Conditions: Wiskott-Aldrich Syndrome Thrombocytopenia Bleeding
Allocation: NON_RANDOMIZED | Intervention model: SINGLE_GROUP
Enrollment: 24
Healthy volunteers: yes

Brief summary:
The purpose of this project is to describe the pathophysiology of thrombocytopenia and bleeding in patients with Wiskott-Aldrich Syndrome (WAS) and determine the response to thrombopoietic agents in vitro and in vivo.

Detailed description:
Wiskott Aldrich Syndrome is an X-linked disease characterized by immunodeficiency, eczema and thrombocytopenia; a milder form of the disease known as X-Linked thrombocytopenia also exists. The thrombocytopenia in both WAS and XLT is characterized by: severe thrombocytopenia with platelet counts frequently less than 10-30,000/ul; small platelets which may be dysfunctional; and, as a result, a high rate of serious bleeding including intracranial hemorrhage.

Because eltrombopag has been shown to be remarkably efficacious in substantially increasing platelet counts in a high percentage of ITP patients, this study seeks to effectively treat patients who exhibit similar pathologies, as well as evaluate the state of platelets in patients with WAS and relate it to clinical bleeding. It also aims to demonstrate whether eltrombopag administered daily will enhance stem cell function, increase platelet production and platelet count, and reduce bleeding in patients with WAS.

Arms:
arm 1: Promacta® is commercially available in 12.5 mg, 25 mg, 50 mg, and 75 mg tablets. For this study, for young children unable to swallow a tablet, eltrombopag powder for oral suspension (Eltrombopag PfOS) will be used. PfOS is only available for investigational use at 20mg. Each sachet contains eltrombopag equivalent to 20mg per gm of powder and is reconstituted to a total of 10 ml so that the concentration is 2 mg/ml. arm 2: WAS patients not receiving treatment to serve as subjects for platelet parameter studies blood drawing once only arm 3: healthy children having blood obtained once as controls for platelet parameters study

Interventions: intervention 1: Promacta intervention 2: blood drawing in patients with WAS intervention 3: blood drawing in healthy controls
Intervention descriptions: intervention 1: WAS Patients receiving treatment will start on 1 mg/kg of eltrombopag daily and be seen weekly for 12 weeks. Dose adjustment will be based on the weekly monitoring of the platelet count as utilized in ongoing studies in ITP as well as on liver tests.

they will also have diagnostic blood testing prior to initiating treatment intervention 2: blood will be drawn for platelet parameters in WAS patients not receiving treatment either because they declined or because they were ineligible intervention 3: blood will be drawn once in healthy children as controls for platelet parameters

Protocol document:
Prot_SAP_000.pdf: 
1 
 
TITLE: Pathobiology of Thrombocytopenia and Bleeding in Patients with Wiskott-Aldrich 
Syndrome 
 
Principal Investigator: James B. Bussel, MD 
 
IRB Protocol Number: 0801009600 
ClinicalTrials.gov ID: NCT00909363 
 
Compound Number: SB-497115 
 
Development Phase: Phase II 
 
Effective Date: August 26th 2010 
 
Updated: September 18, 2015 
 
 
Protocol Versions: 
August 15, 2013 
 
 
 
October 28, 2014 
 
 
 
December 31, 2014 
 
 
 
July 7, 2015 
 
 
 
 
 
 
 
 
 
 
 


2 
 
 
 
TABLE OF CONTENTS  
 
List of Abbreviations 
4
1 INTRODUCTION 
5
1.1 Background 
5
1.2 Rationale    
5
2 OBJECTIVE(S)    
6
2.1 Primary Objective    
6
2.2 Secondary Objectives    
6
3 INVESTIGATIONAL PLAN    
6
3.1 Study Design    
6
3.2 Laboratory Testing    
7
4 SUBJECT SELECTION AND WITHDRAWAL CRITERIA    
 8
4.1 Number of Subjects    
 8
4.2 Inclusion Criteria    
 8
4.3 Exclusion Criteria    
 8
4.4 Withdrawal Criteria    
9
4.4.1 Study Stopping Rules    
 10
4.4.2 Patient Stopping Rules    
 10
5 STUDY TREATMENTS    
 10
5.1 Treatment Assignment    
 10
5.2 Product Accountability    
 11
5.3 Treatment Compliance    
 11
5.4 Concomitant Medications and Non-Drug Therapies    
 11
5.4.1 Permitted Medications and Non-Drug Therapies    
 11
5.4.2 Prohibited Medications and Non-Drug Therapies    
 11
5.5 Treatment after the End of the Study    
 11
5.6 Treatment of Investigational Product Overdose    
 11
5.7 Treatment Plan    
 12
6 STUDY ASSESSMENTS AND PROCEDURES    
 13
6.1 Critical Baseline Assessments    
 13
6.2 Efficacy    
 13
6.3 Safety    
 13
6.3.1 Liver chemistry stopping and follow-up criteria    
 15
6.4 Adverse Events    
 16
6.4.1 Definition of an AE    
 16
6.4.2 Definition of a SAE   
 17
6.4.3 Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as SAEs 
18
6.4.4 Pregnancy 
 18
6.4.5 Time Period and Frequency of Detecting AEs and SAEs 
 18
6.4.6 Prompt Reporting of Serious Adverse Events and Other Events to NOVARTIS   
 18
6.4.6.1 Regulatory reporting requirements for SAEs    
19
6.4.7 Other Safety Outcomes    
19
6.4.8  Data Safety Monitoring Board (DSMB)   
19


3 
 
7 DATA MANAGEMENT    
20
8 DATA ANALYSIS AND STATISTICAL CONSIDERATIONS    
20
8.1 Hypotheses    
20
8.2 Study Design Considerations   
 20
8.2.1 Sample Size Assumptions    
 20
8.2.2 Sample Size Sensitivity    
 20
8.3 Data Analysis Considerations    
 21
8.3.1 Key Elements of Analysis Plan    
 21
8.3.1.1 Efficacy Analyses    
 21
8.3.1.2 Safety Analyses    
 21
9 STUDY CONDUCT CONSIDERATIONS    
 22
9.1 Regulatory and Ethical Considerations, Including the Informed Consent Process   
22
9.2 Quality Control (Study Monitoring)    
22
9.3 Quality Assurance    
22
9.4 Records Retention    
22
10 APPENDICES    
22
10.1 Schedule of Events    
25
10.2 Weekly Dose Adjustment for Platelet Counts Eltrombopag Powder for Oral 
Suspension 
22
10.3 ELTROMBOPAG POWDER FOR ORAL SUSPENSION   
23
10.3.1 Packaging and Labelling Preparation 
23
10.3.3 Handling and Storage 
 23
10.3.4 Dose Adjustment Guidelines for Subjects Receiving the Suspension Formula 
 23
 References 
24


4 
 
LIST OF ABBREVIATIONS:  
 
AE Adverse event  
ALT Alanine aminotransferase (SGPT)  
AST Aspartate aminotransferase (SGOT)  
BUN Blood urea nitrogen  
CBC Complete blood count  
CIB Clinical Investigator’s Brochure  
COPD Chronic obstructive pulmonary disease  
CRF Case report form 
DSMB Data Safety Monitoring Board  
FDA Food and Drug Administration  
GSK Glaxo SmithKline 
HIV Human immunodeficiency virus  
HSCT Human Stem Cell Transplantation  
IB Investigator brochure  
ICH Intracranial hemorrhage  
ICF Informed consent form  
IPF Immature Platelet Fraction  
IRB Institutional Review Board  
ITP Idiopathic thrombocytopenia purpura  
IVIg intravenous immunoglobulin  
Mg Milligram  
mL Milliliter  
NSAID Non-steroidal anti-inflammatory medications  
PI Principal Investigator  
PT Prothrombin Time  
PTT Partial thromboplastin time  
RBC Red blood cell  
REPEAT Repeated ExPosure to Eltrombopag in Adults with  
Idiopathic Thrombocytopenic purpura  
RN Registered nurse  
OPSS Overwhelming post-splenectomy sepsis  
SAE Serious adverse event  
SCF Stem cell factor  
TBI Total Body Irradiation  
TPO Thrombopoietin  
TpoR Thrombopoietin receptor   
ULN Upper limit of normal  
WBC White blood cell  
WAS Wiskott Aldrich Syndrome  
XLT X-Linked Thrombocytopenia  
   


5 
 
1. INTRODUCTION  
 
1.1. Background  
 
Promacta® (Eltrombopag) received accelerated FDA approval on Nov 20, 2008 for the treatment of 
thrombocytopenia in patients with chronic immune (idiopathic) thrombocytopenic purpura (ITP) 
who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy.  
Formerly GlaxoSmithKline (GSK) and now Novartis is also developing eltrombopag for the 
treatment of aplastic anemia, MDS, and chemotherapy-induced thrombocytopenia.    
 
Wiskott Aldrich Syndrome (WAS) is an X-linked disease characterized by immunodeficiency, 
eczema and thrombocytopenia; a milder form of the disease known as X-Linked Thrombocytopenia 
(XLT) also exists. The two forms are on a spectrum but typically patients with XLT may be 
relatively asymptomatic except for signs of bruising and bleeding whereas patients with full blown 
WAS manifest more symptoms making clinical distinction relatively easy. The estimated incidence 
in the US is 1 per million people (Sullivan et al. 1994 and Ochs and Rosen 2007). The 
thrombocytopenia in both WAS and XLT is characterized by: severe thrombocytopenia with platelet 
counts frequently less than 10-30,000/ul; small platelets which may be dysfunctional; and, as a result, 
a high rate of serious bleeding including intracranial hemorrhage. Currently patients are treated using 
platelet transfusion, splenectomy, and/or human stem cell transplantation (HSCT) and 
experimentally with gene therapy. These are effective in different ways but there appears to be a 
clearly increased risk of sepsis after splenectomy and morbidity and mortality with HSCT.  In 
addition, even patients with full blown WAS who will undergo transplantation may benefit from 
waiting until they are 12-24 months of age instead of being transplanted at 2-6 months of age 
because of relentless thrombocytopenia. There is an estimated 10% risk of malignancy, e.g. 
development of lymphoma, but this is not usually an early phenomenon. Perhaps 1-3 of the 15 
patients in the study might be at risk for lymphoma over a lifetime but it is not likely to happen 
during the relatively short time course of the study. If it were to happen in one patient, it would be 
attributed to the natural history of the disease.  There would be no specific way to determine the 
etiology of any lymphoma that developed.   
  
Because eltrombopag has been shown to be efficacious in substantially increasing platelet counts in a 
high percentage of adult and now pediatric chronic ITP patients, this study seeks to effectively treat 
patients who exhibit similar pathologies, as well as to evaluate the state of platelets in patients with 
WAS and relate it to clinical bleeding. Eltrombopag has recently been licensed for children over the 
age of 1 year for treatment of chronic ITP which is pertinent because the great majority of patients 
anticipated to be enrolled on this study are children. The study also aims to demonstrate whether 
eltrombopag administered daily will increase platelet production and platelet count and reduce 
bleeding in patients with WAS.   
  
1.2. Rationale  
 
Eltrombopag has been remarkably efficacious in substantially increasing platelet counts in a high 
percentage of patients with chronic ITP (low platelets). The principal investigator Dr. James Bussel 
has been involved in various trials using eltrombopag; a recently published article detailing the 
success of eltrombopag illustrates the utility of this treatment (Gerrits et al, 2015). To greatly reduce 
or eliminate the risk of intracranial hemorrhage (ICH) in patients with WAS would be highly 
meaningful, as one of the five patients that we currently follow at our institution with XLT has 
already had an ICH; this is in keeping with published data. Even a relatively small increase in 
platelet count could be sufficient to prevent ICH in these patients. The ultimate purpose of providing 


6 
 
thrombopoietic treatment is to prevent serious, primarily intracranial, hemorrhage. Based on its 
utility in other diseases such as chronic ITP, thrombopoietic therapy appears to be the most 
promising approach for relieving the thrombocytopenia in WAS patients.   
  
There is a very high rate of very serious bleeding associated with WAS and XLT patients (Ochs and 
Thrasher, 2006) that far exceeds that seen in almost any other form of childhood thrombocytopenia, 
including ITP (approximately 0.5%) (Kühne et al, 2003). We are targeting a pediatric population in 
the hopes of controlling and managing the excessive bleeding that occurs in a high percentage of 
patients with Wiskott Aldrich Syndrome including X-Linked Thrombocytopenia.   
 
Preliminary analysis of 5 patients enrolled in this study along with 3 additional WAS/XLT patients 
(Gerrits et al, 2015) show that 5 of 8 WAS/XLT patients (3 XLT and 2 WAS) who were on 
eltrombopag treatment of at least 1 month (1 adult and 4 children) were platelet responders, as 
evidenced by achieving at least one platelet count ≥50 X 109/L and double the baseline count. Six of 
8 patients had reduced bleeding symptoms. Four eltrombopag-treated patients had platelet counts 
≥20 X 109/L above baseline counts and 4 patients reached counts ≥100 X 109/L. 
 
  
2. OBJECTIVE(S)  
 
2.1. Primary Objective  
 
 
To describe the pathophysiology of thrombocytopenia and bleeding in patients with Wiskott-
Aldrich Syndrome (WAS) especially those with XLT (since they will be more stable and 
available for study) and determine their response to thrombopoietic agents in vitro and in 
vivo.  
 
  
2.2. Secondary Objective  
 
 
This study aims to explore the functional state of circulating platelets in patients with WAS 
and to relate it to clinical bleeding. Furthermore to demonstrate whether a thrombopoietic 
agent, eltrombopag, administered daily will  increase platelet production and platelet count, 
and reduce bleeding in patients with WAS.   
 
  
3. INVESTIGATIONAL PLAN  
 
3.1. Study Design  
 
Fifteen patients (approximately 80% children) with WAS/ XLT will be enrolled and undergo 
baseline screening including not only blood drawing but also history of illness in the past, while ten 
additional WAS and XLT otherwise ineligible or unwilling patients who will not undergo study 
treatment and ten control subjects will undergo a one-time blood draw.  The pediatric control and 
non-treatment WAS/XLT subjects will be pediatric patients who are having their blood drawn for 
reasons not related to an acute illness and will provide a limited amount of additional blood. The 
pediatric control and non-treatment WAS/XLT subjects will have their blood drawn at Cornell after 
giving consent.  They will not be asked for more than 5-10 ml of blood per year of age up to a 
maximum of 30 ml total in one draw. Blood drawn will be studied for stem cells and 


7 
 
megakaryocytopoiesis, Immature Platelet Fraction (IPF), and platelet function (see table). These 
subjects will have their blood drawn for another purpose e.g. pre-op clearance for surgery and 
therefore it will be a small amount of extra blood posing a minimal risk to the subject. Subsequently, 
treatment patients will start on 2 mg/kg of eltrombopag and be seen every two weeks in the first 
month, and monthly for the first year. Although Promacta is commercially available in 25 mg and 50 
mg tablets, it is also available for clinical studies in 12.5 mg tablets which will be provided by 
Novartis for this study. In this study, the starting dose will be based upon weight; patients over 50 kg 
will start at 50 mg daily unless they are of East Asian origin in which case they will use 25 mg as 
their initial dose. The dose of eltrombopag will be titrated for each subject based on their platelet 
response (see table 1). Overall, in this study, doses between 12.5mg every other day and 75mg once 
daily are anticipated to be required to maintain platelet counts between 50 and 400Gi/L. However, as 
explained in the provided dosing guidelines, the dose of eltrombopag will be reduced whenever the 
platelet count exceeds 200Gi/L in order to prevent it from reaching 400Gi/L. The goal is to have a 
platelet count in a safe hemostatic range, albeit not necessarily a normal platelet count.   
 
Eltrombopag starting doses for children < 50kg will be scaled by body weight and the starting dose 
will be approximately  2 mg/kg once daily unless they are of East Asian origin in which case they 
will use approximately 1 mg/kg as their initial dose. This starting dose is based on the findings of 
GlaxoSmithKline’s PETIT2 study: Eltrombopag for children with chronic immune 
thrombocytopenia (PETIT2): a randomised, multicentre, placebo-controlled trial. 
 
This dosing schedule is based on those used in GlaxoSmithKline’s ’PETIT‘ study: Eltrombopag in 
Pediatric patients with Thrombocytopenia from ITP.   
 
For young children unable to swallow a tablet, eltrombopag powder for oral suspension 
(Eltrombopag PfOS) will be used.  Each sachet contains eltrombopag equivalent to 20mg per gm of 
powder.  Please see Appendix 3 for details and dose adjustment guidelines for subjects receiving the 
suspension formulation. Repeat assessment with the same testing will be performed at week 4. Dose 
adjustment will be based on the monthly monitoring of the platelet count.   
 
The IPF will be measured at each visit with the CBC. Platelet count data will be collected throughout 
the study and used as part of the assessment of efficacy. Platelet count data will be collected as part 
of the CBC monthly during the first year of administration of study drug and at any dose change 
(eltrombopag or concomitant medication). If a subject continues on a stable dose during any stage of 
the study for greater than 4 weeks, a CBC (including platelet count) with differential will be 
performed no less frequently than every 4 weeks. Further information regarding reduction in use of 
concomitant medications for thrombocytopenia, use of rescue therapy, incidence and severity of 
bleeding and other symptoms associated with thrombocytopenia and infections will also be collected 
and summarized.  
  
Platelet function will be assessed by whole blood flow cytometry as described by and in 
collaboration with Dr. Michelson (see appendix for attached abstracts).  
 
Treatment will be initiated at Cornell.Patients will be seen either at Cornell or by a their local doctor 
1-3 months thereafter. A recently developed bleeding score, designed to incorporate the four leading 
bleeding scores, will be administered on study visits to semi-quantitatively assess bleeding.14 The  
Page bleeding score is completed using the information from this questionnaire.  The hypothesis is 
that patients with Wiskott-Aldrich Syndrome will have more bleeding at given platelet counts than 
will patients with ITP.  Furthermore the degree of bleeding will correlate not only with the platelet 
count but with the degree of platelet dysfunction. Platelet size will be explored also. We anticipate 
the platelet function and bleeding scores will improve with the institution of Promacta therapy if the 


8 
 
platelet counts increase.  Even if some of these changes in bleeding are small, the overall direction 
will help to clarify the effect of treatment on these scores.  
 
There is no placebo; thus, patients will be compared to themselves descriptively before and after 
treatment through complete physical examinations, complete blood draws, urinalysis, and platelet 
studies.   
 
Dr. Bussel has an appointment at Memorial Sloan Kettering, so a patient initiated at Cornell can be 
followed with appropriate testing at the MSKCC site. In addition, a patient who comes to the Cornell 
site to provide consent and initiate treatment may be followed at another site for local Laboratory 
Testing.  
 
Urinalysis, Admission Panel (including liver tests), CBC with Platelet and Differential, PT/PTT, 
PFA, Fibrinogen, D-Dimers, Platelet Function Analysis, Immature Platelet Fraction (Platelet 
Reticulocyte Count), and Single Platelet Flow Cytometry will be assessed. 
 
4. SUBJECT SELECTION AND WITHDRAWAL CRITERIA  
 
4.1. Number of Subjects:   
 
25 WAS/XLT Patients (10 of whom will have a blood draw only) + 10 Normal Control Patients = 35 
Total Patients  
 
4.2. Inclusion Criteria:  
 
In order to be eligible for study entry, subjects must comply with the following:   
 
• Males or females from 3 months to 80 years old  
 
• Signed written informed consent obtained prior to study entry   
 
• Clinical diagnosis of WAS or XLT   
 
• Platelet levels less than 75 x 109/L   
 
• Adequate renal and hepatic function (creatinine and bilirubin less than or equal to 1.5 x ULN, AST 
and ALT less than or equal to 2.5 x ULN)   
  
 
4.3. Exclusion Criteria:  
 
Any patient is ineligible for study entry if he/she:  
  
 
Over the age of 80  
 
 
Pregnant or lactating women 
 
 
Fertile men who are not practicing or who are unwilling to practice birth control while 
enrolled in the study or until at least 6 months after treatment   
 


9 
 
 
Aspirin, aspirin-containing compounds, salicylates, non-steroidal anti-inflammatory 
medications (NSAIDS), clopidogrel or ticlopidine, warfarin or other vitamin K antagonists, 
unfractionated or low molecular heparin within 7 days of first treatment   
 
 
Red blood cell transfusion in the past four weeks  
 
 
Elevated (> 1.5 x ULN) prothrombin time (PT) or partial thromboplastin time (PTT)   
 
 
New York Heart Classification III or IV heart disease. Other severe cardiovascular or 
cardiopulmonary disease, including COPD.  
 
 
Known HIV infection, hepatitis B or C infection  
 
 
Any infection requiring antibiotic treatment within 3 days  
 
 
Other concurrent medical or psychiatric conditions that, in the Investigator’s opinion, may be 
likely to confound study interpretation or prevent completion of study procedures and follow-
up examinations.  
 
 
Prior malignancy with less than a 5-year disease-free interval, excluding nonmelanoma skin 
cancers and carcinoma in situ of the cervix   
 
  
Eligibility criteria for controls:  
 
a) Within 5 years of the age of the enrolled patient  
 
b) No overt hematologic diagnosis  
 
c) Male  
 
  
4.4. Withdrawal Criteria:  
 
1. Treatment with eltrombopag should be discontinued because of abnormal liver tests if any of the 
following 4 conditions apply:   
 
 
ALT levels > 3 times upper limit of normal (ULN) and bilirubin levels > 1.5 times (> 35 % 
conjugated bilirubin) ULN,  
 
 
(2) ALT levels > 3 times ULN and appearance or worsening of hepatitis symptoms or rash,   
 
 
(3) ALT levels remain > 3 times ULN for > 4 weeks, or   
 
(4) ALT levels are > 5 times ULN.  
 
If a subject has an adverse experience that would, in the investigator’s judgment, make 
continued participation in the study an unacceptable risk  
 
Note: If the subject’s ALT and bilirubin levels decrease so that both are < 1.5 times ULN, the 


10 
 
investigator may decide to restart the medication and monitor on a weekly basis.   
 
Study medications will be discontinued in the event of any thrombosis   
 
If subject’s platelet count goes above 200,000, the dose of study medication will be reduced.   
 
As indicated on page 5, perhaps 2-3 of the 15 patients in the study might be at risk over a lifetime for 
a malignancy such as lymphoma, but it is not very likely to happen during the relatively short time 
course of the study. If 1 patient develops another type of malignancy or 2 patients develop a Non-
Hodgkin Lymphoma during the course of the study, the study will be stopped. Prior to the study 
being restarted (if this is the desire of the investigators), there will be a formal request to re-open the 
study submitted to the FDA with a letter of support from Novartis.  
 
4.4.1. Study Stopping Rules  
 
1. Two malignancies of any type or 1 malignancy that is not leukemia or lymphoma  
 
2. No platelet increase to > 30,000 in 8 consecutive patients  
 
3. Transaminitis to > 5x ULN in more than 50% of the patients  
 
4. If 33% of patients (with a minimum of 6 patients in the study) achieve the individual          
withdrawal criteria for liver events, the study will be stopped and reviewed with Novartis and the 
FDA.  
  
4.4.2. Patient Stopping Rules  
 
1. Malignancy  
 
2. Transaminase and bilirubin rules  
 
3. Worsening cataracts  
 
4. No increase in the platelet count despite dose increases to > 1.5 mg/kg body weight  
 
5. STUDY TREATMENTS  
 
5.1. Treatment Assignment  
 
 
1)  Review of 
subject’s 
medical history 
2) A routine 
physical 
examination, 
including 
collection of 
subject’s height, 
weight, 
temperature, 
blood pressure, 
and pulse rate, 
and a review of 
all medicines 
3) The study doctor will assess 
subject’s bruising and bleeding by 
physical examination and by asking 
questions. He/she will do this by 
using the  Page ITP Bleeding Score.  
 
4) At Screening, about 10-20 mL of 
blood will be drawn to conduct 
laboratory tests. 
5) The starting dose will be 
based upon weight; patients over 
50 kg will start at 50mg daily 
unless they are of East Asian 
origin in which case they will use 
25 mg as their initial dose. The 
dose of eltrombopag will be 
titrated for each subject based 
on their platelet response. 
Eltrombopag starting doses for 
children <50 kg will be scaled by 
body weight and the starting 


11 
 
that a subject is 
taking. 
dose will be approximately 
2mg/kg once daily. 
 
Note: See schedule of events on page 25 
 
 
5.2. Product Accountability  
 
The pharmacy will track use of the medication. Patients will return their bottles of medication every 
4 weeks.   
 
5.3. Treatment Compliance  
 
This will be assessed by discussion with the patient and with pill counts in the returned bottles. 
Furthermore we would carefully review the diet and, in particular, try to ensure that the pills are 
taken correctly ie on a very empty stomach. 
 
5.4. Concomitant Medications and Non-Drug Therapies  
 
Concomitant ITP medications will be tracked.  None can be used in the first 4 weeks of the study.  
Patients receiving them will be taken off study. The same is true for non-drug therapies of ITP.  
 
5.4.1. Permitted Medications and Non-Drug Therapies  
 
Stable doses of oral corticosteroids are allowed. No other “ITP” therapy is allowed in the study 
except for 3-4 weekly IVIG at doses of 300-500 mg/kg. Medication doses cannot be changed during 
the first 4 weeks of therapy.    
 
5.4.2. Prohibited Medications and Non-Drug Therapies  
 
All other ITP therapies, whether drug or non-drug, are prohibited during the first 4 weeks of therapy.  
Splenectomy is allowed at any time during the study however, if effective, it will end the study 
participation (treatment) for that subject.  
 
5.5. Treatment after the End of the Study  
 
All ITP therapies including thrombopoietic agents can be used after the end of study.  
 
5.6. Treatment of Investigational Product Overdose  
 
Platelet counts will be followed carefully and treatment held for approximately one week if there is a 
significant drug overdose. Calcium-containing products could be used in the very unlikely event of a 
substantial overdose to inactivate the PROMACTA. Aspirin can also be given as needed.  
 
 
 
 
 
 


12 
 
 
 
5.7. Treatment Plan 
 
 
Adults and children > 30 
kg 
Children < 30 kg 
Frequency 
Urinalysis 
10 mL 
5 mL 
One Time (at screen) 
Admission Panel 
(includes ALT, AST, 
bilirubin) 
2 mL 
2 mL 
Every two weeks for the 
first month; monthly for 
year 1; every 2 months for 
year 3; every three 
months for years 3 - 6 
CBC with Platelet and 
Differential and 
Immature Platelet 
Fraction (IPF) 
2 mL 
2 mL 
Every two weeks for the 
first month; monthly for 
year 1; every 2 months for 
year 3; every three 
months for years 3 - 6 
PT/PTT, D-Dimers, 
Fibrinogen 
5 mL 
2.5 mL 
One time (at screen) 
PFA 
5 mL 
2.5 mL 
One time (at month 2) 
Single Platelet Flow 
Cytometry 
10 mL 
2 mL 
3 times (at screen, at 
month 1-3 and at year 1-
2) 
 
NOTE: see schedule of events on page 25 
 
Control subject blood 
draw 
30 mL 
10-20 mL 
One time 
WAS Non-treatment 
subject blood draw 
30mL 
10-20mL 
One time 
 


13 
 
6. STUDY ASSESSMENTS AND PROCEDURES  
 
6.1. Critical Baseline Assessments  
 
Complete Blood Counts (CBCs)   
 
CBCs, including platelet counts and peripheral blood smears, will be monitored prior to initiation, 
throughout, and following discontinuation of therapy with PROMACTA. Prior to the initiation of 
PROMACTA, the peripheral blood differential will be examined to establish the extent of red and 
white blood cell abnormalities. CBCs, including platelet counts and peripheral blood smears, will be 
obtained weekly during the dose adjustment phase of therapy with PROMACTA and then monthly 
following establishment of a stable dose of PROMACTA. CBCs, including platelet counts will be 
obtained weekly to biweekly for at least 4 weeks following discontinuation of PROMACTA.  
 
Liver tests  
 
Serum liver tests (ALT, AST, and bilirubin) will be monitored prior to initiation of PROMACTA, 
every 2 weeks during the dose adjustment phase and monthly following establishment of a stable 
dose. If bilirubin is elevated, fractionation will be performed. If abnormal levels are detected, the 
tests will be repeated within 3 to 5 days. If the abnormalities are confirmed, serum liver tests will be 
monitored weekly until the abnormality(ies) resolve, stabilize, or return to baseline levels. 
PROMACTA will be discontinued based on the stopping rules outlined in section 6.3.1   
 
 
6.2. Efficacy  
 
Collection of platelet counts on week 1 (pre-dose), week 2, monthly during year 1, every two months 
during year 2, and every 3 months during years 3-6, along with platelet function studies.  Bleeding 
symptoms will be monitored by bleeding score assessments.    
 
6.3. Safety  
 
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, urine tests) 
 
SAE and AE events 
 
Bone marrow aspirations/biopsies (if relevant) 
Adverse Events (AEs) will be graded according to Common Terminology Criteria for Adverse 
Events v4.03(CTCAE)The PI will determine the relationship of AEs to the test 
procedure/device/agent as not related, possibly related, probably related or definitely related, using 
standard criteria for clinical trials. Interim assessment of AEs will be conducted semi-annually by the 
data safety monitoring board.  
 
Note: All serious adverse events will be followed until resolution of the events or definitive 
conclusion.  


14 
 
 
Hepatotoxicity  
 
Administration of eltrombopag may cause hepatotoxicity. In the controlled clinical ITP studies, 
serum liver test abnormalities (predominantly Grade 2 or less in severity) were reported in 10% and 
8% of the PROMACTA and placebo groups, respectively. Two patients (1%) treated with 
PROMACTA and two patients in the placebo group (3%) discontinued treatment due to 
hepatobiliary laboratory abnormalities. Seven of the patients treated with PROMACTA in the 
controlled studies with hepatobiliary laboratory abnormalities were re-exposed to PROMACTA in 
the extension study. Six of these patients again experienced liver test abnormalities (predominantly 
Grade 1) resulting in discontinuation of PROMACTA in one patient. In the extension study, one 
additional patient had PROMACTA discontinued due to liver test abnormalities (< Grade 3).  
 
Serum ALT, AST, and bilirubin will be measured prior to initiation of PROMACTA, every 2 weeks 
during the dose adjustment phase and monthly following establishment of a stable dose. If bilirubin 
is elevated, perform fractionation. Evaluate abnormal serum liver tests with repeat testing within 3 to 
5 days. If the abnormalities are confirmed, monitor serum liver tests weekly until the 
abnormality(ies) resolve, stabilize, or return to baseline levels. Discontinue PROMACTA if ALT 
levels increase to  
> 3X the upper limit of normal (ULN) and are:  
 
 
Progressive, or  
 
Persistent for > 4 weeks, or  
 
Accompanied by increased direct bilirubin, or  
 
Accompanied by clinical symptoms of liver injury or evidence for hepatic decompensation.  
 
  
Bone Marrow Reticulin Formation and Risk for Bone Marrow Fibrosis  
 
Eltrombopag is a thrombopoietin (TPO) receptor agonist and TPO-receptor agonists may increase 
the risk for the development or progression of reticulin fiber deposition within the bone marrow.  
 
In the ITP extension study, seven patients had reticulin fiber deposition reported in bone marrow 
biopsies, including two patients who also had collagen fiber deposition. The fiber deposition was not 
clearly associated with cytopenias and did not necessitate discontinuation of eltrombopag. However, 
clinical studies have not yet excluded a risk of bone marrow fibrosis with cytopenias and 
discontinuation of eltrombopag.  
 
Prior to initiation of eltrombopag, examine the peripheral blood smear closely to establish a baseline 
level of cellular morphologic abnormalities. Following identification of a stable dose of eltrombopag, 
examine peripheral blood smears and CBCs monthly for new or worsening morphological 
abnormalities (e.g., teardrop and nucleated red blood cells, immature white blood cells) or 
cytopenia(s). If the patient develops new or worsening morphological abnormalities or cytopenia(s), 
discontinue treatment with eltrombopag and consider a bone marrow biopsy, including staining for 
fibrosis.   
 
Worsened Thrombocytopenia After Cessation of Eltrombopag  
 
Discontinuation of eltrombopag may result in thrombocytopenia of greater severity than was present 
prior to therapy with eltrombopag although this is only seen in a minority of patients who stop the 
drug. This worsened thrombocytopenia may increase the patient's risk of bleeding, particularly if 


15 
 
eltrombopag is discontinued while the patient is on anticoagulants or antiplatelet agents. In the 
controlled ITP clinical studies, transient decreases in platelet counts to levels lower than baseline 
were observed following discontinuation of treatment in 10% and 6% of the eltrombopag and 
placebo groups, respectively. Serious hemorrhagic events requiring the use of supportive ITP 
medications occurred in 3 severely thrombocytopenic patients within one month following the 
discontinuation of eltrombopag; none were reported among the placebo group.   
 
Following discontinuation of eltrombopag, obtain weekly CBCs, including platelet counts for at least 
4 weeks and consider alternative treatments for worsening thrombocytopenia, according to current 
treatment guidelines  
 
History of Thromboembolic Events  
Thrombotic events can occur at any platelet count. Thrombotic/thromboembolic complications may 
result from excessive increases in platelet counts. Excessive doses of eltrombopag or medication 
errors that result in excessive doses of eltrombopag may increase platelet counts to a level that 
produces thrombotic/thromboembolic complications. In the controlled ITP clinical studies, one 
thrombotic/thromboembolic complication was reported within the groups that received eltrombopag 
and none within the placebo groups. Seven patients experienced thrombotic/thromboembolic 
complications in the ITP extension study.   
 
Caution should be used when administering eltrombopag to patients with known risk factors for 
thromboembolism (e.g., Factor V Leiden, ATIII deficiency, antiphospholipid syndrome, etc.).   
 
Malignancies and Progression of Malignancies  
 
Stimulation of the TPO receptor on the surface of hematopoietic cells by eltrombopag may increase 
the risk for hematologic malignancies. In the controlled ITP clinical studies, patients were treated 
with eltrombopag for a maximum of 6 weeks and during this period no hematologic malignancies 
were reported. One hematologic malignancy (non-Hodgkin's lymphoma) was reported in the ITP 
extension study.   
 
Cataracts   
 
Cataracts were observed in toxicology studies of eltrombopag in rodents (see Non-clinical 
Information). The clinical relevance of this finding continues to be evaluated in all ongoing 
NOVARTIS sponsored clinical studies. To date, there is however, no evidence that eltrombopag 
increases the incidence nor progression of cataracts in patients who have received eltrombopag.  In 
the controlled ITP clinical studies, cataracts developed or worsened in five (5%) patients who 
received 50 mg eltrombopag daily and two (3%) placebo-group patients. In the ITP extension study, 
cataracts developed or worsened in 4% of patients who underwent ocular examination prior to 
therapy with eltrombopag. A significant proportion of patients in the ITP clinical studies were also 
exposed to chronic corticosteroid administration.   
  
 
6.3.1. Liver chemistry stopping and follow-up criteria  
 
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 


16 
 
underlying cardiopulmonary disease, and death. No patients in the placebo group experienced Grade 
4 liver test abnormalities. Overall, serum liver test abnormalities (predominantly Grade 2 or less in 
severity) were reported in 10% and 8% of the eltrombopag and placebo groups, respectively. In the 
controlled studies, two patients (1%) treated with eltrombopag and two patients in the placebo group 
(3%) 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 PROMACTA in one 
patient. In the ITP extension study, one additional patient had eltrombopag discontinued due to liver 
test abnormalities (all < Grade 3).  
 
Serum ALT, AST, and bilirubin should be measured prior to initiation of eltrombopag, every 2 
weeks during the dose adjustment phase and monthly following establishment of a stable dose. If 
bilirubin is elevated, perform fractionation. Evaluate abnormal serum liver tests with repeat testing 
within 3 to 5 days. If the abnormalities are confirmed, monitor serum liver tests weekly until the 
abnormality(ies) resolve, stabilize, or return to baseline levels.   
 
Once more than six patients are enrolled in the study: The study will be stopped if 33% of the 
patients develop any of the following labelled hepatotoxicity monitoring criteria for drug cessation.   
 
Treatment with eltrombopag should be discontinued because of abnormal liver tests if any of the 
following 4 conditions apply:   
 
 
ALT levels > 3 times upper limit of normal (ULN) and bilirubin levels > 1.5 times (> 35 % 
conjugated bilirubin) ULN,   
 
(2) ALT levels  > 3 times ULN and appearance or worsening of hepatitis symptoms or rash,   
  
 
(3) ALT levels remain > 3 times ULN for > 4 weeks, or   
 
(4) ALT levels are > 5 times ULN.  
 
If a subject has an adverse experience that would, in the investigator’s judgment, make 
continued participation in the study an unacceptable risk  
 
Note: If the subject’s ALT and bilirubin levels decrease so that both are < 1.5 times ULN, the 
investigator may decide to restart the medication and monitor on a weekly basis.   
 
Exercise caution when administering PROMACTA to patients with hepatic disease. Use a lower 
starting dose (0.3-0.4 mg/kg) of PROMACTA in patients with moderate to severe hepatic disease 
and monitor closely.  
 
6.4. Adverse Events  
 
The investigator or site staff will be responsible for detecting, documenting and reporting events that 
meet the definition of an AE or SAE.  
 
6.4.1. Definition of an AE  
 
Any untoward medical occurrence in a patient or clinical investigation subject, temporally associated 
with the use of a medicinal product, whether or not considered related to the medicinal product.  
  


17 
 
Note: An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of 
a medicinal product. For marketed medicinal products, this also includes failure to produce expected 
benefits (i.e. lack of efficacy), abuse or misuse.  
  
Events meeting the definition of an AE include:  
  
•  Significant or unexpected worsening or exacerbation of the condition/indication under study.  
•  Exacerbation of a chronic or intermittent pre-existing condition including either an increase in 
frequency and/or intensity of the condition.  
•  New conditions detected or diagnosed after investigational product administration even though it 
may have been present prior to the start of the study.  
•  Signs, symptoms, or the clinical sequelae of a suspected interaction.  
•  Signs, symptoms, or the clinical sequelae of a suspected overdose of either investigational product 
or a concurrent medication (overdose per se should not be reported as an AE/SAE).  
•  “Lack of efficacy” or “failure of expected pharmacological action” per se will not be reported as 
an AE or SAE. However, the signs and symptoms and/or clinical sequelae resulting from lack of 
efficacy will be reported if they fulfill the definition of an AE or SAE.  
  
Events that do not meet the definition of an AE include:  
•  Medical or surgical procedure (e.g., endoscopy, appendectomy); the condition that leads to the 
procedure is an AE.  
•  Situations where an untoward medical occurrence did not occur (social and/or convenience 
admission to a hospital).  
•  Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or detected at 
the start of the study that do not worsen.  
•  The disease/disorder being studied, or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the subject’s condition.  
 
  
6.4.2. Definition of a SAE  
 
A serious adverse event (SAE) is any untoward medical occurrence that, at any dose:  
  
a. Results in death  
  
b. Is life-threatening  
  
NOTE: The term 'life-threatening' in the definition of 'serious' refers to an event in which the subject 
was at risk of death at the time of the event. It does not refer to an event, which hypothetically might 
have caused death, if it were more severe.  
  
c. Requires hospitalization or prolongation of existing hospitalization  
  
NOTE: In general, hospitalization signifies that the subject has been detained (usually involving at 
least an overnight stay) at the hospital or emergency ward for observation and/or treatment that 
would not have been appropriate in the physician’s office or out-patient setting. Complications that 
occur during hospitalization are AEs. If a complication prolongs hospitalization or fulfills any other 
serious criteria, the event is serious. When in doubt as to whether “hospitalization” occurred or was 
necessary, the AE should be considered serious. Hospitalization for elective treatment of a pre-
existing condition that did not worsen from baseline is not considered an AE.  


18 
 
  
d. Results in disability/incapacity, or  
  
NOTE: The term disability means a substantial disruption of a person’s ability to conduct normal life 
functions. This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and accidental 
trauma (e.g. sprained ankle) which may interfere or prevent everyday life functions but do not 
constitute a substantial disruption.  
  
e. Is a congenital anomaly/birth defect  
  
f. Medical or scientific judgment should be exercised in deciding whether reporting is appropriate in 
other situations, such as important medical events that may not be immediately life-threatening or 
result in death or hospitalization but may jeopardize the subject or may require medical or surgical 
intervention to prevent one of the other outcomes listed in the above definition. These should also be 
considered serious. Examples of such events are invasive or malignant cancers, intensive treatment in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions that do 
not result in hospitalization, or development of drug dependency or drug abuse.  
  
g. All Grade 4 laboratory abnormalities assessed using the National Cancer Institute (NCI) Common 
Terminology Criteria for Adverse Events (CTCAE) v3.0 Common Terminology Criteria for Adverse 
Events (v 3.0)] except Grade 4 thrombocytopenia.  
  
 
h. Ocular events of clinical concern.  
  
Note: All serious adverse events will be followed until resolution of the events or definitive 
conclusion.  
  
6.4.3. Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as SAEs  
 
During the assessment period, thrombocytopenia that results in administration of rescue treatment 
does not qualify as an AE or SAE. Also during this assessment period, hospital admissions that are 
attributable to such treatment failures or related therapy also do not qualify as AEs or SAEs. 
Hemorrhagic complications of thrombocytopenia not otherwise meeting regulatory serious criteria 
will be reported as AEs.  
  
6.4.4. Pregnancy   
 
Pregnancy will not be allowed on study.  Contraception must be used for all patients of child-bearing 
potential.  
 
6.4.5. Time Period and Frequency of Detecting AEs and SAEs  
 
Subjects will be given an adverse event sheet to complete at every study visit.  This will help us to 
track any adverse events that have occurred and any medications that the subject has taken between 
visits.  Subjects are instructed to notify the PI with any adverse events that he/she experiences.  
 
6.4.6. Prompt Reporting of Serious Adverse Events and Other Events to NOVARTIS  
 
Adverse events will be reported to the Investigational Review Board (IRB) as they occur and any 


19 
 
serious events will be reported to NOVARTIS within 24 hours of learning of the event if they occur. 
CTC criterion version 3.0 will be used as a guideline for reporting adverse events.   
 
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 or email within 24 hours to 
Novartis.   
 
US CPO DS&E  Fax #: 877-778-9739The 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. 
 
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 and to NOVARTIS within 24 hours of learning of the event.  
 
 
6.4.7. Other Safety Outcomes   
 
Liver function tests, marrow reticulin, thromboembolism and other AE’s will be tracked and 
reported.   
 
6.4.8 Data Safety Monitoring Board 
 
Weill Cornell Medical College requires that all research approved by the WCMC IRB include an 
appropriate plan for the monitoring of data to ensure the safety of human subjects. Research 
supported by Federal agencies will be monitored according to all regulations and guidelines of the 
relevant Federal agency.  
The WCMC Data and Safety Monitoring Board (DSMB) will review the IRB approved protocol, 
informed consent documents, and data and safety monitoring plan. During the course of the study, 
the DSMB will review the cumulative study data semi-annually to evaluate safety, efficacy, study 
conduct, and scientific validity and integrity of the trial. The WCMC DSMB may also convene as 
needed if stopping criteria are met or other safety issues arise that the Principal Investigator and/or 
IRB would like the WCMC DSMB to address. The study PI will submit all written DSMB 
recommendations to the IRB upon receipt. 


20 
 
 
7. DATA MANAGEMENT  
 
Case Report Form (CRFs) (see attached) will be filled out by the study coordinator using the raw 
data generated by study visits.   
 
8. DATA ANALYSIS AND STATISTICAL CONSIDERATIONS  
 
8.1. Hypotheses  
 
The primary objective is to describe the pathophysiology of thrombocytopenia and bleeding in 
patients with Wiskott-Aldrich Syndrome (WAS) and determine the response to thrombopoietic 
agents in vitro and in vivo.  
 
SPECIFIC AIMS:  
 
1. To explore stem cell function in patients with WAS  
 
2. To evaluate the functional state of circulating platelets in patients with WAS and relate it 
to clinical bleeding  
 
3. To demonstrate whether a thrombopoietic agent, eltrombopag, administered daily will 
enhance stem cell function, increase platelet production and platelet count, and reduce 
bleeding in patients with WAS  
 
8.2. Study Design Considerations  
 
Limited therapies exist to treat thrombocytopenia in WAS/XLT. IV gammaglobulin and 
corticosteroids, mainstays in ITP, are ineffective in WAS/XLT. Platelet transfusions only last for 
hours. The two treatments that affect the platelets in a more lasting manner are splenectomy and 
human stem cell transplantation (HSCT). Splenectomy successfully increases the platelet count in 
most patients but is associated with an increased risk of overwhelming post splenectomy sepsis 
(OPSS) due to the primary immune dysfunction seen in WAS/XLT. Human Stem Cell 
Transplantation (HSCT) is effective but has significant morbidity and mortality. Furthermore it is 
ideally postponed until after 24 months of age to allow TBI, which is too long to wait for affected 
infants with severe thrombocytopenia in view of the high risk of ICH. It is clearly necessary to 
establish improved therapy for thrombocytopenia in these children. 
 
8.2.1. Sample Size Assumptions  
  
Zero responders among 15 subjects would suggest that the true proportion responding (i.e. what 
would be observed if an inordinate number of subjects were studied) is unlikely to exceed 20%. 
 
 
8.2.2. Sample Size Sensitivity  
 
Zero responders among 15 subjects would suggest that the true proportion responding (i.e., what 
would be observed if an inordinate number of subjects were studied) is unlikely to exceed 20%.    
 


21 
 
8.3. Data Analysis Considerations  
 
Data from all subjects who receive eltrombopag will be summarized.  Results will be summarized by 
visit. All displays should include the number of subjects with available data at that visit.  
  
Study endpoints include bleeding score, platelet count, platelet function, megakaryopoiesis and 
platelet formation.   
  
  
8.3.1. Key Elements of Analysis Plan    
  
Complex statistical analyses would not be appropriate for an exploratory study.  Study endpoints will 
be summarized by visit using descriptive statistics (mean, median, standard deviation, range) or 
frequency counts, (as appropriate).    
  
8.3.1.1. Efficacy Analyses  
 
Primary endpoint will be increasing platelet counts in WAS/XLT patients to above 50,000/ul. The 
generalizability of the data will depend upon including both WAS and XLT patients but no specific 
distribution of patients within these 2 groups is pre-specified. The proportion of patients showing this 
increase will be summarized with 95% confidence intervals. The proportion of patients maintaining 
this increase will be summarized for time points of interest.    
  
Correlations will be evaluated graphically.  In addition, Spearman rank correlation coefficients may 
be used to evaluate the association of platelet count and bleeding score, at each visit.  
 
Any within-subject analyses may be based on Wilcoxon signed rank tests.    
  
Secondary endpoints will involve reduction of bleeding in treated patients within 12 weeks, and to 
specifically examine the reduction in bleeding in those with platelet counts > 100,000/ul and also > 
50,000/ul.  
 
We anticipate that platelet function will improve as the platelet count increases but not normalize.  
  
Therefore efficacy will depend on platelet counts, immature platelet fraction, platelet function by 
flow cytometry, and the bleeding score. Since the dose required may vary from patient to patient and 
may only be changed every 2 weeks, a platelet count > 50,000/ul at any time within the first 12 
weeks will be considered a response.  Similarly, secondary endpoints involving reduction in bleeding 
and improvement in platelet function will also be explored within a 4 to 12 week window for 
assessment.  
  
Toxicity will depend upon adverse events, abnormal liver tests, and other abnormal findings.  
  
8.3.1.2. Safety Analyses  
 
Descriptive statistics will be used to summarize the extent of exposure to eltrombopag.  
 
The number (%) of subjects with Adverse Events and Serious Adverse Events will be reported.  
 
Laboratory parameters will be summarized by visit using descriptive statistics.  
 


22 
 
9. STUDY CONDUCT CONSIDERATIONS  
 
9.1. Regulatory and Ethical Considerations, Including the Informed Consent 
Process  
 
Subjects will be given the consent to review prior to requesting their signature so that sufficient time 
is provided for the subject to consider the study. Risks and benefits will be explained in their entirety 
to patients.  If necessary, an interpreter will be obtained to assist the patient. Any questions that the 
patient has will be answered prior to signing consent.  
 
The study will be conducted in accordance with International Conference on Harmonization 
Guidelines for Good Clinical Practice, and the Declaration of Helsinki.  
 
9.2. Quality Control (Study Monitoring)  
 
None needed for investigator-initiated pilot study.  
 
9.3. Quality Assurance  
 
Pharmacy and clinical records.  
 
9.4. Records Retention  
 
7 years.  
 
10. APPENDICES  
 
1. SCHEDULE OF EVENTS ON THE LAST PAGE OF THE PROTOCOL 
(PAGE 25).  
  
2. WEEKLY DOSE ADJUSTMENT FOR PLATELET COUNTS:   
 
 
PLATELET COUNT 
DOSE ADJUSTMENT 
>200 Gi/L 
 dose reduced by at least 5% 
50 to 200 Gi/L 
Maintain current dose 
<50 Gi/L and/or Significant 
Bleeding 
Increase daily dose by at least 5% up to 75mg daily 
 
3.  ELTROMBOPAG POWDER FOR ORAL SUSPENSION   
 
Eltrombopag powder for oral suspension (Eltrombopag PfOS) is a reddish-brown to yellow powder 
contained inside an elongated sachet.  Each sachet will contain eltrombopag olamine equivalent to 20 
mg of eltrombopag per gram of powder.    
 
 
3.1. Packaging and Labelling  


23 
 
 
Eltrombopag PfOS sachets will be packaged in a carton.  Each carton pack will hold 35 sachets along 
with a plastic reconstitution container and a syringe-adapt cap. The pack will also contain an extra 
syringe-adapt cap as a spare.  The contents of the label will be in accordance with all applicable 
regulatory requirements.  
 
3.2. Preparation  
 
The powder for oral suspension (PfOS) is presented as a reddish brown to yellow powder, which 
when reconstituted with water forms a reddish-brown suspension. The sachet should not be opened 
until ready for use.  Add 9.5 mL of water drawn using a 10cc syringe into the provided plastic 
container.  Cut open the sachet and add the entire content of the sachet into the container containing 
water.  The container is capped and shaken for 10-20 seconds.  The resulting suspension contains 2 
mg/mL of eltrombopag dose.  The prescribed volume (dose) is drawn through the syringe port on the 
cap with a syringe.  Upon dosing, the rest of the remaining suspension in the container is discarded.  
The container and the syringe are rinsed with water and dried.  
 
A fresh dose is prepared everyday just prior to the dosing and no storage of the reconstituted 
suspension is allowed.  
  
3.3. Handling and Storage  
 
Investigational product must be dispensed or administered according to procedures described herein.  
Only subjects enrolled in the study may receive investigational product, in accordance with all 
applicable regulatory requirements.  Only authorized site staff may supply or administer 
investigational product.  All investigational products must be stored in a secure area with access 
limited to the investigator and authorized site staff and under physical conditions that are consistent 
with investigational product-specific requirements. Eltrombopag PfOS will be stored according to 
the requirements listed on the label.  
 
 
 


24 
 
3.4. Dose Adjustment Guidelines for subjects receiving the suspension formulation  
 
The dose of eltrombopag will be increased or decreased according to platelet counts as outlined 
above; these modifications will initially be in strength intervals of 30% (rounded up), but 
intermediate dosing levels may be used if the platelet response warrants it. The dose will be 
documented in the CRF.  
 
 
Table 1: Dose Adjustment Guidelines – Suspension formulation  
 
Weight (kg) 
Initial dose (mg) 
Initial dose (mL) 
Adjust dose by 
(mg) 
Adjust dose by 
(mL)1 
8 
16 
8 
5 
2.51 
9 
18 
9 
6 
31 
10 
20 
10 
6 
3 
11 
22 
11 
7 
3.5 
12 
24 
12 
8 
4 
13 
26 
13 
8 
4 
14 
28 
14 
9 
4.51 
15 
30 
15 
9 
4.51 
16 
32 
16 
10 
5 
17 
34 
17 
11 
5.5 
18 
36 
18 
11 
5.5 
19 
38 
19 
12 
6 
20 
40 
20 
12 
6 
21 
42 
21 
13 
6.5 
22 
44 
22 
14 
71 
23 
46 
23 
14 
71 
24 
48 
24 
15 
7.51 
25 
50 
25 
15 
7.51 
1. For calculated doses of 18mg – 24 mg, patient should receive 20 mg dose (one sachet). For doses of 38 mg 
to 44 mg, the patient should receive 40 mg dose (two sachets). For doses of 58 mg to 65 mg the patient 
should receive 60 mg dose (three sachets). 


25 
 
 
References  
 
Bussel J, Provan D, Shamsi T, Cheng G, Psaila B, Kovaleva L, et al. (2009). Effect of eltrombopag 
on platelet counts and bleeding during treatment of chronic idiopathic thrombocytopenic purpura: a 
randomised, double-blind, placebo-controlled trial. The Lancet, 373, 9664:641-648.  
 
Bussel, J, Cheng G, Saleh M, Psaila B, Kovaleva L, Meddeb B, et al.  (2007). Eltrombopag for the 
treatment of chronic idiopathic thrombocytopenic purpura. N Engl J Med, 357, 22:2237-2247.  
 
Gerrits A, Leven E, Frelinger III A, Brigstocke S, Berny-Lang M, Mitchell W, Revel-Vilk S, Tamary 
H, Carmichael S, Barnard M, Michelson A, Bussel J. (2015). Effects of eltrombopag on platelet 
count and platelet activation in Wiskott-Aldrich syndrome/X-linked thrombocytopenia. Blood, 126, 
11:1367-1378. 
 
Kühne T, Buchanan G, Zimmerman S, Michaels L, Kohan R, et al. A prospective comparative study 
of 2540 infants and children with newly diagnosed idiopathic thrombocytopenic purpura (ITP) from 
the intercontinental childhood ITP study group. The Journal of Pediatrics, 143, 5:605-608.  
 
Mutchinson J, Dusheiko G, Shiffman M, Rodriguez-Torres M, Sigal S, Bourliere M, et al. (2007). 
Eltrombopag for thrombocytopenia in patients with cirrhosis associated with hepatitis C. N Engl J 
Med, 357, 22:2227-36.  
 
Ochs H, Thrasher A. The Wiskott-Aldrich syndrome. (2006). Journal of Allergy and Clinical 
Immunology, 117, 4:725-738.  
 
Ochs HD, Rosen FS. The Wiskott-Aldrich syndrome. In: Ochs HD, Smith CIE, Puck JM, eds.  
Primary Immune Deficiency Disease: A Molecular and Genetic approach. New York, NY: Oxford 
University Press, 2007:454-469.  
 
Sullivan KE, Mullen CA, Blaese RM, Winkelstein JA. A multiinstitutional survey of the Wiskott-
Aldrich syndrome. J Pediatr. 1994, 125:876-885.   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


26 
 
 
 
 
 
 
SCHEDULE OF EVENTS 
“Pathobiology of Thrombocytopenia and Bleeding in Patients with Wiskott-Aldrich 
Syndrome.” Protocol #: 0801009600 
 
 
 
 
Screening 
Day 
1/Baseline 
Week 2 
Week 4 
Months4  
2 – 12 
Months5 
 14 - 24 
Months6  
27 - 72 
Evaluation and Management 
Informed Consent 
x 
 
 
 
 
 
 
Bleeding Score1 
x 
x 
x 
x 
x 
x 
x 
Standard of Care 
Physical 
Examination 
x 
x 
x 
x 
x 
x 
x 
Urinalysis 
x 
 
 
 
 
 
 
Admission Panel 
(Includes liver tests 
such as ALT, AST, 
bilirubin) 
x 
x 
x 
x 
x 
x 
x 
CBC with Platelet 
and Diff 
x 
x 
x 
x 
x 
x 
x 
Diagnostic Tests for Platelet Function 
PT/PTT 
x 
 
 
 
 
 
 
D-Dimers 
x 
 
 
 
 
 
 
Fibrinogen 
x 
 
 
 
 
 
 
PFA2 
 
 
 
 
x 
 
 
Immature Platelet 
Fraction (Platelet 
Reticulocyte 
Count)3 
x 
x 
x 
x 
x 
x 
x 
Single Platelet Flow 
Cytometry7 
x 
 
 
x 
x8 
 
 
 
1. The Page bleeding score will be administered at each visit in order to semi-quantitatively assess 
bleeding 
2. PFA (Platelet function Analysis) will be assessed once for WAS/XLT patients and control patients at 
month 2, provided platelet count is >50 k 
3. IPF will be obtained with each Cornell in-clinic CBC where possible 
4. Subjects will have their blood drawn monthly and be seen every 3 months during the first year 
5. Subjects will have their blood drawn every 2 months and be seen every 4 months in the second year 
6. Subjects will have their blood drawn every 3 months and be seen every 6 months in the 3rd – 6th years 
7. Single Platelet Flow Cytometry tests will be performed by Dr. Alan Michelson at screening, once 
between months 1-3, and once after 1-2 years on study.