Early Initiation of Oral Therapy With Cyclosporine and Eltrombopag for Treatment Naive Severe Aplastic Anemia (SAA)
Phase: PHASE2
Conditions: Severe Aplastic Anemia
Sponsor: National Heart, Lung, and Blood Institute (NHLBI)

 
 Protocol with Statistical Analysis Plan Cover Page:   
 
Official Title: 
Early Initiation of Oral Therapy with Cyclosporine and Eltrombopag for 
Treatment Naïve Severe Aplastic Anemia (SAA) 
NCT number: 
 
NCT04304820 
Document Type:  
Protocol with Statistical Analysis Plan (SAP)  
Document Date: 
November 5, 2025 
 
 

Abbreviated Title: Early Initiation of Oral Therapy for Naïve Severe Aplastic Anemia (SAA) 
Version Date:  11/05/2025 
1 
 
Drug Name: eltrombopag (Promacta®) 
IND:  Exempt 
Version Date: November 05, 2025 
Title: Early Initiation of Oral Therapy with Cyclosporine and Eltrombopag for Treatment Naïve 
Severe Aplastic Anemia (SAA). 
Other Identifying Words: Immunosuppression, T-cells, hematopoiesis, autoimmunity, 
thrombocytopenia, neutropenia, pancytopenia 
Protocol Principal Investigator: 
 
 
Bhavisha Patel, M.D., HB, NHLBI (E) 
Hematology Branch (HB) 
National Heart, Lung and Blood Institute (NHLBI) 
Building 10, Rm 3-5132 
9000 Rockville Pike 
Bethesda, MD 20892 
Phone: 301-402-3477 
E-mail: bhavisha.patel@nih.gov 
 
Project Involves Ionizing Radiation?  
Yes (medically indicated only) 
Off-Site Project?  
 
 
 
No 
Multi-center trial? 
 
 
 
No 
DSMB Involvement?  
 
 
Yes 
Tech Transfer:  
 
 
 
CRADA 
 

Abbreviated Title: Early Initiation of Oral Therapy for Naïve Severe Aplastic Anemia (SAA) 
Version Date:  11/05/2025 
2 
 
SYNOPSIS 
Severe aplastic anemia (SAA) is a life-threatening bone marrow failure characterized by 
pancytopenia and a hypocellular marrow. Allogeneic bone marrow transplantation is curative in 
younger patients, but older age and/or lack of a suitable donor have limited application of this 
procedure. As an alternative to transplant, immunosuppressive treatment (IST) has provided 
durable remissions and similar long term survival [1]. Approximately 2/3 of patients who receive 
IST with horse anti-thymocyte globulin (h-ATG) and cyclosporine (CsA) have blood count 
recovery, but 25-30% do not respond and 30-40% will relapse. A likely explanation for partial 
recovery and relapse is incomplete elimination of auto-reactive T cells and insufficient stem cell 
reserve. 
Thrombopoietin (TPO) is a key regulator of hematopoietic stem cell renewal and survival. To 
improve the hematologic response rate, our group assessed the addition of eltrombopag (EPAG), 
a synthetic mimetic of TPO, to IST in treatment naïve SAA. This combination achieved a higher 
complete response rate to about 50% and an overall response rate to 80%, both superior to historic 
controls [2]. This regimen received FDA approval in November 2018. Combined therapy is now 
being tested in a European randomized study. Furthermore, protocols have been developed 
internationally to determine whether EPAG and CsA, without ATG, are sufficient to improve 
blood counts, in countries where ATG is not available. 
The long-term complications, relapse and clonal evolution, were no worse with the addition of 
EPAG than in our historical cohort, but still remain a problem. Clonal evolution occurs in 10-15% 
of patients and is defined as development of myelodysplastic syndrome or acute myeloid leukemia 
with characteristic cytogenetic abnormalities of aneuploidy, especially monosomy 7 or deletion 
7q. There are no predictive tools to identify patients at higher risk for either of these two long term 
events. 
Because SAA is a rare disease, treatment has been recommended to take place at a specialized 
center. However, delays in reaching such centers and initiating therapy are common. From current 
understanding of the disease, immune destruction of cells is ongoing during this period, likely 
impacting on both short and long term outcomes. We propose early initiation of lower dose CsA 
(2mg/kg/day) and EPAG to decrease ongoing immune destruction and stimulate HSPC while 
awaiting full work up and transfer to the Clinical Center (CC). 
The aim of this study is to test feasibility and safety of initiating oral therapy before arriving to the 
NIH, based on diagnostic tests performed by local physicians and interpretation from experts here. 
Treatment will be initiated remotely but under complete guidance and supervision of the research 
team at the Hematology Branch. All patients except the ones who achieve complete response will 
receive standard three drug regimen upon completion of work up here at the CC. Primary endpoint 
of the study will be to assess feasibility and safety as a composite measure of misdiagnosis, non-
compliance with the regimen or failure to establish care at the Clinical Center within 8 weeks of 
initiating treatment, and TRSAE (treatment related serious adverse events). Initial treatment period 
of 8 weeks may be extended in special circumstances (defined in section 9.6). Secondary endpoints 
are response rates at landmark time points, relapse, overall survival, and clonal evolution.

Abbreviated Title: Early Initiation of Oral Therapy for Naïve Severe Aplastic Anemia (SAA) 
Version Date:  11/05/2025 
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SCHEDULE OF EVENTS (SOE) 
 
EVALUATION AND 
ASSESSMENTS  
  
Screening
/Baseline 
 
Off Site 
Monitoring 
1st Visit at 
Clinical 
Center 
On Site 
Monitoring 
Follow Up Visit 
Relapse 
PROTOCOL 
TIMEPOINT 
  
1 
2 
3 
5 
6 
7 
8 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
Window +/- days 
  
* +/- 4 
weeks 
+/- 8 
Weeks 
* +/- 8 
Weeks 
+/-
10D 
+/-
10D 
+/-
10D 
+/-
10D 
+/- 
30D 
+/- 
90D 
+/- 
90D 
+/- 
90D 
+/- 
90D 
day /month 
  
D
1 
D
2 
D
3 
D
4 
M1 
M2 
M3 
M6 
M12 
M24 
M36 
M48 
M60 
Past History & 
Consents 
  
Review 
Inclusion/Exclusion 
Criteria  
  
x 
Review Medical & 
Family History  
  
x 
Physical Examination  
  
x3 
x 
x 
x 
x 
x 
x 
x 
C 
Review of Concurrent 
Medications 
  
x3 
Vital Signs  
  
x 
x 
x 
x 
PPD  
  
x2 
NHLBI Screening 
Consent 
  
x 
Consent to study  
  
x 
CHEMISTRY LABS 
  

Abbreviated Title: Early Initiation of Oral Therapy for Naïve Severe Aplastic Anemia (SAA) 
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EVALUATION AND 
ASSESSMENTS  
  
Screening
/Baseline 
 
Off Site 
Monitoring 
1st Visit at 
Clinical 
Center 
On Site 
Monitoring 
Follow Up Visit 
Relapse 
PROTOCOL 
TIMEPOINT 
  
1 
2 
3 
5 
6 
7 
8 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
Window +/- days 
  
* +/- 4 
weeks 
+/- 8 
Weeks 
* +/- 8 
Weeks 
+/-
10D 
+/-
10D 
+/-
10D 
+/-
10D 
+/- 
30D 
+/- 
90D 
+/- 
90D 
+/- 
90D 
+/- 
90D 
day /month 
  
D
1 
D
2 
D
3 
D
4 
M1 
M2 
M3 
M6 
M12 
M24 
M36 
M48 
M60 
Female, Pregnancy 
Test (blood or urine) 
  
x1 
x 
x 
x 
x 
x 
x 
x 
x 
x3/C 
Acute care/mineral 
panels 
  
x3 
x3 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x3 
Hepatic Panel 
  
x3 
x3 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x3 
LDH panel 
  
x3 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x3 
Total Protein, uric 
acid, CK 
  
x 
Thyroid Function 
Test 
  
x 
Folate Level, B12 
Level 
  
x 
Iron Panel (ferritin, 
transferrin, % 
saturation)  
  
x 
x 
x 
x 
x 
x 
x 
x 
HEMATOLOGY LABS 
  
CBC with differential 
  
x3 
x3 
x 
x 
x 
x 
x 
x3 
x3 
x 
x 
x 
x 
x 
x 
x 
x3 
Reticulocyte Count  
  
x3 
x3 
x 
x3 
x3 
x 
x 
x 
x 
x 
x 
x 
x3 

Abbreviated Title: Early Initiation of Oral Therapy for Naïve Severe Aplastic Anemia (SAA) 
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EVALUATION AND 
ASSESSMENTS  
  
Screening
/Baseline 
 
Off Site 
Monitoring 
1st Visit at 
Clinical 
Center 
On Site 
Monitoring 
Follow Up Visit 
Relapse 
PROTOCOL 
TIMEPOINT 
  
1 
2 
3 
5 
6 
7 
8 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
Window +/- days 
  
* +/- 4 
weeks 
+/- 8 
Weeks 
* +/- 8 
Weeks 
+/-
10D 
+/-
10D 
+/-
10D 
+/-
10D 
+/- 
30D 
+/- 
90D 
+/- 
90D 
+/- 
90D 
+/- 
90D 
day /month 
  
D
1 
D
2 
D
3 
D
4 
M1 
M2 
M3 
M6 
M12 
M24 
M36 
M48 
M60 
Direct Antiglobulin 
Screen 
  
x 
Type and Screen  
  
x3 
x 
Viral Serologies 
  
Hepatitis A, B, C 
  
x 
HIV 
  
x 
HSV 
  
x 
EBV and CMV 
  
x 
Other Blood & Bone 
Marrow Tests 
  
Lymphocyte 
phenotyping T, B, NK 
  
x 
x 
x 
x 
x 
x 
x 
x 
x3 
Telomere length of 
leukocytes 
  
x 
Flow Cytometry of 
peripheral blood  
  
x 
x 
x 
x 
x 
x 
x 
x 
x3 
HLA typing  
  
x 
Cyclosporine Level  
  
x 
x3 

Abbreviated Title: Early Initiation of Oral Therapy for Naïve Severe Aplastic Anemia (SAA) 
Version Date:  11/05/2025 
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EVALUATION AND 
ASSESSMENTS  
  
Screening
/Baseline 
 
Off Site 
Monitoring 
1st Visit at 
Clinical 
Center 
On Site 
Monitoring 
Follow Up Visit 
Relapse 
PROTOCOL 
TIMEPOINT 
  
1 
2 
3 
5 
6 
7 
8 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
Window +/- days 
  
* +/- 4 
weeks 
+/- 8 
Weeks 
* +/- 8 
Weeks 
+/-
10D 
+/-
10D 
+/-
10D 
+/-
10D 
+/- 
30D 
+/- 
90D 
+/- 
90D 
+/- 
90D 
+/- 
90D 
day /month 
  
D
1 
D
2 
D
3 
D
4 
M1 
M2 
M3 
M6 
M12 
M24 
M36 
M48 
M60 
Bone Marrow 
aspiration and core 
biopsy for standard 
morphologic analysis  
  
x8 
x 
x 
x 
x 
x 
C 
C 
C 
x3/C 
Bone Marrow for 
chromosomal 
analysis  
  
x 
x* 
x* 
x 
x 
C 
C 
C 
X3/C 
Telephone Weekly 
Follow Up (+/- 3 days) 
Appendix B 
  
Clinical Assessment 
A-F with progress 
notes  
  
x 
Laboratory 
Assessment A-D 
  
x 
Review of 
Medications  
  
x 
Local Physician 
Involvement  
  
x 
STUDY MEDICATION  
  
Cyclosporine 
  
x5 
x
6 
x7 
x8 
x5 

Abbreviated Title: Early Initiation of Oral Therapy for Naïve Severe Aplastic Anemia (SAA) 
Version Date:  11/05/2025 
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EVALUATION AND 
ASSESSMENTS  
  
Screening
/Baseline 
 
Off Site 
Monitoring 
1st Visit at 
Clinical 
Center 
On Site 
Monitoring 
Follow Up Visit 
Relapse 
PROTOCOL 
TIMEPOINT 
  
1 
2 
3 
5 
6 
7 
8 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
Window +/- days 
  
* +/- 4 
weeks 
+/- 8 
Weeks 
* +/- 8 
Weeks 
+/-
10D 
+/-
10D 
+/-
10D 
+/-
10D 
+/- 
30D 
+/- 
90D 
+/- 
90D 
+/- 
90D 
+/- 
90D 
day /month 
  
D
1 
D
2 
D
3 
D
4 
M1 
M2 
M3 
M6 
M12 
M24 
M36 
M48 
M60 
Eltrombopag 
  
x 
x8 
x 
h-ATG 
  
x 
x 
x 
x 
EVALUATIONS 
  
EKG (prior to h-ATG) 
  
x 
Central Line 
Placement  
  
C 
Chest X-Ray  
  
C 
Research Samples  
  
60 mL blood sample 
(3 ml/kg not to 
exceed 60 ml for 
pediatric) 
  
x 
x 
x 
x 
x 
x 
x 
x 
x 
15 mL bone marrow 
aspirate sample  
  
x 
x 
x 
x 
x 
x 
x 
x 
10 mL additional 
blood sample (3 
ml/kg not to exceed 
60 ml for pediatric) 
  
x 
x 
x 
x 
x 
x 
x 
  

Abbreviated Title: Early Initiation of Oral Therapy for Naïve Severe Aplastic Anemia (SAA) 
Version Date:  11/05/2025 
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EVALUATION AND 
ASSESSMENTS  
  
Screening
/Baseline 
 
Off Site 
Monitoring 
1st Visit at 
Clinical 
Center 
On Site 
Monitoring 
Follow Up Visit 
Relapse 
PROTOCOL 
TIMEPOINT 
  
1 
2 
3 
5 
6 
7 
8 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
Window +/- days 
  
* +/- 4 
weeks 
+/- 8 
Weeks 
* +/- 8 
Weeks 
+/-
10D 
+/-
10D 
+/-
10D 
+/-
10D 
+/- 
30D 
+/- 
90D 
+/- 
90D 
+/- 
90D 
+/- 
90D 
day /month 
  
D
1 
D
2 
D
3 
D
4 
M1 
M2 
M3 
M6 
M12 
M24 
M36 
M48 
M60 
* = if patients are available to come within 72 hours of referral then baseline and 1st visit at Clinical Center will be performed at same time. 
* = Grace period allows extension of this time frame to report to the Clinical center in special circumstances 
x1 = women of childbearing potential and within 2 weeks of initiation h-ATG 
x2 = per PI discretion: at risk subjects only, based on history or geography and maybe performed off site 
x3 = outside labs results accepted  
x4 = not required if clinically indicated  
x5 = dose is 2mg/kg/day 
x6 = dose increase based on age, section 5.1 
x7 = responders will have dose decrease, 2 mg/kg/day 
x8 = drug discontinued 
X9=outside bone marrow results accepted after verification at the NIH 
x*= Bone marrow aspiration, biopsy, and chromosomal analysis may be omitted if one was performed within 4 weeks of the timepoint analysis. 
C = Considered optional 

Abbreviated Title: Early Initiation of Oral Therapy for Naïve Severe Aplastic Anemia (SAA) 
Version Date:  11/05/2025 
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1 
TABLE OF CONTENTS 
SYNOPSIS ...................................................................................................................................... 2 
SCHEDULE OF EVENTS (SOE) .................................................................................................. 3 
STATEMENT OF COMPLIANCE .............................................................................................. 12 
1 
OBJECTIVE ......................................................................................................................... 13 
2 
BACKGROUND AND SCIENTIFIC JUSTIFICATION .................................................... 13 
2.1 
Pathophysiology of Aplastic Anemia ............................................................................. 13 
2.2 
Clinical Consequences of Aplastic Anemia ................................................................... 13 
2.3 
Treatment of Aplastic Anemia ....................................................................................... 13 
3 
STUDY DESIGN.................................................................................................................. 19 
4 
ELIGIBILITY ASSESSMENT ............................................................................................ 19 
4.1 
Inclusion Criteria ............................................................................................................ 20 
4.2 
Exclusion Criteria ........................................................................................................... 20 
4.3 
Inclusion of Pregnant Women, fetuses or neonates ....................................................... 22 
5 
TREATMENT PLAN ........................................................................................................... 22 
5.1 
Cyclosporine (CsA) ........................................................................................................ 23 
5.2 
Eltrombopag ................................................................................................................... 24 
5.3 
Dose Adjustments of Eltrombopag ................................................................................ 25 
5.4 
Dose Delays, Modifications or Discontinuation of Eltrombopag for Non-Hematologic 
Side Effects ............................................................................................................................... 26 
5.5 
Dose Delays, Modifications or Discontinuation of Eltrombopag for Hematologic Side 
Effects ....................................................................................................................................... 27 
5.6 
Horse Anti-thymocyte-Globulin (h-ATG) Administration ............................................ 27 
5.7 
Pre-medications and Management of Infusion Reactions .............................................. 27 
5.8 
Supportive Care .............................................................................................................. 28 
5.9 
Concurrent Medications ................................................................................................. 28 
5.10 
Infection Prophylaxis and Monitoring ........................................................................ 29 
5.11 
Instructions to Subjects ............................................................................................... 29 
6 
CLINICAL MONITORING ................................................................................................. 30 
6.1 
Pre-study Evaluation/Screening ..................................................................................... 30 
6.2 
On Study Off Site Monitoring, prior to initial Clinical Center visit if enrolled on study 
remotely .................................................................................................................................... 32 
6.3 
On Study Monitoring, Day 1 of h-ATG Through Hospital Discharge .......................... 32 

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6.4 
On Study Monitoring (hospital discharge through 6 months) ....................................... 33 
6.5 
Long Term Follow Up (6 months to 5 years) ................................................................ 35 
6.6 
Genetic and other tests (may be performed in some patients) ....................................... 35 
6.7 
Return of Research Results ............................................................................................ 36 
6.8 
Extended Access for Relapse ......................................................................................... 36 
7 
CRITERIA FOR RESPONSE/CLONAL EVOLUTION/RELAPSE .................................. 37 
8 
EXPLORATORY LABORATORY RESEARCH STUDIES.............................................. 38 
9 
BIOSTATISTICAL CONSIDERATIONS ........................................................................... 39 
9.1 
Primary Endpoints .......................................................................................................... 39 
9.2 
Secondary Endpoints ...................................................................................................... 39 
9.3 
Sample Sizes and Statistical Design............................................................................... 40 
9.4 
Statistical Methods ......................................................................................................... 40 
9.5 
Stopping Rules ............................................................................................................... 41 
9.6 
Off Treatment and Off Study Criteria ............................................................................ 42 
10 
SAFETY AND OTHER ASSESSMENTS ........................................................................ 45 
10.1 
Safety Monitoring ....................................................................................................... 45 
10.2 
Assessment of Safety .................................................................................................. 45 
10.3 
Protocol Deviation (PD) Reporting ............................................................................ 47 
10.4 
Adverse Events (AEs) Characterization ..................................................................... 47 
10.5 
Serious Adverse Events (SAEs) Characterization ...................................................... 47 
10.6 
Event Collection ......................................................................................................... 48 
10.7 
Reporting Events ........................................................................................................ 48 
10.8 
Protocol Monitoring ................................................................................................... 50 
11 
BIOSPECIMEN AND DATA MANAGEMENT PLAN .................................................. 50 
12 
HUMAN SUBJECT PROTECTION ................................................................................. 53 
12.1 
Rationale for Subject Selection .................................................................................. 53 
12.2 
Participation of Children ............................................................................................ 54 
12.3 
Risks and Discomforts ................................................................................................ 55 
12.4 
Risks in Relation to Benefit ........................................................................................ 65 
12.5 
Informed Consent Processes and Procedures ............................................................. 66 
12.6 
Confidentiality and Privacy ........................................................................................ 68 
12.7 
Human Data Sharing, including Genomic Data Sharing, and Publication ................. 69 

Abbreviated Title: Early Initiation of Oral Therapy for Naïve Severe Aplastic Anemia (SAA) 
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12.8 
Conflict of Interest ...................................................................................................... 69 
12.9 
Collaboration(s) .......................................................................................................... 70 
12.10 
Technical Transfer Agreements .................................................................................. 70 
13 
PHARMACEUTICALS .................................................................................................... 70 
13.1 
ELTROMBOPAG (PROMACTA®) ......................................................................... 70 
13.2 
CYCLOSPORINE (Gengraf, Sandimmune, Neoral) ................................................. 72 
13.3 
ANTI-THYMOCYTE GLOBULIN (equine) sterile solution (ATGAM®) .............. 72 
13.4 
PENTAMIDINE ......................................................................................................... 73 
13.5 
VALACYCLOVIR ..................................................................................................... 73 
13.6 
FDA Regulatory Consideration .................................................................................. 74 
14 
REFERENCES: ................................................................................................................. 75 
APPENDIX A: GUIDE FOR LOCAL PHYSICIAN .............................................................. 79 
APPENDIX B: TELEPHONE WEEKLY FOLLOW UP ....................................................... 83 
 
 
 

Abbreviated Title: Early Initiation of Oral Therapy for Naïve Severe Aplastic Anemia (SAA) 
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STATEMENT OF COMPLIANCE 
The trial will be carried out in accordance with International Conference on Harmonisation Good 
Clinical Practice (ICH GCP) and the following: 
• United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 
CFR Part 46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR Part 812)  
National Institutes of Health (NIH)-funded investigators and clinical trial site staff who are 
responsible for the conduct, management, or oversight of NIH-funded clinical trials have 
completed Human Subjects Protection and ICH GCP Training. 
The protocol, informed consent form(s), recruitment materials, and all participant materials will 
be submitted to the Institutional Review Board (IRB) for review and approval.  Approval of both 
the protocol and the consent form must be obtained before any participant is enrolled.  Any 
modification to the protocol will require review and approval by the IRB before the changes are 
implemented to the study.  In addition, all changes to the consent form will be IRB-approved; a 
determination will be made regarding whether a new consent needs to be obtained from 
participants who provided consent, using a previously approved consent form. 
 

Abbreviated Title: Early Initiation of Oral Therapy for Naïve Severe Aplastic Anemia (SAA) 
Version Date:  11/05/2025 
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1 
OBJECTIVE 
Primary Objective: To determine feasibility and safety of early initiation of oral therapy, 
cyclosporine (CsA) and eltrombopag (EPAG), in treatment naïve patients with severe aplastic 
anemia (SAA). 
Secondary Objective: To assess response, relapse and clonal evolution. 
2 
BACKGROUND AND SCIENTIFIC JUSTIFICATION 
2.1 
PATHOPHYSIOLOGY OF APLASTIC ANEMIA 
SAA is a serious hematologic disease characterized by pancytopenia and hypocellular bone 
marrow. It has been associated with certain chemicals, pregnancy, and seronegative hepatitis but 
there is no etiology identified in most cases [1] The bone marrow almost completely lacks 
hematopoietic and precursor stem cells (HPSC), detected by CD34 antigen. Years of clinical and 
laboratory research have identified immune destruction of HPSC to be the main mechanism of 
disease[3] Aberrant increase in activated cytotoxic T-cells particularly oligoclonal expansion of 
high antigen-affinity effector memory T cells (CD8+CD28-CD57+) are found by flow cytometry 
and deep sequencing [4, 5]. These cytotoxic T cells in turn exert their effect by type 1 cytokine 
production, Interferon gamma (IFN γ), via Fas ligand mediated apoptosis [6, 7]. On the other hand, 
the regulatory T cells (Tregs) are low in AA patients on presentation and increase with hematologic 
response to immunosuppressive therapy. [8, 9] [10]. 
2.2 
CLINICAL CONSEQUENCES OF APLASTIC ANEMIA 
Clinical symptoms correlate with severity of cytopenia. Neutropenia, when severe, results in 
susceptibility to bacterial and fungal infections, which account for early morbidity and mortality. 
Thrombocytopenia presents as mucocutaneous bleeding, including epistaxis, gum bleeding, and 
petechiae/ecchymosis; but rarely as life threatening gastrointestinal and intracranial hemorrhage. 
Anemia leads to inability to perform daily activities over time. Patients often have chronic 
transfusion requirements for both red blood cells and platelets, exposing them to risks of 
transfusion overload, acute and delayed transfusion reactions, and alloimmunization. 
2.3 
TREATMENT OF APLASTIC ANEMIA 
2.3.1 Allogeneic Hematopoietic Stem Cell Transplantation 
Allogeneic hematopoietic stem cell transplantation provides cure by rapidly restoring 
hematopoietic and immune systems in majority of the patients. HLA-matched related donor 
(MRD) transplant provide long term survival reaching 80% in younger patients, <40 years of age 
[11]. The occurrence of graft-versus-host disease is age dependent and continues to be the major 
limiting factor in terms of morbidity and mortality as well as long-term quality of life [12]. 
Historically, matched unrelated donor (MUD) transplantation has not been recommended due to 
high rates of GVHD and delay in identifying and recruiting a donor [11]. Recent data suggests 
improved 2 year overall survival and event free survival with MUD as first line treatment 
compared with IST or MUD after IST failure in younger patients [13]. Peripheral bone marrow 
source, older age and the interval from diagnosis to treatment beyond 6 months were strongest 
predictors of poor outcomes [11, 14]. For adults, IST is the standard of care in absence of MRD 
transplant options. Conversely, children have excellent survival with unrelated grafts [15]. 

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Therefore, MUD transplant is recommended as first line treatment by some experts in pediatric 
patients if no delay is anticipated [1]. 
HLA- haploidentical transplant is an attractive option for many patients. The use of posttransplant 
cyclophosphamide (PT-CY) conditioning has produced promising outcomes in small studies [16] 
[17]. Currently, it remains investigational and is only recommended after IST failure and if an 
HLA-matched donor is unavailable [1]. Studies combining haplo-identical donor and umbilical 
cord transplant are underway at NIH and other institutions. 
2.3.2 Immunosuppression with horse Anti-thymocyte Globulin (ATGAM; h-ATG) and 
Cyclosporine (CsA) 
With the recent FDA approval, EPAG + IST is now the standard treatment for newly diagnosed 
SAA. IST with CsA and ATG results in hematologic recovery in 60-70% patients leading to a 5 
year survival of 80-90% among responders [3]. The mechanism by which h-ATG improves bone 
marrow failure in aplastic anemia is not fully understood. ATG preparations contain a variety of 
antibodies to human T cell epitopes, many directed against activated T-cells or activation antigens 
[18] [19]. Decrease in circulating lymphocytes after ATG is transient but number of activated T-
cells are decreased for prolonged periods of time; this effect is also reflected in decreased lFN-γ 
and tumor necrosis factor (TNF) [20]. Although ATGs are mild lymphodepleting agents, even 
minor differences have clinical impact as highlighted by lower response rates with rabbit ATG 
compared to horse ATG in treatment naïve patients with SAA [21]. At our institution, a dose of 
40mg/kg/day for 4 days has been used since 1995 with consistent and similar response rates to 
other groups, who utilize different dosage, formulation and duration of treatment [2, 22]. 
In contrast to ATG, CsA has a selective inhibitory effect on T lymphocytes, suppressing early 
cellular response to antigenic and regulatory stimuli. By blocking expression of nuclear regulatory 
proteins, it leads to reduced T cell proliferation and activation with diminished release of cytokines 
such as interleukin-2 (IL-2) and IFN- [23, 24] Although CsA and h-ATG combination is superior 
than either agent alone, cyclosporine monotherapy is commonly utilized worldwide due to lack of 
ATG preparations, less toxicity, oral route of administration, and relatively inexpensive cost. 
Previous large randomized trials comparing CsA to ATG or CsA and ATG demonstrated an ORR 
of 40-45% in CsA alone arm at 6 months [25] [26] [27]. These results have been replicated by 
many recent studies around the world. [28] [29] [30]. In a small study of 6 patients from 
Netherlands, cyclosporine monotherapy was shown to yield hematologic response even in patients 
with very severe aplastic anemia [31]. Many attempts to improve the response rates achieved by 
this combination had failed until the addition of EPAG. 
2.3.3 Eltrombopag 
Eltrombopag (SB-497115-GR, Promacta®), the bis-monoethanolamine salt form, is an orally 
bioavailable, small molecule 2nd generation thrombopoietin receptor (TPO-R) agonist. EPAG has 
been shown to increase platelets in healthy subjects, patients with chronic immune 
thrombocytopenic purpura (ITP), with hepatitis C associated thrombocytopenia [32] and in 
refractory SAA as single agent and in treatment-naïve SAA in combination with IST [33] [2] 
Thrombopoetin (TPO), a glycoprotein class 1 hematopoietic cytokine, is the main regulator of 
HPSC self-renewal and survival. Upon binding to its receptor, c-mpl, TPO activates cell signaling 
through JAK-STAT and other pathways. This process is tightly balanced by negative regulatory 
signaling. Recent studies indicate that chronic exposure of HPSCs to IFN-γ, as exemplified in 

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subjects with SAA, impairs self-renewal by perturbing TPO signaling pathways. Despite elevated 
levels of TPO in subjects with SAA, EPAG improves trilineage hematopoiesis by binding to a 
non-competitive receptor [34] EPAG, unlike TPO, evades HPSC inhibition caused by chronic 
inflammatory conditions (Alvarado L. Blood. 2017 – Abstract). Recent data also demonstrates that 
intracellular iron chelation property of EPAG contributes to its stem cell stimulatory effect [35] 
Based on our work here at NIH, EPAG is FDA approved for SAA in first line with IST (2018) and 
in refractory setting (2014). In a phase I/II dose escalation trial, nearly half of the patients with 
refractory SAA demonstrated hematologic response in at least one lineage at 3 months [36]. Long 
term analysis of the extension phase including 43 patients showed an ORR of 40% at 3 months 
[33], and an additional 26% by 6 months (Abstract, Winkler T Blood. 2017). In treatment naïve 
SAA patients, EPAG added to immunosuppression resulted in complete hematologic response that 
was significantly better than historical rate of 10%. Long term outcomes, relapse and clonal 
evolution, were 14% and 8% respectively at 2 years [2]. Common side effects included liver 
function abnormalities, and diffuse erythematous skin rash. There were no additional toxicities 
noted with the combination. 
Combination of CsA and EPAG are often used for relapse treatment in 12-H-0150 protocol with 
good hematologic recovery in majority of the patients. There were no unexpected adverse events, 
in fact, LFT abnormalities were observed less frequently (unpublished data). 
2.3.4 Rationale for Dose Selection 
Eltrombopag 150mg orally once daily is selected as the starting dose based on safety and efficacy 
data from two prior studies conducted here at NIH. In a phase II (NCT00922883) trial with 
refractory SAA patients, EPAG proved to be efficacious without dose limiting toxicities at a dose 
of 150mg. Furthermore, no increased or unexpected toxicities were noted with Eltrombopag, CsA, 
and h-ATG combination (12-H-0150). Pharmacokinetics data indicate higher plasma drug 
concentrations with regular dose of EPAG in patients with East Asian and Southeast Asian 
ancestry, therefore, a starting dose of 75mg daily will be administered as in our previous protocols. 
In our previous protocols, a starting dose of cyclosporine 3mg/kg twice a day is given (higher 
dose) with a target drug level between 200 and 400mcg/L. For this protocol, we plan to administer 
2mg/kg/day (lower dose). CsA has been shown to work in SAA at varying doses, schedule, and 
therapeutic trough. However, dedicated dose escalation studies to guide CsA dosing are lacking. 
At the clinical center, initial starting dose of 6mg/kg/day has been prescribed historically whereas 
doses as high as 12mg/kg/day have been used in German trials [37]. Therapeutic goals have also 
varied among trials from different institutions, and in developing countries the dose is typically 
adjusted based on toxicities. Lower dose CsA is not studied previously as the starting dose but we 
have observed ongoing hematologic response and delay in relapses with prolonged administration 
of lower dose CsA after initial response [38]. Lower dose CsA resulted in suppression of cytotoxic 
T cells and increase in T regs in patients with atopic dermatitis, another chronic autoimmune 
condition, suggesting a degree of immunosuppression with this dose [39]. 
Lower dose CsA is also safer to administer because of less toxicities and no requirements to follow 
levels, which may not be readily available in certain outpatient settings. Patients will only continue 
2mg/kg until the initiation of standard therapy at CC, at which time the dose will be increased to 
standard 3mg/kg twice a day with a target goal between 200 and 400mcg/L to complete 6 months. 

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After 6 months, CsA will be decreased to 2mg/kg for 18 months to complete 2 years as employed 
in 12-H-0150. 
2.3.5 Scientific and Clinical Justification of the Protocol 
The current protocol aims to test the risks and benefits of early treatment with orally administered 
drugs in patients who have delay in receiving standard treatment, a combination of CsA, EPAG 
and h-ATG. The desirability of more expeditious treatment is based on the pathophysiology of 
immune aplastic anemia, T cell mediated destruction of hematopoietic stem and progenitor cells 
leading to a deficit in marrow regenerative function. Both drugs individually have activity in 
aplastic anemia as single agents [33, 36, 40] and carry low risk safety profiles over the short term. 
Indeed, the combination of eltrombopag with cyclosporine, without ATG, is currently being tested 
in a multicenter trial (SOAR trial: NCT02998645). 
Appropriate treatment of patients with SAA is often delayed, as most physicians and many 
hematologists are not familiar with the disease or comfortable with its therapy. As a quaternary 
referral center for marrow failure, entry of patients to our protocols maybe delayed for logistical 
reasons. Even when patients can be admitted to the Clinical Center relatively proximate to their 
diagnosis, institution of effective therapy is often postponed while awaiting results of testing, 
intravenous catheter placement, or evaluation of complications or comorbidities. During this 
period, absent definitive therapies, stem and progenitor cell destruction is assumed to be ongoing. 
Morbidity and mortality in severe aplastic anemia patient results from severity and duration of 
pancytopenia. Expeditious commencement of therapy is expected to abbreviate the period of 
severe pancytopenia with its attendant consequences: infections and treatment of febrile 
neutropenia, bleeding from ongoing thrombocytopenia, and anemia. Furthermore, rapid institution 
of treatment should also allow patients who do not respond to medical therapy, or whose response 
is not optimal, to proceed faster to transplantation options. Shorter periods between diagnosis and 
bone marrow transplantation have repeatedly been shown to correlate with transplant outcomes 
[41]. Robust and rapid hematologic recovery has been associated with better survival outcomes 
[42], and in our experience, complete hematologic responders are less likely to evolve to 
myelodysplasia or leukemia (unpublished data). 
In the current protocol, CsA and EPAG will be initiated after consent is obtained by NIH 
physicians by audio/video communication (telephone calls, skype etc.) or in person at the Clinical 
Center if able to arrive here within 72 hours for initial appointment. Hematology branch team will 
follow the patients actively with every week telephone follow ups until patient receives standard 
treatment at the NIH. Drugs will be provided by the Clinical Center; both physicians and patients 
will be informed about side effects, monitoring requirements (clinical and laboratory), and 
measures that may lead to discontinuation of treatment. 
Urgent treatment in absence of full information or the availability of all effective drugs, has 
precedents in medicine and within hematology, based on the benefits of immediate therapy and 
the low risk of the drugs employed. Most notably, acute promyelocytic leukemia, a highly fatal 
and aggressive form of acute myeloid leukemia, has been successfully treated achieving complete 
response rates up to 90-95% and disease free survival up to 86% with early recognition and rapid 
initiation of all-trans retinoic acid (ATRA) based treatments [43]. Other fatal diseases with rapid 
treatment while awaiting complete testing include heparin induced thrombocytopenia, and 
catastrophic anti-phospholipid syndrome. Employing similar concept, we believe rapid treatment 

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of SAA will decrease short term complications of pancytopenia, and long-term complications of 
clonal evolution and relapse rates by salvaging HSPCs and shortening the duration of chronic 
immune destruction. 
The combination of ATG, which lyses lymphocytes, CsA, which blocks T-cell function, and 
EPAG, which stimulates stem cells, has produced excellent survival rates, comparable to bone 
marrow transplantation. In our experience, there are beneficial short-term effects of this 
combination:  blood counts improve rapidly, decreasing the transfusion requirement and risk of 
neutropenic fever and infections. For EPAG added to IST in ongoing Hematology Branch trial, 
the cumulative relapse rate is ~40% and the rate of clonal evolution (progression to MDS/AML, 
or cytogenetic abnormalities) is approximately 15%, both comparable to IST alone. EPAG added 
to immunosuppression has significantly increased complete response rates, however, relapses and 
clonal evolution still remain a problem. As noted above, this may be mitigated by early initiation 
of immunosuppression and EPAG to stabilize immune destruction and stimulate hematopoietic 
stem cells. 
For purposes of analysis, the major endpoints of the study will be the feasibility and safety of the 
design for expeditious treatment. This will be assessed as a composite measure of misdiagnosis, 
TRSAE, and non-compliance with the regimen or failure to establish care at the CC within 8 weeks 
of initiating treatment. Overall and complete response rates will be analyzed to be comparable to 
those established in standard protocols at the NIH for SAA. 
2.3.7 Justification for Extension Cohort 
Protocol specified interim analysis and recent re-analysis after accrual of 36 subjects were 
performed. Primary endpoint to assess the safety and feasibility of early oral therapy initiation was 
met with 0 composite events (non-compliance, treatment related serious adverse events, or 
misdiagnosis). Secondary endpoints including efficacy, relapse and clonal evolution rates were 
also re-analyzed after 36 patients. Compared to our previous protocol (12-H-0150 – cohort 3 and 
extension; Standard group) in which ATG, EPAG and CSA were all started on Day 1, baseline 
characteristics were similar in the Early group (20-H-0033) in terms of age, gender, and ethnicity 
however more patients with very severe aplastic anemia were enrolled in Standard group (52%) 
versus Early group (28%; Table 1).  At 6 months, ORR (80% v 83%), CR (40% v 50%) and PR 
(33% v 40%) were equivalent in Standard and Early group, respectively (Figure 1). Median time 
on oral therapy was 14 days (range 0,86) and even with this short time on oral therapy, we observed 
a significant increase in absolute neutrophil counts, a trend towards increased absolute reticulocyte 
counts and decreased lymphocyte counts between pre-treatment and end of oral therapy (before 
hATG). 
While relapse rates were similar between the two groups, high-risk clonal evolution, defined as 
acquisition of chromosome 7 abnormalities or morphologic diagnosis of myeloid neoplasm, was 
observed at much lower rate at median follow-up time of 363 days in Early group compared to 
Standard group (3.8% vs 8%). In EPAG treated patients in Standard group, most high-risk 
evolution occurred within the first 6 months so the 50% lower rate observed in Early group is 
striking. High-risk clonal evolution is a major contributor of mortality (Groarke EM. Leukemia. 
2023) in SAA patients treated with IST. The lower rates observed in this study maybe by chance 
due to small sample size or biologically explained by reduction in regenerative stress by halting 
immune attack earlier in the disease and preserving stem cell pool or due to immunomodulatory 
activity of CSA and/or EPAG prior to hATG. 

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In the extension cohort, we continue with the same study design and eligibility criteria but plan on 
accruing an additional 41 subjects to specifically address the long-term complications, relapse and 
high risk clonal evolution. 
 Table 1: Patient characteristics 
Early initiation 
 (n=36) 
Standard therapy 
 (n= 139) 
Age (median, range)  
       <18 years (n, %) 
       18-40 years (n, %) 
       >40 years (n, %) 
37 (8, 69) 
5 (14) 
19 (53) 
12 (33) 
33 (3, 82) 
25 (18) 
51 (37) 
63 (45) 
Gender 
       Male (n, %) 
       Female (n,%) 
  
20 (56) 
16 (44) 
  
66 (47) 
73 (53) 
Race (n, %) 
       White 
       Black or African American  
       Asian  
       Multiple Races 
       Unknown  
       Other  
  
16 (44) 
16 (44) 
2 (6) 
1 (3) 
1 (3) 
  
77 (55) 
34 (24) 
10 (7) 
7 (5) 
5 (4) 
6 (4) 
Severity of disease  
       SAA (n, %) 
       VSAA (n, %) 
  
26 (72) 
10 (28) 
  
67 (48) 
72 (52) 
Presence of PNH clone (GPI negative neutrophils >1%, n, %) 
16 (44) 
62 (45) 
Pre-treatment clinical blood counts  
       Absolute neutrophil counts (median, range), K/uL 
       Platelet counts (median, range), K/uL 
       Absolute reticulocyte counts (median, range), K/uL 
       Absolute lymphocyte counts (median, range), K/uL 
  
0.3 (0, 3.6) 
8 (1, 24) 
26.4 (0, 59.5)  
1.5 (0.2, 4.3) 
  
0.2 (0, 20) 
7 (0, 41) 
17.9 (2.0, 97.1) 
1.4 (0.1, 4.0) 

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Figure 1: Comparison of 6 month responses  
3 
STUDY DESIGN 
This study is designed as a non-randomized, pilot study in which subjects with SAA will be started 
with investigational early initiation of CsA and EPAG either before arrival to the NIH or at the 
NIH while work up is being completed. When the treatment is initiated remotely, it will be under 
oversight of investigators at NHLBI. At the CC, patients will receive standard treatment with 
higher dose CsA, EPAG, and h-ATG. h-ATG may be omitted if complete response is achieved. 
Cohort 1 (original, n=39) 
 
*D1 – Patients will be evaluated and enrolled at the NIH if able to arrive for initial visit within 72 hours of referral. If ANC <200 at the initial visit 
at NIH, treatment with all three drugs may be initiated without waiting for the cytogenetics. 
**h-ATG may be omitted in patients who have achieved a complete response at the initial NIH visit after initiating oral treatment remotely 
Note: Study treatment period of 8 weeks may be extended as defined in Section 9.6 
Extension Cohort (n=41, same study design as above) 
4 
ELIGIBILITY ASSESSMENT 
All subjects aged 3 and older with treatment naïve SAA and lack a suitable matched sibling marrow 
donor or are not allogeneic transplantation candidates due to patient choice, advanced age, or 
infeasibility of transplantation will be considered for enrollment. Treatment naïve is defined as not 

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having received a standard course of prior immunosuppressive therapy (ATG, cyclosporine, 
alemtuzumab, and high dose cyclophosphamide), or eltrombopag. 
Eligibility may be determined on an NHLBI screening protocol (97-H-0041). The laboratory and 
clinical data obtained outside NIH may be accepted to determine eligibility. Subjects will be 
asked to sign a release of records to allow medical record review to obtain additional information 
about general and hematologic health. Bone marrow biopsy report (performed at outside facility) 
will be obtained and reviewed at the NIH and if there is any question about the diagnosis then the 
specimen will be obtained and confirmed prior to enrollment. The time between determination of 
eligibility and signing consent to participate on this protocol, and initiate treatment may not 
exceed 4 weeks. The time between initiating oral treatment to first visit at the Clinical Center 
may not exceed 8 weeks unless grace period is granted based on special circumstances (defined 
in Section 9.6). Due to the nature of SAA, counts may fluctuate depending on transfusions. 
Because of this, the lowest clinical laboratory result (absolute neutrophil count, platelet, and/or 
absolute reticulocyte count) obtained within 8 weeks prior to treatment initiation can be used for 
eligibility determination. 
4.1 
INCLUSION CRITERIA 
1. Age ≥3 years old 
2. Weight >12Kg 
3. Severe aplastic anemia:  
 
 
Bone marrow cellularity <30% (excluding lymphocytes) 
 
 
 
AND 
 
 
At least two of the following: 
• Absolute neutrophil count <500/μL 
• Platelet count <20,000/μL 
• Absolute reticulocyte count <60,000/μL 
4.2 
EXCLUSION CRITERIA 
1. Known diagnosis or high suspicion of Fanconi anemia or other constitutional marrow 
failure syndrome 
2. Evidence of a clonal disorder on cytogenetics performed within 12 weeks of study entry 
involving chromosome 7 or complex karyotype. Patient will not be excluded if 
cytogenetics are not done or are pending 
3. A course of prior immunosuppressive therapy (ATG, cyclosporine, alemtuzumab, and 
high dose cyclophosphamide), or eltrombopag 
4. SGOT or SGPT >2.5 times the upper limit of normal or total bilirubin >1.5 x upper limit 
of normal 
5. Subjects with liver cirrhosis (as determined by the investigator). 
6. Subjects with human immunodeficiency virus (HIV) who are not receiving antiretroviral 
therapy, have detectable HIV RNA viral load and have CD4 cell count <200/μL, or are 
on anti-retroviral therapy that interacts with the study drugs.  subjects will not be 
excluded if HIV testing is pending or unavailable. 
7. Glomerular filtration rate (GFR) <40 mL/min/1.73m2 
8. Hypersensitivity to EPAG or its components 

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9. Infection not adequately responding to appropriate therapy 
10. Moribund status or concurrent hepatic, renal, cardiac, neurologic, pulmonary, infectious, 
or metabolic disease of such severity that it would preclude the patient’s ability to tolerate 
protocol therapy, or that death within 7-10 days is likely 
11. Potential subjects with cancer who are on active chemotherapeutic treatment or who take 
drugs with hematological effects will not be eligible 
12. Inability to understand the investigational nature of the study or to give informed consent 
or does not have a legally authorized representative or surrogate that can provide 
informed consent per section 12.6. 
13. Inability to swallow 
14. Unable to participate in audio/video telecommunication 
15. Inability to ship the study drug to participant 
16. History or current diagnosis of cardiac disease indicating significant risk of safety for 
patients participating in the study such as uncontrolled or significant cardiac disease, 
including any of the following: Recent myocardial infarction (within last 6 months), 
uncontrolled congestive heart failure, unstable angina (within last 6 months), clinically 
significant (symptomatic) cardiac arrhythmias (e.g., sustained ventricular tachycardia, 
and clinically significant second or third degree AV block without a pacemaker.), long 
QT syndrome, family history of idiopathic sudden death, congenital long QT syndrome 
or additional risk factors for cardiac repolarization abnormality, as determined by the 
investigator. 
17. Impaired cardiac function, such as: Corrected QTc >450 msec using Fridericia correction 
(QTcF) on the screening ECG (using triplicate ECGs), other clinically significant cardio-
vascular disease (e.g., uncontrolled hypertension, history of labile hypertension), history 
of known structural abnormalities (e.g. cardiomyopathy). 
18. Concurrent participation in an investigational study within 30 days prior to enrollment or 
within 5-half-lives of the investigational product, whichever is longer. Note: parallel 
enrollment in a disease registry is permitted. 
19. Known thrombophilic risk factors. Exception: Subjects for whom the potential benefits of 
participating in the study outweigh the potential risks of thromboembolic events, as 
determined by the investigator. 
20. Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using basic methods of contraception during dosing 
of study treatment. Basic contraception methods include: 
• Total abstinence (when this is in line with the preferred and usual lifestyle of the 
subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation 
methods) and withdrawal are not acceptable methods of contraception  
• Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy), total hysterectomy, or tubal ligation at least six weeks before taking 
study treatment. In case of oophorectomy alone, only when the reproductive status of 
the woman has been confirmed by follow up hormone level assessment  
• Male sterilization (at least 6 months prior to screening). The vasectomized male 
partner should be the sole partner for that subject  
• Barrier methods of contraception: Condom or Occlusive cap.  For the UK:  with 
spermicidal foam/gel/film/cream/ vaginal suppository  

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• Use of oral, injected or implanted hormonal methods of contraception or placement of 
an intrauterine device (IUD) or intrauterine system (IUS), or other forms of hormonal 
contraception that have comparable efficacy (failure rate <1%), for example hormone 
vaginal ring or transdermal hormone contraception. 
o In case of use of oral contraception women should have been stable on the same 
pill for a minimum of 3 months before taking study treatment. 
21. Female subjects who are nursing or pregnant (positive serum or urine B-human chorionic 
gonadotrophin (B-hCG) pregnancy test) at screening or pre-dose on Day 1 
22. Sexually active males unless they use a condom during intercourse while taking the drug 
during treatment, and for 7 days after stopping treatment (and for an additional 12 weeks 
[for genotoxic compounds]) and should not father a child in this period. A condom is 
required to be used also by vasectomized men as well as during intercourse with a male 
partner in order to prevent delivery of the drug via semen. 
4.3 
INCLUSION OF PREGNANT WOMEN, FETUSES OR NEONATES 
The protocol does not intentionally enroll pregnant women due to unknown fetal risk with 
eltrombopag. However, if a patient gets pregnant during the trial participation period, she may 
remain on study for non-invasive safety and outcomes follow-up (see section 9.6 and 10.7.5 for 
details).  
 
5 
TREATMENT PLAN 
Patients will commence therapy with cyclosporine and eltrombopag as outpatients (if transfer to 
the Clinical Center is anticipated to require >72 hours or upon evaluation to the Clinical Center if 
<72 hours). Medications will be shipped to the patient at their provided address. After beginning 
cyclosporine and eltrombopag, monitoring blood work will be obtained at least weekly, more 
frequent if clinically indicated. For outpatients, a member of the NIH bone marrow failure team 
(research nurse, physician assistant, or physician) will speak by telephone with the patient or 
responsible family member every week, to ascertain symptoms and for any evidence of drug 
toxicity or intolerance (Appendix B).Within 8 weeks after consent, all subjects will have their 
evaluation at the Clinical Center except if grace period is granted in special circumstances 
(defined in Section 9.6) and receive the standard treatment with h-ATG, higher dose 
cyclosporine (3mg/kg twice a day), and eltrombopag daily after full work up is completed here. 
For patients without grace period extension, the evaluation will take place within 8 weeks of 
initiation of oral treatment but the administration of the standard treatment may not occur within 
the 8 weeks’ time frame. If ANC <200 at the initial visit at NIH, treatment with all three drugs 
may be initiated without waiting for the cytogenetics. 
If participants are unable to come to the NIH due to unanticipated reason beyond their control, 
the administration of the standard treatment with h-ATG, higher dose cyclosporine, and 
continuation of eltrombopag daily may be performed by subject’s local physician/institution with 
guidance from the NIH bone marrow failure team after the full work up is completed as listed in 
section 6.1 (Clinical studies to be performed at the Clinical Center on first visit) and results 
reviewed by the NIH bone marrow failure team. If this is to occur, specialized studies (marked as 
* in section 6.1) may be omitted.  

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5.1 
CYCLOSPORINE (CSA) 
Day 1 of cyclosporine to Day 1 of admission for h-ATG: 
For all subjects, cyclosporine will be started on day 1 at 2mg/kg/day by mouth administered 
daily at a fixed dose until Day 1 of h-ATG. Given low dose, cyclosporine therapeutic trough 
levels will only be checked per PI or local physician’s discretion if concerning toxicity signs or 
symptoms. Cyclosporine dose may be interrupted or adjusted as clinically indicated at the 
discretion of the investigator for side effects. Interruptions or dose adjustments as a consequence 
of a serious adverse event will be included in the SAE Report. 
Cyclosporine can result in many common side effects including headaches, nausea, 
gastrointestinal upset, hypertension, electrolyte imbalances and kidney injury. A complete list of 
adverse events can be found in section 12.4.2. Additionally, Appendix A will be sent to the 
outside physician to serve as a guiding document about drug administration, drug interactions 
(listed in section 5.11), dosage, adverse events, and monitoring. Our research team will be 
conducting weekly telephone follow up with patients +/- physicians to manage any side effects 
related to medications. 
Day 1 of h-ATG to month 6 dosing: 
For subjects ≥ 12 years of age, cyclosporine will be increased to 3 mg/kg/dose by mouth 
administered every 12 hours (total daily dose of 6 mg/kg/day). Dosing will be based on actual 
body weight except in obese subjects. For obese subjects (defined as a body mass index > 35 in 
adult subjects [> 17 years of age, cyclosporine dosage will be based on an adjusted body weight 
that is calculated as the midpoint between the ideal body weight and actual body weight (see 
below for definition of ideal body weight).  Pediatric patients (aged 17 and under) will dose on 
actual body weight for patients < 125% Ideal Body Weight (IBW). For those >125% IBW, 
dosing will be based on adjusted ideal body weight (see below). 
For subjects < 12 years of age, cyclosporine will be increased to 6mg/kg/dose by mouth 
administered every 12 hours (total daily dose of 12 mg/kg/day). Patients aged 17 and under will 
dose on actual body weight for patients < 125% IBW. For those >125% IBW, dosing will be 
based on adjusted ideal body weight.  
Cyclosporine dosing will be adjusted, at the investigator's discretion, to aim for a therapeutic 
trough level between 200 and 400 mcg/L. In subjects who had a therapeutic CsA level 
established prior to protocol enrollment, the same CsA dose will be initiated with the h-ATG and 
adjusted accordingly. Cyclosporine dose may be interrupted or adjusted as clinically indicated at 
the discretion of the investigator for side effects. Interruptions or dose adjustments are as the 
consequence of a serious adverse event, the interruption will be included in the SAE Report. 
In between NIH landmark visits, only CsA levels will be tracked and recorded into the clinical 
database. 
Ideal Body Weight Definitions: 
Ideal body weight (adult male, age > 17): 50 kg + 2.3 kg per inch over 5 feet 
Ideal body weight (adult female, age > 17): 45.5 kg + 2.3 kg per inch over 5 feet 
Ideal body weight (pediatrics, ages 2–17): 

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a) < 5 feet tall: 
IBW (kg) = [height (cm)]2 x 1.65 / 1000 
b) 5 feet and taller: 
Male IBW (kg) = 39 + (2.27 x height in inches over 5 feet) 
Female IBW (kg) = 42.2 + (2.27 x height in inches over 5 feet) 
Pediatric patients (aged 17 and under) will dose on actual body weight for patients < 125% Ideal 
Body Weight (IBW). For those >125% IBW, will dose based on adjusted ideal body weight as 
follows: 
Adjusted Ideal Body Weight = IBW + 0.25 (Actual weight - IBW). Month 6 to Month 24 
cyclosporine dosing: 
At the 6-month landmark visit, responders will have the CsA dose reduced to 2 mg/kg/day 
administered orally at a fixed dose through the 24 month timepoint as done in 12-H-0150 
protocol. 
In event of relapse during treatment period, cyclosporine dose will be increased to full dose per 
PI discretion. In absence of response to cyclosporine, eltrombopag re-initiation will be 
considered per PI discretion. 
Medication dosing errors, dose delays or dosing interruptions: 
Interruptions such as delays in request for medication refills or medication errors by subjects, or 
during circumstances such as COVID 19 pandemic that do not result in a serious adverse event 
or impact the integrity of the research data, will only be recorded in the medical record. 
5.2 
ELTROMBOPAG 
Subjects will initiate EPAG at a starting daily dose as detailed in Table 3, according to age and 
ethnicity. Pediatric subjects between 12 and 17 years of age will receive the adult dose of 150 mg 
daily. Those between 6 and 11 will start at 75 mg, and children between 3 and 5 years of age will 
be started at 2.5 mg/kg (Table 1). 
To adjust for the higher expected exposure in patients from East Asian and Southeast Asian 
ancestry, the starting dose for East Asian and Southeast Asian subjects between 12 and 85 years 
of age will be 75 mg once daily.  For East Asian and Southeast Asian subjects between 6 and 11 
years of age, the starting dose will be 37.5 mg once daily, and for children between 3 and 5, the 
starting dose will be 1.25 mg/kg (Table 3).  EPAG will be administered orally as tablets or an 
oral suspension from sachet of EPAG powder. If an adult receives the oral suspension 
administration of EPAG, the required number of sachets will be used to administer the below 
adult doses. Detailed information about the supply and tablet/PfOS availability is in section 13.1. 
Table 1. Dosing according to age and ethnicity 

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Age groups 
Daily dose 
Non-Asian 
 
12-85 
150 mg 
6-11 
75 mg 
3-5 
2.5 mg/kg 
East Asian, Southeast Asian 
 
12-85 
75 mg 
6-11 
37.5 mg 
3-5 
1.25 mg/kg 
 
EPAG may be taken on an empty stomach (1 hour before or 2 hours after a meal) or with food 
containing little (<50 mg) or preferably no calcium or dairy products. Allow at least a 4-hour 
interval between EPAG and other medications or products containing polyvalent cations (e.g. 
calcium, magnesium, aluminum, zinc, selenium or iron) such as antacids, dairy products, and 
mineral supplements to avoid significant (70-75%) reduction in eltrombopag absorption due to 
chelation. 
EPAG dose may be interrupted when clinically indicated at the discretion of the investigator (for 
example if the patient is in the intensive care unit and unable to take PO medications).  
Interruptions such as delays in request for medication refills or medication errors by subjects, or 
during circumstances such as COVID 19 pandemic that do not result in a serious adverse event 
or impact the integrity of the research data, will only be recorded in the medical record. 
5.3 
DOSE ADJUSTMENTS OF ELTROMBOPAG 
The daily dose of eltrombopag will be decreased according to the following rules: 
Platelet Count  
Dose Adjustment or Response  
>200,000/L (untransfused) at any time on 
study 
Decrease dosage by 25mg every 2 
weeks to lowest dosage that maintains 
platelet count ≥ 50,000/L. In children 
under 12, the dose will be decreased by 
12.5 mg. 
>400,000/L (untransfused) at any time on 
study 
Discontinue eltrombopag for one week, 
if platelets fall to <200,000/L; restart 

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Platelet Count  
Dose Adjustment or Response  
at dosage decreased by 25 mg/day (or 
12.5 mg in children under 12). 
5.4 
DOSE DELAYS, MODIFICATIONS OR DISCONTINUATION OF ELTROMBOPAG FOR NON-
HEMATOLOGIC SIDE EFFECTS 
5.4.1 Infection 
Subjects who experience an infection requiring intravenous antibiotics will not have EPAG 
discontinued. If the subject experiences infection severe enough to require vasopressors or 
intubation, the drug will be withheld until the subject is stable. 
5.4.2 Liver function abnormalities 
Eltrombopag dose may be interrupted when clinically indicated at the discretion of the 
investigator. Recommend dose modifications for isolated ALT or AST elevation according to the 
following rules:  
Isolated ALT or AST elevation  
Dose modification  
>ULN – 3.0 x ULN 
Maintain dose level  
>3.0 – 5.0 x ULN 
 
Maintain dose level.  Repeat liver function tests 
as soon as possible, preferably within 48-72 
hours, from awareness of the abnormal results.  
If abnormal laboratory values are confirmed 
upon the repeat test, monitor liver function tests 
weekly or more frequently if clinically indicated 
until resolved to ≤3.0 x ULN. 
>5.0 – 10.0 x ULN 
Interrupt dose.  Repeat liver function tests as 
soon as possible; preferably within 48-72 hours 
from awareness of the abnormal results.  
Monitor liver function tests weekly, or more 
frequently if clinically indicated until resolved 
to ≤3.0 x ULN then: 
If resolved in ≤14 days, maintain dose level. 
If resolved >14 days, decrease one dose level 
>10.0-20.0 x ULN 
Interrupt dose.  Repeat liver function tests as 
soon as possible, preferably within 48-72 hours 
from awareness of the abnormal results. 
Monitor liver function tests weekly, or more 
frequently if clinically indicated until resolved 
to baseline.  Then decrease one dose level. 
>20.0 ULN 
Discontinue subject from study drug treatment. 
Repeat liver function tests as soon as possible, 
preferably within 48-72 hours from awareness 

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Isolated ALT or AST elevation  
Dose modification  
of the abnormal results.  Monitor liver function 
tests weekly or more frequently if clinically 
indicated until resolved to baseline or 
stabilization over 4 weeks. 
 
5.4.3 Skin rash 
If the subject experiences diffuse erythematous skin rash that appears to be drug related and no 
other drugs are implicated, EPAG will be discontinued. 
5.4.4  Dose modifications/discontinuation for other reasons 
Study drug dosing is to be temporarily discontinued in subjects unable to ingest the drug due to 
mucositis, persistent vomiting, or any other reasons during which patient is unable to take drug 
by mouth.  
Early discontinuation of treatment 
Eltrombopag must be permanently discontinued if any of the following events occur or is 
identified at any time during the study: 
1. Development of myelodysplastic syndrome, acute myeloid leukemia, or cytogenetic 
clonal evolution to chromosome 7 or complex karyotype 
2. Positive pregnancy test at any time during the study 
3. Difficulties to continue the study treatment due to treatment related AE(s) 
4. Subject is found to be significantly non-compliant with the requirements of the protocol 
(including treatment non-compliance) 
5.5 
DOSE DELAYS, MODIFICATIONS OR DISCONTINUATION OF ELTROMBOPAG FOR 
HEMATOLOGIC SIDE EFFECTS 
5.5.1 Thrombosis/Embolism 
Subjects who experience a deep venous thrombosis (other than a line-related upper extremity 
thrombosis) or a pulmonary embolus, a TIA or stroke, or a myocardial infarction at any time while 
on EPAG, it will be discontinued but CsA and hATG will be continued. Subjects with platelet 
counts of > 50,000/µL at the time of thrombosis will be treated with enoxaparin or another 
appropriate anticoagulant as clinically indicated unless the platelet count drops below 20,000/µL 
or they complete a standard 3-6 months course of anticoagulation. 
5.6 
HORSE ANTI-THYMOCYTE-GLOBULIN (H-ATG) ADMINISTRATION 
A single treatment course of h-ATG will be administered at a dose of 40 mg/kg/day for 4 days. h-
ATG will be administered after the patient establishes care here at the Clinical Center and all 
required tests are performed. Dose will be calculated based on actual body weight.  h-ATG will be 
infused intravenously for approximately 4 hours daily. The infusion time may vary based on the 
patient and circumstances. Infusion times may be extended up to 24 hours to improve tolerance of 
infusion related side effects such as fever, chills and hypotension if necessary. 
5.7 
PRE-MEDICATIONS AND MANAGEMENT OF INFUSION REACTIONS 

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Subjects will receive pre-medication approximately 30 minutes prior to infusion of ATG as 
follows: 
• oral diphenhydramine 1 - 1.5 mg/kg/dose (NTE 50 mg) administered orally or 
intravenously, and; 
• oral acetaminophen 10-15 mg/kg/dose (NTE 650 mg) 
Serum sickness prophylaxis with oral prednisone at 1 mg/kg/d will begin prior to the first dose of 
h-ATG, and will be continued for 10 days total and then tapered over the subsequent 7-14 days. 
Methylprednisone at equivalent doses may be substituted for prednisone. Those subjects who 
develop serum sickness may require a longer tapering schedule and will be dosed individually as 
clinically indicated. Infusion reactions will be treated symptomatically (e.g., antiemetics, IV fluid 
hydration, acetaminophen, antihistamines, inhaled bronchodilators, meperidine).  Prednisone 
dose will be calculated based on actual body weight. 
In case of moderate or severe reactions hydrocortisone will be given and the infusion will be 
discontinued and restarted at a slower rate once the symptoms have subsided. If a subject has a 
persistent severe infusion reaction that does not respond to measures to ameliorate the 
signs/symptoms associated with the infusion, the h-ATG infusion will be discontinued (see 
section off study criteria) and subjects will go off study. 
5.8 
SUPPORTIVE CARE 
• Transfusion support (blood and platelets) as clinically indicated. 
• Hematopoietic growth factors (e.g., G-CSF, GM-CSF, or erythropoietin) if deemed 
necessary by the investigator or treating physician. Romiplostim (N-Plate) or IL-11 
(Neumega) should not be administered. 
• Estrogen, combination OCP’s, or leuprolide as indicated for uterine bleeding (menses 
suppression). 
5.9 
CONCURRENT MEDICATIONS 
Cyclosporine/magnesium: Subjects on CsA are expected to have magnesium wasting as a 
common side effect as long as EPAG is administered 4 hours after oral magnesium. Magnesium 
supplementation will not be given concurrently with EPAG as it may interfere with EPAG’s 
absorption. The drug-drug interaction potential between EPAG and CsA is unknown. Both CsA 
and EPAG are inhibitors of OATP and BCRP drug transporters, and EPAG is a substrate of 
BCRP in vitro. It is not known if the combination will result in any PK changes to either drug. 
Subjects will be monitored for signs of CsA toxicity during the study, and therapeutic drug 
monitoring can be instituted as required. In the event of liver function abnormalities as a 
consequence of a drug-drug interaction between EPAG and CsA, EPAG will be dose-reduced 
according to section 5.4. 
Inhibitors of cytochrome p450: In vitro studies demonstrate that CYP1A2 and CYP2C8 are 
involved in the oxidative metabolism of eltrombopag. Trimethoprim, gemfibrozil, ciprofloxacin, 
fluvoxamine and other moderate or strong inhibitors of CYPs may therefore theoretically result 
enhanced activity of EPAG, however these interactions have not yet been established in clinical 
studies. All subjects on cyclosporine require prophylaxis against PCP and will be given inhaled 
pentamidine instead of Trimethoprim/sulfamethoxazole (TMP/SULF). 

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NIH SAA patients are routinely placed on pentamidine instead of TMP/SULF for PCP 
prophylaxis to avoid potential marrow-suppressive effects of TMP/SULF anyway.  Subjects aged 
5 years and over will receive pentamidine for PCP prophylaxis but children under 5 years of age 
(approximate) are often not able to complete the inhalation treatment with pentamidine and will 
receive dapsone or another prophylactic regimen. Other CYP inhibitors can be used 
concomitantly but with careful attention to possible increased EPAG activity and toxicity. 
Other medications: Subjects may continue on any of the medications that they were prescribed 
prior to study enrollment for co-morbid conditions, with the exception of N-Plate and Neumega 
(See Section 5.8). 
5.10 INFECTION PROPHYLAXIS AND MONITORING 
Pneumocystis jiroveci prophylaxis: During lower dose of CsA, routine Pneumocystis jiroveci 
phrophylaxis (PJP) is not indicated. However, in patients with severe lymphopenia (Absolute 
lymphocyte counts <500/uL), PJP prophylaxis will be considered per PI discretion. It will be 
initiated upon starting h-ATG and higher dose of cyclosporine 3mg/kg q12h (6mg/kg q12h for 
pediatric) at the Clinical Center. Aerosolized pentamidine will be used as prophylaxis against 
Pneumocystis jiroveci, 300 mg approximately every 4 weeks by inhalation beginning the first 
month of higher cyclosporine therapy and to continue until month 6 when the cyclosporine dose 
is reduced. 
Dapsone or another prophylactic regimen against Pneumocystis jiroveci may be substituted at the 
discretion of the PI. Bactrim (TMP/SULF) will be avoided because trimethoprim is a moderate 
to strong inhibitor of CYPs that may theoretically result in enhanced activity of EPAG. Children 
under 5 years of age (approximate) are often not able to complete the inhalation treatment with 
pentamidine and will receive dapsone or another prophylactic regimen at the discretion of the PI. 
Antiviral prophylaxis: During lower dose of CsA, Valcyclovir is not indicated. However, in 
patients with severe lymphopenia (Absolute lymphocyte counts <500/uL), Valacyclovir 
prophylaxis will be considered per PI discretion. Valacyclovir, 500 mg once daily, will be 
administered for at least 1 month in all subjects regardless of HSV serology status at the time of 
h-ATG and higher dose cyclosporine at the Clinical Center. Pediatric subjects less than 40 kg 
will receive acyclovir (or equivalent) at 20mg/kg PO q12h to a maximum dose of 800mg q12h.  
Prophylaxis may be extended at the discretion of the PI. 
Antibacterial and antifungal prophylaxis will not be included systematically with the 
immunosuppressive regimen but may be administered at the discretion of the PI or treating 
physician on a case-by-case basis. 
5.11 INSTRUCTIONS TO SUBJECTS 
Special instructions regarding CsA: 
Regarding concomitant medications: Certain medications can change the level of cyclosporine in 
the blood. Some of these medications are erythromycin, ketoconazole, diltiazem, rifampin, 
phenytoin and phenobarbital. We will ask subjects to inform us of any medication taking 
concomitantly while on the study. 
Regarding prohibited foods: Grapefruit and grapefruit juice may increase the effects of CsA by 
increasing the amount of this medicine in the body. Subjects will be advised not to eat grapefruit 
or drink grapefruit juice while taking this medicine. 

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Regarding Immunizations: While taking CsA and for at least three months following 
discontinuation, immunizations should be avoided, and any planned immunization should be 
discussed with study investigators. There is almost no possibility that a vaccination given during 
this time period will be effective in stimulating immunity. Any live or attenuated vaccine may 
result in an infection, due to compromised immunity on CsA and h-ATG. Subjects should also 
avoid close household contact with individuals receiving the live oral polio vaccine for at least 
72 hours following administration. 
Special instructions regarding eltrombopag: 
Timing in relation to food: Subjects will be advised to take EPAG on an empty stomach (1 hour 
before or 2 hours after a meal), or adhere to a restricted diet of low calcium (dairy products) and 
polyvalent cations at least 4 hours apart from co-administration of EPAG. 
Timing in relation to antacids and polyvalent cations: Because co-administration of EPAG with 
antacids decreased plasma AUC of EPAG by 70%, subjects will be advised to take the EPAG at 
least 4 hours apart from antacids and other products containing polyvalent cations (i.e. 
aluminum, calcium, magnesium, iron, selenium and zinc) such as mineral supplements and dairy 
products. 
5.12 
Complications 
Due to severely low blood counts in this disease process, there are several complications that 
may require urgent care/hospitalizations. Patients may receive this care at any hospital/facility 
that has capabilities of treating the presenting illness. Our research team will remain engaged in 
diagnostic/treatment decisions. Patients may be transferred to the Clinical Center if the treating 
hospital/facility lacks necessary treatment. 
Common reasons for hospitalization in SAA patients may include bleeding, infections, and 
anemia related symptoms. Common reasons for hospitalization for the study treatment may 
include malignant hypertension/posterior reversible encephalopathy syndrome, hepatotoxicity, 
and acute renal failure. 
6 
CLINICAL MONITORING 
Once patient has arrived at the Clinical Center, samples will be ordered and tracked through the 
CRIS Screens. Should a CRIS screen not be available, the NIH form 2803-1 will be completed 
and will accompany the specimen and be filed in the medical record. 
6.1 
PRE-STUDY EVALUATION/SCREENING 
The following general screening procedures will be done either remotely during the initial 
telephone interview based on the labs done outside of NIH or at the NIH for those that are able to 
arrive at the NIH <72 hours. 
• Medical history 
• Physical examination (will be confirmed with the referring hematologist) 
• Family history 
• Concurrent medications 

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PI may accept results from labs done outside of NIH as both screening and baseline as long as they 
are done within 30 days of enrollment, bone marrow aspirate/biopsy results will be accepted as 
long as it is performed within 90 days of enrollment: 
• Complete blood count with differential 
• Reticulocyte count 
• Type and screen 
• Acute care (Na, K, Cl, CO2, creatinine, glucose, and urea nitrogen), Hepatic (Alk 
Phosphatase, ALT, AST, and Total Bilirubin), and lactate dehydrogenase. Direct 
bilirubin will be obtained per PI discretion if total bilirubin is elevated.  
• Pregnancy test (urine or blood HCG in women of childbearing potential) 
• Bone marrow aspiration and core biopsy stained for standard morphologic analysis and 
quantitation of cellularity with hematoxylin and eosin. Marrow sample will be reviewed 
here at the NIH with our pathologist. 
• HIV serology (optional per PI discretion based on the clinical history) 
Clinical studies to be performed at the Clinical Center on first visit: 
• Complete blood count with differential and reticulocyte count 
• Type and screen 
• Acute care (Na, K, Cl, CO2, creatinine, glucose, and urea nitrogen), Mineral 
(Phosphorus, Magnesium, Albumin, and Calcium), Hepatic (Alk Phosphatase, ALT, 
AST, Total Bilirubin), and Other (Total Protein, Uric Acid, and LDH). Direct bilirubin 
will be obtained per PI discretion if total bilirubin is elevated. 
• Thyroid function tests, Folate, B12 level, iron panel (ferritin, transferrin, % saturation), 
DAT (direct antiglobulin test) 
• Viral serologies for hepatitis A, B, C, HIV, HSV, EBV, and CMV (if not already 
available) 
• PPD (at risk subjects only, based on history or geography) per PI discretion 
• Flow cytometry of the peripheral blood to quantitate GPI-negative cells 
• EBV and CMV PCR (if not already available)* 
• HLA typing (if not already available)* 
• Telomere length of leukocytes (if not already available)* 
• Diepoxybutane (DEB) testing for Fanconi anemia per PI discretion (if not already 
available)* 
• Lymphocyte peripheral blood phenotyping (analysis of T, B, and NK subsets via flow 
cytometry)* 
• Bone marrow aspiration and core biopsy to be stained for standard morphologic analysis 
and quantitation of cellularity with hematoxylin and eosin, and special stains to assess 
reticulin and collagen, primitive stem and progenitor cells via CD34 
immunohistochemistry, and other lineage-specific or special stains as indicated to 
classify any abnormalities** 
• Bone marrow chromosomal analysis via standard cytogenetic techniques** 
• EKG (to be done prior to h-ATG) 
• Placement of a central line if subject does not have a pre-existing indwelling central 
venous catheter if treatment with h-ATG is indicated 

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• Chest X-ray - (not required to be performed, per PI discretion)) 
 
* Results if performed within the last 180 days either at NIH or outside NIH may be 
accepted. Only repeated if there are changes in the clinical status that may impact the 
results. 
** At this visit, up to 30 mL total including the 15ml for exploratory/correlative research 
sample may be collected. For minors, the bone marrow biopsy & aspirate procedure will 
be done with general anesthesia. 
 
6.2 
ON STUDY OFF SITE MONITORING, PRIOR TO INITIAL CLINICAL CENTER VISIT IF 
ENROLLED ON STUDY REMOTELY 
Prior to establishing care at the Clinical Center, patient will be followed closely by his/her local 
physician under complete guidance of the team at the Clinical Center (Appendix B). Weekly (+/- 
3 days) telephone follow-up will be established with the patient. All the progress notes and labs 
indicated below will be requested to be sent from home physician to the research nurse. These 
documents will serve as source documents to collect data. 
If a patient is unable to participate in a weekly follow up due to acute illness and hospitalization, 
the team will make contact with the treating physician and document patient’s condition in lieu 
of a telephone follow up. 
• Every 2-4 weeks – Progress note including history and physical examination by local 
physician 
• Complete blood counts at least weekly (+/- 3 days), more frequent if clinically indicated. 
Frequency may be decreased to once every 2 weeks (+/- 4 days) per PI discretion. Only 
the following parameters will be recorded in the clinical database because of their 
relevance to the underlying disease and study treatment: absolute lymphocyte count 
(ALC) or lymphocyte percentage, absolute neutrophil count (ANC), or neutrophil 
percentage and white blood cell count if an absolute neutrophil count is not provided, 
hemoglobin, and platelets. Absolute reticulocyte count (or reticulocyte percentage and 
red blood cells [RBC] if an absolute reticulocyte count is not provided) will be recorded 
if available. 
• Hepatic and renal panels (home panels must include hepatic transaminases, urea nitrogen 
(BUN), serum creatinine, and total bilirubin) at least weekly (+/- 3 days), more frequent 
if clinically indicated. Frequency may be decreased to once every 2 weeks (+/- 4 days) 
per PI discretion. 
• Only the following parameters will be recorded in the clinical database because of their 
relevance to the underlying disease and study treatment: aspartate aminotransferase 
(AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), total bilirubin, 
creatinine, blood urea nitrogen (BUN), glucose, sodium, potassium, CO2 and chloride. 
Direct bilirubin will be obtained per PI discretion if total bilirubin is elevated. 
• CsA blood level will only be obtained per PI/local physician discretion as clinically 
indicated. Due to low dose, there is no therapeutic target. 
6.3 
ON STUDY MONITORING, DAY 1 OF H-ATG THROUGH HOSPITAL DISCHARGE 

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On treatment monitoring will consist of the following, unless the hospitalization is interrupted 
due to the participant leaving the hospital “on pass” but not to exceed more than 7 days: 
• Pregnancy test (urine or blood HCG in women of childbearing potential) does not need to 
be repeated if done within two weeks of initiation of h-ATG unless clinically indicated  
• CBC with differential (daily)* 
• Acute care, Mineral, and Hepatic (every other day)* 
• Reticulocyte count (weekly +/- 3 days)* 
• Vital signs (daily) 
• CsA blood level will be monitored every week (+/- 3 days) while inpatient in the hospital 
and continued per section 6.4. The blood level will be monitored to ensure therapeutic 
range of 200 – 400 ng/ml is achieved. CsA dosage will be adjusted to target this range 
unless otherwise indicated by PI due to toxicities or intolerance. More frequent drug 
serum levels may be obtained as needed to achieve target therapeutic levels and avoid 
toxicity. 
*In case of prolonged hospitalization (beyond 14 days), the marked labs will be required no more 
than twice a week. 
6.4 
ON STUDY MONITORING (HOSPITAL DISCHARGE THROUGH 6 MONTHS) 
After completing h-ATG administration, subjects will remain hospitalized until clinically stable. 
Post-discharge, subjects may be followed by their home physician or at the Clinical Center. 
Progress notes and laboratory results from home physicians will be faxed to the research nurse. 
Standard of care tests will be done as needed and may include the tests listed below. Changes in 
frequency of the tests below will be performed as clinically indicated at the investigator’s 
discretion. 
• Complete blood counts with differential every 1-2 weeks (+/-4 days). Only the following 
parameters will be recorded in the clinical database because of their relevance to the 
underlying disease and study treatment: absolute lymphocyte count (ALC) or lymphocyte 
percentage, absolute neutrophil count (ANC), or neutrophil percentage and white blood 
cell count if an absolute neutrophil count is not provided, hemoglobin, platelets, and 
absolute reticulocyte count (or reticulocyte percentage and red blood cells [RBC] if an 
absolute reticulocyte count is not provided). 
• Hepatic and renal panels (home panels must include hepatic transaminases, urea nitrogen 
(BUN), serum creatinine, and total bilirubin) every 1-2 weeks (+/- 4 days). Magnesium 
may be requested in patients with hypomagnesemia per PI. 
 
Only the following parameters will be recorded in the clinical database because 
of their relevance to the underlying disease and study treatment: aspartate 
aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase 
(ALP), total bilirubin, creatinine, blood urea nitrogen (BUN), glucose, sodium, 
potassium, CO2 and chloride. Direct bilirubin will be obtained per PI discretion 
if total bilirubin is elevated. 
• CsA blood levels will be monitored every week (+/- 3 days) for the first month and then 
every 2 weeks (+/- 4 days) for the remainder of the treatment period once levels are 
stabilized in the therapeutic range of 200 – 400 ng/ml. CsA dosage will be adjusted to 

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target this range unless participants cannot tolerate therapeutic dosing of CsA. More 
frequent drug serum levels may be obtained as needed to achieve target therapeutic levels 
and avoid toxicity, and conversely less frequent levels may be obtained as needed in 
individuals unable to tolerate therapeutic dosing of CsA. The dose may not necessarily be 
adjusted following every out of range CsA level; the decision to adjust the dose will be 
determined by the clinician judgement based on multiple data sources, that could include 
but not limited to time of measurement, prior trend of CsA levels, estimation of steady 
state, concomitant medications that may affect CsA metabolism, and renal function. CsA 
monitoring will be discontinued at 6 months. 
Landmark 1, 2, 3 and 6-month monitoring 
Subjects must be evaluated at the NIH Clinical Center at the 6-month (+/-10 days) time point. 1 
and 2-month (+/- 10 days) landmark time points are for evaluation of early hematological 
response only; therefore, do not require a visit at the Clinical Center. Per PI discretion, the 3 
month time point visit may be conducted with subjects’ local physician during special 
circumstances, where the risk of evaluation at the CC may outweigh the benefit. Tests with * 
below can be omitted from 3 month evaluation if the visit is being conducted with home 
physician. In addition, a tele/video meeting with the patient will be conducted by the bone 
marrow failure team member. 
1- and 2-month 
• Complete blood counts with differential 
• Reticulocyte count 
3- month and 6- month 
• History and physical examination 
• Complete blood counts with differential 
• Acute care (Na, K, Cl, CO2, creatinine, glucose, and urea nitrogen), Mineral 
(Phosphorus, Magnesium, Albumin, and Calcium), Hepatic (Alk Phosphatase, ALT, 
AST, Total Bilirubin), and Other (Total Protein, Uric Acid, and LDH). Direct bilirubin 
will be obtained per PI discretion if total bilirubin is elevated. 
• Reticulocyte count and other (cyclosporine level, ferritin, iron, transferrin, lactate 
dehydrogenase, protein) 
• Urine pregnancy test (woman of childbearing age only) 
• Bone marrow aspiration and core biopsy, to be stained for standard morphologic analysis 
and quantitation of cellularity with hematoxylin and eosin, and special stains to assess 
reticulin and collagen, primitive stem and progenitor cells via CD34 
immunohistochemistry, and other lineage-specific or special stains as indicated to 
classify any abnormalities** 
• Bone marrow chromosomal analysis via standard cytogenetic techniques** 
• Flow cytometry of the peripheral blood to quantitate GPI-negative cells 
• Lymphocyte peripheral blood phenotyping (analysis of T, B, and NK subsets via flow 
cytometry)* 
• EKG will be performed at 3 months 
• Transfusion records to be obtained including number of transfusions since last landmark 
visit as well as date of last transfusion 

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** At each of these visits, up to 30 mL total including the sample for research may be collected. 
Bone marrow aspiration, biopsy, and chromosomal analysis may be omitted if one was 
performed within 4 weeks of the timepoint analysis. 
6.5 
LONG TERM FOLLOW UP (6 MONTHS TO 5 YEARS) 
After the 6-month visit, subjects must be evaluated at the Clinical Center at 12 months (+/- 30 
days) and then yearly thereafter to 5 years (+/- 90 days) except in special circumstances (see 
below). Subjects will be seen by their home physician as clinically indicated and the Hematology 
Branch investigators and home physicians will remain in communication. Home physicians will 
monitor blood counts and other clinical parameters as clinically indicated. The following tests 
will be performed at each Clinical Center visit. At the clinical investigator’s discretion, 
participants may be evaluated more frequently if medically indicated based on disease status. 
PI discretion, during special circumstances (such as COVID 19 outbreak) where the risk of 
evaluation at the CC may outweigh the benefit, a tele/video visit may be conducted and test 
results received from subjects’ local physician may be used. Tests with * below can also be 
omitted. 
• History and physical examination 
• Complete blood counts with differential 
• Acute care (Na, K, Cl, CO2, creatinine, glucose, and urea nitrogen), Mineral 
(Phosphorus, Magnesium, Albumin, and Calcium), Hepatic (Alk Phosphatase, ALT, 
AST, Total Bilirubin), and Other (Total Protein, Uric Acid, and LDH). Direct bilirubin 
will be obtained per PI discretion if total bilirubin is elevated 
• Reticulocyte count and other (ferritin, iron, transferrin, lactate dehydrogenase, protein) 
• Urine pregnancy test (woman of childbearing age only) 
• Bone marrow aspiration and core biopsy, to be stained for standard morphologic analysis 
and quantitation of cellularity with hematoxylin and eosin, and special stains to assess 
reticulin and collagen, primitive stem and progenitor cells via CD34 
immunohistochemistry, and other lineage-specific or special stains as indicated to 
classify any abnormalities (optional for year 3, 4 and 5 depending on the peripheral blood 
counts and concern for clonal evolution)* 
• Bone marrow chromosomal analysis via standard cytogenetic techniques (optional for 
year 3, 4 and 5 depending on the peripheral blood counts and concern for clonal 
evolution)* 
• Flow cytometry of the peripheral blood to quantitate GPI-negative cells 
• Lymphocyte peripheral blood phenotyping (analysis of T, B, and NK subsets via flow 
cytometry) 
• Date of last transfusions (both blood and platelets) to be recorded in database since 
landmark visit 
*At these visits, up to 30 mL total including the 15ml for exploratory/correlative research sample 
may be collected.  For minors, the bone marrow biopsy & aspirate procedure will be done with 
general anesthesia. 
6.6 
GENETIC AND OTHER TESTS (MAY BE PERFORMED IN SOME PATIENTS) 
• Testing for acquired somatic mutations in genes linked to leukemia and bone marrow 

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failure in a CLIA-certified commercial, and flow cytometry may be performed. 
• Presence of mutations in genes known to be associated with inherited bone marrow 
failure disorders and/or telomere length in a CLIA-certified laboratory. When novel 
mutations are found, the respective samples may be further evaluated. 
• Diepoxybutane stimulation testing of peripheral blood may be performed in subjects with 
cytopenias under the age of 40 or if clinical history or characteristics suggest Fanconi 
anemia. 
6.7 
RETURN OF RESEARCH RESULTS 
For tests performed at the Clinical Center, if there are not expected (incidental) research test 
results relevant to subjects’ disease (SAA) and can put them at high risk of other disease, we will 
provide subjects with the test results and the appropriate follow-up information. 
6.8 
EXTENDED ACCESS FOR RELAPSE 
Indicated below are the procedures that can be performed on subjects that re-start oral drugs 
(cyclosporine, eltrombopag or both) due to relapse. At the clinical investigator’s discretion, 
participants may be evaluated as medically indicated based on disease status. The procedures 
may be performed by the subjects’ home physician or at the Clinical Center. If testing is done by 
home physician, progress notes and laboratory results from home physician will be sent to the 
research team. Subjects will be seen at the Clinical Center as clinically indicated while on 
extended access for relapse, but no less than annually until 5 years. Below is the list of 
procedures that may be performed at the clinical center visit at least once per year (+/- 90 days) 
or more frequently as medically indicated. 
Procedures that may be performed when drugs are re-started: 
• History and physical examination 
• Pregnancy test (urine or blood HCG in women of childbearing potential) – Optional  
• Complete blood counts with differential 
• Reticulocyte count 
• Chemistry panel (NIH Acute care, Mineral, Hepatic and Other panel, home laboratory 
chemistry panel must include electrolytes, hepatic transaminases, urea nitrogen (BUN), 
serum creatinine, total bilirubin, and reticulocyte count) 
• CsA blood level will be monitored until levels are stabilized in the therapeutic range of 
200 – 400 ng/ml. CsA dosage will be adjusted to target this range. More frequent drug 
serum levels may be obtained as needed to achieve target therapeutic levels and avoid 
toxicity.  This test is only required if patient is on therapeutic levels of cyclosporine. 
• Bone marrow aspiration and core biopsy, to be stained for standard morphologic analysis 
and quantitation of cellularity with hematoxylin and eosin, and special stains to assess 
reticulin and collagen, primitive stem and progenitor cells via CD34 
immunohistochemistry, and other lineage-specific or special stains as indicated to 
classify any abnormalities (optional for year 3,4, and 5 based on the peripheral blood 
counts and concern for clonal evolution)* 
• Bone marrow chromosomal analysis via standard cytogenetic techniques (optional for 
year 3,4, and 5 based on the peripheral blood counts and concern for clonal evolution)* 
• Flow cytometry of the peripheral blood to quantitate GPI-negative cells 

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• Lymphocyte peripheral blood phenotyping (analysis of T, B, and NK subsets via flow 
cytometry) 
*At these visits, up to 30 mL total including the 15ml for exploratory/correlative research sample 
may be collected.  For minors, the bone marrow biopsy & aspirate procedure will be done with 
general anesthesia. 
6.9 
COVID-19  
The impact of COVID-19 infection on SAA patients with marked neutropenia and with 
immunosuppressive treatment is currently unknown. Known risk factors include high age, and 
comorbidities particularly heart and lung disease. Data is limited and conflicting regarding the 
risks in immunosuppressed patients. Following treatment guidelines are made with current 
available information and may be amended with future evidence. Patients will be monitored with 
clinical vigilance and expedited testing in suspected cases. 
• All patients will be educated on preventative practices.  
• PCR test for SARS-CoV2 and respiratory viral panel will be performed in patients with 
fever, upper or lower respiratory tract symptoms. 
• In patients with mild COVID-19 infection, lower dose CSA and EPAG treatment will not 
be delayed. 
• In patients with severe COVID-19 infection, lower dose CSA and EPAG treatment may 
be delayed per PI discretion. 
• Standard of care treatment (h-ATG, higher dose CSA and EPAG), which is more 
immunosuppressive than lower dose CSA, will be delayed at least 2 weeks from the 
diagnosis of COVID-19 and may be longer in severe cases based on their clinical 
condition. 
7 
CRITERIA FOR RESPONSE/CLONAL EVOLUTION/RELAPSE 
Misdiagnosis is defined as diagnosis of other hematological or non-hematological condition to 
explain peripheral pancytopenia. 
Non-compliance for feasibility is defined as not following up at the Clinical Center by 8 weeks 
(or within allowed grace period in special circumstances defined in section 9.6) or failure to 
comply with the recommended oral treatment or clinical/laboratory assessment. 
Response is defined as blood counts no longer meeting the standard (“Camitta”) criteria for 
severe pancytopenia in SAA (Section 4.1), equivalent to 2 of the following values obtained on 2 
serial blood count measurements at least one week apart at landmark time points (2, 3, and 6 
months). 
• Absolute neutrophil count 500/ L 
• Platelet count  20,000/ L 
• Reticulocyte count  60,000/ L 
A complete response (CR) will be defined as (all 3 must be met): 
• Absolute neutrophil count 1,000/ L 
• Platelet count 100,000/ L 
• Hgb10 g/dL 

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A partial response (PR) will be defined as blood counts that do not meet criteria for severe 
pancytopenia but are not sufficient for a CR. 
Improvement in counts that are dependent upon exogenously administered growth factors or 
transfusion will not be considered as fulfilling response criteria. 
Clonal Evolution: The presence of evolution to PNH will be defined by flow cytometric 
detection of > 1% GPI-deficient neutrophils at baseline and landmark time points through 5 years 
(only the ones where patient is evaluated at the Clinical Center, excludes months 1 and 2). 
Evolution to hyperproliferative/dysplastic myelodysplasia and/or acute leukemia will be assessed 
at landmark time points, or as clinically indicated between landmarks by examination of 
peripheral blood and bone marrow based on diagnosis and classification according to the WHO 
2016 criteria. Evolution to clonal hematopoiesis will be defined by detection of new bone 
marrow cytogenetic abnormalities at landmark time points. 
Relapse: 
In this protocol, relapse is defined as having, EITHER, 
1. Blood count decline to a degree where they again meet “Camitta” criteria (see Section 
4.1) for severe aplastic anemia determined from at least 2 blood count measurements 
done within 14 days, or 
2. Progressive decline in one or more blood counts, not explained by another clinical 
process (e.g. acute infection or medication related) determined from at least 2 blood 
count measurements done within 14 days. 
The date of relapse will be recorded into the clinical database as the date the participant resumed 
immunosuppression with CsA or required higher doses of CsA if on the low dose prior to the 2-
year landmark visit, resumed EPAG or h-ATG (if subject had not received h-ATG previously), 
or proceeded with another treatment for SAA. 
A description of how the clinical assessment was made by the PI will be recorded in the clinical 
database. To corroborate the relapse, the most recent blood counts collected prior to the date of 
relapse will be recorded into the clinical database with the following parameters: absolute 
neutrophil count, or neutrophil percentage and white blood cell count if ANC is not available, 
hemoglobin, absolute reticulocyte count (or reticulocyte percentage and RBC if absolute 
reticulocyte count is not available) and platelets. 
8 
EXPLORATORY LABORATORY RESEARCH STUDIES 
Intended use: During the course of participating on this study, additional 60 cc of blood (3 
ml/kg not to exceed 60 ml of blood for pediatric subjects) at first visit to the Clinical Center and 
at landmark visits at 3, 6, 12 months and annually thereafter, and 15 ml of bone marrow aspirate 
(prior to ATG, 3 months, 6 months, 12 months, and annually thereafter) may be obtained for 
correlative laboratory research studies. Up to an additional 10 cc of blood may be collected 
during follow up every 1-6 months (according to how often they get their counts checked) for 
correlative laboratory studies. The protocol will cover shipment materials/costs for these 
additional samples to be returned to the NIH since they are for research use (no results given). 
Initial samples collected upon first visit at the Clinical Center may be obtained on another 
protocol, such as 04-H-0012. These studies are not used in assessing the primary endpoint but 

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are undertaken as descriptive or exploratory ancillary studies as listed below. Some or all may be 
performed on each subject, and they may be correlated with response. 
• Thrombopoietin level 
• CD34 cell number in whole blood and bone marrow aspirate by flow cytometry 
• T cell receptor V-beta profile in the marrow and peripheral blood 
• Extended peripheral blood flow cytometric phenotyping for cell surface or intracellular 
proteins 
• Evaluation for the presence of abnormalities of the telomere repair complex including 
telomere length, DEB testing for Fanconi anemia.  
• Evaluation for the presence of abnormalities of genes associated with hematopoiesis, via 
genetic testing or gene expression analysis. 
• Evaluation for the presence of abnormalities of genes associated with inherited bone 
marrow failure or inborn errors of immunity. 
• Serum cytokine, chemokines and soluble receptor levels 
• Serum (or plasma) and cells for viral analyses 
• Hematopoietic progenitor colony, long term-culture-initiating cell, and immunodeficient 
mouse engraftment assays for primitive cell content and function 
• Single cell RNAseq or multi-omics on bone marrow specimens to detect chromosomal 
aneuploidy before and after treatment. 
• Telomere length on peripheral blood leukocytes by flow-FISH before and after treatment 
9 
BIOSTATISTICAL CONSIDERATIONS 
9.1 
PRIMARY ENDPOINTS 
The primary endpoint of this pilot study is to evaluate the safety and feasibility of rapid initiation 
of oral treatment regimen, CsA + EPAG prior to receiving standard regimen at the Clinical 
Center in treatment naïve SAA as a composite measure of the following: 
• Rates of TRSAE (treatment related serious adverse events) compared to standard regimen 
(protocol 12-H-0150). TRSAE are defined in section 9.5. 
• Rates of mis- and altered diagnoses compared to standard regimen. Misdiagnosis is 
defined as diagnosis of other hematological or non-hematological condition to explain 
peripheral pancytopenia such as myeloid neoplasm. 
• Number and proportion of patients who are unable to comply with the outpatient early 
drug regimen and withdraw from study or who do not present to the Clinical Center for 
evaluation within 8 weeks (or within allowed grace period in special circumstances 
defined in section 9.6) 
9.2 
SECONDARY ENDPOINTS 
Secondary endpoints will be: (a) hematological response at 1, 2, 3, 6 and 12 months and yearly 
thereafter; (b) relapse; (c) clonal evolution to PNH, clonal chromosomal population in bone 
marrow, myelodysplasia by morphology, or acute leukemia; (d) overall survival; (e) 
hematological response of relapse subjects that re-start treatment with cyclosporine and/or 
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Subjects will be followed up to 60 months so that long-term disease-free and overall survival can 
be estimated. Response and toxicity comparisons will be made with previous IST combined with 
eltrombopag protocol (12-H-0150) 
9.3 
SAMPLE SIZES AND STATISTICAL DESIGN 
Cohort 1: Since safety and feasibility is defined in Section 9.1 to be the primary endpoint of this 
study, the treatment is defined to be “feasible” to a patient if he/she meets the safety and 
feasibility criteria specified in Section 9.1 at the end of study treatment period. Study treatment 
period is defined as the duration from the initiation of oral treatment to the start of standard of 
care treatment here at NIH. “Feasibility” is defined as tolerating treatment without the composite 
of TRSAE/misdiagnoses/noncompliance (defined in section 9.1). Our past experience with the 
standard 3 drug regimen (12-H-0150) suggests that the probability of feasibility for this patient 
population is approximately 90%. We hypothesize that the actual feasibility probability using this 
novel treatment paradigm may decrease to 75%, therefore a probability of 75% or less would 
warrant terminating this novel treatment approach. The hypotheses are equivalent to H0: p ≤75%, 
in which feasibility is unacceptable, and H1: p ≥ 90%, in which feasibility is acceptable. Our 
sample size is determined by testing this hypothesis at a significance level of 0.05 and 0.80 
power. We intend to test this treatment approach using a small number of patients and terminate the 
study if early evidence suggests that the feasibility probability diminishes below the benchmark 
of 75%. We determine the sample size using the Two-Stage Minimax Design of Simon (1989), 
since it requires a smaller total number of subjects (n = 39) compared to the Two-Stage Optimal 
Design (n = 48). At the first stage, 22 subjects will be accrued, and the null hypothesis will be 
accepted if 17 or fewer subjects are determined to be feasible to the treatment within defined 
treatment period. Therefore, if 18 or more subjects are feasible to the treatment at the first stage, 17 
additional subjects will be accrued. The null hypothesis of p ≤75% will be accepted if the total 
number of patients feasible to the treatment are 33 or fewer. 
After 39 patients are accrued on Cohort 1, we will start accruing patients on Extension Cohort.  
The 1-year HR clonal evolution rate of 8% from the 12-H-0150 protocol (Cohort 3 + Extension 
arm) is used as a benchmark for our population. The 1-year HR evolution rate in the 20-H-0033 
study currently stands at 3.8%, with a 95% CI of [0, 10%]. Our objective is to achieve a more 
precise point estimate for the 1-year HR clonal evolution rate. If we increase the sample size to 
80 patients total (Cohort 1 + Extension Cohort) and assume that the HR evolution rate will stay 
at 3.8%, our confidence width narrows to [0, 7.8%], the upper bound of which is below the 8% 
historical rate, in which case we can more confidently conclude a benefit in the rate of HR clonal 
evolution. With 39 subjects already accrued in this study, an additional 41 subjects will need to 
be recruited. 
9.4 
STATISTICAL METHODS 
The planned analyses will be based on the “intention-to-treat” principle and include descriptive 
statistics on the proportions of feasible patients. The feasibility probability will be estimated 
using the sample proportion, and its inferences, including confidence intervals and hypotheses 
testing, will be evaluated using Binomial distributions. Survival analysis for time-to-death and 
time-to-response will include methods based on the Kaplan-Meier estimates and the Cox 
Proportional Hazard regression. If it is appropriate, we will consider additional analyses for the 
primary and secondary endpoints using the analysis of variance, multiple regression and logistic 
regression models. Graphical tools will be used to display the appropriate estimates (i.e. 

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estimated proportions and the Kaplan-Meier curves) and their corresponding 95% confidence 
intervals. 
9.5 
STOPPING RULES 
 
In addition to the safety and feasibility criteria used in the primary endpoint (Section 9.1), we 
will also monitor a specified set of treatment related serious adverse events (TRSAEs) within the 
defined treatment period. This is the period of up to 8 weeks (or the allowed grace period in 
special circumstances defined in section 9.6) from initiation of oral therapy until evaluation at 
the clinical center.  This safety monitoring is to ensure that the rate of TRSAEs does not 
substantially exceed an anticipated rate. The following TRSAEs will be monitored for early 
stopping of the study: 
• Death considered to be probably or definitely related to the oral treatment during the 
study treatment period 
• Any grade IV toxicities considered to be probably or definitely related to the treatment 
• Death related to misdiagnosis and delay in appropriate treatment 
The study will be monitored using the stopping rules as outlined below for early stopping if the 
number of subjects in the study who have developed one or more of the above specified TRSAEs is 
over a pre-specified threshold value. TRSAEs are those attributed as definitely or probably related 
to eltrombopag. 
From our experience using this agent in other clinical settings, we anticipate the rate of developing 
at least one of the above specified TRSAEs for this patient population to be 20% or less. Our 
stopping rule is determined by a Bayesian approach based on Geller et al. publication[44]. The 
stopping boundary for the study is reached if the Bayesian posterior probability that the true 
probability of developing one or more of the above specified TRSAEs exceeds this benchmark rate 
of 20% is at least 90%. We take our prior distribution to be a beta distribution with the sum of the 
two beta parameters to be 5.5, i.e. the parameters of the beta prior distribution are 1.10 and 4.40. 
Since we have seen in the past that the first few subjects to be accrued are possibly sicker than the 
rest of the subjects in the sample, we will start safety monitoring the study when 3 or more subjects 
have developed specified TRSAEs. The following tables summarize the threshold numbers for 
stopping the study: 
Number of Tx subjects enrolled 
Stop if the number of Tx subjects who  
develop any of the specified TRSAEs 
reaches: 
≤ 5 
3 
≤ 8 
4 
≤ 12 
5 
≤ 16 
6 
≤ 20 
7 
≤ 24 
8 

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Number of Tx subjects enrolled 
Stop if the number of Tx subjects who  
develop any of the specified TRSAEs 
reaches: 
≤ 28 
9 
≤ 32 
10 
≤ 36 
11 
≤ 39 
12 
For a simulation study of the stopping rule, we generated a study with 39 independent 
Bernoulli trials, each had a probability p for having the above TRSAE and q=1-p for not 
having such TRSAE and compared the TRSAE outcomes with the above stopping 
boundary to determine whether the study was stopped. We repeated the simulation 
100,000 times and computed the proportion of stopped studies (i.e. “number of stopped 
studies”/100,000), which were stopped using the above stopping rule. The following 
table summarizes the proportions of stopped studies under a number of scenarios for p: 
Probability of 
Monitored”  
TRSAE= p 
5% 
10% 
15% 
20% 
25% 
40% 
Proportion of 
stopped studies 
0.15% 
1.62% 
7.26% 
21.74% 
44.48% 
95.30% 
Average number  
of Tx subjects 
38.95 
38.51 
37.08 
33.80 
28.80 
13.32 
Average number  
of Tx with a  
specified TRSAE 
1.95 
3.85 
5.56 
6.76 
7.20 
5.33 
The above results suggest that the above stopping rules have a low probability of stopping a study 
when the proportion of the corresponding specified TRSAE is below the benchmark value of 20%, 
and the probability of stopping a study is high when the true proportion of the above specified 
TRSAE exceeds this benchmark value. Based on these results, we believe that our Bayesian 
stopping rules have satisfactory statistical properties. 
9.6 
OFF TREATMENT AND OFF STUDY CRITERIA  
All subjects will go off study after 5-year NIH landmark visit. 
Subject choice:  Subjects may be removed from study at their request at any time. The risks 
of withdrawing will be discussed, as will alternative treatment options. The risks of 
withdrawing from the study including high mortality rate with supportive care only (if that 
is chosen) will be discussed in detail with the patient. Those subjects who choose to 

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withdraw will be strongly encouraged to continue to have blood counts monitored until 
initiation of alternative SAA therapy or through the 6 months off study medication to assess 
for late occurring adverse events. 
Principal investigator decision: Should any of the following events occur, study drug 
administration will be discontinued, and the subject will be followed until resolution of the 
event and labs will be monitored at least every week or as clinically indicated until he/she 
initiates alternative SAA therapy or through 6 months off study drug time point. 
Appropriate clinical experts such as ophthalmologist, etc. will be consulted as deemed 
necessary.  
Adverse events related to: 
• Death or any grade IV adverse event considered to be probably or definitely related to 
EPAG 
• Life threatening acute hypersensitivity reactions 
• Intolerance of eltrombopag not resolved by dose reduction 
• Thrombosis/embolism (DVT, PE, stroke or TIA, myocardial infarction) other than line 
associated thrombosis 
• Persistent hepatotoxicity as defined in section 6.4.2 
• Infusion-related h-ATG reactions refractory to all appropriate supportive measures 
 
Should any of the following events occur, study drug administration will be discontinued, 
and the subject will be taken off study. 
Clonal evolution or relapse: 
• Evidence of a poor risk clonal disorder (chromosome 7 abnormalities or complex 
cytogenetics) at any time while on study 
• Evidence of myelodysplastic syndrome or AML according to WHO criteria at any time 
while on study 
• Relapse criteria are met and treatment other than CsA and EPAG are started 
Other 
• Persistent non-compliance or lost to follow-up per PI discretion* 
• Patients who require chemotherapeutic treatment or require drugs with hematological 
effects 
• Initiation of additional immunosuppressive therapy other than steroids or cyclosporine (if 
beyond 6 months then mycophenolate mofetil can also be administered per PI discretion 
in patients who cannot tolerate cyclosporine and who require immunosuppression) or if 
beyond 2 years, enroll in other available clinical trials. 
 
Pregnancy: This protocol does not enroll patients who are pregnant or women of child-bearing 
potential unless they are using contraception during the study treatment period (Section 4.3). 
Because aplastic anemia is a disease of young adults, if a woman becomes pregnant while 
participating in the study despite stringent contraception requirements and education by the study 
team regarding the risks of relapsed aplastic anemia with pregnancy upon study entry and at 

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every landmark visit, patient may remain on study. This limited inclusion of pregnant women on 
this study permits capture of the secondary endpoint (relapse of aplastic anemia) without 
exposing the subject/fetus/neonate to study drugs or invasive protocol procedures.  
- 
If a patient becomes pregnant while on study drugs (CSA and/or EPAG), patient will 
discontinue the medications immediately but may remain on study 
- 
If a patient becomes pregnant during follow-up period and not on any study treatments, 
patient may remain on study  
- 
No investigational interventions or research procedures will be performed during 
pregnancy (if landmark visit is due during pregnancy, it will be delayed till after). All 
clinical decisions about pregnancy management will be made by the patient and the 
treating physician.  
- 
If a patient relapses with aplastic anemia during pregnancy, no treatment will be 
provided on study; recommendations will be provided to the local treating physician for 
clinical management and if pursued any treatment other than supportive care 
(transfusions), patient will be taken off study  
- 
Blood count monitoring with complete blood counts (CBCs) will be obtained with 
increased frequency than otherwise indicated, especially in later gestation, to monitor for 
AA relapse  
- 
Fetus/neonate is not a research subject in this protocol  
- 
No inducements, monetary, or otherwise, will be offered to terminate a pregnancy 
- 
Individuals engaged in the research will have no part in any decisions as to the timing, 
method, or procedures used to terminate a pregnancy. 
- 
Individuals engaged in the research will have no part in determining the viability of a 
neonate. 
- 
At the conclusion of pregnancy, participant may remain on study, and resume protocol 
procedures for both safety and efficacy endpoints. 
*Please note that subjects not following up at the Clinical Center by 8 weeks or who fail to 
comply with the recommended oral treatment or clinical laboratory assessment may be taken off 
the study. However, per PI discretion, a “grace period” of additional 4 weeks may be granted if a 
patient is unable to present to the CC due to logistical reasons beyond their control such as 
inability to obtain visa, critical illness requiring hospitalizations etc., so long as they are 
responding to the oral treatment. During special circumstances such as COVID 19 outbreak, 
“grace period” may be extended up to 6 months per PI discretion.  
Once off study, subjects will be referred back to the referring physician or consented to the 
NHLBI Standard of Care protocol (20H0099) for consideration for standard therapy or they may 
be evaluated for eligibility for another NIH protocol, depending on what is considered to be in 
the best interest of the subject. 
 
 
 
 

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10 SAFETY AND OTHER ASSESSMENTS 
10.1 SAFETY MONITORING 
Principal Investigator: Accrual, efficacy and safety data will be monitored by the Principal 
Investigator, Bhavisha Patel, M.D. Quality assurance and control monitoring will be consistent 
with the NHLBI Division of Intramural Research Clinical Research Quality Assurance and Quality 
Control Policy. 
NHLBI DSMB: The NHLBI Data Safety and Monitoring Board will review the protocol at 6 to 
12 month intervals. A progress report will be forwarded to the DSMB at these times and their 
recommendations will be expeditiously implemented. The DSMB may recommend early 
termination of the study for considerations of safety and efficacy. 
Novartis: An annual progress report, any amendment to the protocol, and any change in the 
status of the protocol will be forwarded to Novartis. 
10.2 ASSESSMENT OF SAFETY 
Definitions 
Adverse Event (AE): Any untoward medical occurrence in a human subject, including any 
abnormal sign (e.g., abnormal physical exam or laboratory finding), symptom, or disease, 
temporally associated with the subject’s participation in the research, whether or not considered 
related to the subject’s participation in the research (21 CFR 312.32 (a)). 
Non-hematologic abnormal laboratory findings used to evaluate the safety of this protocol 
regimen will include any change from laboratory assessments done prior to first dose of 
study medication that result in a progression to a grade 3 or 4 laboratory toxicity or are 
characterized by any of the following: 
• 
Results in discontinuation from the study 
• 
Is associated with clinical signs or symptoms 
• 
Requires treatment or any other therapeutic intervention 
• 
Is associated with death or another serious adverse event, including hospitalization 
• 
Is judged by the Investigator to be of significant clinical impact 
• 
If any abnormal laboratory result is considered clinically significant, the investigator will 
provide details about the action taken with respect to the test drug and about the patient’s 
outcome. 
Serious Adverse Event (SAE): An adverse event or suspected adverse reaction is considered 
“serious” if, in the view of either the investigator or sponsor, it results in any of the following 
outcomes: 
• results in death; 
• is life-threatening (places the subject at immediate risk of death from the event as it 
occurred); 
• results in in-patient hospitalization or prolongation of existing hospitalization; 
• results in a persistent or significant incapacity; 
• results in a congenital anomaly/birth defect; or 

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• based upon appropriate medical judgment, may jeopardize the subject’s health and may 
require medical or surgical intervention to prevent one of the other outcomes listed in this 
definition. 
Suspected adverse reaction: Suspected adverse reaction means any adverse event for which there 
is a reasonable possibility that the drug caused the adverse event. For the purposes of IND safety 
reporting, ‘reasonable possibility’ means there is evidence to suggest a causal relationship 
between the drug and the adverse event. A suspected adverse reaction implies a lesser degree of 
certainty about causality than adverse reaction, which means any adverse event caused by a drug. 
Unexpected adverse reaction: An adverse event or suspected adverse reaction is considered 
“unexpected” if it is not listed in the investigator brochure or is not listed at the specificity or 
severity that has been observed; or, if an investigator brochure is not required or available, is not 
consistent with the risk information described in the general investigational plan or elsewhere in 
the current application. "Unexpected”, also refers to adverse events or suspected adverse 
reactions that are mentioned in the investigator brochure as occurring with a class of drugs or as 
anticipated from the pharmacological properties of the drug but are not specifically mentioned as 
occurring with the particular drug under investigation. 
Unanticipated problem (UP): Any incident, experience, or outcome that meets all of the 
following criteria: 
• 
Unexpected in terms of nature, severity, or frequency in relation to 
o the research risks that are described in the IRB-approved research protocol and informed 
consent document; Investigator’s Brochure or other study documents; and 
o the characteristics of the subject population being studied; and 
• Related or possibly related to participation in the research; and 
• Places subjects or others at a greater risk of harm (including physical, psychological, 
economic, or social harm) than was previously known or recognized. 
Unanticipated Problem that is not an Adverse Event: An unanticipated problem that does not fit 
the definition of an adverse event, but which may, in the opinion of the investigator, involves 
risk to the subject, affect others in the research study, or significantly impact the integrity of 
research data. For example, report occurrences of breaches of confidentiality, accidental 
destruction of study records, or unaccounted-for study drug. 
Protocol Deviation (PD): Any change, divergence, or departure from the IRB approved research 
protocol. 
Non-compliance: The failure to comply with applicable NIH HRPP policies, IRB requirements, 
or regulatory requirements for the protection of human research. Noncompliance may be further 
characterized as: 
1. Serious non-compliance: Non-compliance that: 
a. Increases risks, or causes harm, to participants 
b. Decreases potential benefits to participants 
c. Compromises the integrity of the NIH HRPP 
d. Invalidates the study data 

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2. Continuing non-compliance: Non-compliance that is recurring. An example may be a pattern 
of non-compliance that suggests a likelihood that, absent an intervention, non-compliance will 
continue. Continuing noncompliance could also include a failure to respond to IRB requests to 
resolve previous allegations of non-compliance. 
3. Minor (non-serious) non-compliance: Non-compliance that, is neither serious nor continuing. 
Safety assessments will consist of monitoring and recording AEs and SAEs; measurements of 
protocol-specified hematology, clinical chemistry, and other laboratory variables; measurement 
of protocol-specified vital signs; and other protocol-specified tests that are deemed critical to 
the safety evaluation of the study drug. 
10.3 PROTOCOL DEVIATION (PD) REPORTING 
It is anticipated that approximately 50% of the clinical monitoring laboratory testing 
performed during the first 6 months will not be performed within +/- 3 days of the required 
time points, with the exception of the month 3 and 6 landmark visits. If the clinical 
laboratory monitoring occurs outside the +/- 3 day window at a frequency greater than 50% 
in a single subject or greater than 50% cumulatively for all subjects it will be reported at 
time of continuing review. If the number of events per subject or per cumulative enrolled 
subjects exceeds 50%, this will be reported per Policy 801. Please note, subjects and 
providers are reminded of the importance of the timely completion of the clinical laboratory 
testing. 
Interruptions in EPAG dosing that are clinically indicated per section 5, will only be 
recorded in the medical record. However, when the interruption is a consequence of a 
serious adverse event, the interruption will only be included in the SAE report. 
In addition, CsA interruptions, such as delay in request for medication refills or medication 
errors by subjects, that are not clinically significant or impact the integrity of the research 
data, will only be recorded in the medical record. 
10.4 ADVERSE EVENTS (AES) CHARACTERIZATION 
The AEs will be attributed (unrelated, unlikely, possibly, probably or definitely related) to 
study medication and/or disease. The AEs will be graded by severity utilizing CTCAE 
version 5.0. 
10.5 SERIOUS ADVERSE EVENTS (SAES) CHARACTERIZATION 
Serious adverse events will be attributed as definitely (clearly related to the research), 
probably (likely related to the research), possibly (may be related to the research), 
unlikely (doubtfully related to the research) and unrelated (clear not related to the 
research). 
TRSAEs are those attributed as definitely or probably related to treatment. As detailed in 
section 9.5 stopping rules, TRSAE that will be monitored and considered for early stopping 
the study according to statistically determined criteria include Death and any grade IV 
toxicity considered to be probably or definitely related to study medication. 
Note that hospitalizations for the following reasons will not be captured as serious adverse 
events, as these hospitalizations are not a result of an adverse event: 

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• Routine treatment or monitoring, not associated with any deterioration in condition 
• Hospitalizations for administrative issues (e.g., to receive a transfusion after hours) or 
movement to the ICU for routine monitoring per administrative requirements or 
nosocomial isolation 
• Elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent 
• Social reasons and respite care in the absence of any deterioration in the patient’s 
general condition 
10.6 EVENT COLLECTION 
10.6.1 Duration of Adverse Event Collection 
The collection and recording of AEs will begin on the first day of initiation of the study drug and 
will continue for 30 days after the 6 month landmark visit or for 30 days after treatment is 
discontinued if before the 6 month landmark visit, after which the events will be captured in the 
medical record but not abstracted or recorded in the database. AEs that are abstracted in the 
database will be followed until satisfactory resolution. 
10.6.2 Duration of Serious Adverse Event Collection 
The collection of SAEs will begin on the first day of initiation of the study drug and will continue 
as long as the subject is on study. Starting 30 days after the 6 month landmark visit or 30 days after 
treatment is discontinued (if before the 6 month landmark visit), SAEs will only be captured in the 
research database when deemed possibly, probably or definitely related to the study treatment. 
10.7 REPORTING EVENTS 
All events listed in section10.2 will be reported to Bhavisha Patel, M.D., Principal Investigator of 
this study: 
Bhavisha Patel, M.D. 
Bldg. 10, Room CRC 3-5132 
Phone:  (301) 402-3477 
E-mail:  bhavisha.patel@nih.gov 
10.7.1 Expedited Reporting to the NIH Intramural IRB 
Events requiring expedited reporting will be submitted to the IRB per HRPP Policy 801 
“Reporting Research Events”. 
10.7.2 Reports to the NIH Intramural IRB at the time of Continuing Review (CR) 
The PI or designee will refer to HRPP Policy 801 “Reporting Research Events” to determine 
IRB reporting requirements. 
10.7.3 Reports to the NHLBI Clinical Director (CD) 
The PI or designee will refer to NHLBI DIR guidelines to determine CD reporting requirements 
and timelines. 

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10.7.4 Reporting Serious Adverse Events to a collaborator under Cooperative Research 
and Development Agreement (CRADA) 
Novartis: 
All unexpected and possibly, probably or definitely related SAEs occurring during the study or 
within 30 days of the last administration of eltrombopag will be reported to Novartis within 24 
hours of the research team learning of the event. A copy of the SAE report (NHLBI SAE report 
form) will be forwarded as soon as possible, but no later than seven (7) days in the case of death 
or life-threatening serious adverse events or within fifteen (15) days after the occurrence of all 
other forms of serious adverse events. If the SAE is unexpected and determined possibly, probably 
or definitely related to the study drug the SAE report (in the appropriate format, e.g., NHLBI SAE 
report form, narrative) will be forwarded to Novartis within 24 hours of learning of event. The 
investigator must assess and record the relationship of each SAE to each specific study treatment 
(if there is more than one study treatment), complete the SAE Report Form in English, and send 
the completed, signed form along with the Novartis provided fax cover sheet to the Novartis 
Oncology 
Drug 
Safety 
and 
Epidemiology 
(DS&E) 
department 
by 
e-mail 
(clinicalsafetyop.phuseh@novartis.com) or by fax (fax: 877-778-9739) within 24 hours. 
Any additional information for the SAE including complications, progression of the initial SAE, 
and recurrent episodes must be reported as follow-up to the original episode within 24 hours of 
the investigator receiving the follow-up information. An SAE occurring at a different time 
interval or otherwise considered completely unrelated to a previously reported one should be 
reported separately as a new event. Any SAEs experienced after the 30 day safety evaluation 
follow-up period (or 5 half-lives, if half-life is established, whichever is longer) should only be 
reported to Novartis if the investigator suspects a causal relationship to the study treatment. 
Follow-up information is submitted in the same way as the original SAE Report. Each re-
occurrence, complication, or progression of the original event should be reported as a follow-up 
to that event regardless of when it occurs. The follow-up information should describe whether 
the event has resolved or continues, if and how it was treated, whether the blind was broken or 
not, and whether the patient continued or withdrew from study participation. 
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert (new 
occurrence) and is thought to be related to the Novartis study treatment, an oncology Novartis 
Drug Safety and Epidemiology (DS&E) department associate may urgently require further 
information from the investigator for Health Authority reporting. Novartis may need to issue an 
Investigator Notification (IN), to inform all investigators involved in any study with the same 
drug that this SAE has been reported. Suspected Unexpected Serious Adverse Reactions 
(SUSARs) will be collected and reported to the competent authorities and relevant ethics 
committees in accordance with Directive 2001/20/EC or as per national regulatory requirements 
in participating countries. 
10.7.5 Reporting of Pregnancy 
Subjects who become pregnant during the active treatment portion of the study (CsA and 
eltrombopag) should discontinue the study drugs immediately. See Section 4.3 and 9.6 for 
handling of pregnancy. The investigator, or his/her designee, will collect pregnancy information 

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on any subject who becomes pregnant while receiving study treatment or during the post-
treatment follow-up period.   
The investigator, or his/her designee, will submit pregnancy information to the NHLBI Clinical 
Director and Novartis within two weeks of learning of a subject’s pregnancy.   
Pregnancy will be reported by the investigator to the Novartis Oncology Drug Safety and 
Epidemiology Department (DS&E) by fax (fax: 877-778-9739) or via email 
(clinicalsafetyop.phuseh@novartis.com). Information on the status of the mother and child will 
be forwarded to Novartis. Generally, follow-up will be no longer than 6 to 8 weeks following the 
estimated delivery date. Any premature termination of the pregnancy will be reported.  
The pregnancy will be followed up to determine outcome, including spontaneous or voluntary 
termination, details of the birth, and the presence or absence of any birth defects, congenital 
abnormalities, or maternal and/or newborn complications. While pregnancy itself is not 
considered to be an AE or SAE, any pregnancy complication or elective termination of a 
pregnancy for medical reasons will be recorded and reported to Novartis as an AE or SAE. A 
spontaneous abortion is always considered to be an SAE and will be reported to Novartis. 
Furthermore, any SAE occurring as a result of a post-study pregnancy and is considered 
reasonably related to the investigational product by the investigator, will be reported to Novartis. 
While the investigator is not obligated to actively seek this information in former study 
participants, he/she may learn of an SAE through spontaneous reporting. Pregnancy outcomes 
for the female partners of any males who took study treatment on this study will also be 
collected. 
Further advice on the length of post-natal follow up may be sought from the Novartis Pediatric 
Advisory Group and should be driven by the type of congenital abnormality expected. 
10.8 PROTOCOL MONITORING 
As per ICH-GCP 5.18 and FDA 21 CFR 312.5 clinical protocols are required to be adequately 
monitored by the study sponsor. The monitoring of this study will be conducted by Clinical 
Research Associates (CRAs)/Monitors working under an agreement with NHLBI to monitor 
aspects of the study in accordance with the appropriate regulations and the approved protocol. 
The objectives of a monitoring visit will be: 1) to verify the existence of signed informed consent 
form (ICF) and documentation of the ICF process for each monitored subject; 2) to verify the 
prompt and accurate recording of all monitored data points, and prompt reporting of all SAEs; 3) 
to compare abstracted information with individual subjects’ records and source documents 
(subject’s charts, laboratory analyses and test results, physicians’ progress notes, nurses’ notes, 
and any other relevant original subject information); and 4) to help ensure investigators are in 
compliance with the protocol. The monitors also will inspect the clinical site regulatory files to 
ensure that regulatory requirements (Office for Human Research Protections-OHRP), FDA and 
applicable guidelines (ICH-GCP) are being followed. During the monitoring visits, the 
investigator (and/or designee) and other study personnel will be available to discuss the study 
progress and monitoring visit. 
The investigator (and/or designee) will make study documents (e.g., consent forms and pertinent 
hospital or clinical records readily available for inspection by the local IRB, the FDA, the site 
monitors, and the NHLBI staff for confirmation of the study data. 
11 BIOSPECIMEN AND DATA MANAGEMENT PLAN 

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Biospecimen Management: Specimens and their derivatives (e.g., genomic material, cell lines) 
will be coded and stored in conformity with DIR Policy (e.g., BSI). Coded biospecimens may be 
sent to collaborators outside of the NIH in accordance with applicable NIH and DIR Policy for 
sharing research resources, including an executed material transfer agreement. Biospecimens 
with subject personal identifiers may be sent to associate investigators and collaborators outside 
of the NIH only after approvals of all applicable IRBs, an executed reliance agreement with 
NIH’s IRB, or an extension of the NIH’s FWA through an Individual Investigator Agreement. 
Storage: All samples will be stored in the laboratory of Dr. Young. Collected samples will be de- 
identified prior to storage in the laboratory of the principal investigator following current NHLBI 
DIR BSI Policy. Efforts to ensure protection of patient information include: 
• Each sample is assigned a unique number 
• Vials holding patient samples are labeled with the sequential laboratory accession ID 
number that does not contain any personal identifier information 
• An electronic database is used to store patient information related to the coded samples 
• The laboratory is located in a controlled access building and laboratory doors are kept 
locked. Visitors to the laboratory are required to be accompanied by laboratory staff at all 
times. 
• Hard copy records or electronic copies of documents containing patient information are 
kept in the locked laboratory or other controlled access locations. 
Biospecimen Tracking and Sharing: Samples will be ordered and tracked through the CRIS 
Research Screens. Should a CRIS screen not be available, the NIH form 2803-1 will be completed 
and will accompany the specimen and be filed in the medical record. 
Coded biospecimens (NHLBI investigators hold the key that identifies research subjects) to be 
shared outside of NIH for future research use requires an executed transfer agreement and may 
require IRB approval if results will be returned and re-identified. 
Unlinked biospecimens (no key to identify research subjects exists) to be shared outside of NIH 
for future research use requires an executed transfer agreement. Refusal of a research subject 
participant to allow for future use of identifiable biospecimens--other than required in the protocol 
or for appropriate regulatory purposes, e.g., by the FDA--will be honored. 
Future use of biospecimens: Following analyses of biospecimens for primary research purposes, 
remaining samples suitable for future research will be stored in manner that conforms with DIR 
policy (such as BSI) or in a publicly accessible research biospecimen repository following IRB 
approval, as applicable. Biospecimens may be destroyed only when permitted by the clinical 
director and the IRB. 
Data Management: The principal investigator, associate investigators, research nurses and/or a 
data manager will assist with the data management efforts. Data will be abstracted from Clinical 
Center progress notes as well as intake forms and the case report forms. Laboratory data from NIH 
will be reviewed using CRIS. The principal investigator, associate investigators/research nurses 
and/or a contracted data manager will assist with the data management efforts to ensure that data 
is verifiable and evaluable. Data will be abstracted from Clinical Center progress notes as well as 
from progress notes forwarded from the subjects’ home physician. 

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The PI will be responsible for overseeing entry of data into an in-house password protected 
electronic system and ensuring data accuracy, consistency and timeliness. Laboratory values from 
referring home physicians will be entered into the system. The principal investigator, associate 
investigators/research nurses and/or a contracted data manager will assist with the data 
management efforts to ensure that data is verifiable and evaluable. Data will not be sent outside of 
the NIH without institutional approval. 
Research data will be prospectively collected by authorized Investigator personnel and entered 
into an NHLBI approved Database. The database is a web-based, 21 CFR 11 compliant database 
which will consist of the study specific set of electronic CRFs (e-CRFs) used for capturing, 
managing and reporting clinical research data. 
The database will maintain complete data records on each research subject. 
• 
White blood cell count 
• 
Absolute lymphocyte count (percentage if absolute not available) 
• 
Absolute neutrophil count (percentage if absolute not available) 
• 
Absolute reticulocyte count, if available (percentage if absolute not available, then also 
need the red blood cell count) 
• 
Hemoglobin 
• 
Platelets 
Subjective and objective patient experiences during the duration of the study will be documented 
in the patient medical record notes. These protocol notes will serve as the primary source 
material from which data will be collected in the Database. Any pertinent supplementary 
information obtained from outside laboratories, outside hospitals, radiology reports, laboratory 
reports, or other patient records will be used as additional source for data collection. 
We will maintain the confidentiality of identifiable private information collected in this Clinical 
Trial and protect the privacy of the individual human subjects. Primary data containing 
individually identifiable information obtained during the conduct of the protocol will be kept in 
secure network drives or in approved alternative sites that comply with NIH information security 
standards. Neither individual personal identifiers nor the key linking coded data to individuals 
will be released without prior IRB approval and an executed CDA or MTA. Identifiable data will 
not be sent outside NIH without prior IRB approval or appropriate conditions for disclosure 
outlined in the executed CDA or MTA. Study data will be housed in the Hematology Branch P 
Drive, a secure limited access drive. 
Novartis will receive quarterly accrual and toxicity information as detailed in the CRADA. In order 
to maintain subject confidentiality, all communications relating to the study will identify 
participants by assigned subject study numbers. No personally identifiable information will be sent 
to Novartis. In accordance with local and federal regulations, the Investigator will allow Novartis 
personnel or their designee, access to all pertinent medical records in order to verify the data 
gathered and to audit the data collection process. 
Data sharing and future use of data: Research data may be shared with qualified non- 
collaborator recipients following publication of the primary research results after removal of PII. 
Refusal of a research subject participant to permit future use of data--other than required in the 
protocol or by the FDA--will be honored. Limitations in data sharing and future use of data due 

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to contractual obligations (e.g., CRADAs) or intellectual property proceedings (such as patent 
filings) will be honored. 
End of study procedures: Data will be stored in locked cabinets and in a password protected 
database until it is no longer of scientific value. At the completion of the protocol (termination), 
samples and data will be maintained in a repository for future research. 
Loss or destruction of data: Should we become aware that a major breech in our plan to protect 
patient confidentiality and trial data has occurred, the IRB will be notified. 
Privacy and Confidentiality: All efforts, within reason, will be made to keep subjects’ private 
identifiable information (PII) private. Using or sharing (“disclosure”) such data must follow 
federal privacy rules. Under certain circumstances, the United States Office of Human Research 
Protections (OHRP), The US Food and Drug Administration (FDA), and the IRB, will be able to 
inspect and copy confidential study-related records which identify participants by name. 
Therefore, absolute confidentiality cannot be guaranteed. 
12 HUMAN SUBJECT PROTECTION 
12.1 RATIONALE FOR SUBJECT SELECTION 
The study will be open to all subjects who satisfy the inclusion criteria and provide an informed 
consent to the protocol. No subjects will be excluded from participation based on gender, race or 
ethnicity. We do not anticipate enrollment of NIH staff. This is a rare and debilitating disease.  To 
our knowledge, currently, there are no NIH staff that would qualify for this study. 
This study will be open to all patients who fit the inclusion criteria and provide informed consent to 
protocol participation. Epidemiologic studies suggest that the gender will be approximately evenly 
split between male and females, and that 90% of the patients will be Caucasian. However, previous 
experience at our institution suggests that distribution will be: 
• By gender: 48% males and 52% females; 
• By race/ethnicity: approximately 58% White, 20% Black, 10% Asian and 17% Hispanic; 
• By age: will range between 3 and 82 (median age of 30) and roughly 20% of patients will 
be under the age of 18. 
For subjects of Asian ethnicity: Plasma eltrombopag area under the curve was approximately 70% 
higher in East and Southeast Asian (ethnicity self-reported) subjects as compared to non-Asian 
subjects who were predominantly Caucasian. Therefore, subjects of Asian heritage will be included 
but they will be initiated at a lower dose and monitored closely as described in the treatment plan. 
For subjects with renal impairment: The pharmacokinetics of eltrombopag has been studied in 
adult patients with renal impairment. Following administration of a single 50 mg dose, there was 
a trend for reduced plasma eltrombopag exposure in patients with renal impairment, but there was 
substantial variability and significant overlap in exposures between patients with renal impairment 
and healthy volunteers. Therefore, patients with impaired renal function will be included and given 
the protocol-defined dosages, but participation will be monitored closely. 
For subjects with hepatic impairment: Pharmacokinetics of eltrombopag has been studied in 
adult patients with hepatic impairment. Following the administration of a single 50 mg dose, the 
AUC0-∞ of eltrombopag was increased by 41% in subjects with mild hepatic impairment and by 

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80% to 90% in subjects with moderate or severe hepatic impairment compared with healthy 
volunteers. Therefore, patients with minimally impaired hepatic function will be included but 
participation will be monitored closely. Patients with baseline moderate to severe hepatic 
impairment will be excluded from the study. 
Recruitment efforts: 
A Strategic Recruitment Plan (SRP) will be developed with the NHLBI Patient Recruitment Office 
(PRO). The recruitment strategies to be used for this study may include: 
• Social media postings which may include NHLBI and Clinical Center accounts for 
Facebook and Twitter 
• Listings on official NIH websites to include: 
1. Clinicaltrials.gov website 
2. Clinical Center Recruitment website with dedicated study page mirroring the 
patient recruitment flyer.  Page links to CT.gov and/or Search the Studies. 
3. Clinical Center Research Studies (“Search the Studies”) website 
• The AAMDS website and/or social media accounts (using IRB approved language, flyer, 
and/or social media language with photos.) 
• Use of Clinical Center Office of Patient Recruitment Services (OPR) including OPR 
Listservs (Email list of those interested in receiving study recruitment updates.) (Links to 
one of the above mentioned websites or pages). Includes the OPR Protocols and OPR 
Healthy Volunteers listservs and 3 NIH listservs (NIH Post back, NIH Clinical Fellows & 
NIH Study Volunteers), 
• ResearchMatch, NIH Newsletters 
• Hematologists and Oncologists in the US will be informed about the protocol via email. 
An informational letter to physicians will be available for electronic (and hard copy as 
appropriate) distribution to local and national clinical contacts. 
If recruitment goals are not being met, additional strategies will be planned and implemented by 
the PRO. 
Reimbursement for protocol travel, food, and lodging will be consistent with NIH guidelines. 
In determining reimbursement, the following factors are considered applicable to this protocol: the 
patients are diagnosed with a rare disease; the patient population is sick; the protocol offers the 
potential for direct benefit; the protocol regimen is demanding; and in order to complete accrual 
in a reasonable timeframe a geographically dispersed participant population is required. 
Payment for participation $0. The study participants will not be reimbursed for their time and 
inconvenience. 
Competition between Branch Protocols: There are no competing Branch protocols for this 
patient population. 
12.2 PARTICIPATION OF CHILDREN 
In principle, age is not a consideration. But in practice, we are limiting the protocol to subjects 
who are age 3 years and older because our clinic does not have the expertise to care for infants. 
In addition, per Clinical Center guidelines, we are limiting participation to children who weigh 
>12kg. 

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12.3 RISKS AND DISCOMFORTS 
12.3.1 Related to Horse ATG (ATGAM) 
Potential Serious Adverse Effects: 
Potential side effects related to h-ATG (ATGAM) include: 
Very common side effects (occurring in 10% or more of patients): fever (51%), chills (16%), 
thrombocytopenia (30%), leukopenia (14%), skin rash (27%) 
Common side effects (occurring in 5 to 10% of patients): serum sickness like symptoms, 
dyspnea/apnea, arthralgia, headache, chest, back or flank pain, diarrhea and nausea and/or 
vomiting 
Events reported with frequency of less than 5% of patients in a pre-marketing clinical trial in the 
treatment of aplastic anemia include: diaphoresis, joint stiffness, peri-orbital edema, aches, edema, 
muscle ache, vomiting, agitation, lethargy, listlessness, light-headedness, seizures, diarrhea, 
bradycardia, myocarditis, cardiac irregularity, hepatosplenomegaly, post viral encephalopathy, 
hypotension, congestive heart failure, hypertension, burning soles/palms, foot sole pain, 
lymphadenopathy, post cervical lymphadenopathy, tender lymph nodes, pleural effusion, 
respiratory distress, and proteinuria. 
Related to pregnancy and/or nursing mothers: h-ATG has not been evaluated in either pregnant or 
lactating women therefore administration of h-ATG to pregnant women is not recommended and 
should be considered only under exceptional circumstances. 
Post marketing Experience: 
During approximately 5 years of post-approval marketing experience, the frequency of adverse 
reactions in voluntarily reported cases is as follows: fever 51%; chills 16%; thrombocytopenia 
Anaphylaxis (less than 1% of patients): Rarely, patients may develop potentially fatal 
anaphylaxis. Production by the patient of antibodies to horse proteins leads to the formation of 
immune complexes and the clinical development of serum sickness, characterized by fever, a 
characteristic rash, arthralgia, myalgia and non-specific gastrointestinal and neurologic 
symptoms. Onset is typically at day ten to eleven, and the course is self-limited; symptoms may 
be improved by corticosteroids. Transient reduction in peripheral granulocyte and platelet counts 
and in the hemoglobin may occur during the period of administration of ATG and may lead to a 
temporary increase in transfusion requirements. 
Severe lung injury (less than 1% of patients): Several cases of a severe lung injury related to 
Atgam treatment have been reported. Although this side effect appears extremely rare, it is 
serious and can be fatal. There is no information about the mechanism or specific treatment for 
this condition. A few patients recovered after intensive medical support including use of a 
breathing machine. 
Cardiac Failure and Pulmonary Edema (less than 5% of patients): h-ATG is associated 
with pulmonary edema or congestive heart failure. 

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30%; leukopenia 14%; rashes 27%; systemic infection 13%. Events reported in 5% to 10% of 
reported cases include abnormal renal function tests; serum sickness-like symptoms; 
dyspnea/apnea; arthralgia; chest, back, or flank pain; diarrhea and nausea and/or vomiting. 
Events reported with a frequency of less than 5% include: hypertension, Herpes Simplex 
infection, pain, swelling or redness at infusion site, eosinophilia, headache, myalgias, or leg 
pains, hypotension, anaphylaxis, tachycardia, edema, localized infection, malaise, seizures, GI 
bleeding or perforation, deep vein thrombosis, sore mouth/throat, hyperglycemia, acute renal 
failure, abnormal liver function tests, confusion or disorientation, cough, neutropenia or 
granulocytopenia, anemia, thrombophlebitis, dizziness, epigastric or stomach pain, 
lymphadenopathy, pulmonary edema or congestive heart failure, abdominal pain, nosebleed, 
vasculitis, aplasia or pancytopenia, abnormal involuntary movement or tremor, rigidity, 
sweating, laryngospasm/edema, hemolysis or hemolytic anemia, viral hepatitis, faintness, 
enlarged or ruptured kidney, paresthesia, and renal artery thrombosis. 
12.3.2 Related to CsA 
Potential Serious Side Effects Include: 
Potential side effects: 
Although it is metabolized primarily in the liver, CsA major toxicity is renal. CsA causes 
a decrease in creatinine clearance, which almost always returns to normal range on 
cessation of the drug or lowering of the dose. Rare development of a hemolytic-uremic 
syndrome has been reported in patients with CsA after allogeneic bone marrow 
transplant. In our patients with SAA, frequent creatinine measurements have allowed 
prompt adjustment of dose and serious renal complications are infrequent. 
Evidence of hepatotoxicity is common, usually as transient increases in bilirubin and 
transaminases. These levels often normalize with continued administration of the drug; 
reduction of the dose is uniformly associated with a return to normal levels. 
Additional complications include hypertrichosis, gingival hypertrophy (possibly related 
to pre-existing poor dental hygiene), hyperesthesia, hirsutism, tremors, headaches, nausea 
and nonspecific gastrointestinal complaints. Hypertension may occur and be high enough 
to require treatment. 
Neurologic complications include insomnia, dizziness, anxiety, confusion, and vertigo. 
We have observed seizures in patients receiving CsA, when drug levels were within the 
Infection related: Because of low white blood cell counts, patients with aplastic anemia are 
susceptible to infections. By further blocking the immune system, CsA further increases this 
risk. 
Cancer related: When used at high doses in transplant patients, CsA may be associated with 
an increased risk of cancer, especially lymphoma (4 of every 10,000 patients who receive the 
medication). Transplant patients receive higher doses than you will be given and are treated for 
longer periods than the duration of this study. However, because of the way that CsA acts on 
the body, there is a chance that it may cause effects that may not occur until years after the 
medicine is used. 
Blindness: In very rare instances (less than .01%), CsA has been reported to cause blindness 

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therapeutic range. Posterior Reversible Encephalopathy Syndrome (PRES) is an 
increasingly recognized neurologic disorder seen in 1% of patients on cyclosporine 
following solid organ transplantation which manifest with acute to subacute hypertension 
and/or seizures. In the event of hypertension, subjects will be prescribed 1 or more 
medications to control blood pressure in an effort to decrease the risk of this 
complication. 
Hypomagnesemia and hyperkalemia may occur but are asymptomatic. Increases in uric 
acid may occur and attacks of gout have been rarely reported. Cyclosporine therapy 
may be associated with a modest increase of serum triglycerides or cholesterol. 
Less frequent adverse events include: 
Autonomic Nervous System: dry mouth, increased sweating 
Systemic: allergy, asthenia, hot flushes, malaise, weight decrease, weight increase 
Cardiovascular: abnormal heart sounds, cardiac failure, myocardial infarction, peripheral 
ischemia 
Central and Peripheral Nervous System: hypoesthesia, neuropathy, vertigo 
Endocrine: goiter 
Gastrointestinal: constipation, dysphagia, enanthema, eructation, esophagitis, gastric 
ulcer, gastritis, gastroenteritis, gingival bleeding, glossitis, peptic ulcer, salivary gland 
enlargement, tongue disorder, tooth disorder 
Infection: abscess, bacterial infection, cellulitis, folliculitis, fungal infection, herpes 
simplex, herpes zoster, renal abscess, moniliasis, tonsillitis, viral infection 
Hematologic: anemia, epistaxis, leukopenia, lymphadenopathy 
Liver and Biliary System: bilirubinemia 
Metabolic and Nutritional: diabetes mellitus, hyperkalemia, hyperuricemia, hypoglycemia  
Musculoskeletal System: arthralgia, bone fracture, bursitis, joint dislocation, myalgia, stiffness, 
synovial cyst, tendon disorder 
Neoplasms: breast fibroadenosis, carcinoma 
Psychiatric: anxiety, confusion, decreased libido, emotional lability, impaired 
concentration, increased libido, nervousness, paranoia, somnolence 
Reproductive (Female): breast pain, uterine hemorrhage 
Respiratory System: bronchospasm 
Skin and Appendages: abnormal pigmentation, angioedema, dermatitis, dry skin, 
eczema, nail disorder, pruritus, skin disorder, urticaria 
Special Senses: abnormal vision, cataract, conjunctivitis, deafness, eye pain, taste 
perversion, tinnitus, vestibular disorder, blindness 
Urinary System: abnormal urine, hematuria, increased BUN, micturition urgency, 
nocturia, polyuria, pyelonephritis, urinary incontinence 
Prolonged low dose administration of CsA: 
Patients who undergo solid organ transplantation, such as kidney transplantation, are given 
cyclosporine for life at a high dose (usually 5-10 mg/kg/day) whereas we are proposing to continue 
at low dose, 2mg/kg/day. Cyclosporine is considered a weak immunosuppressant and few 
infectious complications are observed. There is ample data on the use of cyclosporine from long-
term studies where cyclosporine is used for solid organ transplantation. Nephrotoxicity is the main 
toxicity, usually reversible, but is typically only observed when troughs over 200ng/mL are 

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targeted. Nephrotoxicity is rarely observed with low-dose cyclosporine and monitoring of levels is 
unnecessary. The risk of relapse of severe aplastic anemia; however, can be fatal, and this risk far 
exceeds the risks long term cyclosporine poses as is evidenced by our experience and data from 
12-H-0150. 
12.3.3 Related to Promacta (eltrombopag). 
Potential Serious Adverse Effects: 
Warnings and Precautions 
Hepatic Decompensation in Patients with Chronic Hepatitis C 
In patients with chronic hepatitis C, PROMACTA in combination with interferon and ribavirin 
may increase the risk of hepatic decompensation. In two controlled clinical trials in patients with 
chronic hepatitis C and thrombocytopenia, ascites and encephalopathy occurred more frequently 
on the arm receiving treatment with PROMACTA plus antivirals (7%) than the placebo plus 
antivirals arm (4%). Patients with low albumin levels (less than 3.5 g/dL) or Model for End-Stage 
Liver Disease (MELD) score greater than or equal to 10 at baseline had a greater risk for hepatic 
decompensation on the arm receiving treatment with PROMACTA plus antivirals. Discontinue 
PROMACTA if antiviral therapy is discontinued. 
Hepatotoxicity 
PROMACTA may increase the risk of severe and potentially life-threatening hepatotoxicity. 
Measure serum ALT, AST, and bilirubin prior to initiation of PROMACTA, every 2 weeks during 
the dose adjustment phase, and monthly following establishment of a stable dose. PROMACTA 
inhibits UDP- glucuronosyltransferase (UGT)1A1 and organic anion-transporting polypeptide 
(OATP)1B1, which may lead to indirect hyperbilirubinemia. 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 resolved or stabilized. 
Discontinue PROMACTA if ALT levels increase to greater than or equal to 3 x ULN in patients 
with normal liver function or greater than or equal to 3 x baseline (or greater than 5 x ULN, 
whichever is the lower) in patients with pre-treatment elevations in transaminases and are: 
• 
progressively increasing, or 
• 
persistent for greater than or equal to 4 weeks, or 
• 
accompanied by increased direct bilirubin, or 
• 
accompanied by clinical symptoms of liver injury or evidence for hepatic 
WARNING: RISK FOR HEPATIC DECOMPENSATION IN PATIENTS WITH 
CHRONIC HEPATITIS C 
RISK OF HEPATOTOXICITY 
See full prescribing information for complete boxed warning. 
In patients with chronic hepatitis C, PROMACTA in combination with interferon and 
ribavirin may increase the risk of hepatic decompensation. 
PROMACTA may increase the risk of severe and potentially life-threatening 
hepatotoxicity. Monitor hepatic function and discontinue dosing as recommended. 

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decompensation. 
If the potential benefit for reinitiating treatment with PROMACTA is considered to outweigh the 
risk for hepatotoxicity, then consider cautiously reintroducing PROMACTA and measure serum 
liver tests weekly during the dose adjustment phase. Hepatotoxicity may reoccur if PROMACTA 
is reinitiated. If liver test abnormalities persist, worsen, or recur, then permanently discontinue 
PROMACTA. 
Isolated cases of severe liver injury were identified in clinical trials. The elevation of liver laboratory 
values occurred approximately three months after initiation of PROMACTA. In all cases, the event 
resolved following PROMACTA discontinuation. 
Thrombotic/Thromboembolic Complications 
Thrombotic/thromboembolic complications may result from increases in platelet counts with 
PROMACTA. Reported thrombotic/thromboembolic complications included both venous and 
arterial events and were observed at low and at normal platelet counts. 
Consider the potential for an increased risk of thromboembolism when administering 
PROMACTA 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 PROMACTA in an attempt to normalize 
platelet counts. Follow the dose adjustment guidelines to achieve and maintain target platelet 
counts. 
In two controlled clinical trials in patients with chronic hepatitis C and thrombocytopenia, 3% 
(31/955) treated with PROMACTA experienced a thrombotic event compared with 1% (5/484) on 
placebo. The majority of events were of the portal venous system (1% in patients treated with 
PROMACTA versus less than 1% for placebo). 
In a controlled trial in patients with chronic liver disease and thrombocytopenia not related to ITP 
undergoing elective invasive procedures (N = 292), the risk of thrombotic events was increased in 
patients treated with 75 mg of PROMACTA once daily. Seven thrombotic complications (six 
patients) were reported in the group that received PROMACTA and three thrombotic 
complications were reported in the placebo group (two patients). All of the thrombotic 
complications reported in the group that received PROMACTA were portal vein thrombosis 
(PVT). Symptoms of PVT included abdominal pain, nausea, vomiting, and diarrhea. Five of the 
six patients in the group that received PROMACTA experienced a thrombotic complication within 
30 days of completing treatment with PROMACTA and at a platelet count above 200 x 109/L. The 
risk of portal venous thrombosis was increased in thrombocytopenic patients with chronic liver 
disease treated with 75 mg of PROMACTA once daily for 2 weeks in preparation for invasive 
procedures. 
Cataracts 
In the three controlled clinical trials in adults with chronic ITP, cataracts developed or worsened in 
15 (7%) patients who received 50 mg of PROMACTA daily and 8 (7%) placebo-group patients. 
In the extension trial, cataracts developed or worsened in 11% of patients who underwent ocular 
examination prior to therapy with PROMACTA. In the two controlled clinical trials in patients 
with chronic hepatitis C and thrombocytopenia, cataracts developed or worsened in 8% of patients 
treated with PROMACTA and 5% of patients treated with placebo. 

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Cataracts were observed in toxicology studies of eltrombopag in rodents. Perform a baseline ocular 
examination prior to administration of PROMACTA and, during therapy with PROMACTA, 
regularly monitor patients for signs and symptoms of cataracts. 
Clinical Experience: 
For full information on clinical experience with eltrombopag in for the treatment of all approved 
indications, see PACKAGE INSERT. 
Severe Aplastic Anemia: In the single-arm, open-label trial, 43 patients with severe aplastic anemia 
received PROMACTA. Eleven patients (26%) were treated for greater than 6 months and 7 
patients (16%) were treated for greater than 1 year. The most common adverse reactions (greater 
than or equal to 20%) were nausea, fatigue, cough, diarrhea, and headache. 
Adverse Reactions (≥10%) from One Open-label Trial in Adults with Severe Aplastic Anemia  
 
Adverse Reaction 
PROMACTA (n = 43) 
(%) 
Nausea 
33 
Fatigue 
28 
Cough 
23 
Diarrhea 
21 
Headache 
21 
Pain in extremity 
19 
Dyspnea 
14 
Pyrexia 
14 
Dizziness 
14 
Oropharyngeal pain 
14 
Febrile neutropenia 
14 
Abdominal pain 
12 
Ecchymosis 
12 
Muscle spasms 
12 
Transaminases increased 
12 
Arthralgia 
12 
Rhinorrhea 
12 
Rash was reported in 7% of patients. 
In this trial, patients had bone marrow aspirates evaluated for cytogenetic abnormalities. Eight 
patients had a new cytogenetic abnormality reported on therapy, including 5 patients who had 
complex changes in chromosome 7. 
Post marketing Experience 

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Thrombotic microangiopathy with acute renal failure have been identified during post approval 
use of PROMACTA. Because these reactions are reported voluntarily from a population of 
uncertain size, it is not always possible to reliably estimate the frequency or establish a causal 
relationship to drug exposure. 
USE IN SPECIFIC POPULATIONS 
Pregnancy 
Pregnancy Category C 
There are no adequate and well-controlled studies of eltrombopag use in pregnancy. In animal 
reproduction and developmental toxicity studies, there was evidence of embryolethality and 
reduced fetal weights at maternally toxic doses. PROMACTA should be used in pregnancy only 
if the potential benefit to the mother justifies the potential risk to the fetus. 
In an early embryonic development study, female rats received oral eltrombopag at doses of 10, 
20, or 60 mg/kg/day (0.8, 2, and 6 times, respectively, the human clinical exposure based on AUC 
in patients with ITP at 75 mg/day and 0.3, 1, and 3 times, respectively, the human clinical exposure 
based on AUC in patients with chronic hepatitis C at 100 mg/day). Increased pre- and post-
implantation loss and reduced fetal weight were observed at the highest dose which also caused 
maternal toxicity. 
Eltrombopag was administered orally to pregnant rats at 10, 20, or 60 mg/kg/day (0.8, 2, and 6 
times, respectively, the human clinical exposure based on AUC in patients with ITP at 75 mg/day 
and 0.3, 1, and 3 times, respectively, the human clinical exposure based on AUC in patients with 
chronic hepatitis C at 100 mg/day). Decreased fetal weights (6% to 7%) and a slight increase in 
the presence of cervical ribs were observed at the highest dose which also caused maternal toxicity. 
However, no evidence of major structural malformations was observed. 
Pregnant rabbits were treated with oral eltrombopag doses of 30, 80, or 150 mg/kg/day (0.04, 0.3, 
and 0.5 times, respectively, the human clinical exposure based on AUC in patients with ITP at 75 
mg/day and 0.02, 0.1, and 0.3 times, respectively, the human clinical exposure based on AUC in 
patients with chronic hepatitis C at 100 mg/day). No evidence of fetotoxicity, embryolethality, or 
teratogenicity was observed. 
In a pre- and post-natal developmental toxicity study in pregnant rats (F0), no adverse effects on 
maternal reproductive function or on the development of the offspring (F1) were observed at doses 
up to 20 mg/kg/day (2 times the human clinical exposure based on AUC in patients with ITP at 75 
mg/day and similar to the human clinical exposure based on AUC in patients with chronic hepatitis 
C at 100 mg/day). Eltrombopag was detected in the plasma of offspring (F1). The plasma 
concentrations in pups increased with dose following administration of drug to the F0 dams. 
Nursing Mothers 
It is not known whether eltrombopag is excreted in human milk. Because many drugs are excreted 
in human milk and because of the potential for serious adverse reactions in nursing infants from 
PROMACTA, a decision should be made whether to discontinue nursing or to discontinue 
PROMACTA taking into account the importance of PROMACTA to the mother. 

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Pediatric Use 
The safety and efficacy of PROMACTA in pediatric patients 1 year and older with chronic ITP 
were evaluated in two double-blind, placebo-controlled trials. The pharmacokinetics of 
eltrombopag have been evaluated in 168 pediatric patients 1 year and older with ITP dosed once 
daily. The safety and efficacy of PROMACTA in pediatric patients younger than 1 year with ITP 
have not yet been established. 
The safety and efficacy of PROMACTA in pediatric patients with thrombocytopenia associated 
with chronic hepatitis C and severe aplastic anemia have not been established. 
Adverse reactions 
Severe cutaneous reaction 
There is a risk that subject may develop a severe cutaneous reaction that may require 
hospitalization and discontinuation of EPAG. As of November 2018, there have been four 
occurrences of this event in subjects enrolled in 12-H-0150, our previous trial. 
Adverse Drug Reactions (ADRs) selected based upon the weight of all available information, 
including data from the Novartis safety database (Argus), and data from all completed global 
clinical trials (phase I-III) for which the Clinical Study Report is final or there is an appropriate 
final DMC report, up to 28 February 2017 are presented in table below. Please also refer to the 
Investigator Brochure (IB). 
Adverse reactions are listed below for each indication by MedDRA body system organ class and 
by frequency. Frequency category for each adverse drug reaction is based on the following 
convention (CIOMS III). The frequency categories used are: 
Very common: ≥1 in 10 (≥10%) 
Common: ≥1 in 100 and <1 in 10 (≥1% and <10%) 
Uncommon: ≥1 in 1,000 and <1 in 100 (≥0.1% and <1%) 
Rare: ≥1 in 10,000 and <1 in 1,000 (≥0.01% and <0.1%) 
*post-marketing 
 
Adverse Events considered to be expected for Reporting Purposes in SAA 
 
Blood and lymphatic system disorders 
Very common: Anemia 
Gastrointestinal disorders 
Very common: Abdominal pain, diarrhea, nausea 
General disorders and administrative conditions 
Very common: Dizziness, fatigue, febrile neutropenia, pyrexia 
Hepatobiliary disorders 
Very common: Transaminases increased 
Musculoskeletal and connective tissue disorders 
Very common: Arthralgia, muscle spasms, pain in extremity 

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Nervous systems disorders 
Very common: Headache 
Respiratory, thoracic and mediastinal disorders 
Common: Cough, dyspnea, oropharyngeal pain, rhinorrhea 
Skin and subcutaneous tissue disorders 
Very common: Ecchymosis 
Vascular disorders 
Rare: post-marketing cases of Thrombotic microangiopathy with acute renal failure reported 
spontaneously 
Adverse Events considered to be expected for Reporting Purposes in MDS/AML 
** Leukocytosis and white blood cell count increased occur individually with a frequency of common, however the 
terms were grouped as they represent the same medical concept, giving a revised frequency of very common. 
*** Serum discoloration has been reported in investigator sponsored studies in MDS/AML, and can lead to analytical 
interference with some colorimetric analytical methods 
12.3.4 Related to Corticosteroids 
Corticosteroids can make the body retain water and salt, cause diabetes and acne, and worsen high 
blood pressure. In addition, they will probably increase your appetite and may cause insomnia or 
mood changes. Steroids can also cause stomach ulcers and soften bones, leading to osteoporosis. 
The more dangerous problems, like bone thinning, only occur with long-term use; the other side 
effects will stop when the medication is discontinued. A small number of cases of "aseptic 
Blood and lymphatic system disorders 
Very common: Leukocytosis**, white blood cell count increased 
Gastrointestinal disorders 
Very common: Nausea, diarrhea, vomiting, constipation, abdominal pain 
General disorders and administrative conditions 
Very common: Fatigue, pyrexia 
Hepatobiliary disorders 
Uncommon: Drug-induced liver injury 
Investigations 
Rare: Serum discoloration*** 
Nervous systems disorders 
Very common: Dizziness, Headache 
Respiratory, thoracic and mediastinal disorders 
Very common: Cough 
Skin and subcutaneous tissue disorders 
Common: Skin discoloration 
Vascular disorders 
Very common: Hematoma 

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necrosis" have been observed when steroids have been used in high doses for durations comparable 
to those we will use in this study. Aseptic necrosis is a thinning of the bone near the joints, which 
can lead to chronic pain, sometimes requiring joint replacement. Steroids also suppress the immune 
system and raise your susceptibility to infection; taking CsA and steroids together increases this 
risk still further. We will ask that you plan to stay in the hospital for the first two weeks of your 
therapy so that infections, if they occur, can be treated promptly. 
12.3.5 Related to bone marrow aspirate and biopsy 
No major risks are involved with bone marrow aspirate and biopsy. However, a small risk of 
infections, pain, bleeding, and hematoma formation at the site of the aspiration exists with the 
procedure. 
12.3.6 Related to general anesthesia (minors only) 
The risks of general anesthesia include having a decreased breathing rate, aspiration, and low blood 
pressure.  
12.3.7 Related to blood draws 
No major risks are involved with blood draws. Minor complications including bleeding, pain, and 
hematoma formation at the site of blood draws, vasovagal reactions or infections may rarely occur. 
12.3.8 Related to Cardiac Monitoring 
An electrocardiogram (ECG) is a test that measures the electrical activity of the heartbeat. With 
each beat, an electrical impulse (or “wave”) travels through the heart. This wave causes the muscle 
to squeeze and pump blood from the heart. A technician will put patches (electrodes) on the chest, 
arms and legs. The electrodes are soft and don’t cause any discomfort when they’re put on or taken 
off by the technician. The machine only records the ECG. It doesn’t send electricity into the body. 
There’s no pain or risk associated with having an electrocardiogram. 
12.3.9 Related to Central Line Placement 
A catheter may be placed in a large vein of the neck, chest, or arm using local anesthetic. Patients 
will sign a separate consent for the placement procedure. Only trained experienced staff will place 
the line in order to minimize these procedure related risks. 
The risks from the procedure are low; they include bleeding, bruising, or infection at the site of 
insertion. Very rarely (less than 1% of the time), the line placement may nick a vein causing one 
lung to collapse during line insertion. If the lung collapses, a tube may have to be inserted into the 
chest and remain in place until the lung re-expands. Because of this risk, patients will have a chest 
x-ray following the procedure to make sure the line is in the correct place and that the lung is not 
collapsed. Once placed, the line will remain in place until drug administration is complete. 
12.3.10 
Related to Concomitant Medications 
Pentamidine: cough (31-47%), bronchospasm (10-23%), decreased appetite (53-72%), fatigue, 
metallic taste, shortness of breath, decreased appetite, dizziness, rash, nausea, pharyngitis, chest 
pain/congestion, night sweats, chills, vomiting. 
Valacyclovir: Nausea and/or vomiting, headache, dizziness, abdominal pain, dysmenorrhea, 
arthralgia, acute hypersensitivity reactions, elevations in liver enzyme laboratory values (e.g. 
AST). Renal failure and CNS symptoms have been reported in patients with renal impairment who 

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received valacyclovir at greater than the recommended dose. 
12.3.11 
Related to Genetic Testing 
Privacy Risks Associated with Genetic Testing 
Because this study involves collecting personal, identifiable information about you, there is a 
possibility that people who are not supposed to see this information might somehow gain access 
to it. We will take precautions to prevent this, but we cannot ever be certain that it won’t 
happen. To minimize this chance, we will assign you a study number, use that number to label 
your samples and medical information, and save the information linking you to that study number 
in a secure file. All of the information we collect will be stored in a secure manner, such as in a 
locked cabinet or in password-protected computer files. Also, the type of genetic testing that we 
will be doing is not specific to your tissues and therefore could not be used to identify you or your 
family members. 
12.4 RISKS IN RELATION TO BENEFIT 
For adult subjects: The benefits to the subjects could be reduction or even abolition of transfusion 
requirements and/or improvement of cytopenia, resulting in improved quality of life and also 
decreased morbidity and mortality from transfusion-associated viral agents, iron overload, and/or 
a susceptibility to infections. Potentially, treatment with other more toxic therapies could also be 
avoided or postponed. 
The benefits of this study and the acquisition of bone marrow and blood samples important for the 
understanding of the pathophysiology of immune-mediated bone marrow failure states have been 
described in the previous paragraphs. 
For pediatric subjects: 
(a) the risk is justified by the anticipated benefit to the subjects: We are offering pediatric subjects 
with a probably lethal hematological disease an alternative to symptomatic therapy. 
(b) the relation of the anticipated benefit to the risk is at least as favorable to the subjects as that 
presented by available alternative approaches. The benefits to the patients could be reduction or 
even abolition of transfusion requirements and/or improvement of low peripheral blood counts, 
resulting in improved quality of life and also decreased morbidity and mortality from transfusion-
associated viral agents, iron overload, and/or a susceptibility to infections. Potentially, treatment 
with other more toxic therapies could also be avoided or postponed. 
(c) adequate provisions are made for soliciting permission of their parents or guardians, as set forth 
in 46.408. 
For Cognitively Impaired: 
This research provides the prospect of direct benefit; therefore, inclusion is justified. The benefits 
to the participants could be improvement of cytopenias resulting in improved quality of life and 
also decreased morbidity and mortality from transfusion-associated viral agents, iron overload, 
and/or a susceptibility to infections. Potentially, treatment with other more toxic therapies could 
also be avoided or postponed. Not allowing participants who cannot provide consent would deny 
them the potential benefits this protocol offers for their AA. There are no plans to include 
institutionalized participants. 

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12.5 INFORMED CONSENT PROCESSES AND PROCEDURES 
Informed consent will be conducted following OHSRP Policy 301- Informed Consent. 
An IRB-approved consent form will be provided to the participant electronically or by hard copy 
for review prior to consenting. The initial consent process as well as re-consent, when required, 
may take place in person or remotely (e.g., via telephone or other NIH approved platforms). The 
investigational nature and objectives of this trial, the procedures, and their attendant risks and 
discomforts and potential benefits will be carefully explained to the participant in a private setting. 
The participant will be given as much time as they need to review the document and to consult 
with their family, friends, and personal health care providers. In addition, a study team member 
will be available to answer any questions. 
A signed and dated informed consent document will be obtained by any investigator authorized to 
consent (See Key Study Personnel Page) prior to entry onto the study. Consent may be obtained 
with required signatures on the hard copy of the consent or on the electronic document. 
When a document that is in electronic format is used for obtaining consent, this study may use the 
iMed platform which is 21 CFR, Part 11 compliant, to obtain the required signatures. 
During the consent process, participants and investigators may view the same approved consent 
document simultaneously when participant is being consented in person at the Clinical Center or 
both may view individual copies of the approved consent document on screens in their respective 
locations remotely. Signatures may be obtained either by both directly signing on the device that 
the consenting investigator is using (when in person) or through iMed Mobile Signature Capture 
(remotely) which allows texting or emailing a link to the participant. That link allows the 
participant to review the consent, then proceed to sign on the device they are using. 
Whether hard copy or electronic, both the investigator and the participant will sign the document 
with a hand signature using a pen (if using hard copy), finger, stylus, or mouse (if electronic). 
When done remotely, if the participant prefers to sign a hard copy, they may be instructed to sign 
and date the consent document during the discussion and mail, secure email or fax the signed 
document to the consenting investigator. 
Whether in person or remotely, the privacy of the participant will be maintained. 
Finally, the fully signed informed consent document will be stored in the electronic medical record, 
and the participant will receive a copy of the signed informed consent document. 
All patients will identify a local physician. NIH team will establish contact with the local physician 
to provide all protocol specific information and our contact information (Appendix A). 
After the consent, study drug will be shipped to the patient or to the local treating physician within 
24-48 hours. The patient will initiate medications as instructed upon receipt. Patient will notify us 
of the start date, which will be recorded in CRIS. 
Pregnancy-related consent disclosures and documentation: 
The consent form includes pregnancy-related risks and disclosures, which will be reviewed in a 
private setting at enrollment and, if applicable, when pregnancy is reported. Participants will 
have adequate time for questions; interpreter services will be offered as needed; understanding 
will be confirmed (e.g., teach-back); and the consent discussion, including pregnancy-related 
disclosures, will be documented in the medical record. 

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Minor participants: If the subject is a minor, the parent who signs the consent for the minor 
must be a legally recognized parent or guardian. For minors that are 7 years of age (inclusive) 
and up, where deemed appropriate by the clinician, and the child's parent or guardian, the child 
will also be included in all discussions about the trial.  Typically, assent will be obtained as 
appropriate based on age and taking into consideration the child’s level of understanding and 
maturity. 
1. Children under the age of 7 years (exclusive): Will not be required to provide 
assent as they typically do not have the ability to fully understand the nature 
of research.  
2. Children who are 7 years of age (inclusive) but less than 12 years of age 
(exclusive): Verbal assent will be obtained as appropriate. 
3. Children who are 12 years of age (inclusive) but less than 18 years of age 
(exclusive): Will be asked to sign an assent form. 
 
The parent or guardian will sign on the designated line on the informed consent 
providing permission for their child to participate. The consent/assent process will 
be documented in the child’s medical record, including the assessment of the child’s 
ability to provide assent (verbal versus written) as applicable. 
In cases where parents share joint legal custody in making medical decisions of their child (e.g. by 
a custody agreement or court order) both parents must give their parental permissions regardless 
of level of risk of the research. Exceptions may be made if one parent is deceased, becomes 
incompetent or is not reasonably available (e.g. in prison). 
We will inform potential adult and minor female participants during the consent and/or assent 
process that for safety, we need to do a pregnancy test. She will also be told that if it is positive, 
we will counsel her. If the patient does not want to proceed she will be advised not to sign the 
assent and her enrollment on this protocol will end. 
If at any time during participation in the protocol, new information becomes available relating to 
risks, adverse events, or toxicities, this information will be provided orally or in writing to each 
enrolled or prospective patient. Documentation will be provided to the IRB and if necessary, the 
informed consent amended to reflect relevant information. 
12.5.1 Consent for minors when they reach the age of majority: 
When a pediatric subject reaches age 18, continued participation will require consenting of the 
now adult with the standard protocol consent document to ensure legally effective informed 
consent has been obtained. Should sample or data analysis continue following completion of active 
participation and the subject has reached 18 years of age, we will attempt to contact the subject 
using the last known contact information to obtain consent for continued use of data or samples 

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collected during their prior visit. Given the length of time that may have transpired for some of the 
subjects since their last visit for this study, we request waiver of informed consent for those 
individuals who after good faith efforts to contact them, we are unable to contact. 
Requirements for Waiver of Consent consistent with 45 CFR 46.116 (d), each of which must be 
addressed in relation to the protocol: 
(1) The research involves no more than minimal risk to the subjects; 
a) Analysis of samples and data from this study involves no additional risks to subjects. 
(2) The waiver or alteration will not adversely affect the rights and welfare of the subjects; 
a) Samples and data will be kept in secure locations in the laboratory of Dr. Young. Retention 
of samples or data does not affect the welfare of subjects. 
(3) The research could not practicably be carried out without the waiver or alteration; and 
a) Considering the length of time between a minor’s enrollment and their age of majority, it is 
possible that more than a few subjects may be lost to follow up. A significant reduction in the 
number of samples analyzed could impact the quality of the research. 
(4) Whenever appropriate, the subjects will be provided with additional pertinent information 
after participation. 
a) We only plan to request a waiver of reconsent for those subjects who have been lost to 
follow-up. 
12.5.2 Informed consent for adult research participants unable to provide consent: 
If there is an unexpected enrollment of a research participant unable to provide informed consent, 
the procedures per NIH HRPP Policy 403 will be used to enroll these participants in this protocol. 
Consent and Assent: 
Procedures to determine capacity: If documentation of decision making capacity is not present in 
the medical record or the investigator questions the decision-making capacity of the individual, 
then the Ability to Consent Assessment Team (ACAT) (301-496-9675 or 301-496-2429) will be 
contacted to make the determination. 
Procedures for obtaining consent from legally authorized representative (LAR) will be in 
accordance with NIH HRPP Policy 403. 
 
12.6 CONFIDENTIALITY AND PRIVACY 
Participant confidentiality and privacy is strictly held in trust by the participating investigators, 
their staff, and the sponsor(s). This confidentiality is extended to cover testing of biological 
samples and genetic tests in addition to the clinical information relating to participants. Therefore, 
the study protocol, documentation, data, and all other information generated will be held in strict 
confidence. No information concerning the study or the data will be released to any unauthorized 
third party without prior written approval of the sponsor.  
All research activities will be conducted in as private a setting as possible. 

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The study monitor, other authorized representatives of the sponsor, representatives of the 
Institutional Review Board (IRB), and/or regulatory agencies may inspect all documents and 
records required to be maintained by the investigator, including but not limited to, medical records 
(office, clinic, or hospital) and pharmacy records for the participants in this study. The clinical 
study site will permit access to such records. 
The study participant’s contact information will be securely stored at each clinical site for internal 
use during the study. At the end of the study, all records will continue to be kept in a secure location 
for as long a period as dictated by the reviewing IRB, Institutional policies, or sponsor 
requirements. 
Study participant research data, which is for purposes of statistical analysis and scientific reporting, 
will be transmitted to and stored at the NHLBI. This will not include the participant’s contact or 
identifying information. Rather, individual participants and their research data will be identified 
by a unique study identification number. The study data entry and study management systems used 
by clinical sites and by NHLBI research staff will be secured and password protected. At the end 
of the study, all study databases will be de-identified and archived at the NHLBI. 
To further protect the privacy of study participants, a Certificate of Confidentiality has been issued 
by the National Institutes of Health (NIH). This certificate protects identifiable research 
information from forced disclosure. It allows the investigator and others who have access to 
research records to refuse to disclose identifying information on research participation in any civil, 
criminal, administrative, legislative, or other proceeding, whether at the federal, state, or local 
level. By protecting researchers and institutions from being compelled to disclose information that 
would identify research participants, Certificates of Confidentiality help achieve the research 
objectives and promote participation in studies by helping assure confidentiality and privacy to 
participants. 
12.7 HUMAN DATA SHARING, INCLUDING GENOMIC DATA SHARING, AND PUBLICATION 
12.7.1 NIH Data Management and Sharing Policy and NIH Genomic Data Sharing Policy 
Compliance 
This study will comply with the NIH Data Management and Sharing (DMS) Policy, which applies 
to all new and ongoing NIH-funded research in the IRP, as of January 25, 2023, that is associated 
with a ZIA, with a clinical protocol that undergoes scientific review and/or will involve genomic 
data sharing.  
The Genomic Data Sharing (GDS) Policy does not apply to this study. However, genetic data 
collected under this protocol may be deposited in an open or controlled access database and 
shared, as required by scientific journals. 
12.7.2 NIH Public Access Policy Compliance 
This study will comply with the NIH Public Access Policy, which ensures that the public has 
access to the published results of NIH funded research. It requires scientists to submit final peer-
reviewed journal manuscripts that arise from NIH funds to the digital archive PubMed Central 
upon acceptance for publication. 
12.8 CONFLICT OF INTEREST 

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The Principal Investigator assured that each associate investigator listed on the protocol title 
page received a copy of the NIH’s Guide to preventing conflict of interest. Investigators added 
subsequent to the initial circulation were provided a copy of the document when they were 
added. Copies of the Conflict of Interest Statement were forwarded to the Clinical Director. No 
initial or subsequent members of the research team reported a potential conflict of interest. 
12.9 COLLABORATION(S) 
Danielle Townsley, M.D. will collaborate on trial with protocol related questions and 
interpretation of study data. Dr. Townsley has no access to PII and is not participating in direct 
patient care. 
Phillip Scheinberg, M.D. will collaborate on trial with protocol related questions and 
interpretation of study data. Dr. Scheinberg has no access to PII and is not participating in direct 
patient care. 
12.10 TECHNICAL TRANSFER AGREEMENTS 
This protocol has a CRADA. 
13 PHARMACEUTICALS 
13.1 ELTROMBOPAG (PROMACTA®) 
Chemical Name: The chemical name for eltrombopag olamine is 3'-{(2Z)-2-[1-(3,4- 
dimethylphenyl)-3-methyl-5-oxo-1,5-dihydro-4H-pyrazol-4-ylidene]hydrazino}-2'- hydroxy-3-
biphenylcarboxylic acid - 2-aminoethanol (1:2). 
Molecular formula: C25H22N4O4.2(C2H7NO). 
 
Molecular weight is 564.65 for eltrombopag olamine and 442.5 for eltrombopag free  
acid. 
Chemical and structural formula: 
 
Physical form: red/brown solid. 
Solubility: Eltrombopag olamine is practically insoluble in aqueous buffer across a pH range of 
1 to 7.4, and is sparingly soluble in water. 

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Supply: The drug Novartis is providing for this study will be commercial material, based on 
their supply. It is available as tablets of 12.5, 25, 50 and 75mg. It is also in the process of being 
manufactured as a powder for oral suspension. 
• Tablets: 
White, round, film-coated tablets without debossing are provided, containing 
eltrombopag olamine equivalent to 12.5 mg, 25 mg, 50 mg, or 75 mg of 
eltrombopag free acid.  Placebos to match the active tablets are available. Tablets 
are packaged in white HDPE bottles with white plastic, induction-seal, child-
resistant caps. 
Green, oval, film-coated tablets debossed with ‘SLC’ on one side are provided, 
containing eltrombopag olamine equivalent to 200 mg or 300 mg of eltrombopag 
free acid.  A placebo to match the active tablets is available.  Tablets are packaged 
in white HDPE bottles with white plastic, induction-seal, child-resistant caps. 
Desiccant may be included. 
Commercial image actives (12.5 mg - white, 25 mg- orange or white, 50 mg blue 
or brown, 75 mg – pink) which are equivalent to the clinical forms with the 
exception of the film coated color may also be provided for clinical use.  These 
forms are also packed in white HDPE bottles with white plastic, induction -seal, 
child-resistant caps.  Desiccant may be included.  Additionally, the commercial 
image tablets may be provided in aluminum foil blister packages. 
• Powder for Oral Suspension: 
Doses for children between the ages 4 to 5 (2.5mg/kg non-East/South Asian 
participants, and 1.25mg/kg East/South Asian participants) will be provided in the 
form of sachets (when available).  The powder for oral suspension is a reddish 
brown to yellow powder in a sachet.  Two PfOS strengths are available, 
containing eltrombopag olamine equivalent to 12.5 mg and 25 mg of eltrombopag 
free acid. Reconstitution of eltrombopag PfOS will follow instructions outlined in 
the Investigator’s Brochure and Package Insert. 
Stability: Store, both tablets and powder, at 25°C (77°F); excursions permitted to 15o to 30°C 
(59o to 86°F) [see USP Controlled Room Temperature]. 
Shipping: The NIH Investigational Drug Management and Research Section (IMDRS) will be 
responsible for receiving, storing, dispensing and accounting for drug product. The shipping 
address for Novartis supplied investigational agent is: 
National Institutes of Health 
IMDRS, Room 1C230 
10 Center Drive, MSC 1196, Building 10 Bethesda, Maryland 20892-1196 

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Accountability Procedures: Drug accountability records will be maintained for all clinical 
supplies. All empty and partially used vials and clinical trial supplies will be destroyed locally 
according to the institution’s standard operating procedures for drug destruction. The pharmacy 
will maintain detailed documentation of the number and identification of vials, which are 
destroyed, and copies of these documents will be provided to the Sponsor and Novartis. 
Disposition of all unused boxes of study drug will be carried out according to instructions 
provided by the Sponsor and/or Novartis at the end of the study after drug accountability is 
performed. 
13.2 CYCLOSPORINE (GENGRAF, SANDIMMUNE, NEORAL) 
Supply: Cyclosporine will be obtained by the NIH Clinical Center Pharmacy Department from 
commercial sources and is available in capsules (25 mg and 100 mg), USP [MODIFIED], oral 
solution (100 mg/ml), USP [MODIFIED], and as a parenteral concentrate for injection (50 mg/ml). 
When oral capsules are prescribed for this protocol, the cyclosporine capsules, USP [NON-
MODIFIED] should NOT be used. 
Preparation: For parenteral doses, each milliliter of concentrate (50mg/ml) should be diluted in 
20 to 100ml of dextrose 5% in water or sodium chloride 0.9%. Parenteral doses of cyclosporine 
will be prepared in non-PVC containers and infused with non-PVC administration sets/tubing. The 
recommended liquids for dilution of the oral solution to improve palatability include milk, 
chocolate milk or orange juice, preferable at room temperature. 
Storage and Stability: Capsules, oral solution, and ampules of parenteral concentrate bear 
expiration dates and are stored at room temperature and protected from light. Cyclosporine 
concentrate for injection that has been diluted to a final concentration of approximately 2mg/ml is 
stable for 24 hours in 5% dextrose or 0.9% sodium chloride injection in glass, PVC or non-PVC 
plastic containers. To minimize the potential for sorption to PVC plastic bags and tubing as well 
the leaching of phthalate plasticizer (DEHP) into the solution, only non-PVC plastic bags and 
intravenous administration sets should be utilized. 
Administration: Cyclosporine may be given intravenously or orally. 
Toxicities: see section 12.4.2 Risks related to CsA 
13.3 ANTI-THYMOCYTE GLOBULIN (EQUINE) STERILE SOLUTION (ATGAM®) 
Other: Antithymocyte Gammaglobulin, Antithymocyte Globulin, ATGAM, Antithymocyte 
Immunoglobulin, lymphocyte immune globulin and h-ATG  
Supply / availability: commercially available (Pharmacia & Upjohn Company) 
Product description: Anti-thymocyte globulin (equine) sterile solution (ATGAM®) is available 
in 5 ml ampoules containing 50 mg of horse gamma globulin/mL (250 mg per ampoule). 
Preparation: The calculated dose of anti-thymocyte globulin should be diluted in 0.9% sodium 
chloride injection to a concentration not to exceed 4 mg/mL. 
Storage / stability: Anti-thymocyte globulin (equine) ampoules should be stored in a refrigerator 
at 2o to 8o C. Once diluted, anti-thymocyte globulin (equine) is physically and chemically stable 
for up to 24 hours at concentrations of up to 4 mg/mL in the recommended diluents. It is 

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recommended that diluted anti- thymocyte globulin (equine) be stored in a refrigerator if it is 
prepared prior to the time of infusion. 
Administration: Anti-thymocyte globulin (equine) should be administered into a high-flow central 
vein through an in-line filter with a pore size of 0.2 to 1 micron. The dose should be infused over 
no less than 4 hours. Infusion times may be extended to up to 24 hours for intolerance. Patients 
should be closely monitored for infusion / allergic reactions. 
Compound: Principally monomeric IgG, prepared from plasma or serum of healthy horses 
hyperimmunized with human thymus lymphocytes. 
Action: Immunosuppressive agent. Exact mechanism of immunosuppression of ATGAM has not 
been fully elucidated but may involve elimination of antigen-reactive T-cells in peripheral blood 
and/or alteration of T-cell function. 
Side effects: see section 12.4.1 Risks related to h-ATG 
13.4 PENTAMIDINE 
Supply: Commercially available (NebuPent®, American Pharmaceutical Partners, Inc.). 
Product description: Pentamidineisethionate is available as a 300 mg single dose vial containing 
300 mg of lyophilized powder in a 15 mL capacity vial. The contents of one vial must be dissolved 
in 6 mL of sterile water for injection, USP. It is important to use only sterile water; saline solution 
will cause the drug to precipitate. 
Storage and stability: Store dry product at controlled room temperature 15-30oC (59-86oF). 
Route of administration: Inhalation; Once reconstituted, the entire contents of a vial should be 
placed into the Respigard® II nebulizer (Marquest) reservoir for administration by inhalation. Do 
not mix the pentamidine solution with any other drugs. 
Toxicities: see section 12.4.10 Risks related to Concomitant medications. 
13.5 VALACYCLOVIR 
Generic name: valacyclovir 
Brand Name: Valtrex 
Supply: Commercially available. 
Pharmacology: Valacyclovir is the hydrochloride salt of L-valyl ester of the antiviral drug 
acyclovir. After oral administration, valacyclovir is rapidly absorbed from the GI tract and nearly 
completely converted to acyclovir and L-valine by first-pass intestinal or hepatic metabolism.  
Product description: Valacyclovir is available in 500mg tablets and 1gm tablets. Dose adjustment 
is necessary in patients with significant renal impairment (refer to the manufacturer’s labeling for 
dose adjustment guidelines. 
Storage and Stability: Oral tablets should be stored at 15o to 25oC (59o to 77oF). Route of 
administration: Oral 
Toxicities: see section 12.4.10 risks related to concomitant medications. 

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13.6 FDA REGULATORY CONSIDERATION 
An IND application with the FDA is not required for this study.  The proposed research with 
Eltrombopag meets the exemption requirements noted in 21 CRF 312.2, specifically: 
1. The drug product is lawfully marketed in the United States. 
2. The investigation is not intended to be reported to FDA as a well-controlled study in 
support of a new indication and there is no intent to use it to support any other significant 
change in the labeling of the drug. 
3. In the case of a prescription drug, the investigation is not intended to support a significant 
change in the advertising for the drug. 
4. The investigation does not involve a route of administration, dose, patient population, or 
other factor that significantly increases the risk (or decreases the acceptability of the risk) 
associated with the use of the drug product (21 CFR 312.2(b)(1)(iii)). 
5. The investigation is conducted in compliance with the requirements for review by an IRB 
(21 CFR part 56) and with the requirements for informed consent (21 CFR part 50). 
6. The investigation is conducted in compliance with the requirements of § 312.7 (i.e., the 
investigation is not intended to promote or commercialize the drug product). 

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44. 
Nancy L. Geller, D.F., Eric S. Leifer, and Shelly L. Carter, Design of Early Trials in Stem 
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Trial Biostatistics, ed. N. Geller. 2004: Marcel Dekker, Inc.

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APPENDIX A: GUIDE FOR LOCAL PHYSICIAN 
 
1. CYCLOSPORINE (CsA) 
a. Dose: 2mg/kg daily by mouth 
b. Administration: To be taken consistently in relation to time of day and meals. 
*Recommend taking it in the morning same time every day with food 
c. Supportive medication considerations: 
i. Magnesium: Patients are expected to have magnesium wasting. Weekly 
labs should include magnesium levels and low levels need to be treated 
with magnesium supplementation (Goal >2mg/mL) 
d. Food/Medication interactions 
i. Various agents are known interfere with plasma cyclosporine 
concentrations usually by inhibition or induction of CYP3A4 
ii. Common drugs: Erythromycin, ketoconazole, diltiazem, rifampin, 
phenytoin, and phenobarbital. Refer to FDA label when prescribing new 
medications if unsure regarding possible interactions. Avoid using 
concomitantly with cyclosporine.  
iii. Avoid Grapefruit juice and grapefruit 
e. Clinical and Laboratory monitoring 
i. Common side effects: Headaches, hypertension, gastrointestinal upset, 
nausea. Posterior reversible encephalopathy syndrome (PRES) is a rare 
side effect.  
*Recommend Amlodipine for hypertension (Goal <120/80mm/Hg) 
*Recommend ondansetron and pantoprazole for nausea/GI upset 
ii. Renal panel including magnesium at least weekly 
iii. Cyclosporine level per investigators at NIH or local physician as clinically 
indicated only 
f. Dose Delays, Modifications or Discontinuation 
i. Discuss with investigators prior to dose alteration or discontinuation 
unless medically emergent.  Please communicate any changes 
immediately. 
ii. Common reasons: renal impairment, severe gum hyperplasia, severe 
headaches, hyperkalemia 
 
2. ELTROMBOPAG 
a. Dose: 

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Dosing according to age and ethnicity 
Age groups (years) 
Daily dose 
Non-Asian 
 
12-85 
150 mg 
6-11 
75 mg 
2-5 
2.5 mg/kg 
East Asian, South East 
Asian 
 
12-85 
75 mg 
6-11 
37.5 mg 
2-5 
1.25 mg/kg 
 
b. Administration 
i. Take on empty stomach (1 hour before or 2 hours after a meal) or with 
food containing no calcium or dairy products 
ii.  Allow at least 4-hour interval between eltrombopag and other medications 
containing polyvalent cations (e.g. calcium, magnesium, aluminum, zinc, 
selenium or iron) 
* RECOMMEND – EARLY MORNING (4-5AM) IF BREAKFAST PLANNED AFTER 
7AM AND DINNER COMPLETED BEFORE MIDNIGHT 
c. Food/ Medication interactions 
i. Strong inhibitors of cytochrome p450 may enhance eltrombopag activity – 
recommend to not use it 
ii. Examples: Trimethoprim, ciprofloxacin, and gemfibrozil 
iii. Food: Dairy, calcium and other polyvalent cations (as listed above) 
d. Clinical and laboratory monitoring 
i. Skin rash – typically severe diffuse drug rash 
ii. Complete blood counts and hepatic panel at least twice weekly x 2 weeks 
than weekly if clinically acceptable 
e. Dose Delays, Modifications or Discontinuation (discuss with investigators 
immediately prior to making any changes)  

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i. If ALT > 6 times ULN, repeat in 3 days  Hold eltrombopag if ALT still >6 
times ULN. Once ALT < 5 times ULN, restart eltrombopag at a dose level 
that is 25mg/day lower than the prior dose 
ii. Discontinue eltrombopag if deep venous thrombosis (other than a line 
related upper extremity thrombosis), pulmonary embolism, TIA/stroke, or 
myocardial infarction 
iii. Discontinue eltrombopag if diffuse skin rash  
iv. Decrease dose as follows for over correction of platelets  
 
Platelet Count  
Dose Adjustment or Response  
>200,000/L (untransfused) at any time on study 
Decrease dosage by 25mg every 2 weeks to 
lowest dosage that maintains platelet count ≥ 
50,000/L. In children under 12, the dose will 
be decreased by 12.5 mg. 
>400,000/L (untransfused) at any time on study 
Discontinue eltrombopag for one week, if 
platelets fall to <200,000/L; restart at dosage 
decreased by 25 mg/day (or 12.5 mg in children 
under 12). 
 
3. Acceptable supportive treatment while on study  
a. Blood and platelet transfusions 
i. Platelet transfusions are recommended when:  
1. PLT level is <10 × 109/L, or 
2. PLTs <20 × 109/L and with active bleeding, or 
3. Per local standard of care (SOC), or as medically necessary. 
ii. RBC transfusions are recommended when:  
1. Hgb <7 g/dL, or if symptomatic according to local SOC. 
2. Infection management 
b. Hematopoietic growth factors (e.g., G-CSF, GM-CSF, or erythropoietin) if 
deemed necessary. DO NOT ADMINISTER Romiplostim (N-Plate) or IL-11 
(Neumega) 
c. Oral contraceptives or Leuprolide acetate for menses suppression  
d. Antibiotics, anti-fungals and anti-virals are permitted as clinically indicated. The 
local medical guidelines for treatment of infections/febrile neutropenia should be 
followed.  
4. Laboratory monitoring for cytopenias 

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a. CBC weekly and reticulocyte (if testing available) weekly  
b. Transfusion goals: Hb >8g/dL or otherwise clinically indicated, plt >10µL or 
otherwise clinically indicated 
5. Neutropenic fever management 
a. Single temperature of 38.5C or two readings of 38.0C or greater will need 
hospital admission to begin prompt broad-spectrum empiric antibiotics per current 
infectious disease guidelines. Full infectious work up required to identify source.  
b. Notify the NIH care team immediately 
 
Contacts: 
Please contact us if you have any questions or concerns about any of the above information. 
The main point of contact is study coordinator Olga Rios, RN.  She can be contacted at  301-496-
4462 or emailed at olga.rios@nih.gov. 
Other points of contact include: 
Principal Investigator:  
Bhavisha Patel, MD: Ph 301-402-3477, Email 
Bhavisha.patel@nih.gov 
Associate Investigator:  
Emma Groarke, MD: Ph 301-451-7129, Email 
Emma.Groarke@nih.gov 
Associate Investigator: 
 
Neal Young, MD: Ph 301-496-5093, Email 
youngns@nhlbi.nih.gov 

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APPENDIX B: TELEPHONE WEEKLY FOLLOW UP 
 
1. Clinical assessment 
a. Disease related: fever, localizing infectious symptoms, bleeding, fatigue  
b. Cyclosporine related: headache, nausea/other gastrointestinal symptoms, gum 
hyperplasia, high blood pressure 
c. Eltrombopag related: skin rash, swelling/pain of any extremities, chest pain, 
shortness of breath, yellowing of the skin or eyes 
d. Compliance to medication 
e. Evaluation by any physicians, emergency department, or admission 
f. Address other complains by patients 
 
2. Laboratory assessment 
a. Complete blood count 
b. Chemistry panel 
c. Liver function test  
d. Transfusion requirement  
 
3. Medications 
a. Review medication list and update as needed in CRIS  
 
4. Local physician involvement 
a. Will discuss any concerning findings on telephone interview with the local 
physician and discuss work up and/or inform changes to the treatment regimen 
that were recommended to the patient 
b. Brief note will be placed in CRIS if any changes to the treatment plan made