Conditions: Poor Graft Function
Keywords: Eltrombopag Hematological response Poor graft function Stem cell transplantation Adult ELTION Phase II
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 10
Healthy volunteers: no

Brief summary:
The purpose of this study was to evaluate the efficacy of eltrombopag for poor graft function (PGF) on overall hematologic response (partial and complete), as determined by platelet, hemoglobin and neutrophil counts by 16 weeks after the initiation of eltrombopag in patients with poor graft function after allogeneic hematopoietic stem cell transplantation (allo-HSCT).

Detailed description:
This was an open-label, single-arm phase II study, in which participants diagnosed with PGF after allo-HSCT were treated with eltrombopag up to week 36 or until the participant's premature withdrawal.

The study consisted of the following periods:

* Screening Period (baseline): the participant screening criteria was reviewed, and the procedures established in the evaluation schedule were performed.
* Treatment Period: from administration of the first dose of eltrombopag until time when participant permanently stopped taking study treatment for any reason or until 36 weeks had passed. Eltrombopag was initiated on Day 1 at a dose of 150 mg once daily (75 mg daily in Asian ancestry participants). During the Treatment Period, participants were evaluated weekly during the first month, every 2 weeks during the next 2 months and subsequently every 4 weeks until week 24. For the last 3 months, participants were followed every 6 weeks Only participants who had a partial or complete response at Week 16 continued to receive eltrombopag up to Week 36 or until loss of response (defined as a decrease in blood counts to levels that did not continue to meet the criteria for response established in the protocol), unacceptable toxicity, or discontinuation for any other reason.

Participants who discontinued eltrombopag because efficacy, continued in the study and attended the scheduled visits of Treatment Period as per protocol. If loss of response occurred, eltrombopag was reintroduced at the last effective dose.

* Final Visit (or Early Withdrawal): this visit took place 30 days after completion of the Treatment Period, or premature participant withdrawal.
* Follow-up for Survival: all participants who discontinued from the study, regardless the reason of discontinuation, were followed for survival for 24 and 36 weeks, unless they withdrew their consent, died or were lost-to follow-up, in which case study visits were no longer carried out.

Arms:
arm 1: Patients received eltrombopag orally once daily up to 36 weeks.

Interventions: intervention 1: Eltrombopag
Intervention descriptions: intervention 1: Eltrombopag was provided as 50 mg or 25 mg film-coated tablets for oral use administration

Protocol document:
Prot_000.pdf: 
Official Title: 
The ELTION Study - A Multicenter Open-label Interventional Study of 
Eltrombopag in Patients With Poor Graft Function After Allogeneic 
Hematopoietic Stem Cell Transplantation 
NCT Number: 
NCT03718533 
Document Date: 
Protocol Version 1: 10 July 2019 


Clinical Development
Eltrombopag REVOLADE/ETB115 
Clinical Trial Protocol CETB115EES03 
The ELTION study – A multicenter open-label interventional 
study of Eltrombopag in patients with poor graft function 
after allogeneic hematopoietic stem cell transplantation
Coordinating Investigator
Authors
Document type
Amended Oncology Clinical Trial Protocol
EUDRACT number
2018-001129-15.
Version number
01 Clean
Development phase
II
Document status
Final
Release date
10-Jul-2019
Property of Novartis
Confidential
May not be used, divulged, published, or otherwise disclosed
without the consent of Novartis
Template version 15-Feb-2012


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Table of contents
Table of contents .................................................................................................................2
List of figures ......................................................................................................................5
List of tables ........................................................................................................................5
List of abbreviations............................................................................................................6
Glossary of terms.................................................................................................................8
Amendment 1 ......................................................................................................................9
Protocol summary..............................................................................................................13
1
Background........................................................................................................................18
1.1
Overview of graft failure after a stem cell transplantation and current 
treatment ................................................................................................................18
1.2
Introduction to investigational treatment(s) and other study treatment(s).............19
1.2.1
Overview of eltrombopag .....................................................................19
2
Rationale............................................................................................................................22
2.1
Study rationale and purpose...................................................................................22
2.2
Rationale for the study design ...............................................................................22
2.3
Rationale for dose and regimen selection..............................................................23
3
Objectives and endpoints...................................................................................................23
4
Study design ......................................................................................................................27
4.1
Description of study design ...................................................................................27
4.2
Timing of interim analyses and design adaptations...............................................28
4.3
Definition of end of the study................................................................................28
4.4
Early study termination..........................................................................................28
5
Population..........................................................................................................................28
5.1
Inclusion criteria ....................................................................................................28
5.2
Exclusion criteria...................................................................................................29
6
Treatment...........................................................................................................................31
6.1
Study treatment......................................................................................................31
6.1.1
Dosing regimen.....................................................................................31
6.1.2
Treatment duration................................................................................31
6.2
Dose modifications................................................................................................32
6.2.1
Dose modification and dose delay ........................................................32
6.2.2
Follow-up for toxicities.........................................................................35
6.2.3
Anticipated risks and safety concerns of the study drug.......................35
6.2.4
Follow-up on potential drug-induced liver injury (DILI) cases............37
6.3
Concomitant medications ......................................................................................38
6.3.1
Permitted concomitant therapy .............................................................38


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6.3.2
Prohibited concomitant therapy ............................................................39
6.4
Patient numbering, treatment assignment or randomization .................................40
6.4.1
Patient numbering .................................................................................40
6.4.2
Treatment assignment or randomization...............................................40
6.4.3
Treatment blinding................................................................................40
6.5
Study drug preparation and dispensation...............................................................40
6.5.1
Study drug packaging and labeling.......................................................40
6.5.2
Drug supply and storage........................................................................40
6.5.3
Study drug compliance and accountability ...........................................41
6.5.4
Disposal and destruction .......................................................................41
7
Visit schedule and assessments .........................................................................................41
7.1
Study flow and visits schedule ..............................................................................41
7.2
Periods/visits..........................................................................................................46
7.2.1
Screening/baseline.................................................................................46
7.2.2
Treatment Period...................................................................................48
7.2.3
Final visit (or Early withdrawal)...........................................................52
7.2.4
Follow-up for survival...........................................................................53
7.3
Assessment types...................................................................................................53
7.3.1
Efficacy assessments.............................................................................53
7.3.2
Safety assessments ................................................................................54
57
7.3.4
Resource utilization...............................................................................59
7.3.5
Patient reported outcomes.....................................................................59
8
Safety monitoring and reporting........................................................................................59
8.1
Adverse events.......................................................................................................59
8.1.1
Definitions and reporting ......................................................................59
8.1.2
Laboratory test abnormalities................................................................61
8.1.3
Adverse events of special interest.........................................................61
8.2
Serious adverse events...........................................................................................61
8.2.1
Definitions.............................................................................................61
8.2.2
Reporting...............................................................................................62
8.3
Pregnancies............................................................................................................63
8.4
Warnings and precautions......................................................................................63
9
Data collection and management.......................................................................................64
9.1
Data confidentiality ...............................................................................................64
9.2
Site monitoring ......................................................................................................64
9.3
Data collection.......................................................................................................65


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9.4
Database management and quality control............................................................65
10 Statistical methods and data analysis ................................................................................65
10.1
Analysis sets ..........................................................................................................65
10.1.1
Full Analysis Set ...................................................................................65
10.1.2
Safety Set ..............................................................................................65
10.1.3
Per-Protocol Set ....................................................................................66
10.2
Patient demographics/other baseline characteristics .............................................66
10.3
Treatments (study treatment, concomitant therapies, compliance) .......................66
10.4
Primary objective...................................................................................................67
10.4.1
Variable.................................................................................................67
10.4.2
Statistical hypothesis, model, and method of analysis..........................67
10.4.3
Handling of missing values/censoring/discontinuations.......................68
10.4.4
Supportive analyses...............................................................................68
10.5
Secondary objectives .............................................................................................68
10.5.1
Other efficacy objective(s)....................................................................68
10.5.2
Safety objectives ...................................................................................69
10.5.3
Pharmacokinetics ..................................................................................71
71
71
71
10.7
Sample size calculation..........................................................................................72
10.8
Power for analysis of key secondary variables......................................................72
11 Ethical considerations and administrative procedures ......................................................72
11.1
Regulatory and ethical compliance........................................................................72
11.2
Responsibilities of the investigator and IRB/IEC/REB.........................................72
11.3
Informed consent procedures.................................................................................73
11.4
Discontinuation of the study..................................................................................73
11.5
Publication of study protocol and results...............................................................73
11.6
Study documentation, record keeping and retention of documents.......................73
11.7
Confidentiality of study documents and patient records .......................................74
11.8
Audits and inspections...........................................................................................74
11.9
Financial disclosures..............................................................................................75
12 Protocol adherence ............................................................................................................75
12.1
Amendments to the protocol..................................................................................75
13 References (available upon request)..................................................................................76


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List of figures
Figure 4-1 Study design............................................................................................................28
List of tables
Table 3-1
Objectives and related endpoints ..........................................................24
Table 6-1
Dose and treatment schedule.................................................................31
Table 6-2
Criteria for dose management of eltrombopag based on platelets 
count......................................................................................................32
Table 6-3
Criteria for eltrombopag dose adjustment based on liver enzyme 
and bilirubin levels................................................................................33
Table 6-4
Supply and storage of study treatments ................................................41
Table 7-1
Visit evaluation schedule ......................................................................42
Table 7-2
Local clinical laboratory parameters collection plan ............................55
59
Table 10-1
Sample size justification .......................................................................72


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List of abbreviations
Allo-HSCT
Allogeneic- hematopoietic stem cells transplantation
AE
Adverse Event
AESI
Adverse event of special interest
AML
Acute myeloid leukemia
ANC
Absolute neutrophil count
BM
Bone marrow
BMA
Bone marrow aspirate
CBC
Complete blood count
CMV
Cytomegalovirus
CR
Complete response
CRF
Case Report/Record Form; the term CRF can be applied to either EDC or Paper
CRO
Contract Research Organization
CSR
Clinical Study Report
CTCAE
Common Terminology Criteria for AEs
DILI
Drug-induced liver injury
DS&E
Drug Safety and Epidemiology
EBV
Epstein-Barr virus
ECG
Electrocardiogram
EPO
Erythropoietin
GCP
Good clinical practice
G-CSF
Granulocyte colony-stimulating factor
GVHD
Graft versus host disease
HBV
Hepatitis B virus
HCV
Hepatitis C virus 
HIV
Human immunodeficiency virus
HLA
Human leukocyte antigen
HSCT
Hematopoietic stem cells transplantation
ICH
International Conference on Harmonization
ICF
Informed Consent Form
IEC
Independent Ethics Committee
Ig
Immunoglobulin
IRB
Institutional Review Board
IST
Immunosuppressive therapy
ITP
Immune thrombocytopenic purpura 
MAP
Master Analysis Plan documents project standards in the statistical methods 
which will be used within the individual clinical trial RAP documentation
MDS
Myelodysplastic syndrome
PB
Peripheral blood
PGF
Poor graft function
PHI
Protected Health Information
PCR
Polymerase chain reaction
PR
Partial response


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RAP
The Report and Analysis Plan (RAP) is a regulatory document which provides 
evidence of preplanned analyses
REB
Research Ethics Board
SAA
Severe aplastic anemia
SAE
Serious Adverse Event
SCT
Stem cells transplantation
SOP
Standard Operating Procedure
TEEs
Thromboembolic events
TPO
Thrombopoietin
TPO-R
Thrombopoietin receptor


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Glossary of terms
Assessment
A procedure used to generate data required by the study
Enrollment
Point/time of patient entry into the study; the point at which informed 
consent must be obtained (i.e. before starting any of the procedures 
described in the protocol)
Investigational drug
The study treatment whose properties are being tested in the study 
this definition is consistent with US CFR 21 Section 312.3 and is 
synonymous with “investigational new drug.”
Investigational treatment
Drug whose properties are being tested in the study as well as their 
associated placebo and active treatment controls (when applicable). 
This also includes approved drugs used outside of their 
indication/approved dosage, or that are tested in a fixed 
combination. Investigational treatment does not include other study 
treatments administered as concomitant background therapy 
required or allowed by the protocol when used in within approved 
indication/dosage.
Medication number
A unique identifier on the label of each study treatment package 
which is linked to one of the treatment groups of a study
Other study treatment
Any drug administered to the patient as part of the required study 
procedures that was not included in the investigational treatment
Patient Number (Patient 
No.) 
A unique identifying number assigned to each 
patient/subject/healthy volunteer who enrolls in the study.
Period
A subdivision of the study timeline; divides stages into smaller 
functional segments such as screening, baseline, titration, washout, 
etc.
Premature patient 
withdrawal
Point/time when the patient exits from the study before the planned 
completion of all study treatment administration and/or assessments; 
at this time, all study treatment administration is discontinued and no 
further assessments are planned, unless the patient will be followed 
for progression and/or survival
Stage related to study 
timeline
A major subdivision of the study timeline; begins and ends with 
major study milestones such as enrollment, randomization, 
completion of treatment, etc.
Stop study participation
Point/time at which the patient came in for a final evaluation visit or 
when study treatment was discontinued whichever is later
Study treatment
Includes any drug or combination of drugs in any study arm 
administered to the patient as part of the required study procedures, 
including placebo and active drug run-ins.
In specific examples, it is important to judge investigational 
treatment component relationship relative to a study treatment 
combination; study treatment in this case refers to the investigational 
and non-investigational treatments in combination.
Study treatment 
discontinuation
Point/time when patient permanently stops taking study treatment for 
any reason; may or may not also be the point/time of premature 
patient withdrawal
Variable
Identifier used in the data analysis; derived directly or indirectly from 
data collected using specified assessments at specified timepoints


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Amendment 1
Amendment rationale
The purpose of this protocol amendment is to update the eligibility criteria for better clarifying 
the profile of patients to be included, and align with the current eltrombopag program risk 
language.
The amendment also includes modifications in the times to perform some procedures in order 
to facilitate the realization of the Screening and better adapting it to clinical practice. 
Additionally, this protocol amendment includes the correction of typographical errors, 
formatting errors and editorial changes to increase clarity and consistency of the text. 
Consequently, changes were incorporated directly in the protocol with track changes, even if 
not listed specifically in this section.
Changes to the protocol
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol. A selection of the main changes encompasses:
Section 1.2.1.1 - Non-clinical experience
Subsection Non clinical pharmacokinetics and metabolism has been updated by adding that 
additional details of eltrombopag non-clinical pharmacokinetics can be found in the Investigator 
Brochure.
Section 1.2.1.2 - Clinical experience
Clinical experience data of eltrombopag has been updated with new findings in patients with 
severe aplastic anemia (SAA) not previously treated with initial immunosuppressive therapy 
(IST), and also with the new findings in post-allo-HSCT poor graft function presented at the 
EBMT congress 2019.
Section 5.1- Inclusion criteria

Inclusion criterion #5 has been updated to clarify, that the Karnofsky assessment must
be performed within 7 days prior to Day 1 instead within 28 days in the previous version 
of protocol.
Section 5.2 - Exclusion criteria

Exclusion criteria #3, #4, #5, #20 have been added to clarify patient profile

Exclusion criteria #6 has been updated not to restrict the cytogenetic study to the 
Screening visit, and allow the use of a post-transplant cytogenetic analysis proving that 
clonal abnormality has been detected by either conventional cytogenetic or FISH and it 
was done by habitual clinical practice within 8 weeks of Day 1. Also, it was emphasized 
that patients with dry tap bone marrow aspiration are not eligible for the study given that 
the cytogenetic study cannot be analyzed.

Exclusion criteria #7 has been updated to clarify, that the methods to be used for 
evaluating bone marrow involvement or progression will be those that correspond to 
each case.


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
Exclusion criteria #14 has been updated to clarify that patients with a previous line-
related upper extremity thrombosis are not excluded from the study. This criterion 
follows the exposed premise in Section 6.2.2 - Follow-up for toxicities indicating the 
discontinuation of eltrombopag in cases of a deep venous thrombosis other than a line-
related upper extremity thrombosis. 

Exclusion criteria #16 has been updated to restrict the participation of subjects with 
uncontrolled or significant cardiac disease or impaired cardiac function.  

Exclusion criteria #19 has been updated to eliminate the use of QT drugs with a known 
risk to prolong the QT interval as a criterion for being excluded from the study.
Eltrombopag does not lead to QT prolongation as observed in a QTc study where healthy 
volunteers received 150 mg of eltrombopag per day (Please see details in section 6.3.2)
Section 6.2.1.2 – Dose modifications due to liver signals: Table 6-3 has been updated to modify 
the criteria for eltrombopag dose adjustment based on liver enzyme and bilirubin levels and to 
align with the rest of eltrombopag trials. 
Section 6.2.3 – Anticipated risks and safety concerns of the study drug: Updates were included 
to: 
-
Clarify that dose modifications of eltrombopag in response to platelet counts will be 
made according with parameters provided in the protocol, and that the risks of 
thromboembolism and any of the following complications versus the benefit of 
improved platelet counts must be evaluated by the Investigator for each patient with 
known risk of TEEs. These changes have been included to be aligned with the safety 
program of eltrombopag.
-
Add the possible occurrence of the following hepatotoxic events under the use of 
eltrombopag: hepatobiliary laboratory abnormalities, severe hepatotoxicity and 
potentially fatal liver injury.
-
Update the anticipated concern of progression of existing hematopoietic malignancies 
with the inclusion of findings from the CETB115AUS01T study (Townsley et al., 2017)
showing a similar rate of clonal cytogenetic evolution with dysplastic changes between 
eltrombopag in combination with IST and NIH historic cohort with standard IST 
-
Add the possibility of bleeding events following discontinuation of eltrombopag, and 
the monitoring of platelet counts as per protocol. 
Section 6.3.1.2- Permitted concomitant therapy requiring caution and/or action
All relative to avoid the co-administration of QT prolonging drugs (or with potential to increase
the risk of QT prolongation) has been moved from prohibited concomitant therapy to this 
section, along with the requirement of avoiding the concomitant use of any drug with a known 
potential to cause Torsades de Pointes.
Section 6.3.2 – Prohibited concomitant therapy: It was clarified that the dose of prohibited 
corticoids refers to the equivalent dose of prednisone.
Section 7.1 – Study flow and visits schedule

Table 7-1 was updated in a new format to differentiate all procedures required at the 
Screening period within 7 days prior to Day 1. 


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
Table 7-1 was updated to include the hematological response assessments at all visits 
from week 16 and to include cytogenetic analysis/FISH in bone marrow in visit 1.

The foot of the Table 7-1 was updated to clarify that the pregnancy tests other than at 
the Screening can be done in a urine or serum sample. This measure will facilitate some 
centers the realization of pregnancy evaluation given that this analysis is the only one 
required to be performed in a urine sample.

The foot of the Table 7-1 was updated to limit the performance of the screening 
pregnancy test only to women of childbearing potential, instead of all women in the 
previous version of protocol. 

The foot of the Table 7-1 was updated to eliminate the possibility of using a BMA 
available and performed within 30 days prior to Day 1 for screening.
Section 7.2 – Periods/visits
Section 7.2.1 – Screening/baseline: The schedule planned at the Screening/Baseline period was 
updated to add a Central Review of some clinical data recorded at Screening for every patient 
by the Coordinating Investigator and the Novartis’ medical Team to verify the eligibility before 
the inclusion at the site. 
Section 7.2.1.1 – Eligibility screening: Updates were included to add the possibility of the re-
screening of a previously screen failed patient only once in the event that there are exclusionary 
medical conditions, or laboratory, vital signs findings in the Screening period that can be 
resolved or stabilized.
Section 7.2.1.3 – Patient demographics and other baseline characteristics

Updates were made to include at screening serologic testing for HIV, HBsAg and HCV 
according to the exclusion criterion added of subjects with positive results.

Updates were made to eliminate the possibility of using a bone marrow aspirate for 
additional assessments performed within 30 days prior to Day 1 for screening. A bone 
marrow aspirate has to be collected at Screening (within 28 days prior to eltrombopag) 
and sent to a central laboratory for analysis.  

Updates were made to limit the performance of pregnancy test at screening only to 
women of childbearing potential, instead of all women in the previous version of 
protocol.

A blood smear has been added to the procedures required within 7 days prior to Day 1.

Patients are expected to have a conventional post-transplant cytogenetic performed 
within 8 weeks before Day 1 to exclude any clonal abnormality. If conventional 
cytogenetics does not show metaphase, a FISH (fluorescence in situ hybridization) has 
to be available. Otherwise, if cytogenetics/FISH post-transplant was not done by 
habitual clinical practice previous to the study, a cytogenetic analysis/FISH must be 
performed within 28 days prior to Day 1.


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Section 7.2.2 – Treatment Period: It was updated including the possibility of doing the 
pregnancy test in serum, if convenient. 
Section 7.2.2.4 –Monthly visits to month 6 (weeks 16, 20 and 24): It was updated including the 
assessment of haematological response at all visits.
Section 7.2.2.5 – Every 6-weeks visits to month 9 (weeks 30 and 36): It was updated to include 
the assessment of haematological response at all visits.
Section 7.2.3 – Final visit (or Early withdrawal): It was updated including the possibility of 
doing the pregnancy test in serum, if convenient, and the performance of a blood smear. As 
explained above, this measure will facilitate some centers the realization of pregnancy 
evaluation given that this analysis is the only one required to be performed in a urine sample.
Section 7.3.2.5 – Clinical safety laboratory evaluations: some inconsistencies were corrected in 
Table 7-2 concerning the assessments of the blood smear planned. In addition, according to the 
new exclusion criterion added of subjects positive for HIV, HCV and HBsAg, it has been 
included the serology test at the screening for eligibility.
 
The changes herein affect the Informed Consent. Therefore, a revised Informed Consent that 
takes into account the changes described in this protocol amendment will be provided and 
submitted for approval. None of the changes made are due to safety concerns and none of the 
changes have an impact on the conduct of the trial or alter in any way the treatment of study 
subjects.


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Protocol summary
Protocol 
number
CETB115EES03
Title
The ELTION study – A multicenter open-label interventional study of eltrombopag 
in patients with poor graft function after allogeneic hematopoietic stem cell 
transplantation
Brief title
Study of efficacy and safety of eltrombopag in patients with poor graft function
Sponsor 
and 
Clinical Phase
Novartis 
Clinical phase II 
Investigation 
type
Drug
Study type
Interventional
Purpose and 
rationale
The purpose of this phase II clinical trial is to evaluate the effect of eltrombopag in 
patients with poor graft function (PGF) after allogeneic-hematopoietic stem cells 
transplantation (allo-HSCT).
Some studies have reported the off-label use of eltrombopag in the treatment for 
post-transplant thrombocytopenia with successful results. Also, treatment with 
eltrombopag has been associated with multilineage clinical responses in some 
cases of patients who underwent allogeneic stem cells transplantation (allo-SCT)
and were diagnosed with PGF.  
Since PGF can be a serious complication of stem cells transplantation and its 
treatment is limited regarding efficacy and toxicity, new drugs are needed.
Primary 
Objective(s) 
The primary objective of this study is to evaluate the efficacy of eltrombopag for 
poor graft function on overall hematologic response (partial and complete), as 
determined by platelet, hemoglobin and neutrophil counts by 16 weeks after the 
initiation of eltrombopag.
Hematological responses are defined as:
Partial response (PR): when any of the following:

Platelet count >20,000/μL (with platelet transfusion independence), confirmed 
in two consecutive blood tests separated a minimum of 7 days

Absolute neutrophil count (ANC) >1,000/μL (when pretreatment ANC was 
<1,000/μL), confirmed in two consecutive blood tests separated a minimum of
7 days

Hemoglobin >100g/L (when pretreatment Hb was <100g/L) (with red blood 
cells (RBC) transfusion independence), confirmed in two consecutive blood 
tests separated a minimum of 7 days
Complete response (CR): when all three of the following: 

Platelet count >100,000/μL, confirmed in two consecutive blood tests 
separated a minimum of 7 days 

Absolute neutrophil count (ANC) >1,500/μL (when pretreatment ANC was 
<1,000/μL), confirmed in two consecutive blood tests separated a minimum of 
7 days.

Hemoglobin >110 g/L (when pretreatment Hb was <100g/L), confirmed in two 
consecutive blood tests separated a minimum of 7 days.
Secondary 
Objectives
1.
To determine the response in each hematological lineage separately
2.
To evaluate the long-term efficacy of eltrombopag on overall hematologic 
response (partial and complete) at 24 and 36 weeks after the initiation of 
eltrombopag.


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3.
To evaluate the transfusion independence for red blood cells (RBC) and/or
platelets after the initiation of eltrombopag (see Section 7.3.1 for endpoint)
4.
To evaluate the reduction and discontinuation of concomitant granulocyte 
colony-stimulating factor (G-CSF) and/or erythropoietin (EPO) therapy (see 
Section 7.3.1 for endpoint).
5.
To evaluate the overall survival and survival rate at 24 and 36 weeks
6.
To evaluate the safety of eltrombopag. Safety will be assessed by frequency 
and severity of adverse events (AEs), serious AEs (SAEs) based on the 
Common Terminology Criteria for AEs (CTCAE v4.03) and AEs leading to 
discontinuation.
Study design
This is a phase II multicenter, open-label, single-arm 36-week study designed to 
evaluate the efficacy and safety of eltrombopag in patients with poor graft function 
after an allogeneic stem cell transplantation. 
The study includes: 
-
A Screening Period (baseline) where patients will be invited to participate in 
the study after being informed and the screening criteria reviewed.
-
A Treatment Period where all patients eligible to enter the study will initiate 
eltrombopag at a dose of 150 mg daily for 36 weeks. For patients of Asian
ancestry (such as Chinese, Japanese, Taiwanese, Korean or Thai), 
eltrombopag will be administered at a dose of 75 mg once daily.
o
Only patients who have a partial or complete response at week 16 will 
continue to receive eltrombopag until loss of response, unacceptable 
toxicity, discontinuation for any other reason
(see Sections 
6.1.2/7.2.3.1), or until 36 weeks have passed. 
o
Patients who discontinue eltrombopag because efficacy (see Section
6.1.2), must continue in the study and attend the scheduled study 
visits as per protocol. If loss of hematological response occurs, 
eltrombopag will be reintroduced at the last effective dose (see 
Section 6.1.2)
-
A Final Visit (or Early Withdrawal): this visit should be scheduled 30 days after 
Treatment Period completion or premature patient withdrawal. 
-
Follow-up for Survival: all patients who discontinue from the study, regardless 
the reason of discontinuation, will be followed for survival for 24 and 36 weeks, 
unless they withdraw their consent, die or are lost-to follow-up, in which case 
will be censored at the last contact/follow-up.
Patients will be evaluated weekly during the first month, every 2 weeks during the 
next 2 months and subsequently every 4 weeks during the first 24 weeks. For the 
last 3 months of the study, patients will be followed every 6 weeks. As specified 
bellow, withdrawn patients for reasons other than lost to follow-up or withdrawal 
of consent) will be followed for survival at 24 and 36 weeks.
Population
Approximately 33 patients ≥18 years of age diagnosed with primary or secondary
PFG after an allo-HSCT are anticipated to be included.
Inclusion criteria
1.
Patient must be able to understand and communicate with the investigator 
and comply with the requirements of the study and must provide written, 
signed and dated informed consent form before any study assessment is 
performed


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2.
Male of female patients ≥ 18 years of age 
3.
Patients diagnosed with primary or secondary poor graft function (PGF) 
defined as two or more cytopenias after day +30 post-transplant (re-tested in 
a peripheral blood analysis at screening): 
a.
Platelet count <20,000/ µL (mandatory)
b.
Absolute neutrophil count (ANC) <1,000/µL
c.
Hemoglobin <100 g/L
4.
Presence of >90% of donor chimerism in screening visit.
5.
Karnofsky status ≥90% (please remember that Karnofsky evaluation must be 
performed within 7 days of Day 1).
Exclusion
criteria
1.
Pregnant or nursing (lactating women) and women of childbearing potential 
unless they are using highly effective methods of contraception
2.
Evidence of active acute or chronic graft versus host disease (GVHD).
3.
Evidence of any active malignancy
4.
Subjects who are human immune deficiency virus (HIV), hepatitis C virus 
(HCV), and/or hepatitis B surface antigen (HBsAg) positive in screening visit. 
5.
Cytogenetic abnormality in chromosome 7 present before the allo-HSCT
6.
Evidence of any clonal abnormality on cytogenetics (in bone marrow analysis).
- A local post-transplant conventional cytogenetic assessment should be 
available within 8 weeks before Day 1.
- If the cytogenetics is not valuable, i.e. it does not show metaphases, a 
FISH for MDS-related most frequent abnormalities including chromosome 
7 is accepted.
As a consequence, patients with dry tap bone marrow aspiration are NOT 
eligible.
7.
Evidence of bone marrow involvement or progression of the underlying 
disease assessed by the applicable methods in each case.
8.
Evidence of thrombotic microangiopathy.
9.
Evidence of possible causes of cytopenias other than PGF (active infections, 
myelotoxic drugs, hypersplenism…).
10. Prior use of any thrombopoietin receptor (TPO-R) agonists for PGF.
11. AST or ALT levels >3 x ULN.
12. Creatinine level ≥1.5 x ULN.
13. Total bilirubin level ≥1.5 x ULN.
14. Previous thromboembolic event (other than line-related upper extremity 
thrombosis).
15. Hypersensitivity to eltrombopag or its components.
16. Clinically significant ECG abnormality, History or current diagnosis of cardiac
disease indicating significant risk of safety for subjects participating in the 
study such as uncontrolled or significant cardiac disease or impaired cardiac 
function including any of the following: 
a). Corrected QTc > 450 msec (male subjects), > 460 msec (female 
subjects) using Fredericia correction (QTcF) on the screening ECG
b). Myocardial infarction
c). Uncontrolled congestive heart failure
d). Unstable angina 
e). Congenital long QT syndrome.
17. Administration of an investigational drug within 30 days or 5 half-lives, 
whichever is longer, preceding the first dose of study treatment.


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18. Patient with liver cirrhosis.
19. Risk factors for Torsade de Pointes including uncorrected hypokalemia or 
hypomagnesemia.
20. Subjects with any serious and/or unstable pre-existing medical, psychiatric 
disorder or other condition that could interfere with patient´s safety, obtaining 
informed consent or compliance with the study procedures as per investigator 
discretion.
Investigational 
and reference 
therapy
Investigational drug refers to eltrombopag. There is no reference therapy in this 
open-labeled study.
Eltrombopag will be provided as tablets for oral use and self-administered by the 
patients at a dose of 150 mg daily, being the maximum permissible dose. 
Asian ancestry participants will be administered 50% of the eltrombopag dose (75 
mg daily) because of higher eltrombopag exposure due to differences in 
pharmacokinetics observed in this ethnic group.
Efficacy 
assessments
The primary efficacy endpoint is the percentage of patients who have a response 
(partial and complete), by 16 weeks after the initiation of eltrombopag.
All patients exit from the study before week 16 but have a partial or complete 
response will also be considered as responders
The secondary endpoints are as follows:
-
Percentage of patients who have a response in the neutrophil lineage, defined 
as ANC ≥1,000/ µL or ≥ 1500/ µL according with the hematological responses 
defined in the primary objective, confirmed in two consecutive blood tests 
separated a minimum of 7 days. 
-
Percentage of patients who have a response in the platelet lineage, defined 
as Platelet count ≥20,000/µL or ≥ 100000/µL according with the hematological 
responses defined in the primary objective, confirmed in two consecutive 
blood tests separated a minimum of 7 days.
-
Percentage of patients who have a response in the hemoglobin lineage, 
defined as Hb ≥100 g/L or ≥ 110 g/L according with the hematological 
responses defined in the primary objective, confirmed in two consecutive 
blood tests separated a minimum of 7 days.
-
Percentage of patients who maintain a partial or complete response at 24 and 
36 weeks
-
Percentage of patients previously transfusion-dependent who do no longer 
require platelets and/or RBC transfusions before and after the first 16 weeks 
of treatment with eltrombopag.
-
Time period in which patients do not receive platelets and/or RBC
transfusions.
-
Percentage of patients who discontinue or reduce by ≥50% the use of 
concomitant G-CSF and/or EPO therapy.
-
Overall survival.
-
Overall survival rate at weeks 24 and 36.
Safety 
assessments
The safety of eltrombopag will be assessed throughout the study by the following:
-
Occurrence, incidence, severity of adverse events (AEs), and serious adverse 
events (SAEs), based on the Common Terminology Criteria for AEs (CTCAE)
v4.03.
-
Reasons for study withdrawal, including AEs leading to discontinuation.


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-
Physical examination, performance status, height and weight, vital signs, 
safety laboratory evaluations, ECG and ophthalmological monitoring. 
Rationale of the 
sample size
The primary objective is to evaluate the efficacy of eltrombopag on overall 
hematologic response (partial and complete) in patients with PGF after receiving 
an allo-HSCT. When the sample size is 33 patients and the proportion of 
responses with eltrombopag is assumed to be 45% in this sample, a one-sided 
95% confidence interval of this proportion will have a length of 0.149 towards its 
lower end. In other words, this confidence interval will provide enough evidence 
that the actual proportion of responses in the target population is above 30%, 
because its lower limit (as per the sampling distribution) would be 30.1%.
Confidence 
level
Minimally 
acceptable 
response
Distance of 
observed 
response to 
lower limit
Observed 
proportion
Actual 
lower 
limit
Sample 
size
95%
>30%
14.9%
45%
30.1%
33
The calculation of the sample size has been performed using the exact method 
described by Clopper and Pearson (Newcombe RG. Two-sided confidence 
intervals for the single proportion: comparison of seven methods. Stat Med 1998; 
17:857-72) as implemented in the version 15 of the PASS software (NCSS 
statistical software: PASS version 15, available at: ncss.com/software/pass).
Data analysis
A one-sided confidence interval will be constructed for the primary efficacy 
endpoint (proportion of responders by 16 weeks after the initiation of eltrombopag)
using the relationship between the sums of binomial probabilities and the F 
distribution described by Clopper and Pearson using the formulas proposed 
elsewhere (Fleiss JL, Levin B, Paik MC. Statistical Methods for Rates and 
Proportions. Third edition. John Wiley & Sons: New York, 2003, pp. 25):





;
2
,
1
2
0
0
0
0
0
1
x
x
n
L
F
x
n
x
x
P






Where α=0.05, x0 is the observed number of responders in the sample and n the 
sample size.
Key words
Eltrombopag, 
hematological 
response; 
poor 
graft 
function, 
stem 
cell 
transplantation.


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1
Background
1.1
Overview of graft failure after a stem cell transplantation and 
current treatment
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an effective treatment of 
malignant hematopoietic diseases. However, poor graft function (PGF), including early and late 
PGF, remains a life-threatening complication and is associated with serious infections or 
hemorrhagic complications after allo-HSCT (Kong et al., 2016). Variably defined in the 
literature but failure to achieve neutrophil engraftment and/or donor chimerism, it invariably 
represents failure of sustained hematopoietic function by the intended graft (Tsai et al., 2016). 
From the French Group and from a retrospective study of 124 patients, PGF can be defined as 
the existence of two or more cytopenias (hemoglobin <100 g/L, neutrophil count <1.0×109/L, 
platelet count <30×109/L) with transfusion requirements, associated with hypoplastic-aplastic 
bone marrow, in the presence of complete donor chimerism (>95% donor chimerism) and in 
the absence of severe graft versus host disease (GVHD) and relapse. It should not be diagnosed 
before day +30 or +42 (Cornillon et al., 2016, Xiao et al., 2014)
Several mechanisms may contribute to PGF. Risk factors associated include HLA disparity and 
ABO 
mismatching, 
use 
of 
reduced-intensity 
conditioning 
regimens, 
infections, 
myelosuppressive drugs, low nucleated cell dose of the graft, T-cell depletion of the graft and 
treatment for refractory GVHD (Larocca et al., 2006).
Underlying biological mechanisms are being studied and considerable data from murine studies 
have revealed that effective hematopoiesis depends on the specific bone marrow 
microenvironment known as niche where hematopoietic stem cells (HSC) reside. Bone marrow 
endothelial cells, perivascular cells and endosteal cells have been validated as the key cells that 
support HSCs in the murine bone marrow microenvironment.
The increasing of reduced intensity conditioning and wider application of human leukocyte 
antigen (HLA)-mismatched donors in recent years may have turned graft failure into an 
increasing problem reported a rate of PGF of 5-27% (Larocca et al., 2006, Xiao et al., 2014)
analyzed 124 patients with a median age of 28 years (4–60 years) who underwent an allo-SCT 
between 2009-2012. Among the 124 patients who received allo-HSCT, 15 experienced PGF 
(12.1%) with a median follow-up time of 7 months. They identified that patient age, donor-
recipient blood-type matching and cytomegalovirus (CMV) infection (in 30 days) were 
potential risk factors for PGF and suggest that elderly patients or those with incompatible donor-
recipient blood matches and/or at high-risk of CMV infection should receive early medical 
intervention (Xiao et al., 2014).
In the study reported by Sun et al. in 2015 in a series of 464 patients, similar rates were observed, 
but they also reported that subjects with early PGF have significantly poorer overall survival at 
2 years than subjects with good graft function (34.6 vs 87%, p <0.001) (Sun et al., 2015).
Current approaches to treat graft failure and which have been adapted to PGF as well are based 
on pharmacological and cellular-based treatments. Drugs such as cyclosporine, 
cyclophosphamide, antithymocyte globulin or mammalian target of Rapamycin (mTOR)
inhibitors are used, however these approaches are more useful in the prevention rather than in 


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the treatment of this complication. The cellular-based approaches include donor lymphocyte 
infusion (DLIs), regrafting and newer therapies such as infusion of mesenchymal stromal cells. 
DLIs reduces the risk of graft failure and can restore donor chimerism but can induce severe 
and sometimes fatal GVHD. Regrafting involves a second HSCT that can successfully rescue 
a remarkable proportion of patients but with a considerable impact on morbidity and mortality. 
To date, no single drug or strategy has incontrovertibly proven to be superior to another for 
reverting graft failure and current approaches are primarily based on its prevention (Locatelli et 
al., 2014). New drugs are mandatory to cover this medical need.
1.2
Introduction to investigational treatment(s) and other study 
treatment(s)
1.2.1
Overview of eltrombopag
Thrombopoietin (TPO) is the principal cytokine involved in the regulation of megakaryopoiesis 
and platelet production. Native TPO is a 60-70 kDa heavily glycosylated polypeptide of 332 
amino acids produced by the liver parenchymal, bone marrow and sinusoidal epithelial kidney 
cells (Geddis et al., 2002).
Eltrombopag olamine (ETB115) is an orally bioavailable small molecule TPO-R agonist. 
Eltrombopag interacts with the transmembrane domain of the TPO-R (also known as c-MPL) 
leading to increased platelet production. Once TPO-R (c-MPL receptor) is activated, it changes 
conformation, activating JAK family kinases and hence downstream signaling within the 
megakaryocyte via STAT, PI3K and MAPK effectors. This leads to cell proliferation and 
maturation into platelets. 
TPO is also known to be a critical regulator of hematopoiesis. The TPO receptor c-MPL is also 
expressed on HSCs, and knockout mice that lack c-MPL are deficient in HSCs. Eltrombopag 
was originally developed to stimulate thrombopoiesis in patients with immune 
thrombocytopenias. However, animal models and insights from congenital marrow failure 
syndromes indicate involvement of TPO signaling in HSC homeostasis as well as in 
thrombopoiesis (Desmond et al., 2014).
Eltrombopag has been approved for the treatment of adult patients with chronic immune 
thrombocytopenic purpura (ITP) in over 90 countries. Eltrombopag has been approved in the 
USA and the EU for pediatric patients aged 1 year and older with chronic ITP with insufficient 
response to corticosteroids or immunoglobulins. Eltrombopag has also been approved for the 
treatment of adult patients with hepatitis C virus (HCV)-related thrombocytopenia in over 45 
countries, and recently, in both the EU and USA for the treatment of adult patients with severe 
aplastic anemia (SAA) and insufficient responses to IST (Bussel et al., 2009, Erickson-Miller 
et al., 2009).  
Non-clinical pharmacology
Eltrombopag interacts with the transmembrane domain of the TPO-R on megakaryocytes and 
human bone marrow progenitor cells (Erickson-Miller et al., 2010, Sun et al., 2012). 
Eltrombopag increases hematopoiesis by inducing proliferation and differentiation of early 
1.2.1.1
Non-clinical experience


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bone marrow progenitor cells like endogenous TPO (Erickson-Miller et al., 2010, Jenkins et al., 
2007, Jeong and Vanasse, 2010). 
TPO-R is expressed on the surface of HSCs, as well as on cells of the megakaryocytic lineages.
TPO-R is reported to be essential for the maintenance of normal hematopoiesis (Ballmaier et 
al., 2003). Several preclinical experiments have demonstrated a necessary and positive 
influence of TPO and the TPO-R on expansion of HSC (Alexander et al., 1996, Kimura et al., 
1998, Qian et al., 2007, Zeigler et al., 1994). Eltrombopag also induces expansion of the early 
progenitor cells, resulting in an increased number of cells of multiple lineages (Sun et al., 2012). 
Since eltrombopag is capable of activating parts of the c-MPL signaling pathway 
(growth/differentiation factor), there was a theoretical concern that it could stimulate the 
proliferation and differentiation of leukemic cells. However, in several preclinical studies of 
cell lines of myelodysplastic syndrome/acute myeloid leukemia, it was demonstrated that 
eltrombopag given at high concentrations inhibited the proliferation of leukemic cells 
(Erickson-Miller et al., 2009, Kalota et al., 2015). This mechanism was characterized as a non-
TPO-R dependent pathway (Roth 2012). It has also been noted that eltrombopag displays 
trilineage hematopoietic effects and this, may offer benefit to patients with complete bone 
marrow failure (e.g. SAA) (Desmond et al., 2014, Olnes et al., 2012).
The ability of eltrombopag to interact with TPO-R in a non-competitive and additive way with 
TPO (Erickson-Miller et al., 2009) may suggest an additional mechanism for affecting a 
multilineage response from HSCs. Eltrombopag has demonstrated such effects on HSC in 
preclinical research (Sun et al., 2012). In aplastic anemia, eltrombopag may exert effects not 
only on megakaryocytes and their precursors, but also on erythroid and granulocyte lineages 
through stimulation of HSCs.
Non-clinical pharmacokinetics and metabolism
Absorption, distribution, metabolism and elimination (ADME) of eltrombopag have been 
investigated in mice, rats and dogs, the species used for the toxicity evaluation of eltrombopag.
Oral bioavailability of eltrombopag (parent compound) as a solution was low in the rat (26%) 
and high in dog (83%) and in monkey (89%). 
Eltrombopag is highly bound to plasma proteins in mouse, rat, dog, monkey and human 
(>99.9%). The plasma protein binding of eltrombopag to human serum albumin (HSA) was 
greater than to human alpha-1-acid glycoprotein (AAG). Eltrombopag is primarily eliminated
in feces as the intact moiety in nonclinical species. Minor metabolites derived from 
glucuronidation or oxidation were also detected in mouse, rat and dog bile. The predominant 
route of elimination of drug-related materials was via feces (73% to 97%), with urinary 
excretion representing a minor route of elimination (1.5% to 14%). In vitro, eltrombopag was 
shown to be an inhibitor of cytochrome P450 (CYP)2C8, CYP2C9, of several uridine 
diphosphate glucuronosyltransferases (UGT), of organic anion-transporting polypeptide 
(OATP)1B1 and breast cancer resistance protein (BCRP). In vitro studies demonstrated that 
eltrombopag was neither an inhibitor nor a substrate of human P-glycoprotein (Pgp).
Additional details on eltrombopag non-clinical pharmacokinetics (PK) can be found in the 
eltrombopag Investigator’s Brochure (IB).


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Non-clinical safety data
Eltrombopag has undergone a comprehensive non-clinical evaluation to support its safe use in 
adult and pediatric patients. This evaluation includes repeat dose toxicity studies of up to 13 
weeks in mice, 28 weeks in rats and 52 weeks in dogs. The toxic potential of eltrombopag was 
also assessed in a battery of in vitro and in vivo genetic toxicology studies, carcinogenicity 
studies in mice and rats, developmental and reproductive toxicology studies in rats and rabbits 
and immunotoxicity in rats and juvenile toxicity studies (dosing initiated on Day 4 postpartum) 
in rats. The principal non-clinical toxicology findings associated with eltrombopag treatment 
include cataracts (mice and rats), renal tubular toxicity (mice and rats) and hepatotoxicity (mice, 
rats and dogs). At non-tolerated doses, endosteal hyperostosis (femur and tibia) was observed 
in rats and effects on erythroid parameters (bone marrow erythroid hyperplasia in rats and 
decreased reticulocyte counts in rats and dogs) were observed. While eltrombopag was 
phototoxic in vitro, no in vivo phototoxicity was observed following single or repeated dosing 
in rats or mice.
Eltrombopag clinical development program has involved adult patients with SAA, chronic ITP, 
HCV infection, chronic liver disease, myelodysplastic syndrome, acute myeloid leukemia and 
solid tumors. Eltrombopag was also investigated in pediatric population. Two studies were 
designed for pediatric patients 1 to 17 years old with chronic immune thrombocytopenia. 
The use of eltrombopag to treat aplastic anemia as an adjunct to immunosuppressive therapy 
(IST) was reported in a phase II study of 25 patients, demonstrating hematological responses in 
44% of patients with some transitioning to transfusion independence and evidence on serial 
marrow biopsies of normalization of trilineage hematopoiesis (Olnes et al., 2012). The use of 
eltrombopag in this setting supports the notion the TRAs may induce in vivo stem cell 
expansion. Clonal evolution after eltrombopag treatment is one of the major concerns and 
remains under study (Olnes et al., 2012).
In patients with SAA who have not received prior definite IST, eltrombopag has been
investigated added to the standard regimen of h-ATG+CsA in a single-arm pilot phase I/II 
study conducted in the US (Townsley et al., 2017). Patients were consecutively enrolled in 
different cohorts that differed only by the starting date of eltrombopag, the duration of 
eltrombopag regimen and the addition of CsA maintenance regimen. Results from the cohort 3 
corresponding to patients received eltrombopag from day 1 to 6 months and concomitantly with 
h-ATG and CsA showed the highest rates of improvement in hematological parameters and
higher rates of complete and overall hematological response than in an historical cohort 
received IST.
Some studies have reported the off-label use of eltrombopag in the treatment for post-transplant 
thrombocytopenia with successful results (Popat et al., 2015) but recently some small case 
series with not only thrombocytopenia but also anemia and neutropenia have been published. 
Dyba et al. published a case of 56-year-old woman who underwent an allogeneic SCT with an 
unrelated HLA-mismatched donor and was diagnosed on day +121 with poor graft function. 
Eltrombopag 50mg daily was started and she responded quickly becoming transfusion-
independent, with normal blood counts within several weeks of treatment (Dyba et al., 2016).
1.2.1.2
Clinical experience


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In the EBMT 2017 Congress, a series of 6 patients from a cohort of 107 adults who underwent 
allo-HSCT from January 2015- November 2016 from a single center who received Eltrombopag 
150mg/day max for PFG was reported as a poster. Three transplants were from family donor 
(all of them haplo-identical), and 3 from unrelated donor (the three of them HLA 9/10). The 
responses were evaluated at 90 days after being with the maximum dose and multilineage 
responses were seen in 4 patients (66.6%). The 5 thrombocytopenic patients (100%) responded 
to eltrombopag, three anemic patients (75%) responded and finally, the 2 neutropenic patients 
(66.6%) (Lizardi and Vallejo, 2017).
This series of cases has been updated and data were presented in EBMT 2019 Congress. Twelve 
patients from a cohort of 175 initiated eltrombopag at some point during the first 6 months of 
the post-HSCT period due to thrombocytopenia (< 20000/mcL) plus, at least, one other 
cytopenia. Nine out of 12 patients did not have GVHD (population similar to ELTION patients), 
and 8 patients responded (Aguirre et al., 2019). 
2
Rationale
2.1
Study rationale and purpose
Poor graft function can be considered as a bone marrow failure and we hypothesize that the 
same situation of aplastic anemia can occur. Thrombopoietin can increase the hematopoietic 
stem cells number due to the presence of the receptor c-MPL on the cell surface of 
megakaryocytes, hematopoietic and stem cells, and eltrombopag is an oral thrombopoietin 
mimetic that binds to c-MPL, promoting hematopoiesis.  
Up to now, most of the experience of eltrombopag after HSCT has been limited to 
thrombocytopenia after transplantation. However, we think, because of the above reason, that 
other hematopoietic lines can be improved with the drug. The main objective of this study is 
therefore to assess the safety and efficacy of eltrombopag in patients with different cytopenias 
not attributable to other causes than PGF. 
2.2
Rationale for the study design
The lack of effective and safety medical treatments for patients diagnosed with PGF makes the 
use of eltrombopag an attractive therapeutic option to address this unmet medical need.
The design of the study, a pilot, open-label, nonrandomized, 36-week-long treatment is based 
on the previous experience in refractory SAA, the limited published data on patients with PGF 
treated with eltrombopag and the clinical experience of the PI, published as an abstract in the 
EBMT 2017 Congress. 
The hypothesis of the eltrombopag response rate in patients with PGF, the evaluation schedule 
of drug response (16 weeks) and the single arm design are based on Olnes and Desmond's 
studies (Desmond et al., 2014, Olnes et al., 2012) in refractory SAA. Townsley et al. (Townsley 
et al., 2017) have recently published results of the usefulness of eltrombopag in untreated 
patients with severe aplastic anemia. In that study, the primary efficacy endpoint was complete 
response at 24 weeks. Secondary endpoints included partial and overall hematologic responses 
at 12 weeks. The present study adapts this evaluation schedule. No prospective studies for 


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eltrombopag in patients with poor graft function have been reported so far. Given the lack of 
availability of a standard of care, no suitable comparator can be used in this study.
2.3
Rationale for dose and regimen selection
As stated before, there are no prospective studies about eltrombopag in patients diagnosed with 
poor graft function, so studies of eltrombopag in aplastic anemia are the most similar situation 
to PGF. 
The eltrombopag doses proposed in this study are adapted from those administered in a Phase 
II NIH study of triple therapy (eltrombopag + h-ATG + cyclosporine) in treatment naïve SAA 
patients (Townsley et al., 2017) Study NIH 12-H-0150 /ELT116643/CETB115AUS01T]). In 
that NIH study, eltrombopag was administered at 150 mg daily in non-Asian patients > 12 years. 
Eltrombopag was administered daily for a maximum of 24 weeks. The same doses will be 
evaluated in the present trial in non-Asian patients. Asian ancestry participants will be 
administered 50% of the eltrombopag dose (i.e. 75 mg daily) because of higher eltrombopag 
exposure due to differences in pharmacokinetics observed in this ethnic group. Based on 
estimates from the population pharmacokinetic analysis, Asian ancestry patients with VHC had 
approximately 55% higher plasma eltrombopag AUC (0-) values as compared to patients of 
other races predominantly Caucasian; and Asian ancestry patients with ITP had approximately 
49% higher plasma eltrombopag AUC (0-) values as compared to patients of other races 
predominantly Caucasian.
3
Objectives and endpoints
Objectives and related endpoints are described in Table 3-1 below.


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Table 3-1
Objectives and related endpoints
Objective
Endpoint
Analysis
Primary
Refer to Section 10.4
To evaluate the efficacy of eltrombopag for poor graft 
function on overall hematologic response (partial and
complete) as determined by platelets, hemoglobin and 
neutrophil counts, by 16 weeks after the initiation of 
eltrombopag.
Partial and complete response by 16 weeks after 
eltrombopag initiation
All patients exit from the study before week 16 but 
have a partial or complete response will also be 
considered as responders
Secondary
Refer to Section 10.5
To determine the response in each hematological 
lineage separately
-
Percentage of patients who have a response in the 
neutrophil lineage, defined as ANC ≥1,000/ µL or ≥ 
1500/ µL
according 
with the hematological 
responses defined in the primary objective, 
confirmed in two consecutive blood tests separated 
a minimum of 7 days. 
-
Percentage of patients who have a response in the 
platelet 
lineage, 
defined 
as 
Platelet 
count 
≥20,000/µL or ≥ 100000/µL according with the 
hematological responses defined in the primary 
objective, confirmed in two consecutive blood tests 
separated a minimum of 7 days.
-
Percentage of patients who have a response in the 
hemoglobin lineage, defined as Hb ≥100 g/L or ≥ 
110 g/L according with the hematological responses 
defined in the primary objective, confirmed in two 
consecutive blood tests separated a minimum of 7 
days


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Objective
Endpoint
Analysis
To evaluate the long-term efficacy of eltrombopag for 
poor graft function on overall hematologic response 
(partial and complete) at 24 and 36 weeks after 
treatment
Maintenance of hematologic response at 24 weeks 
and 36 weeks after the initiation of eltrombopag
Transfusion independence: To evaluate the 
transfusion independence for red blood cells (RBC) 
and/or platelets after the initiation of eltrombopag
- Percentage 
of 
patients 
previously 
transfusion-
dependent who do no longer require platelets and/or 
RBC transfusion before and after the first 16 weeks of 
treatment.
- Time period in which patients do not receive platelets 
and/or RBC transfusions.
Discontinuation or reduction of concomitant G-
CSF and/or EPO therapy
Percentage of patients who discontinue or reduce by 
≥50% the use of concomitant G-CSF and/or EPO 
therapy.
Overall survival
Time from the date of inclusion until the date of death 
due to any cause. All patients who discontinue from 
the study, regardless the reason of discontinuation, will 
be followed for survival for 24 and 36 weeks, unless 
they withdraw their consent, die or are lost-to follow-
up, in which case will be censored at the last contact.
Overall survival rate
Percentage of patients still alive at 24 weeks and 36 
weeks.
Safety: To evaluate the safety of eltrombopag.
Occurrence, incidence, severity of adverse events 
(AEs), serious adverse events (SAEs) based on the 
CTCAE criteria (v 4.03), and reasons for withdrawal 
from the study including the AEs leading to 
discontinuation.
Refer to Section 10.5.2


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Objective
Endpoint
Analysis
Physical examination, performance status, height and 
weight, vital signs, safety laboratory evaluations, ECG 
and ophthalmological monitoring.


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4
Study design
4.1
Description of study design
This study is designed as an open-label, single-arm phase II study, in which patients diagnosed 
with primary or secondary PGF after allo-HSCT will be treated with eltrombopag up to week 
36 or until the patient’s premature withdrawal. If patient terminates eltrombopag for any of the 
reasons established in the withdrawal criteria (see Sections 6.1.2/7.2.3.1), he/she will be 
followed for safety up to 30 days after the last dose of eltrombopag (Final Visit [or Early 
Withdrawal]), unless he/she withdraws the consent, dies or is lost-to follow-up.
The primary efficacy endpoint is the overall hematologic response rate (partial and complete) 
by 16 weeks after the initiation of eltrombopag. Eltrombopag will be initiated on day 1 at a dose 
of 150 mg once daily (75 mg daily in Asian ancestry patients) and will be continued up to 36
weeks. 
The study will consist of the following periods:
-
Screening Period (baseline): the patient will be invited to participate in the study, after 
being informed of its characteristics. The patient screening criteria will then be reviewed, 
and the procedures established in the evaluation schedule will be performed.
-
Treatment Period: from administration of the first dose of eltrombopag until time when 
patient permanently stops taking study treatment for any reason (see Sections 
6.1.2/7.2.3.1), or until 36 weeks have passed. 
-
Only patients with a partial or complete response at week 16 will continue to receive 
eltrombopag until loss of response (defined as a decrease in blood counts to levels 
that do not continue to meet the criteria for response established in this protocol), 
unacceptable toxicity, or discontinuation for any other reason (Sections 
6.1.2/7.2.3.1)
-
Patients who discontinue eltrombopag because efficacy (See Section 6.1.2), will
continue in the study and attend the scheduled visits of Treatment Period as per 
protocol. If loss of response occurs, eltrombopag will be reintroduced at the last 
effective dose (See Section 6.1.2)
During the Treatment Period, patients will be evaluated weekly during the first month, 
every 2 weeks during the next 2 months and subsequently every 4 weeks until week 24. 
For the last 3 months, patients will be followed every 6 weeks.
-
Final Visit (or Early Withdrawal): this visit will take place 30 days after completion of the 
Treatment Period, or premature patient withdrawal.
-
Follow-up for Survival: all patients who discontinue from the study, regardless the reason 
of discontinuation, will be followed for survival for 24 and 36 weeks, unless they 
withdraw their consent, die or are lost-to follow-up, in which case will be censored at the 
last contact/follow-up, and study visits will no longer be carried out.


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At 36 weeks of the study, the suitability of continuing with eltrombopag will be evaluated by 
the investigator, and the supply of the drug will be only commercial. Novartis will not supply 
eltrombopag after the end of the study.
The number of patients planned to be enrolled for the study is 33.
Figure 4-1    Study design
4.2
Timing of interim analyses and design adaptations
No interim analysis is planned for this study.
4.3
Definition of end of the study
The end of study (Last Patient Last Visit) will occur after all patients in the study have 
completed their last assessment as per protocol (Section 7.2.3.1-Criteria for premature patient 
withdrawal). 
4.4
Early study termination
The study can be terminated at any time for any reason by Novartis. 
If necessary, the patient should be seen as soon as possible and the same assessments should be 
performed as described in Section 7. The investigator may be informed of additional procedures 
to be followed to ensure that adequate consideration is given to the protection of the patient’s 
interests. The investigator will be responsible for informing IRBs and/or ECs of the early 
termination of the trial.
5
Population
The investigator or designee must ensure that only patients with poor graft function after 
hematopoietic stem cell transplantation and who meet all the following inclusion and none of 
the exclusion criteria are offered treatment in the study.
5.1
Inclusion criteria
Patients eligible for inclusion in this study have to meet all of the following criteria:
Written informed consent must be obtained before any screening procedures.
Visits interval
Visits
(weeks)
Screening/ 
baseline
Treatment periodwitheltrombopag 
from day 1 to 36 weeks
Final Visit
(or Early withdrawal)
-28 to day 0
Day 1
Weekly
visits
Biweekly
visits
Monthly
visits
Visits
every 6 weeks
30 days after 
completion of the
Treatment Period
1
2
3 
(w1)
4 
(w2)
5
(w3)
6
(w4)
7
(w6)
8 
(w8)
9
(w10)
10
(w12)
11
(w16)
12
(w20)
13
(w24)
14
(w30)
15
(w36)
16
(w40)
Hematologic
response 
at week 16
▼
Hematologic
response 
at week 36
▼
Hematologic
response 
at week 24
▼


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1. Patient must be able to understand and communicate with the investigator and comply 
with the requirements of the study and must provide written, signed and dated informed 
consent form before any study assessment is performed.
2. Male or female patients ≥ 18 years of age 
3. Patients diagnosed with primary or secondary PGF after allo-HSCT defined as two or 
more cytopenias after day +30 post-transplant (re-tested in a peripheral blood analysis at 
screening): 
-
Platelet count <20,000/ µL (mandatory)
-
Absolute neutrophil count (ANC) <1,000/µL
-
Hemoglobin < 100 g/L
4. Presence of donor chimerism >90% in screening visit
5. Karnofsky status ≥90% (Karnofsky assessment must be performed within 7 days prior to
Day 1)
5.2
Exclusion criteria
Patients eligible for this study must not meet any of the following criteria:
1. Pregnancy statements and contraception requirements:
Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female 
after conception and until the termination of gestation, confirmed by a positive hCG 
laboratory test.
Women of child-bearing potential, defined as all women physiologically capable of becoming 
pregnant (or female partners of male patients), unless they are using highly effective methods 
of contraception during dosing and for 3 months after stopping medication. Highly effective 
contraception methods include:

Total abstinence (when this is in line with the preferred and usual lifestyle of the 
subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation 
methods) and withdrawal are not acceptable methods of contraception.

Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy), or tubal ligation at least six weeks before taking study treatment. In
case of oophorectomy alone, only when the reproductive status of the woman has 
been confirmed by follow up hormone level assessment. 

Male sterilization (at least 6 months prior to screening). For female subjects on the 
study the vasectomized male partner should be the sole partner for that subject 

Use of oral, injected or implanted hormonal methods of contraception or placement of 
an intrauterine device (IUD) or intrauterine system (IUS), or other forms of hormonal 
contraception that have comparable efficacy (failure rate <1%), for example hormone 
vaginal ring or transdermal hormone contraception.
In case of use of oral contraception women should have been stable on the same pill for a 
minimum of 3 months before taking study treatment.


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Sexually active males unless they use a condom during intercourse while taking the drug during 
treatment and for 3 months after stopping treatment and should not father a child in this period. 
A condom is required to be also used by vasectomized men as well as during intercourse with 
a male partner to prevent delivery of the drug via semen.
2. Evidence of active acute or chronic graft versus host disease (GVHD).
3. Evidence of any active malignancy.
4. Subjects who are human immune deficiency virus (HIV), hepatitis C virus (HCV), hepatitis 
B surface antigen (HBsAg) positive in screening visit.
5. Cytogenetic abnormality in chromosome 7 present before the allo-HSC.
6. Evidence of any clonal abnormality on cytogenetics (in bone marrow analysis).
- A local post-transplant conventional cytogenetic assessment should be available 
within 8 weeks before Day 1.
- If the cytogenetics is not valuable, i.e, it does not show metaphases, a FISH for 
MDS-related most frequent abnormalities including chromosome 7 is accepted.
As a consequence, patients with dry tap bone marrow aspiration are NOT eligible.
7. Evidence of bone marrow involvement or progression of the underlying disease assessed 
by the applicable methods in each case.
8. Evidence of thrombotic microangiopathy.
9. Evidence of possible causes of cytopenia other than PGF (active infections, myelotoxic
drugs, hypersplenism…).
10. Prior use of any thrombopoietin receptor (TPO-R) agonists for PGF.
11. AST or ALT levels >3 x ULN.
12. Creatinine level ≥1.5 x ULN.
13. Total bilirubin level ≥1.5 x ULN.
14. Previous thromboembolic event (other than line-related upper extremity thrombosis)
15. Hypersensitivity to eltrombopag or its components.
16. Clinically significant ECG abnormality history or current diagnosis of cardiac disease
indicating significant risk of safety for subjects participating in the study such as 
uncontrolled or significant cardiac disease or impaired cardiac function including any of the
following:  
a). Corrected QTc > 450 msec (male subjects), > 460 msec (female subjects) using 
Fredericia correction (QTcF) on the screening ECG
b). Myocardial infarction
c). Uncontrolled congestive heart failure
d). Unstable angina 
e). Congenital long QT syndrome.
17. Administration of an investigational drug within 30 days or 5 half-lives, whichever is longer, 
preceding the first dose of study treatment.
18. Patient with liver cirrhosis.
19. Risk factors for Torsade de Pointes including uncorrected hypokalemia or 
hypomagnesemia. 


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20. Subjects with any serious and/ or unstable pre-existing medical, psychiatric disorder or other 
conditions that could interfere with patient´s safety, obtaining informed consent or 
compliance with the study procedures as per investigator discretion.
6
Treatment
6.1
Study treatment
The study treatment for this trial is eltrombopag.
6.1.1
Dosing regimen
Table 6-1
Dose and treatment schedule
Study treatments
Pharmaceutical form 
and route of 
administration
Dose
Frequency and 
Regimen
Eltrombopag
Film-coated tablet for 
oral use
Administration at a daily dose 
of 150 mg (75 mg in Asian 
Ancestry participants).
The maximum permissible 
dose of eltrombopag in this 
study will be 150 mg daily and 
75 mg daily for Asian ancestry
participants.
Daily 
Patients will receive 150 mg of eltrombopag orally once daily up to 36 weeks. The starting dose 
will be 150 mg daily, except for Asian ancestry participants, in whom it will be 75 mg daily to 
adjust for the lower eltrombopag apparent clearance observed in this population. 
Eltrombopag doses should be taken at least 2 hours before or 4 hours after any products such 
as antacids, dairy products, or mineral supplements containing polyvalent cations (e.g., 
aluminum, calcium, iron, magnesium, selenium, and zinc). Eltrombopag may be taken with 
food containing little (<50 mg) or preferable no calcium. If the patient forgets to take a dose, 
the dose should be restarted the next day at the usual time.
6.1.2
Treatment duration
The duration of treatment with eltrombopag will based on the reasons described below and 
other reasons for early withdrawal (Section 7.2.3.17.2.3.1):

If no partial or complete hematological response is observed at 16 weeks and maintained 
afterwards, the patient will be withdrawn from the study.

In patients achieving complete response without transfusion support for a minimum of 8 
weeks, the dose of eltrombopag may be reduced by 50%, and discontinued if counts remain 
stable after 8 weeks at the reduced dose. If relapse occurs after eltrombopag discontinuation, 
eltrombopag can be reintroduced at the last effective dosage. 

If new clonal cytogenetic abnormalities associated with dysplastic bone marrow findings 
are observed such as monosomy 7, eltrombopag should be permanently discontinued.


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
If the patient develops myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) 
assessed by sensitive methods, eltrombopag will be permanently discontinued.

If other non-clonal and/or cytogenetic abnormalities with uncertain meaning not previously 
observed and not associated with worsening blood counts or bone marrow dysplastic, the 
decision of discontinuing eltrombopag is up to the investigator, based on a more frequent 
bone marrow aspirate monitoring of cytogenetic abnormalities and dysplastic findings.

If relapse of previous hematological disease occurs, eltrombopag will be permanently 
discontinued. 

If patient receives a new HSCT, eltrombopag will be permanently discontinued
6.2
Dose modifications
6.2.1
Dose modification and dose delay
For patients who do not tolerate the protocol-specified dosing schedule, dose adjustments are 
mandated to allow the patient to continue the study treatment. The daily dose of eltrombopag 
will be decreased to prevent thrombocytosis according to the following guidelines (Table 6-2).
All dose modifications should be based on the worst preceding toxicity. If study treatment is 
being held due to toxicity, scheduled visits and all assessments should continue as scheduled, 
except without dosing. 
These changes must be recorded on the Dosage Administration Record CRF.
Table 6-2
Criteria for dose management of eltrombopag based on platelets 
count
The maximum permissible dose of eltrombopag will be 150 mg daily, except in Asian ancestry
participants that will be 75 mg daily 
Platelet count
Dose adjustment
>20,000/μL to 150,000/μL
Keep the same dose
150,000/μL to 250,000/μL
Decrease dosage by 25 mg every 2 weeks to lowest dose than 
maintains platelet count ≥50,000/μL
>250,000/μL
Discontinue eltrombopag for one week, if platelet count falls to 
<100,000/μL; restart a dosage decreased by 25 mg/day
Eltrombopag can cause hepatobiliary laboratory abnormalities, severe hepatotoxicity, and 
potentially fatal liver injury. Serum ALT, AST and bilirubin should be measured before 
initiation of eltrombopag, and at every clinic visit during the whole study. Abnormal serum
liver tests should be evaluated with repeat testing as described in table 6-3. If the abnormalities 
are confirmed, serum liver tests should be monitored weekly until the abnormalities resolve, 
stabilize, or return to baseline levels. Please follow the dose modifications for isolated 
ALT/AST and bilirubin elevation described in Table 6-3.
6.2.1.1
Dose modifications based on hematologic response
6.2.1.2
Dose modifications due to liver signals


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


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> 5.0 - 10.0 x ULN
Mandatory: Interrupt dose.
Repeat LFTsb as soon as possible; preferably within 
48-72 hours from awareness of the abnormal results. 
Monitor LFTsb weekly, or more frequently if clinically 
indicated until resolved to ≤ 3.0 x ULN then:
If resolved in ≤14 days, maintain dose level
If resolved >14 days, decrease one dose level e
> 10.0 - 20.0 x ULN 
Mandatory: Interrupt dose.
Repeat LFTsb as soon as possible, preferably within 
48-72 hours from awareness of the abnormal results. 
Monitor LFTsb weekly, or more frequently if clinically 
indicated until resolved to ≤ baseline.
Then decrease one dose level e.
> 20.0 x ULN
Mandatory: Discontinue patient from study drug 
treatment.
Repeat LFTsb as soon as possible, preferably within 
48-72 hours from awareness of the abnormal results. 
Monitor LFTsb weekly, or more frequently if clinically 
indicated until resolved to ≤ baseline or stabilization 
over 4 weeks.
Combined c elevations of AST or ALT and total bilirubin
For patients with normal baseline ALT and AST and 
total bilirubin value, [AST or ALT > 3.0 × ULN] 
combined with [total bilirubin > 2.0 × ULN] without 
evidence of cholestasisd
OR 
For patients with elevated baseline AST or ALT [AST 
or ALT > 3 × baseline] OR [AST or ALT > 5.0 × ULN], 
whichever is lower, combined with [total 
bilirubin > 2× baseline AND > 2.0 × ULN]
Mandatory: Permanently discontinue patient from 
study drug treatment.
Repeat as soon as possible, preferably within 48 
hours from awareness of the abnormal results, then 
with weekly monitoring of LFTsb), or more frequently 
if clinically indicated, until AST, ALT, or bilirubin have 
resolved to baseline or stabilization over 4 weeks.
All dose modifications should be based on the worst preceding toxicity.
a Common Toxicity Criteria for Adverse Events (CTCAE Version 4.03)
b Core LFTs consist of ALT, AST, GGT, total bilirubin (fractionated [direct and indirect], if total bilirubin > 2.0 x 
ULN), and alkaline phosphatase (fractionated [quantification of isoforms], if alkaline phosphatase > 2.0 x 
ULN.)
c “Combined” defined as total bilirubin increase to the defined threshold concurrently with ALT/AST increase 
to the defined threshold
If combined elevations of AST or ALT and total bilirubin do not meet the defined thresholds, please follow the 
instructions for isolated elevation of total bilirubin and isolated elevation of AST/ALT, and take a conservative 
action based on the degree of the elevations (e.g. discontinue treatment at the situation when omit dose is 
needed for one parameter and discontinue treatment is required for another parameter). After all elevations 
resolve to the defined thresholds that allow treatment re-initiation, re-start the treatment either at the same 
dose or at one dose lower if criterion for dose reduction is met.
d “Cholestasis” defined as ALP elevation (>2.0 xULN and R value <2) in patients without bone metastasis, or 
elevation of ALP liver fraction in patients with bone metastasis. The R value is calculated by dividing the ALT 
by the ALP, using multiples of the ULN for both values. It denotes whether the relative pattern of ALT and/or 
ALP elevation is due to cholestatic (R ≤ 2), hepatocellular (R ≥ 5), or mixed (R >2 and < 5) liver injury.
e “One dose level” defined as eltrombopag dose reduction by 25 mg.
Eltrombopag dosing is to be temporarily discontinued in patients unable to ingest the drug due 
to mucositis or permanent vomiting.
6.2.1.3
Dose modification for other reasons


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6.2.2
Follow-up for toxicities
Patients whose treatment is interrupted or permanently discontinued due to an adverse event or 
clinically significant laboratory value must be followed up at least once a week (or more 
frequently if required by institutional practices, or if clinically indicated) for 4 weeks, and 
subsequently at approximately 4-week intervals, until resolution or stabilization of the event, 
whichever comes first. Appropriate clinical experts such as ophthalmologist, etc. should be 
consulted as deemed necessary.
All patients must be followed for safety for 30 days following the last dose of eltrombopag. In 
the case of patients who discontinue prematurely eltrombopag because efficacy but continue in 
the study (see Section 6.1.2) they will be followed for safety until complete all the planned visits 
of the study.
Patients who experience a deep venous thrombosis (other than a line-related upper extremity 
thrombosis) or a pulmonary embolus, a transient ischemic attack or stroke, or a myocardial 
infarction at any time while on eltrombopag will discontinue eltrombopag. 
Patients who experience an infection requiring intravenous antibiotics will not discontinue 
eltrombopag. If the patient experiences infection severe enough to require intubation, 
eltrombopag will be withheld until the patient is more clinically stable.
6.2.3
Anticipated risks and safety concerns of the study drug
Thrombotic/Thromboembolic complications
The risk of thromboembolic events (TEEs) has been found to be increased in patients with 
chronic liver disease treated with 75 mg eltrombopag once daily for two weeks in preparation 
for invasive procedures. Six of 143 (4%) adult patients with chronic liver disease receiving 
eltrombopag experienced TEEs (all of the portal venous system) and two of 145 (1%) patients 
in the placebo group experienced TEEs (one in the portal venous system and one myocardial 
infarction). Five of the 6 patients treated with eltrombopag experienced the thrombotic 
complication at a platelet count >200 x 109/L and within 30 days of the last dose of eltrombopag. 
Eltrombopag is not indicated for the treatment of thrombocytopenia in patients with chronic 
liver disease in preparation for invasive procedures. In eltrombopag clinical trials in ITP, TEEs 
were observed at low and normal platelet counts. Caution should be used when administering 
eltrombopag to patients with known risk factors for thromboembolism including but not limited 
to inherited (e.g. Factor V Leiden) or acquired risk factors (e.g. ATIII deficiency, 
antiphospholipid syndrome), patients with prolonged periods of immobilization, malignancies, 
contraceptives and hormone replacement therapy, surgery/trauma, obesity and smoking. 
Platelet counts should be closely monitored and dose modifications must be made in accordance 
with parameters provided in the protocol.
The risks of thromboembolism and any of the following complications versus the benefit of 
improved platelet counts must be evaluated by the Investigator for each patient with known 
risks of TEEs.
6.2.2.1
Management of hematologic side effects
6.2.2.2
Management of non-hematologic side effects


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Risk of hepatotoxicity
Eltrombopag administration can cause hepatobiliary laboratory abnormalities, severe
hepatotoxicity and potentially fatal liver injury. In the controlled clinical studies in chronic ITP 
with eltrombopag, increases in serum ALT, AST and bilirubin were observed. Hepatotoxicity 
should be monitored and eltrombopag should be discontinued if hepatobiliary abnormalities are 
observed as described in section 6.2.1.2. Exercise caution when administering eltrombopag to 
patients with hepatic disease.
Ophthalmic changes
Cataracts were observed in toxicology studies of eltrombopag in rodents but have not been 
reported at significant rates over control groups in human trials. In controlled studies in 
thrombocytopenic patients with HCV receiving interferon therapy (n = 1439), progression of 
pre-existing baseline cataract(s) or incident cataracts was reported in 8% of the eltrombopag 
group and 5% of the placebo group. Retinal hemorrhages, mostly grade 1 or 2, have been 
reported in HCV patients receiving interferon, ribavirin and eltrombopag (2% of the 
eltrombopag group and 2% of the placebo group). Hemorrhages occurred on the surface of the 
retina (preretinal), under the retina (subretinal), or within the retinal tissue. Ophthalmological
examination (see Section 7.3.2.87.3.2.8) should be performed at baseline, 24 weeks, and also at 
Final Visit (or Early Withdrawal). Eltrombopag continuation should be re-considered if 
suspected cataract development or worsening, or in case of retinal hemorrhages. In clinical trials 
of eltrombopag in SAA cataracts have not been reported. There is no evidence of cataracts in 
PGF. 
Bone marrow reticulin formation and risk of bone marrow fibrosis
Eltrombopag may increase the risk for development or progression of reticulin fibers within the 
bone marrow. The relevance of this finding, as with other TPO-R agonists, has not been 
established yet.
If immature or dysplastic cells not linked to primary disease are observed, peripheral blood 
smears should be examined for new or worsening morphological abnormalities (e.g., teardrop 
and nucleated red blood cells, immature white blood cells) or cytopenia(s). If the patient 
develops new or worsening morphological abnormalities and cytopenia(s) not linked to primary 
disease, treatment with eltrombopag should be discontinued. A bone marrow biopsy must be 
considered, including staining for fibrosis. 
Progression of existing myelodysplastic syndrome
TPO-R agonists are growth factors that lead to thrombopoietic progenitor cell expansion, 
differentiation and platelet production. The TPO-R is predominantly expressed on the surface 
of cells of the myeloid lineage. For this class of TPO-R agonists, there is a concern that they 
may stimulate the progression of existing hematopoietic malignancies such as myelodysplastic 
syndrome.
In clinical studies with a TPO-R agonist, romiplostim and eltrombopag, in patients with MDS, 
cases of transient increases in blast cell counts were observed and cases of MDS disease 
progression to AML were reported. 


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In the CETB115AUS01T study, eltrombopag in combination with IST was assessed in patients
with SAA. Published results indicate that clonal cytogenetic evolution with dysplastic changes
occurred at a similar frequency compared to NIH historic experience with standard IST (10-
15%) (Townsley et al., 2017). All patients should be monitored regularly for new or worsening
morphological abnormalities or cytopenia(s), and may require bone marrow evaluation, as
clinically indicated.
Eltrombopag should be discontinued in case of suspected myeloproliferation not linked to the 
primary disease or if there is a suspected myeloproliferation due to eltrombopag treatment. 
Bleeding events after study drug discontinuation
Following discontinuation of eltrombopag, platelet counts return to baseline levels within 2
weeks in the majority of patients, which increases the bleeding risk and, in some cases, may 
lead to bleeding. Platelet counts should be monitored as per protocol following discontinuation 
of eltrombopag.
6.2.4
Follow-up on potential drug-induced liver injury (DILI) cases
Patients with transaminase increase combined with TBIL increase may be indicative of 
potential DILI and should be considered as clinically important events.
The threshold for potential DILI may depend on the patient’s baseline AST/ALT and TBIL 
value; patients meeting any of the following criteria will require further follow-up as outlined 
below:

For patients with normal ALT and AST and TBIL values at baseline: AST or ALT >3.0 x 
ULN combined with TBIL >2.0 x ULN.

For patients with elevated AST or ALT or TBIL value at baseline: [AST or ALT >2.0 x 
baseline AND >3.0 x ULN] OR [AST or ALT >8.0 x ULN], combined with [TBIL >2.0 x 
baseline AND >2.0 x ULN].
Medical review needs to ensure that liver test elevations are not caused by cholestasis, defined 
as alkaline phosphatase (ALP) elevation >2.0 x ULN with R value <2 in patients without bone 
metastasis, or elevation of ALP liver fraction in patients with bone metastasis.
NOTE: The R value is calculated by dividing the ALT by the ALP, using multiples of the ULN 
for both values. It denotes whether the relative pattern of ALT and/or ALP elevation is due to 
cholestatic (R ≤2), hepatocellular (R ≥5), or mixed (R >2 and <5) liver injury.
In the absence of cholestasis, these patients should be immediately discontinued from study 
drug treatment, and repeat LFT testing as soon as possible, preferably within 48 hours from the 
awareness of the abnormal results. 
The evaluation should include laboratory tests, detailed history, physical assessment and the 
possibility of liver metastasis or new liver lesions, obstructions/compressions, etc.:
1. Laboratory tests should include: ALT, AST, albumin, creatine kinase, total bilirubin, direct 
and indirect bilirubin, GGT, prothrombin time (PT)/INR and alkaline phosphatase.


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2. A detailed history, including relevant information, such as review of ethanol, concomitant 
medications, herbal remedies, supplement consumption, history of any pre-existing liver 
conditions or risk factors, should be collected.
3. Further testing for acute hepatitis A, B, C or E infection and liver imaging (e.g. biliary tract) 
may be warranted.
4. Obtain PK sample, as close as possible to last dose of study drug, if PK analysis is performed 
in the study.
5. Additional testing for other hepatotropic viral infection (CMV, EBV or HSV), autoimmune 
hepatitis or liver biopsy may be considered as clinically indicated or after consultation with 
specialist/hepatologist.
All cases confirmed on repeat testing meeting the laboratory criteria defined above, with no 
other alternative cause for LFT abnormalities identified should be considered as “medically 
significant”; thus, they meet the definition of SAE (Section 8.2.1) and should be reported as 
SAE using the term “potential drug-induced liver injury”. 
All events should be followed up with the outcome clearly documented.
6.3
Concomitant medications
The patient must be told to notify the investigational site about any new medications he/she 
takes after the start of the study drug. All medications (other than study drug) and significant 
non-drug therapies (including physical therapy, herbal/natural medications and blood 
transfusions) administered during the study, and those taken 30 days prior to study entry must 
be listed on the Concomitant Medications CRF.  
6.3.1
Permitted concomitant therapy
Granulocyte colony-stimulating factor (G-CSF) and erythropoietin (EPO) therapies are 
permitted.
Transfusions for platelets and/or RBC may be given, as medically needed.
HMG-CoA Reductase Inhibitors (statins)
Patients will be permitted to use HMG-CoA reductase (3-hydroxy-3-methyl-glutaryl-CoA) 
inhibitors during the study, but these drugs should be used with caution and a 50% dose 
reduction of the HMG-CoA reductase inhibitor is recommended, with close monitoring for 
safety, such as liver chemistry and signs and symptoms of myolysis, and efficacy, such as 
cholesterol and triglycerides (refer to individual product information for monitoring 
recommendations).
Preclinical data showed that eltrombopag is an inhibitor of the transporters OATP1B1 and 
BCRP. Therefore, a clinical drug interaction study to evaluate the impact of eltrombopag on the 
PK of rosuvastatin, an OATP1B1 and BCRP substrate, was conducted in healthy patients. 
6.3.1.1
Supportive care
6.3.1.2
Permitted concomitant therapy requiring caution and/or action 


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Co-administration of eltrombopag 75 mg once daily for 5 days with a single 10 mg dose of
rosuvastatin administered on Day 5 increased plasma rosuvastatin Cmax 2.03-fold and AUCinf 
55%.
Concomitant administration of eltrombopag and other OATP1B1 or BCRP substrates should 
be used with caution.
Polyvalent Cations (Chelation)
Eltrombopag chelates with polyvalent cations such as aluminum, calcium, iron, magnesium, 
selenium and zinc. Eltrombopag should be taken at least two hours before or four hours after 
any products such as antacids, dairy products, or mineral supplements containing polyvalent 
cations to avoid significant reduction in eltrombopag absorption.
Food Interaction
Administration of a single 50 mg-dose of eltrombopag with a standard high-calorie, high-fat 
breakfast that included dairy products reduced plasma eltrombopag AUCinf by 59% (90% CI: 
54%, 64%) and Cmax by 65% (90% CI: 59%, 70%). Foods low in calcium (defined as <50 mg 
calcium per serving) including fruit, lean ham, beef and unfortified (no added calcium, 
magnesium, iron) fruit juice, unfortified soy milk, and unfortified grain did not significantly 
impact plasma eltrombopag exposure, regardless of calorie and fat content. To avoid significant 
reduction in eltrombopag absorption, eltrombopag should be taken at least two hours before or
four hours after food containing >50 mg calcium and at least one hour before or two hours after 
food containing little (<50 mg) (or preferably no) calcium.
QT prolonging drugs
A definitive list of drugs associated with QT prolongation and/or TdP is available online at 
www.qtdrugs.org.
A QTc study in healthy volunteers dosed 150 mg eltrombopag per day did not show a clinically 
significant effect on cardiac repolarization. QTc interval prolongation has been reported in 
clinical studies of patients with ITP and thrombocytopenic patients with HCV. The clinical 
significance of these QTc prolongation events is unknown.
There are drugs that can prolong QT interval. Therefore, QT interval should be monitored and 
Summary of product characteristics (SmPC) of the concomitant medications given must be 
followed. Any AEs in this area should be carefully checked and evaluated by the investigators 
for causality taking into consideration all these points.
6.3.2
Prohibited concomitant therapy
The following medications are prohibited:

Any other TPO-R agonists are prohibited during this study (e.g., N-plate [romiplostim]). 

Use of corticoids at doses higher than 0.33 mg/kg/day is also prohibited (equivalent doses
of prednisone).


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6.4
Patient numbering, treatment assignment or randomization
6.4.1
Patient numbering
Each patient is identified in the study by a Patient Number (Patient No.), that is assigned when 
the patient is first enrolled for screening and is retained as the primary identifier for the patient 
throughout his/her entire participation in the trial. The Patient No. consists of the Center 
Number (Center No.) (as assigned by Novartis to the investigative site) with a sequential patient 
number suffixed to it, so that each subject is numbered uniquely across the entire database. 
Upon signing the informed consent form (ICF), the patient is assigned to the next sequential 
Patient No. available to the investigator. Once assigned the patient number will not be used 
again.
6.4.2
Treatment assignment or randomization
This is a single-arm study. 
The investigational treatment (eltrombopag) will be provided by Novartis to all participants:  
No randomization processes will apply in this clinical trial.
6.4.3
Treatment blinding
This is an open-label study.
6.5
Study drug preparation and dispensation
The study drug (eltrombopag) does not need to be prepared.
The investigator or responsible site personnel must instruct the patient or caregiver to take the 
study drug as per protocol. Study drug will be dispensed to the patient by authorized site 
personnel only. All dosages prescribed to the patient and all dose changes during the study must 
be recorded on the Dosage Administration Record CRF.
6.5.1
Study drug packaging and labeling
Eltrombopag will be sourced as local commercial supply (in the locally approved formulation 
and packaging configuration) and labeled in the country. Study treatment labels will be in the 
local language and will comply with the legal requirements of the country.
Eltrombopag will be provided as 25 mg and 50 mg film-coated tablets. They are packaged in 
aluminum blisters. Each package contains 28 film-coated tablets.
6.5.2
Drug supply and storage
Eltrombopag must be received by designated personnel at the study site, handled and stored 
safely and properly, and kept in a secured location to which only the investigator and designated 
site personnel have access. Upon receipt, eltrombopag should be stored according to the 
instructions specified on the drug labels. Eltrombopag does not require any special storage 
conditions. 


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Table 6-4
Supply and storage of study treatments 
Study treatments
Supply
Storage
Eltrombopag
Locally supplied by Novartis
Eltrombopag does not require any 
special storage conditions. 
6.5.3
Study drug compliance and accountability
Patients will be asked to return all unused study treatment and packaging at each visit, at the 
end of the study or at the time of study treatment discontinuation. Compliance will be assessed 
by the investigator and/or study personnel at each patient visit and information provided by the 
patient and/or caregiver will be captured in the Drug Accountability Log (DAL). This 
information must be captured in the source document at each patient visit.
The investigator or designee must maintain an accurate record of the shipment and dispensing 
of study treatment in a drug accountability log. Drug accountability will be monitored by the 
field monitor during site visits and at the completion of the study.
At study close-out, and, as appropriate during the course of the study, the investigator will return 
all used and unused study treatment, packaging, drug labels, and a copy of the completed drug 
accountability log to the Novartis (or designated CRO) monitor, or to the Novartis address 
provided in the investigator folder at each site.
Not applicable.
6.5.4
Disposal and destruction
The study drug supply can be destroyed at the local Novartis facility, Drug Supply group or 
third party, as appropriate.  
7
Visit schedule and assessments
7.1
Study flow and visits schedule
Table 7-1 lists all of the assessments and indicates with an “X”, the visits when they are 
performed. All data obtained from these assessments must be supported in the patient’s source 
documentation.
Tests, procedures, and visits that occur within the planned allowable windows as specified 
below will not constitute protocol deviations. All visit intervals are calculated from the first 
dose of eltrombopag that will take place on Day 1. All attempts should be made to return to the 
original schedule of visits if visits are completed out of window. Weekly and biweekly visits 
should be completed ± 1 day. Monthly visits and every 6-week visits should be completed ± 3
days. Bone marrow testing may be performed ± 1 month from the scheduled time point except 
in the screening visit where BMA must be done in the screening period (within 28 days).
6.5.3.1
Study drug compliance
6.5.3.2
Study drug accountability
6.5.3.3
Handling of other study treatment


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Table 7-1
Visit evaluation schedule
Protocol 
Section 
Screening/
baseline
Day 
1
Weekly visits 
(±1 day)
Visits every 2 weeks
(±1 day)
Monthly visits
(± 3 days)
Approx. 
every 6 
weeks (±3 
days) up to 
36 weeks
Final Visit
(or Early 
Withdrawal) 
*
W
1
W
2
W
3
W
4
W
6
W
8
W
10
W
12
W
16
W
20
W
24
W
30
W
36
W
40
Visit Number
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
Day of visit
-28 to 
day 0
-7 to 
day 0
Day 
1
Day
8
Day 
15
Day 
22
Day 
29
Day 
43
Day 
57
Day 
71
Day 
85
Day
113
Day 
141
Day 
169
Day
211
Day
253
Day 
283
Informed consent
11.3
X
Inclusion/
exclusion criteria
5.1 /5.2
X
Demography
7.2.1.3
X
Relevant medical 
history/current 
medical 
conditions
7.2.1.3
X
Documentation of 
underlying 
disease
7.2.1.3
X
Detailed 
description of the 
transplant
7.2.1.3
X
Documentation of 
conditioning 
regimen
7.2.1.3
X
Review of 
prophylaxis and 
treatment of 
GVHD
7.2.1.3
X


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Protocol 
Section 
Screening/
baseline
Day 
1
Weekly visits 
(±1 day)
Visits every 2 weeks
(±1 day)
Monthly visits
(± 3 days)
Approx. 
every 6 
weeks (±3 
days) up to 
36 weeks
Final Visit
(or Early 
Withdrawal) 
*
W
1
W
2
W
3
W
4
W
6
W
8
W
10
W
12
W
16
W
20
W
24
W
30
W
36
W
40
Visit Number
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
Day of visit
-28 to 
day 0
-7 to 
day 0
Day 
1
Day
8
Day 
15
Day 
22
Day 
29
Day 
43
Day 
57
Day 
71
Day 
85
Day
113
Day 
141
Day 
169
Day
211
Day
253
Day 
283
Cytogenetic 
analysis/FISH in 
bone marrowa
7.2.1.3
X
Supportive care 
6.3.1.1/
7.3.1.2
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical
examination
7.3.2.1
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Karnofsky 
performance 
status
7.3.2.2
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Height b and 
weight
7.3.2.3
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Vital signs
7.3.2.4
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Donor Chimerism
7.3.2.5
X
Hematologyc
7.3.2.5
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Biochemistry/ 
Immunology/ 
Microbiology/ 
Othersc
7.3.2.5
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Serology (HIV, 
HBV, HCV)
7.3.2.5
X
Urinalysis
7.3.2.5
X


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Protocol 
Section 
Screening/
baseline
Day 
1
Weekly visits 
(±1 day)
Visits every 2 weeks
(±1 day)
Monthly visits
(± 3 days)
Approx. 
every 6 
weeks (±3 
days) up to 
36 weeks
Final Visit
(or Early 
Withdrawal) 
*
W
1
W
2
W
3
W
4
W
6
W
8
W
10
W
12
W
16
W
20
W
24
W
30
W
36
W
40
Visit Number
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
Day of visit
-28 to 
day 0
-7 to 
day 0
Day 
1
Day
8
Day 
15
Day 
22
Day 
29
Day 
43
Day 
57
Day 
71
Day 
85
Day
113
Day 
141
Day 
169
Day
211
Day
253
Day 
283
Pregnancy testd
7.3.2.6
X
X
X
X
X
X
X
X
X
X
ECG
7.3.2.7
X
X
X
Ophthalmological 
examination
7.3.2.8
X
X
X
Blood smeare
7.3.2.5
X
X
X
X
X
X
X
X
X
X
Dispense/collect 
eltrombopagg
6.5
X
X
X
X
X
X
X
X
X
X
X
X
X
Xh
Concomitant
Medication inquiry
6.3
Record from signing of Informed Consent Form
Adverse events 
inquiry
8.1
Record from signing of Informed Consent Form 
Hematological 
response
7.3.1.1
X
X
X
X
X
X
Survival status
7.2.4
X
X
X


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a A post-transplant local conventional cytogenetics or FISH will be allowed if has been done as per clinical practice within 8 weeks prior to Day 1. If not 
available, a conventional cytogenetic or FISH (if conventional cytogenetics does not show metaphase) has to be locally performed at Screening within 28 
days prior to Day 1.
b Height will only be assessed at baseline.
c Hematology biochemistry and other analysis do not need to be repeated at Day 1 as they should have been performed within 7 days prior to the start of 
treatment.
d Women of childbearing potential must undergo a serum pregnancy test at screening to confirm eligibility in the study. Subsequently, women of 
childbearing potential must undergo a pregnancy test (urine or serum) at the specified visits.
e Blood smears must also be performed any time if considered necessary.
 
 
g In patients who discontinue eltrombopag because efficacy according to Section 6.1.2, medication will not be dispensed; if a loss of response occurs, 
eltrombopag can be reintroduced at the last effective dose.
h In responder patients, continuation of eltrombopag should be up to the investigator. After the 36 weeks of the study, the suitability of continuing 
eltrombopag in a commercial setting will be evaluated by the investigator.
* Patients who prematurely withdraw from the study should return and complete the assessments associated with Week 40 visit 30 days after the last 
dose of eltrombopag.


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7.2
Periods/visits
7.2.1
Screening/baseline
Prospective patients will be scheduled for a Screening/baseline period by study site staff. The 
window for this visit is Day -28 to Day 0. Informed consent must be signed before any screening 
procedure. 
Several clinical data recorded at screening visit for every patient will be reviewed by the 
Coordinating Investigator and the Novartis’ Medical Team to verify his/her eligibility for the 
study at the site before treatment starts.
Patients must meet all inclusion and exclusion criteria at Screening to be eligible to proceed to 
the treatment period of the study. 
The platelet count needs to be <20,000/µL (mandatory) along with the ANC <1,000/µL and/or 
hemoglobin <100 g/L in a peripheral blood analysis on day +30 or beyond after allo-HSCT to 
qualify the patient for enrolment. Platelets, ANC and hemoglobin re-tests in a peripheral blood 
analysis will be required at Screening within 7 days prior to intended study Day 1, to allow 
sample time for results to be returned before administration of eltrombopag. 
Patient eligibility will be confirmed by the investigative staff and captured within the source 
documents maintained at the site. This information will be made available during planned 
interim monitoring visits and compared against the clinical database for accuracy. Only when 
eligibility has been confirmed will the patient initiate the study treatment. Additionally, 
investigative site staff will enter patient information into the electronic case report form (eCRF), 
and automated queries will be generated for immediate resolution should patient eligibility be 
in question based on the patient information entered.
Re-screening of a previously screen failed patient will be allowed only once. A patient may be 
re-screened once if there are exclusionary medical condition at the Screening that may resolve 
and allow for re-screening. Some examples of re-screening reasons are listed below. In cases of 
re-screening, eligibility must be confirmed with Novartis.

Laboratory value(s) out of range due to sampling error or that might be within range 
after medically-appropriate supplementation. (Note: Before screen failing and then re-
screening the subject, efforts should be made to repeat the laboratory assessment(s) 
during the original initial screening phase).

Vital signs and ECG abnormalities that can be stabilized.

The patient has a medical condition that can be stabilized or resolved prior to the 
repeat screening attempt.
Patients who are rescreened must sign a new informed consent and they will be assigned with 
a new patient identification number. All required screening activities must be performed when 
the patient is rescreened for participation in the study.
7.2.1.1
Eligibility screening 


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Patients who sign an informed consent but fail to be started on treatment for any reason will be 
considered a screen failure. The reason for not being started on treatment and date of screening 
failure will be entered on the Screening Failure Log eCRFs pages and include one of the 
following: unacceptable or past medical history/concomitant diagnosis; intercurrent medical 
event; unacceptable laboratory value(s); unacceptable test procedure result(s); did not meet 
inclusion/exclusion criteria; unacceptable use or excluded medication(s)/therapies; subject 
withdrew consent; unknown; other. 
No other data will be entered into the clinical database for patients who are screen failures, 
unless the patient experienced a Serious Adverse Event (SAE) during the Screening Phase (See 
Section 8).
Patient information to be collected at screening/baseline period will include:

Demographics

Review of medical history and prior medication history (Section 6.3.1). Record the 
identity and dose of all medications used to treat the underlying disease.

Documentation of underlying disease

Detailed description of the transplant
o
Donor age
o
Donor type (unrelated donor, related donor)
o
Related donor-recipient relatedness (siblings, parents)
o
Donor-recipient blood type (mismatch, match)
o
Chimerism in peripheral blood
o
HLA (identical, 1 mismatch, 2 mismatches, >3 mismatches)
o
Source of graft cells (bone marrow (BM), peripheral blood stem cells (PBSC), 
BM+PBSC, blood from umbilical cord)

Documentation of conditioning regimen.

Review of prophylaxis and treatment of GVHD.

Supportive care (see Section 6.3.1.1 / 7.3.1.2)

ECG (See Section 7.3.2.7)

Ophthalmological monitoring (see Section 7.3.2.8)

Serology HIV, HBsAg, HCV.

Cytogenetic analysis/FISH. A post-transplant conventional cytogenetics or FISH will 
be allowed if has been done as per clinical practice within 8 weeks prior to Day 1. If not
available, a conventional cytogenetic or FISH (if conventional cytogenetics does not 
7.2.1.2
Information to be collected on screening failures
7.2.1.3
Patient demographics and other baseline characteristics


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show metaphase) has to be locally performed at Screening within 28 days prior to Day 
1.
 
 
 
 
 

Record concomitant medication (See Section 6.3).

Record adverse events (See Section 8.1).
Furthermore, the following procedures should be performed within a maximum of 7 days of the 
first dose of eltrombopag:

Serum pregnancy test in all women of childbearing potential (see Section 7.3.2.67.3.2.6).

Physical examination (See Section 7.3.2.1).

Karnofsky performance status (See Section 7.3.2.2).

Height and weight (See Section 7.3.2.3).

Vital signs (See Section 7.3.2.4).

Hematology, biochemistry and other analysis (See Section 7.3.2.5).

Urine screening (sediment and systematic).

Blood smear (See Section 7.3.2.5)
7.2.2
Treatment Period
All patients included in the study will be treated with eltrombopag up to week 36 or until the 
patient’s premature withdrawal (see Sections 6.1.2/7.2.3.1) (Final visit [or Early withdrawal]). 
-
Only patients who respond at week 16 will continue to receive eltrombopag until loss of 
response (i.e. declining blood counts that do not continue to meet the criteria for response 
established in this protocol), unacceptable toxicity, or discontinuation for any other reason 
(see Sections 6.1.2/7.2.3.1)
-
Patients who discontinue eltrombopag because efficacy (See Section 6.1.2), will continue 
in the study and attend the scheduled visits as per protocol. If loss of response occurs, 
eltrombopag will be reintroduced at the last effective dose (See Section 6.1.2)
During the treatment period, patients will be evaluated weekly during the first month, every 2 
weeks during the next 2 months and subsequently every 4 weeks until week 24. For the last 3 
months, patients will be followed every 6 weeks.


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The Day 1 visit may occur as soon as all screening /baseline evaluations have been completed, 
and all results are available prior to the first dose of eltrombopag. The following procedures 
will be performed and all observations will be recorded in the eCRF:

Supportive care (see Section 6.3.1.1 / 7.3.1.2)

Physical examination (See Section 7.3.2.1)

Weight (See Section 7.3.2.3)

Vital signs (See Section 7.3.2.4)

Dispense study drug for the first 7 days:

The importance of compliance will be reviewed with the patient.

The patient will be educated on medications and food that should be avoided while 
taking eltrombopag.

Record concomitant medication (See Section 6.3).

Patients will be instructed to call the investigator or designated research staff if they 
experience any unexpected and unfavorable signs and/or symptoms (See Section 8.1). These 
adverse events will be recorded on the eCRF.
NOTE: Hematology and biochemistry will not need to be repeated at Day 1 as they should have 
been performed at the screening period (in the 7 days prior to start study treatment).

Patients will self-administer eltrombopag once a day as instructed in an outpatient setting. 

Supportive care (see Section 6.3.1.1 / 7.3.1.2)

Physical examination (See Section 7.3.2.1).

Karnofsky performance status (See Section 7.3.2.2).

Weight (See Section 7.3.2.3).

Vital signs (See Section 7.3.2.4).

Hematology and biochemistry (See Section 7.3.2.5).

Urine or serum pregnancy test should be performed only in women of childbearing potential 
at week 4 (See Section 7.3.2.6).

Blood smear at week 4 (See Section 7.3.2.5)

Record any concomitant medication (See Section 6.3).

Record adverse events (See Section 8.1).

Eltrombopag will be dispensed for the next 7 days (except at week 4 when it will be 
dispensed for the next 14 days). 
7.2.2.1
Day 1 
7.2.2.2
Weekly visits to month 1 (Weeks 1, 2, 3 and 4)


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
Patients will self-administer eltrombopag once a day as instructed in an outpatient setting. 

Supportive care (see Section 6.3.1.1 / 7.3.1.2)

Physical examination (See Section 7.3.2.1).

Karnofsky performance status (See Section 7.3.2.2).

Weight (See Section 7.3.2.3). 

Vital signs (See Section 7.3.2.4).

Hematology and biochemistry (See Section 7.3.2.5). 

Urine or serum pregnancy test should be performed in women of childbearing potential at 
weeks 8 and 12 (See Section 7.3.2.6).

Blood smear at weeks 8 and 12 (See Section 7.3.2.5).

Record any concomitant medications (See Section 6.3).

Record adverse events (See Section 8.1).

Eltrombopag will be dispensed at every visit for the next 14 days, except at week 12 where 
it will be dispensed for the next 28 days. 

 

Patients will self-administer eltrombopag once a day as instructed in an outpatient setting. 

Supportive care (see Section 6.3.1.1 / 7.3.1.2)

Physical examination (See Section 7.3.2.1).

Karnofsky status (See Section 7.3.2.2).

Weight (See Section 7.3.2.3). 

Vital signs (See Section 7.3.2.4).

Hematology biochemistry and other analysis (See Section 7.3.2.5).

Urine or serum pregnancy test should be performed in women of childbearing potential (See 
Section 7.3.2.6).

ECG at week 24 (See Section 7.3.2.7)

Ophthalmological monitoring at week 24 (see Section 7.3.2.8) 

Blood smear (See Section 7.3.2.5)

Record any concomitant medications (See Section 6.3).
7.2.2.3
Biweekly visits to month 3 (Weeks 6, 8, 10 and 12)
7.2.2.4
Monthly visits to month 6 (weeks 16, 20 and 24)


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
Record adverse events (See Section 8.1).

Survival status (See Section 7.3.1.3).

At weeks 16 and 20, eltrombopag will be dispensed for the next 4 weeks. 

Hematological response assessment

At week 24, eltrombopag will be dispensed for the next 6 weeks. 
 
 
 
 
.
All patients must be evaluated every 6 weeks to month 9. The following procedures will be 
performed at each clinical visit:

Supportive care (see Section 6.3.1.1 / 7.3.1.2)

Physical examination (See Section 7.3.2.1).

Karnofsky performance status (See Section 7.3.2.2)

Weight (See Section 7.3.2.3). 

Vital signs (See Section 7.3.2.4).

Hematology and biochemistry (See Section 7.3.2.5).

Urine or serum pregnancy test should be performed in women of childbearing potential (See 
Section 7.3.2.6).

Blood smear (See Section 7.3.2.5)

Record any concomitant medications (See Section 6.3).

Record adverse events (See Section 8.1).

Hematological response assessment.

Survival status (See Section 7.3.1.3).

If according to the investigator’s criteria, responder patients are able to continue on study 
drug, eltrombopag will be dispensed at week 30 for the next 6 weeks. 
At 36 weeks of the study, the convenience of continuing with eltrombopag will be evaluated by 
the investigator, and the supply of the drug will be only commercial. Novartis will not supply 
eltrombopag after the end of the study.
7.2.2.5
Every 6-weeks visits to month 9 (weeks 30 and 36)


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7.2.3
Final visit (or Early withdrawal) 
For patients who complete the 36-weeks of study treatment administration and/or assessments, 
or permanently stop taking study treatment for any reason, this visit should be performed 30 
days after the last dose of eltrombopag:

Supportive care (see Section 6.3.1.1 / 7.3.1.2)

Physical examination (See Section 7.3.2.1).

Karnofsky performance status (See Section 7.3.2.2)

Weight (See Section 7.3.2.3) 

Vital signs (See Section 7.3.2.4)

Hematology biochemistry and other analysis (See Section 7.3.2.5)

Urine or serum pregnancy test should be performed in women of childbearing potential (See 
Section 7.3.2.6).

Blood smear (See Section 7.3.2.5)

ECG (See Section 7.3.2.7)

Ophthalmological monitoring (see Section 7.3.2.8) 

Record any concomitant medication (See Section 6.3)

Record adverse events (See Section 8.1). If required (per investigator's opinion), another 
visit could be scheduled to follow up properly the patient´s AE/SAE. This will be considered 
as an unscheduled visit, and the assessments to be made will be at the discretion of the 
investigator. Results will become part of the patient's medical history.
Patients lost to follow-up should be recorded as such on the CRF. For patients who are lost to 
follow-up, the investigator should show "due diligence" by documenting in the source 
documents steps taken to contact the patient, e.g., dates of telephone calls, registered letters, etc. 
At a minimum, all patients who discontinue treatment, including those who refuse to return for 
a final visit, will be contacted by phone for safety assessment during the 30 days following the 
last dose of study treatment.
Patients may voluntarily withdraw from the study or be dropped from it at the discretion of the 
investigator at any time. Patients may also be withdrawn from the study if any of the following 
occurs:
-
Presence of any medical condition that in the investigator’s opinion may affect the safety of 
the patient.
-
Toxicity or appearance of any unacceptable AE that, in the investigator’s opinion, may 
justify treatment withdrawal.
7.2.3.1
Criteria for premature patient withdrawal


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-
Concomitant disease that, in the opinion of the investigator, makes it necessary to withdraw 
the patient.
-
Major protocol violations.
-
Systematic noncompliance with the study protocol, including the scheduled visits, without 
any evidence of actions to try to remedy it.
-
Pregnancy of a female patient.
-
Patient lost to follow-up.
-
Use of prohibited medication. Please, refer to Section 6.3.2
-
Reasons for premature discontinuation of eltrombopag displayed at Section 6.1.2
7.2.4
Follow-up for survival
All patients who discontinue from the study, regardless the reason of discontinuation, will be 
followed for survival for 24 and 36 weeks, unless they withdraw their consent, die or are lost-
to follow-up, in which case will be censored at the last contact/follow-up.
7.3
Assessment types
7.3.1
Efficacy assessments
The overall response rate corresponds to the percentage of patients who have a hematological 
response (partial and complete) by 16 weeks after the initiation of eltrombopag.
A partial hematologic response (PR) is defined when any of the following:

Platelet count ≥20,000/μL (with platelet transfusion independence), confirmed in two 
consecutive blood tests separated a minimum of 7 days.

Absolute neutrophil count (ANC) ≥1,000/μL (when pretreatment ANC was <1,000/μL) 
confirmed in two consecutive blood tests separated a minimum of 7 days

Hemoglobin ≥100g/L (when pretreatment Hb was <100g/L) (with red blood cells (RBC) 
transfusion independence), confirmed in two consecutive blood tests separated a minimum 
of 7 days.
A complete response (CR) is defined when all three of the following: 

Platelet count ≥100,000/μL confirmed in two consecutive blood tests separated a minimum 
of 7 days 

Absolute neutrophil count (ANC) ≥1,500/μL (when pretreatment ANC was <1,000/μL), 
confirmed in two consecutive blood tests separated a minimum of 7 days.

Hemoglobin ≥110 g/L (when pretreatment Hb was <100g/L), confirmed in two consecutive 
blood tests separated a minimum of 7 days.
Responses in each hematological lineage separately will be determined at weeks 16, 20, 24, 30 
and 36 after the initiation of eltrombopag. In addition, secondary overall hematological 
7.3.1.1
Overall hematologic response rate


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response outcomes (partial and complete) will be determined at 24 and 36 weeks after the 
initiation of eltrombopag.
Local evaluations will be used for laboratory tests (hematology and biochemistry), and 
whenever possible the same local laboratory will be used throughout the study so that the 
comparison is consistent.
The need for platelets and red cells transfusions will be monitored at each visit as noted in Table 
7-1.
The concomitant use of G-CSF and/or EPO therapy will be recorded at each visit, as outlined 
in Table 7-1.
Overall survival, defined as the time from the date of inclusion until the date of death due to 
any cause, will be assessed. All patients who discontinue from the study will be followed for 
survival for 24 and 36 weeks, unless they withdraw their consent, die or are lost-to follow-up, 
in which case will be censored at the last contact/follow-up.
The survival rate will also be evaluated by the percentage of patients still alive at 24 and 36
weeks.
7.3.2
Safety assessments
Safety will be monitored by assessing physical examination, vital signs and laboratory 
evaluations, as well as recording of the adverse events at every visit. For details on AEs
monitoring and reporting, refer to Section 8.
Significant findings that were present before the signing of informed consent must be included 
in the Relevant Medical History/Current Medical Conditions page on the patient’s CRF. 
Significant new findings that begin or worsen after informed consent must be recorded on the 
Adverse Event page of the patient’s CRF. 
An examination of general appearance will be performed at Screening and at scheduled study 
visits up to Final Visit (or Early Withdrawal), as noted in Table 7-1
Performance status or functional impairment will be assessed using the Karnofsky Performance 
Scale Index at Screening and at scheduled study visits up to Final Visit (or Early Withdrawal), 
as outlined in Table 7-1.
Height in centimeters (cm) will be measured only at Screening. Body weight in kilograms (to 
the nearest 0.1 kilogram (kg) in indoor clothing, but without shoes) will be measured during the 
7.3.1.2
Supportive care
7.3.1.3
Overall survival
7.3.2.1
Physical examination
7.3.2.2
Performance status
7.3.2.3
Height and weight


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Screening visit, and at subsequent visits up to Final Visit (or Early Withdrawal), as noted in 
Table 7-1.
Vital signs (blood pressure (BP), respiratory rate, temperature and pulse) will be collected 
according to the Visit Schedule as outlined in Table 7-1. BP will be taken with the patient in 
the sitting position after 5 minutes of rest.
All laboratory assessments will be performed locally, at the Investigator’s site laboratory. For 
laboratory parameters collection plan, see Table 7-1 and Table 7-2.
Table 7-2
Local clinical laboratory parameters collection plan
Test Category
Test Name
Hematology
(screening, week 16, 
and final visit)
-
CBC [Hematocrit, Hemoglobin, MCH, MCHC, MCV, Platelets, Red blood
cells, White blood cells, Differential (Basophils, Eosinophils, 
Lymphocytes, Monocytes, Neutrophils)] 
-
Reticulocytes
-
Direct antiglobulin (Coombs) test (DAT)
-
Immature platelets (if available) 
-
Lymphocytes subpopulations: CD3, CD4, CD8, CD19, CD56
Hematology
(rest of the visits)
-
CBC [Hematocrit, Hemoglobin, MCH, MCHC, MCV, Platelets, Red blood
cells, White blood cells, Differential (Basophils, Eosinophils, 
Lymphocytes, Monocytes, Neutrophils)] 
-
Reticulocytes
-
Immature platelets (if available)
Biochemistry 
Immunology
Microbiology
Other
(Screening, week 16, 
and final visit)
-
Bilirubin (Total, Direct), Alkaline phosphatase, AST/GOT, ALT/GPT
Urea, Creatinine, Uric acid, LDH, CL, Na, K, Ca, Mg, Creatine kinase, 
haptoglobin 
-
Cholesterol (total, LDL, HDL), Triglycerides 
-
Glucose
-
Albumin, Total Protein, proteinogram, Igs (IgG, A and M)
-
Folate, Vit B12, Vit D 
-
TSH, T4 (free)
-
Ferritin, Transferrin, Transferrin saturation index
-
ANAs
-
CsA, Tacrolimus, other immunosuppressant drugs levels
-
Epstein-Barr virus (EBV) and cytomegalovirus (CMV): Viral load in blood 
test by PCR, if serology positive
-
AGA
Serology
(Screening)
-
Serology HIV, HBV, HCV 
7.3.2.4
Vital signs
7.3.2.5
Clinical safety laboratory evaluations


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Biochemistry
(rest of the visits)
-
Bilirubin (if abnormal: Total, Direct), Alkaline phosphatase, AST/GOT,
ALT/GPT
-
Urea, Creatinine, Uric acid, LDH, CL, Na, K, Ca, Mg, Creatine kinase, 
haptoglobin 
Urine 
(Screening) 
-
Sediment and systematic analysis
Chimerism in 
peripheral blood 
(Screening)
Blood smear
(At screening/baseline, 
monthly up to week 24 
and thereafter every 6 
weeks, and at Final 
visit (or Early 
withdrawal), or 
anytime if considered 
necessary)
-
Including study of schistocytes (if present)
Women of childbearing potential must undergo a serum pregnancy test at screening to confirm 
eligibility in the trial. Subsequently, urine or serum pregnancy tests should be performed in 
women of childbearing potential at weeks 4, 8, 12, 16, 20, 24, 30, 36 and 40.
A standard 12-lead ECG will be obtained for each patient during the study as per Description 
of study visits (Table 7-1). Baseline ECGs will be obtained at Screening. All 12-lead ECGs 
obtained at 24 weeks and Final Visit will be compared with this pre-study treatment 12-lead 
ECG.
Interpretation of the tracing must be made by a qualified physician and documented on the ECG 
CRF page. Each ECG tracing should be labeled with the study number, patient initials (where 
regulations permit), patient number, date, and kept in the source documents at the study site. 
Clinically significant abnormalities present when the patient signed informed consent should 
be reported on the Medical History CRF page. Clinically significant findings must be discussed 
with Novartis prior to enrolling the patient in the study. New or worsened clinically significant 
findings occurring after informed consent must be recorded on the Adverse Events CRF page.
The ophthalmic exam should include the retina, blood vessels, optic disc/nerve. If the presence 
of a cataract(s) is suspected, a slit lamp examination is required. Ophthalmic exams will be 
performed at Screening, week 24 and at Final Visit according to Table 7-1. 
Significant findings that were present prior to the signing of informed consent must be included 
in the Medical History page on the patient’s eCRF. Significant new findings that begin or 
worsen after informed consent must be recorded on the Adverse Event page of the patient’s 
eCRF.
7.3.2.6
Pregnancy and assessments of fertility
7.3.2.7
12-lead ECG
7.3.2.8
Ophthalmological monitoring


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7.3.4
Resource utilization
Not applicable.
7.3.5
Patient reported outcomes
Not applicable.
8
Safety monitoring and reporting
8.1
Adverse events
8.1.1
Definitions and reporting
An adverse event is defined as the appearance of (or worsening of any pre-existing) undesirable 
sign(s), symptom(s), or medical condition(s) that occur after patient’s signed informed consent 
has been obtained. 
Abnormal laboratory values or test results occurring after informed consent constitute adverse 
events only if they induce clinical signs or symptoms, are considered clinically significant, 
require therapy (e.g., hematologic abnormality that requires transfusion or hematological stem 
cell support), or require changes in study medication(s).
Adverse events that begin or worsen after informed consent should be recorded in the Adverse 
Events CRF. Conditions that were already present at the time of informed consent should be 
recorded in the Medical History page of the patient’s CRF. Adverse event monitoring should 
be continued for at least 30 days (or 5 half-lives, whichever is longer) following the last dose 
of study treatment. Adverse events (including lab abnormalities that constitute AEs) should be 
described using a diagnosis whenever possible, rather than individual underlying signs and 


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symptoms. When a clear diagnosis cannot be identified, each sign or symptom should be 
reported as a separate Adverse Event.
Adverse events will be assessed according to the Common Terminology Criteria for Adverse 
Events (CTCAE) version 4.03.
If CTCAE grading does not exist for an adverse event, the severity of mild, moderate, severe, 
and life-threatening, corresponding to Grades 1-4, will be used. CTCAE Grade 5 (death) will 
not be used in this study; rather, information about deaths will be collected through a Death 
form
The occurrence of adverse events should be sought by non-directive questioning of the patient 
(subject) during the screening process after signing informed consent and at each visit during 
the study. Adverse events also may be detected when they are volunteered by the patient 
(subject) during the screening process or between visits, or through physical examination, 
laboratory test, or other assessments. As far as possible, each adverse event should be evaluated 
to determine:
1. The severity grade (CTCAE Grade 1-4). 
2. Its duration (Start and end dates or ongoing).
3. Its relationship to the study treatment 
4. Action taken concerning study or investigational treatment (none, dose adjusted, 
temporarily interrupted, permanently discontinued, unknown, not applicable)
5. Whether medication or therapy was given (no concomitant medication/non-drug therapy, 
concomitant medication/non-drug therapy).
6. Outcome 
(not 
recovered/not 
resolved, 
recovered/resolved, 
recovering/resolving, 
recovered/resolved with sequalae, fatal, unknown) 
7. Whether it is serious, where a serious adverse event (SAE) is defined as in Section 8.2.1
All adverse events should be treated appropriately. If a concomitant medication or non-drug 
therapy is given, this action should be recorded on the Adverse Event CRF.
Once an adverse event is detected, it should be followed until its resolution or until it is judged 
to be permanent, and assessment should be made at each visit (or more frequently, if necessary) 
of any changes in severity, the suspected relationship to the study treatment, the interventions 
required to treat it, and the outcome.
Progression of malignancy (including fatal outcomes), if documented by use of appropriate 
method (for example, as per RECIST criteria for solid tumors or as per Cheson's guidelines for 
hematological malignancies), should not be reported as a serious adverse event.
Adverse events separate from the progression of malignancy (example, deep vein thrombosis 
at the time of progression or hemoptysis concurrent with finding of disease progression) will 
be reported as per usual guidelines used for such events with proper attribution regarding 
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8.1.2
Laboratory test abnormalities
Laboratory abnormalities that constitute an Adverse event in their right (are considered 
clinically significant, induce clinical signs or symptoms, require concomitant therapy or require 
changes in study treatment), should be recorded on the Adverse Events CRF. Whenever 
possible, a diagnosis, rather than a symptom should be provided (e.g. anemia instead of low 
hemoglobin). Laboratory abnormalities that meet the criteria for Adverse Events should be 
followed until they have returned to normal or an adequate explanation of the abnormality is 
found. When an abnormal laboratory or test result corresponds to a sign/symptom of an already 
reported adverse event, it is not necessary to separately record the lab/test result as an additional 
event.
Laboratory abnormalities, which do not meet the definition of an adverse event, should not be 
reported as adverse events. A Grade 3 or 4 event (severe) as per CTCAE does not automatically 
indicate a SAE unless it meets the definition of serious as defined below and/or as per 
investigator’s discretion. A dose hold or medication for the lab abnormality may be required by 
the protocol in which case the lab abnormality would still, by definition, be an adverse event 
and must be reported as such.
8.1.3
Adverse events of special interest 
Adverse events of special interest (AESI) are defined as events (serious or non-serious) which 
are ones of scientific and medical concern specific to the sponsor’s product or program, for 
which ongoing monitoring and rapid communication by the investigator to the sponsor may be 
appropriate. Such events may require further investigation to characterize and understand them.
Adverse events of special interest are defined by an ongoing review of the safety data. AESIs 
are discussed in detail in the Investigator Brochure. 
The AESIs for this study are:

Bleeding events

Hepatobiliary events

Renal related events

Cataract-related events

Thromboembolic events

Hematological malignancy

Abnormal bone marrow analysis/cytogenetic abnormality
8.2
Serious adverse events
8.2.1
Definitions
Serious adverse event (SAE) is defined as one of the following:

Is fatal or life-threatening
8.1.2.1
Definitions and reporting


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
Results in persistent or significant disability/incapacity

Constitutes a congenital anomaly/birth defect

Is medically significant, i.e., defined as an event that jeopardizes the patient or may require 
medical or surgical intervention to prevent one of the outcomes listed above

Requires inpatient hospitalization or prolongation of existing hospitalization, 

Note that hospitalizations for the following reasons should not be reported as serious 
adverse events:
o
Routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition 
o
Elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent
o
Social reasons and respite care in the absence of any deterioration in the patient’s 
general condition

Note that treatment on an emergency outpatient basis that does not result in hospital 
admission and involves an event not fulfilling any of the definitions of a SAE given above 
is not a serious adverse event
8.2.2
Reporting
To ensure patient safety, every SAE, regardless of suspected causality, occurring after the 
patient has provided informed consent and until at least 30 days after the patient has stopped 
study treatment must be reported to Novartis within 24 hours of learning of its occurrence. 
Any SAEs experienced after these 30 days period should only be reported to Novartis if the 
investigator suspects a causal relationship to the study treatment. Recurrent episodes, 
complications, or progression of the initial SAE must be reported as follow-up to the original 
episode within 24 hours of the investigator receiving the follow-up information. An SAE 
occurring at a different time interval or otherwise considered completely unrelated to a 
previously reported one should be reported separately as a new event.
Information about all SAEs is collected and recorded on the Serious Adverse Event Report 
Form; all applicable sections of the form must be completed in order to provide a clinically 
thorough report. The investigator must assess and record the relationship of each SAE to each 
specific study treatment (if there is more than one study treatment), complete the SAE Report 
Form in English, and send the completed, signed form by email (sae.reporting@novartis.com) 
within 24 hours to Novartis patient safety department: 
The telephone, email or telefax number of the contact persons in the local department of 
Novartis patient safety, specific to the site, are listed in the investigator folder provided to each 
site. The original copy of the SAE Report Form and the fax confirmation sheet must be kept 
with the case report form (CRF) documentation at the study site.
Follow-up information is sent to the same contact(s) to whom the original SAE Report Form 
was sent, using a new SAE Report Form stating that this is a follow-up to the previously 
reported SAE and giving the date of the original report. Each re-occurrence, complication, or 


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progression of the original event should be reported as a follow-up to that event regardless of 
when it occurs. The follow-up information should describe whether the event has resolved or 
continues, if and how it was treated, whether the blind was broken or not, and whether the 
patient continued or withdrew from study participation.
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert (new 
occurrence) and is thought to be related to the Novartis study treatment, an oncology Novartis 
Drug Safety and Epidemiology (DS&E) department associate may urgently require further 
information from the investigator for Health Authority reporting. Novartis may need to issue 
an Investigator Notification (IN), to inform all investigators involved in any study with the same 
drug that this SAE has been reported. Suspected Unexpected Serious Adverse Reactions 
(SUSARs) will be collected and reported to the competent authorities and relevant ethics 
committees in accordance with Directive 2001/20/EC or as per national regulatory requirements 
in participating countries.
8.3
Pregnancies
Pregnancy, in and of itself, is not regarded as an AE, unless there is a suspicion that the study 
drug may have interfered with the effectiveness of a contraceptive medication or method. 
To ensure patient safety, each pregnancy occurring while the patient (or the partner of male 
study patients) is on study treatment, should be recorded on a Clinical Trial Pregnancy Form 
and reported by the investigator to the PhV department of Novartis within 24 hours of learning 
of its occurrence. 
The pregnancy should be followed up to determine outcome, including spontaneous or 
voluntary termination, details of the birth, and the presence or absence of any birth defects, 
congenital abnormalities, or maternal and/or newborn complications. Pregnancy follow-up 
should be recorded on the same form and should include an assessment of the possible 
relationship to the study treatment any pregnancy outcome. Any SAE experienced during 
pregnancy must be reported on the SAE Report Form. 
Pregnancy outcomes must be collected for the female partners of any males who took study 
treatment in this study. Consent to report information regarding these pregnancy outcomes 
should be obtained from the mother
8.4
Warnings and precautions
No evidence available at the time of the approval of this study protocol indicated that special 
warnings or precautions were appropriate, other than those noted in the provided Investigator 
Brochure. Additional safety information collected between IB updates will be communicated 
in the form of Investigator Notifications. This information will be included in the patient 
informed consent and should be discussed with the patient during the study as needed.


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9
Data collection and management
9.1
Data confidentiality
Information about study subjects will be kept confidential and managed under the applicable 
laws and regulations. Those regulations require a signed subject authorization informing the 
subject of the following:

What protected health information (PHI) will be collected from subjects in this study

Who will have access to that information and why

Who will use or disclose that information

The rights of a research subject to revoke their authorization for use of their PHI.
If a subject revokes authorization to collect or use PHI, the investigator, by regulation, retains 
the ability to use all information collected before the revocation of subject authorization. For 
subjects that have revoked authorization to collect or use PHI, attempts should be made to obtain 
permission to collect follow-up safety information (e.g. has the subject experienced any new or 
worsened AEs) at the end of their scheduled study period.
The data collection system for this study uses built-in security features to encrypt all data for 
transmission in both directions, preventing unauthorized access to confidential participant 
information. Access to the system will be controlled by a sequence of individually assigned 
user identification codes and passwords, made available only to authorized personnel who have 
completed prerequisite training.
9.2
Site monitoring
Before study initiation, at a site initiation visit or an investigator’s meeting, Novartis personnel
will review the protocol and CRFs with the investigators and their staff. During the study, the 
field monitor will visit the site regularly to check the completeness of patient records, the 
accuracy of entries on the CRFs, the adherence to the protocol to Good Clinical Practice, the 
progress of enrollment, and to ensure that study treatment is being stored, dispensed, and 
accounted for according to specifications. Key study personnel must be available to assist the 
field monitor during these visits.
The investigator must maintain source documents for each patient in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information recorded on CRFs must be traceable to source documents in the 
patient's file. The investigator must also keep the original signed informed consent form (a 
signed copy is given to the patient).
The investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the CRF entries. Novartis monitoring standards require full verification for the 
presence of informed consent, adherence to the inclusion/exclusion criteria and documentation 
of SAEs. Additional checks of the consistency of the source data with the CRFs are performed 
according to the study-specific monitoring plan.


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9.3
Data collection
The study will be conducted using Electronic Data Capture (EDC). The designated investigator 
staff will enter the data required by the protocol into the Electronic Case Report Forms (eCRF). 
The eCRFs have been built using fully validated secure web-enabled software that conforms to 
21 CFR Part 11 requirements. Investigator site staff will not be given access to the EDC system 
until they have been trained. Automatic validation programs check for data discrepancies in the 
eCRFs and, allow modification or verification of the entered data by the investigator staff. 
The Principal Investigator is responsible for assuring that the data entered into eCRF is complete, 
accurate, and that entry and updates are performed promptly.
9.4
Database management and quality control
Novartis personnel will review the data entered by investigational staff for completeness and 
accuracy. Electronic data queries stating the nature of the problem and requesting clarification 
will be created for discrepancies and missing values and sent to the investigational site via the 
EDC system. Designated investigator site staff are required to respond promptly to queries and 
to make any necessary changes to the data.
Concomitant treatments and prior medications entered into the database will be coded using the 
WHO Drug Reference List, which employs the Anatomical Therapeutic Chemical classification 
system. Medical history/current medical conditions and adverse events will be coded using the 
Medical dictionary for regulatory activities (MedDRA) terminology.
Bone marrow aspirate and/or peripheral blood will be processed and analyzed centrally, and the 
results will be sent to the PI of each site. Each PI will introduce the results into the eCRF. 
At the conclusion of the study, the occurrence of any protocol violations will be determined. 
After these actions have been completed and the data has been verified to be complete and 
accurate, the database will be declared locked for data analysis. Authorization is required prior 
to making any database changes to locked data, by joint written agreement between the Global 
Head of Biostatistics and Data Management and the Global Head of Clinical Development.
For EDC studies, after database lock, the investigator will receive a CD-ROM or paper copies 
of the patient data for archiving at the investigational site.
10
Statistical methods and data analysis
10.1
Analysis sets
10.1.1
Full Analysis Set
The Full Analysis Set (FAS) comprises all patients to whom study treatment has been assigned.  
10.1.2
Safety Set
The Safety Set includes all patients who received at least one dose of study treatment. 


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10.1.3
Per-Protocol Set
The Per-Protocol Set (PPS) consists of a subset of the patients in the FAS who are compliant 
with requirements of the clinical study protocol (CSP).
Oncology standards for protocol deviations potentially leading to exclusion from the PPS are:

If the protocol deviation is very likely to confound the scientific analysis of the primary
efficacy endpoint(s) or if it precludes any meaningful efficacy measurement.

If it is in direct conflict with the analysis set definition given in the title of the study (i.e. 
patient diagnosis, stage of disease or use of prior treatment dose not correspond to the 
intended patient population to be studied).

If documentation of pre-baseline disease progression is required and is missing. 

Treatment differs from treatment assigned.

Patient compliance is defined as patient being evaluated for primary efficacy endpoint at 
least once. Patients who discontinue prior to the first efficacy assessment due to adverse 
events, including death, will be included.
Any other deviation leading to exclusion from the PPS will be specified in the study Statistical 
Analysis Plan (SAP) or DHP.
10.2
Patient demographics/other baseline characteristics
Demographic (age of the patient, sex) and other baseline data (disease characteristics, transplant 
data by donor type, source of graft cells, conditioning regimen, GVHD prevention regimen, 
supportive care and infection prophylaxis, other medical history and prior medications will be 
summarized descriptively for the FAS.
Categorical data will be presented as frequencies and percentages. For continuous data, mean, 
standard deviation, median, 25th and 75th percentiles, minimum, and maximum will be 
presented. Categories for missing data will be presented if necessary.
10.3
Treatments (study treatment, concomitant therapies, 
compliance) 
Duration of exposure to study treatment, cumulative dose, average daily dose, actual dose 
intensity and relative dose intensity of study treatment will be summarized.
Categorical data will be summarized as frequencies and percentages. For continuous data, mean, 
standard deviation, median, 25th and 75th percentiles, minimum, and maximum will be 
presented. Safety Set will be used for the analyses.
The number of patients with dose changes/interruptions and their reasons will be summarized 
on the Safety Set and all dosing data will be listed.
Concomitant medications or procedures and significant non-drug therapies taken concurrently 
with the study treatment will be listed and summarized using frequency counts and percentages. 
These summaries will include medications starting on or after the start of study treatment 
(defined as Day 1) or medications starting before the start of study treatment and continuing 
after the start of study treatment.


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Any prior concomitant medications or significant non-drug therapies starting and ending before 
the start of study treatment will be listed. 
The Safety Set will be used for all of the above mentioned concomitant medication tables and 
listings. 
10.4
Primary objective
The primary objective is to evaluate the efficacy of eltrombopag for poor graft function on 
overall hematologic response (partial and complete) as determined by platelet, hemoglobin and 
neutrophil counts, by 16 weeks after the initiation of eltrombopag.
10.4.1
Variable
The primary variable is the overall hematological response (partial and complete) by 16 weeks 
after the initiation of eltrombopag. The primary analysis will be assessed based on the FAS.
A partial hematologic response (PR) is defined when any of the following:

Platelet count ≥20,000/μL (with platelet transfusion independence), confirmed in two 
consecutive blood tests separated a minimum of 7 days.

Absolute neutrophil count (ANC) ≥1,000/μL (when pretreatment ANC was <1,000/μL), 
confirmed in two consecutive blood tests separated a minimum of 7 days.

Hemoglobin ≥100g/L (when pretreatment Hb was <100g/L) (with red blood cells (RBC) 
transfusion independence), confirmed in two consecutive blood tests separated a minimum 
of 7 days.
A complete hematologic response (CR) is defined when all three of the following:

Platelet count ≥100,000/μL, confirmed in two consecutive blood tests separated a minimum 
of 7 days.

Absolute neutrophil count (ANC) ≥1,500/μL (when pretreatment ANC was <1,000/μL), 
confirmed in two consecutive blood tests separated a minimum of 7 days.

Hemoglobin ≥110 g/L (when pretreatment Hb was <100g/L), confirmed in two consecutive 
blood tests separated a minimum of 7 days.
10.4.2
Statistical hypothesis, model, and method of analysis
No hypotheses or models will be considered for these analyses and descriptive statistics will be 
provided; inferences to the target population (when applicable) will be made using interval 
estimation.
The proportion of patients who reach the overall response rate (partial and complete) by 16 
weeks after the initiation of eltrombopag will be calculated and the corresponding 95% 
confidence interval (CI). This CI will be one-sided and will be constructed using the relationship 
between the sums of binomial probabilities and the F distribution described by Clopper and 
Pearson using the formulas proposed elsewhere (Fleiss JL, Levin B, Paik MC. Statistical 
Methods for Rates and Proportions. Third edition. John Wiley & Sons: New York, 2003, pp. 
25):


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




;
2
,
1
2
0
0
0
0
0
1
x
x
n
L
F
x
n
x
x
P






where α=0.05, x0 is the observed number of responders in the sample and n the sample size.
Descriptive statistics will also be provided between baseline and 16 weeks for blood cell counts 
(ANC and platelet) and hemoglobin levels, and appropriate paired exploratory tests will be done 
according to the type of distribution (parametric or not) to assess the statistical significance of 
the changes.
10.4.3
Handling of missing values/censoring/discontinuations
The reason for discontinuation from study will be summarized and listed, along with dates of 
first and last study drug, duration of exposure to study drug and date of discontinuation for each 
patient.
Other missing data will be noted as missing on appropriate tables/listings.
10.4.4
Supportive analyses
Additional supportive analysis may be conducted if appropriate.
10.5
Secondary objectives
Secondary objectives are listed in Table 3-1.
10.5.1
Other efficacy objective(s)

To determine the response in each haematological lineage separately, the absolute 
frequency and valid percentage of patients who have a response in the neutrophil, platelet, 
and Hb lineages separately after 16, 24 and 36 weeks of eltrombopag, will be presented with 
the 95% CI. Descriptive statistics will also be provided between baseline and weeks 16, 24
and 36 for ANC, platelets and hemoglobin levels, and the appropriate paired exploratory
tests will be done according to the type of distribution (parametric or not) to assess the 
statistical significance of the changes.

To evaluate the overall hematological response rate (partial and complete) at 24 and 36
weeks after the initiation of eltrombopag, the frequency and percentage distribution and the 
corresponding 95% CI will be provided. This CI will be constructed as for the primary 
efficacy endpoint. Descriptive statistics will also be provided between baseline and week 
24 and week 36 for ANC, platelets count and hemoglobin levels, and the appropriate paired 
exploratory tests will be done according to the type of distribution (parametric or not) to 
assess the statistical significance of the changes.

To evaluate transfusion independence, the percentage of patients who were previously 
transfusion-dependent and do no longer require a RBC or platelet transfusion before and 
after the first 16 weeks of treatment will be calculated along with the 95% CI. This CI will 
be constructed as for the primary efficacy endpoint. The period where patients did not 
receive any platelet or RBC transfusions during the treatment period and follow-up will also 
be analyzed.


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
To evaluate the discontinuation or reduction of concomitant G-CSF and/or EPO therapy, 
the percentage of patients who discontinue or reduce by ≥50% from baseline the use of 
concomitant G-CSF and/or EPO therapy will be calculated along with the 95% CI. This CI 
will be constructed as for the primary efficacy endpoint.

Overall survival, defined as the duration from inclusion in the study to date of death 
(whatever the cause), will be estimated with the Kaplan-Meier curves method and two-sided 
95% CI for the estimated median. All patients who discontinue from the study, regardless 
the reason of discontinuation, will be followed for survival for 24 and 36 weeks, unless they 
withdraw their consent, die or are lost-to follow-up, in which case will be censored at the 
last contact.

The overall survival rate will be evaluated by the percentage of patients still alive at 24 and 
36 weeks.
10.5.2
Safety objectives
For all safety analyses, the Safety Set will be used. All listings and tables will be presented by 
patients and dose level throughout the overall observation period.
The overall observation period will be divided into three mutually exclusive segments:
1. pre-treatment period: from day of patient’s informed consent to the day before first dose 
of study medication
2. on-treatment period: from day of first dose of study medication to the last dose of study 
medication
3. post-treatment period: up to day 30 after last eltrombopag administration
Summary tables for adverse events (AEs) have to include only AEs that started or worsened 
during the on-treatment period, the treatment-emergent AEs (TEAEs). However, all safety data 
(including those from the pre-and post-treatment periods) will be listed and those collected 
during the pre-treatment and post-treatment period are to be flagged.
The incidence of TEAEs (new or worsening from baseline) will be summarized by system organ 
class and or preferred term, severity (based on CTCAE grades), type of adverse event, dose and 
relation to study treatment 
Deaths reportable as SAEs and non-fatal serious adverse events will be listed by patient and 
tabulated by type of adverse event. 
Specific safety event categories (SEC) will be considered. Such categories consist of one or 
more well-defined safety events which are similar and for which there is a specific clinical 
interest in connection with the study treatment(s).
For each specified SEC, number and percentage of patients with at least one event part of the 
SEC will be reported.
10.5.2.1 Analysis set and grouping for the analyses
10.5.2.2 Adverse events (AEs)


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For laboratory tests covered by the CTCAE version 4.03, the reporting team will grade 
laboratory data accordingly. For laboratory tests covered by CTCAE, a Grade 0 will be assigned 
for all non-missing values not graded as 1 or higher. Grade 5 will not be used.
For laboratory tests where grades are not defined by CTCAE version 4.03, results will be
categorized as low/normal/high based on laboratory normal ranges.
The following summaries will be generated separately for hematology, biochemistry tests and 
urinary laboratory tests:

Worst post-baseline CTCAE grade (regardless of the baseline status). Each patient will be
counted only once for the worst grade observed post-baseline.

Shift tables using CTCAE version 4.03 grades to compare baseline to the worst on treatment 
value.

For laboratory tests where grades are not defined by CTCAE version 4.03, shift tables using 
the low/normal/high/ (low and high) classification to compare baseline to the worst on-
treatment value.
In addition to the above-mentioned tables and listings, other exploratory analyses, for example 
figures plotting time course of raw or change in laboratory tests over time or box plots might 
be specified in the SAP and TLF shells.
ECG

The number (%) of patients with notable values will be presented; also, data on ECG 
results will be listed for all patients with at least one abnormality. 
Vital signs

Data on vital signs will be tabulated and listed, notable values will be flagged. The number 
(%) of patients with notable values will be presented.
Physical examination

Shift table baseline to worst on-treatment result

Table with descriptive statistics at baseline, one or several post-baseline time points and 
change from baseline to this/these post-baseline time points.
Additional supportive analysis may be conducted if appropriate.
Not applicable
10.5.2.3 Laboratory abnormalities
10.5.2.4 Other safety data
10.5.2.5 Supportive analyses for secondary objectives 
10.5.2.6 Tolerability


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10.5.3
Pharmacokinetics
Not applicable
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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10.7
Sample size calculation
The primary objective is to evaluate the efficacy of eltrombopag on overall hematopoietic 
response (partial or complete) by 16 weeks in patients with PGF after receiving an allo-HSCT. 
When the sample size is 33 patients and the proportion of responses with eltrombopag is 
assumed to be 45% in this sample, a one-sided 95% CI of such proportion will have a length of 
0.149 towards its lower end. In other words, this CI will provide enough evidence that the actual 
proportion of responses in the target population is above 30%, because its lower limit (as per 
the sampling distribution) would be 30.1.
Table 10-1
Sample size justification
Confidence 
level
Minimally 
acceptable 
response
Distance of 
observed response 
to lower limit
Observed 
proportion
Actual 
lower 
limit
Sample 
size
95%
>30%
14.9%
45%
30.1%
33
The calculation of the sample size has been performed using the exact method described by 
Clopper and Pearson (Newcombe RG. Two-sided confidence intervals for the single proportion: 
comparison of seven methods. Stat Med 1998; 17:857-72) as implemented in the version 15 of 
the PASS software (NCSS statistical software: PASS version 15, available at: 
ncss.com/software/pass).
Statistical Methodology:  
As mentioned, a one-sided confidence interval will be constructed for the proportion of 
responders using the formula indicated on Section 10.4.2.
10.8
Power for analysis of key secondary variables
Not applicable.
11
Ethical considerations and administrative procedures
11.1
Regulatory and ethical compliance
This clinical study was designed, shall be implemented and reported in accordance with the 
ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable local 
regulations (including European Directive 2001/20/EC and US Code of Federal Regulations 
Title 21), and with the ethical principles laid down in the Declaration of Helsinki.
11.2
Responsibilities of the investigator and IRB/IEC/REB
The protocol and the proposed informed consent form must be reviewed and approved by a 
properly constituted Institutional Review Board/Independent Ethics Committee/Research 
Ethics Board (IRB/IEC/REB) before study start. Prior to study start, the investigator is required 
to sign a protocol signature page confirming his/her agreement to conduct the study in 
accordance with these documents and all of the instructions and procedures found in this 
protocol and to give access to all relevant data and records to Novartis monitors, auditors, 


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Novartis Clinical Quality Assurance representatives, designated agents of Novartis, 
IRBs/IECs/REBs and regulatory authorities as required.
11.3
Informed consent procedures
Eligible patients may only be included in the study after providing written (witnessed, where 
required by law or regulation) IRB/IEC/REB-approved informed consent or, if incapable of 
doing so, after such consent has been provided by a legally acceptable representative of the 
patient. In cases where the patient’s representative gives consent, the patient should be informed 
about the study to the extent possible given his/her understanding. If the patient is capable of 
doing so, he/she should indicate assent by personally signing and dating the written informed 
consent document or a separate assent form.
Informed consent must be obtained before conducting any study-specific procedures (i.e. all of 
the procedures described in the protocol). The process of obtaining informed consent should be 
documented in the patient source documents. The date when a subject’s Informed Consent was 
obtained will be captured in their CRFs.
Novartis will provide to investigators, in a separate document, a proposed informed consent 
form (ICF) that is considered appropriate for this study and complies with the ICH GCP 
guideline and regulatory requirements. Any changes to this ICF suggested by the investigator 
must be agreed to by Novartis before submission to the IRB/IEC/REB, and a copy of the 
approved version must be provided to the Novartis monitor after IRB/IEC/REB approval.
Women of child bearing potential should be informed that taking the study medication may 
involve unknown risks to the fetus if pregnancy were to occur during the study and agree that 
to participate in the study they must adhere to the contraception requirement for the duration of 
the study. If there is any question that the patient will not reliably comply, they should not be 
entered in the study.
Additional consent form 
Not applicable
11.4
Discontinuation of the study
Novartis reserves the right to discontinue this study under the conditions specified in the clinical 
study agreement. Specific conditions for terminating the study are outlined in Section 4.4.
11.5
Publication of study protocol and results
Novartis assures that the key design elements of this protocol will be posted in a publicly 
accessible database such as clinicaltrials.gov. Also, upon study completion and finalization of 
the study report the results of this study will be either submitted for publication and/or posted 
in a publicly accessible database of clinical study results.
11.6
Study documentation, record keeping and retention of 
documents
Each participating site will maintain appropriate medical and research records for this trial, in 
compliance with Section 4.9 of the ICH E6 GCP, and regulatory and institutional requirements 


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for the protection of confidentiality of subjects. As part of participating in a Novartis-sponsored 
study, each site will permit authorized representatives of the sponsor(s) and regulatory agencies 
to examine (and when required by applicable law, to copy) clinical records for quality assurance 
reviews, audits and evaluation of the study safety and progress.
Source data are all information, original records of clinical findings, observations, or other 
activities in a clinical trial necessary for the reconstruction and evaluation of the trial. Examples 
of these original documents and data records include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, subjects’ diaries or evaluation 
checklists, pharmacy dispensing records, recorded data from automated instruments, copies or 
transcriptions certified after verification as being accurate and complete, microfiches, 
photographic negatives, microfilm or magnetic media, x-rays, and subject files and records kept 
at the pharmacy, at the laboratories, and medico-technical departments involved in the clinical 
trial.
Data collection is the responsibility of the clinical trial staff at the site under the supervision of 
the site Principal Investigator. The study case report form (CRF) is the primary data collection 
instrument for the study. The investigator should ensure the accuracy, completeness, legibility, 
and timeliness of the data reported in the CRFs and all other required reports. Data reported on 
the CRF, that are derived from source documents, should be consistent with the source 
documents or the discrepancies should be explained. All data requested on the CRF must be 
recorded. Any missing data must be explained. Any change or correction to a paper CRF should 
be dated, initialed, and explained (if necessary) and should not obscure the original entry. For 
electronic CRFs an audit trail will be maintained by the system. The investigator should retain 
records of the changes and corrections to paper CRFs.
The investigator/institution should maintain the trial documents as specified in Essential 
Documents for the Conduct of a Clinical Trial (ICH E6 Section 8) and as required by applicable 
regulations and/or guidelines. The investigator/institution should take measures to prevent 
accidental or premature destruction of these documents.
Essential documents (written and electronic) should be retained for not less than fifteen (15) 
years from the completion of the Clinical Trial unless Sponsor provides written permission to 
dispose of them or, requires their retention for an additional period because of applicable laws, 
regulations and guidelines.
11.7
Confidentiality of study documents and patient records
The investigator must ensure anonymity of the patients; patients must not be identified by names 
in any documents submitted to Novartis. Signed informed consent forms and patient enrollment 
log must be kept strictly confidential to enable patient identification at the site.
11.8
Audits and inspections
Source data/documents must be available to inspections by Novartis or designee or Health 
Authorities.


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11.9
Financial disclosures
Financial disclosures should be provided by study personnel who are directly involved in the 
treatment or evaluation of patients at the site - prior to study start.
12
Protocol adherence
Investigators ascertain they will apply due diligence to avoid protocol deviations. Under no 
circumstances should the investigator contact Novartis or its agents, if any, monitoring the study 
to request approval of a protocol deviation, as no authorized deviations are permitted. If the 
investigator feels a protocol deviation would improve the conduct of the study this must be
considered a protocol amendment, and unless such an amendment is agreed upon by Novartis 
and approved by the IRB/IEC/REB it cannot be implemented. All significant protocol 
deviations will be recorded and reported in the CSR.
12.1
Amendments to the protocol
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, Health Authorities where required, and the IRB/IEC/REB. Only 
amendments that are required for patient safety may be implemented prior to IRB/IEC/REB 
approval. Notwithstanding the need for approval of formal protocol amendments, the 
investigator is expected to take any immediate action required for the safety of any patient 
included in this study, even if this action represents a deviation from the protocol. In such cases, 
Novartis should be notified of this action and the IRB/IEC at the study site should be informed 
according to local regulations.


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13
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and Marrow Transplantation. , 2019 Frankfurt, Germany.
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Deficiencies in progenitor cells of multiple hematopoietic lineages and defective 
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CHADDERTON, A. 2010. Reduced proliferation of non-megakaryocytic acute 
myelogenous leukemia and other leukemia and lymphoma cell lines in response to 
eltrombopag. Leuk Res, 34, 1224-31.


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GEDDIS, A. E., LINDEN, H. M. & KAUSHANSKY, K. 2002. Thrombopoietin: a pan-
hematopoietic cytokine. Cytokine Growth Factor Rev, 13, 61-73.
JENKINS, J. M., WILLIAMS, D., DENG, Y., UHL, J., KITCHEN, V., COLLINS, D. & 
ERICKSON-MILLER, C. L. 2007. Phase 1 clinical study of eltrombopag, an oral, 
nonpeptide thrombopoietin receptor agonist. Blood, 109, 4739-41.
JEONG, J.-Y. & VANASSE, G. Eltrombopag, a non-peptide thrombopoietin receptor agonist, 
enhances the ex vivo expansion of human hematopoietic stem cells.  AACR 101st 
Annual Meeting 2010, Apr 17-21, 2010 2010 Washington, DC.
KALOTA, A., SELAK, M. A., GARCIA-CID, L. A. & CARROLL, M. 2015. Eltrombopag 
modulates reactive oxygen species and decreases acute myeloid leukemia cell survival. 
PLoS One, 10, e0126691.
KIMURA, T., KABURAKI, H., TSUJINO, T., IKEDA, Y., KATO, H. & WATANABE, Y. 
1998. A non-peptide compound which can mimic the effect of thrombopoietin via c-
Mpl. FEBS Lett, 428, 250-4.
KONG, Y., WANG, Y. T., HU, Y., HAN, W., CHANG, Y. J., ZHANG, X. H., JIANG, Z. F. 
& HUANG, X. J. 2016. The bone marrow microenvironment is similarly impaired in 
allogeneic hematopoietic stem cell transplantation patients with early and late poor graft 
function. Bone Marrow Transplant, 51, 249-55.
LAROCCA, A., PIAGGIO, G., PODESTA, M., PITTO, A., BRUNO, B., DI GRAZIA, C., 
GUALANDI, F., OCCHINI, D., RAIOLA, A. M., DOMINIETTO, A., BREGANTE, 
S., LAMPARELLI, T., TEDONE, E., ONETO, R., FRASSONI, F., VAN LINT, M. T., 
POGLIANI, E. & BACIGALUPO, A. 2006. Boost of CD34+-selected peripheral blood 
cells without further conditioning in patients with poor graft function following 
allogeneic stem cell transplantation. Haematologica, 91, 935-40.
LIZARDI, A. & VALLEJO. Eltrombopag induces responses in post allo-HSCT por graft 
function.  EBMT, 2017.
LOCATELLI, F., LUCARELLI, B. & MERLI, P. 2014. Current and future approaches to treat 
graft failure after allogeneic hematopoietic stem cell transplantation. Expert Opin 
Pharmacother, 15, 23-36.
OLNES, M. J., SCHEINBERG, P., CALVO, K. R., DESMOND, R., TANG, Y., DUMITRIU, 
B., PARIKH, A. R., SOTO, S., BIANCOTTO, A., FENG, X., LOZIER, J., WU, C. O., 
YOUNG, N. S. & DUNBAR, C. E. 2012. Eltrombopag and improved hematopoiesis in 
refractory aplastic anemia. N Engl J Med, 367, 11-9.
POPAT, U. R., RAY, G., JR, R. L. B., POON, M.-Y. C., C, V. B., VALDEZ, B. C., 
KONOPLEV, S., AHMED, S. & ALOUSI, A. M. 2015. Eltrombopag for Post-
Transplant Thrombocytopenia: Results of Phase II Randomized Double Blind Placebo 
Controlled Trial. Blood 126, 738.
QIAN, H., BUZA-VIDAS, N., HYLAND, C. D., JENSEN, C. T., ANTONCHUK, J., 
MANSSON, R., THOREN, L. A., EKBLOM, M., ALEXANDER, W. S. & JACOBSEN, 
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stem/primitive progenitor cell expansion and promotes multi-lineage hematopoiesis. 
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2015. The incidence, risk factors, and outcomes of primary poor graft function after 
unmanipulated haploidentical stem cell transplantation. Ann Hematol, 94, 1699-705.
TOWNSLEY, D. M., SCHEINBERG, P., WINKLER, T., DESMOND, R., DUMITRIU, B., 
RIOS, O., WEINSTEIN, B., VALDEZ, J., LOTTER, J., FENG, X., DESIERTO, M., 
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SAP_001.pdf: 
Official Title: 
The ELTION Study - A Multicenter Open-label Interventional Study of 
Eltrombopag in Patients With Poor Graft Function After Allogeneic 
Hematopoietic Stem Cell Transplantation 
NCT Number: 
NCT03718533 
Document Date: 
Statistical Analysis Plan Version 1.1: 28 September 2020 


Tel: 
 
Fax: 
 
F·B· 10-01-003 
 Barcelona 
Tel: 
/ Fax: 
 
The ELTION Study 
"A multicenter open-label interventional 
study of Eltrombopag in patients with poor 
graft function after allogeneic hematopoietic 
stem cell transplantation'' 
Clinical Trial Protocol CETB115EES03 
Slatistical Analysis Plan for Rnal Analysis 
V1.1 
28 September 2020 
Prepared by: 
Date: 
Signature: 
Approved by:
Date: 
Signature


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TABLE OF CONTENTS 
1 
INTRODUCTION __________________________________________________ 4 
2 
STUDY OBJECTIVES AND DESIGN __________________________________ 4 
2.1 
Study Objectives ____________________________________________________ 4 
2.2 
Study Design _______________________________________________________ 5 
2.3 
Study Population ____________________________________________________ 6 
3 
STATISTICAL METHODS __________________________________________ 9 
4 
ANALYSIS  POPULATIONS ________________________________________ 10 
5 
SCREENING  FAILURES __________________________________________ 10 
6 
DESCRIPTIVE ANALYSIS (SCREENING VISIT) ________________________ 10 
6.1 
Recruitment Period _________________________________________________ 10 
6.2 
Demography _______________________________________________________ 10 
6.3 
Medical history ____________________________________________________ 11 
6.4 
Underlying disease history ___________________________________________ 11 
6.5 
Description of the transplant _________________________________________ 11 
6.6 
Conditioning regimen _______________________________________________ 12 
6.7 
Cytogenetic _______________________________________________________ 12 
 
 12 
6.9 
ECG evaluation ____________________________________________________ 13 
6.10 
Ophthalmologic monitoring __________________________________________ 13 
6.11 
Karnofsky performance status ________________________________________ 13 
6.12 
Anthropometric data / vital signs ______________________________________ 13 
6.13 
Laboratory evaluation _______________________________________________ 14 
6.14 
Blood smear _______________________________________________________ 14 
7 
End of study form _______________________________________________ 14 
8 
Treatment ______________________________________________________ 16 
9 
Adverse events _________________________________________________ 16 
10 Objectives Analyses _____________________________________________ 17 
10.1 
Primary objective ___________________________________________________ 17 
10.2 
Secondary objective 1 _______________________________________________ 17 
10.3 
Secondary objective 2 _______________________________________________ 19 
10.4 
Secondary objective 3 _______________________________________________ 19 
10.5 
Secondary objective 4 _______________________________________________ 20 
10.6 
Secondary objective 5 _______________________________________________ 21 


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10.7 
Secondary objective 6 _______________________________________________ 21 
 
 22 


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LIST OF ABBREVIATIONS 
 
Abbreviation 
Explanation 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
ANC 
Absolute Neutrophil Count 
CI 
Confidence Interval 
EPO 
Erythropoietin 
G-CSF 
Granulocyte Colony Stimulating Factor 
KM 
Kaplan-Meier 
OS 
Overall Survival 
Q1 
First quartile 
Q3 
Third quartile 
PT 
Preferred Term 
SD 
Standard Desviation 
SOC 
System Organ Class 
 
 


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1 
INTRODUCTION 
The analysis plan proposed below details the necessary aspects to know about the study and 
the statistical methods to be used to apply them in the final statistical analysis. 
 
 
2 
STUDY OBJECTIVES AND DESIGN 
2.1 
Study Objectives 
Primary objective 
To evaluate the efficacy of eltrombopag for poor graft function on overall hematologic response 
(partial and complete) as determined by platelets, hemoglobin and neutrophil counts, by 16 
weeks after the initiation of eltrombopag. 
 
Secondary objectives 
1. To determine the response in each hematological lineage separately. 
2. To evaluate the long-term efficacy of eltrombopag on overall hematologic response 
(partial and complete) at 24 and 36 weeks after the initiation of eltrombopag. 
3. To evaluate the transfusion independence for red blood cells (RBC) and/or platelets 
after the initiation of eltrombopag. 
4. To evaluate the reduction and discontinuation of concomitant granulocyte colony-
stimulating factor (G-CSF) and/or erythropoietin (EPO) therapy. 
5. To evaluate the overall survival and survival rate at 24 and 36 weeks. 
6. To evaluate the safety of eltrombopag. 
 
 
 
 


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2.2 
Study Design 
This study is designed as an open-label, single-arm phase II study, in which patients diagnosed 
with primary or secondary PGF after allo-HSCT will be treated with eltrombopag up to week 36 
or until the patient’s premature withdrawal. If patient terminates eltrombopag for any of the 
reasons established in the withdrawal criteria, he/she will be followed for safety up to 30 days 
after the last dose of eltrombopag, unless he/she withdraws the consent, dies or is lost-to 
follow-up. 
 
The primary efficacy endpoint is the overall hematologic response rate (partial and complete) 
by 16 weeks after the initiation of eltrombopag. Eltrombopag will be initiated on day 1 at a dose 
of 150 mg once daily (75 mg daily in Asian ancestry patients) and will be continued up to 36 
weeks.  
 
The study will consist of the following periods: 
 
Screening Period (baseline): the patient will be invited to participate in the study, after being 
informed of its characteristics. The patient screening criteria will then be reviewed, and the 
procedures established in the evaluation schedule will be performed. 
 
Treatment Period: from administration of the first dose of eltrombopag until time when 
patient permanently stops taking study treatment for any reason or until 36 weeks have 
passed. 
o Only patients with a partial or complete response at week 16 will continue to receive 
eltrombopag until loss of response (defined as a decrease in blood counts to levels that 
do not continue to meet the criteria for response established in this protocol), 
unacceptable toxicity, or discontinuation for any other reason. 
o Patients who discontinue eltrombopag because efficacy, will continue in the study and 
attend the scheduled visits of Treatment Period as per protocol. If loss of response 
occurs, eltrombopag will be reintroduced at the last effective dose. 
During the Treatment Period, patients will be evaluated weekly during the first month, every 
2 weeks during the next 2 months and subsequently every 4 weeks until week 24. For the 
last 3 months, patients will be followed every 6 weeks. 
 
Final Visit (or Early Withdrawal): this visit will take place 30 days after completion of the 
Treatment Period, or premature patient withdrawal. 


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 
Follow-up for Survival: all patients who discontinue from the study, regardless the reason of 
discontinuation, will be followed for survival for 24 and 36 weeks, unless they withdraw their 
consent, die or are lost-to follow-up, in which case will be censored at the last 
contact/follow-up, and study visits will no longer be carried out. 
 
At 36 weeks of the study, the suitability of continuing with eltrombopag will be evaluated by the 
investigator, and the supply of the drug will be only commercial. Novartis will not supply 
eltrombopag after the end of the study. 
 
The number of patients planned to be enrolled for the study is 33. 
 
2.3 
Study Population 
Patients will be eligible for study participation as defined by following inclusion and exclusion 
criteria: 
 
Inclusion criteria 
1. Patient must be able to understand and communicate with the investigator and comply 
with the requirements of the study and must provide written, signed and dated informed 
consent form before any study assessment is performed. 
2. Male or female patients ≥ 18 years of age. 
3. Patients diagnosed with primary or secondary PGF after allo-HSCT defined as two or 
more cytopenias after day +30 post-transplant (re-tested in a peripheral blood analysis 
at screening):  
 
Platelet count <20,000/ µL (mandatory). 
 
Absolute neutrophil count (ANC) <1,000/µL. 
 
Hemoglobin < 100 g/L. 
4. Presence of donor chimerism >90% in screening visit. 
5. Karnofsky status ≥90% (Karnofsky assessment must be performed within 7 days prior 
to Day 1). 
 


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Exclusion criteria 
1. Pregnancy statements and contraception requirements: 
Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a 
female after conception and until the termination of gestation, confirmed by a positive 
hCG laboratory test. 
Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant (or female partners of male patients), unless they are using highly 
effective methods of contraception during dosing and for 3 months after stopping 
medication. Highly effective contraception methods include: 
 
Total abstinence (when this is in line with the preferred and usual lifestyle of the 
subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-
ovulation methods) and withdrawal are not acceptable methods of contraception. 
 
Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy), or tubal ligation at least six weeks before taking study treatment. In 
case of oophorectomy alone, only when the reproductive status of the woman has 
been confirmed by follow up hormone level assessment.  
 
Male sterilization (at least 6 months prior to screening). For female subjects on the 
study the vasectomized male partner should be the sole partner for that subject 
 
Use of oral, injected or implanted hormonal methods of contraception or placement 
of an intrauterine device (IUD) or intrauterine system (IUS), or other forms of 
hormonal contraception that have comparable efficacy (failure rate <1%), for 
example hormone vaginal ring or transdermal hormone contraception. 
In case of use of oral contraception women should have been stable on the same pill 
for a minimum of 3 months before taking study treatment. 
Sexually active males unless they use a condom during intercourse while taking the 
drug during treatment and for 3 months after stopping treatment and should not father a 
child in this period. A condom is required to be also used by vasectomized men as well 
as during intercourse with a male partner to prevent delivery of the drug via semen. 
2. Evidence of active acute or chronic graft versus host disease (GVHD). 
3. Evidence of any active malignancy. 
4. Subjects who are human immune deficiency virus (HIV), hepatitis C virus (HCV), 
hepatitis B surface antigen (HBsAg) positive in screening visit. 


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5. Cytogenetic abnormality in chromosome 7 present before the allo-HSC. 
6. Evidence of any clonal abnormality on cytogenetics (in bone marrow analysis). 
 
A local post-transplant conventional cytogenetic assessment should be available 
within 8 weeks before Day 1.  
 
If the cytogenetics is not valuable, i.e, it does not show metaphases, a FISH for 
MDS-related most frequent abnormalities including chromosome 7 is accepted. 
As a consequence, patients with dry tap bone marrow aspiration are NOT eligible. 
7. Evidence of bone marrow involvement or progression of the underlying disease 
assessed by the applicable methods in each case. 
8. Evidence of thrombotic microangiopathy. 
9. Evidence of possible causes of cytopenia other than PGF (active infections, myelotoxic 
drugs, hypersplenism…). 
10. Prior use of any thrombopoietin receptor (TPO-R) agonists for PGF. 
11. AST or ALT levels >3 x ULN. 
12. Creatinine level ≥1.5 x ULN. 
13. Total bilirubin level ≥1.5 x ULN. 
14. Previous thromboembolic event (other than line-related upper extremity thrombosis) 
15. Hypersensitivity to eltrombopag or its components. 
16. Clinically significant ECG abnormality history or current diagnosis of cardiac disease 
indicating significant risk of safety for subjects participating in the study such as 
uncontrolled or significant cardiac disease or impaired cardiac function including any of 
the following: 
a). Corrected QTc > 450 msec (male subjects), > 460 msec (female subjects) using 
Fredericia correction (QTcF) on the screening ECG 
b). Myocardial infarction 
c). Uncontrolled congestive heart failure 
d). Unstable angina  
e). Congenital long QT syndrome. 
17. Administration of an investigational drug within 30 days or 5 half-lives, whichever is 
longer, preceding the first dose of study treatment. 
18. Patient with liver cirrhosis. 


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19. Risk factors for Torsade de Pointes including uncorrected hypokalemia or 
hypomagnesemia.   
20. Subjects with any serious and/ or unstable pre-existing medical, psychiatric disorder or 
other conditions that could interfere with patient´s safety, obtaining informed consent or 
compliance with the study procedures as per investigator discretion. 
 
 
3 
STATISTICAL METHODS 
Quantitative variables are described with measures of central tendency and dispersion: mean, 
median, SD, Q1, Q3, minimum and maximum). 
Qualitative variables are described using absolute and relative frequencies (N, %). Two 
percentage columns are presented, total percentage (total %) and valid percentage (valid %), 
that is, the percentage over the sum of valid responses plus missing values and the percentage 
over the total of valid responses. When there are not missing values both of them are equal, 
and then only one will be show. 
 
In the analysis of contingency tables as well as for the comparison of proportions and / or 
frequency distributions, the chi-square test (or Fisher's exact when appropriate) will be used. 
 
For dependent samples, parametric (t-test paired) or non-parametric (Wilcoxon) statistical tests 
will be performed depending on the distribution of the sample. 
 
The "time to event" variables (overall survival) will be analyzed using the Kaplan-Meier 
method. 
 
These tests will be used in all bilateral cases and with a level of significance of 0.05. In cases 
where a p-value less than 0.05 appears, it refers to the existence of statistical significance. 
 
Data will be analyzed using SPSS v22.0. 


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4 
ANALYSIS  POPULATIONS 
The populations that will be included in the analysis are defined below: 
 
The Full Analysis Set (FAS) comprises all patients to whom study treatment has been 
assigned. All analysis describe in this document, except of AEs analysis (section 9) will 
be performed with this population. 
 
The Safety Set (SS) includes all patients who received at least one dose of study 
treatment. Only AEs analysis (section 9) will be performed with this population. 
 
Per-Protocol Set (PPS) consists of a subset of the patients in the FAS who are 
compliant with requirements of the clinical study protocol. 
 
 
5 
SCREENING  FAILURES 
It will be described the number of screening failure patients. And for these patients, the reason: 
 
Why was the patient not eligible for enrollment? (Did not meet the inclusion criteria / Did 
not meet the exclusion criteria / Unacceptable or past medical history-concomitant 
diagnosis / Intercurrent medical event/ Adverse event / Unacceptable laboratory 
value(s) / Unacceptable test procedure result(s) / Death / Unacceptable use or excluded 
medication(s)-therapies / Patient withdrew consent / Physician decisión / Lost to follow-
up / Unknown). 
In case of “Did not meet the inclusion criteria”, specify the criteria. 
In case of “Did not meet the exclusion criteria”, specify the criteria. 
 
 
6 
DESCRIPTIVE ANALYSIS (SCREENING VISIT) 
This section will be analyzed with Full Analysis Set population. 
 
6.1 
Recruitment Period 
The dates of inclusion of the first and last patient will be provided. 
 
6.2 
Demography 
The continuous variable to be described is: 


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 
Age (years), time from year of birth to year of signed the informed consent. 
 
The categorical variables to be described are: 
 
Sex (Male / Female). In case of female, Female of childbearing potential? (No / Yes). 
 
Race (Caucasian / Asian / Black / Other). In case of other, specify. 
 
 
6.3 
Medical history 
It will be shown a list with all relevant medical history not related to the study indication   
 
6.4 
Underlying disease history 
The categorical variable to be described is: 
 
Diagnosis (Acute myeloid leukemia / Acute lymphoblastic leukemia / Myelodysplastic 
syndromes / Non-Hodgkin's lymphoma / Hodgkin’s lymphoma / Monoclonal 
gammopathy-Multiple Myeloma / Bone marrow failure-aplastic anemia / Myelofibrosis / 
Chronic myelogenous leukemia / Chronic myeloproliferative disorders / Others). In case 
of other, specify. 
 
6.5 
Description of the transplant 
The continuous variable to be described is: 
 
Donor age (years). 
 
Time from transplantation date to start treatment date (months). 
 
The categorical variables to be described are: 
 
Donor chimerism in peripheral blood (%). 
 
Donor chimerism in peripheral blood (Total blood / Myeloid compartment). 
 
Transplant type (Matched family donor / Matched unrelated donor / Mismatched family 
donor / Mismatched unrelated donor / Haploidentical family donor / Unrelated umbilical 
cord blood / Other). For every option, it will be describe the family donor (Brother / 
Sister / Father / Mother / Daughter / Son / Other). 
 
Source of graft cells (Bone marrow (BM) / Peripheral blood stem cells (PBSC) ΟBM + 
PBSC / Umbilical cord blood). 
 
Poor graft function type (Primary / Secondary). 
 


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6.6 
Conditioning regimen 
It will be shown a multiple response table with the following options: 
 
Cyclophosphamide 
 
Fludarabine 
 
Busulfan 
 
Melphalan 
 
Thiotepa 
 
Body irradiation 
 
Other 
 
6.7 
Cytogenetic 
The categorical variables to be described are: 
 
Has been a local conventional cytogenetics or FISH performed at screening? (No 
mandatory, there was one available post-transplant (within 8 weeks before Day 1) / 
Yes). 
 
Were the cytogenetic results obtained by conventional cytogenetics or by FISH? 
(Conventional cytogenetics / FISH). 
 
Results (Negative for clonal abnormalities / Positive for clonal abnormalities) 
 
 
 
 
 
 
 
 
 
 
 


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6.9 
ECG evaluation 
The categorical variables to be described are: 
 
Has been the ECG performed? (Yes / No). In affirmative case,  
o Overall interpretation (Normal / Clinically insignificant abnormality / Clinically 
significant abnormality). 
o Prolongation of QTc-interval (No / Yes). 
 
6.10 Ophthalmologic monitoring 
The categorical variables to be described are: 
 
Has been the ophthalmologic monitoring performed? (Yes / No). In affirmative case, 
o Retin (Normal / Abnormal). 
o Vessels (Normal / Abnormal). 
o Optic disc/nerve (Normal / Abnormal). 
o Cataracts (No / Yes). In affirmative case, 
 Slit-lamp exam performed? (No / Yes). In affirmative case, 
 Slit-lamp exam (Normal / Abnormal). 
 
6.11 Karnofsky performance status 
The categorical variable to be described is: 
 
KPS (100% / 90% / 80% / 70% / 60% / 50% / 40% / 30% / 20% / 10%). 
 
6.12 Anthropometric data / vital signs 
The categorical variable to be described is: 
 
Has been the anthropometric data/vital signs evaluated? In affirmative case, the 
continuous variables to be described are: 
o Weight (kg). 
o Height (cm). 
o Sitting pulse (beats/minute). 
o Sitting systolic blood pressure (mmHg). 
o Sitting diastolic blood pressure (mmHg). 
o Respiratory rate (breaths/minute). 
o Body temperature (ºC). 


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6.13 Laboratory evaluation 
HEMATOLOGY 
The continuous variables to be described are: 
 
Neutrophils (/µL) 
 
Platelet count (/µL) 
 
Hemoglobin (g/L) 
 
In addition, it will be shown: 
 
Number of patients with <20000 platelets, <1000 neutrophils and <100 hemoglobin. 
 
Number of patients with <20000 platelets, <1000 neutrophils and >100 hemoglobin. 
 
Number of patients with <20000 platelets, >1000 neutrophils and <100 hemoglobin. 
 
IMMUNOSUPRESSANTS DRUGS LEVELS 
The categorical variable to be described is: 
 Has been the Immunosupressants drugs levels performed? (No / Yes). In affirmative 
case, the continuous variables to be described are: 
o Tacrolimus (ng/mL). 
o CsA (ng/mL). 
o Other (specify). 
 
6.14 Blood smear 
The categorical variables to be described are: 
 
Has been a blood smear performed and analysed for morphological abnormalities? (No 
/ Yes). 
 
Has been the percentage of schistocytes determined? (No / Yes). In affirmative case, it 
will be shown the percentage schistocyte (%). 
 
7 
END OF STUDY FORM 
The categorical variable to be described is: 
 
Did the patient complete the study? (No / Yes). In negative case, it will be shown a 
multiple response table with the following options: 
o Adverse event(s). In this case, specify the adverse event. 


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o Pregnancy. 
o Abnormal laboratory value(s). 
o Abnormal test procedure result(s). 
o Unsatisfactory therapeutic effect. 
o Study terminated by sponsor. 
o Non compliance with study treatment. 
o Protocol deviation. 
o Physician decision. 
o Subject withdrew consent. 
o Lost to follow-up. 
o Administrative reasons. 
o Death. 
o Study indication. 
o Other. In case of other, specify. 
 


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8 
TREATMENT 
 
Patients with 16 weeks of treatment who discontinue due to no response 
 
Patients with treatment in week 36. 
 
Patients with at least one dose modification (No /Yes). For each dose modification, it 
will be shown the reasons. 
 
Duration of treatment (days, from the start date to the end date). If the patient has 
modified the dose, it will be shown the duration for each dose indicated. 
 
9 
ADVERSE EVENTS 
This section will be analyzed with Safety Set population. 
 
The categorical variables to be described are: 
 
Number of patients with at least one adverse event. 
 
Number of adverse events per patient. 
For total of adverse events, it will be shown: 
 
Description of event. The event will be codified by MedDRA and will be shown PT and 
SOC. 
 
Does the AE meet the definition of serious? (No / Yes). 
 
Severity (1 / 2 / 3/ 4/ 5). 
 
AESI (No / Yes). 
 
Relationship to study drug (Not related / Related). 
 
Action taken (No action taken / Study drug dosage adjusted / Study drug temporarily 
interrupted / Study drug permanently discontinued) 
 
Outcome (Not recovered-Not resolved / Recovered-Resolved / Recovering-Resolving / 
Recovered with sequelae / Fatal / Unknown). 
 
Number of patients with different adverse events reported by severity (1 / 2 / 3 / 4 / 5). A 
list of the different AEs experienced by patients according to the maximum grade, N 
and % will be presented. (Events will be run by SOC and PT). 
 
 


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10 OBJECTIVES ANALYSES 
In this section, it will be shown the confidence intervals to 95%. 
 
10.1 Primary objective 
To evaluate the efficacy of eltrombopag for poor graft function on overall hematologic 
response (partial and complete) as determined by platelets, hemoglobin and neutrophil 
counts, by 16 weeks after the initiation of eltrombopag. 
It will be calculated: 
 
The overall response rate, defined as the percentage of patients who have a 
hematological response (partial and complete) by 16 weeks after the initiation of 
eltrombopag. If the patient hasn’t response in that week because was exit from the 
study before week 16 and in the last evaluation had a partial or complete response, 
also be considered as responder. 
 
10.2 Secondary objective 1 
To determine the response in each hematological lineage separately. 
It will be calculated: 
 
Percentage of patients who have a partial response in the neutrophil lineage, defined as 
Absolute neutrophil count (ANC) ≥1,000/ µL (when pretreatment ANC was <1,000/μL) 
confirmed in two consecutive blood tests separated a minimum of 7 days. 
 
Percentage of patients who have a complete response in the neutrophil lineage, defined 
as Absolute neutrophil count (ANC) ≥1,500/ µL (when pretreatment ANC was 
<1,000/μL) confirmed in two consecutive blood tests separated a minimum of 7 days. 
 
Percentage of patients who have a response in the neutrophil lineage (partial or 
complete). 
 
Percentage of patients who have a partial response in the platelet lineage, defined as 
Platelet count ≥20,000/µL (with platelet transfusion independence), confirmed in two 
consecutive blood tests separated a minimum of 7 days. 
 
Percentage of patients who have a complete response in the platelet lineage, defined 
as Platelet count ≥100,000/µL (with platelet transfusion independence), confirmed in 
two consecutive blood tests separated a minimum of 7 days. 


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 
Percentage of patients who have a response in the platelet lineage (partial or 
complete). 
 
Percentage of patients who have a partial response in the hemoglobin lineage, defined 
as Hemoglobin ≥100g/L (when pretreatment Hb was <100g/L) (with red blood cells 
(RBC) transfusion independence), confirmed in two consecutive blood tests separated 
a minimum of 7 days. 
 
Percentage of patients who have a complete response in the hemoglobin lineage, 
defined as Hemoglobin ≥110g/L (when pretreatment Hb was <100g/L), confirmed in two 
consecutive blood tests separated a minimum of 7 days. 
 
Percentage of patients who have a response in the hemoglobin lineage (partial or 
complete). 
 
Responses in each hematological lineage separately will be determined at weeks 16, 20, 24, 
30 and 36 after the initiation of eltrombopag. 
 
In addition, 
 
To assess if there are statistical significance differences in ANC between baseline and 
week 24, it will be aplied the appopiate paired test (T-test paired or Wilcoxon, 
depending the distribution of sample). 
 
To assess if there are statistical significance differences in ANC between baseline and 
week 36, it will be aplied the appopiate paired test (T-test paired or Wilcoxon, 
depending the distribution of sample). 
 
To assess if there are statistical significance differences in platelets between baseline 
and week 24, it will be aplied the appopiate paired test (T-test paired or Wilcoxon, 
depending the distribution of sample). 
 
To assess if there are statistical significance differences in platelets between baseline 
and week 36, it will be aplied the appopiate paired test (T-test paired or Wilcoxon, 
depending the distribution of sample). 
 
To assess if there are statistical significance differences in hemoglobin between 
baseline and week 24, it will be aplied the appopiate paired test (T-test paired or 
Wilcoxon, depending the distribution of sample). 
 
To assess if there are statistical significance differences in hemoglobin between 
baseline and week 36, it will be aplied the appopiate paired test (T-test paired or 
Wilcoxon, depending the distribution of sample). 
 


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10.3 Secondary objective 2 
To evaluate the long-term efficacy of eltrombopag on overall hematologic response 
(partial and complete) at 24 and 36 weeks after the initiation of eltrombopag. 
It will be calculated: 
 
Percentage of patients who have secondary overall hematological response at 24 
weeks, defined as the maintenance of a partial or complete response at 24 weeks. 
 
Percentage of patients who have secondary overall hematological response at 36 
weeks, defined as the maintenance of a partial or complete response at 36 weeks. 
 
 
10.4 Secondary objective 3 
To evaluate the transfusion independence for red blood cells (RBC) and/or platelets 
after the initiation of eltrombopag. 
It will be calculated: 
 
The patient receive at least one transfusion before start treatment (No / Yes) (data in 
section “Supportive Care Record”). 
 
The patient receive at least one transfusion after start treatment and before week 16 
(No / Yes) (data in section “Supportive Care Record”). 
 
The patient receive at least one transfusion after week 16 and before end treatment (No 
/ Yes) (data in section “Supportive Care Record”). 
In each of the studied moments, it will be shown the number of transfusions per patient. In 
addition, for total of transfusions, it will be shown the type of transfusion (Platelets / RBC). 


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It will be performed: 
 
Analysis of contingency tables between number of patiens with transfusions before start 
treatment and before week 16, using chi-square or Fisher's exact test. 
 
Analysis of contingency tables between number of patiens with transfusions before start 
treatment and after week 16, using chi-square or Fisher's exact test. 
 
It will be calculated: 
 
The period of time where patients did not receive any platelet or RBC transfusions 
during the treatment period, calculated as the difference between the number of days in 
treatment and the number of days with transfusions. 
 
 
10.5 Secondary objective 4 
To evaluate the reduction and discontinuation of concomitant granulocyte colony-
stimulating factor (G-CSF) and/or erythropoietin (EPO) therapy. 
It will be calculated: 
 
The patient receive EPO at start of treatment (No / Yes) (data in section “Supportive 
Care Record”). 
 
The patient receive EPO in visit 6, visit 9, visit 11, visit 13, visit 15 and visit 16 (No / 
Yes) (data in section “Supportive Care Record”). 
 
The patient reduce EPO at least 50% from start of treatment to visit 6, visit 9, visit 11, 
visit 13, visit 15 and visit 16 (No/ Yes) (data in section “Supportive Care Record”). 
 
 
The patient receive G-CSF at start of treatment (No / Yes) (data in section “Supportive 
Care Record”). 
 
The patient receive G-CSF in visit 6, visit 9, visit 11, visit 13, visit 15 and visit 16 (No / 
Yes) (data in section “Supportive Care Record”). 
 
The patient reduce G-CSF at least 50% from start of treatment to visit 6, visit 9, visit 11, 
visit 13, visit 15 and visit 16 (No / Yes) (data in section “Supportive Care Record”). 
 


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It will be realized: 
 
Analysis of contingency tables between number of patiens who receive EPO at start of 
treatment and in visit 6, visit 9, visit 11, visit 13, visit 15 and visit 16, using chi-square or 
Fisher's exact test. 
 
Analysis of contingency tables between number of patiens who receive G-CSF at start 
of treatment and in visit visit 6, visit 9, visit 11, visit 13, visit 15 and visit 16, using chi-
square or Fisher's exact test. 
 
10.6 Secondary objective 5 
To evaluate the overall survival and survival rate at 24 and 36 weeks. 
Overall survival (OS), defined as the time from the date of inclusion until the date of death due 
to any cause, will be calculated using Kaplan-Meier (KM) estimates. The KM graph will show 
the median OS time and the 95% CI will indicate the number of events and patients censored. 
All patients who discontinue from the study will be followed for survival for 24, 36 and 40 
weeks, unless they withdraw their consent, die or are lost-to follow-up, in which case will be 
censored at the last contact/follow-up.  
 
The survival rate will also be evaluated by the percentage of patients still alive at 24, 36 and 40 
weeks. 
 
 
10.7 Secondary objective 6 
To evaluate the safety of eltrombopag. 
This objective has been resolved in this document with: 
 Adverse events analysis (see section 9). 
 Reason for study withdrawal (see section 7). 
 


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