Safety and Efficacy of Eltrombopag at Escalated Doses up to 150mg in Patients With Persistent and Chronic Immune Thrombocytopenia (ITP) Not Responsive to 75 mg
Phase: PHASE2
Conditions: Immune Thrombocytopenia, Platelet Disorder
Sponsor: Weill Medical College of Cornell University

 
 
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Title:  Randomized Double Blind Trial of the Safety and Efficacy of Eltrombopag at 
Escalated Doses up to 150mg in Patients with Persistent and Chronic ITP Not 
Responsive to 75 mg Daily of Eltrombopag 
Protocol Number: 
CETB115BUS23T/1
16862  
 
 
Development Phase 
 Phase II 
Effective Date:  May 23rd, 2012 
Amendment Dated October 13th, 2015 
Author(s) James B. Bussel and Catherine McGuinn 
 
Previous Versions: 
Sponsor Protocol, Phase II, dated May 23, 2012 
Sponsor Protocol, Phase II, dated October 24, 2013 
Sponsor Protocol, Phase II, dated September 23, 2014 
Sponsor Protocol, Phase II, dated October 13, 2015 

 
 
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TABLE OF CONTENTS 
PAGE 
LIST OF ABBREVIATIONS: .............................................................................................. 4 
1. 
INTRODUCTION ........................................................................................................ 5 
1.1. 
Background ...................................................................................................... 5 
1.2. 
Rationale ......................................................................................................... 6 
2. 
OBJECTIVE(S) ........................................................................................................... 6 
2.1. 
Primary Objective ............................................................................................. 6 
2.2. 
Secondary Objectives ........................................................................................ 7 
3. 
INVESTIGATIONAL PLAN ........................................................................................ 7 
3.1. 
Study Design .................................................................................................... 7 
3.2. 
Laboratory Testing .......................................................................................... 11 
4. 
SUBJECT SELECTION AND WITHDRAWAL CRITERIA ......................................... 13 
4.1. 
Number of Subjects: ........................................................................................ 13 
4.2. 
Inclusion Criteria: ........................................................................................... 13 
4.3. 
Exclusion Criteria: .......................................................................................... 14 
4.4. 
Withdrawal Criteria: ....................................................................................... 14 
5. 
STUDY TREATMENTS ............................................................................................ 15 
5.1. 
Treatment Assignment .................................................................................... 15 
5.2. 
Product Accountability .................................................................................... 15 
5.3. 
Treatment Compliance .................................................................................... 15 
5.4. 
Concomitant Medications and Non-Drug Therapies ........................................... 15 
5.4.1. 
Permitted Medications and Non-Drug Therapies................................. 15 
5.5. 
Treatment after the End of the Study ................................................................. 15 
5.6. 
Treatment of Investigational Product Overdose .................................................. 15 
5.7. 
Treatment Plan ............................................................................................... 15 
6. 
STUDY ASSESSMENTS AND PROCEDURES .......................................................... 17 
6.1. 
Critical Baseline Assessments .......................................................................... 17 
6.2. 
Efficacy ......................................................................................................... 17 
6.3. 
Safety ............................................................................................................ 18 
6.3.1. 
Liver chemistry stopping and follow-up criteria .................................. 21 
Liver Event Follow Up Assessments ................................................. 22 
Liver Chemistry Monitoring Criteria ................................................. 23 
6.3.2. 
Adverse Events ............................................................................... 23 
6.3.2.1. 
Definition of an AE ........................................................ 23 
6.3.2.2. 
Definition of a SAE ....................................................... 23 
6.3.3. 
Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as SAEs ......................................................................... 24 
6.3.4. 
Pregnancy ....................................................................................... 24 
6.3.5. 
Time Period and Frequency of Detecting AEs and SAEs ..................... 24 
6.3.6. 
Prompt Reporting of Serious Adverse Events and Other Events 
to  Novartis ..................................................................................... 24 
6.3.6.1. 
Regulatory reporting requirements for SAEs ........................ 25 
6.3.7. 
Other Safety Outcomes ............................................................................. 29 

 
 
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MANAGEMENT .............................................................................................................. 29 
8. 
DATA ANALYSIS AND STATISTICAL CONSIDERATIONS .................................... 29 
8.1. 
Hypotheses..................................................................................................... 29 
8.2. 
Study Design Considerations ........................................................................... 29 
8.2.1. 
Sample Size Assumptions ................................................................ 29 
8.2.2. 
Sample Size Sensitivity / Re-estimation ............................................. 30 
8.3. 
Data Analysis Considerations ........................................................................... 30 
8.3.1. 
Key Elements of Analysis Plan ......................................................... 30 
8.3.1.1. 
Efficacy Analyses ............ Error! Bookmark not defined. 
8.3.1.2. 
Safety Analyses ............................................................. 31 
9. 
STUDY CONDUCT CONSIDERATIONS ................................................................... 32 
9.1. 
Regulatory and Ethical Considerations, Including the Informed Consent 
Process .......................................................................................................... 32 
9.2. 
Quality Control (Study Monitoring) .................................................................. 32 
9.3. 
Quality Assurance ........................................................................................... 32 
9.4. 
Records Retention ........................................................................................... 32 
10. APPENDICES ........................................................................................................... 34 
10.1. 
Appendix 1 .................................................................................................... 34 
        10.2    Appendix 2 ……………………………………...…………………………………..35 

 
 
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LIST OF ABBREVIATIONS: 
μL Microliter 
AE Adverse event 
ALT Alanine aminotransferase (SGPT) 
aPTT Activated partial thromboplastin time 
AST Aspartate aminotransferase (SGOT) 
BUN Blood urea nitrogen 
CBC Complete blood count 
CIB Clinical Investigator’s Brochure 
CPK Creatine phosphokinase 
FDA Food and Drug Administration 
H Hours 
IB Investigator brochure 
ICF Informed consent form 
IND Investigational new drug 
IRB Institutional Review Board 
ITP Idiopathic thrombocytopenia purpura 
IUD Intrauterine device 
IVIg intravenous immunoglobulin 
Mg Milligram 
mL Milliliter 
RBC Red blood cell 
REPEAT Repeated ExPosure to Eltrombopag in Adults with 
idiopathic Thrombocytopenic purpura 
SAE Serious adverse event 
TPO Thrombopoietin 
TpoR Thrombopoietin receptor 
WBC White blood cell 
  

 
 
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1. 
INTRODUCTION 
1.1. 
Background 
In previous clinical studies of eltrombopag in ITP, there are some patients who have been 
reported as non-responders at the maximal approved dose of 75mg daily. The trend in 
both normal volunteers (Jenkins et al Blood 2007) and in patients with ITP suggests an 
increasing response rate with increasing doses of eltrombopag up to a dose of 75 mg . 
(Bussel et al. NEJM 2007)  In fact, at 50 mg there was a 70% response rate and at 75 mg 
there was an 81% response rate in the initial ITP study.(Bussel et al. NEJM 2007) 
Furthermore, the occurrence of platelet counts  > 200,000/ul was substantially more 
frequent at 75 mg compared to 50 mg as well.   In the confirmatory study, approximately 
1/3 of the patients who did not respond to 50 mg did subsequently respond to 75 mg, 
although the response rate overall was only 59% compared to 16% in placebo.( Bussel et 
al. Lancet 2009). In the RAISE study, two key issues emerged. First the majority of 
patients ended up on 75 mg by the end of the study. Second, the odds of responding at 
each assessment point was barely 50% if not very occasionally below 50% during the 
study.  (Cheng et al. Lancet 2011) Altogether these data suggest to us that a higher dose 
of eltrombopag may be useful in some patients 
Data from the PETIT and PETIT2 studies in pediatric patients (who seem to metabolize 
eltrombopag differently especially at younger ages) found that in the middle and lowest 
age cohorts, even doses of 75 mg were sometimes insufficient to obtain a response. This 
was confirmed in the youngest cohort who thus far have required doses > 2 mg/kg in 
almost all cases (and even > 3 mg/kg) in order for the children to respond. In the middle 
cohort this was dose limiting because a ceiling of 75 mg was reached rapidly if the child 
weighed more than 37.5 kg.  (Bussel et al, PETIT in press Lancet Haem 2015)  
Additional data accumulating from the pediatric clinical trials support this observation 
that younger children require an increased weight base dose to reach a platelet response. 
In the PETIT Study, the older pediatric patients (12-17 year olds) average dose was 1.2 
mg/kg compared with 2.9 mg/kg to the youngest cohort (1-5 year olds) ( Bussel et al, in 
press Lancet Haem 2015). The PETIT II study also reported an increased proportional 
dose requirement in the youngest cohort. (Grainger, in press Lancet Haem 2015).  All of 
the available data using eltrombopag in research trials or clinical practice in > 170 
children have not identified any new safety concerns and the side effect profile remains 
favorable, particularly given the alternatives in this age group. (Ramaswamy et al, JPeds, 
2014) 
Published data has shown pharmacokinetics, safety and tolerability of eltrombopag in 
healthy volunteers at an escalated dose range 100-200mg po daily for 5 days. (Matthys et 
al J Clin Pharmacol. 2011).  Healthy volunteer data also showed a dose dependent 
platelet response, with a safety profile similar to placebo. Data recently presented at the 
ASH 2011 Meeting in refractory severe aplastic anemia patients showed safe dose 
escalation of eltrombopag to a maximum of 150mg with a 44% response rate. (Olnes et 
al. NEJM 2013) Additional phase I data presented in stem cell transplant patients, has 
shown doses of up to 300 mg daily have not caused dose limiting toxicities and are also 
well tolerated (Liesveld et al. Blood 2011). 

 
 
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Altogether these data suggest both that a higher dose in ITP may be more efficacious in 
increasing the platelet count. Furthermore the same data also suggests there is no overt 
increase in toxicity in normal volunteers, oncology patients or aplastic anemia patients 
treated with doses as high or higher than those proposed in this study. 
 
1.2. 
Rationale 
It therefore seems possible, even likely, that in ITP patients who did not respond at a dose 
of 75mg daily, eltrombopag could be more effective at a higher dose.  Therefore, we 
would like to explore doses as high as 150 mg po daily in order to see if we can 
demonstrate efficacy in those patients unresponsive to 75 mg daily. We propose a double 
blind randomized controlled trial in ITP patients who have been defined as ‘non-
responders’ at the maximum dose (75mg) of eltrombopag.  The study will also assess 
efficacy and toxicity at higher daily doses (100mg, 125mg, 150mg) in this population.  
The study will be performed at a single center in North America, (Weill Cornell Medical 
College). There will be two parts to it. First the randomized double blind part to be 
described next. Subsequently an open label study similar to the EXTEND study 
(TRA105325;https://www.clinicaltrials.gov/ct2/show/NCT01880047?term=Bussel+Dose
+Escalation&rank=1) in patients who responded at doses of 100 to 150mg to see if they 
maintain or even improve their response and to investigate the eltrombopag safety profile 
over up to 18 months at these higher doses.   
Furthermore, the patients randomized to the placebo arm can go on open label treatment 
at higher doses if they did not increase their counts on placebo. Even though open label, 
they will serve as a confirmatory group. 
2. 
OBJECTIVE(S) 
2.1. 
Primary Objective 
To determine the proportion of patients with chronic ITP who do not respond to 75 mg of 
eltrombopag daily given for at least 3 weeks but then do respond to eltrombopag given 
daily first for 2 weeks at doses of 100, then for 2 weeks at 125 mg and finally for 4 weeks 
at a dose of 150mg daily. The intial double-blind phase will stop if/when the platelet 
count exceeds100,000/uL.   Complete response (CR) will be defined as 2 consecutive  
platelet counts of greater than or equal to 50,000 AND an increase of greater than or 
equal to 20,000 from the study baseline within the 8 week increased dose window not as 
a result of rescue treatment. Partial response (PR) will be defined as 2 consecutive 
platelet counts of greater than or equal to 50,000 OR an increase of greater than or equal 
to 20,000 from the study baseline within the 8 week increased dose window not as a 
result of rescue treatment. 
 
 

 
 
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2.2. 
Secondary Objectives 
To determine efficacy of administration of increased dosage of eltrombopag to subjects 
with chronic ITP who did not respond to current maximally approved daily dose of 75 
mg for at least 3 weeks by measuring: number of weeks of platelet counts of response; 
number of patients achieving a platelet count > 100,000, and number of platelet counts 
per patient > 100,000.  (Note if a platelet count > 100,000 is achieved that week and the 
subsequent weeks of the 8 week study will be considered to all be over 100,000 for 
purposes of all analyses). 
To determine efficacy of administration of increased dosage of eltrombopag to subjects 
with ITP who did not respond to current maximally approved daily dose of 75 mg for at 
least 3 weeks by measuring HRQoL and bleeding scores. 
To determine the safety of administration of increased dosage of eltrombopag to subjects 
with ITP who did not respond to current maximally approved daily dose of 75 mg for at 
least 3 weeks. 
To evaluate if there are subgroups of patients (despite this endpoint being underpowered) 
who are more likely or less likely to either respond or to experience adverse events based 
on: 
Starting platelet counts, splenectomy status, concomitant meds e.g, daily prednisone at a 
maximum dose of 20mg daily, duration of ITP since diagnosis, starting Hemoglobin, 
WBC,  and Absolute Neutrophil Count (ANC), starting ALTs,  bilirubins or Alk Phos 
levels, Platelet Reticulocyte Count.  
 
3. 
INVESTIGATIONAL PLAN 
3.1. 
Study Design 
Double-blind, randomized, placebo-controlled trial in subjects with ITP who are ‘non-
responders’ at the maximum package insert dose (75mg) of eltrombopag; non-responders 
are those with platelet counts < 50,000 despite taking 75 mg/day of eltrombopag for at 
least 3 weeks.  
 
Study Design (First part): 8 Weeks 
   

 
 
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Informed consent and assent of minors will be obtained by the principal investigators or 
sub-investigators. Typically, informed consent/minor assent will be obtained in the 
outpatient clinic, although inpatients may have this discussed with them as well.  Consent 
will be obtained after review of clinical information and satisfaction of eligibility criteria. 
Subjects will be randomly allocated at a two to one ratio to receive active treatment or 
placebo. All subjects must be >3 years old and able to swallow a tablet. in the study will 
receive 75 mg eltrombopag and then be randomized to receive either an additional 25 mg 
of eltrombopag or matching placebo tablet dispensed by the research pharmacy 
 
Subjects and investigators will be blinded to randomization. Randomization will be 
stratified according to splenectomy status. Randomization will be performed at the time 
of informed consent with a computer generated randomization table as per the pharmacy. 
Subjects may enroll and begin taking 75 mg eltrombopag for at least 3 weeks. When 
subject’s platelet count is <50,000, the subject may begin day 1 of the study. Subjects and 
investigators will be blinded to assignment and treatment in this phase. Eltrombopag will 
be administered for 8 weeks or until the platelet count exceeds 100,000; at this point 
dosing will stop, subject will be considered a responder and the subject will eligible for 
entering Part  2 (the long term treatment part of the study) if desired and agreed to be 
appropriate by the subject giving consent, and the treating physician. The dose at which 
the subject achieved the primary endpoint (> 50,000 and increase by > 20,000) will be 
considered the dose of response. Even if a patient achieves a response, if the platelet 
counts remains <100,000, then the dose escalation schema in the figure above will 
continue. 
 
Dose escalation will continue, despite satisfaction of the primary endpoint of study (> 
50,000 and > 20,000 above baseline), until the platelet count reaches 100,000. The 
rationale for this approach is to maximize clinically relevant responses for the subjects 
and standardize data for analysis. Subjects will stop study medication if the platelet count 
is within the normal range, thereby minimizing any safety risk associated with elevated 
platelet count. By continuing to dose escalate subjects  until the platelet count is > 
100,000, the maximum response and correlation of dose will be tracked allowing better 
understanding of sustained response and dose-dependent response, which can be applied 
to future consideration dosage for periods of short-term hemostasis ( i.e surgical 
procedures). The 8 weeks of data collected in enrolled subjects on the standardized 
1 
2 

 
 
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protocol will have the balance of consistency of dosage and unequivocality of response 
while maintaining subject safety.   
 
If agreed on by the P-I, subjects may obtain local counts or see their local hematologist 
for study visits. All study-required procedures will be faxed to the P-I for review. The 
appropriate dosing adjustments will be determined by the P-I. 
 
  
According to the new consensus guidelines (Provan Blood, 2009), male and female 
subjects with > 1 year duration of ITP are diagnosed with chronic ITP. Enrollment began 
with adult subjects ≥ 18 years of age, and was extended to include pediatric patients > 12 
years of age after a review of this unblinded safety information by the independent Data 
Safety Monitoring Officer (DMSO). Additionally, we will now allow the inclusion of 
pediatric patients > 3 year of age to enroll on the protocol. The rationale for treating 
patients on this study is to allow people to be successfully treated and thus increase their 
platelet count by using a higher dose of eltrombopag when they do not respond to 75 mg 
daily of eltrombopag. Since some children do not respond to 75mg, the rationale and the 
dosing (when and how to increase) would be the same. 
. 
 
 
 
 Long Term Treatment Extension (Part 2): (48 months) 
 
 
 
 
 
 
 
 
 
After 8 weeks or once dosing is stopped because the platelet count is >100,000, the 
subject will be unblinded, once the data forms are complete with the assistance of the 
research pharmacy.  
Subjects who received and responded to eltrombopag higher dose treatment will have the 
option to continue therapy with periodic monitoring and ongoing dose adjustment on the 
open-label extension study.  
Subject who had a platelet count > 100,000 can enter Part 2 at the dose at which the 
subject met primary response criteria after the platelet count decreases to < 100,000 /uL 
on serial monitoring in the immediate post-study monitoring period.  
Responders 
Consent BM/Eye Exam 
Continue 
Treatment 
X 48 Months 

 
 
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Subjects randomized to the placebo group who did not respond will have the opportunity 
to receive open label escalated dose eltrombopag over 8 weeks following the study 
protocol as if they had been randomized to active drug in the study. This group will 
provide the “confirmatory group” to see if the rate of response in the randomized group 
can be confirmed in this group. 
Consent will be obtained for additional monitoring with bone marrow aspirate and biopsy 
at 1 year (at year 2, year 3, year 4) and additional ophthalmologic examinations for 
caratacts at 6 months and 18 months.  
It is considered standard of care to monitor all patients as possible who have been on 
eltrombopag treatment for 1 year because of the higher doses of eltrombopag 
administered in this protocol. All subjects will have bone marrow aspiration/biopsies for 
their clinical care, no bone marrows will be performed for research purposes only. 
 
 
Optional PK sampling will be done 4 weeks after the subject has been on active study 
drug (or at another time point if this is not convenient).  There will be 3 samples drawn: 
the 1st sample will be drawn prior to taking the study drug for that day, the 2nd PK sample 
will be drawn 2-4 hours after the dose was taken and the 3rd sample will be drawn 5-8 
hours after the dose was taken.  These PK tests are being done to measure how much 
eltrombopag is in the blood at various time points following administration of 
eltrombopag and can be compared to published data.    
 
The trial will have an 80% statistical power at the 5% level of significance (two sided) to 
detect a difference in the proportion of subjects receiving increased dose of eltrombopag 
with a primary response (2 consecutive platelet counts of > 50,000 and an increase of > 
20,000 from the study baseline with in the 8 week increased dose window not as a result 
of rescue treatment ) to subjects without a primary response in the placebo group 
assuming 50% of subjects randomized to active drug will have a response and 5% of 
subjects randomized to placebo would have a response. The same statistical test will be 
run for subjects who achieve partial response. An interim analysis was performed after 18 
subjects to test for futility and efficacy. 
 
Dose modification during the long term extension portion of the trial will be made on 
the basis of individual platelet response to a maximal dose of 150mg. All subjects can 
be monitored at 4 weeks intervals and then can go to every 8 weeks for the remainder 
of the study at the discretion of the investigator  (investigator may require subjects to 
come in for additional monitoring if deemed necessary).  
If the platelet count is > 150,000 ul and < 400,00 ul the daily dose will be adjusted 
and if > 400,000 ul the medication will be held and monitor will be as per the 
prescribing information for eltrombopag in the package insert. However, if the P-I 
determines that adjusting the subject’s dose will negatively affect the subject, he or 

 
 
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she may decide not to escalate or reduce the subject’s dose. Circumstances in which 
this may occur include, but are not limited to: investigator is tapering other 
medications or the subject has a viral infection. Viral infections have been known to 
both increase and decrease platelet count in patients with ITP. It is suggested that the 
increased presence of inflammatory molecules during a viral infection increases 
platelet production, causing platelet count to increase . Alternatively, platelet count 
may decrease by virtue of activating the reticuloendthelial system causing greater 
phagocytosis of antibody-coated platelets and/or platelet production. 
 
 
Laboratory/Assessment Testing 
 
 
Please see Appendix 1 for Schedule of Events. 
 
Screening 
 
CBC with Differential 
Reticulocyte Count 
Peripheral Smear 
CMP (Sodium, Potassium, Bicarbonate, Chloride, BUN, Creatinine, Glucose, 
Calcium, Total Protein, Albumin, including AST/ALT, Fractionated Bilirubin Level) 
Urine Pregnancy Test (when appropriate) 
 
At  Enrollment: (Part 1) 
 
CBC with Differential 
Reticulocyte Count 
Peripheral Smear 
CMP (Sodium, Potassium, Bicarbonate, Chloride, BUN, Creatinine, Glucose, 
Calcium, Total Protein, Albumin, including AST/ALT, Fractionated Bilirubin Level) 
Platelet Reticulocyte Count 
Eye Examination for caratacts 
History, Physical with Vital Signs and Bleeding Score 
HRQ0L 
 
 
Every 2 Weeks until week 8: 
Reticulocyte count, Platelet Reticulocyte count 
Peripheral Smear (if indicated) 
CMP  
History, Physical with Vital Signs and Bleeding Score 
 
 
Long Term Treatment Extension: (Part 2) 
 
 
Performed at each study visit: 

 
 
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CBC with Differential platelet count, Reticulocyte count, Platelet Reticulocyte count 
 Peripheral Smear (if indicated) 
History, Physical with Vital Signs  
 
After the end of treatment during the dose escalation phase, all subjects can be  
monitored at 4 weeks intervals and then can go to every 8 weeks for the remainder of 
the study at the discretion of the investigator  (investigator may require subjects to 
come in for additional monitoring if deemed necessary).  
 
  
 
After 6 months on therapy: 
Eye Examination 
 
After 12 months on therapy: 
Bone Marrow Aspirate and Biopsy 
HRQ0L 
 
After 18 months on therapy: 
Eye Examination 
 
After 24 months on therapy 
Bone Marrow Aspirate and Biopsy  
*Please Note: A bone marrow aspiration/biopsy will only be performed at 24 months if 
the subject’s reticulin fibrosis grade is a 2 or 3 during the 12 month procedure.  
      HRQ0L 
 
 
 
 
 
After 36 Months on therapy 
Bone Marrow Aspirate and Biopsy  
*Please Note: A bone marrow aspiration/biopsy will only be performed at 36 months if 
the subject’s reticulin fibrosis grade is a 2 or 3 during the 24 month procedure.  
        HRQ0L 
 
After 48 Months on therapy 
Bone Marrow Aspirate and Biopsy  
*Please Note: A bone marrow aspiration/biopsy will only be performed at 48 months if 
the subject’s reticulin fibrosis grade is a 2 or 3 during the 36 month procedure.  
       HRQ0L 
 
Post Study Period after completion of dosing  
 
Weekly 
CBC with Differential platelet count, Reticulocyte count, Platelet Reticulocyte count 
 Peripheral Smear (if indicated) 

 
 
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History, Physical with Vital Signs and Bleeding Score 
HRQ0L (Week 1 – End of  8 Week Blinded study/ End of Extension Study) 
 
 
Every 2 Weeks until week 4: 
CMP  
History, Physical with Vital Signs and Bleeding Score 
 
 
4. 
SUBJECT SELECTION AND WITHDRAWAL CRITERIA 
4.1. 
Number of Subjects:   
60 subjects will be enrolled.   
4.2. 
Inclusion Criteria: 
Subject or their parent/ guardian has signed and dated a written informed consent 
Males and Females aged 3 year or older, who can swallow a tablet, and are 
diagnosed with chronic ITP according to the new consensus guidelines ( Provan, 
Blood, 2009) are eligible.  
No indication of a disease which may cause thrombocytopenia other than ITP----
no specific testing required 
Subjects with thrombocytopenia ≤ 50,000 /uL after at least 21 days of daily 
dosage with eltrombopag 75mg 
Stable dosage of concomitant treatments for ITP  
≥ 2 weeks or longer (corticosteroids);   
 
At least 2 weeks from rescue therapy for ITP ( WinRho, IVIG,  corticosteroids, 
platelet transfusion) or 1 week if therapy has clearly been ineffective 
 
At least 4 weeks from rituximab treatment 
 
Pregnant or Lactating Women are excluded 
Women of child-bearing age with a negative pregnancy test within 7 days of 
enrollment and who agree to use acceptable methods of birth control will be 
eligible for this study 
Female subjects or female partners of male subjects must either be of non-
child bearing potential (hysterectomy, bilateraloophorectomy , bilateral 
tubal ligation or post menopausal for more than one year)   OR, if of child 
bearing potential, using one of the following highly effective methods of 
contraception.  
-complete abstinence from intercourse  

 
 
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-Intrauterine device (IUD)  
-Two forms of barrier contraception. diaphragm plus spermicide, 
or for males condoms plus spermicide.  
-Male partner is sterile and is the only partner of the female.  
-Systemic contraceptives  
 
4.3. 
Exclusion Criteria: 
Previous history of eltrombopag-related LFT elevation that required sustained 
interruption of treatment 
Previous history of immediate or delayed hypersensitivity reaction or 
idiosyncrasy to drugs chemically related to eltrombopag 
Known HIV Infection 
History of Arterial of Venous Thrombosis within the past year or requiring 
ongoing therapy 
Known Active Hepatitis C infection 
Elevated AST/ALT or Creatinine > 1.5 times upper limit of normal in 4 weeks 
prior to enrollment* 
Abnormalities in WBC, ANC and Hemoglobin > 1.5 times upper or lower limit of 
normal* 
 
* Subjects can be rescreened to be included 
4.4. 
Withdrawal Criteria: 
Subject may withdraw consent at any time 
Adverse event that would in the investigators judgement, make continued 
participation in the study an unacceptable risk 
Development or diagnosis of new thrombotic event 
Development of new onset clinically significant ocular changes related to 
cataracts on serial ophthalmologic examination 
Development of  MF3 fibrosis on bone marrow examinations 
Development of Drug Induced Liver Injury necessitating sustained interruption of 
study drug 
Please see Liver Chemistry Stopping and Follow up Criteria  (see 6.3.1) 
 

 
 
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5. 
STUDY TREATMENTS 
5.1. 
Treatment Assignment 
Subjects will be randomly allocated in a two to one ratio to receive treatment or 
placebo. Subjects and investigators will be blinded to randomization. 
Randomization will be stratified according to splenectomy status. Randomization 
will be performed at the time of informed consent with a computer generated 
randomization table 
5.2. 
Product Accountability 
Product will be dispensed from Investigational Pharmacy to investigators and 
study coordinators for distribution to subjects. 
5.3. 
Treatment Compliance 
Subjects will bring in used medication vials at each study visit for review and 
medication compliance will be assessed. 
5.4. 
Concomitant Medications and Non-Drug Therapies 
5.4.1. 
Permitted Medications and Non-Drug Therapies 
Subjects will be allowed to continue with concomitant non-ITP medications, 
but will be excluded from analysis as described (for the subsequent 2 weeks) 
if rescue therapy for treatment of ITP is needed during the duration of the 
study. 
A subject whose platelet count is > 50,000/ul can receive aspirin or Plavix or 
warfarin at the discretion of the investigator. 
5.5. 
Treatment after the End of the Study 
As described for cross-over of placebo patient after unblinding and long term 
extension phase of study. 
5.6. 
Treatment of Investigational Product Overdose 
Treatment of any suspected or confirmed overdose with eltrombopag should 
be symptomatic with supportive care as dictated by good clinical practice. 
There is no known antidote for eltrombopag, although antacids can be 
considered to limit the absorption of eltrombopag. 
5.7. 
Treatment Plan 
 
Bodily Fluid 
Amount 
Frequency 
Total 
 

 
 
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Blood 
10-80cc 
As needed 
amounts 
will be 
adjusted for 
pediatric 
subjects 
Bi-weekly for 8 
weeks, in 4 week 
intervals, then 
every 8 weeks 
(visits at the 
discretion of the 
investigator) 
> 400 cc  
 
Bone Marrow 
Aspiration 
10 cc 
1 time (after 12 
+2 months of 
study medication 
during Part 2 of 
the study) unless 
bone marrow 
fibrosis grade is a 
2 or 3 (then 
annually)  
10 cc per bone 
marrow 
aspiration 
 
Urine 
5- 10 cc 
1 time 
5-10 cc 
 
 

 
 
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STUDY ASSESSMENTS AND PROCEDURES 
Table 1 
See Appendix 1 
6.1. 
Critical Baseline Assessments 
Screening to ensure subject eligibility criteria will occur within 30 days prior to 
administration of study medication. Screening assessments will include CBC, CMP 
(Sodium, Potassium, Bicarbonate, Chloride, BUN, Creatinine, Glucose, Calcium, Total 
Protein, Albumin, including AST/ALT, Fractionated Bilirubin Level), D-Dimer and urine 
pregnancy test (for women of childbearing potential). 
 
6.2. 
If subject meet all other criteria for enrollment, a baseline ophthalmologic 
examination will be performed within 2 weeks of administration of study 
medication.  
6.3. 
Primary Response Criteria: 
Complete Response (CR) will be defined as a 2 consecutive platelet counts ≥ 50,000 /uL  
AND  > 20,000 more than the baseline platelet count  at enrollment within the 8 week 
increased dose window not as a result of rescue treatment. Partial Response (PR) will be 
defined as a 2 consecutive platelet counts ≥ 50,000 /uL  OR  > 20,000 more than the 
baseline platelet count  at enrollment within the 8 week increased dose window not as a 
result of rescue treatment.  
 
 
For uniformity of dosing and data analysis and for better understanding of increased dose 
effects, patients randomized to the treatment arm will automatically take: 
  
100 mg for 2 weeks 
125 mg for 2 weeks  
150 mg for 4 weeks  
 
However, if the platelet count increases to ≥ 100,000 /uL, study drug will be interrupted 
and will not be resumed until platelet count is below 100,000 /uL and the patient desires 
to enroll on the Part 2 long term treatment extension study. The patient will finish with 
the Part 1 of the study at this point but can enter Part 2 the long term treatment extension 
study at dose at which the patient met primary response criteria, after the platelet count 
decreases to < 100,000/uL on serial immediate post-study monitoring period. 
 
Rescue treatment will be defined as new treatment for chronic ITP eg  IV anti-D or IVIG, 
an increased dose of steroids, or platelet transfusion. Use of rescue treatments will be 
allowed, but patients will be regarded as non-responders for the duration of rescue 
treatment and until 2 weeks beyond.  
 
Secondary Response Criteria: 
-Platelet Count ≥ 50,000 and > 20,000 above baseline for at least 3 of the last 4 of 8 
weeks independent of rescue therapy 

 
 
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-Platelet Count ≥ 50,000 /uL and > 20,000 above baseline for any 4 of 8 weeks  
 
independent of rescue therapy 
-At least One Platelet count ≥100,000 
 
-Number of weeks with Platelet Counts ≥ 50,000 /uL and >20 from baseline in 8 Weeks 
reduction of bleeding score from baseline to the last count of the study 
improvement of HRQoL 
-Number of weeks with Platelet Counts > 100,000 in 8 Weeks 
 
Secondary Efficacy Endpoints: 
-Dose required achieving first platelet count ≥ 50,000 /uL and >20 from baseline 
-Average Platelet Count at each dose level 
-Bleeding scores using WHO score 
-Use of Rescue Treatments 
 
 
6.4. 
Safety 
Increased Liver Chemistries 
 
Eltrombopag administration may cause hepatotoxicity. In the ITP controlled clinical 
studies, one patient experienced Grade 4 (NCI Common Terminology Criteria for 
Adverse Events [NCI CTCAE] toxicity scale) elevations in serum liver test values during 
therapy with Eltrombopag, worsening of underlying cardiopulmonary disease, and death. 
One patient in the placebo group experienced a Grade 4 liver test abnormality. In 
controlled studies, elevations of ALT and indirect bilirubin were observed more 
frequently on the eltrombopag arm than placebo.  Overall, serum liver test abnormalities 
(predominantly Grade 2 or less in severity) were reported in 11% and 7% of the 
eltrombopag and placebo groups, respectively. In the three controlled studies, four 
patients (1%) treated with eltrombopag and three patients in the placebo group (2%) 
discontinued treatment due to hepatobiliary laboratory abnormalities. Seven of the 
patients treated with eltrombopag in the controlled studies with hepatobiliary laboratory 
abnormalities were re-exposed to eltrombopag in the ITP extension study. Six of these 
patients again experienced liver test abnormalities (predominantly Grade 1) resulting in 
discontinuation of eltrombopag in one patient. In the ITP extension study, one additional 
patient had eltrombopag discontinued due to liver test abnormalities (all Grade 3). 
Liver chemistry stopping criteria and follow up requirements have been designed to 
assure subject safety and evaluate liver event etiology in alignment with the FDA 
Guidance for Industry – Drug-Induced Liver Injury: Premarketing Clinical Evaluation 
(July 2009, www.fda.gov). 
  
Bone Marrow Reticulin Formation and Risk for Bone Marrow Fibrosis 
Eltrombopag may increase the risk for the development or progression of reticulin fiber 
deposition within the bone marrow.  

 
 
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In the ITP extension study, 151 patients have had bone marrow biopsies evaluated for 
increased reticulin and collagen fiber deposition. Bone marrow biopsies taken after 1 year 
of therapy showed predominantly myelofibrosis (MF) Grade 1 or less in 140/151 (93%) 
of patients (Saleh et al 2013, Blood). There were 11/151 (7%) of patients with MF Grade 
2. Four patients had collagen deposition reported. One patient with a pre-existing MF 
Grade 1 developed a MF Grade 2 and subsequently discontinued treatment with 
eltrombopag.  Clinical studies have not yet excluded a risk of bone marrow fibrosis with 
clinical consequences.  . 
If new or worsening blood morphological abnormalities or cytopenias occur, a bone 
marrow biopsy should be considered, including staining for fibrosis..  
Thrombotic/thromboembolic complications  
Thrombotic/thromboembolic complications may result from increases in platelet counts 
with eltrombopaand those reported in controlled clinical studies in patients with chronic 
ITP included both venous and arterial events and were observed at low and normal 
platelet counts. 
Use caution when administering eltrombopag to patients with known risk factors for 
thromboembolism (e.g., Factor V Leiden, ATIII deficiency, antiphospholipid syndrome, 
chronic liver disease). To minimize the risk for thrombotic/thromboembolic 
complications, do not use eltrombopag in an attempt to normalize platelet counts. Follow 
the dose adjustment guidelines to achieve and maintain a platelet count of 50 x 109/L 
as necessary to decrease the risk for bleeding 
In a placebo-controlled double-blind study (ELEVATE) of 292 patients with chronic 
liver disease who were undergoing an elective  surgical procedure, the risk of portal 
venous thrombosis was increased in patients treated with 75 mg eltrombopag once daily 
for 2 weeks in preparation for their invasive procedure. Seven thrombotic complications 
(six patients) were reported within the group that received eltrombopag and three 
thrombotic complications were reported in the placebo group (two patients). All of the 
thrombotic complications reported within the eltrombopag group were of the portal 
venous system. Five of the six patients in the group that received eltrombopag 
experienced a thrombotic complication within 30 days of completing treatment with 
eltrombopag and at a platelet count above 200 x 109/L. Malignancy is known to increase 
the risk for developing a thrombotic event and four  of the 6 patients either had a 
diagnosis or suspicion of malignancy (2 hepatocellular carcinoma; 1 possible lymphoma 
and 1 brain tumor).     
Caution should be exercised when administering eltrombopag to patients with hepatic 
impairment (Child-Pugh Class A, B, C) and  a lower starting dose of eltrombopag should 
be used in patients with any degree of hepatic impairment.  Such patients should be 
monitored very closely. Eltrombopag is not indicated for the treatment of 
thrombocytopenia in patients with chronic liver disease. 
The ELEVATE study was terminated in November 2009 and a Dear Health Care 
Professional Letter (DHCPL) was sent to all physicians enrolled in Promacta Cares in 
May 2010.   

 
 
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Hematologic Malignancies  
Stimulation of the TPO receptor on the surface of hematopoietic cells by eltrombopag 
may increase the risk for hematologic malignancies. In the controlled clinical studies, 
patients were treated with eltrombopag for a maximum of 6 months. During this period 
no hematologic malignancies were reported in patients treated with eltrombopag. One 
hematologic malignancy (non-Hodgkin's lymphoma) was reported in the extension study. 
Eltrombopag is not indicated for the treatment of thrombocytopenia due to diseases or 
treatments that cause thrombocytopenia (e.g., myelodysplasia or chemotherapy) other 
than chronic ITP.  
Cataracts 
Cataracts were observed in toxicology studies of eltrombopag in rodents (see Non-
clinical Information). To date, there is however, no evidence that eltrombopag increases 
the incidence nor progression of cataracts in patients who have received eltrombopag.  In 
the three placebo-controlled ITP studies, 7% of patients in both the placebo and 
eltrombopag treatment groups had a report of cataract.  A significant proportion of 
patients in the ITP clinical studies were also exposed to chronic corticosteroid 
administration.   
Routine monitoring of patients for cataracts is recommended. Patients treated with 
eltrombopag who experience visual difficulties should have an appropriate 
ophthalmologic evaluation 
 

 
 
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6.4.1. 
Liver chemistry stopping and follow-up criteria 
 
 
Liver chemistry stopping criteria and follow up requirements have been designed to 
assure subject safety and evaluate liver event etiology in alignment with the FDA 
Guidance for Industry – Drug-Induced Liver Injury: Premarketing Clinical Evaluation 
(July 2009, www.fda.gov). 
 
Liver chemistry stopping criteria 1-5 are defined as follows: 
1. ALT 3x ULN and bilirubin 2x ULN (>35% direct bilirubin) (or ALT 3x ULN 
and INR > 1.5, if INR measured) 
 
NOTE: If serum bilirubin fractionation is not immediately available, study drug 
should be discontinued if ALT  3x ULN and bilirubin  2x ULN. Serum bilirubin 
fractionation should be performed if testing is available.  If testing is unavailable, 
record presence of detectable urinary bilirubin on dipstick, indicating direct bilirubin 
elevations and suggesting liver injury. 
1. ALT ≥ 5x ULN 
2. ALT ≥ 3x ULN if associated with symptoms (new or worsening) believed to be 
related to hepatitis (such as fatigue, nausea, vomiting, right upper quadrant pain or 
tenderness, or jaundice) or believed to be related to hypersensitivity (such as fever, 
rash or eosinophilia). 
3. ALT ≥ 3x ULN persists for ≥ 4 weeks 
Phase II Liver Safety Algorithms
ALT>3xULN
plus Bilirubin>2xULN 
(>35% direct) (or plus
INR>1.5, if measured)*
No
Yes
Yes
•Instruct subject to stop investigational product (IP)
•Notify GSK + arrange clinical followup within 24-72h
•Perform liver chemistries and liver event follow up 
assessments (serology, PK sample etc as in protocol) 
•Complete liver event CRF, SAE data collection tool if 
appropriate, + liver imaging +/or biopsy CRFs if these 
tests performed.
•Obtain weekly liver chemistries [**as far as possible] 
until resolved, stabilised or returned to baseline 
•Withdraw subject from study after liver chemistry 
monitoring complete + do not re-challenge with IP
•Instruct subject to stop investigational product (IP)
•Notify GSK + arrange clinical followup within 24h
•Perform liver chemistries and liver event follow up 
assessments (serology, PK sample etc as in protocol) 
•Report as an SAE (excl. hepatic impairment or cirrhosis 
studies)+ and complete liver event CRF, SAE data 
collection tool, + liver imaging +/or biopsy CRFs if tests 
performed.
•Obtain twice weekly liver chemistries until resolved, 
stabilised or returned to baseline values
•Consultation with hepatologist/specialist recommended
•Withdraw subject from study after liver chemistry 
monitoring complete + do not re-challenge with IP
ALT>5xULN
Hepatitis 
symptoms
or rash?
No
Able to 
monitor weekly                       
for 4 wks?
No
Notify GSK within 24h to 
discuss subject safety
Continue IP
Check liver chemistry 
weekly for 4 weeks
No
No**
Yes
Yes
Continue IP
Obtain twice monthly liver 
chemistries until normalised
or back to baseline values
Yes
Yes
ALT>3xULN or bilrubin >2xULN?
Yes
*INR value not applicable to patients on anticoagulants

 
 
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4. ALT ≥ 3x ULN and cannot be monitored weekly for 4 weeks 
When any of the liver chemistry stopping criteria 1 - 5 is met, do the following: 
 
Immediately discontinue study treatment 
 
Report the event to Novartiswithin 24 hours of learning its occurrence 
 
All events of ALT  3x ULN and bilirubin  2x ULN (>35% direct bilirubin) 
(or ALT 3x ULN and INR > 1.5, if INR measured; INR measurement is not 
required and the threshold value stated will not apply to subjects receiving 
anticoagulants), termed ‘Hy’s Law’, must be reported as an SAE (excluding 
studies of hepatic impairment or cirrhosis). 
 
NOTE: if serum bilirubin fractionation is not immediately available, study 
treatment should be discontinued if ALT  3x ULN and bilirubin  2x ULN. 
Serum bilirubin fractionation should be performed if testing is available. If 
testing is unavailable, record presence of detectable urinary bilirubin on dipstick, 
indicating direct bilirubin elevations and suggesting liver injury. 
 
Complete the liver imaging and/or liver biopsy eCRFs if these tests are performed 
 
Perform liver event follow up assessments, and monitor the subject until liver 
chemistries resolve, stabilize, or return to baseline values as described below 
 
Do not rechallenge with investigational product. 
In addition, for subjects meeting liver stopping criterion 1:  
 
Make every reasonable attempt to have subjects return to clinic within 24 hours for 
repeat liver chemistries, liver event follow up assessments (refer to Section 0), and 
close monitoring 
 
A specialist or hepatology consultation is recommended 
 
Monitor subjects twice weekly until liver chemistries (ALT, AST, alkaline 
phosphatase, bilirubin) resolve, stabilize or return to within baseline values. 
For subjects meeting any of the criteria 2 – 5: 
 
Make every reasonable attempt to have subjects return to clinic within 24-72 hrs for 
repeat liver chemistries and liver event follow up assessments (refer to Section 0) 
 
Monitor subjects weekly until liver chemistries (ALT, AST, alkaline phosphatase, 
bilirubin) resolve, stabilize or return to within baseline values;  
subjects meeting criterion 5 should be monitored as frequently as possible 
Liver Event Follow Up Assessments 
For subjects meeting any of the liver chemistry stopping criteria 1 – 5, make every 
attempt to carry out the liver event follow up assessments described below: 
 
Viral hepatitis serology including: 
 
Hepatitis A IgM antibody 
 
Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM)  
 
Hepatitis C RNA  
 
Cytomegalovirus IgM antibody   
 
Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain 
heterophile antibody or monospot testing)   
 
Hepatitis E IgM antibody  
 
Serum creatine phosphokinase (CPK) and lactate dehydrogenase (LDH). 
 
Fractionate bilirubin, if total bilirubin 2x ULN. 
 
Obtain complete blood count with differential to assess eosinophilia. 
 
Record the appearance or worsening of clinical symptoms of hepatitis, or 

 
 
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hypersensitivity, such as fatigue, nausea, vomiting, right upper quadrant pain or 
tenderness, fever, rash or eosinophilia as relevant on the AE form. 
 
Record use of concomitant medications, acetaminophen, herbal remedies, other over 
the counter medications, or putative hepatotoxins, on the concomitant medications 
form. 
 
Record alcohol use on the liver event alcohol intake form. 
The following assessments are required for subjects with ALT 3x ULN and bilirubin 
2x ULN (>35% direct) but are optional for other abnormal liver chemistries: 
 
Anti-nuclear antibody, anti-smooth muscle antibody, and Type 1 anti-liver kidney 
microsomal antibodies 
 
Liver imaging (ultrasound, magnetic resonance, or computerized tomography) to 
evaluate liver disease. 
Liver Chemistry Monitoring Criteria 
For subjects with ALT 3x ULN but <5x ULN and bilirubin <2x ULN, without hepatitis 
symptoms or rash, and who can be monitored weekly for 4 weeks, the following actions 
should be taken: 
 
Notify  Novartis within 24 hours of learning of the abnormality to discuss subject 
safety 
 
Can continue study treatment  
 
Must return weekly for repeat liver chemistries (ALT, AST, alkaline phosphatase, 
bilirubin) until they resolve, stabilize or return to within baseline values  
 
If at any time the subject meets any of the liver chemistry stopping criteria 1 – 5, 
proceed as described above 
 
If, after 4 weeks of monitoring, ALT <3x ULN and bilirubin <2x ULN, monitor 
subjects twice monthly until liver chemistries normalize or return to within baseline 
values.  
 
6.4.2. 
Adverse Events 
6.4.2.1. 
Definition of an AE 
An Adverse Event (AE) is any unfavorable or unintended effect on a research participant 
whether or not the event is deemed study-related.  AEs include new or increased 
symptoms, diagnoses, lab results or changes to a pre-existing condition.  AEs are 
monitored throughout the duration of a study and for a specified period after the 
completion of study procedures (e.g. 30 days after the last treatment). 
6.4.2.2. 
Definition of a SAE 
A Serious Adverse Event (SAE) includes death, life threatening events, hospitalization 
or prolongation of hospitalization, disability or incapacitation, overdose, congenital 
anomalies and any other serious events that may jeopardize the health or well-being of 
the subject or require medical or surgical intervention to prevent one of the outcomes 
listed in this definition.  

 
 
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6.4.3. 
Disease-Related Events and/or Disease-Related Outcomes Not Qualifying 
as SAEs 
6.4.4. 
Pregnancy  
No Pregnant or Lactating Women will be eligible for this study,  
Women with a negative pregnancy test within 7 days of enrollment and agree to use 
acceptable methods of birth control will be eligible for this study 
6.4.5. 
Time Period and Frequency of Detecting AEs and SAEs 
Investigators in writing must notify the NYPH-WCMC IRB as per Human Research 
Protection Policy in an immediate report within 7 working days of the occurrence of all 
serious or unexpected Adverse Events (AEs) in NYPH-WCMC research subjects, 
whether or not the events are considered study-related and within 24 hours of protocol 
deviations to eliminate hazards or breech of confidentiality 
6.4.6. 
Prompt Reporting of Serious Adverse Events and Other Events to 
Novartis 
 
Reporting to Novartis: 
Any serious adverse events which occur during the clinical study or within 30 days of 
receiving the last dose of study medication, whether or not related to the study drug, must 
be reported by the investigator. In addition, any SAEs which occur as a result of protocol 
specific diagnostic procedures or interventions must also be reported. 
 
All serious adverse events must be reported by facsimile within 24 hours toNovartis: 
usdrugsafety.operations@novartis.com .  
The SAE report should comprise a full written summary, detailing relevant 
aspects of the adverse events in question. Where applicable, information from 
relevant hospital case records and autopsy reports should be included. Follow-up 
information should be forwarded to Novartis within 24 hours. 
 
SAEs brought to the attention of the investigator at any time after cessation of 
eltrombopag and considered by the investigator to be related or possibly related to 
eltrombopag must be reported to Novartis if and when they occur. Additionally, in 
order to fulfill international reporting obligations, SAEs that are related to study 
participation (e.g., procedures, invasive tests, change from existing therapy) or are 
related to a concurrent medication will be collected and recorded from the time the 
subject consents to participate in the study until he/she is discharged. 

 
 
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6.4.6.1. 
Regulatory reporting requirements for SAEs 
The PI and/or data coordinator will be reporting unexpected serious adverse events 
promptly to the IRB, FDA and to Novartis within appropriate regulatory timeframe. 
We will be reporting: 
 - WCMC IRB as per WCMC AE Reporting Policy 
 - FDA as per Safety Reporting Requirements for IND and BA/BE ( 21CFR312.32) 
 - Novartis will be informed of all SAE within 24 hours 
 - WCMC Data Safety Monitoring Board 
 
6.4.6.2                  Data Safety Monitoring Plan: 
 
We will be utilizing the Weill Cornell Medical College Data Safety Monitoring Board 
(DSMB) to review the IRB-approved protocol, informed consent forms and safety 
reports. The DSMB will review data semi-annually to evaluate the safety, efficacy, and 
compliance with all local IRB, FDA and ICH regulations/requirements for this study.  
Adverse events and unanticipated problems will be submitted to the DSMB semi-
annually. A Grade 4 or above adverse event will result in an immediate submission of a 
periodic report to the DSMB.  All serious adverse events will be immediately submitted 
to Novartis and to the FDA under the IND.  
The Principal Investigator will submit all written DSMB recommendations at the time of 
the continuing review. Individual recommendations will be submitted upon receipt of 
review comments. 
Safety Evaluation 
This protocol is investigator initiated. The Principal Investigator is responsible for the 
study and will monitor the safety of the patients on the protocol. 
The following safety will be reviewed by the Principal Investigator: 
 Physical Exam 
 Vital Signs 
 Laboratory results (blood count, liver function tests, reticulocyte count) 
 SAE and AE events 
 Bone marrow aspirations/biopsies (if relevant) 
Early Stopping Rules 
Individual Stopping Rules 
 
 Adverse event that would in the investigators judgment, make continued 
participation in the study an unacceptable risk 
 Development or diagnosis of new thrombotic event 

 
 
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 Development of new-onset, clinically-significant, ocular changes related to 
cataracts on serial ophthalmology examinations 
 Development of MF3 fibrosis on bone marrow examinations 
 Development of Drug Induced Liver Injury 
 
Liver chemistry stopping criteria and follow up requirements have been implemented to 
assure subject safety and evaluate liver event etiology in alignment with the FDA 
Guidance for Industry – Drug-Induced Liver Injury: Premarketing Clinical Evaluation. 
Liver chemistry stopping criteria 1-5 are defined as follows: 
 
1. ALT >3x ULN and bilirubin >2x ULN (>35% direct bilirubin) (or ALT >3x ULN 
and INR > 1.5, if INR measured and prolongation not related to another medication 
known to prolong INR) 
NOTE: If serum bilirubin fractionation is not immediately available, study drug 
should be discontinued if ALT >3x ULN and bilirubin > 2x ULN. Serum bilirubin 
fractionation should be performed if testing is available. If testing is unavailable, 
record presence of detectable urinary bilirubin on dipstick, indicating direct bilirubin 
elevations and suggesting liver injury. 
 
2. ALT ≥ 5x ULN 
 
3. ALT ≥ 3x ULN if associated with symptoms (new or worsening) believed to be 
related to hepatitis (such as fatigue, nausea, vomiting, right upper quadrant pain or 
tenderness, or jaundice) or believed to be related to hypersensitivity (such as fever, 
rash or eosinophilia). 
 
4.ALT ≥ 3x ULN persists for ≥ 4 weeks 
 
5. ALT ≥ 3x ULN and cannot be monitored weekly for 4 weeks 
 
When any of the liver chemistry stopping criteria 1 - 5 is met, do the following: 
 Immediately discontinue study treatment 
 Report the event to Novartis and DSMB within 24 hours of learning its 
occurrence 
 All events of ALT > 3x ULN and bilirubin >2x ULN (>35% direct bilirubin)(or 
ALT >3x ULN and INR > 1.5, if INR measured; INR measurement is not 
required and the threshold value stated will not apply to subjects receiving 
anticoagulants), termed ‘Hy’s Law’, must be reported as an SAE (excluding 
studies of hepatic impairment or cirrhosis). 
 NOTE: if serum bilirubin fractionation is not immediately available, study 
treatment should be discontinued if ALT >3x ULN and bilirubin >2x ULN. 
Serum bilirubin fractionation should be performed if testing is available. If testing 
is unavailable, record presence of detectable urinary bilirubin on dipstick, 
indicating direct bilirubin elevations and suggesting liver injury. 
 Perform liver event follow up assessments, and monitor the subject until liver 
chemistries resolve, stabilize, or return to baseline values as described below 

 
 
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 Do not rechallenge with investigational product. 
 
In addition, for subjects meeting liver stopping criterion 1: 
 Make every reasonable attempt to have subjects return to clinic within 24 hours 
for repeat liver chemistries, liver event follow up assessments (refer to Section 0), 
and close monitoring 
 A specialist or hepatology consultation is recommended 
 Monitor subjects twice weekly until liver chemistries (ALT, AST, alkaline 
phosphatase, bilirubin) resolve, stabilize or return to within baseline values. 
 
For subjects meeting any of the criteria 2 – 5: 
 Make every reasonable attempt to have subjects return to clinic within 24-72 hrs 
for repeat liver chemistries and liver event follow up assessments  
 Monitor subjects weekly until liver chemistries (ALT, AST, alkaline 
phosphatase, bilirubin) resolve, stabilize or return to within baseline values; 
subjects meeting criterion 5 should be monitored as frequently as possible 
 
Liver Event Follow Up Assessments 
For subjects meeting any of the liver chemistry stopping criteria 1 – 5, make every 
attempt to carry out the liver event follow up assessments described below: 
 Viral hepatitis serology including: 
o Hepatitis A IgM antibody 
o Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM) 
o Hepatitis C RNA 
o Cytomegalovirus by PCR 
o Epstein-Barr virus by PCR 
 Hepatitis E IgM antibody 
 Serum creatine phosphokinase (CPK) and lactate dehydrogenase (LDH). 
 Fractionate bilirubin, if total bilirubin >2x ULN. 
 Obtain complete blood count with differential to assess eosinophilia. 
 Record the appearance or worsening of clinical symptoms of hepatitis, or 
hypersensitivity, such as fatigue, nausea, vomiting, right upper quadrant pain or 
tenderness, fever, rash or eosinophilia as relevant on the AE form. 
 Record use of concomitant medications, acetaminophen, herbal remedies, other 
over the counter medications, or putative hepatotoxins, on the concomitant 
medications form. 
 Record alcohol use on the liver event alcohol intake form. 
 
The following assessments are required for subjects with ALT >3x ULN and bilirubin 
>2x ULN (>35% direct) but are optional for other abnormal liver chemistries: 
 Anti-nuclear antibody, anti-smooth muscle antibody, and Type 1 anti-liver kidney 
microsomal antibodies 
 Liver imaging (ultrasound, magnetic resonance, or computerized tomography) to 
evaluate liver disease. 
Liver Chemistry Monitoring Criteria 
For subjects with ALT >3x ULN but <5x ULN and bilirubin <2x ULN, without hepatitis 
symptoms or rash, and who can be monitored weekly for 4 weeks, the following actions 

 
 
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should be taken: 
 Notify Novartis and DSMB within 24 hours of learning of the abnormality to 
discuss subject safety 
 Can continue study treatment 
 Must return weekly for repeat liver chemistries (ALT, AST, alkaline phosphatase, 
bilirubin) until they resolve, stabilize or return to within baseline values 
 If at any time the subject meets any of the liver chemistry stopping criteria 1 – 5, 
proceed as described above 
 If, after 4 weeks of monitoring, ALT <3x ULN and bilirubin <2x ULN, monitor 
subjects twice monthly until liver chemistries normalize or return to within 
baseline values. 
 
Protocol Stopping Rules 
Novartis and the Principle Investigator may terminate the study at any time. Early 
termination may occur due to emergent risk information or the decision by Novartis to 
discontinue the development of Eltrombopag.  
 
Dose Escalation Rules 
 
In Part 1 of the study, subjects will be randomly allocated at a two to one ratio to receive 
active treatment or placebo. All subjects in the study will receive 75 mg eltrombopag and 
then be randomized to receive either an additional 25 mg of eltrombopag or matching 
placebo tablet dispensed by the research pharmacy. 
 
Eltrombopag will be administered bi-weekly for 8 weeks. If platelet count does not 
exceed 100,000, the additional eltrombopag or matching placebo tablet will be increased 
by 25 mg until the patient receives 75 mg eltrombopag and 75 mg eltrombopag or 
matching placebo (100mg x 2 weeks, 125 mg x 2 weeks, 150 x 4 weeks).  If the patient’s 
platelet count exceeds 100,000 during part 1dosing will stop, subject will be considered a 
responder, and the subject will eligible for entering Part 2 (the long term treatment part of 
the study).  
 
Dose modification during the long term extension portion of the trial will be made on 
the basis of individual platelet response to as high a dose as 150mg.  If the platelet count 
is > 150,000 ul and < 400,00 ul the daily dose will be adjusted and if > 400,000 ul the 
medication will be held and monitor will be as per the prescribing information for 
eltrombopag in the package insert. However, if the P-I determines that adjusting or 
stopping the subject’s dose will negatively affect the subject, he or she may decide not to 
escalate, reduce, or stop the subject’s dose. Circumstances in which this may occur 
include, but are not limited to: investigator is tapering other medications or the subject 
has a viral infection. Viral infections have been known to both increase and decrease 
platelet count in patients with ITP. It is suggested that the increased presence of 
inflammatory molecules during a viral infection increases platelet production, causing 
platelet count to increase. Alternatively, platelet count may decrease by virtue of 
activating the reticuloendthelial system causing greater phagocytosis of antibody-coated 
platelets and/or platelet production. 

 
 
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Data Collection and Monitoring 
Data will be collected and entered into a Microsoft excel eCRF by the clinical research 
coordinator. Data will be entered into the eCRF after each study visit. The Principal 
investigator will verify the data quarterly to ensure that the data collected and entered is 
accurate. 
Interim Analysis: 
An interim analysis was performed after 18 patients were enrolled in the study. The data 
suggested that non-splectectomized patients tended to have higher average platelet counts 
compared to splectectomized patients for the first 8 weeks in the open-label extension 
phase. When subjects were on active drug, the results revealed that males tended to have 
a higher complete response rate compared to females. Of note, three subjects were 
removed due to SAEs, however only one patient was removed because of a study drug 
related event (elevated LFTs). Further analysis will be performed to evaluate the long 
term efficacy and safety of Eltrombopag at doses higher than 75 mg after 36 and then 60 
patients have completed 8 weeks of active medication. 
 
 
6.4.7. 
Other Safety Outcomes  
7. 
DATA MANAGEMENT 
Data will be kept in locked filing cabinets in a locked room away from the clinical area.  
All data that is computer generated will password protected. The FDA, New York 
Presbyterian Hospital, the IRB, and the Office for Human Research Protection (OHRP) 
may have access to the study records without the patient’s permission and will maintain 
confidentially of the information. 
 
8. 
DATA ANALYSIS AND STATISTICAL CONSIDERATIONS 
8.1. 
Hypotheses 
Subject who did not respond at a dose of 75mg daily, eltrombopag will respond with 
increasing platelet count to > 50,000 and > 20,000 above baseline at a higher daily dose 
of 100, 125 and 150mg. 
8.2. 
Study Design Considerations 
8.2.1. 
Sample Size Assumptions 
The trial will have a 80% statistical power at the 5% level of significance  (two sided) to 
detect a difference in the proportion of patient receiving increased dose of eltrombopag 
with a primary response ( Platelet Count ≥ 50,000 per cubic millimetre and > 20,000 
above baseline) to patients without a primary response in the placebo group. assuming 
50% of patients randomized to active drug will have a response and 5% of patients 

 
 
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randomized to placebo would have a response. An interim analysis will be performed 
after 18 subjects to test for futility and efficacy and also to re-estimate sample size.   If 
neither futility nor efficacy are met the trial would continue to enroll.   Based on the 
observed treatment effect at the interim analysis the sample size would be allowed to 
expand to up to 60 subjects 
8.2.2. 
Sample Size Sensitivity / Re-estimation 
If the estimates of study size are incorrect, a preliminary look will take place after 18 
patients to see if the study size needs to be increased. 
8.3. 
Data Analysis Considerations 
8.3.1. 
Key Elements of Analysis Plan  
The analysis would primarily be descriptive except for the primary endpoint. In order to 
make the study feasible, the current plan for 36 patients does not allow for much 
flexibility. It does allow for a confirmatory study from the patients on placebo who can 
then follow the 8 weeks of dose escalation treatment as an open label study (note they 
will have been on 75 mg of eltrombopag for at least 11 weeks at that time).  All 
secondary analyses will be underpowered but will be descriptive.  
Analysis of efficacy will be based on the intention to treat population of all subjects who 
underwent randomization. 
8.3.1.1. 
Interim analysis  
Results of Interim analysis: 
 
In the interim analysis of 18 subjects, the data suggests that non-splectectomized patients 
tended to have greater average platelet counts compared to splectectomized patients for 
the first 8 weeks in the open-label extension phase. When subjects were on active drug, 
the results revealed that males tended to have a higher complete response rate compared 
to females.  
 
Of note, three subjects were removed due to SAEs, however only one patient was 
removed because of a study drug related event (elevated LFTs). Further analysis will be 
performed after 36 patients and 60 patients are enrolled to evaluate the long term efficacy 
and safety of eltrombopag at doses higher than 75 mg. 
 
Primary Response Criteria: 
 
Complete Response (CR) will be defined as a 2 consecutive platelet counts ≥ 50,000 /uL  
AND  > 20,000 more than the baseline platelet count  at enrollment within the 8 week 
increased dose window not as a result of rescue treatment. Partial Response (PR) will be 
defined as a 2 consecutive platelet counts ≥ 50,000 /uL  OR  > 20,000 more than the 
baseline platelet count  at enrollment within the 8 week increased dose window not as a 
result of rescue treatment. Odds of response will be analyzed using logistical regression 
for binary response variables. 

 
 
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Secondary Response Criteria: 
-Platelet Count ≥ 50,000 and > 20,000 above baseline for at least 3 of the last 4 of 8 
weeks independent of rescue therapy 
-Platelet Count ≥ 50,000 /uL and > 20,000 above baseline for any 4 of 8 weeks  
 
independent of rescue therapy 
-At least One Platelet count ≥100,000 
-Number of weeks with Platelet Counts ≥ 50,000 /uL and >20 from baseline in 8 Weeks 
reduction of bleeding score from baseline to the last count of the study 
improvement of HRQoL 
-Number of weeks with Platelet Counts > 100,000 in 8 Weeks 
 
Secondary Efficacy Endpoints: 
-Dose required achieving first platelet count ≥ 50,000 /uL ?and >20 from baseline 
-Average Platelet Count at each dose level 
-Bleeding scores using Page score and WHO score 
-Use of Rescue Treatment 
 
 
8.3.1.2. 
Safety Analyses 
 
For safety analysis the population for analysis will include all randomized subjects who 
received at least one dose of study medication. Subjects will be evaluated according to 
the treatment they received. 
Malignancy 
Malignancy will be descriptive 
 
Bone Marrow Reticulin Fibrosis 
Bone Marrow Fibrosis monitoring will involve performing bone marrow aspirate and 
biopsy on any consenting patient who elects to remains enrolled in long term extension 
after 12 months of therapy. All marrows will be read by Drs Julia Geyer and Attilio Orazi 
at Weill-Cornell Medical Center. 
 
Re-occurrence of thrombocytopenia 
Re-occurrence of thrombocytopenia will be defined as platelet count < 10,000 uL or 
10,000 ul decrease from baseline platelet count at enrollment in the 4 weeks following 
discontinuation of the study medication 
 
Thrombosis 
Thrombosis will be descriptive 
 
Drug Induced Liver Injury 

 
 
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Elevations in ALT > 3 time upper limit of normal or bilirubin level > 2 times the upper 
limit of normal will be monitored and assessed for continuation or stopping of study drug 
as per Phase II Liver Safety Algorithm ( see Appendix) 
 
Incidence of new and progression of previously identified cataracts 
Cataract assessment will involve a baseline eye exam in all enrolled patients with 
subsequent evaluations at 6 months and 18 months in the patients that continue to receive 
therapy in the long term extension study. If possible re scheduling, all exams will be 
performed by Dr Chris Starr. 
 
9. 
STUDY CONDUCT CONSIDERATIONS 
9.1. 
Regulatory and Ethical Considerations, Including the Informed Consent 
Process 
This study will be conducted in compliance with the protocol approved by the 
Institutional Review Board, and according to Good Clinical Practice standards.  No 
deviation from the protocol will be implemented without the prior review and approval of 
the IRB except where it may be necessary to eliminate an immediate hazard to a research 
subject.  In such case, the deviation will be reported to the IRB as soon as possible. 
All subjects for this study will be provided a consent form describing this study and 
providing sufficient information for subjects to make an informed decision about their 
participation in this study.  This consent form will be submitted with the protocol for 
review and approval by the IRB.  The formal consent of a subject, using the IRB-
approved consent form, will be obtained before that subject is submitted to any study 
procedure.  This consent form must be signed by the subject or legally acceptable 
surrogate, and the investigator-designated research professional obtaining the consent. 
9.2. 
Quality Control (Study Monitoring) 
CRF monitoring will be performed by one of the coordinators not involved in the study. 
The WCMC data safety monitoring board will be used to review the IRB-approved 
protocol, informed consents, and safety reports on a quarterly basis. 
Quality Assurance 
To ensure compliance with good clinical practice and regulatory requirements, regulatory 
agencies may conduct a regulatory inspection at any time during or after the study 
completion. In the event of an audit, the investigator will agree to grant the inspectors 
direct access to all relevant documents and allocate time/staff time to discuss findings and 
relevant issues. 
9.3. 
Records Retention 
Primary data be retained until there is no reasonable possibility that they will be required 
to defend against an allegation of scientific misconduct and as per FDA regulations of 

 
 
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studies conducted under IND until two years after marketing approval or withdrawal of 
IND. 
10. 
APPENDICES 
 
10.1. 
Appendix 1 
Attached Table 1: Study Assessments and Procedures 
 
 
 
*If clinically indicated 
** Bone marrow aspirations/biopsies will be performed annually depending on the 
reticulin fibrosis grade of the bone marrow performed at year 1. A bone marrow 
Part 1 
Screen < 
28 days 
Day 1 
Week 2 
Week 4 
Week 6 
Week 8 
  
  
 
 
Written Informed Consent 
X 
  
  
  
 
 
Inclusion/Exclusion Criteria 
X 
  
  
  
 
 
Demographics 
X 
  
  
  
 
 
Register 
X 
  
  
  
 
 
Eye Exam 
 X 
  
  
 
 
Pregnancy Test * 
 X 
  
  
 
 
Randomization 
 X 
  
  
 
 
History and Physical (Vital Signs) 
  
 X 
X 
X 
X 
X 
Bleeding Score 
  
 X 
X 
X 
X 
X 
HRQ0L 
  
 X 
  
  
 
 
CBC  
X 
 X 
X 
X 
X 
X 
Reticulocyte 
X 
 X 
X 
X 
X 
X 
Platelet Reticulocyte 
X 
 X 
X 
X 
X 
X 
Peripheral Smear* 
X 
 X 
X 
X 
X 
X 
CMP 
X 
 X 
 X 
 X 
X 
X 
Part 2 
6 Month 
12 
Month 
18 
Month 
24 
Month 
30 
Month 
36 
Month 
42 
Month 
 
48 Month 
Eye Exam 
x 
 
x 
 
 
 
 
 
 
Bone Marrow 
Examination 
 
x 
 
X** 
 
X** 
 
 
X** 
HRQ0L 
 
x 
 
x 
 
x 
 
 
x 
CBC  
 
In Part 2, subjects will be seen in 4 weeks then every 8 weeks for the remainder of the 
study at the discretion of the investigator  (investigator may require subjects to come in for 
additional monitoring if deemed necessary) 
Reticulocyte 
 
Platelet 
Reticulocyte 
 
Peripheral Smear * 
 
CMP 
 
 

 
 
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aspiration/biopsy will be repeated the next year if the subject’s recticulin fibrosis grade is 
a 2 or 3. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Post Study Period 
Week 1 
Week 2 
Week 3 
Week 4 
CBC  
X 
X 
X 
X 
Reticulocyte 
X 
X 
X 
X 
HRQ0L 
X 
  
  
  
Platelet Reticulocyte 
X 
X 
X 
X 
Peripheral Smear * 
X 
X 
X 
X 
CMP 
X 
  
X 
  

 
 
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10.2           Appendix 2 
PHARMACOKINETIC SAMPLING 
PK Sample Collection 
After a minimum of 4 weeks on active study drug, 2mL blood samples for PK analysis will be 
collected in K2 EDTA-containing tubes.  One sample will be collected at each of the following 
times: within 1 hour prior to eltrombopag dosing (pre-dose sample), and at 2- 4 hours and 5-8 
hours after eltrombopag dosing. 
Record the date, time, and amount (in mg) of the dose administered prior to the pre-dose sample 
(this dose should have been taken on a day prior to PK sample collection), and record the 
dosing frequency (for example: once daily). 
Record the date, time, and amount (in mg) of the dose administered after the pre-dose PK sample 
(this dose should be administered within a few minutes after collecting the pre-dose PK 
sample). 
Collect each whole blood PK sample as close as possible to the planned time relative to dosing.  
Record the actual date and time that each sample was collected. 
If a cannula is used, the cannula will be inserted into an arm vein within sufficient time prior to 
dosing, will be kept patent with normal saline and will be removed after the last blood sample is 
collected or earlier if the subject requests.  In order to avoid artificial dilution of the PK sample 
by the saline, 0.5-1mL of whole blood will be collected and discarded before each PK sample is 
collected. 
PK Sample Processing and Storage 
Each PK samples will be gently mixed by inversion 8 to 10 times (do not shake).  Place the 
samples on ice immediately after collection.  Within 1 hour of sample collection, the samples will 
be centrifuged in a refrigerated (2°C to 8°C) centrifuge at 1500 RPM for 10 minutes.  The 
resulting plasma will be transferred into a properly-labeled polypropylene tube.  Immediately, 
place the plasma samples upright in a -20°C freezer and retain the samples in the freezer until 
they are shipped for analysis. 
PK Sample Shipment 
Samples should be shipped in batches, no less than every 3 months. 
Samples should be shipped only on Monday, Tuesday, or Wednesday.  Samples must be 
shipped on dry ice via overnight courier to: 
Maria EdwardsPPD 
2244 Dabney Road 
Richmond VA, 23230, USA 
Tel: (804) 254.8430, Fax: (804) 254.1104 
 
 
 
 
Email: Maria.Edwards@ppdi.com