A Phase III Study of Eltrombopag vs Standard Front Line Management for Newly Diagnosed Immune Thrombocytopenia in Children
Phase: PHASE3
Conditions: Immune Thrombocytopenia
Sponsor: Baylor College of Medicine

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ITP CONSORTIUM OF NORTH AMERICA 
 
ICON3 
 
A Phase 3 Study of Eltrombopag vs. Standard First-Line Management for Newly 
Diagnosed Immune Thrombocytopenia (ITP) in Children  
 
CETB115JUS33T 
 
Investigational Product: Eltrombopag 
IND #: 142204 
Study Phase: 3 
 
 
Principal Investigator/IND Holder 
Amanda Grimes 
Baylor College of Medicine/Texas Children’s Hospital 
 
Study Co-Chair 
Kristin Shimano 
UCSF Benioff Children’s Hospital 
 
Data Coordinating Center 
Rachael Grace 
Boston Children’s Hospital 
 
Steering Committee 
Robert Klaassen, Chair 
Ellis Neufeld 
Cindy Neunert 
 
Statistician 
Wendy London 
 
This confidential information about an investigational product is provided for the exclusive 
use of investigators of this product and is subject to recall at any time.  The information in 
this document may not be disclosed unless federal or state law or regulations require such 
disclosure.  Subject to the foregoing, this information may be disclosed only to those 
persons involved in the study who have a need to know, with the obligation not to further 
disseminate this information.   

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Table of Contents 
 
Experimental Design Schema  
 
 
 
 
 
 
3 
1. Background  
 
 
 
 
 
 
 
 
4 
2. Study Rationale 
 
 
 
 
 
 
 
 
5 
3. Study Objectives 
 
 
 
 
 
 
 
 
7 
4. Study Design 
 
 
 
 
 
 
 
 
8 
5. Criteria for Evaluation 
 
 
 
 
 
 
 
9 
6. Subject Selection 
 
 
 
 
 
 
 
 
11 
7. Concurrent Medications 
 
 
 
 
 
 
 
14 
8. Treatment Plan 
 
 
 
 
 
 
 
 
17 
9. Study Procedures and Guidelines  
 
 
 
 
 
23 
10. Safety 
 
 
 
 
 
 
 
 
 
29 
11. Adverse Events Reporting and Documentation  
 
 
 
29 
12. Discontinuation and Replacement of Subjects 
 
 
 
 
36 
13. Protocol Variances and Deviations 
 
 
 
 
 
37 
14. Data Safety Monitoring 
 
 
 
 
 
 
 
38 
15. Steering Committee 
 
 
 
 
 
 
 
38 
16. Statistical Methods and considerations  
 
 
 
 
38 
17. Data collection, retention, and monitoring 
 
 
 
 
45 
18. Administrative, ethical, regulatory considerations 
 
 
 
47 
19. Appendices 
 
 
 
 
 
 
 
 
50 
A1. Bleeding Assessment Tools: WHO scale, Buchanan Scale 
 
51 
A2. HRQoL Tools: KIT, Hockenberry Fatigue Scale, PROMIS, Change Scale 53 
20. References 
 
 
 
 
 
 
 
 
71 
 
 

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EXPERIMENTAL DESIGN SCHEMA 
 
 
 
 
 

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1 BACKGROUND 
ITP is the most common autoimmune cytopenia in children, and causes an often 
severely reduced platelet count, variable bleeding symptoms, and health-related 
quality of life (HRQoL) reductions due to factors such as activity restrictions, frequent 
medical visits and interventions, and fatigue.1-3 In an era when the fields of 
hematology and immunology are advancing rapidly with the development of drugs 
targeted to specific disease mechanisms, the treatment of newly diagnosed ITP 
remains primitive and non-specific, with no novel therapies introduced in the past 30 
years.4 
 
Eltrombopag is an oral, small-molecule, nonpeptide thrombopoietin-receptor agonist 
(TPO-RA). The drug initiates thrombopoietin-receptor signaling by interacting with 
the transmembrane domain of the receptor, thereby inducing proliferation and 
differentiation of cells in the megakaryocytic lineage.  Eltrombopag is a drug that has 
the potential to change the landscape of newly diagnosed ITP for both children and 
adults. While there are myriad drugs available to choose amongst for treatment of 
chronic ITP, including immunosuppressants and thrombopoietin receptor agonists, 
the treatment of newly diagnosed ITP is generally limited to three first-line 
medications: corticosteroids, intravenous immunoglobulin (IVIG), and anti-D globulin.  
Each of these agents has either undesirable side effects, undesirable logistics of 
administration, or both. Additionally, each of these agents acts only transiently to 
raise the platelet count, and in children with continued active ITP, the platelet count 
will decrease days to weeks after the medication is given. As a once daily, non-
immunosuppressant, oral agent, eltrombopag offers the possibility of a sustained 
platelet response over weeks to months with continued use. This could result in 
improved HRQoL and reduction in fatigue, as well as other benefits.5 
 
Eltrombopag is an established therapy for pediatric patients with chronic ITP. Safety 
and efficacy were established in the PETIT6 and PETIT27 trials, and the drug was FDA-
approved for children with chronic ITP in 2015. 
 
Off-label use for adults with newly diagnosed ITP has been described in two small 
single-center trials. A single-arm study of dexamethasone in combination with 4 
weeks of eltrombopag used upfront in adult patients with newly diagnosed ITP 
produced 100% response (platelets >30 x 109/L) at completion of therapy, and 66.7% 
relapse-free survival at 1 year, better outcomes than expected for comparable 
patients treated with steroids alone.8 In a second study, 76% of steroid-
nonresponsive patients had a durable response to eltrombopag after 3 months of 
therapy.9 Based on data from ICON2, pediatric hematologists are already using TPO-
RAs in some cases of newly diagnosed ITP. Of 79 patients described in the ICON2 
retrospective review who were prescribed a TPO-RA, 18% had newly diagnosed ITP.10 
TPO-RAs may be an efficacious first-line therapy for newly diagnosed ITP patients 
who require treatment. 
 

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While age and duration of symptoms at diagnosis are known to predict resolution of 
ITP11, other biologic factors that predispose some patients to resolution of their ITP 
and others to a more chronic course are not known. It is also not known whether the 
development of chronic ITP could be prevented by intervention earlier in the 
patient’s course. A subset of patients with chronic ITP has been reported to have 
resolution of their disease after treatment with TPO-RAs, which was sustained after 
discontinuation of the medication. One postulated mechanism is immune tolerance 
by increasing exposure to platelet antigens, a hypothesis supported by the 
decreasing titer of anti-platelet antibody in one patient who resolved.12 Another 
proposed mechanism is the increase in Treg functionality due to increased TGF-1 
released by megakaryocytes.13 Because of the implication of Tregs in the 
pathogenesis of ITP and the potential immunomodulatory effects of TPO-RA, early 
use of eltrombopag may have an impact on the number of patients who resolve 
versus have persistent or chronic disease. Additionally, there are likely other 
biological factors which influence response to TPO-RA and other therapies that are 
not yet understood. Identification of these biomarkers could lead to a more 
personalized approach to therapy, targeted to an individual patient’s disease biology. 
 
 
2 STUDY RATIONALE 
2.1 Study Design Rationale 
Eltrombopag is an attractive option for pediatric patients needing therapy for ITP 
because it is an oral outpatient therapy and may have fewer side effects than 
standard therapies. The early response rate in this setting is not known. Pilot scale 
studies or observational accounts cannot answer important questions about the 
actual efficacy of this approach. Therefore, we have designed a randomized, two-
arm, Phase 3 trial to evaluate the efficacy of eltrombopag vs. standard first-line 
management in pediatric patients with newly diagnosed ITP. The primary endpoint (≥ 
3 of 4 platelet measurements with platelets >50 x109/L at Weeks 6, 8, 10, and 12 of 
therapy, without rescue) is a measurable outcome clinically equivalent to the 
endpoint of ≥ 6 of 8 platelet measurements with platelets >50 x109/L during weeks 5-
12 used in a previous pediatric study of eltrombopag in chronic ITP7. It is also a 
clinically relevant outcome in the newly diagnosed setting, as patients who are being 
treated because of bleeding symptoms or risk may benefit from a more sustained 
response during this time period, rather than repeated drops in platelet counts after 
transient responses to therapy. 
 
2.2 Dose Rationale 
The PETIT6 trial started with a dose-finding phase, followed by a double-blind 
randomized phase in which starting doses were at the previously established doses. 
PETIT27 used starting doses based on body weight and ethnic origin. PK data 
demonstrate that patients age 12-17 years have similar AUCtau and Cmax values as 
adults for the same dose, while children age 1-11 years have higher levels.14 With 
lower weight-adjusted exposure, however, younger children require higher per-kg 

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doses to achieve the same exposure. Pediatric dosing is now established, and there is 
an FDA label for use in pediatric patients > 1 year of age with chronic ITP. This study 
will use manufacturer label dosing for drug initiation. Dose adjustment after a 
platelet response is modified from the label based on abundant clinical experience 
with rebound thrombocytopenia when eltrombopag is held in this setting. Details for 
dose reduction are outlined after a sustained response after week 12 is prescribed, 
given reports15 of adult patients with sustained responses after discontinuation in the 
setting of “persistent response despite a reduction in dose over time.” As we expect 
the majority of newly diagnosed patients to have resolution of ITP within 1 year, we 
outline standardized discontinuation of drug even in the absence of thrombocytosis. 
 
2.3 Safety Considerations 
Two pediatric trials (PETIT6 and PETIT27) investigated the use of eltrombopag in 
pediatric patients aged 1-17 years with persistent or chronic ITP. The PETIT trial 
established dosing in an open-label dose-finding phase and then randomly assigned 
patients to receive eltrombopag vs placebo. 62% of patients receiving eltrombopag 
vs. 32% of patients receiving placebo (p=0.011) achieved the primary endpoint of 
platelet count ≥50 x109/L at least once in the first 6 weeks of the study without 
rescue. In PETIT2, 40% of patients receiving eltrombopag vs. 3% of patients receiving 
placebo had a sustained platelet response, with primary outcome of platelet count 
≥50 x109/L during 6 of 8 of weeks 5-12 of the study. 
 
Hepatobiliary events: Mild reversible elevations of alanine aminotransferase ≥3x ULN 
occurred in fewer than 10% of pediatric patients and were not associated with 
clinically significant symptoms. However, 3% of patients in the two studies were 
unable to continue eltrombopag. 
 
Marrow fibrosis: There were no findings of bone marrow fibrosis in either pediatric 
trial.14  
 
Thromboembolic events: There were no thromboembolic events in either pediatric 
trial.  
 
Cataracts: In an adult randomized controlled trial (RAISE), there was no difference in 
cataract development between the eltrombopag group and the placebo group. In 
two open label studies (REPEAT and EXTEND), there was a comparable frequency of 
cataract incidence or progression.16 In the pediatric trials, 2 patients in PETIT2 had a 
cataract event (one development of a new cataract, and one progression of a pre-
existing cataract).7 In both the adult and pediatric studies, all patients with cataract 
development or progression had also received corticosteroids. Current consensus 
among experts is that risk of cataract is not higher than baseline during eltrombopag 
treatment. 
 
 

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3 STUDY OBJECTIVES 
3.1 Primary Objective 
To determine if the proportion of patients with a platelet response is significantly 
greater in patients with newly diagnosed ITP treated with eltrombopag than those 
treated with standard first-line treatments 
 
3.2 Secondary Objectives 
3.2.1 To compare the proportion of patients with poor bleeding scores (WHO 
Bleeding Scale≥2 or Modified Buchanan Score≥3) at 1, 2, 3, 4, 12 weeks 
and 1 year in patients with newly diagnosed ITP treated with eltrombopag 
vs. standard first-line agents 
3.2.2 To compare the cumulative number of rescue therapies (defined in 
section 8.4) needed during the first 12 weeks of treatment for patients 
with newly diagnosed ITP treated with eltrombopag vs. those treated with 
standard first-line agents 
3.2.3 To compare platelet response during weeks 6-12 of study in patients 
treated with eltrombopag vs standard first line agents who required a 
rescue treatment during weeks 1-2 of study 
3.2.4 To compare the proportion of patients who do not need ongoing 
treatment at 12 weeks and 6 months for patients with newly diagnosed 
ITP treated with eltrombopag vs. those treated with standard first-line 
agents 
3.2.5 To compare the proportion of patients with a treatment response (4 
binary endpoints (section 5.2.5)) at one year after study enrollment in 
patients with newly diagnosed ITP treated with eltrombopag vs. those 
treated with standard first-line agents 
3.2.6 To compare the number of 2nd-line therapies (defined in section 7.2.1) 
used in weeks 13-52 for patients with newly diagnosed with ITP treated 
with eltrombopag vs. those treated with standard first-line agents 
3.2.7 To compare the absolute change in percentage of CD4+25+Foxp3+ 
regulatory T cells (Tregs) a) from baseline to 12 weeks; and b) from 
baseline to 1 year, in patients with newly diagnosed ITP treated with 
eltrombopag vs. those treated with standard first-line agents 
3.2.8 To compare change in Health Related Quality of Life (HRQoL) from a) 
baseline to 1 week, b) baseline to 4 weeks, c) baseline to 12 weeks, and, 
d) baseline to 1 year, as measured by the parent-proxy report of the Kids 
ITP tools (KIT) and Global Change Scale for patients with newly diagnosed 
ITP treated with eltrombopag vs. those treated with standard first-line 
agents 
3.2.9 To compare fatigue at 1 week, 4 weeks, 12 weeks, and 1 year as measured 
by the parent-proxy report of the Hockenberry Fatigue Scale-Parent (FS-P) 

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for patients with newly diagnosed ITP treated with eltrombopag vs. those 
treated with standard first-line agents 
3.2.10 To compare iron indices at 12 weeks, 6 months, and 1 year in patients 
with newly diagnosed ITP treated with eltrombopag vs. those treated with 
standard first-line agents 
3.2.11 Safety Evaluations: To describe the proportion of patients with abnormal 
liver function tests (LFTs) in patients with newly diagnosed ITP treated 
with eltrombopag. To describe the proportion of patients with adverse 
events and serious adverse events in patients with newly diagnosed ITP 
treated with eltrombopag and standard first-line agents 
 
3.3 Exploratory Objectives 
3.3.1 To compare additional platelet-defined responses in patients with newly 
diagnosed ITP treated with eltrombopag versus those treated with 
standard therapy. 
3.3.2 To compare additional changes in HRQoL (measured by KIT) and fatigue 
(measured by Hockenberry Fatigue scale) at 1 week, 4 weeks, 12 weeks, 
and 1 year in patients with newly diagnosed ITP treated with eltrombopag 
versus those treated with standard therapy. 
3.3.3 To compare cost of therapy (including medications, hospitalizations, the 
PROMIS survey, etc.) between patients treated with eltrombopag versus 
those treated with standard therapy. 
 
 
4 STUDY DESIGN 
This is a prospective, open label, randomized, two-arm, multi-center Phase 3 trial.  
Patients with newly diagnosed ITP are randomized 2:1 to receive the experimental 
treatment, eltrombopag, or investigator’s choice of 3 standard therapies. The 
primary objective is to determine if the proportion of patients with platelet response 
is significantly greater in patients treated with eltrombopag compared to those 
treated with standard therapies. 
 
Randomization at study enrollment will be stratified by the two factors described 
below, using a block size of 3. 
 
a) Age at enrollment 
b) Whether the patient has received a first-line treatment (as defined in inclusion 
criteria): 
o 1) Upfront treatment: Patients within 10 days of ITP diagnosis who have 
not received previous treatment 
OR 
o 2) Treatment failure: Patients who have failed standard management 
(observation or treatment with one or more first-line standard agents) 
 

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Table 4A: Stratification strata and stratum-specific patient enrollment limits 
Stratum 
Patient Age at 
Enrollment 
Patient Up-front 
Treatment Status 
Maximum Number 
of Patients 
Enrolled 
1 
1 – <6 
Requires up-front 
treatment 
27 
2 
1 – <6 
Failed up-front treatment 
27 
3 
6 – <12 
Requires up-front 
treatment 
27 
4 
6 – <12 
Failed up-front treatment 
27 
5 
12 – <18 
Requires up-front 
treatment 
27 
6 
12 – <18 
Failed up-front treatment 
27 
 
 
Patients randomized to the eltrombopag arm will be eligible to continue the 
treatment throughout the 1-year duration of study participation, with guidelines 
given for dose adjustments. 
 
A total of up to 162 patients will be enrolled. The required sample size is 147 
“informative” patients (as defined below), with 104 (estimated 98 informative) in the 
experimental treatment arm and 52 (estimated 49 informative) in the standard 
treatment arm. A conservatively high estimate of 9% of patients are anticipated to 
withdraw from the study prior to the 5-week platelet assessment; these patients will 
be classified as non-responders, and will make a non-informative contribution to the 
analysis response rate for the primary objective. Therefore, to obtain at least 147 
informative randomized patients, we plan to enroll and randomize up to an 
additional 15 patients (9 and 6 for the eltrombopag and standard treatment arms, 
respectively) for a total of 162.  
 
 
5 CRITERIA FOR EVALUATION 
5.1 Primary Efficacy Endpoint 
The primary endpoint is binary, with each patient classified as either a platelet responder 
or a platelet non-responder.  Platelet responders are defined as patients with ≥3 of 4 
platelet measurements >50 x109/L between Weeks 6-12. All platelet counts will be 
reported, and the four measurements closest in time to Weeks 6, 8, 10, and 12 will be 
selected for the determination of the primary endpoint. Within a sliding one-week 
window, only one measurement can be selected.   
 
Patients will be classified as non-responders for any of the following reasons: 

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1) Failing to meet the criteria to be a responder (including having an insufficient 
number of values >50 x109/L due to missing data); or, 
2) Requiring rescue medication at any time within the first 12 weeks of therapy; or, 
3) Withdrawing from protocol therapy prior to week 6. 
 
5.2 Secondary Endpoints 
5.2.1 Poor bleeding score (binary) at 1, 2, 3, 4 weeks, 12 weeks, and 1 year after 
study enrollment defined as WHO Bleeding Scale≥2 or Modified Buchanan 
Scale≥3 
5.2.2 Cumulative number of rescue therapies required during the first 12 weeks 
of treatment 
5.2.3 Platelet response (binary), defined as ≥ 3 of 4 weeks with platelets >50 
x109/L during weeks 6-12 of therapy, but patient required a rescue 
treatment during weeks 1-2 of study 
5.2.4 No further need for treatment (binary) after 12 weeks or 6 months of 
study 
5.2.5 Treatment response (binary endpoints) at 1 year defined as: 
 CR is defined as platelet count >/= 150 x109/L 
 Primary Remission at 1 year is defined as CR at 1 year with no second-
line agents required and >/= 3 months after discontinuing most recent 
platelet active medication  
 Disease resolution at 1 year is defined as CR at 1 year >/= 3 months 
after discontinuing most recent platelet active medication. May have 
received a second-line therapy, excluding rituximab or splenectomy. 
 Disease stability at 1 year is defined as platelets >/=50x109/L but <150 
x109/L >/= 3 months after discontinuing most recent platelet active 
medication. 
5.2.6 Number of 2nd-line therapies (defined in section 7.2.1) in weeks 13-52 
5.2.7 Absolute change in percentage of CD4+25+Foxp3+ regulatory T cells from 
baseline at 12 weeks and 1 year 
5.2.8 Absolute change in parent proxy-reported KIT overall scores from baseline 
to 1 week, 4 weeks, 12 weeks, and 1 year after study enrollment (see 
Appendix A2) 
5.2.9 Total scale intensity ratings (continuous) from the Hockenberry Fatigue 
Scale-Parent (FS-P) at 1 week, 4 weeks, 12 weeks, and 1 year (see 
Appendix A2) 
5.2.10 Serum iron, TIBC, transferrin saturation, ferritin, MCV, and hemoglobin at 
12 weeks, 6 months, and 1 year after study enrollment 
5.2.11 Safety evaluations as defined by: 
 Abnormal LFTs: 
 
 
 
ALT ≥ 3x ULN in patients with normal baseline 
 
 
 
ALT ≥ 3x baseline or ≥ 5x ULN (whichever is lower) in patients with  
 
abnormal baseline 
 
 
 
ALT ≥ 3x ULN AND bilirubin ≥ 1.5xULN (>35% direct) 

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 Incidence of adverse events (see section 9.1.6) 
 Incidence of serious adverse events (see section 12.2) 
 
5.3 Exploratory Endpoints 
5.3.1 Platelet-specific endpoints 
 Time to response (platelets >30x109/L, and at least 2-fold increase in 
the baseline count and absence of bleeding) (IWG definition)17 
 Treatment response (platelets >30x109/L, and at least 2-fold increase 
in the baseline count and absence of bleeding) (IWG definition) at 12 
weeks 
 Time to platelet count >100x109/L and absence of bleeding (IWG 
definition) 
 Treatment response (platelet count >100x109/L and absence of 
bleeding) (IWG definition) at 12 weeks  
 Loss of treatment response (platelet count below 30x109/L, or less 
than 2-fold increase in the baseline count or bleeding) (IWG definition) 
at any time during the study period after achieving response during 
the first 12 weeks  
 Extreme thrombocytosis (platelets >1 x1012/L) 
5.3.2 Patient-reported outcomes endpoints 
 Absolute change in child self-reported and parent impact KIT scores 
from baseline to 1 week, 4 weeks, 12 weeks, and 1 year after study 
enrollment 
 Absolute change in Hockenberry fatigue (FS-C, FS-A, FS-P) scores from 
baseline to 1 week, 4 weeks, 12 weeks, and 1 year after study 
enrollment 
 Global Change Scale scores at 1 week, 4 weeks, 12 weeks, and 1 year 
after study enrollment 
5.3.3 Cost of therapy endpoints 
 Number of hospitalizations 
 
 
6 SUBJECT SELECTION 
Subjects with a diagnosis of ITP who meet the inclusion and exclusion criteria will be 
eligible for participation in this study.   
 
6.1 Inclusion Criteria 
 Age: 1- <18 years 
 Newly diagnosed ITP (<3 months from diagnosis (first abnormal platelet count), 
per international working group definition17) 
 Platelets <30 x109/L at screening 
 Requires pharmacologic treatment from the perspective of the treating clinician. 
Need to treat is at the discretion of the investigator, but there should be clinical 

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equipoise about the use of eltrombopag vs standard treatment options (patients 
should not, in the opinion of the investigator, require concomitant therapy at time 
of enrollment). 
 Treatment options include one of three standard therapies, (IVIg, steroids, or 
Anti-D). For example, if patient has previously shown no response to IVIg or 
steroids and is Rh-negative, patient would not be eligible for study. 
 Patient population includes both: 
o 1) Upfront treatment: Patient within 10 days of ITP diagnosis who has not 
received previous treatment OR 
o 2) Treatment failure: Patients who have failed standard management 
(observation or treatment with one or more first-line agents) 
 Failure of observation: no platelet recovery (>30 x109/L) with observation 
>10 days from diagnosis, with need to treat 
 Poor response to first-line agent (platelets remain <30 x109/L) 
 Initial response to first-line agent, but response wanes and platelets fall 
below 30 x109/L 
 Family willing and able to return for required lab studies 
 
6.2 Exclusion Criteria 
 Severe bleeding: Buchanan Overall Grade 4 or 5 bleeding (see Appendix A1), or 
severe bleeding requiring emergent treatment at the discretion of the provider. 
(e.g., intracranial hemorrhage, pulmonary hemorrhage, bleeding with ongoing 
need for pRBC transfusion) 
 Prior treatment with TPO-RA (eltrombopag or romiplostim) 
 Known secondary ITP (due to lupus, CVID, ALPS) 
 Known HIV (or history of HIV positivity) or Hepatitis C (screening not required if 
no clinical suspicion) 
 Evans Syndrome: positive direct Coombs with evidence of active hemolysis 
(elevated LDH or reticulocyte count not attributable to recent treatment or 
bleeding) 
 Any Malignancy 
 History of stem cell transplant or solid organ transplant 
 AST or ALT >2x ULN 
 Total bilirubin >1.5 × ULN 
 Subjects with liver cirrhosis (as determined by the investigator) 
 Creatinine >2.5 × upper limit of normal (ULN) 
 Known active or uncontrolled infections not responding to appropriate therapy 
 On anticoagulation or anti-platelet agents 
 Known thrombophilic risk factors. Exception: Subjects for whom the potential 
benefits of participating in the study outweigh the potential risks of 
thromboembolic events, as determined by the investigator.  
 Baseline ophthalmic problems that may potentiate cataract development 
 Impaired cardiac function, such as: 

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o Known prolonged QTc, with corrected QTc >450 msec  
o Other clinically significant cardio-vascular disease (e.g., uncontrolled 
hypertension, history of labile hypertension), 
o History of known structural abnormalities (e.g. cardiomyopathy). 
 History or current diagnosis of cardiac disease indicating significant risk of safety 
for patients participating in the study such as uncontrolled or significant cardiac 
disease, including any of the following: 
o Recent myocardial infarction (within last 6 months), 
o Uncontrolled congestive heart failure, 
o Unstable angina (within last 6 months), 
o Clinically significant (symptomatic) cardiac arrhythmias (e.g., sustained 
ventricular tachycardia, and clinically significant second or third degree AV 
block without a pacemaker.) 
o Long QT syndrome, family history of idiopathic sudden death, congenital 
long QT syndrome or additional risk factors for cardiac repolarization 
abnormality, as determined by the investigator. 
 Known immediate or delayed hypersensitivity reaction to eltrombopag or its 
excipient. 
 Pregnant, breastfeeding, or unwilling to practice birth control during participation 
in the study.  Women of childbearing potential (have achieved menarche) must 
have a negative serum or urine pregnancy test and agree to use basic methods of 
contraception (if sexually active) or maintain abstinence for the duration of the 
study until 7 days after the last dose of study treatment. Basic contraception 
methods include: 
o 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  
o Female sterilization (have had surgical bilateral oophorectomy with or 
without hysterectomy), total hysterectomy, or tubal ligation at least six 
weeks before taking study treatment. In case of oophorectomy alone, only 
when the reproductive status of the woman has been confirmed by follow 
up hormone level assessment  
o Male sterilization (at least 6 months prior to screening). The vasectomized 
male partner should be the sole partner for that subject  
o Barrier methods of contraception: Condom or Occlusive cap.  For the UK:  
with spermicidal foam/gel/film/cream/ vaginal suppository  
o 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 

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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. 
 Male patients who are sexually active and do not agree to abstinence or to use a 
condom during intercourse while taking eltrombopag, and for 7 days after the 
last dose of study treatment. 
 History of alcohol/drug abuse 
 Presence of a medical condition that in the opinion of the Investigator would 
compromise the safety of the patient or the quality of the data. 
 Concurrent participation in an investigational study within 30 days prior to 
enrollment or within 5-half-lives of the investigational product, whichever is 
longer. Note: parallel enrollment in a non-therapeutic trial such as disease 
registry or biology study is permitted. 
 
6.3 Other Eligibility Criteria Considerations 
 All patients and/or their parents or legal guardians must sign a written informed 
consent (and assent when applicable) 
 Patients and/or parents who are unable to read at a grade 2 level will be excluded 
from the patient-reported outcome components of the study, as will non-English 
speaking patients and/or parents when there is no availability of translated 
versions in their spoken language(section 9.3). They will not be excluded from all 
other aspects of the study  
 
 
7 CONCURRENT MEDICATIONS 
All subjects should be maintained on the same medications throughout the entire 
study period, as medically feasible, with no introduction of new chronic therapies. 
7.1 Allowed Medications and Treatments 
7.1.1 If necessary, rescue medications are allowed as detailed in the protocol. 
See section 8.3. 
7.1.2 Supportive care medications 
Use of hormonal therapies and anti-fibrinolytic agents is allowed, but 
must be documented on appropriate case report forms (CRFs). 
7.2 Prohibited Medications and Treatments 
7.2.1 The use of second-line platelet-enhancing therapies in weeks 1-12 is not 
allowed and will result in coming off protocol therapy (i.e. subjects will 
discontinue eltrombopag if on study med, but subjects will continue to be 
followed on study for data collection). In the event of severe or 
uncontrolled bleeding (Buchanan Bleeding Score of 4 or 5) requiring an 
emergency intervention listed below during weeks 1-12, the patient will 
come off protocol therapy. The following medications/procedures are 
prohibited during the first 12 weeks of the study: 
 Dexamethasone 
 

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 Rituximab 
 Mercaptopurine 
 Azathioprine 
 Dapsone 
 Sirolimus 
 Cyclosporine 
 Mycophenolate 
 Romiplostim 
 Vinca alkaloids 
 Cyclophosphamide 
 Splenic artery embolization 
 Splenectomy 
 Other medications besides prednisone, IVIg, and anti-D thought to be 
active in the treatment of ITP 
 
The use of these medications/procedures after week 12 for patients not currently 
taking eltrombopag (patients in the standard treatment arm, or patients in the 
eltrombopag arm who are non-responders and have been taken off 
investigational drug) is at the discretion of the treating physician, but must be 
reported on appropriate CRFs. 
 
7.2.2 Other non-platelet-enhancing therapies (other than those described in  
          section 7.1.2) are not allowed in weeks 1-12 and would be a protocol  
          violation if used: 
 Desmopressin acetate (DDAVP) 
 Recombinant Factor VIIa 
 Platelet transfusion 
 
7.2.3 Patients taking anti-platelet agents (including aspirin, NSAIDs, or 
   clopidogrel) or anticoagulants (including heparin, warfarin, or direct oral 
   anticoagulants) are prohibited from enrolling, and these medications are 
   not allowed during the study. 
 
7.3 Concomitant medications and interactions with eltrombopag 
 
The patient must be told to notify the investigational site about any new medications 
he/she takes after the start of the study treatment. Site study personnel should verify 
that there are no interactions with protocol therapy, as described in this section of 
the protocol. If an adjustment in eltrombopag dose is required due to a concomitant 
medication, that should be noted on the eltrombopag dosing CRF. 
 
Any medications administered during the study given for the purpose of treating or 
preventing bleeding (such as hormonal therapies or antifibrinolytic agents), or that 

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are prohibited due to antiplatelet or antithrombotic effects (such as NSAIDs, aspirin, 
or anticoagulants), or that are thought to have effect in ITP must be listed on the 
Concomitant Medications eCRF. 
 
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).  
 
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 
The administration of a single 50 mg-dose of eltrombopag with a standard high-
calorie, high-fat breakfast that included dairy products led to reduced eltrombopag 
exposure. 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 to two hours after food containing little (< 50 mg) (or preferably no) 
calcium. 
 
Patients must abstain from using investigational or not marketed drugs without a 
well-known safety profile and from using prohibited prescription or nonprescription 
drugs within 7 days or 5-half-lives (whichever is longer) prior to the first dose of study 
treatment and until completion of follow-up procedures unless, in the opinion of the 
Investigator and Sponsor, the medication will not interfere with the study (see 
Section 6.2 Exclusion Criteria).   
 
Patients must abstain from taking herbal supplements within 7 days (or 14 days if the 
drug is a potential enzyme inducer) or 5-half-lives (whichever is longer) prior to the 
first dose of study treatment until completion of the 30-day follow-up period, unless 
the Investigator and Sponsor agree that the medication will not interfere with the 
study treatment. 
 

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Any other TPO-R agonists are prohibited for patients on eltrombopag (e.g. 
romiplostim). 
 
Substrates of OATP1B1 or BCRP 
Concomitant administration of eltrombopag and other OATP1B1 or BCRP substrates 
should be undertaken with caution. 
 
Examples of OATP and BCRP substrates 
  
OATP Substrates  
aliskiren, ambrisentan, anacetrapib, atenolol, atrasentan, atorvastatin, bosentan, 
bromociptine, caspofungin, cerivastatin, celiprolol, danoprevir, empangliflozin, 
ezetimibe, fimasartan, fexofenadine, fluvastatin, glyburide, maraviroc, SN-38, 
rosuvastatin, simvastatin acid, pitavastatin, pravastatin, repaglinide, rifampin, 
valsartan, olmesartan, telmisartan, montelukast, ticlopidine.   
  
BCRP Substrates  
atorvastatin daunorubicin, doxorubicin, hematoporphyrin, imatinib, methotrexate, 
mitoxantrone, pitavastatin, rosuvastatin, SN-38 (irinotecan), ethinyl estradiol, 
simvastatin, sulfasalazine, sofosbuvir, topotecan, sulfasalazine   
 
OATP1B1 and OATP1B3 substrates and inhibitors are combined into one list due to 
the following reasons, (1) over-lapping substrate and inhibitor specificity and (2) lack 
of clinical evidence implicating the sole involvement of either OATP in the observed 
PK interaction. 
 
 
8 TREATMENT PLAN 
8.1 Overview of Treatment Plan 
According to the randomized treatment group assignment, patients will be treated 
with either eltrombopag as a single agent or physician’s choice of standard therapy.   
 
8.2 Investigational Product Dosage/Administration 
8.2.1 Standard first-line therapy 
Subjects randomized to the standard therapy arm will receive one of three 
treatments at the discretion of the treating physician. Patients who previously 
failed standard management prior to study entry must be treated with a different 
agent than their original failed agent. e.g. Patient who failed steroids could 
receive either IVIg or anti-D if randomized to the standard treatment arm. 
 
Standard therapy will be administered as commercially available drug. 
 
Investigator may choose amongst the following: 

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8.2.1.1 IVIg: IVIG 1 g/kg x118 (no steroids for pre-medication or adjunctive 
therapy) 
8.2.1.2 Steroids: Prednisone/Prednisolone 4 mg/kg/day (Max 120 mg/day) x 4 
days19 
8.2.1.3 Anti-D: Anti-D globulin 75 mcg/kg x118 (no steroids for pre-medication or 
adjunctive therapy) 
 
Table 8A Standard therapies 
Treatment Dose 
Route 
Duration 
IVIg 1 g/kg (round to 
closest vial size 
without exceeding 
1g/kg) 
IV 
1 dose 
Prednisone/Prednisolone 2 mg/kg/dose BID 
(max 120 mg/day) 
PO 
4 days 
Anti-D globulin 75 mcg/kg (round 
to closest vial size 
without exceeding 
75 mcg/kg) 
IV 
1 dose 
 
8.2.2 Eltrombopag 
Patients randomized to eltrombopag will be treated for 12 weeks, with 
the possibility to continue therapy for up to 1 year depending on 
response. Instructions for titrating dose during the first 12 weeks and 
during weeks 13-52 are given below.  
 
8.2.2.1 Dose initiation 
Starting dose for eltrombopag will be based on manufacturer recommendations, 
and drug will be titrated to effect per guidelines, modified as below 
 Children 1 to 5 years: Initial: 25 mg once daily 
 Children ≥6 years and Adolescents: Initial: 50 mg once daily (25 mg once 
daily for patients of East-Asian ethnicity [e.g., Chinese, Japanese, Korean, 
Taiwanese]) 
 Dose should be titrated based on platelet response. Maximum dose: 75 
mg once daily. Dose should be adjusted only after 2 weeks on the prior 
dose (unless holding for thrombocytosis) 
 Adjust dose based on platelet response (Table 8B, below) 
 
 
8.2.2.2 Dosage adjustment based on platelet response weeks 1-12 
Table 8B Dose adjustment during weeks 1-12 of study 
PLATELET COUNT RESULT 
DOSE ADJUSTMENT OR RESPONSE 

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< 50 x 109/L following at least 2 weeks 
of eltrombopag 
Increase daily dose by 25 mg to a 
maximum of 75 mg/day.  
For patients taking 12.5 mg once daily, 
increase the dose to 25 mg daily before 
increasing the dose amount by 25 mg. 
≥ 50 x 109/L to < 200 x 109/L 
Continue current dose 
≥ 200 x 109/L to ≤ 400 x 109/L at any 
time 
Decrease the daily dose by 25 mg. Wait 2 
weeks to assess the effects of this and any 
subsequent dose adjustments.  
For patients taking 25 mg once daily, 
decrease the dose to 12.5 mg once daily. 
 
For patients taking 12.5 mg once daily, 
discontinue eltrombopag. 
> 400 x 109/L at any time 
Hold eltrombopag; increase the 
frequency of platelet monitoring to 
twice weekly. 
Once the platelet count is < 200 x 109/L, 
reinitiate therapy at a daily dose reduced 
by 25 mg. For patients taking 25 mg once 
daily, reinitiate therapy at a daily dose of 
12.5 mg. 
If platelets remain ≥ 200 x 109/L to <400 x 
109/L after 2 weeks, decrease frequency of 
platelet checks to weekly. 
> 400 x 109/L after 2 weeks of therapy 
at lowest dose of eltrombopag 
Discontinue eltrombopag. 
 
If platelets drop to <50 x 109/L after 
discontinuing eltrombopag, restart at the 
last effective dose (lowest dose that 
achieved platelet count ≥ 50 x 109/L) 
Please note: while platelets are checked weekly per study requirements, adjustments 
are made at time intervals described in the table 
 
8.2.2.3 Eltrombopag Stopping Criteria for Non-Responders 
Discontinue eltrombopag if platelet count <30 x109/L after 4 weeks at the 
maximum daily dose of 75 mg. Non-responders will come off protocol therapy, 
but will continue on study for data collection through duration of 1 year from date 
of consent.  
 

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8.2.2.4 Weaning weeks 13-52 
For patients who have completed 12 weeks of eltrombopag and maintain a 
platelet count ≥ 100 x 109/L, eltrombopag will be weaned, by dose reducing 
12.5mg q2 weeks per guidelines in table 8C below (with treating physicians 
exercising clinical judgement with respect to wean in the context of the patient’s 
status, including intercurrent infections).   
Patients who have been unable to be weaned off of eltrombopag by 1 year will 
discontinue study drug. Continuation on commercially available eltrombopag at 
that point is at the discretion of the investigator. 
 
Table 8C Modified dose adjustment during weeks 13-52 of study 
PLATELET COUNT RESULT 
DOSE ADJUSTMENT OR RESPONSE 
< 30 x 109/L 2 weeks after dose 
adjustment 
Increase dose to last effective dose (to 
attain platelet count ≥ 30 x 109/L) 
≥ 30 x 109/L to < 100 x 109/L  
Continue current dose. 
≥ 100 x 109/L to < 200 x 109/L 
Decrease daily dose by 12.5 mg.  Wait 2 
weeks to assess the effects of this and any 
subsequent dose adjustments.  
If platelets remain ≥ 100 x 109/L after 2 
weeks at lowest dose, discontinue 
eltrombopag. 
≥ 200 x 109/L to ≤ 400 x 109/L  
Decrease the daily dose by 25 mg. Wait 2 
weeks to assess the effects of this and any 
subsequent dose adjustments.  
For patients taking 25 mg once daily, 
decrease the dose to 12.5 mg once daily. 
For patients taking 12.5 mg once daily, 
discontinue eltrombopag. 
> 400 x 109/L 
Discontinue eltrombopag 
< 30 x 109/L after weaning off 
eltrombopag 
Restart at the last effective dose (lowest 
dose prior to weaning). If platelets remain 
< 30 x 109/L, increase per initial dose 
adjustment. 
 
8.2.2.5 Dose Modification for toxicities 
LFTs (AST, ALT, Tbili) will be monitored every 2 weeks during the first 12 weeks of 
study, then monthly for patients continuing on eltrombopag. 
Repeat abnormal liver function tests within 3 to 5 days; if confirmed abnormal, 
monitor weekly until resolves, stabilizes, or returns to baseline.  
If ALT levels ≥3 times the upper limit of normal (ULN) in patients with normal 
hepatic function at baseline or ≥3 times baseline (or >5 times ULN; whichever is 
lower) in those with preexisting transaminase elevations: Discontinue treatment.  

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If Tbili >1.5 times the upper limit of normal (ULN) contact the study PI to discuss 
management. 
 
Eltrombopag must be permanently discontinued if any of the following events 
occur or is identified at any time during the study:  
- Cytogenetic abnormalities  
 
-Monosomy 7 – discontinue eltrombopag  
 
-Other abnormalities – discontinuation at physician discretion  
- Thromboembolism considered related to drug occurs  
- Development of MDS or AML  
- Difficulties to continue the study treatment due to AE(s)  
 
Subjects 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. 
 
8.2.2.6 Dosing Guidelines 
 
Administer on an empty stomach, 1 hour before or 2 hours after a meal. Do not 
administer concurrently with antacids, foods high in calcium, or minerals (e.g., 
iron, calcium, aluminum, magnesium, selenium, zinc); separate by at least 4 
hours. 
 
TABLETS MUST BE SWALLOWED WHOLE.  
 
Eltrombopag for oral suspension delivered 22% higher plasma AUC0-INF than the 
tablet formulation. When switching between the oral suspension and tablet, 
closely monitor platelet counts. 
 
If vomiting occurs within 30 minutes of dose, dose should be re-administered. 
 
 
8.3 Rescue Medications 
Patients who have bleeding, have platelets drop after initial response, or who do not 
respond to the therapy may require rescue medications. Use and choice of rescue 
medications, at protocol specified dosing, is at the discretion of the investigator. 
Standard therapies as described will be allowed for use as rescue medications prior 
to week 12, and the patient may stay on protocol. If patients have an initial response 
to a therapy but response wanes, they may be treated again with the same therapy, 
and this 2nd administration will be considered to be a rescue therapy. If additional 
therapies other than the three medications listed are required prior to week 12, 
patient will be required to come off protocol therapy (but will continue on study). 

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Rescue medications may be used multiple times, but a separate form must be 
submitted for each episode. 
IVIg: IVIG 1 g/kg x1 (no steroids for pre-medication or adjunctive therapy) 
Steroids: Prednisone/Prednisolone 4 mg/kg/day (Max 120 mg/day) x 4 days 
Anti-D: Anti-D globulin 75 mcg/kg x1 
Data will be collected regarding the reason rescue therapies are being used and 
maximum platelet count after rescue therapy 
 
After week 12, non-responders in the Eltrombopag arm or patients in the standard 
care arm requiring additional therapies should be treated at the discretion of the 
investigator. Additional medications administered after week 12 do not require 
patient to come off protocol but they should be documented on the case report 
forms (CRFs). 
 
See section 7.1 for additional allowed and prohibited medications and supportive 
care.  
 
8.4 Packaging and Labeling  
Tablets: White, to almost white, round, film-coated tablets without debossing are 
provided for clinical use, containing eltrombopag olamine equivalent to 12.5 mg, 25 
mg, 50 mg, or 75 mg of eltrombopag free acid. Tablets are packaged in HDPE bottles 
with plastic, induction-seal, child-resistant caps.  
 
Powder for Oral Suspension: The powder for oral suspension (PfOS) is a reddish 
brown to yellow powder in heat-sealed foil laminate stickpack; a stickpack may also 
be referred to as a packet or sachet. Depending on dose and formulation availability 
PfOS contains eltrombopag olamine equivalent to 12.5 or 25 mg of eltrombopag free 
acid per stickpack/sachet.  
The entire contents of the specified number of stickpacks/primary packages is added 
to the specified amount of water to produce a suspension and the appropriate 
patient dose is delivered as described in the study procedures manual.  
8.5 Supply of Study Drug at the Sites 
Novartis will ship eltrombopag directly to the investigational sites. The initial study 
drug shipment will be shipped after site activation (i.e., all required regulatory 
documentation has been received by ICON and Novartis and a contract has been 
executed). Subsequent study drug shipments will be made after site request for 
resupply. 
 
8.6 Study Drug Accountability 
An accurate and current accounting of the dispensing and return of study drug for 
each subject will be maintained on an ongoing basis by a member of the study site 
staff.  The number of study drug dispensed and returned by the subject will be 

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recorded on the Investigational Drug Accountability Record.  The study monitor will 
verify these documents throughout the course of the study. 
 
8.7 Measures of Treatment Compliance 
Subjects will be asked about treatment compliance at study visits, and number of 
missed doses will be noted on CRFs. Study drug containers will be returned to the 
investigational pharmacy at each visit, and pill counts will be performed to confirm 
reported compliance.  
 
 

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9 STUDY PROCEDURES AND GUIDELINES 
EVALUATIONS1 
WEEK 0-12 
SCREENING/DAY 0 
72H 
W1 
W2 
W3 
W4 
W6 
W8 
W10 
W12 
UNSCHEDULED VISITS10 
ELIGIBILITY 
CHECKLIST 
x 
 
 
 
 
 
 
 
 
 
 
PHYSICAL 
EXAM 
x 
 
x2 
 
 
x2 
 
 
 
x2 
x 
BLEEDING 
ASSESSMENT 
x 
 
x 
x3 
x3 
x 
 
 
 
x 
x 
TELEPHONE 
VISIT 
 
 
 
x 
x 
 
 
 
 
 
 
DEMOGRAPHIC 
FORM 
x 
 
 
 
 
 
 
 
 
 
 
BASELINE 
FORM 
x 
 
 
 
 
 
 
 
 
 
 
CONCOMITANT 
MEDICATIONS 
x 
 
x 
 
 
x 
 
 
 
x 
x 
OPHTHALMIC 
ASSESSMENT 
x 
As needed 
30 DAY 
FOLLOW-UP4 
As needed 
AE/SAE 
FORM 
As needed 
RESCUE 
MED FORM 
As needed 
HRQOL: KIT 
x 
 
x 
 
 
x 
 
 
 
x 
 
HOCKENBERRY 
FATIGUE SCORE 
x 
 
x 
 
 
x 
 
 
 
x 
 
PROMIS 
x 
 
 
 
 
 
 
 
 
x 
 
GLOBAL RATE 
OF CHANGE 
 
 
x 
 
 
x 
 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
PLATELET 
COUNT5, 6 
x 
x 
x 
x 
 
x 
x 
x 
x 
x 
x6 
CBC5 
x 
 
 
 
 
x 
 
 
 
x 
x 
AST, ALT, TBILI5 
x7 
 
 
x8 
 
x8 
x8 
x8 
x8 
x 
 
DIR COOMBS 
x7 
 
 
 
 
 
 
 
 
 
 
LDH, RETIC5 
x7 
 
 
 
 
 
 
 
 
x 
 
CREATININE 
x7 
 
 
 
 
 
 
 
 
 
 
PREGNANCY 
TEST5 
x7 
 
 
 
 
x8 
 
 
 
x 
 
FE, TIBC, %SAT 
FERRITIN5  
x7 
 
 
 
 
 
 
 
 
x 
 

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TREGS9 
x 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
SAMPLES FOR 
BANKING 
(OPTIONAL) 
x 
 
 
 
 
 
 
 
 
x 
 
1 72H time point may occur +/- 24h. Week 1 – Week 4 procedures may occur +/- 72h. 
Week 6 – Week 12 procedures may occur +/- 1 week, as long as procedures are 
separated by at least 1 week. 
2 Visits may be performed via telehealth when clinically appropriate if necessary for 
pandemic-related safety or research restrictions 
3 Telephone administration of modified Buchanan scale 
4 Patients will be followed for safety 30 days after the last dose of study treatment 
5 Local labs (performed at outside lab not associated with ICON site) are acceptable for  
  labs obtained between study visits 
6 All platelet counts during Week 5 – Week 12 should be reported. Additional platelet 
measurements between the scheduled Week 6, 8, 10, and 12 measurements should be 
reported as unscheduled visits. 
7 May use previously obtained values for screening assessments if done within past 7   
  days 
8 Patients on eltrombopag arm only (for duration of eltrombopag administration) 
9 Performed at central study lab 
10Physical Exam, Bleeding Assessment, Concomitant Medications, Platelet count, and/or 
CBC to be performed at unscheduled visits when applicable 
 
EVALUATIONS1 
4 MOS – 1 YR 
4 MOS2 
5 MOS2 
6 MOS 
7 MOS2 
8 MOS2 
9 MOS2 
10 MOS2 
11 MOS2 
1 YEAR 
UNSCHEDULED VISITS9 
PHYSICAL 
EXAM 
 
 
x3 
 
 
 
 
 
x3 
x 
BLEEDING 
ASSESSMENT 
 
 
 
 
 
 
 
 
x 
x 
CONCOMITANT 
MEDICATIONS 
 
 
x 
 
 
 
 
 
x 
x 
OPHTHALMIC 
ASSESSMENT 
As needed 
AE/SAE FORM 
As needed  
RESCUE MED 
FORM 
As needed 
30-DAY 
FOLLOW-UP4 
As needed 

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END OF STUDY 
FORM 
 
 
 
 
 
 
 
 
x5 
 
HRQOL: KIT 
 
 
 
 
 
 
 
 
x 
 
HOCKENBERRY 
FATIGUE SCORE 
 
 
 
 
 
 
 
 
x 
 
PROMIS 
 
 
 
 
 
 
 
 
x 
 
GLOBAL RATE 
OF CHANGE 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
PLATELET 
COUNT6 
x7 
x7 
x 
x7 
x7 
x7 
x7 
x7 
x 
x 
CBC6 
 
 
x 
 
 
 
 
 
x 
x 
AST, ALT, TBILI6  
x7 
x7 
x7 
x7 
x7 
x7 
x7 
x7 
x7 
 
PREGNANCY 
TEST6 
 
x7 
 
x7 
 
x7 
 
x7 
 
 
FE, TIBC, %SAT 
FERRITIN6 
 
 
x 
 
 
 
 
 
x 
 
TREGS8 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
SAMPLES FOR 
BANKING 
(OPTIONAL) 
 
 
 
 
 
 
 
 
x 
 
1 6 month procedures may occur +/- 14 days. 1 year procedures may occur +/- 4 weeks 
2 Timepoint +/- 7 days  
3 Visits may be performed via telehealth when clinically appropriate if necessary for 
pandemic-related safety or research restrictions 
4 Patients will be followed for safety for 30 days after the last dose of study treatment 
5 Form should be completed earlier if patient exits study prior to 1 year 
6 Local labs (performed at outside lab not associated with ICON site) are acceptable for  
  labs obtained between study visits 
7 Patients on eltrombopag arm only (for duration of eltrombopag administration) 
8 Performed at central study lab 
9Physical Exam, Bleeding Assessment, Concomitant Medications, Platelet count, and/or 
CBC to be performed at unscheduled visits when applicable 
 
 
All study assessments should be completed for patients enrolled on the study, even if 
subjects discontinue protocol treatment early (including patients on eltrombopag arm 
who discontinue eltrombopag due to non-response and patients on the standard therapy 
arm who receive prohibited therapies during weeks 1-12). 
 
 
9.1 Clinical Assessments 
9.1.1 Concomitant Medications 
All concomitant medication and concurrent therapies will be documented at 
Baseline/Screening and at Study Visits Week 1, Week 4, Week 12, 6 months, and 

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1 year, or at unscheduled visits and at early termination when applicable, and 
updated throughout study participation as indicated.  Dose, route, unit frequency 
of administration, and indication for administration and dates of medication will 
be captured. 
 
9.1.2 Demographics  
Demographic information (date of birth, gender, race) will be recorded at 
Baseline/Screening. 
 
9.1.3 Medical History  
Relevant medical history, including history of current disease, other pertinent 
medical history, and information regarding underlying diseases will be recorded 
at Baseline/Screening and updated throughout study participation as indicated. 
 
9.1.4 Physical Examination 
A complete physical examination will be performed by either the investigator or a 
subinvestigator who is a physician at Baseline/Screening. Qualified staff (MD, NP, 
RN, and PA) may complete the abbreviated physical exam at all other visits.  New 
abnormal physical exam findings must be documented and will be followed by a 
physician or other qualified staff at the next scheduled visit. Exam findings 
consistent with bleeding will be noted on bleeding assessment CRF. Partial 
physical exams as able may be performed via telehealth if associated study visit is 
performed remotely due to pandemic-related safety or research restrictions. 
 
9.1.5 Bleeding Assessment 
An in-person bleeding assessment will be performed at Baseline/Screening, at 
Study Visits Week 1, Week 4, Week 12, and 1 year, at unscheduled visits, and at 
early termination when applicable. Assessments will be performed via telehealth 
if associated study visit is performed remotely due to pandemic-related safety or 
research restrictions. A telephone bleeding assessment will be performed at 
weeks 2 and 3. (See Appendix for details of WHO Bleeding Scale and modified 
Buchanan Scale).  
 
9.2 Clinical Laboratory Measurements  
9.2.1 Hematology 
Blood will be obtained and sent to each site’s clinical hematology lab for a 
complete blood count (hemoglobin, hematocrit, red blood cell count, white blood 
cell count, white blood cell differential, and platelet count). Interval platelet 
counts (between study visits) may be run at the site’s clinical hematology lab or 
at an outside facility. 
 
9.2.2 Blood Chemistry Profile 
Blood will be obtained and sent to each site’s clinical chemistry lab for 
determination of aspartate aminotransferase (AST/SGOT), alanine 

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aminotransferase (ALT/SGPT), iron, Total iron binding capacity (TIBC), transferrin 
saturation, and ferritin. Interval LFTs (between study visits) for patients on 
eltrombopag may be run at the site’s clinical hematology lab or at an outside 
facility. 
 
9.2.3 Pregnancy Test 
A urine or serum pregnancy test will be obtained from female subjects who have 
achieved menarche prior to their participation in the study. 
 
9.3 HRQoL Tools 
The Kids ITP tool (KIT) will be performed at Baseline/Screening, at Study Visits Week 
1, Week 4, Week 12, and 1 year. The KIT is the first disease-specific health related 
quality of life measure developed for ITP, specifically for use with children. It contains 
a child self-report version (to be completed by children ages 7 and older), a parent 
proxy version (to be completed by parents of children age 2 and older), and parent 
version (to assess parental impact of ITP - all ages). Each version consists of 26 items, 
and a single overall score is obtained. Scores range from 0 to 100: a higher score 
represents better quality of life or, as with the parental impact version, less burden. 
Response options are on a 5-point Likert-type scale ranging from “never” to “always”, 
and the timeframe of interest is the “past week”. KIT will be administered in English, 
Spanish, or Quebec French. 
 
Assessment of global change will be performed at Week 1, Week 4, Week 12, and 1 
year using the Parent Proxy-Report and Child Self-Report Change Scales. 
 
Assessment of fatigue will be performed at Baseline/Screening, at Study Visits Week 
1, Week 4, Week 12, and 1 year using the Fatigue Scale-Child (FS-C to be 
administered by children ages 7 to 12 years), the Fatigue Scale–Adolescent (FS-A 
teens ages 13 and older), and the Fatigue Scale-Parent (FS-P to be completed by 
parents of children of all ages). Each item has a 5-point Likert-type format; total scale 
intensity ratings have ben rescaled so that they range from 0 (no fatigue symptoms) 
to 100 (highest possible fatigue score). All of the tools have been evaluated for face, 
content, and construct validity and for internal consistency. The tools take five 
minutes to complete. Fatigue scales will be administered in English. 
 
The National Institute of Health funded and developed the web based patient-
reported outcomes measurement information system (PROMIS®).  PROMIS® contains 
a number of pediatric self-report short items that each assess domains of physical and 
emotional function in general and over a seven-day time interval 20-23. Patients (age 7-
18 years) will complete PROMIS® global health pediatric measures (Appendix A2c).  
These measures have been tested and reliability of each is ≥0.85 over 2 to 4 standard 
deviations 23-27. Each of the measures consists of ten questions. Three questions ask 
the participant to respond based on the past 7 days. Responses utilize a 5-point Likert 
scale ranging from “excellent” to “poor” or “never” to “always” 21,24. The PROMIS® 

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measures will be scored in accordance with their scoring manuals 24-27.PROMIS will be 
administered in English and Spanish.  
 
Patients may be excluded from participation in Patient Reported Outcome Measures 
(PROMIS, KIT, Change Scale, and Hockenberry Fatigue Scale) if a translated tool is not 
available. 
 
HRQoL surveys may be completed remotely and emailed, mailed, or faxed to study site 
if associated study visit is performed remotely due to pandemic-related safety or 
research restrictions. 
 
9.4 Research Laboratory Measurements  
(see the study Manual Of Operations for samples and processing details) 
9.4.1 Regulatory T cells 
Whole blood in EDTA will be sent to Texas Children’s Hospital/Baylor College of 
Medicine for quantification of CD4+25+Foxp3+ regulatory T-cells.  
This is a non-CLIA approved test, and results will not be made available to 
individual investigators or patients. 
 12 ml (two 6 ml EDTA tubes) will be collected unless there are volume 
restrictions for smaller children.  
 For smaller children a minimum of 6 ml will be collected. To avoid clotting in 
cases like this smaller tubes may be used (e.g. three 2ml EDTA tubes). 
 
Blood for the Research Laboratory Measurements will be collected at the 
following time points: 
i. 
Day 0 (Baseline), prior to receiving study drug 
ii. 
Week 12 
iii. 
End of study (1 year) 
iv. 
In the event of sample processing failure or inadequate yield, the site 
will be asked to collect a new sample at the time of a blood draw 
during a later study visit. 
 
9.5 Optional Research Studies  
If consent is obtained for optional studies, baseline and serial blood samples will be 
sent to Texas Children’s Hospital/Baylor College of Medicine for banking and for 
future correlative biology studies. 
 DNA: 6 ml whole blood collected in EDTA tube  
 RNA: 2.5 ml whole blood collected in PaxGene RNA tube. (At Texas Children’s 
Hospital site only, 6mL EDTA tube will be collected as well.)  
 
Blood for the Optional Research Studies will be collected at the following time 
points: 

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i. 
Day 0 (Baseline), prior to receiving study drug: DNA & RNA 
ii. 
Week 12: RNA 
iii. 
End of study (1 year): RNA 
iv. 
In the event of sample processing failure or inadequate yield, the site 
will be asked to collect a new sample at the time of a blood draw 
during a later study visit. 
 
 
10. SAFETY 
10.1 Liver Function Monitoring 
AST/ALT/Tbili will be monitored every 2 weeks during the first 12 weeks of study, 
then monthly for patients continuing on eltrombopag. See section 8.2.2.5 for dose 
modifications 
 
10.2 Ophthalmic Assessments 
Assessment of cataract risk will be completed by investigator at baseline. Patients at 
elevated risk (due to history of radiation, prolonged steroid use, or diabetes) should 
be referred to an ophthalmologist for baseline exam. For patients at standard risk, 
investigator should perform ophthalmologic exam, and if there are any findings of 
concern for cataracts, patient should be referred to ophthalmologist for baseline 
exam. For patients continuing on eltrombopag >12 weeks, consider referral to 
ophthalmologist for monitoring, especially if receiving other medications (such as 
steroids) contributing to cataract risk. 
 
10.3 Pregnancy Testing 
Women of child-bearing potential (achieved menarche) must have a negative serum 
or urine pregnancy test to be eligible. Pregnancy test must be checked every 2 
months for patients continuing on eltrombopag. 
 
10.4 Follow-Up 
Patients will be followed for adverse events for 30 days after the last dose of study 
treatment. Follow up information may be obtained via phone call or email. 
 
11. ADVERSE EVENTS REPORTING AND DOCUMENTATION 
11.1 Adverse Events 
An adverse event (AE) is any untoward medical occurrence in a clinical investigation 
of a patient administered a pharmaceutical product and that does not necessarily 
have a causal relationship with the treatment.  An AE is therefore any unfavorable 
and unintended sign (including an abnormal laboratory finding), symptom or disease 
temporally associated with the administration of an investigational product, whether 
or not related to that investigational product.   
 

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An unexpected AE is one of a type not identified in nature, severity, or frequency in 
the current Investigator’s Brochure or of greater severity or frequency than expected 
based on the information in the Investigator’s Brochure. 
 
Information regarding occurrence of adverse events will be captured throughout the 
study. The collection period for all AEs will begin after informed consent is obtained 
and end after procedures for the final study visit have been completed, or thirty days 
after the subject takes the last dose of study drug, whichever is later.  
 
The Investigator will probe, via discussion with the subject, for the occurrence of AEs 
during each subject visit and record the information in the site’s source documents.  
Adverse events will be recorded in the patient CRF. Adverse events will be described 
by duration (start and stop dates and times), severity, outcome, treatment and 
relation to study drug, or if unrelated, the cause. 
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 other support), or require changes in study medication(s). 
Adverse events that begin or worsen after first dose of study drug 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 
eCRF. Adverse event monitoring should be continued for at least 30 days following 
the last dose of study treatment. 
Once an adverse event is detected, it must be followed until its resolution or until it is 
judged to be permanent, and an assessment must 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. 
If an adverse event occurs more than once in a course of therapy, only the most 
severe grade of the event is reported. If an adverse event progresses through several 
grades during one course of therapy, only the most severe grade is reported.  An 
adverse event that persists from one course (cycle) to another is only reported once 
unless the grade becomes more severe in a subsequent course. An adverse event 
which resolves and then recurs during a different course (cycle), is reported each 
course (cycle) it recurs. 
For reporting purposes, the duration of the AE should be the duration of the highest 
(most severe) grade of the toxicity. The resolution date of the AE is defined as the 
date at which the AE returns to baseline (note that the resolution date may therefore 
be different from the date at which the grade of the AE decreased from its highest 
grade). If the AE does not return to baseline the resolution date is recorded as 
“ongoing”.  Dates used in adverse event reporting for laboratory test abnormalities 
should be the date the sample was collected (not the date the sample was processed 
or the date the results were reported).  Toxicities reported from off site laboratories 

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are graded using normal values of the laboratory processing the specimen. Source 
documents from off site laboratories, such as copies of laboratory test results, are 
filed in patient medical record and/or research chart, as applicable.  
The completed CRF summarizing the non-serious AE should be reviewed and signed 
off by the PI or their designee. 
 
 
AE Severity 
The National Cancer Institute’s Common Terminology Criteria for Adverse Events 
(CTCAE) Version 5.0 should be used to assess and grade any AE or SAE, including 
laboratory abnormalities judged to be clinically significant. Events grade 3 or higher 
should be collected and documented and reported as indicated. The modified criteria 
can be found in the study manual.  If the experience is not covered in the modified 
criteria, the guidelines shown in Table 11A below should be used to grade severity.  It 
should be pointed out that the term “severe” is a measure of intensity and that a 
severe AE is not necessarily serious. 
 
Table 11A.  AE Severity Grading 
Severity (Toxicity Grade) 
Description 
Mild (1) 
Transient or mild discomfort; no limitation in activity; no 
medical intervention or therapy required. The subject may be 
aware of the sign or symptom but tolerates it reasonably well. 
Moderate (2) 
Mild to moderate limitation in activity, no or minimal medical 
intervention/therapy required. 
Severe (3) 
Marked limitation in activity, medical intervention/therapy 
required, hospitalizations possible. 
Life-threatening (4) 
The subject is at risk of death due to the adverse experience as 
it occurred. This does not refer to an experience that 
hypothetically might have caused death if it were more severe. 
 
AE Relationship to Study Drug 
The relationship of an AE to the study drug should be assessed using the following 
the guidelines in Table 11B. 
 
Table 11B.  AE Relationship to Study Drug 
Relationship 
to Drug 
Comment 
Definitely 
Previously known toxicity of agent; or an event that follows a reasonable 
temporal sequence from administration of the drug; that follows a known or 
expected response pattern to the suspected drug; that is confirmed by 
stopping or reducing the dosage of the drug; and that is not explained by any 
other reasonable hypothesis. 

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Probably 
An event that follows a reasonable temporal sequence from administration 
of the drug; that follows a known or expected response pattern to the 
suspected drug; that is confirmed by stopping or reducing the dosage of the 
drug; and that is unlikely to be explained by the known characteristics of the 
subject’s clinical state or by other interventions. 
Possibly 
An event that follows a reasonable temporal sequence from administration 
of the drug; that follows a known or expected response pattern to that 
suspected drug; but that could readily have been produced by a number of 
other factors. 
Unrelated 
An event that can be determined with certainty to have no relationship to 
the study drug. 
 
 
 
11.2 Serious Adverse Events (SAE) and unanticipated problems involving risk to 
subjects or others (UPIRSOs) 
An SAE is defined as any AE occurring at any dose that results in any of the following 
outcomes: 
 
death 
 
a life-threatening adverse experience 
 
inpatient hospitalization or prolongation of existing hospitalization++ 
 
a persistent or significant disability/incapacity 
 
a congenital anomaly/birth defect  
Other important medical events may also be considered an SAE when, based on 
appropriate medical judgment, they jeopardize the subject or require intervention to 
prevent one of the outcomes listed.  
 
++ Note that hospitalizations for the following reasons should not be reported as 
serious adverse events: 
 Routine treatment or monitoring of the studied indication, not associated 
with any deterioration in condition 
 Elective or pre-planned treatment for a pre-existing condition that is 
unrelated to the indication under study and has not worsened since signing 
the informed consent 
 Social reasons and respite care in the absence of any deterioration in the 
patient’s general condition 
 Note that treatment on an emergency outpatient basis that does not result in 
hospital admission and involves an event not fulfilling any of the definitions of 
a SAE given above is not a serious adverse event 
 
Any serious or immediately life-threatening adverse experience, including those 
resulting in death, occurring while the subject is receiving study drug, or within 30 
days of the subject’s last dose of protocol therapy, regardless of the treating 

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physician’s opinion regarding drug relationship, will be reported by telephone and/or 
e-mail (within 24 hours of the event) to the Study PI and appropriate parties. 
 
 
Serious Adverse Experience Reporting 
Study sites will document all SAEs that occur (whether or not related to study drug) 
per IRB Guidelines. The collection period for all SAEs will begin after informed 
consent is obtained and end after procedures for the final study visit have been 
completed, or thirty days after the subject takes the last dose of study drug, 
whichever is later. 
 
In accordance with the standard operating procedures and policies of the local 
Institutional Review Board (IRB)/Independent Ethics Committee (IEC), the site 
investigator will report SAEs to the IRB/IEC.   
 
SAEs (as well as reports of drug exposure during pregnancy and reports of study drug 
misuse or abuse) will be forwarded to Novartis within one business day of Study PI 
becoming aware.  
 
The principal investigator has the obligation to report all serious adverse events to 
the FDA (if applicable), IRB, and Novartis Pharmaceuticals Drug Safety and 
Epidemiology Department (DS&E)  
All events reported to the FDA by the investigator are to be filed utilizing the Form 
FDA 3500A (MedWatch Form), if applicable  
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. Information about all SAEs is collected and recorded on a 
Serious Adverse Event Report Form. 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 along with the Novartis provided fax cover sheet to the Novartis 
Oncology Drug Safety and Epidemiology (DS&E) department by fax (fax: 877-778-
9739) within 24 hours.  
Any additional information for the SAE including complications, progression of the 
initial SAE, and recurrent episodes must be reported as follow-up to the original 
episode within 24 hours of the investigator receiving the follow-up information. An 
SAE occurring at a different time interval or otherwise considered completely 
unrelated to a previously reported one should be reported separately as a new 
event.  
Any SAEs experienced after the 30 day safety evaluation follow-up period should only 
be reported to Novartis if the investigator suspects a causal relationship to the study 
treatment.  

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Follow-up information is submitted in the same way as the original SAE Report. Each 
re-occurrence, complication, or progression of the original event should be reported 
as a follow-up to that event regardless of when it occurs. The follow-up information 
should describe whether the event has resolved or continues, if and how it was 
treated, whether the blind was broken or not, and whether the patient continued or 
withdrew from study participation.  
If the SAE is not previously documented in the Investigator’s Brochure or Package 
Insert (new occurrence) and is thought to be related to the Novartis study treatment, 
an oncology Novartis 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. 
 
To ensure patient safety, each pregnancy occurring while the patient is on study 
treatment must be reported to Novartis within 24 hours of learning of its occurrence. 
The pregnancy should be followed up to determine outcome, including spontaneous 
or voluntary termination, details of the birth, and the presence or absence of any 
birth defects, congenital abnormalities, or maternal and/or newborn complications.  
Pregnancy should be reported by the investigator to the Novartis Oncology Drug 
Safety and Epidemiology Department (DS&E) by fax (fax: 877-778-9739). Pregnancy 
follow-up should include an assessment of the possible relationship to the 
[investigational/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. 
 
All SAEs, regardless of causality, will be reported to: 
• Site Principal Investigator 
• Site IRB of Record (per institutional policy) 
• Coordinating Center within 24 hours of a member of the research team becoming 
aware of the event.   
SAEs should be recorded on the appropriate SAE Form. The SAE Form, along with any 
relevant information or documentation, must be submitted to the Site Principal 
Investigator for review and signature then reported via email to the Coordinating 
Center per contact information in Manual of Operations. 
Protocol Defined Important Medical Findings Requiring Real Time Reporting 
 Grade 5 hemorrhage 
 Thromboembolic event 
 Death 

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 Malignancy 
 
 
 
UPIRSOs 
An UPIRSO is defined as an event that meets all three of the following criteria: 
Unexpected (in terms of the nature, severity or frequency) given  
 The research procedures that are described in the protocol-related documents, 
such as the IRB-approved research protocol and informed consent document; and  
 The characteristics of the subject population being studied. 
 Suggests that the research places subjects or others at a greater risk of harm 
(including physical, psychological, economic or social harm) than was previously 
known or acknowledged.  
 
“Related to the research procedures”: An event is “related to the research 
procedures” if in the opinion of the principal investigator, it was more likely than not 
to be caused by the research procedures or if it is more likely than not that the event 
affects the rights and welfare of current participants.  
 
All UPIRSOs will be reported to: 
 Site Principal Investigator (immediately upon member of research team becoming 
aware) 
 Site IRB of Record (in accordance with site’s institutional policy) 
 Coordinating Center as soon as possible, but no more than 24 hours from the time 
a member of the research team is aware of the event.   
UPIRSOs should be recorded on the appropriate SAE Form. The SAE Form, along with 
any relevant information or documentation, must be submitted to the Site Principal 
Investigator for review and signature then reported via email to the Coordinating 
Center (Boston Children’s Hospital) and Baylor College of Medicine as per manual of 
operations. IRB approval/acknowledgment should also be provided to the 
coordinating center upon site’s receipt. 
 
11.3 Medical Monitoring 
Medical Monitoring is provided by the study PI Dr. Amanda Grimes and Co-
Investigator Dr. Kristin Shimano. For any medical concerns or questions regarding 
eligibility or safety please contact ICONstudy-dl@childrens.harvard.edu.  
SAEs need to be reported within 24 hours of the local PI becoming aware of the 
event. 
 
 
 
 

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12 DISCONTINUATION AND REPLACEMENT OF SUBJECTS 
12.1 Early Discontinuation of Study Treatment 
A subject may be discontinued from study treatment at any time if the subject, the 
investigator, or the study PI feels that it is not in the subject’s best interest to 
continue.   
All subjects are free to withdraw from protocol therapy at any time, for any reason, 
specified or unspecified, and without prejudice. 
 
The following is a list of possible reasons for study treatment discontinuation: 
a) Subject withdrawal of consent (or assent) – see section 12.2 
b) Subject is not compliant with study procedures 
c) Adverse event that in the opinion of the investigator would be in the best 
interest of the subject to discontinue study treatment 
d) Administration of rescue medication or ITP-directed therapy prior to Week 12 
other than those permitted by the study protocol (see section 7.2.1), 
including for emergent intervention in the event of severe or uncontrolled 
bleeding.  
e) Lost to follow-up – see section 12.2 
f) Positive pregnancy test (females) 
g) Change in diagnosis: patient no longer has diagnosis of primary ITP – see 
section 12.2 
h) Death – see section 12.2 
i) Completion of protocol therapy 
 
If a subject is discontinued from treatment due to an adverse event, the subject will 
be followed and treated by the Investigator until the abnormal parameter or 
symptom has resolved or stabilized.   
All subjects who discontinue study treatment should come in for an early 
discontinuation visit as soon as possible. Unless they are withdrawn from the study 
(see section 12.2) subjects should complete all remaining scheduled visits and 
procedures. 
All subjects are free to withdraw from participation at any time, for any reason, 
specified or unspecified, and without prejudice. 
Reasonable attempts will be made by the investigator to provide a reason for subject 
withdrawals.  The reason for the subject’s withdrawal from the study will be specified 
in the subject’s source documents.  
 
12.2 Withdrawal of Subjects from the Study 
All data collected up until the time of subject withdrawal will remain part of the 
study.  Subjects will be followed for 30 days after the last dose of study drug.   
Reasonable attempts will be made by the investigator to provide a reason for subject 
withdrawals.  The reason for the subject’s withdrawal from the study will be specified 
in the subject’s source documents.  As noted above, subjects who discontinue study 
treatment early (i.e., they withdraw prior to Week 12) should have an early 

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discontinuation visit. Subjects who withdraw after Week 12 but prior to 1 year should 
be encouraged to come in for a final visit (and the procedures to be followed would 
include those for their next scheduled visit).   
Reasons for withdrawal from the study are: 
a) Subject withdrawal of consent for data submission 
b) Lost to follow-up 
c) Death 
d) Subject no longer has diagnosis of primary ITP 
Otherwise, all subjects should be followed for collection of data to assess the 
protocol objectives. 
 
12.3 Replacement of Subjects 
A subject who withdraws from the study after enrollment and randomization will not 
be replaced. 
 
 
13 PROTOCOL VARIANCES AND DEVIATIONS 
 
Protocol deviations are defined as unintended variances from the approved protocol. 
The term deviation is often used in contrast to a violation, which is usually seen as 
more serious than a deviation. 
Participating sites should report deviations to the coordinating center and BCM 
PI/designee as soon as possible and to their institution's IRBs per that site's 
institutional guidelines. 
 
Participating sites in addition to their local requirement will be required to complete 
the variance form (see Manual of Operations) for all protocol deviations, and send to 
Baylor College of Medicine and Boston Children’s Hospital Coordinating Center as 
soon as identified and not later than 5 days of occurrence. 
 
As needed, the BCM PI or designee will report these protocol variances to the BCM 
IRB per local policies and to other regulatory agencies as applicable. 
 
All serious adverse events and any unanticipated problems involving risk to subjects 
or others (UPIRSOs) that meet reporting criteria as defined by the BCM IRB as IRB of 
record will be submitted to the BCM IRB per their policy. Expected adverse events 
will not be reported. Expected adverse events are those adverse events that are 
listed or characterized in the Package Insert (P.I) or current Investigator Brochure 
(I.B). 
 
A protocol variance or deviation occurs when the subject or investigator fails to 
adhere to significant protocol requirements affecting the inclusion, exclusion, subject 

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safety and primary endpoint criteria.  Protocol deviations for this study include, but 
are not limited to, the following: 
Failure to meet inclusion/exclusion criteria 
Use of a prohibited concomitant medication 
Failure to comply with Good Clinical Practice (GCP) guidelines will also result in a 
protocol violation. ICON will determine if a protocol violation will result in withdrawal 
of a subject. 
When an event occurs, it will be discussed with the investigator and a Protocol 
Deviation/Variance Form detailing the event will be generated. Baylor College of 
Medicine will determine if the event qualifies as UPIRSO that meet reporting criteria 
as defined by the BCM IRB. 
 
14 DATA SAFETY MONITORING  
The Boston Children’s Hospital will establish a Data Safety Monitoring Committee 
(DSMC) to review data relating to safety and efficacy, to conduct and review interim 
analyses, and to ensure the continued scientific validity and merit of the study, 
according to a DSMC Charter to be established for this protocol. There will be 2 
interim review(s) conducted by the DSMC for the purpose of monitoring study 
conduct and assessing patient safety.  Further details regarding the timing and 
content of the interim reviews is included in the statistical section below. 
 
15 STEERING COMMITTEE 
A Study Steering Committee (SSC) will be appointed.  
The SSC will ensure transparent management of the study according to the protocol 
by recommending and approving study modifications as the need arises. The SSC will 
review protocol amendments as appropriate. Together with the clinical trial team, 
the SSC will also develop recommendations for publications of study results. The SSC 
will consist of investigators participating in the trial and representatives from the 
Clinical Trial Team. 
Other members may be added after consultation with SSC members.  
 
 
16 STATISTICAL METHODS AND CONSIDERATIONS 
Overview 
This is a prospective, open label, randomized, two-arm, multi-center Phase 3 trial. 
Enrolled patients with newly diagnosed ITP are randomized at enrollment 2:1 to the 
experimental treatment arm (eltrombopag) and standard treatment arm 
(investigator’s choice of 3 standard therapies); randomization will be stratified by 
patient’s age at enrollment and up-front treatment status, with block size of 3. Each 
stratum will be limited to a maximum of 27 patients. Hence, the age distribution of 
the final accrued cohort may not be representative of the patient population. This is 
appropriate in the context of this study to ensure sufficient number of patients to 
study treatment effects in each age group. The primary objective is to determine 

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whether the proportion of patients with platelet response is greater in the 
experimental treatment arm compared to the standard therapy arm using a one-
sided Cochran-Mantel-Haenszel (CMH) test at alpha=0.025 (see section 16.b). 
 
Intent-to-Treat and Evaluability 
For the primary objective, all randomized patients will be included in an intent-to-
treat (ITT) analysis. Evaluability for the secondary and exploratory objectives: In the 
experimental treatment arm, patients will be considered evaluable if they receive at 
least one dose of eltrombopag. In the standard treatment arm, patients will be 
considered evaluable if they receive at least one dose of one of the standard of care 
treatments. 
 
Statistical Analysis 
a. Baseline Demographic and Clinical Characteristics 
 
Patient demographic and clinical characteristics at study enrollment will be 
 
summarized using descriptive statistics, including frequencies and proportions for 
 
categorical measures, and means, medians, ranges, and standard errors for 
 
continuous measures. 
 
b. Analysis of Primary Endpoint 
To address the primary objective, we will first test for normality of the 
distribution of the proportion of platelet responders.  If the assumption of 
normality is upheld, a one-sided Cochran-Mantel-Haenszel (CMH) test, at 
alpha=0.025, will be used to compare the proportion of platelet responders 
between the two arms. If the normality assumption is violated, then a one-sided 
Fisher’s exact test will be used.  The monitoring boundaries and levels of 
significance for the interim and final analyses of the primary endpoint are 
detailed in Table 16A. If a monitoring boundary is crossed in an interim analysis, 
an independent Data Safety Monitoring Board (DSMB) will make a non-binding 
recommendation regarding trial conduct or potential closure.  In the final 
analysis, we will reject the null hypothesis if the upper (efficacy) boundary z-value 
of 1.99302 is crossed; in that case, it will be reasonable to conclude that the rate 
of platelet response is significantly greater in patients treated with eltrombopag 
than standard first-line treatments.  Otherwise, we will conclude that there is 
insufficient evidence to support superiority of eltrombopag over standard first-
line treatments.  All randomized patients will be analyzed in the ITT analysis. 
 
Selection of platelet measurements for the determination of platelet response.  
All platelet counts will be reported, and the four measurements closest in time to 
Weeks 6, 8, 10, and 12 will be selected for the determination of the primary 
endpoint. Within a sliding one-week window, only one measurement can be 
selected.  Patients who have <3 platelet measurements due to missing data will 
be classified as non-responders. 
 

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c. Analysis of Secondary Endpoints 
Analyses of all secondary endpoints will be performed in the subset of evaluable 
patients.  To determine the effects of missing data, sensitivity analyses will be 
performed using two approaches: a) assuming missing at random; and, b) 
assuming missing not at random.  For each secondary endpoint, the assumption 
of normality will be tested.  If violated for binary endpoints, a Fisher’s exact test 
will be used.  If violated for continuous endpoints, a Wilcoxon rank-sum test will 
be used. 
 
To address secondary objective 3.2.1, the Cochran-Mantel-Haenszel test will be 
used to compare the proportion of patients with poor WHO Bleeding Score and 
poor Modified Buchanan Score between the two arms. 
 
To address secondary objective 3.2.2, an ANCOVA model will be used to compare 
the number of rescue therapies between the two arms. 
 
To address secondary objective 3.2.3, the observed proportion and 95% 
confidence interval of platelet responders will be calculated in the subset of 
patients who required a rescue treatment during weeks 1-2 of the study. 
 
To address secondary objective 3.2.4, the Cochran-Mantel-Haenszel test will be 
used to compare the proportion of patients who do not need ongoing treatment 
at 12 weeks and 6 months between the two arms. 
 
To address secondary objective 3.2.5, the Cochran-Mantel-Haenszel test will be 
used to compare the proportion of patients with a treatment response at one 
year between the two arms. 
 
To address secondary objective 3.2.6, an ANCOVA model will be used to compare 
the number of 2nd-line therapies between the two arms 
 
To address secondary objective 3.2.7, an ANCOVA model will be used to compare 
the absolute change from baseline in percentage of regulatory T cells at 12 weeks 
and 1 year between the two arms 
 
To address secondary objective 3.2.8, KIT scores will be calculated as per the 
methods described in Klaassen et al.28 Spaghetti plots will be used to visualize the 
KIT scores over time per patient by treatment arm. An ANCOVA model will be 
used to compare the absolute change from baseline in KIT overall score at 1 
week, 4 weeks, 12 weeks, and 1 year between the two arms. An ANCOVA model 
will be used to compare the Change Scale score at 1 week, 4 weeks, 12 weeks, 
and 1 year between the two arms. 
 

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To address secondary objective 3.2.9, fatigue scores will be calculated as per the 
methods described in Hockenberry et al.29  All measures will be rescaled from 0 
(no fatigue) to 100 (high fatigue) for consistency in scoring. Spaghetti plots will be 
used to visualize the fatigue scores over time per patient by treatment arm. The 
PROMIS tired question: “My child (I) got tired easily never to almost always” will 
be used as an anchor with severe fatigue defined as “often” or “ almost always” 
with moderate fatigue being “sometimes”. An ANCOVA model will be used to 
compare the absolute change from baseline in fatigue at 1 week, 4 weeks, 12 
weeks, and 1 year between the two arms. 
 
To address secondary objective 3.2.10, an ANCOVA model will be used to 
compare iron indices at 12 weeks, 6 months, and 1 year between the two arms 
 
To address secondary objective 3.2.11, the frequency and proportion (with 95% 
confidence interval) of patients with abnormal LFTs will be calculated.  Adverse 
event rates will be coded by body system and MedDra classification term.  
Adverse events and serious adverse events will be tabulated by treatment group 
and will include the number of patients for whom the event occurred, the rate of 
occurrence, and the severity and relationship to study drug.  If a patient 
experiences the same toxicity multiple times, a patient will be counted only once 
for a given toxicity at the maximum grade. 
 
d. Analysis of Exploratory Objectives 
Exploratory objectives are hypothesis-generating only. Any exploratory findings 
need to be confirmed in an independent study. 
 
To address the platelet exploratory objectives 3.3.1, a Cochran-Mantel-Haenszel 
test will be used to compare the proportion of patients between treatment arms 
with: (1) specific platelet-defined treatment response at 12 weeks, (2) extreme 
thrombocytosis, and (3) loss of treatment response (in the subgroup of patients 
who achieved treatment response during the first 12 weeks. Cumulative 
incidence curves by treatment arm will be created to describe: (1) time to 
response and (2) time to platelet and bleeding response. Gray’s test will be used 
to compare the cumulative incidence between treatment arms. 
 
To address the patient-reported outcomes exploratory objectives 3.3.2, KIT 
scores and fatigue scores will be calculated as described. Spaghetti plots will be 
used to visualize the scores over time per patient by treatment arm. An ANCOVA 
model will be used to compare the absolute change from baseline at 1 week, 4 
weeks, 12 weeks, and 1 year between the two arms. 
 
To analyze the non-survey endpoints of exploratory objective 3.3.3, a Cochran-
Mantel-Haenszel test (for categorical outcomes) or an ANCOVA model (for 

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continuous outcomes, like the cost of therapy) will be used to compare the the 
two arms. 
 
To address the survey-related aspects of exploratory objectives 3.3.3, the 
PROMIS® measures will be scored as according to the described approach 22. 
Mixed-effects model and the generalized estimating equations (GEE) allow for 
covariate adjustment and can model both within group effects (time) and 
between group effects 30. The results will be summarized with adjusted means 
with associated 95% confidence intervals at each time point for each treatment 
group. For the primary analysis, these models will include the main effect of time 
(T0-T2). PHIS is a confidential database that allows use among the 47 member 
hospitals including a number of prominent pediatric hematology centers that 
participate in ICON. Descriptive analysis will be performed using PHIS data after 
patients have been identified using PHIS diagnosis codes to identify patients with 
ITP. Descriptive statistics will be performed to analyze financial burden measures. 
As instruments have not been validated, item level comparisons will be made 
between standard therapy and eltrombopag.  
 
During the trial, on an ongoing basis the study team will monitor the response 
rate to each of the surveys.  A patient will be counted as having responded to a 
given survey if both the baseline survey and at least one post-baseline survey are 
submitted. If the observed response rate for a given survey falls below 33%, the 
study team may consider halting the collection of that survey from subsequent 
patients, as it is an inappropriate use of resources, and unfair to patients, to 
continue to require survey submission if the survey data will be too sparse to 
address the study objective.  
 
 
e. Interim Analysis 
Interim analysis for efficacy and futility 
To monitor for early evidence of efficacy or lack of efficacy (futility), we will 
perform group sequential analyses for a total of three “looks” at the data.  Power 
calculations were performed using PASS 14 (NCSS, LLC. Kaysville, Utah, USA). We 
will conduct two interim analyses using a two-sided Cochran-Mantel-Haenszel 
test to compare the proportion of platelet responders between the two 
treatment arms, after 33% and after 67% of randomized patients are accrued. If 
the trial has not been terminated due to efficacy or futility, the third and final 
analysis will be conducted after accrual of all randomized patients at the end of 
the trial.  We used the O’Brien-Fleming spending function to determine the 
monitoring boundaries for these three group sequential tests (Table 16A, Figure 
1).  For interim analysis 1, significant evidence that the experimental drug is more 
efficacious than the standard of care will have been provided if we observe a z-
test statistic ≥ 3.71. Significant evidence that the experimental drug is less 
efficacious than the standard therapy will have been provided if z ≤ –3.71.  For 

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interim analysis 2, significant evidence that the experimental drug is efficacious 
or not will have been provided if z ≥ 2.51 or ≤ –2.51, respectively.  For the final 
analysis, significant evidence of the efficacy of the experimental drug will have 
been provided if z ≥ 1.99302. The members of the study committee will remain 
masked to the results of the interim analyses.  Because the results of this trial will 
set a new standard of care for this patient population, an independent Data 
Safety Monitoring Board (DSMB) will make a non-binding recommendation 
if/when it is appropriate to close the trial early on the basis of the statistical 
evidence.  
 
Table 16A: Interim analysis monitoring boundaries and operating characteristics 
Look 
Proportion 
accrued 
Lower 
Bndry 
Upper 
Bndry 
Nominal 
Alpha 
Alpha 
Spent 
Total 
Alpha 
Power 
Spent 
Total 
Power 
1 
0.33 
-3.7103 
3.7103 
0.0002 
0.0002 
0.0002 
0.02009 
0.0201 
2 
0.67 
-2.51142 
2.51142 
0.012 
0.0119 
0.0121 
0.41425 
0.4343 
3 
1 
-1.99302 
1.99302 
0.0463 
0.0379 
0.05 
0.38006 
0.8144 
Definitions: 
- 
Nominal alpha: the significance level to be used for a single, standalone test at 
each interim test. 
- 
Alpha spent: the amount of alpha spent by this interim test. 
- 
Total alpha: the total amount of alpha that is used up to and including the current 
test. 
- 
Power spent: the probability that the significance is found and the trial is 
stopped, given the alternative hypothesis (also called “exit probabilities”). 
- 
Total power: these are the cumulative power values. 
 
Figure 1.  O’Brien-Fleming interim monitoring efficacy (red) and futility (green) 
boundaries for the rate of sustained of platelet response, comparing the eltrombopag 
arm to the standard of care arm using a two-sided Cochran-Mantel-Haenszel test  

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Interim analyses for safety 
AEs and SAEs will also be reviewed at interim analysis 1 and 2. If any toxic deaths, 
or 2 intracranial hemorrhages, or 2 unprovoked thromboses are found at the first 
interim analysis, study will be temporarily halted to accrual for further evaluation. 
 
f. Sample Size and Study Duration 
Power Calculations for the Primary Objective 
147 “informative” (as defined below) patients, randomized 2:1 to the 
experimental treatment arm and standard treatment arm, will be required to 
provide 81.4% power to detect an absolute difference of 25% in the proportion of 
patients who are platelet responders, assuming the response rate is 75% in the 
experimental treatment arm and 50% in the standard treatment arm, using a 
one-sided Cochran-Mantel-Haenszel (CMH) test and a type I error rate of 0.025. 
In order to provide at least 147 informative patients, up to 162 patients will be 
enrolled and randomized. 
 
The first time point at which the primary endpoint, platelet response, will be 
assessed is 5 weeks after enrollment.  A small number of patients, approximately 

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9%, are anticipated to withdraw from the study (i.e., withdraw from protocol 
therapy AND data submission) prior to the 5-week platelet assessment. It is 
reasonable to assume that the study withdrawal rate will be similar across the 
treatment arms. These patients are non-informative for the primary objective to 
assess the efficacy of eltrombopag; such patients dilute the treatment effect and 
as a result the power is diminished.  These “non-informative” patients will be 
classified as non-responders and included in the ITT analysis. We will assume that 
9% of randomized patients, a conservatively high estimate, will be non-
informative. To account for the diluting effect the non-informative patients have 
on the comparison of response rates, we plan to enroll and randomize up to an 
additional 15 patients (~9%). 
 
Total sample size and study duration 
In summary, a total of up to 162 (estimated: 147 informative + 15 non-
informative) patients will be enrolled and randomized 2:1 to the experimental 
treatment arm (N=108) and standard treatment arm (N=54). All randomized 
patients will be included in the ITT analysis of the primary objective.  
 
We anticipate enrolling 45 patients per year (3.7 patients per month).  The total 
accrual duration is expected to be about 3 years, plus 1 year follow-up on the last 
patient, for a total study duration of 4 years. 
 
 
17 DATA COLLECTION, RETENTION, AND MONITORING 
a. Data Collection Instruments 
The Investigator will prepare and maintain adequate and accurate source 
documents designed to record all observations and other pertinent data for each 
subject treated with the study drug.   
Study personnel at each site will enter data from source documents 
corresponding to a subject’s visit into the protocol-specific electronic Case Report 
Form (eCRF) when the information corresponding to that visit is available.  
Subjects will not be identified by name in the study database or on any study 
documents to be collected by the Sponsor (or designee), but will be identified by 
a site number, subject number and initials. 
For eCRFs: If a correction is required for an eCRF, the time and date stamps track 
the person entering or updating eCRF data and creates an electronic audit trail.   
The Investigator is responsible for all information collected on subjects enrolled 
in this study.  All data collected during the course of this study must be reviewed 
and verified for completeness and accuracy by the Investigator.  A copy of the 
CRF will remain at the Investigator’s site at the completion of the study. 
 
b. Data Management Procedures 
The data will be entered into a validated database.  The Data Management group 
will be responsible for data processing, in accordance with procedural 

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documentation.  Database lock will occur once quality assurance procedures have 
been completed. 
All procedures for the handling and analysis of data will be conducted using good 
computing practices for the handling and analysis of data for clinical trials. 
 
c. Data Quality Control and Reporting 
After data have been entered into the study database, a system of computerized 
data validation checks will be implemented and applied to the database on a 
regular basis. The study database will be updated in accordance with the resolved 
queries.   
Archival of Data 
The database is safeguarded against unauthorized access by established security 
procedures; appropriate backup copies of the database and related software files 
will be maintained.   
At critical junctures of the protocol (e.g., production of interim reports and final 
reports), data for analysis is locked and cleaned per established procedures. 
 
d. Availability and Retention of Investigational Records 
The Investigator must make study data accessible to the monitor, other 
authorized representatives of the Sponsor (or designee), IRB/IEC, and Regulatory 
Agency (e.g., FDA) inspectors upon request.  A file for each subject must be 
maintained that includes the signed Informed Consent, HIPAA Authorization and 
Assent Form (if applicable) and copies of all source documentation related to that 
subject.  The Investigator must ensure the reliability and availability of source 
documents from which the information on the CRF was derived. 
All study documents (patient files, signed informed consent forms, copies of CRFs, 
Study File Notebook, etc.) must be kept secured for a period of two years 
following marketing of the investigational product or for two years after centers 
have been notified that the IND has been discontinued.  There may be other 
circumstances for which the Sponsor is required to maintain study records and, 
therefore, the Sponsor should be contacted prior to removing study records for 
any reason. 
 
e. Monitoring 
1. Monitoring of Coordinating Center at BCH 
On site monitoring visit to the Coordinating Center at Boston Children’s Hospital 
Frequency:  At site initiation, following the first patient completion of 
study and then every 6 months or as needed 
Purpose:  Ensure that required documents for study conduct, including 
but not limited to the required IRB documents, are properly maintained 
  
2. Monitoring of Clinical Sites 
Remote monitoring visit with all clinical sites with the exception of Boston 
Children’s Hospital clinical site 

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Frequency:  Every 6 months or as needed 
Purpose:  Review patient records, data entered into database, and 
pharmacy documents for accuracy and completeness.  Ensure all 
regulatory documentation is being maintained 
 
f. Subject Confidentiality 
In order to maintain subject confidentiality, only a site number, subject number 
and subject initials will identify all study subjects on CRFs and other 
documentation submitted to the Sponsor.  Additional subject confidentiality 
issues (if applicable) are covered in the Clinical Study Agreement. 
 
 
18 ADMINISTRATIVE, ETHICAL, REGULATORY CONSIDERATIONS 
The study will be conducted according to the Declaration of Helsinki, Protection of 
Human Volunteers (21 CFR 50), Institutional Review Boards (21 CFR 56), and 
Obligations of Clinical Investigators (21 CFR 312). 
To maintain confidentiality, all laboratory specimens, evaluation forms, reports and 
other records will be identified by a coded number and initials only.  All study records 
will be kept in a locked file cabinet and code sheets linking a patient’s name to a 
patient identification number will be stored separately in another locked file cabinet.  
Clinical information will not be released without written permission of the subject, 
except as necessary for monitoring by the FDA.  The Investigator must also comply 
with all applicable privacy regulations (e.g., Health Insurance Portability and 
Accountability Act of 1996, EU Data Protection Directive 95/46/EC). 
 
a. Protocol Amendments 
Any amendment to the protocol will be written by ICON.  Protocol amendments 
cannot be implemented without prior written IRB/IEC approval except as 
necessary to eliminate immediate safety hazards to patients.  A protocol 
amendment intended to eliminate an apparent immediate hazard to patients 
may be implemented immediately, provided the IRBs are notified within five 
working days. 
 
b. Institutional Review Boards and Independent Ethics Committees 
The protocol and consent form will be reviewed and approved by a central IRB, 
and reliance agreements with participating sites will be utilized. For any sites that 
do not have or choose not to use reliance agreements with the central IRB, the 
IRB/IEC of that participating center will be utilized. Serious adverse experiences 
regardless of causality will be reported to the central IRB/IEC and single site 
IRB/IEC in accordance with the standard operating procedures and policies of the 
IRB/IEC, and the Investigator will keep the IRB/IEC informed as to the progress of 
the study. The Investigator will obtain assurance of IRB/IEC compliance with 
regulations. 

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Any documents that the IRB/IEC may need to fulfill its responsibilities (such as 
protocol, protocol amendments, Investigator’s Brochure, consent forms, 
information concerning patient recruitment, payment or compensation 
procedures, or other pertinent information) will be submitted to the IRB/IEC.  The 
IRB/IECs written unconditional approval of the study protocol and the informed 
consent form will be in the possession of the Investigator before the study is 
initiated.  The IRB/IECs unconditional approval statement will be transmitted by 
the Investigator to ICON prior to the shipment of study supplies to the site.  This 
approval must refer to the study by exact protocol title and number and should 
identify the documents reviewed and the date of review. 
Protocol and/or informed consent modifications or changes may not be initiated 
without prior written IRB/IEC approval except when necessary to eliminate 
immediate hazards to the patients or when the change(s) involves only logistical 
or administrative aspects of the study.  Such modifications will be submitted to 
the IRB/IEC and written verification that the modification was submitted and 
subsequently approved should be obtained.   
The IRB/IEC must be informed of revisions to other documents originally 
submitted for review; serious and/or unexpected adverse experiences occurring 
during the study in accordance with the standard operating procedures and 
policies of the IRB; new information that may affect adversely the safety of the 
patients of the conduct of the study; an annual update and/or request for re-
approval; and when the study has been completed. 
 
c. Informed Consent Form  
Informed consent will be obtained in accordance with the Declaration of Helsinki, 
ICH GCP, US Code of Federal Regulations for Protection of Human Subjects (21 
CFR 50.25[a,b], CFR 50.27, and CFR Part 56, Subpart A), the Health Insurance 
Portability and Accountability Act (HIPAA, if applicable), and local regulations. 
The Investigator or study staff will prepare the informed consent form, assent 
and HIPAA authorization and provide the documents to the Sponsor or designee 
for approval prior to submission to the IRB/IEC.  The consent form generated by 
the Investigator must be acceptable to the Sponsor and be approved by the 
IRB/IEC.  The written consent document will embody the elements of informed 
consent as described in the International Conference on Harmonisation and will 
also comply with local regulations. The Investigator will send an IRB/IEC-approved 
copy of the Informed Consent Form to the Sponsor (or designee) for the study 
file. 
A properly executed, written, informed consent will be obtained from each 
subject prior to entering the subject into the trial.  Information should be given in 
both oral and written form and subjects (or their legal representatives) must be 
given ample opportunity to inquire about details of the study.  If appropriate and 
required by the local IRB/IEC, assent from the subject will also be obtained.  If a 
subject is unable to sign the informed consent form (ICF) and the HIPAA 
authorization, a legal representative may sign for the subject.   A copy of the 

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signed consent form (and assent) will be given to the subject or legal 
representative of the subject and the original will be maintained with the 
subject’s records. 
 
d. Publications  
The preparation and submittal for publication of manuscripts containing the 
study results shall be in accordance with a process determined by mutual written 
agreement among the study Sponsor and participating institutions.  The 
publication or presentation of any study results shall comply with all applicable 
privacy laws, including, but not limited to, the Health Insurance Portability and 
Accountability Act of 1996.  
 
e. Investigator Responsibilities 
By signing the Agreement of Investigator form, the Investigator agrees to: 
1. Conduct the study in accordance with the protocol and only make changes 
after notifying the Sponsor (or designee), except when to protect the safety, 
rights or welfare of subjects. 
1. Personally conduct or supervise the study (or investigation). 
2. Ensure that the requirements relating to obtaining informed consent and IRB 
review and approval meet federal guidelines, as stated in § 21 CFR, parts 50 
and 56. 
3. Report to the Sponsor or designee any AEs that occur in the course of the 
study, in accordance with §21 CFR 312.64. 
4. Ensure that all associates, colleagues and employees assisting in the conduct 
of the study are informed about their obligations in meeting the above 
commitments. 
5. Maintain adequate and accurate records in accordance with §21 CFR 312.62 
and to make those records available for inspection with the Sponsor (or 
designee). 
6. Ensure that an IRB that complies with the requirements of §21 CFR part 56 
will be responsible for initial and continuing review and approval of the 
clinical study. 
7. Promptly report to the IRB and the Sponsor (or designee) all changes in the 
research activity and all unanticipated problems involving risks to subjects or 
others (to include amendments and IND safety reports). 
8. Seek IRB approval before any changes are made in the research study, except 
when necessary to eliminate hazards to the patients/subjects. 
9.    Comply with all other requirements regarding the obligations of clinical      
        investigators and all other pertinent requirements listed in § 21 CFR part 312.

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19. APPENDICES  
A1. Bleeding Assessment Tools 
      
a.  WHO Bleeding Scale 
      
b.  Buchanan Bleeding Scale 
A2. HRQoL Tools  
a. KIT 
b. Hockenberry Fatigue Scale 
c. PROMIS®  v1.0 Global Health 
d. Change Scale 
 
 
 
 
 
 
 
 
 
 
 

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A1. Bleeding Assessment Tools 
 
WHO Bleeding Scale30 
Grade 
Definition 
0 
No bleeding 
1 
Petechiae 
2 
Mild blood loss 
3 
Gross blood loss 
4 
Debilitating blood loss 
WHO, World Health Organization 
 
 
Buchanan Bleeding Score31 
Overall bleeding severity 
0 - None 
Definitely no new hemorrhage of any kid 
1 - Minor 
Few petechiae (≤100 total) and/or ≤5 small bruises (≤3 cm 
diameter); no mucosal bleeding 
2 - Mild 
Many petechiae (>100 total) and/or >5 large bruises (>3 cm 
diameter); no mucosal bleeding 
3 - Moderate 
Overt mucosal bleeding (epistaxis, gum bleeding, 
oropharyngeal blood blisters, menorrhagia, gastrointestinal 
bleeding, etc.) that does not require immediate medical 
attention or intervention 
4 - Severe 
Mucosal bleeding or suspected internal hemorrhage (in the 
brain, lung, muscle, joint, etc.) that requires immediate 
medical attention or intervention 
5 – Life-threatening or fatal 
Documented intracranial hemorrhage or life-threatening or 
fatal hemorrhage in any site 
Grades of epistaxis 
0 - None 
 
1 - Minor 
Spotting on sheet or pillow and/or blood noted in nares, no 
active bleeding or need to apply pressure 
2 - Mild 
Active bleeding on 1 or more occasions with need to apply 
pressure for <15 min 
3 - Moderate 
Active bleeding on 1 or more occasions with need to apply 
pressure for at least 15 min 
4 - Severe 
Repeated, continuous and/or profuse bleeding 
Grades of oral bleeding 
0 - None 
None 
1 - Minor 
Petechiae on palate or buccal mucosa 
2 - Mild 
One or more buccal blood blisters (hemorrhagic bullae or 
infiltrates) with or without petechiae, no active bleeding 

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3 - Moderate 
Intermittent active bleeding from gums, lips, buccal mucosa, 
or posterior oropharynx 
4 - Severe 
Continuous bleeding from gums, lips, buccal mucosa, or 
posterior oropharynx 
Grades of skin bleeding 
0 - None 
No new cutaneous bleeding 
1 - Minor 
Possibly a few new petechiae (≤100 total) 
2 - Mild 
Definitely a few new petechiae (≤100 total) and/or ≤5 small 
bruises (<3 cm diameter) 
3 - Moderate 
Numerous new petechiae (>100 total) and/or >5 large bruises 
(>3 cm diameter) 
4 - Severe 
Extensive (hundreds of) petechiae and >5 large bruises (>3 cm 
diameter) 
 
 
 
 
 
 
 
 
 
 
 
 
 

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A2. HRQoL Tools 
 

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Hockenberry Fatigue Scale 
 
Child 
 
 
Adolescent 
 
 
 
 
 
 
 
 

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Parent 
 
 
 

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PROMIS Pediatric Scale and Parent Proxy Scale v1.0 Global Health 
 
 
 
 
 

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CHANGE SCALE – PARENT PROXY-REPORT 
Instructions:  Please answer the questions below about your child. 
Since the start of the study, how has your child’s overall quality of life 
related to ITP changed? 
  
Much worse 
  
Worse 
  
A little worse 
  
No change 
  
A little better 
  
Better 
  
Much better 
 
CHANGE SCALE – CHILD SELF-REPORT 
Instructions:  Please answer the questions below. 
Since the start of the study, how has your overall quality of life related to 
ITP changed? 
  
Much worse 
  
Worse 
  
A little worse 
  
No change 
  
A little better 
  
Better 
  
Much better 

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20. REFERENCES  
 
1. 
Neunert C, Noroozi N, Norman G, et al. Severe bleeding events in adults and children with 
primary immune thrombocytopenia: a systematic review. J Thromb Haemost. 2015;13(3):457-
464. 
2. 
Kumar M, Lambert MP, Breakey V, et al. Sports Participation in Children and Adolescents with 
Immune Thrombocytopenia (ITP). Pediatr Blood Cancer. 2015;62(12):2223-2225. 
3. 
Hill QA, Newland AC. Fatigue in immune thrombocytopenia. Br J Haematol. 2015;170(2):141-
149. 
4. 
Stasi R, Newland AC. ITP: a historical perspective. Br J Haematol. 2011;153(4):437-450. 
5. 
Grace RF, Neunert C. Second-line therapies in immune thrombocytopenia. Hematology Am Soc 
Hematol Educ Program. 2016;2016(1):698-706. 
6. 
Bussel JB, de Miguel PG, Despotovic JM, et al. Eltrombopag for the treatment of children with 
persistent and chronic immune thrombocytopenia (PETIT): a randomised, multicentre, placebo-
controlled study. Lancet Haematol. 2015;2(8):e315-325. 
7. 
Grainger JD, Locatelli F, Chotsampancharoen T, et al. Eltrombopag for children with chronic 
immune thrombocytopenia (PETIT2): a randomised, multicentre, placebo-controlled trial. The 
Lancet. 2015;386(10004):1649-1658. 
8. 
Gomez-Almaguer D, Herrera-Rojas MA, Jaime-Perez JC, et al. Eltrombopag and high-dose 
dexamethasone as frontline treatment of newly diagnosed immune thrombocytopenia in adults. 
Blood. 2014;123(25):3906-3908. 
9. 
Tripathi AK, Shukla A, Mishra S, Yadav YS, Yadav DK. Eltrombopag therapy in newly diagnosed 
steroid non-responsive ITP patients. Int J Hematol. 2014;99(4):413-417. 
10. 
Neunert C, Despotovic J, Haley K, et al. Thrombopoietin Receptor Agonist Use in Children: Data 
From the Pediatric ITP Consortium of North America ICON2 Study. Pediatr Blood Cancer. 
2016;63(8):1407-1413. 
11. 
Revel-Vilk S, Yacobovich J, Frank S, et al. Age and duration of bleeding symptoms at diagnosis 
best predict resolution of childhood immune thrombocytopenia at 3, 6, and 12 months. J 
Pediatr. 2013;163(5):1335-1339 e1331-1332. 
12. 
Ghadaki B, Nazi I, Kelton JG, Arnold DM. Sustained remissions of immune thrombocytopenia 
associated with the use of thrombopoietin receptor agonists. Transfusion. 2013;53(11):2807-
2812. 
13. 
Bao W, Bussel JB, Heck S, et al. Improved regulatory T-cell activity in patients with chronic 
immune thrombocytopenia treated with thrombopoietic agents. Blood. 2010;116(22):4639-
4645. 
14. 
Novartis. ETB115 Investigator Brochure Ed14. 2017. 
15. 
Gonzalez-Lopez TJ, Pascual C, Alvarez-Roman MT, et al. Successful discontinuation of 
eltrombopag after complete remission in patients with primary immune thrombocytopenia. Am 
J Hematol. 2015;90(3):E40-43. 
16. 
Nieto M, Calvo G, Hudson I, et al. The European Medicines Agency review of eltrombopag 
(Revolade) for the treatment of adult chronic immune (idiopathic) thrombocytopenic purpura: 
summary of the scientific assessment of the Committee for Medicinal Products for Human Use. 
Haematologica. 2011;96(9):e33-40. 
17. 
Rodeghiero F, Stasi R, Gernsheimer T, et al. Standardization of terminology, definitions and 
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