pediatric subjects over 6 years old will be asked to sign an assent form as 
appropriate per local regulations.  
 
Demographic data, including date of birth, sex, ethnicity and race. 
 
Subject-related data from parent study, including parent study protocol number, 
parent study subject treatment number, previous subject number assigned in the 
parent study, start date and dose of eltrombopag treatment, dose of eltrombopag at 
the time of transition to this study; and best response based on last disease 
assessment in parent study for MDS/AML subjects. 
 
Complete physical examination. 
 
12 lead ECG. 
 
Clinical laboratory tests: hematology and clinical chemistry as listed in Table 5. 
 
Documentation of ongoing AEs and SAEs at the time of transition to the rollover 
study. 
 
Review of concomitant medications. 
 
Review and record any blood and blood supportive care products.   
 
Documentation of bone marrow examination if performed, including 
cytomorphology and cytogenetic assessment when performed per SOC and/or 
disease progression. 


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8.2. 
Continuous Dosing Treatment Period 
The following assessments must be performed at each Treatment Visit as per the Time 
and Events Table (Appendix 1). 
 
Complete physical examination. 
 
Clinical laboratory tests: hematology and clinical chemistry as listed in Table 5. 
 
Documentation of AEs and SAEs. 
 
Review of concomitant medications. 
 
Documentation of bone marrow examination if performed, including 
cytomorphology and cytogenetic assessment when performed per SOC and/or 
disease progression. 
 
Document disease response in MDS/AML subjects only if assessed as per SOC.  
 
Document disease progression in MDS/AML subjects only if assessed as per SOC. 
 
Review and record any blood and blood supportive care products.  
8.3. 
Final Study Visit 
If the subject is withdrawn from study treatment or has completed the study, the 
following assessments will be performed within 30 days (+ 7 days) from the last dose of 
study treatment and prior to initiating any other investigational product: 
 
Complete physical examination. 
 
Clinical laboratory tests: hematology and clinical chemistry as listed in Table 5. 
 
Documentation of bone marrow examination if performed as part of standard care, 
including cytomorphology and cytogenetic assessment.  
 
Documentation of AEs and SAEs. 
 
Document disease response for MDS/AML subjects only. 
 
Document disease progression for MDS/AML subjects only. 
 
Review and record any blood and blood supportive care products.   
8.4. 
Safety 
Measurements used to evaluate safety will include physical exams, clinical laboratory 
tests (hematology and clinical chemistry), and monitoring of AEs/SAEs. Planned study 
visits for all safety assessments are listed in the Time and Events Table (Appendix 1). 
Additional, unplanned safety assessments may be performed during the course of the 
study as clinically indicated at the judgment of the investigator. Additional safety tests 
may be added during the course of the study based on newly available data to ensure 
appropriate safety monitoring. 


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NOTE:  The term ‘baseline’ will refer to the value obtained on the date of the first dose 
of study treatment following transition to the rollover study and does not refer to the 
‘baseline’ value recorded for the same assessment in the parent study. 
8.4.1. 
Physical Examination 
A complete physical examination will be performed at the visit schedule as outlined in 
Figure 1 and the Time and Events Table (Appendix 1).   
8.4.2. 
Bone Marrow Examinations 
Disease status may be evaluated in part by means of periodic bone marrow examinations 
throughout the study, as per SOC and should be considered for subjects who have disease 
progression. 
Information from bone marrow examinations that are performed during the study should 
be entered in the eCRF. Bone marrow cytomorphology and cytogenetic assessment 
should also be entered in the eCRF if collected. 
8.4.3. 
Laboratory Assessments 
Clinical laboratory tests (Table 5) will be performed as outlined in the Time and Events 
Table (Appendix 1). At the discretion of the investigator, additional laboratory samples 
may be taken as clinically necessary. 
Local laboratories will be used for hematology and chemistry assessments.  Local 
laboratory reference ranges for all safety parameters should be provided to Novartis by 
the site prior to receiving study medication shipment. 
Table 5 
Laboratory Assessments 
Hematology  
Standard Chemistry  
   Hemoglobin 
   Blood urea nitrogen or urea 
   Hematocrit 
   Creatinine  
   Red blood cell count 
   AST 
   Platelets 
   ALT 
   White blood cell count with differential 
   Total bilirubin 
       Total neutrophils 
   Direct bilirubin 
       Lymphocytes 
   Albumin 
       Monocytes 
Pregnancy2  
       Eosinophils 
   Serum β-hCG (human chorionic gonadotrophin) 
       Basophils 
 
Blast % from peripheral blood smear1 
    
1. 
Subjects from Cohort A only 
2. 
Before the first dose of study treatment (-14 days) and at the investigator discretion 
 
8.4.4. 
Adverse Events 
The investigator or site staff will be responsible for detecting, documenting and reporting 
events that meet the definition of an AE or SAE as outlined in Section 8.4.4.1. 


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Adverse event and serious adverse events will be reported in accordance with the 
Common Terminology Criteria for Adverse Events (CTCAE) v4.0 toxicity grades.  The 
general guidelines for this toxicity grading system are as follows: 
 
Grade 1 - Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated. 
 
Grade 2 - Moderate; minimal, local or non-invasive intervention indicated; limiting 
age appropriate instrumental activities of daily living. 
 
Grade 3 - Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-
care activities of daily living. 
 
Grade 4 - Life threatening consequences; urgent intervention indicated. 
 
Grade 5 - Death related to AE 
8.4.4.1. 
Definition of an AE 
Any untoward medical occurrence in a subject or clinical investigation subject, 
temporally associated with the use of a medicinal product, whether or not considered 
related to the medicinal product. 
Note: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a medicinal product.  For marketed medicinal products, this 
also includes failure to produce expected benefits, abuse, or misuse. Examples of events 
meeting the definition of an AE include: 
 
Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or grade of the condition. 
 
New conditions detected or diagnosed after study treatment administration even 
though it may have been present prior to the start of the study. 
 
Signs, symptoms, or the clinical sequelae of a suspected interaction. 
 
Signs, symptoms, or the clinical sequelae of a suspected overdose of study treatment 
(overdose per se will not be reported as an AE/SAE unless this is an intentional 
overdose taken with possible suicidal/self-harming intent.  This should be reported 
regardless of sequelae). 
The signs and symptoms and/or clinical sequelae resulting from lack of efficacy will be 
reported if they fulfill the definition of an AE or SAE.  Also, “lack of efficacy” or 
“failure of expected pharmacological action” also constitutes an AE or SAE. 
Events that do not meet the definition of an AE include: 
 
Medical or surgical procedure (e.g., endoscopy, appendectomy); the condition that 
leads to the procedure is an AE. 
 
Situations where an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 


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 
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen. 
 
The disease/disorder being studied, or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the subject’s 
condition.  
8.4.4.2. 
Definition of a SAE 
A serious adverse event is any untoward medical occurrence that, at any dose: 
a. 
Results in death 
NOTE: Death due to disease under study is to be recorded on the Death eCRF form 
and does not need to be reported as an SAE.    
b. Is life-threatening 
NOTE:  The term 'life-threatening' in the definition of 'serious' refers to an event in 
which the subject was at risk of death at the time of the event.  It does not refer to an 
event, which hypothetically might have caused death, if it were more severe. 
c. 
Requires hospitalization or prolongation of existing hospitalization 
NOTE:  In general, hospitalization signifies that the subject has been detained 
(usually involving at least an overnight stay) at the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the physician’s 
office or out-patient setting. Complications that occur during hospitalization are AEs. 
If a complication prolongs hospitalization or fulfills any other serious criteria, the 
event is serious.  When in doubt as to whether “hospitalization” occurred or was 
necessary, the AE should be considered serious. 
Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from baseline is not considered an AE. 
d. Results in disability/incapacity, or 
NOTE:  The term disability means a substantial disruption of a person’s ability to 
conduct normal life functions.  This definition is not intended to include experiences 
of relatively minor medical significance such as uncomplicated headache, nausea, 
vomiting, diarrhea, influenza, and accidental trauma (e.g. sprained ankle) which may 
interfere or prevent everyday life functions but do not constitute a substantial 
disruption. 
e. 
Is a congenital anomaly/birth defect.  
f. 
Medical or scientific judgement should be exercised in deciding whether reporting is 
appropriate in other situations, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize 
the subject or may require medical or surgical intervention to prevent one of the 
other outcomes listed in the above definition. These should also be considered 
serious. Examples of such events are invasive or malignant cancers, intensive 
treatment in an emergency room or at home for allergic bronchospasm, blood 


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dyscrasias or convulsions that do not result in hospitalization, or development of 
drug dependency or drug abuse. 
g. Protocol-Specific SAEs 
 
All events of possible drug-induced liver injury with hyperbilirubinaemia 
defined as ALT  3xULN and bilirubin  2xULN (>35% direct) (or ALT  
3xULN and INR>1.5, if INR measured) termed ‘Hy’s Law’ events (INR 
measurement is not required and the threshold value stated will not apply to 
patients receiving anticoagulants). 
 
NOTE: bilirubin fractionation is performed if testing is available. If testing is 
unavailable, record presence of detectable urinary bilirubin on dipstick 
indicating direct bilirubin elevations and suggesting liver injury. If testing is 
unavailable and a subject meets the criterion of total bilirubin  2xULN, then the 
event is still reported as an SAE. If INR is obtained, include values on the SAE 
form. INR elevations >1.5 suggest severe liver injury.  
8.4.4.3. 
Laboratory and Other Safety Assessment Abnormalities Reported as 
AEs and SAEs 
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis), or 
other safety assessments (e.g., ECGs, radiological scans, vital signs measurements) 
including those that worsen from baseline, and events  felt to be clinically significant in 
the medical and scientific judgment of the investigator are to be recorded as an AE or 
SAE, in accordance with the definitions provided.   
In addition, an associated AE or SAE is to be recorded for any laboratory test result or 
other safety assessment that led to an intervention, including permanent discontinuation 
of study treatment, dose reduction, and/or dose interruption/delay.   
Any new primary cancer must be reported as an SAE. 
However, any clinically significant safety assessments that are associated with the 
underlying disease, unless judged by the investigator to be more severe than expected for 
the subject's condition, are not to be reported as AEs or SAEs.   
8.4.4.4. 
Cardiovascular Events 
Investigators will be required to fill out event specific data collection tools for the 
following AEs and SAEs:   
 Myocardial infarction/unstable angina 
 Congestive heart failure 
 Arrhythmias 
 Valvulopathy 
 Pulmonary hypertension 
 Cerebrovascular events/stroke and transient ischemic attack 


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 Peripheral arterial thrombosis 
 Deep Venous Thrombosis 
 Revascularization 
This information should be recorded within one week of when the AE/SAE(s) are first 
reported. 
8.4.4.5. 
Death Events 
In addition, all deaths, whether or not they are considered SAEs, will require a specific 
death data collection tool to be completed.  The death data collection tool includes 
questions regarding cardiovascular (CV) (including sudden cardiac death) and 
noncardiovascular death. 
This information should be recorded within one week of when the death is first reported. 
8.4.4.6. 
Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as SAEs 
8.4.4.6.1. Cohort A (MDS/AML Adult Subjects) 
An event which is part of the natural course of the disease under study (i.e., infections, 
cachexia, anorexia, disease progression or hospitalization due to disease progression) 
should not be reported as an AE or SAE. If the clinical course is worse than that which 
would normally be expected for the subject, or if the investigator considers that there was 
a causal relationship between treatment with study medication(s) or protocol 
design/procedures to the course of the underlying disease, then this must be reported as 
an SAE.  Furthermore, death due to disease under study is to be recorded on the Death 
CRF form and the specific cause of death must be recorded (e.g. sepsis, gastrointestinal 
hemorrhage, etc), rather than ‘disease under study’ or ‘progressive disease’.     
8.4.4.6.2. Cohort B and Cohort C (ITP Adult and Pediatric Subjects) 
During the assessment period, thrombocytopenia that results in the administration of 
rescue medication is to be considered treatment failure rather than AEs or SAEs.  Also 
during this assessment period, hospital admissions that are attributable to such treatment 
failures or related therapy also do not qualify as AEs or SAEs.  Hemorrhagic 
complications of thrombocytopenia not otherwise meeting regulatory serious criteria (see 
Section 8.4.4.2. Definition of a SAE) will be reported as AEs. 
8.4.5. 
Time Period and Frequency of Detecting AEs and SAEs 
The investigator or site staff is responsible for detecting, documenting and reporting 
events that meet the definition of an AE or SAE.  
AEs will be collected from the time of ICF signature until 30 days following 
discontinuation of study treatment regardless of initiation of a new cancer therapy or 
transfer to hospice.  


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SAEs will be collected over the same time period as stated above for AEs.  In addition, 
any SAE assessed as related to study participation (e.g., protocol-mandated procedures, 
invasive tests, or change in existing therapy), will be reported promptly to Novartis 
within 24 hours, as indicated in Section 8.4.7. 
After discontinuation of study treatment, the investigator will monitor all AEs/SAEs that 
are ongoing until resolution or stabilization of the event or until the subject is lost to 
follow-up.  At any time after 30 days the investigator may report any adverse event that 
they believe possibly related to study treatment.    
8.4.6. 
Method of Detecting AEs and SAEs 
Care must be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended 
and non-leading verbal questioning of the subject is the preferred method to inquire about 
AE occurrence. Appropriate questions include: 
“How are you feeling?” or for pediatric studies, “How does your child seem to feel?” 
“Have you had any (other) medical problems since your last visit/contact?” or for 
pediatric studies, “Has your child had any (other) medical problems or seem to act 
differently in any way since his/her last visit/contact?” 
“Have you taken any new medicines, other than those provided in this study, since your 
last visit/contact?” or for pediatric studies, ”Has your child needed to take any medicines, 
other than those provided in this study, since his/her last visit/contact?” 
8.4.7. 
Prompt Reporting of SAEs and Other Events to Novartis 
SAEs, pregnancies, and liver function abnormalities meeting pre-defined criteria will be 
reported promptly by the investigator to Novartis as described in the following table once 
the investigator determines the event meets the protocol definition for that event. 


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Initial Reports 
Follow-up Information on a 
Previous Report 
Type of Event 
Time Frame 
Documents 
Time Frame 
Documents 
All SAEs 
24 hours 
SAE data 
collection tool 
“CV events” 
and/or “death” 
data collection 
tool(s) if 
applicable 
 
24 hours 
Updated SAE data 
collection tool  
“CV events” 
and/or “death” 
data collection 
tool(s) if 
applicable 
Pregnancy 
24 hours 
Pregnancy 
Notification Form 
2 Weeks 
Pregnancy Follow 
up Form 
Liver chemistry abnormalities: 
ALT3xULN and 
bilirubin2xULN 
(>35% direct) (or 
ALT3xULN and 
INR>1.5, if INR 
measured) c 
24 hoursa  
SAE data 
collection tool. 
Liver Event Case 
Report Form 
(CRF) and liver 
imaging and/or 
biopsy CRFs if 
applicableb  
24 hours 
Updated SAE data 
collection tool. 
Updated Liver 
Event CRFb 
ALT5xULN; 
ALT3xULN with 
hepatitis or rash or 
3xULN 4 weeks 
 
24 hoursa 
Liver Event CRFb 
24 hours 
Updated Liver 
Event CRFb 
ALT3xULN and 
<5xULN and bilirubin 
<2xULN 
24 hoursa 
Liver Event CRF 
does not need 
completing unless 
elevations persist  
for 4 weeks or 
subject cannot be 
monitored weekly 
for 4 weeksb 
 
 
a) Novartis to be notified at onset of liver chemistry elevations to discuss subject safety. 
b) Liver Event Documents (i.e., “Liver Event CRF” and “Liver Imaging CRF” and/or “Liver Biopsy CRF”, as 
applicable) should be completed as soon as possible 
c) 
INR measurement is not required; if measured, the threshold value stated will not apply to subjects receiving 
anticoagulants. 
 
Methods for recording, evaluating, and following up on AEs and SAES and procedures 
for completing and transmitting SAE reports to Novartis are provided in the SPM.  
Procedures for post-study AEs/SAEs are provided in the SPM. 
Prompt notification of SAEs by the investigator to Novartis is essential so that legal 
obligations and ethical responsibilities towards the safety of subjects are met. 


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Novartis has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a product under clinical investigation.  Novartis 
will comply with country specific regulatory requirements relating to safety reporting to 
the regulatory authority, Institutional Review Board (IRB)/Independent Ethics 
Committee (IEC) and investigators. 
Investigator safety reports are prepared for suspected unexpected serious adverse 
reactions according to local regulatory requirements and Novartis policy and are 
forwarded to investigators as necessary. 
An investigator who receives an investigator safety report describing a SAE(s) or other 
specific safety information (e.g., summary or listing of SAEs) from Novartis will file it 
with the IB and will notify the IRB/IEC, if appropriate according to local requirements. 
8.4.8. 
Pregnancy, Testing, Prevention and Reporting 
Clear documentation of post-menopausal status (as defined in Section 8.4.8.1.) must be 
included in each subject’s source documents as applicable.  Female subjects with this 
documentation of post-menopausal status are considered to be of non-childbearing 
potential and do not need to have pregnancy tests performed during this trial.  Female 
subjects without documentation of post-menopausal status are considered to be of 
childbearing potential and will be required to undergo pregnancy testing at the Transition 
Visit and prior to first study treatment. 
In the event that a pregnancy does occur, the subject will be immediately withdrawn from 
the study.  The subject will receive counselling from the investigator or his/her designee, 
regarding the nature of the study treatment and the potential risk on fetal development. 
8.4.8.1. 
Pregnancy Testing and Prevention 
The need for a screening pregnancy test depends on whether a female subject is of 
childbearing potential or non-childbearing potential. 
A female of non-childbearing potential (i.e., physiologically incapable of becoming 
pregnant) is defined as any female who is pre menarchal, or who has had a hysterectomy, 
bilateral oophorectomy (ovariectomy) or bilateral tubal ligation, or is post-menopausal. 
A practical definition accepts menopause after 1 year without menses with an appropriate 
clinical profile, e.g., age appropriate, >45 years in the absence of hormone replacement 
therapy (HRT).  In questionable cases, the subject must have a follicle stimulating 
hormone (FSH) value >40 mIU/mL and an estradiol value < 40pg/mL (<140 pmol/L). 
Postmenopausal status must be documented in the subject’s source documentation. 
A female of child-bearing potential is defined as any female who does not meet the 
criteria of non-childbearing potential as described in the previous paragraph.  
If a female subject is of childbearing potential, she must have a serum -HCG pregnancy 
test performed within 14 days prior to the first dose of study treatment. Subjects with a 
positive pregnancy test result must be excluded from the study. Subjects with a negative 


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pregnancy test result must agree to use an effective contraception method as described 
below during the study until 28 days following the last dose of study treatment. 
Novartis acceptable contraceptive methods, when used consistently and in accordance 
with both the product label and the instructions of the physician, are as follow: 
 
An intrauterine device with a documented failure rate of less than 1% per year. 
 
Vasectomized partner who is sterile prior to the female subject’s entry and is the sole 
sexual partner for that female. 
 
Complete abstinence from sexual intercourse for 14 days prior to first dose of study 
treatment, through the dosing period, and for at 28 days after the last dose of study 
treatment. 
 
Double-barrier contraception: condom and occlusive cap (diaphragm or 
cervical/vault caps) with a vaginal spermicidal agent (foam/gel/cream/suppository). 
 
Implants of levonorgestrel where not contraindicated for this patient population or 
per local practice.   
 
Injectable progesterone where not contraindicated for this patient population or per 
local practice.  
 
Oral contraceptives (either combined or progesterone only) where not 
contraindicated for this patient population or per local practice. 
Female subjects who are lactating must discontinue nursing prior to the first dose of study 
treatment and must refrain from nursing throughout the treatment period and 28 days 
following the last dose of study treatment. 
8.4.8.2. 
Pregnancy Reporting 
Any pregnancy that occurs during study participation must be reported using a clinical 
trial pregnancy form.  To ensure subject safety, each pregnancy must be reported to 
Novartis within 24 hours of learning of its occurrence.  The pregnancy must be followed 
up to determine outcome (including premature termination) and status of mother and 
child.  Pregnancy complications and elective terminations for medical reasons must be 
reported as an AE or SAE.  Spontaneous abortions must be reported as an SAE. 
Any SAE occurring in association with a pregnancy brought to the investigator’s 
attention after the subject has completed the study and considered by the investigator as 
possibly related to the study treatment, must be promptly reported to Novartis. 
In addition, the investigator must attempt to collect pregnancy information on any female 
partners of male study subjects who become pregnant while the subject is enrolled in the 
study.  Pregnancy information must be reported to Novartis as described above. 


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9. 
DATA MANAGEMENT 
For this study, subject data will be entered into the electronic case report forms (eCRFs), 
transmitted electronically to Novartis or designee and be combined with data provided 
from other sources in a validated data system.   
Management of clinical data will be performed in accordance with applicable Novartis 
standards and data cleaning procedures to ensure the integrity of the data, e.g., resolving 
errors and inconsistencies in the data.  Adverse events and concomitant medications 
terms will be coded using the Medical Dictionary for Regulatory Authorities (MedDRA) 
and a custom drug dictionary. Electronic case report forms (including queries and audit 
trails) will be retained by Novartis, and copies will be sent to the investigator to maintain 
as the investigator copy. 
In all cases, subject initials will not be collected or transmitted to Novartis according to 
Novartis policy. 
10. 
DATA ANALYSIS AND STATISTICAL CONSIDERATIONS 
10.1. 
Hypotheses 
No statistical hypotheses are being tested.  Only descriptive methods will be used to 
summarize of the data obtained from this study. 
10.2. 
Study Design Considerations 
10.2.1. 
Sample Size Considerations 
The sample size will be based on the number of subjects completing their parent study of 
eltrombopag who are eligible for inclusion in this rollover study. 
10.2.2. 
Sample Size Re-estimation 
Sample size re-estimation is not planned for this study. 
10.3. 
Data Analysis Considerations 
10.3.1. 
Analysis Populations 
The All Treated Subjects (ATS) Population will consist of all subjects that receive at least 
one dose of eltrombopag on this study.  All data will be evaluated based on this 
population. 
10.3.2. 
Analysis Data Sets 
Construction of data sets relating to the reporting and analysis of study data will be 
performed in accordance with applicable Novartis standards and procedures. 


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10.3.3. 
Interim Analysis 
Data will be summarized whenever a sufficient number of subjects in each cohort has 
accrued to warrant the evaluation of safety data.  This will be determined by the study 
team and may occur multiple times.  No decisions will be made at the time of interim 
analyses to alter the study in any way. All available data at the time of an interim analysis 
will be included. 
10.3.4. 
Key Elements of Analysis Plan 
Data will be listed and summarized according to the Novartis reporting standards, where 
applicable.  Complete details will be documented in the Reporting and Analysis Plan 
(RAP).  Any deviations from, or additions to, the original analysis plan described in this 
protocol will be documented in the RAP and final study report. 
As it is anticipated that accrual will be spread thinly across centers and summaries of data 
by center would be unlikely to be informative, data from all participating centers will be 
pooled prior to analysis.   
All data up to the time of study completion/withdrawal from study will be included in the 
analysis, regardless of duration of treatment.   
As the duration of treatment for a given subject will depend on efficacy and tolerability, 
the duration of follow-up will vary between subjects.  Consequently there will be no 
imputation for missing data.  
As this is an open label, single arm study, no statistical comparisons will be made.  Data 
will be summarized where appropriate. 
Demographic and baseline characteristics will be summarized. 
10.3.4.1. 
Safety Analyses 
Safety assessments are described in Section 3 and Section 8.4. 
The ATS population will be used for the analysis of safety data. Complete details of the 
safety analyses will be provided in the RAP. 
The number of subjects administered study medication will be summarized according to 
the duration of therapy. 
10.3.4.1.1. Adverse Events 
Adverse events (AEs) will be coded using the standard MedDRA and grouped by system 
organ class. AEs will be graded by the investigator according to the National Institutes of 
Health (NCI)-CTCAE (version 4.0).   
Events will be summarized by frequency and proportion of total subjects, by system 
organ class and preferred term. Separate summaries will be given for all AEs, drug-
related AEs, serious AEs and AEs leading to discontinuation of study medication. 


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If the AE is listed in the NCI CTCAE (version 4.0) table, the maximum grade will be 
summarized. 
Characteristics (e.g. number of occurrences, action taken, grade, etc) of the following 
AEs of special interest may be summarized separately: hepatotoxicity and 
thromboembolism.  
The incidence of deaths and the primary cause of death will be summarized. 
10.3.4.1.2. Clinical Laboratory Evaluations 
Hematology and clinical chemistry data will be summarized at each scheduled 
assessment according to NCI CTCAE grade (version 4.0).  The proportion of values lying 
outside the reference range will also be presented for laboratory tests that are not graded 
because there are no associated NCI CTCAE criteria.  Summaries will include data from 
scheduled assessments only, and all data will be reported according to the nominal visit 
date for which it was recorded (i.e. no visit windows will be applied).  Unscheduled data 
will be included in “overall” and “any post-screening” summaries which will capture a 
worst case across all scheduled and unscheduled visits post first dose of study 
medication.  Further details will be provided in the RAP. 
11. 
STUDY CONDUCT CONSIDERATIONS 
11.1. 
Posting of Information on Publicly Available Clinical Trial 
Registers 
Study information from this protocol will be posted on publicly available clinical trial 
registers before enrolment of subjects begins  
11.2. 
Regulatory and Ethical Considerations, Including the 
Informed Consent Process 
Prior to initiation of a study site, Novartis will obtain favourable opinion/approval from 
the appropriate regulatory agency to conduct the study in accordance with ICH Good 
Clinical Practice (GCP) and applicable country-specific regulatory requirements. 
The study will be conducted in accordance with all applicable regulatory requirements. 
The study will be conducted in accordance with ICH Good Clinical Practice (GCP), all 
applicable subject privacy requirements, and the ethical principles that are outlined in the 
Declaration of Helsinki 2008, including, but not limited to: 
 
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) review and 
favourable opinion/approval of study protocol and any subsequent amendments. 
 
Subject informed consent. 
 
Investigator reporting requirements. 


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Novartis will provide full details of the above procedures, either verbally, in writing, or 
both. 
Written informed consent must be obtained from each subject prior to participation in the 
study. 
11.3. 
Quality Control (Study Monitoring) 
In accordance with applicable regulations, GCP, and Novartis procedures, Novartis 
personnel (or designated Clinical Research Organization [CRO]) will contact the site  
prior to the start of the study to review with the site staff the protocol, study requirements, 
and their responsibilities to satisfy regulatory, ethical, and Novartis requirements.  When 
reviewing data collection procedures, the discussion will include identification, 
agreement and documentation of data items for which the eCRF will serve as the source 
document. 
The investigator and the head of the medical institution (where applicable) agrees to 
allow Novartis (or designated CRO) personnel direct access to all relevant documents and 
to allocate their time and the time to their staff to monitor to discuss findings and any 
issues. 
Novartis (or designated CRO) personnel will monitor the study to ensure that the: 
 
Data are authentic, accurate, and complete. 
 
Safety and rights of subjects are being protected. 
 
Study is conducted in accordance with the currently approved protocol and any other 
study agreements, ICH GCP, and all applicable regulatory requirements. 
11.4. 
Quality Assurance 
To ensure compliance with ICH GCP and all applicable regulatory requirements, 
Novartis may conduct quality assurance assessment and/or audit of the site. Regulatory 
agencies may conduct a regulatory inspection at any time during or after completion of 
the study.  In the event of an assessment, audit or inspection, the investigator (and 
institution) must agree to grant the advisor(s), auditor(s) and inspector(s) direct access to 
all relevant documents and to allocate their time and the time of their staff to discuss the 
conduct of the study, any findings/relevant issues and to implement any corrective and/or 
preventative actions to address any findings/issues identified. 
11.5. 
Study and Site Closure 
Upon completion or termination of the study, Novartis personnel (or designated CRO) 
will conduct site closure activities with the investigator or site staff (as appropriate), in 
accordance with applicable regulations, ICH GCP, and Novartis Standard Operating 
Procedures. 
Novartis reserves the right to temporarily suspend or terminate the study at any time for 
reasons including (but not limited to) safety issues, ethical issues, or severe 


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noncompliance.  If Novartis determines that such action is required, Novartis will discuss 
the reasons for taking such action with the investigator or head of the medical institution 
(where applicable).  When feasible, Novartis will provide advance notice to the 
investigator or head of the medical institution of the impending action. 
If a study is suspended or terminated for safety reasons, Novartis will promptly inform 
all investigators, heads of the medical institutions (where applicable),and/or institutions 
conducting the study.  Novartis will also promptly inform the relevant regulatory 
authorities of the suspension/termination along with the reasons for such action.  Where 
required by applicable regulations, the investigator or head of the medical institution 
must inform the IRB/IEC promptly and provide the reason(s) for the 
suspension/termination. 
11.6. 
Records Retention 
Following closure of the study, the investigator or head of the medical institution (where 
applicable) must maintain all site study records (except for those required by local 
regulations to be maintained elsewhere) in a safe and secure location.  The records must 
be easily accessible when needed (e.g., for a Novartis audit or regulatory inspection) and 
must be available for review in conjunction with assessment of the facility, supporting 
systems, and relevant site staff. 
Where permitted by local laws/regulations or institutional policy, some or all of the 
records may be maintained in a format other than hard copy (e.g., microfiche, scanned, 
electronic); however, caution must be exercised before such action is taken.  The 
investigator must ensure that all reproductions are legible and are a true and accurate 
copy of the original.  In addition, they must meet accessibility and retrieval standards, 
including regeneration of a hard copy, if required.  The investigator must also ensure that 
an acceptable back-up of the reproductions exists and that there is an acceptable quality 
control procedure in place for creating the reproductions. 
 
Essential documents (written and electronic) should be retained for a period of not less 
than fifteen (15) years from the completion of the Clinical Trial unless the 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. 
The investigator must notify Novartis of any changes in the archival arrangements, 
including, but not limited to archival of records at an off-site facility or transfer of 
ownership of the records in the event that the investigator is no longer associated with the 
site. 
11.7. 
Provision of Study Results to Investigators, Posting of 
Information on Publicly Available Clinical Trials Registers and 
Publication 
Where required by applicable regulatory requirements, an investigator signatory will be 
identified for the approval of the clinical study report.  The investigator will be provided 


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reasonable access to statistical tables, figures, and relevant reports and will have the 
opportunity to review the complete study results at a Novartis site or other mutually-
agreeable location. 
Novartis will also provide the investigator with the full summary of the study results.  
The investigator is encouraged to share the summary results with the study subjects, as 
appropriate. 
Novartis aims to post a results summary will be posted to the Novartis Clinical Trials 
Results website (www.novartisclinicaltrials.com) no later than twelve (12) months after 
the last subject’s last visit (LSLV).  In addition, upon study completion and finalization 
of study report, Novartis aims to submit results of the study for publication. 
When publication is not feasible, please refer to the Novartis Clinical Trial Results 
website (www.novartisclinicaltrials.com) for a summary of the trial results.  


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12. 
REFERENCES 
Bennett JM.  Consensus Statement on Iron Overload in Myelodysplastic Syndromes.  
American Journal of Hematology. 2008; 83:858-861. 
GlaxoSmithKline Document Number UM2005/00217/08. Clinical Investigator’s 
Brochure for SB496115-GR. Version 10. Effective date April 23, 2013. 
James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, Davern TJ, Lee 
WM. Pharmacokinetics of Acetaminophen-Protein Adduct in Adults with 
Acetaminophen Overdose and Acute Liver Failure. Drug Metab Dispos 2009; 37(8): 
1779-1784.  
Le Gal F, Gordien E, Affolabi D, Hanslik T, Alloui C, Dény P, Gault E.  Quantification 
of Hepatitis Delta Virus RNA in Serum by Consensus Real-Time PCR Indicates 
Different Patterns of Virological Response to Interferon Therapy in Chronically Infected 
Patients.  Clin Microbiol. 2005;43(5):2363–2369. 


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13. 
APPENDICES 
13.1. 
Appendix 1 
Time and Events Table 
Procedures 
Transition 
Visit1 
Treatment 
End of Therapy 
Follow-up 
  
  
Weekly/Bi-weekly/Monthly/Bi-
Monthly 
End of Treatment or Early 
Withdrawal  
 
(+7 days) 
30 Days after last study 
treatment  
 
(+7 days) 
Visit Window Per Figure 1 of 
the Protocol 
Informed Consent2 
X 
 
 
 
Inclusion/Exclusion criteria 
X 
 
 
 
Demographic and Parent Study Data 
X 
 
 
 
Physical Examination3 
X 
X 
X 
X 
12-lead ECG 
X 
 
 
 
Concomitant Medication 
X 
X 
X 
 
Adverse Events 
X 
X 
X 
X 
Serious Adverse Events 
X 
X 
X 
X 
Hematology 
X 
X 
X 
X 
Clinical Chemistry4 
X 
X 
X 
X 
Pregnancy test (serum) 5 
X 
○ 
○ 
○ 
Bone Marrow Examination 6 
○
○ 
○ 
○ 
Blood and Blood Supportive Care 
Products 
X 
X 
X 
X 
Disease Response/Progression7 
○ 
○ 
○ 
○ 
Dispense Study Treatment 
X 
X 
 
 
Assess Study Treatment Compliance 
 
X 
X 
 
○ is used to indicate a study procedure is not required at the visit; however, it should be documented in the individual eCRF if it has been performed. 


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            Protocol No. 200170 
 
 
1. All subjects transitioning from parent study will begin this rollover study based on the last day of the study treatment completed during the parent study.  All 
Transition Visit assessments/procedures must be completed prior to the first dose of study treatment in this study.  The Transition Visit must occur within 28 days 
of the end of the last day of the study treatment and may be on the same day as the last study treatment visit of the parent study. Assessments/procedures may 
be used to fulfill the requirements of both the parent study and this study.   
2. Informed consent must be obtained prior to performing any assessments or procedures for this study and before treatment with eltrombopag in this study. 
3. PI must document that subject is acceptable to continue study treatment in the subject’s source documents. 
4. Refer to Table 5 for complete list of clinical laboratory assessments to be performed. 
5. To be performed prior to first study treatment and at the investigators discretion. Pregnancy test only performed in women of child-bearing potential (Section 
8.4.8.1).  Subjects with documentation in source records of post-menopausal status do not need to have any pregnancy tests performed. 
6. To be done as per local SOC and at disease progression in Cohort A. Data to be entered into eCRF when procedures are performed.  
7. Collected in Cohort A subjects only when assessed as per SOC. 
 
 
 


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13.2. 
Appendix 2 
Liver Chemistry Monitoring, Interruption, 
Stopping and Follow-up Criteria 
Figure 2 
Liver Safety Algorithm 
 
  






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Initial Reports 
Follow-up Information on a 
Previous Report 
Type of Event 
Time Frame 
Documents 
Time Frame 
Documents 
All SAEs 
24 hours 
SAE data 
collection tool 
“CV events” 
and/or “death” 
data collection 
tool(s) if 
applicable 
 
24 hours 
Updated SAE data 
collection tool  
“CV events” 
and/or “death” 
data collection 
tool(s) if 
applicable 
Pregnancy 
2 Weeks 
Pregnancy 
Notification Form 
2 Weeks 
Pregnancy Follow 
up Form 
 
REVISED TEXT 
 
Initial Reports 
Follow-up Information on a 
Previous Report 
Type of Event 
Time Frame 
Documents 
Time Frame 
Documents 
All SAEs 
24 hours 
SAE data 
collection tool 
“CV events” 
and/or “death” 
data collection 
tool(s) if 
applicable 
 
24 hours 
Updated SAE data 
collection tool  
“CV events” 
and/or “death” 
data collection 
tool(s) if 
applicable 
Pregnancy 
2 Weeks24 ho
urs 
Pregnancy 
Notification Form 
2 Weeks 
Pregnancy Follow 
up Form 
 
Section 8.4.8.2 Pregnancy Reporting 
PREVIOUS TEXT: 
Any pregnancy that occurs during study participation must be reported using a clinical 
trial pregnancy form.  To ensure subject safety, each pregnancy must be reported to GSK 
within 2 weeks of learning of its occurrence.  The pregnancy must be followed up to 
determine outcome (including premature termination) and status of mother and child.  
Pregnancy complications and elective terminations for medical reasons must be reported 
as an AE or SAE.  Spontaneous abortions must be reported as an SAE. 
REVISED TEXT: 
Any pregnancy that occurs during study participation must be reported using a clinical 
trial pregnancy form.  To ensure subject safety, each pregnancy must be reported to GSK 


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within 2 weeks24 hours of learning of its occurrence.  The pregnancy must be followed 
up to determine outcome (including premature termination) and status of mother and 
child.  Pregnancy complications and elective terminations for medical reasons must be 
reported as an AE or SAE.  Spontaneous abortions must be reported as an SAE. 
Section 9 Data Management 
PREVIOUS TEXT:  
For this study, subject data will be entered into GSK defined electronic case report forms 
(eCRFs), transmitted electronically to GSK or designee and combined with data provided 
from other sources in a validated data system.   
Management of clinical data will be performed in accordance with applicable GSK 
standards and data cleaning procedures to ensure the integrity of the data, e.g., removing 
errors and inconsistencies in the data.  Adverse events and concomitant medications 
terms will be coded using Medical Dictionary for Regulatory Authorities (MedDRA) and 
an internal validated medication dictionary, GSKDrug. Electronic case report forms 
 (including queries and audit trails) will be retained by GSK, and copies will be sent to 
the investigator to maintain as the investigator copy. 
In all cases, subject initials will not be collected or transmitted to GSK according to GSK 
policy. 
REVISED TEXT: 
For this study, subject data will be entered into GSK defined the electronic case report 
forms (eCRFs), transmitted electronically to GSK or designee and be combined with data 
provided from other sources in a validated data system.   
Management of clinical data will be performed in accordance with applicable GSK 
Novartis standards and data cleaning procedures to ensure the integrity of the data, e.g., 
removing resolving errors and inconsistencies in the data.  Adverse events and 
concomitant medications terms will be coded using the Medical Dictionary for 
Regulatory Authorities (MedDRA) and an internal validated medication a custom drug 
dictionary, GSKDrug. Electronic case report forms (including queries and audit trails) 
will be retained by GSKNovartis, and copies will be sent to the investigator to maintain 
as the investigator copy. 
In all cases, subject initials will not be collected or transmitted to GSKNovartis 
according to GSKNovartis policy. 
Section 11.3 Quality Control (Study Monitoring) 
PREVIOUS TEXT: 
In accordance with applicable regulations, GCP, and GSK procedures, the site will be 
contacted prior to the start of the study to review with the site staff the protocol, study 


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requirements, and their responsibilities to satisfy regulatory, ethical, and GSK 
requirements.  When reviewing data collection procedures, the discussion will include 
identification, agreement and documentation of data items for which the eCRF will serve 
as the source document. 
The investigator and the head of the medical institution (where applicable) agrees to 
allow the monitor direct access to all relevant documents and to allocate their time and 
the time to their staff to monitor to discuss findings and any issues. 
GSK will monitor the study to ensure that the: 
 
… 
REVISED TEXT: 
In accordance with applicable regulations, GCP, and GSK Novartis procedures, 
Novartis personnel (or designated Clinical Research Organization [CRO]) will 
contact the site will be contacted prior to the start of the study to review with the site 
staff the protocol, study requirements, and their responsibilities to satisfy regulatory, 
ethical, and GSK Novartis requirements.  When reviewing data collection procedures, 
the discussion will include identification, agreement and documentation of data items for 
which the eCRF will serve as the source document. 
The investigator and the head of the medical institution (where applicable) agrees to 
allow the monitorNovartis (or designated CRO) personnel direct access to all relevant 
documents and to allocate their time and the time to their staff to monitor to discuss 
findings and any issues. 
GSK Novartis (or designated CRO) personnel will monitor the study to ensure that the: 
 
… 
Section 11.5 Study and Site Closure 
PREVIOUS TEXT: 
Upon completion or termination of the study, the monitor will conduct site closure 
activities with the investigator or site staff (as appropriate), in accordance with applicable 
regulations, ICH GCP, and GSK Standard Operating Procedures. 
REVISED TEXT: 
Upon completion or termination of the study, the monitorNovartis personnel (or 
designated CRO) will conduct site closure activities with the investigator or site staff (as 
appropriate), in accordance with applicable regulations, ICH GCP, and GSKNovartis 
Standard Operating Procedures. 
Section 11.6 Records Retention 
PREVIOUS TEXT: 


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GSK will inform the investigator of the time period for retaining the site records in order 
to comply with all applicable regulatory requirements.  The minimum retention time will 
meet the strictest standard applicable to a particular site, as dictated by local 
laws/regulations, GSK standard operating procedures, and/or institutional requirements. 
The investigator must notify GSK of any changes in the archival arrangements, including, 
but not limited to archival of records at an off-site facility or transfer of ownership of the 
records in the event that the investigator is no longer associated with the site. 
REVISED TEXT: 
GSK will inform the investigator of the time period for retaining the site records in order 
to comply with all applicable regulatory requirements.  The minimum retention time will 
meet the strictest standard applicable to a particular site, as dictated by local 
laws/regulations, GSK standard operating procedures, and/or institutional requirements. 
Essential documents (written and electronic) should be retained for a period of not 
less than fifteen (15) years from the completion of the Clinical Trial unless the 
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. 
The investigator must notify GSKNovartis of any changes in the archival arrangements, 
including, but not limited to archival of records at an off-site facility or transfer of 
ownership of the records in the event that the investigator is no longer associated with the 
site. 
Section 11.7 Provision of Study Results to Investigators, Posting of Information on 
Publicly Available Clinical Trials Registers and Publication 
PREVIOUS TEXT: 
The results summary will be posted to the Clinical Study Register no later than eight 
months after the final primary completion date, the date that the final subject was 
examined or received an intervention for the purposes of final collection of data for the 
primary outcome.  In addition, a manuscript will be submitted to a peer reviewed journal 
for publication no later than 18 months after the last subject’s last visit (LSLV).  When 
manuscript publication in a peer reviewed journal is not feasible, a statement will be 
added to the register to explain the reason for not publishing. 
When manuscript publication in a peer-reviewed journal is not feasible, further study 
information will be posted to the GSK Clinical Study Register to supplement the results 
summary.  
REVISED TEXT: 
Novartis aims to post aThe results summary will be posted to the Novartis Clinical 
Study RegisterTrials Results website (www.novartisclinicaltrials.com) no later than 
twelve (12) eight months after the last subject’s last visit (LSLV)final primary 


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completion date, the date that the final subject was examined or received an intervention 
for the purposes of final collection of data for the primary outcome.  In addition, upon 
study completion and finalization of study report, Novartis aims to submit results of 
the study a manuscript will be submitted to a peer reviewed journal for publication no 
later than 18 months after the last subject’s last visit (LSLV).  When manuscript 
publication in a peer reviewed journal is not feasible, a statement will be added to the 
register to explain the reason for not publishing. 
When manuscript publication in a peer reviewed journal is not feasible, further study 
information will be postedplease refer to the GSKNovartis Clinical Study Register Trial 
Results website for a summary of the trialto supplement the results summary.  

SAP_001.pdf: 


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CETB115A2X01B
Document History – Changes compared to previous final version of SAP
Date
Time 
point
Reason for update
Outcome for update
Section and title 
impacted 
(Current)
30-Jun-2017
Prior to 
LPLV
N/A – Initial version
N/A
N/A
14-Feb-2018
Prior 
LPLV
Amendment 1
Added outputs for 
laboratory data and 
listings for ECG and 
vital signs
All
08-Mar-2022
Prior to 
DBL
Amendment 2
Removed analyses for 
Cohort C, since no 
pediatric subjects have 
been enrolled.
Protocol deviations will
be listed, since data has 
been collected after all.
Added tables/listings for 
adverse events of 
special interest.
Platelet counts over 
time will only be 
summarized by a table 
due to small sample 
sizes.
Removed
corresponding 
analyses/listings.
All, in particular 
2.1. Data analysis 
general 
information
2.4.1 
Study/Treatment 
Compliance
2.7.1 Adverse 
events
2.7.3 Laboratory 
data
2.3.2 subject 
demographics and 
other baseline 
characteristics / 
2.7.3 Laboratory 
data / 2.7.4 Other 
safety data
LPLV: Last patient last visit
DBL: Data Base Lock


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Table of contents
Table of contents .................................................................................................................3
List of abbreviations...................................................................................................................4
1.
Introduction .........................................................................................................................5
1.1
Study design.............................................................................................................5
1.2
Study objectives and endpoints ...............................................................................6
2
Statistical methods...............................................................................................................6
2.1
Data analysis general information ...........................................................................6
2.1.1
General definitions..................................................................................6
2.2
Analysis sets ............................................................................................................8
2.3
Subject disposition, demographics and other baseline characteristics ....................8
2.3.1
Subject disposition ..................................................................................8
2.3.2
Subject demographics and other baseline charateristics .........................9
2.4
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance)..............................................................................................................9
2.4.1
Study treatment / compliance..................................................................9
2.4.2
Prior, concomitant and post therapies.....................................................9
2.5
Analysis of the primary objective............................................................................9
2.6
Analysis of the secondary objectives.......................................................................9
2.7
Safety analyses.........................................................................................................9
2.7.1
Adverse events (AEs)..............................................................................9
2.7.2
Deaths....................................................................................................11
2.7.3
Laboratory data .....................................................................................11
2.7.4
Other safety data ...................................................................................11
2.8
Pharmacokinetic endpoints....................................................................................11
2.9
Patient-reported outcomes .....................................................................................12
2.10
Biomarkers.............................................................................................................12
2.11
Other Exploratory analyses....................................................................................12
2.12
Interim analysis......................................................................................................12
3
Sample size calculation .....................................................................................................12
4
Change to protocol specified analyses ..............................................................................12
5
References .........................................................................................................................12
6
Appendix ...........................................................................................................................13
6.1
Imputation rules.....................................................................................................13


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List of abbreviations
AE
AESI
ATS
Adverse Event
Adverse Event of Special Interest
All treated subjects
CSR
Clinical study report
eCRF
eCRS
Electronic Case Report Form
Case Retrieval Strategy
GSK
GlaxoSmithKline
MedDRA
Medical Dictionary for Regulatory Activities
PT
Preferred Term
SAE
Serious Adverse Event
SAP
SMQ
Statistical analysis plan
Standardized MedDRA query
SoC
Standard of care


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1.
Introduction
This first amendment of the statistical analysis plan (SAP) provides detailed statistical 
methodology for the analyses of data which will be used for preparation of the 
CETB115A2X01B (study 200170) clinical study report (CSR) and is based on the study 
protocol amendment 01, dated 06-Apr-2016.
This is a multi-center, non-randomized, open-label, phase IV, rollover study conducted in 
subjects who are currently participating in a Novartis sponsored investigational study with 
eltrombopag (i.e. parent study such as TRC114968/ASPIRE or TRA105325/EXTEND), and 
are receiving clinical benefit without unacceptable toxicity. 
All decisions regarding final analyses, as defined in the SAP document, have been made prior 
to database lock.
Last Patient Last Visit was achieved on 23-Feb-2022. In total, data of 22 subjects will be 
analysed.
1.1
Study design
This Phase IV, multicenter, non-randomized, open-label, uncontrolled, rollover study is
designed to provide continued access to eltrombopag to subjects who are currently participating 
in a Novartis sponsored investigational study of eltrombopag (parent study), and are receiving 
clinical benefit without unacceptable toxicity. Enrollment into this study will be dependent upon 
the mutual agreement between Novartis and a site to participate in this study. Subjects will be 
enrolled into three cohorts (cohort A, cohort B and cohort C) based upon the disease under study 
in their parent study(e.g. myelodysplastic syndrome(MDS), acute myeloid leukemia(AML), 
idiopathic thrombocytopenic purpura(ITP) etc.).
Subjects may continue treatment in this rollover study until they are no longer receiving clinical 
benefit, develop an unacceptable toxicity, withdraw consent, enroll into another interventional 
study, or until another mechanism is available for the subject to receive eltrombopag such as 
compassionate use, named patient program, commercially available for the appropriate 
indication, etc. Subjects participating in Investigator Sponsored Studies will not be eligible to 
participate in this study.
Cohort A (MDS/AML adult subjects) will consist of adult subjects who have completed study 
treatment with eltrombopag during their participation in a parent study for MDS/AML (i.e. 
TRC114968/ASPIRE).
Cohort B (ITP adult subjects) will consist of adult subjects who have completed study 
treatment with eltrombopag during their participation in a parent study for ITP (i.e. 
TRA105325/EXTEND).
Cohort C (ITP pediatric subjects) will consist of pediatric subjects who have completed study 
treatment with eltrombopag during their participation in a parent study for ITP. Once a subject 
turns 18 years of age, they may remain in the study and follow the Cohort B guidelines. The 
study will consist of a Transition Visit, Study Treatment Visits, End of Treatment Visit, and a 
Follow-Up Visit.


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Safety will be evaluated through physical exams, clinical laboratory tests (hematology and 
clinical chemistry), and monitoring of adverse events/serious adverse events. Additional safety 
assessments may be done as per standard of care (SoC) and/or when medically indicated. 
Assessment of clinical benefit will be performed throughout the study using local SoC as 
determined by the investigator to determine continued study participation and treatment with
eltrombopag. Only subjects considered by the investigator to be receiving clinical benefit 
without unacceptable toxicity may continue on study treatment.
1.2
Study objectives and endpoints
The primary objective of this study is to provide continuing treatment with eltrombopag for 
subjects who are currently participating in a Novartis sponsored investigational study of 
eltrombopag (parent study) and to collect long term safety data.
There are no formal endpoints for this study.
2
Statistical methods
2.1
Data analysis general information
The tables, figures and listings will be generated by Novartis programmers. SAS version 9.4 or 
later software will be used to perform all data analyses and to generate tables, figures and 
listings. Since not a single subject was enrolled to Cohort C throughout the entire trial, all tables, 
figures and listings will only include patients from Cohorts A and B.
The final analysis will take place after the last subject, last visit has occurred and the database 
has been locked. All available data will be included. 
Pooling of centers: Unless specified otherwise, data from all study centers will be pooled for 
the analysis. Due to expected small size of centers, no center effect will be assessed. 
Qualitative data (e.g., gender, race, etc.) will be summarized by means of contingency tables; 
a missing category will be included as applicable. Percentages will be calculated using the 
number of subjects in the relevant analysis set or subgroup as the denominator.
Quantitative data (e.g., age, body weight, etc.) will be summarized by appropriate descriptive 
statistics (i.e. mean, standard deviation, median, minimum, and maximum).
2.1.1
General definitions
Investigational drug and study treatment
Investigational drug, study drug and study treatment refer to eltrombopag.
Data will be presented by cohorts in applicable summaries, figures, and listings.
Date of first/last administration of study drug
The date of first administration of study drug is defined as the first date when the first non-zero 
dose of study drug was administered as per the Dosage Administration electronic case report 


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form (eCRF). For simplicity, the date of first administration of study treatment will also be 
referred as start of eltrombopag.
The date of last administration of study drug is defined as the last date when a non-zero dose of 
study drug was administered as per Dose Administration eCRF. This date is also referred to as 
last dose of eltrombopag.
Duration of exposure
The duration of exposure is calculated as:

Duration of eltrombopag exposure (months) =[(last dose date of eltrombopag) – (first dose 
date of eltrombopag) + 1]/ 30.4375. 
If the start or end date of eltrombopag is missing, the duration will be missing. The duration 
includes periods of temporary interruption (planned or actual) for any reason.
Definition of Months and Years
A month will be calculated as (365.25 / 12) = 30.4375 days. Where duration is to be reported 
in months, duration in days will be divided by 30.4375.  Where duration is to be reported in 
years, duration in days will be divided by 365.25.
Study day
The study day for safety assessments (e.g. adverse event onset, laboratory abnormality 
occurrence, vital sign measurement, dose interruption etc.) will be calculated as the difference 
between the date of the event (onset date of an event, assessment date etc.) and the start of study 
treatment plus 1. The first day of study treatment is therefore study day 1. Example: if start of 
study treatment is on 05-Jan-2014 and start date of an adverse event is on 09-Jan-2014 then the 
study day of the adverse event onset is day 5. For safety assessments before start of study 
treatment, the study day is negative and derived by (date of event – start date of study treatment). 
For example: if start of study treatment is on 05-Jan-2014 and date of lab measurement is on 
02-Jan-2014 then the study day of the laboratory abnormality is -3. Note, the day of start of 
study treatment is day 1, and the day before the date of first study treatment is day – 1, not day 
0. 
The study day will be displayed in the data listings.
Baseline
The results of any specified study assessments performed on the day of the Transition Visit will 
serve as the baseline value for the said assessment. On-treatment assessment/event and 
observation periods
Adverse events, serious adverse events, death will be assigned to the treatment periods defined 
below. Flag variables indicating the treatment period will be added to these datasets.
1. Pre-treatment period: prior to start of eltrombopag


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2. On-treatment period: from start of eltrombopag to last dose date of eltrombopag + 30 days
It is noted that if patient withdraws study informed consent or dies before then, then it is till the 
withdrawal/death date
3. Post-treatment from last dose date of eltrombopag + 31 days to end of study
If dates are incomplete in a way that clear assignment to on-, post-treatment period cannot be 
made, then the respective data will be assigned to the on-treatment period.  
Safety summaries (tables, figures) include only data from the on-treatment period with the 
exception of baseline data which will also be summarized where appropriate (e.g. change from 
baseline summaries). In addition, a separate summary for death including on treatment and all
deaths will be provided. Summary tables for adverse events (AEs) will summarize only on-
treatment events, with a start date during the on-treatment period (treatment-emergent AEs).  
However, all safety data (including those from the pre and post-treatment period) will be listed 
and those collected during the post-treatment period will be flagged.
Windows for multiple assessments 
All data will be reported according to the nominal visit date for which it was reported (that is, 
no visit windows will be applied during dataset creation). 
2.2
Analysis sets
The All Treated Subjects (ATS) analysis set includes all subjects who received at least one 
dose of eltrombopag on this study. 
All data will be evaluated based on this analysis set. 
Withdrawal of Informed Consent
Any data collected in the clinical database after a subject withdraws informed consent from all 
further participation in the trial, will not be included in the analysis data sets. The date on which 
a subject withdraws full consent is recorded in the eCRF.
2.3
Subject disposition, demographics and other baseline 
characteristics
The ATS will be used for disposition, demographics and other baseline summaries and listings.
2.3.1
Subject disposition
Disposition data will be summarized descriptively by cohort, including but not limited to:

Number (%) of subjects, who completed the trial

Number (%) of subjects who discontinued the treatment

Number (%) of subjects with primary reason for end of treatment (based on subject status 
entered in the ‘Study Treatment Discontinuation’ page)
Listings will be provided.


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2.3.2
Subject demographics and other baseline characteristics
The demographic characteristics (e.g., age, ethnicity, race, sex, height, and body weight) will 
be summarized descriptively and listed by cohort.  Age will be summarized both as a continuous 
variable and categorized as < 65 and 65 years.
All available data on medical histories and current medical conditions at baseline will be listed.
2.4
Treatments (study treatment, rescue medication, concomitant 
therapies, compliance)
2.4.1
Study treatment / compliance
Duration of eltrombopag exposure (months) will be summarized descriptively and listed for the 
ATS by cohorts.
Duration of eltrombopag exposure (months) will also be categorized and summarized using the 
following time intervals: <1, ≥ 1, ≥ 3, ≥6, ≥ 12, ≥ 24, ≥36, ≥ 48, ≥60.
A listing will also be provided of study treatment compliance (tablets/sachets dispensed and 
returned).
A listing of protocol deviations will be provided.
2.4.2
Prior, concomitant and post therapies
All available data will be listed.
2.5
Analysis of the primary objective
The primary objective is safety, see Section 2.7.
2.6
Analysis of the secondary objectives
Not applicable.
2.7
Safety analyses
All safety analyses will be based on the ATS set. Summaries will be displayed by cohorts.
2.7.1
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. 
AEs will be summarized by number and percentage of subjects having at least one AE, having 
at least one AE in each primary system organ class (SOC) and for each preferred term (PT) 
using the latest version of the medical dictionary for regulatory activities (MedDRA) at the time 
of the analysis for coding. A subject with multiple occurrences of an AE will be counted only 
once in the respective AE category. A subject with multiple CTCAE grades for the same 
preferred term will be summarized under the maximum CTCAE grade recorded for the event.


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In AE summaries, the primary system organ class (SOC) will be presented alphabetically and 
the preferred terms (PT) will be sorted within primary SOC in descending frequency. The sort 
order for the preferred term will be based on descending frequency. 
The following AE summaries will be produced: 

All AEs regardless of relationship to study treatment by primary system organ class 
(SOC), preferred term (PT) and maximum severity

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 treatment discontinuation regardless of relationship to study treatment by 
SOC, PT and maximum severity

In-text table by PT and maximum severity

Serious AEs (SAEs) regardless of relationship to study treatment by SOC, PT and 
maximum severity

In-text table by PT and maximum severity

On-treatment deaths by SOC and PT

In-text table by PT

*Non-SAEs regardless of relationship to study treatment (threshold=x%) by SOC and PT

*On treatment deaths and SAEs by SOC and PT
*For the legal requirements of EudraCT, two required tables on on-treatment/treatment 
emergent AEs which are not SAEs with an incidence greater than x% and on on-
treatment/treatment emergent SAEs and SAE suspected to be related to study treatment will be 
provided by SOC and PT on the ATS.
If for a same patient, several consecutive AEs (irrespective of study treatment causality, 
seriousness and severity) occurred with the same SOC and PT:

a single occurrence will be counted if there is ≤ 1 day gap between the end date of the 
preceding AE and the start date of the consecutive AE

more than one occurrence will be counted if there is > 1 day gap between the end date of 
the preceding AE and the start date of the consecutive AE
For occurrence, the presence of at least one SAE/SAE suspected to be related to study 
treatment/non SAE has to be checked in a block e.g., among AEs in a ≤ 1 day gap block, if at 
least one SAE is occurring, then one occurrence is calculated for that SAE.
The number of deaths resulting from SAEs suspected to be related to study treatment and SAEs 
irrespective of study treatment relationship will be provided by SOC and PT.
A listing will be provided for all AEs. Records outside of on-treatment period will be flagged.
Separate listings/summaries in terms of number and percentage of patients having at least one 
adverse event of special interest (AESI) based on the set of safety topics as defined by the 
“Other search” flag in the latest version of the Case Retrieval Strategy (eCRS) will be provided.


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2.7.2
Deaths
See Section 2.7.1. A listing will be provided of all deaths, deaths outside of the on-treatment 
period will be flagged.
2.7.3
Laboratory data
Laboratory values will be 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 provided. Note that except for baseline value only on-
treatment values will be used in summaries.

Shift tables using CTCAE grades to compare baseline to the worst on-treatment value for 
platelets, hemoglobin and white blood cells (WBCs). 

Summary table for platelet counts over time. 
Listings of all available laboratory data (hematology, biochemistry, urinalysis, coagulation,
pregnancy test etc.) 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.
Liver function parameters
Liver function parameters of interest are total bilirubin (TBL), alanine aminotransferase (ALT), 
aspartate aminotransferase (AST) and alkaline phosphatase (ALP).
The number (%) of patients with worst on-treatment values will be summarized. For single 
lab parameter lines (e.g. AST >3xULN) the worst value post-baseline is considered. For 
combination of various parameters (e.g. ALT or AST > 3xULN & TBL > 2xULN & 
ALP < 2xULN) the lab values need to be from the same assessment (concurrent 
measurements). 
Listings of all available 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 and cardiac imaging data
All available data will be listed.
2.7.4.2
Vital signs
Not applicable.
2.8
Pharmacokinetic endpoints
Data will be listed if any samples are analysed.


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2.9
Patient-reported outcomes
Not applicable. 
2.10
Biomarkers
Not applicable.
2.11
Other Exploratory analyses
Not applicable.
2.12
Interim analysis
Not applicable.
3
Sample size calculation
The sample size is based on the number of subjects completing their parent study of 
eltrombopag who are eligible for inclusion in this rollover study.
4
Change to protocol specified analyses
For laboratory results, grades will be defined by CTCAE version 4.03 and not version 4.0. Vital 
signs and ECG data will only be listed. Existing Pharmacokinetic samples were not analysed
due to instability issues, any future samples, if analysed, will be listed.
5
References
1. Oncology guideline for safety analysis, v1.0, dated 09-Jun-2016
2. Oncology standard outputs safety TFLs, V3.1, dated 03-Aug-2017


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6
Appendix
6.1
Imputation rules
Table 6-1
Imputation of start dates (AE) 
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  
Table 6-2
Imputation of end dates (AE) 
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 with partial/missing dates will be displayed as such in the data listings. Any AEs 
which are continuing as per LPLV will be shown as ‘ongoing’ rather than an imputed end date 
provided.